US2012094987A1PendingUtilityA1
SUBSTITUTED PYRIDO [3', 2': 4, 5] THIENO [3, 2-D] PYRIMIDINES AND PYRIDO [3', 2': 4, 5] FURO [3, 2-D] PYRIMIDINES USED AS INHIBITORS OF THE PDE-4 AND/OR THE RELEASE OF TNF-alpha
Est. expiryJul 23, 2024(expired)· nominal 20-yr term from priority
Inventors:Claudia ReicheltAlexander LudwigAlexander SchulzeMohammed DaghishSiegfried LeistnerAndreas KrödelJochen Heinicke
A61P 9/00A61P 9/10A61P 37/08A61P 25/28A61P 3/10A61P 25/00A61P 35/02A61P 35/00A61P 31/12A61P 25/16A61P 19/02A61P 11/00A61P 1/00C07D 491/14A61P 11/06C07D 495/14A61P 17/00
38
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Claims
Abstract
The invention relates to compounds of general formula (I); 1a, 1b, 1c and 1d. The invention also relates to a method for the production thereof, pharmaceutical preparations containing said compounds and/or physiologically compatible salts thereof which can be produced therefrom and/or solvates thereof, and to the pharmaceutical use of said compounds, salts or solvates thereof as inhibitors of phosphodiesterase 4. The compounds comprise active ingredients for the treatment of diseases which can have a positive influence by inhibiting the activity of phosphodiesterase 4 and/or TNFα-release, for example, in lymphocytes, eosinophile and basophile granulocytes, macrophages and mastocytes.
Claims
exact text as granted — not AI-modified1 ) Compounds of general formulae 1a, 1b, 1c and 1d,
wherein:
Y is S, O or N
R 1 is—hydrogen,
C 1-10 alkyl, —C 2-12 alkenyl, —C 2-12 alkinyl, each straight-chain, branched or cyclic and, where appropriate, substituted singly, doubly or triply with independently selected residues R § ,
aralkyl—having C 6-12 aryl and C 1-5 alkyl, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
phenyl, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
1-naphthyl, 2-naphthyl,
pyridyl-N-oxide, (substituted, where appropriate, with R § ),
monocyclic or bicyclic, saturated or singly or multiply unsaturated heterocycles having 5-14 ring atoms, including 1-4 heteroatoms which are preferably N, O and S, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
C 1-10 alkoxy, straight-chain, branched or cyclic as well as substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
aralkyloxy—having C 6-12 aryl and C 1-5 alkyl, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
C 2-12 alkylacyl (substituted, where appropriate, with R § ),
benzoyl, 1- and 2-naphthoyl (each substituted, where appropriate, with R § ),
hydroxy, sulfhydryl, formyl, carboxyl, CONH 2 , cyano, rhodano, nitro, SO 3 H,
alkylthio, alkylsulfinyl, SO 2 OAlk and alkylsulfonyl, each straight-chain, branched or cyclic C 1-6 , and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl and heteroarylsulfonyl, each substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
alkoxycarbonyl, CONHAlk and CONAlk 2 , each straight-chain, branched or cyclic C 1-6 , and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
aryloxycarbonyl, arylcarbamoyl, arylamido, N-aryl,N-alkylamido, N-aryl,N-alkylcarbamoyl, aralkyloxycarbonyl and aralkylcarbamoyl, with alkyl C 1-5 , aryl C 6-10 and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
heterocyclylcarbonyl, heterocyclylcarbamoyl, heterocyclyl-amido, N-heterocyclyl,N-alkylcarbamoyl, N-heterocyclyl,N-alkylamido, heterocyclylalkyloxycarbonyl and heterocyclyl-alkylcarbamoyl, with a monocyclic or bicyclic, saturated or singly or multiply unsaturated heterocycle having 5-14 ring atoms including 1-4 heteroatoms which are preferably N, O and S, substituted, where appropriate, singly, doubly or triply with independently selected residues R § and alkyl C 1-5 ,
chlorine, bromine, iodine, fluorine,
amino, C 1-6 alkylamino, di(C 1-5 )alkylamino, each straight-chain, branched or cyclic and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
arylamino C 6-10 , substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
heterocyclylamino, monocyclic or bicyclic, saturated or singly or multiply unsaturated, having 5-14 ring atoms including 1-4 heteroatoms which are preferably N, O and S, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
arylhydrazino, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
L A -A-L B -B
wherein:
L A is—single bond,
NR # , O, S, SO, SO 2
