Therapeutic amides

Amides having formula I: ##STR1## wherein E, X, R.sup.2 and R.sup.3 have the meanings given in the specification, and pharmaceutically acceptable salts and pharmaceutically acceptable in vivo hydrolysable esters thereof, which are useful in the treatment of urinary incontinence. Further provided are processes for preparing the amides and pharmaceutical compositions containing them.

This invention relates to compounds useful as cell potassium channel 
openers in mammals such as man. More specifically, the invention relates 
to certain substituted amides which are useful in the treatment of urinary 
incontinence in mammals. Because compounds according to the invention 
function to open cell potassium channels, they may also be useful as 
therapeutic agents in the treatment of conditions or diseases in which the 
action of a therapeutic agent which opens potassium channels is desired or 
is known to provide amelioration. Such conditions or diseases include 
hypertension, asthma, peripheral vascular disease, right heart failure, 
congestive heart failure, angina, ischemic heart disease, cerebrovascular 
disease, renal cholic, disorders associated with kidney stones, irritable 
bowel syndrome, male pattern baldness, premature labor, impotence, and 
peptic ulcers. 
Treatment using a compound of the invention can be remedial or therapeutic 
as by administering a compound following the onset or development of 
urinary incontinence in a patient. Treatment can also be prophylactic or 
prospective by administering a compound in anticipation that urinary 
incontinence may develop, for example in a patient who has suffered from 
incontinence in the past. 
It is known that bladder tissue is excitable and that urinary incontinence 
can be caused by uncontrolled or unstable bladder contractions. It is 
further known that by functioning to open potassium channels, potassium 
channel opening compounds can thereby function to relax smooth muscle. 
While not wishing to be bound by theory, it is accordingly believed that 
the compounds of this invention function by opening potassium channels in 
bladder cells and thereby relax bladder smooth muscle tissue, thus 
preventing or ameliorating uncontrolled bladder contractions which can 
cause urinary incontinence. 
This invention provides an amide having formula I (formula set out, 
together with other formulae referred to in the specification by Roman 
numerals, on pages following the Examples), wherein: 
E is selected from nitrogen and CZ wherein C is a ring carbon and Z is a 
substituent defined below, wherein: 
when E is CZ, X and Z are selected from the group consisting of: 
(A) X is ArY wherein Y is a linking group selected from carbonyl, sulfinyl, 
and sulfonyl and Ar is selected from the group consisting of: 
phenyl substituted with 0-2 substituents selected from halo, hydroxy, 
cyano, (1-4C)alkyl, and (1-4C)alkoxy, provided that the 4-position of said 
phenyl may be substituted by fluoro only, and that the said phenyl may not 
be 3,5-disubstituted; 
six-membered heteroaryl rings containing 1-2 nitrogen atoms as the only 
heteroatoms; 
five-membered heteroaryl rings containing from 1-2 heteroatoms selected 
from nitrogen, oxygen, and sulfur; provided that Ar is not 3-chlorophenyl, 
3-bromophenyl, 3-iodophenyl, 3-(1-4C)alkylphenyl, or 4-pyridyl when Y is 
carbonyl, and that Ar is not 5-pyrimidinyl when Y is sulfonyl or carbonyl; 
and 
Z is selected from hydrogen, cyano, halo, hydroxy, (1-4C)alkyl, and 
(1-4C)alkoxy; 
(B) X is cyano and Z is selected from the group consisting of phenylthio, 
phenylsulfinyl, and phenylsulfonyl the phenyl rings of which are 
substituted with 0-2 substituents selected from halo, hydroxy, cyano, 
nitro, (1-4C)alkyl, and (1-4C)alkoxy; 
when E is nitrogen, X is independently selected from any of the values for 
X given above in (A); 
R.sup.2 and R.sup.3 
are independently selected from the group consisting of (1-3C)alkyl 
substituted by from 0 to 2k+l groups selected from fluoro and chloro 
wherein k is the number of carbon atoms in the said (1-3C)alkyl, provided 
that R.sup.2 and R.sup.3 are not both methyl; or 
together, with the carbon atom to which both R.sup.2 and R.sup.3 are 
attached, form a 3-5 membered cycloalkyl ring optionally substituted by 
from 0 to 2m-2 fluoro groups wherein m is the number of carbon atoms in 
said ring; and pharmaceutically acceptable in vivo hydrolyzable esters of 
said amide; 
and pharmaceutically acceptable salts of said amides and said esters. 
The invention further provides a method for the treatment of urinary 
incontinence, comprising administering to a mammal (including man) in need 
of such treatment an effective amount of an amide of formula I as defined 
above, or a pharmaceutically acceptable in vivo hydrolyzable ester or 
pharmaceutically acceptable salt thereof. 
The invention further provides a pharmaceutical composition suitable for 
the treatment of urinary incontinence comprising an amide of formula I as 
defined above, or a pharmaceutically acceptable in vivo hydrolyzable ester 
or pharmaceutically acceptable salt thereof, and a pharmaceutically 
acceptable diluent or carrier. 
In this specification the terms "alkyl" and "alkoxy" include both straight 
and branched chain radicals, but it is to be understood that references to 
individual radicals such as "propyl" or "propoxy" embrace only the 
straight chain ("normal") radical, branched chain isomers such as 
"isopropyl" or "isopropoxy" being referred to specifically. 
The term "halo" is inclusive of fluoro, chloro, bromo, and iodo unless 
noted otherwise. 
It will be appreciated by those skilled in the art that certain compounds 
of formula I contain an asymmetrically substituted carbon and/or sulfur 
atom, and accordingly may exist in, and be isolated in, optically-active 
and racemic forms. Some compounds may exhibit polymorphism. It is to be 
understood that the present invention encompasses any racemic, 
optically-active, polymorphic or stereoisomeric form, or mixtures thereof, 
which form possesses properties useful in the treatment of urinary 
incontinence, it being well known in the art how to prepare 
optically-active forms (for example, by resolution of the racemic form by 
recrystallization techniques, by synthesis from optically-active starting 
materials, by chiral synthesis, or by chromatographic separation using a 
chiral stationary phase) and how to determine efficacy for the treatment 
of urinary incontinence by the standard tests described hereinafter. 
