WO2001064648A1 - Isoquinoline derivatives - Google Patents
Isoquinoline derivatives Download PDFInfo
- Publication number
- WO2001064648A1 WO2001064648A1 PCT/HU2001/000025 HU0100025W WO0164648A1 WO 2001064648 A1 WO2001064648 A1 WO 2001064648A1 HU 0100025 W HU0100025 W HU 0100025W WO 0164648 A1 WO0164648 A1 WO 0164648A1
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- WIPO (PCT)
- Prior art keywords
- general formula
- hydrogen atom
- group
- salts
- compounds
- Prior art date
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- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 claims abstract description 12
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 claims abstract description 12
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 5
- 208000006673 asthma Diseases 0.000 claims abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 61
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- 150000003839 salts Chemical class 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- -1 pyrrolidino, piperidino, piperazino, 4-methylpiperazino Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 abstract description 8
- 102000004190 Enzymes Human genes 0.000 abstract description 8
- 229940124639 Selective inhibitor Drugs 0.000 abstract 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000002349 favourable effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- AAGOMYYMYXEUDS-UKKPGEIXSA-N 5-chloro-2-cyano-N-[(1R,2R)-2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]pentanamide Chemical compound C1=C(OC)C(OCC)=CC([C@@H]2[C@@H](CCCC2)NC(=O)C(CCCCl)C#N)=C1 AAGOMYYMYXEUDS-UKKPGEIXSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- HBEISVPEKQWAOQ-HRUVVLKGSA-N 2-cyano-N-[(1R,2R)-2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-5-pyrrolidin-1-ylpentanamide Chemical compound C1=C(OC)C(OCC)=CC([C@@H]2[C@@H](CCCC2)NC(=O)C(CCCN2CCCC2)C#N)=C1 HBEISVPEKQWAOQ-HRUVVLKGSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical class C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DGOBNHTVEUJPNS-XMCWYHTOSA-N 2-cyano-N-[(1R,2R)-2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-5-(4-methylpiperazin-1-yl)pentanamide Chemical compound CCOc1cc(ccc1OC)[C@H]1CCCC[C@H]1NC(=O)C(CCCN1CCN(C)CC1)C#N DGOBNHTVEUJPNS-XMCWYHTOSA-N 0.000 description 1
- MFNQKMFJNUSJMG-HRUVVLKGSA-N 2-cyano-N-[(1R,2R)-2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-5-morpholin-4-ylpentanamide Chemical compound C1=C(OC)C(OCC)=CC([C@@H]2[C@@H](CCCC2)NC(=O)C(CCCN2CCOCC2)C#N)=C1 MFNQKMFJNUSJMG-HRUVVLKGSA-N 0.000 description 1
- NZNFOYSBPPFJNF-UHFFFAOYSA-N 2h-1,3-oxazine;2h-1,4-oxazine Chemical compound C1OC=CN=C1.C1OC=CC=N1 NZNFOYSBPPFJNF-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- BYVSMDBDTBXASR-UHFFFAOYSA-N 5,6-dihydro-4h-oxazine Chemical group C1CON=CC1 BYVSMDBDTBXASR-UHFFFAOYSA-N 0.000 description 1
- KKCMBKOBIYZEEZ-UHFFFAOYSA-N 5-chloro-2-cyanopentanoyl chloride Chemical compound ClCCCC(C#N)C(Cl)=O KKCMBKOBIYZEEZ-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101100135868 Dictyostelium discoideum pde3 gene Proteins 0.000 description 1
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 1
- 101100135859 Dictyostelium discoideum regA gene Proteins 0.000 description 1
- 101001117089 Drosophila melanogaster Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 Proteins 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 101150098694 PDE5A gene Proteins 0.000 description 1
- 101100082606 Plasmodium falciparum (isolate 3D7) PDEbeta gene Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 101100135860 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PDE2 gene Proteins 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000025609 Urogenital disease Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- AXLOCHLTNQDFFS-BESJYZOMSA-N azastene Chemical compound C([C@H]1[C@@H]2CC[C@@]([C@]2(CC[C@@H]1[C@@]1(C)C2)C)(O)C)C=C1C(C)(C)C1=C2C=NO1 AXLOCHLTNQDFFS-BESJYZOMSA-N 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AQNQGBUEVCAVML-UHFFFAOYSA-N oxazepane Chemical group C1CCNOCC1 AQNQGBUEVCAVML-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 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 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 208000028394 ureteral disease Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
Definitions
- the invention relates to the PDE4 inhibitors of the general formula (I), to the salts, solvates, geometric or optically active isomers thereof, to the pharmaceutical compositions containing them, to the use of the compounds of the general formula (I) and their salts, solvates. geometric or optically active isomers. to the preparation of the compounds of the general formula (I) ( Figure 1) and their salts, solvates, geometric and optically active isomers, and to the new intermediates of the general formula (II) ( Figure 2) and their preparation.
- PDE4 inhibitors are supposed to be useful in the treatment of diseases like for instance asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiplex sclerosis and dermatological diseases.
- COPD chronic obstructive pulmonary disease
- R 1 stands for straight or branched Cj. alkyl or C 4 . 6 cycloalkyl group
- R 2 stands for straight or branched C]_ 4 alkyl or C 4 . 6 cycloalkyl group
- R J stands for hydrogen atom or straight or branched C alkyl
- R 4 stands for hydrogen atom or straight or branched C
- R 5 stands for hydrogen atom or straight or branched C
- R 6 stands for hydrogen atom or straight or branched C alkyl.
- R 7 stands for hydrogen atom or straight or branched C,. 4 alkyl. with the proviso that one substituent selected from the groups of R 4 .
