US2021317156A1PendingUtilityA1
New polymer linked multimers of guanosine-3', 5'-cyclic monophosphates
Est. expiryAug 31, 2036(~10.1 yrs left)· nominal 20-yr term from priority
A61P 29/00A61P 1/04A61P 21/00A61P 31/00A61P 25/00A61P 19/10A61P 9/12A61P 35/04A61P 9/00A61P 19/00A61P 21/02A61P 19/02A61P 37/00A61P 11/00A61P 33/00A61P 5/14A61P 9/10A61P 35/00C07H 19/213A61P 33/06A61P 37/02
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Claims
Abstract
Embodiments of the invention are directed to new polymer linked multimeric guanosine-3′, 5′-cyclic monophosphate (cGMP) analogues that modulate the cGMP-signaling system, preferably having activating properties, and more preferably being activators of cGMP dependent protein kinase (PKG), and related monomeric precursors thereof. The invention is also directed to related monomeric compounds, which may also show modulating activity and/or may serve as monomeric precursors of the multimers. The invention further relates to the use of such compounds as reagents for signal transduction research and as modulators of cyclic nucleotide-regulated binding proteins and isoenzymes thereof, and as ligands for affinity chromatography, for antibody production or for diagnostic applications e.g. on chip surfaces.
Claims
exact text as granted — not AI-modified1 . A compound having the formula (I) or (II)
wherein:
G units G 1 and G 2 independently are compounds of formula (III) and G units G 3 and G 4 independently from G 1 and G 2 and independently from each other are compounds of formula (III) or absent, wherein in case of formula (II) G 4 is always absent if G 3 is absent
and wherein in formula (III)
X, Y and Z are N
R 1 , R 4 , R 5 , R 7 and R 5 can be equal or individual for each G unit (G 1 , G 2 , G 3 and G 4 ),
while
R 1 can independently be H, halogen, azido, cyano, acyl, aracyl, nitro, alkyl, aryl, aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-aracyl, SH, S-alkyl, S-aryl, S-aralkyl, S-acyl, S-aracyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-acyl, S(O)-aracyl, S(O) 2 -alkyl, S(O) 2 -aryl, S(O) 2 -aralkyl, S(O) 2 -acyl, S(O) 2 -aracyl, SeH, Se-alkyl, Se-aryl, Se-aralkyl, NR9R10, SiR13R14R15 wherein R9, R10, R13, R14, R15 independently from each other can be H, alkyl, aryl, aralkyl;
R 2 is absent;
R 3 is OH;
R 4 can independently be absent, H, amino, alkyl, aralkyl, nitro, N-oxide, or can form together with R 3 , Y and the carbon bridging Y and R 3 an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R 5 and the carbon bridging Y and R 5 an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R 5 and the carbon bridging Y and R 5 an imidazolinone as depicted (structure IV, V, n=1) or an homologous ring (n=2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl;
R 5 can independently be H, halogen, NR30R31, NH-carbamoylR32R33, wherein R30, R31, R32, R33, independently from each other can be H, alkyl, aryl, aralkyl, or can form together with R 4 , Y and the carbon bridging Y and R 5 an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with R 4 , Y and the carbon bridging Y and R 5 an imidazolinone ring as depicted (structure IV, V, n=
1) or an homologous ring (n=2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl;
R 6 is OH;
R 7 is O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, SH, S-alkyl, S-aryl, S-aralkyl, borano (BH 3 ), methylborano, dimethylborano, cyanoborano (BH 2 CN)S-PAP, O-PAP, S-BAP, or O-BAP,
wherein PAP is a photo-activatable protecting group, optionally PAP=o-nitrobenzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro-benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged),
and wherein BAP is a bio-activatable protecting group, optionally BAP=methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4-pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl;
and
R 5 is O-carbamoyl-alkyl, O-carbamoyl-aryl, O-carbamoyl-aralkyl, OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, O-PAP or O-BAP,
wherein PAP is a photo-activatable protecting group with non limiting examples of, optionally, PAP=o-nitro-benzyl, 1-(o-nitrophenyl)-ethylidene, 4,5-dimethoxy-2-nitro-benzyl, 7-dimethylamino-coumarin-4-yl (DMACM-caged), 7-diethylamino-coumarin-4-yl (DEACM-caged) and 6,7-bis(carboxymethoxy)coumarin-4-yl)methyl (BCMCM-caged);
and wherein BAP is a bio-activatable protecting group with non limiting examples of, optionally, BAP=methyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, propionyloxymethyl, butyryloxymethyl, cyanoethyl, phenyl, benzyl, 4-acetoxybenzyl, 4-pivaloyloxybenzyl, 4-isobutyryloxybenzyl, 4-octanoyloxybenzyl, 4-benzoyloxybenzyl;
and wherein
linking residues LR 1 , LR 2 , LR 3 and LR 4 independently can replace or covalently bind to any of the particular residues R 1 , R 4 and/or R 5 of the G units (G 1-4 ) they connect,
wherein in case the particular linking residue (LR 1-4 ) covalently binds to any of the residues R 1 , R 4 and/or R 5 , an endstanding group of the particular residue (R 1 , R 4 and/or R 5 ), as defined above, is transformed or replaced within the assembled compound and is then further defined as part of the particular linking residue (LR 1-4 ) within the assembled compound,
while
LR 1 is (a) a tri- or tetravalent branched hydrocarbon moiety or (b) a divalent hydrocarbon moiety each with or without incorporated heteroatoms, optionally heteroatoms O, N, S, Si, Se, B, wherein the backbone preferably contains 1 to 28 carbon atoms and can be, saturated or unsaturated, substituted or unsubstituted,
while
each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom
and
in case poly ethylene glycole (PEG) moieties are incorporated in accordance to the definition, the preferred number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of
1 to 500 ethylene glycol groups (—(CH 2 CH 2 O) n — with n=1 to 500) in case of divalent linking residue (LR 1 )
or
1 to 750 ethylene glycol groups (—(CH 2 CH 2 O) n — with n=1 to 750) in case of trivalent linking residue (LR 1 )
or
1 to 1000 ethylene glycol groups (—(CH 2 CH 2 O) n — with n=1 to 1000) in case of tetravalent linking residue (LR 1 ),
and if substituted,
substituents include optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, amino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, expoxy, methoxy, ethynyl,
