MXPA01001724A - New compounds - Google Patents
New compoundsInfo
- Publication number
- MXPA01001724A MXPA01001724A MXPA/A/2001/001724A MXPA01001724A MXPA01001724A MX PA01001724 A MXPA01001724 A MX PA01001724A MX PA01001724 A MXPA01001724 A MX PA01001724A MX PA01001724 A MXPA01001724 A MX PA01001724A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- alkyl
- compound
- alkoxy
- formula
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 159
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000011780 sodium chloride Substances 0.000 claims abstract description 14
- 230000002496 gastric Effects 0.000 claims abstract description 12
- 230000027119 gastric acid secretion Effects 0.000 claims abstract description 7
- 200000000018 inflammatory disease Diseases 0.000 claims abstract description 7
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 149
- 239000000203 mixture Substances 0.000 claims description 89
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- -1 trifluoromethylsulfonyloxy Chemical group 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 42
- 229910052799 carbon Inorganic materials 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 13
- 239000012442 inert solvent Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 10
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- USIUVYZYUHIAEV-UHFFFAOYSA-N Diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000004429 atoms Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 claims description 6
- 210000001156 Gastric Mucosa Anatomy 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 239000011592 zinc chloride Substances 0.000 claims description 5
- 235000005074 zinc chloride Nutrition 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 4
- SRTHRWZAMDZJOS-UHFFFAOYSA-N Lithium hydride Chemical compound [H-].[Li+] SRTHRWZAMDZJOS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- OPCPRUQQEJNFIV-UHFFFAOYSA-N disodium;cyanoboron(1-) Chemical compound [Na+].[Na+].[B-]C#N.[B-]C#N OPCPRUQQEJNFIV-UHFFFAOYSA-N 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 claims description 4
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 claims description 4
- 125000005905 mesyloxy group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- CXRIRCXHLHYHFU-UHFFFAOYSA-N 1,2-dimethoxyethane;N,N-dimethylformamide Chemical compound CN(C)C=O.COCCOC CXRIRCXHLHYHFU-UHFFFAOYSA-N 0.000 claims description 3
- QAXZWHGWYSJAEI-UHFFFAOYSA-N N,N-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 claims description 3
- WWECJGLXBSQKRF-UHFFFAOYSA-N N,N-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 claims description 3
- HNPPKZRZKDKXDO-UHFFFAOYSA-N N,N-dimethylformamide;propan-2-one Chemical compound CC(C)=O.CN(C)C=O HNPPKZRZKDKXDO-UHFFFAOYSA-N 0.000 claims description 3
- DSRXQXXHDIAVJT-UHFFFAOYSA-N acetonitrile;N,N-dimethylformamide Chemical compound CC#N.CN(C)C=O DSRXQXXHDIAVJT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 3
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 230000000069 prophylaxis Effects 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 2
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 2
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 claims description 2
- 229940037467 Helicobacter pylori Drugs 0.000 claims 2
- 239000011260 aqueous acid Substances 0.000 claims 2
- 201000009910 diseases by infectious agent Diseases 0.000 claims 2
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 229920000728 polyester Polymers 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 172
- 230000015572 biosynthetic process Effects 0.000 description 117
- 238000003786 synthesis reaction Methods 0.000 description 116
- 230000002194 synthesizing Effects 0.000 description 116
- 101700067048 CDC13 Proteins 0.000 description 76
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- 239000012074 organic phase Substances 0.000 description 38
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- 239000003480 eluent Substances 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 239000000047 product Substances 0.000 description 24
- 239000002253 acid Substances 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 235000019441 ethanol Nutrition 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 238000000746 purification Methods 0.000 description 13
- 239000012047 saturated solution Substances 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 235000011054 acetic acid Nutrition 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000001187 sodium carbonate Substances 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 230000028327 secretion Effects 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 6
- AZFWRMNQBAEVGD-UHFFFAOYSA-N 8-N-[(2,6-dimethylphenyl)methyl]-2,3-dimethylimidazo[1,2-a]pyridine-7,8-diamine Chemical compound NC=1C=CN2C(C)=C(C)N=C2C=1NCC1=C(C)C=CC=C1C AZFWRMNQBAEVGD-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000005712 crystallization Effects 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 210000004211 Gastric Acid Anatomy 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000001184 potassium carbonate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- 230000003248 secreting Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ORGIHYDPMFXTEZ-UHFFFAOYSA-N 1-(bromomethyl)-3-chloro-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1CBr ORGIHYDPMFXTEZ-UHFFFAOYSA-N 0.000 description 3
- KQFIATWLSFGEPF-UHFFFAOYSA-N 2,3-dimethylimidazo[1,2-a]pyridine Chemical compound C1=CC=CN2C(C)=C(C)N=C21 KQFIATWLSFGEPF-UHFFFAOYSA-N 0.000 description 3
- FOEPRWVTHBDGAQ-UHFFFAOYSA-N 2-(bromomethyl)-1-chloro-3-methylbenzene Chemical compound CC1=CC=CC(Cl)=C1CBr FOEPRWVTHBDGAQ-UHFFFAOYSA-N 0.000 description 3
- HPVRFWQMBYLJRL-UHFFFAOYSA-N 2-(chloromethyl)-1,3-dimethylbenzene Chemical compound CC1=CC=CC(C)=C1CCl HPVRFWQMBYLJRL-UHFFFAOYSA-N 0.000 description 3
- DWRFPUBLHDHDFZ-UHFFFAOYSA-N 2-[[(2,3-dimethylimidazo[1,2-a]pyridin-8-yl)amino]methyl]-3-methylphenol Chemical compound C=1C=CN2C(C)=C(C)N=C2C=1NCC1=C(C)C=CC=C1O DWRFPUBLHDHDFZ-UHFFFAOYSA-N 0.000 description 3
- 230000036912 Bioavailability Effects 0.000 description 3
- 210000004369 Blood Anatomy 0.000 description 3
- 210000004051 Gastric Juice Anatomy 0.000 description 3
- 229940083599 Sodium Iodide Drugs 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N Sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 210000002784 Stomach Anatomy 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000035514 bioavailability Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 230000001264 neutralization Effects 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- ZFDBHFFKSQCNML-UHFFFAOYSA-N (2,6-dimethylphenyl)methanamine Chemical compound CC1=CC=CC(C)=C1CN ZFDBHFFKSQCNML-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RTUABNJRTRJMMS-UHFFFAOYSA-N 2,3-dimethylimidazo[1,2-a]pyridin-8-amine Chemical compound NC1=CC=CN2C(C)=C(C)N=C21 RTUABNJRTRJMMS-UHFFFAOYSA-N 0.000 description 2
- QOJQBWSZHCKOLL-UHFFFAOYSA-N 2,6-dimethylbenzaldehyde Chemical compound CC1=CC=CC(C)=C1C=O QOJQBWSZHCKOLL-UHFFFAOYSA-N 0.000 description 2
- QRQATCDZCSIOKN-UHFFFAOYSA-N 2-(2-bromo-3-methylphenyl)ethanol Chemical compound CC1=CC=CC(CCO)=C1Br QRQATCDZCSIOKN-UHFFFAOYSA-N 0.000 description 2
- BLOFOEVKGQMZRO-UHFFFAOYSA-N 2-(chloromethyl)-N-[(2,6-dimethylphenyl)methyl]-3-methylimidazo[1,2-a]pyridin-8-amine Chemical compound C=1C=CN2C(C)=C(CCl)N=C2C=1NCC1=C(C)C=CC=C1C BLOFOEVKGQMZRO-UHFFFAOYSA-N 0.000 description 2
- AOYGBFKVFMLSNA-UHFFFAOYSA-N 2-[[(2,3-dimethylimidazo[1,2-a]pyridin-8-yl)amino]methyl]-3-methylbenzoic acid Chemical compound C=1C=CN2C(C)=C(C)N=C2C=1NCC1=C(C)C=CC=C1C(O)=O AOYGBFKVFMLSNA-UHFFFAOYSA-N 0.000 description 2
- OAMPZQBTXRQKCX-UHFFFAOYSA-N 2-bromo-1-(bromomethyl)-3-methylbenzene Chemical compound CC1=CC=CC(CBr)=C1Br OAMPZQBTXRQKCX-UHFFFAOYSA-N 0.000 description 2
- HWXOHKGATNULJP-UHFFFAOYSA-N 3-(3-methoxyphenyl)-3-oxopropanenitrile Chemical compound COC1=CC=CC(C(=O)CC#N)=C1 HWXOHKGATNULJP-UHFFFAOYSA-N 0.000 description 2
- BNBOUFHCTIFWHN-UHFFFAOYSA-N 3-bromobutan-2-one Chemical compound CC(Br)C(C)=O BNBOUFHCTIFWHN-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-Hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- AITFREYTVOPXOT-UHFFFAOYSA-N 5-methylpyridine-2,3-diamine Chemical compound CC1=CN=C(N)C(N)=C1 AITFREYTVOPXOT-UHFFFAOYSA-N 0.000 description 2
- 230000035533 AUC Effects 0.000 description 2
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- 239000003929 acidic solution Substances 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001262 anti-secretory Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 150000001621 bismuth Chemical class 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- MGLUJXPJRXTKJM-UHFFFAOYSA-L bismuth subcarbonate Chemical compound O=[Bi]OC(=O)O[Bi]=O MGLUJXPJRXTKJM-UHFFFAOYSA-L 0.000 description 1
- 229940036358 bismuth subcarbonate Drugs 0.000 description 1
- 229960004645 bismuth subcitrate Drugs 0.000 description 1
- 229960001482 bismuth subnitrate Drugs 0.000 description 1
- 229960000782 bismuth subsalicylate Drugs 0.000 description 1
- MMJQTYCCEVUELA-UHFFFAOYSA-L bismuth;tripotassium;3-carboxy-3,5-dihydroxy-5-oxopentanoate;3-carboxy-5-hydroxy-3-oxido-5-oxopentanoate Chemical compound [K+].[K+].[K+].[Bi+3].OC(=O)CC(O)(C(O)=O)CC([O-])=O.OC(=O)CC([O-])(C(O)=O)CC([O-])=O MMJQTYCCEVUELA-UHFFFAOYSA-L 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- 101700043453 chch-3 Proteins 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- LVQSCKUKDKAQGO-UHFFFAOYSA-L disodium;diiodide Chemical compound [Na+].[Na+].[I-].[I-] LVQSCKUKDKAQGO-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- WOKCGWMTWRJHQQ-UHFFFAOYSA-N ethyl 2-(bromomethyl)-3-methylbenzoate Chemical compound CCOC(=O)C1=CC=CC(C)=C1CBr WOKCGWMTWRJHQQ-UHFFFAOYSA-N 0.000 description 1
- OXUBOOPFXQOMBI-UHFFFAOYSA-N ethyl 2-bromo-2-phenylpropanoate Chemical compound CCOC(=O)C(C)(Br)C1=CC=CC=C1 OXUBOOPFXQOMBI-UHFFFAOYSA-N 0.000 description 1
- SIOIQIWIQSMQAG-UHFFFAOYSA-N ethyl 3-bromo-2-oxobutanoate Chemical compound CCOC(=O)C(=O)C(C)Br SIOIQIWIQSMQAG-UHFFFAOYSA-N 0.000 description 1
- XDBJEOGPNQHGBZ-UHFFFAOYSA-N ethyl 8-[(2,6-dimethylphenyl)methylamino]-2-methylimidazo[1,2-a]pyridine-3-carboxylate Chemical compound C=1C=CN2C(C(=O)OCC)=C(C)N=C2C=1NCC1=C(C)C=CC=C1C XDBJEOGPNQHGBZ-UHFFFAOYSA-N 0.000 description 1
- KANUDPSCIATZHX-UHFFFAOYSA-N ethyl 8-[(4-fluoro-2,6-dimethylphenyl)methylamino]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Chemical compound C=1C(C)=CN2C(C(=O)OCC)=C(C)N=C2C=1NCC1=C(C)C=C(F)C=C1C KANUDPSCIATZHX-UHFFFAOYSA-N 0.000 description 1
- JCYLOXBHTIKQGL-UHFFFAOYSA-N ethyl 8-amino-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Chemical compound NC1=CC(C)=CN2C(C(=O)OCC)=C(C)N=C21 JCYLOXBHTIKQGL-UHFFFAOYSA-N 0.000 description 1
- XYNZTHJQYHLLSN-UHFFFAOYSA-N ethyl 8-amino-3-methylimidazo[1,2-a]pyridine-2-carboxylate Chemical compound NC1=CC=CN2C(C)=C(C(=O)OCC)N=C21 XYNZTHJQYHLLSN-UHFFFAOYSA-N 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GQKZBCPTCWJTAS-UHFFFAOYSA-N methoxymethylbenzene Chemical compound COCC1=CC=CC=C1 GQKZBCPTCWJTAS-UHFFFAOYSA-N 0.000 description 1
- WYCCMONJHRCNJY-UHFFFAOYSA-N methyl N-[3-methyl-2-[[(2,3,5,6-tetramethylimidazo[1,2-a]pyridin-8-yl)amino]methyl]phenyl]carbamate Chemical compound COC(=O)NC1=CC=CC(C)=C1CNC1=CC(C)=C(C)N2C1=NC(C)=C2C WYCCMONJHRCNJY-UHFFFAOYSA-N 0.000 description 1
- YPNJHWASWDIHAM-UHFFFAOYSA-N methyl N-[[2-[[(2,3-dimethylimidazo[1,2-a]pyridin-8-yl)amino]methyl]-3-methylphenyl]methyl]carbamate Chemical compound COC(=O)NCC1=CC=CC(C)=C1CNC1=CC=CN2C1=NC(C)=C2C YPNJHWASWDIHAM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960000444 pentagastrin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000002980 postoperative Effects 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 1
- CKVKLEFDNAHFMO-UHFFFAOYSA-N sodium;bis(2-methoxyethoxy)alumanide Chemical compound [Na+].COCCO[Al-]OCCOC CKVKLEFDNAHFMO-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
- 239000008107 starch Chemical class 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- RXMRGBVLCSYIBO-UHFFFAOYSA-M tetramethylazanium;iodide Chemical compound [I-].C[N+](C)(C)C RXMRGBVLCSYIBO-UHFFFAOYSA-M 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
Abstract
The present invention relates to novel compounds, and therapeutically acceptable salts thereof of formula (I), which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.
