MXPA00004818A - Substituted dimeric compounds - Google Patents
Substituted dimeric compoundsInfo
- Publication number
- MXPA00004818A MXPA00004818A MXPA/A/2000/004818A MXPA00004818A MXPA00004818A MX PA00004818 A MXPA00004818 A MX PA00004818A MX PA00004818 A MXPA00004818 A MX PA00004818A MX PA00004818 A MXPA00004818 A MX PA00004818A
- Authority
- MX
- Mexico
- Prior art keywords
- ethyl
- formula
- acetylamino
- preparation
- acetamide
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 258
- 230000001193 melatoninergic Effects 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims abstract 7
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims abstract 7
- 238000002360 preparation method Methods 0.000 claims description 282
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 118
- 238000000034 method Methods 0.000 claims description 84
- -1 hydroxy, carboxy, formyl Chemical group 0.000 claims description 77
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 69
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 53
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- 238000007792 addition Methods 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 18
- 239000007858 starting material Substances 0.000 claims description 17
- 125000005842 heteroatoms Chemical group 0.000 claims description 16
- ILAHWRKJUDSMFH-UHFFFAOYSA-N Boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 10
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000004434 sulfur atoms Chemical group 0.000 claims description 9
- 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 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000006684 polyhaloalkyl group Polymers 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000004429 atoms Chemical group 0.000 claims description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 230000000875 corresponding Effects 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 229910015845 BBr3 Inorganic materials 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 4
- 150000002941 palladium compounds Chemical class 0.000 claims description 4
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 4
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 claims description 3
- AEDIXYWIVPYNBI-UHFFFAOYSA-N Heptanamide Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 claims description 3
- 229910004664 ORa Inorganic materials 0.000 claims description 3
- 241000658540 Ora Species 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K Aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 229910017711 NHRa Inorganic materials 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 229910002056 binary alloy Inorganic materials 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 230000001808 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 230000017858 demethylation Effects 0.000 claims description 2
- 238000010520 demethylation reaction Methods 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 150000002816 nickel compounds Chemical class 0.000 claims description 2
- 150000002829 nitrogen Chemical group 0.000 claims description 2
- 230000000269 nucleophilic Effects 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- NUTBUHYTTNKZOR-UHFFFAOYSA-M sodium;N,N-dimethylcarbamothioate Chemical compound [Na+].CN(C)C([O-])=S NUTBUHYTTNKZOR-UHFFFAOYSA-M 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- 229910052718 tin Inorganic materials 0.000 claims description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 241000689227 Cora <basidiomycete fungus> Species 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 229940079593 drugs Drugs 0.000 claims 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 1
- 239000000047 product Substances 0.000 description 42
- 239000000463 material Substances 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 230000002829 reduced Effects 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- 230000000694 effects Effects 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- 230000027455 binding Effects 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 238000002844 melting Methods 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 239000001184 potassium carbonate Substances 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 102000001419 Melatonin receptor family Human genes 0.000 description 8
- 108050009605 Melatonin receptor family Proteins 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 230000033764 rhythmic process Effects 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000035492 administration Effects 0.000 description 7
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000035591 circadian rhythms Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 5
- 210000001367 Arteries Anatomy 0.000 description 5
- 229960003987 Melatonin Drugs 0.000 description 5
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- DNSISZSEWVHGLH-UHFFFAOYSA-N Butyramide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000283898 Ovis Species 0.000 description 4
- 101710030983 RNF138 Proteins 0.000 description 4
- 101710029702 TICAM1 Proteins 0.000 description 4
- 101710021425 TRIM69 Proteins 0.000 description 4
- 102100003447 TRIM69 Human genes 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 206010001897 Alzheimer's disease Diseases 0.000 description 3
- 206010022437 Insomnia Diseases 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- VUVGYHUDAICLFK-UHFFFAOYSA-N Perosmic oxide Chemical compound O=[Os](=O)(=O)=O VUVGYHUDAICLFK-UHFFFAOYSA-N 0.000 description 3
- SONNWYBIRXJNDC-VIFPVBQESA-N Phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 3
- 229960001802 Phenylephrine Drugs 0.000 description 3
- 206010040984 Sleep disease Diseases 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000000949 anxiolytic Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000002060 circadian Effects 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
- 238000001816 cooling Methods 0.000 description 3
- MFNYBOWJWGPXFM-UHFFFAOYSA-N cyclobutanecarboxamide Chemical compound NC(=O)C1CCC1 MFNYBOWJWGPXFM-UHFFFAOYSA-N 0.000 description 3
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000003137 locomotive Effects 0.000 description 3
- 238000004452 microanalysis Methods 0.000 description 3
- 230000001264 neutralization Effects 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 2
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-bromopropan-1-ol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 2
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 2
- 206010060961 Appetite disease Diseases 0.000 description 2
- 210000003169 Central Nervous System Anatomy 0.000 description 2
- 206010009191 Circadian rhythm sleep disease Diseases 0.000 description 2
- 206010012601 Diabetes mellitus Diseases 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N Diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N Glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 229940088597 Hormone Drugs 0.000 description 2
- 208000001456 Jet Lag Syndrome Diseases 0.000 description 2
- 102100013878 MTNR1B Human genes 0.000 description 2
- 101710040394 MTNR1B Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- FJDDSMSDZHURBJ-XSBOKVBDSA-N N-[2-(2-iodanyl-5-methoxy-1H-indol-3-yl)ethyl]acetamide Chemical compound COC1=CC=C2NC([125I])=C(CCNC(C)=O)C2=C1 FJDDSMSDZHURBJ-XSBOKVBDSA-N 0.000 description 2
- SWFFADGCZNYXKT-UHFFFAOYSA-N N-[2-(5-amino-1-benzofuran-3-yl)ethyl]acetamide Chemical compound C1=C(N)C=C2C(CCNC(=O)C)=COC2=C1 SWFFADGCZNYXKT-UHFFFAOYSA-N 0.000 description 2
- MHHJOVZZMYCCGK-UHFFFAOYSA-N N-[2-(5-amino-1-benzothiophen-3-yl)ethyl]pentanamide Chemical compound C1=C(N)C=C2C(CCNC(=O)CCCC)=CSC2=C1 MHHJOVZZMYCCGK-UHFFFAOYSA-N 0.000 description 2
- 206010061536 Parkinson's disease Diseases 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- VZJVWSHVAAUDKD-UHFFFAOYSA-N Potassium permanganate Chemical compound [K+].[O-][Mn](=O)(=O)=O VZJVWSHVAAUDKD-UHFFFAOYSA-N 0.000 description 2
- 206010039775 Seasonal affective disease Diseases 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M Sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
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Abstract
The invention relates to compound of formula (I):wherein:A represents a grouping NR1C(Q)R2, C(Q)NR2R3 or NR1C(Q)NR2R3,B represents a grouping NR1C(Q)R2, NR1C(Q)NR2R3, C(Q)NR2R3, C(Q)OR1, NR1C(Q)OR2 or NR2R3,G1 and G3 represent an optionally substituted alkylene chain, Cy and Cy', which are different, represent a ring structureorG2 represents a chain and medicinal products containing the same are useful in treating or in preventing melatoninergic disorders.
Description
NEW REPLACED DIMERIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT
THEY CONTAIN
DESCRIPTION OF THE INVENTION
The present invention relates to new substituted dimeric compounds, to a process for their preparation and to pharmaceutical compositions containing them. From the prior art, dimeric structures are known in the naphthalene series (J. Chem. Soc., Dalton Trans., 1979, (10), pp. 1497-502) that have been studied for their complex coordination properties. metallic, or in the indole series studied for their "similar to curare" activity (Khim.-Farm, Zh., 1984, 18 (1), pp. 29-31). In addition, applications WO 9600720 and WO 9414771 describe mixed dimeric structures for use as 5-HTj ligands. and synthesis intermediaries, respectively. Due to their novel structure, the compounds of the present invention are novel and have pharmacological properties that are very useful with respect to melatoninergic receptors. Many studies in the last ten years have demonstrated the key role of melatonin (N-acetyl-5-methoxytryptamine) in many pathophysiological phenomena and in the control of the cicardian rhythm. However, its half-life is very short, due to the fact that it is metabolized quickly. Therefore, a great interest is found in the possibility of providing the physician with melatonin analogues that are metabolically more stable, that have an agonist or antagonist character and that can be expected to have a therapeutic effect that is superior to that of the hormone itself. In addition to its beneficial action on disorders in the circadian rhythm (J. Neurosurg, 1985, 63., p • 321-341) and
disorders in sleep (Psychopharmacology, 1990, 100, pp. 222-226), the ligands of the melatoninergic system have useful pharmacological properties with respect to the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8. ( 3-4), pp. 264-152) and analgesic properties (Pharmacopsychiat., 1987, 20, pp. 222-223) as well as for the treatment of Parkinson's disease (J.? Eurosurg, 1985, 63. , pp. 321-341) and Alzheimer's disease (Brain Research, 1990, 528, pp. 170-174). Those compounds have also shown activity in relation to certain
cancers (Melatonin - Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), ovulation (Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology, 1986, 24., pp. 359-364 ) and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20. (4), pp. 443-446).
The various effects are exerted via the intermediary of specific melatonin receptors. Molecular biology studies have demonstrated the existence of many receptor subtypes that are capable of binding that hormone (Trends Pharmacol, Sci., 1995, 16, p 50; WO 97.04094). It has been possible, for various species including mammals, for some of these receptors to be located and characterized. In order to better understand the physiological functions of these receptors, it is a great advantage that specific ligands are available. In addition, such compounds, by selectively interacting with one or other of these receptors, can be excellent medications for the physician in the treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above. In addition to the fact that the compounds of the present invention are novel, they show a very strong affinity for melatonin receptors and / or selectivity for one or other of the melatoninergic receptor subtypes. The present invention relates more especially to compounds of formula (I):
A- ^ 1-Cy-G2-Cy'-G3-B (I)
where: l A represents a grouping of formula
-NR ^ -R2, -N 'C-NR ^ 3 or -C-NR2R3 Q Q Q
wherein: Q represents a sulfur or oxygen atom, R1, R2 and R3, which may be identical or different, represent a hydrogen atom or a group Ra (in which Ra represents a linear or branched, unsubstituted or substituted alkyl group (Ci-Cg), an alkenyl group ( C2-C6) linear or branched, unsubstituted or substituted, a linear or branched, unsubstituted or substituted alkynyl group (C2-C6), an unsubstituted or substituted (C3-C8) cycloalkyl group, a cycloalkyl-alkyl group (C3) -C8) unsubstituted or substituted in which the alkyl portion is linear or branched, a polyhaloalkyl group in which the alkyl portion is linear or branched, an aryl group, an arylalkyl group in which the alkyl portion is linear or branched , an arylalkenyl group (C2-C3) in which the alkenyl portion is linear or branched, a heteroaryl group, a heteroarylalkyl (Cx-C6) group in which the alkyl portion is linear or branched, or a heteroarylalkenyl group (C2-) C3) in which the alkenyl portion is linear or amidated), or the groups R2 and R3 can also form, with the nitrogen atom holding it, a group selected from piperazinyl, piperidinyl and pyrrolidinyl,
B represents a grouping of formula
- R ^ -R2, -NR1C-NR2R3, -C-NR2R3, -C-OR1, -NR ^ -OR2 or NR2R3 where
Q Q Q Q Q Q, R1, R2 and R3 are as defined in the above,
Gx and G3, which may be identical or different, represent a straight or branched alkylene chain containing from 1 to 4 carbon atoms which is optionally substituted by one or more identical or different groups which are selected from hydroxy, carboxy, formyl, Ra, ORa, COORa and C0Ra (where Ra is as defined in the above), Cy and Cy1, which are different, represent
a ring structure of formula (II)
where: * X and Y, which may be identical or different, represent a sulfur, oxygen or carbon atom, or a CH or CH2 group, * R4 represents a hydrogen or a halogen atom, or a CF3, hydroxy group , carboxy, formyl, amino, NHRa, NRaR1a, NHC0Ra, C0NHRa, Ra, 0Ra, C0Ra or COORa, (where Ra is as defined above and R1, »may have any of the meanings of Ra), * the symbol ^ = means that the unions are simple or double, with the condition that it respects the valence of the atoms, where G2 replaces the benzene ring, and G replaces the ring containing X and Y in the case of Cy, and G2 replaces the benzene ring and G3 replaces the ring containing X and Y was the case of Cy ', or a ring structure of the formula (III):
