MXPA01000991A - Substituted pyrazole derivatives condensed with six-membered heterocyclic rings - Google Patents
Substituted pyrazole derivatives condensed with six-membered heterocyclic ringsInfo
- Publication number
- MXPA01000991A MXPA01000991A MXPA/A/2001/000991A MXPA01000991A MXPA01000991A MX PA01000991 A MXPA01000991 A MX PA01000991A MX PA01000991 A MXPA01000991 A MX PA01000991A MX PA01000991 A MXPA01000991 A MX PA01000991A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- substituted
- linear
- branched
- acyl
- Prior art date
Links
- 150000003217 pyrazoles Chemical class 0.000 title claims abstract description 10
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 28
- 239000003814 drug Substances 0.000 claims abstract description 17
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 236
- -1 azido, formyl Chemical group 0.000 claims description 121
- 150000001875 compounds Chemical class 0.000 claims description 115
- 125000000217 alkyl group Chemical group 0.000 claims description 110
- 150000002367 halogens Chemical class 0.000 claims description 78
- 125000002252 acyl group Chemical group 0.000 claims description 68
- 125000003545 alkoxy group Chemical group 0.000 claims description 61
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 49
- 239000001257 hydrogen Substances 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 125000005842 heteroatoms Chemical group 0.000 claims description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 230000000875 corresponding Effects 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- 150000002829 nitrogen Chemical group 0.000 claims description 13
- 125000004442 acylamino group Chemical group 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 230000001603 reducing Effects 0.000 claims description 12
- 238000006722 reduction reaction Methods 0.000 claims description 12
- 150000001409 amidines Chemical class 0.000 claims description 10
- 239000000460 chlorine Chemical group 0.000 claims description 10
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000012442 inert solvent Substances 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 9
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
- VVNCNSJFMMFHPL-VKHMYHEASA-N Penicillamine Chemical group CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 125000004429 atoms Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 7
- 150000002081 enamines Chemical class 0.000 claims description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 6
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 6
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 6
- 125000003003 spiro group Chemical group 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N Trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 5
- 230000002425 cardiocirculatory Effects 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- KEFBAMRFXYKOBI-UHFFFAOYSA-N 1,4$l^{2}-thiazinane 1,1-dioxide Chemical group O=S1(=O)CC[N]CC1 KEFBAMRFXYKOBI-UHFFFAOYSA-N 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 229940082615 Organic nitrates used in cardiac disease Drugs 0.000 claims description 4
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 4
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 4
- 150000002084 enol ethers Chemical class 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 230000015556 catabolic process Effects 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 230000004059 degradation Effects 0.000 claims description 3
- 238000006731 degradation reaction Methods 0.000 claims description 3
- 229940079593 drugs Drugs 0.000 claims description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 238000007034 nitrosation reaction Methods 0.000 claims description 3
- 230000001681 protective Effects 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- KPKNTUUIEVXMOH-UHFFFAOYSA-N 1,4-dioxa-8-azaspiro[4.5]decane Chemical compound O1CCOC11CCNCC1 KPKNTUUIEVXMOH-UHFFFAOYSA-N 0.000 claims description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N Glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 2
- 229940015043 Glyoxal Drugs 0.000 claims description 2
- 206010061255 Ischaemia Diseases 0.000 claims description 2
- 101710003358 SNRPD1 Proteins 0.000 claims description 2
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 230000003110 anti-inflammatory Effects 0.000 claims description 2
- 125000005333 aroyloxy group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 150000003948 formamides Chemical class 0.000 claims description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-O guanidinium Chemical class NC(N)=[NH2+] ZRALSGWEFCBTJO-UHFFFAOYSA-O 0.000 claims description 2
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 2
- 201000001880 sexual dysfunction Diseases 0.000 claims description 2
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N Cyclic Guanosine Monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 claims 4
- ZQGLEEFGEZLSAJ-UHFFFAOYSA-N 1,5-dioxa-9-azaspiro[5.5]undecane Chemical compound O1CCCOC11CCNCC1 ZQGLEEFGEZLSAJ-UHFFFAOYSA-N 0.000 claims 1
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 230000000240 adjuvant Effects 0.000 claims 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 1
- 230000000384 rearing Effects 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 208000008787 Cardiovascular Disease Diseases 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 28
- 239000000203 mixture Substances 0.000 description 26
- 239000002904 solvent Substances 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 239000000126 substance Substances 0.000 description 22
- 229910052681 coesite Inorganic materials 0.000 description 18
- 229910052906 cristobalite Inorganic materials 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 229910052904 quartz Inorganic materials 0.000 description 18
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 18
- 229910052682 stishovite Inorganic materials 0.000 description 18
- 229910052905 tridymite Inorganic materials 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- YSHOWEKUVWPFNR-UHFFFAOYSA-N Burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cells Anatomy 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 230000000638 stimulation Effects 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 230000002829 reduced Effects 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 210000001772 Blood Platelets Anatomy 0.000 description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N DABCO Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 8
- 229940083618 Sodium Nitroprusside Drugs 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 8
- GIRZNGMZUXTPTL-UHFFFAOYSA-N disodium;iron(3+);nitroxyl;pentacyanide;dihydrate Chemical compound O.O.[Na+].[Na+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=N GIRZNGMZUXTPTL-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 150000002170 ethers Chemical class 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N Trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 7
- 239000001184 potassium carbonate Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 6
- 238000004220 aggregation Methods 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229960000583 Acetic Acid Drugs 0.000 description 5
- YYLLIJHXUHJATK-UHFFFAOYSA-N Cyclohexyl acetate Chemical compound CC(=O)OC1CCCCC1 YYLLIJHXUHJATK-UHFFFAOYSA-N 0.000 description 5
- 102000014469 EC 4.6.1.2 Human genes 0.000 description 5
- 108010078321 EC 4.6.1.2 Proteins 0.000 description 5
- 210000002889 Endothelial Cells Anatomy 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 5
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 235000012239 silicon dioxide Nutrition 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- JYVLIDXNZAXMDK-UHFFFAOYSA-N 2-Pentanol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 4
- OQEBBZSWEGYTPG-UHFFFAOYSA-N 3-aminobutanoic acid Chemical compound CC(N)CC(O)=O OQEBBZSWEGYTPG-UHFFFAOYSA-N 0.000 description 4
- 210000004369 Blood Anatomy 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000001187 sodium carbonate Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
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- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N phosphorus trioxide Inorganic materials O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- JVUYWILPYBCNNG-UHFFFAOYSA-N potassium;oxido(oxo)borane Chemical compound [K+].[O-]B=O JVUYWILPYBCNNG-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylaxis Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 229950003776 protoporphyrin Drugs 0.000 description 1
- 150000005229 pyrazolopyridines Chemical class 0.000 description 1
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 200000000008 restenosis Diseases 0.000 description 1
- 230000000284 resting Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000001568 sexual Effects 0.000 description 1
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- UYCAUPASBSROMS-UHFFFAOYSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)F UYCAUPASBSROMS-UHFFFAOYSA-M 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 230000002537 thrombolytic Effects 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000002110 toxicologic Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- KFUSEUYYWQURPO-OWOJBTEDSA-N trans-1,2-dichloroethene Chemical group Cl\C=C\Cl KFUSEUYYWQURPO-OWOJBTEDSA-N 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- PZRXQXJGIQEYOG-UHFFFAOYSA-N zinc;oxido(oxo)borane Chemical compound [Zn+2].[O-]B=O.[O-]B=O PZRXQXJGIQEYOG-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention concerns novel substituted pyrazole derivatives of general formula (I), wherein R1, R2, R3 and A have the indicated meaning. The invention also relates to a method for the production of said derivatives and to their use as medicaments, especially as medicaments for the treatment of cardiovascular diseases.
Description
DERIVATIVES OF PIRAZOL SUBSTITUTED CONDENSED WITH HETEROCICLIC RINGS OF SIX MEMBERS DESCRIPTION OF THE INVENTION The present invention relates to new substituted pyrazole derivatives, to processes for their preparation and to their use as medicaments, especially as medicaments for the treatment of cardiocirculatory disorders according to the claims 1 to 10.
It is already known that pyrazole derivatives condensed with l-benzyl-3- (substituted heteroaryl) inhibit thrombocyte aggregation (see EP 667345 Al).
WO 98/16223 discloses the use of pyrazole derivatives condensed with 1-benzyl-3- (substituted heteroaryl) for the treatment of special disorders of the cardiovascular system and the central nervous system.
WO 98/16507 discloses pyrazole derivatives substituted with heterocyclylmethyl and their use in the treatment of disorders of the cardiocirculatory system.
WO 98/23619 discloses substituted pyrazole derivatives for the treatment of cardiocirculatory disorders.
Ref: 126267
The present invention relates to substituted pyrazole derivatives of general formula (I)
in which
R1 represents a saturated or aromatic 5- or 6-membered heterocycle with up to 3 heteroatoms from the group of S, N and / or O, which may be linked by a nitrogen atom,
and that in its case it is substituted up to 2 times with the same or different rest of the group (i), composed of
hydrogen, amino, azido, formyl, mercaptyl, carboxyl, hydroxy, acyl, alkoxy, alkylthio or straight or branched alkoxycarbonyl of up to 6 carbon atoms each, nitro, cyano, halogen, phenyl or straight or branched alkyl of up to 6 carbon atoms carbon, which may be substituted on its part with hydroxy, amino, azido, carboxyl, acyl, alkoxy, alkoxycarbonyl or straight or branched acylamino of up to 5 carbon atoms each or with a radical of formula -OR4,
in which
R4 means a linear or branched acyl of up to 5 carbon atoms,
and / or is substituted with a remainder of formulas
or -S (0) c-NR6R7
in which
a, b and b 'are the same or different, and mean a number 0, 1, 2 or 3,
R5 means hydrogen or linear or branched alkyl of up to 4
carbon atoms,
means a number 1 or 2 and
R6 and R7 are the same or different and
means hydrogen or linear or branched alkyl of up to 10
carbon atoms, which in its case is substituted by cycloalkyl of 3 to 8 carbon atoms or with aryl of 6 to 10 carbon atoms, which in turn can be substituted by halogen, or, mean aryl of 6 to 10 carbon atoms carbon, which in your case is
substituted with halogen, or means cycloalkyl of 3 to 7 carbon atoms,
R6 and R7 together with the nitrogen atom form a saturated 5- to 7-membered heterocycle, which may contain, in its case, another oxygen atom or a
rest -NR8,
in which
R8 means hydrogen,
linear or branched alkyl of up to 4
carbon atoms or a formula residue
or benzyl or phenyl, where the ring systems are substituted with halogen,
and it is substituted with at least one group (ii), consisting of:
a ring of 3 to 8 members which may be saturated, unsaturated or partially unsaturated, containing 1 to 4 heteroatoms of the group N, O, S, SO, S02 and which may also be linked by N, imidazolyl, imidazolinyl being especially preferred , imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl, t-omorpholinyl, s-oxothiomorpholinyl and S, S-dioxothiomorpholino, and which is substituted once or several times with
a ring of 5 or 6 members, which contains two oxygen atoms as ring members and which forms a
bicyclic structure or a spiro structure with the 3 to 8 member ring; and / or with linear or branched hydroxy, cyano, alkyl, acyl or alkoxycarbonyl of up to 6 carbon atoms each, the alkyl, acyl and alkoxycarbonyl being substituted with hydroxy, amino, halogen, carboxyl, acyl, alkoxy, alkoxycarbonyl or acylamino linear or branched with up to 5 carbon atoms each,
And an aryl ring of 6 to 10 carbon atoms which is substituted with linear or branched alkyl of up to 4 carbon atoms,
alkenyl (C2-C10), alkynyl (C2-C10), alkyl (-Ca,), which are optionally substituted by aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamino, hydroxy, amino, azido, carboxyl, Acyl, alkoxy, alkoxycarbonyl or straight or branched acylamino of up to 5 carbon atoms each or with a radical of formula -OR4
in which
R4 means linear or branched acyl of up to
carbon atoms
And alkyl (C? -C6) which is substituted 1 to 3 times with aryl, heteroaryl, halogen (s), cyano, dialkylamino, alkylamino or cycloalkyl,
and acyl, which is substituted with halogen (s), especially preferred fluorine, or acyloxy, arylthio or heteroarylthio,
-NO or remains of formulas -S03H or -S (0) dR9,
in which
means a number 1 or 2,
R9 means linear or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms or a saturated or unsaturated heterocycle of 5 or 6 members with up to 3 heteroatoms of the group S , N and / or O, being able to be ring systems
substituted, where appropriate, with halogen or with linear or branched alkyl or alkoxy of up to 4 carbon atoms each,
a remainder of formula PO (OR10) (OR "),
in 1st that
R 10 and R "are the same or different and denote hydrogen, linear or branched alkyl of up to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms or benzyl,
And oxicycloalkyl of 3 to 8 ring members or radicals of formulas -C0N = C (NH2) 2, -C = NH (NH2), -NH-C (= NH) NH2 or (CO) .NR12R'3
in which
means a number 0 or 1,
R'2 and R13 are the same or different and denote hydrogen, linear or branched alkyl of
up to 14 carbon atoms or cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 10 carbon atoms or a saturated or unsaturated ring of 3 to 10 members with up to 5 heteroatoms of the group of N, O, S, which may be cited radicals optionally substituted with aryl of 6 to 10 carbon atoms, heterocyclyl, cycloalkyl of 3 to 7 carbon atoms, hydroxy, amino or alkoxy, acyl or
straight or branched alkoxycarbonyl of up to 6 carbon atoms each,
and in the case that e means 1,
R12 and R13 may also form, including the nitrogen atom to which they are attached, a 5- or 6-membered ring with up to 3 heteroatoms from the group of N, O, S, which may be substituted up to 3 times with
hydroxy, alkoxy or alkyl of up to 8 carbon atoms each,
and in the case that e means 0,
R12 and R13 can also mean linear, branched or cyclic acyl of up to 14 carbon atoms.