and/or substituents can further be connected to each other, forming a ringsystem with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic;
LR 2 , LR 3 and LR 4 are divalent hydrocarbon moieties with or without incorporated heteroatoms, optionally heteroatoms O, N, S, Si, Se, B, wherein the backbone preferably contains 1 to 28 carbon atoms and can be, saturated or unsaturated, substituted or unsubstituted,
while
each attachment point independently can be a substituted or unsubstituted carbon- or heteroatom
and
in case poly ethylene glycole (PEG) moieties are incorporated in accordance to the definition, the preferred number of carbon atoms can be exceeded by the number present in the PEG moieties, wherein all PEG moieties together can contain a total amount of 1 to 500 ethylene glycol groups (—(CH 2 CH 2 O) n — with n=1 to 500) and, if substituted,
substituents include optionally one or more alkyl groups, halogen atoms, haloalkyl groups, (un)substituted aryl groups, (un)substituted heteroaryl groups, amino, oxo, nitro, cyano, azido, hydroxy, mercapto, keto, carboxy, carbamoyl, expoxy, methoxy, ethynyl
and/or substituents can further be connected to each other, forming a ringsystem with 1 to 4 rings, with or without incorporated heteroatoms, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic;
wherein in case of formula (II) if G 4 is absent, LR 4 is absent, too, and
wherein in case of formula (II) if G 3 and G 4 are absent, LR 3 and LR 4 are absent, too, and wherein
G 1 , G 2 , G 3 and G 4 can further be salts and/or hydrates
while optionally suitable salts of the particular phosphate moiety are lithium, sodium, potassium, calcium, magnesium, zinc or ammonium, and trialkylammonium, dialkylammonium, alkylammonium, e.g., triethylammonium, trimethylammonium, diethylammonium and octylammonium;
and wherein
G 1 , G 2 , G 3 and G 4 can optionally be isotopically or radioactively labeled, be PEGylated, immobilized or be labeled with a dye or another reporting group,
wherein
the reporting group(s) and/or dye(s)
(a) are coupled to G 1 , G 2 , G 3 and/or G 4 via a linking residue (LR 5 ), bound covalently to or replacing any of the particular residues R 1 , R 4 and/or R 5 independently for each G unit (G 1 , G 2 , G 3 and/or G 4 ) while LR 5 can be as defined for LR 2
or
(b) in case of formula (I) can replace G 3 and/or G 4
and wherein
optionally suitable dyes include fluorescent dyes such as fluorescein, anthraniloyl, N-methylanthraniloyl, dansyl or the nitro-benzofurazanyl (NBD) system, rhodamine-based dyes such as Texas Red or TAMRA, cyanine dyes such as Cy™3, Cy™5, Cy™7, EVOblue™10, EVOblue™30, EVOblue™90, EVOblue™100 (EVOblue™-family), the BODIPY™-family, Alexa Fluor™-family, DY-547P1, DY-647P1, coumarines, acridines, oxazones, phenalenones, fluorescent proteins such as GFP, BFP and YFP, and near and far infrared dyes
and wherein
reporting groups optionally include quantum dots, biotin and tyrosylmethyl ester
and wherein
PEGylated refers to the attachment of a single or multiple LR PEG group(s) independently, wherein LR PEG can be as defined for LR 2 , with the provisos that in this case (i) of LR 2 only one terminus is connected to a G unit (G 1 , G 2 , G 3 and/or G 4 ) by covalently binding to or replacing any of the particular residues R 1 , R 4 and/or R 5 independently for each G unit (G 1 , G 2 , G 3 and/or G 4 ), and (ii) the other terminus of LR 2 is either an alkyl group or a reactive group that allows for conjugation reactions and/or hydrogen bonding
while, optionally, non limiting examples of reactive groups are, —NH 2 , —SH, —OH, —COOH, —N 3 , —NHS-ester, halogen group, epoxide, ethynyl, allyl
and with the proviso (iii) that LR PEG has incorporated ethylene glycol moieties ((CH 2 CH 2 O) n — with n=2 to 500)
with the proviso that the compound of formula (I) and/or (II), is not selected from
Guanosine-3′, 5′-cyclic monophosphate-[8-thioethylsulfonyl-(ethyloxy) n -ethylsulfonylethylthio-8]-guanosine-3′, 5′-cyclic monophosphate (polydispers compound arising from synthesis with polydispers bis vinylsulfonyl-PEG n with M w of 800 g/mol, 1.2 kg/mol, 3.4 kg/mol or 20 kg/mol; or monodispers compound with n=6).
2 . A compound according to claim 1 , wherein at least two G units are unequally substituted.
3 . A compound according to claim 1 , wherein
(a) in case of formula (I) G 3 and G 4 are absent
or
in case of formula (II) G 3 , G 4 , LR 3 and LR 4 are absent;
and wherein
R 4 is not H and/or R 5 is not NH 2
or
(b) in case of formula (I) G 3 and G 4 are absent
or
in case of formula (II) G 3 , G 4 , LR 3 and LR 4 are absent.
4 . A compound according to claim 1 wherein
all R 7 are SH and all R 5 are O
or
all R 7 are O and all R 5 are OH.
5 . A compound according to claim 1 wherein the linking residues LR 1 , LR 2 , LR 3 and LR 4 are further subdivided as depicted in formula (Ib) and (IIb),
wherein:
coupling functions C 1 , C 1′ , C 2 , C 2′ , C 3 , C 3′ , C 4 and C 4′ independently from each other can be absent or as defined by structures selected from the group consisting of
while connectivity can be as depicted or reversed as exemplified by
G 1 -O—C(O)—NH—S 2 versus G 1 -NH—C(O)—O—S 2
an wherein in case the coupling function (C 1 , C 1′ , C 2 , C 2′ , C 3 , C 3′ , C 4 and/or C 4′ ) does not replace the residue of the G unit (R 1 , R 4 and/or R 5 of G 1-4 ) but bind to it, the particular residue (R 1 , R 4 and/or R 5 ) involved in coupling of G units (or G unit with dye(s) or other reporting group(s)) independently from each other is
as defined in any of the preceding claims, wherein an endstanding group is replaced by or transformed to the coupling function
or
selected from the group depicted hereinafter (wherein if present, Q1 connects to the G unit)
and wherein
the linker (L) is selected from the group consisting of
Dimeric Linkers
Trimeric Linkers
Tetrameric linkers
while
n for each sidechain within a particular linker of the list herebefore can have an equal or individual value as defined
and
all chiral, diastereomeric, racemic, epimeric, and all geometric isomeric forms of linkers (L) of the list herebefore, though not explicitly depicted, are included herein