wherein: * Z represents a sulfur or oxygen atom, or a group CH2, NH, NS02Ph or NRa (where Ra is as defined above), * D represents a benzene or pyridine ring, * R4 is as is defined in the above, * the symbol = - = ^ means that the link is simple or double, with the condition that the valence of the atoms is respected, where G2 replaces the ring D and G1 replaces the ring containing Z in the case of Cy, and G2 replaces the ring D and G3 replaces the ring containing Z in the case of Cy1, the two different rings, Cy and Cy 'of the compounds of formula (I) are both represented by a structure of formula (II) or by a structure of formula (III), or one of the two rings is represented by a structure of formula (II) and the other is represented by a structure of formula (III), G2 represents a chain of formula (IV):
Jr,! - ~ -. { CH2) rr "W2 ^ (CH2) vzTW3 ~ (IV)
wherein: W1 # W2 and W3, which may be identical or different, represent a bond, an oxygen or sulfur atom, or a CH2 / CHRa, NH or NRa group (wherein Ra is as defined above) , n represents an integer where 0 = n = 6, m represents an integer where 0 = m = 6, with the proviso that it is not possible to have two consecutive heteroatoms and where the chain of formula (IV) defined in this way it can have one or more unsaturated bonds, it being understood that: "aryl" means the naphthyl, phenyl and biphenyl groups, "heteroaryl" means any saturated or unsaturated monocyclic or bicyclic group containing from 5 to 10 ring atoms and containing from 1 to 3 heteroatoms which are selected from nitrogen, sulfur and oxygen, it is possible that the "aryl" and "heteroaryl" groups are substituted by one or more identical and different radicals which are selected from hydroxy, carboxy, alkoxy (Cj. -C6) linear or branched, alkyl linear or branched, polyhaloalkyl (CC ,;) in which the alkyl portion is linear or branched, formyl, cyano, nitro, amino, linear or branched alkylamino, di-alkyl (CL-Cg) amino, in which each alkyl portion is linear or branched, and halogen atom, the term "substituted" applied to the terms "alkyl," "alkenyl" and "alkynyl" means that these groups are substituted by one or more identical or different radicals that are selected from hydroxy, alkoxy linear or branched, polyhaloalkyl in which the alkyl portion is linear or branched, amino, linear or branched alkylamino (CL-Cg), dialkyl (C 1 -C 6) amino, in which each alkyl portion is linear or branched, and halogen, the term "substituted" applied to the terms "cycloalkyl" and "cycloalkylalkyl" means that the cyclic portion of these groups is substituted by one or more identical or different radicals which are selected from hydroxy, alkoxy
(Cj.-C6) linear or branched, polyhaloalkyl in which the alkyl portion is linear or branched, amino, linear or branched alkylamino, di-alkyl (CL-Cg) amino in which each alkyl portion is linear or branched, and halogen atoms, their enantiomers and diastereoisomers and addition salts thereof, with a pharmaceutically acceptable acid or base. Among the pharmaceutically acceptable acids there can be mentioned, by way of non-limiting example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, etc. Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, terbutylamine, etc. Preferred compounds of the invention are the compounds of formula (I) wherein: Cy and Cy ', which are different, represent a ring structure of formula (II), such as, for example, naphthalene, tetrahydronaphthalene, the groups 1, 4-benzodioxine or chroman, - Cy and Cy1, which are different, represent a ring structure of formula (III), such as, for example, indole, azaindole, benzothiophene or benzofuran, and Cy represents a ring structure of Formula (II) and Cy 'represents a ring structure of formula (III). Advantageously, the invention relates to compounds of formula (I), wherein G2 represents a single bond, or a group -W4- (CH2) _.- W'4- (where W4 and W'4, which may they are identical or different, represent an oxygen or sulfur atom, or an NH or NRa group and p represents an integer where 1 = p = 12), such as, for example, the grouping -0- (CH2) p-0 - (where p is as defined in the above), or a grouping of formula -W4- (CH2) p, -W'4- (CH2) p ,, - W "4- (where W4, W ' 4 and W "4- which may be identical or different, represent an oxygen or sulfur atom, or an NH or Ra group, and p 'and p" are two integers where 2 = p' + p "= 12), such as, for example, the grouping -0- (CH2) p, -0- (CH2) p "-0- (wherein p1 and p" are as defined in the above.) Preferred substituents A and B of the invention are the groupings NR'-C (Q) R2, NR ^ ÍO NR ^ 3 and C (Q) NRR3 and more especially the groupings NR1C0R2 and C0NRR3. More special still, the invention relates to the compounds of formula (I) which are: -N- (2-. { 7- [2- ( { 3- [2 (acetylamino) ethyl] -l-benzofuran-5-yl} oxy) ethoxy] -1-naphthyl} ethyl) acetamide, -N- (2- { 5- [2- ( { 8- [2 (acetylamino) ethyl] -2 -naphthyl}. oxy) ethoxy] -1-benzofuran-3 il.} ethyl) -2-furamide, -N- (2- { 5- [2- ( { 8- [2 (acetylamino) ethyl] -2-naphthyl} oxy] ethoxy] -1 H -pyrrolo [2, 3-b] -pyridin-3-yl.} Ethyl) cyclopropanecarboxamide, -N- (2. {7- [3- ( { 3- [2 (acetylamino) ethyl] ] -l-benzothiophen-5-yl.} oxy) propoxy] -1-naphthyl} ethyl) acetamide, -N- [2- (5- { [6- ( { 8- [ 2- (acetylamino) ethyl] -2 -naphthyl} oxy) hexyl] oxy.} - 2JT-pyrrolo- [2,3-b] pyridin-3-yl) ethyl] acetamide, -N- (2 -. { 7 - [4- ( { 3- [2- (Acetylamino) ethyl] -l-benzofuran-5-yl} oxy) butoxy] -1-naphthyl} -ethyl) acetamide, -N- . { 2- [5- [4- ( { 8- [2- (acetylamino) ethyl] -2 -naphthyl} oxy) utoxy] -1- (phenylsulfonyl) -lH-indol-3-yl] ethyl} cetamide, -N- (2- { 7- [4- ( { 8- [2- (acetylamino) ethyl] -2 -naphthyl}. oxy) butoxy] - 1,2,3, 4- tetrahydro-1-naph alenyl.} ethyl) acetamide, -N- (2- {5- [4- ( { 3- [2- (acetylamino) ethyl] -3a, 7a-dihydro-1- benzofuran-5-yl.}. oxy) -butoxy] -1H-indol-3-yl.} ethyl) acetamide, -N- (2- { 7- [4- (. {3- [2- ( acetylamino) ethyl] -l-benzothien-5-yl} oxy) butoxy] -1-naphthyl.] -ethyl) acetamide, -N- (2-. {5- [4- (. {3 - [2- (acetylamino) ethyl] -l-benzothien-5-yl} oxy) utoxy] -1H-indol-3-yl} ethyl) acetamide, -N- (2-. {5- [4- ( { 3- [2- (Acetylamino) ethyl] -l-benzothien-5-yl} oxy) utoxy] -lH-pyrrolo- [2,3-b] pyridin-3-yl}. ethyl) acetamide,
-N- (2 - { 5 - [4- ( { 3- [2- (acetylamino) ethyl] -l-benzofuran-5-yl} oxy) butoxy] -IH-pyrrolo- [2 , 3-b] pyridin-3-yl.} Ethyl) acetamide,
-N- (2- { 5- [4- ( { 3- [2- (acetylamino) ethyl] -1H-indol-5-yl.} Oxy) butoxy] -lH-pyrrolo- [2 , 3-j] pyridin-3-yl.} Ethyl) acetamide, -N- [2- (7 -. {3 - [2- (acetylamino) ethyl] -1-benzofuran-5-yl.} .-l-naphyl) ethyl] acetamide, -N- [3 - (5- { 8- [2- (acetylamino) ethyl] -2-naphthyl}. -lH-pyrrolo- [2,3 - J] pyridin-3-yl-J-propyl] -heptanamide, - N- [2 - (7 -. {3 - [2- (acetylamino) ethyl] -l-benzothien-5-yl}.-L-naph ) ethyl] acetamide, -N- [2- (5- { 8- [2- (acetylamino) ethyl] -2 -naphthyl}. -lH-pyrrolo- [2,3-] pyridin-3-yl .] ethyl] acetamide, -N- [2- (5- { 3- [2- (Acetylamino) ethyl] -l-benzofuran-5-yl} -1-benzothien-3-yl) ethyl ] -acetamide, -N- [2- (5- { 3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl}. -lff-indol-3-yl) ethyl] -acetamide , - N- [2- (5- { 3- [2- (acetylamino) et il] -1-benzofuran-5-yl.}. -lfi-pyrrolo [2, 3-Jb] pyridin-3 il) ethyl] -acetamide, -N- [2- (5- { 3- [2- (acetylamino) ethyl] -lH-indol-5-yl.}. -pyrrolo [2, 3-b] pyridin-3-yl) ethyl] -acetamide, -N- [2- (5-. { 3- [2- (acetylamino) ethyl -1-benzothiophen-5-yl} - 1 H -pyrrolo [2,3-b] -pyridin-3-yl) ethyl] acetamide. The enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention. The present invention also relates to a process for the preparation of compounds of formula (I), characterized in that they are used as starting material of a compound of formula (V):
- l wherein A, Gx and Cy are as defined for formula (I), which is subjected to demethylation using conventional agents such as HBr, A1C13, AlBr3, BBr3 or Lewis acid / nucleophilic binary systems, such as , for example, AlCl3 / PhCH2SH or BBr3 / Me2S, to obtain a compound of formula
(SAW) :
where A, G_. and Cy are as defined in the above, 4 which is converted, conventionally, by the action, for example, of sodium N, N-dimethylthiocarbamate, to the corresponding thiol of formula (VII):
wherein A, G1 and Cy are as defined in the above, or the corresponding amine compound of formula (VIII):
A-G-L-Cy-NHR ',, (VIII) where A, Gx and Cy are as defined in the above, and R'. can have any of the meanings Ra as defined for formula (I) and can also represent a hydrogen atom, compounds of formulas (VI), (VII) and (VIII) which represent the compound of formula (IX):
A-G-L-Cy-WH. (IX)
wherein W4 represents an oxygen or sulfur atom, or an NH or NRa group (wherein Ra is as defined above), compound of formula (IX) which is condensed with: § a compound of formula (X) :
^ (CH2) r ^ (CH2] m ^ Har W_f "OH (X)
where Hal represents a bromine, chlorine or iodine atom, and n, W2 and m are as defined for formula (I), (with the proviso that it is not possible to have two consecutive heteroatoms and that the chain defined in this way can having one or more unsaturated bonds), 6 or a compound of formula (XI):
? cn2) n ^ CK2) m-: ooAik (XI) Hal '
wherein Hal, n, m and W2 are as defined in the foregoing and Alk represents an alkyl radical (with the proviso that it is not possible to have two consecutive heteroatoms and that the chain defined in this way may have one or more bonds. unsaturated), followed by reduction, to provide a compound of formula (XII):
A-G1-Cy-W4- (CH2) n-W2- (CH2) m-OH (XII)
where A, Ga, Cy, W4, n, m and W2 are as defined in the above (with the proviso that it is not possible to have two consecutive heteroatoms in the chain -W4- (CH2) n-W2- (CH2 ) m-0H and that the chain defined in this way can have one or more unsaturated bonds), the hydroxyl function of which is converted in a conventional manner to a leaving group such as, for example, a mesylate, a tosylate or a halogen compound, to provide a compound of formula (XII '):
A-G.-Cy-W, - (CH2) n-W2- (CH2) m-E (XII
wherein A, Gl t Cy, W 4, n, W 2 and m are as defined above, and E represents a mesyl or tosyl group or a halogen atom, which is subjected to the action of a compound of formula (XIII ):
B-G3-Cy '-W'4H (XIII)
wherein B, G3 and Cy 'are as defined for formula (I) and W'4 may have the same meanings as W4 defined in the foregoing, to provide a compound of formula (I / a), a particular case of the compounds of the formula (I):
A-Gx-Cy-W4- (CH2) n-W2- (CH2 -W '-Cy'-G3-B (1 / a)
wherein A, G ±, Cy, Cy ', W4, n, W2, m, W'4, G3 and B are as defined above, or are converted using, for example, phenylbis (trifluoromethanesulfonimide) in a medium basic, to the corresponding trifluoromethanesulfonate of formula (XIV):
A-G-L-Cy-0S02CF3 (XIV)
wherein A, G and Cy are as defined above, - which is subjected under catalysis conditions by a suitable palladium compound, to the action of the boric acid compound (RbB (0H) 2) or a compound of tin (RbSnBu3) (where Rb represents a grouping of formula (XV):
B-G3-Cy '-W3- (CH2) m-W2- (CHa) n -CH2 (XV)
where B, G3, Cy ', W3, m, W2 and n are as defined in the above, with the proviso that it is not possible to have two consecutive heteroatoms in the -W3- (CH2) m-W2- chain and that the chain defined in this way can have one or more unsaturated bonds), to provide a compound of formula (I / b), a particular case of the compounds of formula (I):
A-Gl-Cy-CHa- (CH2) n-W2- (CH2) m-W3-Cy'-G3-B (1 / b)
where A, G17 Cy, Cy ', n, W2, m, W3, G3 and B are as defined in the above (with the proviso that it is not possible to have two consecutive heteroatoms in the chain -W2- (CH2) m-W3- and that the chain defined in this way can have one or more unsaturated bonds), compounds of formula (I / c) which, a particular case of the compounds of formula (I):
A_G? _Cy-W1- (CH2) n-W2- (CH2) m-CH2-Cy'-G3-B (1 / c)
where A, Gx, Cy, Cy ', Wx, n, W2, m, G3 and B are as defined in the above (with the proviso that it is not possible to have two consecutive heteroatoms in the chain -Wx- (CH2 ) n-W2- and that the chain defined in this way can have one or more unsaturated bonds), is obtained according to a similar procedure starting from a compound of formula (XIV):
B-G3-Cy '-OS02CF3 (XIV)
wherein B, G3 and Cy 'are as defined in the above, or are treated, under coupling conditions using, for example, nickel or palladium compounds, with a compound of formula (XIV) to provide a compound of formula ( I / d), a particular case of the compounds of formula (I):
A-Gi-Cy-Cy1 -G3-B (1 / d) wherein A, Gl t Cy, Cy 1, G 3 and B are as defined in the above, all of the compounds (I / a) to (I / d) constitute the compounds of formula (I) which can be purified, if desired, by a conventional purification technique, and separated, where appropriate, in their isomers according to a conventional separation technique, and convert, if necessary, into addition salts thereof with a pharmaceutically acceptable acid or base. The compounds of formula (V) are easily accessible to a person skilled in the art, according to the methods described in the literature. The compounds of the invention and the pharmaceutical compositions containing them have proven to be useful in the treatment of disorders of the melatoninergic system. The pharmacological study of the compounds of the invention has in fact shown that they are non-toxic, have a high affinity for melatonin receptors and have substantial activities with respect to the central nervous system and with respect to microcirculation, allowing it to be established that the compounds of the invention They are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraine, memory loss, Alzheimer's disease and disorders of the cerebral circulation. In another field of activity, it seems that the compounds of the invention can be used in the treatment of sexual dysfunctions insofar as they have ovulation inhibiting and unmodulatory properties and are capable of being used in the treatment of cancers. The compounds will preferably be used in the treatment of seasonal, effective disorders, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jet lag, appetite disorders and obesity. For example, the compounds will be used in the treatment of seasonal affective disorders and sleep disorders. The present invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) by itself or in combination with one or more pharmaceutically acceptable excipients. Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral, nasal, percutaneous or transcutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets or lozenges, sublingual tablets, sachets, can be especially mentioned. packs, gelatin capsules, coated tablets, pills, suppositories, creams, ointments, dermal gels and ingestible or injectable ampoules. The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated treatment, and varies from 0.01 mg to 1 g per 24 hours in one or more administrations. The following examples illustrate the invention but do not limit it in any way. The following preparations provide compounds of the invention or synthetic intermediates for use in the preparation of the invention.
