MXPA96001515A - Chromone derivatives - Google Patents
Chromone derivativesInfo
- Publication number
- MXPA96001515A MXPA96001515A MXPA/A/1996/001515A MX9601515A MXPA96001515A MX PA96001515 A MXPA96001515 A MX PA96001515A MX 9601515 A MX9601515 A MX 9601515A MX PA96001515 A MXPA96001515 A MX PA96001515A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- compound
- unsubstituted
- ring
- hydroxy
- Prior art date
Links
- 150000004777 chromones Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 230000003042 antagnostic Effects 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims description 52
- 239000011780 sodium chloride Substances 0.000 claims description 52
- -1 3, 5-bistrifluoromethylbenzoyl Chemical group 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 33
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 230000001225 therapeutic Effects 0.000 claims description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- 125000004001 thioalkyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- MAKIKFDCXZZVDX-UHFFFAOYSA-N 4-oxochromene-2-carboxamide Chemical compound C1=CC=C2OC(C(=O)N)=CC(=O)C2=C1 MAKIKFDCXZZVDX-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 102000009493 Neurokinin receptors Human genes 0.000 claims 2
- 108050000302 Neurokinin receptors Proteins 0.000 claims 2
- NFAWOKCQLNHDAO-UHFFFAOYSA-N 6-fluoro-4-oxochromene-2-carboxamide Chemical compound FC1=CC=C2OC(C(=O)N)=CC(=O)C2=C1 NFAWOKCQLNHDAO-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 7
- 239000005557 antagonist Substances 0.000 abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- 239000002253 acid Substances 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000004480 active ingredient Substances 0.000 description 17
- 102100002996 TAC1 Human genes 0.000 description 15
- 101700065588 TAC1 Proteins 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 230000000875 corresponding Effects 0.000 description 13
- ADNPLDHMAVUMIW-CUZNLEPHSA-N (2S)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-y Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- HUMNYLRZRPPJDN-UHFFFAOYSA-N Benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 239000008079 hexane Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 208000006673 Asthma Diseases 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 238000000434 field desorption mass spectrometry Methods 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000003890 substance P antagonist Substances 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 229920001800 Shellac Polymers 0.000 description 4
- 102000003141 Tachykinins Human genes 0.000 description 4
- 108060008037 Tachykinins Proteins 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atoms Chemical group C* 0.000 description 4
- 230000001808 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000004208 shellac Substances 0.000 description 4
- 229940113147 shellac Drugs 0.000 description 4
- 235000013874 shellac Nutrition 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 210000003169 Central Nervous System Anatomy 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 229940095076 benzaldehyde Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000013539 calcium stearate Nutrition 0.000 description 3
- 239000008116 calcium stearate Substances 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000007941 film coated tablet Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 229920001592 potato starch Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- BOSAWIQFTJIYIS-UHFFFAOYSA-N 1,1,1-Trichloro-2,2,2-trifluoroethane Chemical compound FC(F)(F)C(Cl)(Cl)Cl BOSAWIQFTJIYIS-UHFFFAOYSA-N 0.000 description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
- KPKDODIBNVVHBG-UHFFFAOYSA-N 6-bromo-4-oxochromene-2-carboxamide Chemical compound BrC1=CC=C2OC(C(=O)N)=CC(=O)C2=C1 KPKDODIBNVVHBG-UHFFFAOYSA-N 0.000 description 2
- CKWNAIFHYXTWGG-UHFFFAOYSA-N 6-chloro-4-oxochromene-2-carboxamide Chemical compound ClC1=CC=C2OC(C(=O)N)=CC(=O)C2=C1 CKWNAIFHYXTWGG-UHFFFAOYSA-N 0.000 description 2
- SMAMLBKECHKBDA-UHFFFAOYSA-N 6-methoxy-4-oxochromene-2-carboxamide Chemical compound O1C(C(N)=O)=CC(=O)C2=CC(OC)=CC=C21 SMAMLBKECHKBDA-UHFFFAOYSA-N 0.000 description 2
- HUTBNLHYNZCMAW-UHFFFAOYSA-N 6-methyl-4-oxochromene-2-carboxamide Chemical compound O1C(C(N)=O)=CC(=O)C2=CC(C)=CC=C21 HUTBNLHYNZCMAW-UHFFFAOYSA-N 0.000 description 2
- BPJQHSNHLHNXRM-UHFFFAOYSA-N 7-methyl-4-oxochromene-2-carboxamide Chemical compound O1C(C(N)=O)=CC(=O)C=2C1=CC(C)=CC=2 BPJQHSNHLHNXRM-UHFFFAOYSA-N 0.000 description 2
- 206010002855 Anxiety Diseases 0.000 description 2
- 206010057666 Anxiety disease Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 206010006451 Bronchitis Diseases 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- RRKTZKIUPZVBMF-IBTVXLQLSA-N Brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 208000007451 Chronic Bronchitis Diseases 0.000 description 2
- 206010011401 Crohn's disease Diseases 0.000 description 2
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N Ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 241001435619 Lile Species 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 206010027599 Migraine Diseases 0.000 description 2
- 208000008085 Migraine Disorders Diseases 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000007920 Neurogenic Inflammation Diseases 0.000 description 2
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- QMGVPVSNSZLJIA-FVWCLLPLSA-N Strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 201000009961 allergic asthma Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
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- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000002757 inflammatory Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- CWUKFXVGYJPDTG-UHFFFAOYSA-N methyl N-[1-(4-chlorophenyl)pent-4-en-2-yl]-N-(ethoxymethyl)carbamate Chemical compound CCOCN(C(=O)OC)C(CC=C)CC1=CC=C(Cl)C=C1 CWUKFXVGYJPDTG-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
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- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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Abstract
The invention discloses compounds of fórmula I, wherein A and B rings are as defined in the specifications, which have valuable pharmacológical properties and are particularly effective as neuroquinine 1 antagonists, and P substance antagonists.
