CA2224049A1 - Intermediates for producing substituted indoles as phosphodiesterase type iv inhibitors - Google Patents

Abstract

Disclosed are intermediates useful for producing substituted indoles as phosphodiesterase type IV inhibitor.
The intermediates are represented by the formulae (see fig. VI) and (see fig. VII) wherein R9 is hydrogen or (C1-C6)alkyl, R15 is oxygen or hydroxyl and the broken line represents a double bond when R15 is oxygen.

Description

INTERMEDIATES FOR PRODUCING SUBSTITUTED INDOLES AS
PHOSPHODIESTERASE TYPE IV INHIBITORS
This is a dlvisional appllcation of Canadlan Patent Application No. 2,176,506 filed October 12, 1994.
This divlsional applicatlon is dlrected to compounds of formulae VI and VII described herelnunder useful as intermedlates for produclng those compounds of formula I
described herelnunder whlch are clalmed ln the parent application.
The expresslon "the present lnventlon" or the llke should be understood to mean sub~ect matter of thls dlvlslonal appllcation as well as the parent application and another divisional applicatlon flled based on the same parent appllcatlon.
Field of the Invention The present lnventlon relates to novel substituted oxlndoles and related to compounds, pharmaceutlcal composltions comprislng such compounds, and the use of such compounds as lnhibitors of phosphodlesterase ("PDE") type IV.
The compounds of thls lnventlon are useful ln the treatment of AIDS, asthma, rheumatold arthrltls, osteoarthrltls, bronchltls, chronic obstructive airways dlsease, psorlasis, allergic rhlnltls, atoplc dermatltls, shock, and other inflammatory diseases. The inventlon also relates to pharmaceutlcal compositlons contalnlng these compounds and to methods of inhlbiting the actlon of phosphodiesterase type IV.
Background of the Inventlon Since the recognltlon that cycllc adenoslne monophosphate ("cAMP") is an lntracellular second messenger (E.W. Sutherland and T.W. Rall, Pharmacol. Rev., 1960, 12, 265), inhibition of phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. Distinct classes of phosphodiesterases have been recognized (J.A. Beavo and D.H.
Reifsnyder, TIPS, 1990, 11, 150) and thelr selectlve inhibition has led to improved drug therapies (C.D. Nlcholson, R.A. Challlss, and M. Shahld, TIPS, 1991, 12, 19). It has been clalmed that lnhlbition of PDE type IV can lead to inhlbltlon of lnflammatory mediator release (M.W. Verghese, et al., J. Mol. Cell Cardiol., 1989, 12 (Supp. II), S 61) and alrway smooth muscle relaxation ~T.J. Torphy ln Dlrectlons for New Anti-Asthma Druqs, eds. S.R. O'Donnell and C.G.A. Persson, 1988, 37, Birkhauser-Verlag).
Certaln pyrimldone compounds have been described as antidepressants in EP 0 247 725 A2, publlshed December 2, 1987. Certain pyrimidone compounds have been described as useful against asthma and certain skin disorders in WO
91/07178 published May 30, 1991.
The followlng documents relate to inhibitors of phosphodiesterase type IV: WO 87/06576, publlshed November 5, 1987; WO 91/15451, published October 17, 1991; WO 91/16303, publlshed October 31, 1991; WO 92/00968, publlshed January 23, 1992; WO 92/07567, publlshed May 14, 1992; WO 92/12961, published August 6, 1992; EP 0 428 313 A2, publlshed May 22, 1991; EP 0 442 204 A2, published August 21, 1991; EP 0 470 805 Al, published February 12, 1992; EP 0 473 963 Al, published - 2a -March 11, 1992; EP 0 497 564 Al, published August 5, 1992; EP
0 511 865 Al, publlshed November 4, 1992; and EP 0 303 418 A2, published February 15, 1989. The following documents relate to inhibitors of phosphodiesterase type IV in non-pulmonary/non-allergic uses: US 4,582,834, issued Aprll 15, 1986; US 4,971,959, lssued November 20, 1990; US 5,077,290, issued December 31, 1991; DE 3742716 Al, published June 22, 1989; and DE 402592 Al, publlshed March 5, 1992.
Summary of the Invention The present invention relates to a compound of the formula:

1 X ~ R7 ~ O~ I

wherein X is N or CR4;
pl is (Cl-C4)alkyl or phenyl(Cl-C6)alkyl;
R2 is (Cl-C10)alkyl, phenyl(Cl-C6)alkyl, (C3-C7)-cycloalkyl, or (C6-C12)polycycloalkyl;
or Rl and R2, taken together with the oxygens to which they are attached, represent a methylene or ethylene brldge which forms a 5 or 6 membered ring;
R3 is hydrogen, (Cl-C6)alkyl, (Cl-C6)alkyloxycarbonyl, (Cl-C6)alkyloxy, (Cl-C6)alkoxycarbonyl-(Cl-C6)alkyl, - 2b --CONRlORll; or -ICl-C6)alkyl-CONRlORll;
R10 and Rll are lndependently selected from hydrogen and (Cl-C6)alkyl, or R10 and Rll, taken together with the nltrogen to which they are attached, form a pyrrolldlne or plperldlne rlng;
R4, R5, R6 and R7 are lndependently selected from hydrogen, halogen, (Cl-C8)alkoxy, (C3-C7)cycloalkyloxy, hydroxy, (C2-C6)acyloxy, nitro, NR8R12, S02NR8R12, (Cl-C6)-alkyl, (Cl-C6)alkylcarbonyl, phenyl(Cl-C6)alkoxy, and (C6-C12)polycycloalkoxy or any comblnatlon of R4 and R5, R5 and R6, or R6 and R7 whlch together form -OCH20-or -OCH2CH20-, such that, when taken together with the c~,~;r.~ to which they are attached, they form, respectively, a ~ or ~membeleci ring;
R8 and Rl2 are independently s0'ected from hydrogen and (C,-C~,) alkyl, or Re and Rl2, taken toSJett,er with the nitrogen to which they are dtLcted, form a pyrrolidine 5 or piperidine ring;
R9 is hydlo~en or (C1-C~) alkyt;
the broken line represent~ an optional double bond; and the wavy lines indicate that the compounds exist as (E) and/or (Z) st~reoisor. ,ers when the broken line is a double bond;
with the proviso that (a) if Rl and R2 are both methyl, X is CH, R~ is hyJ~oyenland the broken line is a double bond, then (i) at least one of R3, R5, R~, and R' is other than hydrogen; (ii) at least one of R5, R6 and R7 is other than hyJ~ogen or R3 is other than methyt; and (iii) at least one of R3 and R' is other than hydlogen or at least one of R5 and R~ is other than 0-CH3; (b) H R3 is hydrogen, R9 is hydrogen, X is CH, the broken line is a double bond, and Rl and R2 together repr~sent a methylene bridge, then at least one of R5, R~ and R7 is other than hydrogen; and (c) if Rl and R2 are both methyl, X is CH, R9 is hydrogen, and the broken line is a single bond, then at least one of Rs and R~ is other than O-CH3, or R7 is other than hydrogen, or R3 is other than COCH3;
or a pharmaceutically accept~ble salt thereof.
The terrns ~haio' or ~haiogen~, as used herein, unless otherwise indic~ted, includes chloro, fluoro, bromo and iodo.
The term 'aikyl~, as used herein, unless otherwise indicated, includes saturatedmonovaient hydrocarbon radicais having straight or branched moieties, for example, methyl, ethyl, n-propyl, isopropyl and -butyl.
The term 'cycloakyl,~ unless othen,vise indicated, means a saturated carbocyclicradicai, for exarnpie, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term ~aikoxy~, unless otherwise indicated, includes C~ikyl groups wherein ~alkyl~ is defined as above.
The term ~polycycloalkyl- means a saturated carbopolycyclic radicai, such as norbomyl, bicyclo[2.2.2]octyl, or adamantyl.
The term ~aikyloxycarbonyl~ means an aikoxy group ~as defined above) attached to a carbonyl moiety.

The term 'alkyloxy~ means the sarr~e as alkoxy.
The term ~cycloalkyloxy' includes O~ycloalkyl groups wherein cycloalkyl is defined as above.
The term ~acyloxy~ means an alkyl group (as defined above) attached to a carbonyl moiety which is then attached to an oxygen.
The terrn ~alkylcarbonyl- means an alkyl group (defined as above) attached to a carbonyl moiety.
A prefei,ed compound of the present invention is a compound ot the formula I wherein Rl is methyl or ethyl and R2 is (Cl-C~,) alkyl, phenyl-(C,-C~) alkyl, (C3-C7) 10 cycloalkyl, or (C"-C,2) polycycloalkyl; or Rt and R2, taken together with the oxygens to which they are attached, represent a methylene or ethylene bridge which forms a 5 or 6 membered ring.
In a more pre~erred embodiment, X is CH or N, Rl is methyl, R2 is norbomyl, R3 is hydrogen, methyl, ethyl, -COOC2H5, -CONH2, methoxy or -CH2COOC2H5, R~ is 15 hydrogen, bromo, methoxy or chloro, and R5 is hydrogen, hydroxy, cyclopentyloxy, methoxy, bromo, chloro, amino, or -S02NH2, or R5 and R6 together form -OCH20-, R' is hydrogen, and R9 is hydrogen or methyl.
Specific ~r~ d compounds of the present invention are:
~[[3-(Bicyclo[2.2.1]hept-2-yloxy) 4 methoxyphenyl~methylene]-1,3-dihydro-20 [1 a,2a(E),4a]-2H-indol-2-one;
3-[~3-(Bicyclo[2.2.1]hept-2-yloxy) 4 methoxyphenyl]methylene]-1,3-dihydro-1-ethyl-[1 o,2a(E),4a]-21-1-indol-2-one;
3-[[3-(Bicyclo[2.2.1 ]hept-2-yloxy)~methoxyphenyl]methylene]-1 ,3-dihydro-1-methyl-[1 a,2a(Z),4a]-2H-indol-2-one;
26 3-~[3-(Bicyclo [2.2 .1 ] hept-2-yloxy)~methoxyphenyl]methylene~-1 ,3~ihydro-1-ethyl-[1 a,2a(Z) ,4a]-2H-indol-2-one;
3-[~3-(Bicyclo[2.2.1 ]hept-2-yloxy)4-methoxyphenyl]methylene]-6-chloro-1 ,3-dihydro-1-methoxy-[10,20(Z), 40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1 ]hept-2-yloxy)4-methoxyphenyl]methylene]-6-chloro-1 ,3-30 dihydro-[1 o,2a(E),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1 ]hept-2-yloxy)-4-methoxyphenyl]methylene~-5-bromo-1 ,3-dihydro-[1 a.2a(E),4a]-2H-indol-2-one;