Preparation 1: N- [2- (7-hydroxy-l-naphthyl) ethyl] -acetamide
Under an inert atmosphere, 27.5 mmoles of the boron tribromide / dimethyl sulfide complex were dissolved in 100 ml of dichloromethane and stirred for 15 minutes at room temperature. A solution of 13.7 mmole of N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide in 50 ml of dichloromethane is added, and the reaction mixture is refluxed for 30 hours. After cooling, the reaction mixture is hydrolyzed with caution and the dichloromethane is removed by evaporation. The mixture is then extracted with ethyl acetate, and the combined organic phases are washed with an aqueous solution of 1M potassium hydrogen carbonate.
The organic phase is dried over magnesium sulfate and concentrated to give the title compound as a white solid. Melting point: 125-126 ° C Preparations 2 to 35 are obtained by procedures similar to Preparation 1, from the appropriate substrate:
Preparation 2: N- [2 - (5-Hydroxy-1-benzofuran-3-yl) ethyl] acetamide
Preparation N- [2- (5-Hydroxy-l-benzofuran-3-yl) ethyl] cyclopropanecarboxamide
Preparation 4: N- [2- (5-Hydroxy-l-benzofuran-3-yl) ethyl] -2-furamide
Preparation 5: N- [2- (7-Hydroxy-1-naphthyl) ethyl] benzamide
Preparation 6: N- [2- (7-Hydroxy-l-naphthyl) ethyl] -3-butenamide
Preparation 7: N- [2 - (5-Hydroxy-1-benzofuran-3-yl) ethyl] -2-methylpropanamide
Preparation 8: N- [2- (7-Hydroxy-1-naphthyl) ethyl] -2-phenylacetamide
Preparation 9: N- [2- (5-Hydroxy-1-benzothiophen-3-yl) ethyl] acetamide Preparation 10: N- [2- (5-Hydroxy-2-pyrrolo [2, 3-b] pyridin-3 -yl) ethyl] cyclopropanecarboxamide
Preparation 11: N- [2- (5-Hydroxy-IH-indol-3-yl) ethyl] acetamide
Preparation 12: N- [2- (5-Hydroxy-1-pyrrolo [2, 3-Jb] pyridin-3-yl) ethyl] acetamide
Preparation 13: N - [2 - (7 - H i d r or x i naphthyl) ethyl] cyclobutanecarboxamide
Preparation 14. 2.2, 2 -Trif luoro-N- [2- (7-hydroxy-1-naphthyl) ethyl] acetamide
Preparation 15: N- [(6-Hydroxy-2H-chromen-3-yl) methyl] butanamide
Preparation 16: N- [(6-Hydroxy-2H-chromen-3-yl) methyl] acetamide
Preparation 17: N- [(7-Hydroxy-l, 4-benzodioxin-2-yl) methyl] -? ' propylurea
Preparation 8 N- [(7-Hydroxy-1,4-benzodioxin-2-yl) methyl] acetamide
Preparation 19: N- [2- (7-Hydroxy-1-naphthyl) ethyl] furamide Preparation 20: N- [2 - (2-Benzyl-5-hydroxy-2H pyrrolo [2,3-b] pyridin-3-yl) ethyl] acetamide
Preparation 21: N - [2 - (5-Hydroxy-1-benzothiophen-3-yl) ethyl] cyclohexanecarboxamide
Preparation 22: N-Hexy 1 - 2 - (5-hydroxy-1-benzofuran-3-yl) acetamide
Preparation 23: 2,2,2-Trifluoro-N- [2- (5-hydroxy-1-benzothiophen-3-yl) ethyl] acetamide
Preparation 24: N- [2 - (6-Hydroxy-3,4-dihydro-2H-chromen-4-yl) ethyl] acetamide
Preparation 25: N- [2 - (7-Hydroxy-1, 2, 3, 4-t and rahydro-1 naphthalenyl) ethyl] acetamide
Preparation 26: N- [2 - (7-Hydroxy-1,2,3,4-tetrahydro-1-naphthalenyl) ethyl] cyclopropanecarboxamide
Preparation 27: N- [2- (7-Hydroxy-1-naphthyl) ethyl] eptane ida
Preparation 28: Ii- [2 - (5-Hydroxy-1H-indol-3-yl) ethyl] cyclobutanecarboxamide Preparation 29: 4- (7-Hydroxy-1-naphthyl) -N-isopropylbutanamide
Preparation 30 N- [2- (5-Hydroxy-1-benzofuran-3-yl) ethyl] -? ' phenylurea
Preparation 31 N-Benzyl-2 - (5-hydroxy-1-benzothiophen-3-yl) acetamide
Preparation 32: N - [2 - (5-Hydroxy-1 H -inden-3-yl) ethyl] pentanamide
Preparation 33: 3- (5-Hydroxy-l-benzofuran-3-yl) - N -methylpropanamide
Preparation 34: N- [2- (5-Hydroxy-1-pyrrolo [2, 3-blpyridin-3-yl] ethyl] -? ' -methylurea
Preparation 35: 4- (5-Hydroxy-lH-indol-3-yl) -N-methylbutanamide
Preparation 3_6 N- [2 - (5 -Mercapto-1-benzofuran-3-yl) ethyl] acetamide
9 mmol of the product obtained in Step A is added with stirring to a solution of 10 mmol of potassium hydroxide dissolved in 15 ml of water and 16 ml of tetrahydrofuran. The solution is cooled using an ice and salt bath, and 9 mmol of dimethylthiocarbamoyl chloride dissolved in 15 ml of tetrahydrofuran is added dropwise with stirring. After stirring for half an hour while keeping the temperature low, the reaction mixture is extracted with chloroform. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue is taken up in 10 ml of diphenylether and refluxed for 1 hour under a nitrogen atmosphere. Diphenylether is removed by evaporation under reduced pressure until a solution of approximately 2 ml is obtained. The 2 ml of the distillate, which are still hot, are carefully poured into 50 ml of hexane to provide, after cooling, a solid which is isolated by filtration. The solid collected in this way is added to a solution of 380 mg of potassium hydroxide dissolved in a water / methanol mixture (1 ml / 10 ml). The solution is refluxed for 12 hours and then cooled and concentrated under reduced pressure. The residue is taken up in 20 ml of chloroform and extracted 3 times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel to provide the title product.
Preparation 37: N-mercapto-1-benzothiof en-3-yl) ethyl] butanamide
Step A: N - [2 - (5-Hydroxy-1-benzothiophen-3-yl) ethyl] butanamide
The procedure is similar to that of Preparation 1, starting from N- [2- (5-methoxy-l-benzothiophen-3-yl) ethyl] butanamide.
Step N- 12- (5 -Mer capto-1-benzo io fen-3-yl) ethyl] butanamide
The procedure is similar to that of Preparation 36, from the compound obtained in Step A.
Preparation 38: N-. { 5-mercapto-2- [4- (trifluoromethyl) benzyl] -1-benzothiophen-3-yl} ethyl] acetamide
Stage A: N-2-. { 5-Hydroxy -2- [4- (trifluoromethyl] benzyl] -l-benzothiophen-3-ethylcarbonyl] acetamide
The procedure is similar to that of preparation 1, starting from? -2-. { 5-methoxy-2- [4- (trifluoromethyl) benzyl] -1-benzothiophen-3-yl-ethyl) acetamide.
Step B: N- (2- {5-Mercapto-2- [4- (trifluoromethyl) -1- benzothiophen-3-butyl) acetamide F The procedure is similar to that of preparation 36, starting from the compound obtained in Stage A.
Preparation 39: N- [2- (7-mercapto-1,2,3,4-tetrahydro-1-naphthalenyl) ethyl] -cyclopropanecarboxamide
^ 10 The procedure is similar to that of Preparation 36 from the compound obtained in Preparation 26.
Preparation 40: N- [2- (5-amino-1-benzofuran-3-yl) ethyl] acetamide
Stage A -. N- [2 - (5-bromo-l-benzofuran-3-yl) ethyl] acetamide
mmol of triphenylphosphine and 70 ml of acetonitrile are poured into a 150 ml three-necked flask equipped with a dropping funnel, a refrigerant in the upper part of which is mounted a tube filled with calcium chloride, and a mechanical stirrer. . The solution is cooled using an ice bath while stirring is maintained, and 10 mmole of bromine is added. When the addition is complete, the ice bath 25 is removed and then 8 mmoles of the product obtained in preparation 2 are added. The reaction mixture is stirred at 60-70 ° C until the initial material disappears. At the end of the reaction, the mixture is filtered and then the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed with water and then with a saturated solution of potassium hydrogen carbonate, and once more with water, and then dried over magnesium sulfate and concentrated under reduced pressure. The residue is filtered on silica gel to provide the title product.
Step B: N- [2- (5-Iodo-1-benzo furan-3-yl) ethyl] acetamide
A mixture of 2 mmol of the product obtained in Step A, 30 mmol of potassium iodide and 10 mmol of copper iodide (I) in 6 ml of hexamethylphosphoramide is heated to 150-160 ° C with stirring under a nitrogen atmosphere until that a conversion rate of 90% has been reached. Then dilute hydrochloric acid is added, followed by ether, and the mixture is then filtered to remove insoluble copper (I) salts. The organic phase is separated, washed with a sodium sulphite solution and with water, dried over magnesium sulfate and evaporated to give a residue which is subjected to chromatography on silica gel to provide the title product.
Step C: N- [2 - (5-vinyl-1-benzofuran-3-yl) ethyl] acetamide
110 mmol of the product obtained in Step B, 16 mmol of vinyltributyltin and 0.43 mmol of tetrakis (triphenylphosphine) palladium are heated with stirring for 3 hours in 30 ml of N-methylpyrrolidinone. After removal of the solvent by evaporation, the residue is taken up in 20 ml of dichloromethane and treated with a 10% aqueous solution of potassium chloride. Extraction, concentration under reduced pressure and chromatography on silica gel provide the pure title product.
Stage D-. ? - [2 - (5-formyl-1-benzofuran-3-yl) ethyl] acetamide
1.10 g of osmium tetroxide in 2-methyl-2-propanol and then 8.70 g of sodium periodate are added at room temperature to a solution of 10 mmol of the product obtained in Step C in a mixture of 50 ml of dioxane and 25 ml of water. After stirring overnight at room temperature, the suspension is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is taken up in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is purified by chromatography on silica gel to provide the title product.
Step E: 3- [2- (Acetylamino) ethyl] -1-benzo furan-5-carboxylic acid
2.7 g of potassium permanganate in 50 ml of an acetone / water mixture (50/50) are added at room temperature to a solution of 6.88 mmoles of the product obtained in Step D in 30 ml of acetone. The solution is stirred for 2 hours at room temperature and then filtered. The filtrate is concentrated under reduced pressure and subjected to chromatography on silica gel to provide the title product.
Stage F-. 3- [2- (Acetylamino) ethyl] -1- benzofuran -5-carboxylic acid chloride
fc 5 mmoles of the product obtained in the
Step E in 40 ml of thionyl chloride. After shaking low
In an inert atmosphere for 1 hour, the thionyl chloride is removed by evaporation under reduced pressure to provide the title product.
Step G: N- [2 - (5-amino-1-benzofuran-3-yl) ethyl) acetamide A solution of 20 mmol of the product obtained in Step F in 30 ml of dichloromethane containing 20 mg of bromide Tetrabutylammonium is cooled in a bath with ice. After the addition of 25 mmoles of sodium azide dissolved in 5 ml of water, the solution is stirred vigorously at 0 ° C for 2 hours. The organic phase is separated, washed with water (2 x 5 ml) and dried over magnesium sulfate. After filtration, 30 mmoles of trifluoroacetic acid are added and the solution is stirred under reflux for 60 hours. After cooling, the organic phase is washed with a saturated solution of sodium hydrogen carbonate (2 x 5 ml) and concentrated under reduced pressure. The residue is then taken up in 20 ml of methanol and 80 ml of water and then 30 mmoles of potassium carbonate are added. After stirring at room temperature for 20 hours, the reaction mixture is concentrated under reduced pressure to a volume of about 60 ml and then extracted 3 times with ether (3 x 50 ml). After drying over sodium sulfate, the organic phase is filtered and then evaporated under reduced pressure. The residue is chromatographed on silica gel to provide the title product.
Preparation 41 N- [2 - (5-amino-1-benzothiophen-3-yl) ethyl] pentanamide Step A N- [2- (5-Hydroxy-1-benzot-pheno-3-yl) ethyl] pentanamide
The procedure is similar to that of Preparation 1 from N- [2- (5-methoxy-l-benzothiophen-3-yl) ethyl] pentanamide.
Stage B N- [2- (5-amino-1-benzothiophen-3-yl) ethyl] pentanamide
The procedure is similar to that of Preparation 40, from the compound obtained in Step A.
Preparation 42: N-. { 2- [5-amino-2- (3-methoxybenzyl) -l-benzofuran-3-yl] ethyl} -acetamide
Stage A: N-. { 2- [5-Hydroxy-2- (3-methoxybenzyl) -1-benzo furan-3-yl] ethyl} acetamide
The procedure is similar to that of Preparation 1 from N-. { 2- [5-methoxy-2- (3-methoxybenzyl) -1-benzofuran-3-yl] ethyl} acetamide.
Stage B -. N-. { 2- [5-amino-2- (3-methoxybenzyl) -1-benzofuran-3-yl] ethyl} acetamide.
The procedure is similar to that of Preparation 40, from the compound obtained in Step A.