Description
DERIVATIVES OF CROMONA
The present invention relates to compounds of the formula I:
wherein ring A is unsubstituted or substituted, and ring B is unsubstituted or substituted. These compounds have valuable pharmacological properties and are particularly effective as antagonists of neurokinin 1 and substance P antagonists. The invention relates in particular to compounds of formula I wherein ring A is unsubstituted or monosubstituted by lower alkyl, lower alkoxy, halogen, nitro, or trifluoromethyl, and ring B is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of lower alkyl, hydrix, lower alkoxy, lower thioalkyl, halogen, nitro, cyano, and trifluoromethyl, as well as salts thereof, to processes for the preparation of these compounds, to pharmaceutical compositions comprising these compounds, to the use of these compounds for the therapeutic treatment of the human or animal body or for the preparation of pharmaceutical compositions. Since the compounds of this invention contain at least two optically active carbon atoms, according to the same, mixtures of stereoisomers may be present in the form of stereoisomers, as well as in the form of the (substantially) pure diastereomers. The invention also encompasses the corresponding stereoisomers. The compounds of the formula I are preferably in the diastereoisomeric form, as represented by the formula la:
If not otherwise defined, the general terms used hereinafter and subsequently herein have the following meanings.
The term "lower" means that the corresponding groups and compounds each contain 1 up to and including 7, preferably 1 up to and including 4 carbon atoms. Lower alkyl is typically methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl, tertiary butyl, or a pentyl, hexyl, or corresponding heptyl radical. Alkyl of 1 to 4 carbon atoms is preferred. Lower alkoxy is typically methoxy, ethoxy, normal propyloxy, isopropyloxy, normal butyloxy, isobutyloxy, secondary butyloxy, tertiary butyloxy, or a corresponding pentyloxy, hexyloxy or heptyloxy radical. Alkoxy of 1 to 4 carbon atoms is preferred. Halogen is typically fluorine, chlorine, or bromine, but it can also be iodine. Chlorine is preferred. The compounds of the formula I can be in the form of salts, preferably in the form of pharmaceutically acceptable salts. Acid addition salts can be formed with the basic center of the piperidine ring. Suitable acidic components can be, for example, strong inorganic acids, typically mineral acids, for example, sulfuric acid, phosphoric acids, for example, orthophosphoric acid, hydrohalic acids, for example, hydrochloric acid, or strong organic carboxylic acids, typically acidic. lower alkane carboxylic acids which may be substituted, for example, by halogen, such as acetic acid or trifluoroacetic acid. dicarboxylic acids which may be unsaturated, for example, oxalic, malonic, succinic acids. maleic It is aric. Phthalic. or terephthalic. hydroxycarboxylic acids, for example, ascorbic, glycolic, lactic, malic, tartaric, or citric acid, amino acids, for example, aspartic or glutamic acid. or benzoic acid, or organic sulfonic acids, typically lower alkane sulphonic acids which may be substituted, for example, by halogen, typically methanesulfonic acid. or arylsulfonic acids which may be substituted, for example, by lower alkyl, typically p-toluenesulfonic acid. Also included are salts that are not suitable for therapeutic use, but which can be used, for example, to isolate or purify the free compounds of formula I or their pharmaceutically acceptable salts. Only non-toxic pharmaceutically acceptable salts are used for the therapeutic application, and therefore, san preferred ones. The compounds of the formula I - including their pharmaceutically acceptable salts which will hereinafter be included in the present - have valuable pharmacological properties. They act in particular as neuroquipin 1 antagonists (NQ1 antagonists), and accordingly, they are able to prevent the symptoms that are caused, among other things, by the release of substance P. The respiratory tract has sensory nerves that contain a number of neuropeptides. in particular tachykinins and PRGC (= peptides related to the calcitonin gene). The activation of the sensory nerves results in a local release of neuropeptides into the lung. They release mainly substance P and neurokinin A, which trigger an acute inflammatory reaction called neurogenic inflammation. This inflammatory reaction proceeds mainly through the activation of the neurokinin 1 receptor and includes in particular vasodilation. Ichigo leaks. agglomeration of inflammatory leukocytes and excessive secretion of mucus. These effects of substance P are typical symptoms of asthma. The pharmacological effect of the compounds of the formula I is based in particular on the antagonization of the neuraquipine receptor 1. The compounds of the formula I are also capable of inhibiting neurogenic inflammation. as well as tachykinin-induced bronchoconstriction. The convenient effect of the compounds of formula I can be demonstrated by different test methods in vi tro or in vi vo. For example, in the neurokinin 1 bronchospasm test in vivo on guinea pigs that have ED50 values. oral doses of approximately 0.03 milligrams / kilogram are effective, and test substances 2.4 are administered. or 24 hours before the intravenous administration of 3.0 micragrams / ki 1 agramo [Sar9. Met i 02) 11] -sust an i a P [= Sar SP]. The treatment with SarSP induces an increase in intratracheal pressure in the Indian rabbit. The compounds of this invention are distinguished by an extremely good oral activity, as well as by an unusually long duration of efficacy. As antagonists of the neurokinin 1 receptors, the compounds of the formula I are therapeutically useful in the prevention, treatment, or diagnosis of a number of diseases, for example: diseases of the upper and lower respiratory tract, such as bronchial asthma, allergic asthma , non-allergic asthma, allergic hypersensitivity, and conditions of hypersecretion, for example, chronic bronchitis and cystic fibrosis, - lung fibrosis of varied etiology; diseases of the pulmonary and bronchial circulation, such as pulmonary hypertension, angiogenesis, metastasis, - gastrointestinal tract disease, such as Crohn's disease, Hirsprung's disease, diarrhea, malabsorption conditions, inflammatory conditions; affective, traumatic, or inflammatory alterations of the central and peripheral nervous system, such as depressions, anxieties, migraine, and other forms of cranial pain, apoplegies, emesis, - diseases of blood vessels, for example, cranial vessels; diseases related to microcirculation in various tissues such as the skin and eyes; diseases of the immune systems and the reticulohistiocytic system, for example, in splenic and lymphatic tissues; conditions of pain and other diseases that involve the activity of neurokinins, tachykinins, or other related substances in their pathogenesis, pathology