EP2222638A2 - Biaryle als pde4-inhibitoren zur behandlung von entzündungen - Google Patents
Biaryle als pde4-inhibitoren zur behandlung von entzündungenInfo
- Publication number
- EP2222638A2 EP2222638A2 EP08851045A EP08851045A EP2222638A2 EP 2222638 A2 EP2222638 A2 EP 2222638A2 EP 08851045 A EP08851045 A EP 08851045A EP 08851045 A EP08851045 A EP 08851045A EP 2222638 A2 EP2222638 A2 EP 2222638A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- nhc
- mmol
- alkyl
- chosen
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 title abstract description 22
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 title abstract description 22
- 206010061218 Inflammation Diseases 0.000 title description 3
- 230000004054 inflammatory process Effects 0.000 title description 3
- 125000005841 biaryl group Chemical group 0.000 title description 2
- -1 biaryl compounds Chemical class 0.000 claims abstract description 168
- 150000001875 compounds Chemical class 0.000 claims abstract description 159
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 230000002265 prevention Effects 0.000 claims abstract description 11
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 6
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 97
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 86
- 125000000623 heterocyclic group Chemical group 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 51
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 34
- 235000001014 amino acid Nutrition 0.000 claims description 32
- 150000001413 amino acids Chemical class 0.000 claims description 32
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 23
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 20
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims description 19
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims description 19
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 18
- 125000003282 alkyl amino group Chemical group 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 claims description 15
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 150000003852 triazoles Chemical class 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- SLLFVLKNXABYGI-UHFFFAOYSA-N 1,2,3-benzoxadiazole Chemical compound C1=CC=C2ON=NC2=C1 SLLFVLKNXABYGI-UHFFFAOYSA-N 0.000 claims description 12
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 12
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000004442 acylamino group Chemical group 0.000 claims description 11
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 11
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 11
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 11
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 11
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 10
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 9
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 9
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 9
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 208000002193 Pain Diseases 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 8
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 8
- 150000003536 tetrazoles Chemical class 0.000 claims description 8
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 7
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 7
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 7
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- 239000000039 congener Substances 0.000 claims description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 201000000980 schizophrenia Diseases 0.000 claims description 7
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 7
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 6
- 208000023105 Huntington disease Diseases 0.000 claims description 6
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 6
- 239000012964 benzotriazole Substances 0.000 claims description 6
- 230000019771 cognition Effects 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 6
- VMWJCFLUSKZZDX-UHFFFAOYSA-N n,n-dimethylmethanamine Chemical compound [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 claims description 6
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 5
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 claims description 5
- MESFXNGUDNODTJ-UHFFFAOYSA-N 2h-thiazine 1,1-dioxide Chemical compound O=S1(=O)NC=CC=C1 MESFXNGUDNODTJ-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 5
- 208000020358 Learning disease Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 claims description 5
- 125000004945 acylaminoalkyl group Chemical group 0.000 claims description 5
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 5
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 5
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 5
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 5
- 125000005518 carboxamido group Chemical group 0.000 claims description 5
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 5
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical class C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims description 5
- 201000003723 learning disability Diseases 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 5
- OVCXRBARSPBVMC-UHFFFAOYSA-N triazolopyridine Chemical compound C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 4
- DGCOGZQDAXUUBY-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole Chemical compound C1=CC=C2OC(F)(F)OC2=C1 DGCOGZQDAXUUBY-UHFFFAOYSA-N 0.000 claims description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 4
- VTUKKVHSZDBIPA-UHFFFAOYSA-N 3,5,8-trioxabicyclo[2.2.2]octane Chemical compound O1CC2COC1OC2 VTUKKVHSZDBIPA-UHFFFAOYSA-N 0.000 claims description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- 206010065687 Bone loss Diseases 0.000 claims description 4
- 206010037211 Psychomotor hyperactivity Diseases 0.000 claims description 4
- 125000000676 alkoxyimino group Chemical group 0.000 claims description 4
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 4
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 4
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 4
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 4
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 125000004984 dialkylaminoalkoxy group Chemical group 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 4
- 150000003217 pyrazoles Chemical class 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 150000003333 secondary alcohols Chemical class 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 4
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical class C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 claims description 3
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 claims description 3
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 3
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 3
- TZDKFMFJVGNYLS-UHFFFAOYSA-N 4-(1h-pyrazol-4-yl)pyridine Chemical compound C1=NNC=C1C1=CC=NC=C1 TZDKFMFJVGNYLS-UHFFFAOYSA-N 0.000 claims description 3
- BADSZRMNXWLUKO-UHFFFAOYSA-N 4-chloro-1h-pyrazole Chemical compound ClC=1C=NNC=1 BADSZRMNXWLUKO-UHFFFAOYSA-N 0.000 claims description 3
- PYXNITNKYBLBMW-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole Chemical compound FC(F)(F)C1=CC=NN1 PYXNITNKYBLBMW-UHFFFAOYSA-N 0.000 claims description 3
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 claims description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 3
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 3
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 3
- 150000003857 carboxamides Chemical class 0.000 claims description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 3
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 3
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000000075 primary alcohol group Chemical group 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
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Classifications
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Definitions
- the present invention relates to a chemical genus of biaryl inhibitors of phosphodiesterase-4 (PDE4) useful for the treatment and prevention of stroke, myocardial infarct, cardiovascular inflammatory diseases and central nervous system disorders.
- PDE4 phosphodiesterase-4
- PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells.
- PDE4 inhibitors have proven potential as anti- inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD and rhinitis. They suppress the release of cytokines and other inflammatory signals and inhibit the production of reactive oxygen species.
- a large number of PDE4 inhibitors have been developed for a variety of clinical indications (Torphy and Page. 2000. TIPS 21, 157- 159; Burnouf and Pruniaux. 2002. Curr. Pharm. Design 8, 1255-1296; Lipworth. 2005. Lancet 365, 167-175).
- PDE4 inhibitors have been in development as a novel anti-inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications.
- COPD chronic obstructive pulmonary disease
- PDE4 inhibitors of various structural classes including cilomilast, filaminast, lirimilast, piclamilast, tofimilast has been discontinued due to lack of efficacy.
- a primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given.
- the compounds of the present invention are non-competitive inhibitors of cAMP while being gene-specific inhibitors (PDE4D), and, based on the target rationale and in vitro potency, a person of skill in the art would expect the compounds to be useful as anti- inflammatory agents for the treatment, amelioration or prevention of inflammatory diseases and of complications arising therefrom and useful as CNS agents for amelioration of the cognitive decline in Alzheimer's disease, Parkinson's disease, the treatment of schizophrenia and depression, and neuroprotective in Huntington's disease.
- PDE4D gene-specific inhibitors
- the present invention relates to compounds exhibiting PDE4 enzyme inhibition, having the general formula I
- R 1 is an optionally substituted carbocycle or optionally substituted heterocycle of three or fewer rings;
- R 2 is an optionally substituted carbocycle or optionally substituted heterocycle of two or fewer rings;
- R 3 is chosen from H, -C(O)NH 2 , -(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, -(Ci-C 6 )alkyl-R 30 ,
- R 31 is chosen from (Ci-C/Oalkoxy, amino, hydroxy, (Ci-C6)alkylamino and di(Ci-
- R 4 is chosen from H and F;
- R 6 is chosen from H, (Ci-Ce)alkyl and halogen;
- X is N, N ⁇ O, or C-R 5 ;
- RR 55 iiss cchhoosseenn ffrroomm HH,, hhaallogen, OH, (C 1 -C 6 )alkyl, (d-C 6 )alkoxy, CF 3 , CN, NH 2 ,
- n is zero, one or two; and R 20 , R 21 and R 22 are selected independently in each occurrence from H and (Ci-C/Oalkyl.
- the present invention also relates to two subgenera of compounds of formula I.
- the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the general formula I described above.
- the salt should be a pharmaceutically acceptable salt.
- the invention relates to methods for the treatment or prophylaxis of a disease or condition mediated by phosphodiesterase-4.
- the methods comprise administering to a mammal a therapeutically effective amount of a compound having the general formula I.
- the disease or condition may be related to allergic, acute or chronic inflammation.
- the disease may be, for example, atherosclerosis, thrombosis, stroke, acute coronary syndrome, stable angina, peripheral vascular disease, critical leg ischemia, intermittent claudication, abdominal aortic aneurysm or myocardial infarction.
