Novel 3-descladinose-2,3-anhydroerythromycin compounds and pharmaceutically acceptable salts and esters thereof having antibacterial activity.

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 
3-descladinose-2,3-anhydroerythromycin 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): 
##STR1## 
are well-known and potent antibacterial agents, used widely to treat and 
prevent bacterial infection. As with other antibacterial agents, 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. 
Although Agouridas, et al. (U.S. Pat. No. 5,444,051, issued Aug. 22, 1995) 
have disclosed a 9-O-((2-methoxyethoxy)methyl)oxime of 
2-deoxy-2,3-anhydro-3-O-des(2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ri 
bo-hexopyranosyl)-6-O-methyl-erythromycin, no utility nor method of 
preparation was disclosed. 
We have, however, discovered novel 3-descladinose-2,3-anhydroerythromycin 
derivatives that possess significant activity against selected 
microorganisms. 
Likewise, various C3-modified erythromycin compounds are known, but none 
possess the C2-C3 modifications of the present invention (see, for 
example, Agouridas, et al., European application EP 676409, published Oct. 
11, 1995; Kashimura, et al., European application EP 559896, published 
Sep. 15, 1993; and Asaka, et al., PCT application WO 93/21200, published 
Oct. 28, 1993). 
SUMMARY OF THE INVENTION 
The present invention provides a novel class of 
3-descladinose-2,3-anhydroerythromycin compounds which possess 
antibacterial activity. 
In one aspect of the present invention are disclosed novel 
3-descladinose-2,3-anhydroerythromycin compounds selected from the group 
consisting of: 
##STR2## 
or pharmaceutically acceptable salts and esters thereof. 
In formulas (I)-(IV) above, 
R.sup.1 is selected from the group consisting of: 
(a) hydrogen; 
(b) hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 -C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.2 -alkyl; and 
(g) O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; 
R.sup.2 is hydrogen or a hydroxy protecting group; 
R.sup.6 is hydrogen or C.sub.1 -C.sub.6 -alkyl; 
R is selected from the group consisting of: 
(a) hydrogen; 
(b) C.sub.1 -C.sub.6 -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) hydroxy; 
(vi) C.sub.1 -C.sub.6 -alkoxy; 
(vii) NR.sup.3 R.sup.4, where R.sup.3 and R.sup.4 are independently 
selected from hydrogen and C.sub.1 -C.sub.6 -alkyl, or R.sup.3 and R.sup.4 
are taken with the nitrogen atom to which they are connected to form a 3- 
to 7-membered ring which, when the ring is a 5- to 7-membered ring, may 
optionally contain a hetero function consisting of --O--, --NH--, 
--N(C.sub.1 -C.sub.6 -alkyl-)--, --N(aryl)--, --N(aryl-C.sub.1 -C.sub.6 
-alkyl-)--, --N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl)--, --N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, --S-- or 
--S(O).sub.n --, wherein n is 1 or 2; 
(viii) --CH.sub.2 --M--R.sup.5, wherein M is selected from the group 
consisting of: 
(aa) --C(O)--NH--; 
(bb) --NH--C(O)--; 
(cc) --NH-- 
(dd) --N.dbd.; 
(ee) --N(CH.sub.3)-- 
(ff) --O-- 
(gg) --S(O).sub.n --, wherein n is 0, 1 or 2; 
(hh) --CO--O-- 
(ii) --O--CO-- 
(jj) --CO--; and 
R.sup.5 is selected from the group consisting of: 
(aaa) C.sub.1 -C.sub.6 -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; and 
(c) C.sub.3 -C.sub.7 -cycloalkyl; 
(d) aryl; 
(e) substituted-aryl; 
(f) heteroaryl; 
(g) substituted-heteroaryl; 
W is absent or selected from the group consisting of --O--, --NH--CO--, 
--N.dbd.CH--, --NH-- and --N(C.sub.1 -C.sub.6 -alkyl)--; 
A, B, D and E are independently selected from the group consisting of: 
(a) hydrogen; 
(b) C.sub.1 -C.sub.6 -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) C.sub.1 -C.sub.6 -alkoxy; 
(viii) halogen consisting of Br, Cl, F or I; and 
(ix) NR.sup.3 R.sup.4, where R.sup.3 and R.sup.4 are independently selected 
from hydrogen and C.sub.1 -C.sub.6 -alkyl, or R.sup.3 and R.sup.4 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(C.sub.1 -C.sub.6 -alkyl-)--, --N(aryl-C.sub.1 -C.sub.6 
-alkyl-)--, --N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, --S-- or 
--S(O).sub.n --, wherein n is 1 or 2; 
(c) C.sub.3 -C.sub.7 -cycloalkyl; 
(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--R.sup.5, wherein M and R.sup.5 are as defined above; 
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.sub.1 -C.sub.6 -alkyl-)--, 
--N(aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--S-- or --S(O).sub.n --, wherein n is 1 or 2; 
--C(O)--NH--; 
--C(O)--NR.sup.5 --, wherein R.sup.5 is as defined above; 
--NH--C(O)--; 
--NR.sup.5 --C(O)--, wherein R.sup.5 is as defined above; and 
--C(.dbd.NH)--NH--. 
The compounds and compositions of the present invention have antibacterial 
activity. 
In another aspect of the present invention are disclosed pharmaceutical 
compositions for treating bacterial infections comprising a 
therapeutically effective amount of a compound of the invention in 
combination with a pharmaceutically acceptable carrier. Suitable carriers 
and methods of formulation are also disclosed. 
Still another aspect of this invention is a method for treating bacterial 
infections comprising administering to a mammal in need of such treatment 
a pharmaceutical composition containing a therapeutically-effective amount 
of a compound of the invention. 
In a further aspect of the invention are provided processes for the 
preparation of tricyclic macrolide derivatives of Formulas (I)-(IV) above. 
In another aspect of the invention are provided novel compounds (cf. 
compound (4) of Scheme I) having use as intermediates in the preparation 
of compounds of Formulas (I)-(IV) above. 
In still another aspect of the invention is a process for the preparation 
of a novel 3-descladinose-2,3-anhydroerythromycin intermediate compound 
having the Formula of Compound (4) of Scheme 1; R.sup.1 .dbd.OMe (cf. 
Scheme 1 below). 
DETAILED DESCRIPTION OF THE INVENTION 
In one preferred embodiment of the invention are compounds having the 
formula (I): 
##STR3## 
wherein R.sup.1, R.sup.2, R, and W are as defined above. 
In a more preferred embodiment of the invention are compounds of formula 
(I) wherein W is absent or is an --NH-- grouping. 
In another preferred embodiment of the invention are compounds having the 
formula (II): 
##STR4## 
wherein R.sup.1, R.sup.2, A, B, D, and E are as defined above. 
In a further embodiment of the invention are compounds having the formula 
(III): 
##STR5## 
wherein R.sup.1, R.sup.2, A, B, D, and E are as defined above. 
In still another embodiment of the invention are compounds having the 
formula (IV): 
##STR6## 
wherein R.sup.1, R.sup.2, R.sup.6, A, B, D, and E are as defined above. 
Representative compounds of the invention include: 
Compound of Formula (I); R.sup.1 .dbd.H; R.sup.2 .dbd.H; W is absent; 
R.dbd.4-phenylbutyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.4-phenylbutyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-phenoxypropyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-((phenylmethyl)amino)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-(N-methyl-N-phenylamino)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-(4-chlorophenoxy)propyl; 
Compound of Formula (II); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; 
A.dbd.B.dbd.C.dbd.D.dbd.H; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-(1-quinoyloxy)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.4-(4-chlorophenyl)-3(Z)-butenyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-phenylethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(3,4-dichlorophenyl)ethyl; 
Compound of Formula (1); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.phenylmethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-phenylpropyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-(4-phenoxyphenyl)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-phenylpropyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2,2-diphenylethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.H; 
Compound of Formula (IV); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; 
A.dbd.B.dbd.C.dbd.D.dbd.H; R.dbd.H; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.H; C10 methyl is epi-isomer; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.H; C10 methyl is natural isomer; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-quinolinyl)propyl; C10 methyl is natural isomer; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-(2-naphthyloxy)propyl; 
Compound of Formula (I); R.sup.1 .dbd.-methoxy; R.sup.2 .dbd.H; W is 
absent; R.dbd.3-(3-pyridyloxy)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-(2-pyridyloxy)propyl; 
Compound of Formula (I); R.sup.1 .dbd.OH; R.sup.2 .dbd.H; W is absent; 
R.dbd.4-phenylbutyl; 
Compound of Formula (I); R.sup.1 .dbd.OCONH.sup.2 ; R.sup.2 .dbd.H; W is 
absent; R.dbd.4-phenylbutyl; 
Compound of Formula (I); R.sup.1 .dbd.OCONHCO-methyl; R.sup.2 .dbd.H; W is 
absent; 
R.dbd.4-phenylbutyl; 
Compound of Formula (I); R.sup.1 .dbd.OCONHSO.sup.2 -methyl; R.sup.2 
.dbd.H; W is absent; R.dbd.4-phenylbutyl; 
Compound of Formula (I); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; W is absent; 
R.dbd.phenyl; 
Compound of Formula (I); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-pyridyl; 
Compound of Formula (I); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; W is --O--; 
R.dbd.H; 
Compound of Formula (I); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; W is --O--; 
R.dbd.Me; 
Compound of Formula (I); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; W is --NH--CO--; 
R.dbd.phenyl; 
Compound of Formula (II); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; A.dbd.benzyl; 
B,D,E.dbd.H; 
Compound of Formula (II); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; 
A,D.dbd.3,4-pyrrolidinyl; B,E.dbd.H; 
Compound of Formula (III); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; A,B,D,E.dbd.H; 
Compound of Formula (IV); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; A.dbd.benzyl; 
B,D,E.dbd.H; R.dbd.H; 
Compound of Formula (IV); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; 
A,D.dbd.3,4-pyrrolidinyl; B,E.dbd.H; R.dbd.H; 
Compound of Formula (IV); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; A,B,D,E.dbd.H, 
R.dbd.CH.sub.2 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 ; 
Compound of Formula (IV); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; A,B,D,E.dbd.H, 
R.dbd.2,4-dinitrobenzene; 
Compound of Formula (IV); R.sup.1 .dbd.OMe; R.sup.2 .dbd.H; A,B,D,E.dbd.H, 
R.dbd.4-quinolyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.(4H-4-oxo-1-quinolyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(4-nitrophenyl)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(4-aminophenyl)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-ethoxypropyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.isopropyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(4-bromophenyl)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(4-hydroxylphenyl)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(4-fluorophenyl)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(3-methoxyphenyl)ethyl; 
Compound of Formula (1); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-vinyloxypropyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(3-trifluoromethyl)phenylethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-thienylethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(3,4-dibenzyloxyphenyl)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(4-methylphenyl)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.allyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.1,3-dihydroxypropyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.1,3-dihydroxypropyl (10-epi; 
Compound of Formula (I); R.sup.1 .dbd.-methoxy; R.sup.2 .dbd.H; W is 
absent; R.dbd.3-hydroxypropyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-hydroxypropyl (10-epi); 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.isobutyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.2-(benzoylamino)ethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-(benzoylamino)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-(acetylamino)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.H (10-epi); 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-phenylpropyl (10-epi); 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is absent; 
R.dbd.3-(4-phenoxyphenyl)ethyl (10-epi); 
Compound of Formula (I); R.sup.1 .dbd.-methoxy; R.sup.2 .dbd.H; W is 
--NH--; R.dbd.3-(4-chlorophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(3-ehlorophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(2-chlorophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(2,4-dichlorophenyl)propyl; 
Compound of Formula (l); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(4-hydroxyphenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(3-hydroxyphenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(2-hydroxyphenyl)propyl; 
Compound of Formula (l); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(4-methoxyphenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(4-nitrophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(3-nitrophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.-methoxy; R.sup.2 .dbd.H; W is 
--NH--; R.dbd.3-(2-nitrophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-((4-(acetylamino)phenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.trans-3-phenylprop-2-enyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.2-phenylethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.phenylmethyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(3-indolyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-methoxyphenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-acetylaminophenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-chlorophenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-dimethylaminophenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.trans-3-(4-nitrophenyl)prop-2-enyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-nitrophenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(3,4-dihydroxyphenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(2,5-dihydroxyphenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(2-hydroxy-5-nitrophenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-hydroxymethylphenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.trans-3-(5-nitro-2-furanyl)prop-2-enyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-hydroxyphenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(3-hydroxyphenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.-methoxy; R.sup.2 .dbd.H; W is 
--NH--; R.dbd.(2-hydroxyphenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-trifluoromethylphenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-cyanophenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(2-pyridyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(3-pyridyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-pyridyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(2-hydroxy-1-naphthyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-dimethylamino-1-naphthyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-(methylthio)phenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-phenoxyphenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(4-fluorophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(trans-3-(4-nitrophenyl)prop-2-enyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.(4-aminophenyl)methyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(4-aminophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(3-aminophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.-methoxy; R.sup.2 .dbd.H; W is 
--NH--; R.dbd.3-(2-aminophenyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.trans-3-(4-acetylaminophenyl)prop-2-enyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.trans-3-(4-(4-nitrobenzoylamino)phenyl)prop-2-enyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(2-benztriazolyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(1-benztriazolyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(4-phenylimidazolyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-(1-anhydro-1-cladinosyl)propyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-phenylpropyl (10(-epi); 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.isopropyl; 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.1,3-diphenyl-2-propyl; and 
Compound of Formula (I); R.sup.1 .dbd.methoxy; R.sup.2 .dbd.H; W is --NH--; 
R.dbd.3-pentyl. 