and etiology. Substance P is an updecapeptide that occurs naturally in the tachykinin family. It is produced in the mammalian organism, and acts pharmacologically as a neuropeptide. Substance P has an important part in a variety of diseases, for example, in pain conditions. in migraine, and in some disorders of the central nervous system. such as states in anxiety. emesis schizophrenia and depressions, as well as in certain motor disorders, such as in Parkinson's disease. but also in inflammatory diseases, such as rheumatoid arthritis. iritis and conjunctivitis, in diseases of the respiratory organs. such as in asthma and chronic bronchitis, in diseases of the gastrointestinal tract. such as ulcerative colitis and Crohn's disease and hypertension. Many efforts are made to advance the development in the field of substance P antagonists, and to find, for example, suitable substance P antagonists having a broader spectrum of activity, as well as a better activity and a better biodispanibilidad, and also a better chemical stability and cristalipidac. Extensive pharmacological tests have shown that the novel compounds and the salts thereof aptagope the substance P to a particularly preferred degree. they are therefore particularly suitable for the treatment of symptoms caused by substance P. The antagonizing effects of substance P can be detected, for example, as shown hereinafter, by the use of test methods known to the person skilled in the art. expert. These effects are found in vi tro, as well as in vi vi. In the radio-receptor assay according to H. Bittiger, Ciba Foundation Symposium 91 (1982) 196-199, the compounds of formula I, for example, inhibit the H bond of substance P with the bovine retina to an unexpected extent high, with IC50 values of approximately 5 nM. The formation of phosphoinositol in human astrocytoma cells induced by substance P, for example, is also antagonized in vi tro. resulting in IC ™ values of approximately 1 nM. A suitable test model for the detection of this inhibition is. for example, that of C.M. Lee et al., Described in J. Neurochem. 59 (1992) 406-414. The administration i.c.v. of methyl ester of substance P in gerbil rodents, results in abnormal behavior. This effect can be inhibited with peroral administration of compounds of formula I in vivo. The test method used is the process of A. Vassout et al., Which was presented at the congress "Substance P and Related Peptides: Cellular and Molecular Physiology" in Worchester, Mass 1990. There ED5C values of approximately 0.1 milligrams were demonstrated. oral kilogram These data establish the excellent property of the compounds of the formula I for the treatment of disorders of the central nervous system. Compared to neurokinin 1 or substance P antagonists known up to now, the novel compounds have a remarkably higher activity, and also a substantially higher chemical stability, for example, to oxygen, a better crystallinity. as well as a better oral bioavailability. According to the above. The substance P antagonists of the formula I provided by this invention are excellently suited for the therapeutic treatment of the pathological symptoms indicated above. The invention relates in particular to the compounds of the formula I, wherein ring A is unsubstituted or moposubstituted by halogen, and ring B is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, halogen, nitro, and cyano, as well as pharmaceutically acceptable salts thereof. The invention relates primarily to compounds of formula I wherein ring A is unsubstituted or monosubstituted by chlorine, and ring B is unsubstituted or substituted by 1 to 2 substitutes selected from the group consisting of hydroxy. lower alkoxy, chlorine, and bromine.
as well as pharmaceutically acceptable salts thereof. The invention relates in particular to the compounds of the formula I wherein ring A is unsubstituted or monosubstituted by chlorine, and ring B is unsubstituted or monosubstituted by chlorine or fluorine, as well as pharmaceutically acceptable salts thereof. The subgroups of a group of compounds of the formula I that should be emphasized from each are: (a) compounds of the formula I, wherein ring A is unsubstituted or substituted at the 4-position by chlorine; (b) compounds of formula I, wherein ring A is substituted at the 4 position by chlorine, - (c) compounds of formula I, wherein ring B is monosubstituted by chlorine or fluorine; (d) compounds of formula I, wherein ring B is unsubstituted. The invention relates in particular to the specific compounds described in the Examples, and salts, in particular pharmaceutically acceptable salts thereof.
The compounds of the formula I can be prepared in a manner known per se, typically by the reaction of:
a) a compound of the formula lia:
wherein rings A and B are as defined for formula I, with a compound of formula IIb:
wherein Q is hydroxy, which may be etherified, for example, hydroxy, lower alkoxy, or unsubstituted or substituted phenoxy, or esterified reactive hydroxy, for example, halogen, preferably chlorine, or a radical of the formula:
or a salt thereof, or by the reaction of b) a compound of the formula Illa
where ring A is as defined for the formula
I, with a compound of formula IIIb:
wherein ring B is as defined for formula I, and Q, is hydroxy which may be etherified, for example, hydroxy, lower alkoxy, or unsubstituted or substituted phenoxy, or esterified reactive hydroxy, for example halogen, preferably chlorine , or a radical of the formula:
or a salt thereof: and if desired, converting a compound of formula I to another compound of formula I, and / or if desired, converting a salt obtained in the free compound or in another salt, and / or. if desired, convert a free compound of the formula I obtained having salt-forming properties into a salt, and / or, if desired, separate a mixture of stereoisomers and diastereoisomers obtained in the individual stereoisomers and diastereomers. The salts of the starting materials having at least one basic center, for example those of the formula Ia or IIIa, are the corresponding acid addition salts, while the salts of the starting materials containing an acid group, for example, those of the formula I Ib or 11 Ib. they are salts with bases. In the following detailed description of the processes, rings A and B each have the meaning indicated for formula I, unless indicated otherwise. The reactions described in the above variants herein and later herein are performed in a manner known per se, typically in the absence of. or usual in the presence of a suitable solvent or diluent, or of a mixture thereof, and. depending on requirements, with cooling, at room temperature, or with heating, typically on the temperature scale from about -80 ° C to the boiling temperature of the reaction medium, preferably from about -10 ° C to about + 200 ° C, and if required, in a closed vessel, under pressure, in an inert gas atmosphere and / or under anhydrous conditions.