Preparation 43: N- [2- (5-amino-1-benzofuran-3-yl) ethyl] -2-furamide The procedure is similar to that of Preparation 40, from the compound obtained in Step A.
i__P 10 Preparation 44: N- [2 - (5-amino-1-benzofuran-3-yl) ethyl] -? ' - cyclopropylurea
Stage A -. N- [2- (5-Hydroxy-1-benzo furan-3-yl) ethyl] -? ' - cc cl op opi 1 urea 15 The procedure is similar to that of Preparation 1 from N- [2 - (5-methoxy-1-benzofuran-3-yl] ethyl] -? '-dfc cyclopropylurea
Stage B -. ? - [2- (5-amino-l-benzofuran-3-yl) ethyl] -? ' - cyclopropylurea
The procedure is similar to that of Preparation 40, from the compound obtained in Step A. Preparation 45: 3- [2- (Acetylamino) ethyl] -l-benzofuran-5-yl trifluoromethanesulfonate
60 ml of triethylamine are added to a solution of 0.07 mole of the compound obtained in Preparation 2, in one liter of dichloromethane. The reaction mixture is refluxed until dissolved, and then 0.1 moles of phenylbis (trifluoromethanesulfonimide) and 0.75 moles of potassium carbonate are added. After refluxing for 4 hours, the mixture is washed with one liter of 1M sodium hydrogen carbonate and then with one liter of hydrochloric acid. The organic phase is dried, concentrated and purified by chromatography on silica gel to provide the title product. Preparations 46 through 70 are obtained by procedures similar to those of Preparation 45.
Preparation 46 8- [2- (Acetylamino) ethyl] -2-naphthyl trifluoromethanesulfonate
Initial material: Preparation 1
Preparation 47: Trifluoromethanesulfonate of 3-. { 2- [(cyclopropylcarbonyl) amino] ethyl} -1-benzothiophen-5-yl Starting material: N- [2- (5-hydroxy-l-benzothiophen-3-yl) ethyl] cyclopropanecarboxamide which is obtained by the procedure similar to that of Preparation 1 from N- [2- (5-methoxy-1-benzothiophen-3-yl) ethyl] cyclopropanecarboxamide. 5
Preparation 48: 8- (2 { [(Methylamino) carboinl] amino} ethyl) -2-naphthyl trifluoromethanesulfonate
^ 10 Initial material: N- [2- (7-hydroxy-1-naphthyl) ethyl] -N'-methylurea which is obtained by the procedure similar to that of
Preparation 1 from N- [2- (7-methoxy-1-naphthyl) ethyl] -N'-methylurea.
Preparation 49: Trifluoromethanesulfonate of 3-. { 2- [(anilinocarbonyl) amino] ethyl} -l-benzofuran-5-yl
Initial material: Preparation 30
Preparation 50: 3- [2- (2-furoylamino) ethyl] -1-benzothio en-5-yl trifluoromethanesulfonate
Initial material: N- [2- (5-hydroxy-l-benzothiophen-3-yl) ethyl] -2-furamide, which is obtained by the procedure similar to that of Preparation 1 from N- [2- (5 -methoxy-1-benzothiophen-3-yl) ethyl] -2-furamide.
Preparation 51: 3- [2- (Benzylamino) -2-oxoethyl] -lH-indol-5-yl trifluoromethanesulfonate
Initial material:? -Benzyl-2- (5-hydroxy-lH-indol-3-yl) acetamide, which is obtained by the procedure similar to that of Preparation 1 from? -benzyl-2- (5-methoxy) lH-indol-3-yl) acetamide.
Preparation 52: 3- [3- (Benzoylamino) propyl] -1H-indole-5-yl trifluoromethoxylate
Initial material: N- [3 - (5-Hydroxy-lH-indol-3-yl) propyl] benzamide, which is obtained by the procedure similar to that of Preparation 1 from? - [3- (5-methoxy) lH-indol-3-yl) propyl] benzamide.
Preparation 53: Tr i f luoromet ansul onate of 3- [2- (isobutyrylamino) ethyl) -1-benzothiof en-5-yl
Initial material:? - [2- (5-Hydroxy-l-benzothiophen-3-yl) ethyl] -2-methylpropanamide, which is obtained by the procedure similar to that of Preparation 1 from? - [2- (5 -methoxy-1-benzothiof en-3-yl) ethyl] -2-methylpropanamide.
Preparation 54: Trif luorometansulfon 3- [2- (Heptanoylamino) ethyl] -lH-pyrrolo [2, 3-blpyridin-5-yl]
Initial material: N- [2- (5-Hydroxy-lH-pyrrolo [2, 3-i] pyridin-3-yl) ethyl] heptanamide, which is obtained by the procedure similar to that of Preparation 1 from N- [2- (5-methoxy-lH-pyrrolo [2, -Jb] pyridin-3-yl) ethyl] heptanamide.
Preparation 5_5: 3- [2- (Acetylamino) ethyl] -lH-pyrrolo [2, 3-b] pyridin-5-yl trif luorometansulfonate
Initial material: Preparation 12
Preparation 56: 3- [4- (Cyclopentylamino) -4-oxobutyl] -l-benzofuran-5-yl trifluoromethanesulfonate
Initial material: N-Cyclopentyl-4- (5-hydroxy-l-benzofuran-3-yl) butanamide, which is obtained by the procedure similar to that of Preparation 1 from N-cyclopentyl-4- (5-methoxy) l benzof uran-3-yl) butanamide.
Preparation 57: Tr i f luorome tansul f onat o of 3-. { 2- [(Cyclopropylcarbonyl) amino] ethyl) -lH-pyrrolo- [2, 3-b] pyridin-5-yl
Starting material: Preparation 10 Preparation 58: 3- (2- {[[(Allylamino) carbonyl] amino) ethyl) -l-benzothiophen-5-yl trifluoromethanesulfonate
Initial material: N-Allyl-N1 - [2- (5-hydroxy-1-benzothiophen-3-yl) ethyl] urea which is obtained by a procedure similar to that of Preparation 1 from N-allyl-N '- [2- (5-methoxy-l-benzothiophen-3-yl) ethyl] urea.
Preparation 59 [(Acetylamino) ethyl-I, 4-benzodioxin-6-yl trifluoromethanesulfonate
Initial material Preparation 18
Preparation 60: 3- [2 - (Isobutyrylamino) ethyl] -l-benzofuran-5-yl trifluoromethanesulfonate
Initial material: Preparation 7
Preparation 61: 4- (2 - [(2,2,2-Trifluoroacetyl) amino] ethyl] -3,4-dihydro-2H-chromen-6-yltrifluoromethanesulfonate
Initial material: 2, 2, 2-Trifluoro-N- [2- (6-hydroxy-3,4-dihydro-2H-enromenyl) ethyl] acetamide, which is obtained by the procedure similar to that of Preparation 1 a from 2,2,2-trifluoro-N- [2- (6-methoxy-3,4-dihydro-2H-chromen-4-yl) ethyl] acetamide.
Preparation 62: 3- (4-Anilino-4-oxo-butyl) -l-benzothiophen-5-yl trifluoromethanesulfonate
Initial material: 4 - (5 - Hydr oxy - 1 - benz ot iof en - 3 - yl) - - phenylbutanamide, which is obtained by the procedure similar to that of Preparation 1 from 4- (5-methoxy-lbenzothiof in -3-yl) -N-enylbutanamide.
Preparation 63: T r i f 1 u or r ome t an s u 1 t 3-t (Acetylamino) metill -3, 4-dihydro-2H-chromen- 6 -yl
Initial material: N- [(6-Hydroxy-3, 4-dihydro-2H-chromen-3-yl) methyl] acetamide, which is obtained by the procedure similar to that of Preparation 1 from N- [(6- methoxy-3,4-dihydro-2H-chromen-3-yl) methyl] acetamide.
Preparation 64: Tr i f luorome tansul f onat of 3 - [2 - (Acetylamino) ethyl] -2- [4- (trifluoromethyl) benzyl] -1-benzofuran-5-yl
Initial material: N- (2- {5-Hydroxy-2- [4- (trifluoromethyl) benzyl] -1- benz or furan-3-yl.} Ethyl) acetamide, which is obtained by the procedure similar to of Preparation 1 from N- (2- {5-methoxy-2: [4- (trifluoromethyl) benzyl] -l-benzofuran-3-yl} ethyl) acetamide.
Preparation 65: Tr i f luoromet anulin on of 3- (2- ([(Methylamino) carbonyl-amino] ethyl) -lH-indol-5-yl
Initial material: N- [2 - (5-Hydroxy-1H-indol-3-yl) ethyl] -? 'Methylurea, which is obtained by the procedure similar to that of Preparation 1 from? - [2- (5 -methoxy- IHindol-3-yl) ethyl] -? ' -methylurea.
Preparation 66: Trif luorometansulfon 4- ate. { 2 - [(2,2-Dimethylpropanoyl) aminolethyl} -3, 4-dihydro-2H-chromen-6-yl
Initial material:? - [2- (6-Hydroxy-3, 4-dihydro-2H-chromen-4-yl) ethyl] -2, 2-dimethylpropanamide, which is obtained by the procedure similar to that of Preparation 1 starting of? - [2- (6-methoxy-3, -dihydro-2H-chromen-4-yl) ethyl] -2,2-dimethylpropanamide.
Preparation 67: 3- [2- (Acetylamino) ethyl] -1H-indol-5-yl trifluoromethanesulfonate Starting material:? -acetylserotonin Preparation 68_. Trif luorometansulf onate of 3-. { [(Exylcarbonyl) amino] methyl cycle} -1, 4-benzodioxin-6-yl
Initial material: N- [(7-Hydroxy-l, 4-benzodioxin-2-yl) methyl] cyclohexanecarboxamide, which is obtained by the procedure similar to that of Preparation 1 from N - [(7-methoxy-1, 4-benzodioxin-2-yl) methyl] cyclohexanecarboxamide.
Preparation 69: 3- [2- (Acetylamino) ethyl] -2- (3-methoxybenzyl) -1-benzothiof en-5-yltrifluoromethanesulfonate
Initial material: N-. { 2 - [5-Hydroxy-2- (3-methoxybenzyl) -l-benzothiof en-3-yl] ethyl} acetamide, which is obtained by the procedure similar to that of Preparation 1 from N-. { 2- [5-methoxy-2- (3-methoxybenzyl) -1-benzothiof en-3-yl] ethyl} acetamide.
Preparation 70: Tr i f luoromet ansul onate of 3- [3- (acetylamino) propyl] -l-benzofuran-5-yl
Initial material: N- [3 - (5-Hydroxy-l-benzofuran-3-yl) propyl] acetamide, which is obtained by the procedure similar to that of Preparation 1 from N- [3- (5-methoxy- 1-benzofuran-3-yl) propyl] acetamide.
Preparation 71: N-. { 2- [5-Hydroxy-1- (phenylsulfonyl) -lH-indol-3-yl] ethyl} acetamide Stage A -. N-. { 2- [5-Methoxy-1- (phenylsulfonyl) -lH-indol-3-yl-ethyl) acetamide
g of melatonin are dissolved in 150 ml of dichloromethane and then 3.41 g of sodium hydroxide and 0.35 g of tetrabutylammonium acid sulfate are added. The reaction mixture is then cooled in an ice bath and 4.06 ml of benzenesulfonyl chloride are added dropwise. After stirring overnight at room temperature, the excess sodium hydroxide and catalyst are removed by filtration, the solvent is removed by evaporation in vacuo and the resulting solid is recrystallized to give the title compound as white crystals. Melting point: 140-141 ° C
Stage B -. N-. { 2- [5-Hydroxy-1- (phenylsulfonyl) -lR-indol-3-yl] ethyl} acetamide
Dissolve 5 g of the compound obtained in the
Step A, in 100 ml of dichloromethane. The reaction mixture is then cooled in a bath with ice and added dropwise
3. 81 ml of boron tribromide. After stirring at room temperature for 2 hours, the reaction mixture is poured into 500 ml of water and ice. The precipitate formed is separated by filtration, washed with water and dried in the oven at 50 ° C. Melting point: 205-206 ° C
Preparation 72: 3- [2- (Acetylamino) ethyl] -l-benzothien-5-yl trifluoromethanesulfonate
The procedure is similar to that of Preparation 45 from the compound obtained in Preparation 9.
Example 1: N- (2- { 7- [2- ( { 3- [2- (acetylamino) ethyl] -l-benzofuran-5-yl} oxy) ethoxy] -1-naphtyl-ethyl) acetamide
Stage A, -? -. { 2- [7- (2-bromoethoxy) naph t-l -yl] ethyl} acetamide
0.009 mole of the compound obtained in preparation 1 is dissolved in 20 ml of a mixture of 6 ml of dimethyl sulfoxide and 14 ml of butanone. 0.027 moles of potassium carbonate and 0.036 moles of dibromoethane are added, and the mixture is heated at reflux for 48 hours. The reaction mixture is then cooled and poured into water. The aqueous phase is extracted with Et20 and then the organic phase is washed with water until the wash waters are neutral, and subsequently it is dried over magnesium sulphate and evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: acetone / cyclohexane (2/8)) and recrystallized as a white solid. Melting point: 110-lll ° C.
Elemental microanalysis:
% C H N Calculated: 57.15 5.40 4.17 Found: 57.28 5.38 3.91
Stage B -. N- (2- { 7- [2- ( { 3 - [2- (acetylamino) ethyl] -1-benzofuran-5-yl} oxy) ethoxy] -1-naphthyl} ethyl acetamide
In a 100 ml round bottom flask, 0.003 mole of the compound obtained in Preparation 2 and 0.003 mole of the compound obtained in Step A are dissolved in a mixture of 3 ml of dimethyl sulfoxide and 20 ml of butanone. 0.009 mole of potassium carbonate and a potassium iodide crystal are added, and then the mixture is refluxed for 12 hours. The reaction mixture is then cooled and poured into 100 ml of water. The precipitate that forms is separated by suction and recrystallized.
Example 2: N- (2 -. {5- [2 - (. {8- [2 - (acetylamino) ethyl] -2 -naphthyl} oxy) ethoxy] -1-benzofuran-3-yl} ethyl) cyclopropanecarboxamide The procedure is similar to that of Example 1, in Step B the compound obtained in Preparation 2 is replaced by the compound obtained in Preparation 3.