- Selective PDE4 inhibitors of the invention are expected to be useful in improving cognition and thus useful for treating learning disorders, memory loss and other cognitive dysfunctions.
- Selective PDE4 inhibitors of the invention are also useful for treating asthma and Chronic Obstructive Pulmonary Disease (COPD).
- COPD Chronic Obstructive Pulmonary Disease
- Compounds of the invention, which inhibit tumor growth and metastases, also find utility in the treatment and prevention of cancer, including esophageal cancer, brain cancer, pancreatic cancer, and colon cancer.
- alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl.
- Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like. Preferred alkyl groups are those of C 2 0 or below; Ci to Cg are more preferred.
- Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c- pentyl, norbornyl and the like.
- Ci to C 20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
- carbocycle is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
- C3-C 1 0) carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene, cyclopentene and cyclohexene;
- Cs-Ci 2 ) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
- Carbocycle if not otherwise limited, refers to monocycles, bicycles and polycycles.
- Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethyl enedioxy. Alkoxyalkyl refers to ether groups of from 3 to 8 atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an alkyl.
- Alkoxyaryl refers to alkoxy substituents attached to an aryl, wherein the aryl is attached to the parent structure.
- Arylalkoxy refers to aryl substituents attached to an oxygen, wherein the oxygen is attached to the parent structure.
- Substituted arylalkoxy refers to a substituted aryl substituent attached to an oxygen, wherein the oxygen is attached to the parent structure.
- Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy; 3,6,9-trioxadecyl; 2,6,7-trioxabicyclo[2.2.2]octane and the like.
- the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
- thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
- acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
- One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
- Lower-acyl refers to groups containing one to four carbons.
- the double bonded oxygen, when referred to as a substituent itself is called "oxo".
- Aryl and heteroaryl mean (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S.
- Aryl, as understood herein, includes residues in which one or more rings are aromatic, but not all need be.
- aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
- Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl.
- the alkyl group of an arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6 carbons. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
- Heterocycle means a cycloalkyl or aryl carbocycle residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S.
- the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
- a heterocycle may be non-aromatic or aromatic. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic.
- heterocyclic residues that fall within the scope of the invention include pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), morpholine, thiazole, pyridine (including 2-oxopyridine), pyridine N-oxide, pyrimidine, thiophene (i.e.
- furan oxazole, oxazoline, oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine, pyridazine, azepine, pyrazolidine, imidazole, imidazoline, imidazolidine, imidazolopyridine, pyrazine, thiazolidine, isothiazole, 1,2-thiazine- 1,1 -dioxide, quinuclidine, isothiazolidine, benzimidazole, thiadiazole, benzopyran, benzothiazole, benzotriazole, benzoxazole, tetrahydrofuran, tetrahydropyran, benzothiene, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, oxadiazole, triazo
- An oxygen heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygens, as well as other heteroatoms.
- Oxygen heterocycles found in the examples of the invention include tetrahydro furan, benzodioxole, morpholine, isoxazole and 2,6,7-trioxabicyclo[2.2.2]octane.
- a sulphur heterocycle is a heterocycle containing at least one sulphur in the ring; it may contain additional sulphurs, as well as other heteroatoms.
- a nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.
- substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
- substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl (i.e.
- oxo is included among the substituents referred to in "optionally substituted", it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). Additional substituents that are considered within the scope of the term, particularly for R 1 , are the are the residues of amino acids, amino acid amides, protected residues of aminoacids and their amides, and N-methylated (mono- or di-, as appropriate) amino acids and amino acid amides.
- R 1 For the purpose of R 1 , the substituents alkyl, acyl, alkoxyalkyl, hydroxyloweralkyl, phenyl, heteroaryl, benzenesulfonyl, loweralkoxy, haloalkoxy, oxaalkyl, alkoxycarbonyl, alkoxycarbonylamino, carboxamido, alkylaminocarbonyl, amino, alkylamino, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, heterocyclylalkoxy, alkylthio, sulfonylamino, alkylsulfinyl, alkylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, phenoxy, benzyloxy,
- a residue of an amino acid, amino acid amide refers to an amino acid etc. minus the functional groups that are considered part of the bond to the parent structure.
- P- 143 illustrated below:
- haloalkyl and “haloalkoxy” mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms.
- halogen means fluorine, chlorine, bromine or iodine. In one embodiment, halogen may be fluorine or chlorine.
- the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 2 H, 3 H, 13 C, 14 C, 15 N, 35 S, 18 F, and 36 Cl, respectively.
- Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
- Tritiated, i.e. 3 H, and carbon-14, i.e., 14 C, radioisotopes are particularly preferred for their ease in preparation and detectability.
- Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
- a compound is intended to include salts, solvates, co-crystals and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio.
- a compound as described herein including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form.
- the recitation "a compound of formula I" as depicted above, in which R 1 is imidazolyl would include imidazolium salts.
- the term “compound of formula I” refers to the compound or a pharmaceutically acceptable salt thereof.
- the compounds described herein may contain asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
- Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
- the present invention is meant to include all such possible isomers, in any ratio from racemic to optically pure forms.
- Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the prefix "rac" refers to a racemate.
- solvate refers to a compound of Formula I in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
- a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered.
- suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate.
- solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
- Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19 th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
- salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
- salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
- Suitable pharmaceutically acceptable anions for the compounds of the present invention include acetate, benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, glycolate, bromide, chloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, trifluoroacetate, p-toluenesulfonate, acetamidobenzoate, adipate, alginate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, calcium edetate, camphorate, camsylate, caprate, caproate, caprylate, cinnamate,
- suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
- a protecting group refers to a group, which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
- the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
- the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
- the starting materials are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in the art.
- PDE4 inhibitors have been shown to be effective therapeutic agents in clinical studies. For example, administration of cilomilast and roflumilast (PDE4 inhibitors) to patients suffering from asthma and COPD showed initially excellent results, although the effect of cilomilast disappeared on long-term trial [Lipworth, Lancet 365, 167-175 (2005)]. Genetic studies have clearly demonstrated an association between PDE4D and ischemic stroke (Gretarsdottir et al. 2003. Nature Genetics. 35, 1-8). L-454,560, a selective PDE4 inhibitor has been shown to improve learning in a rat model in vivo [Huang et al. Biochemical Pharmacology 73, 1971-1981 (2007)].
- Rolipram another selective PDE4 inhibitor, has been shown to enhance cognition in multiple rodent models [Blokland et al., Current Pharmaceutical Design 12, 2511-2523 (2006)] as well as in primates [Rutten et al., 2008, Psychopharmacology 196, 643-648 (2008)]. Rolipram also improves the outcome in two separate studies in mice in vivo in models accepted by persons of skill in the art as predictive of utility in schizophrenia [Kanes et al., Neuroscience 144. 239-246 (2007); Davis and Gould, Behav.Neurosci. 119. 595-602 (2005)].
- Rolipram has also been shown to exhibit a neuroprotective effect in a rat model of Huntington's disease [DeMarch et al. Neurobiol.Dis. 25, 266-273 (2007)]. This suggests that PDE4 modulators will be useful for treating many CNS disorders. Selective PDE4 inhibitors (e.g. rolipram) are also useful for treating bone loss [Yao et al., J.Musculoskelet.Neuronal Interact. 7. 119-130 (2007)].
- a PDE4 inhibitor YM976 was shown to ameliorate the effects of experimentally-induced interstitial cystitis in rats, resulting in a decrease in the frequency of urination and an increase in the volume of urine at each time of urination [Kitta et al., BJU Int. 102. 1472-1476 (2008)].
- the compounds, compositions and methods of the present invention may be useful in treating cancer.
- Phosphodiesterase activity has been shown to be associated with hematological malignancies [Lerner et al., Biochem.J. 393, 21-41 (2006); Ogawa et al., Blood 99. 3390-3397 (2002)1.
- the compounds may also be administered to overcome cognitive impairment induced by one or more of the following agents, alcohol, amphetamine, antipsychotic medication, anti-retroviral therapy, MDMA ( 3,4-methylenedioxy-N-methylamphetamine, cannabis, cocaine, delta-9 tetrahydrocannabinol, dexamphetamine, haloperidol, heroin and other opiates, ketamine and metamphetamine.
- MDMA 3,4-methylenedioxy-N-methylamphetamine
- cannabis cocaine, delta-9 tetrahydrocannabinol, dexamphetamine, haloperidol, heroin and other opiates, ketamine and metamphetamine.
