Note: Descriptions are shown in the official language in which they were submitted.
CA 02387520 2002-03-15
Z .
Amine derivatives
The invention relates to compounds of the formula I
Ra ~J _ W
\N~~
Rs
R,o \ .Y 1
/~X
Rat ~ S~Z
~~~r
in which
R1, R2 in each case independently of one another are
H, A, OA, OH, Hal, SH, SA, SOA, SOzA, SOZNHZ,
NOz , NH2 , NHA , NA2 , Ac , NHAc , CN , CODA or
COOH,
R1 and R2 together are also alkylene having 3-5 carbon
atoms , -0-CH2-CH2- , -CH2-O-CHz-, -0-CH2-0- or
-0-CHz-CH2-0- ,
X i s R4 , R5 or R6 ,
Y is C or N,
Z is CH or N,
Q is a linear or branched alkylene chain having
1-10 carbon atoms,
R4 is linear or branched alkylene having 1-10
carbon atoms, mono substituted by R', in which
1, 2 or 3 CHZ groups may have been replaced
by -CH=CH- and/or -C---C- groups,
RS iS -(CHz)n-R1'-(CHz)m-R',
CA 02387520 2002-03-15
- 2 -
R6 i s -(CHi)o g (CHZ)P-R',
R' is COOH, CODA, CONH2, CONHA, CON(A)2, CN,
tetrazol-5-yl, S02NH2,
NHS N.O
N~ , N~ ,
H O H S
N O ~O
N-S or ~
H ~~ H \\ ,
O O
R8 is H or A,
R9, Rl°, Rll in each case independently of one another
are H, A, OA, OH, Hal, SH, SA, SOA, SOZA, N02,
NH2, NHA, NA2, Ac, NHAc, CN, COOA or COOH,
A is alkyl having 1 to 10 carbon atoms, it
being possible for 1-7 hydrogen atoms to have
been replaced by F and/or C1,
Ac is acyl having 1-10 carbon atoms,
R12 is cycloalkylene having 4-7 carbon atoms, it
being possible for one or two CH2 groups to
have been replaced by N, 0 and/or S,
Hal is F, C1, Br or I,
n, m, o, p in each case independently of one another
are 0, 1, 2, 3, 4, 5 or 6,
r is 0, 1 or 2,
it being possible for one or 2 carbon atoms in ring A
to have been replaced by N,
CA 02387520 2002-03-15
- 3 -
the ring B being an unsaturated 5- or 6-membered ring
and it being possible for one or two carbon atoms to
have been replaced by N, O and/or S, and in which one,
two or three H atoms may have been replaced by A, OA,
Hal, NOZ and/or CN,
the ring C being a saturated or unsaturated 5- or
6-membered ring and it being possible for one or two
carbon atoms to have been replaced by N, 0 and/or S,
and in which one, two or three H atoms may have been
replaced by A, OA, Hal, NO2 and/or CN,
and their physiologically acceptable salts and
solvates.
Pyrimidine derivatives are known, for example, from
EP 201 188 or WO 93/06104.
The invention was based on the object of discovering
new compounds having valuable properties, especially
those which can be used for the production of
medicaments.
It has been found that the compounds of the formula I
and their salts combine very valuable pharmacological
properties with good tolerability.
In particular, they exhibit a specific inhibition of
cGMP phosphodiesterase (PDE V).
Quinazolines having cGMP phosphodiesterase inhibitor
activity are described, for example, in J. Med. Chem.
36, 3765 (1993) and ibid. 37, 2106 (1994).
The biological activity of the compounds of the formula
I may be determined in accordance with methods as
described, for example, in WO 93/06104. The affinity of
the compounds of the invention for cGMP and CAMP
CA 02387520 2002-03-15
y .
- 4 -
phosphodiesterase is measured by determining their IcSo
values (the concentration of inhibitor required to
achieve 50~ inhibition of the enzyme activity).
The measurements may be carried out using enzymes
isolated by known methods (e. g. W.J. Thompson et al.,
Biochem. 19?1, 10, 311). The experiments may be
conducted using a modified "batch" method of W.J.
Thompson and M.M. Appleman (Biochem. 1979, 18, 5228).
