AU2001278782A1 - Pyrrolidine derivatives and their use as chymase inhibitor - Google Patents
Pyrrolidine derivatives and their use as chymase inhibitorInfo
- Publication number
- AU2001278782A1 AU2001278782A1 AU2001278782A AU7878201A AU2001278782A1 AU 2001278782 A1 AU2001278782 A1 AU 2001278782A1 AU 2001278782 A AU2001278782 A AU 2001278782A AU 7878201 A AU7878201 A AU 7878201A AU 2001278782 A1 AU2001278782 A1 AU 2001278782A1
- Authority
- AU
- Australia
- Prior art keywords
- group
- substituted
- compound
- phenyl
- atom
- 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.)
- Abandoned
Links
- 239000003601 chymase inhibitor Substances 0.000 title description 8
- 229940119334 Chymase inhibitor Drugs 0.000 title description 6
- 150000003235 pyrrolidines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 168
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 108090000227 Chymases Proteins 0.000 claims description 50
- 102000003858 Chymases Human genes 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- -1 isoxazolo[4,3-b]pyridinyl Chemical group 0.000 claims description 32
- 230000002401 inhibitory effect Effects 0.000 claims description 28
- 229920006395 saturated elastomer Polymers 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 125000001041 indolyl group Chemical group 0.000 claims description 17
- 150000003857 carboxamides Chemical class 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 13
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000005518 carboxamido group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 229910052717 sulfur Chemical group 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 5
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 5
- 150000001204 N-oxides Chemical class 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 5
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 claims description 5
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000005493 quinolyl group Chemical group 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- GHJOYRMAYLLOIO-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound CC1=NOC(C)=C1C(N)=O GHJOYRMAYLLOIO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 4
- 230000008728 vascular permeability Effects 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- SJWSGYOCBFJBAX-UHFFFAOYSA-N 4-methylthiadiazole-5-carboxamide Chemical compound CC=1N=NSC=1C(N)=O SJWSGYOCBFJBAX-UHFFFAOYSA-N 0.000 claims 1
- 208000027866 inflammatory disease Diseases 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 115
- 239000000243 solution Substances 0.000 description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000002360 preparation method Methods 0.000 description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000012267 brine Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000000975 dye Substances 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 101000909983 Homo sapiens Chymase Proteins 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 210000003491 skin Anatomy 0.000 description 9
- 241000282693 Cercopithecidae Species 0.000 description 8
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 210000003630 histaminocyte Anatomy 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 241000416162 Astragalus gummifer Species 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 229920001615 Tragacanth Polymers 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000012064 sodium phosphate buffer Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000196 tragacanth Substances 0.000 description 5
- 235000010487 tragacanth Nutrition 0.000 description 5
- 229940116362 tragacanth Drugs 0.000 description 5
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- GIFBWHXYOQJDHH-UHFFFAOYSA-N 2-(3-benzyl-2,5-dioxoimidazolidin-1-yl)acetic acid Chemical compound O=C1N(CC(=O)O)C(=O)CN1CC1=CC=CC=C1 GIFBWHXYOQJDHH-UHFFFAOYSA-N 0.000 description 3
- MMORIWCAQRDZOJ-UHFFFAOYSA-N 2-(3-benzyl-2-oxoimidazolidin-1-yl)acetic acid Chemical compound O=C1N(CC(=O)O)CCN1CC1=CC=CC=C1 MMORIWCAQRDZOJ-UHFFFAOYSA-N 0.000 description 3
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 3
- 102400000345 Angiotensin-2 Human genes 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 3
- 239000001045 blue dye Substances 0.000 description 3
- 238000011088 calibration curve Methods 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 239000013613 expression plasmid Substances 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 3
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
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- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
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- UIZCYEQBMNQVIH-JSGCOSHPSA-N tert-butyl n-[(2s,3s)-1-(1-benzothiophen-3-yl)-4,4,4-trifluoro-3-hydroxybutan-2-yl]carbamate Chemical compound C1=CC=C2C(C[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(F)(F)F)=CSC2=C1 UIZCYEQBMNQVIH-JSGCOSHPSA-N 0.000 description 1
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- RSKHNOFGQRATRE-UHFFFAOYSA-N trifluoromethylsilicon Chemical compound FC(F)(F)[Si] RSKHNOFGQRATRE-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1027—Tetrapeptides containing heteroatoms different from O, S, or N
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- A—HUMAN NECESSITIES
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- A61K38/00—Medicinal preparations containing peptides
Description
DESCRIPTION
PYRROLIDINE DERIVATIVES AND THEIR USE AS CHYMASE INHIBITOR
TECHNICAL FIELD
This invention relates to pyrrolidine derivatives useful as a chymase inhibitor and intermediates for the synthesis thereof.
BACKGROUND ART
Chymase, a chymotrypsin-like serine protease discovered in 1975, is released upon mast cell degranulation. Although it is known that chymase is able to cleave extracellular matrix and other biologically active substances, much attention has been given to its ability to convert angiotensin I, in a manner independent of that of angiotensin-converting enzyme, to the vasoconstrictor angiotensin II. Previous studies have suggested that the formation of angiotensin II within the human heart is mainly controlled by chymase rather than by angiotensin-converting enzyme [Circ. Res. 66, 883-890 (1990)]. Accordingly, it has been assumed that chymase plays an important role in the progression of cardiovascular diseases such as cardiac hypertrophy, myocardial infarction, vascular hyperplasia, and restenosis following angioplasty.
Moreover, it has been shown that chymase enhances histamine release from mast cells and induces a prolonged increase in microvascular permeability independent of histamine [Eur. J. Pharmacol. 352, 91-98 (1998)]. It is, therefore, highly possible that chymase plays
an important role, not only in the immediate type of allergic inflammatory reactions, but also in the delayed ones, which are known to involve mast cells.
Mast cells containing chymase as well as tryptase are mainly distributed in connective tissues, while those containing tryptase, but not chymase, are mainly present in mucosal tissues. In addition, it has been reported that chymase activity increases significantly with the progression of tissue fibrosis including intraperitoneal adhesion formation [FEBS Letters 406, 301-304 (1997), J. Surg. Res. 92, 40-44 (2000)]. These findings indicate that chymase may participate in tissue fibrosis.
In addition to its possible involvement in a range of diseases and complications, chymase is known to have various other physiological activities such as, formation of other active proteases for matrix degradation, activation of the inflammatory cytokine IL-1 β precursor, formation of the active TGF-β in fibrosis, enhancement of foam cell formation and maintenance in atherogenesis, and conversion of big endothelins to contractile 31 -amino acid length endothelins. Accordingly, it is suggested that chymase may play an important role in blood flow regulation, allergy, inflammation, and tissue remodeling.
Combining the information above, it is expected that chymase inhibitors, acting as antiallergic, antiinflammatory, antirestenotic, or antiarterio sclerotic agents, may provide novel treatments for a wide range of diseases and complications. Studies have hitherto been made for finding an excellent chymase inhibitor, and there are reported various kinds of chymase inhibitors, for
example, it is disclosed in WO-A-93/25574 that a wide range of compounds have a chymase inhibitory activity, but no specific data of the activity is disclosed. WO-A-93/25574 includes very broad claims and discloses 28 examples, among which the compound of Example 21 has the following formula (A):
In the following formula (I) of the present compounds, the above compound (A) is not includes. That is, R3 of the following formula (I) means an unsaturated monocyclic heterocyclic group, but not a saturated monocyclic heterocyclic group. In addition, as disclosed in
Experiments as described below, the chymase inhibitory activity of the compound (A) is far weaker than that of the present compounds.
DISCLOSURE OF INVENTION An object of the present invention is to provide novel pyrrolidine derivatives having a chymase inhibitory activity. Another object of the invention is to provide a pharmaceutical composition comprising as an active ingredient said novel pyrrolidine derivative in admixture with a pharmaceutically acceptable carrier or diluent. A further object of the invention is to provide a chymase inhibitory agent.
A pyrrolidine derivative of the present invention has the following formula (I):
wherein R1 is a cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a tetrahydro- naphthyl group, an indanyl group, a thienyl group, a furyl group, a substituted or unsubstituted indolyl group, a substituted or unsubstituted dihydroindolyl group, a benzofuryl group, a dihydro- benzofuryl group, a substituted or unsubstituted benzothienyl group or an S-mono- or di-oxide thereof, or a dihydrobenzothienyl group, said substituted phenyl, naphthyl and benzothienyl groups having each independently one to three substituents independently selected from a halogen atom, a lower alkoxy group, a hydroxy group and a lower alkyl group having optionally one to three halogen atoms; and said substituted indolyl and dihydroindolyl groups having a substituent on (N) at the 1- position selected from a lower alkyl group and a lower alkyl-carbonyl group;
R2 is a hydrogen atom, an alkyl group, a phenyl-lower alkyl group, a cycloalkyl group or a cycloalkyl-lower alkyl group;
R3 is (i) a substituted or unsubstituted, unsaturated monocyclic heterocyclic group; (ii) a substituted or unsubstituted, saturated or unsaturated monocyclic heterocyclic group which is fused by a benzene ring or a pyridine ring, wherein said substituted heterocyclic groups in (i) and (ii) each independently have one to three substituents independently selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a
lower alkyl-carbonyl group, a cyano group, a carboxamido group, a phenyl group and a phenoxy group; said phenyl and phenoxy substituents may further optionally have one to three substituents independently selected from a halogen atom, a lower alkyl group and a halogeno-lower alkyl group; or
(iii) a group of the formula (a):
wherein A is a lower alkylene group, D1 and D2 are both simultaneously a methylene group (-CH2-) or alternatively, one of D1 and D2 is a methylene group (-CH2-) and another is a vinylene group (-CH=CH-) where each methylene group being optionally substituted by an oxo group or a lower alkyl group, and said vinylene group being optionally substituted by a lower alkyl group; R6 is a lower alkyl group substituted by a carboxyl group, a lower alkoxycarbonyl group or a phenyl group; R4 and R5 are each independently a hydrogen atom or a hydroxy group, but R4 and R5 are not simultaneously a hydrogen atom, or both combines to form an oxo group; n is 0, 1, 2 or 3; or a salt thereof. Throughout the description and claims, the term "lower alkyl group" or "lower alkyl" moiety denotes a straight chain and branched alkyl group having 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl.
The term "lower alkoxy group" denotes a straight chain or branched
chain alkoxy group having 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, pentyloxy, and hexyloxy.
The "cycloalkyl group" denotes a cycloalkyl group having 3 to 8 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term "lower alkylene group" denotes a straight chain or branched chain alkylene group having 1 to 6 carbon atoms, and includes, for example, methylene, ethylene, propylene, butylene, isobutylene, pentylene, and hexylene.
