Novel 3'-N-modified 6-O-substituted erythromycin ketolide compounds and pharmaceutically acceptable salts and esters thereof having antibacterial activity having a formula ##STR1## compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier, as well as a method for treating bacterial infections by administering to a mammal a pharmaceutical composition containing a therapeutically-effective amount of a compound of the invention.

TECHNICAL FIELD 
This invention relates to novel semi-synthetic macrolides having 
antibacterial activity, to pharmaceutical compositions comprising these 
compounds, and to a medical method of treatment. More particularly, the 
invention relates to 3'-N-modified 6-O-substituted erythromycin ketolide 
derivatives and methods for preparing them, compositions containing these 
compounds, and a method of treating bacterial infections with such 
compositions. 
BACKGROUND OF THE INVENTION 
Erythromycins A through D, represented by formula (E), 
__________________________________________________________________________ 
Erythromycin 
R.sup.a 
R.sup.b 
__________________________________________________________________________ 
A B C D --OH --H --OH --H 
--CH.sub.3 --CH.sub.3 --H --H 
__________________________________________________________________________ 
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. 
Morimoto et al. describes the preparation of 6-O-methyl erythromycin A in 
J. Antibiotics 37:187 (1984). Morimoto et al. further discloses 6-O-alkyl 
erythromycin A derivatives in J. Antibiotics, 43:286 (1990) and in 
European Patent Application 272,110, published Jun. 22, 1988. European 
Patent Application 215,355, published Mar. 28, 1987, discloses 
6-O-loweralkyl erythromycins as stimulants of gastrointestinal contractile 
motion. 
U.S. Pat. No. 5,444,051 discloses 6-O-substituted-3-oxoerythromycin A 
derivatives in which the substituents are selected from alkyl, 
--CONH.sub.2, --CONHC(O)alkyl and --CONHSO.sub.2 alkyl. PCT application WO 
97/10251, published Mar. 20, 1997, discloses 6-O-methyl 3-descladinose 
erythromycin derivatives, and PCT application WO 97/17356, published May 
15, 1997, discloses 3-deoxy-3-descladinose erythromycin derivatives. PCT 
application WO 92/09614, published Jun. 11, 1992, discloses tricyclic 
6-O-methyl erythromycin A derivatives. Certain intermediates to the 
present invention are disclosed in U.S. patent application Ser. No. 
08/888,350. 
European Patent Application 596802, published May 11, 1994, discloses 
bicyclic 6-O-methyl-3-oxo erythromycin A derivatives. 
SUMMARY OF THE INVENTION 
The present invention provides a novel class of 3'-N-modified 
6-O-substituted erythromycin ketolide derivatives which possess 
antibacterial activity. 
In one aspect of the present invention are compounds, or pharmaceutically 
acceptable salts and esters thereof, having a formula selected from the 
group consisting of 
##STR3## 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein 
R.sup.1 and R.sup.2, with the proviso that R.sup.1 and R.sup.2 are not 
both methyl, are independently selected from the group consisting of 
(1) hydrogen, 
(2) C.sub.1 -C.sub.6 -alkyl optionally substituted with a substituent 
selected from the group consisting of 
(a) halogen, 
(b) C.sub.3 -C.sub.6 -cycloalkyl, 
(c) aryl, 
(d) substituted aryl, 
(e) heteroaryl, 
(f) substituted heteroaryl, 
(g) --CHO, 
(h) --C(O)--C.sub.1 -C.sub.6 -alkyl, and 
(i) --C(O)--NR'R", wherein R' and R" are independently selected from the 
group consisting of hydrogen, C.sub.1 -C.sub.3 -alkyl, C.sub.1 -C.sub.3 
-alkyl substituted with aryl, substituted aryl, heteroaryl, and 
substituted heteroaryl, 
(3) C.sub.2 -C.sub.6 -alkyl optionally substituted with a substituent 
selected from the group consisting of 
(a) C.sub.1 -C.sub.6 -alkoxy, 
(b) --NR'R", wherein R' and R" are as previously defined, 
(c) --NH--C(O)--C.sub.1 -C.sub.6 -alkyl, 
(d) --NH--C(O)--O--C.sub.1 -C.sub.6 -akyl, 
(e) --O--C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
(f) --O--C(O)--C.sub.1 -C.sub.6 -alkyl, 
(g) --CH(.dbd.N--O--C.sub.1 -C.sub.6 -alkyl), 
(h) --C(.dbd.N--O--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 -alkyl, 
(i) --CH(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl), and 
(j) --C(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 -alkyl, 
(4) C.sub.3 -C.sub.6 -alkenyl optionally substituted with a substituent 
selected from the group consisting of 
(a) halogen, 
(b) C.sub.3 -C.sub.6 -cycloalkyl, 
(c) aryl, 
(d) substituted aryl, 
(e) heteroaryl, 
(f) substituted heteroaryl, 
(g) --NH--C(O)--C.sub.1 -C.sub.6 -alkyl, 
(h) --NH--C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
(i) --O--C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
(j) --O--C(O)--C.sub.1 -C.sub.6 -alkyl, 
(k) --CHO, 
(l) --C(O)--C.sub.1 -C.sub.6 -alkyl, 
(m) --C(O)--NR'R", wherein R' and R" are as previously defined, 
(n) --CH(.dbd.N--O--C.sub.1 -C.sub.6 -alkyl), 
(o) --C(.dbd.N--O--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 -alkyl, 
(p) --CH(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl), 
(q) --C(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 -alkyl, and 
(r) --C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
(5) C.sub.3 -C.sub.6 -alkynyl optionally substituted with a substituent 
selected from the group consisting of 
(a) halogen, 
(b) C.sub.3 -C.sub.6 -cycloalkyl, 
(c) aryl, 
(d) substituted aryl, 
(e) heteroaryl, and 
(f) substituted heteroaryl, 
(6) C.sub.3 -C.sub.6 -cycloalkyl, 
(7) --CHO, 
(8) --C(O)--C.sub.1 -C.sub.6 -alkyl, 
(9) --C(O)--NR'R", wherein R' and R" are as previously defined, and 
(10) --C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
or R.sup.1 and R.sup.2 taken together may be --(CH.sub.2).sub.p --, wherein 
p is 3-to-7, which taken together with the nitrogen atom to which they are 
attached, thus form a heterocyclic ring containing one nitrogen atom and 
from 3 to 7 carbon atoms; 
R is selected from the group consisting of 
(1) methyl substituted with a substituent selected from the group 
consisting of 
(a) --CN, 
(b) --F, 
(c) --CO.sub.2 R.sup.3 wherein R.sup.3 is C.sub.1 -C.sub.3 -alkyl, 
aryl-substituted C.sub.1 -C.sub.3 -alkyl, or heteroaryl-substituted 
C.sub.1 -C.sub.3 -alkyl, 
(d) --S(O).sub.n --R.sup.3 wherein n is 0, 1, or 2, and R.sup.3 is as 
previously defined, 
(e) --NH--C(O)--R.sup.3 where R.sup.3 is as previously defined, 
(f) --NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are 
independently selected from the group consisting of 
(i) hydrogen, 
(ii) C.sub.1 -C.sub.3 -alkyl 
(iii) C.sub.1 -C.sub.3 -alkyl substituted with aryl, 
(iv) C.sub.1 -C.sub.3 -alkyl substituted with substituted aryl, 
(v) C.sub.1 -C.sub.3 -alkyl substituted with heteroaryl, and 
(vi) C.sub.1 -C.sub.3 -alkyl substituted with and substituted heteroaryl, 
(g) aryl, 
(h) substituted aryl, 
(i) heteroaryl, and 
(j) substituted heteroaryl, 
(2) C.sub.2 -C.sub.10 -alkyl, 
(3) C.sub.2 -C.sub.10 -alkyl substituted with one or more substituents 
selected from the group consisting of 
(a) halogen, 
(b) hydroxy, 
(c) C.sub.1 -C.sub.3 -alkoxy, 
(d) C.sub.1 -C.sub.3 -alkoxy-C.sub.1 -C.sub.3 -alkoxy, 
(e) oxo, 
(f) --N.sub.3, 
(g) --CHO, 
(h) --O--SO.sub.2 -(substituted C.sub.1 -C.sub.6 -alkyl), 
(i) --NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are selected from the 
group consisting of 
(i) hydrogen, 
(ii) C.sub.1 -C.sub.12 -alkyl, 
(iii) substituted C.sub.1 -C.sub.12 -alkyl, 
(iv) C.sub.1 -C.sub.12 -alkenyl, 
(v) substituted C.sub.1 -C.sub.12 -alkenyl, 
(vi) C.sub.1 -C.sub.12 -alkynyl, 
(vii) substituted C.sub.1 -C.sub.12 -alkynyl, 
(viii) aryl, 
(ix) C.sub.3 -C.sub.8 -cycloalkyl, 
(x) substituted C.sub.3 -C.sub.8 -cycloalkyl, 
(xi) substituted aryl, 
(xii) heterocycloalkyl, 
(xiii) substituted heterocycloalkyl, 
(xiv) C.sub.1 -C.sub.12 -alkyl substituted with aryl, 
(xv) C.sub.1 -C.sub.12 -alkyl substituted with substituted aryl, 
(xvi) C.sub.1 -C.sub.12 -alkyl substituted with heterocycloalkyl, 
(xvii) C.sub.1 -C.sub.12 -alkyl substituted with substituted 
heterocycloalkyl, 
(xviii) C.sub.1 -C.sub.12 -alkyl substituted with C.sub.3 -C.sub.8 
-cycloalkyl, 
(xix) C.sub.1 -C.sub.12 -alkyl substituted with substituted C.sub.3 
-C.sub.8 -cycloalkyl, 
(xx) heteroaryl, 
(xxi) substituted heteroaryl, 
(xxii) C.sub.1 -C.sub.12 -alkyl substituted with heteroaryl, and 
(xxiii) C.sub.1 -C.sub.12 -alkyl substituted with substituted heteroaryl, 
or 
R.sup.6 and R.sup.7 are taken together with the atom to which they are 
attached form a 3-10 membered heterocycloalkyl ring which may be 
substituted with one or more substituents independently selected from the 
group consisting of 
(i) halogen, 
(ii) hydroxy, 
(iii) C.sub.1 -C.sub.3 -alkoxy, 
(iv) C.sub.1 -C.sub.3 -alkoxy-C.sub.1 -C.sub.3 -alkoxy, 
(v) oxo, 
(vi) C.sub.1 -C.sub.3 -alkyl, 
(vii) halo-C.sub.1 -C.sub.3 -alkyl, and 
(vii) C.sub.1 -C.sub.3 -alkoxy-C.sub.1 -C.sub.3 -atkyl, 
(j) --CO.sub.2 R.sup.3 wherein R.sup.3 is as previously defined, 
(k) --C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as previously 
defined, 
(l) .dbd.N--O--R.sup.3 wherein R.sup.3 is as previously defined, 
(m) --C.tbd.N, 
(n) --O--S(O).sub.n --R.sup.3 wherein n and R.sup.3 are as previously 
defined, 
(o) aryl, 
(p) substituted aryl, 
(q) heteroaryl, 
(r) substituted heteroaryl, 
(s) C.sub.3 -C.sub.8 -cycloalkyl, 
(t) substituted C.sub.3 -C.sub.8 -cycloalkyl, 
(u) C.sub.1 -C.sub.12 -alkyl substituted with heteroaryl, 
(v) heterocycloalkyl, 
(w) substituted heterocycloalkyl, 
(x) --NH--C(O)--R.sup.3 where R.sup.3 is as previously defined, 
(y) --NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as 
previously defined, 
(z) .dbd.N--NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are as previously 
defined, 
(aa) .dbd.N--R.sup.3 wherein R.sup.3 is as previously defined, 
(bb) .dbd.N--NH--C(O)--R.sup.4 wherein R.sup.4 is as previously defined, 
and 
(cc) .dbd.N--NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as 
previously defined, 
(4) C.sub.3 -alkenyl substituted with a moiety selected from the group 
consisting of 
(a) halogen, 
(b) --CHO, 
(c) --CO.sub.2 R.sup.3 where R.sup.3 is as previously defined, 
(d) --C(O)--R.sup.4 where R.sup.4 is as previously defined, 
(e) --C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as previously 
defined, 
(f) --C.tbd.N, 
(g) aryl, 
(h) substituted aryl, 
(i) heteroaryl, 
(j) substituted heteroaryl, 
(k) C.sub.3 -C.sub.7 -cycloalkyl, and 
(l) C.sub.1 -C.sub.12 -alkyl substituted with heteroaryl, 
(5) C.sub.4 -C.sub.10 -alkenyl, 
(6) C.sub.4 -C.sub.10 -alkenyl substituted with one or more substituents 
selected from the group consisting of 
(a) halogen, 
(b) C.sub.1 -C.sub.3 -alkoxy, 
(c) oxo, 
(d) --CHO, 
(e) --CO.sub.2 R.sup.3 where R.sup.3 is as previously defined, 
(f) --C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as previously 
defined, 
(g) --NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are as previously 
defined, 
(h) .dbd.N--O--R.sup.3 wherein R.sup.3 is as previously defined, 
(i) --C.tbd.N, 
(j) --O--S(O).sub.n --R.sup.3 wherein n is 0, 1, or 2 and R.sup.3 is as 
previously defined, 
(k) aryl, 
(l) substituted aryl, 
(m) heteroaryl, 
(n) substituted heteroaryl, 
(o) C.sub.3 -C.sub.7 -cycloalkyl, 
(p) C.sub.1 -C.sub.12 -alkyl substituted with heteroaryl, 
(q) --NH--C(O)--R.sup.3 where R.sup.3 is as previously defined, 
(r) --NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as 
previously defined, 
(s) .dbd.N--NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are as previously 
defined, 
(t) .dbd.N--R.sup.3 wherein R.sup.3 is as previously defined, 
(u) .dbd.N--NH--C(O)--R.sup.3 where R.sup.3 is as previously defined, and 
(v) .dbd.N--NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as 
previously defined, 
(7) C.sub.3 -C.sub.10 -alkynyl, and 
(8) C.sub.3 -C.sub.10 -alkynyl substituted with one or more substituents 
selected from the group consisting of 
(a) trialkylsilyl, 
(b) aryl, 
(c) substituted aryl, 
(d) heteroaryl, and 
(e) substituted heteroaryl, 
with the proviso that when R is allyl and R.sup.1 is methyl, R.sup.2 is not 
H; 
R.sup.p is hydrogen or a hydroxy protecting group; 
R.sup.w is selected from the group consisting of 
(1) hydrogen, 
(2) C.sub.1 -C.sub.6 -alkyl, optionally substituted with one or more 
substituents selected from the group consisting of 
(a) aryl, 
(b) substituted aryl, 
(c) heteroaryl, 
(d) substituted heteroaryl, 
(3) a group selected from option (2) as previously defined further 
substituted with --CH.sub.2 --M--R.sup.8, wherein M is selected from the 
group consisting of 
(i) --O--, 
(ii) --NH--, 
(ii) --N(CH.sub.3)--, 
(iv) --S(O).sub.n --, wherein n is as described previously, 
(v) --NH--C(O)--, and 
(vi) --C(O)--NH--, and 
R.sup.8 is selected from the group consisting of 
(i) --(CH.sub.2).sub.n -aryl, wherein n is as described previously, 
(ii) --(CH.sub.2).sub.n -substituted aryl, wherein n is as described 
previously, 
(iii) --(CH.sub.2).sub.n -heteroaryl, wherein n is as described previously, 
(iv) --(CH.sub.2).sub.n -substituted heteroaryl, wherein n is as described 
previously, and 
(v) --(CH.sub.2).sub.n -heterocycloalkyl, wherein n is as described 
previously; and 
W is absent or is selected from the group consisting of --O--, --NH-- and 
--N(CH.sub.3)--. 