3-1~3-(Bicyc~o~2.2.1 ~hept-2-yloxy)~-methoxyphenyl]methylenel-5-bromo-1 ,3-dihydro-1 -methy~-[1 o,20(E),40]-2H-indol-2-one;
~[[3-(Bicyclo[2.2. 1 ]hept-2-yloxy)-4-methoxyphenyl]methylene]-5-chloro-1,3-dihydro-1 -methyl-[1 a,20(Z),40]-2H-indol-2-one;
3-~3-(Bicyclo~2.2.1]hept-2-yloxy)~methoxyphenyl]methyi-~ne]~cy~ tyloxy-1 ,3-dihydro-1 -ethyl-[1 o,2a(E),40]-2H-indol-2-one;
3-[[3-(Bicyclol2.2. 1 ~hept-2-yloxy)~methoxyphenyllmethylene]~methoxy-1,3-dihydro-1-methyl-[1a,20(E),40]-2H-indol-2-one; and 3-[[3-(Bicydo[2.2.1]hept-2-yloxy) 4 methoxyphenyl]methylene]-2,3-dihydro-N,N-dimethyl-2-oxo-[1 o,20(E),40]-1 H-indole-5-sulfonamide.
Other compounds of the present invention include the f~ i."~;
3-[[3-(Bicyclo[2.2. 1 ]hept-2-yloxy)4-methoxyphenyl]methylene]-1 ,3-dihydro-[1 o,2a(Z),40]-2H-indol-2-one;
3-[[3-(Bicydo[2.2.1]hept-2-yioxy)4 methoxyphenyl]methyl]-1,3-dihydro-2H-indol-1 5 2-one;
3-[[3-(Bicyclo[2.2.1 ]hept-2-yloxy)~methoxyphenyl]methylene]-5-hydroxy-1 ,3-dihydro-[1 o,20(Z) ,40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1 ]hept-2-yloxy)~methoxyphenyl]methylene]-~hydroxy-1 ,3-dihydro-~1 o,20(E),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)~h"~ll,oxyphenyllmethyq~hydroxy-1,3 dihydro-2H-indol-2-one;
3-[[3-(Bicyclo [2 .2 .1 ] hept-2-yloxy) 1 methoxyphenyl]methylene]-2,3~ihydro-2-oxo-~1a,2a(E),4a)-1H-indoie-1-carboxylic acid, ethyl ester;
3-[[3-(Bicyclo[2.2.1~hept-2-yloxy) 4 methoxyphenyllmethylene~-1,3-dihydro-1-methyl-11 o20(E),40]-2H-indol-2-one;
3-[[3-(aicyclo[2.2. 1 ]hept-2-yloxy) methoxyphenyl]methylene]-2,3-dihydro-2-oxo-[10,20(Z),40]-1H-indol-1-carboxylic acid, ethyl ester;
5-Acetyloxy-3-[[3-(bicyclo[2.2.1]hept-2-yloxy) 4 methoxyphenyl]methylene]-1,3-dihydro-[1 o,2a(Z),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl]methylene]-6-chloro-1,3-dihydro-1-methoxy-[1 o,2a(E),40]-2H-indol-2-one;
3-[[3-(Bicyclo [2.2.1 ] hept-2-yloxy)~methoxyphenyl]methylene]-5-cyclopentyloxy-1 ,3-dihydro-[1 o,2a(E),4a]-2H-indol-2-cne;

~[~3-(Bicyclo[2.2.1 ]hept-2-yloxy)4-methoxyphenyl]methylene]~cycloperlty10xy-1,3-dihydro-~10,2a(Z),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl]methylene]-6-chloro-1,3-dihydro-[10,2a(Z),40]-2H-indol-2-one;
(Z)~[(2,3-Dihydro-1,4-benzodioxin~yl)methylene]-1,~dihydro-2H-indol-2-one;
3-[(3,4-Dimethoxyphenyl)methylene3-1,3-dihydro-[10,2a(E),40~-2H-indol-2-one;
(E)~[(2,3-Dihydro-1,~benzodioxin~yl)methylene] -1,3-dihydro-2H-indol-2-one;
(E)-3-(1,3-Bel-70 l~cxol-5-ylmethylene)-1,3 dihydro-2H-indol-2-one;
~[[3-(Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]methylene]-5-bromo-1,3-10 dihydro-[1 a,2a(Z~,4a]-2H-indol-2-one;
3-{[3-(Bicyclo[2.2.11hept-2-yloxy)4-,.,~tl ,oxyphenyl]methylene]~cy.,lDp~, h~loxy-1,3-dihydro-1 -methyl-[1 a.20(Z),4a3-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl]methylene]-5-bromo-1,3-dihydro-1 -methyl-[10,20(Z),40]-2H-indol-2-one;
3-~[3-(Bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl]methylenel-5-chloro-1,3-dihydro-[10,2a(E),40]-2H-pyrrolo~3,2-b]pyridin-2-one;
(E)-1,~Dihydro~[[4 r"~tl,oxy~(4-phenylbutoxy)phenyl]-methylene]-2H-indol-2-one;
3-[[3-(Bicyclo [2.2.1] hept-2-yloxy)~methoxyphenyl] methylene]-5-chloro-1,3-dihydro-1 -methyl-[10,2a(E),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl]methylene]-5-chloro-1,3-dihydro-1 -methyl-[1 a,20(E),40]-2H-pyrrolo[3,2-b~pyridin-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)~methoxyphenyl]methylene]-5,7-dinitro-1,3-dihydro-[10,2a(E),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl]methylene]-5-nitro-1,3-dihydro-[10,2a(E),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]methylene]-5-nitro-1,3-dihydro-[10,2a(Z),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)~methoxyphenyl]methylene]-5,~dimethoxy-1,3-dihydro-1-methyl-[1 a,2a(E),40]-2H-indol-2-one;
3-[[3-(Bicycio[2.2.1]hept-2-yloxy)~methoxyphenyl]methylene]-5,~dimethoxy-1,3-dihydro-1 -methyl-~1 a.20(Z),40]-2H-indol-2-one;

3-~[3-(Bicyclo [2.2.1 ] hept-2-yloxy)4-methoxyphenyl]methylene]-5-nitro-1 ,3-dihydro-1 -methyl-[1 o,20(E),40]-2H-indol-2-one;
3-~l3-(Bicyclo[2.2.1]hept-2-yloxy) 4 methoxyphenyllmethylene]-5-hydroxy-1,3-dihydro-1 -ethyl-[1 o,20(Z),40]-2H-indol-2-one;
53-[[3-(Bicyclo[2.2. 1 ]hept-2-yloxy) ~ methoxyphenyl]methylene]-5,7-dinitro-1,3-dihydro-1 -methyl-~1 o,2a(E),40]-2H-indol-2-one;
5-Amino-3-[[3 (bicyclol2.2.1]hept-2-yloxy)~"~ xy pt?enyl]methyl]-1 ,3-dihydro-1 -methyl-2H-indol-2-one;
~ 3-[[3-(Bicyclo[2.2.1]hept-2-yloxy)~methoxyphenyqmethylenel~cyclopentyloxy-101 ,3-dihydro-1 -ethyl-[1 a,20(Z),40]-2H-indol-2-one;
~Amino-3-[[3-(bicyclo[2.2.1 ]hept-2-yloxy)~methoxyphenyl]methylene]-1 ,3-dihydro-1 -methyl-[1 a,2a(Z),40]-2H-indol-2-one;
3-[E3-(Bicyclo[2.2.1]hept-2-yloxy) ~-methoxyphenyl]methylene]-1,3-dihydro-[1 o,2a(E),40]-2H-pyrrolo~3,2-b]pyridin-2-one;
153-[[3-(Bicyclo[2.2.1]hept-2-yloxy) ~ methoxyphenyl]methylene]~methoxy-1,3-dihydro-[1 o,20(Z),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1 ]hept-2-yloxy)~methoxyphenyl]methylene3-~methoxy-1 ,3-dihydro-1 -methyl-[1 o,2a(E),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1 ]hept-2-yloxy)~., l~l ,oxyphenyl]methylene]-5-methoxy-1,3-20dihydro-1 -methyl-[1 o,2a(Z),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy) ~ methoxyphenyl]methylene]~methoxy-1,3-dihydro-1 -methyl-[1 a,2a(Z),4a]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1 3hept-2-yloxy)4-methoxyphenyl]methylene3-1 ,3-dihydro-1-methyl-[1 a,2a(E) ,4a]-2H-pyrrolo [3,2-blpyridin-2-one;
253-[i'3-(Bicyclol2.2.1]hept-2-yloxy)4-methoxyphenyl]methylene]-5-chloro-2,3-dihydro-2-oxo-[1 o,20(E),40]-1 H-indole-1 -carboxamide;
3-[[3-(Bicycio[2.2. 1 3hept-2-yloxy)4-methoxyphenyl]methylene]-5-chloro-2,3-dihydro-2-oxo-[1 a,2a(Z),4a]-1 H-indole-1 -carboxamide;
3-[[3-(Bicyclo[2.2.1 ]hept-2-yloxy)~-methoxyphenyl]methylene]-5-nitro-1 ,3-30dihydro-1 -methyl-[1 o,20(E),40]-2H-indol-2-one;
5-Acetyl-3-[[3-(bicyclo[2.2.1 ]hept-2-yloxy)4-methoxyphenyl]methylene]-1 ,3-dihydro-[1 a,2a(E),4a]-2H-indol-2~ne;