Process variants a) and b): The condensation for the preparation of the respective amide bond can be carried out in a manner known per se, for example, as described in normal works, such as "Houben-Weyl." Methoden der organischen Chemie ", § edition, volume 15/11. Georg Thie e Verlag, Stuttgart 1974, "The Peptides" (ed. E. Gross and J. Meienhofer), Volumes 1 and 2, Academic Press, London and New York, 1979/1980, or M. Bodanszky. "Principies of Peptide Synthesis", Springer-verlag, Berlin 1984. The condensation can be carried out in the presence of one of the usual condensing agents. Customary condensation agents are typically carbo-diimides, for example, diethyl carbodiimide, dipropyl carbodiimide, carbodiimide N-ethyl- '- (3-dimethylaminopropyl), or preferably, carbodiimide dicyclohexyl 1 ica, and also suitable carbonyl compounds, typically di-imidazole carbonyl. 1,2-oxazolium compounds, typically 3'-sulphanate of 2-ethyl-5-phenyl-1,2-oxazole io and tertiary-2-butyl-5-methylisoxazole io-perchlorate. or an appropriate acrylic compound.
typically 1,2-dihydroquinoline 2-ethoxy-1-ethoxycarbonyl ica. and also activated phosphoric acid derivatives, typically azide diphenyl phosphoric acid, cyanide diethyl phosphoric acid, phenyl-N-phenylic acid phosphide, bis (2-oxo-3-oxazolidinyl) chloride. phosphatic, or 1-benzotriazolyloxytris (dimethylamino.) phospho- pheum hexafluorophosphate. If desired, an organic base such as a lower trialkyl amine containing bulky radicals is added, for example, ethyldiisopropyl amine, or a heterocyclic base, typically pyridine, aminapyridine 4-dimethyl, or preferably, N-methyl morphine. . The condensation of an acyl halide. for example, with a corresponding amine, it can also be performed in the presence of a suitable base without the addition of a suitable coupling component. The condensation is preferably carried out in a solvent or polar inert aprotic solvent mixture. preferably anhydrous, typically in a carboxamide, for example, formamide or dimethylformamide, in a halogenated hydrocarbon, for example, methylene chloride, carbon tetrachloride, or benzene chloride, in a ketone, for example, acetone, in a cyclic ether, for example, tetrahydrofuran. in an ester. for example. ethyl acetate. or in a nitrile, for example, acetonitrile, or in mixtures thereof, at a low or high temperature, typically on a temperature scale of from about -40 ° C to about + 100 ° C. preferably about -10 °. C at approximately + 50 ° C. and optionally. under an atmosphere of inert gas, for example, under nitrogen. The reactive acid derivatives can also be formed at the site. The starting materials of formulas I Ib and 11 Ib are known or can be prepared in a manner known per se. The compounds of the formula Illa can be prepared in a manner known per se, starting, for example, from a compound of the formula lile:
wherein Q ^ is, for example, lower alkyl or lower phenylalkyl. This compound is N-alkylated, typically by reaction with lower alkoxy-halomethane, such as ethoxychloromethane, in the presence of a base. The resulting compound of the formula (Illd):
wherein Q ^ is, for example, lower alkyl, is treated with a nitrile, typically acetonitrile, in the presence of a strong acid, typically chlorosulfonic acid. In the resulting compound of the formula lile:
the group -C (= * 0) -0Glj is removed by its treatment with a strong acid, typically bramhydric acid. For the preparation of an enantiomerically pure compound, the secondary amine group in a compound of the formula
Illf:
which can be obtained in this way, is acylated with an optically active compound, typically a corresponding 0-acylated c-hydroxycarboxylic acid or a reactive derivative thereof, for example, 0-acetyl- (+) -malel chloride, and the diaesteresisomeric mixture thus obtained is separated in a manner known per se, for example, by chromatography. A compound of the formula Illg is obtained:
after removing the two N-acyl groups, typically by acid hydrolysis, for example, with hydrochloric acid. The 4-amino group of the compounds of the formula Illg is temporarily protected in a manner known per se, typically by reaction with benzaldehyde. The 3, 5-bistrifluoromethylbenzoyl group is then introduced, for example, as described for the variant of process a), by coupling with a compound of the formula IIb, and then the protecting group is removed, typically by treatment with a acid, such as hydrochloric acid, resulting in a corresponding compound of the formula Illa. The compounds of the formula Ia can be prepared in a manner known per se, typically starting from a compound of the formula Illg and coupling it, as described, for example, for the process variant b), with a compound of the formula 11 Ib in the presence of a coupling reagent, and in this way the corresponding acyl group is introduced. In this way, the corresponding compound of the formula lia is obtained. The salts obtained can be converted in a manner known per se to the free compounds, typically by treatment with a base, for example, with an alkali metal hydroxide, a metal carbonate, or an acid metal carbonate, or ammonia. , or with another salt-forming base mentioned at the outset, or with an acid, typically with a mineral acid, such as hydrogen chloride, or as another salt-forming acid mentioned at the beginning. The salts obtained can be converted in a manner known per se to other salts; in the case of acid addition salts, typically by treatment with a suitable metal salt, for example, sodium, barium, or silver salt, of another acid in a suitable solvent where an inorganic salt is insoluble resulting, and in this way is removed from the equilibrium of the reaction, and in the case of base salts, by generating the free acid and repeated salt formation. The compounds of the formula I, "including their salts, can also be obtained in the form of hydrates, or they can also include the solvent used for the crystallization, because of the close relationship between the novel compounds in the free form and in the form of its salts, the references made throughout this description to the free compounds and their salts, will also be applied by analogy to the corresponding salts or to the free compounds.Due to the physicochemical differences of their components, the mixtures of diastereoisomers and The obtained racemates can be separated into the diastereomers and pure racemates in a known manner, typically by chromatography and / or fractional crystallization.The resulting racemates can be further separated in the optical antipodes by known methods, typically by recrystallization from an optically solvent. active, using microorganisms, or doing reacting the resulting diastereomeric or racemate mixture with an optically active auxiliary compound, for example, depending on the acid, basic groups. or modifiable functional agents present in the compounds of the formula I, with an optically active acid, a base, or with an optically active alcohol, in mixtures of diastereoisomeric salts and functional derivatives such as esters, and are separated in diastereoisomers from which the respective desired enantiomer can be released in the usual usual manner. Bases, acids, and alcohols suitable