The present invention also provides pharmaceutical compositions which 
comprise a therapeutically effective amount of a compound as defined 
previously in combination with a pharmaceutically acceptable carrier. 
The invention further relates to a method of treating bacterial infections 
in a host mammal in need of such treatment comprising administering to a 
mammal in need of such treatment a therapeutically effective amount of a 
compound as defined previously. 
In a further aspect of the present invention, processes are provided for 
the preparation of 3'-N-modified 6-O-substituted erythromycin ketolide 
derivatives of Formula (I), (II), (III), (IV) and (V) as described 
previously. 
DETAILED DESCRIPTION OF THE INVENTION 
Definitions 
As used throughout this specification and the appended claims, the 
following terms have the meanings specified. 
The term "alkanoyl" as used herein refers to an C.sub.1 -C.sub.6 -alkyl 
group, as defined herein, attached to the parent molecular moiety through 
an carbonyl group. Examples of alkanoyl groups include acetyl, propanoyl, 
butanoyl, and the like. 
The terms "C.sub.1 -C.sub.3 -alkyl", "C.sub.1 -C.sub.6 -alkyl", and 
"C.sub.1 -C.sub.12 -alkyl" as used herein refer to saturated, straight- or 
branched-chain hydrocarbon radicals derived from a hydrocarbon moiety 
containing between one and three, one and six, and one and twelve carbon 
atoms, respectively, by removal of a single hydrogen atom. 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, but are not limited to, all the foregoing examples as well as 
n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-docecyl. 
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, iso-propoxy, 
n-butoxy, tert-butoxy, neo-pentoxy and n-hexoxy. 
The term "C.sub.1 -C.sub.12 -alkenyl" denotes a monovalent group derived 
from a hydrocarbon moiety containing from two to twelve carbon atoms and 
having at least one carbon-carbon double bond by the removal of a single 
hydrogen atom. Alkenyl groups include, for example, ethenyl, propenyl, 
butenyl,1-methyl-2-buten-1-yl, and the like. 
The term "C.sub.1 -C.sub.12 -alkynyl" as used herein refers to a monovalent 
group derived from a hydrocarbon containing from two to twelve carbon 
atoms and having at least one carbon-carbon triple bond by the removal of 
a single hydrogen atom. Representative alkynyl groups include ethynyl, 
2-propynyl (propargyl), 1-propynyl and the like. 
The term "alkylene" denotes a divalent group derived from a straight or 
branched chain saturated hydrocarbon by the removal of two hydrogen atoms, 
for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 
2,2-dimethylpropylene, and the like. 
The term "C.sub.1 -C.sub.3 -alkylamino" 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 -alkylamino include, but are not limited to methylamino, 
dimethylamino, ethylamino, diethylamino, and propylamino. 
The term "oxo" denotes a group wherein two hydrogen atoms on a single 
carbon atom in an alkyl group as defined previously are replaced with a 
single oxygen atom (i.e. a carbonyl group). 
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, 
heteroaryl compounds, such as, for example, tetrahydrofuran and 
N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl 
ether. Such compounds are well known to those skilled in the art, and it 
will be obvious to those skilled in the art that individual solvents or 
mixtures thereof may be preferred for specific compounds and reaction 
conditions, depending upon such factors as the solubility of reagents, 
reactivity of reagents and preferred temperature ranges, for example. 
Further discussions of aprotic solvents may be found in organic chemistry 
textbooks or in specialized monographs, for example: Organic Solvents 
Physical Properties and Methods of Purification, 4th ed., edited by John 
A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John 
Wiley & Sons, New York, 1986. 
The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic 
ring system having one or two aromatic rings including, but not limited 
to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. 
Aryl groups (including bicyclic aryl groups) can be unsubstituted or 
substituted with one, two or three substituents independently selected 
from loweralkyl, substituted loweralkyl, cycloalkyl, alkenyl, alkoxy, 
alkanoyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, 
acylamino, cyano, hydroxy, hydroxyalkyl, halo, mercapto, nitro, 
carboxaldehyde, carboxy, alkoxycarbonyl, and carboxamide. In addition, 
substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. 
The term "C.sub.3 -C.sub.12 -cycloalkyl" denotes a monovalent group derived 
from a monocyclic or bicyclic saturated carbocyclic ring compound by the 
removal of a single hydrogen atom. Examples include cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and 
bicyclo[2.2.2]octyl. 
The terms "halo" and "halogen" as used herein refer to an atom selected 
from fluorine, chlorine, bromine and iodine. 
The term "alkylamino" refers to a group having the structure --NHR' wherein 
R' is alkyl, as previously defined, Examples of alkylamino include 
methylamino, ethylamino, isopropylamino and the like. 
The term "dialkylamino" refers to a group having the structure --NR'R" 
wherein R' and R" are independently selected from alkyl, as previously 
defined. Additionally, R' and R" taken together may optionally be 
--(CH.sub.2).sub.k -- wherein k is an integer of from 2 to 6. Examples of 
dialkylamino include, dimethylamino, diethylaminocarbonyl, 
methylethylaminno, piperidino, and the like. 
The term "haloalkyl" denotes an alkyl group, as defined previously, having 
one, two, or three halogen atoms attached thereto and is exemplified by 
such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like, 
The term "alkoxycarbonyl" represents an ester group; i.e. an alkoxy group, 
attached to the parent molecular moiety through a carbonyl group such as 
methoxycarbonyl, ethoxycarbonyl, and the like. 
The term "thioalkoxy" refers to an alkyl group as previously defined 
attached to the parent molecular moiety through a sulfur atom. 
The term "carboxaldehyde" as used herein refers to a group of formula 
--CHO. 
The term "carboxy" as used herein refers to a group of formula --CO.sub.2 
H. 
The term "carboxamide" as used herein refers to a group of formula 
--CONHR'R" wherein R' and R" are independently selected from hydrogen or 
alkyl, or R' and R" taken together may optionally be --(CH.sub.2).sub.k -- 
where k is an integer of from 2 to 6. 
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, pyridyl, pyrazinyl, pyrimidinyl, 
pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, 
thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, 
and the like. 
The term "heterocycloalkyl" as used herein, refers to a non-aromatic 
partially unsaturated or fully saturated 3- to 10-membered ring system, 
which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic 
ring systems which may include aromatic six-membered aryl or heteroaryl 
rings fused to a non-aromatic ring. These heterocycloalkyl rings include 
those having from one to three heteroatoms independently selected from 
oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms 
may optionally be oxidized and the nitrogen heteroatom may optionally be 
quaternized. 
Representative heterocycles include, but are not limited to, pyrrolidinyl, 
pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, 
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, 
isothiazolidinyl, and tetrahydrofuryl. 
Specific heterocycloalkyl rings considered useful in preparing compounds of 
the invention include: 3-methyl-4-(3-methylphenyl)piperazine, 
3-methylpiperidine, 4-(bis-(4-fluorophenyl)methyl)piperazine, 
4-(diphenylmethyl)piperazine, 4-(ethoxycarbonyl)piperazine, 
4-(ethoxycarbonylmethyl)piperazine, 4-(phenylmethyl)piperazine, 
4-(1-phenylethyl)piperazine, 4-(1,1-dimethylethoxycarbonyl)piperazine, 
4-(2-(bis-(2-propenyl)amino)ethyl)piperazine, 
4-(2-(diethylamino)ethyl)piperazine, 4-(2-chlorophenyl)piperazine, 
4-(2-cyanophenyl)piperazine, 4-(2-ethoxyphenyl)piperazine, 
4-(2-ethylphenyl)piperazine, 4-(2-fluorophenyl)piperazine, 
4-(2-hydroxyethyl)piperazine, 4-(2-methoxyethyl)piperazine, 
4-(2-methoxyphenyl)piperazine, 4-(2-methylphenyl)piperazine, 
4-(2-methylthiophenyl)piperazine, 4-(2-nitrophenyl)piperazine, 
4-(2-nitrophenyl)piperazine, 4-(2-phenylethyl)piperazine, 
4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, 
4-(2,3-dimethylphenyl)piperazine, 4-(2,4-difluorophenyl)piperazine, 
4-(2,4-dimethoxyphenyl)piperazine, 4-(2,4-dimethylphenyl)piperazine, 
4-(2,5-dimethylphenyl)piperazine, 4-(2,6-dimethylphenyl)piperazine, 
4-(3-chlorophenyl)piperazine, 4-(3-methylphenyl)piperazine, 
4-(3-trifluoromethylphenyl)piperazine, 4-(3,4-dichlorophenyl)piperazine, 
4-(3,4-dimethoxyphenyl)piperazine, 4-(3,4-dimethylphenyl)piperazine, 
4-(3,4-methylenedioxyphenyl)piperazine, 
4-(3,4,5-trimethoxyphenyl)piperazine, 4-(3,5-dichlorophenyl)piperazine, 
4-(3,5-dimethoxyphenyl)piperazine, 4-(4-(phenylmethoxy)phenyl)piperazine, 
4(4-(1,1-dimethylethyl)phenylmethyl)piperazine, 
4-(4-chloro-3-trifluoromethylphenyl)piperazine, 
4-(4-chlorophenyl)-3-methylpiperazine, 4-(4-chlorophenyl)piperazine, 
4-(4-chlorophenyl)piperazine, 4-(4-chlorophenylmethyl)piperazine, 
4-(4-fluorophenyl)piperazine, 4-(4-methoxyphenyl)piperazine, 
4-(4-methylphenyl)piperazine, 4-(4-nitrophenyl)piperazine, 
4-(4-trifluoromethylphenyl)piperazine, 4-cyclohexylpiperazine, 
4-ethylpiperazine, 4-hydroxy-4-(4-chlorophenyl)methylpiperidine, 
4-hydroxy-4-phenylpiperidine, 4-hydroxypyrrolidine, 4-methylpiperazine, 
4-phenylpiperazine, 4-piperidinylpiperazine, 
4-((2-furanyl)carbonyl)piperazine, 
4-((1,3-dioxolan-5-yl)methyl)piperazine, 6-fluoro-1,2,3,4-tetrahydro-2-met 
hylquinoline, 1,4-diazacycloheptane, 2,3-dihydroindolyl, 
3,3-dimethylpiperidine, 4,4-ethylenedioxypiperidine, 1,2,3 
,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, azacyclooctane, 
decahydroquinoline, piperazine, piperidine, pyrrolidine, thiomorpholine, 
and triazole. 
The term "heteroarylalkyl" as used herein, refers to a heteroaryl group as 
defined previously attached to the parent molecular moiety through an 
alkylene group wherein the alkylene group is of one to four carbon atoms. 
"Hydroxy-protecting group", as used herein, refers to an easily removable 
group which is 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, ethers such 
as methoxymethyl, and esters including acetyl benzoyl, and the like. 
The term "ketone protecting group", as used herein, refers to an easily 
removable group which is known in the art to protect a ketone group 
against undesirable reactions during synthetic procedures and to be 
selectively removable. The use of ketone-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 
ketone-protecting groups include, but are not limited to, ketals, oximes, 
O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, 
1-isopropoxycyclohexyl oxime, and the like. 
A the term "protected-hydroxy" refers to a hydroxy group protected with a 
hydroxy protecting group, as defined previously, 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. II, in the Techniques of Chemistry Series, John 
Wiley & Sons, New York, 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, --CN, 
C.sub.1 -C.sub.3 -alkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 
-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, 
dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, cycloalkyl, 
alkenyl, alkoxy, alkanoyl, hydroxyalkyl, alkoxycarbonyl and carboxamide. 
In addition, any one substitutent may be an aryl, heteroaryl, or 
heterocycloalkyl group. Also, substituted aryl groups include 
tetrafluorophenyl and pentafluorophenyl. 
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, 
--CN, C.sub.1 -C.sub.3 -alkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 
-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, 
dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, 
and carboxamide. In addition, any one substitutent may be an aryl, 
heteroaryl, or heterocycloalkyl group. 
The term "substituted heterocycloalkyl" as used herein, refers to a 
heterocycloalkyl group, as defined previously, substituted by independent 
replacement of one, two or three of the hydrogen atoms thereon with --Cl, 
--Br, --F, --I, --OH, --CN, --C.sub.1 -C.sub.3 -alkyl, C.sub.1 -C.sub.6 
-alkoxy, C.sub.1 -C.sub.6 -alkoxy substituted with aryl, haloalkyl, 
thioalkoxy, arnino, alkylamino, dialkylamino, mercapto, nitro, 
carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any 
one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group. 
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, butyrates, acrylates and 
ethylsuccinates. 
The term "pharmaceutically acceptable prodrugs" as used herein refers to 
those prodrugs of the compounds of the present invention which are, within 
the scope of sound medical judgment, suitable for use in contact with the 
tissues of humans and lower animals with undue toxicity, irritation, 
allergic response, and the like, commensurate with a reasonable 
benefit/risk ratio, and effective for their intended use, as well as the 
zwitterionic forms, where possible, of the compounds of the invention. The 
term "prodrug" refers to compounds that are rapidly transformed in vivo to 
yield the parent compound of the previously formula, for example by 
hydrolysis in blood. A thorough discussion is provided in T. Higuchi and 
V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. 
Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in 
Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, 
both of which are incorporated herein by reference. 
Preferred Embodiments 
In a first embodiment of the invention is a compound having the formula (I) 
as described previously. Compounds of formula (I) also have utility as 
intermediates in the preparation of compounds of formula (II)-(V) of the 
invention. 
In a second embodiment of the invention is a compound having the formula 
(II) as described previously. 
In a third embodiment of the invention is a compound having the formula 
(III) as described previously. 
In a fourth embodiment of the invention is a compound having the formula 
(IV) as described previously. 
In a fifth embodiment of the invention is a compound having the formula (V) 
as described previously. 
Representative compounds of the invention are those selected from the group 
consisting of 
Compound of Formula (I), R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p is 
H, R.sup.1 is methyl, R.sup.2 is hydrogen; 
Compound of formula (II), R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is acetyl, R.sup.1 is H, R.sup.2 is CH.sub.3, W is absent, R.sup.w is H; 
Compound of Formula (H); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p is 
H, W is absent, R.sup.w is H, R.sup.1 is H, R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is acetyl, R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 C(O)--O--CH.sub.2 
CH.sub.3, R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.dbd.CH.sub.2, 
R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.sub.2 F, R.sup.2 
is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -phenyl, R.sup.2 is 
CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -CN, R.sup.2 is 
CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 --C.tbd.CH, R.sup.2 
is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.sub.2 CH.sub.3, 
R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -cyclopropyl, R.sup.2 
is CH.sub.3 ; 
Compound of Formula (Il); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is cyclopropyl, R.sup.2 is 
CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -(3-pyridyl), R.sup.2 
is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -(cyclo-C.sub.3 
H.sub.5), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.sub.2 CH.sub.3, 
R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.dbd.CHC.sub.6 
H.sub.5, R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
C(.dbd.CH.sub.2)C(O)OCH.sub.3, R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
C(.dbd.CH.sub.2)CH.sub.3, R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is cyclo-C.sub.3 H.sub.5, R.sup.2 
is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -(3-pyridyl), R.sup.2 
is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -(3-hydroxyphenyl), 
R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-tert-butyl-5-methylphenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3,4-dimethylphenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methoxy-5-(2-propenyl)phenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methoxy-5-methylphenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-5-cyclopentylphenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-5-carboxan-idophenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is is CH.sub.2 
-(2-hydroxy-3-methoxy-5-(2-methoxycarbonylethyl)phenyl), R.sup.2 is 
CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methyl-5-fluorophenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methoxy-5-acetylphenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-bromophenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methoxy-5-alkoxycarbonylphenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-ethylphenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-5-isobutylphenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methyl-5-diethylamino-6-methylphenyl), R.sup.2 is CH.sub.3 ; 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-4-methyl-5-bromo-6-methylphenyl), R.sup.2 is CH.sub.3 ; and 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-hydroxymethylphenyl), R.sup.2 is CH.sub.3. 