- the compounds, compositions and methods of the present invention may be employed as imaging agents and in other ways for diagnosis and/or treatment.
- immobilization of compounds of the invention on solid support could be of utility for affinity purification and modification of compounds of the invention with chemically active groups may be used for protein labeling.
- cholinesterase inhibitors e.g. tacrine, huperzine, donepezil
- NMDA antagonists e.g. lanicemine, remacemide, neramexane, memantine
- calpain inhibitors e.g. CEP-3122
- antioxidants e.g. vitamin E, coenzyme QlO
- agents that have shown clinical efficacy but whose mechanism is unclear e.g. dimebon).
- Compounds of formula I may also be administered together with one or more of the following agents to improve cognition: amisulpride, atomoxetine, bromocryptine, buspirone, caffeine, chlorpromazine, clonidine, clozapine, diazepam, flumazenil, fluoxetine, galantamine, guanfacine, methylphenidate, idazoxan, modafinil, olanzapine, paroxetine, pergolide, phenserine, quetiapine, risperidone, rivastigmine, SGS742 and sulpiride.
- the terms "methods of treating or preventing” mean amelioration, prevention or relief from the symptoms and/or effects associated with disorders.
- preventing refers to administering a medicament beforehand to forestall or obtund an acute episode.
- prevent is not an absolute term.
- prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended in applicants' claims.
- treatment of a patient is intended to include prophylaxis.
- mamal is used in its dictionary sense. Humans are included in the group of mammals, and humans would be the preferred subjects of the methods.
- the cognitive impairment to be treated may arise from one or more of the following disorders, which may not in themselves be necessarily associated with PDE4 abnormality: acute pain, AD/HD - Attention deficit hyperactivity disorder, AIDS dementia complex, alcoholism, amphetamine addiction, amygdalo-hippocampectomy, anorexia nervosa, anterior parietal damage, antisocial behavior, antisocial personality disorder, anxiety, autism, basal ganglia lesions, bipolar disorder, borderline personality disorder, camptocormia, capgras syndrome, carcinoid syndrome, carotid endarterectomy surgery, chronic drug misuse, chronic fatigue syndrome, chronic occupational solvent encephalopathy, chronic pain, brain ischemia, coronary artery bypass surgery, critical illness requiring intensive care, dementia Alzheimer-type (DAT), dementia Lewy Body type, dementia of frontal type, dementia caused by ischemia, dental pain, developmental dyslexia, diabetes, dorsolateral frontal cortical compression, Down's Syndrome, drug abuse, dysexecutive syndrome,
- a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
- the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient.
- the formulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy.
- Such methods include the step of bringing into association a compound of formula I or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier, which constitutes one or more accessory ingredients.
- active ingredient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
- Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
- the pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier” also encompasses controlled release means. [0050] Pharmaceutical compositions may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like.
- composition may contain other additives as needed, including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.
- excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, disintegrants, lubricants, antimicrobial agents, and coating agents.
- the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of formula I which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
- the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
- a dosage unit (e.g. an oral dosage unit) can include from, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g.
- the agents can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasaly (including using a cannula), or by other routes.
- the agents can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, e.g. WO 97/11682) via a liposomal formulation (see, e.g., EP 736299,WO 99/59550 and WO 97/13500), via formulations described in WO 03/094886 or in some other form.
- a micellar formulation see, e.g. WO 97/11682
- a liposomal formulation see, e.g., EP 736299,WO 99/59550 and WO 97/13500
- the agents can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:1 15)).
- the agents can be administered locally, for example, at the site of injury to an injured blood vessel.
- the agents can be coated on a stent.
- the agents can be administered using high- velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. 20020061336. Additional particle formulations are described in WO 00/45792, WO 00/53160, and WO 02/19989.
- WO 96/11705 provides formulations suitable for transdermal administration.
- the agents can be administered in the form a suppository or by other vaginal or rectal means.
- the agents can be administered in a transmembrane formulation as described in WO 90/07923.
- the agents can be administered non-invasively via the dehydrated particles described in U.S. 6,485,706.
- the agent can be administered in an enteric-coated drug formulation as described in WO 02/49621.
- the agents can be administered intranasaly using the formulation described in U.S. 5,179,079.
- Formulations suitable for parenteral injection are described in WO 00/62759.
- the agents can be administered using the casein formulation described in U.S. 20030206939 and WO 00/06108.
- the agents can be administered using the particulate formulations described in U.S. 20020034536.
- the agents alone or in combination with other suitable components, can be administered by pulmonary route utilizing several techniques including but not limited to intratracheal instillation (delivery of solution into the lungs by syringe), intratracheal delivery of liposomes, insufflation (administration of powder formulation by syringe or any other similar device into the lungs) and aerosol inhalation.
- Aerosols e.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder inhalers (DPIs)
- MDIs metered-dose inhalers
- DPIs dry-Powder inhalers
- Aerosol formulations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium and can be placed into pressurized acceptable propellants, such as hydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114), propane, nitrogen, and the like.
- HFAs hydrofluoroalkanes
- HFA-134a and HFA-227 or a mixture thereof
- dichlorodifluoromethane or other chlorofluorocarbon propellants such as a
- Pulmonary formulations may include permeation enhancers such as fatty acids, and saccharides, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion. Pulmonary formulations may also include surfactants which include but are not limited to bile salts and those described in U.S.
- the surfactants described in U.S. 6,524,557 e.g., a C8-C 1 6 fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation.
- dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-Powder inhaler.
- Absorption enhancers which can be added to dry powder formulations of the present invention include those described in U.S. 6,632,456.
- WO 02/080884 describes new methods for the surface modification of powders. Aerosol formulations may include U.S.
- Pulmonary formulations containing stable glassy state powder are described in U.S. 20020141945 and U.S. 6,309,671.
- Other aerosol formulations are described in EP 1338272A1 WO 90/09781, U. S. 5,348,730, U.S. 6,436,367, WO 91/04011, and U.S. 6,294,153 and U.S. 6,290,987 describes a liposomal based formulation that can be administered via aerosol or other means.
- Powder formulations for inhalation are described in U.S. 20030053960 and WO 01/60341.
- the agents can be administered intranasally as described in U.S. 20010038824.
- Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer.
- Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles.
- More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy.
- Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington.
- the agent can be incorporated into a liposome to improve half-life.
- the agent can also be conjugated to polyethylene glycol (PEG) chains.
- PEG polyethylene glycol
- Methods for pegylation and additional formulations containing PEG-conjugates i.e. PEG-based hydrogels, PEG modified liposomes
- the agent can be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International).
- the agents can be delivered transmucosally (i.e. across a mucosal surface such as the vagina, eye or nose) using formulations such as that described in U.S. 5,204,108.
- the agents can be formulated in microcapsules as described in WO 88/01165.
- the agent can be administered intra-orally using the formulations described in U.S. 20020055496, WO 00/47203, and U.S. 6,495,120.
- the agent can be delivered using nanoemulsion formulations described in WO 01/91728A2.
- compounds of formula I may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
- the present invention relates to compounds exhibiting PDE4 enzyme inhibition, having the general formula I
- X is CR 5
- R 2 is pyrazolyl or substituted phenyl and R 3 is other than H.
- R 1 is a substituted phenyl. In another embodiment, R 1 is phenyl and R 2 is pyrazolyl or substituted phenyl. In another embodiment, R 1 is substituted phenyl and R 2 is pyrazolyl or substituted phenyl.
- R 1 is an unsubstituted heterocycle.
- R 1 is a substituted heterocycle.
- the heterocycle may be chosen from pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole, morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine, thiene, furan, oxazole, oxazoline, oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine, pyridazine, azepine, pyrazolidine, imidazole, imidazoline, imidazolidine, purine, imidazolopyridine, pyrazine, thiazolidine
- R 1 is an optionally substituted heterocycle chosen from pyrazole, benzodioxole, morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine, thiene, oxazolidine, isoxazole, azetidine, piperazine, pyrrolidine, imidazole, imidazolidine, imidazolopyridine, pyrazine, 1,2- thiazine- 1 , 1 -dioxide, benzimidazole, thiadiazole, benzotriazole, benzoxazole, oxadiazole, triazole, tetrazole, isoindole, pyrrolopyridine, triazolopyridine and their dihydro
- the substituted phenyl or substituted heterocycle is substituted with a substituent chosen from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylamin
- One embodiment of compounds of the first genus are those in which R is methyl or fluoromethyl; R 6 is H; and M is -CH 2 - or -CH 2 O-.
