PHENOL AND PYRIDINOL DERIVATIVES AS LUSITROPIC AGENTS

DERIVES PHENOL ET PYRIDINOL UTILISES COMME AGENTS LUSITROPIQUES

English Abstract

2132981 9319754 PCTABS00027
Fused aryl derivatives are described as lusitropic agents for use
in the treatment of cardiovascular disease where there is a
component of diastolic failure.

Claims

WO 93/19754 PCT/GB93/00615
- 4 -
Claims:
1. The use of a compound of the formula (1):
<IMG>
Formula (l)
or a pharmaceutically acceptable salt thereof, wherein:
A is N or CH
R0 is OH or a bioprecursor thereof,
R1 is A0CO2H, P(X)(OH)(OR2), SO2H,SO3H or 5-tetrazolyl or a bioprecursor thereof,
A0 is a single bond, CH2, CHF, CF2, CR3(OR4), CO or C(OR5)(OR6),
R2 is phenyl, C3-5cycloalkyl, C3-5cycloalkyl-C1-4alkyl, or C1-8alkyl optionally
substituted by C1-4alkoxy,
R3 is H, methyl or ethyl,
R4 is H or C1-3alkyl,
and R6 are each C1-3alkyl or together form a 1,2-ethanediyl group or 1,3-propanediyl
group,
X is O or S and
Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1-6alkoxy, 2-
naphthyl optionally substituted in the 1-position by hydroxy or C16alkoxy, 3-phenanthryl,
9-phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl in the
manufacture of a medicament having positive lusitropic activity.
2. A method of enhancing myocardial relaxation which comprises
administering to a host in need thereof an effective amount of a compound of formula (1)
as defined in claim 1 or a pharmaceutically acceptable salt thereof.
3. A method of treating cardiovascular disease where there is a component
of diastolic failure which comprises administering to a host in need thereof an effective

WO 93/19754 PCT/GB93/00615
- 5 -
amount of a compound of formula (1) as defined in claim 1 or a pharmaceutically
acceptable salt thereof.
4. The use according to any one of claims 1 to 3 wherein R1 is
P(O)(OH)(OR2) or a bioprecursor thereof.
5. The use according to any one of claims 1 to 3 wherein the compound of
the formula (1) is selected from :
ethyl pivaloyloxymethyl[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]phosphonate,
6-(2-naphthyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-[2-(1-pentyloxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)one,
4-ethoxy-4-oxo-1,3,4 dioxyphosphono[5,6-b]-7-(1-naphthyl)pyridine, and
ethyl 2-methoxy-2-1[6-(2-naphthyl)-2-oxo-1.2-dihydro-3-pyridyl]propionate.

Description

~O 93/19754 21 ~ 2 9 ,~ l PCT/GB93/00615
I
:
Phenol and pyr~dlnol der1vat1ves as lus~trop1c agents. ~ .
Thc present invention relatcs to thc use of certain fused aryl derivatives as lusitropic agents
in the treatmcnt of cardiovascular diseascs where thcre is a component of diastolic failure.
WO 91/17987 discloses fuscd aryl derivatives as agonists of a cyclic AMP-dependent
protein kinase.
It has now becn found that tncse derivativcs cnhancc myocardial rclaxation i.c. have
positive lusitropic activity and are therefore of use in the trcatment of cardiovascular
diseascs where there is a component of diastolic failurc. ~ ;
Accordingly in a first aspect the prescnt invention provides thc use of a compound of the
15 formula (1):
Ar
A ~;
o .,;.
Fornnula(l)
-
or a pharmaceutically acccptablc salt thercof, whercin: -
A is N or CH
2s R0isOHorabioprccursorthereof,
Rl is AOC02H, P(X)(OH)(OR2), S02H, SO3H or 5-tetrazolyl or a bioprecursor thereof, - ~ ;
A0 is a single bond, CH2, CHF, CF2, CR3(oR4), CO or C(OR~)(OR6),
~ ~ ~
R2 is phenyl, C3 scycloaL~yl, C3 ~cycloaL~cyl-C I 4aLcyl, or C 1 gaLIcyl optionally
subsdtutcd by Cl 4aL~coxy,
R3 is H, mcthyl or ethyl, -~
.
R4 is H or Cl 3all~1, .
R5 and R6 ane cach Cl 3alkyl or togethcr foml a 1.2-cthancdiyl ~roup or 1.3-propanediyl -~ ~
~P, ~,~
Xis O orS and