Antibacterial Activity 
Representative compounds of the present invention were assayed in vitro for 
antibacterial activity as follows: Twelve petri dishes containing 
successive aqueous dilutions of the test compound mixed with 10 mL of 
sterilized Brain Heart Infusion (BHI) agar (Difco 0418-01-5) were 
prepared. Each plate was inoculated with 1:100 (or 1:10 for slow-growing 
strains, such as Micrococcus and Streptococcus) dilutions of up to 32 
different microorganisms, using a Steers replicator block. The inoculated 
plates were incubated at 35-37.degree. C. for 20 to 24 hours. In addition, 
a control plate, using BHI agar containing no test compound, was prepared 
and incubated at the beginning and end of each test. 
An additional plate containing a compound having known susceptibility 
patterns for the organisms being tested and belonging to the same 
antibiotic class as the test compound was also prepared and incubated as a 
further control, as well as to provide test-to-test comparability. 
Erythromycin A was used for this purpose. 
After incubation, each plate was visually inspected. The minimum inhibitory 
concentration (MIC) was defined as the lowest concentration of drug 
yielding no growth, a slight haze, or sparsely isolated colonies on the 
inoculum spot as compared to the growth control. The results of this 
assay, shown below in Table 2 demonstrate the antibacterial activity of 
the compounds of the invention. 
TABLE 1 
__________________________________________________________________________ 
Antibacterial Activity (MIC's) of Selected Compounds 
__________________________________________________________________________ 
Organism Example 
Example 
Example 
Example 
Example 
Microorganism code Ery. A 2 3 4 5 6 
__________________________________________________________________________ 
Staphylococcus aureus ATCC 6538P AA 0.2 0.2 0.2 6.2 6.2 0.05 
Staphylococcus aureus A5177 BB 3.1 0.2 0.2 6.2 12.5 0.05 
Staphylococcus aureus A-5278 CC &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 
Staphylococcus aureus CMX 642A DD 0.39 0.2 0.39 6.2 12.5 0.1 
Staphylococcus aureus NCTC10649M EE 0.39 0.2 0.39 6.2 12.5 0.05 
Staphylococcus aureus 
MX 553 FF 0.39 0.2 
0.39 6.2 12.5 0.05 
Staphylococcus aureus 
775 GG &gt;100 &gt;100 &gt;100 
&gt;100 &gt;100 &gt;100 
Staphylococcus 
epidermidis 3519 HH 
0.39 0.2 0.39 6.2 12.5 
0.2 
Enterococcus faecium ATCC 8043 II 0.05 0.05 0.2 1.56 6.2 0.05 
Streptococcus bovis A-5169 JJ 0.02 &lt;=0.005 0.01 0.2 1.56 0.02 
Streptococcus agalactiae CMX 508 KK 0.05 &lt;=0.005 0.02 0.39 1.56 0.05 
Streptococcus 
pyogenes EES61 LL 0.05 
&lt;=0.005 0.01 0.39 0.39 
0.02 
Streptococcus pyogenes 930 MM &gt;100 25 12.5 -- &gt;100 3.1 
Streptococcus pyogenes PIU 2548 NN 6.2 0.39 0.39 1.56 6.2 0.2 
Micrococcus luteus ATCC 9341 OO 0.05 0.02 0.02 0.39 0.78 0.02 
Micrococcus luteus ATCC 4698 PP 0.2 0.1 0.1 3.1 6.2 0.2 
Escherichia coli JUHL QQ &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 50 
Escherichia coli SS RR 0.78 0.39 0.78 100 25 0.2 
Escherichia coli DC-2 SS &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 100 
Candida albicans CCH 442 TT &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 
Mycobacterium smegmatis ATCC 114 UU 3.1 3.1 12.5 25 25 0.2 
Nocardia Asteroides ATCC9970 VV 0.1 1.56 3.1 12.5 25 0.1 
Haemophilis Influenzae DILL AMP R WW 4 16 16 &gt;128 128 4 
Streptococcus Pheumoniae ATCC6303 XX 0.06 0.03 0.03 0.25 0.25 &lt;=0.004 
Streptococcus 
Pheumoniae GYR 1171 YY 
0.06 0.03 0.03 0.125 
0.25 &lt;=0.004 
Streptococcus Pheumoniae 5979 ZZ &gt;128 128 &gt;128 128 &gt;128 16 
Streptococcus Pheumoniae 5649 ZZA 16 0.5 0.5 0.25 2 0.25 
__________________________________________________________________________ 
Organism 
Example 
Example 
Example 
Example 
Example 
Example 
Example 
Microorganism code 7 8 9 10 13 14 15 
__________________________________________________________________________ 
Staphylococcus aureus ATCC 6538P AA 0.1 0.2 0.1 0.2 1.56 0.39 0.39 
Staphylococcus 
aureus A5177 BB 0.2 
0.2 0.1 0.39 3.1 0.39 
0.39 
Staphylococcus aureus A-5278 CC &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 
Staphylococcus 
aureus CMX 642A DD 
0.1 0.2 0.1 0.2 1.56 
0.39 0.39 
Staphylococcus aureus NCTC10649M EE 0.1 0.2 0.1 0.1 3.1 0.39 0.39 
Staphylococcus 
aureus CMX 553 FF 
0.05 0.2 0.05 0.2 
1.56 0.39 0.39 
Staphylococcus 
aureus 1775 GG &gt;100 
&gt;100 &gt;100 &gt;100 &gt;100 
&gt;100 &gt;100 
Staphylococcus epidermidis 3519 HH 0.2 0.2 0.2 0.2 3.1 0.39 0.39 
Enterococcus faecium 
TCC 8043 II 0.05 0.1 
0.1 0.05 0.39 0.05 
0.05 
Streptococcus bovis A-5169 JJ 0.01 0.02 0.01 0.02 0.2 0.05 0.02 
Streptococcus 
agalactiae CMX 508 KK 
0.05 0.02 0.01 0.01 
0.2 0.2 0.05 
Streptococcus pyogenes EES61 LL 0.01 0.02 0.01 0.01 0.1 0.05 0.02 
Streptococcus 
pyogenes 930 MM 12.5 
&gt;100 12.5 6.2 &gt;100 50 
25 
Streptococcus pyogenes PIU 2548 NN 0.39 0.2 0.39 0.39 0.39 0.39 0.1 
Micrococcus luteus 
ATCC 9341 OO 0.05 
0.05 0.02 0.1 0.39 
0.05 0.05 
Micrococcus luteus ATCC 4698 PP 0.39 0.05 0.2 0.39 0.78 0.39 0.39 
Escherichia coli 
JUHL QQ &gt;100 &gt;100 
&gt;100 &gt;100 &gt;100 &gt;100 
&gt;100 
Escherichia coli SS RR 0.39 0.78 0.2 1.56 3.1 0.78 0.2 
Escherichia coli DC-2 SS &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 
Candida albicans CCH 442 TT &gt;100 &gt;100 &gt;100 &gt;100 50 &gt;100 &gt;100 
Mycobacterium smegmatis ATCC 114 UU 1.56 0.39 12.5 1.56 3.1 0.39 0.78 
Nocardia Asteroides 
ATCC9970 VV 0.39 0.2 
0.78 0.2 3.1 0.2 0.2 
Haemophilis Influenza 
e DILL AMP R WW 8 4 8 
8 
Streptococcus Pheumoniae ATCC6303 XX 0.03 0.03 0.03 0.03 0.03 0.03 0.03 
Streptococcus Pheumoniae GYR 1171 YY 0.03 0.03 0.03 0.03 0.03 0.03 0.03 
Streptococcus Pheumoniae 5979 ZZ 16 &gt;128 128 32 16 &gt;128 &gt;128 
Streptococcus Pheumoniae 5649 ZZA 0.25 0.5 0.5 0.25 0.25 0.25 0.25 
__________________________________________________________________________ 
Organism Example Example Example Example Example Example Example 
Microorganism code 
16 17 18 19 20 21 
__________________________________________________________________________ 
22 
Staphylococcus aureus ATCC 6538P AA 0.39 0.39 0.39 0.2 1.56 0.39 0.2 
Staphylococcus 
aureus A5177 BB 0.39 
0.39 0.39 0.2 3.1 
0.39 0.39 
Staphylococcus aureus A-5278 CC &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 
Staphylococcus 
aureus CMX 642A DD 
0.39 0.39 0.39 0.2 
1.56 0.39 0.39 
Staphylococcus 
aureus NCTC10649M EE 
0.39 0.78 0.39 0.39 
3.1 0.39 0.39 
Staphylococcus 
aureus CMX 553 FF 
0.39 0.39 0.39 0.2 
1.56 0.39 0.39 
Staphylococcus 
aureus 1775 GG &gt;100 
&gt;100 &gt;100 &gt;100 &gt;100 
&gt;100 &gt;100 
Staphylococcus epidermidis 3519 HH 0.39 0.39 0.39 0.2 3.1 0.39 0.39 
Enterococcus faecium 
TCC 8043 II 0.05 0.1 
0.1 0.1 0.39 0.05 0.1 
Streptococcus bovis A-5169 JJ 0.01 0.05 0.02 0.02 0.2 0.05 0.1 
Streptococcus agalactiae CMX 508 KK 0.01 0.05 0.02 0.02 0.2 0.2 0.1 
Streptococcus 
pyogenes EES61 LL 
0.01 0.2 0.05 0.01 
0.1 0.05 0.1 
Streptococcus pyogenes 930 MM 12.5 12.5 25 6.2 &gt;100 50 3.1 
Streptococcus pyogenes PIU 2548 NN 0.1 0.39 0.39 0.2 0.39 0.39 0.1 
Micrococcus luteus 
ATCC 9341 OO 0.02 
0.05 0.02 0.05 0.39 
0.05 0.1 
Micrococcus luteus ATCC 4698 PP 0.39 0.39 0.39 0.1 0.78 0.39 0.1 
Escherichia coli 
JUHL QQ &gt;100 &gt;100 
&gt;100 &gt;100 &gt;100 &gt;100 
&gt;100 
Escherichia coli SS RR 0.2 1.56 0.78 0.78 3.1 0.78 0.39 
Escherichia coli DC-2 SS &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 
Candida albicans CCH 442 TT &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 &gt;100 
Mycobacterium smegmatis ATCC 114 UU 1.56 0.39 6.2 0.2 3.1 0.39 0.78 
Nocardia Asteroides 
ATCC9970 VV 0.1 0.2 
0.2 0.1 3.1 0.2 0.2 
Haemophilis Influenza 
e DILL AMP R WW 8 8 
16 4 64 4 4 
Streptococcus Pheumoniae ATCC6303 XX 0.03 &lt;=0.015 &lt;=0.004 &lt;=0.004 0.03 
0.03 0.03 
Streptococcus Pheumoniae GYR 1171 YY 0.03 &lt;=0.015 &lt;=0.004 &lt;=0.004 0.03 
0.03 0.03 
Streptococcus Pheumoniae 5979 ZZ 128 16 128 128 16 &gt;128 -- 
Streptococcus Pheumoniae 5649 ZZA 0.5 0.25 0.5 0.12 0.25 0.25 0.25 
__________________________________________________________________________ 
*missing data is indicated by "-- 
Pharmaceutical Compositions 
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, degrees, 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 previously. The solid dosage forms of tablets, 
degrees, 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 2000 mg of the 
compound(s) of this invention per day in single or multiple doses. 