A is—phenyl, substituted, where appropriate, singly, doubly or triply with independently selected residues R §
naphthyl, naphthyl substituted singly or multiply with R §
monocyclic or bicyclic, saturated or singly or multiply unsaturated heterocycles having 4-14 ring atoms including 1-5 heteroatoms which are preferably N, O and S which may carry one or more oxygen atoms on C, N and/or S and are substituted, where appropriate, singly, doubly or triply with independently selected residues R §
L A -A can also be a direct bond tricycle-L B , in this case L B being a single bond
L B is—single bond
NR # , O, S, SO, SO 2 , —CHR § —, —CH 2 —O—, —O—CH 2 ,
the following functional groups:
B is—hydrogen
alkyl, substituted, where appropriate, singly, doubly or triply independently with R §
—CONH 2 , —CONHAlk (Alk substituted, where appropriate, with R § ), —CONHAryl (aryl substituted, where appropriate, with R § ), —CONHHetaryl (hetaryl substituted, where appropriate, with R § ), —COOH, —COOAlk (Alk substituted, where appropriate, with R § ),
—COAlk (Alk substituted, where appropriate, with R § ), —COAryl (aryl substituted, where appropriate, with R § ), —COHetaryl (Hetaryl substituted, where appropriate, with R § )
—CH 2 —CONH 2 , —CH 2 —CONHAlk (Alk substituted, where appropriate, with R § ), —CH 2 —CONHAryl (Aryl substituted, where appropriate, with R § ), —CH 2 —CONHHetaryl (hetaryl substituted, where appropriate, with R § ), —CH 2 —COOH, —CH 2 —COOAlk (Alk substituted, where appropriate, with R § )
—CH 2 —COAlk (Alk substituted, where appropriate, with R § ), —CH 2 —COAryl (aryl substituted, where appropriate, with R § ), —CH 2 —COHetaryl (hetaryl substituted, where appropriate, with R § )
phenyl, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
naphthyl, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
monocyclic or bicyclic, saturated or singly or multiply unsaturated heterocycles having 4-14 ring atoms including 1-5 heteroatoms which are preferably N, O and S which may carry one or more oxygen atoms on C, N and/or S and may be substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
R # —hydrogen, alkyl, substituted, where appropriate, with R §
R 2 is—hydrogen,
C 1-12 alkyl,
C 2-12 alkenyl and C 2-12 alkinyl,
benzyl, phenyl(C 2-6 )alkyl (substituted, where appropriate, once or several times equally or unequally with R § at the aromatic and/or aliphatic molecule portion);
phenacyl (substituted, where appropriate, with R § once or several times equally or unequally at the aromatic molecule portion);
carboxyl, C 1-4 alkoxycarbonyl, —CONH 2 , —CONHAlk and CONAlk 2 (“Alk” each being C 1-6 ),
R # C(O)— (wherein R # is as defined above),
cyano, nitro, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, —N═N—C 6 H 5 , —N═N—C 6 H 4 —R § ,
1,3-diphenyl-pyrazol-4-yl, thiazolin-2-yl, imidazolin-2-yl and 3,4,5,6-tetrahydro-pyrimidinyl;
R 3 is—hydrogen,
C 1-10 alkyl, —C 2-12 alkenyl, —C 2-12 alkinyl, each straight-chain, branched or cyclic and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
trifluoromethyl,
aralkyl—with C 6-12 aryl and C 1-5 alkyl, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
phenyl, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
1-naphthyl, 2-naphthyl,
pyridyl-N-oxide, (substituted, where appropriate, with R § ),
C 1-10 alkoxy, straight-chain, branched or cyclic and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
aralkyloxy—with C 6-12 aryl and C 1-5 alkyl, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
C 2-12 alkylacyl (substituted, where appropriate, with R § ),
benzoyl, 1- and 2-naphthoyl (each substituted, where appropriate, with R § ),
hydroxy, sulfhydryl, formyl, carboxyl, CONH 2 , cyano, rhodano, nitro, SO 3 H
alkylthio, alkylsulfinyl, SO 2 OAlk and alkylsulfonyl, each straight-chain, branched or cyclic C 1-6 and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl and heteroarylsulfonyl, each substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
alkoxycarbonyl, CONHAlk and CONAlk 2 , each straight-chain, branched or cyclic C 1-6 , and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
aryloxycarbonyl, arylcarbamoyl, arylamido, N-aryl,N-alkylamido, N-aryl,N-alkylcarbamoyl, aralkyloxycarbonyl and aralkylcarbamoyl, with alkyl C 1-5 , aryl C 6-10 and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