for the purpose, are typically optically active alkaloid bases, such as strychnine, cinchonine or brucine. or amine D- or L- (l-phen? l) ethyl, 3-pi? ecol ina, ephedrine, amphetamine and similar bases obtainable by synthesis, optically active carboxylic or sulfonic acids such as quinic acids or D-acid or L-tartaric, D- or L-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid, or D- or L-capforsulfonic acid, or optically active alcohols, for example, borpeol or D- or L- (l-phenyl) ethanol. The invention also relates to process modalities in which a compound obtainable as an intermediate at any stage of the process is used as the starting material, and the remaining steps are performed, or a starting material is used in the process. form of a salt or preferably, is formed under the conditions of the reaction. The invention also relates to novel starting materials that have been developed especially for the preparation of novel compounds, especially those which result in the compounds of formula I described at the beginning as being particularly preferred, to the processes for their preparation, and to the use of them as intermediaries. The novel compounds of the formula I can be used, for example, in the form of pharmaceutical compositions containing a therapeutically effective amount of the active ingredient, if appropriate together with solid, inorganic or organic carriers; or liquids, pharmaceutically acceptable, suitable for enteral administration, for example, oral, or parepteral. Accordingly, tablets or gelatin capsules are used which contain the active ingredient together with diluents, typically lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or lubricants, for example, diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate and / or polyethylene glycol. The tablets may also contain binders, typically magnesium aluminum silicate, starches, typically corn starch, wheat starch, rice starch, or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, and / or polyvinyl pyrrolidone, and if Desires, disintegrants, typically starches, agar, alginic acid or a salt thereof, for example, sodium alginate, and / or effervescent mixtures, or sorbents, colorants, flavors, and sweeteners. The novel compounds of the formula I can also be used in the form of compositions for parenteral administration or infusion solutions. These solutions are preferably isotonic aqueous solutions or suspensions which, for example, in the case of lyophilized compositions containing the active ingredient by itself or together with a vehicle, such as mannitol, can be prepared before use. The pharmaceutical compositions can be sterilized and / or contain excipients, typically preservatives, stabilizers, wetting agents, and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure, and / or pH regulators. The pharmaceutical compositions thus obtained which, if desired, contain other pharmacologically active substances, are prepared in a manner known per se by conventional methods of mixing, granulation, sugar coating, solution, or lyophilization, and contain about 0.1 per cent by weight. 100 percent to 100 percent, preferably from about 1 percent to about 50 percent lyophilized to about 100 percent active ingredient. The invention also relates to the use of the compounds of the formula I, preferably in the form of pharmaceutical compositions. The dosage may depend on a variety of factors, such as mode of application, species, age, and / or individual status. In the case of oral administration, daily doses are on the scale of about 0.25 to about 10 milligrams / kilogram, and for warm-blooded animals weighing approximately
70 kilograms, preferably are on the scale of approximately 20 milligrams to approximately 500 milligrams. The invention is illustrated by the following Examples, wherein temperatures are given in degrees Celsius, and pressures in mbar. EM-DC = mass spectroscopy by field desorption.
Example 1: 4-oxo-4H-1-benzopyran-2-carboxamide (2R. S) -N- 1 - (3, 5-bistrif luoromethyl-l-benzoyl) -2- (4-chlorobenzyl) -iperidin-4- ilical. 3.77 milliliters of triethyl amine and 2.35 grams of 4-axo-4H-1-bepzopyran-2-carboxylic acid chloride (obtained from the corresponding carboxylic acid, supplied, for example, by Sigma, by reaction with thionyl chloride) , they are added to a solution of 4.36 grams of piperidine (2R, 4S) -4-amino-1- (3,5-bistrifluoromethylbepzoyl) -2- (4-chlorobenzyl) in 200 milliliters of methylene chloride. and the mixture is stirred for 4 hours at 20 ° C. The reaction mixture is washed with 1N aqueous hydrochloric acid, and then with brine and water, dried over magnesium sulfate, and concentrated by evaporation. The obtained foam is crystallized from tertiary butyl methyl ether / hexane / methylene chloride, giving the title compound in the form of colorless crystals, m.p. 211-212"C. [A] D20 = 3.7 ± 2.6 (c = 0.382, methanol).
The starting compound can be prepared as follows:
a) Nf 1- (4-chlorobenzyl) but-3-enyl-N-ethoxymethylcarbamic acid methyl ester: A suspension of 10.0 grams of sodium hydride (80 percent in mineral oil, 333 millimoles) in tetrahydrofuran [THFj anhydrous, it is refluxed under argon. A solution of 60.5 grams (238 millimoles) of [1- (4-chlorobenzyl) but-3-enyl] carbamic acid methyl ester is added dropwise [McCarty FJ et al., J. Med. Chem. 1968, 11 (3 ), 534] in 50 milliliters of anhydrous tetrahydrofuran for 1 hour. The mixture is then refluxed for 2 hours until the evolution of gas ceases. The mixture is cooled to 0 ° C and chloromethyl ethyl ether is added dropwise, so that the temperature of the reaction does not rise above 5 ° C. The mixture is then heated slowly to 25 ° C and stirred for 12 hours. The excess of sodium hydride is carefully destroyed with 1 milliliter of water before more water is added. The phases are separated and the aqueous phase is extracted with tertiary-methyl butyl ether. The combined organic phases are washed with brine, dried over sodium sulfate and concentrated by evaporation. The crude product distills at 0.1 mbar, and has a boiling scale of 120 ° C to 125 ° C. OC: ethyl acetate / hexane (1: 6) R = 0.34, FD-MS: M + = 311 (313).
b) Methyl ester of (2R *, 4S *) -4-acetylamino-2- (4-chlorobenzyl) piperidine-l-carboxylic acid ester; 20.6 grams (308 millimoles) of chlorosulonic acid are added to 500 milliliters of acetonitrile at -40 ° C. A solution of 48.0 grams (154 millimoles) of N- [1- (4-chlorobenzyl) but-3-enyl] -N-ethoxymethylcarbamic acid methyl ester in 50 milliliters of acetonitrile is added dropwise to this mixture in such a manner that the temperature of the reaction does not rise above -10 ° C. The reaction mixture is then stirred for 20 minutes at -15 ° C before adding 370 milliliters of a 2N sodium hydroxide solution and 100 milliliters of a 10 percent solution of aqueous sodium hydrogen carbonate. The phases are separated and the aqueous phase is extracted twice with toluene. The combined organic phases are dried over sodium sulfate. The crude product is crystallized from toluene, giving the title compound in the form of white crystals. P.f .: 169-170 ° C. DC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.42, FD-MS: + = 325.