linear or branched carbon, hydroxyalkyl, alkoxycarbonyl or acyloxyalkyl of up to 6 carbon atoms each or a radical of formula -S02R14
in which
R14 means straight or branched alkyl of up to 4 carbon atoms, 10 and / or R12 and R13 also mean residues of formulas
R "? U" O '
í? * - O-CH (r '0-CO-
Fig. Wherein R, 5-R16 and R'8-R31 are the same or different and denote hydrogen or linear or branched alkyl of up to 4 carbon atoms,
g means a number 0, 1 or 2,
Y
R17 means phenyl, linear or branched alkyl of up to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms,
with the proviso that, if e means 0, R12 and R13 do not represent hydrogen
at the same time,
R 'represents a purine residue, which may be substituted up to three times with halogen, azido, cyano, hydroxy, amino, monoalkylamino of up to 5 carbon atoms, dialkylamino of up to 5 carbon atoms each, alkyl of up to 5 carbon atoms and / or alkoxy of up to 5 carbon atoms,
R2 and R3 form, with the inclusion of the double bond, a 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the group of N, S and / or O,
which in its case is substituted up to 3 times with the same or different substituent formyl, carboxyl, hydroxyl, mercaptile, acyl, alkylthio or straight or branched alkoxycarbonyl of up to 6 carbon atoms each, nitro, cyano, halogen or alkyl or linear alkoxy or branched of up to 6 carbon atoms each which in turn can be substituted with linear or branched hydroxy, amino, carboxyl, acyl, alkoxy or alkoxycarbonyl of up to 5 carbon atoms each,
and / or is substituted where appropriate with a group of formula -NRMR33,
in which
R32 and R33 are the same or different and mean hydrogen or straight or branched alkyl of up to 6 carbon atoms,
R3: means hydrogen and
R33 stands for acyl
and / or is substituted, if appropriate, with phenyl, which in turn can be substituted up to 2 times with the same or different halogen or with linear or branched alkyl or alkoxy of up to 6 carbon atoms each
and / or is substituted where appropriate with a group of formula -N = CH-NR34R35,
in which
R34 and R35 are the same or different and mean
hydrogen, phenyl or straight or branched alkyl of up to 6 carbon atoms,
represents a 5- or 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms of the group consisting of S, N and / or O or represents phenyl, which are optionally substituted up to 3 times with the same or different amino substituent, mercaptyl, hydroxy, formyl, carboxyl, acyl, alkylthio, alkylocyacyl, alkoxy or alkoxycarbonyl of up to 6 carbon atoms each, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight or branched alkyl of up to 6 carbon atoms, which in turn can be substituted with linear or branched hydroxy, carboxyl, acyl, alkoxy or alkoxycarbonyl of up to 5 carbon atoms each, and / or substituted with a group of formula - (CO) h-NRMR37
in which
means a number 0 or 1,
R36 and R37 are the same or different and mean hydrogen, phenyl, benzyl or straight or branched alkyl or acyl of up to 5 carbon atoms each,
and its isomeric forms and salts.
Preferred according to the invention are compounds of general formula (I) in which
R1 represents a 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the group of S, N and / or O, which may be linked by a nitrogen atom,
and it is substituted in its case up to 2 times with the same or different rest of the group (i), composed by
hydrogen, amino, azido, formyl, mercaptyl, carboxyl, hydroxy, acyl, alkoxy, alkylthio or straight or branched alkoxycarbonyl of up to 6 carbon atoms each, nitro, cyano, halogen, phenyl or straight or branched alkyl of up to 6 carbon atoms carbon, which in turn can be substituted with hydroxy, amino, azido, carboxyl, acyl, alkoxy, alkoxycarbonyl or straight or branched acylamino of up to 5 carbon atoms each or with a radical of formula -OR4,
in which
R4 means linear or branched acyl of
up to 5 carbon atoms,
and / or is substituted with a remainder of formulas
in which
a, b and b 'are the same or different and mean a number 0, 1, 2 or 3,
R5 means hydrogen or straight or branched alkyl of up to 4 carbon atoms,
and is substituted with at least one residue of group (ii), composed of
a ring of 3 to 8 members which may be saturated, unsaturated or partially unsaturated, containing from 1 to 4 heteroatoms of the group of N, 0, S, SO, S02 and which may also be linked by N, with imidazolyl being especially preferred, imidazolinyl, imidazolidinyl, morpholino, piperidino, piperazino, pyrrolidino, triazolyl, pyrrole, thiomorpholino, S-oxothiomorpholino and S, S-dioxothiomorpholino, and that is
substituted in its case one or more times with a ring of 5 or 6 members containing two oxygen atoms as ring members, and forming with the ring of 3 to 8 members a bicyclic structure or a spiro, and / or hydroxy structure , cyano, alkyl, acyl or straight or branched alkoxycarbonyl with up to 6 carbon atoms each, the alkyl, acyl and alkoxycarbonyl being substituted with hydroxy, amino, halogen, carboxyl, acyl, alkoxy, alkoxycarbonyl or linear or branched acylamino up to 5 carbon atoms each,
and an aryl ring of 6 to 10 carbon atoms which is substituted with linear or branched alkyl of up to 4 carbon atoms,
alkenyl (C2-C10), alkynyl (C2-C10), alkyl
, which are optionally substituted by aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamino, hydroxy, amino, azido, carboxyl, acyl, alkoxy, alkoxycarbonyl or linear or branched acylamino of up to 5 carbon atoms each or a remainder of formula -OR4
in which
R4 means linear or branched acyl of up to 5 carbon atoms
and (C, -C6) alkyl which is substituted 1 to 3 times with aryl, heteroaryl, halogen (s), cyano, dialkylamino, alkylamino or cycloalkyl,
and acyl, which is substituted by halogen (s), especially preferred F, or acyloxy, arylthio or heteroaryl io,
-NO or remains of formulas -S03H or -S (0) dR9,
in which
means a number 1 or 2,
R9 means linear or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms or a saturated heterocycle or
or 6-membered unsaturated with up to 3 heteroatoms of the group of S, N and / or 0, the ring systems being optionally substituted with halogen or with linear or branched alkyl or alkoxy of up to 4 carbon atoms each,
And a rest of the formula PO (OR10) (OR11),
in which
R 10 and R "are the same or different and denote hydrogen, linear or branched alkyl of up to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms or benzyl,
oxicycloalkyl of 3 to 8 ring members or radicals of formulas -C0N = C (NH2) 2, -C = NH (NH2), -NH-C (= NH) NH2O (CO) «NR12R13
in which
means a number 0 or 1,
R12 and R13 are the same or different and denote hydrogen, linear or branched alkyl of up to 14 carbon atoms or cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 10 carbon atoms or a saturated or unsaturated ring of 3 to 10 members with up to 5 heteroatoms of the group of N, O, S, the said moieties possibly being substituted with aryl of 6 to 10 carbon atoms,
Heterocyclyl, cycloalkyl of 3 to 7 carbon atoms, hydroxy, amino or alkoxy, acyl or straight or branched alkoxycarbonyl of up to 6 carbon atoms each,
and in the case that e means 1,
R12 and R13 can also form, including the nitrogen atom to which they are attached, a 5- or 6-membered ring with up to 3
heteroatoms of the group of N, O, S, which may be substituted in its case up to 3 times with hydroxy, alkoxy or alkyl of up to 8 carbon atoms each,
and in the case where e means 0,
R12 and R13 can also be linear, branched or cyclic acyl of up to 14 carbon atoms, hydroxyalkyl, alkoxycarbonyl or linear or branched acyloxyalkyl of up to 6 carbon atoms each or a radical of formula -S02R14
in which
R14 means linear or branched alkyl of up to 4 carbon atoms,
and / or R12 and R13 also mean remains of formulas
K '-O CK0V) .O-CO-
in which
R15-R16 and R'8-R3 'are the same or different and denote hydrogen or linear or branched alkyl of up to 4 carbon atoms,
g means a number 0, 1 or 2,
R17 means phenyl, linear or branched alkyl of up to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms,
with the proviso that, if e means 0, R12 and R13 do not represent hydrogen
at the same time,
R 'represents a purine residue, which may be substituted up to three times with halogen, azido, cyano, hydroxy, amino, monoalkylamino of up to 5 carbon atoms, dialkylamino of up to 5 carbon atoms each, alkyl of up to 5 carbon atoms and / or alkoxy of up to 5 carbon atoms,
R2 and R3 form, with the inclusion of the double bond, an associated pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, which in its case is substituted up to 2 times by the same or different formyl substituentcarboxyl, hydroxyl, mercaptyl, acyl, alkylthio or straight or branched alkoxycarbonyl of up to 5 carbon atoms each, nitro, cyano, azido, fluoro, chloro, bromo or alkyl or straight or branched alkoxy of up to 5 carbon atoms each which in turn can be substituted with linear or branched hydroxy, amino, carboxyl, acyl, alkoxy or alkoxycarbonyl of up to 4 carbon atoms, and / or the aforementioned heterocyclic ring is substituted with a group of the formula -NR32RM, if appropriate.
in which
R32 and R33 are the same or different and mean hydrogen or linear or branched alkyl of up to 4 carbon atoms,
R3- means hydrogen and
means formyl
and / or the above-mentioned associated pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring is substituted with phenyl, which in turn can be substituted with fluorine, chlorine, bromine or with linear or branched alkyl or alkoxy of up to 4 carbon atoms each .
represents thienyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl, which is optionally substituted up to 2 times with the same or different substituent hydroxy, formyl, carboxyl, acyl, alkylthio, alkyloxycyl, alkoxy or linear alkoxycarbonyl or branched up to 4 atoms
carbon, fluorine, chlorine or bromine,
and its isomeric forms and salts.
According to the invention, especially preferred are compounds of general formula (I) according to claim 1, wherein
R1 represents a pyrimidine moiety,
which is substituted in your case up to 2 times with the same or different group (i), consisting of
hydrogen, amino, hydroxy, alkoxy or alkoxycarbonyl of up to 3 carbon atoms each, cyano or halogen
and is substituted with at least one residue of group (ii), composed of
a ring of 5 to 6 members which may be saturated, unsaturated or partially saturated, containing from 1 to 3 heteroatoms of the group of N, O, S, SO, S02 and which may also be linked by N, with imidazolyl being especially preferred, imidazolinyl, imidazolidinyl, morpholino,
piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl and thiomorpholinyl,
and that it is substituted one or more times with a 5-membered ring containing two oxygen atoms as ring members and forming a bicyclic structure or a spiro structure with the 3- to 8-membered ring, such as, for example, a residue 1, 4-dioxa-8-azaspiro [4, 5] decane and 1,5-10-dioxa-9-azaspiro [5.5] undecane, and / or linear or branched hydroxy, cyano, alkyl, acyl or alkoxycarbonyl of up to 3 carbon atoms each, the alkyl, acyl and alkoxycarbonyl may be substituted with hydroxy, amino, halogen,
carboxyl, acyl or straight or branched alkoxy of up to 3 carbon atoms each,
a tolyl residue, 20 and C7 alkyl, which is substituted with cyano,
Alkyl (C, -C3) which is substituted 1 to 3 times
with halogen (s), cyano, aryl and acyloxy,
and -NO or residues of the formula -S (0) dR9,
in which
means a number 1 or 2,
R9 means linear or branched alkyl of 1 to 4 carbon atoms, aryl of 6 carbon atoms or thienyl,
and 15 a residue of formula PO (OR '°) (OR11),
in which
R10 and R "are the same or different and mean
straight or branched alkyl of up to 3 carbon atoms,
remains of formulas -NH-C (= NH) NH2 or (C0) .NRl2Rl!
in which
means a number 0 or 1,
R12 and R13 are the same or different and denote hydrogen, linear or branched alkyl of up to 4 carbon atoms or cycloalkyl of 3 carbon atoms, where said radicals may be substituted with aryl having 6 carbon atoms, furyl, cycloalkyl
of 3 carbon atoms, hydroxy, linear alkoxy of up to 2 carbon atoms,
and in the case that e means 1,
R12 and R13 may also form, including the nitrogen atom to which they are attached, a 5- or 6-membered ring with up to 2 heteroatoms from the group of N, O, S, which may be substituted up to 2 times with
hydroxy or methyl,
and in the case that e means 0,
R12 and R13 also mean linear acyl
t to 14 carbon atoms
and / or R12 and R13 also mean a residue of the formula
with the proviso that, if e means 0, R12 and R13, they do not represent hydrogen at the same time,
R1 represents a purine residue, which may be substituted up to twice with halogen, azido, amino, monoalkylamino of up to 4 carbon atoms and / or methyl,
R2 and R3 form, including the double bond, a pyridyl or pyrimidinyl ring,
A represents phenyl or pyrimidyl which is substituted, if appropriate, with fluorine, chlorine or bromine,
and its isomeric forms and salts.
According to the invention, compounds of general formula (I) in which
R1 represents a residue of formula
in which
represents NH2
R "represents morpholino, piperidino, piperazino, pyrrolidino, triazolyl or thiomorpholino, if substituted
R '' 'represents hydrogen or NH2
The most especially preferred compounds herein are those in which R "represents morpholinyl.
The compounds according to the invention of general formula (I) can also be present in their salt form. In general, salts with organic or inorganic acids or bases are indicated herein.
In the context of the present invention, physiologically acceptable salts are preferred. The physiologically acceptable salts of the compounds according to the invention can be salts of substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Especially preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid , citric acid, fumaric acid, maleic acid or benzoic acid.
The physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Especially preferred are, for example, sodium, potassium, magnesium or calcium salts, as well as ammonium salts which
derived from ammonia, or organic amines such as for example ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
The compounds according to the invention can exist in stereoisomeric forms which behave as an object and mirror image (enantiomers) or which do not behave as an object and mirror image (diastereoisomers). The invention relates both to the enantiomers or diastereoisomers and to mixtures thereof. The racemic forms can be separated in the same way as the diastereoisomers in a known manner in the individual components.
In the context of the present invention, substituents generally have the following meaning, unless otherwise indicated:
Alkyl generally represents a linear or branched hydrocarbon radical of 1 to 20 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl, dodecyl, eicosyl.
Alkenyl generally represents a linear or branched hydrocarbon radical of 2 to 20 carbon atoms and with one or more,
preferably with one or two, double bonds. Examples are allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl, isooctenyl.
Alcruinyl generally represents a linear or branched hydrocarbon radical of 2 to 20 carbon atoms and with one or more, preferably with one or two, triple bonds. Examples are ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.