chlorine, bromine, iodine, fluorine,
amino, C 1-6 alkylamino, di(C 1-5 )alkylamino, each straight-chain, branched or cyclic and substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
arylamino C 6-10 , substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
arylhydrazino, substituted, where appropriate, singly, doubly or triply with independently selected residues R § ,
R 4 is—C 2-14 alkyl, C 3-14 cycloalkyl, C 2-14 alkenyl, C 3-14 cycloalkenyl, C 2-14 alkinyl (each substituted, where appropriate, on the C-skeleton of the above mentioned aliphatic residues with R § );
phenyl, 4-R § -phenyl, 3-R § -phenyl, 2-R § -phenyl (with the exception of: 2-NO 2 -phenyl), 3-R § ,4-R § -phenyl, 3-R § ,4-R § -,5-R § -phenyl,
1-naphthyl, 2-naphthyl (each substituted, where appropriate, with R § );
S-alkyl, SO-alkyl, SO 2 -alkyl, (each C 1 -C 8 ),
S-alkenyl, SO-alkenyl, SO 2 -alkenyl (each C 2 -C 8 )
S-alkinyl, SO-alkinyl, SO 2 -alkinyl (each C 2 -C 6 )
(each substituted, where appropriate, on the C-skeleton of the above mentioned aliphatic residues with —OH, —CN, —SCN, —NO 2 , phenyl or C 3 -C 7 cycloalkyl);
monocyclic, bicyclic or tricyclic, saturated or singly or multiply unsaturated heterocyclic residue having a total of 4-14 ring atoms including 1-5 heteroatoms which are preferably N, O, S and Se (each substituted, where appropriate, with R § );
OR 6 , wherein R 6 is
CH 3 , C 2 H 5 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , C(CH 3 ) 3 , CH 2 CH 2 OH, CH 2 CH 2 SH, CH 2 CH 2 SCH 3 , CH 2 CF 3 , CH 2 CCl 3 , CH 2 CHF 2 , CH 2 CHCl 2 , CH 2 CH 2 F, CH 2 CH 2 Cl, CH 2 CH 2 Br,
C 3-7 cycloalkyl [e.g. cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl] (substituted, where appropriate, on the C-skeleton with R § ),
C 2-5 alkenyl and C 2-5 alkinyl,
C 3-7 cycloalkenyl,
aryl and heteroaryl as residues of monocyclic, bicyclic or tricyclic aromatic compounds or heteroaromatic compounds with 6-14 ring atoms, where appropriate [e.g. phenyl, 4-R § -phenyl, 3-R § -phenyl, 2-R § -phenyl, 3-R § ,4-R § -phenyl, 3-R § ,4-R § -,5-R § -phenyl],
1-naphthyl, 2-naphthyl (each substituted, where appropriate, with R § ),
pyridyl, isoquinolinyl, quinolinyl, acridinyl;
NR 7 R 8 , wherein this substituent is altogether:
morpholino, thiomorpholino, thiomorpholino-S,S-dioxide, pyrrolidino, piperidino, 1-piperazino, 1-homopiperazino, 4-C 1-6 -alkyl-1-piperazino, 4-(2-hydroxyethyl)-1-piperazino, 4-benzyl-1-piperazino, 4-aryl-1-piperazino (substituted, where appropriate, with R § on the heterocycloaliphatic ring),
further amino residues of secondary, monocyclic or polycyclic cycloaliphatic amines having a total of 5-14 ring atoms, including the representatives substituted with R § on the C-skeleton;
amino residues of secondary aliphatic and aromatic amines, R 7 R 8 NH,
wherein R7 and R8 may independently be equal or unequal and represent:
C 1-6 alkyl, benzyl, phenyl, 1- and 2-naphthyl, 2-, 3- and 4-pyridyl, quinolinyl, isoquinolinyl, 2-thienyl, 2-furyl (each substituted, where appropriate, with R § );
amino residues of primary amines, R 7 NH 2 , (wherein R 7 is the same as above),
amino, NH 2 , with the limitation that in this case R 5 only has the meaning of OR 6 ;
is—OR 6 , wherein R 6 is as defined above,
NR 7 R 8 , which is as defined above but with the limitation that R 4 does not have the meaning of NR 7 R 8 , and with the exception of morpholino when R 4 =aryl,
azido, hydroxylamino, O—(C 1-3 )alkylhydroxylamino,
N—(C 1-3 )alkylhydroxylamino, N,N-di(C 1-3 )alkylhydroxylamino,
hydrazino, (C 1-4 )alkyl- and di(C 1-4 )alkylhydrazino,
benzylhydrazino, acylhydrazino, N,N-diacylhydrazino,
carbamoylamino,
1-imidazolyl, 1,2,4-triazol-1yl, 1-pyridinium,
1-pyrazinium, 1-pyridazinium, including the alkylsubstituted representatives of these azaheterocycles;
R § is —OH, —SH, —O—C 1-8 alkyl, —O—C 6-14 aryl, —S—C 1-4 alkyl, —S—C 6-14 aryl,
—SO—C 1-4 alkyl, —SO—C 6-14 aryl, —SO 2 —C 1-4 alkyl, —SO 2 —C 6-14 aryl,
—SO 3 H,
—OSO 2 C 1-8 alkyl, —OSO 2 C 6-14 aryl, —COOH, —COOC 1-8 alkyl,
—(CO)C 1-8 alkyl,
—COOH, —CONH 2 , —CONHC 1-6 alkyl, —CON(C 1-6 alkyl) 2 ,
—NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NHC 6-14 aryl, —NH-hetaryl,
—N(C 6-14 aryl) 2 , —N(C 1-6 alkyl)(C 6-14 aryl),
