CGMP-PDE INHIBITORS FOR THE TREATMENT OF ERECTILE DYSFUNCTION

INHIBITEURS DE CGMP-PDE DESTINES AU TRAITEMENT DU DYSFONCTIONNEMENT ERECTILE

English Abstract

Compounds which are selective inhibitors of cGMP PDE are useful in the
treatment of erectile dysfunction (impotence) in male
animals, including man.

French Abstract

Ces composés qui sont des inhibiteurs sélectifs des cGMP PDE (guanosine 3',5'-monophosphate cyclique phosphodiestérase) sont utiles dans le traitement du dysfonctionnement érectile (impuissance) chez les animaux mâles, notamment chez l'homme.

Claims

60~

CLAIMS:

1. ~The use of a compound which is a selective cGMP
PDE inhibitor for the manufacture of a medicament for the
treatment of erectile dysfunction in a male animal,
including man, wherein the compound is selected from:
Image
and the pharmaceutically acceptable salts thereof,

in which: R1 is a lower alkyl of from one to six carbon
atoms, a lower alkenyl of from one to six carbon atoms, a
lower hydroxyalkyl of from one to six carbon atoms, a lower
hydroxyalkenyl of from two to six or 2, 3 or 4-pyridyl; and
Ar represents a group of formula:
Image
in which X, Y and Z are, independently, (1) hydrogen; (2)
lower alkyl of from one to six carbon atoms; (3) halogen,
(4) hydroxyl; (5) lower alkoxy of from one to six carbon
atoms; (6) nitro; (7) amino; (8) NR'R" wherein R' and R" are
each, independently, (a) hydrogen or (b) lower alkyl of from
one to six carbon atoms optionally substituted by (i) amino,
(ii) morpholino or (iii) cycloalkyl of from, five to seven
carbon atoms; (9) sulfonyl; or (10) -SO2NR'R" wherein R' and
R" are as defined above; with the proviso that not all of X,
Y and Z can be nitro, amino, or NR'R " at once;




61

Image

and the pharmaceutically acceptable salts thereof,
in which: A represents a group of formula:
Image~~
R1 and R2 are the same or different and each represents a
hydrogen atom, a halogen atom or a group of formula -OR9;

R3 and R4 are the same or different and each represents a
carbamoyl group or a carboxy group;

R5 and R6 both represent hydrogen atoms or together they
represent an extra carbon-carbon bond between the carbon
atoms to which they are a tacked;

R7 represents a hydrogen atom, a halogen atom or a group of
formula- OR9, -NR10R11 or -SR9;

R8 represents a halogen atom or a group of formula -OR9,
-NR-10R11 or -SR9;




62

R9 represents a hydrogen atom, a C1-C6 alkyl group, an
alkylsulphonyl group, a haloalkylsulphonyl group, an
arylsulphonyl group or a hydroxy protecting group;

R10 and R11 are the same or different and each represents a
hydrogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6
hydroxyalkyl group, a C1-C6, aminoalkyl group, an aralkyl
group, an aryl group, a C1-C6 alkoxy group, an aralkyloxy
group, an amino group, a C1-C20 aliphatic acyl group or an
aromatic acyl group; or R10 and R11 together represent a
substituted methylene group, or R10 and R11, together with the
nitrogen atom to which they are attached, represent a
heterocyclic group having 5 or 6 ring atoms, of which, in
addition to the nitrogen atom shown, 0 or 1 are additional
oxygen, nitrogen or sulphur hetero-atoms, said heterocyclic
group being unsubstituted or having from 1 to 3 C1-C4 alkyl
and/or C1-C4 alkoxy substituents;

R12 represents a C1-C6 alkyl group; and
Z represents a hydrogen atom, a hydroxy group or a
substituted hydroxy group;
provided that, when A represents the group of formula (e), R5
and R6 both represent hydrogen atoms;
Image
and the pharmaceutically acceptable salts and esters
thereof,




63

in which A represents a group of formula:
Image
R1 and R2 are the same or different and each represents a
hydrogen atom, a halogen atom or a group of formula -OR9;

R3 and R4 are the same or different and each represents a
carbamoyl group or a carboxy group;

R5 and R6 both represent hydrogen atoms;

R9 represents a hydrogen atom, a C1-C6 alkyl group, an
alkylsulphonyl group, a haloalkylsulphonyl group, an
arylsulphonyl group or a hydroxy-protecting group;

R12 represents a C1-C6 alkyl group;
Image
and pharmaceutically acceptable salts thereof, wherein

R1 is C1-6 alkyl or C2-6 alkenyl, and

R2 is hydrogen or hydroxy;



64~

Image

or a pharmaceutically acceptable salt thereof, wherein

X is O or S;

R1 is C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkylC1-4 alkyl, or C1-4
alkyl substituted by 1 to 6 fluoro groups;

R2 is hydrogen, -CN, -CONR5R6, -CO2R7, 5-tetrazolyl, -NO2, -NH2
or -NHCOR8 wherein R5, R6, R7 and R8 are independently
hydrogen or C1-4 alkyl;

R3 is hydrogen or C1-4 alkyl; and

R4 is hydrogen or C1-4 alkyl;

with the proviso that R1 is not methyl when R2 is -CO2H,
-CO2CH2CH3 or -CN, X is O, R3 is hydrogen and R4 is hydrogen
or methyl;
Image
and pharmaceutically acceptable salts thereof, wherein
Image



65

is a ring of sub-formula (a), (b), (c), (d), (e), (f) or
(g):
Image
R1 is C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkyl C1-6 alkyl, or
C1-6 alkyl substituted by 1 to 6 fluoro groups;

R2 is C1-6 alkythio, C1-6 alkylsulphonyl, C1-6 alkoxy, hydroxy,
hydrogen, hydrazino, C1-6 alkyl, phenyl, -NHCOR3 wherein R3 is
hydrogen or C1-6 alkyl, or -NR4R5, wherein R4 and R5 together
with the nitrogen atom to which they are attached form a
pyrrolidino, piperidino, hexahydroazepino, morpholino or
piperazino ring, or R4 and R5 are independently hydrogen, C3-5
cycloalkyl or C1-6 alkyl which is optionally substistuted by
-CF3, phenyl, -S(O)n C1-6 alkyl wherein n is 0, 1 or 2, -OR6,
-CO2R7 or -NR8R9 wherein R6 to R9 are independently hydrogen or
C1-6 alkyl, provided that the carbon atom adjacent to the
nitrogen atom is not substituted by said -S(O)n C1-6 alkyl,
-OR6 or -NR8R9 groups ; and
R1 can be hydrogen or hydroxy when R2 is hydroxy;
Image
and pharmaceutically acceptable salts thereof, wherein




66

Image

is a ring of sub-formula (a), (b) or (c):

Image

X is oxygen or sulphur, and

R1 is C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkyl C1-4 alkyl, or
C1-4 alkyl substituted by 1 to 6 fluoro groups;

Image

and pharmaceutically acceptable salts thereof, wherein

R1 is C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkyl C1-6 alkyl, or
C1-6 alkyl substituted by 1 to 6 fluoro groups;

R2 is C1-6 alkythio, C1-6 alkylsulphonyl, C1-6 alkoxy, hydroxy,
hydrogen, hydrazino, C1-6 alkyl, phenyl, -NHCOR3 wherein R3 is
hydrogen or C1-6 alkyl, or -NR4R5, wherein R4 and R5 together
with the nitrogen atom to which they are attached form a
pyrrolidino, piperidino, hexahydroazepino, morpholino or
piperazino ring, or R4 and R5 are independently hydrogen, C3-5
cycloalkyl or C1-6 alkyl which is optionally substituted by
-CF3, phenyl, -S(O)n C1-6 alkyl wherein n is 0, 1 or 2, -OR6,





67

-CO2R7 or -NR8R9 wherein R6 to R9 are independently hydrogen
or C1-6 alkyl, provided that the carbon atom adjacent to the
nitrogen atom is not substituted by said -S(O)n C1-6 alkyl,
-OR6 or NR8R9 groups; and

Image

is a ring of sub-formula (a) or (b):


Image

and pharmaceutically acceptable salts thereof, wherein

R1 is C1-6 alkyl, C2-5 alkenyl, C3-5 cycloalkyl C1-6 alkyl,
phenyl C1-4 alkyl, or C1-4 alkyl substituted by 1 to 6 fluoro
groups;

R2 is hydrogen, hydroxy, C1-4 alkyl, phenyl, mercapto, C1-4
alkylthio, CF3 or amino;

R3 is hydrogen, nitro, amino, C1-4 alkanoylamino, C1-6 alkoxy,
C1-4 alkyl, halo, SO2NR4R5, CONR4R5, cyano or C1-4 alkyl S(O)n;

R4 and R5 are independently hydrogen or C1-6 alkyl; and
n is 0, 1 or 2;





68

provided that R3 is not hydrogen when R1 is C1-6 alkyl or C2-6
alkenyl and R2 is other than hydrogen or hydroxy;

Image

and pharmaceutically acceptable salts thereof, wherein

R1 is C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkyl C1-4alkyl, phenyl
C1-4 alkyl or C1-4 alkyl substituted by 1 to 6 fluoro groups;

R2 is hydrogen, C1-6 alkyl, C1-6 alkythio, C1-6 alkoxy, nitro or
-NR3R4 and

R3 and R4 are independently hydrogen or C1-4 alkyl substituted
by hydroxy provided that the carbon atom adjacent to the
nitrogen atom is not substituted by hydroxy; with the
proviso that R1 is not methyl or ethyl when R2 is hydrogen;

Image

and pharmaceutically acceptable salts thereof, wherein

R1 is C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkyl C1-6 alkyl,
phenyl C1-6 alkyl or C1-6 alkyl substituted by 1 to 6 fluoro
groups; and

R2 is C1-6 alkyl, phenyl, hydroxy, C1-6 alkoxy, halo, -NHCOR3,





69

-NHCONHR4, 5-tetrazolyl, -CO2R5, cyano, -CONR6R7, or -NR8R9
wherein R3 to R7 are independently hydrogen or C1-6 alkyl and
R8 and R9 are independently hydrogen or C1-6 alkyl optionally
substituted by hydroxy provided that the carbon atom
adjacent to the nitrogen atom is not substituted by hydroxy;

Image

and pharmaceutically acceptable salts thereof, wherein

A is N or CH;
B is N or CR3;
D is N or CR2;
R and R1 are independently hydrogen, hydroxy, lower alkyl,
lower alkoxy, phenyloxy, R6 -S(O)n-, W-ALK-Q-,

Image

R2 is hydrogen, lower alkyl, phenyl which may be substituted
by up to three methoxy groups, lower alkyl substituted by
phenyl which may be substituted by up to three methoxy
groups, - lower alkyl -N(R8)2,





70

Image

pyridinyl or lower-alkyl pyridinyl;

R3 is hydrogen , lower alkyl, phenyl, lower alkylphenyl,
pyridinyl or loweralkyl pyridinyl;

R4 and R5 are independently hydrogen or lower alkyl;

R6 is lower alkyl, phenyl, lower alkylphenyl or pyridinyl;

each R7 is independently hydrogen, lower alkyl, phenyl,
pyridinyl,

Image

each R8 is independently lower alkyl, phenyl or pyridinyl;

Q is -O-, -NR9-, -CH2O-, or -CH2NR9-,

W is hydroxy, lower alkoxy, phenoxy, -N(R10)2,

Image

ALK is a C1-C4 straight or branched chain alkyl;





71

R9 is hydrogen, lower alkyl or phenyl;

each R10 is independently hydrogen, lower alkyl or phenyl;

each R11 is independently hydrogen or lower alkyl;

X is -CH2-, -O-, -S(O)-n, -NR10;

n is the integer 0, 1 or 2 and

p is the integer 0 or 1,

with the provisos that:

one and only one of B or D must be N;

when A is CH, when D is N, when B is CR3 where R3 is H, when
R2 is hydrogen, lower alkyl or phenyl then one or both of R
and R1 must be

Image

or W-ALK-Q;

Image

and pharmaceutically acceptable salts thereof, wherein

R1 is C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkyl C1-6 alkyl,
phenyl C1-6 alkyl or C1-6 alkyl substituted by 1 to 6 fluoro
groups; and





72

R2 is hydrogen, amino, -NHCOR3, or CONR4R5, wherein R3 is C1-6
alkyl, R4 is C1-6 alkyl and R5 is hydrogen or C1-6 alkyl;

Image

and pharmaceutically salts thereof, wherein

X is O or S:

R1 is C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkyl C1-4 alkyl, or
C1-4 alkyl substituted by 1 to 3 fluoro groups;

R2 is hydrogen, -CN, -CONR5R6, -CO2R7, 5-tetrazolyl, -NO2 or
-NHCOR8 wherein R5 to R8 are independently hydrogen or C1-4
alkyl;

R3 is hydrogen or C1-4 alkyl;
R4 is hydrogen or C1-4 alkyl; and

R is halo, C1-4 alkyl, C1-4 alkoxy, cyano, -CONR9R10, -CO2R11,
-S(O)n C1-4 alkyl, -NO2, - NH2, -NHCOR12, or -SO2NR13R14 wherein n
is 0, 1 or 2 and R9 to R14 are independently hydrogen or C1-4
alkyl;

with the proviso that R1 is not methyl when R2 is -CO2H,
-CO2CH2CH3 or -CN, X is O, R3 is hydrogen, R4 is hydrogen or
methyl and R is 6-methoxy;





73

Image

and pharmaceutically acceptable salts thereof, wherein

R1 is C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkyl C1-6 alkyl, or
C1-6 alkyl substituted by 1 to 6 fluoro groups;

R2 is C1-6 alkythio, C1-6 alkylsulphonyl, C1-6 alkoxy, hydroxy,
hydrogen, hydrazino, C1-6 alkyl, phenyl, -NHCOR3 wherein R3 is
hydrogen or C1-6 alkyl, or -NR4R5, wherein R4 and R5 together
with the nitrogen atom to which they are attached form a
pyrrolidino, piperidino, hexahydroazepino, morpholino or
piperazino ring, or R4 and R5 are independently hydrogen, C3-5
cycloalkyl or C1-6 alkyl which is optionally substituted by
-CF3, phenyl, -S(O)n C1-6 alkyl wherein n is 0, 1 or 2, -OR6,
-CO2R7 or -NR8R9 wherein R6 to R9 are independently hydrogen or
C1-6 alkyl, provided that the carbon atom adjacent to the
nitrogen atom is not substituted by -S(O)n C1-6 alkyl, -OR6 or
-NR8R9;

R is halo, C1-4 alkyl, C1-4 alkoxy, cyano, -CONR10R11, CO2R12,
C1-4 alkyl S(O)n, -NO2, -NH2, -NHCOR13 or SO2NR14R15 wherein n is
0, 1 or 2 and R10 to R15 are independently hydrogen or C1-4
alkyl; and

Image

is a ring of sub-formula (a) or (b):



74

Image

and pharmaceutically acceptable salts thereof,

wherein Image represents a single or double bond;

R1 is hydrogen or C1-4 alkyl;

Y is a single bond or C1-6 alkylene;

A is

-CyA-(R2)1,

-O-R0 or -S(O)p-R0, or

-NR16R17

in which R0 is hydrogen, C1-4 alkyl, hydroxy C1-4 alkyl or CyA-
(R2)1;

R16 and R17 independently are hydrogen or C1-4 alkyl;

p is 0-2;

CyA is

a 3-7 membered, saturated or unsaturated carbocycle,
a 4-7 membered, unsaturated or partially saturated
heterocycle containing one nitrogen atom




75

a 4-7 membered, unsaturated or partially saturated
heterocycle containing one nitrogen atom and one oxygen
atom,

a 4-7 membered, unsaturated or partially saturated
heterocycle containing one nitrogen atom and two oxygen
atoms,

a 4-7 membered, unsaturated or partially saturated
heterocycle containing two nitrogen atoms and one oxygen
atom

a 4-7 membered, unsaturated or partially saturated
heterocyle containing one or two sulfur atoms,

a 4-7 membered, unsaturated, partially saturated or fully
saturated heterocycle containing one or two oxygen atoms,

R2 is (1) hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy,
(4) -COOR5, in which R5 is hydrogen or C1-4 alkyl, (5) -NR6R7,
in which R6 and R7 independently are hydrogen or C1-4 alkyl,
(6) -SO2NR6R7, in which R6 and R7 are as hereinbefore defined,
(7) halogen, (8) trifluoromethyl, (9) nitro or (10)
trifluoromethoxy;

Z is a single bond, methylene, ethylene, vinylene or
ethynylene;

CyB is a 4-7 membered, unsaturated or partially saturated
heterocycle containing one nitrogen atom,

a 4-7 membered, unsaturated or partially saturated
heterocycle containing two nitrogen atmos,

a 4-7 membered, unsaturated or partially saturated
heterocycle containing three nitrogen atoms,





76

a 4-7 membered, unsaturated or partially saturated
heterocycle containing one or two oxygen atoms,

a 4-7 membered, unsaturated or partially saturated
heterocycle containing one or two sulfur atoms,

R3 is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen or
trifluoromethyl;

R4 is (1) hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy,
(4) -COOR8, in which R8 is hydrogen or C1-4 alkyl, (5) -NR9R10,
in which R9 is hydrogen, C1-4 alkyl or phenyl (C1-4 alkyl) and
R10 is hydrogen or C1-4 alkyl, (6) -NHCOR11, in which R11 is
C1-4 alkyl, (7) -NHSO2R11, in which R11 is as hereinbefore
defined, (8) SO2NR9R10 in which R9 and R10 are as hereinbefore
defined, (9) -OCOR11, in which R11 is as hereinbefore defined,
(10) halogen, (1) trifluoromethyl, (12) hydroxy, (13)
nitro, (14) cyano, (15) -SO2N=CHNR12R13 in which R12 is
hydrogen or C1-4 alkyl and R13 is C1-4 alkyl, (16) -CONR14R15 in
which R14 is hydrogen or C1-4 alkyl or phenyl (C1-4 alkyl) and
R15 is C1-4 alky, (17) C1-4 alkylthio, (18) C1-4 alkylsulfinyl,
(19) C1-4 alkylsulfonyl, (20) ethynyl, (21) hydroxymethyl,
(22) tri(C1-4 alkyl) silylethynyl or (23) acetyl; and

l, m and n independently are 1 or 2;

with the proviso that

CyA-(R2)1 does not represent cyclopentyl or
trifluoromethylphenyl when Y is a single bond,