5-Acetyl-3-[[3-(bicyclo[2.2,1]hept-2-yioxy)4-methoxyphenyl]methylene]-1 ,3-dihydro-[1 o,2a(Z),40]-2H-indol-2-one;
(E)-3-[(3,4-Dimethoxyphenyl)methylene]-2,3-dihydro-2-oxo-1 H-indole-1~cetic acid, ethyi ester;
(Z)-3-[(3,4-Dimethoxyphenyl)methylene]-2,3-dihydro-2-oxo-1 H-indol~1 ~cetic acid, ethyl ester;
(E) ~Ch u, I ,o~[(3,~dimethoxyphenyl)methylene]-2,3-dihydro-2-oxo-1 H-indole-1-acetic acid, ethyl ester;
~[[~(Bicydo[2.2.1 ]hept-2-yloxy)4-methoxyphenyl]methylene]-2,~dihydro-N,N-10 dimethyl-2-oxo-[1 o,2a(Z),40]-1 H-indole-5-suHonamide;
(Z)-7-[[3-(Bicyclo[2.2.1]hept-2-yloxy)~methoxyphenyl]methylene]~,7~ihydro-~
oxo-5H-1,3-dioxolo[4,5-fli" 'ole 5 carboxamide;
(E)-7-[[3-(Bicycio[2.2.1 ]hept-2-yloxy)4~ r,~i ,Gxyphenyl]methylene]~,7-dihydro~oxo-5H-1 ,3-dioxolo[4,5-f indole-5-car;box~nide;
3-[[3-(Bicyclol2.2.1]hept-2-yloxy)4-methoxyphenyl]methylenel-5-methyl-1,3-dihydro-[1 o,20(E),40]-2H-indol-2-one;
~[13-(Bicyclo[2.2.1]hept-2-yloxy) ~ methoxyphenyl]methylene]-1,~dimethyl-1,3-dihydro-[1 a,20(E),40]-2H-indol-2-one;
3-[[3-(Bicyclo[2.2.1 ]hept-2-yloxy)4-methoxyphenyl]methylene]-5-methyl-1 ,3-dihydro-[1 o,20(Z),4a]-2H-indol-2~ne;
3-[[3-(Bicyclo[2.2 .1 ] hept-2-yloxy)~-methoxyphenyl] methylene]-5-chloro-1 ,3-dihydro-1-methyl-[1 o,2a(Z),40]-2H-pyrrolo[3,2-b]pyridin-2-one;
3-~[3-(Bicyclo[2.2. 1 ]hept-2-yloxy)-4-methoxypheny~]methylene]-5-chloro-1 ,3-dihydro-[1 o,20(Z),4c3-2i-i-indol-2-one;
3-[[3-(Bicyclol2.2.1]hept-2-yloxy)4-methoxyphenyl]methylene3-5-chloro-1,3-dihydro-[1a,2a(E)~4a]-2H-indol-2-one; and 3-[1 -[3-(Bicyclo [2.2.1 ] hept-2-yloxy)~-methoxyphenyllethylidene'i-1 ,3~ihydro-[1 a,2a(E),4a]-2H-indol-2-one.
The present invention ai~o reiates to a pharmaceutical composition for treating a condition selected from the group oonsisting of acquired immunodeficiency syndrome (~AIDS~), asthma, rheumatoid arthritis, osteoarthrrtis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, atopic dermatitis, shock, and other i"fla",l"atory diseases ir~ a mammal, including a humzn comprising an amount of a ~ompound of the formula 1, or a pharrnaceutically acceptable salt thereof, effe~e in treating such condition, a~d a pharmaceutically acc~ptable carrier.
The present invention also relates to a method of treating a condition s~l~cted from the group consisting of AIDS, asthma; rheumatoid arthritis, o .Li~o~ ll " iti~., 5 bronchitis, chronic obstructive airways ~liseAse, psoriasis, allergic rhinitis, atopic dermatitis, shock, and other i,lfl&m,nato,y dise~ces in a mammal, including a human, co~ l iail ,g rJ~ teli~)9 to said 1ll&ll~ an amount of a compound of the fonnula 1, or a ph&~ oelnir~lly acce~ !e salt thereof, effective in ll~dtillg such condition.
The present invention also relates to a pharm~ceutic~l CGII ,posi~on for inhibiting 10 the effects of phosphodiesterase type IV in a mammal, including a human, c~--".~ i--g a phosphodiesterase type IV illhi~iling amount of a compound of the formula 1, or a pharrnaceutically acceptal~le salt thereof, and a pharmaceutically a._ceptable carrier.
The present invention also relat~s to a method of inhibiting the effects of phosphodiesterase type IV in a mammal, including a human, CO"~pl ising admini~iing 1~ to said mammal a phosphodiesterase type IV inhibiting amount of a compound of the formula 1"or a pharmaceutically Accept~-le salt thereof.
The present invention also relates to a pharmaceutical c; " ,pos~on for ~ tzsti"9 a condition selected from the group consisli"g of AIDS, asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive airways dise~ce~ psG,iasis, allergic rhinitis, 20 atopic dermatitis, shock, and other i"nah,r"atory ~lise~ces in a ,.,&nl.,al, including a human, comprising an amount of a compound of the formula 1, or a phaJ,.,aceutically acceptable salt thereof, effective in inhibiting the action of phospho~die terase type IV, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a condition selected 25 from the group consisting of AIDS, asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive ai~ays disease, psoriasis, ailergic rhinitis, atopic dermatitis, shock, and other inflammatory diseases in a mammal, including a human, comprising administering to said mammal an amount ot a compound of the formula 1, or a pharmaceutically acceptable salt thereof, effective in inhibiting the action of 30 phosphodiesterase type IV.
The present invention aiso relates to a pharmaceutical composition for treating a disorder in a mammal, including a human, the treatment of which is effected orfacilitated by blocking the action of phosphodiesterase type IV, comprising an amount of a compound of the forrnula 1, or a pha""Ar,eutics"y AcceptAhlQ salt thereof, effective in ll~ling such disorder, and a ;Jh~""aceutically accept~ble carrier.
The preseril invention also relates to a method of ll~dtill~ a disorder in a " ,~n " "al, including a human, the l,~:al."e"~ of which is effected or facilitated by blocking the action of phosphodies,t~i ,~,e type IV, CG~ Jlisill~J admin6t~ g to said mammal an amount of a cG",pound of the hrmula 1, or a pharm~ce~tically ~r~ep'~le salt ll ,e" ~of, effective in l~ t;"g such di~,order.
Sorne of the cG",pounds of the pr~,~nt invention have chiral centers and therefore exist in di~f~rent enantiomeric forms. For example, when the broken line 10 represents a single bond and R9 is not hydrogen, the compound can exist in at least four enantiomeric forms. Some of the compounds of the pr~,~n invention can also exist in di~re"l regioisomeric forms. For example, wh~he broken line represents a double bond, both the E and Z isol"er~, can be isolated. This invention relates to all optical iso",e.~" all stereoisolner~" and all regioisomers of compounds of formula 1, and 15 mixtures thereof.
Formula I above includes co" ,pounds idol Itic~l to those deF . ted but for the fact that one or more hydrogen or carbon atoms are repl-~,ed by r~i;cAotive isotopes thereof. Such radiolAhe"ed compounds are useful as research and diag"o ,~ic tools in mePh~' sm studies, ph&lllacol~i"~tic studies and in binding assays. Specific 20 applications in ~,,,aaroh include radioligand binding assays, autoradiography studies and in v~vo binding studies, while specific ~plic~l;or)5 in the diL ~IIO ,lic area include studies of selective inhibition of phosphodiesterase type IV in vivo binding in the relevant tissues for asthma, e.g., immune or inflammatory type cells that are directly or indirectly involved in inflarnmation, and the like.
Also within the scope of this invention are the pharm~ceuti~lly acceptabie saltsof the compounds of the formula I where acidic or basic functionaiities are incorporated as substituents. The pharmaceutically acceptable acid saits are those formed from acids which form non-toxic acid saits, for example, hydrochloride, hydrobromide,suifate, bisuHAte~ phosphate, acid phosphate, acetate, citrate, fumarate, gluconate, 30 lactate, maieate, succinate, tartrate, methanesuifonate, benzenesuifonate, toluenesulfonate and formate saits. Pharmaceutically acceptable cationic salts include those non-toxic salts based on alkaii and alkaiine earth metals, for example, sodium, lithium, pota~sium, caicium and magnesium, as well as non-toxic ammonium, qu~t~,t,a,y ammonium and amine cations, for example, ammonium, t~b~ll~U"rl-"".onium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, N,N'-dibenzylethylenediamine, N-methylglucamine, meglumine, nolarnine and diethanolamine.
The present invention also relates to the f~ .-g jln~lllle~l ''~?5 used in the prep~ralion of coi~pounds of formula l:
R 1 3~,~
>=~ I V
R 14/ \~ N

wherein Rl3 and Rl4 are independently sele~,1ed from h~d~ogen and methoxy;

\~C>=~ V
N
H

v~:.erei" R5 is S02NR9Rl2;
CH30~

--'\r(CH2)40 Vl wherein R9 is hydrogen or (C1-C9) alkyl; and CA 02224049 l998-02-09 CH30\~, o~ V I
C~/

wherein R9 is hyd~ogen or (Cl-C~ kyl, Rl5 is oxygen or hydroxy, and the broken line represents a double bond when R'5 is oxygen.
Detailed DescriPtion of the Invention The compounds of forrnula I may be prepued as des~nL,ed in the following reaction schemes und discussion. Unless othe~wise indicated, X, R1, R2, R3, R~, R5, R6, R7 R5 R9 Rl~ Rl' Rl2 R13 Rl4, R'5, the broken lines, and the wavy lines in the rea~ion scheme~ and discussion that foilow are defined as above. -Scheme 1 R l O ,~yR 9 + 6~ ~=~
~ R7 R3 Rs R6 ~/ ¦ R5 R6 ~--~ t ~