Particular values of Ar as phenyl substituted with 0-2 substitutents 
include phenyl, 2- and 3-halophenyl, 4-fluorophenyl, 2-, and 
3-hydroxyphenyl, 2-, and 3-cyanophenyl, 2- and 3-methylphenyl, 2- and 
3-ethylphenyl, 2- and 3-propylphenyl, 2- and 3-methoxyphenyl, 2- and 
3-ethoxyphenyl, 2- and 3-propoxyphenyl, 2,5-difluorophenyl, and 
2,3-difluorophenyl. 
Particular values of Ar as a six-membered heteroaryl ring containing 1-2 
nitrogen atoms include 2, 3-, and 4-pyridyl, 2-pyrazinyl, 2- and 
4-pyrimidinyl, and 3- and 4-pyridazinyl. 
Particular values of Ar as a five-membered heteroaryl ring containing from 
1-2 heteroatoms selected from nitrogen, oxygen, and sulfur include 3-, 4- 
and 5-isothiazolyl, 2-, 4- and 5-oxazolyl, 2-, 4- and 5-thiazolyl, 2- and 
3-furyl, and 2- and 3-thienyl. 
Particular values of Z as (1-4C)alkyl include methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. 
Particular values of Z as (1-4C)alkoxy include methoxy, ethoxy, propoxy, 
isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. 
Particular values of Z as phenylthio substituted with from 0-2 
substitutents include phenylthio, 2-, 3-, and 4-halophenylthio, 2-, 3-, 
and 4-hydroxyphenylthio, 2-, 3-, and 4-cyanophenylthio, 2-, 3-, and 
4-methylphenylthio, 2-, 3-, and 4-ethylphenylthio, 2-, 3-, and 
4-propylphenylthio, 2-, 3-, and 4-methoxyphenylthio, 2-, 3-, and 
4-ethoxyphenylthio, 2-, 3-, and 4-propoxyphenylthio, 
2,4-difluorophenylthio, and 2,3-difluorophenylthio. 
Particular values of Z as phenylsulfinyl substituted with from 0-2 
substitutents include phenylsulfinyl, 2-, 3-, and 4-halophenylsulfinyl, 
2-, 3-, and 4-hydroxyphenylsulfinyl, 2-, 3-, and 4-cyanophenylsulfinyl, 
2-, 3-, and 4-methylphenylsulfinyl, 2-, 3-, and 4-ethylphenylsulfinyl, 2-, 
3-, and 4-propylphenylsulfinyl, 2-, 3-, and 4-methoxyphenylsulfinyl, 2-, 
3-, and 4-ethoxyphenylsulfinyl, 2-, 3-, and 4-propoxyphenylsulfinyl, 
2,4-difluorophenylsulfinyl, and 2,3-difluorophenylsulfinyl. 
Particular values of Z as phenylsulfonyl substituted with from 0-2 
substitutent include phenylsulfonyl, 2-, 3-, and 4-halophenylsulfonyl, 2-, 
3-, and 4-hydroxyphenylsulfonyl, 2-, 3-, and 4-cyanophenylsulfonyl, 2-, 
3-, and 4-methylphenylsulfonyl, 2-, 3-, and 4-ethylphenylsulfonyl, 2-, 3-, 
and 4-propylphenylsulfonyl, 2-, 3- and 4-methoxyphenylsulfonyl, 2-, 3-, 
and 4-ethoxyphenylsulfonyl, 2-, 3-, and 4-propoxyphenylsulfonyl, 
2,4-difluorophenylsulfonyl, and 2,3-difluorophenylsulfonyl. 
Particular values of R2 and R3 as (1-3C)alkyl substituted by from 0 to 2k+1 
groups selected from fluoro and chloro include methyl, ethyl, propyl, 
isopropyl, chloromethyl, dichloromethyl, chlorodifluoromethyl, 
trichloromethyl, 1-chloroethyl, 1,1-dichloroethyl, 2-chloroethyl, 
2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl, 
1,1,2-trichloroethyl, 1,2,2-trichloroethyl, 1,1,2,2-tetrachloroethyl, 
1,2,2,2-tetrachloroethyl, 1,1,2,2,2-pentachloroethyl, 1-chloropropyl, 
1,1-dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 
1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 
2,2,2-trifluoroethyl, 1,2-difluoroethyl, 1,1,2-trifluoroethyl, 
1,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,2,2,2-tetrafluoroethyl, 
1,1,2,2,2-pentafluoroethyl, 1-fluoropropyl, and 1,1-difluoropropyl. 