- R 3 , R 6 or R always has a meaning different from hydrogen atom, or R ""* and R 1 mean together a
- R stands for hydrogen atom or a straight or branched C ⁇ _ alkyl group
- R stands for hydrogen atom or a straight or branched C alkyl group
- R 10 means saturated 4 to 7 membered ring containing one or two nitrogen atom(s) connecting through the nitrogen atom and optionally substituted by a C
- X stands for -CH 2 - group, m is zero or 1, n is 1 - and their salts, solvates, geometric or optically active isomers and their salts surprisingly fulfil the desired criteria.
- C ⁇ _ 4 alkyl group we mean butyl, isobutyl, sec. -butyl, terc- butyl, propyl. preferably ethyl or methyl group.
- C 4 . 6 cycloalkyl group we mean cyclobutyl. cyclopentyl or cyclohexyl group.
- the saturated 4 to 7 membered ring containing one nitrogen atom means azetidine.
- the ring may optionally be substituted by a
- the saturated 4 to 7 membered ring containing one nitrogen and one oxygen atom means 1,4-oxazine 1,3-oxazine or 1.2-oxazine ring, isoxazol or oxazol ring.
- the ring containing two nitrogen atoms may be for instance imidazoline or piperazine ring.
- the ring may optionally be substituted by a C]. alkyl group.
- salts of the compounds of the general formula (I) we mean salts formed with organic or inorganic acids or salts formed with bases.
- the salts formed with pharmaceutically acceptable acids as for instance with hydrochloric acid, sulfuric acid, phosphoric acid, alkyl-sulfonic acids, tartaric acid, maleic acid, citric acid or oxalic acid.
- solvates we mean solvates formed with various solvents, as for instance with water, or with ethanol.
- the compounds of the general formula (I) show geometrical and optical isomerism. therefore the invention also relates to the mixtures of the geometric isomers. to the racemic or optically active geometric isomers, and the salts and solvates thereof.
- R 1 means methyl- or ethyl-group
- R means methyl- or ethyl-group
- R J means hydrogen atom
- R 4 means hydrogen atom
- R 5 and R 6 mean together a - (CH 2 )z - group - wherein z is 3, 4 or 5,
- R means hydrogen atom
- o R means hydrogen atom
- R 9 means hydrogen atom
- R !0 means pyrrolidino, piperidino, piperazino, 4-methylpiperazino or morpholino- group, m is 1, n is 1 - and their salts and solvates. or their racemic or optically active geometric isomers, and the salts and solvates thereof.
- racemic or optically active cis-isomers of the above compounds as for instance the (+)-cis-2-(3-pyrrolidinopropyl)-2-(9-ethoxy-8-methoxy-l,2,3,4.4a.5.6,10b- octahydrophenanthridine-6-yliden)acetonitrile,
- compositions containing the compounds of the general formula (I), their isomers, salts, solvates which are preferably oral compositions, but inhalable, parentheral and transdermal compositions also constitutes subjects of the present invention.
- the above pharmaceutical compositions may be solids or liquids, for instance tablets, pellets, capsules, solutions, suspensions, or emulsions. Solid compositions, first of all tablets and capsules are preferred.
- the above drug products are prepared by applying excipients and technological operations commonly used in the pharmaceutical production.
- the compounds of the general formula (I) according to the present invention are useful for the treatment of diseases connected with abnormally high PDE4 enzyme activity.
- diseases connected with abnormally high PDE4 enzyme activity are for instance asthma, chronic obstructive pulmonary disease (COPD), allergic diseases, inflammatory diseases, bronchitis, atopic dermatitis. arthritis, emphysema, sclerosis multiplex, septic shock, Crohn-disease. liver damages, pulmonary hypertension, kidney and ureteral diseases, urogenital diseases and osteoporosis.
- an amide of the general formula (II) or (Ila) is reacted with a cyclizing agent and the resulting compound of the general formula (I) is, if desired, transformed into its salt, solvate, or liberated from its salt, solvate. separated into its geometric isomers and/or resolved into its optical isomers.
- cyclizing agent preferably phosphoryl chloride and/or polyphosphoric acid can be applied, but other cyclizing agents known in the organic chemistry can also be used.
- Cyclisation can be effected in a broad temperature range, preferable are temperatures between 60 °C - 180 °C.
- the starting compounds of the general formula (II) or (Ila) may be prepared one of the known methods, as for instance according to Reaction Scheme 1, ( Figure 3 and 4) starting from the 1,2-dihydroxybenzene of the formula (XIII) via the compound of the general formula (V).
- R ] -R 3 , R 8 -R 10 are the same as defined above.
- X and the value of m and n are as defined in claim 1, Hlg stands for halogen atom or alkoxy group - can be accomplished by using methods known per se (DE- 19603321 and WO-97/28131).
- the compounds of the general formula (XII) and (X) may be prepared for instance by using a reagent R -halogen, R -tosyl and R ⁇ -halogen. R ⁇ - tosyl. Further methods are known from the following literature sources: J. Org. Chem. 62. p 4504 (1997), J. Amer. Chem. Soc. 63, p 1482 (1941). J. Org. Chem. 26, p 4165
- R stands for ethyl group, R ⁇ for methyl group.
- R J for hydrogen atom
- R 4 for hydrogen atom.
- R 3 and R 6 form together a - (CH 2 ) 7 - group, wherein the value of z is 4, R is hydrogen atom, R is hydrogen atom.
- R is hydrogen atom, R 1 means pyrrolidino group.
- X means - (CFE) - group, m is 1 , n is 1.