The present invention provides a process for the preparation of a compound 
having the Formula (I): 
##STR7## 
wherein R.sup.1 is selected from the group consisting of: 
(a) hydrogen; 
(b) hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 -C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl; and 
(g) O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; 
R.sup.2 is hydrogen or a hydroxy protecting group; 
R is selected from the group consisting of: 
(a) hydrogen; 
(b) C.sub.1 -C.sub.6 -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) hydroxy; 
(vi) C.sub.1 -C.sub.6 -alkoxy; 
(vii) NR.sup.3 R.sup.4, where R.sup.3 and R.sup.4 are independently 
selected from hydrogen and C.sub.1 -C.sub.6 -alkyl, or R.sup.3 and R.sup.4 
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(C.sub.1 -C.sub.6 -alkyl-)--, --N(aryl-C.sub.1 -C.sub.6 
-alkyl-)--, --N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, --S--or 
--S(O).sub.n --, wherein n is 1 or 2; 
(viii) --CH.sub.2 --M--R.sup.5, wherein M is selected from the group 
consisting of: 
(aa) --C(O)--NH--; 
(bb) --NH--C(O)--; 
(cc) --NH-- 
(dd) --N.dbd.; 
(ee) --N(CH.sub.3)-- 
(ff) --O-- 
(gg) --S(O).sub.n --, wherein n is 0, 1 or 2; 
(hh) --CO--O-- 
(ii) --O--CO-- 
(jj) --CO--; and 
R.sup.5 is selected from the group consisting of: 
(aaa) C.sub.1 -C.sub.6 -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; and 
(c) C.sub.3 -C.sub.7 -cycloalkyl; 
(d) aryl; 
(e) substituted-aryl; 
(f) heteroaryl; 
(g) substituted-heteroaryl; and 
W is absent; 
the method comprising: 
(a) treating a compound having the formula: 
##STR8## 
wherein R.sup.1 is selected from the group consisting of hydrogen, 
protected hydroxy, O--CO--C.sub.1 -C.sub.6 -alkyl, O--C.sub.1 -C.sub.12 
-alkyl, O--CO--NH.sub.2, O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl, and 
O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and R.sup.2 is a hydroxy 
protecting group, with a primary amine RNH.sub.2, wherein R is as defined 
above, in a suitable organic solvent at room temperature to reflux 
temperature for about 4 to about 48 hours, extracting, optionally 
deprotecting, and isolating the desired compound. 
In a preferred embodiment of the process immediately above R is hydrogen, 
C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, aryl, 
substituted-aryl, heteroaryl or substituted-heteroaryl, and the solvent is 
selected from the group consisting of methylene chloride, tetrahydrofuran, 
N-methyl-pyrrolidinone, diethyl ether, bis-methoxymethyl ether, dimethyl 
formamide, acetonitrile, acetone and aqueous mixtures thereof. 
The present invention also provides an alternate process for the 
preparation of a compound having the Formula (I): 
##STR9## 
wherein 
R.sup.1 is selected from the group consisting of: 
(a) hydrogen; 
(b) hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 -C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl; and 
(g) O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; 
R.sup.2 is hydrogen or a hydroxy protecting group; 
R is selected from the group consisting of: 
(a) hydrogen; 
(b) C.sub.1 -C.sub.6 -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) hydroxy; 
(vi) C.sub.1 -C.sub.6 -alkoxy; 
(vii) NR.sup.3 R.sup.4, where R.sup.3 and R.sup.4 are independently 
selected from hydrogen and C.sub.1 -C.sub.6 -alkyl, or R.sup.3 and R.sup.4 
are taken with the nitrogen atom to which they are connected to form a 3- 
to 7-membered ring which, when the ring is a 5- to 7-membered ring, may 
optionally contain a hetero function consisting of --O--, --NH--, 
--N(C.sub.1 -C.sub.6 -alkyl-)--, --N(aryl)--, --N(aryl-C.sub.1 -C.sub.6 
-alkyl-)--, --N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl)--, --N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, --S-- or 
--S(O).sub.n --, wherein n is 1 or 2; 
(viii) --CH.sub.2 --M--R.sup.5, wherein M is selected from the group 
consisting of: 
(aa) --C(O)--NH--; 
(bb) --NH--C(O)--; 
(cc) --NH-- 
(dd) --N.dbd.; 
(ee) --N(CH.sub.3)-- 
(ff) --O-- 
(gg) --S(O).sub.n --, wherein n is (), 1 or 2; 
(hh) --CO--O-- 
(ii) --O--CO-- 
(j) --CO--; and 
R.sup.5 is selected from the group consisting of: 
(aaa) C.sub.1 -C.sub.6 -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; and 
(c) C.sub.3 -C.sub.7 -cycloalkyl; 
(d) aryl; 
(e) substituted-aryl; 
(f) heteroaryl; 
(g) substituted-heteroaryl; and 
W is selected from the group consisting of --NH--CO--, --N.dbd.CH--, --NH-- 
and --N((C.sub.1 -C.sub.6 -alkyl)--; 
the method comprising: 
(a) treating a compound having the formula: 
##STR10## 
wherein R.sup.1 is selected from the group consisting of hydrogen, 
protected hydroxy, O--CO--C.sub.1 -C.sub.6 -alkyl, O--C.sub.1 -C.sub.12 
-alkyl, O--CO--NH.sub.2, O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl, or 
O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and R.sup.2 is a hydroxy 
protecting group, with a reagent selected from the group consisting of 
hydrazine and a substituted hydrazine in a suitable organic solvent at 
room temperature to reflux for about 4 to about 48 hours to afford the 
desired compound; 
(b) optionally acylating the compound of Formula (I) obtained in step (a) 
wherein W is --NH-- and R is H with an acylating agent to afford a 
compound of Formula (I) wherein W is --NH--CO--; 
(c) optionally condensing the compound of Formula (I) obtained in step (a) 
wherein W is --NH-- and R is H with an aldehyde to afford a compound of 
Formula (I) wherein W is --N.dbd.CH--; 
(d) optionally reducing the compound of Formula (I) obtained in step (c) 
wherein W is --N.dbd.CH-- with a reducing agent to afford a compound of 
Formula (I) wherein W is --NH--; 
(e) and extracting, optionally deprotecting, and isolating the desired 
compound. 
A preferred embodiment of the process immediately above is the one wherein 
the solvent is selected from the group consisting of methanol, ethanol, 
propanol, isopropanol, butanol, t-butanol, methylene chloride, 
tetrahydrofuran, N-methyl-pyrrolidinone, diethyl ether, bis-methoxymethyl 
ether, dimethyl formamide, acetone, aqueous acetonitrile, aqueous DMF, and 
aqueous acetone. 
In one embodiment of the process immediately above the product is a 
compound of Formula (I) wherein W is --NH-- and R is H, and the hydrazine 
reagent is hydrazine. 
In another embodiment of the process immediately above the product is a 
compound of Formula (I) wherein W is --N(C.sub.1 -C.sub.6 -alkyl)--, the 
hydrazine reagent is a substituted hydrazine RR.sup.4 NNH.sub.2, wherein R 
is as defined for Formula (I) and R.sup.4 is C.sub.1 -C.sub.6 -alkyl. 