Description
SUBSTITUTE IMIDAZOPIRIDINE DERIVATIVES, PROCESS FOR PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND USING THEM FOR THE MANUFACTURE OF A MEDICINAL PRODUCT
TECHNICAL FIELD The present invention relates to new therapeutically acceptable compounds and salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and, thus,
can be used in the prevention and treatment of gastrointestinal inflammatory diseases. In other aspects, the present invention relates to the compounds of the invention for use in therapy; to processes for the preparation of such new compounds; to compositions
Pharmaceuticals containing at least one compound of the present invention or a therapeutically acceptable salt thereof, as an active ingredient; and to the use of the active compounds in the manufacture of medicaments for the aforementioned medical use. BACKGROUND OF THE INVENTION Substituted imidazo [1, 2-a] -pyridines useful in the treatment of peptic ulcers are known in the art, e.g. European Patent EP-B-0033094 and US Patent 4,450-164 (Schering Corporation);
by the European Patent EP EP-B-0204285 and the Patent Ref: 127103
North American US, 4725.601 (Fujisawa Pharmaceutical Co.); by International Patent Applications WO 9418199 and WO 9510518 (Byk Gulden Lomberg Chem.) and by the publications of J. J. Kaminski et al. in Jorunal of Medical Chemistry (vol.28, 876-892, 1985; vol.30, 2031-2046, 1987; vol.30, 2047-2051, 1987; vol.32, 1686-1700, 1989; and vol.34). , 533-541, 1991). To review the pharmacology of the gastric acid pump (H +, K + -ATPase), see Sachs et al. , (1995) Annu. Rev. Pharmacol. Toxicol 35: 277: 305 DESCRIPTION OF THE INVENTION Surprisingly it was found that the compounds of formula I which are substituted imidazopyridine derivatives, are effective as inhibitors of H +, K + -ATPase and therefore inhibitors of gastric acid secretion. Thus, in one aspect, the present invention relates to compounds of the general formula I:
or a pharmaceutically acceptable salt thereof, (wherein all symbols are as previously defined) R1 is
(a) H, (b) alkyl of 1 to 6 carbon atoms, (c) alkenyl of 1 to 6 carbon atoms, (d) CH2OH, 5 (e) halogen, or (f) thiocyano R2 is (a) alkyl of 1 to 6 carbon atoms, (b) hydroxyalkyl, 10 (c) alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (d) hydroxy-alkoxy of 1 to 6 carbon atoms- alkyl of 1 to 6 carbon atoms, (e) alkylthio of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (f) cyanoalkyl of 1 to 6 carbon atoms, (g) alkyl of 1 to 6 halogenated carbon atoms, or (h) aminocarbonyl-alkyl of 1 to 6 carbon atoms RJ is (a) H, (b) alkoxy of 1 to 6 carbon atoms, (c) alkyl of 1 to 6 carbon atoms carbon, 25 (d) halogen,
s & j? z¿í-¿® r * & amp; ace. ^ j ^^^^^ * ^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 1 to 6 carbon atoms, (f) hydroxyalkoxy of 1 to 6 carbon atoms, (g) alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (h) alkoxy of 1 to 6 carbon atoms carbon-alkoxy of 1 to 6 carbon atoms, (i) alkoxycarbonyl of 1 to 6 carbon atoms, (j) alkanoyl of 1 to 6 carbon atoms, (k) alkyl of 1 carbon atoms halogenated, (1) N02 (m) CN, (n) sulfonyl of 1 to 6 carbon atoms, (o) sulfinyl of 1 to 6 carbon atoms, (P) alkylthio of 1 to 6 carbon atoms, (q) alkylaminosulfonyl of 1 to 6 atoms carbon, (r) (C 6 -alkyl) -amino-sulfonyl, (a) -sulfonyl, (t) alkylsulfonylamino of 1 to 6 carbon atoms, (u) (alkylsulfonyl of 1 to 6 carbon atoms) 2amino, (v) ) trifluoromethylsulfonylamino,
(x) alkylcarbonylamino of 1 to 6 carbon atoms, (y) alkoxycarbonylamino of 1 to 6 carbon atoms, or (z) aminocarbonylamino of 1 to 6 carbon atoms, optionally substituted with one or two alkyl groups of 1 to 6 atoms of carbon, R 4 is (a) H 0 (b) alkyl of 1 to 6 carbon atoms, (c) alkyl of 1 to 6 carbon atoms halogenated, (d) alkoxy of 1 to 6 carbon atoms, or (e) ) halogen, 5 Ar is a phenyl, thienyl, furanyl, naphthyl or pyridyl group substituted with R5, R6 and / or R7, X is
".0. OrW? H. R5 is 0 (a) H, (b) alkyl of 1 to 6 carbon atoms, (c) alkoxy of 1 to 6 carbon atoms, (d) hydroxy,
? jjfc8 * ». fc ». ^. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ g ^^^^^^^^^^^^^^^^ ^^^^^^^ (e) hydroxyalkyl of 1 to 6 carbon atoms, (f) hydroxyalkoxy of 1 to 6 carbon atoms, (g) alkyl of 1 to 6 carbon atoms halogenated, (h) alkoxy of 1 to 6 halogenated carbon atoms, (i) alkoxy of 1 to 6 carbon atoms-alkyl of
1 to 6 carbon atoms, (j) halogen, 10 (k) hydroxy-alkoxy of 1 to 6 carbon atoms- alkyl of 1 to 6 carbon atoms, (1) CN (m) alkoxycarbonyl of 1 to 6 carbon atoms carbon, (n) alkoxycarbonyloxy of 1 to 6 atoms
Carbon, (o) alkylsulfonyloxy of 1 to carbon atoms, (p) trifluoromethylsulfonyloxy, (q) acyloxy of 1 to 6 carbon atoms-alkyl
from 1 to 6 carbon atoms, (r) (C 1-6 alkylsulfonyl- C 1-6 -alkyl, C 1-6 -alkylsulphinyl- C 1-6 -alkyl) carbon,
j ^ | ^ ^ aate * aa-aL ^ - ^^^^ * »« ggisá ||||| É ^^^ rf ^^^ y ^ »! ^^ g¡j¡j ^ j¡¡ ^ ^^ (t) alkylthio of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (u) alkoxycarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (v) aryl, ( x) aminoalkyl of 1 to 6 carbon atoms, (y) NHC = OR12
(z) H or a group with alkyl of 1 to 4 carbon atoms
\ / (aa) H or a group I --- substituted with an alkyl of 1 to 4 carbon atoms (ab) alkylsulfonylamino of 1 to 6 carbon atoms, Rb is (a) H (b) alkyl of 1 to 6 carbon atoms, (c) halogen (d) hydroxyalkyl of 1 to 6 carbon atoms, (e) alkyl of 1 to 6 carbon atoms halogenated, (f) alkoxy of 1 to 6 carbon atoms halogenated, (e) alkoxy from 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or (f) CN
R7 is (a) H (b) alkyl of 1 to 6 carbon atoms, (c) alkoxy of 1 to 6 carbon atoms, (d) halogen, (e) N02 (f) alkyl of 1 to 6 halogen atoms (g) alkoxy of 1 to 6 carbon atoms halogenated, (h) aryloxy, or (i) CN R8 is (a) H or (b) alkyl of 1 to 6 carbon atoms R1- is (a) alkoxy of 1 to 6 carbon atoms, (b) alkoxy of 1 to 6 carbon atoms-alkoxy of 2 to 4 carbon atoms, (c) Nñ, (d) hydroxyalkoxy of 2 to 4 carbon atoms, (e) alkylcarbonyloxy of 1 to 6 carbon atoms-alkoxy of 2 to 4 carbon atoms, (f) alkoxy of 2 to 4 carbon atoms halogenated,
(g) alkyl of 1 to 4 carbon atoms halogenated, (h) hydroxyalkyl of 1 to 4 carbon atoms, (i) alkylcarbonyloxy of 1 to 6 carbon atoms-alkyl of 1 to 4 carbon atoms, (j) aryl, (k) aryl-alkyl of 1 to 4 carbon atoms, (1) sulfañil of 1 to 4 carbon atoms-alkoxy of 2 to 4 carbon atoms, 10 (m) sulfinil of 1 to 4 carbon atoms- alkoxy of 2 to 4 carbon atoms, or (n) sulfonyl of 1 to 4 carbon atoms-alkoxy of 2 to 4 carbon atoms, R ° and R6 are in the ortho positions with relation 15 to XR 'is in the position or in the position para, in relation to X R5 and R8 together can they form a 5- or 6-membered ring substituted with hydroxy- or alkoxy- groups, provided that one of R3 and R4? H or halogen, also provided that at least one of R5, R6 and R7? H
* ^ - ^ - ^^^^^ - ^ - ^^^^^^^^^ - - < > - > - - J ^ as * ^^ also provided that when R5 = (y) (z), (aa) or (ab), then one of R3 and R4? H also provided that when R1 = H or Cl, XAr? OCH2Ar also provided that when R1 = H, halogen or CH2OH, at least one of R5 and R6 is alkyl of 1 to 6 carbon atoms also provided that when R2 is CH2OH or CH2CN, at least one of R5 is and R6 is alkyl of 1 to 6 carbon atoms. The term "aryl" as used herein, includes phenyl, naphthyl, thienyl, furyl, pyridyl or imidazolyl groups, optionally substituted with 1 to 3 substituents that are selected from the group consisting of H, alkyl of 1 to 6 atoms of carbon, alkoxy of 1 to 6 carbon atoms, halogen or CF3. As used herein, the term "alkyl of 1 to 6 carbon atoms" denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of alkyl groups of 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and straight and branched chain pentyl and hexyl groups.
The term "halogen" as used herein, includes fluoro, chloro, bromo and iodo groups. The term "pyridyl" as used herein includes the 2-, 3- and 4- isomers and the terms "thienyl" and "furanyl" include the 2- and 3- isomers. Both the pure enantiomers, racemic mixtures and unequal mixtures of the two enantiomers are within the scope of the present invention. It should be understood that all possible diastereomeric forms (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the present invention. Also included in the invention are derivatives of the compounds of the formula I having the biological function of the compounds of formula I. Depending on the process conditions and the final products of the formula I, they are obtained either in Neutral form or in the form of a salt. Both the free base and the salts of these final products are within the scope of the present invention. The acid addition salts of the new compounds, in a manner known per se, can be transformed into the free base using basic agents such as alkalis, or by ion exchange. Base
Free obtained can also form salts with organic or inorganic acids. In the preparation of the acid addition salts, acids are preferably used in such a way that they form therapeutically acceptable salts. Examples of such acids include the hydrohalic acids such as hydrochloric acid; sulfuric acid, phosphoric acid, nitric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxyleleic acid, acid pyruvic, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethane sulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid. Preferred compounds according to the present invention are those of the formula I (wherein all the symbols are as previously defined) R1 is H, CH3, CHOH; R2 is CH3, CHCH3, CH2CH2OH, CH2CH2SCH3, CH2CH2OCH3 or
^^ ¿jj ^^^^ tt ^^^^^ ~ ° * "» »> * ~ * ** - R3 is H, CH3, CH2CH3, F, Cl, Br, OCH3, OCH2CH3, CH2OH, CH2CH2OH, OCH2CH2OH, CH2CH2OCH3, OCH2CH2OCH3, C = OOCH3, C = OOCH2CH3, C = OCH3, C = OCH2CH3, C = OCH (CH3) 2 or C = OCH2CH2CH3, R4 is H, CH3, CH2CH3, F, Cl, Br, OCH3 or OCH2CH3; Ar is phenyl, thienyl, furyl or naphthyl;
R5 is H, CH3, CH2CH3, OCH3, OH, CH2OH, CH2OCH3, CH2CH2OH, CH2CH2OCH3, OCH2CH2OH, OC = OOCH3, OC = OCH2CH3, OCHF2, OCF3, F, Cl, Br, CN, phenyl, CH2CH2OC = OCH3, CH2NHC = OOCH3 or 10 CH2NHC = OOCH2CH3; R6 is H, CH3, CH2CH3, CF3, OCF3, OCF2H, F, Cl, Br, or CH2OCH3; R7 is H, F, Cl, Br, OCF2H or OCF3; The most preferred compounds according to the present invention are those of the formula I wherein R1 is H, CH3 or CH2OH; R2 is CH3, CH2CH3, CH2OH, CH2SCH3, CH2OCH3 or CH2CN 20 R3 is H, CH3, CH2CH3, OCH3, OCH3, CH2OH, C = OOCH3,
C = OOCH2CH3, C = OCH3, C = OCH2CH3; or C = OCH2CH2CH3; R4 is H or CH3; Ar is phenyl, thienyl or furyl;
^^ u ^^ A ** .. ^^^^ ..- .. ^ ¡, .. ^ .... ^, -._ ^, - .. ^. ^, ..._ ". ^ tJa ^ BCÍ ^ dfaLjj? tfi ^ aMtoa ^^ R5 is H, CH3, CH2CH3, OCH3, OH, CH2OH, CH20CH3, CH2CH2OH, CH2CH2OCH3, OCH2CH2OH, OC = OOCH3, OC = OCH2CH3, OCHF2, OCF3, F, Cl, Br, CN, CH2CH2OC = OCH3, CH2NHC = OOCH3, or CH2NHC = OOCH2CH3; R6 is H, CH3, CH2CH3, CF3, OCF3, OCF2H, F, Cl, Br, or
CH2OCH3; R7 is H, F, Cl, Br, OCF2H, OCF3; R8 is H or CH3. Preparation The present invention also provides the following processes A, B, C, D, E for the manufacture of compounds of the general formula I. Process A The process A for the manufacture of the compounds of the general formula I, comprises the following steps: Compounds of the general formula II R '
wherein X1 is NH2 or OH and R1, R2, R3 and R4 are as defined for formula I, they can be reacted with compounds of general formula III
Ar where "Ar" is as defined for formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy, to obtain the compounds of formula I. It is convenient to carry out this reaction in an inert solvent, e.g. acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide, with or without a base. The base is, e.g. an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide; an alkali metal carbonate such as potassium carbonate and sodium carbonate; or an organic amine such as triethylamine. Process B The process B for the manufacture of the compounds of the general formula I wherein X is NH, comprises the following steps: Compounds of the general formula IV
- ^ ^ ^ a en en en en en R1, R2, R3 and R4 are as defined for formula I, they can be reacted with compounds of general formula V
wherein "Ar" is as defined for formula I, in the presence of a Lewis acid, e.g. zinc chloride, to obtain the compounds of the formula VI
where R1, R2, RJ, R4 and Ar are as defined for the
Formula I, after which the compounds of the general formula VI are subjected to a reduction, e.g. using sodium borohydride or sodium cyanoborohydride, to obtain the compounds of the general formula I wherein X is NH. The reactions can be carried out under the
Standard conditions in an inert solvent, e.g. methanol or ethanol. Process C The process C for the manufacture of the compounds of the general formula I wherein R 1 is CH 2 OH or H, comprises
the following steps:
Compounds of the general formula VII
wherein X1 is NH2 or OH, R2, R3 and R4 are as defined in formula I, they can be reacted with compounds of formula III
(("i) Ar wherein Ar is as defined for formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy group, to obtain compounds of formula VIII
wherein R2, R3, R4, Ar and X are as defined for formula I. It is convenient to carry out this reaction in an inert solvent, e.g. acetone, acetonitrile, dimethoxyethane, methanol, ethanol or N, N-dimethylformamide, with or without a base. The base is, e.g. an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine. The reduction of the compounds of the general formula VIII, e.g. using lithium aluminum hydride in tetrahydrofuran or ether, produces the compounds of the general formula I wherein R1 is CH2OH. Hydrolysis of the compounds of the formula VIII, e.g. using a base such as sodium hydroxide 10 or an acid such as hydrochloric acid and subsequently a decarboxylation in an inert solvent such as diphenyl ether, produces the compounds of the formula I wherein R 1 is H. Process D 15 The process D for the manufacture of the compounds of the general formula I wherein R1 is CH2OH and X is NH, comprises the following steps: Compounds of the formula IX
NH-20 wherein R2, RJ and R4 are as defined for formula I, can be reacted with compounds of general formula V
T (V) Ar wherein Ar is as defined for formula I, in the presence of a Lewis acid, e.g. zinc chloride, to obtain the compounds of the formula X
wherein R2, R3, R4, and Ar are as defined for formula I, after which the compounds of general formula X are subjected to a reduction, e.g. using sodium borohydride or sodium cyanoborohydride, to obtain the compounds of the general formula XI
r wherein R2, R3, R4 and Ar are as defined for formula I. Reactions may be carried out under standard conditions in an inert solvent, e.g. 15 methanol or ethanol. The reduction of the compounds of the general formula XI, e.g. using lithium aluminum hydride in
tetrahydrofuran or ether, produces the compounds of the general formula I wherein Rx is CH2OH and X is NH. Hydrolysis of the compounds of formula XI, e.g. using a base such as sodium hydroxide or an acid such as hydrochloric acid, and after a decarboxylation in an inert solvent such as diphenylether, produces the compounds of the formula I wherein R1 is H. Process E 10 The condensation of the compounds of the general formula XII
wherein R, R and Ar are as defined for formula I, with α-halocarbonyl intermediates of the general formula R 2 COCH (Z) R 1, wherein Z is a leaving group Br or Cl, in an inert solvent such as acetonitrile or ethanol, results in the formation of compounds of the general formula XIII, wherein R2, R3, R4 and Ar are as defined for formula I
Medical Use In a further aspect, the present invention relates to compounds of the formula I for use in therapy, particularly for use against gastrointestinal inflammatory diseases. The present invention also provides the use of a compound of the general formula I in the manufacture of a medicament for the inhibition of gastric acid secretion or for the treatment of gastrointestinal inflammatory diseases. The compounds according to the present invention, therefore, can be used for the prevention and treatment of gastrointestinal inflammatory diseases and diseases related to gastric acid, in mammals, including humans, such as gastritis, gastric ulcer, duodenal ulcer, esophageal reflux and Zollinger-Ellison syndrome. In addition, the compounds can be used for the treatment of other gastrointestinal disorders wherein the antisecretory effect of gastric acid is desirable, e.g. in
^^^^^^^ & ^^^^^^. ^ g * ^? GÉfa patients with gastrinomas and in patients with acute upper gastrointestinal hemorrhage. They can also be used in patients who are in intensive care and in the preoperative and postoperative period, to prevent aspiration of acid and stress ulcerations. The typical daily dose of the active substance varies within a wide range and will depend on various factors such as, for example, the individual requirements of each patient, the route of administration and the disease. In general, oral and parenteral doses will be within the range of 5 to 1000 mg per day of the active substance. Pharmaceutical Formulations In a further aspect, the present invention relates to pharmaceutical compositions containing at least one compound of the present invention or a therapeutically acceptable salt thereof as an active ingredient. The compounds according to the present invention can also be used in formulations together with other active ingredients, e.g. antibiotics such as amoxicillin. For clinical use, the compounds of the present invention are prepared in pharmaceutical formulations for
^ «A ^. . * -.... * ^ &3ts * s &&? &- > e3 > > > - * ^^ j ^? iíz ^^? ^ .. i? i ^ it! a ^ k ^.