The compounds are therefore suitable for treating
disorders of the cardiovascular system, especially
cardiac insufficiency, and for the treatment and/or
therapy of impaired potency (erectile dysfunction).
The use of substituted pyrazolopyrimidinones for
treating impotence is described, for example, in
w0 94/28902.
The compounds are effective as inhibitors of
phenylephrine-induced contractions in cavernous-body
preparations of hares. This biological activity may be
demonstrated, for example, by the method described by
F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993).
The inhibition of contraction shows the efficacy of the
compounds of the invention for the therapy and/or
treatment of impaired potency.
The compounds of the formula I may be used as
pharmaceutical active substances in human and
veterinary medicine. Furthermore, they may be used as
intermediates for preparing further pharmaceutical
active substances.
The invention accordingly provides the compounds of the
formula I and a process for preparing compounds of the
formula I according to Claim 1 and also their salts and
solvates,
characterized in that
. ~ CA 02387520 2002-03-15
- 5 -
a) a compound of the formula II
R9 f
R,o \ .Y
~~ X
I I
R" S~Z
~O)r
in which
X, Y, 2, R9, R1°, R11, r and the ring A are as defined in
Claim 1
and L is C1, Br, OH, SCH3 or a reactive esterified
OH group
is reacted with a compound of the formula III
R~
Ra C RZ
\N~4
I III
H
in which
R1, R2, R8, Q and the ring C are as defined in Claim 1
or
b) one radical X in a compound of the formula I is
converted to another radical X by, for example,
hydrolysing an ester group to a COOH group or
converting a COOH group to an amide or a cyano group
and/or in that a compound of the formula I is converted
to one of its salts.
Above and below, the radicals R1, R2, Ra, R9, R1°, R11, r,
Q, X, Y, Z and L and also the rings A and C are as
CA 02387520 2002-03-15
- 6 -
defined for the formulae I, II and III unless expressly
stated otherwise.
The compounds of the formula I may possess one or more
chiral centres and may therefore exist in two or more
stereoisomeric forms. All of these forms (e.g. D and L
forms) and mixtures thereo f (e.g. the DL forms) are
included in the formula I.
Also included among the compounds of the invention are
so-called prodrug derivatives, i.e. compounds of the
formula I modified with, for example, alkyl or acyl
groups, sugars or oligopeptides, which in the body are
rapidly cleaved to give the active compounds of the
invention.
A is alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
C atoms. In the above formulae, alkyl is preferably
unbranched and has 1, 2, 3, 4, 5 or 6 C atoms and is
preferably methyl, ethyl or propyl, further preferably
isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,
but also n-pentyl, neopentyl, isopentyl or hexyl. A,
furthermore, is for example trifluoromethyl, penta-
fluoroethyl or -CC12-CF3.
Ac is acyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
C atoms, preferably for example, formyl, acetyl,
propionyl, butyryl, and also benzoyl.
R4 is linear or branched alkylene having 1-10 C atoms,
monosubstituted by R', in which one, two or three CHZ
groups may have been replaced by -CH=CH- and/or -C-__C-
groups. Alkylene here is preferably a linear or
branched alkylene radical having 1-10 C atoms, the
alkylene radical being preferably for example
methylene, ethylene, propylene, isopropylene, butylene,
isobutylene, sec-butylene, pentylene, 1-, 2- or
3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene,
1-ethylpropylene, hexylene, 1-, 2-, 3- or
4-methylpentylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or
CA 02387520 2002-03-15
3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-
1-methylpropylene, 1-ethyl-2-methylpropylene, 1,1,2- or
1,2,2-trimethylpropylene, linear or branched heptylene,
octylene, nonylene or decylene.
Alkylene is also for example but-2-enylene or
hex-3-enylene. Very particular preference is given to
ethylene, propylene or butylene.
Q is preferably a linear or branched alkylene radical
having 1-10 C atoms, the alkylene radical being
preferably for example methylene, ethylene, propylene,
isopropylene, butylene, isobutylene, sec-butylene,
pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or
2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-,
2-, 3- or 4-methylpentylene, 1,1-, 1,2-, 1,3-, 2,2-,
2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene,
1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene,
1,1,2- or 1,2,2-trimethylpropylene, linear or branched
heptylene, octylene, nonylene or decylene.