- R 1 stands for ethyl group, R for methyl group, R J for hydrogen atom, R 4 for hydrogen atom, R 5 and R 6 orm together a - (CH 2 ) Z - group, wherein the value of z is 4, R 7 is hydrogen atom, R 8 is hydrogen atom, R 9 is hydrogen atom, R 10 means piperidino group, X means - (CH 2 ) - group, m is 1. n is 1.
- R stands for ethyl group.
- R ⁇ for methyl group.
- R for hydrogen atom, R 4 for hydrogen atom, R 5 and R 6 form together a - (CH 2 )z - group, wherein the value of z is 4, R is hydrogen atom.
- R is hydrogen atom.
- R 10 means morpholino group.
- R stands for ethyl group.
- R for methyl group R " for hydrogen atom, R 4 for hydrogen atom, R 5 and R 6 form together a - (CH 2 )z - group. ⁇ o q wherein the value of z is 4, R is hydrogen atom.
- R is hydrogen atom.
- R 10 means 4-methylpiperazino group.
- R stands for ethyl group, R for methyl group.
- R J for hydrogen atom
- R 4 for ethyl group
- R 5 for hydrogen atom
- R' for hydrogen atom
- R 7 for hydrogen atom
- R 8 for hydrogen atom
- R 9 for hydrogen atom
- R 10 means pyrrolidino group
- X means - (CH 2 ) - group
- m is 1
- n is 1.
- R 1 stands for ethyl group
- R 2 for methyl group
- R J for hydrogen atom
- R 4 for hydrogen atom
- R 5 for hydrogen atom
- R 6 for methyl group
- X means - (CH 2 ) - group
- m is 1
- n is 1.
- PDE4 enzyme inhibitory activity of the compounds of the general formula (I) were determined by the following two-step method:
- the standard assay mixture contains:
- the reaction is initiated by addition of the substrate.
- the samples are incubated at 30 °C for 30 min., then the reaction is stopped by boiling the assay tubes for 2 min.
- 50 ⁇ l of the poison of the Crotalux atrox snake species (0,5 mg/ml distilled water) is added and the samples are incubated at 37°C for 30 min.
- the nonreacted cAMP is removed by chromatography on Dowex 1x8 (chloride form) ion-exchange resin: 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min.
- the mixture of 500 ml supernatant and of 2 ml of the liquid scintillation cocktail is measured to determine the amount of formed [ ⁇ ] adenosine.
- the compounds of the general formula (I) show very high selectivity for PDE4 enzyme.
- the compounds of the general formula (I) show favourable chemical stability. favourable metabolic stability in biological media both in vitro and in vivo, they are readily absorbed in vitro on CaCo 2 model, as well as in vivo after oral administration as compared to the known PDE4 inhibitors. They exhibit good bioavailability and isoenzyme selectivity. Furthermore, their duration of activity after intravenous and oral administration is long, their ED 50 value is low and their toxicological and side effect profile is favourable.
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Abstract
New compounds of the general formula (I) are strong and selective inhibitors of PDE4 enzyme and they are presumably suitable for the treatment of for instance asthma, chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis.
Description
ISOQUINOLINE DERIVATIVES
The invention relates to the PDE4 inhibitors of the general formula (I), to the salts, solvates, geometric or optically active isomers thereof, to the pharmaceutical compositions containing them, to the use of the compounds of the general formula (I) and their salts, solvates. geometric or optically active isomers. to the preparation of the compounds of the general formula (I) (Figure 1) and their salts, solvates, geometric and optically active isomers, and to the new intermediates of the general formula (II) (Figure 2) and their preparation.
A number of compounds and groups of compounds with PDE4 inhibitory activity are known from the literature (Drug News and Perspectives 8_(8) p 514-520 (1995)). PDE4 inhibitors are supposed to be useful in the treatment of diseases like for instance asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiplex sclerosis and dermatological diseases.
However, the PDE4 inhibitory compounds selected for development turned out to exert several side effects during clinical studies, precluding or strongly limiting their therapeutic application. Such side effects are vomiting and cardiovascular reactions. It is supposed that these side effects are consequences of the relatively weak selectivity and unfavourable side effect profile of the PDE4 inhibitors described in the literature.
Additional disadvantages of the known compounds are toxicity, insufficient bioavailability and weak stability.
We aimed to develop isoquinolme type PDE4 inhibitors which exhibit strong inhibitory activity and are selective to the PDE4 enzyme, i.e. they inhibit the PDE4 enzyme in much smaller concentration than the enzymes PDE1. PDE2, PDE3 and PDE5. Further aims were good stability, bioavailability, therapeutic index and low toxicity favouring drug development, and good enteric absorption allowing oral application.
We have found that the compounds of the general formula (I)
- wherein
R1 stands for straight or branched Cj. alkyl or C4.6 cycloalkyl group,
R2 stands for straight or branched C]_4 alkyl or C4.6 cycloalkyl group, RJ stands for hydrogen atom or straight or branched C alkyl,
R4 stands for hydrogen atom or straight or branched C|.4 alkyl.
R5 stands for hydrogen atom or straight or branched C|_4 alkyl.
R6 stands for hydrogen atom or straight or branched C alkyl.
R7 stands for hydrogen atom or straight or branched C,.4 alkyl. with the proviso that one substituent selected from the groups of R4. R3, R6 or R always has a meaning different from hydrogen atom, or R""* and R1 mean together a
-(CH2)Z- group - wherein z is 3 or 4 or 5.