The "lower alkyl-carbonyl group" denotes a carbonyl group substituted by a straight chain or branched chain alkyl having 1 to 6 carbon atoms, and includes, for example, acetyl, propionyl, butyryl, pentanoyl, and hexanoyl. The "halogen atom" denotes fluorine atom, bromine atom, chlorine atom, or iodine atom.
The "unsaturated monocyclic heterocyclic group" for R3 denotes an unsaturated 5- to 7-membered, preferably 5- or 6-membered, monocyclic heterocyclic group containing one to three heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, and includes, for example, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- thiadiazolyl, 1,2,4-oxadiazolyl, and pyridyl.
The "saturated or unsaturated monocyclic heterocyclic group which is fused by a benzene ring or a pyridine ring" for R3 denotes a saturated or unsaturated 5- to 7-membered, preferably 5- or 6-membered, monocyclic heterocyclic group containing one to three heteroatoms selected from
nitrogen atom, oxygen atom and sulfur atom which is fused by a benzene ring or a pyridine ring, and includes, for example, benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofurazanyl or N-oxide thereof, quinolyl, benzodioxolyl, and isoxazolo[4,3-b]pyridinyl.
The group of the formula (a) for R3 includes, for example, the groups of the following formulae:
(a-1) (a-2) (a-3) (a-4) wherein A and R6 are as defined above. Preferred compounds of the present invention are the compounds of the formula (I) wherein R1 is a C3-C8 cycloalkyl group, a phenyl group, a phenyl substituted by one to three substituents independently selected from a halogen atom, a C C4 alkoxy group, a hydroxy group, a C^C^. alkyl group and a halogeno-C^^ alkyl group; a naphthyl group, a tetrahydronaphthyl group, an indanyl group, a thienyl group, a furyl group, an indolyl group, an N-(CrC4 alkyl)indolyl group, an N-(C1-C4 alky Icarbonyl) indolyl group, a dihydroindolyl group, a benzofuryl group, a dihydrobenzofuryl group, a benzothienyl group or an S-mono- or dioxide thereof, or a dihydrobenzothienyl group; R2 is a hydrogen atom, a C C6 alkyl group, a phenyl-C1-C4 alkyl group, a C3-C8 cycloalkyl group or a C3-C8 cycloalkyl-C C4 alkyl group;
R3 is (i) an unsaturated monocyclic heterocyclic group selected from furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-
thiadiazolyl, 1,2,4-oxadiazolyl, and pyridyl;
(ii) a benzene- or pyridine-fused saturated or unsaturated monocyclic heterocyclic group selected from benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofurazanyl or N-oxide thereof, quinolyl, benzodioxolyl, and isoxazolo[4,3-b]pyridinyl, wherein said heterocyclic groups in (i) and (ii) may each independently have one to three substituents independently selected from a fluorine or chlorine atom, a C -C4 alkyl group, a Ci-C4 alkoxy group, a CrC4 alkyl-carbonyl group, a cyano group, a carboxamido group, a phenyl group and a phenoxy group; said phenyl and phenoxy substituents may further optionally have one to three substituents independently selected from a halogen atom, a C -C4 alkyl group and a halogeno-C1-C4 alkyl group; or
(iii) a group of any one of the formulae (a-1) to (a-4):
(a-1) (a-2) (a-3) (a-4) wherein A is a C!-C4 alkylene group, and R6 is a CrC4 alkyl group substituted by a carboxyl group, a Cj-Cs alkoxycarbonyl group or a phenyl group;
R4 and R5 are each independently a hydrogen atom or a hydroxy group but R4 and R5 are not simultaneously a hydrogen atom, or both combines to form an oxo group; n is 1 or 2; or a salt thereof.
More preferred compounds of the present invention are the compounds of the formula (I) wherein R1 is a C5-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by one to three substituents independently selected from fluorine, chlorine or bromine atom, a C^C^ alkoxy group, a hydroxy group, a Cj-G* alkyl group and a trifluoromethyl group; a naphthyl group, a tetrahydronaphthyl group, an indanyl group, a thienyl group, a furyl group, an indolyl group, an N-fCj-C,. alkyl)indolyl group, an N-acetylindolyl group, a dihydroindolyl group, a benzofuryl group, a dihydrobenzofuryl group, a benzothienyl group or an S-mono- or di-oxide thereof, or a dihydrobenzo thienyl group;
R2 is a hydrogen atom, a Cr-C alkyl group, a phenyl-Cj-Ca alkyl group, a C5-C7 cycloalkyl group or a C5-C7 cycloalkyl-Cj-Ca alkyl group;
R3 is (i) an unsaturated monocyclic heterocyclic group selected from furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- thiadiazolyl, 1,2,4-oxadiazolyl, and pyridyl;
(ii) a benzene- or pyridine-fused saturated or unsaturated monocyclic heterocyclic group selected from benzoxazolyl, benzisoxazolyl, benzofurazanyl or N-oxide thereof, quinolyl, benzodioxolyl, and isoxazolo[4,3-b]pyridinyl, wherein said heterocyclic groups in (i) and (ii) may each independently have one to three substituents independently selected from the group consisting of a fluorine or chlorine atom, a C C3 alkyl group, a
alkoxy group, an acetyl group, a cyano group, a carboxamido group, a phenyl group and a phenoxy group, said phenyl and phenoxy substituents may further optionally have one to three substituents selected from a fluorine or chlorine atom, a CrC3 alkyl group and a trifluoromethyl group; or
(iii) a group of any one of the formulae (a-1) to (a-4):
R-
(a-1) (a-2) (a-3) (a-4) wherein A is a
alkyl group substituted by a carboxyl group, a tert-butoxycarbonyl group or a phenyl group;
R4 and R5 are each independently a hydrogen atom or a hydroxy group, but R4 and R5 are not simultaneously a hydrogen atom, or both combines to form an oxo group; n is 1 or 2; or a salt thereof.
The compounds (I) of the present invention may be classified into two groups by the kinds of R4 and R5 groups, that is, when the R4 and R5 groups combine to form an oxo group, the compounds are shown by the following formula (I -A), and when one of the R4 and R5 groups is a hydrogen atom and another is a hydroxy group, the compounds are shown by the following formula (I-B) .
wherein R1, R2, R3 and n are as defined above.
The compound of the formula (I -A) may have a structure wherein the keto group for the corresponding R4 and R5 in the formula (I) is converted into two hydroxy groups by addition of a water molecule.
The compounds of the formula (I-A) have excellent chymase inhibitory activity and hence are useful as a medicament. The compounds of the formula (I-B) can be converted into the compounds of the formula (I-A) by oxidizing them, and hence are useful as an intermediate for preparing the active compounds (I-A).
The compounds of the formula (I-A) have high blood level by oral administration to exhibit excellent chymase inhibitory activity. The characteristic properties of the compounds (I-A) may due to the kinds of substituents of R3, particularly a combination of said R3 with other substituents, such as R1 and others.
In view of the excellent chymase inhibitory activity, particularly preferred compounds are compounds of the formula (I-A'):
wherein R3a and R3b are independently a hydrogen atom, a lower alkyl group, a lower alkyl-carbonyl group, or a phenyl group which may be substituted by a halogen' atom or a halogeno-lower alkyl group; X is a carbon atom or a sulfur atom; Y is an oxygen atom or a nitrogen atom; and the symbol means a single bond or double bond, and R1, R2 and n are as defined above, or a pharmaceutically acceptable salt thereof. Among the preferred compounds (I-A5), especially preferred
compounds are the compounds of the formula (I-A5) wherein X is a carbon atom and Y is an oxygen atom, or X is a sulfur atom and Y is a nitrogen atom, and other symbols are as defined above, or a pharmaceutically acceptable salt thereof. In an especially preferred compounds of the formula (I-A'), wherein R1 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group or a benzothienyl group, said substituted phenyl group and substituted naphthyl group have each independently one to three substituents independently selected from a halogen atom, a methyl group, a methoxy group, a trifluoromethyl group and a hydroxy group.
BEST MODE FOR CARRYING OUT THE INVENTION
Suitable compounds of the formula (I-A5) are exemplified below. Compound 1-A-l:
N-[(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]thiophen-3-ylmethyl)-3,3,3- trifluoro-2-oxopropyl]carbamoyl}pyrrolidinyl)-l-(methylethyl)-2-oxo- ethyl](3,5-dimethylisoxazol-4-yl)carboxamide; Compound l-A-2:
N-[(lS)-2-((2S)-2-{N-[(lS)-3,3,3-trifluoro-l-(2-naphthylmethyl)-2- oxopropyl] carbamoyljpyrrolidinyl) - 1 - (methylethyl) -2-oxoethyl] (3,5- dimethylisoxazol-4-yl)carboxamide; Compound l-A-3:
N-[(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]thiophen-3-ylmethyl)-3,3,3- trifluoro-2-oxopropyl]carbamoyl}pyrrolidinyl)-l-ethyl-2-oxoethyl](3,5- dimethylisoxazol-4-yl)carboxamide; Compound l-A-4:
N-[l-((lR)-l-methylpropyl)(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]-
thiophen-3-ylmethyl)-3,3,3-trifluoro-2-oxopropyl]carbamoyl}pyrrolidin- yl)-2-oxoethyl](3,5- dimethylisoxazol-4-yl)carboxamide; Compound l-A-5:
N-[(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]thiophen-3-ylmethyl)-3,3,3- trifluoro-2-oxopropyl]carbamoyl}pyrrolidinyl)-l-methyl-2-oxoethyl](3,5- dimethylisoxazol-4-yl)carboxamide; Compound l-A-20:
N-[(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]thiophen-3-ylmethyl)-3,3,3- trifluoro-2-oxopropyl]carbamoyl}pyrrolidinyl)-l-(methylethyl)-2-oxo- ethyl](4-methyl(l,2,3-thiadiazol-5-yl))carboxamide;
The compounds (I) of the present invention have several asymmetric carbons and include enantiomers, diastereomers and mixtures thereof. These isomers and mixtures thereof are also included in the present invention. Further, the compounds (I) may be in the form of a hydrate and/ or a salt, which are also included in the present invention. The salts of the compounds of the formula (I) are not limited to any specific one but are preferably pharmaceutically acceptable salts, for example, a salt with an organic base (e.g. trimethylamine, triethylamine, N-methyl- morpholine), a salt with an inorganic metal (e.g. sodium, potassium). Some compounds of the formula (I) may form an acid addition salt with an organic acid such as tartaric acid, fumaric acid, acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid, an amino acid (e.g. aspartic acid), or with an inorganic acid (e.g. hydrochloric acid, phosphoric acid). Processes for the preparation of the compounds (I)
The compounds (I) of the present invention are prepared by the
processes as mentioned below.
One preferred process is shown by the following Reaction Scheme-
1.