Acyl generally represents a linear or branched lower alkyl of 1 to 9 carbon atoms which is linked by a carbonyl group. Examples which may be mentioned are acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
Alkoxy generally represents a linear or branched hydrocarbon radical of 1 to 14 carbon atoms attached via an oxygen atom. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy are mentioned. The concepts "alkoxy" and "alkyloxy" are used as synonyms.
Alkoxyalkyl represents in general an alkyl radical having 1 to 8 carbon atoms which is substituted with an alkoxy radical
of up to 8 carbon atoms.
Alkoxycarbonyl can be represented, for example, by the formula
Alkyl in this case generally represents a linear or branched hydrocarbon radical having from 1 to 13 carbon atoms. Examples which may be mentioned are the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
Cycloalkyl represents in general a cyclic hydrocarbon radical of 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the context of the invention, cycloalkoxy represents an alkoxy radical whose hydrocarbon radical is a cycloalkyl radical. The cycloalkyl moiety generally has up to 8 carbon atoms. Examples which may be mentioned are cyclopropyloxy and cyclohexyloxy. The terms "cycloalkoxy" and "cycloalkyloxy" are used as synonyms.
Aryl represents in general an aromatic radical of 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
Halogen represents, in the context of the invention, fluorine, chlorine, bromine and iodine.
Heterocycle generally represents, in the context of the invention, a saturated, unsaturated or aromatic 3 to 10 membered heterocycle, for example 5- or 6-membered ring which can contain up to 3 heteroatoms from the series S, N and / or O and which, in the case of a nitrogen atom, can also be bound by it. As examples: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1, 2, 3 -triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl . Thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl are preferred. The term "heteroaryl" (or "hetaryl") represents an aromatic heterocyclic moiety.
Another object of the invention is a process for the preparation of compounds of general formula (I), in which, depending on the different meanings of the heterocycles
previously mentioned in R2 and R3,
[A] the compounds of general formula (II)
R'-D (II)
in which
R1 has the meaning given above,
Y
D represents remains of formulas
wherein R38 represents C, -C4 alkyl,
by reaction with compounds of general formula
(III)
A-CH2-NH-NH2 (III)
in which
has the meaning given above,
in inert solvents, where appropriate in the presence of a base; they are transformed into the compounds of general formula (IV) or (IVa)
in which
A and R1 have the meaning given above,
and in the case of compounds of general formula (IVa), they are subsequently cyclized with carboxylic acids, nitriles, formamides or guanidinium salts,
and in the case of compounds of general formula (IV) are cyclized with 1,3-dicarbonyl derivatives, their salts, tautomers, enol ethers or enamines in the presence of acids and, where appropriate, microwaves,
[B] in case R2 and R3 form a pyrazine ring together, the compounds of general formula (IV) are first transformed by nitrosation into the compounds of general formula (V)
in which
A and R1 have the meaning given above,
in a second step, the compounds of general formula (VI) are prepared by reduction
in 1 to that
A and R1 have the meaning given above,
and finally they are cyclized with 1,2-dicarbonyl compounds, preferably aqueous glyoxal solution,
[C] compounds of general formula (VII)
in which
A, R2 and R3 have the meaning given above,
Y
represents a residue of the formula -SNR3 ^ 4 ^ 41, ZnR42, iodo, bromo or triflate,
in which
R39, R40 and R41 are the same or different and mean straight or branched alkyl of up to 4 carbon atoms,
R42 means halogen,
they are reacted with compounds of general formula (VIII)
R] -T (VIII)
in which
R1 has the meaning given above
in the case that L = SnR3 ^ 4 ^ 41 or ZnR42,
T represents triflate or halogen, preferably bromine,
in the case where L = iodine, bromine or triflate,
T represents a radical of the formula SnR ^ 'R ^' R41-, ZnR42 'or BR ^' R44 ',
in which
R39 ', R40', R41 'and R42' have the meaning given for R39, R40, R41 and R42 and are the same or different from these,
R43 'and R44' are the same or different and mean hydroxy, aryloxy of 6 to 10 carbon atoms or straight or branched alkyl or alkoxy of up to 5 carbon atoms each, or together form a carbocyclic ring of 5 or 6 members,
in a reaction catalyzed with palladium in inert solvent, where appropriate in the presence of a base,
[D] in the case that R1 represents a substituted pyrimidine residue, the amidines of general formula (IX)
wherein A, R2 and R3 have the meaning given above,
they are reacted, for example, with compounds of general formulas (X), (Xa), (Xb) or (Xc)
CX) (Xa)
(Xb) (Xc)
I know
R '"represents a cycloalkyl radical, substituted if appropriate, previously mentioned in R 1
Alk represents a linear or branched alkyl of up to 8 carbon atoms, preferably of up to four carbon atoms,
represents an NH2 group, monoalkylamino group of up to 7 carbon atoms, dialkylamino group of up to 7 carbon atoms, a piperidino or morpholino moiety linked by nitrogen, hydroxyl, alkoxy
up to 7 carbon atoms, acyloxy of up to 7 carbon atoms or aroyloxy of 6 to 10 carbon atoms,
and in the case of groups -S (0) _NR6R7 and -S (O) .. NR6'R7 ', starting from unsubstituted compounds of general formula (I), they are first reacted with thionyl chloride and in a second stage with the corresponding amines
and, if appropriate, the substituents mentioned as X, Y, R1, R2, R3 and / or A are varied or introduced according to conventional procedures, preferably by acylation of the amino groups or free hydroxy groups, chlorination, catalytic hydrogenation, reduction, oxidation , separation of protective groups and / or nucleophilic substitution.
The method according to the invention can be explained, for example, by the following formulas schemes:
Procedure [A]
Procedure [C]
Procedure [D]
The heterocycles mentioned as R2 and R3 can also be introduced by reaction of the corresponding substituted compounds according to other known heterocyclic syntheses.
As solvents for the individual process steps [A] and [B], inert organic solvents which do not change under the reaction conditions are suitable here. These include the ethers, such as diethyl ether or tetrahydrofuran, DME, dioxane; alcohols such as methanol and ethanol; halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene; hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents. Especially preferred are tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane.
As bases, inorganic or organic bases can be used in general in the process according to the invention. These preferably include alkali hydroxides, such as, for example, sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as, for example, barium hydroxide;
alkaline carbonates such as sodium carbonate or potassium carbonate; alkaline earth carbonates such as calcium carbonate; or alkali metal or alkaline earth metal alcoholates such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate; or organic amines (trialkyl (C? -C6) amines) such as triethylamine; or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to use alkali metal bases such as sodium and its hydrides as sodium hydride. Sodium carbonate, potassium carbonate, triethylamine and sodium hydride are preferred.
In the reaction of the compounds of formula (II) with the compounds of formula (III), the base is used in an amount of 1 to 5 mol, preferably 1 to 3 mol, relative to 1 mol of compound of general formula (II ).
The reaction of the compounds of general formula (II) with the compounds of general formula (III) is generally carried out in a temperature range from 0 ° C to 150 ° C, preferably from + 20 ° C to + 110 ° C.
This reaction can be carried out at normal, high or reduced pressure (for example from 0.5 to 5 bar). In general, normal pressure is used.
As acids for the cyclization reactions which are carried out, where appropriate, in the process according to the invention, protonic acids are generally suitable. These preferably include inorganic acids such as, for example, hydrochloric acid or sulfuric acid, or organic carboxylic acids of 1 to 6 carbon atoms, optionally substituted with fluorine, chlorine and / or bromine, such as, for example, acetic acid, trifluoroacetic acid, trichloroacetic or propionic acid, or sulfonic acids with C, -C4 alkyl radicals or aryl radicals, such as, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
The catalytic hydrogenation reactions which are carried out in the process according to the invention can, in general, be carried out by hydrogen in water or in inert solvents such as alcohols, ethers or halogenated hydrocarbons, or in mixtures thereof, with catalysts such as Raney nickel , palladium, palladium on animal coal or platinum, or with hydrides or boranes in inert solvents, where appropriate in the presence of a catalyst.
The chlorination reactions that are carried out in the case of the process according to the invention are generally carried out with conventional chlorinating agents, such as PC13, PCl3, P0C13 or elemental chlorine. It is preferred within the framework of
the invention P0C1,
The acylations of the amino groups or free hydroxyl groups which are carried out, where appropriate, in the process according to the invention, can be carried out by conventional methods known to the person skilled in the art. For example, the corresponding free amino groups or hydroxy groups can be converted, by reaction with an acid halide, preferably an acid chloride, or with an acid anhydride in the presence of a base, such as, for example, sodium hydride, pyridine or dimethylaminopyridine in a solvent such as tetrahydrofuran or dichloromethane, in the corresponding amides or esters; or by reaction with a sulfonyl halide, preferably a sulfonyl chloride, in the corresponding sulphonamides or sulfonic acid esters.
Oxidations of thioether groups to sulfoxide groups or sulfone groups which are carried out, where appropriate, in the process according to the invention, can be carried out according to conventional procedures known to the person skilled in the art. For example, said oxidation can be carried out with m-chloroperoxybenzoic acid (MCPBA) in a solvent such as dichloromethane.
The nucleophilic substitutions and Vilsmeier reactions that
they are carried out where appropriate in the process according to the invention are carried out by conventional methods known to the person skilled in the art.
The nitrosation of the compounds of formula (IV) to the compounds of formula (V) present in the first step of process [B] can be carried out according to the instructions of P.G. Baraldi et al., Synthesis 1984, 148.
The reductions which are carried out, where appropriate, in the process according to the invention are generally carried out with reducing agents, preferably with those which are suitable for the reduction of carbonyl to hydroxy compounds. Especially suitable here is reduction with metal hydrides or complex metal hydrides in inert solvents, where appropriate in the presence of a trialkylborane. It is preferred to carry out the reduction with complex metal hydrides such as for example lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkyl hydruroborate, diisobutyl aluminum hydride or lithium aluminum hydride. It is most preferred to carry out the reduction with diisobutylaluminum hydride and sodium borohydride.
The reducing agent is generally used herein in an amount of 1 mol to 6 mol, preferably 1 mol to
4 mol compared to 1 mol of the compounds to be reduced.
The reductions which are carried out, where appropriate, in the process according to the invention are generally carried out in a temperature range from -78 ° C to + 50 ° C, preferably from -78 ° C to 0 ° C in the case of DIBAH and 0 ° C at room temperature in the case of NaBH ».
The reductions that are carried out in the case of the process according to the invention are generally carried out at normal pressure. But it is also possible to work at high or reduced pressure.
The compounds of general formulas (II) and (III) are known per se or preparable by conventional methods (see for this: J. Hromatha et al., Monatsh, Chem. 1976, 107, 233).
The compounds of general formulas (IV), (IVa), (V) and (VI) are partially known and can be prepared as described above.
Suitable solvents for process [C] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME, dioxane; hydrocarbons
halogenated such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichlorethylene; hydrocarbons such as benzene, xylene, toluene, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents. Especially preferred are tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane.
The reaction of the compounds of formula (VII) with the compounds of formula (VIII) is generally carried out in a temperature range from 0 ° C to 150 ° C, preferably from + 20 ° C to + 110 ° C.
This reaction can be carried out at normal, high or reduced pressure (for example from 0.5 to 5 bar). In general, normal pressure is used.
As palladium compounds in the context of the present invention, PdCl 2 (P (C < 5) 3) 2, palladium-bis-dibenzylideneacetone (Pd (dba) 2), chloride of [1, bis- (diphenylphosphino) ferrocene] palladium (II) (Pd (dppf) Cl2) or Pd. { P. { C5l5) 3) i. Pd (P (C < H5) 3) is preferred.
The compounds of general formula (VII) are known per se or preparable by conventional methods (see for example K. Kirschke in: Houben-Weyl, Methoden der organischen Chemie, Thieme-Verlag Stuttgart, 4"ed, volume E8b, part 2 , 399-763, especially for pyrazolopyridines: CR Hardy in AR Katritzky (Hrsg), Adv. Het Chem. 1984, 36, 343-409, especially in respect of pyrazolopyrimidines: MH Elgnadi et al., Adv. Het Chem. 1987, 41, 319-376) The preparation of the corresponding organo-tannin [3, 4-b] pyrimidines and pyrazolo [3,4-b] pyrimidines pyrimidines of formula (VII) is described in WO 98/23619 and can be carried out analogously for the corresponding triflate and organotin compounds of formula (VII).
The compounds of general formula (VIII) are known and preparable by conventional methods (see, for example, MG Hoffmann et al., In: Houben-Weyl, Methoden der organische Chemie, 4 * ed, volume E9b, part 1, page 1-249 A. Weissenberger et al., The Chemistry of heterocyclic compounds- Pyrimidines, 1962, 16, ibid., 1970, 16, Suppl 1, ibid., 1985, 16, Suppl 2, ibid., 1994, 52).
The process [D] is carried out in a temperature range of 80 ° C to 120 ° C, preferably 100 ° C to
110 ° C or reflux.
Reagents of general formula (X), (Xa), (Xb) or (Xc) can function as solvents. However, the reaction can also be carried out in other suitable solvents, for example toluene, methanol or dichloromethane. Volatile solvents, such as dichloromethane, can be distilled during the course of the reaction.
The process [D] can be carried out at normal, high or reduced pressure (for example from 0.5 to 5 bar). In general, normal pressure is used.
The reaction can proceed in one step or through open chain compounds such as for example
It can be carried out in vacuum. It can occur even with or without addition of the solvents, bases or acids mentioned above.
The amidines of the general formula (IX) can be prepared by reacting the compounds of the general formula (XI)
in which
A, R2 and R3 have the meaning given above,
first in ethers with trifluoroacetic anhydride (TPAA) and in the presence of bases, giving the compound of general formula (XII)
in which
A, R2 and R3 have the meaning given above,
and then the compounds of general formula (XIII) are prepared with sodium methanolate
in 1st that
A, R2 and R3 have the meaning given above,
and they are transformed into a next step by reaction with NH "C1 and glacial acetic acid in alcohols in the corresponding amidine HCl salt of general formula (XIV)
wherein A, R2 and R3 have the meaning given above,
and in a last step are reacted with bases, preferably sodium carbonate or alkali alcoholate as sodium methanolate.