oral, rectal, parenteral or other administration route. The pharmaceutical formulation contains a compound of the present invention in combination with one or more pharmaceutically acceptable ingredients. The vehicle can be in the form of a solid, semi-solid or liquid, or a capsule. These pharmaceutical preparations are another object of the present invention. Normally the amount of active compounds is between 0.1 and 95% by weight of the preparation, preferably between 0.1 and 20% by weight of the preparation for parenteral administration and preferably between 0.1 and 50% by weight in preparations for oral administration. In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration, the selected compound can be mixed with solid powder ingredients such as lactose., sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin or other suitable ingredient, as well as disintegrating and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. Then the mixture is processed to obtain granules or compressed into tablets. Soft gelatin capsules can be prepared with capsules containing a mixture of the compound or
Active compounds of the present invention, vegetable oil, fat or any other suitable vehicle for soft gelatine capsules. Hard gelatin capsules may contain granules of the active compound. Hard gelatin capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration can be prepared (i) in the form of suppositories containing the active substance mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance mixed with a vegetable oil, paraffin oil or any other suitable vehicle for rectal gelatin capsules; (iii) in the form of a ready-to-use microenema; or (iv) in the form of a dehydrated microenema to be reconstituted in a suitable solvent just before its administration. Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.1 to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring, flavoring, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations for oral administration can also be prepared in the form of dehydrated powders to be reconstituted with a suitable solvent before use. Solutions for parenteral administration can be prepared as a solution of a compound of the present invention in a pharmaceutically acceptable solvent, preferably in a concentration of 0.1 to 10% by weight. These solutions may also contain stabilizing ingredients and / or ingredients to regulate the pH and are divided into dosage units in the form of ampoules or flasks. Solutions for parenteral administration can also be prepared as dehydrated preparations to be reconstituted with a suitable solvent, extemporaneously before use. The compounds according to the present invention can also be used in formulations together with other active ingredients, e.g. for the treatment or prophylaxis of disorders including Helicobacter pylori infections of the human gastric mucosa. These other active ingredients can be antimicrobial agents, in particular:
ß-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime; • macrolides such as erythromycin or clarithromycin; • tetracyclines such as tetracycline or doxycycline; • aminoglycosides such as gentamicin, kanamycin or amikacin; • quinolones such as norfloxacin, ciprofloxacin or enoxacin; • others such as metronidazole, nitrofurantoin or chloramphenicol; or • preparations containing bismuth salts such as bismuth subcitrate; bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgalate. EXAMPLES 1. PREPARATION OF THE COMPOUNDS OF THE PRESENT INVENTION
Example 1 . 1 Synthesis of 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -6-methoximidazo [1,2-a] -pyridine A mixture of 8-amino-6-methoxy-2,3-imidazo [ 1, 2- a] pyridine (0.4 g, 2.09 mmol), 2,6-dimethylbenzyl chloride (0.32 g, 2.07 mmol), sodium carbonate (0.4
g), potassium iodide (0.2 g) and acetonitrile (5 ml) was refluxed for 5 hours. The solvent was evaporated and the residue was purified by chromatography (methylene chloride / ethyl acetate, 70:30) to obtain 250 mg 5 (39%) of the desired product. Examples 1.2-1.6, 1.9-1.16, 1.18-1.28, 1.30-1.40, 1.48-1.50 and 1.78-1.79 were prepared in accordance with Example 1. Example 1. 2 10 Synthesis of 2, 3-dimethyl-8- (2,6-dimethylbenzylamino) -6-nor troimidazo [1,2-a] pyridine Yield: 86% 1H-PMN (300 MHz, CDC13): d 2.3 (s 3H), 2.35 ( s, 6H), 2.45 (s, 3H), 4.4 (d, 2H), 5.05 (bs, 1H), 6.9 (s, 1H), 15 7.05-7.15 (m, 3H), 8.4 (s, 1H). Example 1 . 3 Synthesis of 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -6-trifluoromethylimidazo [1,2-a] pyridine Yield: 81% H NMR (300 MHz, CDC13): d 2.35 (s, 3H), 2.38 (s, 6H), 2.4 (s, 3H), 4.3 (d, 2H), 4.95 (bs, 1H), 6.25 (s, 1H), 6.75 (d, 2H), 7.6 (s, 1H) ). Example 1 . 4 Synthesis of 8- (2,6-dimethylbenzylamino) -2,3, 5-
trimethylimidazo [1,2-a] pyridine Yield 52%? E NMR (300 MHz, CDC13): d 2.3 (s, 3H), 2.4 (6H), 2.65 (s, 3H), 2.75 (s, 3H), 4.3 (d, 2H), 4.65 (bs, 1H), 6.05 (d, 1H), 6.3 (d, 1H), 6.95-7.15 (m, 3H). Ex empl o 1.5 Synthesis of 8- (2-methylbenzylamino) -2,3,6-trimethylimidazo [1,2-a] pyridine Yield: 60%? E NMR (300 MHz, CDC13): d 2.25 (s, 3H) , 3.32 (s,
3H), 2.36 (s, 3H), 2.38 (s, 3H), 4.38 (d, 2H), 5.20 (t, 1H), 5.93 (s, 1H), 7.02 (s, 1H), 7.17-7.33 (m , 4H). Example 1.6 Synthesis of 8- (2,6-dimethylbenzylamino) -2,3-dimethyl imidazo [1,2-a] pyridine-6-carboxylic acid yield: 37% XH NMR (300 MHz, CDC13): d 1.45 (t, 3H), 2.35 (s, 3H), 2.4 (s, 6H), 2.45 (s, 3H), 4.4-4.5 (m, 4H), 4.85 (bs, 1H), 6.75 (s, 1H) , 7.05-7.15 (m, 3H), 8.05 (s, 1H). Example 1.7 Synthesis of 8- (4-methoxy-2,6-dimethylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine 8-amino-2,3-dimethylimidazo [1,2-a] pyridine was dissolved (0.5 g, 3.1 mmol), 4-methoxy-2,6-dimethylbenzaldehyde (0.51 g, 3.11 mmol) in methanol (10 mL), after which zinc chloride (0.51 g, 3.82 mmol) dissolved in methanol was added. (5 ml). Sodium cyanoborohydride was added in portions and the mixture was refluxed for 3 hours under a nitrogen atmosphere. The mixture was stirred at a temperature of 0 to 5 ° C and 1M sodium hydroxide (20 ml) was added. After extracting with 2 x 50 ml of methylene chloride, the organic phases were combined and the combined was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel (dichloromethane / ethyl acetate, 1: 1), obtaining 0.58 g, 60%, of the title compound. X H NMR (300 MHz, CDCl 3): d 2.35 (s, 12 H), 3.79 (s, 3 H), 4.27 (d, 2 H), 4.75 (t, 1 H), 6.19 (d, 1 H), 6.59 (s, 2 H) ), 6.69-6.75 (m, 1H), 7.24 (d, 1H). Examples 1.8, 1.17 and 1.41-1.45 were prepared according to Example 7. Ex empl o 1.8 Synthesis of 8- [(2,6-bismethoxymethyl) -benzylamino)] - 2,3,6-trimethylimidazo [1, 2 -a] pyridine Yield: 54% XH NMR (300 MHz, CDC13): d 2.25 (s, 3H), 2.3 (s, 6H), 3.35 (s, 6H), 4.45 (d, 2H), 4.5 (s, 4H), 4.95 (bs, 1H), 6.15 (s, 1H), 7.0 (s, 1H), 7.2-7.35 (, 3H). Examples 1.9-1.28 were prepared according to Example 1.1 Example 1.9 Synthesis of 8- (2,6-dimethylbenzylamino) -3-fluoro-2-methylimidazo [1, 2-a] pyridine Yield: 33% XH NMR (300 MHz, CDC13): d 2.3 (s, 3H), 2.35 (s, 6H), 4.3 (d, 2H), 4.8 (bs, 1H), 6.15 (d, 1H), 6.7 (t, 1H), 6.95- 7.15 (m, 3H), 7.25 (d, 1H). Example 1.10 Synthesis of 3-chloro-8- (2,6-dimethylbenzylamino) -2-methylimidazo [1,2-a] pyridine Yield: 0.6% H NMR (300 MHz, CDC13): d 2.4 (s, 6H), 2.45 (s, 3H), 4.35 (d, 2H), 4.8 (bs, 1H), 6.3 (d, 1H), 6.8 (t, 1H), 7.05-7.15 (m, 3H), 7.5 (d, 1H) . Example 1.11 Synthesis of 2,3-dimethyl-8- (2-phenylbenzylamino) -imidazo [1,2-a] pyridine Yield: 15% XH NMR (300 MHz, CDC13): d 2.35 (s, 3H), 2.4 (s, 3H), 4.35 (d, 2H), 5.35 (t, 1H), 5.85 (d, 1H), 6.55 (t, 1H), 7.20 (d, 1H), 7.25-7.4 (m, 8H) 7.55 (m, 1H).
Example 1.12 Synthesis of 2,3-dimethyl -8 - [(2,4-dimethyl-3-f-uryl) methylamino] -imidazo [1,2-a] pyridine Yield: 4% XH NMR (300 MHz, CDC13) : d 1.95 (s, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.4 (s, 3H), 4.1 (d, 2H), 4.9 (bs, 1H), 6.15 (d, 1H) , 6.7 (t, 1H), 7.05 (s, 1H), 7.25 (d, 1H). Ex empl o 1.13 Synthesis of 2,3-dimethyl-8 - [(2-methyl-1-naphthyl) -methylamino] -imidazo [1,2-a] pyridine hydrochloride Yield: 24% XH NMR (300 MHz, DMSO): d 2.35 (s, 3H), 2.45 (s, 3H), 2.6 (s, 3H), 4.8 (d, 2H), 6.6 (bs, 1H), 7.15 (d, 1H), 7.35-7.55 ( m, 4H), 7.8-8.1 (m, 4H). EXAMPLE 1.14 Synthesis of 8- [(1-bromo-2-naphyl) -methylamino] -2,3-dimethylimidazo [1,2-a] pyridine Yield: 21% XH NMR (300 MHz, CDCl 3): d 2.3 (s, 3H), 2.4 (s, 20 3H), 4.8 (d, 2H), 5.8 (t, 1H), 5.95 (d, 1H), 6.55 (t, 1H), 7.2 (d, 1H) , 7.45-7.6 (m, 3H), 7.68 (d, 1H), 7.77 (d, 1H), 8.33 (d, 1H). Ex empl o 1.15 Synthesis of 8- (2-ethoxycarbonyl-6-
methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a] pyridine Yield: 5%? E NMR (300 MHz, CDC13): d 1.25 (t, 3H), 2.35 (s, 6H), 2.45 (s, 3H ), 4.25 (q, 2H), 4.55 (d, 2H), 5.1 (bs, 5 1H), 6.2 (d, 1H), 6.7 (t, 1H), 7.2-7.35 (m, 3H), 7.65 (d) , 1 HOUR) . Example 1.16 Synthesis of 8- (2-methoxy-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine 10 Yield: 39% X H NMR (300 MHz, CDCl 3): d 2.35 (s, 6H), 2.4 (s, 3H), 3.8 (s, 3H), 4.4 (d, 2H), 4.9 (bs, 1H), 6.25 (d, 1H), 6.7-6.85 (m, 3H), 7.15 (d , 1H), 7.2 (d, 1H). Example 1.17 was prepared in accordance with Example 1.7 Example 1.17 Synthesis of 8- (2-methoxymethyl-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine Yield: 52% XH NMR (500 MHz, CDC13): d 2.34 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 3.36 (s, 3H), 4.40 (d, 2H), 4.50 (s, 2H), 4.86 (t, 1H), 6.24 (d, 1H), 6.71-6.74 (m, 1H), 7.15- 7.21 (m, 3H), 7.25 (d, 1H).
Example 1.18 Synthesis of 8- (2,6-dichlorobenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine Yield: 49% 5? E NMR (300 MHz, CDC13): d 2.35 (s, 3H), 2.4 (s, 3H), 4.7 (d, 2H), 5.2 (bs, 1H), 6.3 (d, 1H), 6.7 (t, 1H), 7.1-7.4 (m, 4H). Example 1.19 Synthesis of 8- (2,6-dibromobenzylamino) -2,3- 10 dimethylimidazo [1,2- a] pyridine Yield: 70% X H NMR (500 MHz, CDCl 3): d 2.45 (s, 3H), 2.48 (s, 3H), 4.7 (d, 2H), 5.15 (bs, 1H), 6.3 (d, 1H), 6.7 (t, 1H), 7.0 (t, 1H), 7.25 (d, 1H), 7.55 ( d, 2H). Example 1.20 Synthesis of 2,3-dimethyl-8- (2-trifluoromethoxybenzylamino) -imidazo [1, 2-a] pyridine hydrochloride Yield: 51% E NMR (300 MHz, CDC13): d 2.3 (s, 6H ), 2.4 (s, 20 6H), 4.55 (d, 2H), 5.7 (t, 1H), 5.95 (d, 1H), 6.5 (t, 1H), 7.1-7.3 (m, 4H), 7.45 (d) , 1 HOUR) . Example 1.21 Synthesis of 2,3-dimethyl-8- (2-fluoro-6-trifluoromethylbenzylamino) -imidazo [1,2-a] pyridine hydrochloride
S ^ gg? ^^^ ß ^^^^ ™ ÉÉ ^ S ^ ia ^^^^^^^^^^^^^^^^^^! ^ Gg¡g ^ g ^^^^^^ * Yield: 36% X H NMR (300 MHz, DMSO-d 6): d 2.4 (s, 3 H), 2.45 (s, 3 H), 4.55 (d, 2 H), 6.85 (bs, 1 H), 7.05 (d, 1 H) , 7.35 (t, 1H), 7.7 (bs, 3H), 8.0 (d, 1H). Example 1.22 Synthesis of 2- ([(2,3-dimet i 1 imidazo [1, 2-a] -pyrid? N-8-yl) amino] -methyl-phenylacetate methanesulfonate Yield: 58%? E NMR (600 Hz, CDC13): d 2.04 (s, 3H), 2.43 (s,
3H), 2.57 (s, 3H), 2.68 (s, 3H), 3.08 (t, 2H), 4.31 (t, 2H), 4.60 (s, 3H), 6.47 (d, 1H), 7.03-7.06 (m , 1H), 7.18-7.40 (m, 2H), 7.23-7.24 (m, 2H), 7.38-7.40 (m, 2H), 7.45 (bs, 1H), 14.64 (s, 1H). Example 1.23 Synthesis of 8- (2-ethylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine Yield: 36% X H NMR (300 MHz, CDCl 3): d 1.27 (t, 3H), 2.35 (s, 3H), 2.39 (s, 3H), 2.74 (q, 2H), 4.44 (d, 2H), 5.30 (t, 1H), 6.06 (d, 1H), 6.60-6.66 (m, 1H), 7.10-7.30 (m, 5H), 7.37 (d, 1H). Example 1.24 Synthesis of 8- [[1- (2,6-dimethylphenyl) -ethylamino] -
< * ^ ii ~ S ~ ..i 2, 3-dimethylimidazo [1,2-a] pyridine Yield: 16% Tr, NMR (300 MHz, CDCl3): d 1.65 (d, 3H), 2.3 (s, 3H), 2.4 (s, 3H), 2.45 (s, 6H), 5.0 (m, 1H), 5.4 (d, 1H), 5.55 (d, 1H), 6.45 (t, 1H), 6.9-7.05 (m, 3H) , 7.1 (d, 1H). Example 1.25 Synthesis of 8- [1- (2,6-dimethyl phenyl) -ethoxy] -2,3-dimethylimidazo [1,2-a] pyridine Yield: 24% * H NMR (300 MHz, CDCl 3): d 1.8 (d, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 2.5 (s, 6H), 5.8 (q, 1H), 5.95 (d, 1H), 6.45 (d, 1H), 6.9- 7.0 (m, 3H), 7.30 (d, 1H). Example 1.26 Synthesis of 2,3-dimethyl-8- (2- [2- (methylsulfonyl) -ethyl] -benzylamino) -imidazo [1,2-a] pyridine Yield: 34% lE NMR (000 MHz, CDC13) : d 2.34 (s, 6H), 2.67 (s, 3H), 3.18-3.33 (m, 4H), 4.43 (d, 2H), 5.15 (t, 1H), 6.14 (d, 1H), 6.62-6.68 ( m, 1H), 7.15-7.30 (m, 3H), 7.37 (d, 1H). Example 1.27 Synthesis of 8- (2- [2-methylcarbonyloxy) -ethyl] -4-fluoro-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine Yield: 33%
^^^^^^^^^^^^^^ S ^ ^^^^ t ^^, ^ ¿IB S & s ^ ** XH NMR (300 MHz, CDC13): d 2.01 (s, 3H), 2.33 (s, 3H), 2.35 (s, 3H), 2.37 (s, 3H), 3.00 (t, 2H), 4.25 (t, 2H), 4.31 (d, 2H), 4.78 (bs, 1H), 6.22 (d, 1H), 6.73 (t, 1H), 6.80 (d, 2H), 7.26 (d, 1H). Example 1.28 Synthesis of 8- (3-f-enoxybenzyl amino) -2,3-dimethylimidazo [1,2-a] pyridine Yield: 20%? E NMR (300 MHz, CDCl 3): d 2.3 (s, 3H), 2.4 (s, 3H), 4.4 (m, 2H), 5.5 (m, 1H), 6.0 (d, 1H), 6.55 (t, 1H), 6.85-7.35 (m, 10H). Example 1 .29 Synthesis of 8- (2,6-dimethylbenzylamino) -2,3-dimethyl-7-nor troimidazo [1,2-a] pyridine. 2,3-Dimeti-8- (2,6-dimethylbenzylamine was dissolved. ) -imidazo [1,2-a] pyridine (2.0 g, 7.16 mmol) in acetic acid
(30 ml) and nitric acid (0.53 g, 7.57 mmol) was added. The mixture was heated to a temperature of 80 to 85 ° C and stirred for 3 hours at this temperature. After evaporating most of the acetic acid, the residue was partitioned into methylene chloride and water. The organic phase was washed with a sodium carbonate solution and the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride (100 ml) and
^ afa ^ = ^ g ^ - ^ ... ^^^^^ -..-. . ? fAw &B ^ tas ^^ filtered through silica gel (10 g), after which the methylene chloride was removed under reduced pressure. Chromatography in methylene chloride (100%) afforded 0.4 g (17%) of the title compound. Examples 1.30-1.40 were prepared according to Example 1.1 Examples 1.30 and 1.31 were prepared from a mixture of 2-chloro-6-methylbenzyl bromide and 3-chloro-2-methylbenzyl bromide. The yields refer to 8-amino-2,3-dimethyl-6-methylimidazo [1,2-a] pyridine. Example 1.30 Synthesis of 8- (2-chloro-6-methylbenzylamino) -2,3,6-trimethylimidazo [1,2-a] pyridine Yield: 34%? E NMR (300 MHz, CDC13): d 2.35 (s, 9H), 2.55 (s, 3H), 4.5 (d, 2H), 4.85 (bs, 1H), 6.1 (s, 1H), 7.05 (s, 1H), 7.1-7.3 (m, 3H). Example 1. 31 Synthesis of 8- (3-chloro-2-methylbenzylamino) -2, 3, 6-methylimidazo [1,2-a] pyridine Yield: 27% XE NMR (300 MHz, CDC13): d 2.25 (s) , 3H), 2.35 (s, 3H), 2.4 (s, 3H), 2.45 (s, 3H), 4.4 (d, 2H), 5.25 (t, 1H), 5.85 (s, 1H), 7.0-7.1 ( m, 2H), 7.25-7.35 (m, 2H).
Examples 1.32 and 1.33 were prepared from a mixture of 2-bromo-7-methylbenzyl bromide and 3-bromo-2-methylbenzyl bromide. The yields refer to 8-amino-2,3-dimethylimidazo [1,2-a] pyridine. Example 1.32 Synthesis of 8- (2-bromo-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine Yield: 25% XH NMR (300 MHz, CDC13): d 2.35 (s, 6H) , 2.45 (s, 10 3H), 4.55 (d, 2H), 4.85 (bs, 1H), 6.25 (d, 1H), 6.75 (t, 1H), 7.05-7.2 (m, 2H), 7.25 (d, 1H), 7.4 (d, 1H). Example 1.33 Synthesis of 8- (3-bromo-2-methylbenzylamino) -2,3-dimethylimidazo [1, 2 -a] pyridine 15 Yield: 16% H NMR (300 MHz, CDC13): d 2.35 (s, 3H), 2.4 (s, 3H), 2.45 (s, 3H), 4.45 (d, 2H), 5.35 (bs, 1H), 6.0 (d, 1H), 6.65 (t, 1H), 7.0 (t, 1H) ), 7.2-7.35 (m, 3H), 7.-5 (d, 1H). Examples 1.34 and 1.35 were prepared from a mixture of 2-chloro-6-methylbenzyl bromide and 3-chloro-2-methylbenzyl bromide. The yields refer to 8-amino-2,3-dimethylimidazo [1,2-a] pyridine.