Particular values of 3-5 membered cycloalkyl rings substituted by from 0 to 
2m-2 fluoro groups, which can be formed by R2 and R3 together with the 
carbon atom to which R.sup.2 and R.sup.3 are attached, include 
cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorocyclopropyl, 
2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 
2,2,3-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 
2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,3-difluorocyclobutyl, 
2,4-difluorocyclobutyl, 2,2-difluorocyclobutyl, 2,3,4-trifluorocyclobutyl, 
2,3,3-trifluorocyclobutyl, 2,2,3-trifluorocyclobutyl, 
2,2,4-trifluorocyclobutyl, 2,2,3,4-tetrafluorocyclobutyl, 
2,3,3,4-tetrafluorocyclobutyl, 2,2,3,3-tetrafluorocyclobutyl, 
2,2,4,4-tetrafluorocyclobutyl, 2,2,3,3,4-pentafluorocyclobutyl, 
2,2,3,4,4-pentafluorocyclobutyl, hexafluorocyclobutyl, 
2-fluorocyclopentyl, 3-fluorocyclopentyl, 2,2-difluorocyclopentyl, 
2,3-difluorocyclopentyl, 2,4-difluorocyclopentyl, 2,5-difluorocyclopentyl, 
3,3-difluorocyclopentyl, 2,2,3-trifluorocyclopentyl, 
2,2,4-trifluorocyclopentyl, 2,2,5-trifluorocyclopentyl, 
2,3,3-trifluorocyclopentyl, 3,3,4-trifluorocyclopentyl, 
2,4,4-trifluorocyclopentyl, 2,2,3,3-tetrafluorocyclopentyl, 
2,2,4,4-tetrafluorocyclopentyl, 2,5,5-tetrafluorocyclopentyl, 
3,3,4,4-tetrafluorocyclopentyl, 2,2,3,4-tetrafluorocyclopentyl, 
2,2,3,5-tetrafluorocyclopentyl, 2,2,4,5-tetrafluorocyclopentyl, 
2,3,3,4-tetrafluorocyclopentyl, 2,3,3,5-tetrafluorocyclopentyl, 
3,3,4,5-tetrafluorocyclopentyl, 2,3,4,5-tetrafluorocyclopentyl, 
2,2,3,3,4-pentafluorocyclopentyl, 2,2,3,3,5-pentafluorocyclopentyl, 
2,2,3,4,4-pentafluorocyclopentyl, 2,2,3,5,5-pentafluorocyclopentyl, 
2,2,3,4,5-pentafluorocyclopentyl, 2,3,3,4,4-pentafluorocyclopentyl, 
2,3,3,5,5-pentafluorocyclopentyl, 2,3,3,4,5-pentafluorocyclopentyl, 
2,2,3,3,4,4-hexafluorocyclopentyl, 2,2,3,3,5,5-hexafluorocyclopentyl, 
2,2,3,3,4,5-hexafluorocyclopentyl, 2,3,3,4,4,5-hexafluorocyclopentyl, 
2,3,3,4,4,5-hexafluorocyclopentyl, 2,2,3,4,4,5-hexafluorocyclopentyl, 
2,2,3,3,4,4,5-heptafluorocyclopentyl, 
2,2,3,3,4,5,5-heptafluorocyclopentyl, and octafluorocyclopentyl. 
A more particular value for E is CZ wherein Z is selected from the more 
particular values defined below. 
More particular values of Ar as phenyl substituted with 0-2 substitutents 
include those values of phenyl substituted with 0-1 substituent, including 
phenyl, 2-, 3- and 4-fluorophenyl, 2- and 3-chlorophenyl, 2- and 
3-cyanophenyl, 2- and 3-hydroxyphenyl, 2- and 3-methoxyphenyl, and 2- and 
3-methylphenyl. 
More particular values of Ar as a six-membered heteroaryl ring containing 
1-2 nitrogen atoms include 2, 3-, and 4-pyridyl, and 2- and 4-pyrimidinyl. 
More particular values of Ar as a five-membered heteroaryl ring containing 
from 1-2 heteroatoms include 3- and 4-isothiazolyl, 2- and 4-oxazolyl, 2- 
and 4-thiazolyl, 2- and 3-furyl, and 2- and 3- thienyl. 
More particular values of Z as (1-4C)alkyl include values of (1-2C)alkyl, 
including methyl and ethyl. 
More particular values of Z as (1-4C)alkoxy include values of (1-2C)alkoxy, 
including methoxy and ethoxy. 
More particular values of Z as phenylthio substituted with from 0-2 
substitutents include those values of phenylthio substituted with 0-1 
substituent, including phenylthio, 2-, 3- and 4-fluorophenylthio, 2-, 3-, 
and 4-chlorophenylthio, 2-, 3- and 4-cyanophenylthio, 2-, 3- and 
4-hydroxyphenylthio, 2-, 3- and 4-methoxyphenylthio, and 2-, 3- and 
4-methylphenylthio. 
More particular values of Z as phenylsulfinyl substituted with from 0-2 
substitutents include those values of phenylsulfinyl substituted with 0-1 
substituent, including phenylsulfinyl, 2-, 3- and 4-fluorophenylsulfinyl, 
2-, 3- and 4-chlorophenylsulfinyl, 2-, 3- and 4-cyanophenylsulfinyl, 2-, 
3- and 4-hydroxyphenylsulfinyl, 2-, 3- and 4-methoxyphenylsulfinyl, and 
2-, 3- and 4-methylphenylsulfinyl. 
More particular values of Z as phenylsulfonyl substituted with from 0-2 
substitutents include those values of phenylsulfonyl substituted with 0-1 
substituent, including phenylsulfonyl, 2-, 3- and 4-fluorophenylsulfonyl, 
2-, 3-, and 4-chlorophenylsulfonyl, 2-, 3-, and 4-cyanophenylsulfonyl, 2-, 
3-, and 4-hydroxyphenylsulfonyl, 2-, 3-, and 4-methoxyphenylsulfonyl, and 
2-, 3-, and 4-methylphenylsulfonyl. 
More particular values of R2 and R3 as (1-3C)alkyl substituted by from 0 to 
2k+l groups selected from chloro and fluoro include those substituted with 
fluoro groups only, including fluoromethyl, difluoromethyl, 
trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 
1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, 
1,2,2,2-tetrafluoroethyl, and 1,1,2,2,2-pentafluoroethyl. 