In still another embodiment of the process immediately above the product is 
a compound of Formula (I) wherein W is --NH--CO--, the hydrazine reagent 
is hydrazine, and the product obtained in step (a) having the Formula (I) 
wherein W is --NH-- and R is H is treated with an R-acyl acylating agent, 
wherein R is as defined for Formula (I). In a preferred embodiment the 
acylating agent is selected from the group consisting of an acid chloride, 
an acid fluoride, an acid anhydride, a carboxylic acid in the presence of 
carbonyldiimidazole, and a carboxylic acid in the presence of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. 
In yet another embodiment of the process immediately above the product is a 
compound of Formula (I) wherein W is --N.dbd.CH--, the hydrazine reagent 
is hydrazine, and the product obtained in step (a) having the Formula (I) 
wherein W is --NH-- and R is H is treated with an aldehyde having the 
formula R--CHO, wherein R is as defined for Formula (I). 
In an additional embodiment of the process immediately above the product is 
a compound of Formula (I) wherein W is --NH-- and R is not H, the 
hydrazine reagent is hydrazine, the product obtained in step (a) having 
the Formula (I) wherein W is --NH-- and R is H is treated with an aldehyde 
having the formula R--CHO, wherein R is as defined for Formula (I), and 
the product obtained in step (c) having the Formula (I) wherein W is 
--N.dbd.CH-- is treated with a reducing agent. In a preferred embodiment 
of this process the reducing agent is selected from the group consisting 
of sodium cyanoborohydride, sodium borohydride, sodium 
triacetoxyborohydride, borane-tetrahydrofuran complex, and 
borane-piperidine complex. 
The present invention further provides a process for the preparation of a 
compound having the Formula (I): 
##STR11## 
wherein 
R.sup.1 is selected from the group consisting of: 
(a) hydrogen; 
(b) hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 -C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl; and 
(g) O--CO--NH--SO.sub.d 2 --C.sub.1 -C.sub.12 -alkyl; 
R.sup.2 is hydrogen or a hydroxy protecting group; 
R is selected from the group consisting of: 
(a) hydrogen; 
(b) C.sub.1 -C.sub.6 -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) hydroxy; 
(vi) C.sub.1 -C.sub.6 -alkoxy; 
(vii) NR.sup.3 R.sup.4, where R.sup.3 and R.sup.4 are independently 
selected from hydrogen and C.sub.1 -C.sub.6 -alkyl, or R.sup.3 and R.sup.4 
are taken with the nitrogen atom to which they are connected to form a 3- 
to 7-membered ring which, when the ring is a 5- to 7-membered ring, may 
optionally contain a hetero function consisting of --O--, --NH--, 
--N(C.sub.1 -C.sub.6 -alkyl-)--, --N(aryl)--, --N(aryl-C.sub.1 -C.sub.6 
-alkyl-)--, --N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)-, 
--N(heteroalkyl)--, --N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, --S-- or 
--S(O).sub.n --, wherein n is 1 or 2; 
(viii) --CH.sub.2 --M--R.sup.5, 
wherein M is selected from the group consisting of: 
(aa) --C(O)--NH--; 
(bb) --NH--C(O)--; 
(cc) --NH-- 
(dd) --N.dbd.; 
(ee) --N(CH.sub.3)-- 
(ff) --O-- 
(gg) --S(O).sub.n --, wherein n is 0, 1 or 2; 
(hh) --CO--O-- 
(ii) --O--CO-- 
(jj) --CO--; and 
R.sup.5 is selected from the group consisting of: 
(aaa) C.sub.1 -C.sub.6 -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; and 
(c) C.sub.3 -C.sub.7 -cycloalkyl; 
(d) aryl; 
(e) substituted-aryl; 
(f) heteroaryl; 
(g) substituted-heteroaryl; and 
W is --O--; 
the method comprising: 
(a) treating a compound having the formula: 
##STR12## 
wherein R.sup.1 is selected from the group consisting of hydrogen, 
protected hydroxy, O--C.sub.1 -C.sub.12 -alkyl, O--CO--C.sub.1 -C.sub.6 
-alkyl, O--CO--NH.sub.2, O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl, or 
O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and R.sup.2 is a hydroxy 
protecting group, with a hydroxylamine reagent selected from the group 
consisting of unsubstituted hydroxylamine and an O--C.sub.1 -C.sub.6 
-alkylated hydroxylamine in a suitable organic solvent at room temperature 
to reflux for about 4 to about 48 hours, to give the desired compound; 
(b) optionally treating the product obtained in step (a) having the Formula 
(I) wherein W is --O-- and R is H with a suitable base and an appropriate 
electrophile having the formula R-L, wherein R is selected from the group 
consisting of C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, aryl, 
substituted-aryl, heteroaryl and a substituted-heteroaryl group, wherein 
these terms are as defined for compounds of Formula (I) above and L is 
suitable leaving group, to give the desired compound of formula (I) 
wherein W is --O-- and R is selected from the group consisting of C.sub.1 
-C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, aryl, substituted-aryl, 
heteroaryl and a substituted-heteroaryl group; and 
(c) extracting, optionally deprotecting, and isolating the desired 
compound. 
In one embodiment of the process immediately above the product is a 
compound of Formula (I) wherein W is --O-- and R is H and the 
hydroxylamine reagent is unsubstituted hydroxylamine. 
In one embodiment of the process immediately above the product is a 
compound of Formula (I) wherein W is --O-- and R is O--C.sub.1 -C.sub.6 
-alkyl and the hydroxylamine reagent is an O--C.sub.1 -C.sub.6 -alkylated 
hydroxylamine. 
In still another embodiment of the process immediately above the final 
product is a compound of Formula (I) wherein W is --O-- and R.dbd.C.sub.1 
-C.sub.6 -alkyl, the hydroxylamine reagent is unsubstituted hydroxylamine, 
and the intermediate product having the Formula (I) wherein W.dbd.O and R 
is H is treated with a suitable base and an alkyl halide. 
In still another embodiment of the process immediately above the final 
product is a compound of Formula (I) wherein W is --O-- and R is selected 
from the group consisting of C.sub.3 -C.sub.7 -cycloalkyl, aryl, 
substituted-aryl, heteroaryl and a substituted-heteroaryl group, and the 
intermediate product having the Formula (I) wherein W is --O-- and R is H 
is treated with a suitable base and an electrophile having the formula 
R-L, wherein R is as defined above and L is a suitable leaving group. In a 
preferred embodiment of this process the base is selected from the group 
consisting of sodium hydride, potassium hydride, lithium hydride, lithium 
diethylamide, and butyllithium, and L is selected from the group 
consisting of halide, methanesulfonyl and p-toluenesulfonyl. 
The present invention also provides a process for the preparation of a 
compound having the Formula (II): 
##STR13## 
wherein 
R.sup.1 is selected from the group consisting of: 
(a) hydrogen; 
(b) hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 -C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl; and 
(g) O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; 
R.sup.2 is hydrogen or a hydroxy protecting group; 
A, B, D and E are independently selected from the group consisting of: 
(a) hydrogen; 
(b) C.sub.1 -C.sub.6 -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) C.sub.1 -C.sub.6 -alkoxy; 
(viii) halogen consisting of Br, Cl, F or I; and 
(ix) NR.sup.3 R.sup.4, where R.sup.3 and R.sup.4 are independently selected 
from hydrogen and C.sub.1 -C.sub.6 -alkyl, or R.sup.3 and R.sup.4 are 
taken with the nitrogen atom to which they are connected to form a 3- to 
7-membered ring which, when the ring is a 5- to 7-membered ring, may 
optionally contain a hetero function consisting of --O--, --NH--, 
--N(C.sub.1 -C.sub.6 -alkyl-)--, --N(aryl)--, --N(aryl-C.sub.1 -C.sub.6 
-alkyl-)--, --N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl)--, --N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, --S-- or 
--S(O).sub.n --, wherein n is 1 or 2; 
(c) C.sub.3 -C.sub.7 -cycloalkyl; 
(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-- 
R.sup.5, wherein M is selected from the group consisting of 
(aa) --C(O)--NH--; 
(bb) --NH--C(O)--; 
(cc) --NH-- 
(dd) --N(CH.sub.3)-- 
(ee) --O-- 
(ff) --S(O).sub.n --, wherein n is 0, 1 or 2; 
(gg) --C(.dbd.NH)--NH--; 
(hh) --CO--O-- 
(ii) --O--CO-- 
(jj) --CO--; 
and R.sup.5 is selected from the group consisting of: 
(aaa) C.sub.1 -C.sub.6 -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(C.sub.1 -C.sub.6 -alkyl-)--, 
--N(aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--S-- or --S(O).sub.n --, wherein n is 1 or 2; 
--C(O)--NH--; 
--C(O)--NR.sup.5 --, wherein R.sup.5 is as defined above; 
--NH--C(O)--; 
--NR.sup.5 --C(O)--, wherein R.sup.5 is as defined above; and 
--C(.dbd.NH)--NH--; 
the method comprising: 
(a) treating a compound having the formula: 
##STR14## 
wherein R.sup.1 is selected from the group consisting of hydrogen, 
protected hydroxy, O--C.sub.1 -C.sub.12 -alkyl, O--O--C.sub.1 -C.sub.6 
-alkyl, O--CO--NH.sub.2, O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl, or 
O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and R.sup.2 is a hydroxy 
protecting group, with a compound having the formula: 
##STR15## 
wherein A, B, D, and E are as defined for compounds of Formula (II) above, 
in a suitable solvent at room temperature to reflux temperature for about 
4 to about 48 hours to give the bicyclic intermediate compound having the 
formula: 
##STR16## 
(b) deprotecting said bicyclic intermediate compounds to give the second 
intermediate compounds having the formula: 
##STR17## 
(c) cyclizing said second intermediate compounds by treatment with dilute 
concentration of a strong acid in a suitable organic solvent for a period 
of from about 4 hours to about 10 days at a temperature from ambient to 
reflux temperature of the solvent to give the desired compounds; and 
(d) extracting, optionally deprotecting, and isolating the desired 
compound. 
A preferred embodiment of the process immediately above is the one wherein 
in step (a) the solvent is selected from the group consisting of methanol, 
ethanol, propanol, isopropanol, butanol, t-butanol, methylene chloride, 
tetrahydrofuran, N-methyl-pyrrolidinone, diethyl ether, bis-methoxymethyl 
ether, dimethyl formamide, acetone, aqueous acetonitrile, aqueous DMF, and 
aqueous acetone; and in step (c) the solvent is selected the group 
consisting of methanol, ethanol, propanol, iso-propanol, butanol, 
iso-butanol and t-butanol. 