and
cationic linkers (L) such as ammonium-derivatives are salts containing chloride-, bromide-, iodide- phosphate-, carbonate-, sulfate-, acetate- or any other physiologically accepted counterion
and wherein
spacers (S 1 , S 2 , S 3 and S 4 ) can be equal or individual within a particular compound, be absent or be —(CH 2 ) n1 —(CH 2 CH 2 ß) m -(CH 2 ) n2 — (with ß=O, S or NH; m=1 to 500, n1=0 to 8, n2=0 to 8, while both n1 and n2 can independently be equal or individual) or —(CH 2 ) n — (with n=1 to 24).
6 . A compound according to claim 1 wherein R 1 can independently be H, halogen, azido, nitro, alkyl, acyl, aryl, OH, O-alkyl, O-aryl, SH, S-alkyl, S-aryl, S-aralkyl, S(O)-alkyl, S(O)-aryl, S(O)-aralkyl, S(O)-benzyl, S(O) 2 -alkyl, S(O) 2 -aryl, S(O) 2 -aralkyl, amino, NH-alkyl, NH-aryl, NH-aralkyl, NR9R10, SiR13R14R15 wherein R9, R10, R13, R14, R15 are alkyl; and/or R 4 can independently be absent, H, amino, alkyl, aralkyl, nitro, N-oxide or can form together with Y and R 5 and the carbon bridging Y and R 5 an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with Y and R 5 and the carbon bridging Y and R 5 an imidazolinone as depicted above (structure IV, V, n=1) or an homologous ring (n=2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl. and/or R 5 can independently H, halogen, NH-carbamoyl-alkyl, NH-carbamoyl-aryl, NH-carbamoyl-aralkyl, amino, NH-alkyl, NH-aryl, NH-aralkyl, NR30R31 wherein R30 and R31 are alkyl, or can form together with R 4 , Y and the carbon bridging Y and R 5 an imidazole ring which can be unsubstituted or substituted with alkyl, aryl or aralkyl, or can form together with R 4 , Y and the carbon bridging Y and R 5 an imidazolinone ring as depicted above (structure IV, V, n=1) or an homologous ring (n=2 to 8) which each can be unsubstituted or substituted (not depicted) with alkyl, aryl or aralkyl.; and/or
R 7 is OH, O-alkyl, O-aryl, O-aralkyl, O-acyl, SH, S-alkyl, S-aryl, S-aralkyl, borano (BH 3 ), methylborano, dimethylborano, cyanoborano (BH 2 CN),
and
R 8 is OH, O-alkyl, O-aryl, O-aralkyl, O-acyl,
7 . A compound according to claim 1 wherein R 1 is H, Cl, Br, I, F, N 3 , NO 2 , OH, SH, NH 2 , CF 3 , 2-furyl, 3-furyl, 2-bromo-5-furyl, (2-furyl)thio, (3-(2-methyl)furyl)thio, (3-furyl)thio, 2-thienyl, 3-thienyl, (5-(1-methyl)tetrazolyl)thio, 1,1,2-trifluoro-1-butenthio, (2-(4-phenyl)imidazolyl)thio, (2-benzothiazolyl)thio, (2,6-dichlorophenoxypropyl)thio, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)ethylthio, (4-bromo-2,3-dioxobutyl)thio, [2-[(fluoresceinylthioureido)amino]ethyl]thio, 2,3,5,6-tetrafluorophenylthio, (7-(4-methyl)coumarinyl)thio, (4-(7-methoxy)coumarinyl)thio, (2-naphtyl)thio, (2-(1-bromo)naphtyl)thio, benzimidazolyl-2-thiobenzothiazolylthio, 4-pyridyl, (4-pyridyl)thio, 2-pyridylthio, 5-amino-3-oxopentylamino, 8-amino-3,6-dioxaoctylamino, 19-amino-4,7,10,13,16-pentaoxanonadecylamino, 17-amino-9-aza-heptadecylamino, 4-(N-methylanthranoyl)aminobutylamino, dimethylamino, diethylamino, 4-morpholino, 1-piperidino, 1-piperazino, triphenyliminophosphoranyl or residue R 1 is as depicted hereinafter as residue entry 1 or 2: residue entry 1:
wherein
m=0-6;
Q=S, S(O), S(O) 2 , O, NH, Se, CH 2 , C(O);
X 1 , X 2 and X 3 can be equal or independently be H, OH, NH 2 , N 3 , SH, CN, NO 2 , F, Cl, Br, I, (CH 2 ) n CH 3 (with n=0-5), i-Pr, t-Bu, (CH 2 ) n C≡CH (with n=0-5), (CH 2 ) n C═CH 2 (with n=0-5), CH 2 OH, (CH 2 ) n OCH 3 (with n=1-2), CH 2 N(CH 3 ) 2 , O(CH 2 ) n CH 3 (with n=0-5), Oi-Pr, OCy, OCyp, OBn, OC(O)CH 3 , OC(O)Ph, OCF 3 , N(CH 3 ) 2 , NH(CH 2 ) n CH 3 (with n=0-5), NHC(O)t-Bu, NHC(O)Ph, NHC(O)Ot-Bu, NHC(O)CH 3 , NHC(O)CH 2 N 3 , B(OH) 2 , CF 3 , C(O)OH, C(O)OCH 3 , C(O)Oi-Pr, C(O)Ot-Bu, C(O)OPh, C(O)OBn, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHPh, C(O)NHBn, C(O)CF 3 , CH 2 C(O)OH, CH 2 C(O)OCH 3 , CH 2 C(O)Oi-Pr, CH 2 C(O)Ot-Bu, CH 2 C(O)OBn, S(CH 2 ) n CH 3 (with n=0-5), S(CH 2 ) n OEt (with n=1-4), SBn, SO 2 CH 3 , SO 2 CF 3 ,
(with Y 1 ═H, SH, CN, Ph, F, CH 3 , OCH 3 , SCH 3 , 4-thiophenyl, NO 2 , pentyl),
(with Y 2 ═H, SH, F),
(with Y 3 ═H, SH),
residue entry 2:
wherein
m=0-6;
n=1-6;
Q=S, S(O), S(O) 2 , O, NH, Se;
and/or
R 4 is absent, amino, N-oxide or residue R 4 is as depicted hereinafter as residue entry 1, 2, 3 or 4:
residue entry 1:
wherein
m=1-6;
X 1 , X 2 and X 3 can be equal or independently be H, N 3 , CN, NO 2 , F, Cl, Br, I, (CH 2 ) n CH 3 (with n=0-5), i-Pr, t-Bu, (CH 2 ) n C≡CH (with n=0-5), (CH 2 ) n C═CH 2 (with n=0-5), (CH 2 ) n OCH 3 (with n=1-2), CH 2 N(CH 3 ) 2 , O(CH 2 ) n CH 3 (with n=0-5), Oi-Pr, OBn, OC(O)CH 3 , OC(O)Ph, OCF 3 , N(CH 3 ) 2 , NHC(O)t-Bu, NHC(O)Ph, NHC(O)Ot-Bu, NHC(O)CH 3 , NHC(O)CH 2 N 3 , CF 3 , C(O)OCH 3 , C(O)Oi-Pr, C(O)Ot-Bu, C(O)OPh, C(O)OBn, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHPh, C(O)NHBn, C(O)CF 3 , CH 2 C(O)OCH 3 , CH 2 C(O)Oi-Pr, CH 2 C(O)Ot-Bu, CH 2 C(O)OBn, S(CH 2 ) n CH 3 (with n=0-5), S(CH 2 ) n OEt (with n=1-4), SBn, SPh, SO 2 CF 3 ,
(with Y 1 ═H, CN, Ph, F, CH 3 , OCH 3 , SCH 3 , NO 2 , pentyl),
(with Y 2 ═H, F),
residue entry 2:
wherein
X 1 can be H, CH 3 , Ph;
X 2 can be H, Ph, 2-naphtyl, 9-phenanthryl, 1-pyrenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, dibenzo[b,d]furan-2-yl, 2,3-dihydro-1-benzofuran-5-yl, 1-benzothien-5-yl, 1-benzofuran-5-yl, cyclopropyl, 1-adamantyl, C(Ph) 3 , 2-thienyl, 3-chloro-2-thienyl, 3-thienyl, 1,3-thiazol-2-yl, 2-pyridinyl, 5-chloro-2-thienyl, 1-benzofuran-2-yl,
X 3 , X 4 and X 5 can independently be H, OH, NH, CH 3 , Cl, Br, F, CN, N 3 , CF 3 , OCF 3 , NO 2 , C(O)OH, C(O)OCH 3 , OCH 3 , OBn, O-benzoyl, SCH 3 , t-Bu, N(CH 3 ) 2 , S-phenyl, Ph, S(O) 2 CH 3 , C(O)NH 2 , NHS(O) 2 CH 3 ;
residue entry 3:
wherein deviating from the definition above, any hydrogen atom attached to any of the ring carbon atoms including depicted, implied, or expressly defined hydrogen, or both hydrogen atoms (m=2) attached to the same particular carbon atom, can be replaced by one or two (equal) “floating groups” X 1 respectively, as long as a stable structure is formed,
while m=1 or 2;
n=1-4;
X 1 can be H, CH 3 , Et, Pr, i-Pr, Bu, F, Ph, (CH 2 ) 2 OH*,
Only for first case;
residue entry 4:
wherein
m=1-6;
n=1-6.