As solvents for the reaction of the compounds of general formula (XI) to the compounds of formula (XII) are suitable ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide and dioxane, tetrahydrofuran is preferred.
As bases, amines (trialkyl (C, -C6) amines) such as triethylamine or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec 7 -eno (DBU), pyridine, dimethylaminopyridine, methylpiperidine or morpholine. Pyridine is preferred.
The reaction is carried out in a temperature range of 0 ° C to 40 ° C, preferably at room temperature.
The reaction can be carried out at normal, high or reduced pressure (for example from 0.5 to 5 bar). In general, normal pressure is used.
The amide (XI) can be obtained, for example, by saponification with a corresponding ester base as the starting compound to the acid, which transformation into the acid chloride is carried out according to conventional procedures, for example by S0C12 or P0C13 and subsequent reaction with ammonia. .
The removal of water from the amide (XI) to the nitrile (XII) can be carried out with all conventional dehydrating agents. Trifluoroacetic acid anhydride (TFAA) is preferred according to the invention.
The conversion of the nitrile of formula (XII) into the iminoether of formula (XIII) can be carried out both in acids, such as for example HCl / alcohol mixtures, and in bases, such as for example methanol / sodium methanolate. It is conventionally carried out at 0 ° C to 40 ° C, for example at room temperature.
Solvents such as methanol or ethanol are suitable as solvents for the reaction of the compounds of the general formula (XIII) to the compounds of the formula (XIV). Methanol is preferred.
The reaction is carried out in a temperature range of 0 ° C to 40 ° C, preferably at room temperature.
The reaction can be carried out at normal, high or reduced pressure (for example from 0.5 to 5 bar). In general, normal pressure is used.
As bases for the release of the compounds of general formula (IX) from the compounds of general formula
(XIV) Inorganic or organic bases are suitable. These include, for example, alkali hydroxides such as sodium hydroxide or potassium hydroxide; alkaline earth hydroxides such as barium hydroxide; alkaline carbonates such as sodium carbonate or potassium carbonate; alkaline earth carbonates such as calcium carbonate and alkali alcoholates as sodium methanolate. Sodium carbonate and sodium methanolate are preferred.
The preparation of the pyrimidine ring is carried out according to conventional procedures (see for example MG Hoffmann et al., In: Houben-Weyl, Methoden der organischen Chemie, 4 * ed, volume E9b, part 1, page 1-249; A. Weissenberger et al., The Chemistry of Heterocyclic Compounds-Pyrimidines, 1962, 16, ibid., 1970, 16, Suppl 1, ibid., 1985, 16, Suppl 2, ibid., 1994, 52).
For this purpose, it is possible to start from the iminoethers of formula (XIII) and react them, for example, with a suitable enamine. However, the imino ether can also be converted in the first place by means of ammonia or its salts into the corresponding amidine, and reacting it as free base (IX) or salt (XIV) with enamines, acetals, enol ethers, aldehydes, enolates, malononitrile esters or malonodinitriles.
The enamines used where appropriate in this reaction can be prepared, for example, from acidic C-H compounds as acetonitrile derivatives, by known methods by reaction with dimethylformamide derivatives, such as for example bis (dimethylamino) tere-butoxymethane, and dialkoxydialkylaminomethanes.
The compounds of general formula (XI) can be prepared by transforming the compounds of general formula (XV)
with the compounds of the general formula (XVI) A-CH2NH-NH2 (XVI)
in ethers, preferably dioxane and trifluoroacetic acid, in the compounds of general formula (XVII)
and prepare then, by reaction with the
compounds of general formula (XVIII)
Z-CH = CH-CHO (XVIII:
in which
Z can have the meanings given above, especially -N (CH3) 2,
in inert solvents, preferably dioxane, the compounds of general formula (XIX)
and reacting in a last stage with ammonia in methanol.
Instead of the sodium salt of the enolate (XV), enol ethers, ketones or enamines can also be used.
Where appropriate, the reaction of the compounds of the general formula (XV) and (XVI) to (XVII) can also be carried out by intermediates of formula (A) and (B)
B ambient temperature.
The compounds of general formula (X) can be prepared, for example, by reacting the compounds of formula (XX) or (XXa)
[AlqjNh-CH-OAlq '(XX)
AlqjN-CH- [OAlq '] (XXa)
in which
Alk and Alk 'are the same or different and represent linear or branched alkyl of up to 5 carbon atoms,
with compounds of formula (XXI)
R "- CH2-CN (XXI)
wherein R1 'represents the cycloalkyl moiety mentioned above in R1.
The compounds of general formulas (XX), (XXa) and (XXI) are known or preparable by conventional methods.
The compounds of the general formulas (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII) and (XIX) are partially new and can be prepared as described above.
The pyrimidine moiety can also be formed with the aid of the reagent of formula (Xa), which is accessible, for example, in the following manner:
The compounds of general formula
in which
R1 'has the meaning given above and Alq represents an alkyl moiety of up to 4 carbon atoms,
they are transformed by ammonia into suitable solvents, preferably alcohols such as methanol at temperatures of 0 ° C to 40 ° C, preferably at room temperature, in compounds of general formula (XXIII)
(XI? I),
wherein R1"has the meaning given above,
and then they are reacted by conventional methods with dehydrating agents, such as, for example, Burgess reagent, P0C13, P205, SOCl2, trifluoroacetic acid anhydride / pyridine.
When the Burgess reagent is used, the reaction is preferably carried out in inert solvents such as ethers or chlorinated hydrocarbons. Examples are dichloromethane and tetrahydrofuran. Preferably a 1: 2 mixture of the aforementioned solvents is used. The reaction is carried out at temperatures of 0 ° C to 40 ° C, preferably at room temperature.
The compounds of formula (XXII) are known and / or accessible in a manner that is simple and familiar to the person skilled in the art.
The compounds of formula (X) are partially subject to the keto-enol tautomerism, for example:
(X ') (X ")
The pyrimidine moiety can also be formed with the aid of the reagent of formula (Xa), which is available, for example, in the following manner:
the compounds of general formula (XXIla)
Q? Xlla
in which
R1"has the meaning given above and Alq represents an alkyl moiety of up to 4 carbon atoms
are transformed by ammonia into suitable solvents, preferably alcohols such as methanol at temperatures of 0 ° C to 40 ° C, preferably at room temperature, in compounds of general formula (XXIIla)
(XXIIIa)
wherein R1 'has the meaning given above,
and these are then reacted, by conventional procedures, with dehydrating agents such as, for example, Burgess reagent, POCl3, P203, SOCl2, trifluoroacetic acid anhydride / pyridine.
When the Burgess reagent is used, the reaction is preferably carried out in inert solvents such as ethers or chlorinated hydrocarbons. Examples are dichloromethane and tetrahydrofuran. Preferably a 1: 2 mixture of the aforementioned solvents is used. The reaction is carried out at temperatures of 0 ° C to 40 ° C, preferably at room temperature.
The compounds of formula (XXIIa) are known and / or accessible in a simple manner and familiar to the person skilled in the art.
In the case that typical protective groups are used in the context of the derivatization reactions, their separation is generally carried out in one of the alcohols mentioned above and / or THF or acetone, preferably in methanol / THF, in
presence of hydrochloric acid or trifluoroacetic acid or toluenesulfonic acid in a temperature range of 0 ° C to 70 ° C, preferably at room temperature and normal pressure.
The compounds according to the invention of general formula (I) show a valuable spectrum of pharmacological action not foreseen.
The compounds according to the invention of general formula (I) lead to a relaxation of the vessels, inhibition of thrombocyte aggregation and a drop in blood pressure, as well as an increase in coronary blood flow. These effects are mediated by a direct stimulation of soluble guanylate cyclase and an increase in intracellular cGMP. In addition, the compounds according to the invention of general formula (I) reinforce the effect of substances that increase the level of cGMP, such as EDRF (endothelium-derived relaxant factor), NO donors, protoporphyrin IX, arachidonic acid or derivatives of phenylhydrazine.
Therefore, they can be used in drugs for the treatment of cardiovascular disorders, such as for the treatment of hypertension and heart failure, stable and unstable angina pectoris, disorders
peripheral vascular and cardiac arrhythmias, for the treatment of thromboembolic disorders and ischemia such as myocardial infarction, stroke, transient and ischemic attacks, peripheral circulatory disorders, prevention of restenosis after thrombolysis therapies, percutaneous transluminal angioplasty (PTA), angioplasty percutaneous transluminal coronary artery (PTCA), bypass, as well as for the treatment of arteriosclerosis, asthmatic disorders and diseases of the urogenital system, such as prostate hypertrophy, erectile dysfunction, female sexual dysfunction and incontinence.
The compounds described in the present invention of general formula (I) also represent active substances for controlling diseases of the central nervous system, which are characterized by disorders of the NO / cGMP system. They are especially suitable for the suppression of cognitive deficit, for the improvement of the function of learning and memory and for the treatment of Alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system as states of fear, tension and depression, sexual dysfunctions conditioned by the central nervous system and sleep disorders, as well as for the regulation of pathological disorders in the ingestion of foods, stimulants and drugs
In addition, the active ingredients are also suitable for the regulation of cerebral circulation and therefore represent an effective means to combat migraine.
They are also suitable for the prophylaxis and fight the sequelae of cases of cerebral infarction (cerebral apoplexy), such as stroke, cerebral ischemia and traumas cranioencephalic. The compounds according to the invention of general formula (I) can also be used to combat the pain states.
In addition, the compounds according to the invention have an anti-inflammatory effect and can therefore be used as anti-inflammatory agents.
In addition, the invention comprises the combination of the compounds according to the invention of general formula (I) with organic nitrates and NO donors.
Organic nitrates and NO donors, in the context of the invention, are generally substances that exert their therapeutic effect by releasing NO or NO species. Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.
In addition, the invention comprises the combination with compounds that inhibit the degradation of cyclic guanidine monophosphate (cGMP). These are especially inhibitors of phosphodiesterases 1, 2 and 5, nomenclature according to Beavo and Reifsnyder (1990) TiPS 11, p. 150 to 155. By these inhibitors the effect of the compound according to the invention is enhanced and the desired pharmacological effect is increased.
To verify the cardiovascular effects, the following tests were carried out: in vitro tests on isolated enzyme and on cells of vascular origin, the influence on the formation of cGMP dependent on guanylate cyclase with and without NO donor was tested. Antiagregatory properties were shown in human thrombocytes stimulated with collagen. The vascular relaxing effect was determined in rabbit aortic rings previously contracted with phenylephrine. The blood pressure lowering effects were tested in anesthetized and awake rats.
Stimulation of recombinant soluble quanilatocyclase in vitro
Tests were carried out for the stimulation of the recombinant soluble guanylate cyclase and the compounds according to the invention with and without NO donor according to the procedures
described in detail in the following literature: M. Hoenicka, E.M. Becker, H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer and J.-P. Stasch: Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 system: stimulation by YC-1, nitric oxide, and carbon oxide. J. Mol. Med., 77: 14-23 (1999). The results are shown in figure 1.
Stimulation of soluble quanilatocyclase in primary endothelial cells
Primary endothelial cells of pig aorta were isolated by treatment with collagenase solution. The cells were then cultured in culture medium at 37 ° C / 5% C02 until confluency was achieved. For the assays, the cells were passaged, seeded in 24-well cell culture plates and subcultured to confluence (approximately 2 x 10 5 cells / well). For the stimulation of the endothelial guanylate cyclase, the culture medium was removed by suction and the cells were washed once with Ringer's solution. After separating the Ringer solution, the cells were incubated in stimulation buffer with or without NO donor (sodium nitroprusside, SNP or DEA / NO 1 μM) for 10 minutes at 37 ° C / 5% C02. The test substances (final concentration 1 μm) were then pipetted into the cells and incubated for another 10 minutes. After the end of the incubation time,
the buffer solution was removed by suction and stop buffer was added at 4 ° C to the cells. The cells were then lysed for 16 hours at -20 ° C. Next, the supernatants containing intracellular cGMP were collected and the cGMP concentrations were determined by the cGMP-SPA system (Amersham Buchler, Braunschweig). The results are cited in the following tables 1 and 2.
Table 1: Stimulation of soluble guanylate cyclase in primary endothelial cells
Table 2: Stimulation of soluble guanylate cyclase in primary endothelial cells by 3- (4 # 6-diamino-5N-morpholinopyrimidin-2-yl) -1- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine (example 16)
Vascular relaxing effect in vitro
Rabbits were sacrificed by cervical dislocation and exsanguinated. The aorta was removed, freed from the stuck tissue, divided into rings of 1.5 mm in width and individually taken to a pretension in a 5 ml organ bath with Krebs-Henseleit solution heated at 37 ° C, bubbled with carbogen with the following composition (mM): NaCl: 119; KCl: 4.8; CaCl2 X 2 H20: 1; MgSO < X 7 H20: 1.4; KH2PO < : 1,2; NaHCO 3: 25; glucose: 10. The contraction force is recorded in Statham UC2 cells, intensified and digitized with an A / D converter (DAS-1802 HC, Keithley Instruments München), and also recorded in parallel in a continuous curve recorder. To produce a contraction phenylephrine is added to the bath cumulatively in increasing concentration. After several control cycles, the substance to be tested is tested with increasing doses in each step and the amplitude of the contraction is compared with the amplitude of the contraction reached in the last previous step. This calculates the concentration that is necessary to reduce the amplitude of the control value to 50% (Cía,). The standard application volume amounts to 5 μl, the DMSO part of the bath solution corresponds to 0.1%. The
results are shown below in table 3
Table 3: Vascular relaxing effect in vitro
Blood pressure measurements in anesthetized rats
Male Wistar rats with a body weight of 300-350 g were anesthetized with thiopental (100 mg / kg intraperitoneal). After the tracheotomy, a catheter was inserted into the femoral artery to measure blood pressure. The substances to be tested were administered in Transcutol, Cremophor EL, H20
(19% / 20% / 70%) in a volume of 1 ml / kg oral. The results are shown in the following table 4.