The present invention provides an alternate process for the preparation of 
a compound having the Formula (II): 
##STR18## 
wherein A, B, D, E, R.sup.1 and R.sup.2 are as defined for Formula (II) 
above, the method comprising: 
(a) treating a compound having the formula: 
##STR19## 
wherein R.sup.1 is selected from the group consisting of hydrogen, 
protected hydroxy, O--C.sub.1 -C.sub.12 -alkyl, O--CO--C.sub.1 -C.sub.6 
-alkyl, O--CO--NH.sub.2, O--CO--NH--CO-C.sub.1 -C.sub.12 -alkyl, or 
O-CO-NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and R.sup.2 is a hydroxy 
protecting group, with a compound having the formula: 
##STR20## 
wherein A, B, D, and E are as defined above, in a suitable solvent at 
0.degree.-70.degree. C. for about 4 to about 48 hours to give a bicyclic 
intermediate compound having the formula: 
##STR21## 
(b) treating the bicyclic intermediate compound from step (a) with 
triphenylphosphine and diphenylphosphoryl azide-diethylazodicarboxylate in 
tetrahydrofuran under Mitsunobu reaction conditions to prepare the second 
intermediate azide compound having the formula: 
##STR22## 
(c) reducing the second intermediate azide compound to prepare the third 
intermediate compound having the formula: 
##STR23## 
(d) cyclizing said third intermediate compound by treatment with a dilute 
concentration of a strong acid at ambient temperature to reflux 
temperature for about 4 hours to about 10 days in a aqueous alcohol 
solvent to give the desired compounds; and 
(e) extracting, optionally deprotecting, and isolating the desired 
compound. 
In a preferred embodiment of the process described immediately above in 
step (a) the solvent is selected from the group consisting of methanol, 
ethanol, propanol, isopropanol, butanol, t-butanol, methylene chloride, 
tetrahydrofuran, N-methyl-pyrrolidinone, diethyl ether, bis-methoxymethyl 
ether, dimethyl formamide, acetone, aqueous acetonitrile, aqueous DMF and 
aqueous acetone; in step (c) the reducing agent is selected from the group 
consisting of triphenylphosphine-water, hydrogen with a catalyst, sodium 
borohydride, and dialkylaluminum hydride; and in step (d) the solvent is 
selected the group consisting of methanol, ethanol, propanol, 
iso-propanol, butanol, iso-butanol and t-butanol. 
In an alternate embodiment of the alternate process described immediately 
above, step (b) thereof is replaced with two steps consisting of: 
(b') reacting the hydroxy group of the bicyclic intermediate compound with 
a sulfonating agent selected from the group consisting of sulfonyl 
chloride, alkyl sulfonic anhydride, aryl sulfonic anhydride, and 
trifluoromethanesulfonic anhydride, in an aprotic solvent at -78.degree. 
C. to room temperature to give an intermediate compound wherein the 
hydroxyl group has been replaced with a sulfonate ester moiety; and 
(b") reacting the sulfonate ester of step (b') with an alkali metal azide 
in an aprotic solvent at from about 0.degree. C. to about 100.degree. C. 
to give the second intermediate azide compound. 
The present invention also provides a process for the preparation of a 
compound having the Formula (III): 
##STR24## 
wherein 
A, B, D and E are independently selected from the group consisting of: 
(a) hydrogen; 
(b) C.sub.1 -C.sub.6 -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) C.sub.1 -C.sub.6 -alkoxy; 
(viii) halogen consisting of Br, Cl, F or l; and 
(ix) NR.sup.3 R.sup.4, where R.sup.3 and R.sup.4 are independently selected 
from hydrogen and C.sub.1 -C.sub.6 -alkyl, or R.sup.3 and R.sup.4 are 
taken with the nitrogen atom to which they are connected to form a 3- to 
7-membered ring which, when the ring is a 5- to 7-membered ring, may 
optionally contain a hetero function consisting of --O--, --NH--, 
--N(C.sub.1 -C.sub.6 -alkyl-)--, --N(aryl)--, --N(aryl-C.sub.1 -C.sub.6 
-alkyl-)--, --N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
-N(heteroaryl)--, --N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, --S-- or 
--S(O).sub.n --, wherein n is 1 or 2; 
(c) C.sub.3 -C.sub.7 -cycloalkyl; 
(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-- 
R.sup.5, wherein M is selected from the group consisting of 
(aa) --C(O)--NH--; 
(bb) --NH--C(O)--; 
(cc) --NH-- 
(dd) --N(CH.sub.3)-- 
(ee) --O-- 
(ff) --S(O).sub.n --, wherein n is 0, 1 or 2; and 
(gg) --C(.dbd.NH)--NH--; 
and R.sup.5 is selected from the group consisting of: 
(aaa) C.sub.1 -C.sub.6 -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(C.sub.1 -C.sub.6 -alkyl-)--, 
--N(aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--S-- or --S(O).sub.n --, wherein n is 1 or 2; 
--C(O)--NH--; 
--C(O)--NR.sup.5 --, wherein R.sup.5 is as defined above; 
--NH--C(O)--; 
--NR.sup.5 --C(O)--, wherein R.sup.5 is as defined above; and 
--C(.dbd.NH)--NH--; 
R.sup.1 is selected from the group consisting of: 
(a) hydrogen; 
(b) hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 -C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl; and 
(g) O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and 
R.sup.2 is hydrogen or a hydroxy-protecting group; the method comprising: 
(a) reacting a compound having the formula (II): 
##STR25## 
wherein R.sup.1 is as above or is a hydroxy protecting group and R.sup.2, 
A, B, D, and E are as defined above, with a suitable oxidizing agent to 
oxidize the imine nitrogen to the nitrone and the nitrogen atom on the 
desosamine moiety to the N-oxide to give an N-oxidized intermediate; and 
(b) treating the N-oxidized intermediate with a reducing agent to reduce 
the desosamine N-oxide, and extracting, optionally deprotecting, and 
isolating the desired compound. 
A preferred embodiment of the process described immediately above is the 
one wherein in step (a) the oxidizing agent is selected from the group 
consisting of hydrogen peroxide and a carboxylic peracid; and in step (b) 
the reducing agent is selected from the group consisting of 
triphenylphosphine and hydrogen in the presence of a catalyst. 
The invention further provides a process for the preparation of a compound 
having the Formula (IV): 
##STR26## 
wherein 
A, B, D and E are independently selected from the group consisting of: 
(a) hydrogen; 
(b) C.sub.1 -C.sub.6 -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) C.sub.1 -C.sub.6 -alkoxy; 
(viii) halogen consisting of Br, Cl, F or I; and 
(ix) NR.sup.3 R.sup.4, where R.sup.3 and R.sup.4 are independently selected 
from hydrogen and C.sub.1 -C.sub.6 -alkyl, or R.sup.3 and R.sup.4 are 
taken with the nitrogen atom to which they are connected to form a 3- to 
7-membered ring which, when the ring is a 5- to 7-membered ring, may 
optionally contain a hetero function consisting of --O--, --NH--, 
--N(C.sub.1 -C.sub.6 -alkyl-)--, --N(aryl)--, --N(aryl-C.sub.1 -C.sub.6 
-alkyl-)--, --N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl)--, --N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, --S-- or 
--S(O).sub.n --, wherein n is 1 or 2; 
(c) C.sub.3 -C.sub.7 -cycloalkyl; 
(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-- 
R.sup.5, wherein M is selected from the group consisting of: 
(aa) --C(O)--NH--; 
(bb) --NH--C(O)--; 
(cc) --NH-- 
(dd) --N(CH.sub.3)-- 
(ee) --O-- 
(ff) --S(O).sub.n --, wherein n is 0, 1 or 2; and 
(gg) --C(.dbd.NH)--NH--; 
and R.sup.5 is selected from the group consisting of: 
(aaa) C.sub.1 -C.sub.6 -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(C.sub.1 -C.sub.6 -alkyl-)--, 
--N(aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-aryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, 
--S-- or --S(O).sub.n --, wherein n is 1 or 2; 
--C(O)--NH--; 
--C(O)--NR.sup.5 --, wherein R.sup.5 is as defined above; 
--NH--C(O)--; 
--NR.sup.5 --C(O)--, wherein R.sup.5 is as defined above; and 
--C(.dbd.NH)--NH--; 
R.sup.1 is selected from the group consisting of: 
(a) hydrogen; 
(b) hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 -C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl; and 
(g) O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and 
R.sup.2 is hydrogen or a hydroxy-protecting group; 
R.sup.6 is hydrogen or C.sub.1 -C.sub.6 -alkyl; the method comprising: 
(a) reacting a compound having the formula: 
##STR27## 
wherein R.sup.1 is as above or is a hydroxy protecting group and R.sup.2, 
A, B, D, and E are as defined above with a reducing agent in a suitable 
organic solvent to afford the desired compound wherein R.sup.6 is H; 
(b) optionally reductively alkylating the amino the product of step (a) 
with a reducing reagent in the presence of a C.sub.1 -C.sub.6 -alkyl-group 
precursor to afford the desired compound wherein R.sup.6 is C.sub.1 
-C.sub.6 -alkyl; and 
(c) extracting, optionally deprotecting, and isolating the desired 
compound. 
A preferred embodiment of the process described immediate above is the one 
wherein in step (a) and in optional step (b) the reducing agent is 
selected from the group consisting of sodium cyanoborohydride, sodium 
borohydride, sodium triacetoxyborohydride, borane-tetrahydrofuran complex, 
and borane-piperidine complex. 
The invention also provides for a novel intermediate compound having the 
formula: 
##STR28## 
wherein R.sup.1 is selected from the group consisting of: (a) hydrogen; 
(b) protected hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 -C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl; and 
(g) O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and 
R.sup.2 is hydrogen or a hydroxy-protecting group. 
A preferred embodiment of the intermediate compound is that wherein R.sup.1 
is O--C.sub.1 -C.sub.12 -alkyl. 
A more preferred embodiment of the intermediate compound is that wherein 
R.sup.1 is methoxy. 