- R 2 is chosen from optionally substituted phenyl, optionally substituted monocyclic unsaturated heterocycle, unsubstituted bicyclic unsaturated heterocycle and fluoro-substituted bicyclic unsaturated heterocycle.
- R 2 is chosen from optionally substituted phenyl, indole, benzodioxole, benzoxadiazole, benzodioxan, benzimidazole, oxadiazole, pyrazole, pyridine and pyridine N-oxide.
- R 2 is chosen from meta- substituted phenyl, indole, benzodioxole, 2,2-difluorobenzodioxole, benzooxadiazole, benzimidazole, 5 -(pyridin-4-yl) [1,2,4] oxadiazole, 5 -(pyridin-4-yl) [1,3,4] oxadiazole, benzodioxan, 4-chloropyrazole, 4-(pyridin-4-yl)pyrazole, 6-chloropyridine, 3- (trifluoromethyl)pyrazole, and pyridine N-oxide.
- R 2 is substituted phenyl:
- R 7 is chosen from hydrogen, halogen, nitro, cyano, halo(Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkoxy, (Ci-Ce)oxaalkyl, carboxy, (Ci-Ce)alkoxycarbonyl, aminocarbonyl (- CONH 2 ), (Ci-C 6 )alkylaminocarbonyl, acyl, hydroxy(Ci-Ce)alkyl, halo(Ci-Ce)alkoxy, amino(Ci-C6)alkyl, , amino, (Ci-C6)alkylamino, di[(Ci-C6)alkyl]amino, mercapto, (Ci- C 6 )alkylthio, (Ci-C 6 )alkylsulfinyl, (Ci-C 6 )alkylsulfonyl, (Ci-C 6 )alkylsulfonamido,
- R 8 and R 13 are chosen independently from H and F.
- R 8 and R 1 are H and R 7 is chosen from hydrogen, fluoro, chloro, bromo, nitro, cyano, acetyl, trifluoromethyl, methoxy, trifluoromethoxy, oxadiazolyl, tetrazolyl, methylthio, methanesulfinyl, methanesulfonyl, methansulfonamido, amino, methoxymethyl, hydroxyethyl, and morpholinyl.
- R 1 is chosen from optionally substituted phenyl, optionally substituted five membered heteroaryl, optionally substituted six-membered heteroaryl, optionally substituted 4-7 membered non-aryl heterocycle, and optionally substituted fused bicycle.
- R 1 may be chosen from optionally substituted phenyls; optionally substituted five membered heteroaryls selected from thiazoles, thiadiazoles, pyrazoles, oxadiazole, isoxazoles, triazoles, imidazoles, thiophenes, tetrazoles and oxazoles; optionally substituted six membered hereroaryls selected from pyridines, pyrimidines, pyridazinones, pyrimidinone, pyridinone, pyrazines and diazines; optionally substituted 5-and 6- membered non-aryl heterocyclics selected from tetrahydrothiophenes, piperazine, oxazolidinones, imidazolidinones, morpholines, piperidines, pyrrolidinones, pyrrolidinediones, pyrrolidines, piperidinones, piperidinediones and trio
- R 3 is chosen from -CH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 and -CH 2 F;
- R 5 is chosen from H, -F, -OH, -CH 3 , -OCH 3 , -CF 3 , -CN, -NH 2 and -C ⁇ CH;
- phenyl and R 7 is chosen from H, halogen, nitro, acetyl, hydroxyethyl, -NH 2 , -
- R 9 is chosen from H, (Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, (Ci-C 6 )alkoxycarbonyl, carboxy(Ci-Ce)alkyl, (Ci-C 6 )alkoxycarboxy(Ci-Ce)alkyl;
- R 10 is H, (Ci-C 6 )alkyl, or taken together, or
- R 9 and R 10 together form a heterocycle optionally substituted with (Ci-Ce)alkyl; p is 0 or 1, q is 0, 1 or 2,
- R 11 is linear (Ci-C 6 )alkyl
- R 12 is H or (Ci-C 6 )alkyl; or two adjacent substituents together form an optionally substituted fused heterocyclic ring.
- R 5 is H
- R 3 is -CH 3 and R 1 is substituted or unsubstituted pyrazole
- compounds that have been tested and found active are those in which R 8 is -NO 2 or R 8 represents two adjacent substituents that form an optionally substituted, fused heterocycle.
- R 3 is -CH 3
- R 2 is -CF 3
- R 1 is ⁇ / , the compound does not appear to be active in initial screening.
- R 5 is H
- R 3 is -CH 3
- R 2 is -NO 2
- R 1 is
- the compound does not appear to be active in initial screening.
- R 5 when R 5 is H, R 3 is -CH 3 , R 2 is -OCH 3 or -COCH 3 , and R 1 is , the compound does not appear to be active in initial screening.
- One embodiment of compounds of the second genus has the formula
- R la is phenyl, five-membered heteroaryl, six-membered heteroaryl, 4-7 membered non- aryl heterocycle or fused bicycle;
- R . 1 1 5 3 is chosen from H, NO 2 , OH, NH 2 , and -NHSO 2 NH 2 ; or
- R 27 is chosen from hydrogen, halogen, nitro, cyano, halo(Ci-Ce)alkyl, hydroxy, (Ci-
- R 28 is chosen from H and F, or
- R together with R forms a five-membered ring.
- R 27 and R 28 represent a fused heterocycle at 3- and 4- ppoossiittiioonnss ssoo tthhaatt tthhee rreessiidduuee ffoorrmmsed from R 27 and R 28 together with the phenyl to which they are attached is chosen from:
- R ,27 is chosen from halogen, nitro, acetyl, hydroxyethyl, amino, methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl, trifluoromethoxy, cyano and l,3,4-thiadiazol-2-yl, or taken together R 7 and R 8 are methylenedioxy or difluoromethylenedioxy.
- R la may be chosen from a benzene ring, a triazole, a pyridine or pyridine-N-oxide, a pyrazole, a tetrahydrothiophene, an imidazole, a pyrimidine, a thiadiazole, and an imidazopyridine.
- R is fluoro, H, CN or OH. In other embodiments, R 3 is methyl or fluoromethyl.
- R 3 is methyl or fluorinated methyl
- Y is CH or N
- R 27a is chosen from halogen, cyano, acetyl, methylthio, nitro and trifluoromethyl
- R 16 is
- R . 17 , and R are independently chosen from H, (Ci-Ce)alkyl and halo(Ci- C 6 )alkyl;
- R 19 is chosen from H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, -[(C 1 -C 6 )alkyl]COOH, and -[(Ci-C6)alkyl]COO(Ci-C6)alkyl;
- R 20 is chosen from a carboxylic acid, a carboxamide, a carboxylic ester, a primary, secondary or tertiary alcohol and a primary, secondary or tertiary amine.
- Examples of a carboxylic acid, a carboxamide, a carboxylic ester, a primary, secondary or tertiary alcohol and a primary, secondary or tertiary amine include -COOH, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -COOCH 3 , -CH 2 OH, -CH(CH 3 )OH, -C(CHs) 2 OH, -CH 2 NH 2 , -CH(CH 3 )NH 2 and -C(CH 3 ) 2 NH 2 .
- X is CH, CF or N->O; M is -CH 2 - or -S-; R 2 7a a is chosen from chloro, cyano, acetyl and methylthio; and R is chosen from -NR C(O)NR R
- Y is
- R 16 is -NR 17 C(K))NR 18 R 19 .
- R 16 is -NR 17 C(O)NR 18 R 19 and R 17 , R 18 and R 19 are all hydrogen.
- R 15 is chosen from H, NO 2 , OH, NH 2 , and -NHSO 2 NH 2 ; or R 15 together with R 14 forms methylene dioxy.
- R 3 is chosen from -CH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 and - CH 2 F.
- R 5 is chosen from H, -F, -OH, -CH 3 , -OCH 3 , -CF 3 , -CN, -NH 2 and -C ⁇ CH.
- R 7 is chosen from H, halogen, nitro, acetyl, hydroxyethyl, -NH 2 , -SCH 3 , methoxycarbonyl, -SOCH 3 , -SO 2 CH 3 , -OCH 3 , -OCF 3 , -CN, -CF 3 , -CH 2 OCH 3 and oxadiazole, and a fused heterocycle at 3- and 4- positions.
