NZ627327B2 - Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives - Google Patents
Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives Download PDFInfo
- Publication number
- NZ627327B2 NZ627327B2 NZ627327A NZ62732712A NZ627327B2 NZ 627327 B2 NZ627327 B2 NZ 627327B2 NZ 627327 A NZ627327 A NZ 627327A NZ 62732712 A NZ62732712 A NZ 62732712A NZ 627327 B2 NZ627327 B2 NZ 627327B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- 1hnmr
- mhz
- colorless oil
- acid
- cyclobutyl
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title abstract description 66
- 238000003786 synthesis reaction Methods 0.000 title description 26
- 230000002194 synthesizing Effects 0.000 title description 24
- 230000015572 biosynthetic process Effects 0.000 title description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 230000003405 preventing Effects 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 17
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 230000003287 optical Effects 0.000 claims description 3
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 3
- 230000000052 comparative effect Effects 0.000 claims 3
- 208000008589 Obesity Diseases 0.000 abstract description 32
- 235000020824 obesity Nutrition 0.000 abstract description 32
- GUUQNYXRXDSMBK-UHFFFAOYSA-N 1-[1-(3,4-dimethoxyphenyl)cyclobutyl]-N-(4-ethoxybutyl)-3-methylbutan-1-amine Chemical compound C=1C=C(OC)C(OC)=CC=1C1(C(CC(C)C)NCCCCOCC)CCC1 GUUQNYXRXDSMBK-UHFFFAOYSA-N 0.000 abstract 2
- -1 cycloheteroalkyl Chemical group 0.000 description 111
- 238000005160 1H NMR spectroscopy Methods 0.000 description 91
- 239000012230 colorless oil Substances 0.000 description 75
- 101700067048 CDC13 Proteins 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- 125000000217 alkyl group Chemical group 0.000 description 46
- 201000010099 disease Diseases 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 125000003118 aryl group Chemical group 0.000 description 36
- 150000001408 amides Chemical class 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- 125000001072 heteroaryl group Chemical group 0.000 description 32
- 239000002253 acid Substances 0.000 description 31
- 125000003710 aryl alkyl group Chemical group 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 150000003254 radicals Chemical class 0.000 description 31
- 125000001424 substituent group Chemical group 0.000 description 29
- 125000000753 cycloalkyl group Chemical group 0.000 description 28
- 230000000875 corresponding Effects 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 26
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 238000004809 thin layer chromatography Methods 0.000 description 24
- 150000002148 esters Chemical class 0.000 description 22
- 125000004404 heteroalkyl group Chemical group 0.000 description 22
- 229910052739 hydrogen Inorganic materials 0.000 description 21
- 239000001257 hydrogen Substances 0.000 description 21
- 150000002431 hydrogen Chemical class 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 125000004432 carbon atoms Chemical group C* 0.000 description 15
- 150000002500 ions Chemical class 0.000 description 15
- 125000002947 alkylene group Chemical group 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 239000008079 hexane Substances 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- HQABUPZFAYXKJW-UHFFFAOYSA-N N-Butylamine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 11
- 150000007513 acids Chemical class 0.000 description 11
- 229940079593 drugs Drugs 0.000 description 11
- 230000002829 reduced Effects 0.000 description 11
- 239000003981 vehicle Substances 0.000 description 11
- NKLFLMIOOKWFHK-UHFFFAOYSA-N N-(cyclobutylmethyl)aniline Chemical compound C1CCC1CNC1=CC=CC=C1 NKLFLMIOOKWFHK-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 150000002170 ethers Chemical class 0.000 description 10
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- UNAANXDKBXWMLN-UHFFFAOYSA-N Sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 229960004425 sibutramine Drugs 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 230000002459 sustained Effects 0.000 description 9
- 150000001735 carboxylic acids Chemical class 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 7
- 102100001467 SLC18A2 Human genes 0.000 description 7
- 101710044968 SLC18A2 Proteins 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 239000002830 appetite depressant Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000004166 bioassay Methods 0.000 description 7
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 235000019197 fats Nutrition 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- PETXWIMJICIQTQ-UHFFFAOYSA-N phenylmethoxymethanol Chemical compound OCOCC1=CC=CC=C1 PETXWIMJICIQTQ-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 230000001225 therapeutic Effects 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- 150000002009 diols Chemical class 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 230000001419 dependent Effects 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- NQYKGEPHDRUFJL-UHFFFAOYSA-N ethyl 4-ethoxybutanoate Chemical compound CCOCCCC(=O)OCC NQYKGEPHDRUFJL-UHFFFAOYSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 231100000486 side effect Toxicity 0.000 description 5
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 150000003568 thioethers Chemical class 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AHLBNYSZXLDEJQ-FWEHEUNISA-N Orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 4
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 4
- 125000004429 atoms Chemical group 0.000 description 4
- 238000004296 chiral HPLC Methods 0.000 description 4
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229960001243 orlistat Drugs 0.000 description 4
- NJRWNWYFPOFDFN-UHFFFAOYSA-L phosphonate(2-) Chemical compound [O-][P]([O-])=O NJRWNWYFPOFDFN-UHFFFAOYSA-L 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- 229960001663 sulfanilamide Drugs 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 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
- DLNKOYKMWOXYQA-VXNVDRBHSA-N (+)-Norephedrine Chemical compound C[C@@H](N)[C@@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-VXNVDRBHSA-N 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- SIAZIIRHVGPIPH-UHFFFAOYSA-N 3-methyl-1-[1-(4-methylphenyl)cyclohexyl]butan-1-amine Chemical compound C=1C=C(C)C=CC=1C1(C(N)CC(C)C)CCCCC1 SIAZIIRHVGPIPH-UHFFFAOYSA-N 0.000 description 3
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- 241000229754 Iva xanthiifolia Species 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 230000036740 Metabolism Effects 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- DHHVAGZRUROJKS-UHFFFAOYSA-N Phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 3
- 229940076279 Serotonin Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating Effects 0.000 description 3
- 231100000494 adverse effect Toxicity 0.000 description 3
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 3
- 150000007962 benzene acetonitriles Chemical class 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000001684 chronic 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
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000035786 metabolism Effects 0.000 description 3
- 230000002474 noradrenergic Effects 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 230000003595 spectral Effects 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N γ-lactone 4-hydroxy-butyric acid Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 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
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- WQSACWZKKZPCHN-UHFFFAOYSA-N 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutan-1-amine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N)CC(C)C)CCC1 WQSACWZKKZPCHN-UHFFFAOYSA-N 0.000 description 2
- KFNNPQDSPLWLCX-UHFFFAOYSA-N 1-[1-(4-chlorophenyl)cyclobutyl]-N,N,3-trimethylbutan-1-amine;hydron;chloride;hydrate Chemical compound O.Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 KFNNPQDSPLWLCX-UHFFFAOYSA-N 0.000 description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
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Classifications
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- A61P3/04—Anorexiants; Antiobesity agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/25—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
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- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present disclosure provides phenylcycloalkylmethylamine derivatives, and methods of preparing phenylcycloalkylmethylamine derivatives. The present disclosure also provides methods of using phenylcycloalkylmethylamine derivatives and compositions of phenylcycloalkylmethylamine derivatives. The pharmaceutical compositions of the compounds of the present disclosure can be used for treating and/or preventing obesity and obesity related co-morbid indications and depression and depression related co-morbid indications. An example of the compound is 1-(1-(3,4-dimethoxyphenyl)cyclobutyl)-N-(4-ethoxybutyl)-3-methylbutan-1-amine. armaceutical compositions of the compounds of the present disclosure can be used for treating and/or preventing obesity and obesity related co-morbid indications and depression and depression related co-morbid indications. An example of the compound is 1-(1-(3,4-dimethoxyphenyl)cyclobutyl)-N-(4-ethoxybutyl)-3-methylbutan-1-amine.
Description
COMPOSITIONS, SYNTHESIS, AND S OF USING
PHENYLCYCLOALKYLMETHYLAMINE DERIVATIVES
TECHNICAL FIELD
The present invention relates to phenylcycloalkylmethylamine derivatives, synthesis of
phenylcycloalkylmethylamine derivatives and methods of using phenylcycloalkylmethylamine
derivatives for the pharmacological treatment of obesity, depression and obesity related co-
morbid indications.
BACKGROUND
Obesity is a chronic disease that affects millions of people across the world especially in
the developed countries. It is defined by excess body fat and is generally ed by calculating
a person’s BMI (body mass index). If a ’s BMI is 30 or above, he or she considered to be
obese. Obesity can cause a number of health problems either directly or indirectly, such as, for
example, type 2 diabetes, coronary heart disease, high blood triglycerides, high blood pressure
and stroke. Obesity also raises risk of certain types of cancer. Obese men are more likely than
normal-weight peers to die from cancer of the colon, rectum, and prostate. Obese women are
more likely than ese women to die from cancer of the gallbladder, breast, uterus, cervix
and ovaries. Death from some cancers may be more likely because obesity makes the cancers
harder to detect in the early stages (for example, the initial small lump of breast cancer may not
be felt in an obese woman). Recent studies show obesity increases the risk of Alzheimer’s-type
dementia. Other disease and health problems linked to obesity include: gallbladder disease,
gallstones, osteoarthritis, gout or joint pain, sleep apnea, psychological and social problems.
Obesity is caused by multiple s, the primary factor being genetics which is the one
factor relating to obesity over which individuals have no control. Other important factors
ed in y are: the mechanisms of fat storage; the e between energy intake and
energy iture; an individual’s life style: eating habits and exercise; and psychological,
cultural and conomic influences. Despite the seeming able progression of this
disease, there have been limited advances in the pharmacotherapy of this condition. Drugs to
treat obesity can be d into three groups: those that reduce food intake or appetite
suppressants; those that alter metabolism or block the absorption of fat; and those that increase
WO 02195
thermogenesis. Currently, there are only two drugs approved by the FDA for the erm
treatment of obesity and they are fat absorption blocker orlistat (XENICAL®) and the appetite
suppressant sibutramine (MERIDIA®). The only thermogenic drug combination that has been
tested is ephedrine and caffeine, but this treatment has not been approved by tory agencies.
The fat absorption blocker, orlistat works in the gastrointestinal tract by blocking an
enzyme that is needed to digest fat. Instead of being absorbed from the intestine, up to one-third
of the fat that a person consumes is excreted in the stool. In addition, orlistat blocks the
absorption of needed fat-soluble vitamins A, D, E, and K, as well as beta-carotene. This is one of
the major limitations of this drug for the long term use in the treatment of obesity. Most
commonly reported other side effects of at are bloating, diarrhea and oily stools.
In the appetite suppressant category, a few noradrenergic and serotonergic drugs belong
to a family of 2-arylethylamines are currently available in the market for the treatment of obesity.
The noradrenergic agents such as phenylpropanolamine, (ACUTRIM®, DEXATRIM®),
lpropion (TENUATE®), and phentermine N®, IONAMIN®) are approved for the
short-term treatment of y. Whereas, noradrenergic and serotonergic agent amine
(MERIDIA®) is the only drug currently approved for the long-term treatment of y in the
appetite suppressant category. Sibutramine has cyclobutanemethylamine backbone and it is this
ne mainly responsible for its unique pharmacological properties.
In the last 10 years, a number of reports have been hed on the possible use of
sibutramine, either alone or in combination with other therapeutic agents, for the ent
and/or prevention of a variety diseases and/or disorders in addition to obesity (see, Montana, J.
G., ; Lulla, A. et al., ; Jerussi, T. P. et al., WO 02/060424;
Senanayake, C. H. et al., WO 01/51453; Heal, D. J., WO 05; Birch, A. M. et al., WO
01/00187; Mueller, P., WO 78; Bailey, C., WO 98/1 1884; Kelly, P., WO 98/13034). For
examples: treatment of nausea, emesis, and related conditions; cognitive dysfunctions; eating
disorders; weight gain; irritable bowel syndrome; obsessive compulsive disorders; platelet
adhesion; apnea, affective disorders such as attention deficit disorders, depression, and anxiety;
male and female sexual function disorders; restless leg syndrome; osteoarthritis; substance abuse
ing nicotine and cocaine addiction; narcolepsy; pain such as neuropathic pain, diabetic
neuropathy, and chronic pain; nes; cerebral function disorders; chronic disorders
such as premenstrual syndrome; and inence.
In general, sibutramine has a number of therapeutic benefits because of its
unique pharmacological properties. However, sibutramine’s therapeutic use for the
treatment of obesity, and other diseases and disorders is currently not fully utilized
because of certain limitations and e side effects associated with the drug. The
major adverse events reported, in some cases life threatening, include se in blood
pressure and the side effects derived from the drug-drug interactions, for example,
serotonin syndrome. The majority of these adverse events are, to some extent,
metabolism-based. Sibutramine exerts its pharmacological actions predominantly via its
secondary (M1) and y (M2) amine metabolites. Sibutramine is metabolized in the
liver principally by the cytochrome P450 (3A4) isozymes, to desmethyl metabolites, M1
and M2. These active metabolites are further metabolized by hydroxylation and
conjugation to pharmacologically inactive metabolites, M5 and M6. The elimination half-
lives of therapeutically active primary and secondary lites M1 and M2 are 14 and
16 hours, respectively. It is evident from a number literature reports that cytochrome
P450 mediated metabolism and the long half lives of active lites (M1 and M2) are
to a great extent responsible for adverse events such as sed blood pressure and
other side effects derived from rug interactions of sibutramine.
Therefore, there is a need and great demand for safer and effective next
generation appetite suppressants for the treatment of obesity. An ideal drug in this class
should have potent appetite suppressant activity, a proven effect on fat loss, be well
tolerated during acute and chronic administration and have alleviated side effects when
ed to sibutramine and phentermine.
Any discussion of the prior art throughout the ication should in no way be
considered as an admission that such prior art is widely known or forms part of common
general knowledge in the field.
Unless the context clearly es otherwise, throughout the description and the
claims, the words “comprise”, ising”, and the like are to be construed in an
inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the
sense of “including, but not limited to”.
SUMMARY OF THE INVENTION
ing to a first aspect of the invention there is provided a compound of
structural Formula (I):
or pharmaceutically acceptable salt f, wherein:
n is 1;
SP is a spacer of butylene;
X is O or S;
R1 and R2 are independently H, C1-6 alkoxy, or halogen;
R3 is C1-6 alkyl;
R4 is H;
R5 is C1-6 alkyl;
optionally R1, R2, R3, R4, and R5 is substituted with 2H (deuterium); and
“*” denotes a carbon capable of being lly active.
According to a second aspect of the invention there is provided a pharmaceutical
composition comprising the compound of the invention and a pharmaceutically
acceptable vehicle.
ing to a third aspect of the invention there is provided use of the
compound of the invention in the preparation of a medicament for treating or preventing
obesity in a mammal patient.
According to a fourth aspect of the ion there is provided use of the
compound of the invention in the preparation of a medicament for treating or preventing
depression in a mammal patient.
The present invention is directed towards compositions of novel
cycloalkylmethylamine derivatives and the use of the compositions for the
treatment of obesity, and related co-morbid conditions and depression and related comorbid
conditions. The present invention provides methods for sizing such
cycloalkylmethylamine derivatives. The present invention also provides methods
for using phenylcycloalkylmethylamine derivatives and pharmaceutical composition of
phenylcycloalkylmethylamine derivatives for
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treating or preventing obesity and bid diseases and/or disorders and for treating or
ting depression and co-morbid diseases and/or disorders.
The compounds of the present disclosure are advantageous because of their favorable
metabolic, pharmacokinetics and pharmacological profiles.
The present invention provides phenylcycloalkylmethylamine derivatives of structural
Formula (I):
n R4
H/ ,
or isomer or pharmaceutically acceptable salt thereof, wherein:
nis 0, l, 2, 3, 4, or 5;
SP is a spacer, wherein the spacer is C1_6 ne, and wherein one or more of the
carbons of the C1_6 alkylene is optionally substituted with O, S, or NR6, wherein R6 is H or C1_6
alkyl;
X is o, 8, NR6 or S(O)(O);
R1, R2, R3, R4, and R5 are each ndently hydrogen, C1_6 alkyl, aryl, arylalkyl,
cycloalkyl, cycloheteroalkyl, heteroaryl, heteroarylalkyl, acylalkyloxycarbonyl,
acyloxyalkyloxycarbonyl, acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C1_6
alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylamino, alkylsulfinyl,
alkylsulfonyl, alkylthio, amino, alkylamino, arylalkylamino, dialkylamino, koxy,
arylalkoxycarbonylalkoxy, arylalkoxycarbonylalkylamino, aryloxycarbonyl,
ycarbonylalkoxy, aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,
cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate, sulfate, sulfonate, or
sulfonamide; optionally R1, R2, R3 , R4, and R5 is substituted with the isotopes 2H (deuterium),
3H (tritium), 13C, 15N,17O, 18O, 18F, 31F, 32P, 358, and 36Cl; and
“*” denotes
a carbon e of being optically active.
The compounds of the present disclosure e (R)-isomers, omers, and mixtures
of (R)- and (S)- isomers.
DETAILED DESCRIPTION
This invention provides nds, ceutical compositions and methods for
pharmacological treatment of obesity and related co-morbid diseases and/or disorders. This
invention also es s for synthesis of novel appetite suppressants.
Definitions
The compounds of the ion may contain one or more chiral s and/or double
bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers or diastereoisomers. Accordingly, the chemical structures depicted herein
ass all le enantiomers and stereoisomers of the illustrated compounds ing the
stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or
diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and
stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers
using separation techniques or chiral synthesis techniques well known to the skilled artisan. The
compounds of the ion may also exist in several tautomeric forms including the enol form,
the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein
encompass all possible tautomeric forms of the illustrated nds. The compounds of the
invention also include isotopically labeled compounds Where one or more atoms have an atomic
mass different from the atomic mass of conventionally found in nature. Examples of es
that may be orated into the compounds of the invention include, but are not limited to 2H,
3H, 13C, 15N, 180’ 170’ 31F, 32F, 358, 18F and 36Cl.