ORl I B l_~
( E- l so~er ) ( Z- I somer ) With r~ference to reaction Scheme 1, the compounds of the present invention wherein the broken line of formula I represents a double bond (Forrnulae l-A and l-B), 20 may be pre~ared by an Aldol condens~ion, using cGIlJiitiGns well known to those skilled in the art. Thus, a compound of formula ll is reacted with a cGr"pound of formula lll, plef~r~ly under an inert atmosphere in a reaction inert solvent such as water, methanol, ethanol, butanol, isopropanol, acetone, ether, chlorofo"", methylene chloride, dioxane, tetrahydrofuran, or dimethoxyethane. To this mixture is added a 25 base such as pyrrolidine, piperidine, diethylamine, triethylamine, Hunig's base, aqueous sodium hydroxide, barium hydroxide, aluminum t-butoxide, sodium ethoxide, potassium hydroxide, morpholine, methyl lithium, butyl lithium, sodium hydride, or pyridine. The actuaJ base utilized will depend somewhat upon the solvent utilized. The reaction mixture is stirred for 2 to 72 hours at a temperature of between 0~ and 140~. When 30 the reaction is complete, the compounds of formula l-A (the E isomer) and formula l-B
(the Z isomer) are isolated via methods well known to those skilled in the art.
The co",pounds of formula l-A, wherein R3=hydrogen, can be alkylated to form compounds of formula l-A, wherein R3=(Cl-C~) alkyl, using reaction conditions well known to one skilled in the art. These reaction cor,-litions can also be p~ ,""ed on compounds of formula l-B, wherein R3=hydrogen, and on compounds of formula ll, wherein R3=hydrogen, to effect analogous t,~,;,F~""ations (and to yield, among other compounds, the compounds of furmula lV). Thus, a compound of formula l-A wherein5 R3 is hydrogen can be combined ~,vith a base such as pot~ssium carLor,ate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium -blrtoxide, butyl lithium, and i;~otassium fluoride. The mole ratio of s~ti"g ",~te,ial oxindole to base will pr~f~r~ bly be from about 1.0 to about 0.5. These compounds can be combined in a suiPhle solvent such as acetone, chloro~"", methylene chloride,10 dimethylformamide, ethanol, butanol, isopropanol, dimethyls~ ~lfoxide, or a mixture of two or more ot the foregoing solvents. To this mixture, an alkylaUng agent, such as an alkyl halide or alkyl sulfate, can be added. The reaction can be stirred for a time period from about two to about 72 hours, at a temperature between 0~ and 100~C. Additional reagents, such as phase t,~ er catalysts, can be added. When the reaction is 15 co"" l~t~, the compounds of forrnula l-A can be isol t~d via l"t~U,ods well known to one skilled in the art.
Scheme 2 R10~

R20 ' ~ ' ~ ~ N R3 R23 K9 C

Wlth reference to- reaction Scheme 2, the compounds of the present invention wherein the broken line of formula l represents a single bond (formula l-C) can be prepared by a hydrogenation reaction, using reaction conditions well known to one skilled in the art. These reaction conditions can also be performed on compounds of 30 formula l-B to effect anaiogous transformations. Thus, a compound of formula l-A can be dissolved in a solvent such as ethyl acetate, tetrahydrofuran, methanol, ethanoi, butanol, isopropanol, ether, dioxane, chloroform, methylene chlonde, dimethoxyethane, or a com~..)ation thereof. The mixture can be combined wlth a catalyst such as CA 02224049 l998-02-09 palladium, rhodium, Raney* nickel, platinum, platinum oxide, palladium hydroxide, nickel borlde, ruthenium, zinc oxide, chlorotrls(triphenylphosphine)rhodium (Wilkinson's catalyst), or pentacyanocobaltate(II), and shaken under a hydrogen atmosphere for about two to about 72 hours at a pressure of about atmospheric to about 100 atm., at a temperature between 0~ and 250~. When the reaction is complete, the compounds of formula I-C can be isolated via methods well known to those skilled in the art. Other possible reduclng agents to effect this transformatlon can be used such as sodlum, llthlum, chromous lon, zlnc sodlum hydrophosphate and palladium, trlfluoroacetlc acid and triethylsllane, hydrazlne wlth an oxldlzlng agent under reactlon conditions well known to one skllled ln the art.
The compounds of formula I-A, whereln R3 = hydrogen, can also be acylated to form compounds of formula I-A, wherein R3 = (Cl-C6) alkoxycarbonyl, using reaction conditions well known to those skllled ln the art. These reaction conditions can also be performed on compounds of formula I-B, whereln R3 = hydrogen, and on compounds of formula II, whereln R3 =
hydrogen, to effect analogous transformations. Thus, a compound of formula I-A whereln R3 = hydrogen can be comblned wlth an approprlate acylatlng agent (such as ethyl chloroformate). In the case of llquld acylatlng agents, thls reagent can also be used as the solvent for the reactlon. If, however, the acylatlng agent ls not a liquld, then the solvent for the reactlon could be solvents such as dimethylformamide, *Trade-mark - 15a -ethanol, butanol, isopropanol, dimethylsulfoxide, chloroform, or methylene chlorlde. A base ls then added to the reactlon mixture; sultable bases include but are not llmited to potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxlde, potasslum t-butoxide, butyl lithium, potassium fluoride, and sodium. Phase transfer catalysts can also be added, if appropriate. The reaction can be stirred at a temperature between 0~ and 150~C, for a period of time from about three to about 72 hours. When the reactlon is complete, the compounds of formula I-A can be isolated via methods well known to those skilled in the art.
The compounds of formula I-A, wherein R4, R5, R6 and/or R7 = hydroxy, can also be acylated to form compounds of formula I-A, wherein R4, R5, R6, and/or R7 = (C2-C6) acyloxy, using reaction condltions well known to those skllled ln the art. These reactlon conditlons can also be performed on compounds of formula I-B, wherein R4, R5, R6 and/or R7 =
hydroxy, and on compounds of formula II wherein R4, R5, R6 and/or R7 = hydroxy, to effect analogous transformations.
Thus, a compound of formula I-A

wherein R4, Rs, R~, and/or R7=hydroxy, can be combined with a b~se such as aqueous sodium hydroxide, piperidine, diethyiamine, triethylamine, Hunig's base, barium hydroxide, aluminum -I~utoxi~te, sodium ethoxide, pot..ssium hydroxide, morpholine, methyl lithium, butyl lithium, sodium hydride, pyridine, mercury oxide or potassium 5 c~u L or,&~e in a solvent such as water, methanol, ethanol, butanoi, isoprop&r,ol, acetone, ether, dioxane, chloroform, methylene chloride, tetrahydrofuran, dimethoxyethane, cii."etl,yisuifoxide, dimethylt~ &."i~e, or a mixture of two or more of the for~a..,~
sohents, depending on the choice of base. The resuiting mixture can be stirred at a temperature between 0~ and 150~C. An acyiating agent can then be added to this 10 mixture, such as acyl anhydride or acyl haiide. The rez_tion can be stirred for about one-haif to about 72 hours. Phase l~ fer cataiysts can be added, H appropriate.
When the reaction is complete, the compounds of formula l-A can i~e isoloted viamethods well kno~,vn to those skilled in the art.
The compounds of forrnula l-A, wherein R4, R5, R6, and/or R'=hydroxy, can also 15 be alkylated to form co~"pounds of formula l-A, wherein R4, R5, R~, and/or R'=(Cl-Ca) alkoxy, (C3-C7) cycloalkoxy, phenyl-(C,-C~,)alkoxy, or (C~,-Cl2) polycydoalkoxy, using reaulion conditiGns well known to those skilled in the art. These reaction conditions can aiso be performed on cG",pounds of formula l-B, wherein R4, R5, R6, and/or R'=hydroxy, and on compounds of formula ll, wherein R~, R5, R~, and/or R'=hydroxy, 20 as well as on compounds of formuta lll wherein R' andlor R2=hydroxy, to effect analogous transforrnations (and to yield, among other compounds, the compounds of formuia Vl). Thus, a compound of formula l-A wherein R4, R5, R6, and/or R7=hydroxy, can be dissolved in a reaction inert solvent such as acetone, ether, chloroform,methylene chloride, dioxane, tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, 25 dimethyiformamide, or a mixture of two or more of the foregoing soivents. To this mixture is added a base such as aqueous sodium hydroxide, barium hydroxide, aluminum t-butoxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium carbonate, methyl lithium, butyl lithium, sodium hydride, silver oxide, potassium fluoride, or tetraethylammonium fluoride. The choice of base may depend 30 somewhat on the choice of solvent. The rea-ction mixture can be stirred for about one-half hour to about 3 hours, at a temperature between -78~C and room temperature.Upon folll)Glion of the alkoxide, the alkylating agent such as an alkyl halide, or alkyl sulfate is added. Additional reagents can be added, such as hexamethylphosphorarnide, potassium iodide, sodium iodide, or phase i~ ns(~r catalysts. The reaction mixture is then stirred for one to 24 hours, at a temperature betwe~n -20~C and 150~C. When the reaction is complete, the ct~",pounds of the formula l-A can be isol~ted via methods well known to those skilled in the art.
Aitematively, this l-~,sfo~ ation could be carried out under the follo.~ g reaction conditions. A compound of formula l-A wherein R~, R5, R~, and/or R7=hydroxy, can be dissoived in a reaction inert soivent such as ether, ch'cr~f~ , methylenechloride, dioxane, tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, dimethylforrnamide, or a mixture of two or more of the forego:ng solvents. The 10 aikylation is then performed using an alkylating agent such as an alkyl alcohol, in combination with a triarylphosphine or trialkyl phosphine, and a diaikyiazodicarboxylate.
The reaction mixture can be stirred for about 2 to about 150 hours, at a temperature between 0~ and 150~C. When the reaction is complete, the compounds of forrnula l-A
can be isol~ter~ via methods weil known to those skilled in the art.
The compounds of formula l-A, wherein R3=hydrogen, can also be aikylated to fomm compounds of formula l-A wherein R3=(C,-C~,) alkoxyca iJonyl-(C,-C,,) aikyl, using reaction conditions well known to one skilled in the art. These r~ lior, conditions can also be performed on compounds of formula l-B, wherein R3=hydrogen, and on compounds of formula ll, wherein R3=hydrogen, to effect anaiogous (,~ ,fo",lations.
Thus, a compound of fomm~ l-A w~herein R3 is hydrogen can be dissolved w~ith an alkoxycarbonyl aikylating agent such as ethyl chloroacetate in a solvent such asdimethyiformamide, acetone, ether, chloroform, methylene chloride, dioxane, tetrahydrofuran, dimethoxy ethane, dimethylsulfoxide, or a mixture of t~o or more of the foregoing solvents. The reaction can be cooled, and then a base can be added such as sodium hydride, aqueous sodium hydroxide, barium hydroxide, aluminum t-butoxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium carbonate, methyl lithium, butyl lithium, silver oxide, potassium fiuoride, or tetraethylammonium fluoride. The reaction can then be stirred for about 10 minutes to 72 hours, at a temperature between -20~ and 150~C. Additional reagents can be added such as ~0 hexamethylphosphoramide, potassium iodide, or sodium iodide. When the reaction is complete, the compounds of formula l-A can be isolated via methods well know~n to those skilled in the art.