Reaction Scheme- 1
wherein R is a protecting group for an amino group and W is a leaving group, and R1, R2, R3 and n are as defined above.
The protecting group for an amino group defined by R is inclusive any conventional amino-protecting groups, for example, alkoxycarbonyl groups (e.g. tert-butoxycarbonyl, abbreviated as "Boc") which can be removed by hydrolysis with an acid or a base, or substituted or unsubstituted benzyloxycarbonyl groups (which are usually indicated by the symbol "Z") which can be removed by hydrogenolysis.
The leaving group defined by "W" in the above reaction includes a hydroxy group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, or a lower alkylsulfonyl group.
In the above Reaction Scheme- 1, Step 1, a known compound (1) is treated with paraformaldehyde to give the compound (2). In Step 2, the compound (2) is converted into the compound (3) by reacting it with a tri(lower alkyl) (trifluoromethyl) silane compound (e.g., trimethyl(trifluoro- methyl)silane) in the presence of cesium fluoride, treating the reaction product with methanol, reducing the resulting product to make ring- opening and then de-hydroxymethylating. The reduction for ring-opening is usually carried out with sodium borohydride, and the de- hydroxymethylation is carried out by treating with a base such as potassium carbonate. In Step 3, the amino-protecting group "R" of the compound (3) is removed by a conventional method as mentioned above to give the compound (4). The reaction in these steps 1, 2 and 3 may be done step by step or alternatively by one-pot reaction. In Step 4, the compound (4) obtained above is reacted with a known compound (5). The reaction in this step is carried out by a conventional
amidation reaction which is usually used for production of peptides. For instance, the compound (4) is reacted with the compound (5) by mixing them in a solvent (e.g. methylene chloride, dimethylformamide) or without solvent and stirring the mixture in the presence or absence of a base (e.g. trie hylamine) at room temperature or at an elevated temperature. When the symbol "W" of the compound (5) is a hydroxy group, the reaction in Step 4 is advantageously carried out in the presence of a condensation agent, such as l-ethyl-3-(3-dimethylamino- propyl)carbodiimide, N,N'-dicyclohexylcarbodiimide, 1 , 1 '-carbonyl- diimidazole, or N,N'-disuccinimidyl carbonate. When the symbol "W" is a hydroxy group, the reaction in Step 4 may also be carried out by firstly reacting the compound (5) with ethyl chloroformate in the presence of a tertiary amine such as triethylamine or preferably N-methylmorpholine, followed by reacting the resultant with the compound (4). In Step 5, the amino-protecting group "R" of the compound (6) is removed by a conventional method. For example, when the amino- protecting group is tert-butoxycarbonyl, it is removed by contacting the compound (6) with an acid, such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, or acetic acid. The reaction is carried out in a solvent, such as methylene chloride, ethyl acetate, tetrahydro- furan, benzene, toluene, or a mixture of them. When the amino- protecting group "R" in the compound (6) is a benzyloxycarbonyl group, the removal thereof can be advantageously carried out by treating the compound (6) with hydrogen gas in a solvent (e.g. ethyl acetate, ethanol) in the presence of a catalyst (e.g. platinum, palladium, Raney nickel) at a temperature of lower than 60 °C, usually at room temperature.
The thus-prepared compound (7) is then reacted with the compound (8) in Step 6. The reaction is carried out in the same manner as in Step 4 to give the compound (I-B). The compound (8) is novel when the symbol "R3" is a group of the formula (a), and said compound can be prepared by the process as described hereinafter in Reference Examples or in a similar manner. When the symbol "R3" is a group other than the formula (a), the compound (8) is known, among which the compound of the following formula (II) is particularly important.
wherein R3 , R3b, X, Y, W and the symbol are as defined above.
Although the compounds of the above formula (II) are known, they have never been used for the preparation of the compounds of the formula (I-
A) of the present invention.
The compounds of the formula (I-B) as prepared in the above Step 6 are novel and are useful as an intermediate for preparing the desired compounds of the formula (I-A) of the present invention which have excellent chymase inhibitory activity.
That is, in Step 7, the compound (I-B) (OH-compound) is converted into the compound (I-A) (ketone compound) by oxidizing the OH group thereof. The oxidizing reaction in Step 7 can be carried out by treating the compound (I-B) with an oxidizing agent in a solvent (e.g. methylene chloride, dimethylformamide, tetrahydrofuran, ethyl acetate, toluene).
The oxidizing agent is, for example, Dess-Martin reagent which is an iodobenzene derivative. The oxidation may be carried out with
phosphorus pentoxide in the presence of dimethylsulfoxide, with 1- ethyl-3-(3-dimethyaminopropylcarbodiimide - dichloroacetic acid in the presence of dimethyl sulfoxide, or with a combination of oxalyl chloride and triethylamine in the presence of dimethyl sulfoxide (so-called Swern oxidation).
In the above steps in Reaction Scheme- 1, the compounds having a free carboxyl group may optionally be protected by a conventional protecting group (e.g. tert- butyl, benzyl), and the protecting group can be removed by a conventional method after the reaction. Besides, when the compounds prepared in each step have isomers, these isomers may be resolved by a conventional method. Examples
The present invention is illustrated by the following Examples, Reference Examples and Experiments but should not be construed to be limited thereto.
In these examples, the following abbreviations are used.
Boc : tert-butoxycarbonyl
Ph : phenyl
Me : methyl Et : ethyl
Z : benzyloxycarbonyl or (phenylmethoxy) carbonyl
THF : tetrahydrofuran
DMSO : dimethylsulfoxide
DMF : dimethylformamide LSIMS : liquid secondary ion mass spectrometry
1H-NMR : proton nuclear magnetic resonance spectrometry
APCIMS : atmospheric pressure chemical ionization spectrometry IR : infrared spectrometry Reference Example 1
Preparation of raw compound (8) in Reaction Scheme- 1 : 2-(3-{[(tert-butyl)oxycarbonyl]methyl}-2-oxoimidazolidinyl)acetic acid
(8a):
(1) To a solution of 2-oxoimidazolidine (0.3 g) and tert- butyl bromo- acetate (1.50 g) in anhydrous DMF (10 ml) at 0°C was added lithium tert- butoxide (0.6 g). After stirring at the same temperature for 30 minutes, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and then the precipitate was collected and washed with water and dried. The precipitate was recrystallized with ethyl acetate and filtered off to give tert-butyl 2-(3- {[(tert-butyl)oxycarbonyl]methyl}-2-oxoimidazolidinyl)acetate (0.86 g) as a white solid. m.p. 100-102°C
LSIMS (m/z) : 315[(M+H)+]
Η-NMR (300MHz, CDC13): δ 1.46 (18H, s), 3.54 (4H, s), 3.89 (4H, s). (2) To a solution of tert-butyl 2-(3-{[(tert-butyl)oxycarbonyl]methyl}-2- oxoimidazolidinyl) acetate (1.14 g) in ethanol (10 ml) and water (10 ml) was added potassium hydroxide (0.22 g) and then the reaction mixture stirred at 70°C for 5 hours. After the ethanol was removed under reduced pressure, to the residue was added saturated aqueous sodium
hydrogen carbonate solution. The aqueous phase was washed with ethyl acetate, acidified with 10 % hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The precipitate was recrystallized with ethyl acetate and filtered off to give 2-(3-{[(tert-butyl)- oxycarbonyl]methyl}-2-oxoimidazolidinyl)acetic acid (0.30 g) as a colorless solid. m.p. 112-113°C
LSIMS (m/z): 259 [(M+H)+] 1H-NMR (300MHz, CDC13): δ 1.46 (9H, s), 3.53 (4H, s), 3.89 (2H, s)
4.01 (2H, s), 7.11 (1H, br s).
Reference Example 2
Preparation of raw compound (8) in Reaction Scheme- 1 :
2 - (3 -{[ (tert-butyl) oxycarbonyl] methyl}-2 , 4 -dioxo - 1 , 3 -dihy dropyrimidinyl) - acetic acid (8b):
(1) To a solution of 2,4-dioxopyrimidine (1.0 g) in anhydrous DMF (10 ml) were added benzyl bromoacetate (2.5 g) and potassium carbonate (2.5 g). After stirring at room temperature for 15 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine and then dried with magnesium sulfate, filtered and evaporated under reduced pressure. The precipitate was washed with diethyl ether to give phenylmethyl 2-(2,4-dioxo-l,3- dihy dropyrimidinyl) acetate (1.4 g) as a colorless solid.
m.p. 192-194°C
LSIMS (m/z): 261 [(M+H)+]
1H-NMR (300MHz, d6-DMSO): δ 4.59 (2H, s), 5.20 (2H, s), 5.62 (1H, d), 7.37 (5H, m), 7.65 (1H, d), 11.4 (1H, s). (2) To a solution of phenylmethyl 2-(2,4-dioxo-l,3-dihydro- pyrimidinyl) acetate (1.0 g) in anhydrous DMF (10 ml) at 0°C was added portionwise sodium hydride (0.18 g). After the reaction mixture was stirred for 15 minutes with cooling in an ice bath, tert-butyl bromoacetate (0.9 g) was added. After stirring the mixture at room temperature for 1 hour, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, n- hexane : ethyl acetate 2: 1) to give phenylmethyl 2-(3-{[(tert-butyl)oxy- carbonyl]methyl}-2,4-dioxo-l,3-dihydropyrimidinyl)acetate (1.2 g) as a colorless oil.
LSIMS (m/z): 375[(M+H)+]
XH-NMR (300MHz, CDCL : δ 1.46 (9H, s), 4.51 (2H, s), 4.58 (2H, s) 5.21 (2H, s), 5.81 (1H, d) 7.10 (1H, d) 7.36 (5H, m).
(3) To a solution of phenylmethyl 2-(3-{[(tert-butyl)oxycarbonyl]- methyl}-2,4-dioxo-l,3-dihydropyrimidinyl)acetate (1.2 g) in ethyl acetate (20 ml) was added 20 wt. % palladium hydroxide (50 mg). After stirring the mixture at room temperature under a hydrogen atmosphere for 1 hour, the catalyst was removed by filtration. The filtrate was evaporated under reduced pressure to give 2 -(3 -{[(tert-butyl) oxycarbonyl] methyl}-
2,4-dioxo-l,3-dihydropyrimidinyl)acetic acid as a white powder.
1H NMR (300MHz, CDC13): δ 1.46 (9H, s), 4.51 (2H, s), 4.59 (2H, s),
5.86 (1H, d), 7.17 (1H, d). Reference Example 3 Preparation of raw compound (8) in Reaction Scheme- 1 : 2-(2-oxo-3-benzylimidazolidinyl)acetic acid (8c):
(1) To a solution of N-benzylethylenediamine (6.0 g, 40 mmol) in toluene (50 ml) at 0°C was added l,l'-carbonylbis-lH-imidazole (7.8 g, 48 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was washed with water, 5 % aqueous citric acid solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized with warm ethyl acetate and filtered off to give 1-benzyl- imidazolidin-2-one (3.47 g).