“Alkyl” refers to a saturated or unsaturated, branched, straight-chain or cyclic
monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single
carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not
limited to methyl; ethyls such as ethanyl, l, ethynyl; propyls such as propan-l-yl, propan-
2yl, cyclopropan- l -yl, propenyl, prop- l -enyl, propen- l -yl (allyl), cyclopropen- lyl,
cyclopropen-lyl, prop-l-yn-l-yl, propyn-l-yl, etc.; butyls such as butan-l-yl, butanyl,
2-methyl-propan- l -yl, 2-methyl-propanyl, cyclobutan- l -yl, butenyl, butenyl, 2-
methyl-propenyl, buten- l -yl, butenyl, buta- l , 3 -dien- l -yl, buta- l 3 -dienyl,
, ,
cyclobutenyl, cyclobut- l -en-3 -yl, cyclobuta- l ,3 -dien- l -yl, butyn- l -yl, butyn-3 -yl,
butyn-l-yl, etc.; . The term “C1_6 alkyl” encompasses C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5
alkyl, and C6 alkyl.
The term “alkyl” specifically ed to include radicals having any degree or level of
saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or
more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and
groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level
of saturation is intended, the expressions “alkany,3, (Calkenyl,” and “alkynyl,” are used.
Preferably, an alkyl group comprises from 1-20 carbon atoms, more preferably, from 1 to 10
carbon atoms.
The term “alkylene” refers to the removal of a hydrogen atom from “alkanyl.”
yl” refers to a saturated branched, straight-chain or cyclic alkyl radical derived by
the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl
groups include but are not limited to such as propan-l-yl, propan-
, methanyl; ethanyl; propanyls
2-yl (isopropyl), cyclopropan-l-yl, etc.; butanyls such as butan-l-yl, butanyl (sec-butyl), 2-
-propan- l -yl (isobutyl), 2-methyl-propanyl (t-butyl), utan- l -yl, etc.
“Alkenyl” refers to an unsaturated branched, straight-chain or cyclic alkyl radical having
at least one carbon-carbon double bond d by the removal of one hydrogen atom from a
single carbon atom of a parent alkene. The group may be in either the cis or trans conformation
about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl;
yls such as propenyl, prop- l -enyl, -en- l -yl (allyl), propenyl,
cyclopropenyl, cyclopropen- l -yl; butenyls such as butenyl, butenyl, 2-
methy-propenyl, buten- l -yl, butenyl, buta- l ,3 -dien- l -yl, buta-l ,3 2-yl,
cyclobutenyl, cyclobut- l -en-3 -yl, cyclobuta-l ,3 -dien l-yl, etc.
“Alkylene” refers to a divalent radical that is a branched or unbranched arbon
nt containing the specified number of carbon atoms, and having two points of attachment.
Alkylenes are optionally substituted with one, two or three substituents. The term “C1_6
ne” encompasses C1 alkylene, C2 alkylene, C3 alkylene, C4 alkylene, C5 alkylene, C6
alkylene, and any sub-range thereof Examples of alkylenes include without limitation:
methylene (—CH2—, a C1 alkylene), ethylene (—CHZCH2—, a C2 alkylene), propylene
(-CHZCHZCH2—, a C3 alkylene), and butylene HZCHZCH2—, a C4 alkylene).
“Alkynyl” refers to an unsaturated ed, ht-chain or cyclic alkyl radical having
at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a
single carbon atom of a parent alkyne. Typical alkynyl groups e, but are not limited to,
ethynyl; propynyls such as prop- l -yn- l -yl, propyn- l -yl, etc.; butynyls such as butyn- l -yl,
butyn3 -yl, but-3 -yn- l -yl, etc.
“Acyl” refers to a radical —C(O)R, Where R is hydrogen, alkyl, cycloalkyl,
cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein that
may be ally substituted by one or more substituents as defined herein. Representative
examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl,
cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl.
"Acyloxyalkyloxycarbonyl" refers to a radical —C(O)OCR’R’ ’OC(O)R”’, Where R’, R”,
and R’ ” are each ndently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,
heteroalkyl, aryl, heteroarylalkyl, as defined herein that may be optionally substituted by
one or more substituents as defined herein. Representative examples include, but not limited to —
C(O)OCH20C(O)CH3, —C(O)OCH20C(O)CH2CH3, —C(O)OCH(CH3)OC(O)CH2CH3, —
C(O)OCH(CH3)OC(O)C6H5.
lkyloxycarbonyl” refers to a radical —C(O)OCR’R’ ’C(O)R”’, Where R’, R”, and
R’’ are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,
heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein that may be optionally substituted by
one or more substituents as defined herein. Representative examples include, but not limited to —
C(O)OCH2C(O)CH3, —C(O)OCH2C(O)CH2CH3, CH(CH3)C(O)CH2CH3, —
C(O)OCH(CH3)C(O)C6H5.
"Acyloxyalkyloxycarbonylamino" refers to a radical —NRC(O)OCR’R’ ’OC(O)R”’,
Where R, R’, R’ ’, and R” ’ are each independently hydrogen, alkyl, cycloalkyl, eteroalkyl,
aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein that may be optionally
substituted by one or more substituents as defined . Representative examples include, but
not limited to —NHC(O)OCH20C(O)CH3, )OCH20C(O)CH2CH3, —
NHC(O)OCH(CH3)OC(O)CH2CH3, —NHC(O)OCH(CH3)OC(O)C6H5.
"Acylalkyloxycarbonylamino” refers to a radical —NRC(O)OCR’R’ ’C(O)R”’, Where R,
R’, R’ ’, and R’ ” are each ndently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,
arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein that may be optionally
substituted by one or more substituents as defined herein. Representative examples include, but
not limited to —NHC(O)OCH2C(O)CH3, —NHC(O)OCH2C(O)CH2CH3, —
NHC(O)OCH(CH3)C(O)CH2CH3, )OCH(CH3)C(O)C6H5 .
“Alkylamino” means a radical —NHR Where R represents an alkyl, or cycloalkyl group
as defined herein that may be optionally substituted by one or more substituents as defined
herein. Representative examples include, but are not limited to, methylamino, ethylamino, l-
methylethylamino, cyclohexylamino.
“Alkoxy” refers to a radical —OR Where R represents an alkyl, or cycloalkyl group as
defined herein that may be optionally tuted by one or more substituents as defined herein.
Representative examples include, but are not limited to y, ethoxy, y, butoxy,
cyclohexyloxy.
“Alkoxycarbonyl” refers to a radical —C(O)—alkoxy Where alkoxy is as defined herein.
“Alkoxycarbonylalkoxy” refers to a radical —OCR’R’ ’C(O)-alkoxy Where alkoxy is as
defined herein. Similarly, Where R’ and R” are each independently hydrogen, alkyl, cycloalkyl,
cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, arylalkyl, as defined herein that
may be optionally substituted by one or more tuents as defined herein. Representative
examples include, but are not d to —OCH2C(O)OCH3, —OCH2C(O)OCH2CH3,
H3)C(O)OCH2CH3, —OCH(C6H5)C(O)OCH2CH3, —OCH(CH2C6H5)C(O)OCH2CH3,
—OC(CH3)(CH3)C(O)OCH2CH3.
“Alkoxycarbonylalkylamino” refers to a radical —NRCR’R’ ’C(O)-alkoxy Where alkoxy
is as defined herein. rly, Where R, R’, R’ and R’ ’ are each independently hydrogen, alkyl,
cycloalkyl, eteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined
herein that may be optionally substituted by one or more substituents as defined herein.
Representative examples include, but are not limited to —NHCH2C(O)OCH3,
—N(CH3)CH2C(O)OCH2CH3, —NHCH(CH3)C(O)OCH2CH3, —NHCH(C6H5)C(O)OCH2CH3,
—NHCH(CH2C6H5)C(O)OCH2CH3, and —NHC(CH3)(CH3)C(O)OCH2CH3.
“Alkylsulfonyl” refers to a radical —S(O)2R where R is an alkyl, or cycloalkyl group as
defined herein that may be ally substituted by one or more substituents as defined herein.
Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl,
propylsulfonyl, and butylsulfonyl.
“Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl, or cycloalkyl group as
defined herein that may be optionally substituted by one or more substituents as defined herein.
Representative examples include, but are not d to, methylsulfinyl, ethylsulfinyl,
propylsulfinyl, and ulfinyl.
“Alkylthio” refers to a radical —SR where R is an alkyl or cycloalkyl group as defined
herein that may be optionally substituted by one or more substituents as defined herein.
Representative examples include, but are not limited to methylthio, ethylthio, propylthio, and
butylthio .
“Aryl” refers to a monovalent aromatic hydrocarbon radical derived by the removal of
one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl
groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene,
acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, thene, fluorine,
hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene,
octaphene, ne, ovalene, penta-2,4-diene, pentacene, ene, pentaphene, perylene,
phenalene, phenanthrene, picene, pleidene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene, . Preferable, an aryl group comprises from 6 to 20 carbon atoms, more preferably,
n 6 to 12 carbon atoms.
“Arylalkyl” refers to an acyclic alkyl in which one of the hydrogen atoms bonded to a
carbon atom, typically a al or sp3 carbon atom, is replaced with an aryl group. Typically
arylalkyl groups e, but not limited to, benzyl, ylethan-l-yl, 2-phenylethen-l-yl,
naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethene-l-yl, naphthobenzyl, 2-
naphthophenylethan-l-yl . Where specific alkyl es are intended, the nomenclature
arylalkany, arylalkenyl and/or arylalkynyl is used. Preferably, an arylalkyl group is (C6-
ylalkyl, e. g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Cl-Clo) and
the aryl moiety is (C6-C20), more preferably, an arylalkyl group is (C6-C20) arylalkyl, e. g., the
alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C8) and the aryl moiety is (C6-
lkoxy” refers to an lalkyl radical Where arylalkyl is as defined herein that
may be ally substituted by one or more substituents as defined herein.
"Arylalkoxycarbonylalkoxy" refers to a radical —OCR’R’ ’C(O)—arylalkoxy Where
arylalkoxy is as defined herein. Similarly, Where R’ and R’’ are each independently hydrogen,
alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, aryl, heteroarylalkyl, as
defined herein that may be optionally substituted by one or more substituents as defined herein.
Representative examples include, but are not limited to (O)OCH2C6H5,
—OCH(CH3)C(O)O CH2C6H5, 6H5)C(O)O CH2C6H5, —OCH(CH2C6H5)C(O)O
CH2C6H5, 3)(CH3)C(O)O CH2C6H5.
"Arylalkoxycarbonylalkylamino" refers to a radical —NRCR’R’ ’C(O)-arylalkoxy Where
arylalkoxy is as defined herein. rly, Where R, R’, R’ and R” are each independently
en, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,
heteroarylalkyl, as defined herein that may be optionally substituted by one or more substituents
as defined herein. Representative examples include, but are not limited to
—NHCH2C(O)OCH2C6H5, —N(CH3)CH2C(O)OCH2C6H5, —NHCH(CH3)C(O)OCH2C6H5,
—NHCH(C6H5)C(O)OCH2C6H5, CH2C6H5)C(O)OCH2C6H5,
—NHC(CH3)(CH3)C(O)OCH2C6H5.
“Aryloxycarbonyl” refers to radical —C(O)—O-aryl Where aryl is defined herein that may
be optionally substituted by one or more substituents as defined herein.
“Aryloxycarbonylalkoxy” refers to a radical —OCR’R’ ’C(O)-aryloxy Where aryloxy is
as defined herein. Similarly, Where R’ and R” are each independently hydrogen, alkyl,
cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined
herein that may be optionally substituted by one or more substituents as defined herein.
Representative examples include, but are not limited to —OCH2C(O)OC6H5,
—OCH(CH3)C(O)OC6H5, 6H5)C(O)OC6H5, —OCH(CH2C6H5)C(O)OC6H5,
—OC(CH3)(CH3)C(O)OC6H5.
"Aryloxycarbonylalkylamino" refers to a radical —NRCR’R’ ’C(O)-aryloxy Where
aryloxy is as defined herein. Similarly, Where R, R’, R’ and R’ ’ are each independently
hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,
arylalkyl, as defined herein that may be optionally substituted by one or more substituents
as defined herein. Representative examples include, but are not limited to —NHCH2C(O)OC6H5,
)CH2C(O)OC6H5, —NHCH(CH3)C(O)OC6H5, —NHCH(C6H5)C(O)OC6H5,
—NHCH(CH2C6H5)C(O)OC6H5, —NHC(CH3)(CH3)C(O)OC6H5.
“Carbamoyl” refers to the radical —C(O)NRR Where each R group is independently,
hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, kyl, heteroalkyl, heteroaryl,
heteroarylalkyl, as defined herein that may be optionally substituted by one or more substituents
as defined herein.
“Carbamate” refers to a radical —NR’C(O)OR’ ’, Where R’ and R’’ are each
independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl, heteroarylalkyl, as defined herein that may be optionally substituted by one or more
substituents as defined herein. entative examples include, but are not limited to,
methylcarbamate (—NHC(O)OCH3), ethylcarbamate O)OCH2CH3), benzylcarbamate
(—NHC(O)OCH2C6H5).
“Carbonate” refers to a radical —OC(O)OR, Where R is alkyl, cycloalkyl,
cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein that
may be optionally substituted by one or more tuents as defined herein. Representative
examples include, but are not limited to, methyl carbonate (—C(O)OCH3), exyl ate
OC6H11), phenyl carbonate (—C(O)OC6H5), benzyl carbonate (—C(O)OCH2C6H5).
“Dialkylamino” means a radical —NRR’ Where R and R’ independently represent an
alkyl or cycloalkyl group as defined herein that may be optionally substituted by one or more
substituents as defined herein. Representative examples e, but are not limited to
dimethylamino, methylethylamino, di-(l-methylethyl)amino, (cyclohexyl)(methyl)amino,
hexyl)(ethyl)amino, (cyclohexyl)(propyl)amino.
“Halo” means fluoro, chloro, bromo, or iodo.
“Heteroaryl” refers to a monovalent heteroaromatic radical derived by the removal of one
hydrogen atom from a single atom of a parent heteroaromatic ring . Typical heteroaryl
groups include, but are not limited to, groups derived from acridine, ole, carbazole,
carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline,
indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole,
isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,
phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,
pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole,
azole, thiazole, thiophene, triazole, xanthene. Preferably, the heteroaryl group is between 5-
20 membered heteroaryl, with 5-10 membered heteroaryl being ularly preferred. Preferred
heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole,
pyridine, ine, imidazole, oxazole and ne.
“Heteroaryloxycarbonyl” refers to a radical —C(O)—OR where R is heteroaryl as
defined that may be optionally substituted by one or more substituents as defined herein.
oarylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms
bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl
group. Preferably, the heteroarylalkyl radical is a 6-30 carbon membered heteroarylalkyl, e. g.,
the l, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the
aryl moiety is a 5-20 membered heteroaryl, more ably, a 6-20 ed
heteroarylalkyl, e. g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8
membered and the heteroaryl moiety is a 5-12 membered heteroaryl.
“Isomer” refers to compounds of the present ion that possess asymmetric carbon
atoms (optical centers) or double bonds, the tes, diastereomers, enantiomers, ric
isomers, structural isomers and individual isomers are all ed to be encompassed within the
scope of the present invention.
As used , the term “patient” encompasses mammal patients. Examples of
mammals include, but are not limited to, any member of the mammalian class: humans, non-
human primates such as chimpanzees, and other apes and monkey species; farm animals such as
cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory
animals including rodents, such as rats, mice and guinea pigs.
“Pharmaceutically acceptable” means approved or approvable by a regulatory agency of
the Federal or state government or listed in the US. Pharmacopoeia or other generally
recognized pharmacopoeia for use in animals, and more particularly in humans.
“Pharmaceutically acceptable salt” refers to a salt of a compound of the ion, which
is pharmaceutically acceptable and possesses the desired cological activity of the parent
compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, SlllfilI'lC acid, nitric acid, phosphoric acid, ; or formed with
organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid,
glycolic acid, pyruvic acid, lactic acid, c acid, succinic acid, malic acid, maleic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, ic
acid, mandelic acid, esulfonic acid, ethanesulfonic acid, hanedisulfonic acid, 2-
hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-
naphthalenesulfonic acid, enesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]—
octene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
tertiary butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid,
salicylic acid, stearic acid, muconic acid; or (2) salts formed when an acidic proton present in the
parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an
aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine,
anolamine, or N-methylglucamine.
“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier
with which a compound of the invention is administered.
“Phosphate” refers to a l —OP(O)(OR’)(OR’ ’), where R’ and R’’ are each
independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl, heteroarylalkyl, as defined herein that may be optionally substituted by one or more
tuents as defined herein.
“Phosphonate” refers to a radical —P(O)(OR’)(OR’ ’), where R’ and R’’ are each
independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl, heteroarylalkyl, as defined herein that may be ally substituted by one or more
substituents as defined herein.
“Preventing” or “Prevention” refers to a reduction in risk of acquiring a disease or
disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a
patient that may be exposed to or predisposed to the disease but does not yet experience or
display symptoms of the disease).
cting group” refers to a group of atoms that when attached to a reactive group in a
molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found
in Green et al., “Protective Groups in Organic Chemistry”, (Wiley, 211d ed. 1991) and Harrison et
al., ndium of tic c Methods”, vols. 1-8 (John Wiley and Sons, 1971-1996).
entative amino protecting groups include, but are not limited to, formyl, acetyl,
trifluoroacetyl, benzyl, oxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl
(“TMS”), ethylsilyl-ethanesulfonyl (“SES”), trityl and tuted trityl groups,
allyloxycarbonyl, 9-fluorenylmethyloxy-carbonyl (“FMOC”), nitroveratryloxycarbonyl
(“NVOC”) . Representative hydroxyl protecting groups include, but are not limited to, those
where the hydroxyl group is either acylated or ted such as benzyl, and trialkylsilyl ethers
and allyl ethers.
“Racemate” refers to an equimolar mixture of enantiomers of a chiral molecule.