Example N- (2 -. {5 - [2 - ( { 8 - [2 - (acetylamino) ethyl] -2-naphthyl-oxy) -ethoxy] -l-benzofuran-3-yl} -ethyl) -2 -furamide
The procedure is similar to that of Example 1, in Step B the compound obtained in Preparation 2 ^ 10 is replaced by the compound obtained in Preparation 4.
Example 4: N- (2- { 7- [2- ( { 3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} io) ethoxy] -1-naphthyl} ethyl) enzamide
The procedure is similar to that of Example 1, substituting: in Step A, the compound obtained in Preparation 1 by the compound obtained in Preparation 5, in Step B, the compound obtained in Preparation 2 by the compound obtained in Preparation 36.
Example 5: N- (2- { 7- [2- ( { 3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} amino) ethoxy] -l-naphthyl} ethyl) acetamide The procedure is similar to that of Example 1, in Step B the compound obtained in Preparation 2 is replaced by the compound obtained in Preparation 40.
Example 6: N- (2- { 7- [2- ( { 3- [2- (isobutylamino) ethyl] -1-benzofuran-5-yl} oxy] -ethoxy] -l-naphthyl .}. ethyl) -3-butenamide
The procedure is similar to that of Example 1, substituting: - in Step A, the compound obtained in the
Preparation 1 by the compound obtained in Preparation 6, in Step B, the compound obtained in Preparation 2 by the compound obtained in Preparation 7.
Example 7: N- (2- { 7- [2- ( { 3- [2- (Acetylamino) ethyl] -1-benzothiophen-5-yl}. Oxy) -ethoxy-1-naphthyl} ethyl) -2-phenylacetamide
The procedure is similar to that of Example 1, substituting: in Step A, the compound obtained in Preparation 1 for the compound obtained in Preparation 5, in Step B, the compound obtained in Preparation 2 for the compound obtained in Preparation 9.
Example 8: N- (2- { 5- [2- ( { 8- [2- (acetylamino) ethyl] -2-naphthyl} oxy] -ethoxy] -IH-pyrrolo [2, 3 -b] pyridin-3-yl.} ethyl) cyclopropanecarboxamide
The procedure is similar to that of Example 1, in Step B the product obtained in Preparation 2 is replaced by the compound obtained in Preparation 10.
Example 9: N- (2 -. {5 - [2 - (. {3 - [2 - (acetylamino) ethyl] -3a, 7a-dihydro-1-benzofuran-5-yl}. Oxy) - ethoxy] -1-benzothiophen-3-yl.} ethyl) acetamide
The procedure is similar to that of Example 1, substituting: in Step A, the compound obtained in Preparation 1 for the compound obtained in Preparation 2, - in Step B, the compound obtained in
Preparation 2 for the compound obtained in Preparation 9.
Example 10: N- (2- { 5- [2- ( { 3- [2- (acetylamino) ethyl] -lH-indol-5-yl} oxy] -ethoxy] -3a, 7a -dihydro-l-benzofuran-3-yl.} ethyl) -2-furamide
The procedure is similar to that of Example 1, substituting: in Step A, the compound obtained in Preparation 1 for the compound obtained in Preparation 4, in Step B, the compound obtained in Preparation 2 for the compound obtained in Preparation 11.
Example 11: N- (2-. {5- [2- ( { 3- [2- (acetylamino) ethyl] -lif-pyrrolo [2,3-b] pyridin-5-yl}. oxy) ethoxy) -3a, 7a-dihydro-l-benzofuran-3-yl} ethyl) -2-methylpropanamide
The procedure is similar to that of Example 1, substituting: - in Step A, the compound obtained in the
Preparation 1 by the compound obtained in Preparation 7, in Step B, the compound obtained in Preparation 2 by the compound obtained in Preparation 12.
Example 12: N- (2- { 7- [3- ( { 3- [2- (acetylamino) ethyl] -1-benzothiophen-5-yl}. Oxy) -propoxy] -l-naphthyl .}. ethyl) acetamide
Stage A: N-. { 2- [7- (3-Hydroxypropyloxy) naphth-1 -yl] ethyl} acetamide
In a 100 ml round bottom flask, dissolve
0. 022 moles of the compound obtained in Preparation 1 in 30 ml of dimethylformamide. 0.066 moles of potassium carbonate and 0.033 moles of 3-bromopropan-1-ol are added and then the mixture is heated at 80 ° C for 4 hours. The reaction mixture is cooled and poured into 100 ml of an HCl IM solution. The aqueous phase is extracted 3 times with Et20 and then the organic phase is dried over MgSO4 and evaporated under reduced pressure. The title product is obtained by recrystallization. White solid. Melting point: 141-142 ° C.
Step B: 3 - (. {8- [2- (Acetylamino) ethyl] -2-naphthoxy} methylsulphonate.
In a 250 ml round bottom flask, the alcohol obtained in Step A is dissolved in 50 ml of dichloromethane and 0.012 mol of triethylamine are added. The mixture is cooled in an ice / salt bath at -10 ° C, and then 0.012 moles of mesyl chloride are added dropwise, with stirring with a magnetic stirrer. The reaction mixture is stirred at room temperature for 4 hours. Then add 100 ml of water, followed by extraction with CH ^ Cla. The organic phase is washed with water, dried over MgSO 4 and evaporated under reduced pressure. The resulting oil is purified by chromatography on silica gel (eluent: acetone / cyclohexane (2/8)).
Step _C: N- (2-. {7- [3 - ( { 3 - [2- (acetylamino) ethyl] -1-benzothiophen-5-yl}. Oxy) -propoxy] -l -naf useful.} ethyl) acetamide In a 100 ml round bottom flask containing
ml of methanol is added in small portions 0.06 g of
(sodium.) When sodium has been used completely, they are added
0. 0033 moles of the compound obtained in Preparation 9, and the
The mixture is stirred for 20 minutes. The methanol is removed by evaporation under reduced pressure, the residue is taken in 15 ml of
DMF, and then 0.0027 mol of the compound obtained in Step B are added. After the reaction mixture is refluxed for 12 hours and subsequently cooled and poured into 100 ml.
^ F 10 water and 10 ml 3M HCl. After extraction with ethyl acetate, the organic phase is washed with a 10% sodium hydroxide solution and then with water. After drying over MgSO 4 and removing the solvent by evaporation under reduced pressure, the title compound is purified by gel chromatography.
silica.
Example 13: N- (2- {7- [3- {2- (butyrylamino) ethyl] -1-benzothiophen-5-yl} thio) -propoxy] -l-naphthyl} ethyl) cyclobutanecarboxamide
The procedure is similar to that of Example 12, substituting: in Step A, the compound obtained in Preparation 1 for the compound obtained in Preparation 13, in Step C, the compound obtained in Preparation 9 for the compound obtained in Preparation 37.
E j emp 1 or 14 N-. { 2 - [5 - ( { 3 - [(8 - {2 - [(2-trifluoroacetyl) amino] ethyl} -2-naphthyl) oxy] propyl} amino) -1- < ^ benzothiophen-3-yl] -ethyl} pentanamide
The procedure is similar to that of Example 12, substituting: in Step A, the compound obtained in Preparation 1 for the compound obtained in Preparation 14, in Step C, the compound obtained in Preparation 9 for the compound obtained in Preparation 41.
Example 15: N- ( {6 - [3 - ( { 8 - [2 - (acetylamino) ethyl] -2-naphthyl}. Oxy) propoxy] -2H-chromen-3-yl. methyl) butanamide
The procedure is similar to that of Example 12, in
Step C replaces the compound of Preparation 9 with the compound of Preparation 15.
Example 16: N- (2- { 5- [3- ( { 3- [(acetylamino) methyl] -2 H -chromen-6-yl}. Oxy) propoxy] -l-benzofuran-3 -yl.} ethyl) cyclopropanecarboxamide
The procedure is similar to that of Example 12, substituting: in Step A, the compound obtained in Preparation 1 for the compound obtained in Preparation 16, in Step C, the compound obtained in Preparation 9 for the compound obtained in Preparation 3. i Example 1 7: N -. { 2 - [5 - (3 - { [3 - 5 ( { [(Propylamino) carbonyl] amino.} Methyl) -1,4-benzodioxin-6-yl] oxy} propoxy) -lif -pyrrolo [2, 3-b] pyridin-3-yl] ethyl} -acetamide
The procedure is similar to that of Example 12, its steps being: 10 - in Step A, the compound obtained in the
Preparation 1 by the compound obtained in Preparation 17, in Step C, the compound obtained in Preparation 9 by the compound obtained in Preparation 12.
Example 18: N- ( { 1 - [4 - ( { 8 - [2 - (acetylamino) ethyl] -2-naphthyl}. Oxy) butoxy] -1,4-benzodioxin-2-yl .}. methyl) acetamide
, ^ fc Stage A -. Ethyl 4 - (. {8 - 2 - (acetylamino) ethyl] -2-naphthyl.} Oxy] butanoate 20 In a 100 ml round bottom flask, dissolve
0. 022 moles of the compound obtained in Preparation 1, in 50 ml of acetonitrile. 0.066 moles of potassium carbonate are added and the reaction mixture is stirred at 80 ° C for 30 minutes.
Then 0.033 moles of ethyl 1-bromobutyrate are added dropwise and the reaction mixture is stirred for 1 hour at 80 ° C. The acetonitrile is removed by evaporation under reduced pressure and the residue is dissolved in a solution of IN HCl. After extraction with ethyl acetate, washing of the organic phase with water, drying over MgSO 4 and evaporation under reduced pressure, the title compound is purified by recrystallization. Solid beige. Melting point: 64-66 ° C.
WP 10 Stage B: N-. { 2- [7- (4-hydroxybutyloxy) naphth-1-y] ethyl} acetamide
* In a 250 ml round bottom flask, the ester obtained in Step A (0.009 mol) is dissolved in 100 ml of anhydrous ether. 0.009 mole of lithium aluminum hydride is added in portions and the reaction mixture is stirred for 6 hours at room temperature. The reaction mixture is then hydrolyzed P with a few drops of? MAOH and the precipitate that forms is filtered off. The filtrate is dried over MgSO4 and evaporated under reduced pressure. The resulting residue is precipitated from a mixture of Et20 / petroleum ether (1/1), separated by suction and recrystallized. White solid. Melting point: 82-84 ° C.
Elemental microanalysis
% C H N Calculated: 71.73 7.69 4.64 Found: 72.00 7.58 4.45
Stage C -. Methanesulfonate of 4 - ( { 8 - [2 (acetylamino) ethyl] -2-naphthyl} oxy) butyl
^ 10 The procedure is similar to that of Stage B of the
Example 12, from the compound obtained in Step B.
Stage D -. N- ( { 7 - [4- ( { 8- [2- (acetylamino) ethyl] -2- naphthyl} oxy) butoxy] -1,4-benzodioxin-2-yl. methyl) acetamide 15 The procedure is similar to that of Step C of Example 12, substituting the compound obtained in the P Preparation 9 for the compound obtained in Preparation 18.
Example 19: N-. { 2 - [7 - (4 - { [3 -. {(Acetylamino) et il] -2- (3-methoxybenzyl) -l-benzofuran-5-yl] amino} butoxy) -l -naphthyl] ethyl} -2- furamide
The procedure is similar to that of Example 18, in Step A the compound of Preparation 1 is replaced by the compound of Preparation 19, and in Step D the compound of Preparation 9 is replaced by the compound of Preparation 42 .
Example 20: N- ( { 6- [4- ( { 3 - [(acetyl-ineethyl) -2 -benzyl-1H-pyrrolo [2,3-pyridin-5-yl}. Oxy) butoxy] -4a, 8a-dihydro-2H-chromen-3-yl.} methyl) butanamide
The procedure is similar to that of Example 18, in Step A the compound of Preparation 1 is replaced by the compound of Preparation 15, and in Step D the compound of Preparation 9 is replaced by the compound of
Preparation 20.
Example 21: N- (2 -. {5 - [4 - ( { 3 - [2 - (aceylamino) et il] -2- [4 - (trifluoromethyl) benzyl] -1-benzothiophene-5 il.) thio) utoxy] - 1 H -pyrrolo [2,3-b] pyridin-3-yl.} ethyl) -cycloprancarboxamide
The procedure is similar to that of Example 18, in Step A the compound of Preparation 1 is replaced by the compound of Preparation 10, and in Step D the compound of Preparation 9 is replaced by the compound of
Preparation 38.
Example 22: N- (2- { 5- [4- ( { 3- [(acetylamino) methyl] -4a, 8a-dihydro-2H-chromen-6-yl} oxy) butoxy] - l-benzothiophen-3-yl.} ethyl) cyclohexanecarboxamide
The procedure is similar to that of Example 18, in
Step A: The compound of Preparation 1 is replaced by the compound of Preparation 16, and in Step D the compound of Preparation 9 is replaced by the compound of Preparation 21.
Example 23: 2, 2, 2-trifluoro-N- (2- { 5- [4- ( { 3- [2- (hexylamino) -2-oxoethyl] -3a, 7a-dihydrole -benzofuran-5-yl.}. oxy) butoxy] -1-benzothiophen-3-yl} ethyl) -acetamide
The procedure is similar to that of Example 18, in
Step A: The compound of Preparation 1 is replaced by the compound of Preparation 22, and in Step D the compound of Preparation 9 is replaced by the compound of Preparation 23.
Example 24: N- (2- { 7- [4- ( { 4- [2- (acetylamino) ethyl] -3,4-dihydro-2H-chromen-6-yl}. -oxi) butoxy] -1, 2, 3, 4-tetrahydro-l-naphthalenyl.} ethyl) acetamide The procedure is similar to that of Example 18,
Step A The compound of Preparation 1 is replaced by the compound of Preparation 24, and in Step D the compound of Preparation 9 is replaced by the compound of Preparation 25.