- R 5 may be fluoro, H, CN or OH. In certain embodiments of the compounds I, R may be methyl or fluoromethyl. (Fluoromethyl is intended to include CHF 2 , CH 2 F and CF 3 .)
- the invention in a composition aspect, is all active compounds of formula I except those that are in the public's possession.
- a search of the literature indicates that certain compounds in which X is N, R 3 is methyl, M is CH 2 , R 2 is a five-membered ring heterocycle, and R 1 is a substituted tetralin are known.
- certain compounds in which X is N, R is methyl, M is CH 2 , R 1 is a five-membered ring heterocycle, and R 2 is a substituted tetralin are known.
- the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures.
- Generally compounds of the Formula I, where R 2 is a substituted aryl / heteroaryl and the two biaryl groups are linked by a C-C bond, may be prepared from appropriately functionalized alkoxy-aryl ether derivatives containing desirable functionalities W, where W may for example be CH, N, COH, CF, etc (Route A, Scheme Al).
- the biaryl portion can be constructed first, typically via Suzuki or Stille coupling (Gl -> G2).
- Y halogen or OSO2R (OTf, ONf) and the other reagent would be R2- B(OR)2 or R2-SnR3' or vise versa, where R2 -halogen is coupled with Gl containing boronate/boronic acid or trialkyltin as Y.
- A is a carbon derived substituent, e.g. CH3, CH2OH, CO2R", CN etc. these groups are converted to provide intermediate G3 where D is either a halogen or OTf, ONf, or OCOOR” (carbonate) such that substituent (Rl) is introduced by employing a transition-metal catalyzed coupling reactions such as Suzuki, Stille or Negishi reaction.
- Rl which may be aryl, heterocyclic, acyclic, aliphatic, or any other desirable variety of functionality, to the central aromatic ring (Ar) by a wide rage of tether groups M.
- the central aromatic ring (Ar) may be a biaryl ring system with a R2 group already attached, or the R2 group may be attached subsequent to that of Rl .
- the linker group M may be a linear chain of one or more atoms consisting of C, N, O, or S.
- the linker group M may also consist of functionalities including, but not limited to amide, sulfonamide, sulfone, or ketone.
- halogen allows susceptibility of the aromatic halogen for nucleophilic displacement.
- ArI group containing NO2, CO2R, ketone, CN etc. would allow formation of aryl-M-aryl(heteroaryl) intermediates.
- the linker group M may also be subject to further elaboration.
- sulfides may be oxidized to sulfoxides and sulfones and amines may be subjected to alkylation or reductive amination.
- Well known synthetic transformations can be used to create tether groups M such as ether amide, sulfonamide, and the like.
- the functional group location in the precursor Ar and Rl groups can be used to dictate the nature and type of the linkage (e.g. alternative ethers), as mentioned above.
- aldehyde functionality can subsequently be transformed into a suitable transition-metal catalyzed coupling reaction partner.
- the aldehye could be used for Wittig reaction forming olefin or CH2CH2 linkage to incorporate Rl.
- substituent "A” can be various types of carbonyl (aldehyde or ketone) or imine groups.
- Rl-MgX organometallic Rl group
- aldehyde G9 CHO
- Similar types of transformations could be employed by one skilled in the art if G9 contained A : ketone or imine.
- the C-C bond forming reaction between the Ar and Rl groups could be accomplished by displacement of a leaving group on the Rl by a nucleophile present in the tether region M (Scheme G4) of G 12.
- M-Z is CH2-halide or CH2-O-sulfonate
- Rl fragment can be introduced via formation of ether linkage. This allows attachment of Rl to the central aromatic ring by spacers (M) of varying lengths and compositions. (Scheme A4)
- the Rl group could also be assembled form an acyclic intermediate to form a heterocylic or heteroaromatic ring.
- these chemistries include formation of 5-membered heteroaryls such as oxadiazole, thiadiazole, triazole (G 17) form acyl hydrazide (G 16); thiazole from 2-halo-ketone or dipolar cycloaddition reactions from olefin or acetylic group to form 5-membered heterocycles or 5-membered heteroaryls (Gl 8) [Scheme A5].
- 6-membered heteroaryl or heterocyclic rings could be formed using Diels-Alder or hetero- Diels-Alder chemistries using appropriately substituted alkyl aryl ether bearing either a dienophile or a diene functionalities.
- the necessary acyclic precursors could be synthesized by standard methods according to previously described intermediates (e.g. aldehyde, alkyl halide) schemes.
- Rl and R2 The diverse selection of substituents present in Rl and R2 could be formed by standard functional group transformations that are well know in the art. Some of these include formation of amide, sulfonamide, ureas, imidazolone, oxazolones, carbamates from the R2, R3, or Ar ring fragments bearing appropriate amine, carboxylic acid, alcohol, or phenol groups.
- a particularly useful aromatic ring functionalization technique, in which either the R2 or Rl rings can be employed, is the nucleophilic displacement of ortho-halo N-containing aromatic rings (G20, scheme A7). Examples of ring substrates useful in this type of transformation include 2-halo-pyridine, 2-halo- pyrimidine and 2-halo-imidazole.
- nucleophiles (R) useful in this type of transformation include amines (primary, secondary, acyclic, or cyclic), alcohols, phenols, NH-containing heterocycle groups (imidazole, or pyrrazole) groups capable of performing nucleophilic displacement.
- Rl group contains additional functional groups, such as amine, ester/acid /alcohols many of which may have be masked or protected during the previous chemistries, these could be used for further functional group manipulations.
- additional functional groups such as amine, ester/acid /alcohols many of which may have be masked or protected during the previous chemistries
- Rl functionalities may be achieved using well established synthetic procedures including, but not limited to, alkylation, reductive amination, nucleophilic displacement, cyclization, saponification, and oxidation/reduction.
- ArI mono-cyclic may be further transformed to a bi-cyclic ring.
- Examples of such ring transformations may be represented by elaboration of pyridine derivatives to imidazo[l,2-a]pyridine and imidazo[l,5-a]pyridine. These functional group manipulations and bicyclic ring elaborations maybe accomplished at any chemically suitable point in the synthesis prior to or post incorporation of R2 or other synthetic transformations.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound as described above.
- Methods of the invention parallel the compositions and formulations.
- the methods comprise administering to a patient in need of treatment a therapeutically effective amount of a compound according to the invention.
- the present invention also provides a method for inhibiting phosphodiesterase 4.
- Buffer A containing 50 mM Tris, pH 8.0, 16 mM MgCl 2 and 80 mM KCl is prepared and stored at room temperature.
- Buffer B containing 50 mM Tris, pH 8.0 is prepared and stored at toom temperature.
- Stock solutions of the following reagents are prepared in Buffer B and stored at -20 0 C: Adenosine-5 '-triphosphate (ATP), cyclic adenosine-5' -monophosphate (cAMP), phosphoenolpyruvate (PEP) and NADH.
- ATP Adenosine-5 '-triphosphate
- cAMP cyclic adenosine-5' -monophosphate
- PEP phosphoenolpyruvate
- An assay mix is prepared by mixing Buffer A, trichloroethylphosphine (TCEP), ATP, PEP, NADH, myokinase (MK), pyruvate kinase (PK), lactate dehydroganese (LDH) and PDE4 to a final volume of 20 mL, which is enough for a single 96-well assay plate.
- Assay mix 180 ⁇ L
- test article (10 ⁇ L ) in 1: 1 DMSO/H2O mixture is pre-incubated at room temperature for 10 min. The enzymatic reaction is initiated by addition of cAMP (10 ⁇ L).
- Final concentration of all components in the assay (200 ⁇ L/well) are as follows: 10 mM MgCl 2 , 50 mM KCl, 5 mM TCEP, 2.5% DMSO, 0.4 mM NADH, 1 mM PEP, 0.04 mM ATP, 5 units MK, 1 unit PK, 1 unit LDH and appropriate amount of PDE4.
- Reaction progress curves are monitored in a plate reader capable of measuring light absorbance at 340 nM. A decrease in light absorbance at 340 nm is due to oxidation of NADH.
- Positive controls containing no test article and negative controls containing no test article and no cAMP are included on every assay plate. Reaction rates are determined from the slopes of the linear portions of the progress curves. All data is percent normalized with respect to controls and presented as percent inhibition.