c) Acetamide (2R.4S) N-T2- (4-chlorobenzyl) pjperidin-4-lical; 51.8 milliliters of 33% hydrogen bromide in acetic acid are added to (2R *, 4S *) -4-acetylamino-2- (4-chlorobenzyl) piperidine-l-carboxylic acid methyl ester (30.0 grams, 92.3 millimoles ). After 16 hours, 200 milliliters of water are added to the mixture, which is then washed twice with toluene. The aqueous phase is basified and extracted twice with ethyl acetate. The organic phases are dried over potassium and concentrated by evaporation on a rotary evaporator. The title compound is crystallized as the hydrochloride from ethanol / ethyl acetate. P.f. 288-289 ° C DC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.17, FD-MS: (M + l) + = 267.
d) Ester 2-f4-acetylamino-2- (4-chlorobenzyl) piperi in-l-ill-2-oxo-l-phenylethyl of (2'S.2R.4S) acetic acid: Acetamide hydrochloride N- [2 - (racemic (4-chlorobenzyl) piperidin-4-llica] (20.5 grams, 67.6 mmol) at 0 ° C, with vigorous stirring, at 34 milliliters of a 2N sodium hydroxide solution, 150 milliliters of a 10-fold solution one hundred percent aqueous sodium carbonate, and 50 milliliters methylene chloride. S (+) - 0-acetylmandelic acid chloride [Pracejus G, Ann., 1959, 622, 10] (14.9 grams, 70 mmol) was added dropwise over 1 hour. The mixture is then stirred for 1 hour at + 4 ° C. The phases are separated and the organic phase is dried over sodium sulphate and concentrated by evaporation on a rotary evaporator. After being crystallized twice from methylene chloride / tertiary-butyl methyl ether. the title compound is isolated as a pure diastereomer. P.f .: 209-211 ° C. DC: methylene chloride / isopropapol (9: 1) R = 0.65, FD-MS: M + = 443. [alpha] = +77.5 degrees (c = 1, methylene chloride). The mother liquors mainly contain the non-crystalline diastereoisomer acetamide (2 'S, 2S.4R) N- [2- (4-c lorobe'nci 1) - 1- (ace tox ifenil aceil) pi per idi p-4- í 1 ica]. DC: methylene chloride / isoprapanol (9: 1) Rf = 0.70.
e) Piper id ina (2R, S) -4-amino-1- (3, 5-b is trifluoro-methylbenzoyl-2- (4-chlorobenzyl): Reflux 2- [4-acetyl ester 2- (4-chlorobenzyl) -Iperidin-1-yl] -2-oxo-1-phenylethyl (2 'S, 2R, 4S) acetic acid (37.4 grams, 84.5 mmol) for 2 days in 370 milliliters of 6N hydrochloric acid After cooling, the mixture is basified with solid sodium hydroxide and extracted with methylene chloride, the combined organic phases are dried over potassium carbonate and concentrated by evaporation on a rotary evaporator. which consists of almost pure piperidin-4-amine (2R, 4S) -2- (4-chlorobenzyl) (19.0 grams, 84.5 millimoles, 100 percent), is recovered in 8.5 milliliters (84.5 millimoles) of benzaldehyde, and Concentrate twice with 150 milliliters of toluene on a rotary evaporator.The oily residue is recovered in 180 milliliters of methylene chloride and 15.3 milliliters (110 millimoles) of triethyl amine, and cool to 10 ° C. Bistrifluoromethylbenzoyl chloride (25.7 grams, 92.9 mmol) is added dropwise over 15 minutes, and then the mixture is stirred for 1 hour at 25 ° C. 250 milliliters of 1N hydrochloric acid are added to the reaction mixture, and the methylene chloride is removed under reduced pressure on a rotary evaporator. Hexane and ethanol are added until two homogeneous phases are obtained. The organic phase is removed and the mixture is washed with hexane until the benzaldehyde is completely removed. The mixture is basified with solid sodium hydroxide, and extracted repeatedly with sodium hydroxide. The organic phases are dried over sodium sulphate and concentrated on a rotary evaporator. Crystallization from tertiary-methyl butyl ether / hexane gives the title compound in the form of white crystals. P.f .: 79-81 ° C. DC: methylene chloride / metapol / concentrated ammonia (90: 9: 1) Rf = 0.21. FD-MS: (M + l) + = 465. [alpha] D = -12.7 degrees (c = 1, methylene chloride).
The following compounds can also be prepared according to the general procedure described in Example 1. The preparation of the corresponding starting material, piperidine (2R, 4S) -4-amino-1- (3, 5-bistrifluoromethylbepzoyl) -2- benzylic, is described in European Patent Number A-532,456, Example 38f:
Example 1/1: 4-Oxo-4H-l-benzapyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2-benzylpiperidip-4-lly], m.p. 107-108 ° C. [a] D20 = 18.3 ± 2.6 (c = 0.388, methanol).
Example 1/2: 7-chloro-4-oxo-4H-l-benzopyrap-2-carboxamide
(2R.4S) -N- [l- (3,5-bistrifluoromethylbenzoyl) -2-benzylpiperidin-4-lly], m.p. 224-226 ° C, [a (c = * 0.40 methanol)
Example 1/3: 7-methoxy-4-oxo-4H-l-benza? Iran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrif luorometi Ibenzoi 1) -2-benzylpiper idin-4 -lica], pf 190-192 ° C, [s] D20 = 25.7 ± 2.3 (c = 0.44 methanol).
Example 1/4: 7-thiomethyl-4-oxo-4H-l-benzopyran-2-carboxy-ida (2R, 4S) -N- [1- (3, 5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-ylica ]
Example 1/5: 6-methoxy-4-oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl] .
• g-j tn ift 1/6; 6-chloro-4-oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl].
Example 1/7; 6-bromo -4 -oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl].
Example 1/8; 6-Fluorine or-4 -oxo-4H-1-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2-benzylpiperidin-4-yl].
Example 1/9; 6-methyl-4 -oxo-4H-l-benzopyran-2-carboxamide
(2R, 4S) -N- [1- (3, 5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl].
Example 1/10; 6-Cyano-4 -oxo-4H-1-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2-benzylpiperidin-4-yl].