In another aspect, the present invention is a process for preparing a 
compound selected from the group consisting of 
##STR4## 
wherein R.sup.1 and R.sup.2, with the proviso that R.sup.1 and R.sup.2 are 
not both methyl, are independently selected from the group consisting of 
(1) hydrogen, 
(2) C.sub.1 -C.sub.6 -alkyl optionally substituted with a substituent 
selected from the group consisting of 
(a) halogen, 
(b) C.sub.3 -C.sub.6 -cycloalkyl, 
(c) aryl, 
(d) substituted aryl, 
(e) heteroaryl, 
(f) substituted heteroaryl, 
(g) --CHO, 
(h) --C(O)--C.sub.1 -C.sub.6 -alkyl, and 
(i) --C(O)--NR'R", wherein R' and R" are independently selected from the 
group consisting of hydrogen, C.sub.1 -C.sub.3 -alkyl, C.sub.1 -C.sub.3 
-alkyl substituted with aryl, substituted aryl, heteroaryl, and 
substituted heteroaryl, 
(3) C.sub.2 -C.sub.6 -alkyl optionally substituted with a substituent 
selected from the group consisting of 
(a) C.sub.1 -C.sub.6 -alkoxy, 
(b) --NR'R", wherein R' and R" are as previously defined, 
(c) --NH--C(O)--C.sub.1 -C.sub.6 -alkyl, 
(d) --NH--C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
(e) --O--C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
(f) --O--C(O)--C.sub.1 -C.sub.6 -alkyl, 
(g) --CH(=N--O--C.sub.1 -C.sub.6 -alkyl), 
(h) --C(.dbd.N--O--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 -alkyl, 
(i) --CH(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl), and 
(j) --C(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 -alkyl, 
(4) C.sub.3 -C.sub.6 -alkenyl optionally substituted with a substituent 
selected from the group consisting of 
(a) halogen, 
(b) C.sub.3 -C.sub.6 -cycloalkyl, 
(c) aryl, 
(d) substituted aryl, 
(e) heteroaryl, 
(f) substituted heteroaryl, 
(g) --NH--C(O)--C.sub.1 -C.sub.6 -alkyl, 
(h) --NH--C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
(i) --O--C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
(j) --O--C(O)--C.sub.1 -C.sub.6 -alkyl, 
(k) --CHO, 
(l) --C(O)--C.sub.1 -C.sub.6 -alkyl, 
(m) --C(O)--NR'R", wherein R' and R" are as previously defined, 
(n) --CH(.dbd.N--O--C.sub.1 -C.sub.6 -alkyl), 
(o) --C(.dbd.N--O--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 -alkyl, 
(p) --CH(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl), 
(q) --C(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 -alkyl, and 
(r) --C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
(5) C.sub.3 -C.sub.6 -alkynyl optionally substituted with a substituent 
selected from the group consisting of 
(a) halogen, 
(b) C.sub.3 -C.sub.6 -cycloalkyl, 
(c) aryl, 
(d) substituted aryl, 
(e) heteroaryl, and 
(f) substituted heteroaryl, 
(6) C.sub.3 -C.sub.6 -cycloalkyl, 
(7) --CHO, 
(8) --C(O)--C.sub.1 -C.sub.6 -alkyl, 
(9) --C(O)--NR'R", wherein R' and R" are as previously defined, and 
(10) --C(O)--O--C.sub.1 -C.sub.6 -alkyl, 
or R.sup.1 and R.sup.2 taken together may be --(CH.sub.2).sub.p --, wherein 
p is 3-to-7, which taken together with the nitrogen atom to which they are 
attached, thus form a heterocyclic ring containing one nitrogen atom and 
from 3 to 7 carbon atoms; 
R is selected from the group consisting of 
(1) methyl substituted with a substituent selected from the group 
consisting of 
(a) --CN, 
(b) --F, 
(c) --CO.sub.2 R.sup.3 wherein R.sup.3 is C.sub.1 -C.sub.3 -alkyl, 
aryl-substituted C.sub.1 -C.sub.3 -alkyl, or heteroaryl-substituted 
C.sub.1 -C.sub.3 -alkyl, 
(d) --S(O).sub.n --R.sup.3 wherein n is 0, 1, or 2, and R.sup.3 is as 
previously defined, 
(e) --NH--C(O)--R.sup.3 where R.sup.3 is as previously defined, 
(f) --NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are 
independently selected from the group consisting of 
(i) hydrogen, 
(ii) C.sub.1 -C.sub.3 -alkyl 
(iii) C.sub.1 -C.sub.3 -alkyl substituted with aryl, 
(iv) C.sub.1 -C.sub.3 -alkyl substituted with substituted aryl, 
(v) C.sub.1 -C.sub.3 -alkyl substituted with heteroaryl, and 
(vi) C.sub.1 -C.sub.3 -atkyl substituted with and substituted heteroaryl, 
(g) aryl, 
(h) substituted aryl, 
(i) heteroaryl, and 
(j) substituted heteroaryl, 
(2) C.sub.2 -C.sub.10 -alkyl, 
(3) C.sub.2 -C.sub.10 -alkyl substituted with one or more substituents 
selected from the group consisting of 
(a) halogen, 
(b) hydroxy, 
(c) C.sub.1 -C.sub.3 -alkoxy, 
(d) C.sub.1 -C.sub.3 -alkoxy-C.sub.1 -C.sub.3 -alkoxy, 
(e) oxo, 
(f) --N.sub.3, 
(g) --CHO, 
(h) --O--SO.sub.2 -(substituted C.sub.1 -C.sub.6 -alkyl), 
(i) --NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are selected from the 
group consisting of 
(i) hydrogen, 
(ii) C.sub.1 -C.sub.12 -atkyl, 
(iii) substituted C.sub.1 -C.sub.12 -alkyl, 
(iv) C.sub.1 -C.sub.12 -alkenyl, 
(v) substituted C.sub.1 -C.sub.12 -alkenyl, 
(vi) C.sub.1 -C.sub.12 -alkynyl, 
(vii) substituted C.sub.1 -C.sub.12 -alkynyl, 
(viii) aryl, 
(ix) C.sub.3 -C.sub.8 -cycloalkyl, 
(x) substituted C.sub.3 -C.sub.8 -cycloalkyl, 
(xi) substituted aryl, 
(xii) heterocycloalkyl, 
(xiii) substituted heterocycloalkyl, 
(xiv) C.sub.1 -C.sub.12 -atkyl substituted with aryl, 
(xv) C.sub.1 -C.sub.12 -alkyl substituted with substituted aryl, 
(xvi) C.sub.1 -C.sub.12 -alkyl substituted with heterocycloalkyl, 
(xvii) C.sub.1 -Ci.sub.2 -alkyl substituted with substituted 
heterocycloalkyl, 
(xviii) C.sub.1 -C.sub.12 -atkyl substituted with C.sub.3 -C.sub.8 
-cycloalkyl, 
(xix) C.sub.1 -C.sub.12 -alkyl substituted with substituted C.sub.3 
-C.sub.8 -cycloalkyl, 
(xx) heteroaryl, 
(xxi) substituted heteroaryl, 
(xxii) C.sub.1 -C.sub.12 -alkyl substituted with heteroaryl, and 
(xxiii) C.sub.1 -C.sub.12 -alkyl substituted with substituted heteroaryl, 
or 
R.sup.6 and R.sup.7 are taken together with the atom to which they are 
attached form a 3-10 membered heterocycloalkyl ring which may be 
substituted with one or more substituents independently selected from the 
group consisting of 
(i) halogen, 
(ii) hydroxy, 
(iii) C.sub.1 -C.sub.3 -alkoxy, 
(iv) C.sub.1 -C.sub.3 -alkoxy-C.sub.1 -C.sub.3 -alkoxy, 
(v) oxo, 
(vi) C.sub.1 -C.sub.3 -alkyl, 
(vii) halo-C.sub.1 -C.sub.3 -alkyl, and 
(vii) C.sub.1 -C.sub.3 -alkoxy-C.sub.1 -C.sub.3 -alkyl, 
(j) --CO.sub.2 R.sup.3 wherein R.sup.3 is as previously defined, 
(k) --C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as previously 
defined, 
(l) .dbd.N--O--R.sup.3 wherein R.sup.3 is as previously defined, 
(m) --C.tbd.N, 
(n) --O--S(O).sub.n --R.sup.3 wherein n and R.sup.3 are as previously 
defined, 
(o) aryl, 
(p) substituted aryl, 
(q) heteroaryl, 
(r) substituted heteroaryl, 
(s) C.sub.3 -C.sub.8 -cycloalkyl, 
(t) substituted C.sub.3 -C.sub.8 -cycloalkyl, 
(u) C.sub.1 -C.sub.12 -alkyl substituted with heteroaryl, 
(v) heterocycloalkyl, 
(w) substituted heterocycloalkyl, 
(x) --NH--C(O)--R.sup.3 where R.sup.3 is as previously defined, 
(y) --NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as 
previously defined, 
(z) .dbd.N--NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are as previously 
defined, 
(aa) .dbd.N--R.sup.3 wherein R.sup.3 is as previously defined, 
(bb) .dbd.N--NH--C(O)--R.sup.4 wherein R.sup.4 is as previously defined, 
and 
(cc) .dbd.N--NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as 
previously defined, 
(4) C.sub.3 -alkenyl substituted with a moiety selected from the group 
consisting of 
(a) halogen, 
(b) --CHO, 
(c) --CO.sub.2 R.sup.3 where R.sup.3 is as previously defined, 
(d) --C(O)--R.sup.4 where R.sup.4 is as previously defined, 
(e) --C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as previously 
defined, 
(f) --C.tbd.N, 
(g) aryl, 
(h) substituted aryl, 
(i) heteroaryl, 
(j) substituted heteroaryl, 
(k) C.sub.3 -C.sub.7 -cycloalkyl, and 
(l) C.sub.1 -C.sub.12 -alkyl substituted with heteroaryl, 
(5) C.sub.4 -C.sub.10 -alkenyl, 
(6) C.sub.4 -C.sub.10 -alkenyl substituted with one or more substituents 
selected from the group consisting of 
(a) halogen, 
(b) C.sub.1 -C.sub.3 -alkoxy, 
(c) oxo, 
(d) --CHO, 
(e) --CO.sub.2 R.sup.3 where R.sup.3 is as previously defined, 
(f) --C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as previously 
defined, 
(g) --NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are as previously 
defined, 
(h) .dbd.N--O--R.sup.3 wherein R.sup.3 is as previously defined, 
(i) --C.tbd.N, 
(j) --O--S(O).sub.n --R.sup.3 wherein n is 0, 1, or 2 and R.sup.3 is as 
previously defined, 
(k) aryl, 
(l) substituted aryl, 
(m) heteroaryl, 
(n) substituted heteroaryl, 
(o) C.sub.3 -C.sub.7 -cycloalkyl, 
(p) C.sub.1 -C.sub.12 -alkyl substituted with heteroaryl, 
(q) --NH--C(O)--R.sup.3 where R.sup.3 is as previously defined, 
(r) --NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as 
previously defined, 
(s) .dbd.N--NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are as previously 
defined, 
(t) .dbd.N--R.sup.3 wherein R.sup.3 is as previously defined, 
(u) .dbd.N--NH--C(O)--R.sup.3 where R.sup.3 is as previously defined, and 
(v) .dbd.N--NH--C(O)--NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are as 
previously defined, 
(7) C.sub.3 -C.sub.10 -alkynyl, and 
(8) C.sub.3 -C.sub.10 -alkynyl substituted with one or more substituents 
selected from the group consisting of 
(a) trialkylsilyl, 
(b) aryl, 
(c) substituted aryl, 
(d) heteroaryl, and 
(e) substituted heteroaryl, 
with the proviso that when R is allyl and R.sup.1 is methyl, R.sup.2 is not 
H; 
R.sup.p is hydrogen or a hydroxy protecting group; 
R.sup.w is selected from the group consisting of 
(1) hydrogen, 
(2) C.sub.1 -C.sub.6 -alkyl, optionally substituted with one or more 
substituents selected from the group consisting of 
(a) aryl, 
(b) substituted aryl, 
(c) heteroaryl, 
(d) substituted heteroaryl, 
(3) a group selected from option (2) as previously defined further 
substituted with --CH.sub.2 --M--R.sup.8, wherein M is selected from the 
group consisting of 
(i) --O--, 
(ii) --NH--, 
(ii) --N(CH.sub.3)--, 
(iv) --S(O).sub.n --, wherein n is as described previously, 
(v) --NH--C(O)--, and 
(vi) --C(O)--NH--, and 
R.sup.8 is selected from the group consisting of 
(i) --(CH.sub.2).sub.n -aryl, wherein n is as described previously, 
(ii) --(CH.sub.2).sub.n -substituted aryl, wherein n is as described 
previously, 
(iii) --(CH.sub.2).sub.n -heteroaryl, wherein n is as described previously, 
(iv) --(CH.sub.2).sub.n -substituted heteroaryl, wherein n is as described 
previously, and 
(v) --(CH.sub.2).sub.n -heterocycloalkyl, wherein n is as described 
previously; and 
W is absent or is selected from the group consisting of --O--, --NH-- and 
--N(CH.sub.3)--, the method comprising: 
(a) sequentially desmethylating 3'-nitrogen of a compound selected from the 
group consisting of 
##STR5## 
wherein R, R.sup.p, W and R.sup.w are as defined previously; and (b) 
sequentially reacting the compound from step (a) with a R.sup.1 -and a 
R.sup.2 -precursor compound. 
Abbreviations 
Abbreviations which have been used in the descriptions of the scheme and 
the examples that follow are: AIBN for azobisisobutyronitrile; Bu.sub.3 
SnH for tributyltin hydride; CDI for carbonyldiimidazole; DBU for 
1,8-diazabicyclo[5.4.0]undec-7-ene; DEAD for diethylazodicarboxylate; DMF 
for dimethylformamide; DMSO for dimethylsulfoxide; DPPA for 
diphenylphosphoryl azide; Et.sub.3 N for triethylamine; EtOAc for ethyl 
acetate; Et.sub.2 O for diethyl ether; EtOH for ethanol; HOAc for acetic 
acid; MeOH for methanol; NaN(TMS).sub.2 for sodium 
bis(trimethylsilyl)arnide; NMMO for N-methylmorpholine N-oxide; TEA for 
triethylarnine; THF for tetrahydrofuran; and TPP for triphenylphosphine. 
Synthetic Methods 
The compounds and processes of the present invention will be better 
understood in connection with the following synthetic schemes 1-9 which 
illustrate the methods by which the compounds of the invention may be 
prepared. The compounds of the present invention are prepared by the 
representative methods described below. The groups R.sup.1, R.sup.2, R, 
R.sup.p and R.sup.w are as defined previously. 
The preparation of the compounds of the invention of formula (I)-(V) from 
erythromycin A is outlined in Schemes 1-9. The preparation of protected 
erythromycin A is described in the following United States patents, U.S. 
Pat. No. 4,990,602; U.S. Pat. No. 4,331,803, U.S. Pat. No. 4,680,368, and 
U.S. Pat. No. 4,670,549 which are incorporated by reference. Also 
incorporated by reference is European Patent Application EP 260,938. 
As shown in Scheme 1, the C-9-carbonyl group of compound 1 is protected 
with an oxime to give the compound 2, wherein V is .dbd.N--O--R.sup.3 or 
.dbd.N--O--C(R.sup.8) (R.sup.9)--O--R.sup.3 where R.sup.3 is defined 
previously and R.sup.8 and R.sup.9 are each independently selected from 
the group consisting of (a) hydrogen, (b) unsubstituted C.sub.1 -C.sub.12 
-alkyl, (c) C.sub.1 -C.sub.12 -alkyl substituted with aryl, and (d) 
C.sub.1 -C.sub.12 -alkyl substituted with substituted aryl, or R.sup.9 and 
R.sup.10 taken together with the carbon to which they are attached form a 
C.sub.3 -C.sub.12 -cycloalkyl ring. An especially preferred carbonyl 
protecting group V is O-(1-isopropoxycyclohexyl) oxime. 
The 2'- and 4"-hydroxy groups of 2 are protected by reaction with a 
suitable hydroxy protecting reagent, such as those described by T. W. 
Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 2nd 
ed., John Wiley & Son, Inc., 1991, which is incorporated by reference. 
Hydroxy protecting groups include, for example, acetic anhydride, benzoic 
anhydride, benzyl chloroformate, hexamethyldisilazane, or a trialkylsilyl 
chloride in an aprotic solvent. Examples of aprotic solvents are 
dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl 
pyrrolidinone, dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, 
N,N-dimethylacetamide, hexamethylphosphoric triamide, a mixture thereof or 
a mixture of one of these solvents with ether, tetrahydrofuran, 
1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. 
Aprotic solvents do not adversely affect the reaction, and are preferably 
dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl 
pyrrolidinone or a mixture thereof. Protection of 2'- and 4"-hydroxy 
groups of 2 may be accomplished sequentially or simultaneously to provide 
compound 3 where R.sup.p is a hydroxy protecting group. A preferred 
protecting group R.sup.p is trimethylsilyl. 
The 6-hydroxy group of compound 3 is then alkylated by reaction with an 
alkylating agent in the presence of base to give compound 4. Alkylating 
agents include alkyl chlorides, bromides, iodides or alkyl sulfonates. 
Specific examples of alkylating agents include allyl bromide, propargyl 
bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 
4-chlorobenzyl bromide, 4-methoxybenzyl bromide, 
.alpha.-bromo-p-tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, 
crotyl bromide,1-bromo-2-pentene, 3-bromo-1-propenyl phenyl sulfone, 
3-bromo-1-trimethylsilyl-1-propyne, 3-bromo-2-octyne, 1-bromo-2-butyne, 
2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl 
quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, 
bromonitromethane, methyl bromoacetate, methoxymethyl chloride, 
bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromo 
chloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene, and the 
like. Examples of alkyl sulfonates are: allyl-O-tosylate, 
3-phenylpropyl-O-trifluoromethane sulfonate, n-butyl-O-methanesulfonate 
and the like. Examples of the solvents used are aprotic solvents such as 
dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, 
N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric 
triamide, a mixture thereof or a mixture of one of these solvents with 
ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, 
acetone and the like. Examples of the base which can be used include 
potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, 
sodium hydride, potassium hydride, potassium isopropoxide, potassium 
tert-butoxide, potassium isobutoxide and the like. Additional procedures 
for further elaboration of the 6-position moiety of the compounds of the 
invention are described in Schemes 2-4 below. 