C 1-6 alkyl, —C 2-12 alkenyl, —C 2-12 alkinyl, each straight-chain, branched or cyclic and independently substituted, where appropriate, singly, doubly or triply with halogen,
halogen (F, —Cl, —Br, —I),
—CH 2 CH 2 OH, —CH 2 CH 2 SH, —CH 2 CH 2 SCH 3 ,
sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl with alkyl C 1-5 substituted, where appropriate, with methoxy,
amidino, hydroxyamidino
sulfo, phosphono,
—CN, —NO 2 , and —SCN
The following compound of formula 1(a) is not protected:
Y═S, R 1 ═OC 2 H 5 , R 2 ═CN, R 3 ═C 6 H 5 , R 4 ═N(CH 3 ) 2 , R 5 ═OC 2 H 5
Y is—sulfur, nitrogen or oxygen,
A is—anellated carbocycle having 5 to 8 ring atoms, singly or multiply unsaturated and aromatic (substituted, where appropriate, with R* and/or substituted, where appropriate, with R § );
anellated bicycle having 6 to 11 ring atoms, singly or multiply unsaturated, which may also contain nitrogen, oxygen and/or sulfur (substituted, where appropriate, with R* and/or substituted, where appropriate, with R § );
annelated heterocycle having 5 to 8 ring atoms, singly or multiply unsaturated and aromatic, which may independently contain nitrogen, oxygen and sulfur singly, multiply, equally or unequally in the cycle (substituted, where appropriate, with R* and/or substituted, where appropriate, with R § ),
R 1 and R 3 are
hydrogen (except when A is an anellated unsubstituted cyclopentene ring combined with R 4 , R 5 equals —OH)
C 1-10 alkyl (substituted, where appropriate, with R § ),
C 2-12 alkenyl and C 2-12 alkinyl (each substituted, where appropriate, with R § ),
difluoromethyl, trifluoromethyl,
benzyl, phenyl-(C 2-6 )alkyl (each substituted, where appropriate, with R § ),
phenyl (substituted, where appropriate, with R § ), in particular: 4-R § -phenyl, 3-R § -phenyl, 2-R § -phenyl, 3-R § ,4-R § -phenyl, 3-R § ,4-R § -,5-R § -phenyl, 2-R § ,4-R § -phenyl,
1-naphthyl, 2-naphthyl (each substituted, where appropriate, with R § ),
C 3-14 cycloalkyl, C 3-14 cycloalkenyl (each substituted, where appropriate, with R § ),
monocyclic or bicyclic, saturated or singly or multiply unsaturated heterocycles having 4-14 ring atoms including 1-5 heteroatoms which are preferably N, O and S which may carry one or more oxygen atoms on C, N and/or S and, where appropriate, can be substituted singly, doubly or triply with independently selected residues R § ,
C 2-12 alkylacyl (substituted, where appropriate, with R § ),
benzoyl, 1- and 2-naphthoyl (each substituted, where appropriate, with R § ),
heterocyclylacyl [e.g. nicotinoyl, isonicotinoyl, 2-picolinoyl, 2-thienoyl, 2-furoyl] (substituted, where appropriate, with R § )
hydroxy,
sulfhydryl,
C 1-10 alkoxy,
alkylthio, alkylsulfinyl and alkylsulfonyl (each C 1-6 )
formyl, carboxyl, C 1-4 alkoxycarbonyl;
CONH 2 , CONHAlk and CONAlk2 (with “Alk” each C 1-6 ),
cyano, rhodano, nitro, SO 3 H, SO 2 OAlk (with “Alk”: C 1-5 ),
chlorine, bromine, iodine, fluorine,
amino, C 1-6 alkylamino, di(C 1-5 )alkylamino (each substituted, where appropriate, with R § on the alkyl residue),
morpholino, thiomorpholino, thiomorpholino-S-oxide, thiomorpholino-S,S-dioxide, pyrrolidino,
piperidino, 1-piperazino, 4-methyl-1-piperazino, 4-hydroxyethyl-1-piperazino, 4-phenyl-1-piperazino,
cycloalkylamino, C 3-14 arylamino and heteroarylamino [e.g. phenyl-, 1- and 2-naphthyl-, 2-, 3- or 4-pyridyl-, quinolinyl-, isoquinolinyl-, acridinyl-, phenothiazinyl-, 2-thienyl- and 2- furylamino] (each substituted, where appropriate, on the carbocyclic and/or heterocyclic rings with R § );
R 4 is—C 2-14 alkyl, C 3-14 cycloalkyl, C 2-14 alkenyl, C 3-14 cycloalkenyl, C 2-14 alkinyl (each substituted, where appropriate, with R § on the C-skeleton of the above mentioned residues);
benzyl, phenyl-(C 2-6 )alkyl (each substituted, where appropriate, with R § ),
phenyl (substituted, where appropriate, with R § ), in particular:
4-R § -phenyl, 3-R § -phenyl, 2-R § -phenyl, 3-R § ,4-R § -phenyl, 3-R § ,4-R § -,5-R § -phenyl, 2-R § ,4-R § -phenyl,
1-naphthyl, 2-naphthyl (each substituted, where appropriate, with R § );
S-alkyl (C 3 -C 8 ), SO-alkyl, SO 2 -alkyl, (each C 1 -C 8 ),
S-alkenyl, SO-alkenyl, SO 2 -alkenyl (each C 2 -C 8 )
S-alkinyl, SO-alkinyl, SO 2 -alkinyl (each C 2 -C 6 )
(each substituted, where appropriate, with —OH, —CN, —SCN, —NO 2 , phenyl or C 3 -C 7 cycloalkyl on the C-skeleton of the above-mentioned residues);