Example 1/11; 6-Nitro-4-oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl].
gJ *? mP 'r- 1/12; 7-f luoro-4-oxo-4H-1-benzopyran -2 -carboxamide (2R, 4S) -N- [1- (3,5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl].
Example 1/13: 7-bromo-4-oxo-4H-1-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl] .
Example 1/14: 7-methyl-4-oxo-4H-1-benzopyran-2-carboxamide
(2R, 4S) -N- [1- (3, 5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl].
Example 1/15; 7-n-4-oxo-4H-1 • -benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl].
Example 1/16; 6,7-dimethoxy-4-oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrif luoromethylbenzoyl) -2-benzylpiperidin-4-yl].
Example 2: 7-hydroxy-or-4H-1-benzopyran-2-carboxamide (2R.4S) -N-1 - (3,5-bistrifluoromethylbenzoyl-2-benzylpiperidin-4-lical) A solution of 0.127 grams of piperidipa (2R, 4S) -4- "amino-1- (3,5-bistrifluoromethylbenzoyl) -2-benzyl in 3.1 milliliters of methylene chloride, is recovered in 0.038 grams of amidopyridine 4-dimethyl, 0.059 grams of carbodihydrochloride N- (3-dimethylaminopropyl) -N'-ethyl ester, and 0.064 grams of 7-hydroxy-4-oxo-4H-l-benzopyran-2-carboxylic acid in 2 milliliters of methylene chloride / dimethylated ida form (1 : 1), and stirred for 24 hours at 20 ° C. The reaction mixture is concentrated by evaporation, and the residue is chromatographed on silica gel with methylene chloride and methylene chloride / methanol (19: 1). , giving the title compounds in the form of a pale yellow powder having a mp of 224-225 ° C; [a] D20 = 23.3 ± 3.5 (c = 0.288, methanol).
The following compound can also be prepared according to the general procedure described in Example 2: * Example 2/1: 6-bromo-7-hid oxy-4-oxo-4H-1-benzopyran-2-carboxamide (2R, S) -N- [1- (, 5-b ist r if luo rometi lbenzo il) -2- benzylpiperidin-4-ylicaJ. P.f. 173-174 ° C.
Example 3: The following compounds can also be prepared according to the general procedure described in Example 1, starting from piperidine (2R, 4S) -4-amino-1- (3, 5-bistrif luoromethylbenzoyl) -2- (4-chlorobenzyl) [Example le)]:
Example 3/1: 7-Chloro-4-oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [l- (3,5-bistrifluoromethylbenzoyl) -2 - (4-chlorobenzyl) piperidine -4-idol]. P.f. 218-220 ° C, [a] D20 = 31.5 ± 2.0 (c = 0.50, methanol).
Example 3/2: 7-methoxy -4 -oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine- 4- Ilica]. P.f. 198-200 ° C, [a] D20 = 29.7 ± 2.2 (c = 0.45, methanol).
Example 3/3: 7- thiomethyl-4 -oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifl oromethylbenzoyl) -2- (4-chlorobenzyl) piperidine -4-idol]. P.f. 137-140 ° C, [a] D20 = 20.8 ± 2.8 (c = 0.355, methanol).
Example 3/4: 6-methoxy-4-oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin- 4-ílica].
Example 3/5: 6- chloro-4-oxo-4H-1-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3, 5-bistrif luoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine -4-llica].
Example 3/6: 6-bromo-4-oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [l- (3, 5-bistrif luoromethybenzyl) -2- (4-chlorobepcyl) piperidin-4-lica].
Example 3/7: 6-fluoro-4-oxo-4H-l-benzapyran-2-carboxamide (2R, 4S) -N- [1- (3, 5-bistri f-loromethyl-l-benzoyl) -2- (4-chlorobepcyl ) piperidin-4-ica]. P.f. 215-218 ° C; Rf (ethyl acetate / hexapo, 4: 1) = 0.58. The acid chloride called 6-f luoro-4-oxo-4H-l-benzopyran-2-carboxylic acid chloride required as the starting material is described, inter alia, in Chemical Abstracts: 96: 52132w or 88: 106066 and has CAS Reg. No. 65843-87-0.
Example 3/8: 6-methyl-4-oxo-4H-l-benzopyran-2-carboxamide (2R.4S) -N- [1- (3, 5-bistrif luoromethyl-l-benzoyl) -2- (4-chlorobepcyl) piperidin-4-llica]. P.f. 240-241 ° C; Rf (ethyl acetate / hexane, 4: 1) = 0.65.
Example 3/9: 6-cyano-4-oxo-4H-l-benzopyrap-2-carboxamide (2R.4S) -N- [l ~ (3, 5-bistri f lusrometi lbepzoyl) -2- (4-chlorobepcyl ) piperidin-4-llica].
Example 3/10: 6-n-tro-4 -oxo-4 Hl-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine- 4-ílica].
Example 3/11; 7-f luoro-4-oxo-4H-l-benzopyran-2-carboxamide (2R.4S) -N- [l- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] .
g fttt? pi > ? / ?? t 7 -bromo-4-oxo-4H-1-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin- 4-ílica].
• g g-m ift 3/13; 7-methyl-4-oxo-4H-1-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl].
Example 3/14; 7-nitro-4-oxo-4H-1-benzopyran-2-carboxamide (2R, 4S) -N- [l- (3,5-bistrif 1 uo r ome ti 1 ben zoi 1) -2 - (4 - chlorobenzyl) piperidin-4-yl].
g mpio 3/15: 6, 7-dimethoxy-4-oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) ) piperidin-4-ica].
Example 4: Tablets containing 50 milligrams of active ingredient each can be prepared as follows:
Composition (10,000 tablets) active ingredient 500.0 grams lactose 500.0 grams potato starch 352.0 grams gelatin 8.0 grams talcum 60.0 grams magnesium stearate 10.0 grams silicon dioxide (highly dispersed) 20.0 grams ethanol q.s.
The active ingredient is mixed with the lactose and 292 grams of potato starch, and the mixture is then moistened with an ethanolic solution of the gelatin, and granulated through a sieve. After drying, the rest of the potato starch, magnesium stearate, talc, and silicon dioxide are mixed, and the mixture is compressed to obtain tablets weighing 145.0 milligrams each, and having an active ingredient content. of 50.0 iligramcs. If desired, the tablets may have indentation notches to allow a finer adjustment of the dose.