Table 4
Effect on mean blood pressure in spontaneously hypertensive awake rats
Continuous blood pressure measurements were carried out for 24 hours in female rats (MOL.-SPRD) of 200-250 g of spontaneously hypertensive weight free movements. To this end, a chronic manometric recorder (Data Sciences Inc., St. Paul, MN, USA) was implanted in the animals in the descending abdominal aorta below the renal artery and the emitter attached to it in the cavity was fixed. abdominal.
The animals were individually placed in type III cages in which the individual reception stations were placed and adjusted at a 12-hour light / dark pace. They were freely provided with water and food.
For recording data, blood pressure was recorded in each rat every 5 minutes for 10 seconds. They met
the punctual measurements of each one during a period of 15 minutes and the average value was calculated with these values.
The test compounds were dissolved in a mixture of Transcutol (10%), Cremophor (20%), H20 (70%) and orally administered by means of an exophageal probe with a volume of 2 ml / kg of body weight. The trial doses were between 0.3-30 mg / kg of body weight. The results are shown in the attached figure 2.
Inhibition of thrombocyte aggregation in vitro
For the determination of thrombocyte aggregation, blood was used from healthy test subjects of both sexes. As an anticoagulant, 1 part of 3.8% solution of sodium citrate was mixed with 9 parts of blood. The blood was centrifuged at 900 rpm for 20 minutes. The pH value of the platelet-rich plasma obtained was adjusted with a solution of ACD (sodium citrate / citric acid / glucose) at a pH = 6.5. The thrombocytes were then separated by centrifugation, suspended in buffer and centrifuged again. The thrombocyte precipitate was suspended in buffer and further mixed with 2 mmol / L CaCl 2.
For the aggregation measurements aliquots of the platelet suspension were incubated with the test substance during
minutes at 37 ° C. The aggregation was then dissolved by the addition of collagen in an aggregometer and determined by the turbomimetic method of Born (Born, G.V.R., J. Physiol. (London), 168, 178-195, 1963) at 37 ° C. The results are presented below in table 5.
Table 5
Measurement of the erection enhancing effect of guanylate cyclase stimulants
To perform a complete and sustained erection, the cavernous arteries and the joint architecture of the spongy bodies, which is formed by a network of smooth muscle cells and collagen connective tissue, dilate to the maximum, so that the corpus cavernosum can Fill completely with blood. (Anderson, K.-E. and Wagner G. "Physiology of Penile Erection" Physiological Reviews 75,
191-236 (1995); Meinhardt W., Kropmann R.F., Vermeig P.,
Lycclama to Nigelholt and Zwartendijk J. "The influence of
Medication on Erectile Disfunction ", Int. J. of Impotence
Res. 9, 17-26 (1997). Relaxation of the smooth muscle is mediated by NO, which is released in sexual stimulation
of non-cholinergic non-adrenergic nerve fibers in the endothelial cells of the blood vessels of the corpus cavernosum. NO activates guanylate cyclase, whose resultant increase in cGMP leads to dilation of the smooth muscle of the corpus cavernosum and therefore to an erection. Rabbits were used to test the effect of the substances according to the invention. The rabbit was chosen because the neurophysiology, the hemodynamics and the control of the contraction and relaxation of the smooth muscles of the spongy body are very similar in rabbits and men (Meyer MF, Taher, H., Krah, H., Staubesand, J., Becker, AJ, Kircher, M., Mayer, B., Jonas, U., Forsmann, WG, Stief, Ch. G., "Intracavernous Application of SIN-1 in Rabbit and Man: Functional and Toxicological Results "Annals, Urol. 27, 179-182 (1993); Taub, HC, Lerner, SE, Melman, A., Christ, GJ" Relationship between contraction and relaxation in human and rabbit corpus cavernosum "Urology 42, 698-671 (1993).
Procedure to
Adult male Chinchilla rabbits with a weight of 3-5 kg are adapted for several days after delivery in individual accommodations. They have free access to water and can take food for 2 hours a day. The animals were placed on a day / night rhythm of 10/14 hours (light from
from 8:00), raising the ambient temperature to 22-24 ° C.
The animals were weighed directly before the start of the test. For intravenous administration, the substances according to the invention were diluted in a mixture of Transcutol (GATTEFOSSE GmbH) with 20% Cremophor (BASF) and water dissolved in 3/7 proportion. The sodium nitroprusside was dissolved in 0.9% NaCl. The substances were injected in the dosages given in the table with a volume of 0.5 ml / kg in the atrial vein. For the oral intake, the test substances were dissolved in a mixture of glycerin: water: polyethylene glycol 6: 10: 9.69 and were applied in the dosages given in the table with a volume of 1 ml / kg by esophageal tube.
The effect of guanylate cyclase stimulants is reinforced by NO donors. This was demonstrated with the additional intake of sodium nitroprusside.
The sodium nitroprusside was injected into the atrial vein in a dosage of 0.2 mg / kg at the same time as the substance according to the invention. In case of oral administration of the substance according to the invention, sodium nitroprusside was injected into the auricular vein 30 minutes after oral intake. The corresponding controls were carried out with the solvent and the
Sodium nitroprusside alone.
In resting conditions the rabbit's penis is not visible in the pubic region and is completely covered by its skin. The erection is estimated by measuring the length of the prominent penis with a mobile gauge. The measurement is carried out 5, 10, 15, 30, 45, 60, 120 and 180 minutes after the administration of the substance. The effect is calculated as the product of the length of the penis not covered by the skin in (mm) and the duration of the erection in (min).
Intravenous injection of sodium nitroprusside results in a sustained erection of approximately 10 minutes (110 [mm x min]).
To the present invention belong pharmaceutical preparations containing, together with non-toxic pharmaceutically suitable inert vehicles, the compounds according to the invention of general formula (I), as well as processes for the preparation of these preparations.
The active ingredients can be present, if appropriate, in one or several of the above-mentioned vehicles, also in the form of microcapsules.
The therapeutically active compounds of the general formula
(I) should be provided in the pharmaceutical preparations cited above in a concentration of about
0.1 to 99.5, preferably from about 0.5 to 95% by weight of the total mixture.
The pharmaceutical preparations mentioned above may contain, in addition to the compounds according to the invention of the general formula (I), also other pharmaceutical active ingredients.
In general, it has proven advantageous both in human and veterinary medicine, that the active ingredients according to the invention are administered in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight every 24 hours , in its case in the form of several individual shots, to achieve the desired result. An individual dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, especially 3 to 30 mg / kg of body weight.
The present invention is presented in more detail below, based on the following non-limiting illustrative examples. Unless otherwise indicated, the quantity data refers to percentages by weight.
Examples
Abbreviations
RT: Ambient temperature EE: Ethyl acetate MCPBA: m-chloroperoxybenzoic acid BABA: n-butyl acetate / n-butanol / glacial acetic acid / phosphate buffer pH 6 (50: 9: 25: 15, organic phase)
Mobile phase of thin layer chromatography
TI El: toluene-ethyl acetate (1: 1) TI EtOHl: toluene-methanol (1: 1) Cl El: Cyclohexane-ethyl acetate (1: 1) Cl E2: Cyclohexane-ethyl acetate (1: 2)
Starting compounds
General instructions for the preparation of 3'-substituted 2'-ethylaminoacrylonitriles
To a solution of 5.95 g (50.0 mmol) of N, N-dimethylformamide dimethylacetal in 25 ml of absolute methanol is added with cooling with water, 50.0 mmol of 2-substituted acetonitrile derivative and stirred for 1 hour at room temperature.
Sulfone: The precipitate is separated by filtration with suction and dried under high vacuum. Phosphonic acid ester: The solution is released from methanol first at 40 ° C and 20 mbar in a rotary evaporator and then at room temperature under high vacuum.
Example 3A 3- (Dimethylamino) -2N-morpholinoacrylonitrile
8.13 g (64.5 mmol) of morpholinoacetonitrile and 13.3 ml (64.5 mmol) of tert-butoxy-bis (dimethylamino) methane were stirred overnight at 80 ° C. The mixture cooled to room temperature was concentrated in a rotary evaporator and then distilled in vacuo.
Yield: 11.0 g (94%) (cis and trans isomer)
Boiling point; 119 ° C / 0.008 mbar
Example 4A 3- (Dimethylamino) -2N-thiomorpholinoacrylonitrile
6.65 g (46.8 mmol) of N-thiomorpholinoacetonitrile (Wise, LD et al., J. Med. Chem., 17, 1974, 1232-1234) and 9.70 ml (47.0 g. mmol) of tert-butoxy-bis (dimethylamino) methane overnight at 80 ° C. The cooled mixture was concentrated to room temperature with rotary evaporator and then distilled in vacuo.
Yield: 9.98 g (88% based on the content of pure substance, cis and trans isomers) Boiling point: 96 ° C / 0,008 mbar
Example 5A Ethyl ester of the acid 3-dimethyl-lamino-2-methylsulphonylaryl
6.65 g (40 mmol) of methanesulfonylacetic acid ethyl ester and 5.72 g (48 mmol) of N, N-dimethylformamide dimethylacetal were mixed and heated at 85 ° C overnight. The solution was evaporated on a rotary evaporator and the solid triturated with cyclohexane and filtered with suction. Yield: 8.36 g (94.5% of theory).
Example 6A 2- (4-methylpiperazino) malonic acid diamide
1.00 g (5.52 mmol) of 2-bromomalonic acid diamide were mixed (obtained analogous to Bakes, West and Whiteley, J. Chem. Soc., 1921, 119, 359), 0.61 g ( 6.10 mmol) of N-methylpiperazine and 1.15 g (8.29 mmol) of potassium carbonate in 10 ml of acetonitrile were heated overnight at 50 ° C. The mixture was filtered and the solid was digested with
hot ethanol and filtered with suction. The filtrate was evaporated on a rotary evaporator and the product was reacted again without purification. Yield: 1.14 g (crude yield) Rf (Si02, BABA): 0.06.
Example 7A Diamide of 2- (4-acetylpiperazine) malonic acid
6.16 g (25.8 mmol) of 2-bromomalonic acid diethyl ester, 3.63 g (28.3 mmol) of N-acetylpiperazine and 5.34 g (38.6 mmol) of potassium carbonate are mixed. in 100 ml of acetonitrile, and heated for 28 hours at 50 ° C. The reaction mixture is cooled, suspended in 50 ml of ethyl acetate and washed with water. The organic phase is dried over magnesium sulphate and evaporated. Yield: 8.57 g. Dissolve 7 g of the crude product in 70 ml of ammonia solution in methanol and stir at room temperature for 90 hours. The solid is filtered off with suction, washed with cold methanol and dried.
Yield: 2.76 g (49.6% of theory)
Example 8A 2 - (4-Methylpiperazin) malonodinitrile
441 mg (2.04 mmol) of 2- (4-methylpiperazine) malonic acid diamide from Example 6A are dissolved in 20 ml of tetrahydrofuran: dichloromethane (3: 1). 1.70 g (7.15 mmol) of total Burgess reagent are added in three equal portions in 30 minute intervals. After another thirty minutes the reaction mixture is chromatographed directly on silica gel with ethyl acetate as eluent. Yield: 233 mg (69.4% of theory) Rf (SiO2, EE): 0.22
The following examples were obtained analogously to examples 6A to 8A:
NC CN R
The preparation of 2-N-morpholinomalonodiniyl, 2- (N, -dimethylamino) -malonodinitrile and 2- (N, N-diethylamino) malonodinitrile is carried out according to H. Gold and O. Bayer, Chem. Ber 1961, 94 , 2594. 2- (1, 3-thiazole-z-yl) -malononitrile is prepared according to Yamanaka H., Ohba, S., Sakamoto, T. Heterocycles, 1990, 1, 1115.
1990, 31, 1115.
Example 19A 2- (5-Methyl-1,3,4-thiadiazol-2-yl) -malononitrile,
400 mg (10.0 mmol) of sodium hydride (60% suspension in oil) are suspended under argon in 40 ml of THF at room temperature. A solution of 661 mg (10.0 mmol) of malonodinitrile in 10 ml of THF is added dropwise and the reaction mixture is stirred for 15 minutes. A solution of 891 mg (5.0 mmol) of 2-methyl-5-methylsulfonyl-1,3,4-thiadiazole in 10 ml of THF is added drop by drop. The reaction mixture is heated to 50 ° C and stirred overnight, cooled and evaporated on a rotary evaporator. The residue is dissolved in water and adjusted with HCl to pH = 3. Precipitate a brown solid that is filtered and dried under vacuum. Yield: 714 mg (87.0% of theory) P.F. : 210 ° C (Desc.)
Example 20A
-Amino-l- (2-fluorobenzyl) -1H-pyrazole-3-carboxylic acid ethyl ester
100 g (0.613 mol) of sodium salt of cyanopyric acid ethyl ester (obtained analogous to that of Borsche and Manteuffel, Liebigs Ann. 1934, 512, 97) are mixed with good agitation, under argon, at 2.5 1 dioxane at room temperature, with 111.75 g (75 ml, 0.98 mol) of trifluoroacetic acid and stirred for 10 minutes, thereby dissolving a large part of the reactant. Then 85.93 g (0.613 mol) of 2-fluorobenzylhydrazine are added and the mixture is heated to boiling overnight. After cooling, the precipitated crystals of sodium trifluoroacetate are filtered off with suction, washed with dioxane and the solution is reacted again without purification.
Example 21A 1- (2-Fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carboxylic acid ethyl ester
The above solution of Example 20A is mixed with 61.25 ml (60.77 g, 0.613 mol) of dimethylaminoacrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid and is heated to boiling under an argon atmosphere. for 3 days. The solvent is then removed by evaporation in vacuo, the residue is added in 2 l of water and extracted three times with 1 l of ethyl acetate each time. The combined organic phases are dried with magnesium sulfate and evaporated on a rotary evaporator. Chromatograph on 2.5 kg of silica gel and elute with a gradient of toluene / toluene-ethyl acetate 4: 1. Yield: 91.6 g (49.9% of the theory in two stages) P.F. : 85% Rf (Si02, T1E1): 0.83
Example 22A 1- (2-Fluorobenzyl) -IH-pyrazolo [3,4-b] pyridin-3-carboxamide 10.18 g (34 mmol) of the ester of Example 21A are provided in
150 ml of methanol saturated with ammonia at 0-10 ° C. The mixture is stirred at room temperature for two days and then concentrated in vacuo. Rf (SiO ,, T1E1): 0, 33
Example 23A 3-Cyano-1- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine
36.1 g (133 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] iridin-3-carboxamide of example 22A are dissolved in 330 ml of THF and mixed with 27 g (341 g). mmol) of pyridine. Subsequently, 47.76 ml (71.66 g, 341 mmol) of trifluoroacetic acid anhydride are added over 10 minutes.
the temperature rises to 40 ° C. It is stirred overnight at room temperature. The reaction mixture is then added to 1 1 of water and extracted three times with 0.5 1 of ethyl acetate each time. The organic phase is washed with a saturated solution of sodium hydrogencarbonate and with 1 N HCl, dried over MgSO, and evaporated on a rotary evaporator. Yield: 33.7 g (100% of theory) P.F. : 81 ° C. Rf (Si02, T1E1): 0.74.