The deprotection of the 2'- and 4"-hydroxyl groups is then carried out 
according to methods described in literature, for example, by T. W. Greene 
and P. G. M. Wuts in Protective Groups in Organic Synthesis, 2nd ed., John 
Wiley & Son, Inc., 1991, which is incorporated herein by reference. The 
conditions used for the deprotection of the 2'- and 4"-hydroxyl groups 
usually results in the conversion of X to .dbd.N--OH. (For example, using 
acetic acid in acetonitrile and water results in the deprotection of the 
2'- and 4"-hydroxyl groups and the conversion of X from .dbd.N--O--R.sup.3 
or .dbd.N--O--(R.sup.8)(R.sup.9)--O--R.sup.3 where R.sup.3, R.sup.8 and 
R.sup.9 are as defined previously to .dbd.N--OH.) If this is not the case, 
the conversion is carried out in a separate step. 
The deoximation reaction can be carried out according to the methods 
described in the literature, for example by Greene (op. cit.) and others. 
Examples of the deoximating agent are inorganic sulfur oxide compounds 
such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, 
sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, 
sodium dithionate, potassium thiosulfate, potassium metabisulfite and the 
like. Examples of the solvents used are protic solvents such as water, 
methanol, ethanol, propanol, isopropanol, trirnethylsilanol or a mixture 
of one or more of the mentioned solvents and the like. The deoximation 
reaction is more conveniently carried out in the presence of an organic 
acid such as formic acid, acetic acid and trifluoroacetic acid. The amount 
of acid used is from about 1 to about 10 equivalents of the amount of 
compound 5 used. In a preferred embodiment, the deoximation is carried out 
using an organic acid such as formic acid in ethanol and water to give the 
desired 6-O-substituted erythromycin compound 6. 
Schemes 2-4 describe representative procedures for further elaboration of 
the 6-O-substituted moiety of the compounds of the invention. It will be 
appreciated by one skilled in the art that the decision as to when to 
perform these reactions may be dependent upon the presence of other 
reactive moieties within the molecule. Therefore, suitable protection and 
deprotection steps may be required, as are well known and applied within 
the art. It will sometimes be desirable to perform these modifications 
upon macrolide molecules such as the erythromycin derivative 6. In other 
instances it will be desirable to perform the operation upon a later 
intermediate in the preparation of compounds of the invention. 
Specifically, the modifications may be performed upon certain compounds of 
the invention, including selected compounds of formulas (I)-(V) wherein R 
is allyl, in order to prepare additional compounds of formulas (I)-(V). 
Scheme 2 illustrates reactions suitable for modification of 6-O-allyl 
substituted macrolide compounds. For example, compound 7 wherein M' 
represents a selected macrolide derivative can be further derivatized. The 
double bond of the allyl compound can be (a) catalytically reduced to give 
the 6-O-propyl compound 8; (b) treated with osmium tetraoxide to give the 
2,3-dihydroxypropyl compound 9 which in turn may be functionalized, such 
as by esterification with an acylating agent such as an acyl halide or 
acyl anhydride, at each oxygen atom to give 10; (c) oxidized with 
m-chloroperoxybenzoic acid in an aprotic solvent to give the epoxy methyl 
compound 11 which can be opened with nucleophilic compounds, for example, 
amines or N-containing heteroaryl compounds, to give compounds with 
N-containing side chains 12; (d) oxidized under Wacker conditions as 
described by Henry in "Palladium Catalyzed Oxidation of Hydrocarbons", 
Reidel Publishing Co., Dordrecht, Holland (1980), to give the 
6-O--CH.sub.2 --C(O)--CH.sub.3 compound 13; and (e) ozonized to give the 
aldehyde 14 which can in turn converted to oximes 15 and 16 by reaction 
with H.sub.2 NOR.sup.3 or H.sub.2 NOH respectively, or reductively 
aminated, such as with a suitable amine in the presence of a borohydride 
reducing agent or by formation of the imine and subsequent catalytic 
reduction, to give the amnine 17. Reaction of the oxime 16 with 
diisopropyl carbodiimide in an aprotic solvent in the presence of CuCl 
gives the nitrile 18. Reaction of 7 with an aryl halide under Heck 
conditions in the presence of (Pd(II) or Pd(O), phosphine, and amine or 
inorganic base (see Organic Reactions, 1982, 27, 345-390) gives 19. 
Reduction of the double bond in 19, for example using H.sub.2 and 
palladium on carbon gives 20. 
Representative examples of still further elaboration of the 6-position are 
shown in Scheme 3. The desired 6-O-substituted compound may be prepared by 
chemical modification of an initially prepared 6-O-propargyl compound. 
##STR6## 
For example, compound 21, which illustrates a compound of the invention 
where R is propargyl and M' represents the macrolide ring system, can be 
further derivatized. The triple bond of compound 21 can be treated with an 
aryl halide, a substituted aryl halide, a heteroaryl halide or substituted 
heteroaryl halide in the presence of Pd(triphenylphosphine).sub.2 Cl.sub.2 
and CuI in the presence of an organic amine, such as triethylamine, to 
give the compound 22. Compound 22 can be further selectively reduced to 
the corresponding cis-olefin compound 23 by catalytic hydrogenation in 
ethanol at atmospheric pressure in the presence of 5% Pd/BaSO.sub.4 and 
quinoline (Rao et al., J. Org. Chem., (1986), 51: 4158-4159). Compound 21 
may also be treated with a boronic acid derivative HB(OR.sup.ZZ), wherein 
R.sup.ZZ is H or C.sub.1 -C.sub.10 -alkyl, in an aprotic solvent at 
0.degree. C. to ambient temperature to give compounds 24, which are then 
treated with Pd(triphenylphosphine).sub.4 and an aryl halide, a 
substituted aryl halide, an heteroaryl halide or substituted heteroaryl 
halide under Suzuki reaction conditions to give compounds 25. Compound 21 
may also be treated with N-halosuccinimide in acetic acid to give 
compounds 26. Also, compound 21 may be treated with a substituted alkenyl 
halide, such as Ar--CH.dbd.CH-halogen, wherein Ar is aryl, substituted 
aryl, heteroaryl or substituted heteroaryl, in the presence of 
Pd(triphenylphosphine).sub.2 Cl.sub.2 and CuI in the presence of an 
organic amine, such as triethylamine, to give the appropriately 
substituted compounds 27. 
Scheme 4 describes the preparation of intermediates to compounds of formula 
(I) of the invention from the 6-substituted erythromycin derivative 6 
prepared in Scheme 1. The cladinose moiety of macrolide 6 is removed 
either by mild aqueous acid hydrolysis or by enzymatic hydrolysis to give 
28. Representative acids suitable for this procedure include dilute 
hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, 
dichloroacetic acid or trifluoroacetic acid. Suitable solvents for the 
reaction include methanol, ethanol, isopropanol, butanol, and the like. 
Reaction times are typically 0.5 to 24 hours, and the reaction temperature 
is preferably -10.degree. C. to 35.degree. C. 
The 2'-hydroxy group of 28 is protected to give the compound 29 by means of 
a suitable hydroxy protecting reagent such as acetic anhydride, benzoyl 
anhydride, benzyl chloroformate or trialkylsilyl chloride in an aprotic 
solvent, as defined previously, preferably dichloromethane, chloroform, 
DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. A 
particularly preferred protecting group R.sup.p is benzoate. It is 
possible to reverse the order of the steps for removing the cladinose and 
protecting the hydroxy groups without affecting the yield of the process. 
The 3-hydroxy group of 29 is oxidized to the ketone 30 using a modified 
Swern oxidation procedure. Suitable oxidizing agents are 
N-chlorosuccinimide-dimethyl sulfide or carbodiimide-dimethylsulfoxide. In 
a typical example, 29 is added into a pre-formed N-chlorosuccinimide and 
dimethyl sulfide complex in a chlorinated solvent such as methylene 
chloride at -10.degree. C. to 25 C. After being stirred for about 0.5 to 4 
hours, a tertiary amine, such as triethylamine or Hunig's base, for 
example, is added to produce the ketone 30 wherein R.sup.p is a hydroxy 
protecting group. The conversion of intermediate compound 30 to a compound 
of the invention is shown below in Scheme 9. 
##STR7## 
Scheme 5 illustrates the preparation of the compounds of formula (II). 
Accordingly, compound 6 is first protected with a suitable hydroxy 
protecting group to give compound 31, by the procedures referenced 
previously. Compound 31 is then treated with an excess of sodium 
hexamethyldisilazide or a hydride base in the presence of 
carbonyldiimidazole in an aprotic solvent for 8 to 24 hours at about 
-30.degree. C. to room temperature to give compound 32. The hydride base 
may be, for example, sodium hydride, potassium hydride, or lithium 
hydride, and the aprotic solvent may be one as defined previously. The 
reaction is preferably maintained under an inert atmosphere, such as 
nitrogen or argon, for example. The reaction may require cooling or 
heating from about -20.degree. C. to about 70.degree. C., depending on the 
conditions used, and preferably from about 0.degree. C. to about room 
temperature. The reaction requires about 0.5 hours to about 10 days, and 
preferably about 1-5 days, to complete. Portions of this reaction sequence 
follow the procedure described by Baker et al., J. Org. Chem., 1988, 53, 
2340, which is incorporated herein by reference. 
##STR8## 
Compound 32 can then be used to form a wider series of intermediate 
compound to formula (II). For example, treatment of compound 32 with 
aqueous ammonia results in formation of the cyclic carbamate 33 wherein W 
is absent and R.sup.w is H. Likewise, reaction of compound 6B with a 
substituted arnide of the formula H.sub.2 N--R.sup.w results in formation 
of the cyclic carbamate 33 
Treatment of compound 32 with a substituted amine compound of the formula 
H.sub.2 N--W--R.sup.w, wherein W is absent and R.sup.w is as previously 
defined except not H gives 33 in which W is --NH-- and R.sup.w is as 
previously defined except not H. 
Also, treatment of compound 32 with a hydroxylamine compound of the formula 
H.sub.2 N--W-R.sup.w, wherein W --O-- and R.sup.w is as previously 
defined, results in formation of 33 wherein W is --O-- and R.sup.w is as 
previously defined. 
Treatment of compound 32 with unsubstituted hydrazine results in formation 
of the cyclic carbamate 33 wherein W is --NH-- and R.sup.w is H. 
Treatment of compound 32 with a substituted hydrazine compound of the 
formula H.sub.2 N--NH--R.sup.w, wherein R.sup.w is as previously defined 
except not H, results in formation of 33 wherein W is --NH-- and R.sup.w 
is as previously defined except not H. 
Alternate or additional procedures may be used to prepare intermediates of 
formula (II). For example, treatment of a compound 32 wherein W is absent 
and R.sup.w is H with an alkylating agent having the formula R.sup.w 
-halogen, wherein R.sup.w is as previously defined except not H, gives a 
compound 33 wherein W is absent and R.sup.w is not hydrogen. 
Similarly, treatment of a compound 32 wherein W is --NH-- and R.sup.w is H 
with an alkylating agent having the formula R.sup.w -halogen, wherein 
R.sup.w is as previously defined except not H, gives a compound 33 wherein 
W is --NH-- and R.sup.w is not hydrogen. 
Treatment of compound 32 wherein W is absent and R.sup.w is H with an 
acylating agent selected from the group consisting of the acyl halide 
R.sup.w --C(O)-halogen and the acid anhydride (R.sup.w --C(O)).sub.2 --O, 
wherein R.sup.w is as previously defined except not H, gives a compound 33 
wherein W is --NH--CO-- and R.sup.w is as previously defined. 
Treatment of a compound 32 wherein W is --NH-- and R.sup.w is H with an 
aldehyde R.sup.w --CHO, wherein R.sup.w is as previously defined, gives a 
compound 33 wherein W is --N.dbd.CH-- and R.sup.w is as previously 
defined. 
Removal of the cladinose moiety from a compound 33 by acid hydrolysis as 
described previously gives a compound 34. The 3-hydroxy group of 34 is 
oxidized to the ketone 35 using a modified Swern oxidation procedure as 
described previously. The conversion of intermediate compound 35 to a 
compound (II) of the invention is shown below in Scheme 9. 
Scheme 6 describes the preparation of intermediate compounds for formula 
(III). Compound 32 is treated with ethylenediamine 36 in a suitable 
solvent such as aqueous acetonitrile, DMF or aqueous DMF, to give the 
bicyclic carbamate intermediate (not shown) which is then cyclized by 
treatment with dilute acid, such as acetic acid or HCl, in a suitable 
organic solvent such as ethanol or propanol, to give compound 37. 
The cladinose moiety is then removed from compound 37 to give compound 38. 
The 3-hydroxy group of 38 is oxidized to the ketone 39 using a modified 
Swern oxidation procedure as described previously. The conversion of 
intermediate compound 39 to a compound (III) of the invention is shown 
below in Scheme 9. 
##STR9## 
Scheme 7 illustrates the preparation of the cyclic carbonate compounds of 
formula (IV). In particular, the 2'-protected compound 30, prepared as 
shown in Scheme 4, is converted to the cyclic carbonate 40 by controlled 
reaction at low temperatures (about -30.degree. C.) for a short period 
(about 30 minutes) with carbonyldiimidazole and sodium 
hexamethyldisilazide. Alternately, compound 40 is prepared from 30 by 
careful reaction with sodium hydride or lithium hydride and phosgene, 
diphosgene or triphosgene under anhydrous conditions with careful control 
of the amount of base present in order to prevent base catalyzed 
decarboxylation. The conversion of intermediate compound 40 to a compound 
(IV) of the invention is shown below in Scheme 9. 
##STR10## 
Scheme 8 illustrates the preparation of the cyclic methylene compounds of 
formula (V). Compound 31 may be treated with formaldehyde in the presence 
of an acid, or with chloroiodomethane in the presence of base (according 
to the procedure of Hunt et al., J. Antibiotics, (1988), 41: 1644) to give 
the protected 11,12-methylenedioxy compound 41 which is an intermediate to 
compounds of formula (V). Compound 41 is hydrolyzed to give compound 42. 
The 3-hydroxy group of 42 is oxidized to the ketone 43 using a modified 
Swern oxidation procedure as described previously. The conversion of 
intermediate compound 43 to a compound (IV) of the invention is shown 
below in Scheme 9. 
##STR11## 
Scheme 9 describes procedures whereby compounds 30, 35, 39, 40, or 43 can 
be converted to the desired compound of formulas (I)-(V) of the invention. 
Compounds 30, 35, 39, 40, or 43 are treated with N-iodosuccinimide to give 
compound 44 wherein one of R.sup.1 and R.sup.2 is H and the other is 
methyl. For convenience R.sup.2 is shown as the methyl group. 
Compound 44 can be reacted in the presence of base with a suitable R.sup.1 
-precursor compound such as R.sup.1 --X, wherein R.sup.1 is as defined 
previously and X is a suitable leaving group, such as a halide or a 
sulfonate, such as methyl sulfonate, tosylate or trifluoromethylsulfonate, 
for example, to give compound 45. Alternately, compound 44 can be 
reductively alkylated with an aldehyde of formula R*--CHO, which when 
reduced becomes R*--CH.sub.2 --which is the R.sup.1 moiety described 
previously, in the presence of a reducing agent such as NaBH.sub.3 CN or 
H.sub.2 and Pd/C. Typically, suitable R.sup.1 -precursor compounds are 
C.sub.1 -C.sub.6 -alkyl halides or sulfonates optionally substituted with 
a group such as halogen, C.sub.3 -C.sub.6 -cycloalkyl, aryl, 
substituted-aryl, heteroaryl, and substituted-heteroaryl. 