and/or
R 5 is H, NH 2 , F, Cl, Br, I, methylamino, NH-benzyl, NH-phenyl, NH-4-azidophenyl, NH-phenylethyl, NH-phenylpropyl, 2-aminoethylamino, n-hexylamino, 6-amino-n-hexylamino, 8-amino-3,6-dioxaoctylamino, dimethylamino, 1-piperidino, 1-piperazino or can form together with R 4 , Y and the carbon bridging Y and R 5 a ring system as depicted in the list hereinabove (entry 2 and 3);
and/or
R 7 OH, methyloxy, ethyloxy, cyanoethyloxy, acetoxymethyloxy, pivaloyloxymethyloxy, methoxymethyloxy, propionyloxymethyloxy, butyryloxymethyloxy, acetoxyethyloxy, acetoxybutyloxy, acetoxyisobutyloxy, phenyloxy, benzyloxy, 4-acetoxybenzyloxy, 4-pivaloyloxybenzyloxy, 4-isobutyryloxybenzyloxy, 4-octanoyloxybenzyloxy, 4-benzoyloxybenzyloxy, acetyloxy, propionyloxy, benzoyloxy, SH, methylthio, acetoxymethylthio, pivaloyloxymethylthio, methoxymethylthio, propionyloxymethylthio, butyryloxymethylthio, cyanoethylthio, phenylthio, benzylthio, 4-acetoxybenzylthio, 4-pivaloyloxybenzylthio, 4-isobutyryloxybenzylthio, 4-octanoyloxybenzylthio, 4-benzoyloxybenzylthio, borano (BH 3 ), methylborano, dimethylborano, cyanoborano (BH 2 CN);
and
R8 is OH, methyloxy, ethyloxy, cyanoethyloxy, acetoxymethyloxy, pivaloyloxymethyloxy, methoxymethyloxy, propionyloxymethyloxy, butyryloxymethyloxy, acetoxyethyloxy, acetoxybutyloxy, acetoxyisobutyloxy, phenyloxy, benzyloxy, 4-acetoxybenzyloxy, 4-pivaloyloxybenzyloxy, 4-isobutyryloxybenzyloxy, 4-octanoyloxybenzyloxy, 4-benzoyloxybenzyloxy, acetyloxy, propionyloxy, benzoyloxy;
8 . A compound according to claim 1 wherein R 1 is H, Cl, Br, I, F, N 3 , NO 2 , OH, SH, NH 2 , CF 3 , 2-furyl, 3-furyl, (2-furyl)thio, (3-(2-methyl)furyl)thio, (3-furyl)thio, 2-thienyl, 3-thienyl, (5-(1-methyl)tetrazolyl)thio, 1,1,2-trifluoro-1-butenthio, (2-(4-phenyl)imidazolyl)thio, (2-benzothiazolyl)thio, (2,6-dichlorophenoxypropyl)thio, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)ethylthio, (4-bromo-2,3-dioxobutyl)thio, [2-[(fluoresceinylthioureido)amino]ethyl]thio, 2,3,5,6-tetrafluorophenylthio, (7-(4-methyl)coumarinyl)thio, (4-(7-methoxy)coumarinyl)thio, (2-naphtyl)thio, (2-(1-bromo)naphtyl)thio, benzimidazolyl-2-thio, benzothiazolylthio, 4-pyridyl, (4-pyridyl)thio, 2-pyridylthio, 5-amino-3-oxopentylamino, 8-amino-3,6-dioxaoctylamino, 19-amino-4,7,10,13,16-pentaoxanonadecylamino, 17-amino-9-aza-heptadecylamino, 4-(N-methylanthranoyl)aminobutylamino, dimethylamino, diethylamino, 4-morpholino, 1-piperidino, 1-piperazino, triphenyliminophosphoranyl or residue R 1 is as depicted hereinafter as residue entry 1 or 2: residue entry 1:
wherein
m=0-6;
Q=S, S(O), S(O) 2 , NH;
X 1 , X 2 and X 3 can be equal or independently be H, OH, NH 2 , N 3 , SH, CN, NO 2 , F, Cl, Br, I, (CH 2 ) n CH 3 (with n=0-5), i-Pr, t-Bu, Ph, (CH 2 ) n C≡CH (with n=0-5), (CH 2 ) n C═CH 2 (with n=0-5), CH 2 OH, (CH 2 ) n OCH 3 (with n=1-2), CH 2 N(CH 3 ) 2 , O(CH 2 ) n CH 3 (with n=0-5), Oi-Pr, OCy, OCyp, OPh, OBn, OC(O)CH 3 , OC(O)Ph, OCF 3 , N(CH 3 ) 2 , NH(CH 2 ) n CH 3 (with n=0-5), NHC(O)t-Bu, NHC(O)Ph, NHC(O)Ot-Bu, NHC(O)CH 3 , NHC(O)CH 2 N 3 , B(OH) 2 , CF 3 , C(O)OH, C(O)OCH 3 , C(O)Oi-Pr, C(O)Ot-Bu, C(O)OPh, C(O)OBn, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHPh, C(O)NHBn, C(O)CF 3 , CH 2 C(O)OH, CH 2 C(O)OCH 3 , CH 2 C(O)Oi-Pr, CH 2 C(O)Ot-Bu, CH 2 C(O)OBn, S(CH 2 ) n CH 3 (with n=0-5), S(CH 2 ) n OEt (with n=1-4), SBn, SPh,
residue entry 2:
wherein
m=0-6;
n=1-6;
Q=S, S(O), S(O) 2 , NH;
and/or
R 4 is absent, amino, N-oxide or residue R 4 is as depicted hereinafter as residue entry 1, 2, 3 or 4:
residue entry 1:
wherein
m=1-3;
X 1 , X 2 and X 3 can be equal or independently be H, N 3 , CN, NO 2 , F, Cl, Br, I, (CH 2 ) n CH 3 (with n=0-5), i-Pr, t-Bu, Ph, (CH 2 ) n C≡CH (with n=0-5), (CH 2 ) n C═CH 2 (with n=0-5), (CH 2 ) n OCH 3 (with n=1-2), CH 2 N(CH 3 ) 2 , O(CH 2 ) n CH 3 (with n=0-5), Oi-Pr, OPh, OBn, OC(O)CH 3 , OC(O)Ph, OCF 3 , N(CH 3 ) 2 , NHC(O)t-Bu, NHC(O)Ph, NHC(O)Ot-Bu, NHC(O)CH 3 , NHC(O)CH 2 N 3 , CF 3 , C(O)OCH 3 , C(O)Oi-Pr, C(O)Ot-Bu, C(O)OPh, C(O)OBn, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHPh, C(O)NHBn, C(O)CF 3 , CH 2 C(O)OCH 3 , CH 2 C(O)Oi-Pr, CH 2 C(O)Ot-Bu, CH 2 C(O)OBn, S(CH 2 ) n CH 3 (with n=0-5), S(CH 2 ) n OEt (with n=1-4), SBn, SPh, SO 2 CF 3 ,
residue entry 2:
wherein
X 1 can be H, CH 3 , Ph;
X 2 can be H, Ph, 2-naphtyl, 9-phenanthryl, 1-pyrenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, dibenzo[b,d]furan-2-yl, 2,3-dihydro-1-benzofuran-5-yl, 1-benzothien-5-yl, 1-benzofuran-5-yl, cyclopropyl, 1-adamantyl, C(Ph) 3 , 2-thienyl, 3-chloro-2-thienyl, 3-thienyl, 1,3-thiazol-2-yl, 2-pyridinyl, 1-benzofuran-2-yl;
X 3 , X 4 and X 5 can independently be H, OH, NH, CH 3 , Cl, Br, F, CN, N 3 , CF 3 , OCF 3 , NO 2 , C(O)OH, C(O)OCH 3 , OCH 3 , OBn, O-benzoyl, SCH 3 , t-Bu, N(CH 3 ) 2 , S-phenyl, Ph, S(O) 2 CH 3 , C(O)NH 2 , NHS(O) 2 CH 3 ;
residue entry 3:
wherein deviating from the definition above, any hydrogen atom attached to any of the ring carbon atoms including depicted, implied, or expressly defined hydrogen, or both hydrogen atoms (m=2) attached to the same particular carbon atom, can be replaced by one or two (equal) “floating groups” X 1 respectively, as long as a stable structure is formed;
while m=1 or 2;
n=1-4;
X 1 can be H, CH 3 , Et, Pr, i-Pr, Bu, F, Ph, (CH 2 ) 2 OH*,