Very particular preference is given to ethylene,
propylene or butylene.
RS is cycloalkylene having 4-7 C atoms, preferably for
example cyclopentylene or cyclohexylene. It is also
possible for one or two CH2 groups therein to have been
replaced by N, 0 and/or S. R5 is therefore also for
example 1,4-piperidyl or 1,4-piperazinyl.
Hal is preferably F, C1 or Br, but also I.
The radicals R1 and R~ may be identical or different and
are preferably in position 3 or 4 of the phenyl ring.
They are, for example, in each case independently of
one another H, A, OA, OH, Hal, SH, SA, SOA, SOZA,
3 5 SOZNH2 , N02 , NH2 , NHA, NAz , Ac , NHAc , CN , COOA or COOH .
The ring A preferably contains no heteroatom. However,
it is possible for 1 or 2 C atoms to have been replaced
by nitrogen.
CA 02387520 2002-03-15
The ring B is preferably 1,4-phenylene which is mono-
or disubstituted by A, OA, Hal and/or CN. Ring B is
also an unsaturated heterocycle such as, for example,
thiophene-2,5-diyl or pyrimidine-2,4-diyl or pyridine-
2,6-diyl.
Ring C is a saturated or unsaturated 5- or 6-membered
ring in which one or two C atoms may have been replaced
by N, 0 and/or S and in which one, two or three H atoms
may have been replaced by A, OA, Hal, NOZ and/or CN.
If the ring C is unsaturated and contains one or more
heteroatoms as stated, it is preferably for example 2-
or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-,
2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,
4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or
5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or
4-pyridyl, 2-, 4-, 5- or 6-pyrimidyl, further
preferably 1,2,3-triazol-1-, -4- or -5-yl,
1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl,
1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or
-5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thia
diazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-,
3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or
4-4-H-thiopyranyl, 3- or 4-pyridazinyl or pyrazinyl.
If the ring C is saturated and contains one or more
heteroatoms as stated, it is preferably for example
2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-,
-3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl,
1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,
2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,
2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or
3-pyrrolidyl, tetrahydro-1-, -2- or -4-imidazolyl,
2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,
tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-,
-2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-,
-3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidyl,
2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or
-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl,
CA 02387520 2002-03-15
_ g _
hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-,
-4- or -5-pyrimidyl, 1-, 2- or 3-piperazinyl.
With very particular preference the ring C is phenyl.
R12 is cycloalkylene having 4, 5, 6 or 7 C atoms in
which one or two CHZ groups may have been replaced by
N, 0 andlor S. R12 is preferably cyclopentylene or
cyclohexylene, and also, for example 1,2-, 2,3- or
1,3-pyrrolidinyl, 1,2-, 2,4-, 4,5- or 1,5-
imidazolidinyl, 1,2-, 2,3-, or 1,3-pyrazolidinyl, 2,3-,
3,4-, 4,5- or 2,5-oxazolidinyl, 1,2-, 2,3-, 3,4- or
1,4-isoxazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-thiazol-
idinyl, 2,3-, 3,4-, 4,5- or 2,5-isothiazolidinyl, 1,2-,
2,3-, 3,4- or 1,4-piperidyl, 1,4- or 1,2-piperazinyl,
further preferably 1,2,3-tetrahydrotriazol-1,2- or
-1,4-yl, 1,2,4-tetrahydrotriazol-1,2- or 3,5-yl, 1,2-
or 2,5-tetrahydrotetrazolyl, 1,2,3-tetrahydrooxa-
diazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4-tetrahydro-
oxadiazol-2,3-, -3,4- or -4,5-yl, 1,3,4-tetrahydro-
thiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4-tetra-
hydrothiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl,
1,2,3-thiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 2,3- or
3,4-morpholinyl, 2,3-, 3,4- or 2,4-thiomorpholinyl.
For the entire invention it is the case that all
radicals occurring more than once may be identical or
different, i.e. are independent of one another.