“Spacer” refers to a C1_6 alkylene in which one or more of the carbons of the C1_6
alkylene can optionally be replaced with O, S, or NR6, wherein R6 can be H or C1_6 alkyl. The
C1_6 alkylene is optionally substituted. In certain aspects, the C1_6 alkylene is optionally
substituted by kyloxycarbonyl, acyloxyalkyloxycarbonyl, acylalkyloxycarbonylamino,
acyloxyalkyloxycarbonylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy,
alkoxycarbonyllalkylamino, alkylsulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino,
arylalkylamino, lamino, arylalkoxy, arylalkoxycarbonylalkoxy,
arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy,
aryloxycarbonylalkylamino, carboxy, carbamoyl, ate, carbonate, cyano, halo,
heteroaryloxycarbonyl, hydroxy, ate, phosphonate, sulfate, sulfonate, or sulfonamide.
“Substituted” refers to a group in which one or more hydrogen atoms are each
independently replaced with the same or different substituents(s). Typical substituents include,
but are not limitedto, x, R54, o-,—o, OR54, SR54, s,—s, NR54R55,=NR54,
cxs, CF3, CN, OCN, SCN, NO, N02,—N2, N3, S(O)20',—S(O)20H,
—S(O)20R54, —OS(O)2031, —OS(O)2R54, —P(O)(O-)2, —P(O)(OR14)(O31),
—OP(O)(OR54)(OR55), —C(O)R54, —C(S)R54, —C(O)OR54, —C(O)NR54R55, ',
—C(S)OR54, —NR56C(O)NR54R55, (S)NR54R55, —NR57C(NR56)NR54R55, and
—C(NR56)NR54R55, where each X is independently a halogen; each R54, R55, R56 and R57 are
independently hydrogen, alkyl, substituted alkyl, aryl, tuted aryl, arylalkyl, substituted
arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,
heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted heteroarylalkyl.
“Sulfate” refers to a radical —OS(O)(O)OR, where R is hydrogen, alkyl, cycloalkyl,
cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein that
may be optionally substituted by one or more substituents as defined herein.
“Sulfonamide” refers to a radical —S(O)(O)NR’R”, where R’ and R” are independently
en, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,
heteroarylalkyl, as defined herein that may be optionally tuted by one or more substituents
as defined herein or optionally R’ and R” together with the atom to which they are both attached
form a cycloheteroalkyl or substituted cycloheteroalkyl ring. Representative examples include
but not limited to azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-(NR’”)-piperazinyl or
imidazolyl group n said group may be optionally substituted by one or more substituents
as defined herein. R’” hydrogen, alkyl, lkyl, cycloheteroalkyl, aryl, kyl, heteroalkyl,
heteroaryl, heteroarylalkyl, as defined herein that may be optionally tuted by one or more
substituents as defined herein.
“Sulfonate” refers to a radical —S(O)(O)OR, where R is hydrogen, alkyl, cycloalkyl,
cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, aryl, heteroarylalkyl, as defined herein that
may be optionally substituted by one or more tuents as defined herein.
“Thio” means the radical —SH.
“Treating” or “Treatment” of any disease or disorder refers, in one embodiment, to
ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or
at least one of the clinical symptoms thereof). In another ment “treating” or “treatment”
refers to ameliorating at least one physical parameter, which may not be discernible by the
t. In yet another embodiment, “treating” or ment” refers to inhibiting the disease or
disorder, either ally (e.g., stabilization of a discernible symptom), logically, (e.g.,
stabilization of a al parameter), or both.
“Therapeutically effective amount” means the amount of a compound that, when
administered to a patient for treating a disease, is sufficient to effect such treatment for the
disease. The “therapeutically effective amount” will vary depending on the nd, the
e and is severity and the age, weight, etc., of the patient to be treated, and can be
determined by one of skill in the art without undue experimentation.
nds of the Invention
The present invention provides phenylcycloalkylmethylamine derivatives of Formula (I):
n R4
R1l\\L / *
or isomer or pharmaceutically acceptable salt thereof, wherein:
n is 0, l, 2, 3, 4, or 5; preferably 11 is 0 (cyclopropyl), l (cyclobutyl), 2 (cyclopentyl), or 3
(cyclohexyl), and more preferably 11 is 1.
SP is a spacer, wherein the spacer is C1_6 alkylene, and wherein one or more of the
carbons of the C1_6 ne is optionally substituted with O, S, or NR6, wherein R6 is H or C1_6
alkyl;
X is o, 8, NR6 or S(O)(O);
R1, R2, R3, R4, and R5 are each independently hydrogen, C1_6 alkyl, aryl, arylalkyl,
cycloalkyl, cycloheteroalkyl, heteroaryl, heteroarylalkyl, acylalkyloxycarbonyl,
acyloxyalkyloxycarbonyl, acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C1_6
alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylamino, alkylsulfinyl,
alkylsulfonyl, alkylthio, amino, alkylamino, arylalkylamino, dialkylamino, arylalkoxy,
arylalkoxycarbonylalkoxy, arylalkoxycarbonylalkylamino, aryloxycarbonyl,
aryloxycarbonylalkoxy, aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,
cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate, sulfate, sulfonate, or
sulfonamide; optionally R1, R2, R3 , R4, and R5 is substituted with the isotopes 2H (deuterium),
3H (tritium), 13C, 15N,17O, 18O, 18F, 31F, 32F, 358, and 36Cl; and
“*” denotes
a carbon capable of being optically active.
The nds of the present invention include (R)—isomers, omers, and mixtures
of (R)- and (S)— isomers. In one embodiment, the nds are optically pure (R)—isomers, as
they often are more active. In another embodiment, the compounds are optically pure (S)-
isomers. Yet in another embodiment, the compounds are racemic nds.
In one preferred embodiment, R1 and R2 are independently H, C1_6 alkoxy (e. g., methoxy,
ethoxy), holo (e. g., fluoro, chloro), or hydroxyl.
In one preferred embodiment, R3 is H or C1_6 alkyl (e.g., isobutyl).
In one preferred embodiment, R4 is H.
In one preferred embodiment, SP is C1_6alkylene.
In one preferred embodiment, R5 is C1_6 alkyl.
In one red embodiment, R6 is C1_6 alkyl.
The compounds of this invention described herein can have one or more of the following
characteristics or properties:
1. Compounds of the invention can have dopamine transporter (DAT),
norepinephrine transporter (NET) and serotonin transporter (SERT) tory
properties;
2. Oral bioavailability of the compounds is consistent with oral administration using
standard cological oral formulations; however, the compounds, and
compositions f, can also be administered using any delivery system that
produces constant and controllable blood levels over time.
2012/072283
In some embodiments, the subject ion provides compounds having any two or
more of the above identified characteristics or properties. In a preferred embodiment the
compounds of the invention have all four characteristics or properties.
Additional modifications of the compounds disclosed herein can readily be made by
those skilled in the art. Thus, analogs and salts of the exemplified compounds are within the
scope of the subject invention. With knowledge of the nds of the subject invention
d chemists can use known procedures to size these compounds from available
substrates. As used in this application, the term “derivatives” refers to compounds which are
ntially the same as another compound but which may have been d by, for example,
adding additional side groups. The term “derivatives” as used in this application also may refer
to compounds which are substantially the same as r compound but which have atomic or
molecular substitution at n locations in the compound.
The subject invention further pertains to enantiomerically isolated nds, and
compositions comprising the compounds. The isolated enantiomeric forms of the compounds of
the invention are substantially free from one another (i.e., in enantiomeric excess). In other
words, the “R” forms of the compounds are substantially free from the “S” forms of the
compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the
compounds are substantially free of “R” forms of the compounds and are, thus, in enantiomeric
excess of the “R” forms. In one embodiment of the ion, the isolated enantiomeric
compounds are at least about in 80% enantiomeric excess. In a preferred embodiment, the
compounds are at least about in 90%, 95%, 97%, or 99% enantiomeric excess.
Synthesis of the Compounds of the Invention
The compounds of the invention can be obtained via the synthetic methods illustrated in
Schemes 1. Several methods have been described in the art for the synthesis of
cycloalkylmethylamine analogs (see, e.g. US. Pat. No. 5,596,019; ; WO
02/083631; WO 02/36540; WO 02/060424; y, J. E. et al., J. Chem. Soc. Perkin Trans 1,
1996, 25 83-25 89.). Other methods are known in the art for synthesizing
cycloalkylmethylamines, which are readily accessible to the skilled artisan. The starting
materials and intermediates used in the sis of target molecules (Scheme 1-8) thereof are
commercially available or can be prepared by established procedures (See e.g., Green et al.,
“Protective Groups in Organic Synthesis,”(Wiley 4rd ed., 2006); Harrison et al “Compendium
of Synthetic Organic s,” vols. 1-8 (John Wiley and Sons, 1971-1996); “Beilstein
Handbook of Organic try, Frankfurt, y; Feiser et al, “Reagents for Organic
Synthesis,” Volumes 1-45, Karger, 1991; March Advanced Organic Chemistry,” Wiley
Interscience, 4th ed., 1992; Larock ehensive Organic Transformations,” Wiley-VCH
Publishers, 2Ild ed., 1999; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John
Wiley and Sons, 1st ed., 1995).
Accordingly, starting als useful for preparing compounds of the invention and
intermediates thereof are commercially available or can be prepared by well-known synthetic
methods. Other methods for the synthesis of cycloalkylmethylamines bed herein are either
described in the art or will be readily nt to the skilled n in view of the references
provided above and may be used to synthesize the compounds of the invention. Accordingly, the
methods presented in the Schemes herein are illustrative rather than comprehensive.
Methods
In one method, phenylcycloalkylmethylamine derivatives (7, 8) of Formula (I) are
prepared as described in Scheme 2. The starting phenylcycloalkylamine building blocks (6) are
prepared by modifying a reported procedure by Jeffery et al. (J. Chem. Soc., Perkin Trans. 1,
1996, 25 83-25 89) as illustrated in Scheme 1. The typical procedure involves reaction of a
cycloalkylnitrile (3) with an appropriate Grignard reagent (R3MgBr) in presence of toluene at a
gentle reflux temperature for 10 to 24 hours followed by treating the intermediate with sodium
borohydride in methanol or ethanol to get the corresponding lkylmethylamine (6). The
cycloalkylnitriles (3) used in the preparation of cycloalkylamines (6) are either sed from
Sigma-Aldrich or sized from the corresponding phenylacetonitriles (1) using standard
chemistries. The selected racemic amines (6) are separated into corresponding optically pure (R)-
and (S)-isomers by a standard chiral crystallization method using optically pure tartaric acid.
Scheme 1
R11 BrAflfBr n
Ll\/:>/\CN R11 R3MgBr
R[|\\11 2 fl\\ CN 4 NMgBr
R12 base/solvent // toluene // R13
1 R12 12
3 R
NaBH4/MeOH
R\\11 * NH2
The phenylcycloalkylmethylamines (6) are ted with appropriate 4-
nitrophenylsulfonyl esters (9) using cesium carbonate in N,N—dimethylformamide (DMF) t
at room temperature to get the corresponding cycloalkylmethylamine ether derivatives (7, 8) in
moderate to good yields as illustrated in scheme 2. The building blocks, ophenylsulfonyl
esters (9) are synthesized as illustrated in scheme 6.
Scheme 2
O\\ /O
00SQ \GD—OR“ n n
Rfl\\11
H R11
NH2 OZN 9
* fl\\ * N®—OR14
// R 13 // R13
DMF, 032003, rt,15 h
R12 R12
6 7 (R11 = H), 8
DCC/DMAP
DCM, rt HO)K@‘OR14
11 H
R\\ LiAIH /THF
* N OR14 —4, 7(R11= H),8
fl// reflux
R13 O
In another method, the phenylcycloalkylmethylamine ether derivatives (7, 8) are prepared
by coupling with appropriate alkoxyalkylcarboxylic acids (10) followed by reduction of the
amide intermediates (1 l) with lithium aluminum hydride (LAH) in anhydrous THF in moderate
yields as illustrated in Scheme 2. The alkylcarboxylic acids (10) are prepared as illustrated
in scheme 7.
In another method, phenylcycloalkylmethylamine derivatives (12, 13) of Formula (I) are
prepared as described in Scheme 3. The phenylcycloalkylamines (6) are coupled with
riate alkylthioalkylcarboxylic acids (14) to get the amides (15) which after reduction with
lithium aluminum hydride give the corresponding phenylcycloalkylmethylamine thioether
derivatives (12, 13). The hioalkylcarboxylic acids (14) are synthesized as illustrated in
Scheme 8.
Scheme 3
1 H
R11\\ NH2 14
1 |\\L / ”@SR14
R130
R12 6 R12 15
i LiAIH4/TH F, reflux
H \ @SR“
/ R13
R 12(R11= H), 13
In another method cycloalkylmethylamine derivatives (17) of Formula (I) are
prepared as described in Scheme 4. The phenylcycloalkylamines (15) are oxidized using m-
chloroperbenzoic acid (mCPBA) to get the amides (16) which after reduction with lithium
aluminum hydride give the ponding phenylcycloalkylmethylamine derivatives (17).
Scheme 4
7! ZI
\ * s—R14 mCPBA R\\11
H / “Hm/GD—s——R14
R13 0 fl// R13 0
R12 15 R12 16
l LiAIH4/THF, reflux
R11 H o
\\ *N ®_5-R14
fl// R13 6
R12 17
In another method, phenylcycloalkylmethylamine derivatives (19) of Formula (I) are
prepared as described in Scheme 5. The phenylcycloalkylamines (6) are d with
appropriate alkylaminoalkylcarboxylic acid esters (20) in presence of trimethylaluminum in
toluene to get the amides (21) which after reduction with -dimethylsulfide (BHg-DMS)
solution in toluene or LAH in THF give the corresponding phenylcycloalkylmethylamine
derivatives (1 9).
Scheme 5
EtO N 11
R‘|\\11 \ R
NH2 20 R16
L H\\ Wfi’:
// R13 // R13 0
AIMe3, toluene
R12 6 R12 21
iBHDMS, toluene or«LAH THF
6_Me
R15 R16: -(CH 2,)4- -(CH2)5 R12/hijéérsnN’\<§|D_l\l:5
The optically pure (R)- and (S)-phenylcyclalkylmethylamine derivatives having Formula
I are either prepared from the corresponding optically pure amines (6) or by subjecting the
corresponding racemic phenycycloalkylmethylamine derivatives (7, 8, l2, l3, l7 and 19) using
chiral HPLC separation techniques. All phenycycloalkylmethylamine derivatives (7, 8, l2, l3,
l7 and 19) are converted into corresponding hydrochloride salts by ng with 2N HCl
on in ether under standard conditions.
The building blocks p-nitrophenylsulfonyl protected ethers (9) used in the synthesis of
phenylcycloalkylmethylamine derivatives are synthesized in four steps as illustrated in scheme 6.
The mono-benzyl protected diols (24) are synthesized by benzylating the corresponding diols
(23) using sodium hydride as base in ous tetrahydrofuran (THF) at 0 °C followed by
refluxing the reaction mixture in good yields. The benzyl protected alcohols (24) are alkylated
with appropriate alkyl halide using sodium hydride as base in anhydrous N,N—
dimethylformamide (DMF) to get the ethers (25). The benzyl protecting group is cleaved under
standard hydrogenation conditions to give the corresponding alcohol (26) which are reacted with
p-nitrophenylsulfonylchloride using the mild base triethylamine in romethane solvent to
get the p-nitrophenylsulfonyl protected ethers (9) in overall good .
Scheme 6
NaH/PhCH Br/THF2 OH NaH/R14Br/DMF OR14
—> GD
HO 2 0°C to rt, 4 h
0°C to reflux, 15 h
23 24 25
C3. ,CI H2-Pd/C/EtOH
0SQ rt, 15 h
@258 @—OR14’0 OZN 27 OR“
OZN DCM, Et3N
0°C, 2 h
The ng building blocks 4-alkoxyalkylcarboxylic acid (10) is synthesized in two steps
as illustrated in scheme 7. The gamma-butyrolactone (28) is reacted with ethylorthoformate (29)
in the presence of ethanol and sulfuric acid to get the ponding 4-ethoxybutyric acid ester
(30) in good yields. The saponif1cation of ester (30) under standard reaction conditions give the
corresponding 4-ethoxybutyric acid (10) in good yield.
Scheme 7
650 —> R14OJJ\/\/OR14—> HOJJ\/\/O\/O29, (R14O)3CH NaOH (N
THF rt 12h
28 30 10
R14—Et
The ng building blocks alkylthioalkylcarboxylic acids (14) are synthesized in two
steps as rated in scheme 8. The sodium thiolates (32) are alkylated with
bromoalkylcarboxylic acids (3 l) in anhydrous DMF to get the esters (33) which after
saponif1cation give the corresponding alkylthioalkylcarboxylic acids (14).
Scheme 8
RMSNa O
MWB'.# /\00 NaOH(2N)
32 R4 R14
—> HO S,
DMF, rt, 15 h EtOH, rt, 3 h, 90%
100% 33 14
Therapeutic Uses of Compounds of Formula (I)
In various aspects, the present disclosure provides methods of treating or preventing
obesity, sion, and associated co-morbid ions in a patient. The method comprises
administering to a patient in need of such treatment an effective amount of any one of the
nds of structural Formula (I). In fithher aspects, the method treats y, depression
and related co-morbid symptom.
The present invention provides methods of treating and preventing obesity and associated
co-morbid conditions. The term “co-morbid conditions associated with obesity” used in this
document means medical conditions known to those skilled in the art to be associated with
obesity. The term includes but not limited to the following: diabetes ing sulin
dependent diabetes mellitus, impaired glucose tolerance, hypertension, coronary thrombosis,
stroke, depression, y, psychoses (for example schizophrenia), tardive dyskinesia, drug
addiction, drug abuse, ive disorders, Alzheimer’s disease, cerebral ischaemia, obsessive-
compulsive behavior, panic attacks, social phobias, eating disorders such as bulimia, anorexia,
snacking and binge eating, lipid syndromes, hyperglycemia, hyperlipidemia, and stress in
mammals ularly humans.