*H-NMR (300MHz, d5-DMSO): δ 7.22-7.37 (5H, m), 6.41 (1H, br s),
4.23 (2H, s), 3.14-3.26 (4H, m).
APCIMS: 177 (MH+) mp. 131-131.5°C (2) To a solution of l-benzylimidazolidin-2-one (3.5 g, 19.9 mmol) in
DMF (50 ml) at 0°C were added lithium tert-butoxide (1.9 g, 23.8 mmol) and tert-butyl bromoacetate (3.2 ml, 21.8 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate.
The organic phase was washed with water, 10 % aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline residue was washed with n-hexane, and dried to give tert-butyl 2- (2- oxo-3-benzylimidazolidinyl)acetate (5.08 g).
Η-NMR (300MHz, CDC13): δ 7.24-7.36 (5H, m), 4.40 (2H, s), 3.90 (2H, s), 3.40-3.46 (2H, m), 3.26-3.20 (2H, m). (3) To a solution of tert-butyl 2-(2-oxo-3-benzylimidazolidinyl)acetate (2.51 g, 8.64 mmol) in dichloromethane (15 ml) was added triiluoroacetic acid (10 ml). After stirring the mixture at room temperature for 1 hour, the solvent was removed under reduced pressure. The oily residue was crystallized by treating with ethyl acetate and filtered off to give 2-(2- oxo-3-benzylimidazolidinyl)acetic acid (1.56 g). 1H-NMR (300MHz, d6-DMSO): δ 7.65 (1H, br s), 7.26-7.36 (5H, m),
4.41 (2H, s), 4.04 (2H, s), 3.45-3.50 (2H, m), 3.25-3.30 (2H, m).
APCIMS: 235 (MH+) mp. 132-133°C Reference Example 4 Preparation of raw compound (8) in Reaction Scheme- 1 : 2-(2,5-dioxo-3-benzylimidazolidinyl)acetic acid (8d):
(1) To a solution of hydantoin (10.0 g, 0.10 mol) in DMF (100 ml) at 60°C were added potassium carbonate (20.7 g, 0.15 mol) and benzyl bromo-
acetate (18.9 ml, 0.12 mol). After stirring the mixture at 60°C overnight, the reaction mixture was poured into water (250 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with 5 % aqueous citric acid solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline residue was washed with diethyl ether, and dried to give phenylmethyl 2-(2,5-dioxoimidazolidinyl)acetate (14.9 g).
XH-NMR (300MHz, CDC13): 6 8.24 (1H, br s), 7.32-7.42 (5H, m), 5.17 (2H, s), 4.23 (2H, s), 4.03 (2H, s).
APCIMS: 249 (MH+) mp. 142-144°C (2) To a solution of phenylmethyl 2-(2,5-dioxoimidazolidinyl)acetate (4.0 g, 16.1 mmol) in DMF (50 ml) at 0°C were added lithium tert-butoxide (1.6 g, 19.3 mmol) and benzyl bromide (2.1 ml, 17.7 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, 10 % aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chrornatography (silica gel, n-hexane : ethyl acetate = 3: 1) to give phenylmethyl 2-(2,5-dioxo-3-benzylimidazolidinyl)- acetate (3.42 g). XH-NMR (300MHz, CDC13): δ 7.22-7.41 (10H, m), 5.20 (2H, s), 4.59
(2H, s), 4.34 (2H, s), 3.81 (2H, s).
(3) To a solution of phenylmethyl 2-(2,5-dioxo-3-benzylimidazolidin- yl)acetate (3.42 g, 10.0 mmol) in THF-H2O (3: 1, 40 ml) was added lithium hydroxide monohydrate (0.85 g, 20.0 mmol). After stirring the mixture at 50°C for 6 hours, the reaction mixture was alkalized with saturated aqueous sodium hydrogen carbonate solution and washed with ethyl acetate. The aqueous phase was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized with ethyl acetate and filtered off to give 2-(2,5-dioxo-3-benzylimidazolidinyl)acetic acid (1.28 g).
Η-NMR (300MHz, CDC13): δ 7.24-7.38 (10H, m), 4.57 (2H, s), 3.99
(2H, s), 3.96 (2H, d, J= 5.0Hz).
APCIMS: 249 (MH+) mp. 125-127°C
Reference Example 5
Preparation of raw compound (8) in Reaction Scheme- 1: 2-(5-methyl-2,4-dioxo-3-benzyl- 1 ,3-dihy dropyrimidinyl) acetic acid (8e) :
The compound 8e was obtained in the same manner as described in
Reference Example 4.
Η-NMR (300MHz, CDC13): δ 8.42 (1H, br s), 7.23-7.44 (5H, m), 6.91 (1H, s), 5.13 (2H, s), 4.45 (2H, s), 1.94 (3H, s).
APCIMS: 275 (MH+) mp. 130-131°C Reference Example 6
Preparation of raw compound (4) in Reaction Scheme 1 : (2S,3S)-3-amino-4-benzo[b]thiophen-3-yl-l, l, l-trifluorobutan-2-ol hydrochloride (Compound 4-1)
(1) To a suspension of Compound 1: (2S)-3-benzo[b]thiophen-3-yl-2- [(tert-butoxy)carbonylamino]propanoic acid (20.0 g, 62.2 mmol) in toluene (220 ml) were added paraformaldehyde (6.2 g) and p-toluene- sulfonic acid monohydrate (375 mg). After stirring the mixture at 90°C for 3 hours, the reaction mixture was cooled in an ice bath and then washed with saturated aqueous sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane: ethyl acetate 5: 1) to give Compound 2: tert-butyl(4S)-4-(benzo[b]thiophen-3-yl-methyl)-5-oxo-l,3- oxazolidine-3-carboxylate (17.4 g).
1H NMR (300MHz, CDC13): δ 7.79-7.86 (2H, m), 7.32-7.37 (2H, m), 7.25 (1H, s), 5.11-5.41 (1H, m), 4.60 (1H, brs), 4.16-4.48 (1H, m), 3.37-3.74 (2H, m), 1.44 (9H, s) LSIMS (m/z): 334 [(M+H)+] (2) To a solution of Compound 2 (25.3 g, 75.9 mmol) and trimethyl-
(trifluoromethyl)silane (13.5 g, 94.9 mmol) in THF (75 ml) at room temperature was added cesium fluoride (2.3 g, 15.2 mmol). The mixture was stirred for 1 hour. After adding methanol (25 ml) to the reaction mixture, the mixture was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate and then washed with water and brine. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure.
The residue was dissolved in methanol (100 ml), and to the solution was added sodium borohydride (2.9 g, 75.9 mmol) at 0°C. After stirring the mixture for 1 hour, the reaction mixture was acidified with 10 % aqueous citric acid solution and extracted with ethyl acetate. The organic phase was washed with 10 % aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over sodium sulfate, filtered and evaporated under reduced pressure.
The residue was dissolved in DMF (100 ml) and water (75 ml), and to the solution was added potassium carbonate (12.6 g, 91.1 mmol) at room temperature. After stirring the mixture for 1 hour, the reaction mixture was acidified with 10 % aqueous citric acid solution and extracted with ethyl acetate. The organic phase was washed with 10 % aqueous citric
acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane: ethyl acetate 10: 1) to give Compound 3: N-[(lS,2S)-l-(benzo[b]thiophen-3-yl-methyl)-3,3,3- trifluoro-2-hydroxypropyl](tert-butoxy)carboxamide (22.4 g).
XH NMR (300MHz, CDC13): δ 7.80-7.89 (2H, m), 7.35-7.44 (2H, m),
7.25 (1H, s), 5.05 (1H, brs), 4.81-4.83 (1H, d, J=7.5 Hz), 3.99-4.02
(2H, m), 3.23-3.40 (2H, m), 1.44 (9H, s) LSIMS (m/z): 376 [(M+H)+] m.p.: 118-120°C (3) To Compound 3 (3.75 g, 10 mmol) was added 4 mol/ 1000 ml- hydrogen chloride in 1,4-dioxane solution (25 ml). After stirring the mixture at room temperature for 30 minutes, the solvent was removed under reduced pressure. The residue was crystallized by treating with diethyl ether and filtered off to give Compound 4-1 : (2S,3S)-3-amino-4- benzo[b]thiophen-3-yl-l,l, l-trifuluorobutan-2-ol hydrochloride (3.1 g).
Η NMR (300MHz, CDC13): δ 8.02-8.05 (1H, m), 7.91-7.94 (1H, m),
7.71 (1H, brs), 7.40-7.50 (2H, m), 4.12-4.15 (1H, m), 3.70 (1H, brs), 3.28-3.32 (2H, m)
APCIMS: 276 (MH+) m.p.: 123-125°C Reference Example 7
Preparation of raw compound (4) in Reaction Scheme- 1: (2S,3S)-3-amino-l,l, l-trifuluoro-4-(2-naphthyl)butan-2-ol (Compound 4-2):
(1) To a suspension of Compound 1 : (2S)-3-(2-naphthyl)-2-[(phenyl- methoxy)carbonylamino]propanoic acid (14.3 g, 40.9 mmol) in toluene (140 ml) were added paraformaldehyde (2.0 g) and p-toluenesulfonic acid monohydrate (600 mg). After refluxing the mixture for 30 minutes, the reaction mixture was cooled in an ice bath and then washed with saturated aqueous sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was crystallized by treating with isopropyl ether to give Compound 2: phenylmethyl (4S)-4-(2-naphthyl- methyl)-5-oxo-l,3-oxazolidine-3-carboxylate (11.8 g).
Η NMR (300MHz, CDC13): δ 7.68-7.81 (3H, m), 7.40-7.60 (8H, m), 7.18 (1H, brs), 5.21-5.29 (3H, m), 4.64 (1H, s), 4.23 (1H, s), 3.36 (1H, s) APCIMS: 362 (MH+) m.p.: 88-89°C
(2) To a solution of Compound 2 (11.8 g, 32.7 mmol) and trimethyl- (trifluoromethyl)silane (5.8 g, 40.8 mmol) in THF (30 ml) with cooling in
an ice bath was added cesium fluoride (1.0 g, 6.53 mmol). The mixture was stirred at room temperature for 30 minutes, and the solvent was removed under reduced pressure. After adding methanol (60 ml) to the residue, the mixture was stirred at room temperature for 15 minutes. The solution was cooled at 0°C in an ice bath and sodium borohydride (1.2 g, 32.7 mmol) was added thereto. After stirring the mixture for 30 minutes, to the solution were added water (45 ml) and potassium carbonate (5.4 g, 39.2 mmol). After the solution was stirred at room temperature for 30 minutes, methanol was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic phase was washed with 10 % aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane: ethyl acetate 9: 1) to give
Compound 3: N-[(lS,2S)-3,3,3-trifluoro-2-hydroxy-l-(2-naρhthyl- methyl)propyl](phenylmethoxy)carboxamide (8.4 g).