Accordingly, the invention in particular provides those
compounds of the formula I in which at least one of the
specified radicals has one of the preferred definitions
stated above. Some preferred groups of compounds may be
expressed by means of the following subformulae Ia to
Ip, which correspond to the formula I and in which the
radicals not designated in any greater detail have the
definition stated for the formula I, but in which
in Ia Z is N,
Y is C;
CA 02387520 2002-03-15
- 10 -
in Ib Z is CH,
Y is N;
in Ic RS is A;
in Id R7 is tetrazol-5-yl, SOzNHz,
NHS N.O
N ~ , N \\ ,
H O H S
N
~N~O
_ or ~(
H S~ H~ ,
O O
in Ie R1, Rz in each case independently of one
another are SH, SA, SOA, SOzA, SOzNHz, NOz,
NHz , NHA, NAz , Ac , NHAc , .CN, COOA or COOH,
in If R9, Rl°, Rll are H,
r is 0,
Z is N,
Y is N,
R$ is H,
Q is CHz,
Rl, Rz in each case independently of
one another are SH, SA, SOA,
SOzA, SOzNHz, NOz, NHz, NHA,
NAz, Ac, NHAc, CN, COOA or
COOH,
in Ig R9, R1°, Ril are H,
r is 0,
n, m are 0,
Z is N,
Y is N,
R8 is H,
Q i s CHz ,
CA 02387520 2002-03-15
- 11 -
R' is tetrazol-5-yl, SOzNHz,
NHS N.O
N \\ , N \\ ,
H O H S
N ~ N~O
N-S or
H '' N
4 H O
in Ih Rl, RZ in each case independently of
one another are H, A, OA, OH
or Hal,
R9, Rlo, Rii are H,
r is 0,
X is R6,
Z is N,
Y is N,
Re is H,
Q is CH2,
o, p in each case independently of
one another a re l, 2 or 3,
and
the ring B being an unsaturated 5- or
6-membered ring and it being possible for one
or two C atoms to have been replaced by N, 0
and/or S, and in which one, two or three H
atoms may have been replaced by A, OA, Hal, NOZ
and/or CN,
in Ii R1, RZ in each case independently of
one another are H, A, OA, OH
or Hal,
R9, R1°, R11 are H,
r is 0,
Z is N,
CA 02387520 2002-03-15
- 12 -
Y is N,
X is R5,
R8 is H,
Q is CH2,
n, m in each case independently of
one another are 1, 2 or 3,
R12 is cyclopentylene or
cyclohexylene in which one or
two CHz groups have been
replaced by N, 0 and/or S;
in Ik R1, RZ in each case independently of
one another are H, A, OA, OH
or Hal,
R9, Rl~, R11 are H,
r is 0,
Z is N,
Y is N,
X is R5,
R8 is H,
Q i s CHz ,
R' is tetrazol-5-yl, SOZNHz
NHS i .O
N--~ ' N--~ '
O H S
N.O N.O
or ~
H_S~ H \\
O O
Rg i s H , and
the ring C is phenyl;
in I1 R1, R2 in each case independently of
one another are SH, SA, SOA,
S02A, SO2NHz , NOZ , NH2 , NHA,
CA 02387520 2002-03-15
- 13 -
NAz, Ac, NHAc, CN, COOA or
COOH,
X is RS
and
the ring C is phenyl;
in Im R9, R1°, R11 are H,
r is 0,
Z is N,
Y is N,
RS is H,
RlZ is H,
Q is CHz,
Rl, R2 in each case independently of
one another are SH, SA, SOA,
S02A , S02NHz , NOz , NHZ , NHA,
NA2, Ac, NHAc, CN, COOA or
COOH,
X is R5
and the ring C is phenyl;
in In R9, R1°, R11 are H,
r is 0,
Z is N,
Y is N,
Rg is H,
Q i s CH2 ,
R' is tetrazol-5-yl, SOzNH2,
NwS N10
N-~ ' N-
H O H S
/N
O ~N~O
N S N
H ~O H O ,
X is RS or R6,
CA 02387520 2002-03-15
- 14 -
n is 0, 1 or 2,
m is 0, 1 or 2,
o is 0, 1 or 2,
p is 0, 1 or 2,
R12 is cyclopentylene or
cyclohexylene,
and
the ring B is 1,4-phenylene and the ring C is
phenyl;
in Io R1, R2 in each case independently of
one another .are H, A, OA, OH
or Hal,
R9 , R1° , R11 are H,
r is 0,
X is RS or R6,
Z is N,
Y is N,
Re is H,
Q is CH2,
o, p in each case independently of
one another are 1, 2 or 3,
and
the ring B is an unsaturated 5- or 6-membered
ring and one C atom has been replaced by N, 0
or S, and one, two or three H atoms may have
been replaced by A, OA, Hal, NOZ and/or CN,
and the ring C is phenyl;
in Ip R1, Rz in each case independently of
one another are H, A, OA, OH
or Hal,
R9~ Rio, Rii are H,
r is 0,
Z is N,
Y is N,
X i s RS or R6 ,
R8 is H,
~
. CA 02387520 2002-03-15
- 15 -
Q i s CHZ ,
n, m in each case independently of
one another are 1, 2 or 3,
R12 is cyclopentylene or
cyclohexylene in which one or
two CH2 groups have been
replaced by N, O and/or S,
and
the ring B is an unsaturated 5- or 6-membered
ring and one C atom has been replaced by N, O
or S, and one, two or three H atoms may have
been replaced by A, OA, Hal, NOZ and/or CN,
and the ring C is phenyl.