Example 24A 1- (2-Fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carboximidic acid methyl ester
.37 g (562 mmol) of sodium methylate are dissolved in 1.5 1 of methanol and 36.45 g (144.5 mmol) of 3-cyano-1- (2-fluorobenzyl) -lH-pyrazolo are added. [3, 4-b] pyridine from example 23A. The mixture is stirred for two hours at room temperature and the directly obtained solution is used for the next stage.
Example 25A
1- (2-Fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carboxamidine
The above solution of 1- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-carboximide acid methyl ester of Example 24A in methanol is mixed with 33.76 g (32.19 ml, 562 mg). mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride and stir at reflux overnight. The solvent is evaporated in vacuo, the residue is thoroughly sprayed with acetone and the precipitated solid is filtered off with suction. It is added to 2 l of water, stirred with 31.8 g of sodium carbonate and extracted three times with 1 l of ethyl acetate in total, the organic phase is dried with magnesium sulphate and evaporated in vacuo. . Yield: 27.5 g (76.4% of theory in two steps) P.F. : 86 ° C. Rf (Si02, TIEtOHl): 0.08.
Preparation Examples Example 1 3- (4-Amino-5-methylsulfonylpyrimidin-2-yl) -1- (2-fluorobenzyl) 1 H -pyrazolo [3,4-b] pyridine
2 g (7.42 mmol) of the 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-carboxamidine from Example 25A, 1.39 g (7 mmol) of 3 - are stirred. (dimethylamino) -2- (methylsulfonyl) -2-propenenitrile (which is prepared analogously to example 1A), 0.79 ml (7 mmol) of piperidine and 200 ml of isoamyl alcohol for 12 hours at 110 ° C. After cooling, the precipitated crystals are filtered off with suction and washed with diethyl ether. 0.94 g (31.8% of theory) of the title compound are obtained. P.F. : 272 ° C. Rf (Si02, EE): 0.72.
They are obtained analogously:
The corresponding 3-dimethylaminoacrylonitriles with the corresponding substituents R in the 2-position, which are reacted as starting compounds of examples 2 to 13 with the amidine 25A, can be prepared analogously to examples 1A and 3A.
Example 14 3- [5-Cyano-4- (4-methylphenyl) pyrimidin-2-yl] -1- (2 f luorobenzyl) -lH-pyrazolo [3,4-b] pyridine
200 mg (0.74 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3, -b] pyridin-3-carboxamidine from example 25A, 171 mg (0.8 mmol) of (dimethylamino) - are stirred. 2- (4-methylbenzoyl) -2-propenenitrile (prepared analogously to Example 1), 0.68 mg (0.8 mmol) of piperidine and 20 ml of 2-pentanol for 12 hours at 110 ° C. After cooling, the solvent is evaporated in vacuo and the residue is chromatographed on silica gel. 217 mg (69.5% of theory) of the title compound are obtained.
P.F. 229 ° C.
Example 15 3 - (4,6-Diamino-5-benzylpyrimidin-2-yl) -1- (2-f luorobenzyl) -1H-pyrazolo [3,4-b] pyridine
200 mg (0.74 mmol) of 1- (2-f-luorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamidine from Example 25A, 125 mg (0.8 mmol) of 2 - are stirred. benzylamlodinitrile (which is prepared from malodinitrile and benzyl bromide with a base such as potassium carbonate), 0.68 mg (0.8 mmol) of piperidine and 20 ml of 2-pentanol for 12 hours at 110 ° C. After cooling, the solvent is evaporated in vacuo and the residue is chromatographed on silica gel. 165 mg (52.5% of theory) of the title compound are obtained. P.F. : 193 ° C.
Example 16 3- (4,6-Diamino-5N-morpholinopyrimidin-2-yl) -1- (2
fluorobenzyl) -IH-pyrazolo [3,4-b] pyridine
Under vacuum at 105 ° C, 200 mg (0.74 mmol) of l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carboxamidine from Example 25A and 400 mg (2.65 mmol) are heated. mmol) of 2-N-morpholinomalonodinitrile (synthesis of H. Gold and O. Bayer, Chem. Ber. 1961, 94, 2594) for 12 hours. The solid residue is dissolved in DMF, silica gel is added and the solvent is evaporated in vacuo. After chromatography, 222 mg (71.1% of theory) of the title compound are obtained. P.F. : 261 ° C. Rf (EE): 0.2.
They were obtained analogously:
Example 36 üariaril -
50 mg (19 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-carboxamidine from example 25A and 42 mg (20 mmol) of 1, 1, 1, 5 are heated. , 5, 5-hexafluoroacetylacetone at 110 ° C for 5 hours. After chromatography 33 mg (40.3% of theory) of the title compound are obtained. P.F. ": 109 ° C.
Rf (tol): 0, 35
Example 37 3 - (5-Ethoxycarbonyl-4-trif luoromethylpyrimidin-2-yl) -1 - (2 -f luorobenzyl) -lH-pyrazolo [3,4-b] pyridine
600 mg of crude 1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-b] pyridin-3-carboxamidine hydrochloride (which can be prepared from amidine 25A by reaction with HCl) is stirred at 30 ° C. ml of methanol with 106 mg of sodium methanolate and mixed with 472 mg (1.96 mmol) of 3-ethoxy-2-rifluoroacetylacrylic acid ethyl ester. After heating to boiling for 12 hours, the precipitate is filtered off with suction and washed with ether. 249 mg (27.5% of theory) of crystals are obtained. P.F. : 174 ° C. Rf: Si02 T1E1: 0.76.
Example 38
Diethyl ester of 4-amino-2- acid. { 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl} pyrimidin-5-phosphonic
2.44 g (9.00 mmol) of the amidine from Example 25A and 3.71 g (16.0 mmol) of 1-cyano-1- (dimethylamino) methylenemethane phosphonic acid diethyl ester (Aboujaoude, Elie Elia) were mixed well. Collignon, Noel; Savignac, Phillipe, Tetrahedron, 41, 1985, 427-434), were sonicated for 5 minutes and then stirred under vacuum at 100 ° C (membrane pump) overnight. The mixture cooled to room temperature was stirred with hot methanol and freed from the insoluble components by filtration. The filtrate was concentrated and chromatographed on silica gel (C-> C: E 1: 1-> E). Yield: 638 mg (16%) P.f .: 185 ° C Rf value: 0.09 (C: E 1: 1).
Example 39 3- (4-Amino-5-N-morpholinopyrimidin-2-yl) -1- (2-fluorobenzyl)
lH-pyrazolo [3, 4-b] pyridine
1.00 g (3.72 mmol) of the amidine from example 25A and 2.00 g (11.0 mmol) of 3- (dimethylamino) -2-morpholinoacrylonitrile from example 3A were stirred well, subjected to ultrasound for 5 minutes. minutes and then it was stirred under vacuum at 120 CC (membrane pump) overnight. The cooled mixture was stirred at room temperature with tert-butyl methyl ether, the resulting precipitate was filtered off with suction and chromatographed on silica gel (C: E 100: 1 -> C: E 1: 1). Yield: 262 mg (17%) P.F. : 205 ° C Value of R,: 0.05 (C: E 1: 1)
Example 40 3- (4-Amino-5-N-thiomorpholinopyrimidin-2-yl) -1- (2-f luorobenzyl) -lH-pyrazolo [3,4-b] pyridine
.00 g (18.6 mmol) of the amidine from example 25A and 9.98 g (50.7 mmol) of 3- (dimethylamino) -2-thiomorpholinoacrylonitrile from example 4A were mixed well, subjected to ultrasound for 5 minutes. minutes and then stirred under vacuum at 100 ° C (membrane pump) overnight. The cooled mixture was stirred at room temperature with tert-butyl methyl ether and the resulting precipitate was suction filtered. Yield: 1.43 g (18%) P.F. : > 250 ° C Value of R,: 0.06 (C: EE 1: 1).
Example 41 3- (4-Hydroxy-5- (methylsul-fonyl) pyrimidin-2-yl) -1- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine
2.32 g (8.61 mmol) of the amidine from example 25A and 5.71 g (25.8 mmol) of the enamine from example 5A are mixed and heated in an open vessel at 100-105 ° C for 4 hours. hours. The residue is cooled, digested with toluene, filtered and washed with toluene. Yield: 1.16 g (33.6% of theory) Rf (SiO2, EE): 0.23.
Example 42 3- (6-Chloro-8-methyl-9H-purin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine
650 mg (1.65 mmol) of the hydroxypyrimidine of Example 19 are suspended in 3 ml of phosphorus oxytrichloride, two drops of N, N-dimethylaniline are added and the solution is heated under reflux for three hours. The reaction mixture is cooled and evaporated. The residue is suspended in ethyl acetate, washed carefully with a saturated solution of sodium bicarbonate, dried and evaporated. The crude product is reacted again. Yield: 580 mg (89.1% of theory). Rf (Si02, EE): 0.21.
The following compounds were obtained analogously to Example 42:
The reactant of example 43 was prepared as in example 17. The reactant of example 44 was prepared as in example 20. The reactant of example 45 was prepared as in example 41.
Example 46 3 - (5-Ethyl -4 - (2-hydroxyethylaminocarbonyl) pyrimidin-2-yl) -1 - (2-f-luorobenzyl) -lH-pyrazolo [3,4-b] pyridine.
70.0 mg (0.179 mmol) of the methyl ester (prepared from 25A and 4- (dimethylamino) -3-ethyl-2-oxo-3-butanoic acid methyl ester are dissolved in a manner analogous to example 36) in 109 , 3 mg (1.78 mmol) of the amine and stirred for 3 hours at 60 ° C. Dichloromethane is added and washed once with a 0.5 N hydrochloric acid solution. The organic phase is washed with magnesium sulfate and evaporated in vacuo. Yield: 30.6 mg (40.7% of theory) Rf (SiQ2, E) 0.31.
They are prepared analogously by reaction with the corresponding amines:
The amines used as starting compounds are commercially available or readily available by conventional methods known to the person skilled in the art, as described for example in J. March, Advanced Organic Chemistry, 3 * ed. , Wiley, 1985, p. 1153 and following.
Example 58 3- (4- (4, 5-Dihydro-lH-imidazol-2-yl) -5-ethylpyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine
Dissolve 68.9 mg (1.15 mmol) of ethylenediamine in 10 ml of toluene, add 60 ml (1.15 mmol) of 2 M trimethylaluminum solution in toluene at 0 ° C and stir for 2 hours at room temperature. ambient. Then 155 mg (0.38 mmol) of the ethyl ester (prepared from 25A and 4- (dimethylamino) -3-ethyl-2-oxo-3-butenoic acid ethyl ester are added analogously to example 36). It is stirred for five days at 75 ° C, cooled, washed once with a solution of sodium potassium tartrate and the aqueous phase is extracted once with dichloromethane. The combined organic phases are dried over magnesium sulfate, mixed with 500 mg of silica gel and evaporated.
The substance is chromatographed for purification on 10 g of silica gel 60 (grain size 0.040-0.063 mm) with ethyl acetate to ethyl acetate / methanol 9: 1 as eluents. Yield: 75.0 mg (49% of theory). Rf (Si02, C1E1): 0, 04.
Example 59 3- [5-ethyl-4- (lH-imidazol-2-yl) pyrimidin-2-yl] -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine.
reflux 62 mg (0.15 mmol) of the dihydroimidazole from example 58 and 100 mg of palladium on carbon (10%) in 5 ml of toluene. It is filtered after 6 days and the solvent is evaporated in vacuo.
The substance is chromatographed for purification on 8 g of silica gel 60 (grain size 0.040-0.063) with cyclohexane / ethyl acetate 2: 1 to 1: 2 as eluents. Yield: 8.8 mg (14.3% of theory) Rf (SiO2, C1E2): 0.24.
Example 60 3- (5-Ethyl-4- (lH-imidazol-1-yl) pyrimidin-2-yl) -1- (2-fluorobenzyl) -lH-pyrazolo [3, -b] pyridine
60 mg (0.16 mmol) of the chlorine compound (prepared from 25A and 2-formylbutanoic acid ethyl ester are dissolved analogously to example 36 and then by reaction with phosphorus oxytrichloride analogously to example 42) and 22.2 mg (0.33 mmol) of imidazole in 5 ml of dimethylformamide and mix with 33.8 mg (0.24 mmol) of potassium carbonate. Stir overnight at 100 ° C. It is cooled, diluted with ethyl acetate and washed twice with water. The organic phase is dried with magnesium sulfate and evaporated in vacuo. Yield: 47.4 mg (72.7% of theory).
They were prepared analogously to Example 60 by reaction with the corresponding amines:
Examples 71-79 The chloro group of the compounds of examples 42 to 45
it can be reduced by known processes with ammonium formate and palladium on carbon or exchanged by reaction with nucleophiles such as azide anion, ammonia, amines or methanol. The azide group thus introduced can, in turn, be reduced with sodium dithionite. In this way the following compounds are obtained:
Example 80 3 - (4-Diacetylamino-5-ethylpyrimidin-2-yl) -1- (2-f luorobenzyl) lH-pyrazolo [3, -b] pyridine
50.0 mg (0.14 mmol) of the amine (which can be prepared analogously to Example 60 by dissolving the chlorine compound described therein with ammonia or sodium azide and then by reduction with sodium dithionite) are dissolved. ) in dichloromethane and mixed with 33.8 mg (0.43 mmol) of acetyl chloride and 68.1 mg (0.86 mmol) of pyridine. The solution is stirred for 4 hours at room temperature, washed once with 1 N HCl, then with a
saturated solution of NaHCO3. The organic phases are dried over magnesium sulfate and concentrated by evaporation in vacuo. The substance was chromatographed for purification on silica gel 60 (grain size 0.040-0.063) with cyclohexane / ethyl acetate 1: 1 as eluents. Yield: 33.2 mg (53.5% of theory). Rf (Si02, C1E2): 0.41.