1H NMR (300MHz, CDC13): δ 7.74-7.84 (3H, m), 7.65 (1H, brs),
7.46-7.51 (2H, m), 7.33 (6H, m), 5.22-5.25 (1H, m), 5.12 (2H, s), 4.10-4.12 (2H, m), 3.98 (1H, m), 3.28 (1H, m) 3.17-3.19 (1H, m)
APCIMS: 404 (MH+) m.p.: 172-174°C (3) To a solution of Compound 3 (8.4 g, 20.8 mmol) in ethyl acetate 100 ml was added 20 wt. % palladium hydroxide (1.5 g). After stirring the mixture at room temperature under a hydrogen atmosphere for 3 hours, the catalyst was removed by filtration. The filtrate was evaporated
under reduced pressure and the residue as white solid was washed with n-hexane to give Compound 4-2: (2S,3S)-3-amino-l, l, l-trifuluoro-4-(2- naphthyl)butan-2-ol (5.3 g).
1H NMR (300MHz, CDC13): δ 7.79-7.85 (3H, m), 7.66(1H, s), 7.45- 7.53 (2H, m), 7.33-7.36 (IH, m), 3.71-3.78 (IH, m), 3.62-3.68 (IH, m), 3.02-3.09 (IH, m), 2.78-2.90 (IH, m)
APCIMS: 270 (MH+) p.: 122-125°C Reference Example 8 Preparation of raw compound (4) in Reaction Scheme- 1 :
The compounds as shown in Table 1 were obtained in the same manner as described in Reference Example 6 or 7.
Table 1
* APCIMS ** diastereomer mixture
* APCIMS ** diastereomer mixture
Example 1
Preparation of N-[(lS)-2-((2S)-2-{N-[(lS)- l-(benzo [b]thiophen-3-yl- methyl) -3,3, 3 - trifluoro-2 - oxopropyl] carbamoyljpy rrolidinyl) - 1 - (methyl- ethyl)-2-oxoethyl](3,5-dimethylisoxazol-4-yl)carboxamide (Compound I-
A-l):
(1) (Step 4) To a solution of Compound 4: (2S,3S)-3-amino-4-benzo- [b]thiophen-3-yl- 1, 1, 1 -trifuluorobutan-2-ol hydrochloride (14.1 g, 45.2 mmol) in pyridine (135 ml) were added N- (tert-butoxycarbonyl) -L-valyl- L-proline (Compound 5 in reaction Scheme- 1) (14.2 g, 45.2 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.1 g, 47.5 mmol). The reaction mixture was stirred at room temperature for 15 hours and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and then washed with 5 % aqueous potassium hydrogen sulfate solution, water and brine. The organic solution was dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane: ethyl acetate 2: 1) to give Compound 6: N-[(lS)-2-((2S)-2-{N-[(lS,2S)-l-(benzo[b]thiophen-3-yl- methyl)-3,3,3-trifluoro-2-hydroxypropyl]carbamoyl}pyrrolidinyl)-l- (methylethyl)-2-oxoethyl](tert-butoxy)carboxamide (19.8 g). APCIMS: 572 (MH+) (2) (Step 5) To Compound 6 (19.8 g, 34.6 mmol) was added 4 mol/ 1000 ml hydrogen chloride in 1,4-dioxane solution (90 ml). After stirring at room temperature for 30 minutes, the solvent was removed under reduced pressure. The residue as white powder was washed with n-hexane to give Compound 7: [(2S)- l-((2S)-2-amino-3-methyl- butanoyl) ρyrrolidin-2 -yl]-N- [( 1 S, 2 S) - 1 - (benzo [b]thioρhen-3-yl-methyl) - 3,3,3-trifluoro-2-hydroxypropyl]carboxamide hydrochloride (17.6 g). APCIMS: 472 (MH+) (3) (Step 6) To a solution of Compound 7 (10.2 g, 20.1 mmol) in pyridine (100 ml) were added 3,5-dimethylisoxazole-4-carboxylic acid (Compound 8 in Reaction Scheme- 1) (2.8 g, 20.1 mmol) and l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (4.0 g, 21.1 mmol). The reaction mixture was stirred at room temperature for 15 hours and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and then washed with 5 % aqueous potassium hydrogen sulfate solution, water and brine. The organic solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography on CHP20P (Mitsubishi Chemical Co. Ltd.), and eluted with a gradient of 30 to 70 % acetonitrile in water under a medium
pressure to give Compound I-B-1: N-[(lS)-2-((2S)-2-{N-[(lS,2S)-l-(benzo- [b]thiophen-3-yl-methyl)-3,3,3-trifluoro-2-hydroxypropyl]carbamoyl}- pyrrolidinyl) - 1 - (methylethyl) -2 -oxoethyl] (3 , 5-dimethylisoxazol-4-yl) - carboxamide (8.2 g). APCIMS: 595 (MH+)
(4) (Step 7) To a solution of Compound I-B-1 (8.2 g, 13.8 mmol) in dichloromethane (160 ml) were added tert-butyl alcohol (1.4 ml, 13.8 mmol) and Dess-Martin periodinane (11.7 g, 27.6 mmol). The reaction mixture was stirred at room temperature for 15 hours and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and then washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography on CHP20P, and eluted with a gradient of 30 to 70 % acetonitrile in water under a medium pressure to give Compound I-A-l : N-[(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]- thiophen-3-yl-methyl)-3,3,3-trifluoro-2-oxopropyl]carbamoyl}pyrrolidin- yl)-l-(methylethyl)-2-oxoethyl](3,5-dimethylisoxazol-4-yl)carboxamide (5.9 g).
APCIMS: 572 (MH+)
*H NMR (300MHz, d6-DMSO): δ 0.93 (3H, d), 0.95 (3H, d) 1.69-2.13 (4H, m), 2.25 (3H, s), 2.47 (3H, s), 2.89 (IH, dd), 3.28-3.45 (3H, m), 3.52-3.59 (IH, m), 3.73-3.80 (IH, m), 4.37-4.46 (2H, m), 7.26-7.48 (4H, m), 7.78 (IH, d), 7.93-8.11 (2H, m).
Elemental Analysis for C28H31F3N4O5S-0.25 H2O:
Calcd.: C 56.32, H 5.32, F 9.54, N 9.38, S 5.37 Found: C 56.04, H 5.51, F 9.34, N 9.11, S 5.13 Example 2
Preparation of N-[(lS)-2-((2S)-2-{N-[(lS)-3,3,3-trifluoro-l-(2-naphthyl- methyl)-2-oxopropyl]carbamoyl}pyrrolidinyl)-l-(methylethyl)-2-oxoethyl]- (3,5-dimethylisoxazol-4-yl)carboxamide (Compound I-A-2):
(1) (Step 4) To a solution of Compound 4: (2S,3S)-3-amino- 1, 1, 1- trifuluoro-4-(2-naphthyl)butan-2-ol (0.93 g, 3.44mmol) in dichloro- methane 15ml were added N- (benzyloxycarbonyl) -L-valyl-L-proline
(Compound 5 in Reaction Scheme- 1) (1.20 g, 3.44 mmol) and l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g, 3.62 mmol). The reaction mixture was stirred at room temperature for 15 hours and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and then washed with 10 % hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine. The
organic solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography on CHP20P, and eluted with a gradient of 20 to 70 % acetonitrile in water under a medium pressure to give Compound 6: N- [(lS)-2-((2S)-2-{N-[(lS,2S)-3,3,3-trifluoro-2-hydroxy-l-(2-naphthyl- methyl)propyl]carbamoyl}pyrrolidinyl)-l-(methylethyl)-2-oxoethyl]- (phenylmethoxy)carboxamide (1.6 g). APCIMS: 600 (MH+)
(2) (Step 5) To a solution of Compound 6 (1.6 g, 2.67 mmol) in ethyl acetate (20 ml) was added 20 wt. % palladium hydroxide (0.3 g). After stirring at room temperature under a hydrogen atmosphere for 3 hours, the catalyst was removed by filtration. The filtrate was evaporated under reduced pressure to give Compound 7: [(2S)-l-((2S)-2-amino-3- methylbutanoyl)pyrrolidin-2-yl]-N-[(lS,2S)-3,3,3-trifluoro-2-hydroxy-l- (2-naphthylmethyl)propyl]carboxamide (1.24 g).
APCIMS: 466 (MH+)
(3) (Step 6) To a solution of Compound 7 (1.24 g, 2.67 mmol) in dichloromethane (20 ml) were added 3,5-dimethylisoxazole-4-carboxylic acid (Compound 8 in Reaction Scheme 1) (0.38 g, 2.67 mmol) and 1- ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (0.54 g,
2.80 mmol). The reaction mixture was stirred at room temperature for 15 hours and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and then washed with 10 % hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was
subjected to column chromatography on CHP20P, and eluted with a gradient of 20 to 70 % acetonitrile in water under a medium pressure to give Compound I-B-2: N-[(lS)-2-((2S)-2-{N-[(lS,2S)-3,3,3-trifluoro-2- hydroxy- 1 - (2 -naphthylmethyl) propyl] carbamoyl}pyrrolidinyl) - 1 - (methyl- ethyl)-2-oxoethyl](3,5-dimethylisoxazol-4-yl)carboxamide (1.2 g). APCIMS: 589 (MH+) (4) (Step 7) To a solution of Compound I-B-2 (1.2 g, 2.04 mmol) in dichloromethane (25 ml) were added tert-butyl alcohol (0.20 ml, 2.04 mmol) and Dess-Martin periodinane (1.7 g, 4.08 mmol). The reaction mixture was stirred at room temperature for 15 hours and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and then washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography on CHP20P, and eluted with a gradient of 20 to 70 % acetonitrile in water under a medium pressure to give Compound I-A-2: N-[(lS)-2-((2S)-2-{N-[(lS)-3,3,3-tri- fluoro- 1 - (2 -naphthylmethyl) -2-oxo propyl] carbamoyl}pyrrolidinyl) - 1 - (methylethyl)-2-oxoethyl](3,5-dimethylisoxazol-4-yl)carboxamide (0.60 g)-
APCIMS: 587 (MH+)
1H NMR (300MHz, d6-DMSO): δ 8.05 (IH, d), 7.71-7.94 (4H, m), 7.40-7.45 (2H, m), 7.16-7.22 (2H, m), 4.28-4.42 (3H, m), 3.70 (IH, m), 3.50 (IH, m), 3.30-3.34 (3H, m), 2.88 (IH, dd), 2.40 (3H, s), 2.30
(3H, s), 1.99-2.07 (IH, m), 1.58-1.91 (2H, m), 0.87 (3H, d), 0.85 (3H,
d)
Elemental Analysis for C30H33F3N4O5-0.75 H2O Calcd.: C 60.04, H 5.79, F 9.50, N 9.34 Found: C 60.06, H 5.85, F 9.53, N 9.16 Example 3 Preparation of Compounds I-A:
The following compounds disclosed in Tables 2 to 12 were obtained in the same manner as described in Example 1 or 2. In these tables, the mass spectrometry is APCIMS unless specified otherwise.
