CA2203379C - Cgmp-pde inhibitors for the treatment of erectile dysfunction - Google Patents

Abstract

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

Description

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 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.

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;

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:

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;

and the pharmaceutically acceptable salts thereof, in which: A represents a group of formula:

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;

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, 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;

X

\ ~ R3 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

\N
ORS
and pharmaceutically acceptable salts thereof, wherein -'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

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

\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, -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) ~ \

,N
N
O
H
HN N
~~ R2 \ \N N

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;

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

~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, -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;

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 --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, lower alkyl ~
lower alkyl-N X N' \' N lower alkyl N

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~

~N~
N
- N -N X

N \ ~ -N (CHZ)p 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 ~N~
-N X N

or W-ALK-Q;
O

HN I
\ \N
ORS
and pharmaceutically acceptable salts thereof, wherein 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;

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;

O
HN
A

\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) 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 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 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, 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, 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 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, 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 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;

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, 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;

A B

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, 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~-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, 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 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 o Ris 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 (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 ~I9 ~20 _~r..~~'~2> r p (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

~N N 2 N

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 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;

H N \\
N
~\ /
R6' _N N

and pharmaceutically acceptable addition salts thereof, wherein 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;

N
R2 ~~ R1 N

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);

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:

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

(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:

(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);

OR3 HN ~ \\
N
\ \N N
\R1 w/

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 ;

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;

Y represents O or S;

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 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;

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

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, 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 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);

-~-R6 _ /(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 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, 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;

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, (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, (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 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°

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 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

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 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 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 (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 /\N R2 R6 HN
(R4)n A BH3 ~~ /N
\N~z-C B R3 R6~N N
yyR3)m R4 ~R5 \R1 and 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)), 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)), 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;

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:

~~N / Y- R2 HN
'N N
R1 \ N
R5 (R3A)I
R4 N"z-R1 , NR~R2 R1 Y ~ W R6 N / \ R2 / Ns(CHZ)n 'N R7 X
R3 ~ ~ iA
N ~N ~N

R~ ,Y-A
N
,R1 N
(R4)n ~\
\N C g _R3 N z (R3)m R1~ ,R2 R6~ ,RT

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.

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.

Claims (13)

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:
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:
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;

and the pharmaceutically acceptable salts thereof, in which: A represents a group of formula:
~~
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;

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;
and the pharmaceutically acceptable salts and esters thereof, in which A represents a group of formula:
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;
and pharmaceutically acceptable salts thereof, wherein R1 is C1-6 alkyl or C2-6 alkenyl, and R2 is hydrogen or hydroxy;

64~

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;
and pharmaceutically acceptable salts thereof, wherein is a ring of sub-formula (a), (b), (c), (d), (e), (f) or (g):
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;
and pharmaceutically acceptable salts thereof, wherein is a ring of sub-formula (a), (b) or (c):

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;

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 said -S(O)n C1-6 alkyl, -OR6 or NR8R9 groups; and is a ring of sub-formula (a) or (b):

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;

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

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;

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, -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;

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

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 or W-ALK-Q;

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

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;

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

and pharmaceutically acceptable salts thereof, wherein 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 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 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, 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;

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;

(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 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 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;

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 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;

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 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 (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 (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, 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 (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 (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 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 (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 a radical represented by the formula a radical represented by the formula a radical represented by the formula (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 (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 (where R50 in this formula signifies a hydroxyl group, a halogen atom, a lower alkyl radical, a lower alkoxy radical, an optionally protected carboxyl radical, a cyano radical, a hydroxyalkyl radical or a carboxyalkyl radical), a radical represented by the formula (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 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 (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);
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 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;
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;
and pharmaceutically acceptable addition salts thereof, wherein 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;

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;
(2-phenyl-8-ethoxycycloheptimidazole);
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 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:
(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:
(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);

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;

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;

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, 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:
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;

R DD is methyl, n-propyl, isopropyl or benzyl; and R EE is hydrogen or methyl;
and the compound of formula:
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, 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 (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;
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 (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 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, 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 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;
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;

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 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;

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;

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 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;

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, 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, 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 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 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:
and as defined in claim 1.

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;

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:

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 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;

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:

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.