Example 81 3- [4- (2-Benzoyloxymethylbenzoylamino) -5-ethylpyrimidin-2-yl] -1- (2-fluorobenzyl-1H-pyrazolo [3,4-b] pyridine
9 mg (0.23 mmol) of sodium hydride (60% strength oil solution) are suspended at room temperature in 1 ml of tetrahydrofuran (THF). A solution of 40 mg (0.11 mmol) of amine (see example 80) in 0.8 ml of THF is added and then a solution of 34.7 mg (0.13 mmol) of 2-chloro is added. (benzoyloxymethyl) benzoyl. After 30 minutes, 5 ml (0.12 mmol) of sodium hydride (60%) and 14 mg (0.05 mmol) of the above acid chloride are added again. After 1 hour the mixture is mixed with water, extracted with ethyl acetate and the organic phase is washed with
1 M hydrochloric acid and saturated NaHCO 3 solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The substance is crystallized with cyclohexane / ethyl acetate. Yield: 25 mg (37.1% of theory). Rf (Si02, CiEl): 0, 50.
EXAMPLE 82 3- (4-Acetoxy-5-ethylpyrimidin-2-yl) -1- (2-f-luorobenzyl) -1H-pyrazolo [3,4-b] pyridine and 3- (3-acetyl-5-ethylpyrimidin- 4-on-2-yl) -1- (2-f luorobenzyl) -1 H -pyrazolo [3,4-b] pyridine
Dissolve 73.8 mg (0.21 mmol) of the hydroxypyrimidine compound (prepared from 25A and 2-formylbutanoic acid ethyl ester analogously to example 36) in 2 ml of dichloromethane and mix with 27.9 mg (0.27 mmol) of triethylamine and 25.9 mg (0.25 mmol) of acetic anhydride. The solution is stirred for 3 hours at room temperature, suspended in ethyl acetate, washed once with water and the aqueous phase is extracted once with ethyl acetate.
ethyl. The combined organic phases are washed twice more with water, dried over magnesium sulphate and evaporated on a rotary evaporator. Yield: 42.0 mg (50.8% of theory) Rf (SiO2, C1E2): 0.5.
Example 83 3- (5-Ethyl-4- (methylsulfinyl) pyrimidin-2-yl) -1- (2-f-luorobenzyl) -lH-pyrazolo [3,4-b] pyridine and 3- (5-ethyl-4) - (methylsulfonyl) irimidin-2-yl) -1- (2-f luorobenzyl) -1H-pyrazolo [3,4-b] pyridine.
45.2 mg (0.12 mmol) of the methylthioether (prepared from the chlorine compound used in Example 60 by reaction with sodium methanethiolate in toluene) and 30.8 mg (0.18 mmol) of MCPBA are stirred in 2 ml of dichloromethane at 0 ° C. After three hours the reaction mixture is mixed with a solution of sodium bicarbonate and ethyl acetate, separated, dried and evaporated on a rotary evaporator.
The substance is chromatographed on 8 g of silica gel 60 (grain size 0.040-0.063 mm) with cyclohexane / ethyl acetate 1: 1 to 1: 4 as eluants for purification.
B: yield: 36.0 mg (76.4% of theory). Rf (SiO2, C1E2) 0.057 C: yield: 7.1 mg (14.5% of theory). Rf (Si02, C1E2) 0.79.
EXAMPLE 84 3- (4,6-Diamino-5-N-4-oxothiomorpholinopyrimidin-2-yl) -1- (2-fluorobenzyl) -1-H-pyrazolo [3,4-b] pyridine and 3- (4 , 6-diamino-5-N-4, 4-dioxothiomorpholinopyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine.
230 mg (0.53 mmol) of the thiomorpholine of Example 23 and 130 mg (0.53 mmol) of MCPBA in 5 mL of dichloromethane are stirred at 0 ° C. After 30 minutes, the same amount of MCPBA is added again. After 1.5 hours, the reaction mixture is mixed with silica gel and evaporated in a rotary evaporator. Chromatograph for purification the substance on silica gel 60 (grain size 0.040-0.063) with
cyclohexane / ethyl acetate. B: yield: 86 mg (36.1% of theory). Rf (Si02, BABA) 0, 18. C: yield: 14 mg (5.7% of theoretical). Rf (Si02, BABA) 0.41.
Claims (4)
1 . Substituted pyrazole derivatives of general formula (I) characterized because: R1 represents a saturated or aromatic 5- or 6-membered heterocycle with up to 3 heteroatoms from the group of S, N and / or O, which may be linked by a nitrogen atom, and that in its case it is substituted up to 2 times with the same or different rest of the group (i), composed of hydrogen, amino, azido, formyl, mercaptyl, carboxyl, hydroxy, acyl, alkoxy, alkylthio or straight or branched alkoxycarbonyl of up to 6 carbon atoms each, nitro, cyano, halogen, phenyl or straight or branched alkyl of up to 6 carbon atoms carbon, which may be substituted on its part with hydroxy, amino, azido, carboxyl, acyl, alkoxy, alkoxycarbonyl or linear or branched acylamino of up to 5 carbon atoms each or with a rest of formula -OR4, in which R * means a linear or branched acyl of up to 5 carbon atoms, and / or is substituted with a remainder of formulas or - S (0) c-NR6R7, 15 in which a, b and b 'are the same or different, and mean a number 0, 1, 2 or 3, R5 means hydrogen or straight or branched alkyl of up to 4 carbon atoms, means a number 1 or 2 and 25 R6 and R7 are the same or different and they mean hydrogen or linear or branched alkyl of up to 10 carbon atoms, which is optionally substituted by cycloalkyl of 3 to 8 carbon atoms or by aryl of 6 to 10 carbon atoms, which in turn can be substituted by halogen, or, 10 means aryl of 6 to 10 carbon atoms, which in its case is substituted with halogen, or mean cycloalkyl of 3 to 7 15 carbon atoms, or R6 and R7 together with the nitrogen atom form a saturated heterocycle of 5 20 to 7 members, which in its case may contain another oxygen atom or a residue -NR8, wherein 25 R5 means hydrogen, to the ineffective branched chain of up to 4 carbon atoms or a residue of the formula or benzyl or phenyl, where the ring systems are substituted with halogen, and it is substituted with at least one group (ii), consisting of: a ring of 3 to 8 members which may be saturated, unsaturated or partially unsaturated, containing 1 to 4 heteroatoms of the group N, O, S, SO, S02 and which may also be linked by N, imidazolyl, imidazolinyl being especially preferred , imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl, t -omorpholinyl, S-oxothiomorpholinyl and S, S-dioxothiomorpholino, and which is substituted once or several times with a ring of 5 or 6 members, which contains two oxygen atoms as ring members and which forms a bicyclic structure or a spiro structure with the ring of 3 to 8 members; and / or with linear or branched hydroxy, cyano, alkyl, acyl or alkoxycarbonyl of up to 6 carbon atoms each, the alkyl, acyl and alkoxycarbonyl being substituted with hydroxy, amino, halogen, carboxyl, acyl, alkoxy, alkoxycarbonyl or acylamino linear or branched with up to 5 carbon atoms each, and an aryl ring of 6 to 10 carbon atoms which is substituted with linear or branched alkyl of up to 4 carbon atoms, and alkenyl (C2-C, 0), alkynyl (C2-C? 0), alkyl (CC ^), which are optionally substituted with aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamino, hydroxy, amino, azido, carboxyl, acyl, alkoxy, alkoxycarbonyl or straight or branched acylamino of up to 5 carbon atoms each or with a radical of formula -OR4 in which R * means linear or branched acyl of up to 5 carbon atoms and alkyl (C? -C6) which is substituted 1 to 3 times with aryl, heteroaryl, halogen (s), cyano, dialkylamino, alkylamino or cycloalkyl, and acyl, which is substituted with halogen (s), especially preferred fluorine, or acyloxy, arylthio or heteroaryl io, and -NO or remains of formulas -S03H or -S (0) dR9, in which means a number 1 or 2, means linear or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms or a saturated or unsaturated heterocycle of 5 or 6 members with up to 3 heteroatoms of the group of S, N and / or O, it being possible for the ring systems to be substituted, if appropriate, with halogen or with linear or branched alkyl or alkoxy of up to 4 carbon atoms each, a remainder of formula PO (OR10) (OR "), in which R 10 and R "are the same or different and denote hydrogen, linear or branched alkyl of up to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms or benzyl, and oxicycloalkyl of 3 to 8 ring members or radicals of formulas -C0N = C (NH2) 2, -C = NH (NH2), -NH-C (= NH) NH2 or (CO) «NR" R13 in which means a number 0 or 1, R12 and R13 are the same or different and mean hydrogen, linear or branched alkyl of up to 14 carbon atoms or cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 10 carbon atoms or a saturated or unsaturated ring of 3 to 10 members with up to 5 heteroatoms of the group of N, O, S, the said moieties may be substituted, if appropriate, with aryl of 6 to 10 carbon atoms, heterocyclyl, cycloalkyl of 3 to 7 atoms 10 carbon, hydroxy, amino or alkoxy, acyl or straight or branched alkoxycarbonyl of up to 6 carbon atoms each, and in the case that e means 1, 15 R'2 and R13 can also form, including the nitrogen atom to which they are attached, a 5- or 6-membered ring with up to 3 heteroatoms from the group of N, O, S , which can 20 to be substituted in its case up to 3 times with hydroxy, alkoxy or alkyl of up to 8 carbon atoms each, and in the case that e means 0, 25 R12 and R13 can also mean acyl linear, branched or cyclic of up to 14 carbon atoms, hydroxyalkyl, alkoxycarbonyl or straight or branched acyloxyalkyl of up to 6 carbon atoms each or a radical of formula -S02RH in which R 14 is linear or branched alkyl of 10 to 4 carbon atoms, and / or R12 and R13 also mean remains of formulas 25 R ^ -0-CH (R27) -0-CO- 20 25 in which R13-R16 and R18-R31 are the same or different and mean hydrogen or linear or branched alkyl of up to 4 carbon atoms, g means a number 0, 1 or 2, Y R17 means phenyl, linear or branched alkyl of up to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms, with the proviso that, if e means 0, R'2 and R13 do not represent hydrogen at the same time, R1 represents a purine residue, which may be substituted up to three times with halogen, azido, cyano, hydroxy, amino, monoalkylamino of up to 5 carbon atoms, dialkylamino of up to 5 carbon atoms each, alkyl of up to 5 atoms carbon and / or alkoxy up to 5 carbon atoms, R3 forms, with the inclusion of the double bond, a 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the group of N, S and / or O, which in its case is substituted up to 3 times with the same or different substituent formyl, carboxyl, hydroxyl, mercaptile, acyl, alkylthio or straight or branched alkoxycarbonyl of up to 6 carbon atoms each, nitro, cyano, halogen or alkyl or linear alkoxy or branched of up to 6 carbon atoms each which in turn can be substituted with linear or branched hydroxy, amino, carboxyl, acyl, alkoxy or alkoxycarbonyl of up to 5 carbon atoms each, and / or it is substituted where appropriate with a group of formula NR32R33, in which R32 and R33 are the same or different and mean hydrogen or straight or branched alkyl of up to 6 carbon atoms, R3: means hydrogen and R3: means acyl and / or is substituted, if appropriate, with phenyl, which in turn can be substituted up to 2 times with the same or different halogen or with linear or branched alkyl or alkoxy of up to 6 carbon atoms each and / or is substituted where appropriate with a group of formula -N = CH-NR34R35, in which R34 and R35 are the same or different and denote hydrogen, phenyl or linear or branched alkyl of up to 6 carbon atoms, represents a 5- or 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms of the group consisting of S, N and / or O or represents phenyl, which are optionally substituted up to 3 times with the same or different amino substituent, mercaptyl, hydroxy, formyl, carboxyl, acyl, alkylthio, alkyloxy acyl, alkoxy or alkoxycarbonyl up to 6 carbon atoms each, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight or branched alkyl of up to 6 carbon atoms, which in turn can be substituted with linear hydroxy, carboxyl, acyl, alkoxy or alkoxycarbonyl or branched chain of up to 5 carbon atoms each, and / or is substituted with a group of formula - (CO) h-NR36R37 in which h means a number 0 or 1, R36 and R37 are the same or different and mean hydrogen, phenyl, benzyl or straight or branched alkyl or acyl of up to 5 carbon atoms each, • and its isomeric forms and salts.