Example 5: Film-coated tablets containing 100 milligrams of active ingredient each can be prepared as follows:
Composition (for 1,000 film-coated tablets) active ingredient 100.0 grams lactose 100.0 grams corn starch 70.0 grams talc 8.5 grams calcium stearate 1.5 grams hydroxypropylmethyl cellulose 2.36 grams "shellac" (shellac) 0.64 grams water q.s. methylene chloride 'c.s.
The active ingredient, lactose, and 40 grams of corn starch, are mixed and moistened with a paste prepared from 15 grams of corn starch and water (with heating), and granulated. The granulate is dried, and the rest of the corn starch, talc, and calcium stearate are added, and mixed with the granulate. The mixture is compressed to obtain tablets (weight: 280 milligrams), which are then coated with a solution of hydroxypropylmethyl cellulose and shellac (shellac) in methylene chloride. The final weight of the film-coated tablet is 283 milligrams.
Example 6: Dry filled gelatin capsules containing 100 milligrams of the active ingredient can be prepared, for example, as follows:
Composition (for 1,000 capsules) active ingredient 100.0 grams lactose 250.0 grams microcrystalline cellulose 30.0 grams sodium lauryl sulfate 2.0 grams magnesium stearate 8.0 grams
Sodium lauryl sulfate is added by sieving through a sieve having a mesh size of 0.2 millimeters, to the lyophilized active ingredient. Both components are intimately mixed. Subsequently, the lactose is added, first sieved through a sieve having a mesh size of 0.6 millimeters, and then the microcrystalline cellulose ta ized through a sieve having a mesh size of 0.9 millimeters is added. The mixture is again intimately combined for 10 minutes. The magnesium stearate is added at the end by sieving through a sieve having a mesh size of 0.8 millimeters. After further mixing for 3 minutes, 390 milligrams of the formulation thus obtained are filled into each of the 0-size dry-filled gelatin capsules.
Example 7: A suspension for inhalation containing propelept, which contains 0.1 weight percent active ingredient:
Composition% by weight active ingredient, micronized 0.1 triolate of sorbitan 0.5 propellant A (trichlorotrifluoroethane) 4.4 propellant B (dichlorofluoromethane and 15.0 1, 2-dichlorotetrafluoroethane) 80.0
Using one of the conventional homogenizers, the active ingredient is suspended, excluding moisture, with the addition of the sorbitan triolate in the trichlorotrifluoroethane, and the suspension is then introduced into an aerosol container equipped with a metering valve. The container is closed and filled under pressure with propellant B.
Claims (14)
1. A compound of the formula I wherein ring A is unsubstituted or monosubstituted by lower alkyl, lower alkoxy, halogen, nitro, or trifluoromethyl, and ring B is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy lower, lower thioalkyl, halogen, nitro, cyano, and trifluoromethyl, or a salt thereof.
2. A compound of the formula I according to claim 1, wherein ring A is unsubstituted or monosubstituted by halogen, and ring B is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of lower alkyl , hydroxy, lower alkoxy, lower thioalkyl, halogen, nitro, and cyano, or a pharmaceutically acceptable salt thereof.
3. A compound of formula I according to claim 1, wherein ring A is unsubstituted or monosubstituted by chlorine, and ring B is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of hydroxy, lower alkoxy, chlorine, and bromine, or a pharmaceutically acceptable salt thereof.
4. A compound of the formula I according to claim 1, wherein ring A is unsubstituted or monosubstituted by chlorine, and ring B is unsubstituted or monosubstituted by chlorine or fluorine, or a pharmaceutically acceptable salt thereof.
5. A compound of the formula I according to any of claims 1 to 4, wherein the compound of the formula I is in the diastereoisomeric form represented in the form:
6. 4-Oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3, 5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] according to claim 1, or a pharmaceutically acceptable salt thereof.
7. 4-Oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3, 5-bistrifluoromethylbenzoyl) -2-benzylpiperidin-4-yl] according to claim 1, or a pharmaceutically acceptable salt thereof.
8. 6-Fluoro-4-oxo-4H-l-benzopyran-2-carboxamide (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-ylica ] according to claim 1, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound according to any of claims 1 to 8, and at least one pharmaceutically acceptable carrier.
10. A compound according to any of claims 1 to 8, for use in a process for the therapeutic treatment of the animal or human body.
11. A compound according to any of claims 1 to 8 for use in the treatment of diseases responsive to an antagonism of the neurokinin receptor 1.
12. The use of a compound according to any of claims 1 to 8 for the preparation of a pharmaceutical composition.
13. The use of a compound according to any of claims 1 to 8 for the preparation of a pharmaceutical composition for the treatment of diseases that respond to an antagonization of the neurokinin receptor 1.
14. A process for the preparation of a compound of the Formula I according to claim 1, which comprises: a) reacting a compound of the formula lia: wherein the rings A and B are as defined for formula I, with a compound of the formula Ilb: wherein Q is hydroxy, which may be etherified, for example, hydroxy, lower alkoxy, or unsubstituted or substituted phenoxy, or esterified reactive hydroxy, for example, halogen, preferably chlorine, or a radical of the formula: or a salt thereof; or b) reacting a compound of the formula Illa: wherein ring A is as defined for formula I, with a compound of formula IIIb: wherein ring B is as defined for formula I, and Q, is hydroxy which may be etherified, for example, hydroxy, lower alkoxy, or unsubstituted or substituted phenoxy, or esterified reactive hydroxy, for example halogen, preferably chlorine , or a radical of the formula: or a salt thereof; and if desired, converting a compound of the formula I into another compound of the formula I, and / or if desired, converting a salt obtained in the free compound or in another salt, and / or, if desired, converting a free compound of formula I obtained having salt-forming properties in a salt, and / or, if desired, stopping a mixture of stereoisomers and diastereoisomers obtained in the individual stereoisomers and diastereomers.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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CH1157/95-3 | 1995-04-24 | ||
CH115795 | 1995-04-24 |
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MX9601515A MX9601515A (en) | 1997-09-30 |
MXPA96001515A true MXPA96001515A (en) | 1998-07-03 |
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