The compounds of the formula I and also the starting
substances for their preparation are otherwise prepared
by methods known per se, such as are described in the
1 i terature ( a . g . in the s tandard works such as Houben-
Weyl, Methoden der organischen Chemie [Methods of
organic chemistry], Georg-Thieme-Verlag, Stuttgart),
i.e. under reaction conditions which are known and
suitable for the specified reactions. Use may also be
made in this case of variants which are known per se
and are not mentioned here in any greater detail.
In the compounds of the formula II or III, X, Y, Z, R9,
Rio , Rii , r and the ring A, Rl , R2 , R8 , Q and the ring C
have the stated definitions, especially the stated
preferred definitions.
If L is a reactive esterified OH group, it is
preferably alkylsulfonyloxy having 1-6 C atoms
(preferably methylsulfonyloxy) or arylsulfonyloxy
having 6-10 C atoms (preferably phenyl- or
p-tolylsulfonyloxy, and also 2-naphthalenesulfonyloxy).
CA 02387520 2002-03-15
- 16 -
The compounds of the formula I may preferably be
obtained by reacting compounds of the formula II with
compounds of the formula III.
If desired, the starting substances may also be formed
in situ, so that they are not isolated from the
reaction mixture but instead are reacted further
immediately to the compounds of the formula I.
It is also possible to carry out the reaction in
stages.
In general, the starting compounds of the formulae II
and III are known. Where they are not known, they may
be prepared by methods which are known per se.
Compounds of the formula II may be obtained, for
example, by reaction with POC13 from the corresponding
hydroxypyrimidines, which are synthesized from
thiophene derivatives and CN-substituted alkylenecarb-
oxylic esters (Eur. J. Med. Chem. 23, 453 (1988)).
The hydroxypyrimidines are prepared either by
dehydrogenating corresponding tetrahydrobenzothieno
pyrimidine compounds or by the cyclization customary
for preparing pyrimidine derivatives, i.e. that of
2-aminobenzothiophene-3-carboxylic acid derivatives
with aldehydes or nitrites (e. g. Houben Weyl E9b/2).
Specifically, the reaction of the compounds of the
formula II with the compounds of the formula III takes
place in the presence or absence of an inert solvent at
temperatures between about -20 and about 150°,
preferably between 20 and 100°.
The addition of an acid-binding agent, for example of
an alkali metal or alkaline earth metal hydroxide,
carbonate or bicarbonate or of another salt of a weak
acid of the alkali metals or alkaline earth metals,
preferably of potassium, sodium or calcium, or the
addition of an organic base such as triethylamine,
CA 02387520 2002-03-15
' - 17 -
dimethylamine, pyridine or quinoline or of an excess of
the amine component, may be favorable.