^ ggft »**», mM? J¡ai¡m ?? - '-x ^ - ^^^^^ Example 1.34 Synthesis of 8- (2-chloro-6-methylbenzylamino) -2,3-dimethylimidazo [1, 2-a] pyridine Yield: 24% XH NMR (300 MHz, CDC13): d 2.35 (s, 6H), 2.45 (s,
3H), 4.5 (d, 2H), 4.85 (bs, 1H), 6.25 (d, 1H), 6.7 (t, 1H), 7.1-7.35 (m, 4H). Example 1.35 Synthesis of 8- (3-chloro-2-methylbenzylamino) -2,3-dimethylimidazo [1,2- a] pyridine Yield: 19% X H NMR (300 MHz, CDCl 3): d 2.35 (s, 3H), 2.4 (s, 3H), 2.45 (s, 3H), 4.45 (d, 2H), 5.3 (t, 1H), 6.0 (d, 1H), 6.6 (t, 1H), 7.05 (t, 1H), 7.25 -7.35 (m, 3H). Example 1.36 Synthesis of 8- (2-chloro-4,6-dimethylbenzylamino) -2,3-dimethylimidazo [1,2- a] pyridine Yield: 7% XH NMR (300 MHz, CDC13): d 2.28 (s) , 3H), 2.34 (s, 6H), 2.38 (s, 3H), 4.46 (d, 2H), 4.86 (t, 1H), 6.22 (d,
1H), 6.28-6.74 (m, 1H), 6.90 (s, lh), 7.07 (s, 1H), 7.25 (d, 1H). Ex empl o 1.37 Synthesis of 8- (2,4-dichloro-6-methylbenzylamino) -
- «$! ** '^^^^^^^ & ^^^^^^ - 2,3-dimethylimidazo [l, 2-a] pyridine Yield: 28% XE NMR (500 MHz, CDC13): d 2.34 (s, 3H), 2.35 (s, 3H), 2.41 (s, 3H), 4.46 (d, 2H), 4.86 (t, 1H), 6.21 (d, 1H), 6.69-6.72 (m, 1H) ), 7.10 (d, 1H), 7.24-7.28 (m, 2H). Example 1.38 Synthesis of 8- (2-cyano-6-methylbenzylamino) -2,3-dimethylimidazofl, 2-a] pyridine Yield: 49% 2 H NMR (300 MHz, CDCl 3): d 2.35 (s, 6H), 2.45 ( s, 3H), 4.6 (d, 2H), 4.95 (bs, 1H), 6.25 (d, 1H), 6.7 (t, 1H), 7.25-7.35 (m, 2H), 7.4 (d, 1H), 7.55 (d, 1H). Example 1.39 Synthesis of 8- (3-cyano-2-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine Yield: 26% H NMR (300 MHz, CDCl 3): d 2.35 (s, 3H), 2.4 (s, 3H), 2.6 (s, 3H), 4.45 (d, 2H), 5.35 (t, 1H), 5.95 (d, 1H), 6.65 (t, 1H), 7.2-7.3 (m, 2H) 7.55 (t, 2H). Example 1.40 Synthesis of 8- (3-difluoromethoxybenzylamino) -2, 3-dimethylimidazo [1, 2-ajpyridine hydrochloride Yield: 45%
X H NMR (300 MHz, CDC13): d 2.25 (s, 3 H), 2.35 (s, 3 H), 4.5 (d, 2 H), 5.65 (t, 1 H), 5.95 (d, 1 H), 6.5 (d, 1 H) ), 6.55 (t, 1H), 7.0-7.25 (m, 4H), 7.4 (d, 1H). Examples 741-45 were prepared in accordance with Example 7. Example 1.41 Synthesis of 8- (2-methoxymethyl-6-methylbenzylamino) -2,3,6-trimethyl-imidazo [1,2-a] pyridine Yield: 60% 10? E NMR (300 MHz, CDCI3): d 2.25 (s, 3H), 2.3 (s,
6H), 2.4 (s, 3H), 3.35 (s, 3H), 4.4 (d, 1H), 4.5 (s, 3H), 4.85 (bs, 1H), 6.1 (s, 1H), (7.0 s, 1H) ), 7.05-7.2 (m, 3H). Example 1.42 Synthesis of 8- (2,6-dimethyl-3-nitrobenzylamino) -l, 2,3-dimethyllimidazo [1,2-a] pyridine Yield: 15% XH NMR (300 MHz, CDC13): d 2.32 (s, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 2.5 (s, 3H), 4.4 (d, 2H), 4.75 (m, 1H), 6.22 (d, 1H), 6.75 (t, 1H) ), 7.17 (d, 1H), 7.3 (d, 1H), 7.7 20 (d, 1H). Example 1.43 Synthesis of 2,3-dimethyl-8- [2- (2-methoxyethyl) -6-methylbenzylamino] -6-methylimidazo [1, 2-ajpyridine hydrochloride
O ^ Ja w. - «'- • faith» ^ 5MgA. ^ Iafe-S.S5 ,. < n ^^ Yield: 11% XH NMR (300 MHz, CDC13): d 2.35 (s, 3H), 2.38 (s, 3H), 2.44 (s, 3H), 2.46 (s, 3H), 3.02 (t, 2H) ), 3.30 (s, 3H), 3.59 (t, 2H), 4.41 (s, 2H), 6.46 (s, 1H), 7.10-7.35 5 (m, 4H). Example 1. 44 Synthesis of 8- [2,6-dimethylbenzylamino] -2,3,7-trimethylimidazo [1,2-a] pyridine hydrochloride Yield: 11% XH NMR (300 MHz, CDC13): d 2.35 ( s, 9H), 2.4 (s, 3H), 2.6 (s, 3H), 4.65 (s, 2H), 6.95-7.15 (m, 4H), 7.5 (bs, 1H), (neutral form). Example 1. Synthesis of 2,3-dimethyl-8 - [(2,4-dimethyl-3-thienyl) -5-methylamino] -imidazo [1,2-a] pyridine Yield: 44% XH NMR (300 MHz, CDCI3): d 2.2 (s, 3H), 2.35 (s, 3H), 2.36 (s, 3H), 2.45 (s, 3H), 4.2 (d, 2H), 4.8 (bs, 1H), 6.2 (d, 1H), 6.65-6.75 (d, 2H), 7.25 (d, 1H). 20 Example 1. 46 Synthesis of 2,6-dimethyl-3-hydroxymethyl-8- (2-methoxymethyl-6-methylbenzylamino) -imidazo [1,2-a] pyridine. Lithium aluminum hydride (0.29 g, 7.7 mmol) was added to tetrahydrofuran. (30 ml) and 3- was added
^ j¡É ^ ^ _ ^ afa -_ ^ ¿i_ ^ i ^ _¡¡ »* g» > ^ sjiSiBwaatoasteMft at ^., - carboethoxy-8- (2-methoxymethyl-6-methylbenzylamino) -2-methylimidazo [1,2- a] pyridine (1.4 g, 3.8 mmol) dissolved in tetrahydrofuran (30 ml) by dripping into a period of 80 minutes, at room temperature, and the mixture was stirred for 4 hours. Water (0.29 ml) was added per drop, followed by sodium hydroxide (15%, 0.29 ml) and finally 0.93 ml of water. After stirring for 30 minutes, the solids were filtered and washed well with tetrahydrofuran. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (methylene chloride / methanol, 9: 1), obtaining (0.97 g, 75%) the title compound as a white solid. lE NMR (300 MHz, CDC13): d 2.0 (s, 3H), 2.3 (s, 15 3H), 2.4 (s, 3H), 3.35 (s, 3H), 3.6 (bs, 1H), 4.4 (d, 2H), 4.5 (s, 2H), 4.6 (s, 2H), 4.9 (bs, 1H), 6.15 (s, 3H), 7.1- 7.25 (m, 3H), 7.35 (s, 1H). Example 1.47 was prepared according to Example 1.46 Example 1. 47 Synthesis of 8- (2-chloro-6-methylbenzylamino) -2,6-dimethyl-3-hydroxymethylimidazo [1,2-a] pyridine Yield: 46 % XE NMR (300 MHz, CDCl 3): d 2.25 (s, 3H), 2.3 (s,
3H), 2.45 (s, 3H), 4.5 (d, 2H), 4.8 (s, 2H), 4.85 (bs, 1H), 6.2 (s, 1H), 7.1-7.25 (m, 3H), 7.4 (s) , 1 HOUR) . Examples 1.48-1.49 were prepared according to Example 1.1 5 Example 1.48 Synthesis of 8- (2,6-dimethylbenzylamino) -2-methylimidazo [1,2-a] pyridine Yield: 70% XH NMR (300 MHz, CDCl3 ): d 2.35 (s, 9H), 4.3 (d, 10 2H), 4.8 (bs, 1H), 6.2 (d, 1H), 6.65 (t, 1H), 7.0-7.15 (m, 3H), 7.25 ( s, 1H), 7.45 (d, 1H). Example 1.49 Synthesis of 8- (4-fluoro-2,6-dimethylbenzylamino) -2-methylimidazo [1,2-a] pyridine. Yield: 71%! H NMR (300 MHz, CDCl 3): d 2.35 (s) , 6H), 2.4 (s, 3H), 4.3 (d, 2H), 4.75 (bs, 1H), 6.2 (d, 1H), 6.65 (t, 1H), 6.75 (d, 2H), 7.25 (s, 1H), 7.5 (d, 1H). Example 1.51 Synthesis of 2,6-dimethyl-8- (4-fluoro-2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine A mixture of 8- (4-fluoro-2,6-dimethylbenzylamine ) -2-methy1-6-methy1imidazo [1,2-a] pyridine-3-carboxylic acid (0.35 g, 1.03 mmol) and diphenylether was subjected to
reflux for 10 minutes. Petroleum ether 40-60 was added at room temperature, followed by hydrogen chloride in diethyl ether. The petroleum ether and diphenyl ether phase was removed from the formed precipitate. The precipitate was washed with petroleum ether and then dissolved in methylene chloride and basified with sodium hydroxide (2M). The phases were separated and the organic phase was washed with water. The solvent was evaporated and the residue was chromatographed (hexane / ethyl acetate, 2: 1) to obtain 0.17 g (50%) of the title compound. XH NMR (300 MHz, CDC13): d 2.25 (s, 1H), 2.35 (s, 9H), 4.25 (d, 2H), 4.75 (bs, 1H), 6.05 (s, 1H), 6.75 (d, 2H) ), 7.1 (s, 1H), 7.25 (s, 1H). Example 1.52 was prepared in accordance with Example 1.51. Example 1.52 Synthesis of 2,6-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine Yield: 40% XH NMR (300 MHz, CDC13): d 2.25 (s, 1H ), 2.35 (s, 3H), 2.4 (s, 6H), 4.3 (d, 2H), 4.75 (bs, 1H), 6.05 (s, 1H), 6.95-7.15, (, 4H), 7.2 (s, 1 HOUR) .
^ a ^ - ^ - = a¿¿ - ^ a ^? = ^ __ ^ - ^^^ ía - ^ - ^^^ «feA? ^ atei3íis Example 1.53 Synthesis of hydrochloride of 8- (2, 6- dimethylbenzylamino) -3-ethyl-2-methylimidazo [1,2-a] pyridine To a stirred mixture of l- [8- (2,3- 5 dimethylbenzylamino) -2-methylimidazo [1, 2-a] -pyridin -3-yl] -1- ethanol (0.3 g, 0.98 mmol), boron trifluoride diethyletherate (0.14 ml, 3.2 mmol) in tetrahydrofuran (10 ml) was added sodium cyanoborohydride (0.13 g, 2.0 mmol). The reaction mixture was stirred for 2.5 hours and the
The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride and washed twice with a saturated solution of sodium bicarbonate. The organic phase was separated, dried and evaporated under reduced pressure. Purification twice by chromatography on
column of silica gel using 1) methylene chloride / ethyl acetate (100: 7), 2) methylene chloride / methanol (100: 3) as eluent and a treatment with HCl / diethyl ether yielded 0.1 g (31% ) of the title compound. 20 XH NMR (300 MHz, CDC13): d 1.2 (t, 1H), 2.35 (s, 3H), 2.4 (s, 6H), 2.85 (q, 2H), 4.35 (d, 2H), 4.8 (bs, 1H), 6.2 (d, 1H), 6.7 (t, 1H), 7.05-7.15 (m, 3H), 7.35 (d, 1H). Example 1.54 Synthesis of 8- (2,6-dimethylbenzylamino) -2-methyl-3-vinylimidazofl, 2-a] pyridine
A mixture of 1- [8- (2,3-dimethylbenzylamino) -2-methylimidazo [1,2- a] pyridin-3-yl] -l-ethanol (0.2 g, 0.65 mmol) and p-toluenesulfonic acid (0.029) g, 0.15 mmol) in benzene (40 ml) was refluxed for 20 hours with 5 a Dean-Stark water separator. The solvent was evaporated under reduced pressure, the residue was dissolved in methylene chloride and washed with a saturated solution of sodium bicarbonate. The organic phase was separated, dried and evaporated under reduced pressure. The purification of
The residue was chromatographed on a silica gel column using methylene chloride / ethyl acetate (10: 1) to yield 0.062 g (33%) of the title compound. X H NMR (300 MHz, CDCl 3): d 2.4 (s, 6H), 2.5 (s, 3H), 4.35 (d, 2H), 4.85 (bs, 1H), 5.35 (d, 1H), 5.55 (d,
1H), 6.25 (d, 1H), 6.75-6.85 (m, 2H), 7.05-7.15 (m, 3H), 7.6 (d, 1H). Example 1 . 55 Synthesis of 2-cyanomethyl-8- (2,6-dimethylbenzylamino) -3-methylimidazo [1,2-a] pyridine 20 A mixture of 2-chloromethyl-8- (2,6-dimethylbenzylamino) -3-methylimidazo [ 1,2-a] pyridine (2.4 mmol) and potassium cyanide (2.4 mmol) was added to dimethylsulfoxide (25 ml) and the mixture was stirred for 2 hours at room temperature. Chloride was added
methylene and water to the reaction mixture and the organic phase
it was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using methylene chloride / methanol (10: 1) as eluent. Crystallization with acetonitrile yielded 0.25 g (34%) of the title compound. XH NMR (500 MHz, CDC13): d 2.4 (s, 6H), 2.45 (s, 3H), 3.8 (s, 2H), 4.35 (d, 2H), 4.8 (bs), 1H), 6.3 (d, 1H), 6.8 (t, 1H), 7.1 (d, 2H), 7.15 (t, 1H), 7.3 (t, 1H). Example 1. 56 Synthesis of 8- (2,6-dimethylbenzylamino) -3-methyl-2-methyl sulphoylmethyl-imidazo [1, 2-a] pyridine A mixture of 2-chloromethyl-8- (2,6-dimethylbenzylamine ) -3-methylimidazo [1,2-a] pyridine (0.2 g, 0.64 mmol) and sodium methanethiolate (0.1 g, 1.3 mmol) was added to acetonitrile (10 ml) and stirred for 4 hours at room temperature. The solvent was evaporated under reduced pressure and to the residue were added methylene chloride and water. The organic phase was separated, dried (Na 2 SO) and evaporated under reduced pressure. Purification of the residue by silica gel column chromatography using diethyl ether / petroleum ether (1: 2) as eluent, and crystallization from diethyl ether / petroleum ether (1: 2), afforded 0.05 g (24%) of the desired product.
? E NMR (400 MHz, CDCI3-)? d 2.1 (s, 3H), 2.4 (s, 6H), 2.45 (s, 3H), 3.85 (s, 2H), 4.4 (s, 2H), 4.9 (bs, 1H), 6.25 (d, 1H), 6.75 (t, 1H), 7.1 (d, 2H), 7.15 (t, 1), 7.3 (d, 1H). 5 Example 1.57 Synthesis of 8- (2,6-dimethylbenzylamino) -2-methoxymethyl-3-methylimidazo [1,2-a] pyridine. 2-Chloromethyl-8- (2,6-mdimethylbenzylamino) -3- was dissolved. methylimidazo [1,2-a] pyridine (0.3 g,
0.96 mmol) in methanol (20 ml) and the mixture was stirred for 20 hours at room temperature and refluxed for 20 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and washed with a solution of sodium bicarbonate. The phase
The organic material was separated, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using diethyl ether / petroleum ether (2: 1) as eluent and crystallization from diethyl ether / petroleum ether (2: 1), yielded 0.13 g (44%) of the
desired product. lE NMR (500 MHz, CDCl 3): d 2.4 (s, 6H), 2.45 (s, 3H), 3.4 (s, 3H), 4.35 (d, 2H), 4.55 (s, 2H), 4.95 (bs, 1H ), 6.25 (d, 1H), 6.8 (t, 1H), 7.05 (d, 2H), 7.15 (t, 1H), 7.3 (d, 1H).