The co,.,pounds of formula l-A, wherein R4, R5, R~, and/or R'=nitro, can also bereduced to form compounds of formula l-A, wherein R4, R5, R~, and/or R'=amino, using re&_tiGn cor.~ o, ~s well known to those skilled in the art. These reactions can aiso be pe.f~,...~ on co,~,~ounds of formula l-B, wherein R~, R5, R~, and/or R7=nitro, and on 5 compounds of formula ll, wherein R4, R5, R~, andlor R7=nitro, to effect analogous l- ~nsft,,..,&li~r,s. Thus, a compound of fommula l-A v.~ i" R4, R5, R~, and/or R'=nitro can be combined with a reducing agent in a sotvent such as water, ...t~ti,&nol, ethanol, butanol, iso~ropanol, acetone, ether, di~ane, chloro~---" methylene chloride, tetrahydrofuran, dimethoxyethane, dimethylsuHoxide, dimethylf-,,-,~nide, or a mixture 10 of two or more of the foregoing soh~ents. Exarnples of reducing agents are iron powder, zinc, tin, hyJlu~en chloli~e, acetic acid, formic acid, sulfuric acid, catalytic hydrogenation, titanium l.ichlc,ide, sodium sulfide, ~,n,onP~rn sulfide, polysl~lfides, sodium dihydro(trithio)borate, sodium borohydride with nickel chloride or cobaltchloride, or h~Jli~i"e with a catalyst (e.g. palladium on carbon). The mixture can be 15 stirred at a te,.,~a.ature bet~,veen 0~ and 200~C, for a time period of from about one half to about 72 hours. When the ~ ~lion is complete, the compounds of formula l-A
can be isol-led via methods well known to those skilled in the art.
Reaction schemes 3 and 4 illustrate the pr~dtiGn of intei..,e~iales of the pr~sen~ invention.
Scheme 3 ~ c . ~,li i: "

I I I I ~/

With reference to reaction Scheme 3, the compounds of forrnula ll', wherein R~, R5, R6, and/or R7=hydrogen, can aiso be alkylated, acylated, or suKonylated to form 30 compounds of formula ll'', wherein R4, R5, R6, and/or R'=(C1-C5) alkyl, (C,-C6) aikylcarbonyl, or SO2NR8Rl2 (of which the compounds of formula V are an example), using reaction conditions well known to those skilled in the art. Thus, to a suspension of a Lewis acid such as aiuminum chloride, boron trifluoride, zinc chloride, gailium chloride, ferric cl-lGride, or tin chl~ride, in a solvent such as carbon disuHide, acetone, ether, chlorofc n " " methylene chloride, dioxane, tetrahydrofuran, dimethoxyethane, nitrobenzene, acetic acid, or a mixture of two or more of the foregoing solvents, was added an alkyl halide, such as ethyl chloride, an acyl ha~ide, such as acetyl chloride, 5 or a s~ stituted suHuryl halide, such as dimett,ytsuHamoyl chloride. This is f~ w2d by ~d~ition of a compound of formula 11~ wherein R~, Rs, R~, and/or R'=hyd~o~en. The 1.3&~iOIl can be stirred at a te",perdt.lre between 0~ and 250~C, for a period of time from about 2 to about 72 hours. When the reaction is complete, the compounds of forrnula 11'' can be isolated via methods well known to those skilled in the art. The 10 cG",pounds of formula 11' are generally commercially available or are known to those skilled in the art.

Scheme 4 Rio~' R10 ~ ' 2 ~'~ R R20 ~,I

~ OH
I l I VI I I

With reference to reaction Scheme 4, the compounds of formula lll, wherein R9=hyarogen, can be reacted to form compounds of formula Vlll, wherein R9=(C,-C~,) 10 alkyl (of which the compounds of formula Vll are an ex&n Ipl~, using l~;~atiGI) condHions well known to those skilled in the art. Thus, a co")pound of formula lll wherein R9 is H can be dissolved in a solvent such as ether, dioxane, tetrahydrofuran, dimethoxyethane, hexane, pentane, or a mixture of two or more of the foregoing solvents. The reaction mixture can be cooled to a temperature between -100~ and 15 20~C, and then a suitable organGr.,~:~llic r~ag~.lt can be add~d such as organomagnesium halide, organolithium, ~Iy~nocuprate, or~ano~i-,c, org~r-oti~n.um, organc,~i,conium, or oryanGr"anganese. Other addHives can also be ~~ ed. such ashexarnethylphosphoramide, N,N,N',N'-tetramethylenedi&"i"e, amino alcohol, titanium halide, zirconium halide, dibromoethane, iodine, or comb.. IsC~iGnS thereof. The re~- 1ion 20 can be stirred for a period of time of from about one half to about 150 hours, at a temperature between 0~C and 150~C. When the ~e~_1ion is w"~pl_le, compounds of formula Vlll can be isolated via methods well known to those skilled in the art. The compounds of formula lll are generally commercially available or known to those skilled in the art.
2~ The compounds of formula Vlll, wherein R9=(C,-C6) alkyl, can be oxidized to form compounds of formula lll, wherein R9=(C1-C5) alkyl, using reaction conditions well known to those skilled in the art. Thus, a compound of formula Vlll can be combined wTth a solvent such as water, acetone, acetic acid, trifluoroacetic acid, dimethylformamide, dimethylsulfoxide, ether, dioxane, tetrahydrofuran, 30 dimethoxyethane, hexane, pentane, pyridine, chloroform, methylene chloride, benzene, or a mixture of two or more of the foregoing solvents, and the mixture can be cooled to a temperature between -20~ and 15~C. An oxidizing reagent can then be added, such as acid dichromate, potassium permanganate, bromine, manganese dioxide, ruthenium tetroxide, Jones reagent (chro",ic acid and sulfuric acid in water), Collin's re~-~ent (dipyridine chron~ rn (\/I) oxide), pyridinium chlorochro",ate, pyridinium dichromate, sodium hypochlorite, dimethyl sulfoxide, t~ropyla"",onium perruthenate, ceric ammonium nitrate, silver carbonate, hydrogen peroxide, Fremy's 5 salt, m-chloroperbenzoic acid, aluminum t-butoxide, N-halosuccinimide, dicyclohexylcarbodiimide, or chromium trioxide. The mixture can then be r"3vIe~', to warm to about room temperature and then stirred for about one ha~f to about 150 hours. Additiona, additives can be utilized, such as heAn"~ ylphospl,or~"-d~, phase l.~,a~er catalysts, or tetrabutylammonium iodide. When the reaction is complete, the 10 compounds of the formula lll can be isol~ted via methods well known to those skilled in the art.
-~he preparation of other compounds of the present invention not specifica,ly described in the foregoing experimental section can be accomplished using co",~ lions of the reactions des~,ibed above that will be apparent to those skilled in 15 ~e art.
In each of the reactions riisc~issed or ill~,al,ated above, pressure is not critica, unless othelwise indicated. Pressures from about 0.5 allllospheres to about 5 allllOa~Jher~s are generally acceptable, and ambient pressure, i.e. about 1 atmosphere, is pr~e"e:d as a matter of conveniEnce.
20The novel compounds of the formula I and their ph&",~-ce~ti~ y .,coeyt~blc salts (herei~a~ler referred to, collectively, as the active compounds of the present invention~) are useful as selective inhibitors of phosphodiesterase type IV, i.e., they possess the ability to inhibit the effects of phosphodiesterase type IV in mammals, and therefore they are able to function as therapeutic agents in the treatment of the 25aforementioned disorders and diseases in an afflicted mammal.
Those-compounds of the present invention which are basic in nature (such as those compounds of formula 1, wherein R4, Rs, R6, andlor R7=NR~R'2) are capable of forming a wide variety of different salts with various inorganic and organic acids.
Although such salts must be pharmaceutically acceptable for administration to animals, 30it is often desirable in practice to initiaily isolate a compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid ..