CyB does not bond to Z through a nitrogen atom when Z is
vinylene or ethynylene,

CyB is not pyridine or thiophene when CyA is a 4-7 membered
unsaturated, partially saturated or fully saturated
heterocycle containing one or two oxygen atoms, and




Y is not a single bond when A is -O-R0 or -NR16R17;

Image

and pharmaceutically acceptable salts thereof,

wherein the phenyl ring either in position 6, 7, 8 or 9 may
contain a nitrogen atom instead of a CH-moiety and the
residues R1, R2, R3 and R4 have the following meanings:

R1: C2-C6-alkenyl, C2-C6-alkynyl, hydroxy, C1-C6-alkoxy, C3-C6-
alkenyloxy, C3-C6-alkynyloxy, C2-C6-alkanoyloxy, benzoyloxy,
morpholinocarbonyloxy, C1-C6-alkyloxycarbonyloxy, C1-C6-
alkylaminocarbonyloxy, C1-C6-dialkylaminocarbonyloxy or the
moiety

-Alk-A

wherein Alk is: C1-C6-alkyl, C2-C6-hydroxy-alkyl or C3-C6-
cycloalkyl and the symbol A means:

(1) hydrogen, halogen, hydroxy, C1-C6-alkoxy, C2-C6-
alkanoyloxy, phenyl;

(2) -NHR5, -NR5R6, NR5R6R7, pyridylamino, imidazolyl,
pyrrolidinyl, N-C1-C6-alkylpyrrolidinyl, piperidylamino, N-
(phenyl-C1-C4-alkyl)-piperidylamino, wherein R5 and R6 are
identical or different and mean hydrogen, C1-C6-alkyl, C3-C7-
cycloalkyl, C3-C7-hydroxycycloalkyl, morpholino-C1-C6-alkyl,
phenyl, phenyl-C1-C6-alkyl or phenyl-C2-C6-oxyalkyl, wherein
the phenyl residues also may be substituted with halogen and
R7 is hydrogen or C1-C6-alkyl;





78

(3) The moiety

-CO-D

wherein D is phenyl, C1-C6-alkyl, C3-C7-cycloalkyl, hydroxy,
C1-C6-alkoxy, C3-C7-cycloalkyloxy, morpholino, pyrrolidino,
piperidino, homopiperidino, piperazino, -NHR5 or -NR5R6 and R5
and R6 have the above given meanings;

(4) The moiety

Image

wherein n may be an integer of 1-3 and E means CH2, oxygen,
sulphur, NH, CHOH, CH-C1-C6-alkyloxy, CH-C2-C6-alkanoyloxy,
CHC6H5, CHCOD, CH-CN2C6H5, N-C1-C6-alkyl, N-C1-C6-hydroxyalkyl,
N-C6H5, N-CH2C6H5, N-CH(C6H5)2, N-(CH2)2-OH, N-(CH2)3-OH or NCOD
and phenyl residues (C6H5) may also be substituted with
halogen, C1-C6-alkoxy, trifluoromethyl, C1-C6-alkyl,
methylenedioxy or cyano and D has the above given meaning;

R2 and R3, which may be identical or different:

hydrogen, halogen, hydroxy, C1-C6-alkyl, trifluoromethyl,
-CN, C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, -NHR5,
-NR5R6, NR5R6R7 (R5, R6, R7 have the meanings as given above),
or the moiety -G-Alk-A, wherein Alk and A have the above
given meanings and G is oxygen, sulphur, NH or NR5;

R4: hydrogen or halogen,

wherein R1 also may be hydrogen, if R2 is the moiety

Image





79

and R5 means phenyl, C1-C4-alkoxy-phenyl or diphenylmethyl
and R3 and R4 are hydrogen,

and the physiologically acceptable acid addition salts and
quarternary ammonia salts thereof, excluding the compounds
of formula I wherein R1 is methyl, dimethylamino-propyl,
dimethylamino-ethyl, morpholino-ethyl or pyrrolidino-ethyl,
R2, R3 and R4 are hydrogen and the phenyl ring does not
contain a nitrogen atom;

Image

and pharmaceutically acceptable salts thereof,

wherein J is oxygen or sulfur,

R1 is hydrogen, alkyl or alkyl substituted with aryl or
hydroxy;

R2 is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl
substituted with aryl, heteroaryl, hydroxy, alkoxy, amino,
monoalkylamino, dialkylamino, or -(CH2)m TCOR20 wherein m is
an integer from 1 to 6, T is oxygen or -NH- and R20 is
hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with
aryl or heteroaryl;

R3 is hydrogen, halo, trifluoromethyl, alkoxy, alkylthio,
alkyl, cycloalkyl, aryl, aminosulfonyl, amino,
monoalkylamino, dialkylamino, hydroxyalkylamino,
aminoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl or





80

alkyl substituted with aryl, hydroxy, alkoxy, amino,
monalkylamino or dialkylamino;

R a, R b, R c and R d independently represent hydrogen, alkyl,
cycloalkyl or aryl; or (R a and R b) or (R c and R d) or (R b and
R c) can complete a saturated ring of 5- to 7-carbon atoms, or
(R a and R b) taken together and (R b and R c) taken together,
each complete a saturated ring of 5- to 7-carbon atoms,
wherein each ring optionally can contain a sulfur or oxygen
atom and whose carbon atoms may be optionally substituted
with one or more of the following: alkenyl, alkynyl,
hydroxy, carboxy, alkoxycarbonyl, alkyl or alkyl substituted
with hydroxy, carboxy or alkoxycarbonyl; or such saturated
ring can have two adjacent carbon atoms which are shared
with an adjoining aryl ring; and

n is zero or one;

Image

and pharmaceutically acceptable salts thereof,

wherein, ring A signifies a benzene ring, pyridine ring or
cyclohexane ring, ring B signifies a pyridine ring,
pyrimidine ring or imidazole ring,

rings A and B are bonded by sharing two atoms, and
the atoms that are shared may be either carbon or nitrogen
atoms,

except for the event that ring A is a pyridine
ring and ring B shares a nitrogen atom of this pyridine ring
for bonding, ring A shall be as shown by the formula





81

Image

wherein, R1, R2, R3 and R4 independently represent a hydrogen
atom, a halogen atom, an optionally halogen-substituted
lower alkyl radical, an optionally substituted cycloalkyl
radical, a lower alkoxy radical, a hydroxyalkyl radical, a
nitro radical, an amino radical, an acyl-amino radical, an
optionally protected carboxyl radical, a radical represented
by the formula

Image

(where R7 in this formula signifies a lower alkyl radical and
n may be 0 or an integer with a value of 1 - 2), or a
radical represented by the formula

Image

(where R45 and R46 in this formula independently represent a
hydrogen atom or a lower alkyl radical, or R45 and R46 may
unite with the nitrogen atom to which they are bonded to
form a ring optionally containing one or more heteroatoms in
addition to the nitrogen atom to which R45 and R46 are bonded
selected from nitrogen and oxygen, and this ring may be
substituted),

further, two of the R1, R2, R3, and R4 radicals may combine to
form a methylenedioxy, ethylenedioxy or phenyl ring,





82

R5 signifies a hydrogen atom, a halogen atom, a
hydroxyl group, a hydrazino radical, an optionally
substituted cycloalkyl radical, a lower alkoxy radical, a
lower alkenyl radical, an optionally protected carboxyalkyl
radical, an optionally protected carboxyalkenyl radical, a
hydroxy alkyl radical, an optionally protected carboxyl
radical, a radical represented by the formula

Image

(where R3 in this formula signifies a lower alkyl radical and
m may be either 0 or an integer with a value from 1 - 2), a
radical represented by the formula -O-R9 (where R9 in this
formula signifies an optionally protected hydroxyalkyl
radical, an optionally protected carboxyalkyl radical or an
optionally substituted benzyl radical), a radical
represented by the formula

Image

(where R23 in this formula signifies a hydroxyl group, a
lower alkyl radical, a hydroxyalkyl radical or a
hydroxyalkyloxy radical), an optionally substituted
heteroaryl radical, an optionally substituted 1,3
benzodioxolyl radical, an optionally substituted 1,4
benzodioxyl radical, an optionally substituted 1,3
benzodioxolyl alkyl radical, an optionally substituted 1,4
benzodioxyl alkyl radical, a radical represented by the
formula C(R24)=X (where X in this formula signifies an oxygen
atom, a sulphur atom or a radical represented by the formula
=N-R10 (where R10 in this formula signifies a hydroxyl group
or an optionally protected carboxyalkyloxy radical) and R24




83

signifies a hydrogen atom or a lower alkyl radical), or a
radical represented by the formula -NR11R12 (where R11 and R12
in this formula independently represent a hydrogen atom, a
lower alkyl radical, a hydroxyalkyl radical, an aminoalkyl
radical, an optionally protected carboxyalkyl radical, an
alkyl carbamoyl radical, an optionally protected
carboxyalkylcarbamoyl radical, an optionally substituted
heteroaryl alkyl radical, a 1,3 benzoxolyl alkyl radical or
a 1,4 benzodioxyl alkyl radical, and where, furthermore, R11
and R22 may unite with the nitrogen atom to which they are
bonded to form a ring optionally containing one or more
heteroatoms in addition to the nitrogen atom to which R11 and
R12 are bonded selected from nitrogen and oxygen, and this
ring may also be substituted),

R6 signifies a hydrogen atom, a halogen atom, a
hydroxyl group, an amino group, a lower alkyl radical, a
lower alkoxy radical, a lower alkenyl radical, a 1,3-
benzodioxolyl alkyloxy radical, a 1,4-benzodioxyl alkyloxy
radical, an optionally substituted phenyl alkyloxy radical,
a radical represented by the formula

Image

(where R13 and R14 in this formula independently represent a
hydrogen atom, a lower alkyl radical or an alkoxy radical,
furthermore, R13 and R14 may combine to form methylenedioxy
or ethylenedioxy), a radical represented by the formula

Image





84

a radical represented by the formula

Image

a radical represented by the formula

Image

a radical represented by the formula

Image

(where R15 and 16 used in these formulae independently
represent a hydrogen atom, a lower alkyl radical or a lower
alkoxy radical, furthermore, R15 and R16 may combine to form
methylenedioxy or ethylenedioxy), a piperidine-4-spiro-2'-
dioxane-1-yl radical, a radical represented by the formula

Image

(where R48 and R49 in this formula independently represent a
hydrogen atom, a lower alkyl radical or a lower alkoxy
radical, furthermore, R48 and R49 may combine to form
methylenedioxy or ethylenedioxy, Z signifies a sulphur atom
or an oxygen atom), a radical represented by the formula

Image

(where R50 in this formula signifies a hydroxyl group, a
halogen atom, a lower alkyl radical, a lower alkoxy radical,





85

an optionally protected carboxyl radical, a cyano radical, a
hydroxyalkyl radical or a carboxyalkyl radical), a radical
represented by the formula

Image

(where R17 in this formula stands for a hydrogen atom, a
lower alkyl radical, an acyl radical, a lower alcoxyalkyl
radical, an optionally protected carboxyalkyl radical or a
hydroxyalkyl radical, Y stands for a radical represented by
the formula

~(CH2)q~

(where q in this formula signifies 0 or an integer from
1 - 8), or a radical represented by the formula

Image

furthermore, when q in the radical represented by the
formula

~(CH2)q~


has the value of an integer from 1 - 8, the respective
carbon atoms may also possess 1 - 2 substitutuents, R18
signifies a hydrogen atom, a hydroxyl group, an optionally
protected carboxyl radical, a cyano radical, an acyl
radical, an optionally substituted heteroaryl radical, or an
optionally substituted cycloalkyl radical), or a radical
represented by the formula


86


Image
(where R19 in this formula stands for a hydrogen atom, a
lower alkyl radical, a lower alkoxyalkyl radical, an acyl
radical, an optionally protected carboxyalkyl radical or a
hydroxyalkyl radical R20, R21, and R22 independently represent
a hydrogen atom, a halogen atom, a hydroxyl group, an amino
group, a nitro radical, a lower alkyl radical, a lower
alkoxy radical, a lower alkoxyalkyl radical, a lower alkenyl
radical, an acyl radical, an acylamino radical, an
alkylsulphonylamino radical, a hydroxyiminoalkyl radical, a
alkyloxycarbonylamino radical, an alkyloxycarbonyloxy
radical or an optionally substituted heteroaryl radical,
furthermore, any two of R20, R21, and R22 may combine to form
a saturated or unsaturated ring that may contain one or more
heteroatoms selected from nitrogen, sulphur and oxygen, and
r signifies 0 or an integer from 1 to 8);
Image
and pharmaceutically acceptable salts thereof, wherein:
R1, R2 and R3 are independently selected from the group
consisting of hydrogen, lower alkyl, lower alkoxy, halogeno,
hydroxy, (di-lower alkyl) amino, 4-morpholinyl, 1-
pyrrolidinyl, 1-pyrrolyl, -CF3, -OCF3, phenyl and
methoxphenyl; or R1 and R2 together are methylenedioxy; or R1


87


and R2 together with the carbon atoms to which they are
attached form a benzene ring; and
R a is hydrogen and R b and R c, together with the carbon atoms
to which they are attached, form a saturated ring of 5
carbons; or R a is lower alkyl, R b is hydrogen or lower alkyl,
and R c is hydrogen; or R a, R b and the carbon atom to which
they are attached form a saturated ring of 5-7 carbons, and
R c is hydrogen; or R a is hydrogen, and R b, R c and the carbon
atoms to which they are attached form a tetrahydrofuran
ring; or R a and R b, together with the carbon atom to which
they are attached, and R b and R c, together with the carbon
atoms to which they are attached, each form a saturated ring
of 5-7 carbons;
Image
and pharmaceutically acceptable salts thereof, wherein:
R is amino or hydrazino;
R1 is cycloalkyl having 3 to 8 ring carbon atoms inclusive or
cycloalkenyl having 4 to 8 ring carbon atoms inclusive;
Image
and pharmaceutically acceptable addition salts thereof,
wherein


88


R1 is hydrogen, alkyl, C4 to C7 cycloalkyl, C4 to C7
cycloalkyl substituted by C1 to C10 alkyl or hydroxyl, 2- or
3-tetrahydrothienyl, 1,1, -dioxide, C4 to C7 cycloalkyl-C1 to
C10 alkyl, carboxy-C1 to C10 alkyl, carbo-C1 to C4 lower alkoxy
C1 to C10 alkyl, dialkylamino C1 to C10 alkyl, phenyl-C1 to C4
lower-alkyl, phenyl-C1 to C4 lower-alkyl in which the phenyl
ring is substituted in the 2, 3 or 4 position by one or two
substituents, the same or different, selected from the group
consisting of amino, halogen, C1 to C10 alkyl, carboxyl,
carbo-C1 to C4 lower-alkoxy, carbamoyl, NHSO2 (quinolinyl),
nitro and cyano;
R3 is C1 to C4 lower alkyl, phenyl C1 to C4 lower alkyl,
lower-alkoxyphenyl-C1 to C4 lower-alkyl, di-C1 to C4 lower-
alkoxy-phenyl-C1 to C4 lower alkyl, pyridyl-C1 to C4 lower
alkyl, C4 to C7 cycloalkyl-C1 to C4 lower-alkyl, phenylamino,
di-C1 to C1-4 alkylamino, halogen, trifluoromethyl, C1 to C4
lower-alkylthio, cyano or nitro; and
R6 is a nine or ten membered bicyclic ring containing carbon
and from one to two nitrogen atoms, and the ring is made up
of fused 5 or 6 membered rings, optionally substituted at
any available carbon atom by one or two substituents, the
same or different, selected from the group consisting of C1
to C4 lower-alkyl, halogen, C1 to C4 lower-alkoxy, C4 to
cycloalkyloxy, 4-morpholinyl, C1 to C4 lower-alkoxy-C1 to C4
lower-alkoxy, hydroxy, imidazolyl, oxo and 4-morpholinyl-C1
to C4 lower-alkoxy, or optionally substituted at any
available nitrogen atom at any time by C1 to C4 lower-alkyl,
C2 to C4 lower-alkanoyl, or trifluoroacetyl;


89


Image
and pharmaceutically acceptable salts thereof,
where R1 stands for a lower alkyl radical or a lower
cycloalkyl radical;
R2 for a carboxy radical, esterified carboxy radical or an
amidized carboxy radical; and
R3 and R4 each stand for a hydrogen atom, a halogen atom, a
carboxy radical, an esterified carboxy radical or a lower
alkyl radical optionally substituted by 1 - 3 halogen atoms,
respectively;
Image
(2-phenyl-8-ethoxycycloheptimidazole);
Image
and pharmacologically acceptable salts thereof,
in which ring A represents a benzene, pyridine or
cyclohexane ring and B represents a pyridine, imidazole or
pyrimidine ring, with the proviso that rings A and B are
bonded to each other with two atoms being shared by the


90


rings, and the shared atoms may be any of carbon and
nitrogen atoms;
R1 represents a group represented by the formula: -NR4R5
(wherein R4 and R5 may be the same or different from each
other and each represents a hydrogen atom, a lower alkyl or
acyl group or a carboxyl group which may be protected, or
alternatively R4 and R5 may form a ring together with the
nitrogen atom to which they are bonded, wherein the ring may
be substituted), or a heteroaryl group which has one or two
nitrogen atoms and may be substituted;
R2 represents a hydrogen atom, a group represented by the
formula:
Image
(wherein R8 represents a carboxyl or tetrazolyl group which
may be protected), or a halogen atom; and
R3 represents a hydrogen atom or a group represented by the
formula:
Image
(wherein R6 and R7 each represent a hydrogen or halogen atom
or a lower alkoxy group, or alternatively R6 and R7 may
together form a methylenedioxy or ethylenedioxy group);