Other suitable precursor compounds are C.sub.2 -C.sub.6 -alkyl halides or 
sulfonates optionally substituted with a substituent group such as C.sub.1 
-C.sub.6 -alkoxy, an amine group --NR'R", wherein R' and R" are 
independently selected from hydrogen, C.sub.1 -C.sub.3 -alkyl, C.sub.1 
-C.sub.3 -alkyl substituted with aryl, substituted aryl, heteroaryl, and 
substituted heteroaryl, --NH--C(O)--C.sub.1 -C.sub.6 -alkyl, 
--NH--C(O)--O--C.sub.1 -C.sub.6 -alkyl, --O--(O)--O--C.sub.1 -C.sub.6 
-alkyl, --O--(O)--C.sub.1 -C.sub.6 -alkyl, --CHO, --C(O)--C.sub.1 -C.sub.6 
-alkyl, --C(O)--NR'R", wherein R' and R" are as previously defined, 
CH(.dbd.N--O--C.sub.1 -C.sub.6 -alkyl), C(.dbd.N--O--C.sub.1 -C.sub.6 
-alkyl)--C.sub.1 -C.sub.6 -alkyl, C(.dbd.N--NH--C.sub.1 -C.sub.6 
-alkyl)--H, and C(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 
-alkyl. 
Other additional precursor compounds are C.sub.3 -C.sub.6 -alkenyl halides 
optionally substituted with a substituent group such as halogen, C.sub.3 
-C.sub.6 -cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted 
heteroaryl, C.sub.1 -C.sub.6 -alkoxy, an amine group --NR'R", wherein R' 
and R" are independently selected from hydrogen, C.sub.1 -C.sub.3 -alkyl, 
C.sub.1 -C.sub.3 -alkyl substituted with aryl, substituted aryl, 
heteroaryl, and substituted heteroaryl, --NH--C(O)--C.sub.1 -C.sub.6 
-alkyl, --NH--C(O)--O--C.sub.1 -C.sub.6 -alkyl, --(O)--O--C.sub.1 -C.sub.6 
-alkyl, --(O)--C.sub.1 -C.sub.6 -alkyl, --C(O)--H C(O)--C.sub.1 -C.sub.6 
-alkyl, --C(O)--NR'R", wherein R' and R" are as previously defined, 
--CH(.dbd.N--O--C.sub.1 -C.sub.6 -alkyl), --C(.dbd.N--O--C.sub.1 -C.sub.6 
-alkyl)--C.sub.1 -C.sub.6 -alkyl, --CH(.dbd.N--NH--C.sub.1 -C.sub.6 
-alkyl), and C(.dbd.N--NH--C.sub.1 -C.sub.6 -alkyl)--C.sub.1 -C.sub.6 
-alkyl. It will be obvious to those skilled in the art that certain of the 
substituents may not be directly substituted upon an unsaturated carbon 
atom. 
Other additional precursor compounds are C.sub.3 -C.sub.6 -alkynyl halides 
optionally substituted with a substituent group such as halogen, C.sub.3 
-C.sub.6 -cycloalkyl, aryl, substituted-aryl, heteroaryl, and 
substituted-heteroaryl. 
Further additional precursor compounds are C.sub.3 -C.sub.6 
-cycloalkylhalides optionally substituted with a substituent group such as 
halogen, C.sub.3 -C.sub.6 -cycloalkyl, aryl, substituted-aryl, heteroaryl, 
and substituted-heteroaryl. 
Also, however, the compound 44 may be treated with a formulating agent or 
an acylating agent of the formula X--C(O)--R', wherein X is halogen and R' 
is as defined previously, or O--(C(O)--R').sub.2 to prepare the 
appropriate derivative wherein R.sup.1 is formyl or C(O)--R', 
respectively, to give compound 45. Alternately, compound 44 can be reacted 
with carbonyldiimidazole to give an intermediate compound 45 wherein 
R.sup.1 is imidazolylcarbonyl, and this intermediate is reacted with an 
amine having the formula HNR'R", to give the compound 45 wherein R.sup.1 
is C(O)--NR'R". Further, compound 44 can be reacted with an alcohol of the 
formula HOR' to give a compound wherein R.sup.1 is C(O)--OR', wherein R' 
is as previously defined, to give a compound 45 wherein R.sup.1 is 
C(O)--O--R'. 
Compound 44 can also be reacted with a substituted or unsubstituted aryl 
alcohol in the presence of a homologating agent such as formaldehyde or 
paraformaldehyde to give a compound wherein R.sup.1 is methyl substituted 
with substituted aryl. 
Compound 44 can be treated again with N-iodosuccinimide or with iodine in 
the presence of light to give compound 46 wherein both R.sup.1 and R.sup.2 
are H. Compound 46 may then be treated in the presence of base with one of 
the R.sup.1 -precursor reagents described previously to give compound 47. 
Compound 47 may then be treated with a R.sup.2 -precursor reagent similar 
to the R.sup.1 -precursor reagent described previously and under similar 
conditions to give the appropriately disubstituted compound 48. 
In the instance wherein R.sup.1 and R.sup.2 taken together may be 
--(CH.sub.2).sub.p --, wherein p is 3-7, which taken together with the 
nitrogen atom to which they are attached thus forms a heterocyclic ring 
containing one nitrogen atom and from 3 to 7 carbon atoms, the precursor 
can be a suitable alkyl dihalide, such as 1,3-dibromopropane, 
1,4-dibromobutane, 1,5-dibromopentane, 1,6-dibromohexane, or 
1,7-dibromoheptane, for example. 
When R.sup.p of formula (I)-(V) is a hydroxy protecting group such as 
acetate or benzoate, the compound may be deprotected by treatment with 
methanol or ethanol to give a compound of formula (I) wherein R.sup.p is 
hydrogen. When R.sup.p is a trialkylsilyl group, the compound may be 
deprotected by treatment with fluoride in THF or acetonitrile to give a 
compound of formula (I)-(V) wherein R.sup.p is hydrogen.

The foregoing may be better understood by reference to the following 
examples which are presented for illustration and not to limit the scope 
of the inventive concept. 
##STR12## 
Example 1 
Compound of Formula (I), R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p is 
H, R.sup.1 is methyl, R.sup.2 is hydrogen 
Step 1a: Compound 4 from Scheme 1, V is N--O-(1-isopropoxycyclohexyl), R is 
allyl, R.sup.p is trimethylsilyl 
To a 0.degree. C. solution of 2',4"-bis-O-trimethylsilylerythromycin A 
9-[O-(1-isopropoxycyclohexyl)oxime (1.032 g, 1.00 mmol), prepared 
according to the method of U.S. Pat. No. 4,990,602 in 5 mL of DMSO and 5 
mL of THF was added freshly distilled allyl bromide (0.73 mL, 2.00 mmol). 
After approximately 5 minutes, a solution of potassium tert-butoxide (1 M 
2.0 mL, 2.0 mL) in 5 mL of DMSO and 5 mL of THF was added dropwise over 4 
hours. The reaction mixture was taken up in ethyl acetate and washed with 
water and brine. The organic phase was concentrated in vacuo to give the 
desired compound (1.062 g) as a white foam. 
Step 1b: Compound 5 from Scheme 1, V is NOH, R is allyl 
To a solution of the compound resulting from step 1a (1.7 g) in 17 mL of 
acetonitrile and 8.5 mL of water was added 9 mL of acetic acid at ambient 
temperature. After several hours at ambient temperature, the reaction 
mixture was diluted with 200 mL of toluene and concentrated in vacuo. The 
residue obtained was found to contain unreacted starting material, so 
additional acetonitrile (15 mL), water (70 mL) and HOAc (2 mL) was added. 
After 2 hours, an additional 1 mL aliquot of HOAc was added. After 
approximately three more hours, the reaction mixture was placed in the 
freezer overnight. The reaction mixture was allowed to warm to ambient 
temperature, diluted with 200 mL of toluene and concentrated in vacuo. The 
residue was chased twice with toluene and dried to constant weight (1.524 
g). 
Step 1c: Compound 6 from Scheme 1, R is allyl 
The compound resulting from step 1b (1.225 g) in 16 mL of 1:1 ethanol-water 
was treated with NaHSO.sub.3 (700 mg) and formic acid (141 .mu.L) and 
warmed at 86.degree. C. for 2.5 hours. The reaction mixture was allowed to 
cool to ambient temperature, diluted with 5-6 mL of water, basified with 1 
N NaOH to pH 9-10 and extracted with ethyl acetate. The combined organic 
extracts were washed with brine (2.times.), dried over MgSO.sub.4, 
filtered and concentrated in vacuo. The crude material was purified by 
column chromatography eluting with 1% MeOH in methylene chloride 
containing 1% ammonium hydroxide to give 686 mg (57%) of the title 
compound. .sup.13 C NMR (CDCl.sub.3) .delta. 219.3 (C-9), 174.8 (C-1), 
135.5 (C-17), 116.3 (C-18), 101.9 (C-1'), 95.9 (C-1"), 79.7 (C-5), 78.8 
(C-6), 78.5 (C-3), 74.1 (C-12), 72.4 (C-3"), 70.6 (C-11), 68.1 (C-5'), 
65.5 (C-16), 65.1 (C2'), 49.0 (C-3" O--CH.sub.3), 45.0 (C-2), 44.1 (C-8), 
39.7 (NMe.sub.2), 37.9 (C-4), 37.1 (C-10), 34.6 (C-2"), 28.4 (C-4'), 21.0, 
20.6 (C3" CH3, C-6' CH.sub.3), 20.8 (C-14), 18.3 (C-6"), 18.1 (C-8 
CH.sub.3), 15.7, 15.6 (C-2 CH.sub.3, C-6 CH.sub.3), 11.9 (C-10 CH.sub.3), 
10.1 (C-15), 8.9 (C-4 CH.sub.3). MS (FAB)+m/e 774 (M+H).sup.+, 812 
(M+K).sup.+. 
Step 1d: Compound 28 from Scheme 4, R is allyl 
To a suspension of the compound prepared in step 1c (7.73 g, 10.0 mmol) in 
ethanol (25 mL) and water (75 mL) was added aqueous 1 M HCl (18 mL) over 
10 minutes. The reaction mixture was stirred for 9 hours at ambient 
temperature and then was left standing in the refrigerator overnight. 
Aqueous 2 M NaOH (9 mL, 18 mmol) which resulted in the formation of a 
white precipitate. The mixture was diluted with water and filtered. The 
solid was washed with water and dried under vacuum to give the 
des-cladinosyl compound 7 (3.11 g). 
Step 1e: Compound 29 from Scheme 4, R is allyl, R.sup.p is benzoyl 
To a solution of the product of step 1d (2.49 g, 4.05 mmol) in 
dichloromethane (20 mL) was added benzoic anhydride (98%, 1.46 g, 6.48 
mmol) and triethylamine (0.90 mL, 6.48 mmol) and the white suspension was 
stirred for 26 hours at ambient temperature. Aqueous 5% sodium carbonate 
was added and the mixture was stirred for 20 minutes. The mixture was 
extracted with dichloromethane. The organic phase was washed with aqueous 
5% sodium bicarbonate and brine, dried over sodium sulfate and 
concentrated in vacuo to give a white foam. Chromatography on silica gel 
(30% acetone-hexanes) gave the title compound (2.46 g) as a white solid. 
Step 1f: Compound 30 from Scheme 4, R is allyl, R.sup.p is benzoyl 
To a -10.degree. C. solution under N.sub.2 of N-chlorosuccinimide (0.68 g, 
5.07 mmol) in dichloromethane (20 mL) was added dimethylsulfide (0.43 mL, 
5.92 mmol) over 5 minutes. The resulting white slurry was stirred for 20 
minutes at -10.degree. C. and then a solution of the compound resulting 
from step 1e (2.43 g, 3.38 mmol) in dichloromethane (20 mL) was added and 
the reaction mixture was stirred for 30 minutes at -10 to -5 .degree. C. 
Triethylamine (0.47 mL, 3.38 mmol) was added dropwise over 5 minutes and 
the reaction mixture was stirred for 30 minutes at 0 .degree. C. The 
reaction mixture was extracted with dichloromethane. The organic phase was 
washed twice with aqueous 5% sodium bicarbonate and once with brine, dried 
over sodium sulfate, and concentrated in vacuo to give a white foam. 
Chromatography on silica gel (30% acetone-hexanes) gave the title compound 
(2.27 g) as a white foam. 
Step 1g: Compound of Formula (I), R is allyl, R.sup.p is benzoyl, R.sup.1 
is methyl, R.sup.2 is hydrogen 
To a sample of the compound from step 1f (215 mg, 0.30 mmol) in 
acetonitrile (10 mL) at 0.degree. C. under nitrogen was added 
N-iodosuccinimide (101 mg, 0.45 mmol), and the mixture was warmed to room 
temperature. After 5 hours dichloromethane (50 mL) was added, and the 
mixture was washed with 1:1 5% NaHSO3/Na2CO.sub.3 (pH 9) and brine, dried 
(Na2SO4) and concentrated. The residue was chromatographed on silica gel, 
eluting with 3:7 acetone/hexane to give the crude product. This material 
was dissolved in THF (5 mL) and stirred with 5% Na2CO3 (5 mL) for 2 hours. 
The mixture was diluted with ethyl acetate (30 mL), and the resulting 
solution was washed with 5% Na2CO3 and brine, dried (Na2SO4) and 
concentrated. The residue was chromatographed on silica gel, eluting with 
3:7 acetone/hexane to give the title compound (75.5 mg). 
Step 1h: Compound of Formula (I), R is allyl, R.sup.p is H, R.sup.1 is 
methyl, R.sup.2 is hydrogen 
The compound from step 1g was heated at reflux in methanol under nitrogen 
for 6 hours, then the solvent was removed. The residue was chromatographed 
on silica gel, eluting with 95:5:0.5 dichlormethane/methanol/NH4OH to give 
the title compound (48.7 mg). Anal. Calcd. for C.sub.31 H.sub.53 
NO.sub.10.0.5 H.sub.2 O: C, 61.16; H, 8.94; N, 2.30; Found: C, 61.33; H, 
8.89; N, 2.24. MS m/e 600 (M+H).sup.+. 
Step 1i: Compound of Formula (I), R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), 
R.sup.p is H, R.sup.1 is methyl, R.sup.2 is hydrogen 
A mixture of the compound from Step 1h, palladium(II)acetate and 
tri-o-tolylphosphine in acetonitrile (400 ml) is flushed with nitrogen. To 
this solution is added 3-bromoquinoline and triethylamine. The reaction 
mixture is heated at 50.degree. C. for 1 hour and stirred at 90.degree. C. 
for 4 days. The reaction mixture is taken up in ethyl acetate and washed 
with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, 
filtered, and concentrated in vacuo. Chromatography on silica gel gives 
the title compound. 
Example 2 
Compound of formula (II), R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is acetyl, R.sup.1 is H, R.sup.2 is CH.sub.3, W is absent, R.sup.w is H 
Step 2a. Compound 31 from Scheme 5: R is --CH.sub.2 CH.dbd.CH.sub.2, 
R.sup.p is acetyl 
To a sample of the compound from Example 1 step c (405.2 g, 528 mmol) in 
dichloromethane (20 mL) was added dimethylaminopyridine(0.488 g, 4 mmol) 
and acetic anhydride (3.39 mL, 36 mmol), and the mixture was stirred at 
room temperature for 3 hours. The mixture was diluted with methylene 
chloride, then washed with 5% aqueous sodium bicarbonate and brine and 
dried over Na.sub.2 SO.sub.4. The residue was dried and recrystallized 
from acetonitrile to give the title compound (491 g). MS m/e 857 
(M+H).sup.+. 