A particular amide has formula Id wherein: 
X and Z are selected from the group consisting of: 
(A) X is ArY wherein 
Y is a linking group selected from carbonyl, sulfinyl, and sulfonyl and Ar 
is selected from the group consisting of phenyl, 2-, 3- and 
4-fluorophenyl, 2- and 3-chlorophenyl, 2- and 3-cyanophenyl, 2- and 
3-hydroxyphenyl, 2- and 3-methoxyphenyl, 2- and 3-methylphenyl, 2, 3-, and 
4-pyridyl, 2- and 4-pyrimidinyl, 3- and 4-isothiazolyl, 2- and 4-oxazolyl, 
2- and 4-thiazolyl, 2- and 3-furyl, and 2- and 3-thienyl; 
Z is selected from hydrogen, cyano, halo, hydroxy, (1-2C)alkyl, and 
(1-2C)alkoxy; 
(B) X is CN, Z is phenylsulfonyl; 
R.sup.2 and R.sup.3 are independently selected from the group consisting of 
(1-3C)alkyl substituted by from 0 to 2k+l fluoro groups wherein k is the 
number of carbon atoms in the said (1-3C)alkyl, provided that R.sup.2 and 
R.sup.3 are not both methyl; 
and pharmaceutically acceptable in vivo hydrolyzable esters of said amide; 
and pharmaceutically acceptable salts of said amides and said esters. 
A preferred amide has formula Id wherein X is ArY, and wherein: 
Ar, Y, and Z are selected from the group consisting of: 
(i) Y is sulfonyl, Z is hydrogen, and Ar is selected from the group 
consisting of: 
phenyl substituted with 0-1 substituents, selected from phenyl, 2-, 3-, and 
4-fluorophenyl, 2- and 3-chlorophenyl, 2- and 3-methoxyphenyl, 2- and 
3-cyanophenyl, 2- and 3-hydroxyphenyl, and 2- and 3-methylphenyl; 
six-membered heteroaryl rings selected from 2-, 3- and 4-pyridyl, and 
2-pyrimidinyl; 
five-membered heteroaryl rings selected from 2-thienyl and 2-thiazolyl; 
(ii) Y is sulfonyl, Ar is phenyl or 4-pyridyl, and Z is selected from the 
group consisting of cyano, fluoro, hydroxy, methoxy and methyl; and 
(iii) Y is carbonyl, Z is hydrogen, and Ar is selected from the group 
consisting of phenyl and 2-pyridyl; and 
R.sup.2 and R.sup.3 are independently selected from the group consisting of 
(i) R.sup.2 is trifluoromethyl and R.sup.3 is selected from methyl, ethyl, 
and trifluoromethyl; and 
(ii) R.sup.2 is difluoromethyl and R.sup.3 is difluoromethyl; and the 
pharmaceutically acceptable in vivo hydrolyzable esters of said amide, 
and pharmaceutically acceptable salts of said amide and said hydrolyzable 
esters. 
Where applicable, the S-configuration generally represents a preferred 
sterochemistry for compounds according to the invention. 
Specifically preferred amides include the following: 
N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanami 
de; 
S-(-)-N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpro 
panamide; 
N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide; 
S-(-)-N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropan 
amide; 
N-[4-(4-Pyridylsulfonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoromethylprop 
anamide; 
N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoroethylprop 
anamide; 
N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl 
propanamide; and 
N-[3-Hydroxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methy 
lpropanamide. 
The above compounds are preferred because they are selective for the 
bladder without significant effect on the cardiovascular system, as 
measured by blood pressure effects, in the in vivo test predictive of 
selectivity which is described herein. 
Amides of formula I can be made by processes which include processes known 
in the chemical arts for the production of structurally analogous 
compounds. Such processes for the manufacture of an amide of formula I as 
defined above are provided as further features of the invention and are 
illustrated by the following procedures in which the meanings of generic 
radicals are as given above unless otherwise qualified. Such a process can 
be effected, generally, 
(a) by coupling an aniline of formula II with an acid of formula III 
wherein G is a hydroxy group. The reaction can be conducted in a suitable 
solvent and in the presence of a suitable coupling reagent. Suitable 
coupling reagents generally known in the the art as standard peptide 
coupling reagents can be employed, for example thionyl chloride, (see 
Morris et. al., J. Med. Chem., 34, 447, (1991)), carbonyldiimidazole (CDI) 
and dicyclohexylcarbodiimide, optionally in the presence of a catalyst 
such as dimethylaminopyridine (DKAP) or 4-pyrrolidinopyridine. Suitable 
solvents include dimethylacetamide, dichloromethane, benzene, 
tetrahydrofuran, and dimethylformamide. The coupling reaction can be 
conducted in a temperature range of about -40.degree. to 40.degree. C.; 
(b) by deprotecting a protected amide having formula IV wherein "PG" is a 
suitable protecting group such as a benzyl group; Examples of suitable 
reactants for use in cleaving the ether moiety to yield a hydroxyl group 
include (1) hydrogen in the presence of palladium-on-carbon catalyst, i.e. 
hydrogenolysis; (2) hydrogen bromide or iodide; (3) trimethylsilyl iodide; 
and (4) alkyl sulfides or phosphides. The reaction can be conducted in a 
suitable solvent such as ethanol, methanol, acetonitrile, or 
dimethylsulfoxide and at a temperature in the range of about -40.degree. 
to 100.degree. C. 
(c) in a compound of formula I wherein X is substituted or unsubstituted 
phenylsulfinyl or phenylsulfonyl, by oxidizing a corresponding substituted 
or unsubstituted phenylsulfide. Suitable oxidizing agents include 
potassium permanganate, oxone, sodium periodate, and hydrogen peroxide. 
The reaction can be conducted in a suitable solvent such as diethyl ether, 
methanol, ethanol, water, acetic acid, and mixtures of two or more of the 
aforementioned. The reaction can be conducted at a temperature of 
-40.degree. to 70.degree. C. 
(d) by reacting an amide of formula V with a base sufficiently basic ( 
e.g., a lithium dialkylamide such as lithium diisopropyl amide) to yield 
an amide dianion, followed by reacting the dianion thereby produced with 
oxygen in the presence of a reducing agent (e.g., such as triphenyl 
phosphine) to yield the corresponding compound of formula I; The sequence 
of reactions can be conducted at a temperature in the range of about 
-100.degree. to -20.degree. C. in a suitable solvent such as 
tetrahydrofuran or diethyl ether. 