Example 25: N-. { 2- [5- ( { 4- [(8- { 2- [(cyclopropylcarbonyl) amino] -ethyl] -5,6,7,8-tetrahydro-2-naphthalenyl) oxy] butyl .}. amino) -1-benzo-uran-3-yl] ethyl} -2-furamide
The procedure is similar to that of Example 18, in
Step A The compound of Preparation 1 is replaced by the compound of Preparation 26, and in Step D the compound of Preparation 9 is replaced by the compound of Preparation 43.
EXAMPLE 26 N- (2- { 5- [4- ( { 8- [2- (heptanoylamino) ethyl] -2-naphthyl} oxy) butoxy] -1H-indol-3-yl. ethyl) cyclobutanecarboxamide
The procedure is similar to that of Example 18, in
Step A: The compound of Preparation 1 is replaced by the compound of Preparation 27, and in Step D the compound of Preparation 9 is replaced by the compound of Preparation 28.
Example 27: N- [2- (5- { [6- ( { 8- [2- (acetylamino) ethyl] -2-naphthyl-oxy) hexyl] oxy}. -lif-pyrrolo [2, 3 -b] pyridin-3-yl) ethyl] acetamide
Stage A. - N - (2 - { 7 - [(6 - h i drox i hex i 1) or x i] - 1 -naphthyl} ethyl) acetamide
The procedure is similar to that of Step A of Example 12, substituting 3-bromopropan-1-ol for 6-bromohexan-1-ol. White solid. Melting point: 58-61 ° C.
Elemental microanalysis
% C H? Calculated: 72.91 8.41 4.25 Found: 73.22 8.17 4.02
Stage B -. ( { 8 - [2 - (acetylamino) ethyl] -2-naphthyl} oxy) hexyl methanesulfonate
The procedure is similar to that of Step B of Example 12. White solid. Melting point: 66-67 ° C Stage C: N- [2- (5- { [6- ( { 8- [2- (acetylamino) ethyl] -2-naphthyl}. Oxy) hexyl ] oxy.} - 1 H -pyrol [2,3-b] pyridin-3-yl) ethyl] acetamide
The procedure is similar to that of Stage C of the
Example 12, substituting the compound obtained in Preparation 9 for the compound obtained in Preparation 12.
Example 28: 4- (7- { [6- ( { 3 - [(acetylamino) methyl] - H -chromen-6-yl}. Oxy) hexyl.} Oxy]. naphthyl) -N-isopropylbutanamide
The procedure is similar to that of Example 27, in
Step A The compound obtained in Preparation 1 is replaced by the compound obtained in Preparation 29, and in Step C the compound obtained in Preparation 9 is replaced by the compound obtained in Preparation 16.
Example 29: N-. { [7- ( { 6- [(3- {2- [(anilinocarbonyl) amino] ethyl} -1-benzofuran-5-yl) -oxi] hexyl.} Oxy] -l, 4 -benzodioxin-2-yl] methyl} acetamide
The procedure is similar to that of Example 27, in Step A the compound obtained in Preparation 1 is replaced by the compound obtained in Preparation 30, and in Step C the compound obtained in Preparation 9 is replaced by the compound obtained in Preparation 18
Example 30: N- [2- (7- { [6- ( { 3- [2- (benzylamino) -2-oxoethyl] -1-benzothiophen-5-yl}. Oxy) hexyl] thio .}. -1, 2, 3, 4-tetrahydro-l-naphthalenyl) ethyl] -cyclopropancarboxamide
The procedure is similar to that of Example 27, substituting: - in Step A, the compound of Preparation 1 for the compound of Preparation 31, in Step C, the compound of Preparation 9 for the compound of Preparation 26.
Example 31: N- [2- (5-. {[[6- ( { 3- [3- (methylamino) -3-oxopropyl] -1-benzofuran-5-yl} oxy) hexyl] oxy .}. - 1 H -inden-3-yl) ethyl] pentanamide
The procedure is similar to that of Example 17, in
Step A The compound of Preparation 1 is replaced by the compound obtained in Preparation 32, and in Step C the compound of Preparation 9 is replaced by the compound of
Preparation 33.
Example 32: N-cyclopropyl-N '- (2- {5 - [(6- { [3- (2 -. {[[(Methylamino) carbonyl] amino} -ethyl) -IH- pyrrolo [2, 3-b] pyridin-5-yl] oxy}. hexyl) amino] -l-benzofuran-3-yl.} ethyl) urea
The procedure is similar to that of Example 27, in the
Step A The compound of Preparation 1 is replaced by the compound obtained in Preparation 34, and in Step C the compound of Preparation 9 is replaced by the compound of Preparation 44. Example 33: N- [2- ( 7- { [6- ( { 3- [4- (methylamino) -4-oxo-butyl] -1H-indol-5-yl} oxy) -hexyl] oxy} -l-naphthyl) ethyl] -3-butanamide
The procedure is similar to that of Example 27, 15 substituting: in Step A, the compound of Preparation 1 for the compound of Preparation 6, tk- in Step C, the compound of Preparation 9 for the compound of Preparation 35. EXAMPLE 34:? - [2- (7- { 3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl].-L-naphthyl) -ethyl] acetamide
Suspend in 20 ml of anhydrous DMF 2.76 mmoles of the compound obtained in preparation 45, 2.76 mmoles of the compound obtained in preparation 46, 1.94 mmoles of dichlorobis (triphenylphosphine) nickel, 3.87 mmoles of triphenylphosphine k and 8.30 mmoles of zinc, under nitrogen . After heating for 48 hours at 120 ° C under nitrogen, the reaction mixture is concentrated and the resulting residue is partitioned between CH2C12 and NaHCO3 M. The organic phase is then dried over Na2SO4 and concentrated in vacuo. The title compound is separated by chromatography on silica gel. In Examples 35 to 48, the procedure is similar to 10 in Example 34 from the appropriate preparations.
Example 35: N- (2- { 5- [8- (2- {[[methylamino) carbonyl} ethyl) -2- naphthyl] -1-benzothiophen-3-yl} ethyl) Cyclopropanecarboxamide 15 Starting materials: Preparations 47 and 48
Example 36: N- (2- { 5- [8- (2- {[[(anilinocarbonyl) amino} ethyl) -1- benzofuran-5-yl) -1-benzo-iofen-3-yl ] ethyl} - 2 - 20 furamide
Starting materials: Preparations 49 and 50
Example 37: 2- (5- { 3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl.} - 25 1H-indol-3-yl) -N-benzylacetamide Starting materials: Preparations 45 and 51
Example 38: N - [3 - (5 -. {3 - [2 - (is obu tiri 1 amino) eti 1] - 1-benzothiophen-5-yl.} - lH-indol-3-yl) - propyl] -benzamide
Initial materials: Preparations 52 and 53
Example 39: N- [3- (5- { 8- [2- (acetylamino) ethyl] -2 -naphthyl} -1H-pyrrolo [2,3-b] -pyridin-3-yl) propyl ] heptanamide
Starting materials: Preparations 46 and 54
Example 40: 4- (5-. {3- [3- (Acetylamino) ethyl] -lH-pyrrolo [2, 3-b] -pyridin-5-yl}.-L-benzofuran-3-yl) - N - cyclopentylbutanamide
Initial materials: Preparations 55 and 56
Example 41: N- (2- { 5- [3- (2- {[[(allylamino) carbonyl] amino} ethyl] -1- benzothiophen-5-yl] -1H-pyrrolo [2, 3-b] -pyridin-3-yl.} Ethyl) cyclopropanecarboxamide
Starting Materials: Preparations 57 and 58 Example 42: N- [2- (5- {3- [(acetylamino) methyl] 1,4-benzodioxin-6-yl}. -lH-pyrrolo [2, 3- b] -pyridin-3-yl) -ethyl] cyclopropanecarboxamide
Starting materials: Preparations 57 and 59 Example 43: 2 -met il -N-. { 2 - [5 - (4 - {2 - [(2, 2, 2-trifluoroacetyl) amino] ethyl] -3,4-dihydro-2H-chromen-6-yl) -1-benzof uran-3-yl] ethyl} propanamide
Initial materials: Preparations 60 and 61
Example 44: 4- (5 - { 3 - [(acetylamino) methyl] -3,4-dihydro-2H-chromen-6-yl.} -1-benzot-iof en-3-yl) -N- phenylbutanamide
Starting materials: Preparations 62 and 63
Example 45: N- (2- { 5- { 8- [2- (acetylamino) ethyl] -2-naphthyl} -2- [4- (trifluoromethyl) -benzyl] -1-benz of uran-3-yl.} ethyl) acetamide
Starting Materials: Preparations 64 and 46 Example 46: 2,2-Dimethyl-N- (2 -. {6- [3- (2. {[[(Methylamino) -carbonyl] amino} ethyl) - 1H-indol-5-yl] -3,4-dihydro-2H-chromen-4-yl} ethyl) propanamide
Initial materials: Preparations 65 and 66
Example 47: N- [(7- { 3- [2- (Acetylamino) ethyl] -1H-indol-5-yl.} -1, 4-benzodioxin-2-yl) methyl] cyclohexanecarboxamide
Initial materials: Preparations 67 and 68
Example 48: N- (3 -. {5 - [3- [2- (acetylamino) ethyl] -2- (3-methoxybenzyl) -1-benzothiof en-5-yl] -1-benzof uran- 3- il.}. propyl) acetamide 15 Starting materials: Preparations 69 and 70
Example 49: N- (2- { 7- [4- ( { 3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy] -l-naphthyl} ethyl) acetamide 20 Stage A: N-. { 2- [7- (4-bromobutoxy) -l-naphthyl] ethyl} acetamide
In a 100 ml round bottom flask, 25 mmoles of the compound obtained in preparation 1 are dissolved in 50 ml of acetonitrile, 30 mmoles of potassium carbonate are added and the mixture is stirred at reflux using a magnetic stirrer for 30 minutes. , and then add 10 mmoles of 1,4-dibromobutane. After 12 hours at reflux, the acetonitrile is removed by evaporation in vacuo and the resulting residue is taken up in a 1M sodium hydroxide solution. The resulting precipitate is filtered off and recrystallized to give the title product.
Stage B: N-. { 2- . { 7- [4- ( { 3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy] -l-naphthyl} ethyl) acetamide
In a 100 ml round bottom flask containing 30 ml of methanol, small portions of sodium are added (0.07 g, 0.0030 at.g). When the sodium has been completely used, 3.6 mmoles of compound obtained in preparation 2 are added. After stirring for 20 minutes, the methanol is removed by evaporation under reduced pressure and the residue is taken up in 15 ml of DMF. 3 mmol of the compound obtained in step A are added and the mixture is refluxed for 12 hours. The reaction mixture is cooled and poured into a mixture of 100 ml of water and 10 ml of 3 M hydrochloric acid. The extraction of the aqueous phase is carried out twice with ethyl acetate and the organic phase is washed with a solution of 10% sodium hydroxide and then with water. The resulting solid is recrystallized from acetonitrile to provide the title product. Melting point: 160-162 ° C
Example 50 N-. { 2- [5- [4- ( { 8- [2- (acetylamino) ethyl] -2-naphthyl} oxy) butoxy] -1- (phenylsulfonyl) -lH-indol-3-yl] ethyl} acetamide
In a 100 ml round bottom flask, 10 mmoles of the compound obtained in Preparation 71 are dissolved in 50 ml of acetonitrile and then 4.17 g of potassium carbonate are added and the reaction mixture is stirred under reflux using a magnetic stirrer, for 30 minutes. Then 10 mmoles of the compound obtained in step A of example 49 are added and the mixture is heated to reflux for 12 hours. The acetonitrile is removed by evaporation in vacuo and the resulting residue is taken up in an aqueous solution of 1 M sodium hydroxide. The resulting precipitate is filtered off and recrystallized from alcohol at 95 °. Melting point: 135-137 ° C
Example 51: N- (2- { 7- [4- ( { 8- [2- (acetylamino) ethyl] -2-naphthyl} oxy) butoxy] -1,2,4,4-tetrahydro Naf talenyl.) ethyl) acetamide The procedure is similar to that of example 49, in step B the product obtained in preparation 2 is replaced by the product obtained in preparation 25. Recrystallization from acetonitrile. 5 Melting point: 63-65 ° C
Example 52: N- (2- { 5- [4- ( { 3- [2- (acetylamino) ethyl] -1-benzofura-5-yl}. Oxy) butoxy] -lH-indole 3-yl.} Ethyl) acetamide
Step A: Ethyl 4- (. {3- [2- (acetylamino) ethyl] -lH-indol-5-yl} oxy) butanoate
.9 g of the compound obtained in preparation 11 are dissolved in 100 ml of acetonitrile, and then added
11.22 g of potassium carbonate and 5.81 ml of ethyl 4-bromobutanoate. After refluxing overnight, the potassium carbonate is filtered off, the acetonitrile is removed by evaporation and the residue is taken up in 100 ml of water. The extraction is carried out three times with 50 ml of
Ethyl acetate each time, and the organic phase is washed with water at neutral pH, dried over magnesium sulfate and evaporated in vacuo. The resulting oil precipitates from isopropyl ether. Melting point: 107-108 ° C Stage B: N-. { 2- [5- (4-hydroxybutoxy) -lH-indol-3-yl] -ethyl} acetamide
A solution of 6.2 g of the compound obtained in step A in 50 ml of anhydrous THF is added dropwise to a suspension of 1.42 g of lithium aluminum hydride in 50 ml of anhydrous THF cooled in an ice bath. After stirring for 30 minutes at room temperature, a 5% sodium hydroxide solution is added dropwise until gas production ceases. The precipitate that forms is separated by filtration, the organic phase is evaporated and the residue is taken up in 70 ml of ethyl acetate. The organic phase is washed with water until neutral, dried over magnesium sulfate and evaporated in vacuo to give the title product as an oil.
Stage C: N-. { 2- [5- (4-bromobutoxy) -lH-indol-3-yl] ethyl} acetamide
3.92 g of the compound obtained in step B are dissolved in 50 ml of acetonitrile, and then 5.31 g of triphenylphosphine and 6.71 g of carbon tetrabromide are added with stirring. After leaving at room temperature overnight, the acetonitrile is removed by evaporation in vacuo and the resulting residue is purified by chromatography on a column of silica gel (eluent: dichloromethane / methanol 96/4).
