1. A compound of the formula (I)
143
in which
R1 represents a saturated or aromatic 5- or 6-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, which may be attached via a nitrogen atom,
and which is optionally substituted up to 2 times by identical or different radicals from the group (i) consisting of
hydrogen, amino, azido, formyl, mercaptyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms which for its part may be substituted by hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula OR4
in which
R4 represents straight-chain or branched acyl having up to 5 carbon atoms
andor is substituted by a radical of the formula
144
or
S(O)cNR6R7
in which
a, b and b are identical or different and each represents a number 0, 1, 2 or 3,
R5 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
c is a number 1 or 2 and
R6 and R7 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms which for its part may be substituted by halogen,
or
represents aryl having 6 to 10 carbon atoms which is optionally substituted by halogen,
or
represents cycloalkyl having 3 to 7 carbon atoms,
or
R6 and R7 together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further oxygen atom or a radical NR8
in which
R8 represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula
145
or benzyl or phenyl where the ring systems are optionally substituted by halogen,
and which is substituted by at least one radical from the group (ii) consisting of
a 3- to 8-membered ring which may be saturated, unsaturated or partially unsaturated, contains 1 to 4 heteroatoms from the group consisting of N, O, and S, said S heteroatoms optionally bearing 1 or 2 oxygens, and which may also be attached via N,
and which is optionally mono- or polysubstituted by a 5- or 6-membered ring which contains two oxygen atoms as ring members and forms a bicyclic unit or a spiro unit with the 3- to 8-membered ring, andor by hydroxyl, cyano, straight-chain or branched alkyl, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, where alkyl, acyl and alkoxycarbonyl may be substituted by hydroxyl, amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms, and
an aryl ring having 6 to 10 carbon atoms which is substituted by straight-chain or branched alkyl having up to 4 carbon atoms,
and
(C2-C10)alkenyl, (C2-C10)alkinyl, (C7-C20)alkyl, which is optionally substituted by aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamine, hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula OR4
in which
R4 represents straight-chain or branched acyl having up to 5 carbon atoms
and
(C1-C6)alkyl which is substituted 1- to 3 times by aryl, heteroaryl, halogen(s), cyano, dialkylamino, alkylamino or cycloalkyl
and
acyl, which is substituted by halogen(s), or by acyloxy, arylthio or heteroarylthio,
and
NO or radicals of the formulae SO3H and S(O)dR9,
in which
d represents a number 1 or 2,
R9 represents straight-chain or branched alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or an unsaturated 5- to 6-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, where the ring systems may optionally be substituted by halogen or by straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
and
a radical of the formula PO(OR10)(OR11)
in which
R10 and R11 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,
and
oxycycloalkyl having 3 to 8 ring members or radicals of the formulae CONC(NH2)2, CNH(NH2), NHC(NH)NH2 or (CO)eNR12R13
in which
e represents a number 0 or 1,
R12 and R13 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, aryl having 6 to 10 carbon atoms or a saturated or unsaturated 3- to 10-membered ring having up to 5 heteroatoms from the group consisting of N, O, S, where the abovementioned radicals may optionally be substituted by aryl having 6 to 10 carbon atoms, heterocyclyl, cycloalkyl having 3 to 7 carbon atoms, hydroxyl, amino or straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms,
and, in the case that e1,
R12 and R13, together with the nitrogen atom to which they are attached, may also form a 5- or 6-membered ring having up to 3 heteroatoms from the group consisting of N, O, S, which may optionally be substituted up to 3 times by hydroxyl, alkoxy or alkyl having in each case up to 8 carbon atoms,
and, in the case that e0,
R12 and R13 may also represent straight-chain, branched or cyclic acyl having up to 14 carbon atoms, hydroxyalkyl, straight-chain or branched alkoxycarbonyl or acyloxyalkyl having in each case up to 6 carbon atoms, or a radical of the formula SO2R14
in which
R14 represents straight-chain or branched alkyl having up to 4 carbon atoms,
andor
R12 and R13 also represent radicals of the formulae
146
in which R15-R16 and R18-R31 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
g represents a number 0, 1 or 2,
and
R17 represents phenyl, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
with the proviso that, if e0, R12 and R13 do not simultaneously represent hydrogen,
or
R1 represents a purine radical which may optionally be substituted up to three times by halogen, azido, cyano, hydroxyl, amino, monoalkylamino having up to 5 carbon atoms, dialkylamino having in each case up to 5 carbon atoms, alkyl having up to 5 carbon atoms andor alkoxy having up to 5 carbon atoms,
R2 and R3, together with the double bond, form a 6-membered saturated or aromatic heterocycle having up to 3 heteroatoms from the group consisting of N, S and O,
which is optionally substituted up to three times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms which for its part may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,
andor which is optionally substituted by a group of the formula NR32R33
in which
R32 and R33 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
or
R32 represents hydrogen and
R33 represents acyl,
andor which is optionally substituted by phenyl which for its part may be substituted up to 2 times by identical or different substituents from the group consisting of halogen and straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,
andor which is optionally substituted by a group of the formula NCHNR34R35
in which
R34 and R35 are identical or different and each represents hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
A represents a 5- or 6-membered aromatic or saturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O or represents phenyl,
which are optionally substituted up to 3 times by identical or different substituents from the group consisting of amino, mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms which for its part may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,
andor is substituted by a group of the formula (CO)hNR36R37
in which
h represents a number 0 or 1,
R36 and R37 are identical or different and each represents hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms,
or a stereoisomeric form or salt thereof.