91


Image
and pharmaceutically acceptable salts and solvates thereof,
in which:
R1 represents arylmethyl or C1-6 alkyl optionally substituted
by one or more fluorine atoms;
R2 represents methyl;
R3 represents C2-4 alkyl;
R4 represents nitro, cyano, C1-6 alkoxy, C(=X)NR6R7, NR8R9,
(CH2)m NR10C(=Y)R11 or a 5-membered heterocyclic ring selected
from thienyl, thiazolyl and 1,2,4-triazolyl each ring
optionally substituted by a C1-4 alkyl or aryl group; or when
R1 is arylmethyl or C1-6 alkyl substituted by one or more
fluorine atoms then R4 may also represent hydrogen;
R5 represents hydrogen or C1-6 alkyl;
R6 represents hydrogen or C1-6 alkyl;
R7 represents hydrogen, amino, hydroxyl, C1-6 alkyl, aryl or
arylC1-4 alkyl;
R8 represents hydrogen or C1-6 alkyl;
R9 represents hydrogen, C1-6 alkyl, SO2R12, CO2R12, C(=NCN)SR12
or C(=NCN)NR13R14;
R10 represents hydrogen or C1-6 alkyl;


92


R11 represents C1-6 alkyl optionally substituted by one or
more halogen atoms, or R11 represents aryl, aryl C1-4 alkyl,
thienyl, NR15R16, CH2NR17R18 or R10 and R11 together represent
-A(CH2)n-;
R12 represents C1-6 alkyl, aryl or arylC1-4alkyl;
R13 represents hydrogen or C1-6 alkyl;
R14 represents hydrogen, C1-6 alkyl, aryl, aryl C1-4 alkyl or
R13 and R14 together with the nitrogen atom to which they are
attached form a morpholino, piperazino or N-C1-4
alkylpiperazino ring;
R15 represents hydrogen or C1-6 alkyl or R10 and R15 together
represent -A(CH2)n-;
R16 represents hydrogen, C1-6 alkyl, aryl, aryl C1-4 alkyl,
CO2R12, CH2CO2R12 or R15 and R16 together with the nitrogen atom
to which they are attached form a morpholino, piperazino or
N-C1-4alkyl-piperazino ring;
R17 represents hydrogen or C1-6 alkyl;
R18 represents hydrogen, C1-6 alkyl, aryl, aryl C1-4 alkyl,
COR12 or R17 and R18 together with the nitrogen atom to which
they are attached form a morpholino, piperazino, or N-C1-4
alkylpiperazino ring;
A represents CH2 or C = O;
m represents zero or 1;
n represents 1,2 or 3;
X represents S or NH, or when R7 represents amino then X may
also represent O;
Y represents O or S;


93


Image
and pharmaceutically acceptable salts thereof,
wherein A is a bond, C1-4 alkylene or C1-4 oxyalkylene;
Y is a bond, C1-4 alkylene, C1-4 alkyleneoxy, C1-4
alkoxyphenylene or phenyl (C1-4) alkylene;
Z is a bond or vinylene;
R1 is a 4-15 membered heterocyclic ring containing one or
two nitrogen atoms optionally substituted by one or two
groups chosen from C1-4 alkyl, C1-4 alkoxy, halogen,
trifluoromethyl, and nitro;
R2 is
(i) 4-15 membered heterocyclic ring containing one or
two heteroatoms chosen from nitrogen, oxygen and sulphur,
not more than one heteroatom being sulphur, optionally
substituted by one or two groups chosen from C1-4 alkyl,
C1-4 alkoxy, halogen, trifluoromethyl, nitro and groups of
formula: - COOR10, wherein R10 is hydrogen or C1-4 alkyl,
(ii) C4-15 carbocyclic ring,
(iii) C1-4 alkoxy,
(iv) hydroxy(C1-4 alkoxy) or
(v) hydroxy,


94


R3 is
4-15 membered heterocyclic ring containing one or two
heteroatoms chosen from nitrogen, oxygen and sulphur, not
more than one heteroatom being oxygen or sulphur, optionally
substituted by one or two groups chosen from C1-4 alkyl, C1-
4 alkoxy, halogen, trifluoromethyl, nitro, cyano, ethynyl
and groups of formula: - SONR7R8, wherein R7 and R8 are
independently hydrogen or C1-4 alkyl,
C4-15 carbocyclic ring,
a group of formula:CH2 = CH(X)- wherein X is halogen, or
hydrogen;
and 1 is 1 or 2;
provided that R2 is not hydroxy when Y is a bond; R1 is not
bonded through its nitrogen atom when Z is vinylene; and
excluding compounds of the formula:
Image
wherein R AA is methyl or n-propyl;
R BB is cyclopentyl, cyclohexyl, 2-hydroxyethyl, methoxyethyl,
2-(1-piperindinyl)ethyl, phenyl or benzyl which may be
substituted by 1 or 2 of methyl, methoxy, chloro, nitro and
trifluoromethyl;
R CC is hydrogen or methyl;


95


R DD is methyl, n-propyl, isopropyl or benzyl; and
R EE is hydrogen or methyl;
and the compound of formula:
Image
and pharmaceutically acceptable salts thereof,
where R1 and R2 independently represent hydrogen, lower alkyl
(the respective alkyls may be cycloalkyl with a substitution
number of 1 - 3, either identical or different), hydroxy,
lower alkoxy, carboxy, lower alkoxycarbonyl, amino,
monoalkyl-substituted amino, dialkyl-substituted amino,
nitro, halogen, an alicyclic heterocyclic radical (the
respective alicyclic heterocyclic radicals may be
independently substituted by lower alkyl with a substitution
number of 1 - 3, aralkyl, aryl optionally substituted by a
lower alkoxy radical with a substitution number from 1 - 3
or an aromatic heterocyclic radical), cycloalkyl, di-
cycloalkyl, benzocycloalkyl (the respective benzoalkyls may
be independently substituted by lower alkyl with a
substitution number of 1 - 3, hydroxy, lower alkoxy,
carboxy, lower alkoxycarbonyl, amino, aminoalkyl-substituted
amino, dialkyl-substituted amino, nitro, sulphonamide,


96


halogen, or trifluoromethyl), lower alkenyl, aryl (the
respective aryls may be independently substituted by lower
alkyl with a substitution number of 1 - 3, hydroxy, lower
alkoxy, carboxy, low alkoxycarbonyl, amino, monoalkyl-
substituted amino, di-alkyl substituted amino, nitro,
sulphonamide, halogen or trifluoromethyl), aromatic
heterocyclic radical-substituted alkyl (the respective
aromatic heterocyclic radical-substituted parts may be
independently substituted by lower alkyl with a substitution
number of 1 - 3, hydroxy, lower alkoxy, carboxy, lower
alkoxycarbonyl, amino, monoalkyl-substituted amino, di-alkyl
substituted amino, nitro, sulphonamide, halogen, or
trifluoromethyl, or the respective alkyl parts may be
substituted by aryl), aromatic heterocyclic radicals (the
respective aromatic heterocyclic radicals may be
independently substituted by lower alkyl with a substitution
number of 1 - 3, hydroxy, lower alkoxy, carboxy, lower
alkoxycarbonyl, amino, monoalkyl-substituted amino, di-alkyl
substituted amino, nitro, sulphonamide, halogen or
trifluoromethyl), or aralkyl (the aryl parts of the
respective aralkyls may be independently substituted by
lower alkyl with a substitution number of 1 - 3, lower
alkoxy, di-alkoxy-substituted amino, halogen or
trifluoromethyl); and, furthermore,
R1 and R2 may stand for a heterocyclic radical formed by R1
and R2 combining with the nitrogen (N) atom to which they are
bonded (the heterocyclic radical may be substituted by alkyl
with a substitution number of 1 - 3, aryl, or aralkyl);
R3 stands for hydrogen, lower alkyl (the lower alkyl may be
substituted by cycloalkyl with a substitution number of
1 - 3, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl,
amino, monoalkyl-substituted amino, di-alkyl-substituted
amino, nitro, halogen, or alicyclic heterocyclic radical


97


(the alicyclic heterocyclic radical may be substituted by
lower alkyl with a substitution number of 1 - 3, aralkyl,
aryl optionally substituted by a lower alkoxy radical with a
substitution number from 1 - 3 or an aromatic heterocyclic
radical.)), cycloalkyl, lower alkenyl, aryl (the aryl may be
subsituted by lower alkyl with a substitution number of
1 - 3, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl,
amino, monoalkyl-substituted amino, di-alkyl substituted
amino, nitro, sulphonamide, halogen or trifluoromethyl),
aromatic heterocyclic radical-substituted alkyl (the
aromatic heterocyclic radical-substituted part may be
substituted by lower alkyl with a substitution number of
1 - 3, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl,
amino, monoalkyl-substituted amino, di-alkyl substituted
amino, nitro, sulphonamide, halogen, or trifluoromethyl, or
the alkyl part may be substituted by aryl), aromatic
heterocyclic radical (the aromatic heterocyclic radical may
be substituted by lower alkyl with a substitution number of
1 - 3, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl,
amino, monoalkyl-substituted amino, di-alkyl substituted
amino, nitro, sulphonamide, halogen or trifluoromethyl), or
aralkyl (the aryl part of the aralkyl may be substituted by
lower alkyl with a substitution number of 1 - 3, lower
alkoxy, di-alkoxy-substituted amino, halogen or
trifluoromethyl.), and
X stands for oxygen or sulphur;
Image


98


and pharmaceutically acceptable salts thereof,
where R1, R2, R3 and R4 independently represent a hydrogen
atom, a halogen atom, a hydroxyl group, an optionally
halogen-substituted lower alkyl radical, an optionally
halogen-substituted lower alkoxy radical, a nitro radical, a
hydroxyalkyl radical, a cyano radical, a radical represented
by the formula
Image
(where R9 and R10 independently represent a hydrogen atom, an
optionally halogen-substituted lower alkyl radical, an aryl-
alkyl radical, a heteroaryl-alkyl radical, an acyl radical,
an optionally protected carboxyl radical, and, where
furthermore R9 and R10 may combine with the nitrogen to which
they are bonded to form a ring, and where, moreover, this
ring may be substituted, p stands for 0 or an integer having
a value from 1 - 6), a carbamoyl radical which may be
substituted, a pyrazolyl radical which may be substituted,
an imidazolyl radical which may be substituted, or a radical
represented by the formula
Image
where R13 signifies a hydrogen atom or an optionally halogen-
substituted lower alkyl radical; and, where q is 0 or an
integer with a value of 1 - 2,
furthermore, R1 and R2, R2 and R3 or R3 and R4 may combine
with the carbon atoms to which they are bonded to form a
ring,


99


R5 and R6 stand for a hydrogen atom, a halogen atom, a
hydroxyl group, a cyano radical, an optionally halogen-
substituted lower alkyl radical, or an optionally halogen-
substituted lower alkoxy radical, furthermore, R5 and R6 may
combine with the carbon atoms to which they are bonded to
form an oxolane ring, a 1,3-di-oxolane ring or a 1,4 di-
oxane ring,
W signifies the radical represented by the formula -N= or a
radical represented by the formula -CH=,
R7 and R8 independently represent a hydrogen atom, an
optionally halogen-substituted lower alkyl radical,
furthermore, R1 and R7 may combine with the carbon and
nitrogen atoms to which they are bonded to form a ring that
may contain one or more heteroatoms in addition to the
nitrogen atom to which R7 is bonded selected from nitrogen,
oxygen and sulphur, and this ring may be substituted,
A stands for a hydrogen atom, an optionally halogen-
substituted lower alkyl radical, or a radical represented by
the formula -X-(CH2)m-Z (where X stands for a radical
represented by the formula -CO-, a radical represented by
the formula -CS-, a radical represented by the formula
-CH2-, or a radical represented by the formula -C(O)2,
Z signifies a hydroxyl group, an optionally halogen-
substituted lower alkoxy radical, a cyano radical, a halogen
atom, an optionally protected carbamoyl radical, an
optionally substituted aryl radical, an optionally
substituted aryloxy radical, an optionally substituted
heteroaryl radical, an optionally substituted heteroaryl
alkyloxy radical, a radical represented by the formula
-NR11R12 (where R11 and R12 independently represent a hydrogen
atom, an optionally halogen-substituted lower alkyl


100


radicals, an optionally substituted aryl-alkyl radical, an
optionally substituted heteroaryl-alkyl radical, an aryl
radical, an optionally protected carboxy radical, or an
optionally substituted carbamoyl radical, furthermore, R11
and R12 may combine with the nitrogen atom to which they are
bonded to form a ring, which may be substituted), or a
cycloalkyl radical which may be substituted,
m may be either 0 or an integer with a value from 1 - 6,
Y stands for an oxygen or sulphur atom,
n signifies either 0 or an integer with a value from 1 - 6;
Image
and pharmaceutically acceptable salts, addition salts or
hydrates thereof,
wherein R1 is hydrogen or C1-4 alkyl;
Y is a single bond or C1-6 alkylene;
A is
-CyA-(R2)1,
-O-R0 or -S(O)p - R0,
in which R0 is R0A or R0B,
R0A is -CyA- (R2)1;
R0B is hydrogen or C1-4 alkyl;
p is 0-2;


101


CyA is
(1) 3-7 membered, saturated or unsaturated, monocyclic
carbocyclic ring,
(2) 7-membered, unsaturated or partially saturated,
monocyclic hetero ring containing as heteroatoms, one
nitrogen atom, one nitrogen and one oxygen atoms, two
nitrogen and one oxygen atoms, or one nitrogen and two
oxygen atoms,
(3) 6-membered, unsaturated or partially saturated,
monocyclic hetero ring containing as heteroatoms, one
nitrogen and one oxygen atoms, two nitrogen and one oxygen
atoms, or one nitrogen and two oxygen atoms,
(4) 6-membered, unsaturated or partially saturated,
monocyclic hetero ring containing as a heteroatom, one
nitrogen atom,
(5) 4- or 5-membered, unsaturated or partially
saturated, monocyclic hetero ring containing as heteroatoms,
one nitrogen atom, one nitrogen and one oxygen atoms, two
nitrogen and one oxygen atoms, or one nitrogen and two
oxygen atoms,
(6) 4-7 membered, unsaturated or partially saturated,
monocyclic hetero ring containing as heteroatoms, one or two
sulfur atoms or
(7) 4-7 membered, unsaturated or partially or fully
saturated, monocyclic hetero ring containing as heteroatoms,
one or two oxygen atoms;
R2 is R2A or R2B;
R2A is (1) - NR6A AR7A, in which R6A and R7A independently are
hydrogen or C1-4 alkyl (with the proviso that R6A and R7a are


102


not both hydrogen at the same time), (2) -SO2NR6R7, in which R6
and R7 independently are hydrogen or C1-4 alkyl, (3)
trifluoromethyl or (4) trifluoromethoxy;
R2B is (1) hydrogen (2) C1-4 alkyl, (3) C1-4 alkoxy,
(4) -COOR5 in which R5 is hydrogen or C1-4 alkyl,
(5) halogen, (6) nitro or (7) -NR6B GBR7B, in which R6B and R7B
are hydrogen;
Z is Z A or Z B
Z A is methylene, ethylene, vinylene or ethylene;
Z B is single bond;
CyB is
(1) 7-membered, unsaturated or partially saturated
monocyclic hetero ring containing as heteroatoms, one, two
or three nitrogen atoms,
(2) 6-membered, unsaturated or partially saturated
monocyclic hetero ring containing as heteroatoms, two or
three nitrogen atoms,
(3) 6-membered, unsaturated or partially saturated,
monocylic hetero ring containing as a heteroatom, one
nitrogen atom,
(4) 4- or 5- membered, unsaturated or partially
saturated, monocyclic, hetero ring containing as
heteroatoms, one, two or three nitrogen atoms, or
(5) 4-7 membered, unsaturated or partially saturated,
monocyclic hetero ring containing as heteroatoms, one or two
oxygen atoms, or one or two sulfur atoms;


103


R3 is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen or
trifluoromethyl;
R4 is R4A or R4B;
R4A is (1) -NHSO2R11 in which R11 is C1-4 alkyl, (2) SO2NR9R10,
in which R9 is hydrogen, C1-4 alkyl or phenyl (C1-4 alkyl)
and R10 is hydrogen or C1-4 alkyl, (3) -OCOR11, in which R11
is as hereinbefore defined, (4) hydroxy, (5) -SO2N=CHNR12R13
in which R12 is hydrogen or C1-4 alkyl and R13 is C1-4 alkyl,
(6) -CONR14R15 in which R14 is hydrogen or C1-4 alkyl and R15
is C1-4 alkyl or phenyl (C1-4alkyl), (7) ethynyl, (8)
tri(C1-4 alkyl) silylethynyl or (9) acetyl;
R4H is (1) hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy,
(4) -COOR8, in which R8 is hydrogen or C1-4 alkyl,
(5) -NR9R10, in which R9 and R10 are as hereinbefore defined,
(6) -NHCOR11, in which R11 is as hereinbefore defined,
(7) halogen, (8) trifluoromethyl, (9) nitro, (10) cyano,
(11) C1-4 alkylthio, (12) C1-4 alkylsulfinyl, (13) C1-4
alkylsulfonyl, (14) hydroxymethyl, and
l, m and n independently are 1 or 2;
with the proviso that the group of the formula: -CyA-(R2),
does not represent a cyclopentyl and trifluoromethylphenyl
group when Y is a single bond, that a CyB ring does not bond
to Z through a nitrogen atom in the CyB ring when Z is
vinylene or ethynylene, that a CyB ring is not pyridine or
thiophene when CyA is a 4-7 membered, unsaturated or
paritally or fully saturated, monocyclic hetero ring,
containing as heteroatoms, one or two oxygen atoms, that Y
is not a single bond, when A is -O-R0 or -S(O)p- R0 and that
A is not -CyA - (R2B)1 and OR0B, when Z is Z B and R4 is R4B;