-~- -addition salt. The acid c~ ol, salts of the basic compounds of this invention uereadily p-epared by treating the basic compound with a sul,st~ r,tially equivalent amount of the chosen mineral or organic acid in an A~lueous solvent medium or in a su;P~le organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, 5 the desired solid salt is readily obtained. Pl,a ,.,aeeutically-accept~le acid addition salts of the compounds ot this invention include, but are not limited to, those formed ~nth hy~ d ,' o . ic acid (HCI), hy~, uL, or, .. c acid (HBr), nHric acid (HNO3J, sulfuric acid (H2SO4), phosphoric acid (H3PO~), I"~ nesuHonic acid (CH3SO3H), toluenesuHonic acid (E~-CH3C~H4SO3H), acetic acid (CH3C02H), gluconic acid, tartaric acid, maleic acid and succinic acid. Those compounds of the present invention which are acidic in nature are ~pAhle of fo, ."i. ,~ a wide variety of Ji~rerlt salts with various inorganic and organic bases. Pharrnaceutically acceptable ca~i~n ~ salts of the compounds of this invention include, but are not limited to, those of sodium, ~otassium, calcium, magnesium, ammonium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanQlamine and diethanolamine.
The compounds of the prese"~ invention and their ph~l,,A~tic~''y aoc~ptable satts are believed to exhibit phospho~ er~se type IV r~eptor-binding activity and therefore are of value in the lle~l-ll~lll of a wide variety of ciinicaJ conditions the treatment of which are effected or f~c;~ by a decrease in phosphG~ se type IV me~ t~cl activ~ty. Such conditions indude AIDS, asthma, rheumatoid arthritis,osteoarthritis, bronchitis, chronic obstn~ctive airways ~lisePce, psoriasis, allergic rhinitis, atopic dermatitis, shock, and other inflammatory diseases. Hence, these compounds are readily adapted to therapeutic use as selective inhibitors of phosphodiesterase type IV for the control and/or treatment of any of the aforesaid clinical conditions in mammals, including humans.
The compounds of the present invention are readily adapted to clinical use as selective inhibitors of phosphodiesterase type IV. The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit phosphodiesterase type IV may be shown by the following Human Lung In vitro assay.
Thirty to forty grams of human lung tissue is placed in 50 ml of pH 7.4 Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenized using aTekmar Tissumizera (Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249) at full speed for 30 seconds. The homogenate is centrifuged at 48,000 x 9 for 70 minutes at -23~

4 ~ C. The supematant is filtered t~nce through a o.~ ,um filter and applied to a Mono-Q
FPLC column (Pharmacia LKB Biotechnology,800 Centennial Avenue, Piscal~v/ay, NewJersey 08854) pre-equilibrated wrth pH 7.4 Tris/PMSF buffer. A flow rate of 1 ml/minute is used to apply the sample to the column, followed by a 2 ml/minute flow rate for subse~ent v/--hi.,g and elution. Sarnple is eluted using an i.,cr~:asi"~, step-w~se sodium chloride gradient in the pH 7.4 Tris/PMSF buffer. Eight ml fractions are cc'lP l ~. Fractions are assayed for specific PDE IV activity, determined by [3H]cAMP
hydrolysis and the ability of a known PDE IV inhibrtor (e.g. rolipram) to inhibit that hydrolysis. Appropriate fractions are pooied, diluted with ethylene glycol (2 ml ethylene 10 glycol/5 ml of enzyme prep) and stored at -20~C until use.
Compounds are dissolved in dimethylsulfoxide (DMS0) at a conce~-,l-alion of 10 mM and diluted 1 :25 in water (400 ~M compound, 4% DMSO). Further serial dilutions are made in 4% DMS0 to achieve desired concentrations. Final DMS0 concentration in assay tube is 1%. In duplicate the foilowing are added, in order, to a 12 X 75 mm 15 glass tube (all concentrations are given as final concer,l,clions in assay tube).
i) 25 ~1 co~-,pound or DMSO (1%, for control and blank) ii) 25 ~I pH 7.5 Tris butfer iii) [3H]cAMP (1 ~M) iv) 25,ul PDE IV enzyme ffor blank, enzyme is preincubated in boiling water for 5 minutes) The reaction tubes are shaken and placed in a water bath (37~C) for 20 minutes, at which time the reaction is stopped by placing the tubes in a boiling water bath for 4 minutes. Wsshing buffer (0.5 ml, 0.1M 4-(2-t~ydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES)/0.1 M NaCI, pH 8.5) is added to each tube on an ice bath.
25 The contents of each tube are applied to an Affi-Gel 601 column (Biorad Laboratories, PØ Box 1229, 85A Marcus Drive, Melville, New York 11747) (boronate affinity gel, 1 ml bed volume) previously equilibrated with washing buffer. [3H]cAMP is washed with 2 x 6 ml washing buffer, and [3H]5'AMP is then eluted with 4 ml of 0.25M acetic acid.
After vortexing, 1 ml of the elution is added to 3 ml scintillation fluid in a suitable vial, 30 vortexed and counted for [3H].

% Inhibition = 1 - averaqe cpm (test compound~ - averaqe cpm lblank) average cpm ~control) - average cpm (blank) IC50 is defined as that concent,alion of compound which inhibits 50% of spe~i~c hydrolysis of [3H]cAMP to [3H]5'AMP.
For treatment of the various conditions described above, the compounds of the invention and their pl)&lllAceutic~lly ac ept~ble salts can be admin;~l~r~d to the patient 5 either alone or, preferably, in CG~ naliGn with ph~,-,~ce~ttic~lly acf~t~ble carriers or diluents in a pharmaceutical composition according to st~nd~r~ ph~ ~"~ceuticAI
pra~lice. Such ~..ini~hc,liGn may be carried out in single or muitiple doses. A
compound can be admini~ered via a variety of conve~,liGnal routes of admi"i~dtion including orally, I~&reoterally, by inhalation, and topically. 'When the compounds are 10 administered orally, the dose range will generally be from about 0.1 to about 500 mg/day for an average adult patient pO kg), preferably from about 7 to about 70 mg/day in single or divided doses. If p~",ler~l admini;,ll~tion is desired, then an effective dose will generally be from about 0.1 to about 70 mg/day. For illllanasal or inhaler ad~"iui~l~alion~ the dosage will generally be formulated as a 0.1 to 1% (wh) 15 solution. In some instances it may be necessAry to use dosnges outside these limits, since the rlos~ge will necessP..il~ vary according to the sp~:!es, age, weight, and response of the individual patient, severity of the patient's sy",~tc,i"s, potency of the particuiar compound being ad",inialered, type of pharm~rtic~l forrnulation chosen, and time period and interval at which administration is carried out.
The co" "~ounds of the invention and their pha " ,~-ceutically acc~ptable salts can be administered in a wide variety of di~erent dosage forrns, such as in the form of tablets, powders, lozenges, troches, hard candies, sprays, crearns, salves, suppositories, jellies, gels, pastes, lotions, ointments, syrups or capsules, aqueous solutions or suspensions, injectable solutions, elixirs, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, ~ic~lcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably com, potato or tapioca starch), alginic acid and certain complex si~iC~te togetherwith granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia.

Additionally, luL,i~til ,9 agents such as magnesium stearate, sodium lauryl sulfate ~md taic are often very useful for tabietting purposes. Solid compoaitiG"s of a similar type may also be employed as fillers in gelatin c~rs~'ss; i~ref~"dd materials in thiscGrl~ iGn also include lactose or milk sugar as well as high m~lecu'-- weight 5 polyethylene glycols. When aqueous susi~aer)sions and/or elixirs are desired for oral a~ i"6balion~ the active ingredient may be combined with various sweetening or flavoring agents, colc.i"g matter or dyes, and, if so desired, emulsHying and/orsuspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like co~ ations thereof.
For par~nte,~1 administration (intrarnuscular, intraperitoneal, subcutaneous andintravenous use) a sterile injectable solution of the active ingredient is usually prepared.
Solutions of a ~~,erapeutic compound of the preser,~ invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutionsshould be suitably adjusted and buffered (preferably pH greater than 8) H necess~y and t'ne liquid diluent first rendered isotonic. These aqueous solutions are suitable intravenous injection purposes. The oily solutions are suitable for intraarticular.
intramusc~ r and subcutaneous injection purposes. The pr~p&ra-i~n of all these solutions under sterile conditions is readily acco"~plished by ~t~ndard pharmaceuticai techniques well known to those skilled in the art.
Additionaily, it is aiso possible to administer the compounds of the present invention topically and this may preferably be done by way of creams, jellies, gels, pastes, oi,lt",ents and the like, in accordance with standard pharmaceuticai practice.
The present invention is illustrated by the following i-xamples and Preparations.
It will be understood, however, that the invention is not limited to the specific details of these Examples and Preparations. All meiting points are uncorrected. In the procedures and tables that follow, Ustchm' means stereochemistry, 'Ex.~ means Example, ~mp(~C)~ means melting point in degrees Celcius, 'MF~ means molecular formula, ~Anai.~ means elementai anaiysis, ~Caic~ means caiculated, ~m/z' means mass to charge ratio, 'H~ means hydrogen, ~C" means carbon, ~0' means oxygen, ~Me"
means methyl, ~Et~ means ethyl, ~Br" means bromine, and ~CI' means chlonne.

EXAMPLES
E'XAMPLES 1 AND 2 3-~i'3-(Bicycloi'2.2.1 lhePt-2-vloxv)~methoxvPhenvllmethylenel-5-chloro-1 ,3-dihvdro-1 rnethyl-~1o,2afZ~,4al-2H-indol-2-one (ExarnPle 1) and 3-ri~3-(BiCYClor2.2.
5 hePt-2-v~oxv)~"~U ,oxvphenvllmethylenel-~chloro-1 ,3-dihvdro-1 -methvl-i'1 a.2a(E).4OI-2H-indol-2-one (Example 2) 3-(~-Bicyclo ~2.2.1] hept-2-yloxy)~methoxybenzaldehyde (677 mg, 2.75 mmol; disclosed in WO 87/06576 pui-l ~hed November 5, 1987), and 5-chloro-1-methyloxindole (500 mg, 2.75 mmol; Chemical Abstracts registry number 41192-3~0,10 were dissolved in 10 ml of methanol under an inert al-"osphere. To this brown, homogeneous mixture w~ added 0.23 ml of pyrrolidine (2.75 mmol) via syringe. Thereaction mixture was stirred at room temperature for ten hours. The solvent w~ then stripped off and the resuiting yellow oil was purified via flash chr~r"atography (1:1 ethyl ether/hexane) to provide the desired Z-adduct 3-[[3-(bicyclo[2.2.1]hept-2-yloxy)~
15 methoxyphenyi]methylen~-5-chloro-1,3-dihydro-1-methyl-[1O,2O(Z),4O]-2H-indol-2-one (125 mg, 11% yield) as a yellow solid (i:xample 1): m.p. 149-151 ~. Analysis ~-'cvlatPd for C24H24CINO3: C, 70.32; H, 5.gO; N, 3.42. Found: C, 70.26; H, 5.87; N, 3.38. The CGI ,esponding E-adduct ~[[3-(bicycio[2.2. 1 ]hept-2-yioxy)~methoxyphenyl~-methylene3-~chloro-1,3-dihydro-1-methyl-[1O,2O(E),4a~-2H-indol-2-one (txample 2)20 w~ also obtained in 6~~ yield, m.p. 142-144~C. Analysis c~'c~ ted for C24H24CINO3:
C, 70.32; H, 5.90; N, 3.42. Found: C, 70.34; H, 5.85; N, 3.36.