Examples of suitable inert solvents are hydrocarbons
such as hexane, petroleum ether, benzene, toluene or
xylene; chlorinated hydrocarbons such as
trichloroethylene, 1,2-dichloroethane, carbon
tetrachloride, chloroform or dichloromethane; alcohols
such as methanol, ethanol, isopropanol, n-propanol,
n-butanol or tert-butanol; ethers such as diethyl
ether, diisopropyl ether, tetrahydrofuran (THF) or
dioxane; glycol ethers such as ethylene glycol
monomethyl or monoethyl ether (methyl glycol or ethyl
glycol), ethylene glycol dimethyl ether (diglyme);
ketones such as acetone or butanone; amides such as
acetamide, dimethylacetamide, N-methylpyrrolidone or
dimethylformamide (DMF); nitriles such as acetonitrile;
sulfoxides such as dimethyl sulfoxide (DMSO); nitro
compounds such as nitromethane or nitrobenzene; esters
such as ethyl acetate, or mixtures of the said
solvents.
It is also possible to convert one radical X in a
compound of the formula I to another radical X, for
example, by hydrolysing an ester or a cyano group to a
COOH group.
Ester groups may be hydrolysed, for example, with NaOH
or KOH in water, water-THF or water-dioxane at
temperatures between 0 and 100°.
Carboxylic acids may be converted, for example, with
thionyl chloride to the corresponding carbonyl
chlorides, and these may be converted to carboxamides.
Carbonitriles are obtained from these carboxamides in a
known manner by elimination of water.
An acid of the formula I may be converted into the
associated acid addition salts using a base, for
example by reacting equivalent amounts of the acid and
the base in an inert solvent such as ethanol, followed
CA 02387520 2002-03-15
- 18 -
by evaporative concentration. Particularly suitable
bases for this reaction are those which give
physiologically acceptable salts.
For instance, the acid of the formula I may be
converted with a base (e. g. sodium or potassium
hydroxide or carbonate) to the corresponding metal
salt, especially alkali metal or alkaline earth metal
salt, or to the corresponding ammonium salt.
Suitable bases for this reaction also include, in
particular, organic bases which give physiologically
acceptable salts, such as ethanolamine, for example.
Alternatively, a base of the formula I may be converted
to the associated acid addition salt using an acid, for
example by reacting equivalent amounts of the base and
the acid in an inert solvent such as ethanol, followed
by evaporative concentration. Particularly suitable
acids for this reaction are those which give
physiologically acceptable salts. For instance,
inorganic acids may be used, examples being sulfuric
acid, nitric acid, hydrohalic acids such as
hydrochloric acid or hydrobromic acid, phosphoric acids
such as orthophosphoric acid, sulfamic acid, and also
organic acids, especially aliphatic, alicyclic,
araliphatic, aromatic or heterocyclic mono- or
polybasic carboxylic, sulfonic or sulfuric acids,
examples being formic acid, acetic acid, propionic
acid, pivalic acid, diethylacetic acid, malonic acid,
succinic acid, pimelic acid, fumaric acid, malefic acid,
lactic acid, tartaric acid, malic acid, citric acid,
gluconic acid, ascorbic acid, nicotinic acid,
isonicotinic acid, methane- or ethanesulfonic acid,
ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid,
naphthalene-mono- and -disulfonic acids, and
laurylsulfuric acid. Salts with physiologically
unacceptable acids, e.g. picrates, may be used for
CA 02387520 2002-03-15
- 19 -
isolating and/or purifying the compounds of the formula
I.
The invention additionally provides for the use of the
compounds of the formula I and/or their physiologically
acceptable salts for producing pharmaceutical
preparations, especially by a non-chemical route. In
this case they may be brought into a suitable dosage
form together with at least one solid, liquid and/or
semi-liquid excipient or auxiliary and, if appropriate,
in combination with one or more further active
substances.
The invention also provides medicaments of the formula
I and their physiologically acceptable salts as
phosphodiesterase ~l inhibitors.
The invention additionally provides pharmaceutical
preparations comprising at least one compound of the
formula I and/or one of its physiologically acceptable
salts.