In addition, the compounds, compositions, and methods of the present invention can be
used in the treatment or prevention of metabolic diseases and conditions arising therefrom, or for
example non exercise activity thermogenesis and sed metabolic rate, sexual dysfunction,
sleep apnoea, premenstrual syndrome, urinary incontinence including stress incontinence,
ctivity disorders, l hernia, and reflux esophagitis, pain, especially neuropathic pain,
weight gain associated with drug treatment, chronic fatigue syndrome, osteoarthritis and gout,
cancers associated with weight gain, menstrual dysfiJnction, gallstones, orthostatic hypotension
and pulmonary hypertension.
The nds, compositions, and methods of the present invention can be useful in
preventing cardiovascular disease, and in reducing et adhesiveness, in aiding weight loss
after pregnancy, reducing the g to smoke and in aiding weight loss after smoking
ion. The present invention can also be useful in lowering uric acid levels and lipid levels in
s particularly humans.
In accordance with the invention, a compound and/or a composition containing a
compound of structural a (I) is administered to a patient, ably a human, suffering
from y and associated with co-morbid diseases and/or disorders. In certain embodiments,
the compounds and/or compositions of the invention are administered to a patient, preferably a
human, as a preventive measure against various diseases or disorders. Thus, the nds
and/or compositions containing compound(s) of structural Formula (I) may be administered as a
preventive measure to a patient having a predisposition for obesity and associated co-morbid
diseases and/or disorders (see WO 58237; ; WO 02/060424; WO
01/51453; WO 0 1/00205; WO 01/00187; Mueller, P. International Application Publication No.
WO 00/32178; WO 98/11884; WO 98/13034).
WO 02195
Thus, those of skill in the art may readily assay and use the compounds and/or
compositions ning compound(s) of Formulae (I) to treat obesity and associated co-morbid
diseases and/or disorders.
Therapeutic/Prophylactic Administration
The compounds and/or compositions of the invention can be administered or applied
singly, or in combination with other pharmaceutically active agents, to a patient.
The present compounds and/or compositions of the invention are preferably administered
orally. The nds and/or compositions of the invention may also be administered by any
other convenient route, for example, by infusion or bolus injection, by absorption through
epithelial or mucocutaneous linings (e. g., oral mucosa, rectal and intestinal mucosa, etc.).
Administration can be systemic or local. Various ry s are known, (e.g.,
encapsulation in liposomes, microparticles, apsules, capsules, etc.) that can be used to
administer a nd and/or composition of the invention. Methods of administration include,
but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,
intranasal, epidural, oral, sublingual, intranasal, erebral, intravabinal, transdermal, rectally,
by inhalation, or topically, particularly to the ears, nose, eyes or skin.
In particularly, preferred embodiments, the compounds and/or compositions of the
invention can be red via sustained release s, ably oral ned release
systems. In one embodiment, a pump may be used (see, Langer, supra; Sefton, 1987, CRC Crit.
RefBiomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J. Med. 321574).
In another embodiment, polymeric materials can be used (see “Medical Applications of
Controlled Release,” Langer and Wise (eds.), Wiley, New York (1984); Ranger and Peppas,
1983, J. Macromol. Sci. Rev. Macromol Chem. 23:61; see also Levy et al., 1985, Science
228: 190; During et al., 1989, Ann. Neurol. 25:351; Howard et al, 1989, J. Neurosurg. 71 : 105). In
a preferred embodiment, polymeric materials are used for oral sustained release delivery.
Preferred polymers include sodium carboxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose and hydroxyethylcellulose (more preferred
hydroxypropylmethylcellulose). Other preferred cellulose ethers have been described in the art
(Bamba et al., Int. J. Pharm., 1979, 2, 307).
In another ment, enteric-coated preparations can be used for oral sustained release
stration. Preferred coating materials include polymers with a pH-dependent solubility (i.e.,
trolled release), polymers with a slow or pH-dependent rate of swelling, dissolution or
erosion (i.e., time controlled release), polymers that are ed by enzymes (i.e., enzyme
controlled release) and polymers that form firm layers that are destroyed by an increase in
pressure (i.e., pressure-controlled release).
In still another embodiment, osmotic delivery systems are used for oral sustained release
administration (Verma et al., Drug Dev. Ind. , 2000, 26:695-708). In a preferred
embodiment, OROS® osmotic delivery systems (Alza ation, Mountain View, CA) are
used for oral sustained release delivery devices (See for example, US. Pat. Nos. 3,845,770 and
3,916,899).
In yet r ment, a controlled-release system can be placed in proximity of the
target of the compounds and/or composition of the invention, thus requiring only a fraction of the
systemic dose (See, e.g., Goodson, in al Applications of Controlled Release,” supra, vol.
2, pp. 115-138 (1984)). Other controlled-release systems discussed in Langer, 1990, Science
249: 1527-1533 may also be used.
The compounds, and/or compositions containing compound(s) of Formula (I) of the
ion may be cleaved either chemically and/or enzymatically. One or more enzymes present
in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any other suitable tissue
of a mammal may enzymatically cleave the compounds and/or compositions of the ion.
itions of the Invention
In various aspects, the present disclosure provides pharmaceutical compositions
comprising any one of the compounds of structural Formula (I), and a pharmaceutically
acceptable vehicle.
When administered to a t, the compounds of the invention and pharmaceutically
acceptable vehicles are preferably sterile. Water is a preferred vehicle when the compound of the
invention is administered enously. Saline solutions and aqueous dextrose and glycerol
solutions can also be employed as liquid vehicles, particularly for inj ectable solutions. Suitable
pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin,
malt, rice, flour, chalk, silica gel, sodium stearate, glycerol earate, talc, sodium de,
dried skim milk, glycerol, propylene, glycol, water, ethanol, or pH buffering . In addition,
ary, izing, thickening, lubricating and coloring agents may be used.
The pharmaceutical compositions may be manufactured by means of conventional
mixing, ving, granulating, and emulsifying, encapsulating, entrapping or lyophilizing
process. Pharmaceutical compositions may be formulated in conventional manner using one or
more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate
processing of compounds of the invention into preparations which can be used pharmaceutically.
Proper ation is dependent upon the route of administration chosen.
The present compositions can take the form of solutions, suspensions, emulsion, tablets,
pills, pellets, and capsules, capsules containing liquids, powders, sustained-release ations,
suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one
embodiment, the pharmaceutically acceptable vehicle is a capsule (see e. g., US. Pat. No.
,698,155). Other es of suitable pharmaceutical vehicles have been described in the art
(see Remington’s Pharmaceutical Sciences, Philadelphia College of cy and Science, 17th
Edition, 1985). Preferred compositions of the invention are formulated for oral delivery,
particularly for oral sustained release administration.
Compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily
sions, granules, powders, ons, capsules, syrups or elixirs, for example. Orally
administered compositions may contain one or more optionally agents, for example, sweetening
agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of
wintergreen, or cherry ng agents and ving agents to provide a pharmaceutically
palatable preparation. When in tablet or pill form, the compositions may be coated to delay
disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action
over an extended period of time. Selectively permeable membranes nding an osmotically
active driving nd are also suitable for orally administered compounds of the invention. In
these later platforms, fluid from the environment surrounding the capsule is imbibed by the
driving compound, which swells to displace the agent or agent composition h an aperture.
These delivery platforms can provide an essentially zero order delivery profile as opposed to the
spiked profiles of immediate release formulations. A time delay material such as glycerol
monostearate or glycerol stearate may also be used. Oral compositions can include standard
vehicles such as mannitol, lactose, starch, magnesium stearate, sodium rine, cellulose,
magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.
For oral liquid preparations such as sions, elixirs and solutions, suitable carriers,
excipients or diluents include water, saline, alkyleneglycols (e.g., propylene ),
kylene glycols (e.g., polyethylene glycol), oils, alcohols, slightly acidic buffers between
pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at between about 1 mM to about 50 mM) etc.
Additionally, ng agents, vatives, coloring agents, and bile salts may be added.
Compositions for administration via other routes may also be contemplated. For buccal
administration, the compositions may take the form of tablets, lozenges, etc. formulated in
conventional manner. Liquid drug formulations suitable for use with nebulizers and liquid spray
devices and EHD aerosol devices will typically include a compound of the invention with a
ceutically acceptable vehicle. ably, the pharmaceutically acceptable vehicle is a
liquid such as alcohol, water, hylene glycol or a rocarbon. Optionally, another
material may be added to alter the aerosol ties of the on or suspension of compounds
of the invention. Preferably, this material is liquid such as alcohol, glycol, polyglycol or fatty
acid. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol
devices are known to those of skill in the art (see, e.g., US. Pat. Nos. 5, 112,598 and 5,556,611).
A compound of the invention may also be formulated in rectal or vaginal compositions such as
suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa,
butter or other ides. In addition to the formulations described previously, a compound of
the invention may also be formulated as depot preparation. Such long acting formulations may
be administered by implantation (for example, subcutaneously or intramuscularly) or by
intramuscular injection. Thus, for example, a nd of the invention may be formulated with
suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or
ion exchange resins, or as sparingly soluble tives, for example, as a sparingly soluble salt.
When a nd of the invention is acidic, it may be included in any of the above-
bed formulations as the free acid, a pharmaceutically acceptable salt, a solvate or hydrate.
ceutically acceptable salts substantially retain the activity of the free acid, may be
prepared by reaction with bases and tend to be more soluble in aqueous and other protic ts
than the corresponding free acid form.
Methods of Use and Doses
The present invention provides methods of treating or preventing obesity in a patient, the
method comprising administering to a patient in need of such treatment an effective amount of
any one of the compounds of structural Formula (I).
The amount of a compound of the invention effective in the treatment of a particular
disorder or condition disclosed herein will depend on the nature of the disorder or condition, and
can be determined by standard clinical techniques known in the art as previously described. In
addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage
ranges. The amount of a compound of the invention administered is dependent on, among other
s, the subject being treated, and the weight of the subject, the severity of the affliction, the
manner of administration and the judgment of the prescribing physician. For example, the dosage
may be delivered in a pharmaceutical composition by a single administration, by multiple
applications or controlled release. In a preferred embodiment, the nds of the invention
are delivered by oral sustained release administration. Preferably, in this embodiment, the
compounds of the ion are administered twice per day (or preferably, once per day). Dosing
may be repeated intermittently, may be ed alone or in ation with other drugs and
may continue as long as required for ive treatment of the disease state or disorder.
The compounds of structural Formula (I) may be administered in the range 0.1-500 mg,
preferably l-lOO mg per day, given in one or more doses, and more preferably 5 mg, 10 mg, 15
mg, 20 mg, 25 mg, 35 mg, or 50 mg per day, and most preferably 25 mg.
The compounds of the invention are preferably assayed in vitro and in vivo, for the
desired therapeutic or prophylactic activity, prior to use in humans. The compounds of the
invention may also be demonstrated to be effective and safe using animal model systems.
The therapeutically ive dose of a compound of the ion described herein will
provide eutic benefit t g substantial toxicity. Toxicity of compounds of the
invention may be determined using standard pharmaceutical procedures and may be readily
WO 02195
ascertained by the skilled artisan. The dose ratio between toxic and therapeutic effect is the
therapeutic index. The dosage of a compound of the inventions described herein is within a range
of circulating concentrations that include an effective dose with little or no ty.
The invention is further defined by reference to the following examples, which describe
in detail preparation of compounds and compositions of the invention and assays for using
compounds and compositions of the invention. It will be nt to those d in the art that
many modifications, both to materials and methods, may be practiced without departing from the
scope of the invention.
EXAMPLES
In the examples below, the following abbreviations have the following meanings. If an
abbreviation is not defined, it has its generally accepted g.
CDI = 1,1 ’-Carbonyldiimidazole
DCM = dichloromethane
DMAP = dimethylaminopyridine
DMF = N,N—dimethylformamide
h = hours
HATU = 0-(7-azabenzotriazol- l -yl)-N,N,N’,N’-tetramethyluronium
hexafluorophosphate
LC/MS = liquid chromatography/mass spectroscopy
= molar
MTBE = methyl tert-butyl ether
rt = room temperature
TEA = triethylamine
THF = tetrahydrofuran
TFA = trifluoroacetic acid
General procedure for synthesis of phenylcycloalkylmethylamine 6 (Scheme 1)
To a stirred solution of Grignard reagent (2M solution in ether, 0 065 mol) under nitrogen
atmosphere was added drop wise a solution of phenylcycloalkylcarbonitrile (3) (0.026 mol) in 50
rnL of e at 0°C. Then the reaction mixture was slowly heated at 92°C for 18 h. The
progress of the reaction was monitored by thin layer chromatography (TLC). The on
mixture was cooled to room temperature and concentrated under reduced pressure. The residue
was diluted with 30 mL of anhydrous methanol and cooled down at 0°C, and NaBH4 (2.5 g) was
added slowly portion wise. The resulting mixture was stirred until complete conversion of imine
intermediate to the corresponding amine. After the reaction was completed, methanol was
removed by evaporation. The residue was diluted with ethyl acetate, washed with saturated
sodium onate, dried over MgSO4 and evaporated under reduce pressure to give
corresponding phenylcyclobutylmethylamine (6) which was purified by column tography
on silica gel using a gradient of hexane and ethyl acetate. The pure ts 6a-rn gave
satisfactory 1H NMR and/0r Mass spectral data.
Example 1
3-Methyl(1-(p-tolyl)cyclopropyl)butanamine (6a). Colorless oil (1.66 g, 61%). 1HNMR
(400 MHz,CDC13): 8 .70 (m, 3H); 0.77-0.80 (m, 1H); 0.85 (d, J = 6.8 Hz, 6H); 0.98-1.11
(m, 2H); 1.22-1.30 (m, 2H); 1.70-1.77 (m, 1H); 2.10-1.13 (m, 1H); 2.28 (s, 3H); 7.09 (d, J =
8.0Hz, 2H); 7.20 (d, J = 8.0Hz, 2H). MS (ESI): m/z = 218.20 (M+H+).
Example 2
1-(1-(4-Chlorophenyl)cyclopropyl)methylbutanamine (6b). Colorless oil (1.60 g, 60%).
1HNMR (400 MHz, CDC13): 8 0.65-0.70 (m, 3H); 0.77-0.80 (m, 1H); 0.85 (d, J = 6.8 Hz, 6H);
0.87-1.01 (m, 1H); 1.18-1.27 (m, 3H); .73 (m, 1H);2.16 (d, J = 10.4Hz, 1H); 7.23-7.24 (m,
4H). MS (ESI): m/z = 238.20 (M+H+).
1-(1-(4-Florophenyl)cyclobutyl)methylbutanamine (6c). Colorless oil (2.2 g, 70%).
1HNMR (400 MHz,CDC13): 8 0.58-0.65 (m, 1H); 0.84 (d, J = 6.8 Hz, 3H); 0.88 (d, J = 6.8 Hz,
3H); 1.15-1.21 (m, 1H); 1.67-1.70 (m, 1H); 1.80-1.86 (m, 1H); 1.93-1.98 (m, 1H); 2.12-2.18 (m,
1H); 2.28-2.37 (rn, 3H); 2.97 (dd, J = 2.0Hz; 10.8Hz, 1H); 6.93- 7.08 (rn, 3H); 7.12-7.16 (rn,
1H).
Example 4
1-(1-(4-Chlorophenyl)cyclobutyl)—3-methylbutan-l-amine (6d). Colorless oil (4.7 g, 72%).
1HNMR (400 MHz, CDC13): 8 0.84 (d, J = 6.8 Hz, 3H); 0.88 (d, J = 6.8 Hz, 3H); 1.13-1.23 (rn,
2H); 1.66-1.68 (rn, 1H); 1.79-1.84 (rn, 1H); 1.90-1.96 (rn, 1H); 2.15-2.16 (rn, 1H); 2.25-2.33 (rn,
3H); 2.98 (d, J = 10.8Hz, 1H); 7.06 (dd, J = 1.6; 8.4Hz, 2H); 7.24 (dd, J = 1.6; 8.4Hz, 2H).
Example 5
1-(1-(3,4-Dichlor0phenyl)cyclobutyl)—3-methylbutan-l-amine (6e). Colorless oil (3.6 g, 70%).
1HNMR (400 MHz, CDC13): 8 0.53-0.60 (rn, 1H); 0.84 (d, J = 6.8 Hz, 3H); 0.88 (d, J = 6.8 Hz,
3H); .13 (rn, 1H); 1.63-1.67(rn,1H); 1.77-1.83(rn,1H);1.91-1.97(rn,1H);2.12-2.16(rn,
1H); 2.21-2.33 (rn, 3H); 2.97 (d, J = 10.8Hz, 1H); 6.96 (dd, J =2.0Hz; 8.4Hz, 1H); 7.19 (d, J =
2Hz; 1H); 7. 32 (d, J = 8.4Hz, 1H).
Example 6
1-(1-(2,4-Dichlor0phenyl)cyclobutyl)—3-methylbutan-l-amine (6i). Colorless oil (1.5 g, 72%).
1HNMR (400 MHz, CDC13): 8 0.84 (d, J = 6.8 Hz, 3H); 0.88 (d, J = 6.8 Hz, 3H); 1.13-1.15 (rn,
1H); 1.23-1.26 (rn, 1H) .81 (rn, 2H); 1.92-2.03 (rn, 1H); .43 (rn, 4H); 3.24 (dd, J =
2.0Hz; 10.8Hz, 1H); 7.02 (d, J = 8.4Hz, 1H); 7.16 (dd, J = 2Hz; 8.4Hz, 1H); 7. 29 (d, J = 2.4Hz,
1H).
Example 7
3,4-Dimeth0xyphenyl)cyclobutyl)—3-methylbutan-l-amine (6g). Colorless oil (3.6 g,
70%). 1HNMR (400 MHz, CDC13): 8 0.53-0.60 (rn, 1H); 0.84 (d, J = 6.8 Hz, 3H); 0.88 (d, J =
6.8 Hz, 3H); 1.10-1.13(rn,1H); 1.63-1.67(rn,1H);1.77-1.83(rn,1H);1.91-1.97(rn,1H);2.12-
2.16 (rn, 1H); 2.21-2.33 (rn, 3H); 2.97 (d, J = 10.8Hz, 1H); 3.87 (s, 6H); 6.77-6.82 (rn, 3H).