2. The compound of formula (I) according to claim 1
in which
R1 represents a saturated or aromatic 6-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, which may be attached via a nitrogen atom,
and which is optionally substituted up to 2 times by identical or different radicals from the group (i) consisting of
hydrogen, amino, azido, formyl, mercaptyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms which for its part may be substituted by hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula OR4
in which
R4 represents straight-chain or branched acyl having up to 5 carbon atoms
andor is substituted by a radical of the formula
147
in which
a, b and b are identical or different and each represents a number 0, 1, 2 or 3,
R5 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and which is substituted by at least one radical from the group (ii) consisting of
a 3- to 8-membered ring which may be saturated, unsaturated or partially unsaturated, contains 1 to 4 heteroatoms from the group consisting of N, O, and S, said S heteroatoms optionally bearing 1 or 2 oxygens and which may also be attached via N,
and which is optionally mono- or polysubstituted by a 5- or 6-membered ring which contains two oxygen atoms as ring members and forms a bicyclic unit or a spiro unit with the 3- to 8-membered ring, andor by hydroxyl, cyano, straight-chain or branched alkyl, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, where alkyl, acyl and alkoxycarbonyl may be substituted by hydroxyl, amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms,
and
an aryl ring having 6 to 10 carbon atoms which is substituted by straight-chain or branched alkyl having up to 4 carbon atoms,
and
(C2-C10)alkenyl, (C2-C10)alkinyl, (C7-C20)alkyl, which is optionally substituted by aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamine, hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula OR4
in which
R4 represents straight-chain or branched acyl having up to 5 carbon atoms
and
(C1-C6)alkyl which is substituted 1- to 3 times by aryl, heteroaryl, halogen(s), cyano, dialkylamino, alkylamino or cycloalkyl
and
acyl, which is substituted by halogen(s), or by acyloxy, arylthio or heteroarylthio,
and
NO or radicals of the formulae SO3H and S(O)dR9,
in which
d represents a number 1 or 2,
R9 represents straight-chain or branched alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or an unsaturated 5- to 6-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, where the ring systems may optionally be substituted by halogen or by straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
and
a radical of the formula PO(OR10)(OR11)
in which
R10 and R11 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,
and
oxycycloalkyl having 3 to 8 ring members or radicals of the formulae CONC(NH2)2, CNH(NH2), NHC(NH)NH2 or (CO)eNR12R13
in which
e represents a number 0 or 1,
R12 and R13 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, aryl having 6 to 10 carbon atoms or a saturated or unsaturated 3- to 10-membered ring having up to 5 heteroatoms from the group consisting of N, O, S, where the abovementioned radicals may optionally be substituted by aryl having 6 to 10 carbon atoms, heterocyclyl, cycloalkyl having 3 to 7 carbon atoms, hydroxyl, amino or straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms,
and, in the case that e1,
R12 and R13, together with the nitrogen atom to which they are attached, may also form a 5- or 6-membered ring having up to 3 heteroatoms from the group consisting of N, O, S, which may optionally substituted up to 3 times by hydroxyl, alkoxy or alkyl having in each case up to 8 carbon atoms,
and, in the case that e0,
R12 and R13 may also represent straight-chain, branched or cyclic acyl having up to 14 carbon atoms, hydroxyalkyl, straight-chain or branched alkoxycarbonyl or acyloxyalkyl having in each case up to 6 carbon atoms, or a radical of the formula SO2R14
in which
R14 represents straight-chain or branched alkyl having up to 4 carbon atoms,
andor
R12 and R13 also represent radicals of the formulae
148
in which
R15-R16 and R18-R31 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
g represents a number 0, 1 or 2,
and
R17 represents phenyl, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
with the proviso that, if e0, R12 and R13 do not simultaneously represent hydrogen,
or