- the activity of PDE4 inhibitors decribed in the present invention was also measured using in an ex- vivo assay measuring leukotriene E4 (LTE4) in human whole blood after Sephadex stimulation.
- LTE4 leukotriene E4
- the anti- inflammatory activity of therapeutic agents of the present invention is demonstrated by the inhibition of eosinophil activation as measured by sephadex bead stimulated LTE4 production in whole human blood.
- 356 ⁇ l of heparinized human whole blood (Vacutainer tube #6480) is added to wells of a 96 well plate.
- Persons of skill in the art accept that positive results in PDE4 models are predictive of therapeutic utility as discussed above.
- reaction mixture was then heated to 60 0 C for 15 minutes, and allowed to cool naturally to room temperature, and stirred for 16 hours.
- the reaction mixture was then extracted with two portions of diethyl ether, and the combined ethereal layers washed with brine, dried over magnesium sulfate, filtered through a layer of celite and concentrated.
- the resultant mixture was stirred at the same temperature for 10 minutes, and to it was added a solution of 4-fluorobenzonitrile (18.2 mmol; 2 eq.) in tetrachloroethane and aluminum chloride (10.0 mmol; 1.1 eq.).
- the reaction was heated to 110 0 C for 5 hours, and allowed to cool to room temperature and stir for 16 hours.
- the reaction mixture was added 10 mL of 3N HCl, and the resultant mixture was heated to 90 0 C for 1 hour, and cooled to room temperature.
- the pH was adjusted with 6N NaOH to 11-12, and extracted with dichloromethane. The organics were washed with a brine solution, dried over magnesium sulfate, and filtered.
- the reaction was stirred at 70 0 C for 16 hours, and cooled to room temperature.
- the reaction was diluted with water, and extracted with two portions of ethyl acetate.
- the combined organics were washed with three portions of water, brine, dried over magnesium sulfate, and filtered through celite.
- reaction mixture was cooled to 0 0 C, diluted with water (3 mL), basified with ammonium hydroxide solution (28%), filtered, washed with water dried to afford 0.08 g (81%) of l-[4-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3- ylmethyl)-phenyl]-lH-tetrazole (P-404) as off-white solid.
- the mixture was heated to 90 0 C for 18 hours and then cooled to room temperature. After water (30 mL) and 5% aqueous potassium carbonate (30 mL) were added, the aqueous portion was extracted with ethyl acetate (2 x 35 mL) and the organic portions were combined, washed brine (30 mL), dried (magnesium sulfate) and concentrated.
- the aqueous layer was extracted with ethyl acetate (100 mL) and the organic extracts were combined.
- the organic solution was washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and the solvent removed under vacuum .
- the residue was purified by flash silica gel column chromatography (10-33% acetone in dichloromethane), triturated in diethyl ether (5 mL), filtered, washed with hexanes (5 mL) and diethyl ether (2 mL) to give P-252 (190 mg, 15 % yield) as a beige powder.
- reaction mixture was diluted with water, neutralized with 6N HCl, extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. After it was concentrated in vacuo, the residue was purified by a chromatography on silica gel to yield N-[5-(3'-chloro-2-fluoro- 6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methanesulfonamide (P-258) (25 mg, 32%).
- reaction mixture was bubbled with nitrogen gas for 5 minutes. Then the yellow reaction mixture was stirred at 80 0 C. After overnight stirring the reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was diluted in EtOAc (2OmL) and washed with water (30 mL). The aqueous layer was extracted with EtOAc (2 x 2OmL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in-vacuo.
- the mixture was heated to 90 0 C for 16 hours and then cooled to room temperature.
- the palladium catalyst was removed via filtration and to the filtrate was added IM HCl (50 mL) and water (50 mL).
- the aqueous portion was Extracted with ethyl acetate(2 x 75 mL), the organic portions were combined, washed with brine (75 mL), dried (MgSO 4 ) and concentrated.
- the crude material was purified by column chromatography utilizing 75% EtOAc/hexanes as the eluent to produce 207 mg of the free base as a dark orange oil in 82% yield.
- the free base was treated with 4.0 M HCl in 1,4-dioxane (1.0 mL) and stirred for 3 hours at room temperature.
- the reaction mixture was treated with diethyl ether (4 mL) and the solid was collected via suction filtration.
- the aqueous wash was extracted into ethyl acetate (50 mL), and the organic extracts combined.
- the ethyl acetate solution was washed with 1 N aqueous hydrochloric acid (50 mL), water (2 x 50 mL), and brine (50 mL), dried over sodium sulfate, and the solvent removed under vacuum.
- the resultant solid was triturated with diethyl ether (5 mL), filtered, washed with diethyl ether (2 x 3 mL), and dried to give product (P-448) (109.2 mg, 51% yield).
- [00175] 1 -[4-(3'-Chloro-6-methoxy-biphenyl-3-sulfonyl)-phenyl]-3 -ethyl-urea (P- 450).
- To the solution was added 290 uL of 10% v/v (30% w/w hydrogen peroxide in water) in acetic acid.
- R2 R4 Cl, 4-pyr ⁇ dyl
- the mixture was degassed with nitrogen for 30 minutes and then added tetrakis(triphenylphosphine)palladium(0) (5.17 g, 4.48 mmol).
- the mixture was heated to 60 0 C for 4 hours and then the palladium catalyst was filtered off.
- To the filtrate were added water (100 mL) and a saturated ammonium chloride solution (150 mL). After extracting with ethyl acetate (3 x 100 mL), the organic portions were combined, washed with brine (150 mL), dried (MgSO 4 ) and concentrated.
- the mixture was heated to 190 0 C in a Biotage Initiator microwave reactor for 1 hour.
- the mixture was quenched with water (50 mL) and a saturated ammonium chloride solution (50 mL) followed by an extraction with ethyl acetate (2 x 100 mL).
- the organic portions were combined, dried (MgSO 4 ) and concentrated.
- the residue was purified via column chromatography utilizing 15% acetone/dichloromethane as the eluent. After a failed recrystallization attempt with dichlormethane/hexanes, 41 mg of P- 389 as a viscous, yellow oil in 13% yield.
- the mixture was heated to 190 0 C in a Biotage Initiator microwave reactor for 1 hour.
- the mixture was quenched with water (30 mL) and a saturated ammonium chloride solution (30 mL) followed by an extraction with ethyl acetate (2 x 60 mL).
- the organic portions were combined, dried (MgSO 4 ) and concentrated.
- the residue was purified via column chromatography utilizing 20% ethyl acetate/hexanes as the eluent to produce 20 mg of P-396 as a viscous, yellow oil in 7% yield.
- R1 H, Me, CHF2, CF3 I-62
- R2 Cl, CH3CO, CN, NO2, Br, fused heterocycle
- reaction mixture was diluted with ethyl acetate (80 mL) and washed with water (2 x 40 mL), brine and dried over Na 2 SO 4 . After removal of solvent, the residue was triturated with Et 2 O (20 mL) to give 2.18 g of product; Yield: 81 %.
- R1 H, Me, CHF2, CF3
- R2 Cl, CH3CO, CN, NO2, Br, fused heterocycle
- R2 R3 substituted aryl groups
- the reaction mixture was stirred at rt. After overnight stirring the reaction mixture was quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 and concentrated in- vacuo. The crude was purified by silica gel column chromatography, eluted with dichloromethane/MeOH (200:5) to produce 77.1 mg (39% yield) of the product (P-479) as a pale yellow solid.
- R1 H, Me, CHF2, CF3
- R2 Cl, CH3CO, CN, NO2, Br, fused heterocycle
- Y H, F, OH, NH2, CN, OCH3, OEt
- R1 H, Me, CHF2, CF3
- R2 Cl, CH3CO, CN, NO2, Br, fused heterocycle
- R1 H, Me, CHF2, CF3
- R2 Cl, CH3CO, CN, NO2, Br, fused heterocycle
- R3 substituted aryl groups
- Reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (2 x 40 mL). The combined organic phase was washed with water (2 x 30 mL), brine and dried over Na 2 SO 4 . After removal of solvent, the residue was purified by silica gel column chromatography with ethyl acetate/hexane as eluent to give 39 mg g of the product (P-015) Yield: 40 %.
- the reaction was heated to 108 0 C and stirred at this temperature overnight.