Example 8
1 1-(1-(4-Eth0xyphenyl)cyclobutyl)methylbutanamine (6h). ess oil (1.06 g, 72%).
1HNMR (400 MHz, CDC13): 8 0.57-0.64 (m, 1H); 0.84 (d, J = 6.8 Hz, 3H); 0.88 (d, J = 6.8 Hz,
3H); 1.15-1.21 (m, 1H); 1.40 (tJ = 6.8Hz, 3H); 1.67-1.69 (m, 1H); 1.79-1.84 (m, 1H); 1.90-1.96
(m, 1H); 2.14-2.16 (m, 1H); 2.27-2.36 (m, 3H); 2.98 (dd, J = 2.0 Hz; 10.8Hz, 1H); 4.02 (q, J =
6.8Hz, 2H); 6.83 (d, J = 8.4Hz, 2H); 7.05 (dd, J = 8.4Hz, 2H).
Example 9
3-Methyl—1-(1-(4-(methylthi0)phenyl)cyclobutyl)butanamine (6i). Colorless oil (1.7 g,
34%). 1HNMR (400 MHz, CDC13): 8 0.56-0.62 (m, 1H); 0.83 (d, J = 6.8 Hz, 3H); 0.88 (d, J =
6.8 Hz, 3H); 1.04-1.06 (sbroad, 2H); 1.13-1.20 (m, 1H); 1.64-1.68 (m, 1H); 1.79-1.83 (m, 1H);
1.90-1.95 (m, 1H); 2.11-2.17 (m, 1H); 2.26-2.37 (m, 3H); 2.46 (s, 3H); 2.96 (d, J = , 1H);
7.05 (d, J = 8.4Hz, 2H); 7.19 (d, J = 8.4Hz, 2H). MS (ESI): m/z = 264.20 (M+H+).
Example 10
3-Methyl(1-(p-tolyl)cyclopentyl)butanamine (6j). Colorless oil (1.46 g, 60%). 1HNMR
(400 MHz, CDC13)C 8 0.68-0.78 (m, 1H); 0.83 (d, J = 6.8 Hz, 6H); 0.99 (sbroad, 2H); 1.20-1.24
(m, 1H); 1.50-1.56 (m, 2H); .68 (m, 3H); 1.72-1.78 (m, 1H); 1.84-1.91 (m, 1H); 2.02-2.08
(m, 2H); 2.28 (s, 3H); 2.73 (d, J = 10.8Hz, 1H); 7.09 (d, J = 8.0Hz, 2H); 7.20 (d, J = 8.0Hz, 2H).
MS (ESI): m/z = 246.20 (M+H+).
Example 11
1-(1-(4-Meth0xyphenyl)cyclopentyl)methylbutanamine (6k). Colorless oil (1.43 g,
55%). 1HNMR (400 MHz, CDC13): 8 0.66-0.77 (m, 2H); 0.81 (d, J = 6.8 Hz, 6H); 0.97-1.02
(sbroad, 2H); 1.12-1.18 (m, 1H); .55 (m, 1H); 1.58-1.68 (m, 3H); 1.71-1.77 (m, 1H); 1.82-
1.89 (m, 2H); 2.07-2.06 (m, 1H); 2.70 (d, J = 10.8Hz, 1H); 3.78 (s, 3H); 6.82 (d, J = 8.8Hz, 2H);
7.23 (d, J = 8.8Hz, 2H). MS (ESI): rn/z = 262.20 (M+H+).
Example 12
3-Methyl—1-(1-(p-tolyl)cyclohexyl)butanamine (61). ess oil (1.46 g, 60%). 1HNMR
(400 MHz, CDC13): 8 0.63-0.76 (m, 1H); 0.77 (d, J = 6.8Hz, 3H); 0.83 (d, J = 6.8 Hz, 3H); 1.17-
1.32 (m, 5H); 1.37-1.66 (m, 6H); .36 (m, 4H); 2.52 (d, J = 10.4Hz, 1H); 7.09 (d, J = 8.0Hz,
2H); 7.20 (d, J = 8.0Hz, 2H). MS (ESI): m/z = 260.20 (M+H+).
Example 13
1-(1-(4-Chlorophenyl)cyclohexyl)methylbutanamine (6m). Colorless oil (0.8 g, 32%).
1HNMR (400 MHz, CDC13)I 8 0.60-0.66 (m, 1H); 0.75 (d, J = 6.8 Hz, 3H); 0.81 (d, J = 6.8Hz,
3H); 0.95-1.00 (sbroad, 2H); 1.11-2.25 (m, 5H); 1.41-1.62 (m, 5H); 2.20-2.30 (m, 2H); 2.53 (d, J
= 10.8Hz, 1H); 7.22 (d, J = 8.8Hz, 2H); 7.27 (d, J = 8.8Hz, 2H). MS (ESI): m/z = 280.20
(M+H+).
General procedure for synthesis of phenylcyclobutylmethylamine ether derivatives 7 and 8
(Scheme 2)
To a stirred solution of cesium carbonate (1 .4 g, 5.0 eq) in 10 mL ofDMF was added appropriate
phenylcyclobutylmethylamine (6) 9 mol) and the resulting mixture was stirred at room
temperature for 4 hrs. Then a solution suitable 4-nitrobenzenesulfonate (0.0045 mol. 5 eq) in 5
mL ofDMF was added over a period of 5 minutes. The resulting mixture was stirred at rt
temperature for ght. The progress of the reaction was monitored by thin layer
chromatography (TLC). The reaction mixture was filtered, diluted with 10 mL of ethyl acetate,
washed with brine and dried over Na2S04, evaporated to give the ponding
phenylcyclobutylmethylamine ether derivaties (7, 8) which were purified by silica gel column
chromatography using a gradient of hexane and ethyl acetate. The pure products (7, 8) gave
satisfactory 1H NMR and/or Mass spectral data. The selected racemic ether derivatives (7, 8)
were subjected to chiral HPLC to get the corresponding optically pure (R)- and (S)—isomers. The
chiral HPLC conditions: column — CHIRAL PAK IA 4.6 X 250 mm, 5 MM; mobile phase —
0.1% DEA in hexane and ethanol; tic method with 0.8 ml per minute flow rate; injection
volume 1.00 111; and run time 20 min. All ether tives (7, 8) were converted in to the
corresponding HCl salts by ng them with lN HCl e/water followed by lyophilization.
The hydrochloride salts of ether derivatives (7, 8) were tested in monoamine transporters
(MATs) in vitro pharmacology assays.
WO 02195
Example 14
4-Eth0xyphenyl)cyclobutyl)—N-(2-methoxyethyl)—3-methylbutanamine (7a).
Colorless oil (100 mg, 28% yield). 1HNMR (400 MHz, CDC13)C 8 0.57-0.66 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 1.08-1.12 (m, 1H); 1.41 (t, J = 9.2Hz, 3H); 1.59-1.68 (m,
1H); 1.71-1.89 (m, 2H); 2.16-2.38 (m, 4H); 2.73 (dbroad, J = 3.2Hz, 1H); 2.88 (t, J = 6.8Hz,
2H); 3.32 (s, 3H); 3.45 (t, J = 7.2Hz, 2H); 4.03 (q, J = 7.2Hz, 2H); 6.83 (d, J = 8.4Hz, 2H); 7.16
(d, J = 8.4Hz, 2H). MS (ESI): m/z = 320. 61 (M+H+).
Example 15
N-(2-Eth0xyethyl)—1-(1-(4-ethoxyphenyl)cyclobutyl)—3-methylbutanamine (7b). Colorless
oil (70 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 .66 (m, 1H); 0.83 (d, J = 6.8Hz,
3H); 0.88 (d, J = 6.8Hz, 3H); 1.08-1.12 (m, 1H); 1.21 (t, J = 9.6Hz, 3H); 1.38-1.44 (m, 4H);
1.59-1.66 (m, 1H); .86 (m, 2H); 2.15-2.18 (m, 1H); 2.28-2.37 (m, 3H); 2.73 (dbroad, J =
11.6Hz, 1H); 2.73-2.92 (m, 2H); 3.43-3.50 (m, 3H); 4.03 (q, J = 7.2Hz, 2H); 6.83 (d, J = 8.4Hz,
2H); 7.16 (d, J = 8.4Hz, 2H). MS (ESI): m/z = 334.72 (M+H+).
Example 16
1-(1-(4-Eth0xyphenyl)cyclobutyl)—3-methyl-N-(Z-pr0p0xyethyl)butanamine (7c).
Colorless oil (80 mg, 27% yield). 1HNMR (400 MHz, CDClg): 8 0.57-0.66 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 0.91-0.92 (m, 6H); 1.00-1.08 (m, 1H); 1.39-1.46 (m, 4H);
1.52-1.64 (m, 3H); 1.73-1.86 (m, 2H); 2.17-2.40 (m, 4H); 2.73 (sbroad, 1H); 2.88-2.94 (m, 2H);
3.36 (t, J = 6.8Hz, 2H); 3.48 (d, J = 10.8Hz, 2H); 4.03 (q, J = 7.2Hz, 2H); 6.83 (d, J = 8.4Hz,
7.16 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 348.40 (M+H+).
Example 17
N-(2-But0xyethyl)—1-(1-(4-ethoxyphenyl)cyclobutyl)—3-methylbutanamine (7d). Colorless
oil (100 mg, 27% . 1HNMR (400 MHz, CDClg): 8 0.57-0.66 (m, 1H); 0.83 (d, J = 6.8Hz,
3H); 0.88 (d, J = 6.8Hz, 3H); 0.92 (t, J = 9.6Hz, 3H); .12 (m, 1H); 1.32-1.44 (m, 5H);
1.49-1.64 (m, 3H); 1.78-1.86 (m, 1H); 2.04-2.15 (m, 1H); 2.26-2.39 (m, 2H); 2.73 (dbroad, J =
11.6Hz, 1H); 2.86-2.91 (m, 2H); 3.38-3.48 (m, 4H); 3.64 (t, J = 7.2H, 1H); 4.03 (q, J = 7.2Hz,
2H); 4.277 (t, J = 6.8Hz, 1H); 6.82 (d, J = 8.4Hz, 2H); 7.15 (d, J = 8.4Hz, 2H). MS (ESI): m/z =
362.57 (M+H+).
Example 18
1-(1-(4-Eth0xyphenyl)cyclobutyl)—N-(2-is0butoxyethyl)—3-methylbutanamine (7e).
Colorless oil (90 mg, 27% yield). 1HNMR (400 MHz, CDClg): 8 0.57-0.66 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 0.90-1.04 (m, 6H); 1.08-1.12 (m, 1H); 1.38-1.44 (m, 4H);
1.60-1.68 (m, 1H); .91 (m, 3H); 2.13-2.20 (m, 1H); 2.27-2.42 (m, 3H); 2.71 (d, J = 8.4Hz,
1H); 2.85-2.92 (m, 2H); 3.17 (d, J = 6.4Hz, 2H); 3.58 (t, J = 7.2H, 1H); 4.03 (q, J = 7.2Hz, 2H);
6.82 (d, J = 8.4Hz, 2H); 7.15 (d, J = 8.4Hz, 2H). MS (ESI): m/z = 362.57 (M+H+).
Example 19
N-(2-Eth0xyethyl)—3-methyl—1-(1-(4-(methylthi0)phenyl)cyclobutyl)butanamine (71).
Colorless oil (0.20 g, 20%). 1HNMR (400 MHz, CDC13)C 8 0.60-0.66 (m, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 1.06-1.09 (m, 1H); 1.17 (t, J = 7.2Hz, 3H); 1.61-1.60 (m,
1H); 1.70-1.77 (m,1H); 1.82-1.88 (1H); 2.14-2.19 (m, 3H); 2.23-2.29 (m, 2H); .41 (m,
1H); 2.46 (s, 3H); 2.72 (d, J = 10Hz, 1H); 2.88 (t, J = 7.2H, 2H); 3.42-3.48 (m, 3H); 7.02 (d, J =
8.8Hz, 2H); 7.20 (d, J = 8.8Hz, 2H). MS (ESI): m/z = 336.20 (M+H+).
Example 20
N-(4-Eth0xybutyl)—3-methyl(1-(4-(methylthi0)phenyl)cyclobutyl)butanamine (7g).
Colorless oil (0.21 g, 20%). 1HNMR (400 MHz, C 8 0.60-0.66 (m, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 1.87 (t, J = 7.2Hz, 3H); 1.47-1.83 (m, 6H); 2.04-2.22 (m,
3H); 2.27-2.32 (m, 2H); 2.46 (s, 3H); 3.40-3.49 (m, 5H); 4.10-4.15 (m, 4H); 7.02 (d, J = 8.8Hz,
2H); 7.20 (d, J = 8.8Hz, 2H). MS (ESI): m/z = 364.20 (M+H+).
Example 21
1-(1-(4-Chlorophenyl)cyclobutyl)—N-(2-eth0xyethyl)—3-methylbutanamine (7h). 1HNMR
(400 MHz, C 8 0.63-0.71 (m, 1H); 0.81 (d, J = 6.8Hz, 3H); 0.86 (d, J = 6.8Hz, 3H); 1.01-
1.07 (m, 1H); 1.17 (t, J = 7.2Hz, 3H); 1.59-1.66 (m, 1H); 1.70-1.77 (m, 1H); 1.83-1.90 (m, 1H);
2.12-2.17 (m, 1H); 2.22-2.29 (m, 2H); 2.36-2.43 (m, 1H); 2.73 (dd, J = 2.4Hz; 10.0Hz, 1H); 2.88
(t, J =5.6Hz, 2H); 3.43-3.48 (m, 4H); 7.16 (d J = 8.4Hz, 2H); 7.23 (d, J = 8.4Hz, 2H). MS (ESI):
m/z = 325.10 (M+H+).
Example 22
N-(2-Eth0xyethyl)—1-(1-(4-flu0rophenyl)cyclobutyl)methylbutanamine (7i). 1HNMR
(400 MHz, CDC13): 8 0.64-0.71 (m, 1H); 0.82 (d, J = 6.8Hz, 3H); 0.86 (d, J = 6.8Hz, 3H); 1.02-
1.08 (m, 1H); 1.17 (t, J = 7.2Hz, 3H); 1.59-1.66 (m, 1H); .78 (m, 1H); 1.83-1.92 (m, 1H);
2.12-2.17 (m, 2H); 2.21-2.31 (m, 2H); 2.36-2.43 (m, 1H); 2.72 (dd, J = 2.4Hz; 10.0Hz, 1H); 2.88
(t, J =5.6Hz, 2H); 3.43-3.44 (m, 4H); 6.95 (t, J = 8.8Hz, 2H); 7.18 (dd, J = 5.2Hz; 8.8Hz, 2H).
MS (ESI): m/z = 308.67 (M+H+).
Example 23
N-(2-Eth0xyethyl)—3-methyl(1-(p-tolyl)cyclopr0pyl)butanamine (7j). Colorless oil (0.24
g, 22%). 1HNMR (400 MHz, CDC13): 8 .50 (m, 1H); 0.67-0.72 (m, 1H); .79 (m,
1H); 0.80 (d, J = 6.8Hz, 3H); 0.83 (d, J = 6.8Hz, 3H);; 1.04-1.13 (m, 1H); 1.16-1.20 (m, 4H);
.31 (m, 1H); .76 (m, 1H); 1.94-1.98 (m, 1H); 2.30 (s, 3H); 2.75-2.80 (m, 1H); 3.21-
3.27 (m, 1H); 3.45-3.54 (m, 4H); 7.06 (d, J = 7.2Hz, 2H); 7.20 (d, J = 7.2Hz, 2H). MS (ESI): m/z
= 290.20 (M+H+).
Example 24
1-(1-(4-Chlorophenyl)cyclopr0pyl)—N-(2-eth0xyethyl)—3-methylbutanamine (7k).
Colorless oil (0.22 g, 24%). 1HNMR (400 MHz, CDC13): 8 0.47-0.52 (m, 1H); 0.65-0.71 (m,
1H); 0.75-0.89 (m, 7H); 1.02-1.09 (m, 1H); 1.18 (t, J = 7.2Hz, 3H); 1.19-1.27 (m, 1H); 1.44
(sbroad, 2H); 1.68-1.73 (m, 1H); 1.95-1.98 (m, 1H); 2.73-2.79 (m, 1H); 3.17-3.23 (m, 1H); 3.47-
3.53 (m, 2H); 7.06 (d, J = 7.2Hz, 2H); 7.17 (d, J = 7.2Hz, 2H). MS (ESI): m/z = 310.20 (M+H+).
Example 25
N-(2-Eth0xyethyl)—3-methyl(1-(p-tolyl)cyclopentyl)butanamine (7l). Colorless oil (0.27
g, 22%). 1HNMR (400 MHz, CDC13): 8 0.60-0.75 (m, 1H); 0.75 (d, J = 6.8Hz, 3H); 0.78 (d, J =
6.8Hz, 3H); 1.06-1.21 (m,1H); 1.18 (t, J = 7.2Hz, 3H); 1.26-1.47 (m, 3H); 1.57-1.65 (m, 3H);
.80 (m, 1H); 1.84-2.00 (m, 3H); 2.34 (s, 3H); 2.54 (d, J = 8.4Hz, 1H); 2.78-2.85 (m, 1H);
2.86-2.90 (m, 1H); 3.15—3.49 (m, 4H);; 6.81 (d, J = 8.8Hz, 2H); 7.26 (d, J = 8.8Hz, 2H). MS
(ESI): m/z = 317.20 (M+H+).