104


Image
and pharmaceutically acceptable salts and solvates thereof,
in which:
R0 represents hydrogen, halogen or C1-6 alkyl;
R1 represents hydrogen, C1-6 alkyl, Ca-6 alkenyl, C2-6 alkynyl,
halo C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-3 alkyl,
aryl C1-3 alkyl or heteroaryl C1-3 alkyl ;
R2 represents an optionally substituted monocyclic aromatic
ring selected from benzene, thiophene, furan and pyridine or
an optionally substituted bicyclic ring
Image
attached to the rest of the molecule via one of the benzene
ring carbon atoms and wherein the fused ring A is a 5- or 6-
membered ring which may be saturated or partially or fully
unsaturated and comprises carbon atoms and optionally one or
two heteroatoms selected from oxygen, sulphur and nitrogen;
and
R3 represents hydrogen or C1-3 alkyl, or R1 and R3 together
represent a 3- or 4-membered alkyl or alkenyl chain;


105


Image
and pharmaceutically acceptable salts thereof,
wherein R1 and R2 are the same or different and represent
hydrogen, lower alkyl (which is optionally substituted with
one to three substituents which are the same or different
and are cycloalkyl, hydroxy, lower alkoxy, carboxy, lower
alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-
substituted amino, nitro or halogen), alicyclic heterocycle
group (which is optionally substituted with one to three
substituents which are the same or different and are lower
alkyl, aralkyl, aryl optionally substituted with one to
three substituents which are the same or different and are
lower alkoxy, or aromatic heterocycle group), cycloalkyl,
bicycloalkyl, benzocycloalkyl (which is optionally
substituted with one to three substituents which are the
same or different and are lower alkyl, hydroxy, lower
alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-
substituted amino, dialkyl-substituted amino, nitro,
sulfonamide, halogen, or trifluormethyl), lower alkenyl,
aryl (which is optionally substituted with one to three
substituents which are the same or different and are lower
alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl,
amino, monoalkyl-substituted amino, dialkyl-substituted
amino, nitro, sulfonamide, halogen, or trifluoromethyl)
aromatic heterocycle group-substituted alkyl (where the
aromatic heterocycle group part is optionally substituted
with one to three substituents which are the same or
different and are lower alkyl, hydroxy, lower alkoxy,




106

carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted
amino, dialkyl-substituted amino, nitro, sulfonamide,
halogen or trifluoromethyl and where the alkyl part is
optionally substituted with aryl), aromatic heterocycle
group (which is optionally substituted with one to three
substituents which are the same or different and are lower
alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl,
amino, monoalkyl substituted amino, dialkyl-substituted
amino, nitro, sulfonamide, halogen or trifluoromethyl), or
aralkyl (where the aryl part of the aralkyl is optionally
substituted with one to three substituents which are the
same or different and are lower alkyl, lower alkoxy, dialkyl
substituted amino, halogen or trifluoromethyl), or R1 and R2
are taken together with the nitrogen atom to which they are
bonded to form a heterocycle group containing nitrogen atom
(which heterocycle group is optionally substituted with one
to three substituents which are the same or different and
are lower alkyl, aryl or aralkyl),

R3 represents hydrogen, lower alkyl (which is optionally
substituted with one to three substituents which are the
same or different and are cycloalkyl, hydroxy, lower alkoxy,
carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted
amino, dialkyl substituted amino, nitro or halogen)
alicyclic heterocycle group (which is optionally substituted
with one to three substituents which are the same or
different and are lower alkyl, aralkyl, aryl optionally
substituted with one to three substituents which are the
same or different and are lower alkoxy, or aromatic
heterocyle group), cycloalkyl, lower alkenyl, aryl (which is
optionally substituted with one to three substituents which
are the same or different and are lower alkyl, hydroxy,
lower alkoxy, carboxy, lower alkoxycarbonyl, amino,
monoalkyl-substituted amino, dialkyl-substituted amino,




107

nitro, sulfonamide, halogen or trifluoromethyl), aromatic
heterocycle group-substituted alkyl (where the aromatic
heterocycle group part is optionally substituted with one to
three substituents which are the same or different and are
lower alkyl, hydroxy, lower alkoxy, carboxy, lower
alkoxycarbonylamino, monoalkyl-substituted amino, dialkyl-
substituted amino, nitro, sulfonamide, halogen or
trifluoromethyl, and where the alkyl part is optionally
substituted with aryl), aromatic heterocycle group (where
the aromatic heterocycle group is optionally substituted
with one to three substituents which are the same or
different and are lower alkyl, hydroxy, lower alkoxy,
carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted
amino, dialkyl-substituted amino, nitro, sulfonamide,
halogen or trifluoromethyl), or aralkyl (where the aryl part
of the aralkyl is optionally substituted with one to three
substituents which are the same or different and are lower
alkyl, lower alkoxy, dialkyl-substituted amino, halogen, or
trifluoromethyl), and

X represents oxygen atom or sulfur atom; and
Image
and pharmacologically acceptable salts thereof
(wherein R1, R2, R3, R4 and R5 may be the same or different
from each other and each represents a hydrogen atom, a
halogen atom, a lower alkyl group or a lower alkoxy group;
and




108

R6 and R7 may be the same or different from each other and
each represents a hydrogen atom, a lower alkyl group, a
hydroxyalkyl group, a lower alkoxyalkyl group, a cyanoalkyl
group, a heteroarylalkyl group, a cycloalkyl group, a
cycloalkylalkyl group or a carboxyl alkyl group which may be
protected, or alternatively R6 and R7 may form a ring
together with the nitrogen atom to which they are bonded,
this ring optionally having a substituent).


2. The use of a compound as claimed in claim 1
wherein the compound which is a selective cGMP PDE inhibitor
is selected from:
Image
and
Image
as defined in claim 1.




109

3. The use of a compound as claimed in claim 1
wherein said compound is:
1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one;
2-(2-propoxyphenyl)-6-purinone;
6-(2-propoxyphenyl)-1,2-dihydro-2-oxopyridine-3-carboxamide;
2- (2-propoxyphenyl) pyrido [2,3-d] pyrimid-4 (3H) -one;
7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-
dihydropyrimido[4,5-d]pyrimidine;
6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide;
1-ethyl-3-methylimidazo[1,5a]quinoxalin-4(5H)-one;
4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)quinazoline;
5-ethyl-8-[3-(N-cyclohexyl-N-methylcarbamoyl)-propyloxy]-
4,5-dihydro-4-oxo-pyrido[3,2-a]pyrrolo[1,2-a]pyrazine;
5'methyl-3'-(phenylmethyl)-spiro[cyclopentane-1,7'(8'H)-
(3'H) -imidazo [2, 1-b]purin] 4' (5'H) -one
1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-
yl)piperidine-4-carboxylic acid;
(6aR,9aS)-2-(4-trifluoromethylphenyl)methyl-5-methyl-
3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-
b]purin-4-one;
1-tert-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-
d]pyrimid-4-one;
1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimid-4-one;
2-butyl-1-(2-chlorobenzyl)6-ethoxycarbonylbenzimidazole;




110

2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-
nitroquinazoline;
or 2-phenyl-8-ethoxycycloheptimidazole.

4. The use of a compound as claimed in claim 3 where
said compound is:
4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)quinazoline;
1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-
yl)piperidine-4-carboxylic acid;
(6aR,9aS)-2-(4-trifluoromethylphenyl)methyl-5-methyl-
3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-
b]purin-4-one;
1-tert-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-
d]pyrimid-4-one;
1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimid-4-one;
or
2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-
nitroquinazoline;

5. The use of a compound which is a selective cGMP
PDE inhibitor for the manufacture of a medicament for the
treatment of erectile dysfunction in a male animal,
including man, wherein said compound is selected from:




111

Image
as defined in claim 1.

6. The use of a compound which is a selective cGMP
PDE inhibitor for the manufacture of a medicament for the
curative or prophylactic treatment of female sexual
dysfunction, premature labour or dysmenorrhea, wherein the
compound is a compound as defined in any one of claims 1




112

to 5 for use in the treatment of erectile dysfunction in a
male animal.

7, Use of a selective cGMP PDE inhibitor as defined
in any one of claims 1 to 5 for the treatment of erectile
dysfunction in a male animal or female sexual dysfunction,
premature labour or dysmenorrhea.

8. The use according to any one of claims 1 to 7,
wherein the male animal is a male human.

9. A medicine for treating erectile dysfunction in a
male animal, or female sexual dysfunction, premature labour
or dysmenorrhea, comprising an effective amount of the
compound which is a selective cGMP-PDE inhibitor, as defined
in claim 1, 2 or 5, and a pharmaceutically acceptable
diluent or carrier.

A medicine for treating erectile dysfunction in a
male human, which comprises a pharmaceutically acceptable
diluent or carrier, and an effective amount of a compound
that is:
1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one;
2-(2-propoxyphenyl)6-purinone;
6-(2-propoxyphenyl)-1,2-dihydro-2-oxopyridine-3-carboxamide;
2- (2-propoxyphenyl)pyrido [2, 3-d] pyrimid-4 (3H) -one;
7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-
dihydropyrimido[4,5-d]pyrimidine;
6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide;




113

1-ethyl-3-methylimidazo[1,5a]quinoxalin-4(5H)-one;
4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)quinazoline;
5-ethyl-8-[3-(N-cyclohexyl-N-methylcabamoyl)-propyloxy]-4,5-
dihydro-4-oxo-pyrido[3,2-a]pyrrolo[1,2-a]pyrazine;
5'-methyl-3'-(phenylmethyl)-spiro[cyclopentane-1,7'(8'H)-
(3'H)-imidazo[2,1-b]purin]4'(5'H)-one
1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-
yl)piperidine-4-carboxylic acid;
(6aR,9aS)-2-(4-trifluoromethylphenyl)methyl-5-methyl-
3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-
b]purin-4-one;
1-tert-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-
d]pyrimid-4-one;
1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimid-4-one ;
2-butyl-1-(2-chlorobenzyl)6-ethoxycarbonylbenzimidazole;
2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-
nitroquinazoline; or
2-phenyl-8-ethoxycycloheptimidazole.

11. A medicine for treating erectile dysfunction in a
male human, which comprises a pharmaceutically acceptable
diluent or carrier, and an effective amount of a compound
that is:




114

4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)quinazoline;
1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-
yl)piperidine-4-carboxylic acid;
(6aR,9aS)-2-(4-trifluoromethylphenyl)methyl-5-methyl-
3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-
b]purin-4-one;
1-tert-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-
d]pyrimid-4-one;
1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimid-4-one ; or
2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-
nitroquinazoline.

12. A commercial package comprising the medicine of
claim 9, together with a written matter providing
instructions for treating erectile dysfunction in a male
animal, or female sexual dysfunction, premature labour or
dysmenorrhea.

13. A commercial package comprising the medicine of
claim 10 or 11, together with a written matter providing
instructions for treating erectile dysfunction in a male
human.

Description

CA 02203379 1997-04-22
WO 96/16644 PCT/EP95/04066
cGMP-PDE INHIBITORS FOR THE
TREATMENT OF ERECTILE DYSFUNCTION
This invention relates to the use of compounds which~are selective
inhibitors of cyclic guanosine 3',5'-monophosphate phosphodiesterases (cGMP
PDEs) in the treatment of erectile dysfunction (impotence) in male animals,
including man.
impotence can be defined literally as a lack of power, in the male, to
copulate and may involve an inability to achieve penile erection or
ejaculation, or
both. More specifically, erectile impotence or dysfunction may be defined as
an
inability to obtain or sustain an erection adequate for intercourse. Its
prevalence
is claimed to be between 2 and 7% of the human male population, increasing
with
age, up to 50 years, and between 18 and 75% between 55 and 80 years of age.
In the USA atone, for example, it has been estimated that there are up to 10
million impotent males, with the majority suffering from problems of organic
rather
than of psychogenic origin.
Reports of well-controlled clinical trials in man are few and the efficacy of
orally administered drugs is low. Although many different drugs have been
shown
to induce penile erection, they are only effective after direct injection into
the
penis, e.g. intraurethrally or intracavernosally (i.c.), and are not approved
for
erectile dysfunction. Current medical treatment is based on the i.c. injection
of
vasoactive substances and good results have been claimed with
phenoxybenzamine, phentolamine, papaverine and prostaglandin E,, either alone
or in combination; however, pain, priapism and fibrosis of the penis are
associated with the i.c. administration of some of these agents. Potassium
channel openers (KCO) and vasoactive intestinal polypeptide (VIP) have also
been shown to be active i.c., but cost and stability issues could limit
development
of the latter. An alternative to the i.c. route is the use of giyceryl
trinitrate (GTN)
patches applied to the penis, which has been shown to be effective but
produces
side-effects in both patient and partner.
As a general alternative to pharmacological intervention, a variety of penile
prostheses has been used to assist achievement of an erection. The short term


CA 02203379 1997-04-22
WO 96/16644 PCT/EP95/04066
success rate is good, but problems with infection and ischaemia, especially in
diabetic men, make this type of treatment a anal option rather than fiirst-
line
therapy.
According to the specification of our international patent application no
PCTIEP94/01580, (publication no W094128902), we describe and claim the use
of a series of pyrazolo [4,3-dlpyrimidin-7-ones for the treatment of
impotence.
The compounds are potent and selective inhibitors of cGMP PDE in contrast to
their inhibition of cyclic adenosine 3',5'-monophosphate phosphodiesterases
(CAMP PDEs). This selective enzyme inhibition leads to elevated cGMP levels
which, in tum, provides the basis for the utilities previously disclosed for
the
compounds in the treatment of stable, unstable and variant (Prinzmetal)
angina,
hypertension, pulmonary hypertension, congestive heart failure,
atheroscierosis,
conditions of reduced blood vessel patency, peripheral vascular disease,
stroke,
bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, and
diseases characterised by disorders of gut motility, e.g. irritable bowel
syndrome.
The specification goes on to describe investigations which identified three
PDE
isoenzymes in human corpus cavenosum tissue, relaxation of which leads to
penile erection. The predominant enzyme was found to be the cGMP-specific
PDE", while cGMP-stimulated CAMP PDE" and cGMP-inhibited CAMP PDE",,
were also present. The compounds described were found to be potent and
selective inhibitors of the PDEv enzyme but demonstrated only weak inhibitory
activity against the PDE" and PDE", enzymes. This activity is believed to be
responsible for the action of the compounds in the treatment of erectile
dysfunction.
A number of cGMP-PDE inhibitors have previously been described in the
literature for a variety of utilities, these include use in treating
obstructive lung
diseases such as asthma and brochitis, in combatting allergic diseases such as
allergic asthma, allergic rhinitis, urticaria, and irritable bowel syndrome;
and in
combatting angina, hypertension and congestive heart failure. Utility has also
been claimed as diuretics, as antiinflammatory agents, in the treatment of
baldness, for conditions of reduced blood vessel patency, and in glaucoma.
However there has not previously been any suggestion that any of these
compounds would be of utility in the treatment of erectile dysfunction.


CA 02203379 1997-04-22
WO 96/16644 PCT/EP95/04066
3
Thus the present invention provides the use of a compound which is a
selective cGMP PDE inhibitor for the manufacture of a medicament for the
treatment of erectile dysfunction in a male animal, including man, wherein
said
compound is:
i a 5-substituted pyrazolo [4,3-dJpyrimidine-7-one as disclosed in European
patent application 0201188;
ii a griseolic acid derivative as disclosed in European patent applications
nos
0214708 and 0319050;
iii a 2-phenyfpurinone derivative as disclosed in European patent application
0293063;
iv a phenyipyridone derivative as disclosed in European patent application
0347027;
v a fused pyrimidine derivative as disclosed in European patent application
0347146;
vi a condensed pyrimidine derivative as disclosed in European patent
application 0349239;
vii a pyrimidopyrimidine derivative as disclosed in European patent
application 0351058;
viii a purine compound as disclosed in European patent application 0352960;
ix a quinazolinone derivative as disclosed in European patent application
0371731;
x a phenylpyrimidone derivative as disclosed in .European patent application
0395328;
xi an imidazoquinoxa(inone derivative or its aza analogue as disclosed in
European patent application 0400583;
xii a phenyipyrimidone derivative as disclosed in .European patent application
0400799;
xiii a phenylpyridone derivative as disclosed in European patent application
0428268;
J
xiv a pyrimidopyrimidine derivative as disclosed in European patent 0442204;
xv a 4-aminoquinazoline derivative as disclosed in European patent
application 0579496;


CA 02203379 2001-10-11
69886-5
4
xvi a 4,5-dihydro-4-oxo-pyrrolo[1,2-a]quinoxaline
derivative or its aza analogue as disclosed in European
patent application 0584487;
xvii a polycyclic guanine derivative as disclosed in
International patent application W091/19717;
xviii a nitrogenous heterocyclic compound as disclosed
in International patent application W093/07124;
xix a 2-benzyl-polycyclic guanine derivative as
disclosed in International patent application W094/19351;
xx a quinazoline derivative as disclosed in US patent
4060615;
xxi a 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-one
as disclosed in US patent 5294612;
xxii a benzimidazole as disclosed in Japanese patent
application 5-222000; or
xxiii a cycloheptimidazole as disclosed in European
Journal of Pharmacology, 251, (1994), 1.
xxiv a N-containing heterocycle as disclosed in
International patent application W094/22855.
More specifically, the present invention provides
the use of a compound which is a selective cGMP PDE
inhibitor for the manufacture of a medicament for the
treatment of erectile dysfunction in male animals, including
man, wherein the compound is selected from:


CA 02203379 2003-06-16
69886-5
3T
and the pharmaceutically acceptable salts thereof,
in which: R' is a lower alkyl of from one to six carbon
atoms, a lower alkenyl of from one to six carbon atoms, a
5 lower hydroxyalkyl of from one to six carbon atoms, a lower
hydroxyalkenyl of from two to six or 2, 3 or 4-pyridyl; and
Ar represents a group of formula:
x
Y
z
in which X, Y and Z are, independently, (1) hydrogen; (2)
lower alkyl of from one to six carbon atoms; (3) halogen,
(4) hydroxyl; (5) lower alkoxy of from one to six carbon
atoms; (6) nitro; (7) amino; (8) NR'R" wherein R' and R" are
each, independently, (a) hydrogen or (b) lower alkyl of from
one to six carbon atoms optionally substituted by (i) amino,
(ii) morpholino or (iii) cycloalkyl of from, five to seven
carbon atoms; (9) sulfonyl; or (10) -SOZNR'R" wherein R' and
R" are as defined above; with the proviso that not all of X,
Y and Z can be nitro, amino, or NR'R " at once;