R stands for hydrogen atom or a straight or branched Cι_ alkyl group,
R stands for hydrogen atom or a straight or branched C alkyl group, R10 means saturated 4 to 7 membered ring containing one or two nitrogen atom(s) connecting through the nitrogen atom and optionally substituted by a C |_4 alkyl group, or a saturated 4 to 7 membered ring containing one nitrogen atom and one oxygen atom connecting through the nitrogen atom and optionally substituted by a C]_ alkyl group,
X stands for -CH2- group, m is zero or 1, n is 1 - and their salts, solvates, geometric or optically active isomers and their salts surprisingly fulfil the desired criteria.
Detailed meanings of the above listed substituents are as follows: By straight or branched Cι_4 alkyl group we mean butyl, isobutyl, sec. -butyl, terc- butyl, propyl. preferably ethyl or methyl group. By C4.6 cycloalkyl group we mean cyclobutyl. cyclopentyl or cyclohexyl group.
j
The saturated 4 to 7 membered ring containing one nitrogen atom means azetidine. pyrrolidine, piperidine or perhydroazepine ring connected to the other part of the molecule through the nitrogen atom. The ring may optionally be substituted by a
Cι_4 alkyl group. The saturated 4 to 7 membered ring containing one nitrogen and one oxygen atom means 1,4-oxazine 1,3-oxazine or 1.2-oxazine ring, isoxazol or oxazol ring. saturated 2-oxa-azetidine or 3-oxa-azetidine ring, or perhydro-oxazepine ring, connected to the other part of the molecule through the nitrogen atom.
The ring containing two nitrogen atoms may be for instance imidazoline or piperazine ring. The ring may optionally be substituted by a C]. alkyl group.
By salts of the compounds of the general formula (I) we mean salts formed with organic or inorganic acids or salts formed with bases. Preferable are the salts formed with pharmaceutically acceptable acids, as for instance with hydrochloric acid, sulfuric acid, phosphoric acid, alkyl-sulfonic acids, tartaric acid, maleic acid, citric acid or oxalic acid.
By solvates we mean solvates formed with various solvents, as for instance with water, or with ethanol.
The compounds of the general formula (I) show geometrical and optical isomerism. therefore the invention also relates to the mixtures of the geometric isomers. to the racemic or optically active geometric isomers, and the salts and solvates thereof.
Favourable selections of the compounds of the general formula (I) are those
- wherein
R1 means methyl- or ethyl-group,
R means methyl- or ethyl-group, RJ means hydrogen atom,
R4 means hydrogen atom,
R5 and R6 mean together a - (CH2)z - group - wherein z is 3, 4 or 5,
R means hydrogen atom, o R means hydrogen atom ,
R9 means hydrogen atom ,
R!0 means pyrrolidino, piperidino, piperazino, 4-methylpiperazino or morpholino- group, m is 1, n is 1 - and their salts and solvates. or their racemic or optically active geometric isomers, and the salts and solvates thereof.
Especially favourable are the racemic or optically active cis-isomers of the above compounds, as for instance the (+)-cis-2-(3-pyrrolidinopropyl)-2-(9-ethoxy-8-methoxy-l,2,3,4.4a.5.6,10b- octahydrophenanthridine-6-yliden)acetonitrile,
(±)-cis-2-(3-piperidinopropyl)-2-(9-ethoxy-8-methoxy- 1,2, 3,4,4a.5.6,10b- octahydrophenanthridine-6-yliden)acetonitrile
(±)-cis-2-(3-morpholinopropyl)-2-(9-ethoxy-8-methoxy- 1,2, 3,4.4a.5, 6,10b- octahydrophenanthridine-6-yliden)acetonitrile
(-)-cis-2-(3-pyrrolidinopropyl)-2-(9-ethoxy-8-mefhoxy-l,2,3,4,4a.5.6, 10b- octahydrophenanthridine-6-yliden)acetonitrile;
Further subjects of the present invention are pharmaceutical compositions containing the compounds of the general formula (I), their isomers, salts, solvates, which are preferably oral compositions, but inhalable, parentheral and transdermal compositions also constitutes subjects of the present invention. The above pharmaceutical compositions may be solids or liquids, for instance tablets, pellets, capsules, solutions, suspensions, or emulsions. Solid compositions, first of all tablets and capsules are preferred. The above drug products are prepared by applying excipients and technological operations commonly used in the pharmaceutical production.
The compounds of the general formula (I) according to the present invention are useful for the treatment of diseases connected with abnormally high PDE4 enzyme activity. Such are for instance asthma, chronic obstructive pulmonary disease (COPD), allergic diseases, inflammatory diseases, bronchitis, atopic dermatitis.
arthritis, emphysema, sclerosis multiplex, septic shock, Crohn-disease. liver damages, pulmonary hypertension, kidney and ureteral diseases, urogenital diseases and osteoporosis.
Further subject of the invention is the use of the compounds of the general formula (I) in the treatment of the diseases listed above.
In another aspect of the present invention there is provided a process for the preparation of the compounds of the general formula (I) and of the intermediates (II) and (Ila): According to the present invention an amide of the general formula (II) or (Ila) is reacted with a cyclizing agent and the resulting compound of the general formula (I) is, if desired, transformed into its salt, solvate, or liberated from its salt, solvate. separated into its geometric isomers and/or resolved into its optical isomers.
As cyclizing agent preferably phosphoryl chloride and/or polyphosphoric acid can be applied, but other cyclizing agents known in the organic chemistry can also be used.
Cyclisation can be effected in a broad temperature range, preferable are temperatures between 60 °C - 180 °C.