- the reaction was diluted with ethyl acetate (200 mL) and water (200 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (200 mL). The organic extracts were combined, washed with water (400 mL) and brine (300 mL), dried over sodium sulfate, filtered, and the solvent removed under vacuum to give crude product.
- the crude material was purified by flash silica gel column chromatography (0-5% methanol in dichloromethane) to give I-89a (1.53 g, 77% yield) as a beige powder.
- Reaction mixture was concentrated to a 1/3, and then it was diluted with ethyl acetate (300 ml) and washed with 0.6 N sodium hydrogen sulfate solution (300 ml), water (2x 150 ml), brine and dried over Na 2 SO 4 . After removal of solvent, 7.75 g of product (1-100) was obtained as oil. Yield: 100 %.
- the reaction was heated to 80 0 C over night. Additional palladium acetate (8.9 mg, 0.039 mmol) and triphenylphosphine (20.6 mg, 0.0788 mmol) was added and the mixture was stirred an additional night at 80 0 C. The solvent was removed under vacuum and taken up in ethyl acetate (50 mL). The organic solution was washed with saturated aqueous ammonium chloride (2 x 75 mL), water (3 x 75 mL) water, and the combined aqueous layers were extracted with ethyl acetate (50 mL).
- the organic suspension was washed with saturated aqueous ammonium chloride (2 x 50 mL), 1 N aqueous sodium hydroxide (3 x 50 mL), water (50 mL), and brine (50 mL), decolorized over activated carbon, dried over sodium sulfate, and removed under vacuum to give crude product.
- the product was purified by flash silica gel column chromatography eluting with 1% methanol in dichloromethane to give P-014 (102.1 mg, 36% yield) as an off white powder.
- the aqueous wash was extracted with ethyl acetate (2 x 150 mL), and all the ethyl acetate extracts combined, washed with saturated aqueous ammonium chloride (3 x 300 mL), water (2 x 300 mL), and brine (300 mL), dried over sodium sulfate and the solvent removed under vacuum to give 1-110 as a yellow oil (11.39 g; 77% yield) which solidified to a greasy yellow solid.
- the reaction was stirred at 80 0 C under argon for 20 h.
- the reaction was cooled to room temperature, concentrated, and H2O (60 mL) and dichloromethane (80 mL) were added.
- the layers were separated and the aqueous was extracted with dichloromethane (2 x 40 mL).
- the combined organic extracts were dried with Na 2 SO 4 , filtered, and concentrated.
- the residue was purified by silica gel column chromatography using 10% ethyl acetate/hexanes as eluent to afford 1.69 g (65%) of 1-81 as a white solid.
- the reaction was stirred at 80 0 C under argon for 18 h.
- the reaction was cooled to room temperature, concentrated, and diluted with H 2 O and dichloromethane (40 mL each).
- the organic layer was separated and the aqueous was extracted with dichloromethane (2 x 25 mL).
- the combined organic extracts were dried with Na 2 SO 4 , filtered, and concentrated.
- the residue was purified by preparative TLC using 3% MeOH in dichloromethane to afford 0.051 g (51%) of P-019 as a light brown viscous liquid.
- the reaction was stirred at 80 0 C under argon for 18 h.
- the reaction was cooled to room temperature, concentrated, and diluted with H2O and dichloromethane (40 mL each).
- the organic layer was separated and the aqueous was extracted with dichloromethane (2 x 25 mL).
- the combined organic extracts were dried with Na 2 SO 4 , filtered, and concentrated.
- the residue was purified by silica gel column chromatography using 1 : 1 dichloromethane-hexanes then dichloromethane to afford 0.08 g (71%) of P-021 as a light brown viscous liquid.
- the reaction mixture was slowly warmed to room temperature and stirred for 20 h.
- the reaction was poured on to crushed ice-water and extracted with ethyl acetate (2 x 40 mL).
- the combined organic extracts were dried with Na2SO4, filtered, and concentrated.
- the residue was purified by silica gel column chromatography using dichloromethane to afford 0.027 g (47%) of P-030 as a viscous liquid.
- the reaction mixture was slowly warmed to room temperature and stirred for 20 h.
- the reaction was poured on to crushed ice-water and extracted with ethyl acetate (2 x 40 mL).
- the combined organic extracts were dried with Na 2 SO4, filtered, and concentrated.
- the residue was purified by silica gel column chromatography using dichloromethane to afford 0.047 g (77%) of P-038 as a viscous liquid.
- the reaction was stirred at 80 0 C under argon for 20 h.
- the reaction was cooled to room temperature, concentrated, and H 2 O and dichloromethane (40 mL each) were added.
- the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 25 mL).
- the combined organic extracts were dried with Na 2 SO 4 , filtered, and concentrated.
- the residue was purified by silica gel column chromatography using 1 : 1 dichloromethane-hexanes then dichloromethane to afford 1.36 g (86%) of 1-117 as a light yellow solid.
- the reaction was diluted with saturated aqueous ammonium chloride (100 mL) and the suspension was extracted with ethyl acetate (100 mL).
- the purple organic extract was washed with water (3 x 50 mL) water, saturated aqueous ammonium chloride (3 x 50 mL), brine (50 mL) dried over anhydrous sodium sulfate, and the solvent removed under vacuum to afford 476.1 mg of 1-119 as a purple powder in 72% yield.
- triphenylphosphine (33.5 mg, 0.128 mmol), solid potassium carbonate (265 mg, 1.92 mmol) and a mixture of ethanol and water (1: 1, 1 mL) was added, and the reaction was stirred under nitrogen for 10 min.
- To the reaction was added palladium(II)acetate, and the reaction heated to 80 0 C with stirring overnight.
- the solvent was removed under vacuum and the residue was suspended in saturated aqueous ammonium chloride (50 mL), and the aqueous slurry was extracted with ethyl acetate (2 x 50 mL).
- the reaction was cooled to room temperature and diluted with ethyl acetate (150 mL).
- the organic solution was washed with water (5 x 100 mL), brine (100 mL), dried over sodium sulfate, and the solvent removed under vacuum.
- the residue was purified by flash silica gel column chromatography eluting with 0-2% methanol in dichloromethane followed by flash silica gel column chromatography with 50% ethyl acetate in hexanes, and the residue wash dissolved in ethyl acetate (10 mL).
- the organic solution was washed with water (2 x 10 mL) and the wash extracted with ethyl acetate (2 x 10 mL).
- triphenylphosphine (58.8 mg, 0.112 mmol), solid potassium carbonate (463 mg, 3.36 mmol), ethanol (1 mL), water (1 mL), and palladium(II)acetate (25.1 mg, 0.112 mmol) under nitrogen.
- the reaction was stirred at 100 0 C for 18 h.
- the solvent was removed under vacuum and the residue taken up in ethyl acetate (50 mL).
- the organic solution was washed with saturated aqueous ammonium chloride (50 mL), the residual palladium was filtered, and the organic extract was washed with water (2 x 50 mL), brine (50 mL), dried over sodium sulfate, and removed under vacuum.
- the crude product was purified by flash silica gel column chromatography eluting with 5% methanol in dichloromethane, followed by a second flash silica gel column eluting with 5% acetone in dichloromethane.
- the solid thus obtained was recrystallized in diethyl ether (5 mL) and hexanes (10 mL), filtered, and washed with hexanes (5 mL) to give P-058 (65 mg; 21% yield) as a white powder.
- P-084 Synthesis of l-(6-Methoxy-3'-trifluoromethoxy-biphenyl-3-ylmethyl)-lH- [l,2,4]triazole (P-084).
- P-084 was synthesized from 1-110 (200 mg, 0.746 mmol) and 3-trifluoromethoxyphenylboronic acid (169 mg, 0.821 mmol) by the same reaction conditions that were used for P-081. After removal of the solvent under vacuum, the residue was diluted with ethyl acetate (30 mL) and washed with water (30 mL).
- the aqueous wash was extracted with ethyl acetate (30 mL), and the combined organic extracts were washed with water (2 x 50 mL), saturated aqueous ammonium chloride (50 mL), brine (50 mL), dried over sodium sulfate, decolorized over activated charcoal, and the solvent removed under vacuum.
- the residue was purified by flash silica gel column chromatography eluting with 5% acetone in dichloromethane to give P-084 as a yellow oil (187.3 mg, 54% yield).