Example 1 . 58 Synthesis of 2-aminocarbonylmethyl-3-methyl-8- (2,6-dimethylbenzylamine) -7-imidazo [1, 2-a] pyridine A mixture of example 55 (40 mg, 0.13 mmol), potassium hydroxide ( 30 mg) in t-butanol (1.0 ml), refluxed for 10 minutes. The mixture was filtered and methylene chloride (2 ml) was added to the filtrate and washed with water. The organic phase was dried over sodium sulphate and evaporated, yielding 26 mg (64%) of the compound
of the title. XH NMR (300 MHz, CDC13): d 2.35 (s, 3H), 2.4 (s, 6H), 3.6 (s, 2H), 4.35 (d, 2H), 4.8 (bs, 1H), 5.55 (bs, 1H) ), 6.3 (d, 1H), 6.8 (t, 1H), 7.0-7.35 (m, 5H). Example 1 . 59 15 Synthesis of 8- (2-hydroxymethyl-6-methylbenzylamino) -2,3-dimethyl-midazo [1,2-a] pyridine hydrochloride To an ice-cooled mixture of 2 - (((2,3- dimethylimidazo [1,2- a] pyridin-8-yl) -amino) -methyl) -3-methylbenzoic acid (0.18 g, 0.59 mmol) in toluene (30 ml) was
added dropwise Red-Al (5 ml) in toluene (7 ml) and stirred at room temperature for 20 hours. The mixture was cooled with ice and water (10 ml) and methylene chloride were added. After filtration, the filtrate was evaporated under reduced pressure and the residue was purified by
column chromatography on silica gel using
methylene chloride / methanol (*? 00: 5) as eluent. The product was dissolved in methylene chloride / ether and treated with HCl / diethyl ether, to obtain 0.024 g (12%) of the title compound. ? E NMR (300 MHz, CDC13): d 2.25 (s, 3H), 2.3 (s,
3H), 2.4 (s, 3H), 4.4 (d, 1H), 4.65 (s, 2H), 5.05 (bs, 1H), 6.25 (d, 1H), 6.75 (t, 1H), 7.1-7.25 (m , 4H). Ex empl o 1. 60 Synthesis of 8- (2-hydroxy-6-methylbenzylamino) -2,3-dimethylimidazo [1,2- a] pyridine 8- (2-methoxy-6-methylbenzylamino) -2, 3 dimethylimidazo [1,2-a] pyridine (0.14 g, 0.48 mmol) in methylene chloride (9 ml) and the mixture was cooled to -73 ° C. Boron tribromide in methylene chloride (1M) (2.37 ml, 2.37 mmol) was added dropwise and the reaction mixture was stirred for 20 hours under a nitrogen atmosphere and the temperature was allowed to rise to room temperature. The reaction mixture was cooled on ice and water and methylene chloride were added. The organic phase was separated, washed with a saturated solution of sodium bicarbonate, dried and evaporated under reduced pressure, to obtain 0.077 g (57%) of the title compound. X H NMR (500 MHz, CDCl 3): d 2 .25 (s, 3 H), 2. 35 (s, 3H), 2. 4 (s, 3H), 4. 4 (d, 2H), 4. 95 (t, 1H), 6. 3 (d, 1H), 6.55 (d, 1H), 6.7 (t, 1H), 6.8 (d, 1H), 6.9 (t, 1H), 7.25 (d, 1H) . Ex empl o 1.61 Synthesis of 8- (2-aminomethyl-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine To a solution of 8- (2-cyano-6-methylbenzylamino) -2,3 -dimethylimidazo [1, 2-a] pyridine (0.42 g, 1.44 mmol) in a saturated solution of ammonia in ethanol / methanol (10 / 2.5) (30 ml), was added Raney nickel (50% in water) (0.45 g). The mixture was hydrogenated at room temperature and atmospheric pressure until the incorporation of hydrogen ceased. After filtering through celite, the solvents were evaporated under reduced pressure and the residue was purified by silica gel column chromatography using methylene chloride / methanol (10: 2) as eluent. Recrystallization from methylene chloride / diethyl ether yielded 0.052 g (12%) of the desired product. XH NMR (300 MHz, CDC13): d 2.35 (s, 6H), 2.4 (s, 3H), 3.95 (s, 2H), 4.4 (s, 2H), 6.25 (d, 1H), 6.75 (t, 1H ),
7. 1-7.25 (m, 4H). Ex empl o 1.62 Synthesis of N- (2- (((2,3-dimethylimidazo [1, 2-a] pyridin-8-yl) -amino) -methyl) -3-methylbenzyl) -carbamic acid methyl ester
To an ice-cooled solution of 8- (2-aminomethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a] pyridine (0.17 g, 0.58 mmol), pyridine (0.046 g, 0.58 mmol) in chloride of methylene (8 ml), 5 methyl chloroformate (0.055 g, 0.58 mmol) was added and the reaction mixture was stirred for 1.5 hours and the temperature was allowed to rise to 12 ° C. Methylene chloride was added and the solution was washed twice with water. The organic phase was separated, washed with a saturated bicarbonate solution of
Sodium, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride / methanol (100: 5) as eluent. Recrystallization from diethyl ether yielded 0.052 g (25%) of the title compound. 15? E NMR (300 MHz, CDC13): d 2.35 (s, 6H), 2.45 (s, 3H), 3.55 (s, 3H), 4.4 (d, 2H), 4.45 (d, k2H), 4.75 ( bs, 1H), 5.25 (bs, 1H), 6.25 (d, 1H), 6.75 (t, 1H), 7.1-7.3 (m, 4H). Example 1 . 63 20 Synthesis of 2- (((2,3-dimethylimidazo [1, 2-a] py? Din-8-yl) -amino) -methyl) -3-methyl phenylmethyl carbamate hydrochloride A mixture of 8- (2 -hydroxy-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine (0.068 g, 0.24 mmol),
sodium carbonate (0.12 g, 1.1 mmol) and hydroxide of
Potassium (0.019 g, 0.34 mmol) in acetone (12 mL) was stirred for 15 minutes at room temperature under a nitrogen atmosphere. Methyl chloroformate (0.023 g, 0.24 mmol) was added and the reaction mixture was stirred for 70 minutes. Methylene chloride was added and the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in methylene chloride, washed with a saturated solution of sodium bicarbonate and with water and the organic phase was separated, dried and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using methylene chloride / methanol (100: 5) as eluent and treated with HCl / diethyl ether, to obtain 0.025 g (28%) of the title compound. XE NMR (300 MHz, CDC13): d 2.35 (s, 3H), 2.5 (s,
3H), 2.6 (s, 3H), 3.9 (s, 3H), 4.5 (d, 2H), 6.75 (d, 1H), 6.95-7.3 (m, 5H), 8.0 (t, 1H), 15.6 (bs) , 1 HOUR) . Example 1. 64 Synthesis of 2- (2- (((2,3-dimethylimidazo [l, 2-a] pyridin-8-yl) -amino) -methyl) -3-methyl phenoxy) -2-ethanol To a Solution of 8- (2-hydroxy-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine (0.14 g, 0.5 mmol) in N, N-dimethylformamide (3 mL) was added with lithium hydride. (0.004 g, 0.51 mmol) and the mixture was stirred for 10 minutes at 100 ° C. Carbonate was added
^ A ». ^ ..- ^^^. ^^. ^. ^. ^ Y ^^^ i ^^^ = aa & faith. ^ .... ^^^^^^ ethylene (0.055 g, 0.63 mmol) and the mixture was stirred for 10 minutes at 130 ° C. Tetramethylammonium iodide (0.054 g, 0.63 mmol) was added and the mixture was stirred for 12 hours at a temperature of 140 to 145 ° C. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and washed twice with a saturated solution of sodium bicarbonate. The organic phase was separated, dried and evaporated under reduced pressure and the residue was purified by chromatography on a silica gel column.
using methylene chloride / ethanol (100: 6) as eluent, to obtain 0.067 g (41%) of the title compound. X H NMR (500 MHz, CDCl 3): d 2.3 (s, 3 H), 2.35 (s, 3 H), 2.45 (s, 3 H), 4.0 (t, 2 H), 4.15 (t, 2 H), 4.5 (d, 2 H) ),
6.25 (d, 1H), 6.35 (t, 1H), 6.7 (t, 1H), 6.75 (d, 1H), 6.8 (d, 1H), 7.1 (t, 1H), 7.2 (d, 1H). Ex empl o 1. 65 Synthesis of 2- (((2,3-dimethylimidazo [l, 2-a] pyridin-8-yl) -amino) -methyl) -3-methylphenyl trifluoromethanesulfonate 20 To a solution of 8 - (2-hydroxy-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine (0.1 g, 0.32 mmol) in methylene chloride (7 ml), triethylamine (0.07 g, 0.69 mmol) was added. ) and the reaction mixture was cooled in ice. N, N-dimethylaminopyridine was added
(0.077 g, 10 mmol) and trifluoromethanesulfonic anhydride
(0.12 g, 0.41 mmol) in methylene chloride (0.5 ml) and N-phenyltrifluoromethanesulfonimide (0.28 g, 0.78 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and the reaction mixture was stirred for 135 minutes at 18 °. C. 5 Methylene chloride was added and the solution was washed with water / NH 4 Cl, with a saturated solution of sodium bicarbonate and with water. The organic phase was separated, dried and evaporated under reduced pressure. Purification of the residue by silica gel column chromatography using either methylene chloride / ethyl acetate (10: 2) as eluent and crystallization from diethyl ether / petroleum ether, afforded 0.053 g (40%) of the title compound . ? E NMR (500 MHz, CDC13): d 2.33 (s, 3H), 3.35 (s, 3H), 2.45 (s, 3H), 4.45 (d, 2H), 5.0 (bs, 1H), 6.25 (d, 5 1H), 6.75 (t, 1H), 7.15 (d, 1H), 7.2-7.35 (m, 3H). Example 1. Synthesis of 8- [2- (2-hydroxyethyl) -benzylamino] -2,3-dimethylimidazo [1,2-a] pyridine A mixture of the compound of Example 22 (xCH3S03H) 0 (0.8 g, 1.85 mmol ) and sodium hydroxide (0.2 g) was refluxed in ethyl alcohol for 3 hours. The solvent was evaporated and methylene chloride / water was added to the residue. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. Trituration 5 of the solid residue with diethyl ether yielded 0.48 g (88%)
of the title compound. X H NMR (300 MHz, CDC13): d 2.33 (s, 3 H), 2.34 (s, 3 H), 2.91 (t, 2 H), 3.50 (bs, 1 H), 3.87 (t, 2 H), 4.40 (s, 2 H) ), 5.63 (bs, 1H), 6.12 (d, 1H), 6.62-6.68 (m, 1H), 7.14-7.27 (, 4H), 7.36 (d, 1H). Example 1.67 Synthesis of 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -6-hydroxymethyl-imidazo [1,2-a] pyridine To a stirring solution of 2,3-dimethyl-8- (2, 6-dimethylbenzylamio) -imidazo [1,2-a] pyridine-6-carboxylic acid ethyl ester (1.2 g, 3.4 mmol) in tetrahydrofuran (30 ml), L1AIH4 (0.7 g, 18.5 mmol) was added over a period of 20 g. minutes at 5 ° C. 0.7 ml of water were added dropwise, followed by 0.7 ml of 15% sodium hydroxide and then 2.1 ml of water. The solids were removed by filtration and washed well with methylene chloride / methanol (1: 1). The filtrate and washings were combined and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride / methanol (10: 1) as eluent. Treatment of the residue with diethyl ether and subsequent filtration afforded 0.7 g (67%) of the title compound. L NMR (400 MHz, CDCl 3): d 2.35 (s, 6H), 2.4 (s,
t * ^ * - ***** - • ^ «irtda ^^^ 6H), 4.35 (d, 2H), 4.65 (s, 2H), ~ 4.9 (bs, 1H), 6.2 (s, 1H) , 7.05-7.15 (m, 3H), 7.25 (s, 1H). Ex empl o 1. 68 Synthesis of 2,3-dimethyl-8- (2,6- 5 dimethylbenzylamino) -6-methoxymethylimidazo [1,2-a] pyridine hydrochloride To a stirring solution of 2,3-dimethyl- 8- (2,6-diethylbenzylamino) -6-hydroxymethylimidazo [1,2-a] pyridine (0.08 g, 0.26 mmol) in methylene chloride (5 ml), thionyl chloride (0.038 ml, 0.52 mmol) was added and the mixture
was stirred for 2 hours. A saturated solution of sodium bicarbonate was added and the organic phase was separated, dried (Na 2 SO 4) and evaporated under reduced pressure. Methanol (5 ml) was added to the residue and the mixture was stirred overnight. The solvent was evaporated under reduced pressure and
The residue was purified by chromatography on a silica gel column using methylene chloride / methanol (100: 5) as eluent. Treatment of the residue with HCl / diethyl ether and filtration yielded 0.01 g (11%) of the title compound. 20 XH NMR (300 MHz, CDC13): d 2.35 (s, 3H), 2.4 (s,
3H), 2.45 (s, 6H), 3.55 (s, 3H), 4.35 (d, 2H), 4.45 (s, 2H), 4.85 (bs, 1H), 6.2 (s, 1H), 7.05-7.15 (, 3H), 7.3 (s, 1H). Example 1 . 69 25 Synthesis of N- (8- ((2,6-dimethylbenzyl) -amino) -2, 3-
»* Fete jf. 'S & »H dimethylimidazo [1,2-a] -pyridin-7-yl) -acetamide 7-amino-2 was dissolved, 3-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine (from example 77) (0.16 g, 0.53 mmol) in methylene chloride (5 ml) and acetic anhydride was added (60 mg). The mixture was stirred overnight at room temperature. A small amount of triethylamine was added and the solvent was removed under reduced pressure. The reaction mixture was first subjected to chromatography using methylene chloride / methanol, 95: 5 and then with methylene chloride / ethyl acetate, 50:50, obtaining, after trituration with diethyl ether, 87 mg (47%). %) of the desired product in the form of a white solid. XH NMR (300 MHz, CDC13): d 2.00 (s, 3H), 2.35 (s, 15 6H), 2.39 (s, 6H), 2.39 (s, 6H), 4.0 (bs, 1H), 4.36 (d, 2H), 7.0-7.15 (m, 3H), 7.44 (d, 1H), 7.55 (d, 1H), 7.65 (bs, 1H). Example 1 . 70 Synthesis of N- (8- ((2,6-dimethylbenzyl) -amino) -2, 3- 20 dimethylimidazo [1,2- a] -pyridin-7-yl) -N-methylsulfonyl-methansulphonamide was dissolved. -amino-2, 3-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine (Example 77) (0.1 g, 0.34 mmol) in methylene chloride (2 ml), followed
by the addition of sodium carbonate (0.2 g, 1.9 mmol) and
^ A "^" "* * * * - • * - ** -: s: ^ ¡^^ ^^ k. ^^ - ^^^ ^^ i ^^^ Z ^ l. ^ C ^ Áá chloride of methanesulfonyl (0.1 g, 0.87 mmol) The mixture was stirred at room temperature for 30 minutes and after the addition of 2 ml of water, the mixture was stirred for 1 hour, the organic phase was dried over sodium sulfate and the The solvent was evaporated in vacuo, chromatography of the residue with methylene chloride / ethyl acetate, 50:50 yielded 4 mg (2.6%) of the desired compound:? E NMR (300 MHz, CDC13): d 2.35 (s, 3H) , 2.36 (s, 3H), 2.40 (s, 6H), 3.34 (s, 6H), 4.7 (t, 1H), 5.09 (d, 2H), 6.54 (d, 1H), 7.05-7.15 (m, 3H) ), 7.24 (d, 1H) Ex empl o 1. 71 Synthesis of N- (8- ((2,6-dimethylbenzyl) -amino) -2,3-dimethylimidazo fl, 2-a] -pyridin-7- il) (trifluoro) -metansulfonamide A mixture of 7-amino-2,3-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine (example 77) (0.1 g, 0.34 mmol ), N-phenyl-bis (trifluoromethanesulfon) -amide (125 mg, 0.35 mmol) and 3 ml of acetonitrile, was subjected to reflux for 20 hours. The solvent was evaporated in vacuo and the residue was chromatographed with methylene chloride / methanol, 97: 3 as eluent. The isolated product was treated with ethyl acetate and with diethyl ether, obtaining 23 mg (16%) of the desired product. XH NMR (300 MHz, CDC13): d 2.16 (s, 6H), 2.22 (s,
** < < »*» ** ". .... - ^. ^ .J * - -. s fegBaÉ-aS fte ^. «-« a > A «jw» »«, ^ M, ¿^ ». J? T ^ * tís & ^ 3H), 2.23 (s, 3H), 3.85 (bs, 2H), 4.12 (s, 2H), 6.70 (d, 1H), 6.85-7.0 (, 3H), 7.56 (d, 1H). Example 1. Synthesis of 8- (2,6-dimethyl-4-f-luorobenzyloxy) -3- 5-chloro-2-methylimidazo [1,2- a] pyridine To a solution of 8- (2,6-dimethyl- 4- fluorobenzyloxy) -2-methylimidazo [1,2-a] pyridine (0.6 g, 2.1 mmol) in acetic acid (13 ml), Cl2 1.1M in acetic acid (2.2 ml, 2.43 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The organic phase was separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride / ethyl acetate (100: 4) as eluent. Treatment of the residue with diethyl ether and subsequent filtration yielded 0.3 g (45%) of the title compound. 20 X H NMR (300 MHz, CDC13): d 2.4 (s, 6H), 2.45 (s, 3H), 5.2 (s, 2H), 6.65 (d, 1H), 6.75 (d, 2H), 6.8 (t, 1H), 7.7 (d, 1H). Ex empl o 1. 73 Synthesis of 8- (2- (2,6-dimethyl phenyl) -ethenyl) -2,3- 25 dimethylimidazo [1,2-a] pyridine
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^ To an ice-cooled suspension of sodium hydride (0.2 g, 5 mmol) (50% in oil) in 1,2-dimethoxyethane (2 ml) was added (2,3-dimethylimidazo [1,2-a] ] pyridin-8-yl) -methylphosphonate of 5-diethyl and 2,6-dimethylbenzaldehyde. The reaction mixture was stirred under a nitrogen atmosphere for 1 hour at 0 ° C and for 80 minutes at room temperature. The solvent was decanted and evaporated under reduced pressure. The residue was dissolved in methylene chloride and washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was separated, dried and evaporated under reduced pressure. Purification of the residue by silica gel column chromatography using petroleum ether / ethyl acetate (30: 8) as eluent afforded 0.415 g (69%) of the title compound. XH NMR (300 MHz, CDC13): d 2.45 (s, 9H), 2.5 (s, 3H), 6.85 (t, 1H), 7.05 (s, 3H), 7.1 (d, 1H), 7.25 (d, 1H) ), 7.75 (d, 1H), 7.95 (d, 1H). Example 1 . 74 20 Synthesis of 8- (2,6-dimethyl-eethyl) -2,3-dimethylimidazo [1,2-a] pyridine 8- (2- (2,6-dimethylphenyl) -ethenyl) -2, 3- dimethylimidazo [1,2-a] pyridine in methanol (3 ml) and ethanol (2 ml) and Pd / C (10%) (40 mg) were added. The mixture was subjected to hydrogenation at room temperature and
^^ a ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^ l ^^^^^^^^^^^^^^^^ atmospheric pressure, until the incorporation of hydrogen ceases. After filtration through celite, the solvents were evaporated under reduced pressure to obtain the title compound (0.069 g, 100%). 5? E NMR (300 MHz, CDC13): d 2.35 (s, 6H), 2.4 (s, 3H), 2.45 (s, 3H), 3.05-3.2 (m, 4H), 6.7 (t, 1H), 6.85 (d, 1H), 7.0 (s, 3H), 7.7 (d, 1H). Ex empl o 1. 75 Synthesis of N- ((2,3- 10 dimethylimidazo [1,2- a] pyridin-8-yl) -methyl) -2,6-dimethyl indigo hydrochloride A mixture of 8-chloromethyl -2, 3-dimethylimidazo [1, 2-a] pyridine (0.06 g, 0.31 mmol), 2,6-dimethylaniline (0.039 g, 0.32 mmol), sodium carbonate (0.15 g, 1.4 mmol) and
Sodium iodide (0.06 g, 0.4 mmol) in acetone (3 ml) was stirred for 20 hours at room temperature. Methylene chloride was added and the solids were isolated by filtration and the solvents were evaporated under reduced pressure. The residue was purified by chromatography on
column of silica gel using methylene chloride / methanol (2: 1) as eluent. The oily product was dissolved in methylene chloride and treated with HCl / diethyl ether, to obtain the title compound (0.02 g) (18%).