monocyclic, bicyclic or tricyclic, saturated or singly or multiply unsaturated heterocyclic residue having a total of 4-14 ring atoms including 1-5 heteroatoms which are preferably N, O, S and Se (each substituted, where appropriate, with R § );
OR 6 , wherein R 6 is
hydrogen
CH 3 , C 2 H 5 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 OH, CH 2 CH 2 SH, CH 2 CH 2 SCH 3 , CH 2 CF 3 , CH 2 CCl 3 , CH 2 CHF 2 , CH 2 CHCl 2 , CH 2 CH 2 F, CH 2 CH 2 Cl, CH 2 CH 2 Br,
C 3-7 cycloalkyl [e.g. cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl] (substituted, where appropriate, with R § on the C-skeleton),
C 2-5 alkenyl and C 2-5 alkinyl,
C 3-7 cycloalkenyl,
aryl and heteroaryl as residues of monocyclic, bicyclic or tricyclic aromatic compounds or heteroaromatic compounds with optionally 6-14 ring atoms [e.g. phenyl, 4-R § -phenyl, 3-R § -phenyl, 2-R § -phenyl, 3-R § , 4-R § -phenyl, 3-R § ,4-R § -,5-R § -phenyl],
1-naphthyl, 2-naphthyl (each substituted, where appropriate, with R § ),
pyridyl, isoquinolinyl, quinolinyl, acridinyl;
NR 7 R 8 , wherein this substitutent is altogether:
morpholino, thiomorpholino, thiomorpholino-S-oxide, thiomorpholino-S,S-dioxide, pyrrolidino, piperidino, 1-piperazino, 1-homopiperazino, 4-C 1-6 alkyl-1-piperazino, 4-(2-hydroxyethyl)-1-piperazino, 4-benzyl-1-piperazino, 4-aryl-1-piperazino (each substituted, where appropriate, with R § on the heterocycloaliphatic ring),
further amino residues of secondary, monocyclic or polycyclic cycloaliphatic amines having a total of 5-14 ring atoms, including the representatives substituted with R § on the C-skeleton;
amino residues of secondary aliphatic and aromatic amines, R 7 R 8 H,
wherein R 7 and R 8 may be independently equal or unequal and represent:
C 1-6 alkyl, benzyl, phenyl, 1- and 2-naphthyl, 2-, 3- and 4-pyridyl, quinolinyl, isoquinolinyl, 2-thienyl, 2-furyl (each substituted, where appropriate, with R § );
amino residues of primary amines, R 7 NH 2 , (wherein R 7 is as defined above),
amino, NH 2 , with the limitation that in this case R 5 only has the meaning of —OR 6 ;
R 5 is—hydrogen,
heterocyclyl, five-membered to seven-membered, substituted, where appropriate, by R 3 ,
phenyl, substituted, where appropriate, by R 3 ,
OR 6 , wherein R 6 is as defined above,
NR 7 R 8 , with the same meaning as above
azido, hydroxylamino, O—(C 1-3 )alkylhydroxylamino,
N—(C 1-3 )alkylhydroxylamino, N,N-di(C 1-3 )alkylhydroxylamino,
hydrazino, (C 1-4 )alkyl- and di(C 1-4 )alkylhydrazino,
benzylhydrazino, acylhydrazino, N,N-diacylhydrazino,
carbamoylamino,
1-imidazolyl, 1,2,4-triazol-1yl, 1-pyridinium,
1-pyrazinium, 1-pyridazinium, including the alkyl-substituted representatives of these azaheterocycles;
═O, ═S, ═N—H, ═N—C 1-8 alkyl, ═N-Aryl, ═N—OH, ═N—O—C 1-8 alkyl,
═N—O—C 6-14 aryl
R § as defined above (in formula 1a or 1b)
wherein the following compounds of formula 1(c) are not protected:
1,4-dihydro-2,2-dimethyl-5-(4-morpholinyl)-10-propylthio-2H-pyrano[4″,3″:4′,5′]pyrido[3′,2′:4′,5′]thieno[3,2-d]pyrimidin-8(9H)-one, 10-buthylthio-1,4-dihydro-2,2-dimethyl-5-(4-morpholinyl)-2H-pyrano[4″,3″:4′,5′]pyrido[3′,2′:4′,5′]thieno[3,2-d]pyrimidin-8(9H)-one and 2-methyl-5-thiophen-2-yl-1,2,3,4-tetrahydro-11H-7-thia-2,6,9,11-tetraaza-benzo[c]fluorene-8,10-dione
and pharmaceutically compatible salts, solvates, active metabolites, tautomers and prodrugs of these compounds.
2 ) The compound according to claim 1 , comprising general formula 1(a)(I) or 1(a)(II):
wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and Y have the meanings mentioned above with respect to formula 1(a).
3 ) The compound according to claim 1 , comprising formula 1(a), wherein Y═S and substituents R 1 , R 2 , R 3 , R 4 , R 5 are as defined below:
R 1
R 2
R 3
R 4
R 5
3,4-(MeO) 2 —Ph
H
Me
Piperazin-1-
OEt
yl
4-MeO—Ph
H
Me
Piperazin-1-
OEt
yl
4-F—Ph
H
Me
Piperazin-1-
OEt
yl
Ph
H
Me
Piperazin-1-
OiPr
yl
Ph
H
Me
Piperazin-1-
OCH 2 CHF 2
yl
Ph
H
Ph
Piperazin-1-
OEt
yl
Me
4′-
Me
Piperazin-1-
OEt
NO 2 —Ph—CH 2
yl
Me
4′-
Me
Piperazin-1-
OEt
NH 2 —Ph—CH 2
yl
3,4-Methylene-
H
Me
Piperazin-1-
OEt
dioxyphenyl
yl
Ph
H
Me
Piperazin-1-
OnPr
yl
Ph
H
Me
Piperazin-1-
OEt
yl
Ph
H
Me
Piperazin-1-
OCH 2 CH 2 OH
yl
3,4-(MeO) 2 —Ph
H
Me
OEt
Piperazin-1-
yl
4-MeO—Ph
H
Me
OEt