Oil.
Step D: N- (2- { 5- [4- ( { 3- [2-Acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy] -lH-indole-3 -il} ethyl) acetamide
Dissolve 0.72 g of the compound obtained in step C in 20 ml of acetonitrile, and then add 0.57 g of potassium carbonate and 0.30 g of the compound obtained in preparation 2. After refluxing overnight, the mixture of reaction is poured into 200 ml of ice water. The resulting precipitate is filtered off, washed with ether, dried and recrystallized to give the title compound as a white powder. Melting point: 164-166 ° C
Example 53: N- (2- { 7- [4- ( { 3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy] -l-naphthyl} ethyl) acetamide
The procedure is similar to that of example 49 in stage B when replacing the product obtained in preparation 2 with the product obtained in preparation 9. Recrystallization from acetonitrile / methanol (2/1). Melting point: 169-170 ° C Example 54: N- (2- { 5- [4- ( { 3- [2- (acetylamino) ethyl] -1-benzothien-5-yl}. oxy) butoxy] -lH-indol-3-yl.} ethyl) acetamide
The procedure is similar to that of example 49 in stage A when replacing the product obtained in preparation 1 with the product obtained in preparation 9, and in stage B the product obtained in preparation 2 is replaced by the product obtained in preparation 11.
Example 55: N- (2- { 5- [4- ( { 3- [2- (Acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy] -1H-pyrrolo [ 2, 3-b] pyridin-3-yl.} Ethyl) acetamide
The procedure is similar to that of example 49 in stage A when replacing the product obtained in preparation 1 with the product obtained in preparation 9, and in stage B the product obtained in preparation 2 is replaced by the product obtained in preparation 12.
Example 56: N- (2- { 5- [4- ( { 3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy] -1H-pyrrolo [ 2,3-b] pyridin-3-yl} ethyl) acetamide
The procedure is similar to that of Example 49, in step A when replacing the product obtained in preparation 1 with the product obtained in preparation 2, and in step B the product obtained in preparation 2 is replaced by the product obtained in the preparation 12.
Example 57: N- (2- { 5- [4- ( { 3- [2- (acetylamino) ethyl] -lH-indol-5-yl} oxy) butoxy] -lH-pyrrolo [ 2, 3-b] pyridin-3-yl-ethyl) acetamide
The procedure is similar to that of example 49, in step A when replacing the product obtained in preparation 1 with the product obtained in preparation 11, and in step B the product obtained in preparation 2 is replaced by the product obtained in Preparation 12. Examples 58 to 64 are obtained by procedures similar to those of Example 34, from the appropriate preparations.
Example 58: N- [2- (7- { 3- [2- (Acetylamino) ethyl] -1-benzothien-5-yl}.-L-naphthyl) ethyl] acetamide
Initial materials: Preparations 46 and 72
Example 59: N- [2- (5- { 8- [2- (acetylamino) ethyl] -2-naphthyl} -1 H -pyrrolo [2,3-b] -pyridin-3-yl) ethyl ] Acetamide Starting materials: Preparations 46 and 55
Example 60: N- [2- (5- { 3 - [2- (acetylamino) ethyl] -1-benzofuran-5-yl.} - l-benzothien-3-yl) ethyl] acetamide 5 Materials initials: Preparations 72 and 45
Example 61: N- [2- (5- { 3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl}.-LH-indol-3-yl) ethyl] acetamide (10 Materials initials: Preparations 67 and 45
Example 62: N- [2- (5- { 3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl.}.-LH-pyrrolo [2, 3-b] -pyridin-3 -yl) ethyl] acetamide
Initial materials: Preparations 55 and 45
Example 63: N- [2- (5- { 3 - [2- (acetylamino) ethyl] -lH-indol-5-yl.} - lH-pyrrolo [2, 3-b] pyridin-3 -yl) ethyl] acetamide 20 Starting materials: Preparations 55 and 67
Example 64: N- [2- (5- { 3- [2- (acetylamino) ethyl] -1-benzothien-5-yl}.-LH-pyrrolo [2, 3-b] -pyridin-3 -yl) ethyl] acetamide 25 Starting materials: Preparations 55 and 72
PHARMACOLOGICAL STUDY
EXAMPLE A: Acute toxicity study
The acute toxicity of oral administration was evaluated in several groups, each with 8 mice (26 + 2 grams). The
animals were observed at regular intervals during the course of the first day, and daily for 2 weeks after treatment. The LD50 (the dose causing the death of 50% of the animals) was evaluated and showed low toxicity of the compounds of the invention. EXAMPLE B: Melatonin receptor binding study in sheep pars fcuJberalis cells
The melatonin receptor binding studies of the 20 compounds of the invention were carried out according to conventional techniques in sheep pars tuberalis cells. The pars tuberalis of the adenohypophysis is in fact characterized in mammals by a high density of melatonin receptors (Journal of Neuroendocrinology, 1, provides 1-4, 25 1989).
Protocol
1) Sheep pars tuberalis membranes are prepared and used as target tissue in saturation experiments to determine binding capacities and affinities for 2- [125I] - iodomelatonin.
2) Sheep pars tuberalis membranes are used as the target tissue in competitive binding experiments using the various test compounds compared to melatonin.
Each expetimento is carried out in triplicate and for each compound a range of different concentrations is tested. The results, after statistical processing, allow the binding affinities of the tested compounds to be determined.
Results
The compounds of the invention appear to have strong affinity for melatonin receptors.
EXAMPLE C: Melatonin receptor binding study mtx and MT2
The mtx or MT2 receptor binding experiments were carried out using 2- [125I] -iodomelatonin as a reference radioligand. The retained radioactivity was determined using a liquid scintillation counter. Competitive binding experiments were then carried out in triplicate using the various test compounds. For each compound a range of different concentrations were tested. The results allow the binding affinities of the tested compounds (IC50) to be determined. Therefore, the IC50 values found for the compounds of the invention show the binding for one of the other subtypes of rnt-L and MT2 receptors, these values are < . 10 μM.
EXAMPLE D: Action of the compounds of the invention in the circadian rhythms of rat locomotor activity
The relationship of melatonin altering most of the physiological, biochemical and behavioral circadian rhythms by day / night alterations has made it possible to establish a pharmacological model to analyze the melatoninergic ligands. The effects of the compounds are tested in relation to many parameters, and in particular, in relation to the circadian rhythms of locomotor activity, which are a reliable indicator of the activity of the endogenous circadian clock. In this study, the effects of such compounds were evaluated in a particular experimental model, specifically the rat placed in temporary isolation (permanent darkness).
Experimental protocol
Male 1-month-old rats are subjected, as soon as they arrive at the laboratory, to a light cycle of 12 hours of light for 24 hours (LD 12:12). After 2 to 3 weeks of adaptation, they are placed in cages that are placed with a network connected to a recording system in order to detect the locomotor activity bases and therefore monitor the nictemeral (LD) or circadian rhythms (DD ). As soon as the recorded rhythms show a stable pattern in the light cycle 12:12, the rats are placed in permanent darkness (DD). Two to three weeks later, when a free course has been established (rhythm that reflects that of the endogenous clock), the rats are given a daily administration of the compound to be tested. The observations are made by visualizing the rhythms of activity: - influence of the rhythm of light on the rhythms of activity, - disappearance of the influence on the rhythms, in the permanent darkness, influence by the daily administration of the compound; transient or durable effect.
A software package makes it possible to: - measure the duration and intensity of the activity, the period of the rhythm of the animals during the free course and during the treatment, - possibly demonstrate by spectral analysis the existence of circadian and non-circadian components (for example ultradianos).
Results
The compounds of the invention clearly appear to have a powerful action on the circadian rhythm via the melatoninergic system.
EXAMPLE E: Test in the light / dark cage
The compounds of the invention are tested in a behavioral model, the test of the light / dark cage, which allows the anxiolytic activity of the compounds to be revealed. The equipment includes two polyvinyl boxes covered with Plexiglas. One of the boxes is in the dark. One lamp is placed above the other box, which provides a light intensity of approximately 4,000 lux in the center of the box. An opaque plastic tunnel separates the light box from the dark one. The animals are tested individually for a 5-minute section. The floor of each box is cleaned between each session. At the start of each test, a mouse is placed in the tunnel, facing the dark box. It records the time spent by the mouse in the illuminated box and the number of passes through the tunnel, after its first entry to the dark box. After administration of the compounds 30 minutes before the start of the test, the compounds of the invention significantly increase the time spent in the illuminated cage and the number of passages through the tunnel, demonstrating the anxiolytic activity of the compounds of the invention. the invention.
EXAMPLE F: Activity of the compounds of the invention is the caudal artery of the rat. The compounds of the invention were tested in the caudal artery of the rat. Melatoninergic receptors are present in these vessels, so a relevant pharmacological model is provided to study the activity of the melatoninergic ligand. The stimulation of the receptors can induce vasoconstriction or dilation, depending on the arterial segment studied.
Protocol
One-month old rats are accustomed to a light / dark cycle of 12 h / 12 h for a period of 2 to 3 weeks. After sacrifice, the caudal artery is isolated and maintained in a highly oxygenated medium. The arteries are then cannulated at both ends, suspended vertically in an organ chamber in a suitable medium and perfused through the proximal end. The changes of pressure in the infusion flow allow the evaluation of the vasoconstriction or vasodilator effect of the compounds. The activity of the compounds is evaluated in segments that have been previously contracted by phenylephrine (1 μM). A concentration / response curve is determined non-cumulatively by the addition of a concentration of the test compound to the opposite segment previously. When the observed effect reaches equilibrium, the medium is changed and the preparation is left 20 minutes before the addition of the same phenylephrine concentration and the additional concentration of the test compound.
Results
The compounds of the invention significantly modify the diameter of the caudal arteries previously restricted by phenylephrine.
EXAMPLE G: Pharmaceutical composition: tablets
1000 tablets are prepared containing a dose of 5 mg of N- [2 -. { l - [4- ( { 3- [2- (Acetylamino) ethyl] -l-benzofuran-5-yl} -oxi) butoxy] -l-naphthyl} ethyl) acetamide (Example 49) 5 g Wheat starch 20 g Corn starch 20 g Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropyl cellulose 2 g
Claims (14)
- ^ A represents a grouping of formula -NR ^ -R2, -NR ^ -NR'R3 O -C-NR2R3 Q Q Q wherein: Q represents a sulfur or oxygen atom, R1, R2 and R3, which may be identical or different, represent a hydrogen atom or a group Ra (where Ra represents a linear or branched alkyl group, unsubstituted or substituted, a straight or branched (C2-C6) alkenyl group, unsubstituted or substituted, a straight or branched (C2-C6) alkynyl group, unsubstituted or substituted, an unsubstituted or substituted (C3-C3) cycloalkyl group, a an unsubstituted or substituted cycloalkyl (C3-C8) alkyl group in which the alkyl portion is linear or branched, a polyhaloalkyl group in which the alkyl portion is linear or branched, an aryl group, an arylalkyl group in which the alkyl portion is linear or branched, an arylalkenyl group (C2-C6) in which the alkenyl portion is straight or branched, a heteroaryl group, a heteroarylalkyl group (C-C-) in which the alkyl portion is linear or branched, or a heteroarylalkenyl group ( C2-C6) in which the alkenyl portion is linear or branched), or the groups R2 and R3 can also form, with the nitrogen atom supporting it, a group selected from piperazinyl, piperidinyl and pyrrolidinyl, B represents a grouping of formula -NR ^ -R2, -NR ^ -NR'R3, -C-NR2R3, -C-OR1, -NR ^ -OR2 or NR2R3 wherein 15 || || II II II Q Q Q Q Q Q, R1, R2 and R3 are as defined in the above, G and G3, which may be identical or • 20 different, represent a straight or branched alkylene chain containing from 1 to 4 carbon atoms which is optionally substituted by one or more identical or different groups which are selected from hydroxy, carboxy, formyl, Ra, ORa, COORa and CORa ( where Ra is as defined in the above), 25 4 Cy and Cy ', which are different, represent a ring structure of formula (II) where: * X and Y, which may be identical or different, represent a sulfur, oxygen or carbon atom, or a CH or CH2 group, * R4 represents a hydrogen or a halogen atom, or a CF3, hydroxy group , carboxy, formyl, amino, NHRa, NRaR1a, NHCOR, CONHRa, Ra, ORa, CORa or COORa, (where Ra is as defined in the above and R1a can have any of the meanings of Ra), * the symbol ^ = means that the bonds are simple or double, with the proviso that it respects the valence of the atoms, where G2 replaces the benzene ring, and G ± replaces the ring containing X and Y in the case of Cy, and G2 replaces the benzene ring and G3 replaces the ring containing X and Y in the case of Cy ', or a ring structure of the formula (III): wherein: * Z represents a sulfur or oxygen atom, or a group CH2, NH, NS02Ph or? Ra (where Ra is as defined above), * D represents a benzene or pyridine ring, * R4 is as defined in the above, * the symbol - ^ = means that the link is simple or double, provided that the valence of the atoms is respected, where G2 replaces the ring D and Gx replaces the ring containing Z in the case of Cy, and G2 replaces ring D and G3 replaces the ring containing Z in the case of Cy ', the two different rings, Cy and Cy' of the compounds of formula (I) are both represented by a structure of formula (II) or by a structure of formula (III), or one of the two rings is represented by a structure of formula (II) and the other is represented by a structure of formula (III), 4 G2 represents a chain of formula (IV): wherein: Wx, W2 and W3, which may be identical or different, represent a bond, an oxygen or sulfur atom, or a group CH2, CHRa, NH or NRa (where Ra is as defined in 10 above) ), n represents an integer where 0 = n = 6, m represents an integer where 0 = m = 6, with the proviso that it is not possible to have two consecutive heteroatoms and where the chain of formula (IV) defined from This way can have one or more unsaturated bonds, it being understood that "aryl" means the naphthyl, phenyl and biphenyl groups, "heteroaryl" means any saturated or unsaturated monocyclic or bicyclic group containing from 5 to 10 ring atoms and containing 1 to 3 heteroatoms which are selected from nitrogen, sulfur and oxygen, it is possible that the "aryl" and "heteroaryl" groups are substituted by one or more identical and different radicals which are 25 select linear or branched hydroxy, carboxy, alkoxy (C.sub._-Ce), linear or branched alkyl (C.-C-;), polyhaloalkyl (Ci-Cg) in which the alkyl portion is linear or branched, formyl, cyano, nitro, amino, linear or branched alkylamino (Ci-Cg), di-alkyl amino, in which each alkyl portion is linear or branched, and halogen atom, the term "substituted" applied to the terms "alkyl," "alkenyl" and "alkynyl" means that these groups are substituted by one or more identical or different radicals which are selected from hydroxy, linear or branched alkoxy, polyhaloalkyl wherein the alkyl portion is linear or branched, amino, linear or branched alkylamino, dialkyl (CL-Cg) amino, in which each alkyl portion is linear or branched, and halogen atom, the term "substituted" applied to the "Cycloalkyl" and "cycloalkylalkyl" mean that the cyclic portion of these groups is substituted by one or more identical or different radicals that are selected from hydroxy, alkoxy (Cj.-C6) linear or branched, polyhaloalkyl (CL-Cg) in which the alkyl portion is linear or branched, amino, linear or branched alkylamino (C ^ Cg), di-alkyl amino in which each alkyl portion is linear or branched, and halogen atoms, their enantiomers and diastereoisomers and addition salts thereof, with a pharmaceutically acceptable acid or base.