XH NMR (300 MHz, CDC? 3): d 2.25 (s, 6H), 2.4 (s, 3H), 2.45 (s, 3H), 4.5 (s, 2H), 6.7 (t, 1H), 6.8 (t , 1H), 6.95 (d, 2H), 7.05 (d, 1H), 7.75 (d, 1H) (base). Example 1. 76 5 Synthesis of 8- ((2,6-dimethyl phenoxy) -methyl) -2,3-dimethylimidazo [1,2-a] pyridine To a suspension of potassium hydroxide (0.035 g, 0.62 mmol), 2, 6-dimethylphenol (0.075 g, 0.62 mmol) and 18-crown-6 (0.035 g) in 1,2-dimethoxyethane, was added 8-10 chloromethyl-2,3-dimethylimidazo [1,2-a] pyridine. (0.1 g, 0.51 mmol) in 1,2-dimethoxyethane (3 ml). The reaction mixture was stirred for 1.5 hours at room temperature and sodium iodide (0.035 g, 0.23 mmol) was added. The mixture was stirred for 3.5 hours and N, N-dimethylformamide (1
ml) and the solids were isolated by filtration. The filtrate was evaporated under reduced pressure, the residue was dissolved in methylene chloride and washed with a saturated solution of sodium bicarbonate. The organic phase was separated, dried and evaporated under reduced pressure. The residue was purified
by column chromatography on silica gel using methylene chloride / methanol (100: 3.5) as eluent, to obtain 0.11 g (78%) of the title compound. XH NMR (400 MHz, CDC13): d 2.3 (s, 6H), 2.4 (s, 3H), 2.45 (s, 3H), 5.3 (s, 2H), 6.9 (t, 1H), 6.95 (t, 1H) ),
7. 05 (d, 2H), 7.55 (d, 1H), 7.75 (d, 1H). Example 1. Synthesis of 7-amino-2,3-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine 5 A mixture of 2,3-dimethyl-8- (2, 6- dimethylbenzyla ino) -7-nitroimidazo [1,2-a] pyridine (45 mg, 0.139 mmol), Raney nickel (0.1 g) and ethyl alcohol (4 ml), was subjected to hydrogenation (H2, 1 bar ) at 40 ° C for 3 hours. The mixture was filtered using a small amount of silica gel and the solvent was removed under reduced pressure. 40 mg (97%) of the title compound were obtained. XH NMR (300 MHz, CDC13): d 2.30 (s, 3H), 2.34 (s, 3H), 2.49 (s, 6H), 3.85 (bs, 2H), 4.24 (2, 2H), 6.35 (d, 15 1H), 7.05-7.15 (m, 3H), 7.35 (d, 1H). Examples 1.78-1.79 were prepared according to Example 1.1 Example 1. 78 Synthesis of 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3,6-trimethylmethylimidazo [1,2-a] pyridine Yield: 37 %? E NMR (300 MHz, CDC13): d 2.35 (s, 9H), 2.4 (s, 3H), 3.7 (s, 3H), 4.35 (d, 2H), 4.75 (bs, 1H), 6.2 (s) , 1H), 6.95 (d, 1H), 7.1 (s, 1H), 7.2 (m, 1H), 7.5 (bs, 1H), 7.7
(bs, 1H). Example 1 . 79 Synthesis of 2,3-dimethyl-8- (4-trifluoromethoxybenzylamino) -imidazo [1, 2-a] pyridine 5 Hydrochloride Yield: 35%? E NMR 2.3 (s, 3H), 2.4 (s, 3H) , 4.4 (d, 2H), 5.65 (t, 1H), 5.95 (d, 1H), 6.55 (t, 1H), 7.05-7.2 (m, 3H), 7.35 (d, 2H). PREPARATION OF INTERMEDIARIES 10 Example 2. 1 Synthesis of 2, 6-dimethyl-4-f luorobenzyl bromide A mixture of 3,5-dimethylfluorobenzene (5 g, 0.04 mol), paraformaldehyde (15 g), hydrobromic acid (70 ml) (30% acetic acid) and acetic acid (25 ml) was stirred
at room temperature for 4.5 hours. To the mixture was added water and petroleum ether and the organic phase was separated and dried over anhydrous sodium sulfate and carefully evaporated under reduced pressure. The residue was purified by silica gel column chromatography
using petroleum ether as eluent, to obtain the desired product (3.7 g, 43%). ? E NMR (300 MHz, CDC13): d 2. 5 (s, 6H), 4. 55 (s, 3H), 6.75 (d, 2H). Example 2.2 25 Synthesis of 2-chloro-4,6-dimethylbenzyl bromide
2-Chloro-3,5-dimethylbenzene (1.42 g, 0.01 mol) and paraformaldehyde (0.31 g, 0.01 mol) were added to 2 ml of hydrogen bromide (33%) in acetic acid. The mixture was stirred overnight at + 70 ° C. The reaction mixture was poured into 25 ml of water and the product was extracted with diethyl ether. The organic phase was washed with water. The organic phase was dried (Na2SO4) and evaporated. 1.1 g of the product (oil) was obtained. The 1 H-NMR spectrum shows that the substance was a mixture of the title compound and 4-chloro-2,6-dimethylbenzyl bromide. The product was used as such without further purification in the next synthesis step (Example 1.15). XH NMR (300 MHz, CDC13): d 2.28 (s, 6H), 4.51 (s, 2H), 7.04 (s, 2H). Examples 2.3-2.4 were prepared according to Example 2.1 Example 2.3 Synthesis of 2,4-dichloro-6-methylbenzyl bromide Yield: 0.7% XH NMR (300 MHz, CDC13): d 2.43 (s, 3H), 4.61 (s, 2H), 7.11 (d, 1H), 7.27 (d, 1H). Ex empl o 2. 4 Synthesis of 4-fluoro-6-methyl -2- [2-
1 ih *. '£' - > - ^ '~ i? r * -r- 1 • ^ < ¿& * gt¡¡¡¿ & @ Bi¡) i * (methylcarbonyloxy) -ethyl] -benzyl Performance: 31% XH NMR (300 MHz, CDC13): d 2.12 (s, 3H), 2.32 (s) , 3H), 2.88 (t, 2H), 4.26 (t, 2H), 4.66 (s, 2H), 6.65-6.8 (m, 5 2H). Example 2.5 Synthesis of 8-amino-2,3,6-trimethylimidazo [l, 2-ajpyridine To a solution of 2,3-diamino-5-methylpyridine (2.0
g, 16 mmol) in ethanol (100 ml), 3-bromo-2-butanone (2.4 g, 16 mmol) was added. The reaction mixture was refluxed for 16 hours. An additional amount of 3-bromo-2-butanone (1.0 g, 6.7 mmol) and triethylamine (1.0 g, 9.9 mmol) were added and the reaction mixture was added.
refluxed for 2 hours. The ethanol was evaporated under reduced pressure and the residue was treated with methylene chloride and with a solution of sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is
purified by silica gel column chromatography using methanol / methylene chloride (1:20) as eluent, to obtain the desired product (1.05 g, 37%). X H NMR (300 MHz, DMSO-d 6): d 2. 15 (s, 3H), 2 .25 (s, 3H), 2. 3 (s, 3H), 5.45 (bs, 2H), 6. 05 (s, 1H), 7.20 (s,
1 HOUR) . Example 2. 6 Synthesis of 8-amino-3-carboethoxy -2,6-dimethylimidazofl, 2-a] pyridine 5 A stirring mixture of 2,3-diamino-5-methylpyridine (4.0 g, 32.5 mmol) and (5.9) g, 36.0 mmol) of ethyl chloroacetoacetate in 75 ml of absolute ethanol was refluxed overnight. The ethanol was evaporated under reduced pressure. The residue was dissolved in 2M HCl and
washed 3 times with diethyl ether, the pH was adjusted to 9 and the mixture was extracted 3 times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel using dichloromethane / methanol,
95: 5 as eluent, to obtain the title compound 2.0 g (28%). ? E NMR (300 MHz, CDC13): d 1.42 (t, 3H), 2.28 (s, 3H), 2.65 (s, 3H), 4.40 (q, 2H), 4.47 (s, 2H), 6.40 (s, 1H), 8.55 (s, 1H). Example 2. 7 Synthesis of 3-carboethoxy-2,6-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine A stirred mixture of 8-amino-2,6-dimethylimidazo [1,2-a] pyridine (1.2 g, 5.1 mmol), chloride
zinc (II) (0.84 g, 6.2 mmol) and 2,6-dimethylbenzaldehyde
(0.85 g, 6.2 mmol) in 50 ml of methanol, treated with sodium cyanoborohydride (0.39 g, 6.2 mmol) and refluxed for 5 hours. The methanol was evaporated under reduced pressure and the residue was dissolved in dichloromethane and 40 ml of 2M sodium hydroxide. The organic phase was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether (40-60) / isopropyl ether, 8: 2 as eluent, yielding 0.8 g, (44%) of the title compound. X H NMR (30 MHz, CDC13): d 1.44 (t, 3 H), 2.35 (d, 9 H), 2.60 (s, 3 H), 4.33 (d, 2 H), 4.40 (q, 2 H), 4.6 (s, 1 H) ), 6.60 (s, 1H), 7.10 (d, 2H), 7.25 (m, 1H), 8.50 (s, 1H). Ex empl o 2. 8 Synthesis of 3-carboethoxy-2,6-dimethyl-8- (2,6-dimethyl-4-fluorobenzylamino) -imidazo [1,2-a] pyridine A stirring mixture of 8-amino- 3-carboethoxy-2,6-dimethylimidazo [1,2-a] pyridine, 2,6-dimethyl-4-fluorobenzyl bromide (1.2 g, 5.7 mmol), potassium carbonate (1.0 g, 7.5 mmol) and sodium iodide Sodium (0.1 g) in 15 ml of acetonitrile was refluxed overnight. After evaporating the solvent under reduced pressure, the residue was dissolved in dichloromethane and washed with water, the organic phase was separated and dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by
- ^ - A- ^ "- - - ***« - «* n5- • - - - -. ^ AawK ^^^ M ^^ aa ^ & jte ^ A ^ t column chromatography on silica gel eluting with petroleum ether (40-60) / isopropyl ether, 7: 3 as eluent, to obtain 0.8 g (47%) of the title compound. X H NMR (300 MHz, CDC13): d 1.42 (t, 3 H), 2.36 (s, 5 9 H), 2.62 (2, 3 H), 4.45 (d, 2 H), 4.48 (q, 2 H), 4.54 (s, 1H), 6.30 (s, 1H), 6.75 (d, 2H), 8.55 (s, 1H). Example 2. Synthesis of 2,6-dimethyl-8- (2,6-dimethyl-4-fl uorobenzylamino) -imidazo [1,2-a] pyridine-3-carboxylic acid 10 A mixture of 3-carboethoxy-2 , 6-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine (0.4 g, 1.1 mmol), sodium hydroxide (2M, 6 ml) and dioxane (6 ml), was subjected at reflux for 20 minutes. Dioxane was removed under reduced pressure, the pH was adjusted to pH = 7 with 15 2M HCl and the precipitate formed filtered to give 0.23 g (75%) of the title compound. Example 2.10 was prepared according to Example 2.9 Example 2. Synthesis of 2,6-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine-3-carboxylic acid yield: 100% Example 2. 11 Synthesis of ethyl 8-amino-3-methylimidazo [1, 2-a] pyridine-2-carboxylate
^ '^^ g ^ ^^^^^^^^^^^^ £ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^ gj ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ (6.8 g, 62 mol) and 3-bromo-2-oxobutyric acid ethyl ester (13 g, 62 mmol) in 1,2-dimethoxyethane (150 ml), was refluxed for 2 hours. Sodium carbonate (6.5 g, 62 mmol) was added and the reaction mixture was refluxed for 2 hours. The solids were isolated by filtration and washed with dichloromethane / methanol (10: 1). The filtrate and the washings were combined and the combined solvent was removed under reduced pressure. The oily residue was washed with petroleum ether and purified twice by silica gel column chromatography using 1) dichloromethane / ethanol (10: 1) and 2) ethyl acetate, as eluents, to obtain 4.6 g (34 g). %) of the title compound. XH NMR (300 MHz, CDC13): d 1.45 (t, 3H), 2.75 (s, 15 H), 4.5 (q, 2H), 4.65 (bs, 2H), 6.35 (d, 1H), 6.7 (t, 1H), 7.35 (d, 1H). Example 2. Synthesis of ethyl 8- (2,6-diemylbenzylamino) -3-methylimidazofl, 2-a] pyridine-2-carboxylate. 8-amino-3-methylimidazo [1,2- a] pyridine was dissolved. Ethyl 2-carboxylate (4.6 g, 21 mmol), 2,6-dimethylbenzyl chloride (3.2 g, 21 mmol (, sodium carbonate (4.4 g, 42 mmol) and a catalytic amount of potassium iodide, in acetonitrile ( 50 ml) and the mixture was refluxed for 3 hours.The reaction mixture was stirred
^^^^^^^^^^^^^^^^ ¿^^^ v ^^ j ^^^^^^^^^ ^^^^^^^^^^^^^^^^^ ^^ ^ m ^^^^ a ^^^^^^^^^^^^^^^^^^ t ^^^^^^^^^^ for 20 hours at room temperature and refluxed for 1 hour. The solids were removed by filtration and the solvents were evaporated under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The organic phase was separated, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by silica gel column chromatography using methylene chloride / methanol (10: 1) as eluent and after crystallization from ethyl acetate gave 4.0 g (56%) of the desired product. ? E NMR (300 MHz, CDC13): d 1.4 (t, 3H), 2.4 (s, 6H), 2.75 (s, 3H), 4.35 (d, 2H), 4.45 (q, 2H), 5.15 (t, 1H), 6.25 (d, 1H), 6.85 (t, 1H), 7.05-7.2 (m, 3H), 7.35 (d, 1H). Example 2. 13 Synthesis of 8- (2,6-dimethylbenzylamino) -2-hydroxymethyl-3-methylimidazo [1,2-a] pyridine 8- (2,6-dimethylbenzylamino) -3-methylimidazo [1, 2] -a] -pyridine-2-carboxylic acid ethyl ester (5.2 g, 0.015 mol) in tetrahydrofuran (100 ml) and L1AIH4 was added
(1.15 g, 0.03 mol). After stirring the mixture at room temperature for 45 minutes, 1.15 ml of water was added dropwise, followed by 1.15 ml of a 15% sodium hydroxide solution and then 3.45 ml of water. The solids were removed by filtration and washed well with methylene chloride. The filtrate and washings were combined and the combined dried and the solvents were removed under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride / methanol (10: 2) as eluent, produced
3. 2 g (73%) of the title compound. NMR (300 MHz, DMSO-d6): d 2.35 (s, 6H), 2.4 (s, 3H), 4.35 (d, 2H), 4.5 (d, 2H), 4.85 (t, 1H), 4.9 ( t, 1H),
6. 3 (s, 1H), 6.8 (t, 1H), 7.05-7.2 (m, 3H), 7.55 (d, 1H). Example 2. 14 Synthesis of 8- (2,6-dimethylbenzylamino) -2-chloromethyl-3-methylimidazo [1,2-a] pyridine To a solution of 8- (2,6-dimethylbenzylamino) -2-hydroxymethyl-3 -methylimidazo [1, 2-a] pyridine (1.0 g, 3.4 mmol) in methylene chloride (50 ml), thionyl chloride (0.5 g, 3.4 mmol), dissolved in methylene chloride (10 ml) was added dropwise. ) at 5 ° C. The reaction mixture was stirred for 2 hours at 5 ° C. The mixture was washed with a saturated solution of sodium bicarbonate, the organic phase was separated, dried (Na2SO4) and evaporated under reduced pressure, to obtain 1.0 g (93%) of the title compound. X H NMR (300 MHz, CDCl 3): d 2.4 (s, 6H), 2.5 (s, 3H), 4.35 (d, 2H), 4.75 (s, 2H), 4.9 (bs, 1H), 6.25 (d,