Piperazin-1-
yl
Ph
H
Me
OCH 2 CHF 2
Piperazin-1-
yl
Me
4′-
Me
OEt
Piperazin-1-
NO 2 —Ph—CH 2
yl
Ph
4′-
Me
OEt
Piperazin-1-
NO 2 —Ph—CH 2
yl
3,4-(MeO) 2 —Ph
H
Me
nPr
Piperazin-1-
yl
Ph
H
Me
OCH 2 CH 2 OH
Piperazin-1-
yl
Ph
H
Me
OEt
Piperazin-1-
yl
Ph
H
Me
OiPr
Piperazin-1-
yl
3,4-Methylene-
H
Me
OEt
Piperazin-1-
dioxyphenyl
yl
4-(Pyrimidyl-2-
H
Et
Piperazin-1-
OEt
yl)piperazin-1-
yl
yl)-
4-Me—Ph
H
Et
Piperazin-1-
OEt
yl
4-EtO—Ph
H
Et
Piperazin-1-
OEt
yl
4-EtO—Ph
H
Et
Piperazin-1-
OProp
yl
4-MeS—Ph
H
Et
Piperazin-1-
OEt
yl
4-Me—Ph
H
Et
Piperazin-1-
OiPr
yl
4-(4-
H
Et
Piperazin-1-
OEt
MeOPhO)Ph
yl
2,3-Dihydro-
H
Et
Piperazin-1-
OEt
benzo[b][1,4]-
yl
dioxin-6-yl
3,4-Methylene-
H
Et
Piperazin-1-
OEt
dioxyphenyl
yl
4-MeO—Ph
H
Et
Piperazin-1-
OEt
yl
4-(1H-pyrazol-
H
Et
Piperazin-1-
OEt
1-yl)-Ph
yl
4-Br—Ph
H
Et
Piperazin-1-
OEt
yl
4-Cl—Ph
H
Et
Piperazin-1-
OEt
yl
4-I—Ph
H
Et
Piperazin-1-
OEt
yl
Morpholine
H
Ph
Piperazin-1-
OEt
yl
4-MeO—Ph
H
CF 3
Piperazin-1-
OEt
yl
4-Me—Ph
H
CF 3
Piperazin-1-
OEt
yl
2,3-Dihydro-
H
CF 3
Piperazin-1-
OEt
benzo[b][1,4]-
yl
dioxin-6-yl
4-Imidazol-1-
H
CF 3
Piperazin-1-
OEt
yl-Ph
yl
4-Imidazol-1-
H
CF 3
Piperazin-1-
OCH 2 CH 2 OH
yl-Ph
yl
4-(Piperidin-1-
H
CF 3
Piperazin-1-
OEt
yl)-Ph
yl
4-Morpholino-
H
CF 3
Piperazin-1-
OEt
Ph
yl
3,4-Methylene-
H
CF 3
Piperazin-1-
OEt
dioxyphenyl
yl
4-MeS—Ph
H
CF 3
Piperazin-1-
OEt
yl
4-EtOOC—Ph
H
CF 3
Piperazin-1-
OEt
yl
4-(1H-pyrazol-
H
CF 3
Piperazin-1-
OEt
1-yl)-Ph
yl
4-F—Ph
H
CF 3
Piperazin-1-
OEt
yl
4-I—Ph
H
CF 3
Piperazin-1-
OEt
yl
3-NO 2 —Ph
H
CF 3
Piperazin-1-
OEt
yl
4-NO 2 —Ph
H
CF 3
Piperazin-1-
OEt
yl
3-CN—Ph
H
CF 3
Piperazin-1-
OEt
yl
4-CN—Ph
H
CF 3
Piperazin-1-
OEt
yl
3-NH 2 —Ph
H
CF 3
Piperazin-1-
OEt
yl
4-NH 2 —Ph
H
CF 3
Pipenazin-1-
OEt
yl
4-MeS—Ph
H
CF 3
Piperazin-1-
OEt
yl
4-MeS(O)—Ph
H
CF 3
Piperazin-1-
OEt
yl
Pyridin-4-yl
H
CF 3
Piperazin-1-
OEt
yl
Pyridin-4-yl-N-
H
CF 3
Piperazin-1-
OEt
oxide
yl
Pyridin-3-yl
H
CF 3
Piperazin-1-
OEt
yl
4-(Pyrazin-2-
H
CF 3
Piperazin-1-
OEt
yl)
yl
4(HCONH)—Ph
H
CF 3
Piperazin-1-
OEt
yl
4-(Pyridin-4-yl-
H
CF 3
Piperazin-1-
OEt
CONH)—Ph
yl
4-(Pyridin-3-yl-
H
CF 3
Piperazin-1-
OEt
CONH)—Ph
yl
4-(Pyridin-3-yl-
H
CF 3
Piperazin-1-
OEt
N-Oxide-
yl
CONH)—Ph
4-(1H-1,2,4-
H
CF 3
Piperazin-1-
OEt
triazol-4-yl)-Ph
yl
4-(1H-pyrrol-1-
H
CF 3
Piperazin-1-
OEt
yl)-Ph
yl
4(CH 3 OOCNH)—Ph
H
CF 3
Piperazin-1-
OEt
yl
isoPr
H
isoPr
Piperazin-1-
OEt
yl
2,3-Dihydro-
H
Et
OEt
Piperazin-1-
benzo[b][1,4]-
yl
dioxin-6-yl
4-EtO—Ph
H
Et
OEt
Piperazin-1-
yl
4-Me—Ph
H
Et
OEt
Piperazin-1-
yl
4-Me—Ph
H
Et
OCH 2 CH 2 OH
Piperazin-1-
yl
4 ) The compound according to claim 1 , comprising formula 1(a), wherein Y═O and substituents R 1 , R 2 , R 3 , R 4 , R 5 are as defined below:
R 1
R 2
R 3
R 4
R 5
Ph
H
Me
Piperazin-1-
OEt
yl
Ph
H
Me
OEt
Piperazin-1-
yl
5 ) The compound according to claim 1 , comprising formula 1(b), wherein Y═S and substituents R 1 , R 3 , R 4 , R 5 are as defined below:
R 1
R 3
R 4
R 5
3-NH 2 —Ph-4-Ph
Me
Piperazin-1-
OEt
yl
4-(3-furyl)-Ph
Me
Piperazin-1-
OEt
yl
4-(2-furyl)-Ph
Me
Piperazin-1-
OEt
yl
4-(3-pyridyl)-Ph
Me
Piperazin-1-
OEt
yl
4-(4-pyridyl)-Ph
Me
Piperazin-1-
OEt
yl
4-NH 2 —Ph—Ph
Me
Piperazin-1-
OEt
yl
3,4,5-(CH 3 O) 3 —Ph—Ph
Me
Piperazin-1-
OEt
yl
4-PhO—Ph
Me
Piperazin-1-
OEt
yl
2-NH 2 -4-
Me
Piperazin-1-
OEt
CH 3 OOC—Ph—Ph
yl
3-CH 3 OOC—Ph—Ph
Me
Piperazin-1-
OEt
yl
3,4-(CH 3 O) 2 —Ph—Ph
Me
Piperazin-1-
OEt
yl
3,5-(CH 3 ) 2 -
Me
Piperazin-1-
OEt
isoxazol-4-yl-Ph
yl
Phenyl
Me
Piperazin-1-
OEt
yl
4-Br—Ph
Me
Piperazin-1-
OEt
yl
3-NH 2 —Ph
Me
Piperazin-1-
OEt
yl
4-(pyrrol-3-yl)-Ph
Me
Piperazin-1-
OEt
yl
4-(pyrimidin-5-
Me
Piperazin-1-
OEt
yl)-Ph
yl
4-(pyrid-3-yl-
Me
Piperazin-1-
OEt
hydroxymethyl)-
yl
Ph
Ph—Ph
Me
Piperazin-1-
OEt
yl
4-(isoPropO)—Ph
Me
Piperazin-1-
OEt
yl
4-Vinyl-Ph
Me
Piperazin-1-
OEt
yl
6 ) The compound according to claim 1 , comprising formula 1(a) or 1(b), which are:
2-(2-Hydroxyethoxy)-9-methyl-7-phenyl-4-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 2-Ethoxy-7-(3,4-dimethoxy-phenyl)-9-methyl-4-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 2-Ethoxy-7-(4-methoxy-phenyl)-9-methyl-4-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3′,2-d]pyrimidine 2-Ethoxy-9-ethyl-7-(4-methyl-phenyl)-4-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 2-Ethoxy-7-(4-ethoxy-phenyl)-9-ethyl-4-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 2-Ethoxy-9-ethyl-7-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-9-trifluoromethyl-7-(pyrazin-2-yl)-2-piperazino-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-9-ethyl-7-(4-(pyrimidyl-2-yl)piperazin-1-yl)-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-morpholino-9-phenyl-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-phenyl-9-methyl-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 4-Ethoxy-7,9-dimethyl-8-(4-nitro-benzyl)-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(3,4-dimethoxy-phenyl)-9-methyl-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-9-ethyl-7-(4-methyl-phenyl)-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(4-fluorophenyl)-9-methyl-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 7-(4-Ethoxy-phenyl)-9-ethyl-2-(piperazin-1-yl)-4-n-propoxy-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(4-ethoxy-phenyl)-9-ethyl-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(4-(pyrimidin-2-yl)piperazin-1-yl)-9-ethyl-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-9-ethyl-7-(4-methylthio-phenyl)-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(4-methyl-phenyl)-9-iso-propyl-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine 4-Ethoxy-9-ethyl-7-[4-(4-methoxyphenoxy)phenyl]-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-9-ethyl-7-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-9-ethyl-7-(3,4-methylenedioxyphenyl)-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine 4-Ethoxy-7-(4-methoxy-phenyl)-2-(piperazin-1-yl)-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(4-methyl-phenyl)-2-(piperazin-1-yl)-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 7-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-ethoxy-2-(piperazin-1-yl)-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(4-(1H-imidazol-1-yl)phenyl)-2-(piperazin-1-yl)-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-[4-Ethoxy-2-(piperazin-1-yl)-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl-benzoic acid ethyl ester 4-Ethoxy-2-(piperazin-1-yl)-7-(4-(piperidin-1-yl)phenyl)-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-9-ethyl-7-(4-methoxyphenyl)-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(3,4-methylenedioxyphenyl)-2-piperazin-1-yl-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine 4-Ethoxy-7-(4-methylthiophenyl)-2-(piperazin-1-yl)-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3 ,2-d]pyrimidine 4-Ethoxy-7-(4-(1H-pyrazol-1-yl)-phenyl)-9-ethyl-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(4-iodo-phenyl)-2-(piperazin-1-yl)-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(4-(1H-pyrazol-1-yl)-phenyl)-2-piperazin-1-yl-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3 ,2-d]pyrimidine 7-(4-Bromo -phenyl)-4-ethoxy-9-ethyl-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-9-ethyl-7-(4-iodo-phenyl)-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-7-(3-nitro-phenyl)-2-piperazin-1-yl-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 7-(3-Cyano-phenyl)-4-ethoxy-2-piperazin-1-yl-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 7-(4-Cyano-phenyl)-4-ethoxy-2-piperazin-1-yl-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 7-(3-Amino-phenyl)-4-ethoxy-2-piperazin-1-yl-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 7-(4-Amino-phenyl)-4-ethoxy-2-piperazin-1-yl-9-trifluoromethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 4-Ethoxy-9-methyl-7-(4-methylsulfinyl-phenyl)-2-(piperazin-1-yl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine N-(4-(4-Ethoxy-9-trifluoromethyl-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl )-phenyl)-formamide N-(4-(4-Ethoxy-9-trifluoromethyl-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-phenyl)-isonicotinamide 4-Ethoxy-9-trifluoromethyl-2-piperazin-1-yl-7-(4-(1H-pyrrol-1-yl)-phenyl)-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine N-(4-(4-Ethoxy-9-trifluoromethyl-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-phenyl)-nicotinamide-N-oxide 4-(4-Ethoxy-9-trifluoromethyl-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-phenyl-carbamic acid ethyl ester N-(4-(4-Ethoxy-9-trifluoromethyl-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-phenyl)-nicotinamide