- The starting compounds of the general formula (II) or (Ila) may be prepared
one of the known methods, as for instance according to Reaction Scheme 1, (Figure 3 and 4) starting from the 1,2-dihydroxybenzene of the formula (XIII) via the compound of the general formula (V). Preparation of the compounds of the general formula (XII)-(II) - wherein the meanings of R5 , R6 and R7, R4 are the same as defined above. R]-R3, R8-R10. X and the value of m and n are as defined in claim 1, Hlg stands for halogen atom or alkoxy group - can be accomplished by using methods known per se (DE- 19603321 and WO-97/28131). The compounds of the general formula (XII) and (X) may be prepared for instance by using a reagent R -halogen, R -tosyl and R^-halogen. R~- tosyl.
Further methods are known from the following literature sources: J. Org. Chem. 62. p 4504 (1997), J. Amer. Chem. Soc. 63, p 1482 (1941). J. Org. Chem. 26, p 4165
(1961 ). J. Chem. Soc. p. 4280 (1956).
Compounds of the general formula (I) -wherein R4. R\ R6 and R7 stand for hydrogen atom or straight or branched C alkλ l group, with the proviso that one substituent selected from the groups of R4. R\ R6 or R7 always has a meaning different from hydrogen atom- can be prepared according to Reaction Scheme 2 (Figures 5 and 6); starting from the compound of the general formula (XVI) - wherein the meanings of R1, R2, R R4, R3, R6. R7 are as defined above- obtained as described in Berichte 58 S 1281 (1925), J. Am. Chem Soc. 74 p 461 1-14 ( 1952); via the compounds of the general formulae (XV) and (Ila); by reacting the compound of the general formula (XV) - wherein the meanings of R1, R2, R3, R4, R5, R7, R8. R9 m and n are as defined in claim 1 - with a compound of the general formula R10 - H - wherein the meaning of R1 is as defined in claim 1- or with its salt, and if desired liberating the resulting compound of the general formula (Ila) from its salt or transforming it to its salt.
Further subjects of the present invention are the intermediates of the general formulae (II) and (Ila) - wherein the meanings of R1, R2. R3. R4, R5. R6. R7, R8. R9. R10, X and the value of m and n are as defined in claim 1 - and their salts. The compounds of the general formulae (I), (II) and (III) according to the present invention, as well as their preparation and biological activity are demonstrated in the following examples, without limiting the claims to the examples.
Examples
Example 1
(+)-cis-2-(3-pyrroIi inopropyl)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
In the general formula (I) R stands for ethyl group, R~ for methyl group. RJ for hydrogen atom, R4 for hydrogen atom. R3 and R6 form together a - (CH2)7 - group, wherein the value of z is 4, R is hydrogen atom, R is hydrogen atom. R is hydrogen atom, R1 means pyrrolidino group. X means - (CFE) - group, m is 1 , n is 1.
a.) (±)cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5-chloro-valeryl amide
Into the solution made of 0,83 g of (±) cis- (3-ethoxy-4- methoxyphenyl)cyclohexylamine and 0.80 g of 4-(dimethylamino)pyridine in 8 ml of dichloromethane is added dropwise under stirring at 0°C 0.65 g of 2-cyano-5- chlorovaleryl chloride in 2 ml of dichloromethane. The reaction mixture was stirred for 1 h at 0 °C, then for 2 hours at 20 °C. then it was washed successively with 10 ml of water, 10 ml of 5 w/w% hydrochloric acid, 10 ml of IN NaHC03 solution and 10 ml of water. After drying over sodium sulfate the mixture was evaporated, the residue was crystallized from 5 ml of ethanol. 0,4 g of the title material was obtained, mp: 130,5 °C.
b.) (±)cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5- pyrrolidinovaleryl amide
0,34 g of (±)cis-N-[2-(3-ethoxy-4-mefhoxyphenyl)cyclohexyl]-2-cyano-5- chorovaleryl amide and 2 ml of pyrrolidine were refluxed for 4 hours, then the
reaction mixture was evaporated in vacuo. The residue was extracted with the mixture of 10 ml of water and 15 ml of dichloromethane, the organic layer was dried over sodium sulfate and evaporated. The oily residue was chromatographed on aluminium oxide column w ith toluene-ethyl acetate 10: 1 mixture eluent. From the pure fractions 100 mg of the title compound was obtained. Rf: 0,8.
c.) (±)cis-2-(3-pyrrolidinopropyl)-2-(9-ethoxy-8-methoxy- 1,2,3.4.4a,5, 6,10b- octahydrophenanthridin-6-ylidene)acetonitrile;
The mixture of 160 mg of (±)cis-N-[2-(3-ethoxy-4-mefhoxyphenyl)cyclohexyl]-2- cyano-5-pyrrolidinovaleryl amide, 0,5 ml of abs. acetonitrile and 0,1 ml of phosphoryl chloride was refluxed for 1.5 h, then after cooling it w as poured onto 5 ml of 10 m/m% sodium hydroxide solution and extracted with 10 ml of ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. The residue was crystallized from 0,5 ml of ethanol to obtain 30 mg of the title (I) compound, mp: 135 °C.
Example 2
(±)-cis-2-(3-piperidinopropyl)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
In the general formula (I) R1 stands for ethyl group, R for methyl group, RJ for hydrogen atom, R4 for hydrogen atom, R5 and R6 orm together a - (CH2)Z - group, wherein the value of z is 4, R7 is hydrogen atom, R8 is hydrogen atom, R9 is hydrogen atom, R10 means piperidino group, X means - (CH2) - group, m is 1. n is 1.
The (±)cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5-chloro-valeryl amide prepared as described in Example 1 and piperidine were transformed into
(+)cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5-piperidinovale l amide analogously as described in Example 1 , and cyclized into the title compound of the general formula (I), mp of the title compound: 102 °C.