Step 2b. Compound 32 from Scheme 5: R is --CH.sub.2 CH.dbd.CH.sub.2, 
R.sup.p is acetyl 
To a sample of the compound from step 2a (85.8 g, 100 mmol) in dry THF (500 
mL) cooled to -40.degree. C. and flushed with nitrogen was added sodium 
bis(trimethylsilyl)amide (125 mL, 125 mmol) over 20 minutes, and the 
mixture was stirred at -40.degree. C. for 40 minutes. To this mixture was 
added a solution of carbonyldiimidazole (3.65 g, 22.56 mmol) in 5:3 
THF/DMF (800 mL) under nitrogen at -40.degree. C. over 30 minutes, and the 
mixture was stirred at -20.degree. C. for 30 minutes. The mixture was 
stirred at room temperature for 27 hours, then diluted with ethyl acetate. 
The mixture was washed with 5% sodium bicarbonate and brine, dried over 
Na.sub.2 SO.sub.4, and concentrated to give the title compound (124 g), 
which was taken directly to the next step. 
Step 2c. Compound 33 from Scheme 5: R is --CH.sub.2 CH.dbd.CH.sub.2, 
R.sup.p is acetyl, W is absent, R.sup.w is H 
The compound from step 2b (124 g) was dissolved in 9:1 acetonitrile/THF 
(1100 mL), ammonium hydroxide (28%, 200 mL) was added, and the mixture was 
stirred at room temperature under nitrogen for 8 days. The solvent was 
removed, and the residue was dissolved in ethyl acetate. This solution was 
washed with 5% sodium bicarbonate and brine, dried over Na.sub.2 SO.sub.4, 
and concentrated to give the title compound. MS (FAB)+m/e 882 (M+H).sup.+. 
Step 2d. Compound 34 from Scheme 5: R is --CH.sub.2 CH.dbd.CH.sub.2, 
R.sup.p is acetyl, W is absent, R.sup.w is H 
To a sample of the compound from step 2c (69.0 g, 78.2 mmol) suspended in 
ethanol (200 mL) and diluted with water (400 mL) was added HCl (0.972 N, 
400 mL) dropwise over 20 minutes. The mixture was stirred for 4 hours, and 
additional HCl was added (4 N, 100 mL) over 20 minutes. The mixture was 
stirred for 18 hours, cooled to 0.degree. C., then NaOH (4 N, 200 mL) was 
added over 30 minutes to approximately pH 9. The title compound was 
isolated by filtration (35.56 g) 
Step 2e. Compound 35 from Scheme 5; R is --CH.sub.2 CH.dbd.CH.sub.2, 
R.sup.p is acetyl, W is absent, R.sup.w is H 
To a -10.degree. C. solution under nitrogen of N-chlorosuccinimide (2.37 g, 
17.8 mmol) in dichloromethane (80 mL) was added dimethylsulfide (1.52 mL, 
20.8 mmol) over 5 minutes. The resulting white slurry was stirred for 10 
minutes at -10.degree. C., a solution of the compound from step 2d (8.10 
g, 11.9 mmol) in dichloromethane (60 mL) was added and the reaction 
mixture was stirred for 30 minutes at -10 to -5.degree. C. Triethylamine 
(1.99 mL, 14.3 mmol) was added dropwise over 10 minutes and the reaction 
mixture was stirred for 1 hour at 0.degree. C. The reaction mixture was 
extracted with dichloromethane. The organic phase was washed with aqueous 
5% sodium bicarbonate and brine, dried over sodium sulfate, and 
concentrated in vacuo to give a white foam. Chromatography on silica gel 
(eluting with 50:50:0.5 acetone/hexanes/ammonium hydroxide) gave the title 
compound (8.27 g) as a white foam. Anal. Calcd. for C.sub.35 H.sub.56 
N.sub.2 O.sub.11 : C, 61.75; H, 8.29; N, 4.11; Found: C, 62.25; H, 8.50; 
N, 4.28. 
Step 2f. Compound 35 from Scheme 5: R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), 
R.sup.p is acetyl, W is absent, R.sup.w is H 
A mixture of the compound from Step 2e (46.36 g, 68.2 mmol), 
palladium(II)acetate (3.055 g, 13.6 mmol), and tri-o-tolylphosphine (8.268 
g, 27.2 mmol) in acetonitrile (400 mL) was flushed with nitrogen. To this 
solution was added 3-bromoquinoline (18.45 mL, 136 mmol) and triethylamine 
(18.92 mL, 13.6 mmol) via syringe. The reaction mixture was heated at 
50.degree. C. for 1 hour and stirred at 90.degree. C. for 4 days. The 
reaction mixture was taken up in ethyl acetate and washed with aqueous 5% 
sodium bicarbonate and brine, dried over sodium sulfate, filtered, and 
concentrated in vacuo. Chromatography on silica gel (eluting with 
50:50:0.5 acetone/hexanes/ammonium hydroxide) gave the title compound 
(46.56 g) as a white foam. MS m/e 808 (M+H).sup.+. 
Step 2g. Compound of formula (II), R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), 
R.sup.p is acetyl, R.sup.1 is H, R.sup.2 is CH.sub.3, W is absent, R.sup.w 
is H 
To a sample of the compound from step 2f (2.65 g, 3.3 mmol) in dry 
acetonitrile (110 mL) at 0.degree. C. under nitrogen was added 
N-iodosuccinimide (0.887 g, 3.94 mmol) in portions, and the mixture was 
held at 5.degree. C. overnight. Then the mixture was again cooled to 
0.degree. C., and additional N-iodosuccinimide (371 mg) was added. The 
mixture was then allowed to warm to ambient temperature, diluted with 
methanol and stirred overnight. The solvent was removed under vacuum, and 
the residue was dissolved in dichloromethane. The solution was washed with 
5% Na.sub.2 CO.sub.3 and brine, dried (Na.sub.2 SO.sub.4) and 
concentrated. The residue was chromatographed on silica gel, eluting with 
5-10% methanol in dichloromethane containing 0.5% NH.sub.4 OH. The product 
was rechromatographed with 1: 1:0.5 to 3:1;).5 acetone/hexane/NH4OH to 
give the title compound (260 mg). MS m/e 794 (M+H).sup.+. 
Example 3 
Compound of Formula (11); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is H, R.sup.2 is CH.sub.3 
Step 3a. Compound 35 from Scheme 5: R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), 
R.sup.p is H, W is absent, R.sup.w is H 
A sample of the compound from Example 2, Step 2f was stirred in methanol 
overnight. The solvent was removed, and the product was used without 
further purification. 
Step 3b. Compound of formula (II), R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), 
R.sup.p is H, R.sup.1 is H, R.sup.2 is CH.sub.3, W is absent, R.sup.w is H 
To a sample of the compound from Step 3a (382 mg, 0.500 mmol) in dry 
acetonitrile (20 mL) at 0.degree. C. under nitrogen was added 
N-iodosuccinimide (125 mg, 0.600 mmol), and the mixture was allowed to 
warm to room temperature. After standing overnight, the mixture was 
diluted with ethyl acetate. The solution was washed with 5% Na.sub.2 
SO.sub.3, 5% Na.sub.2 CO.sub.3 and brine, dried (Na.sub.2 SO.sub.4) and 
concentrated. The residue was chromatographed on silica gel, eluting with 
5-10% methanol in dichloromethane containing 0.5% dimethylamine to give 
the title compound (201 mg). High Res. M.S. calcd for C.sub.41 H.sub.57 
N.sub.3 O.sub.10 : 752.4122; observed: 752.4145. 
Example 4 
Compound of Formula (II), R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is acetyl, R.sup.2 is CH.sub.3 
To a sample of the compound from Example 3 (193 mg, 0.260 mmol) in 
dichloromethane at 0.degree. C. was added triethylamine (0.109 mL, 0.780 
mmol). The solution was stirred for 5 minutes, then acetic anhydride 
((0.024 mL, 0.260 mmol ) was added, and the mixture was stirred for 2 
hours. Another portion of acetic anhydride was added (0.005 mL), then the 
mixture was stirred at room temperature overnight and at reflux for 30 
minutes. The mixture was diluted with ethyl acetate, and this solution was 
washed with 5% aqueous Na.sub.2 CO.sub.3 and brine, dried (Na.sub.2 
SO.sub.4) and concentrated. The residue was chromatographed on silica gel, 
eluting with 5% methanol in dichloromethane containing 0.5% NH.sub.4 OH to 
give the title compound (91.7 mg). MS m/e 794 (M+H).sup.+. 
Example 5 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 C(O)--O--CH.sub.2 
CH.sub.3, R.sup.2 is CH.sub.3 
To a sample of the compound from Example 3 (120 mg, 0.160 mmol) in 
acetonitrile was added NaHCO.sub.3 (67.2 mg, 0.800 mmol) and ethyl 
bromoacetate (0.020 mL, 0.180 mmol), and the mixture was stirred under 
nitrogen at room temperature for 4 days. The mixture was diluted with 
ethyl acetate, and this solution was washed with 5% aqueous NaHCO.sub.3 
and brine, dried (Na.sub.2 SO.sub.4) and concentrated. The residue was 
chromatographed on silica gel, eluting with 5-10% methanol in 
dichloromethane containing 0.5% NH.sub.4 OH to give the title compound (60 
mg). MS m/e 838 (M+H).sup.+. 
Example 6 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.dbd.CH.sub.2, 
R.sup.2 is CH.sub.3 
To a sample of the compound from Example 3 (120 mg, 0.160 mmol) in 
acetonitrile was added NaHCO.sub.3 (67.2 mg, 0.800 mmol) and allyl bromide 
(0.016 mL, 0.180 mmol ), and the mixture was stirred under nitrogen at 
room temperature for 4 days. The mixture was diluted with ethyl acetate, 
and this solution was washed with 5% aqueous NaHCO.sub.3 and brine, dried 
(Na.sub.2 SO.sub.4) and concentrated. The residue was chromatographed on 
silica gel, eluting with 5-10% methanol in dichloromethane containing 0.5% 
MH.sub.4 OH to give the title compound (69 mg). MS mi/e 792 (M+H).sup.+. 
Example 7 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.sub.2 F, R.sup.2 
is CH.sub.3 
To a sample of the compound from Example 2 (150 mg, 0.200 mmol) in 
acetonitrile was added NaHCO.sub.3 (84 mg, 1.00 mmol) and 
1-bromo-2-fluoroethane (0.016 mL, 0.220 mmol), and the mixture was stirred 
under nitrogen at room temperature for 4 hours. Another portion of 
1-bromo-2-fluoroethane (0.010 mL, 0.100 mmol) was added, then the mixture 
was stirred at room temperature overnight and at reflux for 2 hours. 
Another portion of 1-bromo-2-fluoroethane (0.005 mL, 0.050 mmol) was 
added, then the mixture was stirred at reflux overnight. The mixture was 
diluted with ethyl acetate, and this solution was washed with 5% aqueous 
NaHCO.sub.3 and brine, dried (Na.sub.2 SO.sub.4) and concentrated. The 
residue was chromatographed on silica gel, eluting with 5-10% methanol in 
dichloromethane containing 0.5 % NH.sub.4 OH to give the title compound 
(73.3 mg). MS m/e 798 (M+H).sup.+. 
Example 8 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -phenyl, R.sup.2 is 
CH.sub.3 
To a sample of the compound from Example 2 (150 mg, 0.200 mmol) in 
acetonitrile was added NaHCO.sub.3 (84 mg, 1.00 mmol) and benzyl bromide 
(0.020 mL, 0.220 mmol), and the mixture was stirred under nitrogen at room 
temperature for 48 hours. The mixture was diluted with ethyl acetate, and 
this solution was washed with 5% aqueous NaHCO.sub.3 and brine, dried 
(Na.sub.2 SO.sub.4) and concentrated. The residue was chromatographed on 
silica gel, eluting with 5-10% methanol in dichloromethane containing 0.5% 
NH.sub.4 OH to give the title compound (118 mg). MS m/e 842 (M+H).sup.+. 
Example 9 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 --CN, R.sup.2 is 
CH.sub.3 
To a sample of the compound from Example 3 (150 mg, 0.200 mmol) in 
acetonitrile was added NaHCO.sub.3 (84 mg, 1.00 mmol) and 
bromoacetonitrile (0.015 mL, 0.220 mmol), and the mixture was stirred 
under nitrogen at room temperature for 48 hours. The mixture was diluted 
with ethyl acetate, and this solution was washed with 5% aqueous 
NaHCO.sub.3 and brine, dried (Na.sub.2 SO.sub.4) and concentrated. The 
residue was chromatographed on silica gel, eluting with 5-10% methanol in 
dichloromethane containing 0.5% NH.sub.4 OH to give the title compound 
(106.7 mg). MS m/e 791 (M+H).sup.+. 
Example 10 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 --C.tbd.CH, R.sup.2 
is CH.sub.3 
To a sample of the compound from Example 3 (150 mg, 0.200 mmol) in 
acetonitrile was added NaHCO.sub.3 (84 mg, 1.00 mmol) and propargyl 
bromide (80% in toluene, 0.026 mL, 0.220 mmol), and the mixture was 
stirred under nitrogen at room temperature for 48 hours. The mixture was 
diluted with ethyl acetate, and this solution was washed with 5% aqueous 
NaHCO.sub.3 and brine, dried (Na.sub.2 SO.sub.4) and concentrated. The 
residue was chromatographed on silica gel, eluting with 5% methanol in 
dichloromethane containing 0.5% NH.sub.4 OH to give the title compound (90 
mg). MS m/e 790 (M+H).sup.+. 
Example 11 
Compound of Formula (H); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p is 
H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.sub.2 CH.sub.3, 
R.sup.2 is CH.sub.3 
To a sample of the compound from Example 3 (150 mg, 0.200 mmol) in 
acetonitrile was added NaHCO.sub.3 (84 mg, 1.00 mmol) and 1-bromopropane 
(0.020 mL, 0.220 mmol), and the mixture was stirred under nitrogen at room 
temperature for 48 hours and at 60.degree. C. for 16 hours. The mixture 
was diluted with ethyl acetate, and this solution was washed with 5% 
aqueous NaHCO.sub.3 and brine, dried (Na.sub.2 SO.sub.4) and concentrated. 
The residue was chromatographed on silica gel, eluting with 5% methanol in 
dichloromethane containing 0.5% NH.sub.4 OH to give the title compound (80 
mg). MS m/e 794 (M+H).sup.+. 
Example 12 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -cyclopropyl, R.sup.2 
is CH.sub.3 
To a sample of the compound from Example 3 (150 mg, 0.200 mmol) in 
acetonitrile was added NaHCO.sub.3 (84 mg, 1.00 mmol) and 
(bromomethyl)cyclopropane (0.021 mL, 0.220 mmol), and the mixture was 
stirred under nitrogen at room temperature for 48 hours. The mixture was 
diluted with ethyl acetate, and this solution was washed with 5% aqueous 
NaHCO.sub.3 and brine, dried (Na.sub.2 SO.sub.4) and concentrated. The 
residue was chromatographed on silica gel, eluting with 5% methanol in 
dichloromethane containing 0.5% NH.sub.4 OH to give the title compound 
(90.5 mg). MS m/e 806 (M+H).sup.+. 