Example 26
N-(2-Eth0xyethyl)—1-(1-(4-meth0xyphenyl)cyclopentyl)—3-methylbutanamine (7m)
Colorless oil (0.27 g, 22%). 1HNMR (400 MHz, CDC13)C 8 0.60-0.75 (m, 1H); 0.75 (d, J =
6.8Hz, 3H); 0.78 (d, J = 6.8Hz, 3H); .21 (m,1H); 1.18 (t, J = 7.2Hz, 3H); 1.26-1.47 (m,
3H); 1.57-1.65 (m, 3H); 1.72-1.80 (m, 1H); .00 (m, 3H); 2.51 (d, J = 8.4Hz, 1H); 2.78-
2.85 (m, 1H); 2.86-2.90 (m, 1H); 3.15-3.45 (m, 4H); 3.77 (s, 3H); 6.81 (d, J = 8.8Hz, 2H); 7.26
(d, J = 8.8Hz, 2H). MS (ESI): m/z = 334.20 (M+H+).
Example 27
N-(4-eth0xybutyl)—3-methyl(1-(p-tolyl)cyclohexyl)butan-l-amine (7n). Colorless oil (0.18
g, 20%). 1HNMR (400 MHz, C 8 0.67-0.72 (m, 1H); 0.75 (d, J = 6.8Hz, 3H); 0.78 (d, J =
6.8Hz, 3H); 1.13-1.26 (m, 8H); 1.36-1.44 (m, 3H); 1.49-1.59 (m, 7H); 2.16 (d, J = 12.8Hz, 1H);
2.21-2.35 (m, 5H); 2.44-2.50 (m, 1H); 2.65-2.69 (m, 1H); 3.34-3.48 (m, 4H); 7.23 (d, J = 8.8Hz,
2H); 7.28 (d, J = 8.8Hz, 2H). MS (ESI): rn/z = 360.20 (M+H+).
Example 28
1-(1-(4-Chlorophenyl)cyclohexyl)—N-(4-eth0xybutyl)—3-methylbutan-l-amine (70). Colorless
oil (0.18 g, 20%). 1HNMR (400 MHz, CDClg): 8 .65 (m, 1H); 0.75 (d, J = 6.8Hz, 3H);
0.78 (d, J = 6.8Hz, 3H); 1.07-1.13 (m, 1H); 1.56-1.26 (m, 6H); 1.38-1.63 (m, 10H); 2.13 (d, J =
14.0Hz, 1H); 2.21 (d, J = 10Hz, 1H); 2.28 (d, J = 13.6Hz, 1H); 2.45-2.51 (m, 1H); 2.68-2.74 (m,
1H); 3.36-3.48 (m, 4H); 7.23 (d, J = 8.8Hz, 2H); 7.28 (d, J = 8.8Hz, 2H). MS (ESI): m/z =
381.20 .
Example 29
1-(1-(3,4-Dichlor0phenyl)cyclobutyl)-N-(2-eth0xyethyl)—3-methylbutan-l-amine (83).
Colorless oil (87 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 0.61-0.68 (m, 1H); 0.84 (d, J =
6.8Hz, 3H); 0.89 (d, J = 6.8Hz, 3H); 1.03-1.04 (m, 1H); 1.08 (t, J = 7.2Hz, 3H); 1.62-1.63 (m,
1H); 1.75-1.78 (m, 1H); 1.88-1.91 (m, 1H); 2.21-2.38 (m, 4H); 2.75 (dd, J = 2.4Hz; 10.0Hz, 1H);
2.96-3.02 (m, 2H); 3.41 (q, J = 7.2Hz, 2H); 3.44 (t, J = 4.4Hz, 2H); 7.06 (dd, J = 2.4Hz; 8.4Hz,
1H); 7.31 (d, J = 2.0Hz, 1H); 7.34 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 360.10 (M+H+).
Example 30
(1-(3,4-Dichlor0phenyl)cyclobutyl)—N-(2-methoxyethyl)—3-methylbutanamine (8b).
Colorless oil (60 mg, 28% yield). 1HNMR (400 MHz, CDC13): 8 0.64-0.71 (m, 1H); 0.84 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 1.04 (t, J = 12Hz, 1H); 1.53 (sbroad, 1H); 1.62-1.65 (m,
1H); 1.73-1.81 (m, 1H); 1.88-1.91 (m, 1H); 2.15-2.25 (m, 3H); .44 (m, 1H); 2.74 (d, J =
8.4Hz, 1H); .94 (m, 2H); 2.96 (s, 3H). 3.44 (t, J = 10.8Hz, 2H); 7.06 (d, J = 8.0Hz, 1H);
7.33 (s, 1H); 7.34 (d, J = 8.0Hz, 1H). MS (ESI): m/z = 346.03 (M+H+).
Example 31
(S)(1-(3,4-Dichlor0phenyl)cyclobutyl)—N-(2-methoxyethyl)—3-methylbutanamine (8c).
ess oil (100 mg, 27% yield). 1HNMR (400 MHz, CDC13): 8 0.64-0.71 (m, 1H); 0.84 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 1.04 (t, J = 12Hz, 1H); 1.53 (sbroad, 1H); 1.62-1.65 (m,
1H); 1.73-1.81 (m, 1H); 1.88-1.91 (m, 1H); .25 (m, 3H); 2.37-2.44 (m, 1H); 2.74 (d, J =
8.4Hz, 1H); 2.75-2.94 (m, 2H); 2.96 (s, 3H). 3.44 (t, J = 10.8Hz, 2H); 7.06 (d, J = 8.0Hz, 1H);
7.33 (s, 1H); 7.34 (d, J = 8.0Hz, 1H). MS (ESI): m/z = 346.03 (M+H+).
Example 32
(R)(1-(3,4-Dichlor0phenyl)cyclobutyl)—N-(3-pr0p0xypr0pyl)—3-methylbutanamine
(8d). Colorless oil (87 mg, 27% yield). 1HNMR (400 MHz, CDC13): 8 0.57-0.66 (m, 1H); 0.83
(d, J = 6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 0.91 (t, J = 9.6Hz, 3H); 1.00-1.08 (m, 1H); 1.56-1.64
(m, 5H); 1.66-1.80 (m, 2H); 1.83-1.96 (m, 1H); 2.09-2.30 (m, 3H); 2.37-2.46 (m, 1H); 2.72-2.94
(m, 3H); 3.37 (t, J = 10.8Hz, 2H); 3.49 (t, J = 10.8Hz, 2H); 7.07 (dd, J = 3.2Hz, 11.2Hz, 1H);
7.32 (s, 1H); 7.33 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 388.30 (M+H+).
Example 33
(S)(1-(3,4-Dichlor0phenyl)cyclobutyl)—N-(3-pr0p0xypr0pyl)—3-methylbutanamine (8e).
Colorless oil (60 mg, 27% yield). 1HNMR (400 MHz, CDC13): 8 0.57-0.66 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 0.91 (t, J = 9.6Hz, 3H); 1.00-1.08 (m, 1H); 1.56-1.64 (m,
2012/072283
5H); 1.66-1.80 (m, 2H); 1.83-1.96 (m, 1H); 2.09—2.30 (m, 3H); 2.37-2.46 (m, 1H); 2.72—2.94 (m,
3H); 3.37 (t, J = 10.8Hz, 2H); 3.49 (t, J = 10.8Hz, 2H); 7.07 (dd, J = 3.2Hz, ll.2Hz, 1H); 7.32 (s,
1H); 7.33 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 388.30 .
Example 34
(R)-N-(3-But0xypr0pyl)—1-(1-(3,4-dichlorophenyl)cyclobutyl)—3-methylbutanamine (8i).
Colorless oil (130 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 0.59-0.64 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 0.91 (t, J = 9.6Hz, 3H); 1.04-1.07 (m, 1H); 1.32-1.40 (m,
2H); 1.50-1.56 (m, 3H); 1.57-1.79 (m, 4H); 1.87-1.92 (m, 1H); 2.10-2.27 (m, 3H); 2.38-2.42 (m,
1H); 2.72-2.94 (m, 3H); 3.37 (t, J = 10.8Hz, 2H); 3.49 (t, J = 10.8Hz, 2H); 7.07 (dd, J = 2.0Hz,
8.0Hz, 1H); 7.32 (s, 1H); 7.33 (d, J = 8.0Hz, 1H). MS (ESI): m/z = 402.03 (M+H+).
Example 35
(3-But0xypr0pyl)—1-(1-(3,4-dichlorophenyl)cyclobutyl)—3-methylbutanamine (8g).
Colorless oil (130 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 0.59-0.64 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 0.91 (t, J = 9.6Hz, 3H); 1.04-1.07 (m, 1H); 1.32-1.40 (m,
2H); 1.50-1.56 (m, 3H); 1.57-1.79 (m, 4H); 1.87-1.92 (m, 1H); .27 (m, 3H); 2.38-2.42 (m,
1H); 2.72-2.94 (m, 3H); 3.37 (t, J = 10.8Hz, 2H); 3.49 (t, J = 10.8Hz, 2H); 7.07 (dd, J = 2.0Hz,
8.0Hz, 1H); 7.32 (s, 1H); 7.33 (d, J = 8.0Hz, 1H). MS (ESI): m/z = 402.03 (M+H+).
Example 36
(R)(1-(3,4-Dichlor0phenyl)cyclobutyl)—N-(4-methoxybutyl)—3-methylbutanamine (8h).
Colorless oil (60 mg, 27% yield). 1HNMR (400 MHz, CDClg): 8 0.57-0.66 (m, 1H); 0.84 (d, J =
8.8Hz, 3H); 0.89 (d, J = 8.8Hz, 3H); 1.00-1.08 (m, 1H); 1.43-1.68 (m, 6H); 1.71-1.94 (m, 2H);
2.10-2.45 (m, 4H); 2.66-2.84 (m, 3H); 3.31 (s, 3H). 3.37 (t, J = 10.8Hz, 2H); 7.07 (dd, J = 3.2Hz,
11.6Hz, 1H); 7.32 (s, 1H); 7.34 (d, J = 11.6Hz, 1H). MS (ESI): m/z = 374.26 (M+H+).
Example 37
(S)(1-(3,4-Dichlorophenyl)cyclobutyl)—N-(4-meth0xybutyl)methylbutanamine (8i).
Colorless oil (60 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 .66 (m, 1H); 0.84 (d, J =
8.8Hz, 3H); 0.89 (d, J = 8.8Hz, 3H); 1.00-1.08 (m, 1H); 1.43-1.68 (m, 6H); 1.71-1.94 (m, 2H);
2.10—2.45 (m, 4H); 2.66-2.84 (m, 3H); 3.31 (s, 3H). 3.37 (t, J = 10.8Hz, 2H); 7.07 (dd, J = 3.2Hz,
11.6Hz, 1H); 7.32 (s, 1H); 7.34 (d, J = 11.6Hz, 1H). MS (ESI): m/z = 374.26 (M+H+).
Example 38
(1-(3,4-Dichlor0phenyl)cyclobutyl)—N-(4-eth0xybutyl)—3-methylbutanamine (8j).
Colorless oil (100 mg, 27% yield). 1HNMR (400 MHz, CDClg): 8 0.57-0.66 (m, 1H); 0.84 (d, J =
9.2Hz, 3H); 0.89 (d, J = 9.2Hz, 3H); 1.01-1.08 (m, 1H); 1.20 (t, J = 9.2Hz, 3H); 1.43-1.64 (m,
6H); 1.71-1.94 (m, 2H); 2.09-2.41 (m, 4H); 2.66-2.84 (m, 3H); 3.40-3.51 (m, 4H). 7.08 (dd, J =
2.8Hz, 10.8Hz, 1H); 7.32 (s, 1H); 7.34 (d, J = 10.8Hz, 1H). MS (ESI): m/z = 388.26 (M+H+).
Example 39
(S)(1-(3,4-Dichlor0phenyl)cyclobutyl)—N-(4-eth0xybutyl)methylbutanamine (8k).
Colorless oil (100 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 0.57-0.66 (m, 1H); 0.84 (d, J =
9.2Hz, 3H); 0.89 (d, J = 9.2Hz, 3H); 1.01-1.08 (m, 1H); 1.20 (t, J = 9.2Hz, 3H); 1.43-1.64 (m,
6H); 1.71-1.94 (m, 2H); .41 (m, 4H); 2.66-2.84 (m, 3H); 3.40-3.51 (m, 4H). 7.08 (dd, J =
2.8Hz, 10.8Hz, 1H); 7.32 (s, 1H); 7.34 (d, J = , 1H). MS (ESI): m/z = 388.26 (M+H+).
Example 40
1-(1-(3,4-Dichlorophenyl)cyclobutyl)—N-(4-is0butoxybutyl)—3-methylbutanamine (81).
Colorless oil (87 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 0.59-0.64 (m, 1H); 0.84 (d, J =
9.2Hz, 3H); 0.89 (d, J = 9.2Hz, 3H); 0.91 (sbroad, 6H); 1.01-1.07 (m, 1H); 1.45-1.63 (m, 6H);
1.66-1.92 (m, 3H); 2.10-2.31 (m, 2H); 2.37-2.49 (m, 2H); 2.68-2.82 (m, 3H); 3.16 (d, J = 6.4Hz,
2H); 3.40 (t, J = 6.4H, 2H); 7.08 (dd, J = 2.8Hz, 10.8Hz, 1H); 7.32 (s, 1H); 7.33 (d, J = 10.8Hz,
1H). MS (ESI): m/z = 416.26 (M+H+).
Example 41
1-(1-(3,4-Dichlor0phenyl)cyclobutyl)-N-(2-ethoxyethyl)propanamine (8n). 1HNMR (400
MHz, CDC13)C 8 0.69-0.74 (m, 1H); 0.89 (d, J = 6.8Hz, 3H); 1.19 (t, J = 6.8Hz, 3H); .47
(m, 1H); .78 (m, 1H); .96 (m, 1H); 2.17-2.27 (m, 3H); 2.36-2.43 (m, 1H); 2.54 (dd,
J = 2.4Hz; 10.0Hz, 1H); 2.79-2.85 (m, 1H); 2.88-2.94 (m, 1H); 3.43-3.49 (m, 4H); 7.06 (dd, J =
2.4Hz; 8.4Hz, 1H); 7.30 (s, 1H); 7.32 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 332.60 (M+H+).
e 42
1-(1-(3,4-Dimethoxyphenyl)cyclobutyl)—N-(2-meth0xyethyl)methylbutanamine (80).
Colorless oil (100 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 0.72-0.78 (m, 1H); 0.84 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 1.06-1.12 (m, 1H); .68 (m, 1H); 1.77-1.91 (m, 2H);
.20 (m, 1H); 2.28-2.40 (m, 3H); 2.72 (dbroad, J = 9.2Hz, 1H); 2.89 (t, J = 5.6Hz, 2H); 3.32
(s, 3H); 3.45 (t, J = 7.2Hz, 2H); 3.87 (s, 6H); 6.77-6.82 (m, 3H). MS (ESI): m/z = 336.70
(M+H+).
Example 43
1-(1-(3,4-Dimethoxyphenyl)cyclobutyl)—N-(2-eth0xyethyl)methylbutanamine (8p).
Colorless oil (88 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 .78 (m, 1H); 0.84 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 1.06-1.12 (m, 1H); 1.18 (t, J = 6.8Hz, 3H); 1.52 (sbroad,
1H); 1.62-1.67 (m, 1H); 1.77-1.89 (m, 2H); 2.15-2.18 (m, 1H); 2.29-2.32 (m, 2H); 2.36-2.40 (m,
1H); 2.72 (dd, J = 3.2Hz; 6.8Hz, 1H); 2.88 (t, J = 1.6Hz, 2H); 3.45-3.49 (m, 3H); 3.87 (s, 6H);
6.77-6.82 (m, 3H). MS (ESI): m/z = 350.80 (M+H+).
Example 44
1-(1-(3,4-Dimethoxyphenyl)cyclobutyl)—N-(3-methoxypr0pyl)—3-methylbutanamine (8q).
Colorless oil (80 mg, 27% yield). 1HNMR (400 MHz, CDClg): 8 0.70-0.74 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 1.06-1.12 (m, 1H); .72 (m, 3H); 1.76-1.88 (m, 2H);
2.13-2.16 (m, 1H); 2.27-2.32 (m, 2H); 2.37-2.40 (m, 1H); 2.71 (dd, J = 2.4Hz; 9.6Hz, 1H); 2.80-
2.84 (m, 2H); 3.32 (s, 3H); 3.45 (t, J = 6.4Hz, 2H); 3.87 (s, 6H); .82 (m, 3H). MS (ESI):
m/z = 350.80 (M+H+).
Example 45
1-(1-(3,4-Dimethoxyphenyl)cyclobutyl)—N-(3-ethoxypr0pyl)—3-methylbutanamine (8r).
Colorless oil (100 mg, 27% yield). 1HNMR (400 MHz, CDClg): 8 0.70-0.74 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 1.08-1.12 (m, 1H); 1.19 (t, J = 6.8Hz, 3H); 1.63-1.72 (m,
3H); 1.76-1.88 (m, 2H); 2.13-2.16 (m, 1H); 2.27-2.32 (m, 2H); 2.37-2.40 (m, 1H); 2.71 (dd, J =
2.4Hz; 9.6Hz, 1H); 2.82 (t, J = 6.4Hz, 2H); 3.43-3.50 (m, 4H); 3.87 (s, 6H); 6.76-6.82 (m, 3H).
MS (ESI): m/z = 364.62 (M+H+).
e 46
1-(1-(3,4-Dimethoxyphenyl)cyclobutyl)—N-(4-meth0xybutyl)methylbutan-l-amine (8s).
Colorless oil (130 mg, 27% yield). 1HNMR (400 MHz, CDC13)C 8 0.70-0.74 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 1.08-1.12 (m, 1H); 1.57-1.64 (m, 6H); 1.78-1.89 (m, 3H);
2.13-2.16 (m, 1H); 2.27-2.32 (m, 2H); 2.37-2.40 (m, 1H); 2.74 (sbroad, 1H); 3.27 (sbroad, 3H);
3.36 (t, J = 5.6Hz, 2H); 3.87 (s, 6H); 6.76-6.82 (m, 3H). MS (ESI): m/z = 364. 62 (M+H+).
Example 47
1-(1-(3,4-dimeth0xyphenyl)cyclobutyl)—N-(4-ethoxybutyl)methylbutanamine (8t).