Example 3
(+)-cis-2-(3-morphoIinopropyI)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-yIidene)acetonitrile
In the general formula (I) R stands for ethyl group. R~ for methyl group. R for hydrogen atom, R4 for hydrogen atom, R5 and R6 form together a - (CH2)z - group, wherein the value of z is 4, R is hydrogen atom. R is hydrogen atom. R is hydrogen atom, R10 means morpholino group.
The (±)cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5-chloro-vale l amide prepared as described in Example 1 and morpholine were transformed into (±)cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5-morpholinovaleryl amide, analogously as described in Example 1 , and cyclized into the title compound of the general formula (I), mp of the title compound: 105 °C.
Example 4
(±)-cis-2-(3-(4-methylpiperazino)propyl)-2-(9-ethoxy-8-methoxy- l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-ylidene)acetonitrile
In the general formula (I) R stands for ethyl group. R for methyl group, R" for hydrogen atom, R4 for hydrogen atom, R5 and R6 form together a - (CH2)z - group. η o q wherein the value of z is 4, R is hydrogen atom. R is hydrogen atom. R is hydrogen atom, R10 means 4-methylpiperazino group.
The (±)cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5-chloro-valen l amide prepared as described in Example 1 and 4-methylpiperazine were transformed into (±)cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5-(4-
methylpiperazino)valeryl amide, analogously as described in Example 1. and cyclized into the title compound of the general formula (I). 1 H-NMR spectrum of the title compound is shown below:
1.52 ppm, t, 3H 9- 0-CH2-CH3
1.9 ppm-1.2 ppm, m, 10H 1-, 2-, 3-, 4-, 3'-, H2
3.1 ppm-2.1 ppm, m, 13H 2'-, A'-, 2"-, 3"-, 5 *-, 6"-, H2 es
10b- H
3.12 ppm, s, 3H N-CH3 3.52 ppm. m, 1H 4a- H 3.98 ppm. s, 3H 8- 0-CH3 4.12 ppm, q, 2H 9- 0-CH2 6.41 ppm, s, 1H NH 6.58 ppm. s, 1H 10- H 7.92 ppm, s, 1H 7- H
Example 5
(-)-cis-2-(3-pyrroIidinopropyl)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
The (-)-cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5-chloro-valeryl amide prepared as described in Example 1 and pyrrolidine were transformed into (-)-cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-2-cyano-5-pyrrolidinovaleryl amide analogously as described in Example 1, and cyclized into the title (-)isomer, mp: 151-152 °C, [α] = - 235 ° (c= 1.5, ethanol).
Example 6
(±)-cis-2-(3-pyrrolidinopropyl)-2-(3-ethyl-6-ethoxy-7-methoxy-l,2,3,4- tetrahydroisoquinolinylidene)acetonitrile
In the general formula (I) R stands for ethyl group, R for methyl group. RJ for hydrogen atom, R4 for ethyl group, R5 for hydrogen atom, R' for hydrogen atom, R7 for hydrogen atom, R8 for hydrogen atom, R9 for hydrogen atom, R10 means pyrrolidino group, X means - (CH2) - group, m is 1, n is 1.
The appropriate amine of the formula (XIV) - wherein the meanings of R . R~. R . R5, R' and R7 are as defined above - is reacted according to Example 1 with the appropriate acid chloride of the general formula (IV) - wherein Hlg means chloro atom, X means - CH2 - group, R2 and R9 means hydrogen atom, m is 1 , n is 1 - to give the acid amide of the general formula (XV), which was transformed with pyrrolidine into the amide of the general formula (II), which was cyclized analogously as described in Example 1. to obtain the title compound of the general formula (I). Η-NMR data of the title compound are shown below:
1.7 ppm- 1.0 ppm, m, 15H 3"-, 4"-, 3'-, H2 es 9- -O-CH CF es 4a- CH2-CH3
3.0 ppm-2.2 ppm, m, 10H 2'-, 4'-, 2"-, 5"-, 10b-H2 3.48 ppm, m, 1H 4a- H
3.92 ppm, s, 3H 8- O-CH3 4.16 ppm, q 2H 9- O-CH2 6.65 ppm, s, 1H 10- H 6.72 ppm, s, 1H NH
8.01 ppm, s, 1H 7- H
Example 7 (±)-cis-2-(3-pyrrolidinopropyI)-2-(4,4-dimethyl-6-ethoxy-7-methoxy-l,2,3,4- tetrahydroisoquinolinylidene)acetonitrile
In the general formula (I) R1 stands for ethyl group, R2 for methyl group, RJ for hydrogen atom, R4 for hydrogen atom, R5 for hydrogen atom, R6 for methyl group, R for methyl group, R for hydrogen atom, R for hydrogen atom, R means pyrrolidino group, X means - (CH2) - group, m is 1 , n is 1.
Analogously as described in Example 1 the appropriate amine of the formula (XIV)
- wherein the meanings of R1, R2, R4, R5, R6 and R7 are as defined above - is reacted with the appropriate acid chloride of the formula (IV) - wherein Hlg stands
for chloro atom and the meaning of R , R , X, m and n are as defined above - to give the acid amide of the general formula (XV). which is transformed with pyrrolidine into the amide of the general formula (Ila), which is cyclized to the title compound of the general formula (I).