Example 13 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is cyclopropyl, R.sup.2 is 
CH.sub.3 
To a sample of the compound from Example 3 (150 mg, 0.200 mmol) in methanol 
was added acetic acid (0.114 mL, 2.00 mmol) and 
((1-ethoxycyclopropyl)oxy)trimethylsilane (0.200 mL, 1.00 mmol), and the 
mixture was stirred under nitrogen. NaBH.sub.3 CN (63 mg, 1.00 mmol) was 
added under nitrogen, and the mixture was stirred at room temperature for 
2 hours and at reflux for 12 hours. The mixture was diluted with ethyl 
acetate, and this solution was washed with 5% aqueous Na.sub.2 CO.sub.3 
and brine, dried (Na.sub.2 SO.sub.4) and concentrated. The residue was 
chromatographed on silica gel, eluting with 5% methanol in dichloromethane 
containing 0.5% NH.sub.4 OH to give the title compound (54.4 mg). MS m/e 
792 (M+H).sup.+. 
Example 14 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -(3-pyridyl), R.sup.2 
i s CH.sub.3 
To a sample of the compound from Example 3 (150 mg, 0.200 mmol) in methanol 
was added acetic acid (0. 114 mL, 2.00 mmol) and 3-pyridine carboxaldehyde 
(0.094 mL, 1.00 mmol), and the mixture was stirred at 0.degree. C. under 
nitrogen. NaBH.sub.3 CN (63 mg, 1.00 mmol) was added under nitrogen, and 
the mixture was allowed to warm to room temperature anid stirred for 6 
hours. The mixture was diluted with ethyl acetate, and this solution was 
washed with 5% aqueous Na.sub.2 CO.sub.3 and brine, dried (Na.sub.2 
SO.sub.4) and concentrated. The residue was chromatographed on silica gel, 
eluting with 5% methanol in dichloromethane containing 0.5% NH.sub.4 OH to 
give the title compound (132 mg). MS m/e 843 (M+H).sup.+. 
Example 15 
Compound of Formula (II); R is --CH.sub.1 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -(cyclo-C.sub.3 
H.sub.5), R.sup.2 is CH.sub.3 
A solution of a sample of Example 1 (150 mg, 0.20 mmol) in acetonitrile (2 
mL) at room temperature under N.sub.2 was treated sequentially with 
NaHCO.sub.3 (84 mg, 1.1I mmol) and (bromomethyl)cyclopropane (21 .mu.L, 
0.22 mmol), stirred at room temperature for 18 hours, treated with an 
additional equivalent of (bromomethyl)cyclopropane, stirred for 18 hours, 
treated with N,N-diisopropylethylamine (174 .mu.L, 1.1 mmol) and an 
additional 2 equivalents of (bromomethyl)cyclopropane, stirred for 4 days, 
diluted with ethyl acetate (10 mL), washed sequentially with 5% 
NaHCO.sub.3 and brine, dried (Na.sub.2 SO.sub.4), filtered, and 
concentrated. The residue was purified by column chromatography on silica 
gel with 1% methanol in methylene chloride containing I% ammonium 
hydroxide to provide 90.5 mg of the desired compound as a white solid. MS 
(ESI(+)) 806 (M+H).sup.+. 
Example 16 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.sub.2 CH.sub.3, 
R.sup.2 is CH.sub.3 
A solution of a sample of Example 1(150 mg, 0.20 mmol) in acetonitrile (2 
mL) at room temperature under N.sub.2 was treated sequentially with 
NaHCO.sub.3 (84 mg, 1.1 mmol) and 1-bromopropane (20 .mu.L, 0.22 mmol), 
stirred at room temperature for 18 hours, treated with an additional 
equivalent of 1-bromopropane, stirred for 18 hours, treated with 
N,N-diisopropylethylamine (174 .mu.L, 1.1 mmol), warmed to 60.degree. C. 
for 18 hours, cooled to room temperature, treated with an additional 2 
equivalents of 1-bromopropane, diluted with ethyl acetate (10 mL), washed 
sequentially with 5% NaHCO.sub.3 and brine, dried (Na.sub.2 SO.sub.4), 
filtered, and concentrated. The residue was purified by column 
chromatography on silica gel with 1% methanol in methylene chloride 
containing 1% ammonium hydroxide to provide 80 mg of the desired compound 
as a white solid. MS (ESI(+)) 794 (M+H).sup.+. 
Example 17 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 CH.dbd.CHC.sub.6 
H.sub.5, R.sup.2 is CH.sub.3 
A solution of a sample of Example 1 (260.64 mg, 0.33 mmol) in acetonitrile 
(2 mL) at at room temperature under N.sub.2 was treated with K.sub.2 
CO.sub.3 (230 mg, 1.1 mmol) and cinnamyl bromide (55.5 .mu.L, 0.37 mmol), 
stirred at room temperature for 48 hours, diluted with ethyl acetate (10 
mL), washed sequentially with 5% NaHCO.sub.3 and brine, dried (Na.sub.2 
SO.sub.4), filtered, and concentrated. The residue was purified by column 
chromatography on silica gel with 5% methanol in methylene chloride 
containing 1% ammonium hydroxide to provide 180 mg of the desired compound 
as a white solid. MS (ESI(+)) 869 (M+H).sup.+. 
Example 18 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
C(.dbd.CH.sub.2)C(O)OCH.sub.3, R.sup.2 is CH.sub.3 
A solution of a sample of Example 1 (260.64 mg, 0.33 mmol) in acetonitrile 
(2 mL) at at room temperature under N.sub.2 was treated with K.sub.2 
CO.sub.3 (230 mg, 1.1 mmol) and methyl-2-(bromomethyl)acrylate (45.08 
.mu.L), stirred at room temperature for 48 hours, diluted with ethyl 
acetate, washed sequentially with 5% NaHCO.sub.3 and brine, dried 
(Na.sub.2 SO.sub.4), filtered, and concentrated. The residue was purified 
by column chromatography on silica gel with 5% methanol in methylene 
chloride containing 1% ammonium hydroxide to provide 233 mg of the desired 
compound as a white solid. MS (ESI(+)) 850 (M+H).sup.+. 
Example 19 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
C(.dbd.CH.sub.2)CH.sub.3, R.sup.2 is CH.sub.3 
A solution of a sample of Example 1 (260.64 mg, 0.33 mmol) in acetonitrile 
(2 mL) at at room temperature under N.sub.2 was treated with K.sub.2 
CO.sub.3 (230 mg, 1.1 mmol) and 3-bromo-2-methylpropene (37.81 .mu.L), 
stirred at room temperature for 48 hours, diluted with ethyl acetate, 
washed sequentially with 5% NaHCO.sub.3 and brine, dried (Na.sub.2 
SO.sub.4), filtered, and concentrated. The residue was purified by column 
chromatography on silica gel with 5% methanol in methylene chloride 
containing 1% ammonium hydroxide to provide 176.4 mg of the desired 
compound as a white solid. MS (ESI(+)) 804 (M+H).sup.+. 
Example 20 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is cyclo-C.sub.3 H.sub.5, R.sup.2 
is CH.sub.3 
A solution of a sample of Example 1 (1 50mg, 0.200 mmol) in methanol (5 mL) 
at room temperature under N.sub.2 was treated sequentially with acetic 
acid (114 .mu.L, 2.00 mmol), [(1-ethyoxycyclopropyl)oxy]trimethylsilane 
(200 .mu.L, 1.00 mmol), and NaBH.sub.3 CN (63 mg, 1.00 mmol), stirred at 
room temperature for two hours, heated to reflux for 12 hours, diluted 
with ethyl acetate (30 mL), washed sequentially with 5% Na.sub.2 CO.sub.3 
and brine, dried (Na.sub.2 SO.sub.4), filtered, and concentrated. The 
residue was purified by column chromatography on silica gel with a 
gradient of 2% methanol in methylene chloride to 5% methanol in methylene 
chloride containing 1% ammonium hydroxide to provide 54.4 mg of the 
desired compound as a white solid. MS (ESI(+)) 792 (M+H).sup.+. HRMS 
(ESI(+)) m/z calcd for C.sub.44 H.sub.61 N.sub.3 O.sub.10 : 814.4249 
(M+Na).sup.+. Found 814.4243. 
Example 21 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -(3-pyridyl), R.sup.2 
is CH.sub.3 
A solution of a sample of Example 1 in methanol (5 mL) at 0.degree. C. 
under N.sub.2 was treated sequentially with acetic acid (114 .mu.L, 2.00 
mmol), 3-pyridinecarboxaldehyde (94 .mu.L, 1.00 mmol), and sodium 
cyanoborohydride (63 mg 1.00 mmol), warmed to room temperature with 
stirring over 18 hours, diluted with ethyl acetate (30 mL), washed 
sequentially with 5% Na.sub.2 CO.sub.3, 2% 
tris(hydroxymethyl)aminomethane, and brine, dried (Na.sub.2 SO.sub.4), 
filtered, and concentrated. The residue was purified by column 
chromatography on silica gel with 5% methanol in methylene chloride 
containing 1% ammonium hydroxide to provide 132 mg (78%) of the desired 
compound as an off-white foam. 
MS (APCl) 843 (M+H)+. 
HRMS (ESI(+)) m/z calcd for C.sub.47 H.sub.63 N.sub.4 O.sub.10 : 843.4544 
(M+H).sup.+. Found: 843.4562. 
Anal. calcd for: C, 66.96; H, 7.41, N, 6.65. Found C, 66.97; H, 7.45; N, 
6.57. 
Example 22 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 -(3-hydroxyphenyl), 
R.sup.2 is CH.sub.3 
A solution of a sample of Example 1 (150 mg, 0.200 mmol) in methanol (5 mL) 
at 0 .degree. C. under N.sub.2 was treated with 3-hydroxybenzaldehyde (122 
mg, 1.0 mmol), stirred for 5-10 minutes, treated with acetic acid (114 
.mu.L, 2.00 mmol), stirred at 0.degree. C. for 10-15 minutes, treated with 
sodium cyanoborohydride (63 mg, 1.00 mmol), warmed to room temperature 
over 18 hours, stirred for 48 hours, treated with ethyl acetate (20 mL), 
washed sequentially with 5% NaHCO.sub.3, 2% 
tris(hydroxymethyl)aminomethane, and brine. If any aqueous extract was too 
basic (pH 10-12) and contained product, it was treated with NH.sub.4 Cl 
and back-extracted with ethyl acetate. The combined organic extracts were 
washed with brine, dried (Na.sub.2 SO.sub.4), filtered, and concentrated. 
The residue was purified by column chromatography on silica gel with a 
gradient of 5% methanol in methylene chloride containing 1% ammonium 
hydroxide to provide to provide 97.1 mg of the desired compound as a 
yellow solid. MS (ESI(+)) m/z 858 (M+H).sup.+. 
Example 23 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-tert-butyl-5-methylphenyl), R.sup.2 is CH.sub.3 
A solution of a sample of Example 1 (28 mg, 0.037 mmol) and 
3-tert-butyl-5-methylphenol (1.5-2.0 equivalents) in toluene (1 mL) in a 1 
dram vial was treated with paraformaldehyde (2 equivalents), warmed to 
90.degree. C. for 18 hours, and concentrated. If necessary, the vial was 
uncapped and warmed to permit the toluene to evaporate and drive the 
reaction to completion. The residue was purified by column chromatography 
on silica gel with acetone to provide the desired product. 
MS (ESI(+)) m/z 928 (M+H).sup.+. 
Example 24 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3,4-dimethylphenyl), R.sup.2 is CH.sub.3 
A sample of Example 1, paraformaldehyde, and 3,4-dimethylphenol were 
processed as described in Example 9 to provide the desired compound. MS 
(ESI(+)) m/z 886 (M+H).sup.+. 
Example 25 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methoxy-5-(2-propenyl)phenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-allyl-5-methoxyphenol were processed as described in Example 9 to 
provide the desired compound. 
MS (ESI(+)) m/z 928 (M+H).sup.+. 
Example 26 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methoxy-5-methylphenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-methoxy-5-methylphenol were processed as described in Example 9 to 
provide the desired compound. 
MS (ESI(+)) m/z 902 (M+H).sup.+. 
Example 27 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w i s H, R.sup.1 is CH.sub.2 
-(2-hydroxy-5-cyclopentylphenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-cyclopentylphenol were processed as described in Example 9 to provide 
the desired compound. 
MS (ESI(+)) m/z 926 (M+H).sup.+. 
Example 28 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-5-carboxamidophenyl), R.sup.2 is CH.sub.2 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-hydroxybenzamide were processed as described in Example 9 to provide the 
desired compound. 
MS (ESI(+)) m/z 901 (M+H).sup.+. 
Example 29 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is is CH.sub.2 
-(2-hydroxy-3-methoxy-5-(2-methoxycarbonylethyl)phenyl), R.sup.2 is 
CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-(3-hydroxyphenyl)-propionic acid methyl ester were processed as 
described in Example 9 to provide the desired compound. 
MS (ESI(+)) m/z 944 (M+H).sup.+. 
Example 30 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methyl-5-fluorophenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-fluoro-5-methylphenol were processed as described in Example 9 to 
provide the desired compound. 
MS (ESI(+)) m/z 890 (M+H).sup.+. 
Example 31 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methoxy-5-acetylphenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
1-(3-hydroxy-5-methoxy-phenyl)ethanone were processed as described in 
Example 9 to provide the desired compound. 
MS (ESI(+)) m/z 930 (M+H).sup.+. 
Example 32 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w i s H, R.sup.1 i s CH.sub.2 
-(2-hydroxy-3-bromophenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-bromophenol were processed as described in Example 9 to provide the 
desired compound. 
MS (ESI(+)) m/z 936 (M+H).sup.+. 
Example 33 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl, R.sup.p is 
H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methoxy-5-alkoxycarbonylphenvl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-hydroxy-5-methoxybenzoic acid methyl ester were processed as described 
in Example 9 to provide the desired compound. 
MS (ESI(+)) m/z 946 (M+H).sup.+. 
Example 34 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-ethylphenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-ethylphenol were processed as described in Example 9 to provide the 
desired compound. 
MS (ESI(+)) m/z 886 (M+H).sup.+. 
Example 35 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-5-isobutylphenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-sec-butylphenol were processed as described in Example 9 to provide the 
desired compound. 
MS (ESI(+)) m/z 914 (M+H).sup.+. 
Example 36 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-methyl-5-diethylamino-6-methylphenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-diethylaminomethyl-2,5-dimethylphenol were processed as described in 
Example 9 to provide the desired compound. 
MS (ESI(+)) m/z 971 (M+H).sup.+. 
Example 37 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-4-methyl-5-bromo-6-methylphenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-bromo-2,4-dimethylphenol were processed as described in Example 9 to 
provide the desired compound. 
MS (ESI(+)) m/z 964 (M+H).sup.+. 
Example 38 
Compound of Formula (II); R is --CH.sub.2 CH.dbd.CH-(3-quinolyl), R.sup.p 
is H, W is absent, R.sup.w is H, R.sup.1 is CH.sub.2 
-(2-hydroxy-3-hydroxymethylphenyl), R.sup.2 is CH.sub.3 
A sample of Example 1 (28 mg, 0.037 mmol), paraformaldehyde, and 
3-hydroxymethylphenol were processed as described in Example 9 to provide 
the desired compound.