CA 02203379 2001-10-11
69886-5
6
and the pharmaceutically acceptable salts thereof,
in which: A represents a group of formula:
R7 NHZ NH2
N ~ N zN~~ N O.~N / N
(a) ~ / ~~ fib) ~ ~~ ~c)
R8 N ~ H2N ~ N
NH NHR~z
O ~ N / N
~d) N\ ~ ~~ Vie) N\
~N N \N N
R1 and R2 are the same or different and each represents a
hydrogen atom, a halogen atom or a group of formula -OR9;
R3 and R4 are the same or different and each represents a
carbamoyl group or a carboxy group;
RS and R6 both represent hydrogen atoms or together they
represent an extra carbon-carbon bond between the carbon
atoms to which they a.re attached;
R7 represents a hydrogen atom, a halogen atom or a group of
formula -OR9, -NR1°R11 or -SR9;
Ra represents a halogen atom or a group of formula -OR9,
-NR-1°R11 or -SR9;


CA 02203379 2001-10-11
69886-5
7
R9 represents a hydrogen atom, a C1-C6 alkyl group, an
alkylsulphonyl group, a haloalkylsulphonyl group, an
arylsulphonyl group or a hydroxy protecting group;
R1° and R11 are the same or different and each represents a
hydrogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6
hydroxyalkyl group, a C1-C6 aminoalkyl group, an aralkyl
group, an aryl group, a C1-C6 alkoxy group, an aralkyloxy
group, an amino group, a C1-C2° aliphatic acyl group or an
aromatic acyl group; or R1° and R11 together represent a
substituted methylene group, or R1° and R11, together with
nitrogen atom to which they are attached, represent a
heterocyclic group having 5 or 6 ring atoms, of which, in
addition to the nitrogen atom shown, 0 or 1 are additional
oxygen, nitrogen or sulphur hetero-atoms, said heterocyclic
group being unsubstituted or having from 1 to 3 C1-C4 alkyl
and/or C1-C4 alkoxy substituents;
R12 represents a C1-C6 alkyl group;
Z represents a hydrogen atom, a hydroxy group or a
substituted hydroxy group; and
W represents an alkoxy group or an aralkoxy group;
provided that, when A represents said group of formula (e),
RS and R6 both represent hydrogen atoms;
and the pharmaceutically acceptable salts and esters
thereof,


CA 02203379 2001-10-11
69886-5
8
in which A represents a group of formula:
NHR~2
N / N
\ N
N
R1 and R2 are the same or different and each represents a
hydrogen atom, a halogen atom or a group of formula -OR9;
R3 and R4 are the same or different and each represents a
carbamoyl group or a carboxy group;
RS and R6 both represent hydrogen atoms;
R9 represents a hydrogen atom, a C1-C6 alkyl group, an
alkylsulphonyl group, a haloalkylsulphonyl group, an
arylsulphonyl group or a hydroxy-protecting group;
R12 represents a C1-C6 alkyl group;
O
H
HN N
~~ R2
\ \N N
ORS
and pharmaceutically acceptable salts thereof, wherein
R1 is C1_6 alkyl or CZ_6 alkenyl, and
R2 is hydrogen or hydroxy;

CA 02203379 2001-10-11
69886-5
9
X
HN R2
\ ~ R3
14
ORS
or a pharmaceutically acceptable salt thereof, wherein
X is O or S;
Rl is C1_6 alkyl , C2_6 alkenyl , C3_5 cycloalkylCl_4 alkyl , or C1_4
alkyl substituted by 1 to 6 fluoro groups;
R2 is hydrogen, -CN, -CONRSR6, -CO2R7, 5-tetrazolyl, -NO2, -NH2
or
-NHCOR$ wherein R5, R6, R7 and R$ are independently hydrogen
or Cl_4 alkyl;
R3 is hydrogen or Cl_4 alkyl; and
R4 is hydrogen or C1_4 alkyl;
with the proviso that R1 is not methyl when R2 is -C02H,
-C02CH2CH3 or
-CN, X is O, R3 is hydrogen and R4 is hydrogen or methyl;
O
HN
A
R2
\N
ORS
and pharmaceutically acceptable salts thereof, wherein


CA 02203379 2001-10-11
69886-5
-'J
is a ring of sub-formula (a) , (b) , (c) , (d) , (e) , (f) or
(g)
N
\~
(a) \ (b) ~ \~ (c) N (d) \
/ /N
N
N N N
(e) \ (f) ~ ~ (J) N
/ ,N J
5 N N~ N
R1 is C1_6 alkyl, Cz-6 alkenyl, C3-5 cycloalkylCl-6 alkyl, or C1_6
alkyl substituted by 1 to 6 fluoro groups; R2 is C1_s
alkythio, Cl_6 alkylsulphonyl, Cl-6 alkoxy, hydroxy, hydrogen,
hydrazino, C1_6 alkyl, phenyl, -NHCOR3 wherein R3 is hydrogen
10 or C1_6 alkyl, or -NR4R5, wherein R4 and R5 together with the
nitrogen atom to which they are attached form a pyrrolidino,
piperidino, hexahydroazepino, morpholino or piperazino ring,
or R4 and R5 are independently hydrogen, C3-5 cycloalkyl or
C1_6 alkyl which is optionally substistuted by -CF3, phenyl,
-S(O)nCl_6 alkyl wherein n is 0, 1 or 2, -OR6, -C02R7 or -NR8R9
wherein R6 to R9 are independently hydrogen or C1_6 alkyl ,
provided that the carbon atom adjacent to the nitrogen atom
is not substituted by said -S(O)nCl-6 alkyl, -OR6 or -NR$R9
groups; and
R is hydrogen and can also be hydroxy when R2 is hydroxy;
O
HN
A
\ \N
ORS


CA 02203379 2001-10-11
69886-5
11
and pharmaceutically acceptable salts thereof, wherein
,rJ~
is a ring of sub-formula (a) , (b) or (c)
N
~\ ~ ~ \x
N/N S wN/
H
(
X is oxygen or sulphur, and
R1 is C1_6 alkyl, C2_6 alkenyl, C3_5 cycloalkyl Cl_4 alkyl, or
C1_4 alkyl substituted by 1 to 6 fluoro groups;
O
HN
A
R2
\N
ORS
and pharmaceutically acceptable salts thereof, wherein
R1 is Cl_6 alkyl, CZ_6 alkenyl, C3_s cycloalkyl C1_6 alkyl, or C1_
6 alkyl substituted by 1 to 6 fluoro groups;
Rz is Cl_6 alkythio, CZ_6 alkylsulphonyl, C1_6 alkoxy, hydroxy,
hydrogen, hydrazino, Cl_6 alkyl, phenyl, -NHCOR3 wherein R3 is
hydrogen or C1_6 alkyl, or -NR4Rs, wherein R4 and RS together
with the nitrogen atom to which they are attached form a
pyrrolidino, piperidino, hexahydroazepino, morpholino or
piperazino ring, or R4 and Rs are independently hydrogen, C3_s
cycloalkyl or C1_6 alkyl which is optionally substituted by
-CF3, phenyl, -S (O)nCl_6 alkyl wherein n is 0, 1 or 2, -OR6,


CA 02203379 2001-10-11
69886-5
12
-COZR' or -NR$R9 wherein R6 to R9 are independently hydrogen
or C1_6 alkyl, provided that the carbon atom adjacent to the
nitrogen atom is not substituted by said -S(O)nCl_6 alkyl,
-OR6 or NR$R9 groups; and
A
is a ring of sub-formula (a) or (b)
\~N (b) ~ \
N1
,N
N
O
H
HN N
~~ R2
\ \N N
R3
ORS
and pharmaceutically acceptable salts thereof, wherein
R1 is C1_6 alkyl, CZ_5 alkenyl, C3_5 cycloalkyl C1_6 alkyl,
phenyl C1_4 alkyl, or C1_4 alkyl substituted by 1 to 6 fluoro
groups;
R2 is hydrogen, hydroxy, C1_4 alkyl, phenyl, mercapto, C1_4
alkylthio, CF3 or amino;
R3 is hydrogen, nitro, amino, C1_4 alkanoylamino, C1_6 alkoxy,
Cl_4 alkyl, halo, S02NR4R5, CONR4R5, cyano or C1_4 alkyl S (O) n;
R4 and RS are independently hydrogen or C1_6 alkyl; and
n is 0, 1 or 2;


CA 02203379 2001-10-11
69886-5
13
provided that R3 is not hydrogen when R1 is Cl_6 alkyl or Cz_s
alkenyl and R2 is not hydrogen or hydroxy;
O
HN
R2
~N
ORS
and pharmaceutically acceptable salts thereof, wherein
R1 is C1_6 alkyl, C2_6 alkenyl, C3_5 cycloalkyl C1_4alkyl, phenyl
C1_4 alkyl or Cl_4 alkyl substituted by 1 to 6 fluoro groups;
R2 is hydrogen, C1_6 alkyl, Cl_6 alkythio, C1_6 alkoxy, nitro or
-NR3R4 and
R3 and R4 are independently hydrogen or Cl_4 alkyl substituted
by hydroxy provided that the carbon atom adjacent to the
nitrogen atom is not substituted by hydroxy; with the
proviso that R1 is not methyl or ethyl when R2 is hydrogen;
O
HN
\N R2
ORS
and pharmaceutically acceptable salts thereof, wherein
R1 is C1_6 alkyl, C2_6 alkenyl, C3_5 cycloalkyl C1_6 alkyl,
phenyl C1_6 alkyl or Cl_6 alkyl substituted by 1 to 6 fluoro
groups; and
R2 is Cl_6 alkyl, phenyl, hydroxy, Cl_6 alkoxy, halo, -NHCOR3,


CA 02203379 2001-10-11
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14
-NHCONHR4, 5-tetrazolyl, -C02R5, cyano, -CONR6R7, or -NRSR9
wherein R3 to R7 are independently hydrogen or C1_6 alkyl and
R$ and R9 are independently hydrogen or C1_6 alkyl optionally
substituted by hydroxy provided that the carbon atom
adjacent to the nitrogen atom is not substituted by hydroxy;
R 6 NS O
a
s
N Wigs
R1 s
D
R2 1 z
and pharmaceutically acceptable salts thereof, wherein
A is N or CH;
B i s N CR3 ;
D is N or CR2;
R, R1 are the same or independently hydrogen, hydroxy, lower
alkyl, lower alkoxy, phenyloxy, R6 S(O)n-, W-ALK-Q-,
N~ROz -N -
R4
-NR and ~N~
NR~~ N-R11 ~~ N
N
NR~~ R5
R2 is hydrogen, lower alkyl, phenyl which may be substituted
by up to three methoxy groups, lower alkyl substituted by
phenyl which may be substituted by up to three methoxy
groups, - lower alkyl -N (Re) 2,


CA 02203379 2001-10-11
69886-5
R4
lower alkyl ~
lower alkyl-N X N' \'
N lower alkyl N
R5
pyridinyl or lower-alkyl pyridinyl;
R3 is hydrogen, lower alkyl, phenyl, lower alkylphenyl,
pyridinyl or loweralkyl pyridinyl;
5 R4, RS are the same or independently hydrogen or lower alkyl;
R6 is lower alkyl, phenyl, lower alkylphenyl or pyridinyl;
R7 are the same or independently hydrogen, loweralkyl,
phenyl, pyridinyl,
-NR~~ N-R11 or -
N
NR~ ~
10 R$ are the same or independently lower alkyl, phenyl or
pyridinyl;
Q is -O- , -NR9- , -CH20- , or -CH2NR9- ,
W is hydroxy, lower alkoxy, phenoxy, -N(Rlo)2~
R4
~N~
N
- N -N X
R5
N \ ~ -N (CHZ)p


CA 02203379 2001-10-11
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16
ALK is a C1-C4 straight or branched chain alkyl;
R9 is hydrogen, lower alkyl or phenyl;
Rlo are the same or independently hydrogen, lower alkyl or
phenyl;
R11 are the same or independently hydrogen or lower alkyl;
X is -CH2-, -O- S (O) n, -NRlo;
n is the integer 0, 1 or 2 and
p is the integer 0 or 1,
with the provisos that:
one and only one of B or D must be N;
when A is CH, when D is N, when B is CR3 where R3 is H, when
RZ is hydrogen, lower alkyl or phenyl then R and/or R1 must
be
R4
~N~
-N X N
R5
or W-ALK-Q;
O
R2
HN I
\ \N
ORS
and pharmaceutically acceptable salts thereof, wherein


CA 02203379 2001-10-11
69886-5
17
R1 is Cl_6 alkyl, CZ_6 alkenyl, C3_5 cycloalkyl C1_6 alkyl,
phenyl C1_6 alkyl or Cl_6 alkyl substituted by 1 to 6 fluoro
groups; and
R2 is hydrogen, amino, -NHCOR3, or CONR4R5, wherein R3 is Cl_6
alkyl, R4 is C1_6 alkyl and RS is hydrogen or C1_6 alkyl;
R2
R3
m y
and pharmaceutically salts thereof, wherein
X is O or S:
Rl is C1_6 alkyl, CZ_6 alkenyl, C3_5 cycloalkyl Cl_4 alkyl, or Cl_
4 alkyl substituted by 1 to 3 fluoro groups;
R2 is hydrogen, -CN, -CONRSR6, -COZR', 5-tetrazolyl, -N02 or
-NHCOR$ wherein RS to R8 are independent7_y hydrogen or C1_4
alkyl;
R3 is hydrogen or Cl_4 alkyl;
R4 is hydrogen or C1_4 alkyl; and
R is halo, Cl_4 alkyl, C1_4 alkoxy, cyano, -CONR9R1°, -COZRll,
-S (O) nCl_4 alkyl, -N02, - NH2, -NHCOR12, or -SOZNR13R14 wherein n
is 0, 1 or 2 and R9 to R14 are independently hydrogen or C1_4
alkyl; with the proviso that R1 is not methyl when R2 is
-C02H, -C02CH2CH3 or -CN, X is O, R3 is hydrogen, R4 is
hydrogen or methyl and R is 6-methoxy;


CA 02203379 2001-10-11
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18
O
HN
A
R2
\N
R
ORS
and pharmaceutically acceptable salts thereof, wherein
R1 is Cl_6 alkyl, Cz_6 alkenyl, C3_s cycloalkyl Cl_6 alkyl, or
C1_6 alkyl substituted by 1 to 6 fluoro groups;
z
R is C1_6 alkythio, C1_6 alkylsulphonyl, C1_6 alkoxy, hydroxy,
hydrogen, hydrazino, C1_6 alkyl, phenyl, -NHCOR3 wherein R3 is
hydrogen or Cl_6 alkyl, or -NR4Rs, wherein R4 and Rs together
with the nitrogen atom to which they are attached form a
pyrrolidino, piperidino, hexahydroazepino, morpholino or
piperazino ring, or R4 and Rs are independently hydrogen, C3_s
cycloalkyl or C1_6 alkyl which is optionally substituted by
-CF3, phenyl, -S (O) nCl_6 alkyl wherein
n is 0, 1 or 2, -OR6, -C02R7 or -NRSR9 wherein R6 to R9 are
independently hydrogen or C1_6 alkyl, provided that the
carbon atom adjacent to the nitrogen atom is not substituted
by said -S (O) n C1_6 alkyl, or -OR6 or -NRaR9 atoms;
R is halo, C1_4 alkyl, C1_4 alkoxy, cyano, -CONRl°Rll, COzRl2~
C1_4 alkyl S (O) n, -NOz, -NHz, -NHCOR13 or SOZNRI4Rls wherein n is
0, 1 or 2 and Rl° to Rls are independently hydrogen or C1_4
alkyl; and
a is a ring of sub-formula (a) or (b)


CA 02203379 2001-10-11
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19
N\
) \~N (b) I \\
N
N
R1 ~ /Y-A
N
~ ~N
(Ra)n
N_ 'z-C B
Y
a~Rs)m
and pharmaceutically acceptable salts thereof,
wherein --- represents a single or double bond;
R1 is hydrogen or Cl_4 alkyl;
Y is a single bond or C1_6 alkylene;
A is
-CyA- (R2) 1.
-O-R° or -S (O) p-R°, or
-NR16R17
in which R° is hydrogen, C1_4 alkyl, hydroxy Cl_4 alkyl or
CyA- ( RZ ) 1;
R16 and R17 independently are hydrogen or C1_4 alkyl ;
p is O-2;
CyA is
a 3-7 membered, saturated or unsaturated carbocycle,
a 4-7 membered, unsaturated or partially saturated
heterocycle containing one nitrogen atom


CA 02203379 2001-10-11
69886-5
a 4-7 membered, unsaturated or partially saturated
heterocycle containing one nitrogen atom and one oxygen
atom,
a 4-7 membered, unsaturated or partially saturated
5 heterocycle containing one nitrogen atom and two oxygen
atoms,
a 4-7 membered, unsaturated or partially saturated
heterocycle containing two nitrogen atoms and one oxygen
atom
10 a 4-7 membered, unsaturated or partially saturated
heterocyle containing one or two sulfur atoms,
a 4-7 membered, unsaturated, partially saturated or fully
saturated heterocycle containing one or two oxygen atoms,
R2 is ( 1 ) hydrogen, ( 2 ) C1_4 alkyl , ( 3 ) C1_4 alkoxy,
15 (4) -COORS, in which RS is hydrogen or C1_4 alkyl, (5) -NR6R7,
in which R6 and R7 independently are hydrogen or C1_4 alkyl,
(6) -S02NR6R7, in which R6 and R7 are as he reinbefore defined,
(7) halogen, (8) trifluoromethyl, (9) nitro or (10)
trifluoromethoxy;
20 Z is a single bond, methylene, ethylene, vinylene or
ethynylene;
CyB is a 4-7 membered, unsaturated or partially saturated
heterocycle containing one nitrogen atom,
a 4-7 membered, unsaturated or partially saturated
heterocycle containing two nitrogen atmos,
a 4-7 membered, unsaturated or partially saturated
heterocycle containing three nitrogen atoms,