* Only for first case;
residue entry 4:
or
wherein
m=1-6;
n=1-6;
and/or
R 5 is H, NH 2 , F, Cl, Br, I, methylamino, NH-benzyl, NH-phenyl, NH-4-azidophenyl, NH-phenylethyl, NH-phenylpropyl, 2-aminoethylamino, n-hexylamino, 6-amino-n-hexylamino, 8-amino-3,6-dioxaoctylamino, dimethylamino, 1-piperidino, 1-piperazino or can form together with R 4 , Y and the carbon bridging Y and R 5 a ring system as depicted in the list hereinabove (entry 2 and 3);
and/or
residues involved in connecting a G unit with another G unit or a dye or another reporting group can be R1, R4 and/or R5 in which case the particular residue is
as defined just above (for the particular residue), wherein an endstanding group is transformed to or replaced by a coupling function
or
as depicted in the following list (if present Q1 connects to the G unit):
and/or
coupling functions (C 1-4 and C 1′-4 ) are selected from the group consisting of
and/or
the linker (L) can be absent or as depicted in the following list of linker (L):
while n for each sidechain within a particular linker can have an equal or individual value as defined. and/or
R 7 is OH, methyloxy, ethyloxy, cyanoethyloxy, acetoxymethyloxy, pivaloyloxymethyloxy, methoxymethyloxy, propionyloxymethyloxy, butyryloxymethyloxy, acetoxyethyloxy, acetoxybutyloxy, acetoxyisobutyloxy, phenyloxy, benzyloxy, 4-acetoxybenzyloxy, 4-pivaloyloxybenzyloxy, 4-isobutyryloxybenzyloxy, 4-octanoyloxybenzyloxy, 4-benzoyloxybenzyloxy, acetyloxy, propionyloxy, benzoyloxy, SH, methylthio, acetoxymethylthio, pivaloyloxymethylthio, methoxymethylthio, propionyloxymethylthio, butyryloxymethylthio, cyanoethylthio, phenylthio, benzylthio, 4-acetoxybenzylthio, 4-pivaloyloxybenzylthio, 4-isobutyryloxybenzylthio, 4-octanoyloxybenzylthio, 4-benzoyloxybenzylthio, borano (BH 3 ), methylborano, dimethylborano, cyanoborano (BH 2 CN);
and
R 8 is OH, methyloxy, ethyloxy, cyanoethyloxy, acetoxymethyloxy, pivaloyloxymethyloxy, methoxy, methyloxy, propionyloxymethyloxy, butyryloxymethyloxy, acetoxyethyloxy, acetoxybutyloxy, acetoxyisobutyloxy, phenyloxy, benzyloxy, 4-acetoxybenzyloxy, 4-pivaloyloxybenzyloxy, 4-isobutyryloxybenzyloxy, 4-octanoyloxybenzyloxy, 4-benzoyloxybenzyloxy, acetyloxy, propionyloxy, benzoyloxy;
9 . A compound according to claim 1 wherein R 1 is H, Cl, Br, SH, 2-furyl, 3-furyl, (2-furyl)thio, (3-(2-methyl)furyl)thio, (3-furyl)thio, 2-thienyl, 3-thienyl, (5-(1-methyl)tetrazolyl)thio, 1,1,2-trifluoro-1-butenthio, (2-(4-phenyl)imidazolyl)thio, (2-benzothiazolyl)thio, (2,6-dichlorophenoxypropyl)thio, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)ethylthio, (4-bromo-2, 3-dioxobutyl)thio, [2-[(fluoresceinylthioureido)amino]ethyl]thio, 2,3,5,6-tetrafluorophenylthio, (7-(4-methyl)coumarinyl)thio, (4-(7-methoxy)coumarinyl)thio, (2-naphtyl)thio, (2-(1-bromo)naphtyl)thio, benzimidazolyl-2-thio, benzothiazolylthio, 4-pyridyl, (4-pyridyl)thio, 2-pyridylthio, triphenyliminophosphoranyl or residue R 1 is as depicted hereinafter as residue entry 1 or 2: residue entry 1:
wherein
m=0-3;
Q=S;
X 1 , X 2 and X 3 can be equal or independently be H, OH, NH 2 , N 3 , SH, CN, NO 2 , F, Cl, Br, I, (CH 2 ) n CH 3 (with n=0-5), i-Pr, t-Bu, Ph, (CH 2 ) n C≡CH (with n=0-5), (CH 2 ) n C═CH 2 (with n=0-5), CH 2 OH, (CH 2 ) n OCH 3 (with n=1-2), CH 2 N(CH 3 ) 2 , O(CH 2 ) n CH 3 (with n=0-5), Oi-Pr, OCy, OCyp, OPh, OBn, OC(O)CH 3 , OC(O)Ph, OCF 3 , N(CH 3 ) 2 , NH(CH 2 ) n CH 3 (with n=0-5), NHC(O)t-Bu, NHC(O)Ph, NHC(O)Ot-Bu, NHC(O)CH 3 , NHC(O)CH 2 N 3 , B(OH) 2 , CF 3 , C(O)OH, C(O)OCH 3 , C(O)Oi-Pr, C(O)Ot-Bu, C(O)OPh, C(O)OBn, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHPh, C(O)NHBn, C(O)CF 3 , CH 2 C(O)OH, CH 2 C(O)OCH 3 , CH 2 C(O)Oi-Pr, CH 2 C(O)Ot-Bu, CH 2 C(O)OBn, S(CH 2 ) n CH 3 (with n=0-5), S(CH 2 ) n OEt (with n=1-4), SBn, SPh,
residue entry 2:
wherein
m=0-6;
n=1-6;
Q=S.
and/or
R 4 is absent or as depicted hereinafter as residue entry 1, 2, 3 or 4:
residue entry 1:
wherein
m=1-3;
X 1 , X 2 and X 3 can be equal or independently be H, N 3 , CN, NO 2 , F, Cl, Br, I, (CH 2 ) n CH 3 (with n=0-5), i-Pr, t-Bu, Ph, (CH 2 ) n C≡CH (with n=0-5), (CH 2 ) n C═CH 2 (with n=0-5), (CH 2 ) n OCH 3 (with n=1-2), CH 2 N(CH 3 ) 2 , O(CH 2 ) n CH 3 (with n=0-5), Oi-Pr, OPh, OBn, OC(O)CH 3 , OC(O)Ph, OCF 3 , N(CH 3 ) 2 , NHC(O)t-Bu, NHC(O)Ph, NHC(O)Ot-Bu, NHC(O)CH 3 , NHC(O)CH 2 N 3 , CF 3 , C(O)OCH 3 , C(O)Oi-Pr, C(O)Ot-Bu, C(O)OPh, C(O)OBn, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHPh, C(O)NHBn, C(O)CF 3 , CH 2 C(O)OCH 3 , CH 2 C(O)Oi-Pr, CH 2 C(O)Ot-Bu, CH 2 C(O)OBn, S(CH 2 ) n CH 3 (with n=0-5), S(CH 2 ) n OEt (with n=1-4), SBn, SPh, SO 2 CF 3 ,
residue entry 2:
wherein
X 1 can be H, CH 3 , Ph;
X 2 can be H, Ph, 2-naphtyl, 9-phenanthryl, 1-pyrenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, dibenzo[b,d]furan-2-yl, 2,3-dihydro-1-benzofuran-5-yl, 1-benzothien-5-yl, 1-benzofuran-5-yl, cyclopropyl, 1-adamantyl, C(Ph) 3 , 2-thienyl, 3-chloro-2-thienyl, 3-thienyl, 1,3-thiazol-2-yl, 2-pyridinyl, 1-benzofuran-2-yl;
X 3 , X 4 and X 5 can independently be H, OH, NH, CH 3 , Cl, Br, F, CN, N 3 , CF 3 , OCF 3 , NO 2 , C(O)OH, C(O)OCH 3 , OCH 3 , OBn, O-benzoyl, SCH 3 , t-Bu, N(CH 3 ) 2 , S-phenyl, Ph, S(O) 2 CH 3 , C(O)NH 2 , NHS(O) 2 CH 3 ;
residue entry 3:
wherein
n=1-4;
residue entry 4:
wherein
m=1-3;
n=1-6.