R1 represents a purine radical which may optionally be substituted up to three times by halogen, azido, cyano, hydroxyl, amino, monoalkylamino having up to 5 carbon atoms, dialkylamino having in each case up to 5 carbon atoms, alkyl having up to 5 carbon atoms andor alkoxy having up to 5 carbon atoms,
R2 and R3, together with the double bond, form a fused pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring,
which are optionally substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl, alkylthio or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms which for its part may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
andor
the abovementioned heterocyclic rings are optionally substituted by a group of the formula NR32R33
in which
R32 and R33 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
or
R32 represents hydrogen
and
R33 represents formyl
andor the abovementioned fused pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl rings are optionally substituted by phenyl which for its part may be substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
A represents thienyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl which are optionally substituted up to 2 times by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine and bromine,
or a stereoisomeric form or salt thereof.
3. The compound of formula (I) according to claim 1
in which
R1 represents a pyrimidine radical
which is optionally substituted up to 2 times by identical or different radicals from the group (i) consisting of
hydrogen, amino, hydroxyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, cyano or halogen,
and which is substituted by at least one radical from the group (ii) consisting of
a 5- to 6-membered ring which may be saturated, unsaturated or partially unsaturated, which contains 1 to 3 heteroatoms from the group consisting of N, O, and S, said S heteroatoms optionally bearing 1 or 2 oxygens, and which may also be attached via N,
and which is optionally mono- or polysubstituted by a 5-membered ring which contains two oxygen atoms as ring members and which forms, with the 3- to 8-membered ring, a bicyclic unit or a spiro unit, such as, for example, a 1,4-dioxa-8-azaspiro4.5decane or 1.5-dioxa-9-azaspiro5.5undecane radical, andor by hydroxyl, cyano, straight-chain or branched alkyl, acyl or alkoxycarbonyl having in each case up to 3 carbon atoms, where alkyl, acyl and alkoxycarbonyl may be substituted by hydroxyl, amino, halogen, carboxyl, straight-chain or branched acyl or alkoxy having in each case up to 3 carbon atoms,
and
a tolyl radical,
and
C7-alkyl which is optionally substituted by cyano,
and
(C1-C5)alkyl, which is 1- to 3-times substituted by halogen(s), cyano, aryl and acyloxy,
and
NO or radicals of the formula S(O)dR9,
in which
d represents a number 1 or 2,
R9 represents straight-chain or branched alkyl having 1 to 4 carbon atoms, aryl having 6 carbon atoms or thienyl,
and
a radical of the formula PO(OR10)(OR11),
in which
R10 and R11 are identical or different and each represents straight-chain or branched alkyl having up to 3 carbon atoms,
and
radicals of the formulae NHC(NH)NH2 and (CO)eNR12R13
in which
e represents a number 0 or 1,
R12 and R13 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 carbon atoms, where the abovementioned radicals may optionally be substituted by aryl having 6 carbon atoms, furyl, cycloalkyl having 3 carbon atoms, hydroxyl, straight-chain alkoxy having up to 2 carbon atoms,
and, in the case that e1,
R12 and R13, together with the nitrogen atom to which they are attached, may also form a 5- or 6-membered ring having up to 2 heteroatoms from the group consisting of N, O, S which may optionally be substituted up to 2 times by hydroxyl or methyl,
and, in the case that e0,
R12 and R13 may also represent straight-chain acyl having up to 14 carbon atoms,
andor
R12 and R13 also represent a radical of the formula
149
with the proviso that in the case that e0, R12 and R13 do not simultaneously represent hydrogen,
or
R1 represents a purine radical which may optionally be substituted up to two times by halogen, azido, amino, monoalkylamino having up to 4 carbon atoms andor methyl,
R2 and R3 together with the double bond form a pyridyl or pyrimidinyl ring,
A represents phenyl or pyrimidyl, which are optionally substituted by fluorine, chlorine or bromine,
or a stereoisomeric form or salt thereof.