1H-NMR data of the title compound are shown below:
1.30 ppm , s,6H: 10b- (-CH3)2
1.42 ppm, t, 3H 9- -O-CH2-CH3
1.8-1.6 ppm,m, 4H 3"-, 4 "-H2
3.0-2.4 ppm, m, 8H 2'-, 4' -, 2"-, 5"- H7
3.58 ppm, m, 2H 4a- H2
3.96 ppm, s, 3H 8- O-CH3
4.19 ppm, q, 2H 9- 0-CH2
6.51 ppm, s, 1H NH
6.63 ppm, s, 1H 10- H
8.06 ppm, s, 1H 7- H
Biological investigations
PDE4 enzyme inhibitory activity of the compounds of the general formula (I) were determined by the following two-step method:
The standard assay mixture contains:
30 μl human PDE4 enzyme
20 μl of one of the test compounds of the general formula (I) or its solution
20 μl [3H] cAMP substrate (220000 dpm)
30 μl 40 mM Tris buffer (pH=7,6) containing 2.5mM magnesium sulfate
The reaction is initiated by addition of the substrate. The samples are incubated at 30 °C for 30 min., then the reaction is stopped by boiling the assay tubes for 2 min. After cooling the tubes 50 μl of the poison of the Crotalux atrox snake species (0,5 mg/ml distilled water) is added and the samples are incubated at 37°C for 30 min. The nonreacted cAMP is removed by chromatography on Dowex 1x8 (chloride form) ion-exchange resin: 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min. The mixture of 500 ml supernatant and of 2 ml of the liquid scintillation cocktail is measured to determine the amount of formed [Η] adenosine.
The following results were obtained by that method compound of the general formula (I) PDE4-ICso (mol/1)
Example 2.
[(±)-cis-2-(3-Piperidinopropyl)-2-(9-ethoxy-8- methoxy-l,2,3,4,4a,5,6,10b-octahydro- 6- 10"9 phenanthridin-6-yliden)acetonitrile;
The compounds of the general formula (I) show very high selectivity for PDE4 enzyme.
The compounds of the general formula (I) show favourable chemical stability. favourable metabolic stability in biological media both in vitro and in vivo, they are readily absorbed in vitro on CaCo2 model, as well as in vivo after oral administration as compared to the known PDE4 inhibitors. They exhibit good bioavailability and isoenzyme selectivity. Furthermore, their duration of activity after intravenous and oral administration is long, their ED50 value is low and their toxicological and side effect profile is favourable.
All the above features make the compounds of the general formula (I) in all probability suitable for therapeutic use and demonstrate their advantage over the known PDE4 inhibitory compounds.
Claims
1. Compounds of the general formula (I) - wherein R1 stands for straight or branched C].4 alkyl or C4.6 cycloalkyl group, R2 stands for straight or branched C alkyl or C .6 cycloalkyl group. RJ stands for hydrogen atom or straight or branched CM alkyl, R4 stands for hydrogen atom or straight or branched CM alkyl, R5 stands for hydrogen atom or straight or branched C alkyl. R6 stands for hydrogen atom or straight or branched CM alkyl, R7 stands for hydrogen atom or straight or branched CM alkyl, with the proviso that one substituent selected from the groups of R4, R\ R6 or R7 always has a meaning different from hydrogen atom, or R~ or R6 mean together a -(CH2)Z - group - wherein z is 3 or 4 or 5, R8 stands for hydrogen atom or a straight or branched C].4 alkyl group, R9 stands for hydrogen atom or a straight or branched C alkyl group,
R10 means saturated 4 to 7 membered ring containing one or two nitrogen atom(s) connecting through the nitrogen atom and optionally substituted by a C]_ alkyl group or a saturated 4 to 7 membered ring containing one nitrogen atom and one oxigen atom connecting through the nitrogen atom and optionally substituted by a C].4 alkyl group,
X stands for -CH2- group, m is zero or 1 , n is 1 - and their salts, solvates, geometrical or optically active isomers and their salts.
2. Compounds of the general formula (I) according to claim 1 - wherein the meanings of R1 - R10, X and the value of m and n are the same as defined in claim 1 - and their racemic or optically active cis isomers and their salts.
3. Compounds of the general formula (I) according to claim 1 - wherein the meanings of R - R1 , X and the value of m and n are the same as defined in claim
1 - and their racemic or optically active trans isomers and their salts.
4. Compounds of the general formula (I) according to claim 1 - wherein
R1 means methyl- or ethyl-group,
R" means methyl- or ethyl-group,
RJ means hydrogen atom,
R4 means hydrogen atom, R3 and R6 mean together a - (CH2)Z - group - wherein z is 3, 4 or 5,
R7 means hydrogen atom,
R8 means hydrogen atom ,
R9 means hydrogen atom , R10 means pyrrolidino, piperidino, piperazino, 4-methylpiperazino or morpholino- group, m is 1, n is 1 - and their salts and solvates, or their racemic or optically active geometric isomers. and the salts and solvates thereof.
5. (±)-cis-2-(3-pyrrolidinopropyl)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
6. (±)-cis-2-(3-piperidinopropyl)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
7. (±)-cis-2-(3-mo holinopropyl)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
8. (-)-cis-2-(3-pyrrolidinopropyl)-2-(9-ethoxy-8-methoxy-1.2,3,4.4a.5,6.10b- octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
9. Pharmaceutical compositions characterized in that, they contain one or more of the compounds of the general formula (I) - wherein the meanings of
R1 — R10, X and the value of m and n are the same as defined in claim 1 - or their salts, solvates, racemic or optically active geometric isomers and the salts, solvates thereof, and one or more excipients used in the pharmaceutical industry.
10. Pharmaceutical compositions according to claim 9. characterized in that, they contain one or more of the compounds of the general formula (I) according to claim 4 or their racemic or optically active geometric isomers and their salts, solvates and one or more excipients used in the pharmaceutical industry.
1 1. Pharmaceutical composition according to claim 9 characterized in that, they contain a compound of the general formula (I) that falls under claims 5-8.