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~0 ~0 3-r~3-~Bicvclo~2.2.11hePt-2-yloxy~methoxvphenvllmethvlenel-5-bromo-1,3-dihydro-1 -methyl-~1 o.2O(E).4O1-2H-indol-2-one (ExamPle 46) and 3-~3-(Bicyclo~2.2.11hePt-2-vloxv)~-methoxvphenvllmethvlenel-5-bromo-1,3-dihydro-1 -methyl-~1 o,2a(Z~,4~1-2H-indol-2-one (Example 47~
3-[[3-(Bicyclo[2.2.1]hept-2-yloxy) ~ methoxyphenyl]methylene]-5-bromo-1.3-15 dihydro-[1a,2O(Z),4O]-2H-indol-2~ne (Ex. 16) (374 mg, 0.85 mmol) and ,t~otassium carbonate (177 mg, 1.28 mmol) were co,l,tn.~ed in 10 ml of acetone under an inert all.~osphere. To this orange, h~ u~eneous mixture, was added 0.08 ml of methyl iodide (1.28 mmol) via syringe. The ~a.,tion was heated to 65~ for 16 hours. Thepotassium carbonate was filtered off and washed well with CH2CI2. The solvent was 20 removed by rotary evaporation to yield a yellow oil which was purified via flash chromatography (1:1 Et20/hexane) to provide the desired methylated E isomer (89 mg, 23% yield) as a yellow, fluffy solid: mp 133-135~ (Example 46). Analysis calculated for C24H249rNO3: C, 63.44; H, 5.32; N, 3.08. Found: C, 63.45, H, 5.22; N, 3.02. The corresponding Z adduct 3-[[3-(bicyclo[2.2.1]hept-2-yloxy)4-25 methoxyphenyl]methylene]-5-bromo-1,3~ihydro-1 rnethyl-[1a,2a(Z),4a]-2H-indol-2-one was also obtained in 32% yield (124 mg) as a yellow solid (Example 47): mp 157-158~. Analysis calculated for C24H24BrN03: C, 63.44; H, 5.32; N, 3.08. Found: C,63.22; H, 5.23; N, 3.08.

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._ Z I I I I I ~ ~ _ Z ~ ~ 0 E--,x, O _ c~ c c u~ o 3-[~3-(Bicyclo[2.2.1]hept-2-yloxy)-4 methoxyphenyl]-methyl]-1,3-dihydro-2H-indol-2-one 3-[[3-Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]-methylene]-1,3-dlhydro-[la, 2a(E), 4a]-2H-lndol-2-one (Example 3,500 mg, 1.38 mmol) was dlssolved ln 50 ml of ethyl acetate and 25 ml of tetrahydrofuran, placed ln a Parr shaker wlth 180 mg of 10% palladium on carbon and shaken for 2 hours at 50 psl H2. After fllterlng the reaction mlxture through Cellte~, the solvent was strlpped off and the resultlng clear oll was recrystalllzed with 1:2 Et2O/hexane to provlde the tltle compound (447 mg, 89% yleld) as a flne whlte powder: mp 157-158~. Analysls calculated for C23H25NO3 1/4 H2O : C 75.08;
H 6.99; N 3.81. Found: C 75.25; H 6.85; N 3.85. M/z calculated for C23H25NO3: 363.1834. Found 363.18699.

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ExamPle 59 8 60 3-~Bicyclo~2.2.1lhePt-2-vloxy)4 rnethoxyphenvllmethylenel2~3-dihydro-2 ~10,20(E),401-1H-indol-1 carboxvlic acid, ethyl ester (ExarnPle 59~ and ~r~3-Bicyc10~2.2.1 lllePt-2-vloxY)-4-methoxvPhenYllmethvlenel2~3-dihvdro-2 5 ~1a.2a(Z~.4al-1 H-indol-1 carboxvlic acid. ethyl ester (ExamPle 60) The title cor"~ound of Example 3 (1 .0 9, 2.77 mmol), ethyl chlorufo, "~ate (10.0 ml), and pot.,ssium carbonate (770 mg, 5.6 mmol) were combined under an inert atmosphere. The reaction mixture was stirred at room t~:~"per~ture ovemight and then at 100~C for 6 hours. The solvent was then stripped off and the resulting ye~low oil 10 was purified via flash chromatography (1:1 ethyl ether/hexsne) to provide the E isomer (82.6 mg, 7% yield) as bright yellow crystals (Example 59): m.p. 123-124~C. Analysis cAIcl~lsted for C2~H27NO5C, 72.04; H, 6.28; N, 3.23. Found: C, 71.99; H, 6.20; N, 3.22. The corresponding Z isomer (Example 60) was also obtained in 16% yield:
m.p. 6~iooc. An~ysis calculated for C2~,H27NO5: C, 72.04; H, 6.28; N, 3.23. Found:
15 C, 72.14; H, 6.09; N, 3.18.
Example 61 3-~3-(Bicyc10~2.2. 1 lhePt-2-vloxv) 1 methoxvphenvllmethylenel-~acetoxv-1,~
dihydro-~1 o,2~.(Z),401-2H-indol-2-one The title compound of Example 10 (1.0 9, 2.65 mmol) was combined with 10 20 ml of 2N NaOH solution and heated to 55~C. To this darlc red, heterog~,eous mixture was added 0.25 ml of acetic anhydride (2.65 mmol) via syringe. The reaction mixture was stirred at 55 ~ C for 1 hour. The reaction mixture was then taken up in 200 ml H20, adiusted to pH 7.5 with 1N HCI, extracted with 3 x 150 ml ethyl ether, dried over MgSO~, filtered, and the solvént stripped off. The resulting yellow-orange oil was 25 purified via flash chromatography (1:1 ethyl ether/hexane) to provide the title compound (57.8 mg, 5% yieldJ as a yellow-orange powder: m.p. 192-194~C. Mlz calculated for C2sH2cNOc: 419.1733. Found: 419.1731.

ExamPle 62 8 63 3-~3-(BicYclo~2.2~11hePt-2-vloxy~methoxyphenyllmethylenel-~cvclopentyl-1 .3-dihvdro-~10.2~.(E).401-2H-indol-2-one(Example62)and3-rf3-(7cvclo~2.2.11hePt-2-yloxv~ 1 methoxvphenyllmethylenel-5~clopertvl-1,3-dihvdro-~10,20,(Z),4al-2H-indol-2-6 one (ExamPle 63) The We compound of Example 10 (1.0 g 2.65 mmol) was dissolved in 25 ml of DMF (dimethylf~,""ainide) under an inert al."osphe~: and cooled to 0~C. To this bright orange ho" ,ogeneous solution was added NaH (60% dispersion in oil 225 mg5.63 mmol) in one portion. The reaction mixture was stirred for 1 hour at 0~C and 10 cyclopentyl chloride (0.3 ml 2.88 mmol) was then added via syringe. The reaction mixture was then stirred at room temperature for 10 hours. The solvent was removed by Kugelrohr .lialillalion and the black residue was taken up in 500 ml of ethyl ether.
The resulting solution was washed twice with 300 ml H2O and once wrth 300 ml saturated brine solution and then dried over MgS04. The solution was then filtered 15 and the solvent was stripped off. The resulting purple oil was purified via flash chromatography (1:1 ethyl ether/hexane) to provide the E isomer (53 mg, 5~~ yield) as a bright red powder (Example 62): m.p. 186187~C. Analysis calculated for C28H3,NO4-'~2H20: 73.98; H 7.10; N, 3.08. Found: C 74.26; H 6.9~; N, 3.06. Mlz calcul~te~ for C28H3l N04: 445.2253. Found: 445.2258. The corresponding Z isomer20 (Example 63) was also obtained in 1 1% yield: m.p. 190 191 ~C. Analysis c~ic~ ted for C28H3lN0,: C 75.48; H 7.01; N 3.14. Found: C 75.39; H 7.16; N 2.97. M/z calculAted for C2llH3lNO~: 445~2253. Found: 445.2229.
Examples 64 & 65 3-~3-Bicyclo ~2 .2.1 lhePt-2-vloxv) 4 methoxyphen~llmethvlenel-~cyclopentvl-1 3-25 dihydro-1-ethvl-~1a2a(E~4al-2H-indol-2-one (ExamPle 64l and 3-~3-Bicyclo~2.2.11hept-2-yloxv)~methoxvphenyllmethYlenel-5-cYcloPentvl-1 .3-dihvdro-1 -ethvl-~1 o,20(Z~,401-2H-indol-2-one (ExamPle 65~
The title compound of Example 11 (1.06 9 2.61 mmol) cyclopentanol (0.31 ml 3.42 mmol) and triphenylphosphine (1.028 g 3.92 mmol) were combined in 60 ml 30 of tetrahydrofuran under an inert atmosphere. To this dark red homogeneous solution was added 0.62 ml of diethylazodicarboxylate (3.94 mmol) via syringe. The reaction mixture was stirred at room temperature for 72 hours. The solvent was then stripped off and the resuiting orange oil was purified via flash chromatography (1:1 ethyl ether/hexane) to provide the E isomer (200 mg, 16% yield) as an orange foam (Exarnple 64). Analysis calculated for C30H35NO4: C, 76.08; H, 7.45; N, 2.96. Found:
C, 76.32; H, 7.39; N, 2.90. The corresponding Z isomer (Example 65) was also obtained in 66% yield (821 mg) as an orange foam. Analysis calculated for 5 C30H35NO4: C, 76.08; H, 7.45; N, 2.96. Found: C, 76.07; H, 7.~0; N, 3.00.
ExamPle 66 3-~3-(Bicvc10~2.2.1 lhePt-2-vloxY)~methoxyphenvllmethvlenQl~romo-2~3 dihvdro-2-oxo-~1a,20(E),4al-1H-indole-1~cetic acid, ethvl ester The title compound of Example 16 (287 mg, 0.65 mmol) and ethyl 10 chloro~cet~te (0.07 ml, 0.77 mmol) were dissolved in 30 ml of DMF
(dimethylf~,."&"ide) under an inert al"~osphere. The reaction mixture was cooled to 0~C whereupon 31.1 mg of NaH (60% dispersion in oil, ~78 mmol) W8S added. The reaction mixture was stirred at 0~C for 20 minutes and then ~'~weJ to warm to room temperature. The reaction mixture was poured in 100 ml of H20, extracted with three - 15 100 ml portions of ethyl ether, dried ~ver MgSO., filtered, and the solvent :,tlipped off.
The remaining DM~ was removed via Kugelrohr distillation and the resulting oil was purified via flash chrot~aloy,aphy (1 :1 ethyl etherlhexane) to provide the title compound (40 mg, 12% yield) as a yellow solid: m.p. 141-143~C.