The present invention also provides a process for the preparation of a 
compound having the formula: 
##STR29## 
wherein R.sup.1 is selected from the group consisting of: 
(a) hydrogen; 
(b) protected hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 -C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl; and 
(g) O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and 
R.sup.2 is hydrogen or a hydroxy-protecting group; the method comprising: 
(a) treating an erythromycin A compound having the formula: 
##STR30## 
wherein R.sup.1 is as defined above, with dehydrating reagents consisting 
of an organocarbonate in the presence of base at reflux temperature in an 
aprotic solvent to form an intermediate compound having the formula: 
##STR31## 
(b) hydrolytically removing the cladinose moiety from the intermediate 
compound of step (a) by treatment in an aqueous alcohol suspension with a 
dilute concentration of a strong acid at ambient temperature for about 0.5 
to about 24 hours, extracting and optionally isolating the compound having 
the formula: 
##STR32## 
(c) treating the compound of step (b) with a suitable hydroxy group 
protecting reagent in an aprotic solvent, and extractively isolating the 
compound wherein R.sup.2 is a hydroxy protecting group; 
(d) treating a solution of the compound of step (c) with a sulfonylating 
agent at from about 0.degree. C. to ambient temperature for about 1 to 
about 24 hours, and extractively isolating the compound having the 
formula: 
##STR33## 
wherein R.sup.7 is alkyl or aryl; 
(e) dehydrating the compound of step (d) with a hydride base in the 
presence of carbonyldiimidazole in an aprotic solvent at a temperature 
from about --20.degree. C. to about 70.degree. C. for from about 0.5 hours 
to about 10 days, and extracting, optionally deprotecting, and isolating 
the desired compound. 
In a preferred embodiment of the process immediately above, in step (a) the 
dehydrating reagents consist of an organocarbonate compound selected from 
the group consisting of ethylene carbonate, propylene carbonate, 
trimethylene carbonate, dipropyl carbonate, dibenzyl carbonate, isobutyl 
carbonate, dimethyl carbonate and diethyl carbonate, in the presence of a 
base selected from the group consisting of triethylamine, 
diisopropylethylamine, pyridine, 2,6-dimethylpyridne, 
1,8-diazabicyclo5.4.0!undec-7-ene, N-methylmorpholine, 
N-methylpyrrolidine, N-methylpiperidine, sodium carbonate, potassium 
carbonate, sodium bicarbonate and potassium carbonate; in step (b) the 
alcohol is chosen from the group consisting of methanol, ethanol, 
propanol, iso-propanol, butanol, iso-butanol and t-butanol, and the acid 
is selected from the group consisting of hydrochloric acid, sulfuric acid, 
dichloroacetic acid and trichloroacetic acid; in step (c) the hydroxy 
group protecting reagent is selected from the group consisting of acetyl 
chloride, acetic anhydride, benzoic anhydride, benzyl chloroformate, 
trimethylsilyl chloride and triethylsilyl chloride, and the aprotic 
solvent is selected from the group consisting of methylene chloride, 
chloroform, dimethylformamide, tetrahydrofuran, N-methylpyrrolidinone and 
mixtures thereof; in step (d) the sulfonylating agent is selected from the 
group consisting of methanesulfonyl anhydride, methanesulfonyl chloride, 
ethanesulfonyl chloride and p-toluenesulfonyl chloride, and the base is 
selected from the group defined in step (a) above; in step (e) the hydride 
base is selected from the group consisting of sodium hydride, potassium 
hydride and lithium hydride and the aprotic solvent is as defined for step 
(c). 
In a more preferred embodiment of the process immediately above R.sup.1 is 
H and steps (d) and (e) are replaced with a single step (d') consisting 
of: 
(d') treatment of the compound from step (c) with sodium 
hexamethyldisilazane at from about -50.degree. to about -28.degree. C. 
under an inert atmosphere followed by addition of carbonyldiimidazole at 
from about 0.degree. C. to about ambient temperature for about 15 minutes 
to about 6 hours, and extracting, optionally deprotecting, and isolating 
the desired compound. 
The present invention also provides an alternate process for the 
preparation of a novel 3-descladinose-2,3-anhydroerythromycin intermediate 
compound having the formula: 
##STR34## 
wherein 
R.sup.1 is selected from the group consisting of: 
(a) hydrogen; 
(b) protected hydroxy; 
(c) O--C.sub.1 -C.sub.12 -alkyl; 
(d) O--CO--C.sub.1 --C.sub.6 -alkyl; 
(e) O--CO--NH.sub.2 ; 
(f) O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl; and 
(g) O--CO--NH--SO.sub.2 --C.sub.1 -C.sub.12 -alkyl; and 
R.sup.2 is hydrogen or a hydroxy-protecting group; the method comprising: 
(a) hydrolytically removing the cladinose moiety from an erythromycin A 
compound having the formula: 
##STR35## 
wherein R.sup.1 is as described above by treatment in an aqueous alcohol 
suspension with a dilute concentration of a strong acid at ambient 
temperature for about 0.5 to about 24 hours, extracting and optionally 
isolating the first intermediate compound having the formula: 
##STR36## 
(b) optionally treating the first intermediate compound with a suitable 
hydroxy group protecting reagent, and extractively isolating the second 
intermediate compound having the formula of the compound of step (a) 
wherein R.sup.2 is a hydroxy-protecting group; 
(c) treating the second intermediate compound with an excess of a 
carbonylating reagent and isolating by aqueous work up the third 
intermediate compound having the formula: 
##STR37## 
wherein R.sup.1 may not be hydrogen but is otherwise as defined above; 
(d) treating the third intermediate compound with a sulfonylating agent at 
from about 0.degree. C. to ambient temperature for about 1 to about 24 
hours, and extractively isolating the fourth intermediate compound having 
the formula: 
##STR38## 
wherein 
R.sup.7 is alkyl or aryl; 
(e) treating the fourth intermediate compound with a base, extracting and 
optionally isolating the to afford the fifth intermediate compound having 
the formula: 
##STR39## 
(f) treating the fifth intermediate compound with a hydride base and 
carbonyldiimidazole in an aprotic solvent at a temperature from about 
--20.degree. C. to about 70.degree. C. for from about 0.5 hours to about 
10 days, and extracting, optionally deprotecting, and isolating the 
desired compound. 
In a preferred embodiment of the process immediately above in step (a) the 
alcohol is chosen from the group consisting of methanol, ethanol, 
propanol, iso-propanol, butanol, iso-butanol and t-butanol, and the acid 
is selected from the group consisting of hydrochloric acid, sulfuric acid, 
dichloroacetic acid and trichloroacetic acid; in step (b) the hydroxy 
group protecting reagent is selected from the group consisting of acetyl 
chloride, acetic anhydride, benzoic anhydride, benzyl chloroformate, 
trimethylsilyl chloride and triethylsilyl chloride, and the aprotic 
solvent is selected from the group consisting of methylene chloride, 
chloroform, dimethylformamide, tetrahydrofuran, N-methylpyrrolidinone and 
mixtures thereof; in step (c) the carbonylating reagent is selected from 
the group consisting of phosgene, diphosgene and triphosgene; in step (d) 
the sulfonylating agent is selected from the group consisting of 
methanesulfonyl anhydride, methanesulfonyl chloride, ethanesulfonyl 
chloride and p-toluenesulfonyl chloride; in step (e) the base is selected 
from the group consisting of triethylamine, diisopropylethylamine, 
pyridine, 2,6-dimethylpyridne, 1,8-diazabicyclo5.4.0!undec-7-ene, 
N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, sodium 
carbonate, potassium carbonate, sodium bicarbonate and potassium 
carbonate; in step (f) the hydride base is selected from the group 
consisting of sodium hydride, potassium hydride and lithium hydride. 
In a more preferred embodiment of the process immediately above, in step 
(b) the hydroxy protecting reagent is benzoic anhydride and R.sup.2 is 
benzoyl, and steps (c), (d) and (e) are replaced with a single step (c') 
consisting of: 
(c') treatment of the compound from step (b) with sodium 
hexamethyldisilazane at from about -50 to about -28.degree. C. under an 
inert atmosphere followed by addition of carbonyldiimidazole at from about 
0.degree. C. to about ambient temperature for about 15 minutes to about 6 
hours, and extracting, optionally deprotecting, and isolating the desired 
compound. 
Definitions 
The terms "C.sub.1 -C-alkyl", "C.sub.1 -C.sub.6 -alkyl", "C.sub.1 -C.sub.12 
-alkyl" or "C.sub.1 -C.sub.18 -alkyl" as used herein refer to saturated, 
straight- or branched-chain hydrocarbon radicals containing between one 
and three, one and six, one and twelve, or one and eighteen carbon atoms, 
respectively. Examples of C.sub.1 -C.sub.3 alkyl radicals include methyl, 
ethyl, propyl and isopropyl, examples of C.sub.1 -C.sub.6 -alkyl radicals 
include, but are not limited to, methyl, ethyl, propyl, isopropyl, 
n-butyl, tert-butyl, neopentyl and n-hexyl, examples of C.sub.1 -C.sub.12 
-alkyl radicals include all of the preceding examples and n-heptyl, octyl, 
n-decyl, n-undecyl and n-dodecyl, for example, and examples of C.sub.1 
-C.sub.18 -alkyl radicals include all of the preceding examples and 
n-triadecane, n-tetradecane, n-pentadecane, n-hexadecane, n-heptadecane, 
and n-octadecane, for example. 
The term "C.sub.1 -C.sub.6 -alkoxy" as used herein refers to an C.sub.1 
-C.sub.6 -alkyl group, as previously defined, attached to the parent 
molecular moiety through an oxygen atom. Examples of C.sub.1 -C.sub.6 
-alkoxy, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, 
n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. 
The term "C.sub.1 -C.sub.3 -alkyl-amino" as used herein refers to one or 
two C.sub.1 -C.sub.3 -alkyl groups, as previously defined, attached to the 
parent molecular moiety through a nitrogen atom. Examples of C.sub.1 
-C.sub.3 -alkyl-amino include, but are not limited to methylamino, 
dimethylamino, ethylamino, diethylamino, and propylamino. 
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, ethers such as diethyl ether and bis-methoxymethyl 
ether, as well as various other compounds like dimethyl formamide, 
acetonitrile, acetone and ethyl acetate. 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: Organic Solvents Physical Properties and Methods of 
Purification, 4th ed., edited by John A. Riddick, et al., Vol. 11, in the 
Techniques of Chemistry Series, John Wiley & Sons, N.Y., 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 "C.sub.3 -C.sub.5 -cycloalkyl- and C.sub.3 -C.sub.7 -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 terms "C.sub.1 -C.sub.3 -alkyl-C.sub.3 -C.sub.5 -cycloalkyl", as used 
herein refers to a C.sub.3 -C.sub.5 -cycloalkyl radical, as defined above, 
attached to a C.sub.1 -C.sub.3 -alkyl radical by replacement of a hydrogen 
atom on the latter. 
The terms "halo" and "halogen" as used herein refer to an atom selected 
from fluorine, chlorine, bromine and iodine. 
The term "halo-C.sub.1 -C.sub.3 -alkyl" as used herein refers to a C.sub.1 
-C.sub.3 -alkyl group as defined above wherein 1, 2 or 3 hydrogen atoms 
thereon are independently replaced by a halogen atom. 