CA 02203379 2001-10-11
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21
a 4-7 membered, unsaturated or partially saturated
heterocycle containing one or two oxygen atoms,
a 4-7 membered, unsaturated or partially saturated
heterocycle containing one or two sulfur atoms,
R3 is hydrogen, C1_4 alkyl, Cl_4 alkoxy, halogen or
trifluoromethyl;
R4 i s ( 1 ) hydrogen, ( 2 ) Cl_4 alkyl , ( 3 ) C1_4 alkoxy,
( 4 ) -COORa , in which R$ i s hydrogen or C1_4 alkyl , ( 5 ) -NR9Rlo
in which R9 is hydrogen, C1_4 alkyl or phenyl (C1_4 alkyl) and
Rl° is hydrogen or C1_4 alkyl, (6) -NHCORll, in which Rll is
C1_4 alkyl, (7) -NHS02R11, in which Rll is as hereinbefore
defined, (8) S02NR9R1° in which R9 and Rl° are as hereinbefore
defined, (9) -OCORll, in which Rll is as hereinbefore
defined, (10) halogen, (11) trifluoromethyl, (12) hydroxy,
(13) nitro, (14) cyano,
(15) -S02N=CHNR12R13 in which R12 is hydrogen or C1_4 alkyl and
R13 is C1_4 alkyl, (16) -CONRI4Rls in which R14 is hydrogen or
C1_4 alkyl or phenyl ( C1_4 alkyl ) and Rls is C1_4 alkyl or ( 17 )
C1_4 alkylthio, (18) C1_4 alkylsulfinyl, (19) Cl_4
alkylsulfonyl, (20) ethynyl, (21) hydroxymethyl, (22)
tri (C1_4 alkyl) silylethynyl or (23) acetyl; and 1, m and n
independently are 1 or 2;
with the proviso that
CyA-(R2)1 does not represent cyclopentyl or
trifluoromethylphenyl when Y is a single bond,
CyB does not bond to Z through a nitrogen atom when Z is
vinylene or ethynylene,


CA 02203379 2001-10-11
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22
CyB is not pyridine or thiophene when CyA is a 4-7 membered
unsaturated, partially saturated or fully saturated
heterocycle containing one or two oxygen atoms, and
Y is not a single bond when A is (ii) -O-R° or (iii) -NR16R17;
Ra
1 - 2
N~s
R2 ~ s ,CO
s
R~
and pharmaceutically acceptable salts thereof,
wherein the phenyl ring either in position 6, 7, 8 or 9 may
contain a nitrogen atom instead of a CH-moiety and the
residues R1, R2, R3 and R4 have the following meanings
Rl: C2-C6-alkenyl, C2-C6-alkynyl, hydroxy, C1-C6-alkoxy, C3-C6-
alkenyloxy, C3-C6-alkynyloxy, Cz-C6-alkanoyloxy, benzoyloxy,
morpholinocarbonyloxy, C1-C6-alkyloxycarbonyloxy, C1-C6-
alkylaminocarbonyloxy, C1-C6-dialkylaminocarbonyloxy or the
moiety
-AIk-A
wherein Alk is: C1-C6-alkyl, C2-C6-hydroxy-alkyl or C3-C6-
cycloalkyl and the symbol A means:
(1) hydrogen, halogen, hydroxy, C1-C6-alkoxy, C2-C6-
alkanoyloxy, phenyl;
(2) -NHRS, -NRSR6, NRSR6R7, pyridylamino, imidazolyl,
pyrrolidinyl, N-C1-C6-alkylpyrrolidinyl, piperidylamino, N-
(phenyl-C1-C4-alkyl)-piperidylamino, wherein RS and R6 are
identical or different and mean hydrogen, C1-C6-alkyl, C3-C7-
cycloalkyl, C3-C7-hydroxycycloalkyl, morpholino-C1-C6-alkyl,


CA 02203379 2001-10-11
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23
phenyl, phenyl-C1-C6-alkyl or phenyl-Cz-C6-oxyalkyl, wherein
the phenyl residues also may be substituted with halogen and
R7 is hydrogen or C1-C6-alkyl;
(3) The moiety
-CO-D
wherein D is phenyl, C1-C6-alkyl, C3-C7-cycloalkyl, hydroxy,
C1-C6-alkoxy, C3-C7-cycloalkyloxy, morpholino, pyrrolidino,
piperidino, homopiperidino, piperazino, -NHRS or -NR5R6 and RS
and R6 have the given meaning;
(4) The moiety
/ (CH2)n\
N\ ~CHZ) /E
n
wherein n may be an integer of 1-3 and E means CH2, oxygen,
sulphur, NH, CHOH, CH-C1-C6-alkyloxy, CH-CZ-C6-alkanoyloxy,
CHC6H5, CHCOD, CH-CN2C6H5, N-C1-C6-alkyl, N-C1-C6-hydroxyalkyl,
N-C6H5, N-CH2C6H5, N-CH (C6H5) 2, N- (CHz) 2-OH, N- (CH2) 3-OH or NCOD
and die phenyl residues (C6H5) may also be substituted with
halogen, C1-C6-alkoxy, trifluormethyl, C1-C6-alkyl,
methylenedioxy, cyan and D has the above given meaning;
RZ and R3, which may be identical or different:
hydrogen, halogen, hydroxy, C1-C6-alkyl, trifluormethyl, -CN,
C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, -NHRS,
-NRSR6, NRSR6R~ (meanings R5, R6, R7 as given) , or the moiety
-G-Alk-A, wherein Alk and A have the given meanings and G is
oxygen, sulphur, NH or NRS;
R4: hydrogen or halogen,
wherein R1 also may be hydrogen, if R2 is the moiety


CA 02203379 2001-10-11
69886-5
24
R5 ~ -CHZ i H-CHZ O-
OH
and R5 means phenyl, C1-C4-alkoxy-phenyl or diphenylmethyl
and R3 and R4 are hydrogen,
and the physiologically acceptable acid addition salts and
quarternary ammonia salts thereof, excluding the compounds
of formula I wherein R1 is methyl, dimethylamino-propyl,
dimethylamino-ethyl, morpholino-ethyl or pyrrolidino-ethyl,
R2, R3 and R4 are hydrogen and the phenyl ring does not
contain a nitrogen atom;
J R2 J
R1~N N R1~ N
N
/~R3 ~~R3
N~ N N Ni -N N
and
Ra (CH2)n Ra (CH2)n
Rb
Rc \Rd Rb Rc Rd
and pharmaceutically acceptable salts thereof,
wherein J is oxygen or sulfur,
R1 is hydrogen, alkyl or alkyl substituted with aryl or
hydroxy;
R2 is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl
substituted with aryl, heteroaryl, hydroxy, alkoxy, amino,
monoalkyl amino or dialkylamino, or -(CH2)m TCOR2° wherein m
is an integer from 1 to 6, T is oxygen or -NH- and RZ° is
hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with
aryl or heteroaryl;
R3 is hydrogen, halo, trifluromethyl, alkoxy, alkylthio,
alkyl, cycloalkyl, aryl, aminosulfonyl, amino,


CA 02203379 2001-10-11
69886-5
monoalkylamino, dialkylamino, hydroxyalkylamino,
aminoalkylamino, carboxy, alkoxycarbonyl or aminocarbonyl or
alkyl substituted with aryl, hydroxy, alkoxy, amino,
monalkylamino or dialkylamino;
5 Ra, Rb, R° and Rd independently represent hydrogen, alkyl,
cycloalkyl or aryl; or (Ra and Rb) or (R~ and Rd) or (Rb and
R°) can complete a saturated ring of 5- to 7-carbon atoms, or
(Ra and Rb) taken together and (Rb and R°) taken together,
each complete a saturated ring of 5- to 7-carbon atoms,
10 wherein each ring optionally can contain a sulfur or oxygen
atom and whose carbon atoms may be optionally substituted
with one or more of the following: alkenyl, alkynyl,
hydroxy, carboxy, alkoxycarbonyl, alkyl or alkyl substituted
with hydroxy, carboxy or alkoxycarbonyl; or such saturated
15 ring can have two adjacent carbon atoms which are shared
with an adjoining aryl ring; and
n is zero or one;
R2 R1
R6
A B
R3
R5
R4
and pharmaceutically acceptable salts thereof,
20 wherein, ring A signifies a benzene ring, pyridine ring or
cyclohexane ring, ring B signifies a pyridine ring,
pyrimidine ring or imidazol ring,
rings A and B are bonded by sharing two atoms, and
the atoms that are shared may be either carbon or nitrogen
25 atoms,


CA 02203379 2001-10-11
69886-5
26
except for the event that ring A is a pyridine
ring and ring B shares a nitrogen atom of this pyridine ring
for bonding, ring A shall be as shown by the formula
Rx
R~-
R3 N
wherein, R1, R2, R3 and R4 may be identical or different
hydrogen atoms, halogen atoms, possibly halogen-substituted
low alkyl radicals, possibly substituted cycloalkyl
radicals, low alcoxy radicals, hydroxyalkyl radicals, nitro
radicals, amino radicals, acyl-amino radicals, possibly
protected carboxyl radicals, radicals represented by the
formula
Co) m
I(
(where R' in this formula signifies a low alkyl radicals and
n may be 0 or be an integer with a value of 1 - 2), or a
radical represented by the formula
~~16
2 o N~Rm
where R45 (where R45and R46 in this formula signify identical
or different hydrogen atoms or low alkyl radicals, R45 and R4s
may unite with the nitrogen atom to which they are bonded to
form a ring possibly containing different nitrogen and/or
oxygen atoms, or, alternatively, this ring may also be
substituted,


CA 02203379 2001-10-11
69886-5
27
further, two of the R1, R2, R3, and R4 radicals may combine to
form a methylene dioxy, ethylene dioxy or phenyl ring,
RS signifies a hydrogen atom, halogen atom,
hydroxyl group, hydrazino radical, a possibly substituted
cycloalkyl radical, a low alcoxy radical, a low alkenyl
radical, a possibly protected carboxyalkyl radical, a
possibly protected carboxyalkenyl radical, a hydroxy alkyl
radical, a possibly protected carboxyl radical, a radical
represented by the formula
CO).
1f
_~_gE
(where R3 in this formula signifies a low alkyl radical and m
may be either 0 or an integer with a value from 1 - 2), a
radical represented by the formula -O-R9 (where R9 in this
formula signifies a possibly protected hydroxyalkyl radical,
a possibly protected carboxyalkyl radical or a possibly
substituted benzyl radical), a radical represented by the
formula
~R:a
(where R23 in this formula signifies a hydroxyl group, a low
alkyl radical, a hydroxyalkyl radical or a hydroxyalkyl oxy
radical), a possibly substituted heteroaryl radical, a
possibly substituted 1,3 benzodioxolyl radical, a possibly
substituted 1,4 benzodioxyl radical, a possibly substituted
1,3 benzodioxolyl alkyl resin, a possibly substituted 1,4
benzodioxyl alkyl radical radical represented by the formula
C(R24)=X (where X in this formula signifies an oxygen atom, a
sulphur atom or a radical represented by the formula =N-Rlo
(where R1° in this formula signifies a hydroxyl group or a


CA 02203379 2001-10-11
69886-5
28
possibly protected carboxyalkyloxy radical) and (R24
signifies a hydrogen atom or a low alkyl radical), or a
radical represented by the formula -NRllRiz (where R11 and R12
in this formula signify identical or different hydrogen
atoms, low alkyl radicals, hydroxyalkyl radicals, aminoalkyl
radicals, possibly protected carboxyalkyl radicals, alkyl
carbamoyl radicals, possibly protected carboxy alkyl
carbamoyl radicals, possibly substituted heteroaryl alkyl
radicals, 1,3 benzoxolyl alkyl radicals or 1,4 benzodioxyl
alkyl radicals, and where, furthermore, R11 and R22 may unite
with the nitrogen atom to which they are bonded to form a
ring possibly containing different nitrogen and/or oxygen
atoms, or, alternatively, this ring may also be
substituted),
R6 signifies a hydrogen atom, a halogen atom,
hydroxyl group, amino group, low alkyl radical, low alcoxy
radical, low alkenyl radical, a 1,3-benzodioxolyl alkyloxy
radical, 1,4-benzodioxyl alkyloxy radical, a possibly
substituted phenyl alkyloxy radical, a radical represented
by the formula
\\~ ~ 1 3
~11
(where R13, R14 in this formula signify identical or different
hydrogen atoms, low alkyl radicals or alcoxy radicals,
furthermore, R13 and R14 may combine to form methylene dioxy
or ethylene dioxy), a radical represented by the formula
0
o Ris


CA 02203379 2001-10-11
69886-5
29
a radical represented by the formula
~zs
~i6
a radical represented by the formula
'~ ~
a radical represented by the formula
a R='
i
'I
p R"
(where R15 and 16 used in these formulae signify identical or
different hydrogen atoms, low alkyl radical or low alkoxy
radical,
furthermore, R15 and R16 may combine to form methylene dioxy
or ethylene dioxy), a piperidine-4-spiro-2'-dioxane-1-yl
radical, a radical represented by the formula
~aa
._ Z-~CH~~
~aa
(where R4$ and R49 in this formula signify identical or
different hydrogen atoms, low alkyl radicals or low alcoxy
radicals, furthermore, R4$ and R49 may combine to form
methylene dioxy or ethylene dioxy, Z signifies a sulphur
atom or an oxygen atom), a radical represented by the
formula
~~54


CA 02203379 2001-10-11
69886-5
(where RS° in this formula signifies s hydroxyl group, a
halogen atom, a low alkyl radical, a low alcoxy radical, a
possibly protected carboxyl radical, a cyano radical, a
hydroxyalkyl radical or a carboxyalkyl radical), a radical
represented by the formula
~~z
~~p~r_~r~
(where R17 in this formula stands for a hydrogen atom, low
alkyl radical, aryl radical, low alcoxyalkyl radical, a
possibly protected carboxyalkyl radical or a hydroxyalkyl
radical, Y stands for a radical represented by the formula
'CCHz~ a-
(where q in this formula signifies 0 or an integer from 1 -
8), or a radical represented by the formula
~-
furthermore, when q in the radical represented by the
formula
2 5 -(Gliz) a-
has the value of an integer from 1 - 8, the respective
carbon atoms may also possess 1 - 2 substituted radicals, R1$
signifies a hydrogen atom, hydroxyl group, a possibly
protected carboxylradical, a cyano radical, an aryl radical,
a possibly substituted heteroaryl radical, or a possibly
substituted cycloalkyl radical), or a radical represented by
the formula


CA 02203379 2001-10-11
69886-5
31
~I9
~20
_~r..~~'~2> r
p
722
(where R19 in this formula stands for a hydrogen atom, low
alkyl radical, low alkoxyalkyl radical, aryl radical, a
possibly protected carboxyalkyl radical or a hydroxyalkyl
radical Rz°, Rzl, and Rzz signify identical or different
hydrogen atoms, halogen atoms, hydroxyl groups, amino
groups, nitro radicals, low alkyl radicals, low alkoxy
radicals, low alcoxyalkyl radicals, low alkenyl radicals,
acyl radicals, acylamino radicals, alkyl sulphonyl amino
radicals, hydroxy imino alkyl radicals, alkyloxy carbonyl
amino radicals, alkyloxy carbonyloxy radicals or possibly
substituted heteroaryl radicals, furthermore, any two of Rzo,
Rzl, and Rzz may also combine to form a saturated or
unsaturated ring that may contain nitrogen, sulphur or
oxygen atoms, R signifies 0 or an integer from 1 to 8;
O ~ R1
H3C~ N N
R2
~N N 2
N
R3
HRa Rc
2 0 Rb
and pharmaceutically acceptable salts thereof, wherein:
R1, Rz and R3 are independently selected from the group
consisting of hydrogen, lower alkyl, lower alkoxy, halogeno,
hydroxy, (di-lower alkyl) amino, 4-morpholinyl, 1-
pyrrolidinyl, 1-pyrrolyl, -CF3, -OCF3, phenyl and
methoxphenyl; or R1 and R2 together are methylenedioxy; or R1


CA 02203379 2001-10-11
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32
and Rz together with the carbon atoms to which they are
attached form a benzene ring; and
Ra is hydrogen and Rb and R°, together with the carbon atoms
to which they are attached, form a saturated ring of 5
carbons; or Ra is lower alkyl, Rb is hydrogen or lower alkyl,
and R° is hydrogen; or_ Ra, Rb and the carbon atom to which
they are attached form a saturated ring of 5-7 carbons, and
R° is hydrogen; or Ra is hydrogen, and Rb, R° and the
carbon
atoms to which they are attached form a tetrahydrofuran
ring; or Ra and Rb, together with the carbon atom to which
they are attached, and Rb and R°, together with the carbon
atoms to which they are attached, each form a saturated ring
of 5-7 carbons;
R
Me0
/ I \N
Me0 \ ' _N
~N
~C(O)R~
and pharmaceutically acceptable salts thereof, wherein:
R is amino or hydrazino;
R1 is cycloalkyl having 3 to 8 ring carbon atoms inclusive
and cycloalkenyl having 4 to 8 ring carbon atoms inclusive;
R3
H N \\
N
~\ /
R6' _N N
R9
and pharmaceutically acceptable addition salts thereof,
wherein