- P-085 [00335] Synthesis of 1 -(6-Methoxy-3 '-methylsulfanyl-biphenyl-3 -ylmethyl)- 1 H- [l,2,4]triazole (P-085).
- P-085 was synthesized from 1-110 (200 mg, 0.746 mmol) and 3-methylsulfanylphenylboronic acid (138 mg, 0.821 mmol) using the same conditions as P-081. The reaction was worked up by diluting with ethyl acetate (30 mL) and washing with water (30 mL).
- the aqueous wash was extracted with ethyl acetate (30 mL), and the organic extractions combined, washed with water (2 x 50 mL), saturated aqueous ammonium chloride (50 mL), brine (50 mL), decolorized with activated carbon, dried over sodium sulfate, and the solvent removed under vacuum.
- the residue was purified by flash silica gel column chromatography eluting with 5% acetone in dichloromethane to give P-085 (117.1 mg, 50% yield) as a yellow gum.
- the organic extracts were washed with water (3 x 30 mL), saturated aqueous ammonium chloride (2 x 30 mL), brine (30 mL), decolorized with activated carbon, dried over sodium sulfate, and the solvent removed under vacuum.
- the product was purified by flash silica gel column chromatography eluting with 0-25% acetone in dichloromethane, and was run on a silica gel preparatory plate eluting with 1% acetone in dichloromethane for three developments to obtain P-108 (49.0 mg, 19% yield) as a yellow oil.
- the reaction mixture was stirred for 10 min at 0 0 C, then added to a suspension of Cu(I)CN (0.031 g, 1.2 mmol) in water (0.5 mL) and toluene (1 mL) over 5 min at 0 0 C.
- the reaction mixture was slowly warmed to room temperature, stirred at room temperature for 2 h, then at 50 0 C for 30 min.
- the reaction was extracted with dichloromethane (3 x 5 mL), and the combined organic extracts were washed with brine, dried with Na 2 SO4, filtered, and concentrated under vacuum.
- the residue was purified by silica gel column chromatography using 1 : 1 dichloromethane-hexanes then dichloromethane to afford 1-123 (0.201 g, 61% yield) as white solid.
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EP13000717.2A EP2674417A3 (de) | 2007-11-21 | 2008-11-20 | Biaryl-PDE4-Inhibitoren zur Behandlung von Entzündungen |
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US98955107P | 2007-11-21 | 2007-11-21 | |
PCT/US2008/084193 WO2009067600A2 (en) | 2007-11-21 | 2008-11-20 | Biaryl pde4 inhibitors for treating inflammation |
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EP13000717.2A Division EP2674417A3 (de) | 2007-11-21 | 2008-11-20 | Biaryl-PDE4-Inhibitoren zur Behandlung von Entzündungen |
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EP08851045A Withdrawn EP2222638A2 (de) | 2007-11-21 | 2008-11-20 | Biaryle als pde4-inhibitoren zur behandlung von entzündungen |
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EP (1) | EP2222638A2 (de) |
JP (1) | JP2011505341A (de) |
CN (1) | CN102089279A (de) |
AU (1) | AU2008326381B2 (de) |
CA (1) | CA2722582A1 (de) |
WO (1) | WO2009067600A2 (de) |
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WO2010059838A2 (en) * | 2008-11-20 | 2010-05-27 | Decode Genetics Ehf | Pde4 inhibitors selective for the long form of pde4 for treating inflammation and avoiding side effects |
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CN103338767B (zh) * | 2010-08-04 | 2018-06-22 | 弗吉尼亚大学专利基金会 | 治疗炎症性疾病的组合物和方法 |
CN103402515B (zh) | 2010-11-09 | 2017-05-17 | 铁木医药有限公司 | sGC刺激剂 |
WO2012084711A1 (en) * | 2010-12-24 | 2012-06-28 | Msd Oss B.V. | N-substituted azetidine derivatives |
CN102617457A (zh) * | 2011-01-28 | 2012-08-01 | 天津药物研究院 | 一种制备罗氟司特的新方法 |
CN103012255B (zh) * | 2011-09-21 | 2014-06-11 | 天津康鸿医药科技发展有限公司 | 罗氟司特晶型化合物、其制备方法、组合物及应用 |
CN102603676B (zh) * | 2012-02-20 | 2014-02-12 | 徐江平 | 一种能避免呕吐反应的磷酸二酯酶4抑制剂 |
US8865723B2 (en) | 2012-10-25 | 2014-10-21 | Tetra Discovery Partners Llc | Selective PDE4 B inhibition and improvement in cognition in subjects with brain injury |
MX2015006156A (es) | 2012-11-20 | 2015-08-05 | Vertex Pharma | Compuestos utiles como inhibidores de endolamina 2,3-dioxigenasa. |
CN103012408B (zh) * | 2012-11-28 | 2015-02-04 | 中国科学院广州生物医药与健康研究院 | 依匹斯汀的合成方法 |
MX370188B (es) * | 2013-03-14 | 2019-12-04 | Dart Neuroscience Cayman Ltd | Compuestos de piridina y pirazina sustituidos como inhibidores de pde4. |
IN2014MU00858A (de) | 2014-03-14 | 2015-09-25 | Wockhardt Ltd | |
PL3209655T3 (pl) | 2014-10-24 | 2020-12-28 | Landos Biopharma, Inc. | Leczenie oparte na białku 2 podobnym do syntetazy lantioniny C |
EP3165224A1 (de) | 2015-11-09 | 2017-05-10 | Albert-Ludwigs-Universität Freiburg | Verwendung von pde4 hemmern zur prophylaxe und/oder therapie von dyslipoproteinaemie und verwandten erkrankungen |
WO2017089347A1 (en) | 2015-11-25 | 2017-06-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas |
AU2017294231B2 (en) | 2016-07-05 | 2021-09-09 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd | Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof |
CA3083442A1 (en) | 2017-11-30 | 2019-06-06 | Landos Biopharma, Inc. | Therapies with lanthionine c-like protein 2 ligands and cells prepared therewith |
EP3733659B1 (de) | 2017-12-29 | 2023-12-20 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Aromatisches vinyl- oder aromatisches ethylderivat, herstellungsverfahren dafür, zwischenprodukt, pharmazeutische zusammensetzung und anwendung |
CN110041253B (zh) * | 2018-01-17 | 2022-03-29 | 上海翰森生物医药科技有限公司 | 吡啶类n-氧化衍生物及其制备方法和应用 |
JP2022531129A (ja) | 2019-04-23 | 2022-07-06 | テトラ ディスカバリー パートナーズ インコーポレイテッド | Pde4d阻害剤としての3-ヒドロキシ-2-フェニル-6-(ピラゾール-4-イルメチル)ピリジン誘導体 |
BR112022002387A2 (pt) | 2019-12-20 | 2022-09-06 | Landos Biopharma Inc | Composto da fórmula z-y-q-y' ou um sal ou éster farmaceuticamente aceitável do mesmo |
WO2022057928A1 (zh) | 2020-09-18 | 2022-03-24 | 上海医药集团股份有限公司 | 一种羰基杂环类化合物及其应用 |
CN112374984A (zh) * | 2020-11-06 | 2021-02-19 | 苏州求索生物科技有限公司 | 一种2-溴-4-羟基苯甲醚的制备工艺 |
KR102514860B1 (ko) * | 2020-12-01 | 2023-03-29 | 한국과학기술연구원 | 5-ht7 세로토닌 수용체 활성 저해용 바이페닐 피롤리딘 및 바이페닐 다이하이드로이미다졸 유도체 및 이를 유효성분으로 포함하는 약학 조성물 |
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2008
- 2008-11-20 JP JP2010535064A patent/JP2011505341A/ja active Pending
- 2008-11-20 CN CN2008801251758A patent/CN102089279A/zh active Pending
- 2008-11-20 EP EP08851045A patent/EP2222638A2/de not_active Withdrawn
- 2008-11-20 AU AU2008326381A patent/AU2008326381B2/en not_active Expired - Fee Related
- 2008-11-20 WO PCT/US2008/084193 patent/WO2009067600A2/en active Application Filing
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CA2722582A1 (en) | 2009-05-28 |
WO2009067600A3 (en) | 2009-07-30 |
AU2008326381A1 (en) | 2009-05-28 |
JP2011505341A (ja) | 2011-02-24 |
CN102089279A (zh) | 2011-06-08 |
WO2009067600A2 (en) | 2009-05-28 |
AU2008326381B2 (en) | 2014-10-23 |
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