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, isoxazolyl, 
thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, 
and the like. 
The term "heterocycloalkyl" as used herein, refers to a non-aromatic 5-, 6- 
or 7-membered ring or a bi- or tri-cyclic group comprising fused 
six-membered rings having between one and three heteroatoms independently 
selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered 
ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double 
bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be 
oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and 
(iv) any of the above heterocyclic rings may be fused to a benzene ring. 
Representative heterocycles include, but are not limited to, pyrrolidinyl, 
pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, 
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, 
isothiazolidinyl, and tetrahydrofuryl. 
"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 Groups in Organic Synthesis. 2nd 
edition, John Wiley & Sons, New York (1991). Examples of 
hydroxy-protecting groups include, but are not limited to, 
methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acyl 
substituted with an aromatic group and the like. 
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 
Physical Properties and Methods of Purification, 4th ed., edited by John 
A. Riddick, et al., Vol. 11, in the Techniques of Chemistry Series, John 
Wiley & Sons, N.Y., 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, F, I, OH, cyano, mercapto, 
nitro, C.sub.1 -C.sub.3 -alkyl, halo-C.sub.1 -C.sub.3 -alkyl, C.sub.1 
-C.sub.6 -alkoxy, thio-C.sub.1 -C.sub.6 -alkoxy, methoxymethoxy, amino, 
C.sub.1 -C.sub.3 -alkyl-amino, di(C.sub.1 -C.sub.3 -alkyl-amino, formyl, 
carboxy, alkoxycarbonyl, C.sub.1 -C.sub.3 -alkyl-CO--O--, C.sub.1 -C.sub.3 
-alkyl-CO--NH--, or carboxamide; except that tetrafluorophenyl and 
pentafluorophenyl are also included within the definition of "substituted 
aryl". 
The term "substituted heteroaryl" as used herein refers to a heteroaryl 
group as defined herein substituted by independent replacement of one, two 
or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, C.sub.1 
-C.sub.3 -alkyl, C.sub.1 -C.sub.6 -alkoxy, methoxymethoxy, amino, or 
C.sub.1 -C.sub.3 -alkyl-amino, or may also refer to a mono-oxo substituted 
heteroaryl compound, such as 4-oxo-1H-quinoline, for example. 
The term "substituted heterocycloalkyl" as used herein, refers to a 
heterocycloalkyl group, as defined above, substituted by independent 
replacement of one, two or three of the hydrogen atoms thereon with Cl, 
Br, F, I, OH, cyano, mercapto, nitro, C.sub.1 -C.sub.3 -alkyl, 
halo-C.sub.1 -C.sub.3 -alkyl, C.sub.1 -C.sub.6 -alkoxy, thio-C.sub.1 
-C.sub.6 -alkoxy, methoxymethoxy, amino, C.sub.1 -C.sub.3 -alkyl-amino, 
di(C.sub.1 -C.sub.3 -alkyl-)amino, carboxaldehydo, carboxy, 
alkoxycarbonyl, C.sub.1 -C.sub.3 -alkyl-CO--O--, C.sub.1 -C.sub.3 
-alkyl-CO--NH--, or carboxamide. 
Numerous asymmetric centers may exist in the compounds of the present 
invention. Except where otherwise noted, the present invention 
contemplates the various stereoisomers and mixtures thereof. Accordingly, 
whenever a bond is represented by a wavy line, it is intended that a 
mixture of stereo-orientations or an individual isomer of assigned or 
unassigned orientation may be present. 
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), incorporated herein by reference. The salts can be 
prepared in situ during the final isolation and purification of the 
compounds of the invention, or separately by reacting the free base 
function with a suitable organic acid. Examples of pharmaceutically 
acceptable, nontoxic acid addition salts are salts of an amino group 
formed with inorganic acids such as hydrochloric acid, hydrobromic acid, 
phosphoric acid, sulfuric acid and perchloric acid or with organic acids 
such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, 
succinic acid or malonic acid or by using other methods used in the art 
such as ion exchange. Other pharmaceutically acceptable salts include 
adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, 
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, 
cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, 
formate, fumarate, glucoheptonate, glycerophosphate, gluconate, 
hemisulfate, heptanoate, hexanoate, hydroiodide, 
2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, 
malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, 
nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, 
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, 
stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, 
undecanoate, valerate salts, and the like. Representative alkali or 
alkaline earth metal salts include sodium, lithium, potassium, calcium, 
magnesium, and the like. Further pharmaceutically acceptable salts 
include, when appropriate, nontoxic ammonium, quaternary ammonium, and 
amine cations formed using counterions such as halide, hydroxide, 
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl 
sulfonate. 
As used herein, the term "pharmaceutically acceptable ester" refers to 
esters which hydrolyze in vivo and include those that break down readily 
in the human body to leave the parent compound or a salt thereof. Suitable 
ester groups include, for example, those derived from pharmaceutically 
acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, 
cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety 
advantageously has not more than 6 carbon atoms. Examples of particular 
esters includes formates, acetates, propionates, butryates, 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 carriers. 
As used herein, the term "pharmaceutically acceptable carrier" means a 
non-toxic, inert solid, semi-solid or liquid filler, diluent, 
encapsulating material or formulation auxiliary of any type. Some examples 
of materials which can serve as pharmaceutically acceptable carriers are 
sugars such as lactose, glucose and sucrose; starches such as corn starch 
and potato starch; cellulose and its derivatives such as sodium 
carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered 
tragacanth; malt; gelatin; talc; excipients such as cocoa butter and 
suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; 
sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene 
glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering 
agents such as magnesium hydroxide and 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, tetrahydrofurfuryl alcohol, 
polyethylene glycols and fatty acid esters of sorbitan, and mixtures 
thereof. Besides inert diluents, the oral compositions can also include 
adjuvants such as wetting agents, emulsifying and suspending agents, 
sweetening, flavoring, and perfuming agents. 
Injectable preparations, for example, sterile injectable aqueous or 
oleaginous suspensions may be formulated according to the known art using 
suitable dispersing or wetting agents and suspending agents. The sterile 
injectable preparation may also be a sterile injectable solution, 
suspension or emulsion in a nontoxic parenterally acceptable diluent or 
solvent, for example, as a solution in 1,3-butanediol. Among the 
acceptable vehicles and solvents that may be employed are water, Ringer's 
solution, U.S.P. and isotonic sodium chloride solution. In addition, 
sterile, fixed oils are conventionally employed as a solvent or suspending 
medium. For this purpose any bland fixed oil can be employed including 
synthetic mono- or diglycerides. In addition, fatty acids such as oleic 
acid are used in the preparation of injectables. 
The injectable formulations can be sterilized, for example, by filtration 
through a bacterial-retaining filter, or by incorporating sterilizing 
agents in the form of sterile solid compositions which can be dissolved or 
dispersed in sterile water or other sterile injectable medium prior to 
use. 
In order to prolong the effect of a drug, it is often desirable to slow the 
absorption of the drug from subcutaneous or intramuscular injection. This 
may be accomplished by the use of a liquid suspension of crystalline or 
amorphous material with poor water solubility. The rate of absorption of 
the drug then depends upon its rate of dissolution which, in turn, may 
depend upon crystal size and crystalline form. Alternatively, delayed 
absorption of a parenterally administered drug form is accomplished by 
dissolving or suspending the drug in an oil vehicle. Injectable depot 
forms are made by forming microencapsule matrices of the drug in 
biodegradable polymers such as polylactide-polyglycolide. Depending upon 
the ratio of drug to polymer and the nature of the particular polymer 
employed, the rate of drug release can be controlled. Examples of other 
biodegradable polymers include poly(orthoesters) and poly(anhydrides). 
Depot injectable formulations are also prepared by entrapping the drug in 
liposomes or microemulsions which are compatible with body tissues. 
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 mixed with at least one inert, pharmaceutically acceptable 
excipient or carrier such as sodium citrate or dicalcium phosphate and/or 
a) fillers or extenders such as starches, lactose, sucrose, glucose, 
mannitol, and silicic acid, b) binders such as, for example, 
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, 
sucrose, and acacia, c) humectants such as glycerol, d) disintegrating 
agents such as agar-agar, calcium carbonate, potato or tapioca starch, 
alginic acid, certain silicates, and sodium carbonate, e) solution 
retarding agents such as paraffin, f) absorption accelerators such as 
quaternary ammonium compounds, g) wetting agents such as, for example, 
cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and 
bentonite clay, and i) lubricants such as talc, calcium stearate, 
magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and 
mixtures thereof. In the case of capsules, tablets and pills, the dosage 
form may also comprise buffering agents. 
Solid compositions of a similar type may also be employed as fillers in 
soft and hard-filled gelatin capsules using such excipients as lactose or 
milk sugar as well as high molecular weight polyethylene glycols and the 
like. 
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 also be of a composition that 
they release the active ingredient(s) only, or preferentially, in a 
certain part of the intestinal tract, optionally, in a delayed manner. 
Examples of embedding compositions which can be used include polymeric 
substances and waxes. 
Solid compositions of a similar type may also be employed as fillers in 
soft and hard-filled gelatin capsules using such excipients as lactose or 
milk sugar as well as high molecular weight polyethylene glycols and the 
like. 
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 art. In such solid 
dosage forms the active compound may be admixed with at least one inert 
diluent such as sucrose, lactose or starch. Such dosage forms may also 
comprise, as is normal practice, additional substances other than inert 
diluents, e.g., tableting lubricants and other tableting aids such a 
magnesium stearate and microcrystalline cellulose. In the case of 
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 ingredient(s) only, or 
preferentially, in a certain part of the intestinal tract, optionally, in 
a delayed manner. Examples of embedding compositions which can be used 
include polymeric substances and waxes. 
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 specific 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 
compound(s) 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: 9-BBN for 9-borabicyclo3.3.1!nonane; AIBN 
for azobisisobutyronitrile; Bu.sub.3 SnH for tributyltin hydride; CDI for 
carbonyldiimidazole; DBU for 1,8-diazabicyclo5.4.0!undec-7-ene; DEAD for 
diethylazodicarboxylate; DMAP for 4-dimethylaminopyridine; DMF for 
dimethyl formamide; DPPA for diphenylphosphoryl azide; EtOAc for ethyl 
acetate; MeOH for methanol; NaHMDS for sodium hexamethyldisilazane; 
NaN(TMS).sub.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, R.sup.1 and R.sup.2 are as defined above 
unless otherwise noted below. 