4. The compound according to claim 1
where
R1 represents a radical of the formula
150
in which
R represents NH2,
R represents optionally substituted morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl or thiomorpholinyl
and
R represents hydrogen or NH2.
5. The compound according to claim 4 in which R represents morpholinyl.
6. A process for preparing the compounds of the formula (I) according to claim 1,
characterized in that
depending on the various meanings of the heterocycles listed above under R2 and R3
A a compound of the formula
R1D(II)
in which
R1 is as defined above in claim 1
and
D represents a radical selected from the formulae
151
in which
R38 represents C1-C4-alkyl
is converted, by reaction with a compound of the formula (III)
ACH2NHNH2(III)
in which
A is as defined above in claim 1
in inert solvent, if appropriate in the presence of a base, into a compound of the formula (IV) or (IVa)
152
in which
A and R1 are each as defined above in claim 1,
and, in the case of the compound of the formula (IVa), is subsequently cyclized with a carboxylic acid, nitrile, formamide or guanidium salt,
and, in the case of the compound of the formula (IV), is cyclized with a 1,3-dicarbonyl derivative, its salt, tautomer, enol ether or enamine, in the presence of acid,
or
B in the case that R2 and R3 together form a pyrazine ring, a compound of the formula (IV) is initially converted by nitrosation into a compound of the formula (V)
153
in which
A and R1 are each as defined above, in claim 1
in a second step, compound of the formula (VI)
154
in which
A and R1 are each as defined above in claim 1
is prepared by a reduction,
and these are this is subsequently cyclized with a 1,2-dicarbonyl compound,
or
C a compound of the formula (VII)
155
in which
A1, R2 and R3 are each as defined above in claim 1
and
L represents a radical of the formula SnR39R40R41, ZnR42, iodine, bromine or triflate
in which
R39, R40 and R41 are identical or different and each represents straight-chain or branched alkyl having up to 4 carbon atoms
and
R42 represents halogen
is reacted with a compound of the formula (VIII)
R1T(VIII),
in which
R1 is as defined above in claim 1
and
in the case that LSnR39R40R41 or ZnR42,
T represents triflate or represents halogen,
and,
in the case that Liodine, bromine or triflate,
T represents a radical of the formula SnR39R40R41, ZnR42 or BR43R44
in which
R39, R40, R41 and R42 have the meanings of R39, R40, R41 and R42 given above and are identical to or different from them,
R43 and R44 are identical or different and each represents hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring
in a palladium-catalysed reaction in inert solvent,
or
D in the case that R1 represents an optionally substituted pyrimidine radical, an amidine of the formula (IX)
156
in which
A, R2 and R3 are each as defined above in claim 1
is reacted with a compound of the formula (X), (Xa), (Xb) or (Xc)
157
in which
R1 represents the optionally substituted cycloalkyl radical listed above under R1;
Alk represents straight-chain or branched alkyl having up to 8 carbon atoms,
and
Z represents an NH2 group, a monoalkylamino group having up to 7 carbon atoms, a dialkylamino group having up to 7 carbon atoms, a piperidinyl or morpholinyl radical which is attached via the nitrogen, hydroxyl, alkoxy having up to 7 carbon atoms, acyloxy having up to 7 carbon atoms or aroyloxy having 6 to 10 carbon atoms,
and, in the case of the groups S(O)cNR6R7 and S(O)cNR6R7, starting from the unsubstituted compound of the formula (I), reacted initially with thionyl chloride and, in a second step, with an appropriate amine
and, if appropriate, the substituents listed under X, Y, R1, R2, R3 andor R4 are modified or introduced by acylation of free amino groups or hydroxyl groups, chlorination, catalytic hydrogenation, reduction, oxidation, removal of protective groups andor nucleophilic substitution.
7. A pharmaceutical composition comprising a compound of the formula (I) according to claim 1 and a pharmaceutically acceptable carrier.
8. Cancelled
9. A pharmaceutical composition comprising at least one compound of the general formula (I) according to claim 1 in combination with an organic nitrate or NO donor.
10. A pharmaceutical composition comprising at least one compound of the formula (I) according to claim 1 in combination with a compound which inhibits the degradation of cyclic guanosine monophosphate (cGMP).