2. Compounds of general formula (I) according to claim 1, characterized because: R1 represents a 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the group of S, N and / or Or, which may be linked by a nitrogen atom, and it is substituted in its case up to 2 times with the same or different rest of the group (i), composed by hydrogen, amino, azido, formyl, mercaptyl, carboxyl, hydroxy, acyl, alkoxy, alkylthio or straight or branched alkoxycarbonyl of up to 6 carbon atoms each, nitro, cyano, halogen, phenyl or straight or branched alkyl of up to 6 carbon atoms carbon, which in turn can be substituted with hydroxy, amino, azido, carboxyl, acyl, alkoxy, alkoxycarbonyl or straight or branched acylamino of up to 5 carbon atoms each or with a radical of formula -OR4, in which R4 means linear or branched acyl of up to 5 carbon atoms, and / or is substituted with a radical of formulas O CH2 p (CHa) b \ OCH2 (CHA 0 (CH? N. ORJ in which a, b and b 'are the same or different and mean a number 0, 1, 2 or 3, R5 means hydrogen or straight or branched alkyl of up to 4 carbon atoms, and is substituted with at least one residue of group (ii), composed of a ring of 3 to 8 members which may be saturated, unsaturated or partially unsaturated, containing from 1 to 4 heteroatoms of the group of N, O, S, SO, S02 and which may also be linked by N, imidazolyl being especially preferred, imidazolinyl, imidazolidinyl, morpholino, piperidino, piperazino, pyrrolidino, triazolyl, pyrrole, thiomorpholino, S-oxothiomorpholino and S, S-dioxothiomorpholino, and which is substituted one or more times with a 5- or 6-membered ring containing two oxygen atoms as ring members, and which forms with the 3 to 8 membered ring a bicyclic structure or a spiro, and / or hydroxy, cyano, alkyl, acyl or straight or branched alkoxycarbonyl structure with up to 6 carbon atoms each , being able to be the alkyl, acyl and alkoxycarbonyl substituted with hydroxy, amino, halogen, carboxyl, acyl, alkoxy, alkoxycarbonyl or straight or branched acylamino of up to 5 carbon atoms each, and an aryl ring of 6 to 10 carbon atoms which is substituted with linear or branched alkyl of up to 4 carbon atoms, and (C2-C10) alkenyl, (C2-C10) alkynyl, (C7-C20) alkyl, which are optionally substituted by aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamino, hydroxy, amino, azido, carboxyl , acyl, alkoxy, alkoxycarbonyl or linear or branched acylamino of up to 5 carbon atoms each or with a radical of formula -OR4 in which R4 means linear or branched acyl of up to 5 carbon atoms and alkyl (C, -C6) which is substituted 1 to 3 times with aryl, heteroaryl, halogen (s), cyano, dialkylamino, alkylamino or cycloalkyl, and acyl, which is substituted by halogen (s), especially preferred F, or acyloxy, arylthio or heteroarylthio, and -NO or remains of formulas -S03H or -S (0) dR ", in which d means a number 1 or 2, R9 represents linear or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms or a saturated or unsaturated heterocycle of 5 or 6 members with up to 3 heteroatoms of the group S , N and / or 0, wherein the ring systems may be substituted, if appropriate, with halogen or with linear or branched alkyl or alkoxy of up to 4 carbon atoms each, and a remainder of formula PO (OR10) (OR11), in which R10 and R11 are the same or different and denote hydrogen, linear or branched alkyl of up to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms or benzyl, oxicycloalkyl of 3 to 8 ring members or formula residues -CON = C (NH2) 2, -C = NH (NH2), -NH-C (= NH) NH2 or (CO) .NR, 2R13 in which e means a number 0 or 1, R12 and R'3 are the same or different and denote hydrogen, linear or branched alkyl of up to 14 carbon atoms or cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 10 carbon atoms or a saturated or unsaturated ring of 3 to 10 members with up to 5 heteroatoms of the group of N, O, S, the said radicals possibly being substituted with aryl of 6 to 10 carbon atoms, heterocyclyl, cycloalkyl of 3 to 7 carbon atoms, hydroxy, amino or alkoxy, acyl or linear alkoxycarbonyl or branched of up to 6 carbon atoms each, and in the case that e means 1, R12 and R13 can also form, including the nitrogen atom to which they are attached, a 5- or 6-membered ring with up to 3 heteroatoms from the group of N, O, S, which can 15 to be substituted in its case up to 3 times with hydroxy, alkoxy or alkyl of up to 8 carbon atoms each, and in the case where e means 0, R12 and R13 can also mean linear, branched or cyclic acyl of up to 14 carbon atoms, hydroxyalkyl, alkoxycarbonyl or linear acyloxyalkyl or 25 branched of up to 6 carbon atoms each or a residue of formula -S02R14 in which R 14 is linear or branched alkyl of up to 4 carbon atoms, and / or R12 and R13 also mean remains of formulas 20 25 R * -? - CH (R ") -? - C? - n those that R "-R16 and R18-R31 are the same or different and denote hydrogen or linear or branched alkyl of up to 4 carbon atoms, means a number 0, 1 or 2, R17 means phenyl, linear or branched alkyl of up to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms carbon, with the proviso that, if e means 0, R12 and R13 do not represent hydrogen at the same time, R1 represents a purine residue, which may be substituted up to three times with halogen, azido, cyano, hydroxy, amino, monoalkylamino of up to 5 carbon atoms, dialkylamino of up to 5 carbon atoms each, alkyl of up to 5 atoms carbon and / or alkoxy of up to 5 carbon atoms, R2 and R3 form, with the inclusion of the double bond, an associated pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, which in its case is substituted up to 2 times by the same or different substituent. formyl, carboxyl, hydroxyl, mercaptyl, acyl, alkylthio or straight or branched alkoxycarbonyl of up to 5 carbon atoms each, nitro, cyano, azido, fluoro, chloro, bromo or alkyl or straight or branched alkoxy of up to 5 carbon atoms each one which in turn can be substituted with hydroxy, amino, carboxyl, acyl, alkoxy or linear or branched alkoxycarbonyl of up to 4 atoms of carbon, and / or the above-mentioned heterocyclic ring is substituted with a group of the formula -NR32R33, in which R32 and R33 are the same or different and mean hydrogen or linear or branched alkyl of up to 4 carbon atoms, R3- means hydrogen and R3: means formyl and / or the above-mentioned associated pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring is substituted with phenyl, which in turn can be substituted with fluorine, chlorine, bromine or with linear or branched alkyl or alkoxy of up to 4 carbon atoms each . represents thienyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl, which are optionally substituted up to 2 times with the same or different hydroxy, formyl, carboxyl, acyl, alkylthio, alkyloxycyclic, alkoxy or linear or branched alkoxycarbonyl substituent of up to 4 carbon atoms, fluorine, chlorine or bromine, and its isomeric forms and salts.
3. Compounds of general formula (I) according to claim 1 characterized because: R1 represents a pyrimidine moiety, which is substituted in your case up to 2 times with the same or different group (i), consisting of hydrogen, amino, hydroxy, alkoxy or alkoxycarbonyl of up to 3 carbon atoms each, cyano or halogen and is substituted with at least one residue of group (ii), composed of a ring of 5 to 6 members which may be saturated, unsaturated or partially saturated, containing from 1 to 3 heteroatoms of the group of N, O, S, SO, S02 and which may also be linked by N, imidazolyl being especially preferred, imidazolinyl, imidazolidinyl, morpholino, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl and thiomorpholinyl, 10 and that it is substituted one or more times with a 5-membered ring containing two oxygen atoms as ring members and forming a bicyclic structure or a spiro structure with the ring of 3 to 8 members, for example A 1,4-dioxa-8-azaspiro [4, 5] decane and 1,5-dioxa-9-azaspiro [5.5] undecane, and / or hydroxy, cyano, alkyl, acyl or straight or branched alkoxycarbonyl moiety up to 3 carbon atoms each, may be substituted alkyl, acyl and Alkoxycarbonyl with hydroxy, amino, halogen, carboxyl, acyl or straight or branched alkoxy of up to 3 carbon atoms each, and 25 a tolyl residue, C7 alkyl, which is substituted with cyano, and alkyl (Cj-C3) which is substituted 1 to 3 times with halogen (s), cyano, aryl and acyloxy, and 10 -NO or residues of the formula -S (0) dR ', in 1st that d means a number 1 or 2, 15 R 'means linear or branched alkyl of 1 to 4 carbon atoms, aryl of 6 carbon atoms or thienyl, 20 a remainder of formula PO (OR10) (OR "), in which R 10 and R "are the same or different and mean linear or branched alkyl of up to 3 atoms carbon and remains of formulas -NH-C (= NH) NH2 or (C0) «NR, 2R'3 in which means a number 0 or 1, R12 and R13 are the same or different and mean hydrogen, linear or branched alkyl of up to 4 carbon atoms or cycloalkyl of 3 carbon atoms, said residues may be 15 substituted, if appropriate, with C 6 aryl, furyl, cycloalkyl of 3 carbon atoms, hydroxy, linear alkoxy of up to 2 carbon atoms, 20 and in the case that e means 1, R12 and R13 can also form, including the nitrogen atom to which they are attached, a 5- or 6-membered ring with up to 2 25 heteroatoms of the group of N, 0, S, which may be substituted in its case up to 2 times with hydroxy or methyl, and in the case that e means 0, R12 and R13 also mean linear acyl of up to 14 carbon atoms and / or R12 and R13 also mean a residue of the formula with the proviso that, if e means 0, R12 and R '\ do not represent hydrogen at 20 same time, R1 represents a purine residue that can be 25 substituted in its case up to twice with halogen, azido, amino, monoalkylamino of up to 4 atoms carbon and / or methyl, R2 and R3 form, including the double bond, a pyridyl or pyrimidinyl ring, represents phenyl or pyrimidyl which is substituted, if appropriate, with fluorine, chlorine or bromine, and its isomeric forms and salts. Four . Compounds according to one of the preceding claims characterized in that: R1 represents a residue of formula in which R1 represents NH2 R1 'represents morpholino, piperidino, piperazino, pyrrolidino, triazolyl or thiomorpholino where appropriate replaced Y R "1 represents hydrogen or NB Compounds according to claim 4, wherein R 1 represents morpholinyl. A process for the preparation of compounds of general formula (I) according to claim 1, characterized in that depending on the different meanings of the heterocycles previously mentioned in R2 and R3, [A] the compounds of general formula (II) R'-D (II) in which R1 has the meaning given above, Y represents remnants of formulas in which R38 represents C? -C alkyl? < , by reaction with compounds of general formula :neither ) A-CH2-NH-NH2 (III) in which A has the meaning given above, in inert solvents, where appropriate in the presence of a base; they are transformed into the compounds of general formula (IV) or (IVa) in which A and R1 have the meaning given above, and in the case of compounds of general formula (IVa), they are subsequently cyclized with carboxylic acids, nitriles, formamides or guanidinium salts, and in the case of compounds of general formula (IV) are cyclized with 1,3-dicarbonyl derivatives, their salts, tautomers, enol ethers or enamines in the presence of acids and, where appropriate, microwaves, [B] in case R2 and R3 form a pyrazine ring together, the compounds of general formula (IV) are first transformed by nitrosation into the compounds of general formula (V) in which A and R1 have the meaning given above, in a second step, the compounds of general formula (VI) are prepared by reduction in which A and R1 have the meaning given above. and finally they are cyclized with 1,2-dicarbonyl compounds, preferably aqueous glyoxal solution, [C] compounds of general formula (VII) in which A, R2 and R3 have the meaning given above, Y represents a residue of the formula -SnR ^ 4 ^ 41, ZnR42, iodine, bromine or triflate, in which R39, R40 and R41 are the same or different means linear or branched alkyl of up to 4 carbon atoms, Y R42 means halogen, they are reacted with compounds of general formula (VIII) R'-T (VIII) in which R1 has the meaning given above Y in the case that L = SnR3 ^ 4 ^ 41 or ZnR42, T represents triflate or halogen, preferably bromine, Y in the case where L = iodine, bromine or triflate, T represents a radical of the formula SnR ^ 'R ^' R41 ', ZnR42' or BR ^ 'R44', in which R39, R40 ', R41' and R42 'have the meaning given for R39, R40, R4' and R42 and are the same or different from these, R43 'and R44' are the same or different and mean hydroxy, aryloxy of 6 to 10 carbon atoms or straight or branched alkyl or alkoxy of up to 5 carbon atoms each, or together form a carbocyclic ring of 5 or 6 members, in a reaction catalyzed with palladium in inert solvent, where appropriate in the presence of a base, [D] in the case that R1 represents a substituted pyrimidine residue, the amidines of general formula (IX) wherein A, R2 and R3 have the meaning given above, they are reacted, for example, with compounds of general formulas (X), (Xa), (Xb) or (Xc) PC) (Xa) where (Xb) (Xc) R1 'represents a cycloalkyl radical, substituted 10 where appropriate, previously cited in R1 Alk represents a linear or branched alkyl of up to 8 carbon atoms, preferably up to four carbon atoms, represents an NH2 group, monoalkylamino group of up to 7 carbon atoms, group 20 dialkylamino of up to 7 carbon atoms, a piperidino or morpholino moiety linked by nitrogen, hydroxyl, alkoxy of up to 7 carbon atoms, acyloxy of up to 7 carbon atoms or aroyloxy of 6 to 10 atoms 25 carbon, and in the case of groups -S (0) .NR6R7 and -S (O) eNR6'R7 ', starting from unsubstituted compounds of general formula (I), they are first reacted with thionyl chloride and in a second step with the corresponding amines and, if appropriate, the substituents mentioned as X, Y, R1, R2, R3 and / or A are varied or introduced according to conventional procedures, preferably by acylation of the amino groups or free hydroxy groups, chlorination, catalytic hydrogenation, reduction, oxidation , separation of protective groups and / or nucleophilic substitution. The macacanepto characterized as an acptiepe park has at least one aampjeste of general formula (I) according to claim 1. A process for the preparation of medicaments, characterized in that at least one compound of formula (I) according to claim 1 is converted, where appropriate with conventional adjuvants and additives, into a suitable administration form. Lh madicana-ito characterized in that ccntiaie at least one ocmpuesto of the general formula (I) according to claim 1, combined with organic nitrates or donors of NO. The rearing characterized by the park contains the trains in prpjesto of the general formula (I) according to claim 1, combined with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP). The use of compounds of general formula (I) according to claim 1 for the preparation of medicaments. The use of compounds of general formula (I) according to claim 1 for the preparation of medicaments for the treatment of cardiocirculatory disorders. The use of compounds of general formula (I) according to claim 1 for the preparation of medicaments for the treatment of hypertension. The use of compounds of general formula (I) according to claim 1 for the preparation of medicaments for the treatment of thromboembolic disorders and ischemia. The use of compounds of general formula (I) according to claim 1 for the preparation of medicaments for the treatment of sexual dysfunction. The use of compounds of general formula (I) according to Claim 1 for the preparation of medicaments with anti-inflammatory properties. The use according to one of claims 11 to 16, wherein the compounds of general formula (I) according to claim 1 are used in combination with organic nitrates or NO donors or combined with compounds that inhibit the degradation of cyclic guanosine monophosphate ( cGMP). EESMNIELA EWENZK The present invention relates to novel substituted pyrazole derivatives of general formula (I), in which R1, R2, R3 and A have the meaning given above, as well as to processes for their preparation and their use as medicaments, especially as medicines for the treatment of cardiocirculatory disorders.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE19834044.3 | 1998-07-29 |
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MXPA01000991A true MXPA01000991A (en) | 2001-12-13 |
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