CA 02203379 2001-10-11
69886-5
33
R1 is hydrogen, alkyl, C4 to C7 cycloalkyl, C4 to C7
cycloalkyl, substituted by C1 to Clo alkyl or hydroxyl, 2- or
3-tetrahydrothienyl, 1,1, -dioxide, C4 to C7 cycloalkyl-C1 to
Clo alkyl, carboxy-C1 to Clo alkyl, carbo-C1 to C4 lower alkoxy
Cl to Clo alkyl, dialkylamino C1 to Clo alkyl, phenyl-C1 to C4
lower-alkyl, phenyl-C1 to C4 lower-alkyl in which the phenyl
ring is substituted in the 2, 3 or 4 position by one or two
substituents, the same or different, selected from the group
consisting of amino, halogen, C1 to Clo alkyl, carboxyl,
carbo-C1 to C4 lower-alkoxy, carbamoyl, 1VHS02 (quinolinyl),
nitro and cyano;
R3 is C1 to C4 lower alkyl , phenyl C1 to C4 lower alkyl ,
lower-alkoxyphenyl-C1 to C4 lower-alkyl, diCl to C4 lower-
alkoxy-phenyl-C1 to C4 lower alkyl, pyridyl-C1 to C4 lower
alkyl, C4 to C7 cycloalkyl-C1 to C4 lower-alkyl, phenylamino,
diCl to C1_ alkyl amino, halogen, trifluoromethyl, C1 to C4
lower-alkylthio, cyano or nitro; and
R6 is a nine or ten membered bicyclic ring having carbon and
from one or two nitrogen atoms, and the heterocycle is made
up of fused 5 or 6 membered rings or such ring substituted
at any available carbon atom by one or two substituents, the
same or different, selected from the group consisting of C1
to C4 lower-alkyl, halogen, C1 to C4 lower-alkoxy, C4 to C7
cycloalkyloxy, 4-morpholinyl, Clto C4 lower-alkoxy-Cl to C4
lower-alkoxy, hydroxy, imidazolyl, oxo and 4-morpholinyl-C1
to C4 lower-alkoxy, or at any time available nitrogen atom by
C1 to C4 lower-alkyl, C2 to C4 lower-alkanoyl, or
trifluoroacetyl;


CA 02203379 2001-10-11
69886-5
34
N
R2 ~~ R1
N
R4
R3
and pharmaceutically acceptable salts thereof,
where R1 stands for a low alkyl radical or (low) cycloalkyl;
Rz for a carboxy radical, esterified carboxy radical or an
amidized carboxy radical; and
R3 and R4 each stand for hydrogen, halogen atoms, carboxy
radicals, esterified carboxy radicals or low alkyl radicals
that may possess 1 - 3 halogen atoms, respectively;
N
i
\ / N ~
OEt
(2-phenyl-8-ethoxycycloheptimidazole);
R2
R1
R3
and pharmacologically acceptable salts thereof,
in which ring A represents a benzene, pyridine or
cyclohexane ring and B represents a pyridine, imidazole or
pyrimidine ring, with the proviso that rings A and B are
bonded to each other with two atoms being shared by the, and
the shared atoms may be any of carbon and nitrogen atoms:


CA 02203379 2001-10-11
69886-5
R1 represents a group represented by the formula: -NR4R5
(wherein R4 and RS may be the same or different from each
other and each represent a hydrogen atom, a lower alkyl or
aryl group or a carboxyl group which may be protected, or
5 alternatively R4 and RS may form a ring together with the
nitrogen atom to which they are bonded, provided that the
ring may be substituted), or a heteroaryl group which has
one or two nitrogen atoms and may be substituted;
R2 represents a hydrogen atom, a group represented by the
10 formula:
-- N
R8
(wherein R$ represents a carboxyl or tetrazolyl group which
may be protected),
or a halogen atom:
15 and
R3 represents a hydrogen atom or a group represented by the
formula:
R6
NHCH2
R7
(wherein R6 and R' each represent a hydrogen or halogen atom
20 or a lower alkoxy group, or alternatively R6 and R' may
together form a methylenedioxy or ethylenedioxy group);


CA 02203379 2001-10-11
69886-5
36
O R2
OR3 HN ~ \\
N
\ \N N
\R1
w/
R5
and pharmaceutically acceptable salts and solvates (eg.
hydrates) thereof, in which:
R1 represents arylmethyl or C1_6 alkyl optionally substituted
by one or more fluorine atoms;
Rz represents methyl;
R3 represents C2_4 alkyl;
R4 represents nitro, cyano, Cl_6 alkoxy, C (=X) NR6R7, NRaR9,
(CHz) mNRl°C (=Y) Rll or a 5-membered heterocyclic ring selected
from thienyl, thiazolyl and 1,2,4-triazolyl each ring
optionally substituted by a
C1_4 alkyl or aryl group; or when R1 is arylmethyl or C1_6
alkyl substituted by one or more fluorine atoms then R4 may
also represent hydrogen;
RS represents hydrogen or C1_6 alkyl;
R6 represents hydrogen or C1_6 alkyl;
R7 represents hydrogen, amino, hydroxyl, C1_6 alkyl, aryl or
arylCl_4 alkyl;
R$ represents hydrogen or C1_6 alkyl;
R9 represents hydrogen, C1_6 alkyl, S02Rlz, C02Rlz, C (=NCN) SRlz
or C ( =NCN) NR13R14 ;


CA 02203379 2001-10-11
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37
R1° represents hydrogen or Cl_6 alkyl;
Rll represents C1_6 alkyl optionally substituted by one or
more halogen atoms, or R11 represents aryl, aryl C1_4 alkyl,
thienyl, NR15R16, CH2NR17R1a or R1° and R11 together represent -
A ( CH2 ) n- ;
R12 represents Cl_6 alkyl, aryl or arylCl_4alkyl;
R13 represents hydrogen or Cl_6 alkyl;
R14 represents hydrogen, Cl_6 alkyl , aryl , aryl Cl_4 alkyl or
R13 and R14 together with the nitrogen atom to which they are
attached form a morpholine, piperazine or N-C1_4
alkylpiperazine ring;
R15 represents hydrogen or C1_6 alkyl or R1° and R15 together
represent -A (CH2) n- ;
R16 represents hydrogen, C1_6 alkyl, aryls aryl C1_4 alkyl,
C02R12, CH2CO2R12 Or R15 and R16 together with the nitrogen atom
to which they are attached form a morpholine, piperazine or
N-C1_4alkyl-piperazine ring;
R17 represents hydrogen or C1_6 alkyl ;
Rl8 represents hydrogen, C1_6 alkyl, aryl, aryl C1_4 alkyl,
2 0 CORlz or Rl7 and Rl$ together with the nitrogen atom to which
they are attached form a morpholine, piperazine, or N-C1_4
alkylpiperazine ring;
A represents CH2 or C = O;
m represents zero or 1;
n represents 1,2 or 3;
X represents S or NH, or when R7 represents amino then X may
also represent O;


CA 02203379 2001-10-11
69886-5
38
Y represents O or S;
Y- R2
HN
~~ N
(R3A)I
N"z-R1
and pharmaceutically acceptable salts thereof,
wherein A is a bond, C1-4 alkylene or C1-4 oxyalkylene;
Y is a bond, Cl-4 alkylene, Cl-4 alkyleneoxy, Cl-4
alkoxyphenylene or phenyl (C1-4) alkylene;
Z is a bond or vinylene;
Rl is a 4-15 membered heterocyclic ring containing one or
two nitrogen atoms optionally substituted by one or two
groups chosen from C1-4 alkyl, Cl-4 alkoxy, halogen,
trifluoromethyl, and nitro;
R2 is
(i) 4-15 membered heterocyclic ring containing one or
two hetero atoms chosen from nitrogen, oxygen and sulphur,
not more than one hetero atom being sulphur, optionally
substituted by one or two groups chosen from C1-4 alkyl,
Cl-4 alkoxy, halogen, trifluoromethyl, nitro and groups of
formula: - COOR10
wherein R10 is hydrogen or C1-4 alkyl,
C4-15 carbocyclic ring,
Cl-4 alkoxy,
hydroxy(Cl-4 alkoxy) or
hydroxy


CA 02203379 2001-10-11
69886-5
39
R3 i s
4-15 membered heterocyclic ring containing one or two hetero
atoms chosen from nitrogen, oxygen and sulphur, not more
than one hetero atom being oxygen or sulphur, optionally
substituted by one or two groups chosen from Cl-4 alkyl, C1-
4 alkoxy, halogen, trifluoromethyl, nitro, cyano, ethynyl
and groups of formula: - SONR7R8
wherein R7 and R8 are independently hydrogen or C1-4 alkyl.
C4-15 carbocyclic ring,
a group of formula:CH2 - CH(X)- wherein X is halogen, or
hydrogen
and 1 is 1 or 2;
provided that R2 is not hydroxy when Y is a bond: Rl is not
bonded through its nitrogen atom when Z is vinylene; and
excluding compounds of the formula:
,RBB
HN
CCR
\~ N
N RAA
DDR N \
REE
wherein R~ is methyl or n-propyl;
RB$ is cyclopentyl, cyclohexyl, 2-hydroxyethyl, methoxyethyl,
2-(1-piperindinyl)ethyl or phenyl or benzyl which may be
substituted by 1 or 2 of methyl, methoxy, chloro, nitro and
trifluoromethyl;
R~~ is hydrogen or methyl;


CA 02203379 2001-10-11
69886-5
RDD is methyl or n-propyl, isopropyl or benzyl; and
REE is hydrogen or methyl;
and the compound of formula:
OH
HN
~~ N
N ~ \
N
N R~ R2
H
N ~ ~ ~N
X
N
R3
and pharmaceutically acceptable salts thereof,
where R1 and R2 may stand for identical or different
hydrogen atoms, low alkyl radicals (the respective alkyls
may be cycloalkyl with a substitution number of 1 - 3,
10 either identical or different, hydroxy, low alkoxy, carboxy,
low alcoxycarbonyl, amino, monoalkyl-substituted amino,
dialkyl-substituted amino, nitro, halogen or alicyclic
heterocyclic radical (the respective alicyclic heterocyclic
radical may be substituted by identical or different low
15 alkyls with a substitution number of 1 - 3, aralkyl, aryl
possibly substituted by a low alcoxy radical with a
substitution number from 1 - 3 or an aromatic heterocyclic
radical), a cycloalkyl., di-cycloalkyl, benzocycloalkyl (the
respective benzoalkyl may be substituted by identical or
20 different low alkyls with a substitution number of 1 - 3,
hydroxy, low alcoxy, carboxy, low alcoxycarbonyl, amino,
aminoalkyl-substituted amino, dialkyl-substituted amino,


CA 02203379 2001-10-11
69886-5
41
vitro, sulphonamide, halogen, or trifluoromethyl), low
alkenyl, aryl (the respective aryl may be subsituted by
identical or different low alkyls with a substitution number
of 1 - 3, hydroxy, low alcoxy, carboxy, low alcoxycarbonyl,
amino, monoalkyl-substituted amino, di-alkyl substituted
amino, vitro, sulphonamide, halogen or trifluoromethyl),
aromatic heterocyclic radical-substituted alkyl (the
respective aromatic heterocyclic radical-substituted part
may be substituted by identical or different low alkyls with
a substitution number of 1 - 3, hydroxy, low alcoxy,
carboxy, low alcoxycarbonyl, amino, monoalkyl-substituted
amino, di-alkyl substituted amino, vitro, sulphonamide,
halogen, or trifluoromethyl, or the alkyl part may be
substituted by aryl), aromatic heterocyclic radical (the
respective aromatic heterocyclic radical may be substituted
by identical or different low alkyls with a substitution
number of 1 - 3, hydroxy, low alcoxy, carboxy, low
alcoxycarbonyl, amino, monoalkyl-substituted amino, di-alkyl
substituted amino, vitro, sulphonamide, halogen or
trifluoromethyl), or aralkyl (the aryl part of the
respective aralkyl may be substituted by identical or
different low alkyls with a substitution number of 1 - 3,
low alcoxy, di-alcoxy-substituted amino, halogen or
trifluoromethyl); and, furthermore,
R1 and Rz may stand for heterocyclic radicals formed by R1
and R2 combining with the inclusion of nitrogen (N) (the
respective heterocyclic radical may be substituted by
identical or different alkyls with a substitution number of
1 - 3, aryl, or aralkyl);
R3 stands for hydrogen, low alkyl (the respective low alkyl
may be substituted by identical or different cycloalkyls
with a substitution number of 1 - 3, hydroxy, low alcoxy,
carboxy, low alcoxycarbonyl, amino, monoalkyl-substituted


CA 02203379 2001-10-11
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42
amino, di-alkyl-substituted amino, vitro, halogen, or
alicyclic heterocyclic radical (the respective alicyclic
heterocyclic radical may be substituted by identical or
different low alkyls with a substitution number of 1 - 3,
aralkyl, aryl possibly substituted by a low alcoxy radical
with a substitution number from 1 - 3 or an aromatic
heterocyclic radical.)), cycloalkyl, low alkenyl, aryl (the
respective aryl may be subsituted by identical or different
low alkyls with a substitution number of 1 - 3, hydroxy, low
alkoxy, carboxy, low alcoxycarbonyl, amino, monoalkyl-
substituted amino, di-alkyl substituted amino, vitro,
sulphonamide, halogen or trifluoromethyl.), aromatic
heterocyclic radical-substituted alkyl (the respective
aromatic heterocyclic radical-substituted part may be
substituted by identical or different low alkyls with a
substitution number of 1 - 3, hydroxy, low alcoxy, carboxy,
low alcoxycarbonyl, amino, monoalkyl-substituted amino, di-
alkyl substituted amino, vitro, sulphonamide, halogen, or
trifluoromethyl, or the alkyl part may be substituted by
aryl), aromatic heterocyclic radical (the respective
aromatic heterocyclic radical may be substitued by identical
or different low alkyls with a substitution number of 1 - 3,
hydroxy, low alcoxy, carboxy, low alcoxycarbonyl, amino,
monoalkyl-substituted amino, di-alkyl substituted amino,
vitro, sulphonamide, halogen or trifluoromethyl), or aralkyl
(the aryl part of the respective aralkyl may be substituted
by identical or different low alkyls with a substitution
number of 1 - 3, low alcoxy, di-alcoxy-substituted amino,
halogen or trifluoromethyl.); and X stands for O (oxygen) or
S (sulphur);


CA 02203379 2001-10-11
69886-5
43
R2
R3
R4 R8
R5
-~-R6
R1 Y 1 / W
_ /(CH2)n
N~R7
\ ~ A
~N~
and pharmaceutically acceptable salts thereof,
where R1, R2, R3 and R4 signify identical or different
hydrogen atoms, halogen atoms, hydroxyl groups, possibly
halogen-substituted low alkyl radicals, possible halogen-
substituted low alcoxy radicals, nitro radicals,
hydroxyalkyl radicals, cyano radicals, radicals represented
by the formula
h9
'- ~CH~~p "~j~ iyl o
where R9 and Rl° stand for identical or different hydrogen
atoms, possibly halogen-substituted low alkyl radicals,
aryl-alkyl radicals, heteroaryl-alkyl radicals, acyl
radical, possibly protected carboxyl radicals,
and, where furthermore R9 and R1° may combine with the
nitrogen to which they are bonded to form a ring,
and where, moreover, this ring may also possess a substitute
radical,
P stands for 0 or an integer having a value from 1 - 6.), a
carbamoyl radical which may have a substitute radical, a
pyrazolyl radical which may have a substitute radical, an
imidazolyl radical which may have a substitute radical, or a
radical represented by the formula


CA 02203379 2001-10-11
69886-5
44
C~)~
_s_A~3
where R13 signifies a hydrogen atom or a possibly halogen-
substituted low alkyl radical. And, where q is 0 or an
integer with a value of 1 - 2,
furthermore, the two mutually adjacent substitute radicals
selected from R1, R2, R3, and R4 may combine with the carbon
atom to which they are bonded to form a ring,
RS and R6 stand for hydrogen atoms, halogen atoms, hydroxyl
groups, cyano radicals, possibly halogen-substituted low
alkyl radicals, or possibly halogen-substituted low alcoxy
radicals, furthermore, RS and R6 may combine with the carbon
atom to which they are bonded to form an oxolane ring, a
1,3-di-oxolane ring or a 1,4 di-oxane ring,
W signifies the radical represented by the formula -N= or a
radical represented by the formula -CH=. R7 and R8 stand for
identical or different hydrogen atoms, possibly halogen-
substituted low alkyl radicals,
furthermore, R1 and R' may combine with the carbon atom to
which they are bonded to form rings that may also contain
nitrogen, oxygen, or sulphur atoms. Furthermore, this ring
may also possess substitute radicals,
A stands for a hydrogen atom, a possibly halogen-substituted
low alkyl radical, or a radical represented by the formula -
X-(CH2)m-Z (where x stands for a radical represented by the
formula -CO-, a radical represented by the formula -CS-, a
radical represented by the formula -CH2-, or a radical
represented by the formula -C(O)2,


CA 02203379 2001-10-11
69886-5
Z signifies the hydroxyl group, a possibly halogen-
substituted low alcoxy radical, a cyano radical, a halogen
atom, a possibly protected carbamoyl radical, an aryl
radical which may possess substitute radicals, an aryloxy
5 radical which may possess substitute radicals, a heteroaryl
radical which may possess substitute radicals, a hetero aryl
alkyloxy radical which may possess substitute radicals, a
radical represented by the formula -NRllRlz (where R11 and Rlz
signify identical or different hydrogen atoms, possibly
10 halogen-substituted low alkyl radicals, aryl-alkyl radicals
which may possess substitute radicals, heteroaryl-alkyl
radicals which may possess substitute radicals, acyl
radicals, possibly protected carboxy radicals, or carbamoyl
radicals which may possess substitute radicals,
15 furthermore, R11 and Rlz may combine with the nitrogen atom to
which they are bonded to form a ring, moreover, this ring
may have substitute radicals.), or a cycloalkyl radical
which may possess substitute radicals,
m may be either 0 or an integer with a value from 1 - 6,
20 Y stands for an oxygen or sulphur atom,
N signifies either 0 or an integer with a value from 1 - 6;
R!~ ,Y-A
N
~N
(RQ)n
w ~ /CYB
N z (R3)m
and pharmaceutically acceptable salts, addition salts or
hydrates thereof,
25 wherein R1 is hydrogen or Cl-4 alkyl;
Y is a single bond or C1-6 alkylene;


CA 02203379 2001-10-11
69886-5
46
A is
-CyA- (R2) 1,
-O-R° or -S (O) p - R°,
in which R° is R°A or R°s,
R°A i s -CyA- ( R2 ) 1;
R°B is hydrogen or C1-4 alkyl;
p is 0-2;
CyA is
(1) 3-7 membered, saturated or unsaturated, monocyclic
carbocyclic ring,
(2) 7-membered, unsaturated or partially saturated,
monocyclic hetero ring containing as hetero atoms, one
nitrogen atom, one nitrogen and one oxygen atoms, two
nitrogen and one oxygen atoms, or one nitrogen and two
oxygen atoms,
(3) 6-membered, unsaturated or partially saturated,
monocyclic hetero ring containing as hetero atoms, one
nitrogen and one oxygen atoms, two nitrogen and one oxygen
atoms, or one nitrogen and two oxygen atoms,
(4) 6-membered, unsaturated or partially saturated,
monocyclic hetero ring containing as a hetero atom, one
nitrogen atom,
(5) 4- or 5-membered, unsaturated or partially
saturated, monocyclic hetero ring containing as hetero
atoms, one nitrogen atom, one nitrogen and one oxygen atoms,
two nitrogen and one oxygen atoms, or one nitrogen and two
oxygen atoms,