(e) in a compound of formula Id wherein X is substituted or unsubstituted 
phenylsulfonyl, by reacting a corresponding substituted or unsubstituted 
compound of formula VI, wherein the value corresponding to X is 
substituted or unsubstituted phenylsulfonyl and Hal indicates a halogen 
substituent (e.g., the corresponding chloride), with a corresponding 
alkali metal amide dianion having formula VII wherein Am is an alkali 
metal such as sodium or lithium; The reaction can be conducted at a 
temperature in the range of about -40.degree. to about 100.degree. C. and 
in a suitable solvent such as dimethylformamide, dimethylsulfoxide, or 
tetrahydrofuran. 
(f) by reacting an (alkyl ester) compound of formula VIII, wherein R.sup.4 
is a (1-4C)alkyl group (e.g. methyl, ethyl, or propyl) with a (2-3C)alkyl 
magnesium halide (i.e., a Grignard reagent); The reaction, a Grignard 
addition to an ester, can be conducted at a temperature of about 
-100.degree. to about 20.degree. C. in a suitable solvent such as 
tetrahydrofuran or diethyl ether. Higher alkyl esters can be employed, but 
they provide no synthetic advantage. 
(g) when X is substituted or unsubstituted benzoyl (in formula I), by 
reacting a corresponding compound of formula IXa with a corresponding 
substituted or unsubstituted triphenylaluminum or tetraphenyltin and 
carbon monoxide in the presence of a suitable catalyst such as 
bis-(triphenylphosphine)palladium (II) chloride; The reaction may be 
conducted at a temperature of from about -20.degree. to about 100.degree. 
C. in a suitable solvent such as benzene, toluene, tetrahydrofuran, or 
diethyl ether. 
(h) when X is substituted or unsubstituted benzoyl, by oxidizing a compound 
of formula IXb to the corresponding compound of formula I wherein X is the 
corresponding substituted or unsubstituted benzoyl moiety; Oxidizing 
agents such as bromine and pyridinium dichromate and solvents such as, 
respectively, methanol and dichloromethane can be suitably employed. 
If not commercially available, the necessary starting materials for the 
procedures such as that described above may be made by procedures which 
are selected from standard organic chemical techniques, techniques which 
are analogous to the synthesis of known, structurally similar compounds, 
or techniques which are analogous to the above described procedure or the 
procedures described in the examples. In the discussion which follows, 
"Ar" refers to an unsubstituted or substituted phenyl group or a 
heterocyclic radical, as previously defined. 
In general, compounds of formulae IV, V, VIII, IXa, and IXb can be made in 
a manner analogous to that described in procedure (a) above for making an 
amide of formula I; that is, by coupling an appropriate corresponding 
aniline with an appropriate corresponding acid. Thus, to make a protected 
amide of formula IV, a corresponding aniline of formula II can be coupled 
with an acid of formula III wherein the group corresponding to G is OPG. 
The protected acid can be made by a conventional procedure, for example by 
(i) esterifying an acid of formula III wherein G is hydroxy by means of a 
conventional esterification procedure such as reaction with a lower 
alcohol (e.g., methanol) in the presence of an acid catalyst (for example 
sulfuric acid); (ii) reaction of the ester thus formed with an agent which 
provides the protecting group PG, such as benzyl chloride (to provide a 
benzyl protecting group) or any of the conventional silylating agents 
known and used for such purpose (such as 2-trimethylsilylethoxymethyl 
chloride, SEM, in the presence of a suitable base such as sodium hydroxide 
or triethylamine optionally in the presence of a catalyst such as DKAP); 
and (iii) cleavage of the ester group under mild alkaline conditions 
(i.e., employing a base such as potassium carbonate) to yield the desired 
protected acid. 
As a further example, a compound of formula IXa can be made by coupling an 
acid of formula III wherein G is hydroxy with an aniline of formula II 
wherein the group corresponding to X is iodo and E is CH. It will be 
appreciated by those skilled in the art that compounds having the other 
formulae noted above can be prepared in an analogous manner using 
appropriate corresponding starting materials. 
An aniline of formula XI wherein n=0, 1, or 2 (i.e., an aniline of formula 
II wherein X is ArS, ARSO, or ARSO.sub.2) can be made by reducing the 
corresponding nitro compound of formula XII with a suitable reducing agent 
as generally known in the art, see A. Courtin, Helv, Chime. Acta, 66, 1046 
(1983); and H. Gilman et. al., J. Amer. Chem. Soc., 69, 2053, (1947). 
Suitable reducing agents include stannous chloride dehydrate in ethanol 
conducted at a temperature of 20.degree. to reflux, iron in water-ethanol 
conducted at a temperature of 20.degree. to reflux, and catalytic 
hydrogenation using palladium or platinum catalyst conducted at a 
temperature of 20.degree. to 50.degree. C. 
An aniline of formula XI wherein n=2 can also be made by the acid 
hydrolysis (aqueous HCl/ethanol at reflux) of an acetanilide of formula 
XIII to afford the corresponding aniline. 
A nitro compound of formula XII wherein n=1 or 2 can be made by oxidizing 
the corresponding compound of formula XII wherein n=0 (i.e. the 
corresponding sulfide), thereby yielding the corresponding compound of 
formula XII wherein n=1 or 2, as desired. Suitable reagents for the 
preparation of n=1 are sodium periodate in a suitable solvent such as 
methanol or dioxane conducted at a temperature of 20.degree. to 
80.degree.; bromine and potassium carbonate in methylene chloride/water 
conducted at room temperature; and 30% hydrogen peroxide in acetic acid 
conducted at room temperature. Suitable reagents for the preparation of 
n=2 are potassium permanganate in acetic acid/water conducted at room 
temperature; 30% hydrogen peroxide in acetic acid conducted at 70.degree. 
oxone in methanol/water conducted at room temperature; and 
m-chloroperbenzoic acid in methylene chloride conducted at a temperature 
of 0.degree. to reflux. 