12. Pharmaceutical composition useful in the treatment of diseases developing due to abnormally high PDE4 concentration as for instance asthma, chronic obstructive pulmonary disease (COPD) or rheumatoid arthritis, characterized in that, they contain contain one or more of the compounds of the general formula (I) - wherein the meaning of R1 - R10, X and the value of m and n are the same as defined in claim 1 - or their geometric or optical isomers and the salts, solvates thereof.
13. Use of the compounds of the general formula (I) - wherein the meaning of R1, R2. R3, R4, R5, R6, R7, R8. R9, R10, X and the value of m and n are the same as defined in claim 1 - in the treatment of diseases developing due to abnormally high PDE4 concentration, as for instance asthma, chronic obstructive pulmonary disease (COPD) or rheumatoid arthritis.
14. Process for the preparation of the compounds of the general formula (I)
- wherein the meaning of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and the value of m and n are the same as defined in claim 1 - characterized in that, an acid amide of the general formula (II) or (Ila) is reacted with a cyclizing agent and. if desired, the resulting compound of the general formula (I) is transformed into its salt, solvate, or liberating it from its salt, solvate, or separating it into its geometric or optical isomers.
15. Process according to claim 14, characterized in that, phosphoiyl chloride and/or polyphosphoric acid is/are used as cyclizing agent.
16. Process according to claim 14, characterized in that, the cyclizing agent and the compound of the general formula (II) are reacted at a temperature between 60-180 °C.
17. The compounds of the general formula (II) and (Ila) - wherein the meaning of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and the value of m and n are the same as defined in claim 1 - and their salts and isomers.
18. The compounds of the general formula (Ila) according to claim 17 - wherein R1 stands for ethyl-group, R2 stands for methyl-group, RJ means hydrogen atom. R3 and R mean together a - (CH2)z group - wherein z is 3, 4 or 5, R8 and R9 mean hydrogen atom, R10 means pyrrolidino, piperidino, piperazino, 4-methylpiperazino or morpholino-group, X means - (CH2) - group the value of m is 1, the value of n is 1.
19. Process for the preparation of the compounds of the general formula (II)
- wherein the meaning of R1, R2, R3. R4, R5, R6, R7. R8, R9. R10. X and the value of m and n are the same as defined in claim 17 - characterized in that, the compound of the general formula (III) - wherein the meaning of R1, R2, RJ, R4, R5.
R6, R7, R8, R9, X and the value of m and n are the same as defined in claim 1- is reacted with a compound of the general formula R10 - H - wherein the meaning of
R10 is as defined in claim 1 - or with its salt and, if desired, the resulted compound of the general formula (II) is liberated from its salt, or it is transformed into its salt.
20. Process for the preparation of the compounds of the general formula (Ila) - wherein the meanings of R1, R2, R3, R4, R5, R6, R7. R8. R9. R10. X and the value of m and n are the same as defined in claim 1 - characterized in that, the compound of the general formula (XV) - wherein the meanings of R1, R2, R°. R4, R5, R6, R7, R8, R and the value of m and n are the same as defined in claim 1 - is reacted with a compound of the general formula R1 - H - wherein the meaning of R10 is as defined in claim 1 - or with its salt and, if desired, the resulted compound of the general formula (Ila) is liberated from its salt, or it is transformed into its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2001242664A AU2001242664A1 (en) | 2000-02-28 | 2001-02-27 | Isoquinoline derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0000919A HUP0000919A3 (en) | 2000-02-28 | 2000-02-28 | Pde4 inhibitor isoquinolinydene-derivatives, process for their preparation and medicaments containing them |
| HUP0000919 | 2000-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001064648A1 true WO2001064648A1 (en) | 2001-09-07 |
Family
ID=89978125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2001/000025 WO2001064648A1 (en) | 2000-02-28 | 2001-02-27 | Isoquinoline derivatives |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2001242664A1 (en) |
| HU (1) | HUP0000919A3 (en) |
| WO (1) | WO2001064648A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0486211A1 (en) * | 1990-11-14 | 1992-05-20 | CHINOIN Gyògyszer és Vegyészeti Termékek Gyára RT. | Isoquinoline derivatives |
-
2000
- 2000-02-28 HU HU0000919A patent/HUP0000919A3/en unknown
-
2001
- 2001-02-27 AU AU2001242664A patent/AU2001242664A1/en not_active Abandoned
- 2001-02-27 WO PCT/HU2001/000025 patent/WO2001064648A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0486211A1 (en) * | 1990-11-14 | 1992-05-20 | CHINOIN Gyògyszer és Vegyészeti Termékek Gyára RT. | Isoquinoline derivatives |
Non-Patent Citations (4)
| Title |
|---|
| ACTA UNIV. CAROL., MED., MONOGR. (1972), 52, 79-82 * |
| CHEMICAL ABSTRACTS, vol. 132, no. 11, 13 March 2000, Columbus, Ohio, US; abstract no. 131985, KAPUI, Z. ET AL: "Behavioral effects of selective PDE4 inhibitors in relation to inhibition of catalytic activity and competition for [3H]rolipram binding" XP002170085 * |
| CHEMICAL ABSTRACTS, vol. 81, no. 5, 5 August 1974, Columbus, Ohio, US; abstract no. 20841, MARKWARDT, F.: "Inhibition of platelet aggregation by isochinoline derivatives" XP002170086 * |
| NEUROBIOLOGY (BUDAPEST) (1999), 7(1), 71-73 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2001242664A1 (en) | 2001-09-12 |
| HUP0000919A3 (en) | 2002-03-28 |
| HUP0000919A2 (en) | 2002-02-28 |
| HU0000919D0 (en) | 2000-04-28 |
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