and/or
R 5 is NH 2 , or can form together with R 4 , Y and the carbon bridging Y and R 5 a ring system as depicted in the list hereinabove (entry 2 and 3);
and/or
residues involved in connecting a G unit with another G unit or a dye or another reporting group can be R 1 , R 4 and R 5 , in which case the particular residue is
as defined just above (for the particular residue), wherein an endstanding group is transformed to or replaced by a coupling function
or
as depicted in the following list (if present Q1 connects to the G unit)
R 1
R 4
R 4 + R 5
and/or
coupling functions (C 1-4 and C 1′-4′ ) are as depicted by structures selected from the group consisting of
and/or
R 7 OH, methyloxy, ethyloxy, cyanoethyloxy, acetoxymethyloxy, pivaloyloxymethyloxy, methoxy, methyloxy, propionyloxymethyloxy, butyryloxymethyloxy, acetoxy ethyloxy, acetoxybutyloxy, acetoxyisobutyloxy, phenyloxy, benzyloxy, 4-acetoxybenzyl oxy, 4-pivaloyloxybenzyloxy, 4-isobutyryloxybenzyloxy, 4-octanoyloxybenzyloxy, 4-benzoyloxybenzyloxy, acetyloxy, propionyloxy, benzoyloxy, SH, methylthio, acetoxymethylthio, pivaloyloxymethylthio, methoxymethylthio, propionyloxymethylthio, butyryloxymethylthio, cyanoethylthio, phenylthio, benzylthio, 4-acetoxybenzylthio, 4-pivaloyloxybenzylthio, 4-isobutyryloxybenzylthio, 4-octanoyloxybenzylthio, 4-benzoyloxybenzylthio;
and
R 5 is OH, methyloxy, ethyloxy, cyanoethyloxy, acetoxymethyloxy, pivaloyloxymethyloxy, methoxy, methyloxy, propionyloxymethyloxy, butyryloxymethyloxy, acetoxy ethyloxy, acetoxybutyloxy, acetoxyisobutyloxy, phenyloxy, benzyloxy, 4-acetoxybenzyloxy, 4-pivaloyloxybenzyloxy, 4-isobutyryloxybenzyloxy, 4-octanoyloxybenzyloxy, 4-benzoyloxybenzyloxy, acetyloxy, propionyloxy, benzoyloxy;
10 . A compound according to claim 1 selected from the group consisting of
(1) Guanosine-3′, 5′-cyclic monophosphate-[8-thio-(pentaethoxy)-ethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(2) Guanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamidomethyl-(pentaethoxy)propylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(3) Guanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamido-(octaethoxy)ethylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(4) Guanosine-3′, 5′-cyclic monophosphate-[8-(4-thiophenylthio)-(pentaethoxy)-ethyl(4-thiophenylthio)-8]-guanosine-3′, 5′-cyclic monophosphate
(5) β-Phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamido(octaethoxy)-ethylamidomethylthio-8]-β-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(6) 8-Bromoguanosine-3′, 5′-cyclic monophosphate-[1, N 2 -etheno-β-phenyl-4-yl-(1-[1, 2, 3]-triazole-4-yl)-methoxy-(hexaethoxy)-methyl-(4-(4-[1, 2, 3]-triazole-1-yl)-β-phenyl-1, N 2 -etheno)]-8-bromoguanosine-3′, 5′-cyclic monophosphate
(7) Guanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamido-(octaethoxy)ethylamidomethylthio-8]-β-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(8) Guanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamido-(nonadecaethoxy)ethylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(9) Guanosine-3′, 5′-cyclic monophosphate-[8-(1-[1, 2, 3]-triazole-4-yl)-methoxy(hexaethoxy)-methyl-(4-[1, 2, 3]-triazole-1-yl)-8]-guanosine-3′, 5′-cyclic monophosphate
(10) Guanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamido-(PEG pd 2000)amidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(11) β-Phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamido(nonadecaethoxy)-ethylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(12) β-Phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamido(nonadecaethoxy)-ethylamidomethylthio-8]-β-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(13) β-Phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamido(PEG pd 2000)-amidomethylthio-8]-0-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(14) Benzene-1, 3, 5-tri-[(8-amidomethyl-(pentaethoxy)propylamidomethylthio)guanosine-3′, 5′-cyclic monophosphate]
(15) Ethylene glycol-bis(2-aminoethylether)-N, N, N′, N′-tetra-[(8-methylamidoethylthio)guanosine-3′, 5′-cyclic monophosphate]
(16) Guanosine-3′, 5′-cyclic monophosphate-[8-thio-(dodecanyl)-thio-8]-guanosine-3′, 5′-cyclic monophosphate
(17) β-Phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate-[8-thio-(dodecanyl)thio-8]-0-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate, triethyl ammonium salt
(18) Guanosine-3′, 5′-cyclic monophosphate-[8-thioethylamidomethyl-(1-[1, 2, 3]-triazole-4-yl)-methoxy-(hexaethoxy)-methyl-(4-[1, 2, 3]-triazole-1-yl)methylamidoethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(19) Guanosine-3′, 5′-cyclic monophosphate-[8-thioethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(20) Guanosine-3′, 5′-cyclic monophosphate-[8-thioethyl-(1-[1, 2, 3]-triazole-4-yl)methoxy-(hexaethoxy)-methyl-(4-[1, 2, 3]-triazole-1-yl)-ethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(21) Guanosine-3′, 5′-cyclic monophosphate-[8-thio-(dodecanyl)-(4-thiophenyl-4″-thiophenylthio)-(dodecanyl)-thio-8]-guanosine-3′, 5′-cyclic monophosphate
(22) Guanosine-3′, 5′-cyclic monophosphate-[8-thioethylamidomethyl-(1-[1, 2, 3]-triazole-4-yl)-methoxy-(hexaethoxy)-methyl-(4-(4-[1, 2, 3]-triazole-1-yl)-β-phenyl-1, N 2 -etheno)]-8-bromoguanosine-3′, 5′-cyclic monophosphate
(23) β-Phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate-[8-thioethyl-(1-[1, 2, 3]-triazole-4-yl)-methoxy-(hexaethoxy)-methyl-(4-[1, 2, 3]-triazole-1-yl)-ethylthio-8]-β-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(24) 8-Bromoguanosine-3′, 5′-cyclic monophosphate-[1-propylamidomethyl(pentaethoxy)-propylamidomethylthio-8]-β-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(25) 8-Bromoguanosine-3′, 5′-cyclic monophosphate-[1-(pentaethoxy)-ethyl-1]-8-bromoguanosine-3′, 5′-cyclic monophosphate
(26) 8-Bromoguanosine-3′, 5′-cyclic monophosphate-[1-propylamidomethyl(pentaethoxy)-propylamidopropyl-1]-8-bromoguanosine-3′, 5′-cyclic monophosphate
(27) 8-Bromoguanosine-3′, 5′-cyclic monophosphate-[1-propylamidomethyl(pentaethoxy)-propylamidomethylthio-8]-guanosine-3′, 5′-cyclic monophosphate
(28) Guanosine-3′, 5′-cyclic monophosphate-[8-(phenyl-4-thio)-(pentaethoxy)-ethyl-(4-thiophenyl)-8]-guanosine-3′, 5′-cyclic monophosphate
(29) β-1, N 2 —Acetyl-guanosine-3′, 5′-cyclic monophosphate-[8-thiomethylamido(octaethoxy)-ethylamidomethylthio-8]-β-1,N 2 -acetyl-guanosine-3′, 5′-cyclic monophosphate
(30) 8-Phenylguanosine-3′, 5′-cyclic monophosphate-[1, N 2 -etheno-0-phenyl-4-yl-(1-[1, 2, 3]-triazole-4-yl)-methoxy-(hexaethoxy)-methyl-(4-(4-[1, 2, 3]-triazole-1-yl)-β-phenyl-1, N 2 -etheno)]-8-phenylguanosine-3′, 5′-cyclic monophosphate
11 . A monomeric compound of formula (III) and/or a monomeric precursor of formula (III) of a compound according to claim 1 , wherein the monomeric compound of formula (III) and/or the monomeric precursor of formula (III) is defined as in any of the preceding claims, and preferably wherein the monomeric compound of formula (III) and/or the monomeric precursor of formula (III) complies with the following proviso:
R 7 is O and R 8 is OH
and further complies with at least one of the following provisos:
R 4 is not H and R 5 is NH 2
wherein R 4 is attached via a —CH 2 — bridge, which is part of R 4
or
R 5 together with R 4 , Y and the carbon bridging Y and R 5 form a ring system, which can be
a) an imidazolinone ring as depicted hereinafter (n=1) or an homologous ring (n=2 to 8)
or
b) an imidazole ring, which can be unsubstituted or substituted as depicted hereinafter as residue entry 1 and 2
residue entry 1
wherein
X 1 is H;
X 2 can be H, 2-naphtyl, 9-phenanthryl, 1-pyrenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, dibenzo[b,d]furan-2-yl, 2,3-dihydro-1-benzofuran-5-yl, 1-benzothien-5-yl, 1-benzofuran-5-yl, cyclopropyl, 1-adamantyl, C(Ph) 3 , 2-thienyl, 3-chloro-2-thienyl, 3-thienyl, 1,3-thiazol-2-yl, 2-pyridinyl, 5-chloro-2-thienyl, 1-benzofuran-2-yl;
X 3 , X 4 and X 5 can independently be OH, NH, CH 3 , Cl, Br, F, CN, N 3 , CF 3 , OCF 3 , NO 2 , C(O)OH, C(O)OCH 3 , OCH 3 , OBn, O-benzoyl, SCH 3 , t-Bu, N(CH 3 ) 2 , S-phenyl, Ph, S(O) 2 CH 3 , C(O)NH 2 , NHS(O) 2 CH 3 , while X 4 and X 5 can also independently be H;
residue entry 2
while R 1 is as in any of the compounds 31 to 107.