These preparations may be used as medicaments in human
or veterinary medicine. Suitable excipients include
organic or inorganic substances suitable for enteral
(e. g. oral), parenteral or topical application, which
do not react with the novel compounds, examples of such
excipients being water, vegetable oils, benzyl
alcohols, alkylene glycols, polyethylene glycols,
glycerol triacetate, gelatin, carbohydrates such as
lactose or starch, magnesium stearate, talc and
petroleum jelly. For oral administration, use is made
in particular of tablets, pills, coated tablets,
capsules, powders, granules, syrups, juices or drops;
for rectal administration, use is made of
suppositories; for parenteral administration, use is
made of solutions, preferably oily or aqueous
solutions, and also suspensions, emulsions or implants;
and for topical administration, use is made of
CA 02387520 2002-03-15
' - 20 -
ointments, creams or powders. The novel compounds may
also be lyophilized and the resulting lyophilisates
used, far example, to produce preparations for
injection. The stated formulations may be sterilized
and/or may contain auxiliaries such as lubricants,
preservatives, stabilizers and/or wetting agents,
emulsifiers, salts for influencing the osmotic
pressure, buffer substances, colorants, flavourings and
one or more further active substances, e.g. one or more
vitamins.
The compounds of the formula. I and their
physiologically acceptable salts may be used in
controlling diseases where an increase in the cGMP
(cyclic guanosine monophosphate) level leads to
inhibition or prevention of inflammation and to muscle
relaxation.
The invention also provides for the use of the
compounds of the formula I and their physiologically
acceptable salts and/or solvates for producing a
medicament for treating angina, high blood pressure,
high pulmonary pressure, congestive heart failure,
atherosclerosis, conditions of reduced circulation
through the cardiac vessels, peripheral vascular
diseases, stroke, bronchitis, allergic asthma, chronic
asthma, allergic rhinitis, glaucoma, irritable bowel
syndrome, tumours, renal insufficiency, cirrhosis of
the liver, and for treating male and female impotence.
In these indications, the substances are generally
administered preferably in doses of between
approximately 1 and 500 mg, in particular between 5 and
100 mg per dose unit. The daily dose is preferably
between approximately 0.02 and 10 mg/kg of body weight.
The specific dose for each patient depends, however, on
a wide variety of factors, for example on the efficacy
of the specific compound used, on the age, body weight,
general state of health, gender, on the diet, on the
~
. CA 02387520 2002-03-15
- 21 -
time and route of administration, and on the excretion
rate, medicament combination and severity of the
respective disorder to which the therapy is applied.
Oral administration is preferred.
Above and below, all temperatures are stated in °C. In
the following examples, "customary workup" means the
following: water is added if necessary, the formulation
is adjusted if necessary, depending on the constitution
of the end product, to a pH of between 2 and 10 and
extracted with ethyl acetate or dichloromethane, the
organic phase is separated off, dried over sodium
sulfate and concentrated by evaporation, and the
residue is purified by chromatography on silica gel
and/or by crystallization.
Mass spectrometry (MS): EI (electron impact
ionization) M'
FAB (fast atom bombardment)
(M+H)+
Example 1
Methyl 3-(4-chlorobenzothieno[2,3-d]pyrimidin-2-yl)-
propionate [obtainable by cyclizing methyl 2-amino-
5,6,7,8-tetrahydrobenzothiophene-3-carboxylate with
methyl 3-cyanopropionate, dehydrogenating the product
with sulfur and then chlorinating that product with
phosphorus oxychloride/dimethylamine] and 4-(3-amino-1-
methylpropyl)benzenesulfonamide in N-methylpyrrolidone
are stirred at 110° for 5 hours. The solvent is removed
and the remaining product is subjected to customary
workup. This gives methyl 3-{4-[3-(4-sulfamoyl-
phenyl)butylamino]benzo[4,5]thieno[2,3-d]pyrimidin-2-
yl}propionate
CA 02387520 2002-03-15
- 22 -
HN'~
/ ,.~ N ~o
p ~'NHZ
S N
O
/O
Example 2
Methyl 3-(4-[3-(4-sulfamoylphenyl)butylamino]benzo-
[4,5]thieno[2,3-d]pyrimidin-2-yl}propionate is dis-
solved in ethylene glycol monomethyl ether and
following addition of 32o NaOH the solution is stirred
at 110° for 5 hours. Following the addition of 20~ HC1
it is extracted with dichloromethane. Addition of
petroleum ether gives 3-t4-[3-(4-sulfamoylphenyl)-
butylamino]benzo[4,5]thieno[2,3-d]pyrimidin-2-yl}-
propionic acid.
The precipitated crystals are dissolved in isopropanol,
and ethanolamine is added. Crystallization gives
3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]-
pyrimidin-2-yl]propionic acid, ethanolamine salt.