11. Cancelled
12. A method for treating a cardiovascular disease comprising administering to a mammal an effective amount of a compound according to claim 1.
13. The method of claim 12, wherein said cardiovascular disease is hypertension.
14. A method of treating thromboembolic disorders and ischemia comprising administering to a mammal an effective amount of a compound according to claim 1.
15. A method of treating sexual dysfunction comprising administering to a mammal an effective amount of a compound according to claim 1.
16. A method of treating inflammation comprising administering to a mammal an effective amount of a compound according to claim 1.
17. The method of claim 12, 13, 14, 15, or 16 wherein the a compound of the general formula (I) according to claim 1 is administered in combination with an organic nitrate or NO donor.
18. The compound of claim 1, wherein when said radical from group (ii) is a 3- to 8-membered ring, this ring is selected from the group consisting of imidazolyl, imidazolinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl, thiomorpholinyl, S-oxothiomorpholinyl and S,S-dioxothiomorpholinyl.
19. The compound of claim 2, wherein when said radical from group (ii) is a 3- to 8-membered ring, this ring is selected from the group consisting of imidazolyl, imidazolinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl, thiomorpholinyl, S-oxothiomorpholinyl and S,S-dioxothiomorpholinyl.
20. The compound of claim 3, wherein when said radical from group (ii) is a 5- to 6-membered ring, this ring is selected from the group consisting of imidazolyl, imidazolinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl and thiomorpholinyl.
21. The process of claim 6, wherein when said compound of the general formula (IV) is cyclized with a 1,3-dicarbonyl derivative, its salt, tautomer, enol ether or enamine in the presence of acid, this is carried out under microwave radiation.
22 The process of claim 6 wherein in part B the 1,2-dicarbonyl compound used in said cyclization with the compound of formula (VI) is aqueous glyoxal solution.
23. The method of claim 12, 13, 14, 15 or 16 wherein the compounds of general formula (I) according to claim 1 are administered in combination with a compound which inhibits the degradation of cyclic guanosine monophosphate (cGMP).
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An implantable heart stimulator comprising:
a pulse generator and an electrode lead connected thereto for delivering electrical stimulation pulses to a heart of a patient, said pulse generator having an electrically conductive housing, said housing comprising a connector header in which said electrode lead is mechanically and electrically connected;
said electrode lead having a proximal portion which, after implantation of said electrode lead, is configured to extend substantially from the housing to a location situated beyond entry of the electrode lead into the venous system and before entry of the electrode lead into the superior vena cava, said proximal portion having an exterior with an electrically conductive surface; and
a current source for supplying an infection control current between said housing and said electrically conductive surface of said proximal portion of said electrode lead for counteracting bacterial growth at least on an exterior of said housing, said connector header having an exterior surface that is entirely electrically conductive and is in a flow path of said infection control current.
2. An implantable heart stimulator as claimed in claim 1 wherein at least one of said electrically conductive surface on the exterior of said proximal portion of said electrode lead and said electrically conductive surface on said exterior of said connector header is formed by an electrically conducting polymer.
3. An implantable heart stimulator as claimed in claim 1 wherein at least one of said electrically conductive surface on the exterior of said proximal portion of said electrode lead and said electrically conductive surface on said exterior of said connector header is formed by an ion implantation.
4. An implantable heart stimulator as claimed in claim 1 wherein at least one of said electrically conductive surface on the exterior of said proximal portion of said electrode lead and said electrically conductive surface on said exterior of said connector header is formed by ion beam assisted deposition.
5. An implantable heart stimulator as claimed in claim 1 wherein at least one of said electrically conductive surface on the exterior of said proximal portion of said electrode lead and said electrically conductive surface on said exterior of said connector header is formed by a coating process selected from the group consisting of vapor deposition and sputtering.
6. An implantable heart stimulator as claimed in claim 1 wherein said electrically conductive surface on said exterior of said connector header is electrically isolated from said electrically conductive surface on said exterior of said proximal portion of said electrode lead.
7. An implantable heart stimulator as claimed in claim 1 wherein said conductive surface at the exterior of said proximal portion of said electrode lead is formed by an electrically conductive coil.
8. An implantable heart stimulator as claimed in claim 1 wherein said housing has an exterior coated with a metal selected from the group consisting of platinum, palladium, indium, platinum alloys, palladium alloys and indium alloys.
9. An implantable heart stimulator as claimed in claim 1 wherein said electrically conductive surface at said exterior of said proximal portion of said electrode lead is electrically isolated from said housing.