or
R 1 is attached via a —S(O)— or —S(O) 2 — bridge or via a carbon atom of an aromatic ring system, which in each case is part of R 1
while R 4 is H and R 5 is NH 2
and in addition complies with the proviso that the monomeric compound of formula (III) and/or the monomeric precursor compound of formula (III) is not selected from the group of compounds consisting of
and/or
the monomeric compound of formula (III) and/or the monomeric precursor of formula (III) is selected from the group consisting of
(31) 8-Amidomethylthioguanosine-3′, 5′-cyclic monophosphate
(32) 8-(4-Boronatephenylthio)-guanosine-3′, 5′-cyclic monophosphate
(33) 8-(4-Cyanobenzylthio)guanosine-3′, 5′-cyclic monophosphate
(34) 8-(4-(2-Cyanophenyl)-benzylthio)guanosine-3′, 5′-cyclic monophosphate
(35) 8-Cyclohexylmethylthioguanosine-3′, 5′-cyclic monophosphate
(36) 8-(2, 4-Dichlorophenylthio)guanosine-3′, 5′-cyclic monophosphate
(37) 8-Diethylphosphonoethylthio-guanosine-3′, 5′-cyclic monophosphate
(38) 8-Ethylthioguanosine-3′, 5′-cyclic monophosphate
(39) 8-Hexylthioguanosine-3′, 5′-cyclic monophosphate
(40) 8-(4-Isopropylphenylthio)guanosine-3′, 5′-cyclic monophosphate
(41) 8-(3-(2-Methyl)furanyl)thioguanosine-3′, 5′-cyclic monophosphate
(42) 8-(5-(1-Methyl)tetrazolyl)thioguanosine-3′, 5′-cyclic monophosphate
(43) 8-(4-Methoxybenzylthio)guanosine-3′, 5′-cyclic monophosphate
(44) 8-(7-(4-Methyl)coumarinyl)thio-guanosine-3′, 5′-cyclic monophosphate
(45) 8-Methylacetylthioguanosine-3′, 5′-cyclic monophosphate
(46) 8-(5-(1-Phenyl)tetrazolyl)thioguanosine-3′, 5′-cyclic monophosphate
(47) 8-(2-Phenylethyl)thioguanosine-3′, 5′-cyclic monophosphate
(48) 8-(2-(4-Phenyl)imidazolyl)thioguanosine-3′, 5′-cyclic monophosphate
(49) 8-(2-Thiophenyl)thioguanosine-3′, 5′-cyclic monophosphate
(50) 8-(1, 1, 2-Trifluoro-1-butenthio)guanosine-3′, 5′-cyclic monophosphate
(51) 8-Amidopropylthioguanosine-3′, 5′-cyclic monophosphate
(52) 8-Amidoethylthioguanosine-3′, 5′-cyclic monophosphate
(53) 8-Amidobutylthioguanosine-3′, 5′-cyclic monophosphate
(54) 8-Acetamidoethylthioguanosine-3′, 5′-cyclic monophosphate
(55) 8-(2-Benzothiazolyl)thioguanosine-3′, 5′-cyclic monophosphate
(56) 8-(2-Boronatebenzylthio)guanosine-3′, 5′-cyclic monophosphate
(57) 8-(4-Boronatebutylthio)guanosine-3′, 5′-cyclic monophosphate
(58) 8-(4-Boronatebenzylthio)guanosine-3′, 5′-cyclic monophosphate
(59) 8-(3-Boronatebenzylthio)guanosine-3′, 5′-cyclic monophosphate
(60) 8-Azidomethylamidoethylthio-guanosine-3′, 5′-cyclic monophosphate
(61) 8-(3-Boronatephenyl)amidobutylthio-guanosine-3′, 5′-cyclic monophosphate
(62) 8-Benzylamidobutylthioguanosine-3′, 5′-cyclic monophosphate
(63) 8-Benzamidoethylthioguanosine-3′, 5′-cyclic monophosphate
(64) 8-(3-Boronatephenyl)amidomethyl-thioguanosine-3′, 5′-cyclic monophosphate
(65) 8-Benzylamidomethylthio-guanosine-3′, 5′-cyclic monophosphate
(66) 8-(3-Boronatephenyl)amidoethylthio-guanosine-3′, 5′-cyclic monophosphate
(67) 8-(3-Boronatephenyl)amidopropylthioguanosine-3′, 5′-cyclic monophosphate
(68) 8-Carboxypropylthioguanosine-3′, 5′-cyclic monophosphate
(69) 8-Carboxybutylthioguanosine-3′, 5′-cyclic monophosphate
(70) 8-(2, 6-Dichlorophenoxypropyl)thio-guanosine-3′, 5′-cyclic monophosphate
(71) 8-(4-Dimethylaminophenyl)amido-methylthioguanosine-3′, 5′-cyclic monophosphate
(72) 8-(4-Dimethylaminophenyl)amido-butylthioguanosine-3′, 5′-cyclic monophosphate
(73) 8-Ethylbutyrylthioguanosine-3′, 5′-cyclic monophosphate
(74) 8-Methylpropionylthioguanosine-3′, 5′-cyclic monophosphate
(75) 8-Methylvalerianylthioguanosine-3′, 5′-cyclic monophosphate
(76) 8-Methoxyethylamidobutylthio-guanosine-3′, 5′-cyclic monophosphate
(77) 8-Methoxyethylamidomethylthio-guanosine-3′, 5′-cyclic monophosphate
(78) 8-Methoxyethylamidoethylthio-guanosine-3′, 5′-cyclic monophosphate
(79) 8-Phenylamidomethylthio-guanosine-3′, 5′-cyclic monophosphate
(80) 8-Phenylpropylthioguanosine-3′, 5′-cyclic monophosphate
(81) 8-(3-Butynylthio)guanosine-3′, 5′-cyclic monophosphate
(82) 8-(4-Acetamidophenylthio)guanosine-3′, 5′-cyclic monophosphate
(83) 8-(4-Chlorophenylsulfonyl)guanosine-3′, 5′-cyclic monophosphate
(84) 8-(4-Chlorophenylsulfoxide)-guanosine-3′, 5′-cyclic monophosphate
(85) 8-((2-Ethoxyethyl)-4-thiophenylthio)guanosine-3′, 5′-cyclic monophosphate
(86) 8-(4-Thiophenyl-4″-thiophenylthio)guanosine-3′, 5′-cyclic monophosphate
(87) 8-(2-Azidoethylthio)guanosine-3′, 5′-cyclic monophosphate
(88) 8-(3-Aminopropyl)-(pentaethoxy)-methylamidomethylthio-guanosine-3′, 5′-cyclic monophosphate
(89) 8-(2-Aminoethyl)-(octaethoxy)-amidomethylthioguanosine-3′, 5′-cyclic monophosphate
(90) 8-(2-Bromoethyl)-(pentaethoxy)-(4-thiophenylthio)guanosine-3′, 5′-cyclic monophosphate
(91) 8-(4-(Propargyloxy-(hexaethoxy)-methyl)-[1, 2, 3]-triazole-1-yl)methylamidoethylthio guanosine-3′, 5′-cyclic monophosphate
(92) 8-(4-Carboxyphenylthio)guanosine-3′, 5′-cyclic monophosphate
(93) 8-(4-Hydroxyphenylsulfonyl)-guanosine-3′, 5′-cyclic monophosphate
(94) 8-(4-Isopropylphenylsulfonyl)-guanosine-3′, 5′-cyclic monophosphate
(95) 8-(4-Methylcarboxyphenylthio)-guanosine-3′, 5′-cyclic monophosphate
(96) 8-Methylsulfonylguanosine-3′, 5′-cyclic monophosphate
(97) 8-(1-Bromo-2-naphthyl)methylthioguanosine-3′, 5′-cyclic monophosphate
(98) 8-(2-(1-Benzyl-[1, 2, 3]-triazole-4-yl)-ethylthio)guanosine-3′, 5′-cyclic monophosphate
(99) 8-(3-Fluoro-5-methoxybenzylthio)guanosine-3′, 5′-cyclic monophosphate
(100) 8-Pentafluorobenzylthioguanosine-3′, 5′-cyclic monophosphate
(101) 8-Triphenyliminophosphoranyl-guanosine-3′, 5′-cyclic monophosphate
(102) 8-(4-Chlorophenyl)guanosine-3′, 5′-cyclic monophosphate
(103) 8-(4-Fluorophenyl)guanosine-3′, 5′-cyclic monophosphate
(104) 8-(2-Furyl)guanosine-3′, 5′-cyclic monophosphate
(105) 8-(4-Hydroxyphenyl)guanosine-3′, 5′-cyclic monophosphate
(106) 8-(4-Isopropylphenyl)guanosine-3′, 5′-cyclic monophosphate
(107) 8-Phenylguanosine-3′, 5′-cyclic monophosphate
(108) β-Phenyl-1, N 2 -etheno-8-thioguanosine-3′, 5′-cyclic monophosphate