rf -y -..... «? g ^ pfty-, .. ífr - ', - - lf iÍlffifiÍwÍ8É ^^ 1H), 6.8 (t, 1H), 7.05-7.15 (m, 3H), 7.25 (d , 1 HOUR) . Example 2. Synthesis of 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine 5 A mixture of 8-amino-2,3-dimethylimidazo [1, 2-a] ] pyridine (0.7 g, 4.34 mmol), sodium carbonate (2.0 g), sodium iodide (0.3 g), 2,6-dimethylbenzyl chloride (0.671 g, 4.34 mmol) and acetone (30 ml), was subjected to Agitation during one night. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in methylene chloride and washed with an aqueous solution of NaHC 3. The organic phase was separated and the solvent was evaporated. The crude product was purified by flash chromatography eluting with CH2Cl2 / MeOH, to obtain 0.7 g of the title compound. ? E NMR (300 MHz, CDC13): d 7.25 (d, J = 7.7 Hz, 1H), 7.14-7.09 (m, 1H), 7.03 (d, J = 7.7 Hz, 2H), 6.73 (t, J = 7.7 Hz, 1H), 6.21 (d, J = 7.7 Hz, 1H9, 4.79 (br "t", 1H), 4.34 (d, J = 4.5 Hz, 2H), 2.38 (s, 6H), 2.34 (s, 6H) 20 Example 2. 16 Synthesis of 8-amino-3-acetyl-2-methylimidazo [1, 2-ajpyridine A mixture of 2,3-diaminopyridine (7 g, 64.1 mmol), 3-chloroacetylacetone (8.6 g, 64.1 mmol) in alcohol
ethyl acetate (80 ml) was refluxed for 9 hours. The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride. A solution of sodium bicarbonate was added and the organic phase was separated. The aqueous phase was extracted twice with methylene chloride. The organic phases were combined and the combined was dried and evaporated under reduced pressure. Chromatography of the residue on silica gel (methylene chloride / methanol, 100: 5) yielded a product which, after recrystallization from ethyl acetate, yielded 1.9 (15%) of the title compound. X H NMR (300 MHz, CDC13): d 2.6 (s, 3 H), 2.75 (s, 3 H), 4.5 (bs, 2 H), 6.6 (d, 1 H), 6.8 (t, 1 H), 9.15 (t, 1 H) ). Example 2.17 was prepared according to Example 1. Example 2.17 Synthesis of 3-acetyl-8- (2,6-dimethylbenzylamino) -2-methyl-1-imidazo [1,2-a] pyridine Yield: 72% XH NMR (300 MHz, CDC13): d 2.4 (s, 6H), 2.6 (s,
3H), 2.7 (s, 3H), 4.35 (d, 2H), 4.85 (bs, 1H), 6.55 (d, 1H), 7.9 (t, 1H), 7.0-7.2 (m, 3H), 9.1 (d) , 1 HOUR) . Example 2.18 Synthesis of l- [8- (2,3-dimethylbenzylamino) -2-
* **** - * --- ~ «* Baa &-« r «» - fc7 ^ ¡^^^ ... ^ met il imidazo [1, 2-a] -pyridin-3-yl] -1-Ethanol To a mixture of 3-acetyl-8- (2,6-dimethylbenzylamino) -2-methylimidazo [1, 2-a] pyridine (500 mg, 1.63 mmol) and methanol (20 ml) was added by portions 5 sodium borohydride (62 mg, 1.63 mmol). Tetrahydrofuran was added and the mixture was stirred for 1 hour. Thin layer chromatography showed that there was still raw material and sodium borohydride (62 mg, 1.63 mmol) was added and the mixture was stirred for 1.5 hours. The solvent is
removed under reduced pressure and methylene chloride was added to the residue. The pH was adjusted to pH = 3 with hydrogen chloride (concentrated) and then alkalized with sodium bicarbonate. The methylene chloride phase was separated, washed with water, dried over sodium sulfate and
evaporated in vacuo. The residue was treated with ethanol / ethyl acetate and after filtration 410 mg, 81% of the desired product was obtained. X H NMR (300 MHz, CDC13): d 1.6 (d, 3 H), 2.15 (s, 3 H), 2.4 (s, 3 H), 4.35 (d, 2 H), 4.8 (bs, 1 H), 5.2 (q, 1 H) ), 6.25 (d, 1H), 6.7 (t, 1H), 7.0-7.2 (m, 3H), 6.8 (d, 1H). Example 2. 19 and 2.20 Synthesis of 2-chloro-6-methylbenzyl bromide and 3-chloro-2-methylbenzyl bromide A mixture of 3-chloro-o-xylene (20 g, 142.2 mmol), N-bromosuccinimide ( 26.57 g, 149.3 mmol), peroxide
dibenzoyl (0.67 g) and tetrachloromethane (200 ml) was refluxed for 5 hours. After filtration, the filtrate was washed with sodium hydrogensulfite and water. The organic phase was dried over sodium sulfate and evaporated in vacuo. Chromatography (si02) (petroleum ether / ethyl acetate, 100: 4) yielded a 10 g fraction containing a mixture of the two title compounds 2-chloro-6-methylbenzylbromide (2.19): bromide 3 -2-methylbenzyl (2.20), 1: 0.7. This mixture was used without further purification. Example 2.21 was prepared according to Example 2.8 Example 2.21 Synthesis of ethyl 8- (2,6-dimethylbenzylamino) -2-methylimidazo [1, 2-a] pyridine-3-carboxylate Yield: 34% XH NMR (300 MHz, CDC13): d 1.4 (t, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 2.6 (s, 3H), 4.4 (q, 2H), 4.5 (d, 2H), 4.9 ( bs, 1H), 6.35 (s, 1H), 7.05-7.35 (, 3H), 8.5 (s, 1H). Examples 2.22, 2.23 (mixture), 2.24, 2.25 and 2.26 were prepared according to Examples 219 and 2.20 Examples 2.22 and 2.23 Synthesis of 2-bromo-6-methylbenzyl bromide (2.22) and 3-bromo-2 bromide -methylbenzyl (2.23)
- ^ kx'ß Xd ^ i & ia Í: ZX ^, S ^^^ SW ^ ii ^^^ 'tfca &S ^ Wfcr.gSe t Yield: 78% (16.8 g of a fraction containing a mixture of the two title compounds (2.22 / 2.23, 1: 0.7) Example 2. 24 5 Synthesis of ethyl 2-bromomethyl-3-methylbenzoate Yield: 26% XH NMR (300 MHz, CDC13): d 1.4 (t, 3H), 2.45 (s, 3H), 4.4 (q, 2H), 5.0 (s, 2H), 7.2-7.4 (m, 2H), 7.75 (d, 1H) 10 Examples 2. 25 and 2. 26 Synthesis of 2-bromomethyl-3-methylbenzonyl trile (2.25) and 3-bromomethyl-2-methylbenzonyl trile (2.26) Yield: 5.6% (2.25) 18% (7.6 g of a fraction containing one mix 15 of the two compounds (2.25 / 2.26, 1.8: 1).? E NMR (300 MHz, CDC13) Example 2.25: d 2.45 (s, 3H), 4.70 (s, 2H), 7.2-7.6 (m, 3H Example 2. 27 Synthesis of 2- (2,3-dimethylimidazo [1,2- a] pyridin-8-yl) -4-methyl-1-isoindoline The title compound was obtained in the synthesis of Example 1.15. (8- (2-ethoxycarbonyl-6-methylbenzylamino) -2,3-dimethylimidazo [1, 2- a] pyridine) Yield: 24%
^? ^^^^^^^^^^^^^^^^^^^^^? ^^^^^^^^^^^^^^^^^ fc ^^^^ XH NMR (300 MHz, CDC13): d 2.91 (s, 3H), 2.92 (s, 3H), 2.94 (s, 3H), 5.4 (s, 2H), 6.9 (t, 1H), 7.35 -7.45 (m, 2H), 7.65 (d, 1H), 7.7-7.85 (m, 2H). Example 2.28 Synthesis of 2- (((2,3-dimethylimidazo [1, 2-a] pyridin-8-yl) -amino) -methyl) -3-methylbenzoic acid A mixture of the compound of Example 2.27 (700 mg, 2.4 mmol), sodium hydroxide (15 ml, 10M) and ethyl alcohol (30 ml) and water (7.5 ml) was refluxed for 4 days. The organic solvent was evaporated in vacuo. The residue was partitioned into methylene chloride and water. The aqueous phase was cooled and hydrogen chloride (concentrated) was added. After extraction with methylene chloride, a mixture of the title compound and the compound of example 2.27 (150 mg) was obtained. The product was crystallized from ethyl alcohol and after filtration the precipitate was washed with ethyl alcohol and with methylene chloride. 60 mg (8%) of the title compound were obtained. XH NMR (300 MHz, CD3OD): d 2.35 (s, 3H), 2.45 (s,
3H), 2.47 (s, 3H), 4.65 (s, 2H), 6.95 (d, 1H), 7.2-7.45 (m, 3H), 7.6 (d, 1H), 7.8 (d, 1H). Example 2. 29 Synthesis of 2-bromo-l-methoxymethyl-3-methylbenzene
To a stirring solution of 2-bromo-3-methylbenzyl bromide (5.2 g, 0.0197 mol) in methanol (30 ml), a saturated solution of sodium bicarbonate (5 ml) was added and the mixture was refluxed. during one night. The mixture was neutralized with acetic acid and the solvent was evaporated under reduced pressure. Chromatography of the residue on silica gel using hexane / methylene chloride (7: 3) as eluent yielded 4.2 g (99%) of the title compound. XH NMR (300 MHz, CDC13): d 2.43 (s, 3H), 3.47 (s,
3H), 4.55 (s, 2H), 7.18-7.30 (m, 3H). Example 2.30 was prepared according to Example 2.29 Example 2. Synthesis of 2-bromo-lr 3 -bis (methoxymethyl) -benzene Yield: 94% XH NMR (500 MHz, CDCl 3): d 3.5 (s, 6H) , 4.6 (2, 4H), 7.35-7.45 (m, 3H). Example 2. 31 Synthesis of 2-bromo-3-methylbenzyl cyanide A mixture of 2-bromo-3-methylbenzyl bromide
(25 g, 0.095 mol) and potassium cyanide (16 g, 0.25 mol) in dimethylformamide (100 ml) was stirred at 90 ° C for 20 hours. The solvent was evaporated under reduced pressure and the residue was
they added toluene and water, the organic phase was separated, washed with water, re-separated and evaporated under reduced pressure. Purification of the residue by silica gel column chromatography using methylene chloride as eluent afforded 8.8 g (44%) of the title compound. ? E NMR (300 MHz, CDC13): d 2.42 (s, 3H), 3.83 (s, 2H), 7.21-7.35 (m, 3H). Example 2.32 Synthesis of 2-bromo-3-methyl phenylacetic acid 2-Bromo-3-methylbenzyl cyanide (8.8 g, 42 mmol) was added to a mixture of concentrated sulfuric acid (50 ml) and water (60 ml). ml) and the mixture was refluxed overnight. Water (150 ml) and diethyl ether were added, and the organic phase was separated. To the organic phase was added a saturated solution of sodium bicarbonate and the aqueous phase was separated. The aqueous phase was acidified by the addition of concentrated sulfuric acid. The aqueous acidic solution was subjected to extraction with diethyl ether and the organic phase was washed with water, dried (Na 2 SO 4) and evaporated under reduced pressure, to obtain 6.5 g of the title compound. ? E NMR (300 MHz, CDC13): d 2.43 (s, 3H), 3.87 (s, 3H), 7.1-7.2 (m, 3H).
Example 2.33 Synthesis of ethyl 2-bromo-methylphenylacetate To a stirred mixture of 2-bromo-3-methylphenylacetic acid (4.8 g, 21 mmol) in ethanol (50 ml), a small amount of sulfuric acid was added. concentrated and the mixture was refluxed overnight. Sodium carbonate (1 g) was added and the solvent was evaporated under reduced pressure. Methylene chloride and water were added to the residue. The organic phase was separated and evaporated under reduced pressure. Purification of the residue by silica gel column chromatography using methylene chloride as the eluent afforded 2.0 g (37%) of the desired product as an oil. XH NMR (300 MHz, CDC13): d 1.27 (t, 3H), 2.43 (s, 3H), 3.81 (s, 2H), 4.18 (q, 2H), 7.2-7.4 (m, 3H). Example 2. Synthesis of 2- (2-bromo-3-methylphenyl) -ethanol To a stirred solution of 2-bromomethylphenyl acetate (2 g, 7.9 mmol) in tetrahydrofuran (30 ml), L1AIH4 ( 0.8 g, 21 mmol) at a temperature of 0 to 5 ° C. After the mixture was stirred at 0-5 ° C for 2 hours, 0.8 ml of water was added dropwise, followed by 0.8 ml of 15% sodium hydroxide and then 2.4 ml of water. The solids were removed by filtration and washed with tetrahydrofuran and with a mixture of
AZ-j ^? ^^% s ^^ & * ^ ^.?. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^ S ^? ^ Iim ^ ¿^ ^ ^ ^ ^ gjyZs | ^ M & *? J | Mí £ ig ^? g ^^ M tetrahydrofuran / methanol (9: 1). The filtrate and the washings were combined and the solvents were removed under reduced pressure. The residue was dissolved in methylene chloride / methanol (9: 1) and filtered through silica gel (0.5 g). The solvent was evaporated under reduced pressure to obtain 1.6 g (95%) of the title compound. E NMR (300 MHz, CDC13): d 2.43 (s, 3H), 3.07 (t, 2H), 3.89 (t, 2H), 7.1-7.3 (m, 3H). Example 2. Synthesis of 2- (2-bromo-3-methylphenyl) -ethyl methyl ester To a stirred solution of 2- (2-bromo-3-methylphenyl) -ethanol (1.6 g, 7.4 mmol) in tetrahydrofuran
(20 ml) was added sodium hydride (50% in oil) (0.46 g, 9.6 mmol). After stirring the mixture for 15 minutes, methyl iodide (1.6 g, 11.3 mmol) was added and the reaction mixture was stirred for 3 hours at room temperature. Water (0.2 g) was added and then acetic acid
(0.2 g). The solvents were evaporated under reduced pressure and purification of the residue by column chromatography on silica gel using methylene chloride as eluent, yielded 1.5 g (89%) of the desired product as an oil. XH NMR (300 MHz, CDC13): d 2.42 (s, 3H), 3.07 (t,
2H), 3.38 (s, 3H), 3.62 (t, 2H), 7.1-7.25 (m, 3H). Example 2.36 Synthesis of 2- (2-methoxyethyl) -6-methylbenzaldehyde To a stirring solution of 2- (2-bromo-3-methylphenyl) -ethyl methyl ether (1.5 g, 6.5 mmol) in anhydrous tetrahydrofuran (10 mg). ml), magnesium was added
(0.16 g, 6.6 mmol). The mixture was refluxed under a nitrogen atmosphere until the reaction started and then stirred without heating for 15 minutes. The mixture was stirred at 50 ° C overnight. The reaction mixture was cooled to room temperature and N, N-dimethylformamide (0.7 g) was added and the mixture was stirred for 30 minutes. A saturated solution of ammonium chloride (10 ml) was added and the mixture was stirred for 1 hour at room temperature. Toluene (20 ml) was added and the organic phase was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using methylene chloride as eluent, to separate the lipophilic by-products and with methylene chloride / diethyl ether (7: 3) as eluent to isolate the title compound (0.17 g, %) in the form of an oil. ? E NMR (300 MHz, CDC13): d 2.61 (s, 3H), 3.25 (t, 2H), 3.36 (s, 3H), 3.61 (t, 2H), 7.1-7.4 (m, 3H). Examples 2.37, 2.38 and 2.39 were prepared from
J '& st s &, - < > ».» J, 'As > -i: .-. ' - 6Mri ^ sira-¡«« AdlÍEfa «M ¡* ^ conformance with Example 2.36 Example 2.37 Synthesis of 2-methoxymethyl-6-methylbenzaldehyde Yield: 90% 5 XH NMR (300 MHz, CDC13): d 2.64 (s, 3H ), 3.43 (s, 3H), 4.78 (s, 2H), 7.2-7.45 (, 3H), 10.55 (s, 1H). Example 2.18 Synthesis of 2,6-bis (methoxymethyl) -benzaldehyde Yield: 79% XE NMR (500 MHz, CDC13). d 3.5 (s, 6H), 4.85 (s, 4H), 7.6 (s, 3H), 10.55 (s, 1H). Example 2.39 Synthesis of 2,5-dimethyl thio phen-3-carbaldehyde Yield: 57% X H NMR (300 MHz, CDCl 3): d 2.41 (s, 3 H), 2.74 (s, 3 H), 6.62 (s, 1 H) , 10.11 (s, 1H). BIOLOGICAL TESTS 1. In vitro experiments Inhibition of acid secretion in isolated rabbit gastric glands The inhibitory effect on the secretion of in vi tro acid was measured in rabbit gastric glands isolated in the manner described by Berglindh et al. (1976) Acta Physiol. Scand. 97, 401-414.