##STR40## 
In accordance with Scheme I is prepared an intermediate compound 
12-O-acylimidazolide-2,3 anhydroerythromycin compound (4) used as a 
starting material in Schemes 3-5 below. An erythromycin A compound (I) 
(wherein R.sup.1 is hydrogen, protected hydroxy, O--C.sub.1 -C.sub.12 
-alkyl, O--CO--C.sub.1 -C.sub.6 -alkyl, O--CO--NH.sub.2, 
O--CO--NH--CO--C.sub.1 -C.sub.12 -alkyl, or O--CO--NH--SO.sub.2 --C.sub.1 
-C.sub.12 -alkyl, and R.sup.2 .dbd.H or a hydroxy protecting group) is 
dehydrated at the 11-hydroxy position to form an intermediate compound 
(1a, not shown) having a C10-C11 double bond. The dehydration may be 
accomplished by treatment of compound (I) at reflux temperature in an 
aprotic solvent with an organocarbonate in the presence of base. Suitable 
organocarbonate compounds include, but are not limited to, ethylene 
carbonate, propylene carbonate, trimethylene carbonate, dipropyl 
carbonate, dibenzyl carbonate, isobutyl carbonate, dimethyl carbonate and 
diethyl carbonate. Suitable bases which may be utilized, include for 
example, triethylamine, diisopropylethylamine, pyridine, 
2,6-dimethylpyridne, 1,8-diazabicyclo5.4.0!undec-7-ene, 
N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, sodium 
carbonate, potassium carbonate, sodium bicarbonate and potassium 
carbonate. 
The cladinose sugar moiety is then removed from intermediate compound (1a) 
by the reaction with a dilute concentration of a strong acid at ambient 
temperature for about 0.5 to about 24 hours. Suitable strong acids 
include, but are not limited to, hydrochloric acid, sulfuric acid, 
dichloroacetic acid, trichloroacetic acid and the like. The reaction may 
be accomplished with a suspension of the reagents in aqueous alcohol, such 
as for example, methanol, ethanol, propanol, iso-propanol, butanol, 
iso-butanol and t-butanol, for example. The reaction mixture is then 
neutralized with an alkali metal base, the product is extracted with a 
suitable organic solvent, such as ether, ethyl acetate or methylene 
chloride, for example, and the organic layer washed and dried. The 
compound is optionally isolated, but preferably is carried forward in 
solution. 
The 2'-hydroxyl group is then protected by reaction with a suitable hydroxy 
group 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 acetyl chloride, acetic anhydride, benzoic anhydride, benzyl 
chloroformate, trimethylsilyl chloride or triethylsilyl chloride in an 
aprotic solvent that does not adversely affect the reaction, preferably 
methylene chloride, chloroform, dimethylformamide, tetrahydrofuran, 
N-methylpyrrolidinone or a mixture thereof, in the presence of a base such 
as triethylamine, with stirring at ambient temperature for 0.5 to 24 
hours, for example. Preferably, a trialkylsilyl chloride or acetic 
anhydride is the protecting reagent. Extractive workup as before affords 
the desired 2'-protected macrolide of the formula (2) wherein R.sup.1 is 
as above and R.sup.2 is a hydroxy protecting group. When R.sup.1 is a 
protected hydroxy group, it is preferred that the protecting group portion 
of it be the same as the R.sup.2 protecting group. 
Compounds of formula (2) are then reacted with a sulfonylating agent, such 
as methanesulfonyl anhydride, methanesulfonyl chloride, ethanesulfonyl 
chloride, or p-toluenesulfonyl chloride, in a aprotic solvent with 
stirring at from about 0.degree. C. to ambient temperature for about 1 to 
about 24 hours. The crude product is isolated via an extractive workup 
similar to that described above to afford the desired 
3-O-methanesulfonylated macrolide of the formula (3), wherein R.sup.7 is 
an alkyl or aryl residue, such as methyl, ethyl or p-tolyl. 
Treatment of compound (3) with a hydride base in the presence of 
carbonyldiimidazole in an aprotic solvent gives, after an extractive 
workup, the desired 12-O-acylimidazolide-2,3 anhydro macrolide (4). The 
hydride base may be, for example, sodium hydride, potassium hydride, or 
lithium hydride, and the aprotic solvent may be one as defined above. The 
reaction may require cooling or heating, depending on the conditions used. 
The reaction temperature may be from about -20.degree. C. to about 
70.degree. C., and preferably from about 0.degree. C to about room 
temperature. The reaction may require about 0.5 hours to about 10 days, 
and preferably about 1-5 days, to complete. 
In an alternate process for compounds wherein R.sup.1 is H, it is possible 
replace the sulfonylating and dehydrating steps described above with two 
different steps: first treatment with NaHMDS at from about -50.degree. to 
to about -28.degree. C. under an inert atmosphere followed by addition of 
carbonyldimidazole at from about 0.degree. C. to about ambient temperature 
for about 15 minutes to about 6 hours, or until the reaction is complete. 
The compound (4) is obtained after quenching of the reaction and 
extraction of the product. 
Scheme 2 provides for an alternate method of synthesis of the macrolide 
compound (4). Hydrolytic removal of the cladinose moiety from compound 
(1), wherein R.sup.1 is as defined in Scheme I and R.sup.2 is H is 
accomplished by the procedure described for Scheme 1, followed by 
protection of the 2'-hydroxyl group, also by the procedure of Scheme 1, 
affords the macrolide compound (5). When R.sup.1 is a protected hydroxy 
group, it is preferred that the protecting group portion of it be the same 
as the R.sup.2 protecting group. 
Subsequent treatment of compound (5) with an excess of carbonylating 
reagent, such as phosgene, diphosgene, or triphosgene, for example, in an 
aprotic solvent followed by aqueous workup yields the 11,12-carbonate (Sa, 
not shown) in which the 3-hydroxy group is unprotected. 
Sulfonylation of the 3-hydroxy group of compound (5a) by procedures similar 
to those described above for macrolide compound (3) in Scheme I affords 
the desired compound (6) wherein R.sup.7 is as defined in Scheme 1. 
Treatment of compound (6) with a base in an aprotic solvent affords the 
diene macrolide (7). Suitable bases which may be utilized, include for 
example, triethylamine, diisopropylethylamine, pyridine, 
2,6-dimethylpyridne, 1,8-diazabicyclo5.4.0!undec-7-ene, 
N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, sodium 
carbonate, potassium carbonate, sodium bicarbonate and potassium 
carbonate. Compound (7) can be treated with a hydride base and 
carbonyldiimidazole in an aprotic solvent to give the key intermediate 
macrolide (4). 
In an alternate procedure for Scheme 2 wherein compound (1) is the 
6-deoxy-erythromycin A compound (R.sup.1 is H), removal of the cladinose 
residue from compound (1) and protection of the 2'-hydroxyl group to give 
the macrolide compound (5), wherein R.sup.1 is H and R.sup.2 is benzoyl 
follows the methods described above. However, the compound (5), wherein 
R.sup.1 is H and R.sup.2 is benzoyl may then be treated directly with an 
excess of sodium hexamethyldisilazane at -28.degree. to -50.degree. C. 
under an inert atmosphere, then with carbonyldiimidazole at 0.degree. C. 
or at ambient temperature stirring for 15 minutes to 6 hours or until the 
reaction is complete to obtain the compound (4). 
##STR41## 
In accordance with Scheme 3 compound (4), wherein R.sup.1 and R.sup.2 are 
as defined in Scheme 1, is converted to desired compounds of the invention 
having Formulas (I) or (II). 
To prepare a compound of Formula (I) wherein W is absent, compound (4) is 
reacted with a primary amine RNH.sub.2 in a suitable solvent at room 
temperature to reflux temperature for about 4 to about 48 hours. Suitable 
solvents include alcohols such as methanol, ethanol, propanol, 
isopropanol, butanol, t-butanol, and the like, aprotic solvents such as 
methylene chloride, tetrahydrofuran, N-methyl-pyrrolidinone, diethyl 
ether, bis-methoxymethyl ether, dimethyl formamide, and acetone, for 
example, as well as aqueous mixtures thereof. Preferred solvents are 
aqueous acetonitrile, aqueous DMF, and aqueous acetone. 
In the primary amine RNH.sub.2 and in the resulting compound of Formula 
(I), R may be hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 
-cycloalkyl, aryl, substituted-aryl, heteroaryl or substituted-heteroaryl. 
When R is a C.sub.1 -C.sub.6 -alkyl substituent, the alkyl group may be 
optionally substituted with one or more substituents such as aryl, 
substituted-aryl, heteroaryl, substituted-heteroaryl, hydroxy, C.sub.1 
-C.sub.6 -alkoxy, NR.sup.3 R.sup.4, wherein R.sup.3 and R.sup.4 are 
independently selected from hydrogen and C.sub.1 -C.sub.6 -alkyl, or 
NR.sup.3 R.sup.4, wherein R.sup.3 and R.sup.4 are taken with the nitrogen 
atom to which they are connected to form a 3- to 7-membered ring. 
In the instance wherein the NR.sup.3 R.sup.4 substituent is a 5- to 
7-membered ring, the ring may optionally contain a hetero function 
consisting of --O--, --NH--, --N(C.sub.1 -C.sub.6 -alkyl-)--, --N(aryl)--, 
--N(aryl-C.sub.1 -C.sub.6 -alkyl-)--, --N(substituted-aryl-C.sub.1 
-C.sub.6 -alkyl-)--, --N(heteroaryl)--, --N(heteroaryl-C.sub.1 -C.sub.6 
-alkyl-)--, --N(substituted-heteroaryl-C.sub.1 -C.sub.6 -alkyl-)--, --S-- 
or --S(O).sub.n --, wherein n is 1 or 2. Additionally, when R is C.sub.1 
-C.sub.6 -alkyl it may bear an optional substituent of the formula 
--CH.sub.2 --M--R.sup.5, wherein M may be --C(O)--NH--, --NH--C(O)--, 
--NH--, --N.dbd., --N(CH.sub.3)--, --O--, --S(O).sub.n --, wherein n is 0, 
1 or 2, --CO--O--, --O--CO--, or --CO--; and R.sup.5 may be aryl, 
substituted-aryl, heteroaryl, substituted-heteroaryl, heterocycloalkyl, or 
a C.sub.1 -C.sub.6 -alkyl optionally bearing one or more substituents such 
as aryl, substituted-aryl, heteroaryl, or substituted-heteroaryl. 
Chromatographic treatment of the crude reaction product affords both the 
natural and epi isomers at position C-10 of the molecule. 