A nitro compound of formula XII wherein n=0 or 2 can also be made by 
reacting a corresponding alkali metal acid salt of formula ArSO.sub.n Am, 
wherein Am is an alkali metal such as sodium, lithium, or potassium, with 
a halide of formula XIV wherein Hal indicates a halo substituent (such as 
chloro). The reaction is conducted in solvents such as ethanol/water, 
dimethylformamide or dimethylacetamide at a temperature of 20.degree. to 
155.degree.. 
A nitro compound of formula XII, wherein n=0 or 2, can also be made by 
reacting a corresponding compound of formula ArHal wherein Hal is halogen 
(for example 2-chloro-5-nitropyridine) with a corresponding salt of 
formula XV (n=0 or 2) wherein Am is an alkali metal such as sodium, 
lithium or potassium. The reaction is conducted in solvents such as 
ethanol/water, dimethylformamide or dimethylacetamide at a temperature of 
20.degree. to 155.degree.. 
An aniline of formula XVI can be made by reacting a corresponding acid of 
formula ArCO.sub.2 H or a corresponding anhydride of formula ArCO--O--COAr 
with aniline in the presence of polyphosphonic acid. See, for example, B,. 
Staskum, J. Org. Chem., 29, 2856, (1964) and A. Denton et. al., J. Chem. 
Soc., 4741, (1963). 
It is noted that many of the starting materials for synthetic methods as 
described above are commercially available and/or widely reported in the 
scientific literature. 
In cases where compounds of formula I (or Id) are sufficiently basic or 
acidic to form stable acid or basic salts, administration of the compound 
as a salt may be appropriate, and pharmaceutically acceptable salts can be 
made by conventional methods such as those described following. Examples 
of suitable pharmaceutically acceptable salts are organic acid addition 
salts formed with acids which form a physiologically acceptable anion, for 
example, tosylate, methanesulfonate, acetate, tartrate, citrate, 
succinate, benzoate, ascorbate, .alpha.-ketoglutarate, and 
.alpha.-glycerophosphate. Suitable inorganic salts may also be formed such 
as sulfate, nitrate, and hydrochloride. Pharmaceutically acceptable salts 
may be obtained using standard procedures well known in the art, for 
example by reacting a sufficiently basic compound of formula I (or its 
ester) with a suitable acid affording a physiologically acceptable anion. 
It is also possible with most compounds of the invention to make a 
corresponding alkali metal (e.g., sodium, potassium, or lithium) or 
alkaline earth metal (e.g., calcium) salt by treating an amide of formula 
I (and in some cases the ester) with one equivalent of an alkali metal or 
alkaline earth metal hydroxide or alkoxide (e.g. the ethoxide or methoxide 
in aqueous medium followed by conventional purification techniques. 
In vivo hydrolyzable esters of compounds of the invention can be made by 
coupling with a pharmaceutically acceptable carboxylic acid or an 
activated derivative thereof. For example, the coupling can be carried out 
by treating a parent amide of formula I with an appropriate acid chloride 
(for example, acetyl chloride, propionyl chloride, or benzoyl chloride) or 
acid anhydride (for example, acetic anhydride, propionic anhydride, or 
benzoic anhydride) in the presence of a suitable base such as 
triethylamine. Those skilled in the art will appreciate that other 
suitable carboxylic acids (including their activated derivatives) for the 
formation of in vivo hydrolyzable esters are known to the art and these 
are also intended to be included within the scope of the invention. 
Catalysts such as 4-dimethylaminopyridine can also be usefully employed. 
When used to treat urinary incontinence, a compound of formula I is 
generally administered as an appropriate pharmaceutical composition which 
comprises a compound of formula I as defined hereinbefore together with a 
pharmaceutically acceptable diluent or carrier, the composition being 
adapted for the particular route of administration chosen. Such 
compositions are provided as a further feature of the invention. They may 
be obtained employing conventional procedures and excipients and binders 
and may be in a variety of dosage forms. For example, they may be in the 
form of tablets, capsules, solutions or suspensions for oral 
administration; in the form of suppositories for rectal administration; in 
the form of sterile solutions or suspensions for administration by 
intravenous, intravesicular (i.e., directly into the bladder), 
subcutaneous or intramuscular injection or infusion; or in the form of a 
patch for transdermal administration. 
The dose of compound of formula I which is administered will necessarily be 
varied according to principles well known in the art taking account of the 
route of administration, the severity of the incontinence condition, and 
the size and age of the patient. In general, a compound of formula I will 
be administered to a warm blooded animal (such as man) so that an 
effective oral dose is received, generally a daily dose in the range of 
about 50 to about 500 mg. For the specific compounds previously noted as 
being preferred because they are bladder selective, an effective oral dose 
can range from a total daily dose of 50 mg up to a dose of about 2000 mg. 
No untoward effects have been observed in laboratory animals following 
administration of compounds according to the invention at several 
multiples of the minimum effective dose in the animal tests described 
hereinafter. 
It will be apparent to those skilled in the art that a compound of formula 
I can be co-administered with other therapeutic or prophylactic agents 
and/or medicaments that are not medically incompatible therewith. 
The actions of compounds of formula I as smooth muscle relaxants useful as 
therapeutic agents for the treatment of urinary incontinence can be shown 
using suitably designed in vitro tests, such as the one described 
following. Compounds according to the invention typically exhibit an 
IC.sub.50 on the order of 30 micromolar or less in the test. "IC50" is a 
well understood term and means the concentration of test compound which 
causes a 50% decrease in the in vitro contraction of the bladder tissue 
decribed in the following test. 
Male albino Hartley guinea pigs (450-500 g) are sacrificed by cervical 
dislocation. The lower abdominal cavity is opened and the urinary bladder 
located. Once located, it is cleaned of surrounding connective and adipose 
tissue. The two pelvic nerves on the ventral surface of the bladder are 
cut away, then the bladder body is removed above the entrance of the 
ureters. The bladder is washed in Krebs-Henseleit buffer solution 
(composition (MM): NaCl 118.0, KCl 4.7, MgSO.sub.4 1.2, KH.sub.2 PO.sub.4 
1.2, CaCl.sub.2 2.5, NaHCO.sub.3 25 and D-Glucose 11.1) and then placed on 
a buffer-soaked gauze in a petri dish. The dome of the bladder is cut off 
and discarded. 