Table 2
Table 3
Table 4
Table 5
Table 6
Table 7
Table 8
Table 9
Table 9 (continue)
Table 10
Table 12
Reference Example 9
Preparation of Reference Compound (A) disclosed in WO-A-93/25574.
A. {(2S)-l-[(2S)-2-({4-[(tert-butoxy)-N-methylcarbonylamino]piρeridyl}- carbonylamino)-3-methylbutanoyl] pyrrolidin-2-yl}-N-[( 1 S,2S)-3,3,3- trifluoro-2-hydroxy- 1 -benzylpropyljcarboxamide:
A solution of [(2S)-l-((2S)-2-amino-3-methylbutanoyl)pyrrolidin-2- yl]-N-[(lS,2S)-3,3,3-trifluoro-2-hydroxy-l-benzylpropyl]carboxamide hydrochloride (2.7 g, 6.03 mmol) and triethylamine (0.67 g, 6.63 mmol) in dichloromethane (15 ml) was added to a stirred 0-5°C slurry of carbonyldiimidazole (1.1 g, 6.63 mmol) and imidazole (0.82 g, 12.1 mmol) in dichloromethane (30 ml) and the resulting mixture was stirred at 25°C for 30 min. A solution of 4-[N-[(l, l-dimethylethoxy)carbonyl]methyl- aminojpiperidine (1.3 g, 6.03 mmol) in dichloromethane (10 ml) was added and the mixture stirred at 25°C for 2 days. The resulting solution was washed with 5 % aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was subjected to column chromatography on CHP20P, and eluted with a gradient of 20 to 70 % acetonitrile in water under a medium pressure to give the title compound (1.0 g, yield; 25 %). 1H NMR (300MHz, CDC13): δ 0.96-0.98 (3H, d, J=6.8 Hz), 1.00-1.02
(3H, d, J=6.6 Hz), 1.46 (9H, s), 1.57-1.77 (7H, m), 1.84-1.90 (IH, m), 2.36-2.42 (IH, m), 2.72 (3H, s), 2.90-3.06 (4H, m), 3.13-3.20 (IH, m), 3.43-3.53 (IH, m), 3.84-4.05 (5H, m), 4.35-4.38 (IH, d, J=7.3 Hz), 4.85-4.90 (2H, m), 6.08-6.12 (IH, d, J=11.7Hz), 7.19-7.30 (5H, m), 7.78-7.81 (IH, d, J=9.9 Hz)
APCI-MS: 656 (MH+)
B. {(2S)-l-[(2S)-2-({4-[(tert-butoxy)-N-methylcarbonylamino]ρiperidyl}- carbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl}-N-[(lS,2S)-3,3,3- trifluoro-2-oxo- 1 -benzylpropyl]carboxamide:
To a solution of {(2S)-l-[(2S)-2-({4-[(tert-butoxy)-N-methylcarbonyl- amino]piperidyl}carbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl-N- [(lS,2S)-3,3,3-trifluoro-2-hydroxy-l-benzylpropyl]carboxamide (1.0 g, (1.52 mmol) in dichloromethane (10 ml) were added tert-butyl alcohol (0.15 ml, 1.52 mmol) and Dess-Martin periodinane (1.3 g, 3.05mmol). The reaction mixture was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and then washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over
sodium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography on CHP20P, and eluted with a gradient of 30 to 70 % acetonitrile in water under a medium pressure to give the title compound (0.8 g, yield; 81 %). Η NMR (300MHz, CDC13): δ 0.94-0.96 (3H, d,J=6.8 Hz), 0.99-1.01
(3H, d, J=6.6 Hz), 1.47 (9H, s), 1.56-1.86 (7H, m), 2.11-2.17 (IH, m), 2.73 (3H, s), 2.76-3.05 (4H, m), 3.28-3.36 (IH, m), 3.85-4.13 (4H, m), 4.36-4.39 (IH, d, J=8.1 Hz), 4.65 (IH, m), 4.82-4.85 (IH, d, J=7.9Hz), 5.76 (IH, s), 6.16 (IH, s), 7.14-7.31 (5H, m), 7.37-7.40 (IH, d, J=9.0Hz)
APCI-MS: 654 (MH+)
C. [(2S)-l-((2S)-3-methyl-2-{[4-( methylamino)piperidyl] carbonyl- amino}butanoyl)pyrrolidin-2-yl]-N-[(lS)-3,3,3-trifluoro-2-oxo-l-benzyl- propyl] carboxamide hydrochloride:
To {(2S)-l-[(2S)-2-({4-[(tert-butoxy)-N-methylcarbonylamino]- piperidyl}carbonylamino)-3- methylbutanoyl]pyrrolidin-2-yl-N-[(lS,2S)- 3,3,3-trifluoro-2-oxo-l-ben--ylpropyl]carboxamide (0.5 g, 0.77 mmol) was added 4N-hydrogenchloride in 1,4-dioxane solution (10 ml). After stirring at 0-5°C for 1 hour, the solvent was removed under reduced pressure. The residue was treated with isopropyl alcohol and evaporated under reduced pressure to give the title compound (0.35 g, yield; 78 %). Η NMR (300MHz, d6-DMSO): δ 0.87-0.89 (3H, d), 0.89-0.93 (3H, d),
1.32-1.39 (3H, m), 1.63-1.76 (2H, m), 1.93-1.96 (3H, m), 2.52 (3H, s),
2.61-2.73 (2H, m), 3.11-3.15 (2H, m), 3.37-3.39 (IH, m), 3.86 (4H, m), 4.04-4.37 (4H, m), 6.48-6.50 (IH, d, J=8.1Hz), 7.12-7.24 (5H, m),
7.79-7.82 (IH, d, J=9.3Hz), 8.93 (IH, m)
APCI-MS: 554 (MH+) Elemental Analysis: C27H38F3N5O4- 1.25 HC1- 1.50 H2O-0.50 dioxane
Calcd.: C 51.97, H 6.96, F 8.50, N 10.45, Cl 6.61 Found: C 51.99, H 7.23, F 8.23, N 10.23, Cl 6.66
PHARMACOLOGICAL PROPERTIES The pharmacological properties of the present compounds (I-A) are explained below.
The present compounds (I-A) exhibit an excellent chymase inhibitory activity as seen in Experiment 1 and can be used in the treatment of various diseases including allergic conditions in which mast cells play a main role. In these allergic conditions, acceleration of vascular permeability following mast cells degranulation causes inflammatory reactions by inducing inflammatory cells infiltration as well as immune complexes deposition in the vascular walls.
As shown in Experiment 2, the present compounds (I-A) inhibit the acceleration of vascular permeability induced by chymase, resulting in a suppression of skin inflammation. This finding suggests that the present compounds (I-A) are useful as skin anti-inflammatory agents. In addition to the properties mentioned above, the present compounds (I-A) sustain high levels in the plasma even after oral administration and exhibit low toxicity (Experiments 3 and 4).
Combining the pharmacological properties above, it is believed the
present compounds (I-A) are useful as medicaments.
PHARMACOLOGICAL EXPERIMENTS Experiment 1: Chymase inhibitory activity (IC50) The inhibitory activities of the compounds on monkey chymase and human chymase were tested in vitro. The test compounds are as shown by Compound Nos. in Tables 13 and 14. Preparation of monkey chymase
Chymase was purified from monkey cheek pouch and stomach in the following manner.
Briefly, chymase was extracted from homogenized monkey cheek pouch and stomach with 0.01 mol/ 1000 ml sodium phosphate buffer, pH 7.4, containing 2 mol/ 1000 ml KCl and 0.1 % Nonidet P-40 (Amresco Inc.). The solution containing chymase was applied to a heparin actigel column, and the chymase-rich fractions were collected. Preparation of human chymase
Human chymase was produced in mammalian cells using a recombinant DNA technique.
Construction of a human prochymase expression plasmid was performed in the following manner. Briefly, single stranded cDNA was synthesized from human heart mRNA (Clontech Laboratories, Inc.). Polymerase chain reaction amplification was carried out using the cDNA as a template and appropriate pairs of primers. The primer sequences were determined based on the human preprochymase. The amplified product was cloned into the plasmid pUC18, and then recloned into the plasmid pBluescript II KS(+) (Stratagene) . Finally, the DNA fragment
carrying the entire protein-coding sequences of the human preprochymase was inserted to a transient expression vector by the usual method to yield the human prochymase expression plasmid.
Transfection of COS7 cells with the human prochymase expression plasmid was carried out using the FuGene™ 6 tansfection reagent
(Boehringer Mannheim). About 7 hours after exposure to DNA, the culture medium was changed to a serum-free one. The culture supernatant was collected after 2 days culture.
Human prochymase was purified from the culture supernatant using a heparin actigel column as described above in the preparation of monkey chymase.
In order to produce active chymase, the human prochymase was incubated with dipeptidylpeptidase I (Sigma) . The resultant active human chymase was purified using a heparin actigel column as described above. The active human chymase was eluted with 0.01 mol/ 1000 ml sodium phosphate buffer pH 7.4 containing 2 mol/ 1000 ml
NaCl.
Measurement of chymase inhibitory activity (in vitro assay)
The chymase inhibitory activities of compounds I-A of this invention were measured according to the following method. Briefly, the purified monkey or human chymase was diluted to an appropriate concentration with 0.01 mol/ 1000 ml sodium phosphate buffer, pH 7.4, containing 2 mol/ 1000 ml KC1 and 0.1 % Nonidet P-40 and used as enzyme solution. Angiotensin I (Peptide Institute Inc.) was diluted with water to 5 mg/ml and used as substrate solution. Test compounds were serially diluted with 10 % DMSO. Ten μl of the enzyme solution and 10 μl of the diluted
test compound were mixed with 60 μl of 0.1 mol/ 1000 ml sodium phosphate buffer, pH 7.4, and kept at room temperature. After pre- incubation of the mixture at 37 °C, 20 μl of the substrate solution was added to the enzyme-test compound mixture and the new mixture was incubated at 37 °C. Fifty μl of 30 % trichloroacetic acid solution was finally added to stop the enzymatic reaction.