Colorless oil (100 mg, 27% yield). 1HNMR (400 MHz, C 8 0.69-0.74 (m, 1H); 0.83 (d, J =
6.8Hz, 3H); 0.88 (d, J = 6.8Hz, 3H); 1.04-1.12 (m, 1H); 1.19 (t, J = 6.8Hz, 3H); 1.24-1.30 (m,
3H); 1.45-1.51 (m, 2H); 1.58-1.65 (m, 2H); 2.14-2.18 (m, 1H); 2.27-2.40 (m, 3H); 2.69-2.78 (m,
3H); 3.39-3.42 (m, 4H); 3.87 (s, 6H); .82 (m, 3H). MS (ESI): m/z = 378.20 (M+H+).
General ure for synthesis of phenylcyclobutylmethylamine her tives 12
and 13 (Scheme 3)
To a d solution of phenylcycloalkylmethylamine (6) (1eq), alkylthioalkylcarboxylic acid
(14) (1.2 eq) and DMAP (0.6 g, 1eq) in 20 mL ofDCM at 0°C under nitrogen atmosphere was
added dropwise a solution of dicyclohexylcarbodiimide (DCC) (1.4 g., 0.0070 mol. 1.2eq) in 10
mL ofDCM. After the addition was completed, the on mixture was stirred at room
temperature for 15 h. The progress of the reaction was monitored by thin layer chromatography
(TLC). The reaction mixture was filtered and the e was concentrated under reduced
pressure. The residue the residue was purified by silica gel column chromatography to give the
corresponding amides (15) as white color solid in 70-90% yield. To a suspension of lithium
aluminum hydride (LAH) (0.417 g, 4.2eq) in 20 mL of THF anhydrous was added a solution of
amide (15) (1 eq) in in 20 mL of THF dropwise at 0°C under nitrogen atmosphere. After the
addition was complete, the reaction mixture was brought to rt and then to reflux for 24 h. The
progress of the reaction was monitored by thin layer chromatography (TLC). The reaction
mixture was cooled to 0°C and quenched by adding 2.5 mL of water, followed by 4.5 mL 10%
NaOH and finally 2 mL of water. After stirring for a while, ether was added. The mass was
2012/072283
filtered through celite, washed with ethyl acetate. The combined filtrates was evaporated and the
residue was d by silica gel chromatography using a gradient of hexane and ethyl acetate as
eluents to get the corresponding pure thioether derivatives (12, 13). The pure thioethers (12, 13)
gave satisfactory 1H NMR and/or Mass al data. The selected racemic ether derivatives (12,
13) were subjected to chiral HPLC to get the ponding optically pure (R)- and (S)—isomers
using similar conditions described for ether derivatives (7,8) in scheme 2. All thioether
derivatives (12, 13) were converted in to the corresponding HCl salts by treating them with 1N
HCl dioxane/water followed by lyophilization. The hydrochloride salts of thioether derivatives
(12, 13) were tested in monoamine transporters (MATs) in Vitro pharmacology assays.
Example 48
N-(4-(Ethylthi0)butyl)—1-(1-(4-fluorophenyl)cyclobutyl)methylbutanamine (12a).
Colorless oil (0.47g, 51% yield). 1HNMR (400 MHz, CDCl3)C 8 .63 (m, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 1.03-1.06 (m, 1H); 1.26 (t, J = 7.2Hz, 3H); 1.47-1.54 (m,
2H); 1.56-1.67 (m, 3H); 1.71-1.77 (m, 1H); 1.84-1.92 (m, 1H); 2.10-2.17 (m, 1H); 2.20-2.26 (m,
2H); 2.34-2.38 (m, 1H); .55 (m, 3H); 2.65-2.72 (m, 2H); 2.74-2.80 (m, 2H); 6.97 (dd, J =
8.4Hz; 11.6Hz, 1H); 7.06 (dd, J = 1.6 Hz; 7.6 Hz, 1H); 7.12-7.17 (m, 2H). MS (ESI): m/z =
352.20 (M+H+).
Example 49
1-(1-(4-Chlorophenyl)cyclobutyl)—N-(4-(ethylthi0)butyl)methylbutanamine (12b).
Colorless oil (0.48g, 51% yield). 1HNMR (400 MHz, CDCl3)C 8 .66 (m, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 1.03-1.09 (m, 3H); 1.25 (t, J = 7.2Hz, 3H); 1.47-1.54 (m,
2H); 1.58-1.65 (m, 2H); 1.73-1.78 (m, 1H); 1.84-1.91 (m, 1H); 2.11-2.18 (m, 1H); 2.21-2.29 (m,
2H); 2.35-2.42 (m, 1H); 2.50-2.55 (m, 4H); 2.67-2.77 (m, 3H); 7.16 (d, J = 8.8Hz, 2H); 7.25 (d,
J = 8.8Hz, 2H). MS (ESI): m/z = 369.20 (M+H+).
Example 50
1-(1-(4-Eth0xyphenyl)cyclobutyl)-N-(2-(ethylthi0)ethyl)methylbutanamine (12c).
Colorless oil (0.37g, 52% 1HNMR (400 MHz, CDCl3)C 8 0.69-0.75 (m, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 1.05-1.11 (m, 1H); 1.26 (t, J = 7.2Hz, 3H); 1.40 (t J =
7.2Hz, 3H); 1.54-1.66 (rn, 2H); 1.72—1.74 (rn, 1H); 1.82-1.88 (rn, 1H); 2.03-2.18 (rn, 1H); 2.25—
2.36 (rn, 2H); 2.52 (q, J = 7.6Hz, 2H); 2.61 (t, J = 6.8Hz, 2H); 2.70 (dd, J = 2.0Hz; 9.6Hz, 1H);
2.90 (t, J = 6.8Hz, 2H); 4.01 (q, J = 7.2Hz, 2H); 6.82 (d, J = 8.4Hz, 2H); 7.15 (d, J = 8.4Hz, 2H).
MS (ESI): m/z = 350.20 (M+H+).
Example 51
4-(Butylthi0)—N-(1-(1-(4-ethoxyphenyl)cyclobutyl)pr0pyl)butan-l-amine (12d).
Colorless oil , 53% yield)1HNMR (400 MHz, CDC13)C 8 .80 (rn, 1H); 0.84-0.91 (rn,
6H); 1.34-1.46 (rn, 6H); 1.48-1.65 (rn, 6H); .80 (rn, 1H); 1.82-1.89 (rn, 1H); 2.15-2.37 (rn,
4H); 2.46-2.51 (rn, 5H); 2.63-2.75 (rn, 2H); 4.01 (q, J = 7.2Hz, 2H); 6.82 (d, J = 8.4Hz, 2H); 7.15
(d, J = 8.4Hz, 2H). MS (ESI): rn/z = 378.20 (M+H+).
Example 52
1-(1-(3,4-Dichlorophenyl)cyclobutyl)—N-(2-(ethylthi0)ethyl)—3-methylbutanamine (13a).
Colorless oil (0.4lg, 53% . 1HNMR (400 MHz, CDC13)C 8 .67 (rn, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 1.03-1.06 (rn, 2H); 1.26 (t, J = 7.2Hz, 3H); 1.55-1.61 (rn,
1H); 1.70-1.74 (rn, 1H); 1.80-1.86 (rn, 1H); 2.08-2.14 (rn, 1H); 2.18-2.23 (rn, 2H); 2.30-2.35 (rn,
1H); 2.43-2.50 (rn, 2H); 2.53-2.60 (rn, 2H); 2.68 (d, J = 10.0Hz, 1H); .91 (rn, 2H); 7.04
(dd, J = 2.0Hz; 8.4Hz, 1H); 7.30 (d, J = 2.0H, 1H); 7.32 (d, J = 8.4Hz, 1H). MS (ESI): m/z =
376.20 (M+H+).
Example 53
N-(2-(Butylthi0)ethyl)—1-(1-(3,4-dichlor0phenyl)cyclobutyl)—3-methylbutanamine (13b).
Colorless oil (0.27g, 50% yield). 1HNMR (400 MHz, CDC13)C 8 0.60-0.67 (rn, 1H); 0.81-0.92
(rn, 9H); 1.04-1.10 (rn, 1H); 1.34-1.45 (rn, 2H); 1.50-1.58 (rn, 2H); 1.60-1.65 (rn, 1H); 1.73-1.78
(rn, 1H); 1.85-1.91 (rn, 1H); 2.15-2.19 (rn, 1H); 2.23-2.30 (rn, 2H); 2.35-2.40 (rn, 1H); 2.46-2.50
(rn, 2H); 2.58-2.62 (rn, 2H); 2.68 (dd, J = 2.4Hz; 10.0Hz, 1H); 2.85-2.93 (rn, 2H); 7.04 (dd, J =
2.0Hz; 8.4Hz, 1H); 7.30 (d, J = 2.0H, 1H); 7.32 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 403.20
(M+H+).
Example 54
1-(1-(3,4-Dichlorophenyl)cyclobutyl)—N-(4-(ethylthi0)butyl)methylbutanamine (13c).
Colorless oil (0.37g, 52% yield). 1HNMR (400 MHz, C 8 0.57-0.63 (m, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 1.03-1.06 (m, 1H); 1.26 (t, J = 7.2Hz, 3H); 1.47-1.54 (m,
2H); 1.56-1.67 (m, 3H); 1.71-1.77 (m, 1H); 1.84-1.92 (m, 1H); 2.10-2.17 (m, 1H); 2.20-2.26 (m,
2H); 2.34-2.38 (m, 1H); 2.50-2.55 (m, 3H); 2.65-2.72 (m, 2H); 2.74-2.80 (m, 2H); 7.04 (dd, J =
2.0Hz; 8.4Hz, 1H); 7.30 (d, J = 2.0H, 1H); 7.32 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 403.20
(M+H+).
Example 55
N-(4-(Butylthi0)butyl)—1-(1-(3,4-dichlor0phenyl)cyclobutyl)methylbutanamine (13d).
Colorless oil (0.45g, 55% . 1HNMR (400 MHz, CDClg): 8 .63 (m, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 0.88 (t, J = 7.2Hz, 3H); 1.02-1.05 (m, 1H); 1.36-1.43 (m,
2H); 1.48-1.65 (m, 7H); 1.73-1.77 (m, 1H); 1.85-1.90 (m, 1H); 2.10-2.16 (m, 1H); 2.18-2.25 (m,
2H); 2.34-2.39 (m, 1H); 2.48-2.52 (m, 4H); 2.65-2.80 (m, 3H); 7.04 (dd, J = 2.0Hz; 8.4Hz, 1H);
7.30 (d, J = 2.0H, 1H); 7.32 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 431.20 .
Example 56
1-(1-(2,4-Dichlorophenyl)cyclobutyl)—N-(4-(ethylthi0)butyl)methylbutanamine (13e).
Colorless oil , 51% yield). 1HNMR (400 MHz, C 8 0.57-0.63 (m, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 1.03-1.06 (m, 1H); 1.26 (t, J = 7.2Hz, 3H); 1.47-1.54 (m,
2H); 1.56-1.67 (m, 3H); 1.71-1.77 (m, 1H); 1.84-1.92 (m, 1H); 2.10-2.17 (m, 1H); 2.20-2.26 (m,
2H); 2.34-2.38 (m, 1H); 2.50-2.55 (m, 3H); 2.65-2.72 (m, 2H); 2.74-2.80 (m, 2H); 7.02 (d, J =
8.4Hz, 1H); 7.16 (dd, J = 2H2; 8.4Hz, 1H); 7. 29 (d, J = 2.4Hz, 1H). MS (ESI): m/z = 403.20
(M+H+).
Example 57
1-(1-(3,4-dichlor0phenyl)cyclobutyl)-N-(2-(ethylthi0)ethyl)pr0panamine (131).
Colorless oil (0.27g, 52% yield). 1HNMR (400 MHz, CDC13)C 8 0.72-0.79 (m, 1H); 0.92 (t, J =
7.6Hz, 3H); 1.23 (t, J = 7.6Hz, 3H); 1.42-1.48 (m, 1H); 1.72-1.79 (m, 1H); 1.86-1.93 (m, 1H);
2.18-2.30 (m, 3H); 2.34—2.41 (m, 1H); 2.49—2.55 (m, 3H); .69 (m, 2H); 2.80-2.89 (m, 1H);
2.86-2.97 (m, 1H); 7.04 (dd, J = 2.0Hz; 8.4Hz, 1H); 7.30 (d, J = 2.0H, 1H); 7.32 (d, J = 8.4Hz,
1H). MS (ESI): m/z = 347.20 (M+H+).
Example 58
4-(Butylthi0)-N-(1-(1-(3,4-dichlor0phenyl)cyclobutyl)pr0pyl)butanamine (13g).
Colorless oil (0.37g, 50% yield). 1HNMR (400 MHz, CDClg): 8 0.69-0.83 (m, 1H); 0.84-0.91
(m, 6H); .05 (m, 1H); 1.34-1.41 (m, 4H); 1.51-1.65 (m, 6H); 1.72-1.77 (m, 1H); 1.85-1.92
(m, 1H); 2.17-2.30 (m, 2H); 2.34-2.41 (m, 1H); 2.45-2.50 (m, 4H); 2.62-2.68 (m, 1H); 2.72-2.78
(m, 1H); 7.04 (dd, J = 2.0Hz; 8.4Hz, 1H); 7.30 (d, J = 2.0H, 1H); 7.32 (d, J = 8.4Hz, 1H). MS
(ESI): m/z = 403.20 (M+H+).
General procedure for synthesis of phenylcyclobutylmethylamine alkylsulfonyl derivatives
17 (Scheme 4)
Synthesis of amide derivatives (16, Step 1): To a stirred solution of m-CPBA (m-
chloroperbenzoic acid) (0.94 g, 2.leq ) in 10 rnL of THF was added at -30°C (dry Ice /acetone)
drop wise over 30 minutes a solution of amide (15) (0.0026 mol) in 10 rnL of THF. The reaction
progress was monitored by TLC. After the reaction was completed, 3 rnL of triethylarnine (TEA)
was added ed by a solution of 10 rnL ted sodium bicarbonate. The organic layer was
separated, washed with brine, dried over Na2S04 and evaporated. The residue was purified by
silica gel tography using a gradient of hexane and ethyl e as eluents to get the
corresponding pure amides (16).
Synthesis of alkylsulfonyl derivatives (17, Step 2): To a suspension of Lithium aluminum
hydride (LAH) (0.3 g, 4.2eq) in 20 rnL of THF anhydrous was added amide (l6) (leq) in 10 rnL
of THF dropwise at 0°C under nitrogen atmosphere. After the addition was complete, the
reaction mixture was brought to room temperature and then to reflux for 15 h. The progress of
the reaction was monitored by thin layer tography (TLC). The reaction mixture was
cooled to 0°C and quenched by adding 5 rnL of water, followed by 9 rnL 10% NaOH and finally
4mL of water. After stirring for a while, ether was added. The mass was filtered through celite
and washed with ethyl e. The combined filtrates were ated and the residue was
purified by silica gel column chromatography using a gradient of hexane and ethyl acetate to get
the corresponding yl derivatives (17). The pure sulfonyl derivatives (17) gave satisfactory
1H NMR and/or Mass spectral data. All sulfonyl derivatives (17) were converted in to the
corresponding HCl salts by treating them with 1N HCl dioxane/water followed by lyophilization.
The hydrochloride salts of alkylsulfonyl derivatives (17) were tested in monoamine transporters
(MATs) in vitro pharmacology assays.
Example 59
N-(l-(1-(3,4—Dichlorophenyl)cyclobutyl)methylbutyl)(ethylsulfonyl)butanamide (16a).
Colorless oil (0.85g, 73% yield). 1HNMR (400 MHz, CDCl3)C 8 0.57-0.71 (m, 1H); 0.80 (d, J =
6.8Hz, 3H); 0.90 (d, J = 6.8Hz, 3H); 1.13-1.19 (m, 1H); 1.24 (t, J = 7.2Hz, 3H); 1.78-1.84 (m,
1H); 2.05-2.23(m, 5H); 2.25-2.32 (m, 2H); 2.37-2.47 (m, 2H); 2.96-3.07 (m, 4H); 4.47-4.53 (m,
1H); 4.93 (d, J =10.4Hz, 1H); 6.94 (dd, J = 2.0Hz; 8.4Hz, 1H); 7.16 (d, J = 2.0H, 1H); 7.38 (d, J
= 8.4Hz, 1H). MS (ESI): m/z = 449.20 .
Example 60
ylsulf0nyl)—N-(1-(1-(3,4-dichlorophenyl)cyclobutyl)—3-methylbutyl)butanamide (16b).
Colorless oil (0.85g, 73% yield). 1HNMR (400 MHz, CDCl3)C 8 0.57-0.71 (m, 1H); 0.80 (d, J =
6.8Hz, 3H); 0.91 (t, J = 7.2Hz, 3H); 0.95 (d, J = 6.8Hz, 3H); 1.13-1.19 (m, 1H); .50 (m,
3H)1.75-1.85 (m, 3H); 2.05-2.23(m, 5H); .32 (m, 2H); 2.37-2.47 (m, 2H); .97 (m,
2H); 3.01-3.05 (m, 2H); .53 (m, 1H); 4.93 (d, J = 10.4Hz, 1H); 6.94 (dd, J = 2.0Hz; 8.4Hz,
1H); 7.16 (d, J = 2.0H, 1H); 7.38 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 477.20 (M+H+).
Example 61
1-(1-(3,4-Dichlor0phenyl)cyclobutyl)—N-(4-(ethylsulfonyl)butyl)—3-methylbutanamine
(17a)
Colorless oil (0.11g, 31% yield)1HNMR (400 MHz, CDClg): 8 0.58-0.65 (m, 1H); 0.82 (d, J =
6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 1.03-1.08 (m, 1H); 1.38 (t, J = 7.2Hz, 3H); 1.52-1.59 (m,
3H); 1.74-1.78 (m, 1H); 1.84-1.93 (m, 3H); 2.08-2.15 (m, 1H); 2.17-2.28 (m, 2H); 2.31-2.36 (m,
1H); 2.66-2.71 (m, 2H); 2.78-2.83 (m, 1H); 2.93-3.00 (m, 4H); 7.04 (dd, J = 2.0Hz; 8.4Hz, 1H);
7.30 (d, J = 2.0H, 1H); 7.32 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 435.20 (M+H+).