To prepare a compound wherein W is --NH--, compound (4) is reacted with a 
hydrazine reagent such as unsubstituted hydrazine or a substituted 
hydrazine in a solvent such as described immediately above to afford the 
desired compound of Formula (I). The natural and C-10 epimers of these 
compounds may be isolated from the reaction mixture. 
Thus, treatment of compound (4) with unsubstituted hydrazine affords the 
compound of Formula (I) wherein W is --NH-- and R is H. 
Also, treatment of (4) with a substituted hydrazine RR.sup.4 NNH.sub.2, 
wherein R is as defined for Formula (I) and R.sup.4 is C.sub.1 -C.sub.6 
-alkyl, gives the compounds of Formula (I) wherein W is --N(C.sub.1 
-C.sub.6 -alkyl)--. 
Optionally, the compound of Formula (I) wherein W is --NH-- and R is H can 
be treated with an R-acyl acylating agent, wherein R is as defined for 
Formula (I), to afford a compound of Formula (I) wherein W is --NH--CO--. 
The acylating agents can be, for example, an acid chloride, an acid 
fluoride, an acid anhydride, or a carboxylic acid in the presence of a 
carbodiimide coupling reagent such as carbonyldiimidazole or 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, for example, 
wherein R is as defined above. 
Optionally, the compound of Formula (I) wherein W is --NH-- and R is H can 
be treated with an aldehyde R--CHO, wherein R is as defined for Formula 
(I), to afford a compound of Formula (I) wherein W is --N.dbd.CH--. 
Optionally, the compounds of Formula (I) wherein W is --N.dbd.CH-- can be 
reduced to yield additional compounds of Formula (I) above, wherein W is 
--NH-- using reducing reagents such as sodium cyanoborohydride, sodium 
borohydride, sodium triacetoxyborohydride, borane-tetrahydrofuran complex, 
and borane-piperidine complex, for example. 
Also shown in Scheme 3 is the procedure by which compounds of Formula (I) 
wherein W is --O-- and R is H or O--C.sub.1 -C.sub.6 -alkyl may be 
prepared. Under reaction conditions similar to those shown above for 
hydrazine reagents, treatment of compound (4) with unsubstituted 
hydroxylamine or an O--C.sub.1 -C.sub.6 -alkylated hydroxylamine affords 
the desired compound. 
For example, treatment of compound (4) with an excess of hydroxylamine 
affords the compound of formula (I) wherein W is --O-- and R is H. 
Treatment of compound (4) with an O--C.sub.1 -C.sub.6 -alkylated 
hydroxylamine affords the desired compound of Formula (I) wherein W is 
--O-- and R is C.sub.1 -C.sub.6 -alkyl. 
Optionally, it is possible to further treat the compound of Formula (I) 
wherein W is --O-- and R is H with a suitable base and an appropriate 
electrophile to prepared a compound wherein W is --O-- and R is C.sub.1 
-C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, aryl, substituted-aryl, 
heteroaryl or a substituted-heteroaryl group, wherein these terms are as 
defined for compounds of Formula (I) above. The base may be an alkali 
metal hydride or an organo-alkali metal compound, including but not 
limited to sodium hydride, potassium hydride, lithium hydride, lithium 
diethylamide, and butyllithium. The electrophile is a compound having the 
formula R-L, wherein R is as defined immediately above, and L is halide or 
another suitable leaving group, such as a methanesulfonyl or 
p-toluenesulfonyl moiety. 
Optional deprotection of any of the compounds wherein W is --O-- may be 
accomplished by standard methods as described by Wuts and Greene (op. 
cit.). 
Compounds of Formula (II) may also be synthesized as outlined in Scheme 3. 
Thus, a starting material compound of formula (4) is reacted with a 
1,2-diamine compound with a compound having the formula: 
##STR42## 
wherein A, B, D, and E are as defined above, in a suitable solvent at room 
temperature to reflux temperature for about 4 to about 48 hours to give 
the bicyclic compound of formula (8). The 1,2-diamine compound may have 
substituents A, B, D and E, as defined above for the compounds of Formula 
(II), but with C.sub.2 or Cs symmetry or A.dbd.B.dbd.H. Suitable solvents 
include alcohols such as methanol, ethanol, propanol, isopropanol, 
butanol, t-butanol, and the like, aprotic solvents such as methylene 
chloride, tetrahydrofuran, N-methylpyrrolidinone, diethyl ether, 
bis-methoxymethyl ether, dimethyl formamide, and acetone, for example, as 
well as aqueous mixtures thereof. Preferred solvents are aqueous 
acetonitrile, aqueous DMF, and aqueous acetone. 
The 2'-hydroxy protecting group on compound (8) is then removed by standard 
methods as described by Wuts and Greene (op. cit.). When OR.sup.2 is an 
ester, for example, such as acetate or benzoate, the compound is 
preferably deprotected by treatment with methanol or ethanol. When R.sup.2 
is a trialkylsilyl group, the compound may be deprotected by treatment 
with fluoride in THF or acetonitrile. The reaction time required may be 
from about 1 to about 24 hours. 
The deprotected compound of formula (8) wherein R.sup.2 is H is then 
cyclized to give compounds of Formula (II) by treatment with a dilute 
concentration of a strong acid at ambient temperature to reflux 
temperature for about 4 hours to about 10 days in a suitable organic 
solvent. Suitable acids include, but are not limited to, hydrochloric 
acid, sulfuric acid, dichloroacetic acid, trichloroacetic acid and the 
like. The reaction may be accomplished with a suspension of the reagents 
in aqueous alcohol, such as for example, methanol, ethanol, propanol, 
iso-propanol, butanol, iso-butanol and t-butanol, for example. 
Optional deprotection may be accomplished by standard methods as described 
by Wuts and Greene (op. cit.). 
Scheme 4 illustrates an alternate preparation for compounds of formula 
(II). Starting material (4) is reacted with a compound having the formula: 
##STR43## 
wherein A, B, D, and E are as defined above, in a suitable solvent at 
0.degree.-70 .degree. C. for about 4 to about 48 hours to give compound 
(9) where Y.dbd.OH. Suitable solvents are those such as methanol, ethanol, 
propanol, isopropanol, butanol, t-butanol, methylene chloride, 
tetrahydrofuran, N-methyl-pyrrolidinone, diethyl ether, bis-methoxymethyl 
ether, dimethyl formamide, acetone, aqueous acetonitrile, aqueous DMF, and 
aqueous acetone, for example. 
##STR44## 
The azido intermediate, compound (9) Y.dbd.N.sub.3, is prepared by 
Mitsunobu reaction by treating compound (9) wherein Y.dbd.OH with 
triphenylphosphine and diphenylphosphoryl azide-DEAD in tetrahydrofuran 
under Mitsunobu reaction conditions. Compound (9) wherein Y.dbd.N.sub.3 is 
then deprotected by standard methods as described by Wuts and Greene (op). 
cit.). When OR.sup.2 is an ester, for example, such as acetate or 
benzoate, the compound may be preferably deprotected by treatment with 
methanol or ethanol. When R.sup.2 is a trialkylsilyl group, the compound 
may be deprotected by treatment with fluoride in THF or acetonitrile, for 
example. 
The azido intermediate, compound (9) wherein Y.dbd.N.sub.3, is then reduced 
to the amino compound (9) wherein Y.dbd.NH.sub.2. Preferable reducing 
reagents are triphenylphosphine-water, hydrogen with a catalyst, sodium 
borohydride, or dialkylaluminum hydride. 
Compound (9) wherein Y.dbd.NH.sub.2 is then cyclized to prepare the 
compound of Formula (II) by treatment with a dilute concentration of a 
strong acid at ambient temperature to reflux temperature for about 4 hours 
to about 10 days in a suitable organic solvent. 
Suitable acids include, but are not limited to, hydrochloric acid, sulfuric 
acid, dichloroacetic acid, trichloroacetic acid and the like. The reaction 
may be accomplished with a suspension of the reagents in aqueous alcohol, 
such as for example, methanol, ethanol, propanol, iso-propanol, butanol, 
iso-butanol and t-butanol, for example. This treatment also removes 
protecting groups at positions R.sup.1 and R.sup.2. 
Alternately, the hydroxy group (Y.dbd.OH) in compound (9) may be activated 
by treatment with a sulfonating agent, such as 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) to give the compound (9) 
wherein Y is a sulfonate ester. The reaction requires cooling or heating, 
depending on the conditions used. The reaction temperature is preferably 
-100.degree. C. to 10.degree. C. 
The reaction may require 20 minutes to 24 hours to complete. The sulfonate 
ester activated hydroxy group in (9) (e.g. Y.dbd.--OSO.sub.2 CF.sub.3) is 
then converted to an azide to give the second intermediate azide compound 
(9, Y.dbd.N.sub.3) by reacting with an alkali metal azide, such as lithium 
azide or sodium azide, in the same solvent defined above. The reaction 
temperature is preferably about 0.degree. C. to about 100.degree. C. The 
azido compound is then converted to compound (8) according to the 
procedures described above. 
As outlined in Scheme 5 below, the tricyclic macrolides of formula (II), 
wherein substituents A, B, D and E are as defined above, can be further 
transformed into macrolides having the formulas (III) and (IV). Treatment 
of the imine nitrogen atom of compound (II) with a suitable oxidizing 
agent, such as hydrogen peroxide or a carboxylic peracid, oxidizes the 
imine nitrogen to the nitrone and the nitrogen atom on the desosamine 
moiety to the N-oxide, to give an N-oxidized intermediate which is 
directly treated with a reducing agent such as triphenylphosphine or 
hydrogen in the presence of a catalyst, for example, to reduce the 
desosamine N-oxide, to give the desired compound of formula (III). 
Optional deprotection may be accomplished by standard methods as described 
by Wuts and Greene (op. cit.). 
Macrolides of the formula (II) can also be treated with reducing agents 
such as sodium cyanoborohydride at pH 4-5 or sodium borohydride in a 
suitable organic solvent to yield the tricyclic amine of the formula 
(IVa), which is a compound of formula (IV) wherein R.sup.6 is H. Compounds 
of the formula (IVa) can be further transformed into compounds of type 
(IVb), which are compounds of formula (IV) wherein R.sup.6 is C.sub.1 
-C.sub.6 -alkyl, via reductive alkylation of the amine with a reducing 
reagent, preferably sodium cyanoborohydride, sodium borohydride, sodium 
triacetoxyborohydride, borane-tetrahydrofuran complex, or 
borane-piperidine complex, in the presence of a C.sub.1 -C.sub.6 
-alkyl-group precursor. Optional deprotection may be accomplished by 
standard methods as described by Wuts and Greene (op. cit.). 
##STR45## 
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.