The following compounds are obtained analogously:
3-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno-
[2,3-b]pyridin-2-yl]propionic acid;
3-~1-[(benzo[1,3]dioxo-5-ylmethyl)amino]benzo[4,5]-
thieno[3,2-c]pyridin-3-yl}propionic acid;
3-{4-[(3-chloro-4-methoxybenzyl)methylamino]benzo[4,5]-
thieno[2,3-d]pyrimidin-2-yl}propionic acid;
4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno-
[2,3-b]pyridin-2-yl]cyclohexanesulfonamide;
CA 02387520 2002-03-15
- 23 -
3-{4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]-
thieno[2,3-b]pyridin-2-yl]cyclohexyl}-4H-
[1,2,4]thiadiazol-5-one;
{4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno-
[2,3-d]pyrimidin-2-ylmethyl]phenyl}acetic acid;
3-t6-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]-
thieno[2,3-d]pyrimidin-2-ylmethyl]pyridin-2-
yl}propionic acid;
3-~1-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]
thieno[2,3-d]pyrimidin-2-ylmethyl]piperidin-4-yl}
propionic acid;
(3-chloro-4-methoxybenzyl)-[2-(2-{4-[2-(1H-tetrazol-5-
yl)ethyl]piperazin-1-yl}ethyl)benzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl]amine;
3-(4-(2-[4-(3-chloro-4-methoxybenzylamino)-9-thia-
1,3,7-triazafluoren-2-yl]ethyl}cyclohexyl)propionic
acid;
methyl 4-{3-[2-(4-carboxycyclohexyl)-9-thia-1,3,7-
triazafluoren-4-ylamino]-1-methylpropyl}benzoate.
The examples below relate to pharmaceutical
preparations:
Example A: Injection vials
A solution of 100 g of an active substance of the
formula I and 5 g of disodium hydrogen phosphate in 3 1
of double-distilled water is adjusted to a pH of 6.5
using 2 N hydrochloric acid, subjected to sterile
filtration, dispensed into injection vials, lyophilized
under sterile conditions and aseptically sealed. Each
injection vial contains 5 mg of active substance.
,' CA 02387520 2002-03-15
- 24 -
Example H: Suppositories
A mixture of 20 g of an active substance of formula I
is melted with 100 g of soya lecithin and 1400 g of
cocoa butter, poured into moulds and allowed to cool.
Each suppository contains 20 mg of active substance.
Example C: Solution
A solution is prepared from 1 g of an active substance
of the formula I, 9.38 g of NaH2P04 ~ 2H20, 28.48 g of
Na2HP04 ~ 12H20 and 0.1 g of benzalkonium chloride in
940 ml of double-distilled water. The solution is
adjusted to a pH of 6.8, made up to 1 1 and sterilized
by irradiation. This solution may be used in the form
of eye drops.
Example D: Ointment
500 mg of an active substance of the formula I are
mixed with 99.5 g of petroleum jelly under aseptic
conditions.
Example E: Tablets
A mixture of 1 kg of active substance of the formula I,
4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of
talc and 0.1 kg of magnesium stearate is compressed to
tablets in a customary manner such that each tablet
contains 10 mg of active substance.
Example F: Coated tablets
As in Example E, tablets are pressed, and are
subsequently coated in a customary manner with a
coating of sucrose, potato starch, talc, tragacanth and
colorant.
CA 02387520 2002-03-15
- 25 -
Example G: Capsules
2 kg of active substance of the formula I are filled in
a customary manner into hard gelatin capsules, so that
each capsule contains 20 mg of the active substance.
Example H: An:poul~s
A solution of 1 kg of active substance of the formula I
in 60 1 of double-distilled water is subjected to
sterile filtration, dispensed into ampoules,
lyophilized under sterile conditions and aseptically
sealed. Each ampoule contains 10 mg of active
substance.
Example I: Inhalation spray
14 g of active substance of the formula I are dissolved
in 10 1 of isotonic NaCl solution and the solution is
filled into commercially customary spray containers
having a pump mechanism. The solution may be sprayed
into the mouth or nose. One spray burst (approximately
0.1 ml) corresponds to a dose of approximately 0.14 mg.