The amount of L-His-L-Leu was measured as angiotensin II produced by the enzymatic reaction. Briefly, lOμl of the reaction mixture and 10 μl of 1 % orthophthalaldehyde solution dissolved in methanol were mixed with 100 μl of 2 mol/ 1000 ml NaOH and kept at room temperature. The reaction was then stopped by adding 10 μl of 6 mol/ 1000ml HCl. Finally, the fluorescence induced by the reaction was measured using in a photometer with an excitation wavelength of 355 nm and an emission wavelength of 460 nm. Chymase inhibitory activities of test compounds were expressed as 50 % inhibitory concentration (IC50). Results
The chymase inhibitory activities of the compounds of the present invention are shown in Table 13 as to inhibitory activity on monkey chymase and in Table 14 as to the inhibitory activity on human chymase.
Table 13 (Continue)
Table 14 Human Chymase inhibitory activity
As is shown in Tables 13 and 14, the compounds of the present invention showed excellent inhibitory activities on both of monkey chymase and human chymase. On the other hand, Reference Compound (A), which is disclosed in Example 28 of WO-A-93/25574, has a very low chymase inhibitory activity. Experiment 2: Inhibition of vascular permeability
Experiment 2 was carried out using a dye as maker in order to prove that the acceleration of vascular permeability induced by chymase is inhibited by the administration of the present compounds.
Skin permeability test
Skin permeability test was carried out according to the following method. Briefly, male Hartley guinea pigs (350-460 g, Shizuoka Laboratory Animal Center, Japan) were anesthetized by intraperitoneal
injection of Nembutal ™ (30 mg/kg; Dainippon Pharmaceutical Co., Ltd., Japan). After shaving the guinea pigs dorsa, 50 μl of purified human chymase (Elastin Products Inc., USA) diluted with phosphate buffered saline (PBS) to a concentration of 1.8 units / 55 μg protein/ml (1 unit of chymase represents the amount of chymase required to hydrolyze 1.0 μmole of N-benzoyl-L-tyrosine-ethyl ester (BTEE) per minute at 25°C; pH 7.8) were injected intradermally into three dorsal sites of each animal. Solvent (0.05 mol/ 1000 ml sodium acetate and 1 mol/ 1000 ml sodium chloride mixture diluted with PBS) was injected similarly into three other dorsal sites of the same animal. Following the final injection, 1 % (w/v)
Evans Blue dye in saline (0.4 ml/ 100 g body weight) was injected intravenously into the saphenous vein. The animals were killed 30 minutes thereafter by exsanguination under anesthesia, and their dorsal skins were removed. The amounts of dye leakage into the dorsal skins were measured according to the following method.
Briefly, the area around each injection site (16 mm diameter) was punched out from the inside of the skin, and the leaked dye was extracted by incubation of the punched skin in N,N-dimethylformamide (DMF, 3 ml) at 55°C overnight. The absorbance of the dye extract was then measured using a spectrophotometer at a wavelength of 620 nm. To measure the amount of dye leakage into the dorsal skin, the calibration curve was obtained from external standards of Evans Blue dye as follows: Evan's Blue dye (3.75 - 30 μg) was added into the control skin in DMF (3 ml). Control skins were treated in the same manner as the punched skins, and their dye extracts were used as external standards. The amount of chymase-induced dye leakage (ACDL) and the amount of
solvent-induced dye leakage (ASDL) in each animal were calculated as the average of dye leakage from the three treated dorsal sites in each case.
Treatment with Test-compounds Animals were orally administrated 0.5 % tragacanth or test- compounds (100 mg/kg) suspended in 0.5 % tragacanth solution 1 hour before intradermal injection of human chymase. Test-compounds inhibition rate of chymase-induced dye leakage was calculated using the following formula: Dye leakage inhibition rate (%) = {(A-B)-(C-D)} / (A-B) x 100
A: ACDL in tragacanth-treated group B: ASDL in tragacanth-treated group C: ACDL in test-compound-treated group D: ASDL in test- compound-treated group Results
Test-compounds (I-A-1) and (I-A-20) significantly inhibited the dye leakage by 34 % and 59 %, respectively. Experiment 3: Plasma level
Plasma levels of test compounds were measured in the following manner.
Briefly, test compounds were dissolved in DMSO to 100 mg/ml, and suspended with 0.5 % tragacanth solution 1 mg/ml. Male ddy mice, weighing about 30 g, were orally administered the test compound solution. After one hour, blood was collected from the heart under anesthesia with Nembutal (Dainippon Pharmaceutical Co., Ltd.) and centrifuged to obtain plasma. The collected plasma (125 μl) was mixed
with 10 % DMSO (120 μl) and ethyl acetate (720 μl) . After centrifugation, the ethyl acetate layer was collected and evaporated. The residue was dissolved and diluted serially as test samples with 10 % DMSO. Chymase inhibitory activities of test samples were measured in the same manner as described in Experiment 1. In this chymase inhibitory assay of test samples, 0.1 mol/ 1000ml sodium phosphate buffer, pH 7.4 contained 5 mmol/ 1000ml ethylenediaminetetraacetic acid (EDTA) disodium salt, 0.77 mmol/ 1000ml diisopropyl fluorophosphate (DFP) and 8 mmol/ 1000ml dipyridyl. Plasma concentrations of test compounds were calculated from calibration curves.
The calibration curve was obtained in the following manner. Test compounds (0.06-60 ng) were added into the control plasma. The control plasma was treated in the same manner as for test samples. Finally, chymase inhibitory activities of the 10 % DMSO-dissolved residues were measured and plotted against the amount of test compounds. Results
The results are shown in Table 15.
Table 15 Plasma level
As is shown in Table 15, the compounds of the present invention showed high blood levels even by oral administration. Experiment 4: Toxicity study
Five-week-old male ddy mice were administered orally once a day for 2 weeks with the compound I-A-1 at dose levels of 30 and 300 mg/kg/ day. In these mice, there was no treatment-related finding observed in any of parameters including body weight, diet consumption, heart weight, liver weight, kidney weight, necropsy finding, hematology, and blood chemistry.
As is clear from the above experimental results, the compounds of the present invention are an excellent chymase inhibitor and are useful for the treatment of various diseases in which chymase participates.
The compounds of the present invention can be administered orally, parenterally, dermally/ trans dermally, ocularly, etc., but preferably oral rout. The dose of the compounds may vary depending on the administration routes, severity of diseases, and body weight and age of the patients, etc. For example, when the present compounds are administered orally, the dose thereof is usually in the range of about 0.5 to about 5000 mg/60 kg of body weight per day, preferably about 5 to about 2000 mg/60 kg of body weight per day, most preferably 15 to 300 mg/60 kg of body weight per day. When the present compounds are administered in the form of a drop preparation, the dose thereof is usually in the range of 0.06 to 30 mg, preferably in the range of 0.3 to 6 mg/60 kg of body weight per day.
The compounds of the present invention are used in the form of a
conventional pharmaceutical preparation. Such pharmaceutical preparations include tablets, capsules, granules, fine granules, powders aqueous or oily liquids, ointments and the like. These pharmaceutical preparations may be prepared in the usual manner using conventional pharmaceutically acceptable components. Any components can be used so long as they do not react with the compounds (I-A) of the present invention.
Concrete examples of the component in solid preparations include maize starch (i.e., corn starch), mannitol, lactose, low substituted HPC (i.e., low substituted hydroxypropylcellulose), HPC (i,e.,hydroxypropyl- cellulose), crystalline cellulose, carboxymethylcellulose calcium, magnesium stearate, light anhydrous silicic acid, and the like. An example of the component in liquid preparations includes water for injection, soybean oil, surfactant such as sorbitan mono-oleate, Poloxamer 188 and Polysorbate 80, and the like. An example of the component in ointments preparation includes white petrolatum.
The pharmaceutical preparation of the present invention will explained by Preparations. In the following Preparations, the present compounds of the active ingredient are used after being micronized to a size of 5 μm or below.
Preparations A .B and C : Tablets
The components of granule as listed in Table 16 are granulated in a conventional manner, and thereto are added external excipients, and the mixture is tabletted to give tablets weighting 120 mg to 300 mg.
Table 16
Amount (m ri
Components
Pre. A Pre. B Pre. C
Granule Compound I-A- 1 1 10 100
Lactose 84.2 75.2 117.5
Maize starch - 12 -
Low substituted HPC 12 - 30
HPC 3 3 8
External Crystalline cellulose 18 18 40 excipients Magnesium stearate 1.2 1.2 3.0
Light anhydrous silicic acid 0.6 0.6 1.5
Total (mg) 120 120 300
Preparations D, E and F: Granules
The components of granule as listed in Table 17 are granulated in a conventional manner, and thereto are added external excipients to give granules.
Table 17
Amount (wt.%)
Components
Pre. D Pre. E Pre. F
Compound I-A-1 1 10 50
D-Mannitol 85.5 76.5 36.5
Granule
Low substituted HPC 10 10 10
HPC 3 3 3
External Light anhydrous silicic acid 0.5 0.5 0.5 excipient
Total (%) 100 100 100
Preparations G and H: Aqueous liquids
The components as listed in Table 18 are mixed uniformly in a conventional manner to give an aqueous liquid, which can be used as a drop or an injection.
Table 18
Amount (wt.%)
Components
Pre. G Pre. H
Compound I-A-20 1 10 Poloxamer 188 0.5 1 Sodium chloride 0.9 0.9 Water for injection q.s. q.s.
Total (%) 100 100
Preparations J, K and L: Oily liquids
The components as listed in Table 19 are mixed uniformly in a conventional manner to give an oily liquid, which can be used as an injection, or can be filled in soft capsules and used as an oral preparation.
Table 19
Amount (wt.%)
Component
Pre. J Pre. K Pre. L
Compound I-A-5 1 10 50
Soybean oil 98.9 89.9 49.9
Sorbitan mono-oleate 0.1 0.1 0.1
Total (%) 100 100 100
Preparations M. N and P: Ointments
The components as listed in Table 20 are mixed uniformly in a conventional manner to give ointments, which can be used as a dermal administration preparation.
Table 20
Amount (wt.%)
Component
Pre. M Pre. N Pre. P
Compound I-A- 1 10 20 30 White petrolatum 90 80 70
Total (%) 100 100 100
INDUSTRIAL APPLICABILITY
The compounds (I-A) of the present invention have excellent chymase inhibitory activity and are useful as chymase inhibitor for the prevention or treatment of various diseases in which chymase participates, for example, as an antiallergic and antiinflammatory agent, an antirestenosis agent, or an antiarteriosclerotic agent. The compounds (I-B) are useful as an intermediate for the preparation of said active compounds (I-A).