A mid-ventral longitudinal cut is made with scissors and the bladder laid 
flat on the gauze. Strips are cut from the dome edge and the base edge and 
discarded. The remaining detrusor mid-section is cut into two latitudinal 
(horizontal) strips, with an approximate width of 2.0 mm. These two strips 
are cut in half at the mid-dorsal section, creating four strips of similar 
dimensions. Each strip thus contains both dorsal and ventral portions of 
the bladder. 
Each individual strip is tied at one end directly to a glass support rod 
and a length of 4-0 black braided silk suture is tied to the other end. 
The glass rods are secured in 20 ml tissue baths and the length of suture 
attached to a force-displacement transducer (Grass model FT03). 
The tissues are bathed in Krebs-Henseleit buffer solution. The bathing 
solution is warmed to 37.degree. C. and gassed with 5% CO.sub.2 and 95% 
O.sub.2, with vigorous bubbling. The solution should have a pH value close 
to 7.4. 
The transducers are connected to a polygraph (Grass model 7E) and 
interfaced with a Modular Instrument Micro 5000 signal processing system 
and Biowindow Data Acquisition Software (run on Microsoft OS/2 with an 
IBM-compatible PC). 
The polygraph is calibrated at 5 mV/cm and calibration checked for 
linearity with weights of 5 and 0.5 grams. 
The tissue is incubated in the buffer for 15 minutes without preload 
tension, then 30 minutes with tension applied. The preload tension applied 
is 2 grams that relaxes to approximately 1 gram. The tissue is washed at 
15 minute intervals, with tension adjusted to 2 grams just prior to 
washing. After this 45 minute equilibration period, a priming dose of 15 
mM KCl (total concentration in bath) is applied. The tissue is washed 
after 10 minutes and washed twice more at 15 minute intervals with tension 
adjusted to 2 grams before each washing. 
When the tissue relaxes to a steady state after the final washing, 15 mM 
KCl is again dosed. Once the tissue reaches a steady state the base line 
data are acquired on the Biowindows Data Acquisition System. This is done 
by averaging 5 minutes of data, sampling at 32 Hz. Once the baseline is 
acquired, the experimental compounds are dosed in a cumulative manner in 
half log unit increments. The contact time for each dose is 10 minutes 
with the final 5 minutes being the period of time that the dose response 
data are acquired. If 30 .mu.M of the test compound does not abolish 
detrusor mechanical activity, then 30 .mu.M cromakalim is dosed to 
establish a maximum response. The effects of the compounds are expressed 
as % of maximum relaxation of agonist induced tension. 
Typical IC.sub.50 values in the above test are 1.27.+-.0.31 .mu.M for the 
compound of Example 1 and 5.14.+-.1.89 .mu.M for the compound of Example 
2. 
It will be further appreciated by those skilled in the art that the 
efficacy of compounds according to the invention can be demonstrated by 
standard assays in vivo. The following is a description of such a standard 
test which is used to evaluate smooth muscle relaxing capability of test 
compounds. 
Male Wistar rats weighing 450-550 grams are anesthetized with 20 mg/kg, 
intraperitoneal (i.p.) Nembutal and 80 mg/kg, i.p. Ketamine. The trachea 
is cannulated to prevent airway obstruction. Body temperature is 
maintained by means of a heating pad. Arterial blood pressure and heart 
rate are measured with a pressure transducer connected to a polyethylene 
tube (PE 50) which has been inserted into the right carotid artery. The 
right jugular vein is cannulated for drug administration. The urinary 
bladder is exposed through a midline abdominal incision and emptied of 
urine by application of slight manual pressure. A catheter (PE 50) is 
inserted through the apex of the bladder dome around 3-4 mm into its lumen 
and tied with suture (4-0 silk) to prevent leakage. The bladder catheter 
is connected to a pressure transducer for the measurement of bladder 
pressure. The bladder is then placed back into the abdominal cavity and 
the incision is stitched closed except where the catheter exits the 
cavity. The bladder is allowed to equilibrate for approximately 15 
minutes. After the equilibration period, the rats are infused with saline 
directly into the bladder at a rate of 0.05 ml/min for the entire time of 
the experiment. The bladder pressure is then monitored for the start of 
bladder contractions. When the contractions start, the animal is then 
allowed to stabilize its pattern of contractions around 30 to 45 minutes 
before drug administration. 
The test compounds are given intravenous and the cutoff dose is 3 mg/kg. 
The reference drug cromakalim (Smithkline-Beecham) has been evaluated in 
this model and administered intravenous over the dose range of 0.05 to 0.5 
mg/kg. 
The above in vivo assay enables an assessment of both the blood pressure 
and cystometric activity of test compounds. Blood pressue is measured 
immediately after drug injection and at 5, 15 and 30 minutes later. 
Micturition contractions are induced by a slow continuous infusion of 
saline directly into the bladder. The average change (in seconds from 
control) in the duration of the intercontraction interval (the time 
between contractions) over an approximate 20-min period is reported for 
each compound. 
Typical results are indicated for the Examples noted in Table 1 which 
follows: 
TABLE 1 
__________________________________________________________________________ 
CHANGE IN MBP 
CMPD DOSE Immed. 
5 min 
15 min 
30 min 
CHANGE IN IC 
__________________________________________________________________________ 
Example 5 
3 -63 -52 -37 -28 +77 
__________________________________________________________________________ 
Dose is mg/kg. 
MBP = mean arterial blood pressure. The values are mmHg and reflect 
changes from control. The times shown are the immediate (Immed.) effect 
and the effects at 5, 15, and 30 minutes after i.v. compound 
administration. 
IC = intercontraction interval. Change in IC = peak response in seconds 
from control. 