10. An implantable heart stimulator as claimed in claim 1 wherein said current source comprises a battery contained in said housing, which also supplies power to said pulse generator.
11. An implantable heart stimulator comprising:
a pulse generator and an electrode lead connected thereto for delivering electrical stimulation pulses to a heart of a patient, said pulse generator having an electrically conductive housing;
said electrode lead having a proximal portion which, after implantation of said electrode lead, is configured to extend substantially from the housing to a location situated beyond entry of the electrode lead into the venous system and before entry of the electrode lead into the superior vena cava, said proximal portion having an exterior with an electrically conductive surface; and
an extracorporeal current source, and an inductive coupling arrangement to inductively couple said extracorporeal current source with said housing and said electrically conductive surface on said exterior of said proximal portion of said electrode lead supplying an infection control current between said housing and said electrically conductive surface of said proximal portion of said electrode lead for counteracting bacterial growth at least on an exterior of said housing.
12. An implantable heart stimulator as claimed in claim 11 wherein said inductive coupling arrangement comprises a thin inductive coil attached at an outer surface of said housing, and electrically connected to said housing and to said electrically conductive surface on said exterior of said proximal portion of said electrode lead.
13. An implantable heart stimulator as claimed in claim 11 wherein said inductive coupling arrangement comprises a thin inductive coil disposed inside of said housing, and electrically connected to said housing and to said electrically conductive surface on said exterior of said proximal portion of said electrode lead.
14. An implantable heart stimulator as claimed in claim 11 wherein said inductive coupling arrangement includes a diode for producing a d.c. current as said infection control current.
15. An implantable heart stimulator as claimed in claim 11 wherein said inductive coupling arrangement includes transcutaneous electrodes connected between said extracorporeal current source and said housing and said electrically conductive surface on said exterior of said proximal portion of said electrode lead.
16. An implantable heart stimulator comprising:
a pulse generator which generates electrical stimulation pulses;
an electrically conductive housing containing said pulse generator and having a connector header;
an electrode lead mechanically and electrically connected in said header, and thereby connected to said pulse generator, for delivering said stimulation pulses to a heart of a patient;
said header having an exterior surface that is entirely electrically conductive;
said electrode lead having a proximal portion extending substantially from said housing to a location, after implantation of said electrode lead, adapted to be situated beyond entry into the venous system and before entry into the superior vena cava, said proximal portion having an exterior with an electrically conductive surface thereon;
a current source which supplies an infection control current in a flowpath including at least two of said housing, said electrically conductive surface on said exterior of said header and said electrically conductive surface on said exterior of said proximal portion of said electrode lead, to counteract bacterial growth at least one an exterior of said housing; and
at least one of said electrically conductive surface on the exterior of said proximal portion of said electrode lead and said exterior electrically conductive surface of said connector header being formed by an electrically conducting polymer.
17. An implantable heart stimulator as claimed in claim 16 wherein said conductive surface at the exterior of said proximal portion of said electrode lead is formed by an electrically conductive coil.
18. An implantable heart stimulator as claimed in claim 16 wherein said housing has an exterior coated with a metal selected from the group consisting of platinum, palladium, indium, platinum alloys, palladium alloys and indium alloys.
19. An implantable heart stimulator as claimed in claim 16 wherein said electrically conductive surface at said exterior of said proximal portion of said electrode lead is electrically isolated from said housing.
20. An implantable heart stimulator as claimed in claim 16 wherein said current source comprises a battery contained in said housing, which also supplies power to said pulse generator.
21. An implantable heart stimulator as claimed in claim 16 wherein said current source is an extracorporeal current source, and wherein said apparatus comprises an inductive coupling arrangement to inductively couple said extracorporeal current source with said housing and said electrically conductive surface on said exterior of said proximal portion of said electrode lead.
22. An implantable heart stimulator as claimed in claim 21 wherein said inductive coupling arrangement comprises a thin inductive coil attached at an outer surface of said housing, and electrically connected to said housing and to said electrically conductive surface on said exterior of said proximal portion of said electrode lead.
23. An implantable heart stimulator as claimed in claim 21 wherein said inductive coupling arrangement comprises a thin inductive coil disposed inside of said housing, and electrically connected to said housing and to said electrically conductive surface on said exterior of said proximal portion of said electrode lead.