CA 02203379 2001-10-11
69886-5
47
(6) 4-7 membered, unsaturated or partially saturated,
monocyclic hetero ring containing as hetero atoms, one or
two sulfur atoms or
(7) 4-7 membered, unsaturated or partially or fully
saturated, monocyclic hetero ring containing as hetero
atoms, one or two oxygen atoms;
R2 is R2A or RZB;
R2A is (1) -NR6AR'A, in which R6A and R'A independently are
hydrogen or Cl-4 alkyl (with the proviso that R-6A and R'A
are not hydrogen at same time), (2)-S02NR6R', in which R6 and
R' independently are hydrogen or C1-4 alkyl, (3)
trifluoromethyl or (4) trifluoromethoxy;
R2B is (1) hydrogen (2) C1-4 alkyl, (3) Cl-4 alkoxy,
(4) -COORS in which RS is hydrogen or C1-4 alkyl, (5)
halogen, (6) nitro or
( 7 ) -NRGBR'B, in which R6B and R'B are hydrogen;
Z is ZA or ZB
ZA is methylene, ethylene, vinylene or ethnylene;
ZB is single bond;
CyB is
(1) 7-membered, unsaturated or partially saturated
monocyclic hetero ring containing as hetero atoms, one, two
or three nitrogen atoms,
(2) 6-membered, unsaturated or partially saturated
monocyclic hetero ring containing as hetero atoms, two or
three nitrogen atoms,


CA 02203379 2001-10-11
69886-5
48
(3) 6-membered, unsaturated or partially saturated,
monocylic hetero ring containing as a hetero atom, one
nitrogen atom,
(4) 4- or 5- membered, unsaturated or partially
saturated, monocyclic, hetero ring containing as hetero
atoms, one, two or three nitrogen atoms, or
(5) 4-7 membered, unsaturated or partially saturated,
monocyclic hetero ring containing as hetero atoms, one or
two oxygen atoms, or one or two sulfur atoms;
R3 is hydrogen, Cl-4 alkyl, C1-4 alkoxy, halogen or
trifluoromethyl;
R4 1S R4A Or R4B;
R4A is (1) -NHS02R11 in which Rll is Cl-4 alkyl, (2). SOZNR9Rlof
in which
R9 is hydrogen, Cl-4 alkyl or phenyl (C1-4 alkyl) and R1° is
hydrogen or C1-4 alkyl, (3) -OCORll, in which Rll is as
hereinbefore defined, (4) hydroxy, (5) -S02N=CHNR12R13 in
which R12 is hydrogen or Cl-4 alkyl and R13 is Cl-4 alkyl, (6)
-CONRI4Rls in which R14 is hydrogen or Cl-4 alkyl and R15 is
C1-4 alkyl or phenyl (C1-4alkyl), (7) ethynyl, (8) tri(C1-4
alkyl) silylethynyl or (9) acetyl;
R4B is (1) hydrogen, (2) C1-4 alkyl, (3) Cl-4 alkoxy,
(4) -COORs, in which R$ is hydrogen or C1-4 alkyl,
(5) -NR9R1°, in which R9 and Rl° are as hereinbefore defined,
(6) -NHCORll, in which Rll is as hereinbefore defined,
(7) halogen, (8) trifluoromethyl, (9) nitro, (10) cyano,
(11) Cl-4 alkyl-thio, (12) C1-4 alkylsulfinyl, (13) Cl-4
alkylsulfonyl, (14) hydroxymethyl, and 1, m and n
independently are 1 or 2; with the proviso that the group of
the formula: -CyA-(R2), does not represent a cyclopentyl and


CA 02203379 2001-10-11
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49
trifluoromethylphenyl group when Y is a single bond, that a
CyB ring does not bond to Z through a nitrogen atom in the
CyB ring when Z is vinylene or ethynylene, that a CvB rina
is not pyridine or thiopene when CyA is a ring of CyA is a
ring of CyA - (7) that Y is not a single bond, when A is
(ii) -O-R° or -S (O)p- R° and that A is not -CyA - (R2B) 1 and
OR°B, when Z is ZB and R4 is R4s;
O
,R1
/ ~ ~ ~N
R°
R3
R2 O
and pharmaceutically acceptable salts and solvates thereof,
in which:
R° represents hydrogen, halogen or C1_6 alkyl;
R1 represents hydrogen, Cl_6 alkyl, C2_6 alkenyl, C2_6 alkynyl,
halo C1_6 alkyl, C3_$ cycloalkyl, C3_8 cycloalkyl Cl_3 alkyl,
aryl Cl_3 alkyl or heteroaryl C,,_3 alkyl ;
Rz represents an optionally substituted monocyclic aromatic
ring selected from benzene, thiopene, furan and pyridine or
an optionally substituted bicyclic ring
A
attached to the rest of the molecule via one of the benzene
ring carbon atoms and wherein the fused ring A is a 5- or 6-
membered ring which may be saturated or partially or fully
unsaturated and comprises carbon atoms and optionally one or


CA 02203379 2001-10-11
69886-5
two heteroatoms selected from oxygen, sulphur and nitrogen;
and
R3 represents hydrogen or Cl_3 alkyl, or R1 and R3 together
represent a 3- or 4-membered alkyl or alkenyl chain;
R1~ ~R2
N
i i N
x~
N ~ ~N J
5 R3
and pharmaceutically acceptable salts thereof,
wherein R1 and R2 are the same or differ-ent and represent
hydrogen, lower alkyl (which is optionally substituted with
one to three substituents which are the same or different
10 and are cycloalkyl, hydroxy, lower alkoxy, carboxy, lower
alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-
substituted amino, vitro, halogen, alicyclic heterocycle
group (which is optionally substituted with one to three
substituents which are the same or different and are lower
15 alkyl, aralkyl, aryl optionally substituted with one to
three substituents which are the same or different and are
lower alkoxy, or aromatic heterocycle group) cycloalkyl,
bicycloalkyl, benzocycloalkyl (which is optionally
substituted with one to three substituents which are the
20 same or different and are lower alkyl, hydroxy, lower
alkoxy, carboxy, lower alkoxycarbonyl, amino, monalkyl-
substituted amino, dialkyl-substituted amino, vitro,
sulfonamide, halogen, or trifluormethyl) lower alkenyl, aryl
(which is optionally substituted with one to three
25 substituents which are the same or different and are lower
alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl,
amino, monoalkyl-substituted amino, dialkyl-substituted


CA 02203379 2001-10-11
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51
amino, nitro, sulfonamide, halogen, or trifluoromethyl)
aromatic heterocycle group-substituted alkyl (which is
optionally substituted with one to three substituents which
are the same or different and are lower alkyl, hydroxy,
lower alkoxy, carboxy, lower alkoxycarbonyl, amino,
monalkyl-substituted amino, dialkyl-substituted amino,
nitro, sulfonamide, halogen or trifluoromethyl and where
said alkyl part is optionally substituted with aryl),
aromatic heterocycle group (which is optionally substituted
with one to three substituents which are the same or
different and are lower alkyl, hydroxy, lower alkoxy,
carboxy, lower alkoxycarbonyl, amino, monalkyl substituted
amino, dialkyl-substituted amino, nitro, sulfonamide,
halogen or trifluoromethyl), or aralkyl (where the aryl part
of the said aralkyl is optionally substituted with one to
three substituents which are the same or different and are
lower alkyl, lower alkoxy, dialkyl substituted amino,
halogen or trifluoromethyl), or R1 and R2 are taken together
to represent heterocycle group containing nitrogen atom
(which is optionally substituted with one to three
substituents which are the same or different and are lower
alkyl, aryl or aralkyl), R3 represents hydrogen, lower alkyl
(which is optionally substituted with one to three
substituents which are the same or different and are
cycloalkyl, hydroxy, lower alkoxy, carboxy, lower
alkoxycarbonyl, amino, monalkyl-substituted amino, dialkyl
substituted amino, vitro, halogen, or alicyclic heterocycle
group (which is optionally substituted with one to three
substituents which are the same or different and are lower
alkyl, aralkyl, aryl optionally substituted with one to
three substituents which are the same or different and are
lower alkoxy, or aromatic heterocyle group), cycloalkyl,
lower alkenyl, aryl (which is optionally substituted with
one to three substituents which are the same or different


CA 02203379 2001-10-11
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52
and are lower alkyl, hydroxy, lower alkoxy, carboxy, lower
alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-
substituted amino, nitro, sulfonamide, halogen or
trifluoromethyl), aromatic heterocycle group-substituted
alkyl (where said aromatic heterocycle group part is
optionally substituted with one to three substituents which
are the same or different and are lower alkyl, hydroxy,
lower alkoxy, carboxy, lower alkoxycarbonyl amino,
monoalkyl-substituted amino, dialkyl-substituted amino,
nitro, sulfonamide, halogen or trifluoromethyl, and where
the alkyl part is optionally substituted with aryl),
aromatic heterocycle group (where said aromatic heterocycle
group is optionally substituted with one to three
substituents which are the same or different and are lower
alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl,
amino, monoalkyl-substituted amino, dialkyl-substituted
amino, nitro, sulfonamide, halogen or trifluoromethyl), or
aralkyl (where the aryl part of said aralkyl is optionally
substituted with one to three substituents which are the
same or different and are lower alkyl, lower alkoxy,
dialkyl-substituted amino, halogen, or trifluoromethyl), or
aralkyl (where the aryl part of said aralkyl is optionally
substituted with one to three substituents which are the
same or different and are lower alkyl, lower alkoxy, dialkyl
substituted amino, halogen, or trifluoromethyl), and X
represents oxygen atom or sulfur atom; and
R6 ~ _ ., R7
R2 / /~N
R3 ~ ~N~R5
and pharmacologically acceptable salts thereof


CA 02203379 2001-10-11
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53
(wherein R1, R2, R3, R4 and RS may be the same or different
from each other and each represents a hydrogen atom, a
halogen atom, a lower alkyl group or a lower alkoxy group;
and
R6 and R' may be the same or different from each other and
each represents a hydrogen atom, a lower alkyl group, a
hydroxyalkyl group, a lower alkoxyalkyl group, a cyanoalkyl
group, a heteroarylalkyl group, a cycloalkyl group, a
cycloalkylalkyl group or a carboxyl alkyl group which may be
protected, or alternatively R6 and R' may form a ring
together with the nitrogen atom to which they are bonded,
this ring optionally having a substituent.
The invention includes the use of any compound
within the scope of the claims of the patents listed above
as well as the particular individual compounds disclosed
therein.
Of particular interest for use in the present
invention are compounds disclosed in EP 0579496, W093/07124,
US 5294612 and W094/22855 (xv, xviii, xxi and xxiv above);
the compounds of EP 0579496 and W094/22855 being especially
preferred.
More specifically, the present invention provides
the use of a compound as described herein, wherein the
compound which is a selective cGMP PDE inhibitor is selected
from:
R1 ~ ,Y-A
N ~ R3
R1
/\N R2 R6 HN
(R4)n A BH3 ~~ /N
\N~z-C B R3 R6~N N
yyR3)m R4 ~R5 \R1


CA 02203379 2001-10-11
69886-5
54
and
R2
R1 A BH3
R3
as described herein.
Examples of particular and preferred compounds
from these patents and publications for use in the present
invention include:
1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one
(preparation as described in European patent application
201188, Example 1),
2-(2-propoxyphenyl)-6-purinone (preparation as described in
European patent application 0293063, Example 1),
6-(2-propoxyphenyl)-1,2-dihydro-2-oxopyridine-3-carboxamide
(preparation as described in European patent application
0347027, Example 2),
2- (2-propoxyphenyl) pyrido [2., 3-d] pyrimid-4 (3H) -one
(preparation as described in European patent application
0347146, Example 1),
7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-
dihydropyrimido[4,5-d]pyrimidine (preparation as described
in European patent application 0351058, Example 1),
6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide
(preparation as described in European patent application
0395328, Example 15),
1-ethyl-3-methylimidazo[1,5a]quinoxalin-4(5H)-one
(preparation as described in European patent application
0400583),
4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)-quinazoline
(preparation as described in European patent application
0579496, Example 5(c)),


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5-ethyl-8-[3-(N-cyclohexyl-N-methylcarbamoyl)-propyloxy]-
4,5-dihydro-4-oxopyrido[3,2-a]pyrrolo[1,2-a]pyrazine
(preparation as described in European patent application
0584487, Example 1),
5 5'-methyl-3'-(phenylmethyl)-spiro[cyclopentane-1,7'(8'H)-
(3'H) -imidazo [2, 1-b]purin] 4' (5'H) -one (preparation as
described in International patent application
W091/19717, Example 9A3),
1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-
10 yl)piperidine-4-carboxylic acid (preparation as described in
International patent application W093/07124),
(6aR,9aS)-2-(4-trifluoromethylphenyl)methyl-5-methyl-
3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-
b]purin-4-one (preparation as described in International
15 Patent application W094/19351, Example 14),
1-tert-butyl-3-phenylmethyl-6-(4-pyridyl.)pyrazolo[3,4-
d]pyrimid-4-one (preparation as described in US patent
5294612, Example 90),
1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-
20 pyrazolo[3,4-d]pyrimid-4-one (preparation as described in US
patent 5294612, Example 83),
2-butyl-1-(2-chlorobenzyl)6-ethoxycarbonylbenzimidazole
(preparation described in Japanese patent application 5-
222000) ,
25 2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-
nitroquinazoline (preparation as described in.International
patent application W094/22855, Example 11),
and 2-phenyl-8-ethoxycycloheptimidazole (KT2-734).
Of particular interest for use in the present
30 invention are the compounds:
4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)quinazoline
(preparation as described in European patent application
0579496, Example 5(c)),


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1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-
yl)piperidine-4-carboxylic acid (preparation as described in
International patent application W093/07124),
(6aR,9aS)-2-(4-trifluoromethylphenyl)methyl-5-methyl-3,4,
5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4
one (preparation as described in International Patent
application W094/19351, Example 14),
1-tert-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-
d]pyrimid-4-one (preparation as described in US patent
5294612, Example 90),
1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimid-4-one, (preparation as described in
US patent 5294612, Example 83), or
2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-
nitroquinazoline (preparation as described in International
patent application W094/22855, Example 11).
Further cGMP PDE inhibitors for use in the
treatment of erectile dysfunction are:
xxv a pyrazolopyrimidine derivative as disclosed in
European patent application 0636626;
xxvi a 4-aminopyrimidine derivative as disclosed in
European patent application 0640599;
xxvii a imidazoquinazoline derivative as disclosed in
International patent application W095/06648;
xxviii an anthranilic acid derivative as disclosed in
International patent application W095/18097;
xxix a 4-aminoquinazoline derivative as disclosed in US
patent 5436233;
xxx a tetracyclic derivative as disclosed in
International patent application W095/19978;


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57
xxxi an imidazoquinazoline derivative as disclosed in
European patent application 0668280; or
xxxii a quinazoline compound as disclosed in European
patent application 0669324.
More specifically, the present invention provides
the use of a compound which is a selective cGMP PDE
inhibitor for the manufacture of a medicament for the
treatment of erectile dysfunction in a male animal,
including man, wherein said compound is selected from:
R2
~~N / Y- R2
HN
'N N
R1 \ N
R5 (R3A)I
R4 N"z-R1
,
R5
NR~R2 R1 Y ~ W R6
N / \ R2 / Ns(CHZ)n
'N R7
X
R3 ~ ~ iA
N ~N ~N
R3 R4 R8
R~ ,Y-A
N
,R1
N
(R4)n ~\
\N C g _R3
N z (R3)m


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58
R1~ ,R2 R6~ ,RT
R1 N
N R2 ~ ~\ N
R3 ~
\N"R5
and
as mentioned above.
The compounds may be evaluated as selective
inhibitors of cGMP-PDE using any of the methods previously
described but in particular their activity against cGMP-PDEV
may be assessed as described in our International patent
application PCT/EP94/01580, (W094/28902).
Generally, in man, oral administration is the
preferred route, being the most convenient and avoiding the
disadvantages associated with i.c. administration. A
preferred dosing regimen for a typical man is 5 to 75 mg of
compound daily, however the dosage may be increased
depending on the potency of the compound being administered
and higher dosages are within the scope of the invention.
Alternative dosage regimes are also possible depending upon
the individual patients circumstances such as the frequency
of sexual intercourse. In circumstances where the recipient
suffers from a swallowing disorder or from impairment of
drug absorption after oral administration, the drug may be
administered parenterally, e.g. sublingually or buccally.
For veterinary use, a compound of the invention or
a non-toxic salt thereof is administered as a suitably
acceptable formulation in accordance with normal veterinary
practice and the veterinary surgeon will determine the
dosing regimen and route of administration which will be
most appropriate for a particular male animal.


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Although the compounds of the invention are
envisaged primarily for the treatment of erectile
dysfunction or male sexual dysfunction, they are also useful
for the treatment of female sexual dysfunction including
orgasmic dysfunction related to clitoral disturbances,
premature labour and dysmenorrhea.
The invention also provides a method of treating
erectile dysfunction in a male animal which comprises
administering an effective amount of a compound which is a
selective cGMP-PDE inhibitor as defined above.
The invention also provides a medicine for
treating erectile dysfunction in a male animal, or female
sexual dysfunction, premature labour or dysmenorrhea,
comprising an effective amount of the compound which is a
selective cGMP-PDE inhibitor, as mentioned above, and a
pharmaceutically acceptable diluent or carrier.
The invention further provides a commercial
package which comprises the above-mentioned medicine and a
written matter providing instructions for treating the
disorder described hereinbefore.