(109) 8-(2-Aminophenylthio)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(110) 8-Cyclohexylthioß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(111) 8-Cyclopentylthio-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(112) 8-(4-Methylphenylthio)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(113) 8-(4-Methoxyphenylthio)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(114) 8-(3-(2-Methyl)furanyl)thio-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(115) 8-(7-(4-Methyl)coumarinyl)thio-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(116) 8-(2-Naphthyl)thio-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(117) ß-Phenyl-1, N 2 -etheno-8-(2-thiophenyl)thioguanosine-3′, 5′-cyclic monophosphate
(118) ß-Phenyl-1, N 2 -etheno-8-(2-phenylethyl)thioguanosine-3′, 5′-cyclic monophosphate
(119) 8-Amidomethylthio-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(120) 8-Carboxymethylthio-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(121) 8-(4-Boronatephenylthio)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(122) 8-Ethylthio-ß-phenyl-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphate
(123) 8-(4-Fluorophenylthio)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(124) 8-Methylthio-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(125) ß-Phenyl-1, N 2 -etheno-8-propylthio-guanosine-3′, 5′-cyclic monophosphate
(126) 8-Azidoethylthio-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(127) ß-Phenyl-1, N 2 -etheno-8-(4-trifluoromethylphenylthio)guanosine-3′, 5′-cyclic monophosphate
(128) 8-(4-Chlorophenylsulfonyl)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(129) 8-(4-Isopropylphenylthio)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(130) 8-(4-Isopropylphenylsulfonyl)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(131) 8-(4-Chlorophenyl)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(132) 8-(4-Hydroxyphenyl)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(133) 8-(4-Isopropylphenyl)-ß-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
(134) 8-Bromo-(4-methoxy-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(135) 8-Bromo-(4-methyl-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(136) alpha-Benzoyl-beta-phenyl-1, N2-etheno-8-bromoguanosine-3′, 5′-cyclic monophosphate
(137) 8-Bromo-(4-chloro-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate (138) 8-Bromo-(3-nitro-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(139) 8-Bromo-(ß-tert.-butyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate (140) 8-Bromo-(2-methoxy-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(141) 8-Bromo-(3-methoxy-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(142) 8-Bromo-(2, 4-dimethoxy-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(143) 8-Bromo-(4-pyridinyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(144) 8-Bromo-(3-thiophen-yl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(145) 8-Bromo-(4-fluoro-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(146) 8-Bromo-1, N2-ethenoguanosine-3′, 5′-cyclic monophosphate
(147) 8-Bromo-(3-hydroxy-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(148) 8-Bromo-(4-hydroxy-ß-phenyl-1, N 2 -etheno)guanosine-3′, 5′-cyclic monophosphate
(149) 8-Bromo-(ß-(2, 3-dihydro-1, 4-benzodioxin)-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(150) 8-Bromo-(4-methylsulfonamido-ß-phenyl-1, N2-etheno)guanosine-3′, 5′-cyclic monophosphate
(151) 8-Bromo-(4-cyano-β-phenyl-1, N 2 -etheno)guanosine-3′, 5′-cyclic monophosphate
(152) 8-Bromo-(α-phenyl-β-methyl-1, N 2 -etheno)guanosine-3′, 5′-cyclic monophosphate
(153) β-(4-Aminophenyl)-1, N 2 -etheno-8-bromoguanosine-3′, 5′-cyclic monophosphate
(154) 8-Bromo-(6-methoxy-2-naphthyl-1, N 2 -etheno)guanosine-3′, 5′-cyclic monophosphate
(155) 8-Bromo-(9-phenanthrenyl-1, N 2 -etheno)guanosine-3′, 5′-cyclic monophosphate
(156) 8-Bromo-(4-trifluoromethyl-β-phenyl-1, N 2 -etheno)guanosine-3′, 5′-cyclic monophosphate
(157) (4-Fluoro-ß-phenyl-1, N2-etheno)-8-methylthioguanosine-3′, 5′-cyclic monophosphate
(158) (4-Methoxy-ß-phenyl-1, N2-etheno)-8-methylthioguanosine-3′, 5′-cyclic monophosphate
(159) 1, N 2 -Etheno-8-(2-phenylethyl)thioguanosine-3′, 5′-cyclic monophosphate
(160) (4-Methoxy-ß-phenyl-1, N2-etheno)-8-propylthioguanosine-3′, 5′-cyclic monophosphate
(161) β-1, N 2 -Acetyl-8-bromoguanosine-3′, 5′-cyclic monophosphate
(162) 8-Bromo-δ-1, N 2 -butyrylguanosine-3′, 5′-cyclic monophosphate
(163) 8-Bromo-1-(3-carboxypropyl)guanosine-3′, 5′-cyclic monophosphate
(164) 1-[Aminomethyl-(pentaethoxy)-propylamidopropyl]-8-bromoguanosine-3′, 5′-cyclic monophosphate
(165) 1-Benzyl-8-bromoguanosine-3′, 5′-cyclic monophosphate
(166) 2′-O-(2-Azidoacetyl)-8-bromo-β-phenyl-1, N 2 -ethenoguanosine-3′, 5′-cyclic monophosphate
12 . A compound according to claim 1 or a monomeric compound of formula (III) according to claim 11 for use in the treatment of a disease or disorder, preferably a disease or disorder selected from the group consisting of cancer, cardiovascular disease or disorder, or autoimmune disease or disorder, or neurodegenerative disease or disorder.
13 . A compound according to claim 1 or a monomeric compound of formula (III) for use in the treatment of at least one of:
a) neurodegenerative diseases associated with insufficient synaptic function and learning and memory defects.
b) neuromuscular junction defects including motor neuron diseases (including Amyotrophic lateral sclerosis (ALS), Primary lateral sclerosis), also forms caused by certain infectious diseases (including paralytic Poliomyelitis)
c) cancer, including the initiation of cancer cell apoptosis and the prevention of metastasis
d) cardiovascular diseases, including hypertension, cardiac hypertrophy, angina pectoris, ischemia and stroke
e) parasitic diseases caused by trypanosomes, including Malaria, Chagas, sleeping sickness
f) borelliosis (lyme disease)
g) pulmonary diseases and conditions, such as pulmonary fibrosis and pulmonary hypertension
h) osteoporosis
i) Autoimmune diseases associated with an excessive proliferation of B- and T-cells, including multiple sclerosis, Crohn's disease, Hashimoto's disease, juvenile arthritis, myocarditis, and rheuma.
14 . Method of compound according to claim 1 or of a monomeric compound of formula (III) as research tool compound, preferably as research tool compound in regard of a disease or disorder, preferably a disease or disorder selected from the group consisting of cancer, cardiovascular disease or disorder, or autoimmune disease or disorder, or neurodegenerative disease or disorder.Join the waitlist — get patent alerts
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