24. An implantable heart stimulator as claimed in claim 21 wherein said inductive coupling arrangement includes a diode for producing a d.c. current as said infection control current.
25. An implantable heart stimulator as claimed in claim 21 wherein said inductive coupling arrangement includes transcutaneous electrodes connected between said extracorporeal current source and said housing and said electrically conductive surface on said exterior of said proximal portion of said electrode lead.
26. An implantable heart stimulator comprising:
a pulse generator which generates electrical stimulation pulses;
an electrically conductive housing containing said pulse generator and having a connector header;
an electrode lead mechanically and electrically connected in said header, and thereby connected to said pulse generator, for delivering said stimulation pulses to a heart of a patient;
said header having an exterior surface that is entirely electrically conductive surface;
said electrode lead having a proximal portion extending substantially from said housing to a location, after implantation of said electrode lead, adapted to be situated beyond entry into the venous system and before entry into the superior vena cava, said proximal portion having an exterior with an electrically conductive surface thereon;
a current source which supplies an infection control current in a flowpath including at least two of said housing, said electrically conductive surface on said exterior of said header and said electrically conductive surface on said exterior of said proximal portion of said electrode lead, to counteract bacterial growth at least one an exterior of said housing; and
at least one of said electrically conductive surface on the exterior of said proximal portion of said electrode lead and said exterior electrically conductive surface of said connector header being formed by an ion implantation.
27. An implantable heart stimulator comprising:
a pulse generator which generates electrical stimulation pulses;
an electrically conductive housing containing said pulse generator and having a connector header;
an electrode lead mechanically and electrically connected in said header, and thereby connected to said pulse generator, for delivering said stimulation pulses to a heart of a patient;
said header having an exterior surface that is entirely electrically conductive surface;
said electrode lead having a proximal portion extending substantially from said housing to a location, after implantation of said electrode lead, adapted to be situated beyond entry into the venous system and before entry into the superior vena cava, said proximal portion having an exterior with an electrically conductive surface thereon; and
a current source which supplies an infection control current in a flowpath including at least two of said housing, said electrically conductive surface on said exterior of said header and said electrically conductive surface on said exterior of said proximal portion of said electrode lead, to counteract bacterial growth at least one an exterior of said housing; and
at least one of said electrically conductive surface on the exterior of said proximal portion of said electrode lead and said exterior electrically conductive surface of said connector header being formed by ion beam assisted deposition.
28. An implantable heart stimulator comprising:
a pulse generator which generates electrical stimulation pulses;
an electrically conductive housing containing said pulse generator and having a connector header;
an electrode lead mechanically and electrically connected in said header, and thereby connected to said pulse generator, for delivering said stimulation pulses to a heart of a patient;
said header having an exterior surface that is entirely electrically conductive surface;
said electrode lead having a proximal portion extending substantially from said housing to a location, after implantation of said electrode lead, adapted to be situated beyond entry into the venous system and before entry into the superior vena cava, said proximal portion having an exterior with an electrically conductive surface thereon; and
a current source which supplies an infection control current in a flowpath including at least two of said housing, said exterior electrically conductive surface of said header and said electrically conductive surface on said exterior of said proximal portion of said electrode lead, to counteract bacterial growth at least one an exterior of said housing; and
at least one of said electrically conductive surface on the exterior of said proximal portion of said electrode lead and said exterior electrically conductive surface of said connector header being formed by a coating process selected from the group consisting of vapor deposition and sputtering.
29. An implantable heart stimulator comprising:
a pulse generator which generates electrical stimulation pulses;
an electrically conductive housing containing said pulse generator and having a connector header;
an electrode lead mechanically and electrically connected in said header, and thereby connected to said pulse generator, for delivering said stimulation pulses to a heart of a patient;
said header having an exterior surface that is entirely electrically conductive;
said electrode lead having a proximal portion extending substantially from said housing to a location, after implantation of said electrode lead, adapted to be situated beyond entry into the venous system and before entry into the superior vena cava, said proximal portion having an exterior with an electrically conductive surface thereon; and
a current source which supplies an infection control current in a flowpath including at least two of said housing, said exterior electrically conductive surface of said header and said electrically conductive surface on said exterior of said proximal portion of said electrode lead, to counteract bacterial growth at least one an exterior of said housing; and
said electrically conductive exterior surface of said connector header being electrically isolated from said electrically conductive surface on said exterior of said proximal portion of said electrode lead.