rcllDw;. ,g the method of Example 66, the following products were prepared by reacting ethyl chloroacetate with the appropriate oxindole in place of the titlecompound of Example 16. The starting material oxindole is known in the literature.
The wavy lines indicate that these compounds can exist as either the E or Z
stereoisomers, as indicated below.
H H
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e r~ ~ / N ~ , C O O E t ~1 0 Ex. Stchm. mD (C~) MF for Anal. C H N
Analvsis 67 E 143 144 C2lH2,NO5 Calc: 68.65 5.76 3.81 Found: 68.21 5.59 3.98 68 Z 14~149 C2,H2,NO5 Calc: 68.65 5.76 3.81 Found: 68.57 5.64 3.83 ExamPle 69 3-r~3-(Bicyclo~2.2.11hept-2-yloxy~ 4 ",ethGx~phenvl1methylene1-~amino-1,3-dihvdro-1 -methvl-~1 O,2O(Z),4O1-2H-indol-2-one The title compound of Exarnple 49 (446 mg,1.06 mmol) and iron powder (355 mg, 6.36 mmol) were combined in 9 ml of 1:1 ethanol/water and heated to 96~C
10 under an inert atmosphere. To this yellow, heter~geneous mixture was added 0.03 ml of t2N HCI in 0.29 ml ethanol via syringe. The reaction mixture was stirred at 100~C for 1 hour, whereupon 1N NaOH solution was added until the pH was equal to 8. The iron was filtered off through a pad of diatomaceous earth (CEUTE~). The pad was washed with water and then with ethyl ~cet~te The two layers were then 15 separated, the organic layer was washed with 100 ml of saturated brine solution, dried over MgSO., fiitered, and stripped to a red oil. This crude oil was purffied via flash chromatography (ethyl ether) to provide the title compound (151 mg, 36% yield) as a red powder: m.p. 170-172~C. M/z c~'c~ ted for C24H2~,N2O: 390.1943. Found:
390.18906.
PREPARATIONS
PREPARATION A
N-methvl-5-methoxyoxindole 5-methoxy oxindole (450 mg, 2.76 mmol) and potassium carbonate (585 mg, 4.23 mmol) were combined in 45 ml of acetone under an inert atmosphere. To this white, heterogenous mixture was added 0.33 ml of methyl iodide (5.30 mmol~ via syringe. The reaction mixture was stirred at room temperature for 10 hours and then at 75~C for 3 hours. Additional potassium carbonate and methyl iodide were added(2g0 mg and 0.11 ml, respectively), and the reaction mixture was stirred at 75~C for 6 more hours. The reaction mixture was then poured into 300 ml of saturated brine 30 solution and extracted with 3 x 200 ml ether. The combined organic layers were dried over MgSO8, filtered, and stripped to a yellow oil. This was purified via flash chromdtGy, ~ y (3:1 ethyl ether/hexane) to provide the fflle CGII ,pound (307 mg, 63%
yield) as white crystals: m.p. 9~94~C. M/z calculated for CloHllNO2: 177.0790, Found: 177.08066.

~ O ~ o ~ O
c o c~ ~ 2 ~
E ~
E O o T ~L T =--~ Zl r~ U~
.~ ~D

Tl N ~O

-c O

~~ ~ Z
O~ \ /
T

L.O ~D Z
E
_ ~ O a-_ O

Qo ~ E a~ --_ o ~D o I

-- o O o ,.
o a:l ~ I O
.~
Q ~ m o U~ O
N

~6-PREPARATION D
~(N ,N-dimethylsuHonamidvl)oxindole To a suspension of AIC13 (108 9, 0.81 mol) in CS2 ~370 ml) was added dimethylsulfamoyl chloride (17.2 ml, 0.16 mol), f~ll3wod by oxindole (17.6 9, 0.132 5 mol, ALDRICH). The reaction mixture was heated to reflux for 4.5 hours. The CS2 solution was decanted off, leaving a gummy solid. The solid was s~r~?~d into crushed ice and stirred for 30 minutes. The solid was filtered to yield the title compound (9.3 9, 39% yield) as a tan solid: m.p. 208-215~C.
PREPARATION E
1 0 ~Methoxy-3-(~phenvlbutyroxv)benzaldehyde ~ ollo~ving the method of Exarnple 64, the title compound was prepared from3-hydroxy~methoxybenzaldehyde (ALDRICH) and 4-phenyl-1-butanol (Aldrich). M/z c~culated for C,8H20O3: 284.1412. Found: 234.1435.-PREPARATION F
2-(3-~3-fBicvclo~2.2.11hept-2-yloxv)1~methoxvphenv1)-2-hvdroxvethane 3-(~-Bicycio ~2.2.1] hept-2-yloxy)~methoxybenzaldehyde (as rIisclQsed in 6 published November 5,1987) (7.0 g, 28.4 mmol) was d;ssolved in 100 ml of tetrahydrofuran under an inert atmosphere and cooled to 0~C, whereupon 10.42 ml of 3.0M methyl magnesium bromide in ethyl ether was added via syringe. The 20 reaction mixture was stirred at 0~C for 1 hour and then at room temperature for 1 hour. The reaction mixture was slowly poured into a mixture of 500 ml of saturated brine solution and 500 ml of ethyl ether. The layers were separated and the aqueous layer was extracted with two 300 ml portions of ethyl ether. 'The combined organic layers were dried over MgSO4, filtered and stripped to a yellow oil. This was purified 25 by flash chromatography (2:1 hexane/ethyl ether) to provide the title compound (4.98 9, 67% yield) as a yellow solid: m.p. 60-61.5~C. Analysis calculated for C,6H22O3:
C, 73.25; H, 8.45. Found: C,73.54; H,8.59. M/z calculated for C,6H22O3: 262.1569.
Found: 262.1564.
PREPARATION G
Aceto-(3-~3-bicvclo~2.2.11hept-2-yloxy~l~methoxv~phenone The title compound of Prepa;ration F (4.98 9,19 mmol) and 27 ml of H2O were combined and cooled to 0~C. To this yellow suspension was added 2.17 ml of concentrated su~furic acid. Acetone (103 ml~ was then added and the reaction mixture ~7-was s~irred at 0~C until the mixture became homogeneous. Finally, 27.1 ml of Jones reagent was added rapidly by syringe, whereupon the reaction mixture was stirred at 0~ C for 15 minutes and room temperature for 1 hour. The reaction mixture was then slowly poured into 500 ml saturated bicarbonate solution and stirred for 15 minutes 5 at room ter"perature. This mixture was e~ 1ed with three 300 ml po, I;GI IS of ethyl ether and once with 300 ml CH2C12. The cG,.,Lined organic layers were dried overMgSO,, filtered, and stripped to a yellow oil. This crude material was recrystallized in 150 ml warm hexane to yield the title compound (4.19 9, 85% yield) as light brown crystals: m.p. 9~97~C. Analysis c~lcLIl~tPd for C,~,H20O3: C, 73.82; H, 7.74. Found:
10 C, 73.73; H, 7.65. M/z calculated for Cl~,H20O3: 260.1412. Found: 260.1404.

Claims (8)

1. A compound of the formula:

, VI

wherein R9 is hydrogen or (C1-C6)alkyl.

2. The compound 4-methoxy-3-(4-phenylbutyroxy) benzaldehyde.

3. A compound of the formula:

, VII

wherein R9 is hydrogen or (C1-C6)alkyl, R15 is oxygen or hydroxyl, and the broken line represents a double bond when R15 is oxygen.

4. The compound 2-(3-[3-(bicyclo[2.2.1]hept-2-yloxy)]-4-methoxyphenyl)-2-hydroxyethane.

5. The compound aceto-(3-[3-bicyclo[2.2.1]hept-2-yloxy]-4-methoxy)phenone.

6. A process for the preparation of a compound of the formula VI of claim 1 or the formula VII of claim 3, wherein R9 is (C1-C6)alkyl, and R15 is oxygen, which comprises oxidation of a compound of the formula:

XIII

(whereln R1 is methyl, R2 is phenyl-(C1-C6)alkyl, or 3-[3-bicyclo[2.2.1]hept-2-yloxy]-4-methyl) and R9 is (C1-C6)alkyl) with an oxidizing agent.

7. The process of claim 6, wherein the oxidation is carried out with an oxidizing agent selected from the group consisting of acid dichromate, potassium permanganate, bromine, manganese dioxide, ruthenium tetraoxide, Jone's reagent, Collin's reagent, pyridinium chlorochromate, pyridinium dichromate, sodium hypochlorite, dimethyl sulfoxide, tetrapropylammonium perruthenate, ceric ammonium nitrate, silver carbonate, hydrogen peroxide, Fremy's salt, m-chloroperbenzoic acid, aluminum t-butoxide, N-halosuccinamide, and chromium trioxide.

8. A process for the preparation of a compound of the formula VII of claim 3, wherein R15 is hydroxyl, and R9 is (C1-C6)-alkyl, which comprises reacting a compound of the formula:
III' wherein R1 is methyl, and R2 is (3-[3-bicyclo[2.2.1]hept-2-yloxy]-4-methyl), with an organometallic reagent selected from the group consisting of an organomagnesium halide, organolithium, organocuprate, organozinc, organotitanium, organozirconium, and organomanganese reagent.