The following is a description of a test in vivo which is complimentary to 
the above described tests and which can be used to ascertain if a test 
compound is active and, additionally, if the test compound exhibits 
selectivity for the bladder without significant cardiovascular effects 
when dosed orally. The specifically preferred compounds noted previously 
are active and selective in this test. 
Male Wistar rats (400-500 g) were anesthetized with 50 mg/kg Nembutal, i.p. 
For each rat, the abdominal region and the front and back of the neck were 
shaved and povidone-iodine was applied to the skin. For carotid 
catheterization, the left carotid artery was exposed via a small ventral 
cervical incision. The exposed area was flushed with a 2% lidocaine HCl 
solution to relax the vessel. The catheter, filled with 0.9% saline, was 
introduced approximately 2.4 cm into the artery so that its tip resided in 
the aortic arch. The distal end of the catheter was exteriorized at the 
nape of the neck, filled with heparin (1000 units/ml) and heat sealed. For 
bladder catheterization, the catheters were implanted according to the 
method of Yaksh TL, Durant , Brent CR. Micturition in rats: A chronic 
model for study of bladder function and effect of anesthesia. Am. J. 
Physiol. 251 (Regulatory Integrative Comp. Physiol. 20): R1177-R1185, 
1986. The bladder was exposed through a midline abdominal incision. A 
trocar was passed through the abdominal muscle about 1 cm from the upper 
end of the incision and then tunneled subcutaneously to emerge through the 
skin at the back of the neck. A saline-filled catheter was passed through 
the trocar. A small opening in the bladder dome was created with an 
Accu-Temp cautery. The catheter was placed into the bladder and secured 
with a 4-0 silk ligature. The catheter was flushed with saline and patency 
was noted. The external end of the catheter was heat-sealed to prevent 
urine leakage. The abdominal muscles and the skin were sutured. Both 
catheters were threaded through a stainless steel anchor button (Instech), 
which was then sutured to the subcutaneous muscle at the point of 
exteriorization. The skin was sutured closed over the button. The animals 
were allowed to recover from anesthesia. 
24-48 hours after surgery, each rat was placed in a metabolism cage and 
connected via the anchor button to an Instech spring tether and swivel 
system to protect the catheters from damage and to allow the animal free 
movement in the cage. The carotid catheter was connected to a Gould P23XL 
pressure transducer for blood pressure measurement. The bladder catheter 
was connected to a pump for saline infusion and to a pressure transducer 
by means of PE50 tubing and a 4-way stopcock. A toploading balance with a 
collection cup was placed under the cage for urine output measurement. 
The rats were weighed, orally sham-dosed (dosing needle introduced, but no 
fluid expelled), and transvesical saline infusion (0.18 ml/min) was begun 
and continued throughout the experiment. Variations in blood pressure, 
heart rate, intravesical pressure and urine output were recorded on either 
a Grass Polygraph or a Gould TA4000 recording system. The animals were 
allowed to equilibrate until the micturition pattern became consistent 
(approx. 45-90 min.). At this point, a basal level of each experimental 
parameter was recorded and the rats were administered by oral gavage the 
appropriate dose of compound (in a 75% PEG 400 - saline vehicle) in 
concentrations such that the volume was 1 ml/kg body weight. The effects 
of the compounds on experimental parameters were followed for five hours 
after administration. Cromakalim (Smithkline-Beecham) was used as the 
reference standard. 
Experimental results for both the interval between contractions and also 
heart rates were expressed as the mean.+-.S.E.M. change from basal level, 
with each animal serving as its own control. MAP is expressed as 
mean.+-.S.E.M mm Hg change from basal level. Typical values are listed in 
Table 2 for the Examples noted. 
TABLE 2 
______________________________________ 
Com- Dose CHBP.sup.4 
pound (mg/kg).sup.1 
Time.sup.2 
CIC.sup.3 
(mm Hg) % CHR.sup.5 
______________________________________ 
croma- 1.0 1 54 .+-. 5 
-18 .+-. 4 
20 .+-. 5 
kalim 2 76 .+-. 15 
-18 .+-. 6 
15 .+-. 4 
3 104 .+-. 5 
-14 .+-. 5 
13 .+-. 2 
4 129 .+-. 5 
-11 .+-. 4 
10 .+-. 4 
5 114 .+-. 25 
-12 .+-. 3 
9 .+-. 4 
example 
3 mg/kg 1 35 .+-. 3 
1 .+-. 1 
-3 .+-. 2 
61 2 53 .+-. 5 
-1 .+-. 1 
-4 .+-. 3 
3 65 .+-. 5 
-2 .+-. l 
-2 .+-. 4 
4 57 .+-. 5 
-1 .+-. 2 
-2 .+-. 3 
5 90 .+-. 10 
-4 .+-. 1 
-2 .+-. 2 
example 
3 mg/kg 1 39 .+-. 5 
0 .+-. 2 
1 .+-. 1 
59 2 74 .+-. 11 
1 .+-. 2 
2 .+-. 3 
3 96 .+-. 9 
-1 .+-. 1 
0 .+-. 4 
4 108 .+-. 6 
-2 .+-. 1 
2 .+-. 2 
5 124 .+-. 9 
-7 .+-. 1 
3 .+-. 4 
______________________________________ 
.sup.1 mg/kg is milligrams per kilogram of body weight. 
.sup.2 Time is measured in hours following (post) dosage. 
.sup.3 CIC is an acronym for change in intercontraction interval of the 
bladder. 
.sup.4 CHBP is an acronym for change in the mean arterial blood pressure. 
.sup.5 % CHR is an acronym for percentage of change in heart rate. 
Note: All values are relative to controls. 
Compounds according to the invention are active in one or more of the 
above-described tests. With reference to those (preferred) compounds 
previously listed as exhibiting selectivity for the bladder, most 
compounds from that list have also been tested in vivo in a dog model, and 
all which were tested exhibited activity and selectivity.