N-(4-Ethoxy-9-trifluoromethyl-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-benzamide trifluoroacetate N′-Hydroxy-4-(4-ethoxy-9-trifluoromethyl-2-piperazin-1-yl-pyrido[3′,2′:4, 5 ]thieno[3,2-d]pyrimidin-7-yl)-benzamidine bistrifluoroacetate 7-(3′-Aminobiphen-4-yl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine 4-Ethoxy-7-(4-[3-furyl]-phenyl)-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine 4-Ethoxy-7-(4-[2-furyl]-phenyl)-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine 4-Ethoxy-9-methyl-2-piperazin-1-yl-7-(4-[3-pyridyl]-phenyl)-thieno[2,3-d:4,5-d′]dipyrimidine 4-Ethoxy-9-methyl-2-piperazin-1-yl-7-(4-[4-pyridyl]-phenyl)-thieno[2,3-d:4,5-d′]dipyrimidine 7-(4′-Aminobiphen-4-yl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine 4-Ethoxy-9-methyl-2-piperazin-1-yl-7-(3′,4′,5′-trimethoxybiphen-4-yl)-thieno[2,3-d:4,5-d′]dipyrimidine 4-Ethoxy-9-methyl-7-(4-phenoxy-phenyl)-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine 2′-Amino-4-(4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidin-7-yl)-biphenyl-4′-carboxylic acid methyl ester 7-(3′,4′-Dimethoxybiphen-4-yl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine
7 ) The compound according to claim 1 , comprising formula 1(c)(I) or 1(c)(II):
wherein R 1 , R 6 , R 7 , R 8 as well as A and Y have the meanings mentioned above with respect to formula 1(c).
8 ) The compound according to claim 1 , comprising formula 1(c) or 1(d), which is selected from the group:
10-Ethoxy-5-morpholino-8-piperazin-1-yl-pyrimido[4′,5′:4,5]thieno[2,3-c]-1,2,3,4-tetrahydro-isoquinoline 7-Ethoxy-2,3-dihydro-4-morpholino-9-piperazin-1yl-1H-cyclopenta[4′,5′pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 8-Ethoxy-5-piperidino-10-piperazin-1-yl-pyrimido[4′,5′:4,5]thieno[2,3-c]-1,2,3,4-tetrahydro-isoquinoline-hydrochloride 8-Ethoxy-5-morpholino-10-piperazin-1-yl-pyrimido[4′,5′:4,5]thieno[2,3-c]-1,2,3,4-tetrahydro-isoquinoline-hydrochloride 8-Ethoxy-5-phenyl-10-piperazin-1-yl-pyrimido[4′,5′:4,5]thieno[2,3-c]-1,2,3,4-tetrahydro-isoquinoline-hydrochloride 10-Ethoxy-5-phenyl-8-piperazin-1-yl-pyrimido[4′,5′:4,5]thieno[2,3-c]-1,2,3,4-tetrahydro-isoquinoline 8-Ethoxy-5-morpholino-10-piperazin-1-yl-pyrimido[4′,5′:4,5]thieno[2,3-c]-1,2,3,4-tetrahydro-isoquinoline 7-Ethoxy-2,3,4,5-tetrahydro-4-morpholino-9-piperazin-1yl-1H-cyclohepta[4′,5′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine
9 ) A pharmaceutical composition containing at least one of the compounds according to any of claims 1 to 8 and, where appropriate, pharmaceutically compatible excipients and/or carriers.
10 ) The pharmaceutical composition according to claim 9 additionally containing one or more of the following active substances:
β 2 -adrenoceptor agonists
disodium cromoglycate
corticosteroids
leukotriene antagonists (either enzyme inhibitors [such as 5-lipoxygenase inhibitors or arachidonic acid enzyme inhibitors] or receptor antagonists),
antihistaminics (preferably those having mast cell-stabilizing properties or leukotriene-antagonizing aspects)
theophylline
muscarine receptor antagonists
(monoclonal) antibodies against TNF-alpha or other active substances inhibiting the formation and/or release of TNF-alpha or the activity of TNF-alpha.
11 ) Use of at least one of the compounds according to any of claims 1 to 8 for the production of a medicament for inhibiting the phosphodiesterase 4 (PDE4) enzyme and/or TNF alpha release.
12 ) Use according to claim 11 for treating bronchial asthma, COPD, rheumatoid arthritis (RA), osteoarthritis, cystic fibrosis, Guillain-Barré syndrome, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, allergic eczemas, allergic rhinitis, allergic conjunctivitis, systemic scleroderma, graft versus host disease (GvHD), systemic lupus erythematosus (SLE), diabetes mellitus type I, neurodegenerative diseases, in particular Alzheimer's disease and Parkinson's disease, post-traumatic multiorgan failure, toxic shock syndrome, acute glomerulonephritis, acute and chronic pains, arteriosclerosis, cardiac infarction, apoplexy, tumoral diseases, axonal degeneration, viral diseases.
13 ) Use according to claim 12 , wherein the tumoral disease is leukemia.
14 ) Use according to claim 13 , wherein the tumoral disease is CLL.Cited by (0)
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