Wo ~3/l97S4 ~ 13 2 9 81 pcr/cB93/oo61
Ar is l-naphthyl optionally substituted in the 4-position by hvdroxy or C 1 6aL~coxy, 2-
naphthyl optionallv substituted in the l-position by hydroxy or Cl 6alkoxy, 3-phenanthryl,
9-phenanthryl, 2-quinolinyl,4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl in the
manufacture of a medicament having positive lusitropic activity.
In a second aspect the prescnt invention provides ~ mcthod of cnhancing myocardial
relaxation which compriscs administcring to a host in nccd thercof an cffcctivc amount of
a eompound of formula (1) as hercinbcfore dcfincd or a pharmaccutically acceptable salt - ,
thereof.
In a third aspect the prcscnt invcntion provides a mcthod of trcating cardiovascular discasc
wherc therc is a componcnt of diastolie failurc which compriscs administcring to a host in
nced thcrcof an cffcetive amoun~ of a eompound of formula (1) as hcrcinbcforc dcfincd or
a pharmaecudeallv aeecptable salt thcrcof. Examplcs of such discascs ineludc eongcstivc -
hcart failurc. angina, hypcncnsion and eardiomyopathy (~Ccnakin ~ 1., J. Pharmaeol. Exp.
Thcr. 1991, 257,1189- 1197).
Examplcs of eompounds of thc formula (1) and suitablc substitucnt valucs are as diseloscd
in WO 91/17987.
Prcfcrably R1 is P(O)(OH)(OR2) or a bioprceursor thcrcof as dcfincd in WO 91/17987.
Partieular compounds of thc formula (1) ineludc:
cthyl pivaloyloxvmethyl[6-(1-naphthyl)-2-<Jxo-1.2-dihydro-3-pyridyllphosphonatc.
~(2-naphthyl)-3-(5-tctrazolyl)pyridin-2(1H)-onc,
~[2-(1-pentyloxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)-one, ; - `
4-ethoxy-4-oxo-1,3.4-dioxyphosphono[5,~b~-7-(1-naphthyl)pyridine, and -~
ethyl 2-methoxy-2- [~(2-naphthyl)-2-oxo- 1,2~ihydro-3-pyridyl]propionate. ;~
30 :-:
Compounds of the fonnula (1~ can be prepared and administcred as pharrnaccutical compositions as described in WO 91/17987.
Thc positivc lusitropic effect of the compounds of the fonnula (1) can be demonstratcd by
3s mcasurement of cardiac muscle rclaxation time in rabbit ventricle.
Papillary muscles from the right vcntricle of female Albino New Zealand rabbits were
mounted in standard organ baths eontaining oxygenated Krebs solu~ion. One end of the
muselc was eonnec~ed to an isomctrie transducer whieh allowed reeording of eontraetilc
forcc and its first derivativc on ehanrceardas. Test eompounds wcre addcd to thc bath in
a eumuladve manna. Rdaxadon dmc was ealeulated as thc ume takcn from pcalc tcnsion
to thc poirl~ of half relaxadon. At conecntrauons of 30-300 ~lM, and stimulation ratcs at
0.5, 1 or 2 Hz, the fo11Owing test eompounds eaused a 5-30% decrcase in thc relaxauon

PCl /GB93/00615 ;
2132981 ~3
umc indicadng a positive lusitropic effect of use in thc treannent of cardiovascular
diseases where there is a component of diastolic failure as hereinbcfore dcscribed.
Compounds tcstcd includc:
cthyl pi~valoyloxymcthyl~(l-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]phosphonate,
~(2-naphthyl)-3-(5-tetrazolyl)pyridin-2(1H)-onc,
~[2-(1-pcntyloxy)naphthyl]-3-(5-tetrazolyl)pyndin-2(1H)-onc,
4cthoxy~oxo-1,3,4-dioxyphosphono[5,~b]-7-(1-naphthyl)pyridinc, and
0 cthyl 2-mcthoxy-2-1~(2-naphthyl)-2-oxo-1,2-d;ihydro-3-pyridyl]propionate. .
''~ .,
"'-..,.,.:: ',,
''''-.' ,~;
~''-~" ''
~, . ' .