- 2. The compounds of formula (I), as described in claim 1, wherein Cy and Cy 'which are different from each other, represent a ring structure of formula (II), its enantiomers and diastereoisomers, and addition salts of the same with a pharmaceutically acceptable acid or base.
- 3. The compounds of formula (I), as described in claim 1, wherein Cy and Cy1 which are different, represent a ring structure of formula * f 10 (III), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
- 4. The compounds of formula (I), as described in claim 1, wherein Cy represents a structure of The ring of formula (II) and Cy 'represents a ring structure of formula (III), its enantiomers and diastereoisomers, and addition salts thereof, with a pharmaceutically acceptable acid or base.
- 5. The compounds of formula (I), as described in claim 1, wherein G2 represents a single bond, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
- 6. The compounds of formula (I), as described in claim 1, wherein G2 represents a grouping B -W4- (CH2) p-W'4- wherein W4 and W'4 which may be identical or different , represent an oxygen or sulfur atom or a group NH or NRa, and p represents an integer where 1 = p = 12, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
- 7. The compounds of formula (I), as described W 10 in claim 1, wherein G 2 represents a grouping -0- (CH2) p0-, where p represents an integer where 1 = p = 12, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
- 8. The compounds of formula (I), as described in claim 1, wherein A and B, which may be the same or different, represent a group NR1C0R2 or C0NR2R3 their enantiomers and diastereoisomers, and addition salts of the • themselves with a pharmaceutically acceptable acid or base.
- 9. The compounds of formula (I), as described in claim 1, which are -N- (2- {7- [2- (. {3- [2 (acetylamino) ethyl] - 1-benzofuran-5-yl.} Oxy) ethoxy] -l-naphthyl} -ethyl) acetamide, -N- (2- { 5- [2- ( { 8- [2 (acetylamino) ethyl] -2- 25 naphtyloxy) ethoxy] -l-benzofuran-3-yl.} ethyl) -2-furamide, -N- (2-. {5- [2- ( { 8- [2 (acetylamino) ethyl] -2-naphyl}. Oxy) ethoxy] -IH-pyrrolo [2, 3-b] -pyridin-3-yl} ethyl) cyclopropanecarboxamide, -N- (2 - { 7- [3- ( { 3- [2 (acetylamino) ethyl] -l-benzothiophen-5-yl} oxy) propoxy] -1-naphtyl-ethyl) acetamide, -N- [2- (5- { [6- ( { 8- [2- (acetylamino) ethyl] -2-naphthyl}. Oxy) hexyl] oxy.}. -IH-pyrrolo- [2, 3-ib] pyridin-3-yl) ethyl] acetamide, -N- (2 { 5- [4- ( { 3- [2- (acetylamino) ethyl] -1-benzothien-5-yl.} oxy ) butoxy] -WH- indol-3-yl.} ethyl) acetamide, -N- (2- {5- [4- ( { 3- [2- (acetylamino) ethyl] -l-benzothien -5-yl.}. Oxy) butoxy] -líi-pyrrolo- [2, 3-b] pyridin-3-yl} ethyl) acetamide, -N- (2- {5- [4- ( { 3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} oxy} butoxy] -lif -pyrrolo- [2,3-jb] pyridin-3-yl.} ethyl) acetamide, -N- (2 -. {5 - [4- ( { 3- [2 - (acetylamino) ethyl] -lH-indol-5-yl.}. oxy) butoxy] -lH-pyrrolo- [2,3-Jb] pyridin-3-yl.} ethyl) acetamide and addition salts thereof with an acid or base pharmaceutically acceptable.
- 10. The compounds of formula (I), as described in claim 1, which are -N- (2. {7- [4- (. {3- [2 (acetylamino) ethyl] -l-benzofuran -5-yl.}. Oxy) butoxy] -l-naphthoxy] -ethyl) acetamide, -N-. { 2- [5- [4- ( { 8- [2 (acetylamino) ethyl] -2-naphthyl-oxy) -butoxy] -1- (phenylsulfonyl) -lH-indol-3-yl] ethyl} acetamide, -N- (2- { 7- [4- ( { 8- [2- (acetylamino) ethyl] -2-naphthoxy oxy) butoxy] - 1, 2, 3, 4 - tetrahydro - l -naphthalenyl.} ethyl) acetamide, -N- (2- {5- [4- ( { 3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} oxy) -butoxy] -1H-indol-3-yl.} ethyl) acetamide, -N- (2- {7- [4- ( { 3- [2- (acetylamino) ethyl] - L-benzothien-5-yl}. oxy) butoxy] -l-naphthoxyethyl-acetylamide and acid addition salts thereof, with a pharmaceutically acceptable acid or base.
- 11. The compounds of formula (I), as described in claim 1, which are -N- [2- (7- { 3- [2- (acetylamino) ethyl] -l-benzofuran-5-yl}-l-naphyl) ethyl] acetamide, -N- [3- (5- { 8- [2- (acetylamino) ethyl] -2 -nafyl}. -li? -pyrrolo- [2,3-jb] pyridin-3-yl.} propyl] heptanamide, -N- [2- (7- { 3- [2 - (acetylamino) ethyl] -l-benzothien-5-yl} -l-naph il) ethyl] acetamide, -N - [2- (5- { 8- [2- (acetylamino) ethyl] -2 -naphthyl]. -li? -pyrrolo- [2,3-b] pyridin-3-yl.} Ethyl] acetamide, -N- [2- (5- { 3- [2- (acetylamino) ethyl] -l-benzofuran-5-yl}. -l-benzothien-3-yl) ethyl] -acetamide, - N- [2- (5- { 3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl}. -1H-indol-3-yl) ethyl] -acetamide, -N- [ 2- (5- { 3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl}. -li? -pyrrolo [2, 3-yl] pyridin-3-yl) ethyl ] -acetamide, -N- [2- (5- { 3- [(acetylamino) ethyl] -1H-indol-5-yl.}. -li? -pyrrolo [2,3-jb] pyridin-3 -yl) ethyl] acetamide, -N- [2- (5- { 3- [2- (acetylamino) ethyl] -1-benzothiophen-5-yl}. -li? -pyrrolo [2, 3- b] pyridin-3-yl) ethyl] -acetamide and addition salts thereof, with a pharmaceutically acceptable acid or base.
- 12. The process for the preparation of compounds of formula (I), as described in claim 1, characterized in that a compound of formula (V) is used as starting material: wherein A, G ± and Cy are as defined for formula (I), which is subjected to demethylation using conventional agents such as HBr, A1C13, AlBr3, BBr3 or Lewis acid / nucleophilic binary systems, such as, for example, AlCl3 / PhCH2SH or BBr3 / Me2S, to obtain a compound of formula (VI): wherein A, Gx and Cy are as defined in the foregoing, 4 which is converted, conventionally, by the action, for example, of sodium N, N-dimethylthiocarbamate, to the corresponding thiol of formula (VII) : A-G ^ Cy-SH (VII) where A, Gj. and Cy are as defined in the above, or the corresponding amine compound of formula (VIII): AG ^ Cy-NHR1 (VIII) where A, Gx and Cy are as defined in the above, and R'a may have any of the meanings Ra as defined for formula (I) and may also represent an atom of hydrogen, compounds of formulas (VI), (VII) and (VIII) which represent the compound of formula (IX): A-G-L-Cy-W ^ (IX) wherein W4 represents an oxygen or sulfur atom, or an NH or NRa group (wherein Ra is as defined above), compound of formula (IX) which is condensed with: a compound of formula (X): where Hal represents a bromine, chlorine or iodine atom, and n, W2 and m are as defined for formula (I), (with the proviso that it is not possible to have two consecutive heteroatoms and that the chain defined in this way can have one or more unsaturated bonds), or a compound of formula (XI): ^? K2) x. ÍCH2) m-i? OAlk (XI) Hal where Hal, n, m and W2 are as defined in the above and Alk represents an alkyl radical (with the proviso that it is not possible to have two consecutive heteroatoms and that the chain defined in this way may have one or more unsaturated bonds) , followed by reduction, to provide a compound of formula (XII): A-G ._- Cy-W4- (CH2) n-W2- (CH2) m-0H (XII) where A, Gx, Cy, W4, n, and W2 are as defined in the above (with the proviso that it is not possible to have two consecutive heteroatoms in the chain -W4- (CH2) n-W2- (CH2) m-0H and that the chain defined in this way may have one or more unsaturated bonds), the hydroxyl function of which is converted in a conventional manner to a leaving group such as, for example, a mesylate, a tosylate or a halogen, to provide a compound of formula (XII '): A-G1-Cy-W4- (CH2) n-W2- (CH2) m-E (XII ') wherein A, Glf Cy, W4, n, W2 and m are as defined in the foregoing, and E represents a mesyl or tosyl group or a halogen atom, which is subjected to the action of a compound of formula (XIII) : B-G, -Cy '-W'4H (XIII) wherein B, G3 and Cy 'are as defined for formula (I) and W'4 may have the same meanings as W4 defined in the foregoing, to provide a compound of formula (I / a), a particular case of the compounds of the formula (I): A-G1-Cy-W4- (CH2) n-W2- (CH2) m-W'4-Cy, -G3-B (1 / a) where A, Gx, Cy, Cy1, W4, n, W2, m, W'4, G3 and B are as defined above, 4 or are converted using, for example, phenylbis (trifluoromethanesulfonimide) in a basic medium , to the corresponding trifluoromethanesulfonate of formula (XIV): A-G3.-Cy-OSO_.CF3 (XIV) wherein A, G and Cy are as defined above, - which is subjected under catalysis conditions by a suitable palladium compound, to the action of the boric acid compound (RbB (OH) 2) or a compound of tin (RbSnBu3) (where Rb represents a grouping of formula (XV): B-G3-Cy '-W3- (CH2) m-W2- (CH2) n -CH2- (XV) where B, G3, Cy ', W3, m, W2 and n are as defined in the above, with the proviso that it is not possible to have two consecutive heteroatoms in the -W3- (CH2) m-W2- chain and that the chain defined in this way can have one or more unsaturated bonds), to provide a compound of formula (I / b), a particular case of the compounds of formula (I): A-G, _- Cy-CH2- (CH2) n-W2- (CH2) m-W3-Cy '-G3-B (1 / b) where A / G_., Cy, Cy ', n, W2, m, W3, G3 and B are as defined in the above (with the proviso that it is not possible to have two consecutive heteroatoms in the chain -W2- ( CH2) m-W3- and that the chain defined in this way can have one or more unsaturated bonds), compounds of formula (I / c) which, a particular case of the compounds of formula (I): A-Gj.-Cy-, .- (CH2) n-W2- (CH2) m-CH2-Cy '-G3 -B (I / C) where A, G? ? Cy, Cy ', W1 (n, W2, m, G3 and B are as defined in the above (with the proviso that it is not possible to have two consecutive heteroatoms in the chain -W_- (CH2) n-W2- and that the chain defined in this way can have one or more unsaturated bonds), is obtained according to a similar procedure starting from a compound of formula (XIV): B-G3-Cy '-0S02CF3 (XIV) wherein B, G3 and Cy 'are as defined in the above, or are treated, under coupling conditions using, for example, nickel or palladium compounds, with a compound of formula (XIV) to provide a compound of formula ( I / d), a particular case of the compounds of formula (I): A-G1-Cy-Cy'-G3-B (I / d) where A, G, Cy, Cy ', G3 and B are as defined in the above,. { B all of the compounds (I / a) to (I / d) constitute the compounds of formula (I) which can be purified, if desired, by a conventional purification technique, and separated, when appropriate , in their isomers according to a conventional separation technique, and converted, if necessary, into addition salts thereof with a pharmaceutically acceptable acid or base. W 10
- 13. Pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), as described in any of claims 1 to 11, or an addition salt thereof with an acid or base 15 pharmaceutically acceptable, in combination with one or more pharmaceutically acceptable excipients.
- 14. The pharmaceutical compositions as described in claim 13, for use in the production of a 20 medicine for the treatment of disorders associated with the melatoninergic system. SUMMARY OF THE INVENTION The invention relates to compounds of formula (I): A - ^ - Cy - ^ - Cy '-G3-B: D where: A represents a grouping NR1C (Q) R2, C (Q) NR2R3 OR ^ Q NR ^ 3, B represents a grouping of formula -NR1C (Q) R2, NR1C (Q) NR2R3, C (Q) NR2R3, C (C_ ) OR \ NR ^ OR OR2 or NR2R3 G_. and G3, represent an optionally substituted alkylene chain, Cy and Cy1, which are different, represent one is G2 represents a chain Medicines
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR99.06331 | 1999-05-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00004818A true MXPA00004818A (en) | 2002-05-09 |
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