^ i ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ minutes at + 37 ° C in 18 mM Pipes / Tris buffer pH 7.4, containing 2 mM MgCl 2, 10 mM KCl and 5 mM ATP. ATPase activity was estimated in the form of inorganic phosphate released from ATP, in the manner described by LeBel et al. (1978) Anal. Biochem. 85, 86-89. 2. In vivo experiments Inhibitory effect of acid secretion in female rats
Female rats of the Sprague-Dawly breed were used. These were cannulated in the stomach (lumen) and in the upper part of the duodenum, to collect the gastric secretions and for the administration of the test substances, respectively. A period of
recovery 14 days after surgery before starting the test. Before the secretory tests, the animals were deprived of food but not of water for 20 hours. The stomach was washed repeatedly through the
gastric cannula with running water (+ 37 ° C) and with 6 ml of Ringer-Glucose administered subcutaneously. The secretion of acid was stimulated by an infusion for 2.5-4 hours (1.2 ml / h, subcutaneously) of pentagastrin and carbacol (20 and 110 nmol / kg-h,
respectively), during which time the secretions
gastric samples were collected in fractions of 30 minutes. The test substances or the vehicle were administered either 60 minutes after the stimulation started (intravenous and intraduodenal administration, 1 ml / kg) or 2 5 hours before initiating the stimulation (oral dose, 5 ml / kg, closed gastric cannula). ). The time interval between dosing and stimulation can be increased in order to study the duration of the action. Samples of gastric juice were titrated until pH 7.0 with NaOH, 0.1M, and the acid output was calculated as the product of the titration volume by concentration. Other calculations were based on the average responses of groups of 4 to 6 rats. In the case of administration during the stimulation, the acid exit during the periods subsequent to the administration of the test substance or the vehicle, was expressed as fractionated responses, establishing in 1.0 the acid exit in the period of 30 minutes precedents to the administration. Percent inhibition was calculated from the fractional responses induced by the test compound and the vehicle. In the case of administration prior to stimulation, the percentage inhibition was calculated directly from the acid output recorded after the test compound and the vehicle. 25
- ^ - ^^^ 5 a HieilíMMi-i | riM ^ ¡^ ^ ^ ^ ^ ^ ^^^^^ ^ ^ ^ ^ ^ ^ ^ A ^^^ 't ^^^ "a?« «Ta Bioavailability in rats Adult rats of the Sprague-Dawley breed were used. One to three days before the experiments, all rats were prepared by cannulation of the left carotid artery under anesthesia. Rats used for intravenous experiments were also cannulated in the jugular vein (Popovic (1960) J. Appl. Physiol. 15, 727-728). The cannulas were exteriorized by the nape. Blood samples (0.1 to 0.4 g) were taken repeatedly from the carotid artery at intervals up to 5.5 hours after the given dose. The samples were frozen until analysis of the test compound was carried out. Bioavailability was evaluated by calculating the quotient between the area under the blood curve / area under the plasma concentration curve (i) for intraduodenal administration (id) or for oral administration (po) and (ii) for intravenous administration ( iv) in rats or dogs, respectively. The area under the blood concentration versus time curve was determined by the trapezoidal rule log / linear and extrapolated to infinity by dividing the last blood concentration determined between the elimination rate constant in the terminal phase. The
Systemic bioavailability (% F) after intraduodenal or oral administration was calculated as follows (%) F = (AUC (po / id) / AUC (iv)) x 100. Inhibition of gastric acid secretion and bioavailability in conscious dogs Labrador Cobrador or Harrier dogs of both sexes were used. They were placed duodenal fistulas for the administration of the test or vehicle compounds and a cannulated gastric fistula or in the Heidenhaim pouch for the collection of gastric secretion. Prior to the secretory tests, the animals were fasted for approximately 18 hours, but were allowed to drink water freely. The secretion of gastric acid was stimulated for up to 6.5 hours by an infusion of histamine dihydrochloride (12 ml / h) at a dose that produced approximately 80% of the individual maximum secretory response, and the gastric juice was collected in consecutive fractions of 30 minutes. The substance or vehicle was administered orally, i.d. or i.v., from 1 to 1.5 hours after initiating the histamine infusion, in a volume of 0.5 ml / kg of body weight. In the case of oral administration, it should be noted that the test compound was administered in the main secretory stomach of
-* goes "- - . »" * £! & * < i) &Blt ^ itttl iS &ii £ * v ~ *? ^^ ^ acid of the Heidenhaim bag in dogs. The acidity of the gastric juice samples was determined by titration up to pH 7.0 and the acid output was calculated. The acid exit in the collection periods after the administration of the test substance or the vehicle was expressed as fractionated responses, establishing the acid exit in the fraction preceding the administration in 1.0. Percent inhibition was calculated from the fractional responses induced by the test compound and the vehicle. Blood samples for analysis of the concentration of the test compound in the plasma were taken at intervals of up to 4 hours after the dose. The plasma was separated and frozen within a period of 30 minutes after collection and analyzed afterwards. The systemic bioavailability (% F) after oral administration or i.d., was calculated in the manner previously described in the model in rats. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
* a¿ * & -te ^ • «.» g-y
Claims (15)
- REGVTNDICATIONS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. A compound of the formula I or a pharmaceutically acceptable salt thereof, characterized in that R1 is 10 (a) H, (b) alkyl of 1 to 6 carbon atoms, (c) alkenyl of 1 to 6 carbon atoms, (d) CH2OH, (e) halogen, or 15 (f) thiocyano R2 is (a) alkyl of 1 to 6 carbon atoms, (b) hydroxyalkyl, (c) alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, ( d) hydroxy-alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (e) alkylthio of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (f) cyanoalkyl of 1 to 6 carbon atoms, or (g) alkyl of 1 to 6 carbon atoms halogenated, or (h) aminocarbonyl-alkyl of 1 to 6 carbon atoms, R3 is (a) H, (b) alkoxy of 1 to 6 carbon atoms, (c) alkyl of 1 to 6 carbon atoms, (d) halogen, (e) ) hydroxy-alkyl of 1 to 6 carbon atoms, (f) hydroxy-alkoxy of 1 to 6 carbon atoms, (g) alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (h) alkoxy of 1 to 6 carbon atoms-alkoxy 1 to 6 carbon atoms, (i) alkoxycarbonyl of 1 to 6 carbon atoms, (j) alkanoyl of 1 to 6 carbon atoms, (k) alkyl of 1 to 6 carbon atoms halogenated, (1) N02 (m) ) CN, (n) sulfonyl of 1 to 6 carbon atoms, (o) sulfinyl of 1 to 6 atoms of carbon, (p) alkylthio of 1 to 6 carbon atoms, (q) alkylaminosulfonyl of 1 to 6 carbon atoms, 5 (r) (alkyl of 1 to 6 carbon atoms) ) 2-amino-sulfonyl, (s) aminosulfonyl, (t) alkylsulfonylamino of 1 to 6 carbon atoms, 10 (u) (alkylsulfonyl of 1 to 6 carbon atoms) 2amino, or (v) trifluoro-ethelsulfonylamino, (x) alkylcarbonylamino of 1 to 6 carbon atoms, 15 (y) alkoxycarbonylamino of 1 to 6 carbon atoms, or (z) aminocarbonylamino of 1 to 6 carbon atoms, optionally substituted with one or two alkyl groups of 1 to 6 carbon atoms, R4 is (a) H (b) alkyl of 1 to 6 carbon atoms, (c) alkyl of 1 to 6 carbon atoms halogenated, 25 (d) alkoxy of 1 to 6 carbon atoms, or (e) halogen, Ar is a phenyl, thienyl, furanyl, naphthyl or pyridyl group substituted with R5, R6 and / or R7, X represents / CH2 Rs is (a) H, (b) alkyl of 1 to 6 carbon atoms, (c) alkoxy of 1 to 6 carbon atoms, (d) hydroxy, (e) hydroxyalkyl of 1 to 6 carbon atoms, (f) hydroxyalkoxy of 1 to 6 carbon atoms, (g) alkyl of 1 to 6 carbon atoms halogenated, (h) alkoxy of halogenated carbon atoms, (i) alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (j) halogen, (k) hydroxy-alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (1) CN, (m) alkoxycarbonyl of 1 to 6 carbon atoms , ^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^ H ^^^^^^^^^^^ ß ^^? ^^^^^ ^ ^^ (n) alkoxycarbonyloxy of 1 to 6 carbon atoms, (o) alkylsulfonyloxy of 1 to 6 carbon atoms, (p) trifluoromethylsulfonyloxy, (q) acyloxy of 1 to 6 carbon atoms-alkyl of 1 to 6 atoms carbon, (r) alkylsulfonyl of 1 to 6 carbon atoms - alkyl of 1 to 6 carbon atoms, (s) alkylsulfinyl of 1 to 6 carbon atoms - alkyl of 1 to 6 carbon atoms, (t) alkylthio 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, (u) alkoxycarbonylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or (v) aryl, (x) alkylamino of 1 to 6 carbon atoms, (y) NHC = OR12 x \ * ° (z) H or a group ° substituted with alkyl of 1 to 4 carbon atoms (Aa) H or a group 'substituted with alkyl of 1 to 4 carbon atoms (ab) alkylsulfonylamine of 1 to 6 carbon atoms, R6 is (a) H (b) alkoyl of 1 to 6 carbon atoms, (c) halogen (d) hydroxyalkyl of 1 to 6 carbon atoms, (e) alkyl of 1 to 6 carbon atoms halogenated, (f) alkoxy of halogenated carbon atoms, (e) alkoxy of 1 to 6 carbon atoms-alkyl of 10 to 6 carbon atoms, or (f) CN R is (a) H, (b) alkyl of 1 to 6 carbon atoms, 15 (c) alkoxy of 1 to 6 carbon atoms, (d) halogen, (e) N02 (f) alkyl of halogenated carbon atoms, 20 (g) alkoxy of halogenated carbon atoms, (h) aryloxy, or (i) CN RB is 25 (a) H or (b) alkyl of 1 to 6 carbon atoms, R12 is (a) alkoxy of 1 to 6 carbon atoms, (b) alkoxy of 1 to 6 carbon atoms-alkoxy of 2 to 4 carbon atoms, (c) NH2, (d) hydroxyalkoxy of 2 to 4 carbon atoms, (e) alkyl of 1 to 6 carbon atoms - carbonyloxy-alkoxy of 2 to 4 carbon atoms, (f) alkoxy of halogenated carbon atoms, (g) alkyl of 1 carbon atoms halogenated, (h) hydroxyalkyl of 1 to 4 carbon atoms, (i) alkyl of 1 to 6 carbon atoms-carbonyloxy-alkyl of 1 to 4 carbon atoms, (j) aryl, (k) ) arylalkyl of 1 to 4 carbon atoms, (1) sulfañil of 1 to 4 carbon atoms-alkoxy of 2 to 4 carbon atoms, (m) sulfinil of 1 to 4 carbon atoms-alkoxy of 2 to 4 carbon atoms carbon, (n) sulfonyl of 1 to 4 carbon atoms-alkoxy of 2 to 4 carbon atoms, R5 and R6 are in the ortho positions in relation to X R7 is in the meta position or in the para position, in relation to X R5 and R8 together can form a 5- or 6-membered ring substituted with hydroxy- or alkoxy- groups, provided that one of between R3 and R4? H or halogen, also provided that at least one of R5, R6 and R7? E, also provided that when R5 = (y), (z), (aa) or (ab), then one of R3 and R4? H, also provided that when R1 = H then R7? CH3, also provided that when R2 = CH2OH or CH2CN, then one of between R5 and R6? E.
- 2 . A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R1 is H, CH3, CH2OH; R2 is CH3, CH2CH3, CH2CH2OH, CH2CH2SCH3, CH2CH2OCH3, or CH2CH2CN, ** * > + * - > *** - * - > - ^^ jg Mt ^. . ^ BMJt ?. .? sj ^ * x *? &8bl R3 is H, CH3, CH2CH3, F, Cl, Br, OCH3 OCH2CH3, CH2OH, CH2CH2OH, OCH2CH2OH, CH2CH2OCH3, OCH2CH2OCH3, C = OOCH3, C = OOCH2CH3, C = OCH3 , C = OCH2CH3, C = OCH (CH3) 2, or C = OCH2CH2CH3, R4 is H, CH3, CH2CH3, F, Cl, Br, OCH3 or OCH2CH3, Ar is a phenyl, thienyl, furyl or naphthyl group, R5 is H, CH3, CH2CH3, OCH3, OH, CH2OH, CH2OCH3, CH2CH2OH, CH2CH2OCH3, OCH2CH2OH, OC = OOCH3, OC = OCH2CH3, OCHF2, OCF3, F, Cl, Br, CN, phenyl, CH2CH2OC = OCH3, CH2NHC = OOCH3 or 10 CH2NHC = OOCH2CH3, R6 is H, CH3, CH2CH3, CF3, OCF3, OCF2H, F, Cl, Br, or R7 is H, F, Cl, Br, OCF2H or OCF3; R8 is H, CH3 or CH2CH3. 15 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R1 is H, CH3 or CH2OH, R2 is CH3, CH2CH3, CH2OH, CH2SCH3, CH2OCH3 or CH2CN, R3 is H, CH3, CH2CH3, OCH3 , OCH3, CH2OH, C = OOCH3, C = OOCH2CH3, C = OCH3, C = OCH2CH3, or C = OCH2CH2CH3, R4 is H or CH3; Ar is phenyl, thienyl or furyl, S ^ - ^ ^ - ~ ^ ~ x: .x ^^ .-. - - - .. ^. XA i¿l¿fegJ ^ ^ .J ^ ..., ', ¿. ^,?, .. R5 is H, CH3, CH2CH3, OCH3, OH, CH2OH, CH2OCH3, CH2CH2OH, CH2CH2OCH3, OCH2CH2OH, OC = OOCH3, OC = OCH2CH3, OCHF2, OCF3, F, Cl, Br, CN, CH2CH OC = OCH3, CH2NHC = OOCH3 , or 5 CH2NHC = OOCH2CH3; R6 is H, CH3, CH2CH3, CF3, OCF
- 3, OCF2H, F, Cl, Br, or R7 is H, F, Cl, Br, OCF2H, OCF3; R8 is H or CH3.
- 4. A process for the preparation of a compound according to any of claims 1 to 3, characterized in that it comprises: reacting a compound of the general formula II Wherein X1 is NH2 or OH and R1, R2, R3 and R4 are as defined for formula I, they can be reacted with compounds of the general formula III ^^ gg ^ l ^ í ^ g¡gwg * ^^ where "Ar" is as defined for formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy group, in an inert solvent such as acetone, acetonitrile, dimethoxyethane, methanol, ethanol or N, N-dimethylformamide and optionally in the presence of a base, such as an alkali metal hydroxide, alkali metal carbonate or an organic amine, to obtain a compound of the general formula I.
- 5. A process for the preparation of a compound according to any of claims 1 to 3, wherein X is NH, characterized in that it comprises: a) reacting a compound of the general formula IV R ' wherein R1, R2, R3 and R4 are as defined for formula I, with a compound of the general formula V °? H (V) Ar wherein "Ar" is as defined for formula I, in a solvent inert in the presence of a Lewis acid, such as zinc chloride, under standard conditions to obtain a compound of the general formula VI wherein R1, R2, R3, R4 and Ar are as defined for formula I; b) treating the compound of the general formula VI wherein R1, R2, R3, R4 and Ar are as defined in formula I, with sodium borohydride or sodium cyanoborohydride, under standard conditions in a solvent such as methanol or ethanol , to obtain a compound of the general formula I wherein X is NH.
- 6. A process for the preparation of a compound according to any of claims 1 to 3, wherein R1 is CH2OH or H, characterized in that: a) a compound of the general formula VII is reacted wherein X1 is NH2 or OH, R2, R3 and R4 are as defined for formula I, with a compound of general formula III ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^ A¡ I ("O Ar where Ar is as defined for formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy group, to obtain a compound of the formula General VIII wherein R2, R3, R4, Ar and X are as defined for formula I, in an inert solvent, such as acetone, acetonitrile, dimethoxyethane, methanol, ethanol or N, N-dimethylformamide, and optionally in the presence of a base , such as an alkali metal hydroxide, alkali metal carbonate or an organic amine under standard conditions; b) treating a compound of the general formula VIII, wherein R2, R3, R4, Ar and X are as defined for formula I, with lithium aluminum hydride under standard conditions in a solvent such as tetrahydrofuran or ether, to obtaining a compound of the general formula I wherein R1 is CH2OH, or c) treating a compound of the general formula VIII wherein R2, R3, R4, Ar and X are as defined for the z ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^ formula I, with a base or an aqueous acid in an inert solvent such as diphenylether, under standard conditions, to obtain a compound of the formula I wherein R1 is H
- 7. A process for the preparation of a compound according to any of claims 1 to 3, wherein R1 is CH2OH and X is NH, characterized in that it comprises: a) reacting a compound of the general formula IX NH, with a compound of the general formula V T (V) Ar wherein Ar is as defined for formula I, in an inert solvent, under standard conditions, in the presence of a Lewis acid, such as zinc chloride, to obtain a compound of general formula X «-. ^ ". ^^^. ~ - - '• -. ^^^^^^^^^ - ^^. ^ A ^,;, ^^^^^, ^, "_ ^, d ^. ,, where R2, R3, R4 , and Ar are as defined for formula I; b) reacting a compound of the general formula X wherein R2, R3, R4 and Ar are as defined for formula I, with sodium borohydride or sodium cyanoborohydride, under standard conditions in a solvent such as methanol or ethanol, to obtain a compound of the general formula XI 10 wherein R > 2, R, R and Ar are as defined for formula I, c) reacting a compound of general formula XI wherein R2, R3, R4 and Ar are as defined for formula I, with lithium hydride and aluminum under standard conditions in a solvent such as tetrahydrofuran or ether, to obtain a compound of the general formula I wherein R1 is CH2OH and X is NH, or; d) treating a compound of the general formula XI wherein R2, R3, R4 and Ar are as defined for formula I, with a base or an aqueous acid in an inert solvent such as diphenylether, under standard conditions, - "- - ..-. ^. ^ .. ^^ -. * ... ^^, ^ ^? ^^. Í ^ MSt ^^^: ^ ¿z. ^^ ^ ^. J .. ^ ... ^ ... to obtain a compound of the general formula I wherein R1 is H.
- 8. A process for the preparation of a compound according to any of claims 1 to 3, wherein X is CH20, characterized in that it comprises: a) reacting a compound of the general formula XII with an α-halocarbonyl compound of the general formula R2C0CH (Z) R1, wherein R1 and R2 are as defined for formula I and Z is a leaving group such as Br or Cl, in an inert solvent such as acetonitrile or ethanol, under standard conditions, to obtain compounds of the general formula XIII wherein R1, R2, R3, R4 and Ar are as defined for formula I. ^^^ - ^ ^^ __ ^^ __ ^ ¿^^ t ^ ^^^^ ^ ^ ^ ^ ^ S ^ ^^^^^^^^ A * a * £ ¿? T & ß ** *
- 9. A pharmaceutical formulation characterized in that it contains a compound according to any of claims 1 to 3 as an active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
- 10. The use of a compound according to any of claims 1 to 3 for the manufacture of a medicament for the inhibition of gastric acid secretion.
- 11. The use of a compound according to any of claims 1 to 3 for the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases.
- 12. The use of a compound according to any of claims 1 to 3 for the manufacture of a medicament for the treatment or prophylaxis of conditions including infections by Helicobacter pylori of the gastric mucosa, characterized in that the compound is adapted to be administered in combination with at least one antimicrobial agent.
- 13. A pharmaceutical formulation for use in the inhibition of gastric acid secretion, characterized in that the active ingredient is a compound according to any of claims 1 to 3.
- 14. A pharmaceutical formulation for use in the treatment of gastrointestinal inflammatory diseases, characterized in that the active ingredient is a compound according to any one of claims 1 to 3.
- 15. A pharmaceutical formulation for use in the treatment or prophylaxis of disorders including infections by Helicobacter pylori of the human gastric mucosa, characterized in that the active ingredient is a The compound according to any one of claims 1 to 3 in combination with at least one antimicrobial agent. Jmai? - .aafe &
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SE9802794-9 | 1998-08-21 |
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