Claims (17)
1. A compound of the formula (I):
wherein R1 is a cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a tetrahydronaphthyl group, an indanyl group, a thienyl group, a furyl group, a substituted or unsubstituted indolyl group, a substituted or unsubstituted dihydroindolyl group, a benzofuryl group, a dihydro- benzofuryl group, a substituted or unsubstituted benzothienyl group or an S-mono- or di-oxide thereof, or a dihydrobenzothienyl group, said substituted phenyl, naphthyl and benzothienyl groups having each independently one to three substituents independently selected from a halogen atom, a lower alkoxy group, a hydroxy group and a lower alkyl group having optionally one to three halogen atoms; and said substituted indolyl and dihydroindolyl groups having a substituent on (N) at the 1- position selected from a lower alkyl group and a lower alkyl-carbonyl group;
R2 is a hydrogen atom, an alkyl group, a phenyl-lower alkyl group, a cycloalkyl group or a cycloalkyl-lower alkyl group;
R3 is (i) a substituted or unsubstituted, unsaturated monocyclic heterocyclic group;
(ii) a substituted or unsubstituted, saturated or unsaturated monocyclic heterocyclic group which is fused by a benzene ring or a pyridine ring, wherein said substituted heterocyclic groups in (i) and (ii) each independently have one to three substituents independently selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkyl-carbonyl group, a cyano group, a carboxamido group, a phenyl group and a phenoxy group; said phenyl and phenoxy substituents may further optionally have one to three substituents independently selected from a halogen atom, a lower alkyl group and a halogeno-lower alkyl group; or (iii) a group of the formula (a):
wherein A is a lower alkylene group, D1 and D2 are both simultaneously a methylene group or alternatively, one of D1 and D2 is a methylene group and another is a vinylene group where each methylene group being optionally substituted by an oxo group or a lower alkyl group, and said vinylene group being optionally substituted by a lower alkyl group; R6 is a lower alkyl group substituted by a carboxyl group, a lower alkoxycarbonyl group or a phenyl group;
R4 and R5 are each independently a hydrogen atom or a hydroxy group, but R4 and R5 are not simultaneously a hydrogen atom, or both combine to form an oxo group; n is 0, 1, 2 or 3; or a salt thereof.
2. A compound according to claim 1, wherein R1 is a C3-C8 cycloalkyl group, a phenyl group, a phenyl group substituted by one to three substituents independently selected from a halogen atom, a C!-C4 alkoxy group, a hydroxy group, a C C4 alkyl group and a halogeno-C1-C4 alkyl group; a naphthyl group, a tetrahydronaphthyl group, an indanyl group, a thienyl group, a furyl group, an indolyl group, an N-(C1-C4 alkyl)indolyl group, an N-(C C4 alkyl-carbonyl)indolyl group, a dihydroindolyl group, a benzofuryl group, a dihydrobenzofuryl group, a benzothienyl group or an S-mono- or di-oxide thereof, or a dihydrobenzothienyl group;
R2 is a hydrogen atom, a Ci-Cg alkyl group, a phenyl-C1-C4 alkyl group, a C3-C8 cycloalkyl group or a C3-C8 cycloalkyl-C1-C4 alkyl group; R3 is (i) an unsaturated monocyclic heterocyclic group selected from furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- thiadiazolyl, 1,2,4-oxadiazolyl, and pyridyl; (ii) a benzene- or pyridine-fused saturated or unsaturated monocyclic heterocyclic group selected from benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofurazanyl or N-oxide thereof, quinolyl, benzodioxolyl, and isoxazolo[4,3-b]pyridinyl, wherein said heterocyclic groups in (i) and (ii) may each independently have one to three substituents independently selected from a fluorine atom or chlorine atom, a CrC4 alkyl group, a
C C4 alkoxy group, a CrC4 alkyl-carbonyl group, a cyano group, a carboxamido group, a phenyl group and a phenoxy group; said phenyl and phenoxy substituents may further optionally have one to three substituents independently selected from a halogen atom, a C1-C4 alkyl group and a halogeno-C1-C4 alkyl group; or
(iii) a group of any one of the formulae (a-1) to (a-4):
(a-1) (a-2) (a-3) (a-4) wherein A is a C C4 alkylene group, and R6 is a C C4 alkyl group substituted by a carboxyl group, a C^^ alkoxycarbonyl group or a phenyl group; R4 and R5 are each independently a hydrogen atom or a hydroxy group, but R4 and R5 are not simultaneously a hydrogen atom, or both combine to form an oxo group; n is 1 or 2; or a salt thereof. 3. A compound according to claim 2, wherein R1 is a C5-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by one to three substituents independently selected from fluorine, chlorine or bromine atom, a C^C* alkoxy group, a hydroxy group, a Cj-C4 alkyl group and a trifluoromethyl group; a naphthyl group, a tetrahydronaphthyl group, an indanyl group, a thienyl group, a furyl group, an indolyl group, an N-(C1-C4 alkyl) indolyl group, an N-acetylindolyl group, a dihydroindolyl group, a benzofuryl group, a dihydrobenzofuryl group, a benzothienyl group or an S-mono- or di-oxide thereof, or a dihydrobenzothienyl group; R2 is a hydrogen atom, a C C4 alkyl group, a phenyl-CrC2 alkyl group, a C5-C7 cycloalkyl group or a C5-C7 cycloalkyl-Ci-Cj alkyl group;
R3 is (i) an unsaturated monocyclic heterocyclic group selected from furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- thiadiazolyl, 1,2,4-oxadiazolyl, and pyridyl;
(ii) a benzene- or pyridine-fused saturated or unsaturated monocyclic heterocyclic group selected from benzoxazolyl, benzisoxazolyl, benzofurazanyl or N-oxide thereof, quinolyl, benzodioxolyl, and isoxazolo[4,
3-b]pyridinyl, wherein said heterocyclic groups in (i) and (ii) may each independently have one to three substituents independently selected from a fluorine or chlorine atom, a alkoxy group, an acetyl group, a cyano group, a carboxamido group, a phenyl group and a phenoxy group, said phenyl and phenoxy substituents may further optionally have one to three substituents selected from a fluorine or chlorine atom, a Cj-Cg alkyl group and a trifluoromethyl group; or
(iii) a group of any one of the formulae (a-1) to (a-4):
(a-1) (a-2) (a-3) (a-4) wherein A is a Cx-C2 alkylene group, and R6 is a C^Ca alkyl group substituted by a carboxyl group, a tert-butoxycarbonyl group or a phenyl group;
R4 and R5 are each independently a hydrogen atom or a hydroxy group, but R4 and R5 are not simultaneously a hydrogen atom, or both combines to form an oxo group; n is 1 or 2; or a salt thereof.
4. A compound of the formula (I-A): wherein R1, R2, R3 and n are as defined in claim 1.
5. A compound according to claim 4, wherein R1, R2, R3 and n are as defined in claim 2.
6. A compound according to claim 4, wherein R1, R2, R3 and n are as defined in claim 3.
7. A compound of the formula (I-A'):
wherein R3a and R3b are independently a hydrogen atom, a lower alkyl group, a lower alkyl-carbonyl group, or a phenyl group which may be substituted by a halogen atom or a halogeno-lower alkyl group; X is a carbon atom or a sulfur atom; Y is an oxygen atom or a nitrogen atom; and the symbol means a single bond or double bond, and R1, R2 and n are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 7, wherein X is a carbon atom and Y is an oxygen atom.
9. A compound according to claim 7, wherein X is a sulfur atom and Y is a nitrogen atom.
10. A compound according to any one of claim 7, 8 or 9, wherein R1 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group or a benzothienyl group, said substituted phenyl group and substituted naphthyl group have each independently one to three substituents independently selected from a halogen atom, a methyl group, a methoxy group, a trifluoromethyl group and a hydroxy group.
11. A compound according to claim 10, wherein R2 is isopropyl.
12. A compound which is independently selected from a following compounds:
N-[(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]thiophen-3-ylmethyl)-3,3,3- trifluoro-2 -oxopropyl] carbamoyljpyrrolidinyl) - 1 - (methylethyl) -2 -oxoethyl] (3,5-dimethylisoxazol-4-yl)carboxamide;
N-[(lS)-2-((2S)-2-{N-[(lS)-3,3,3-trifluoro-l-(2-naphthylmethyl)-2- oxopropyl]carbamoyl}pyrrolidinyl)- 1 -(methylethyl) -2-oxoethyl] (3,5- dimethylisoxazol-4-yl)carboxamide; N-[(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]thiophen-3-ylmethyl)-3,3,3- trifluoro-2-oxopropyl]carbamoyl}pyrrolidinyl)-l-ethyl-2-oxoethyl](3,5- dimethylisoxazol-4-yl)carboxamide;
N-[l-((lR)-l-methylpropyl)(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]- thiophen-3-ylmethyl)-3,3,3-trifluoro-2-oxopropyl]carbamoyl}- pyrrolidinyl)-2-oxoethyl](3,5-dimethylisoxazol-4-yl)carboxamide;
N-[(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]thiophen-3-ylmethyl)-3,3,3- trifluoro-2-oxopropyl]carbamoyl}pyrrolidinyl)-l-methyl-2-oxoethyl](3,5- dimethylisoxazol-4-yl)carboxamide; and
N-[(lS)-2-((2S)-2-{N-[(lS)-l-(benzo[b]thiophen-3-ylmethyl)-3,3,3- trifluoro-2-oxopropyl]carbamoyl}pyrrolidinyl)-l-(methylethyl)-2-oxo- ethyl] (4-methyl( 1 ,2,3-thiadiazol-5-yl))carboxamide.
13. A pharmaceutical composition, which comprises as an active ingredient the compound as set forth in any one of claim 4 to 12 in admixture with a pharmaceutically acceptable carrier or diluent.
14. A chymase inhibitory agent which comprises as the active ingredient as set forth in any one of claim 4 to 12.
15. The inhibitory agent according to claim 14, wherein the compound is any one of the compound as set forth in claim 12.
16. A vascular permeability inhibitory agent for inflammatory diseases which comprises as the active ingredient the compound as set forth in any one of claim 4 to 12.
17. The inhibitor agent according to claim 16, wherein the compound is any one of the compound as set of claim 12.
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GBGB0021315.7A GB0021315D0 (en) | 2000-08-30 | 2000-08-30 | Heterocyclic compounds and intermediates thereof |
GB0021315 | 2000-08-30 | ||
PCT/JP2001/007137 WO2002018378A1 (en) | 2000-08-30 | 2001-08-21 | Pyrrolidine derivatives and their use as chymase inhibitor |
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EP (1) | EP1313730A1 (en) |
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GB0021315D0 (en) | 2000-10-18 |
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US20040102384A1 (en) | 2004-05-27 |
JP2004507539A (en) | 2004-03-11 |
WO2002018378A1 (en) | 2002-03-07 |
CN1471528A (en) | 2004-01-28 |
US6852744B2 (en) | 2005-02-08 |
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