2012/072283
e 62
N-(4-(Butylsulf0nyl)butyl)(1-(3,4-dichlorophenyl)cyclobutyl)—3-methylbutan-l-amine
(17b). Colorless oil (0.07g, 37% yield)1HNMR (400 MHz, CDClg): 8 0.59-0.65 (m, 1H); 0.82 (d,
J = 6.8Hz, 3H); 0.87 (d, J = 6.8Hz, 3H); 0.95 (t, J = 7.2Hz, 3H); 1.03-1.05 (m, 1H); 1.43-1.51
(m, 2H); 1.52-1.62 (m, 3H); 1.72-1.86 (m, 4H); 1.88-1.93 (m, 3H); 2.08-2.38 (m, 4H); 2.66-2.71
(m, 2H); 2.78-2.84 (m, 1H); 2.91-2.97 (m, 4H); 7.04 (dd, J = 2.0Hz; 8.4Hz, 1H); 7.30 (d, J =
2.0H, 1H); 7.32 (d, J = 8.4Hz, 1H). MS (ESI): m/z = 463.20 (M+H+).
General procedure for synthesis of cycloalkylamine derivates 19 (Scheme 5)
Synthesis of amides (21, Step 1): To a stirred solution of trimethylaluminum 2 M solution (4
rnL, 0.008 mol) in toluene was added dropwise a on of phenylcycloalkylamine ( 6) (0.0053
mol, 1eq) and ester (20) (0.0053 mol, 1eq) in toluene under en atmosphere at 0 0C in a
sealed tube. The reaction e was stirred at 80 0C for 5 h. The reaction progress was
monitored by TLC. After completion of the reaction, the mixture was concentrated under
vacuum, quenched with crushed ice and extracted with ethyl acetate (15 mL x 3). The combined
t was dried over sodium sulfate and concentrated under reduced pressure. The residue was
passed through a short column to get the pure amide (21). The amides (21a-d) were prepared
according to this protocol. The starting esters (20) were ed by alkylating the cyclic
pyrrolidine and piperidine with appropriate bromoalkylcarboxylic acid esters under standard
conditions using triethylamine (TEA) as a base in DCM as a solvent in good yields.
The amides (2le-f) were prepared by ng 4-N,N-dimethylbutanoic acid with
phenylcycloalkylamine (6) using HATU as a coupling agent. To a stirred solution of amine (6) (1
eq) acid (1 eq) and HATU (2 eq) solution in DCM was added
, 4-N,N-dimethylbutanoic
dropwise a solution of N,N—diisopropylethylamine (DIEA) (3 eq) under nitrogen atmosphere at 0
0C. The reaction mixture was stirred at room temperature for 5 h. The reaction progress was
monitored by TLC. After completion of the reaction, the e was quenched with water and
extracted with DCM, the combined extracts was dried over Na2S04, and then ated under
reduced pressure. The residue was purified by silica gel column chromatography using a gradient
ofDCM and methanol as eluents to get the pure amides (21e-f). The amides (21a-f) gave
satisfactory 1H NMR and mass (LC/MS) mass data. As a representative example, the 1H NMR
and mass data of amide (21d) is given herein.
Synthesis of amines (19, Step 2): -DMS (1.5 eq) in THF was added dropwise to an ice
cooled solution of amide (21) (1 eq) in THF. The reaction mixture was stirred at 60 CC for 3h.
After completion of reaction, reaction mass was quenched with ice cooled water and then
extracted twice with EtOAc. The combined organic layers were washed with brine and dried
over Na2S04. The organic layer was ated under reduced pressure. The crude product was
in the form of amine-borane adduct or complex. The free base form of amine derivative (19) was
obtained by treating the amine-borane complex according to the reported methods using Raney
Nickel in methanol (Couturier, M. et al, Organic Letters, 2001, vol 3 (No. 3), 465-467) or
piperazine in methanol (Zhou, Q. et al, Organic letters 2011, vol 13 (No. 3), 526-529). The crude
free base form of amine derivatives (19) were purified by preparative HPLC using a gradient of
hexane and ethanol as eluents to obtain the pure amine tives (19).
Example 63
N-(l-(1-(3,4—Dimethoxyphenyl)cyclobutyl)—3-methylbutyl)(piperidinyl)butanamide
(21d)
Colorless oil (0.85g, 39% yield); 1HNMR (300 MHz, ): 8 0.73-0.76 (m, 6H); 0.85-0.98
(m, 2H); 1.39-1.59 (m, 8H); 1.71 (b, 3H); 1.83-1.89 (m, 2H); 2.11-2.17 (m, 6H); 2.27-2.49 (m,
4H); 3.73 (s, 3H); 3.74 (s, 3H); .25 (m, 1H), 6.62 (s, 1H), 6.64 (bs, 1H), 6.89 (d, J = 7.8
Hz, 1H); 7.30 (bd, 1H, D20 exchangeable); MS (ESI): rn/z = 431.17 .
Example 64
1-(1-(3,4-Dichlor0phenyl)cyclobutyl)methyl-N-(4-(pyrrolidinyl)butyl)butanamine
(19a)
Colorless oil (0.092g, 18.7% yield); 1HNMR (300 MHz, DMSOd6): 8 0.61-0.67 (m, 1H); 0.85
(d, J = 7.2 Hz, 3H); 0.90 (d, J = 6.4 Hz, 3H); 1.04-1.10 (m, 1H); 1.36-1.43 (m, 3H); 1.56-1.62
(m, 2H); 1.67-1.78 (m, 2H); .90 (m, 4H); 1.95-2.30 (m, 4H); 2.67-2.84 (m, 7H); 3.21 (bt,
2H); 7.07 (dd, J = 2Hz, 8Hz, 1H), 7.31 (d, J = 2Hz, 1H); 7.34 (d, J = 8.4 Hz, 1H); MS (ESI): m/z
= 411.16 (M+).
Example 65
1-(1-(3,4-Dimeth0xyphenyl)cyclobutyl)—3-methyl-N-(4-(pyrrolidinyl)butyl)butan
amine (19b)
Colorless oil (0.085g, 17.7% yield). 1HNMR (300 MHz, C 8 0.69-0.75 (m, 1H); 0.84 (d, J
= 6.6 Hz, 3H); 0.88 (d, J = 6.6 Hz, 3H); 1.07-1.14 (m, 1H); .48 (m, 5H); 1.80-1.86 (m,
6H); 2.14-2.17 (m, 2H); .35 (m, 2H); 2.67-2.77 (m, 7H); 3.19 (bt, 2H); 3.87 (s, 6H); 6.79-
6.81 (m, 3H); MS (ESI): m/z = 403.23 (M+H+).
Example 66
1-(1-(3,4-Dichlor0phenyl)cyclobutyl)—3-methyl-N-(4-(piperidinyl)butyl)butanamine
(19c)
Colorless oil (0.015g, 15.6 % yield); 1HNMR (300 MHz, DMSOd6): 8 0.59-0.62 (m, 1H); 0.79
(d, J = 6.6 Hz, 3H); 0.84 (d, J = 6.6 Hz, 3H); 0.94-1.02 (m, 1H); 1.33-1.38 (m, 2H); 1.46-1.48
(m, 3H); 1.59-1.75 (m, 8H); 2.11-2.16 (m, 2H); 2.43-2.50 (m, 2H); 2.65-2.77 (m, 9H); 7.20 (dd,
J = 5.1Hz; 8.4Hz, 1H); 7.42 (d, J =1.8Hz, 1H); 7.51 (d, J = 8.1Hz, 1H). MS (ESI): m/z = 425.13
(M+).
Example 67
1-(1-(3,4-Dimeth0xyphenyl)cyclobutyl)—3-methyl-N-(4-(piperidinyl)butyl)butanamine
(19d).
Colorless oil (0.060g, 15.5% yield). 1HNMR (400 MHz, CDC13)C 8 .67 (m, 1H); 0.85 (d, J
= 6.8Hz, 3H); 0.97 (d, J = 6.8Hz, 3H); 1.07-1.14 (m, 1H); 1.22-1.28 (m, 2H); 1.33-1.47 (m, 3H);
1.58-1.71 (m, 2H); 1.61-1.67 (m, 2H); 1.73-2.30 (m, 6H); 2.35-2.42 (m, 1H); .84 (m, 8H);
3.23 (sbroad, 2H); 3.87 (s, 6H); 6.79-6.81 (m, 3H). MS (ESI): m/z = 417.20 (M+H+).
Example 68
N1-(1-(1-(3,4-dichlor0phenyl)cyclobutyl)methylbutyl)—N4,N4-dimethylbutane-1,4-
e (19e)
Colorless oil (0.045g, 11.6% yield). 1HNMR (400 MHz, CDC13)C 8 0.59-0.65 (m, 1H); 0.80 (d, J
= 6.8Hz, 3H); 0.84 (d, J = 6.8Hz, 3H); 0.95—1.02 (m, 1H); 1.22-1.28 (m, 1H); 1.33—1.47 (m, 3H);
1.59—1.71 (m, 4H); 1.81-1.87 (m, 2H); 1.73—2.30 (m, 3H); 2.35—2.42 (m, 2H); 2.36-2.58 (m, 6 H);
2.60-2.74 (m, 2H); 7.06 (dd, J = 2.0Hz; 8.4Hz, 1H); 7.31 (d, J = 2.0H, 1H); 7.35 (d, J = 8.4Hz,
1H). MS (ESI): rn/z = 386.20 (M+H+).
Example 69
N1-(1-(1-(3,4-dimethoxyphenyl)cyclobutyl)methylbutyl)-N4,N4-dimethylbutane-1,4-
diamine (191)
Colorless oil (0.08g, 20% yield). 1HNMR (400 MHz, CDC13)C 8 0.59-0.65 (m, 1H); 0.80 (d, J =
6.8Hz, 3H); 0.84 (d, J = 6.8Hz, 3H); .02 (m, 1H); 1.22-1.28 (m, 1H); 1.33-1.47 (m, 3H);
1.59-1.71 (m, 4H); 1.81-1.87 (m, 2H); .30 (m, 3H); 2.35-2.42 (m, 2H); 2.36-2.58 (m, 6 H);
2.60-2.74 (m, 2H); 3.87 (s, 6H); 6.79-6.81 (m, 3H). MS (ESI): m/z = 377.20 (M+H+).
General procedure for synthesis of alkoxyalkyl 4-nitr0benzenesulf0nates 9 (Scheme 6)
Synthesis of monobenzyloxy carbinols (24, Step 1): To a stirred suspension of NaH (3. 5 g,
) in dry THF (50mL) was added diol (23) (3eq) over 0.5 h at 0°C. After the addition was
complete, the mixture was t to reflux and benzyl bromide (10 mL, 0.084 mol., leq) was
added dropwise. The reaction mixture was stirred at reflux for 12 h. The progress of the on
was monitored by thin layer chromatography (TLC). After the reaction was complete, the
mixture was allowed to cool to room temperature, and diluted with ether. The combined extracts
were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was
passed through a short silica gel column using a gradient of hexane and ethyl e as eluents
to get the pure monobenzyloxycarbinol (24) as a colorless oil in moderate yields.
Synthesis of alkoxyalkylbenzyl ethers (25, Step 2): To a stirred suspension of NaH (0.75 g,
l.5eq) in dry DMF (20mL) was added monobenzyloxycarbinol (24) (leq) in 10 mL of DMF at
0°C. After the addition was complete, the mixture was stirred for lh and then added dropwise a
solution of appropriate alkyl bromide or iodide (2eq). The reaction mixture was stirred for 15 h
and the progress of the reaction was monitored by thin layer chromatography (TLC). After
completion of the reaction, the mixture was diluted with 25 mL water, ted with ethyl
acetate, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The
ing oil was ed by silica gel column chromatography using a gradient of hexane and
ethyl acetate as eluents to get the corresponding alkoxyalkyl benzyl ethers (25) as colorless oil.
Alkoxyalkylsulfonates (9, Step 3): To a stirred suspension of Pd/C (10%)(activated)(0.8 g) in
ethanol (10 mL) was added solution of alkoxyalkyl benzyl ether (25) (0.001 mol) in 10 mL of
ethanol. The reaction mixture was kept under hydrogen pressure for 15 h. The progress of the
reaction was monitored by thin layer chromatography (TLC). After the reaction was complete,
the mixture was filtered through Celite, washed with ethyl e and the filtrate solution was
concentrated under reduced pressure. The e was passed through a short silica gel column
using a gradient of hexane and diethyl ether as s to get the corresponding carbinolether
(26) as colorless oil. The carbinolether (26) was treated with 4-nitrosulfonyl chloride in presence
a mild base triethylamine (TEA) in DCM at 0°C to 5 0C. The progress of the reaction was
monitored by TLC. After the reaction was complete, the mixture was washed with water, dried
over anhydrous ium sulfate and concentrated under reduced pressure. The residue was
purified by silica gel tography using a gradient of hexane and ethyl acetate as s to
get the alkoxyalkylsulfonates (9).
Example 70
xyethyl 4-nitr0benzenesulf0nate (9a). White solid (1.87g, 93% yield). 1HNMR (400
MHz, CDC13)C 8 1.08 (t, J = 7.2Hz, 3H); 3.41(q, J = 7.2Hz, 2H); 3.61 (t, J = 4.4Hz, 2H); 4.28 (t, J
= 4.4 Hz, 2H); 8.16 (d, J = 8.8Hz, 2H); 8.37 (d, J = 8.8Hz, 2H).
Example 71
2-Meth0xyethyl 4-nitr0benzenesulf0nate (9b). White solid (1.87g, 93% yield). 1HNMR (400
MHz, CDC13)C 8 3.28 (s, 3H); 3.59 (t, J = 4.4Hz, 2H); 4.30 (t, J = 4.4 Hz, 2H); 8.13 (d, J = 8.8Hz,
2H); 8.40 (d, J = 8.8Hz, 2H).
Example 72
2-Eth0xybutyl 0benzenesulf0nate (90). White solid (1.87g, 93% yield). 1HNMR (400
MHz, CDClg): 8 1.08 (t, J = 6.8Hz, 3H); 1.59-1.63 (m, 2H); 1.76-1.83 (m, 2H); 3.37-3.45 (m,
4H); 4.19 (t, J = 6.4Hz, 2H); 8.11 (d, J = 8.8Hz, 2H); 8.40 (d, J = 8.8Hz, 2H).
Example 73
2-Meth0xybutyl 4-nitr0benzenesulf0nate (9d). White solid (1.87g, 93% yield). 1HNMR (400
C13): 8 1.57-1.63 (m, 2H); 1.72-1.82 (m, 2H); 3.28 (s, 3H); 3.33-3.44 (m, 3H); 4.10 (t, J
= 6.4Hz, 2H); 8.11 (d, J = 8.8Hz, 2H); 8.40 (d, J = 8.8Hz, 2H).
Example 74
4-Pr0p0xybutyl 4-nitr0benzenesulf0nate (9e). White solid (1.87g, 93% yield). 1HNMR (400
MHz, CDClg): 8 0.84 (t, J = 7.2Hz, 3H); 1.44-1.51 (m, 2H); 1.91-1.97 (m, 2H); 3.28 (t, J =
6.8Hz, 2H); 3.43 (t, J = 4.26 (t, J = 6.4Hz, 2H); 8.11
, 5.6Hz, 2H); (d, J = 8.8Hz, 2H); 8.40 (d, J =
8.8Hz, 2H).
Example 75
xypr0pyl 4-nitr0benzenesulf0nate (91). White solid (1 .87g, 93% yield). 1HNMR (400
MHz,CDC13): 8 0.88 (t, J = 7.2Hz, 3H); 1.25-1.31 (m, 2H); 1.41-1.47 (m, 2H); 1.94 (t, J =
6.0Hz, 2H); 3.31 (t, J = 6.4Hz, 2H); 3.42 (t, J = 4.26 (t, J = 6.4Hz, 2H); 8.11
, 5.6Hz, 2H); (d, J =
8.8Hz, 2H); 8.40 (d, J = 8.8Hz, 2H).
Example 76
Ethyl 4-eth0xybutan0ate (30) (Scheme 7). ic acid 0.25 mL (0.0045 mmol, 0.035eq) was
added to an ice cooled solution of rolactone (28) (11.2 g, 0.13009 mmol, 1.0eq), triethyl
orthoformate (29) (41.1 mL, 0.2497 mmol, 1.92eq) in 100 mL of l. The mixture was
heated at 50 CC for 12h while monitoring the reaction by TLC. The on mixture was cooled
to room temperature and most of the solvent was evaporated under reduced pressure. The
concentrated reaction mixture was quenched with cold saturated NaHC03 on and extracted
with ethyl acetate twice. The combined organic extracts was dried over anhydrous Na2S04 and
concentrated under vacuum to yielded 20 g (95%) of ethyl 4-ethoxybutanoate (30) as light
yellow oil. 1HNMR (400 MHz, CDClg): 8 1.16-1.28 (m, 6H); 1.87-1.91 (m, 2H); 2.39(t, J =
9.6Hz; 2H); 3.42-3.50 (m, 2H); 3.57-3.64 (m, 2H); 4.13 (q, J = 6Hz, 2H).
Example 77
4-Eth0xybutan0ic acid (10) (Scheme 7). To an ice cold stirred solution of ethyl 4-
butanoate (30) (~l g) in 10 mL of tetrahydrofuran (THF) was added aqueous NaOH
solution (0.62 g in 7 ml of H20) and stirred at room temperature for 12h, while monitoring the
reaction by TLC. Most of the solvent was evaporated under reduced pressure and the residue was
diluted with water (10 mL). The s layer was acidified with 1N HCl solution (PH ~ 2) and
then ted with ethyl acetate (15 mL x 3). The combined organic extracts was dried over
anhydrous NaZSO4 and concentrated under vacuum to yield 0.6 g (73.14) of 4-ethoxybutanoic
acid as light yellow oil. 1HNMR (400 MHz, CDC13)C 8 1.20 (t, J = 9.2Hz, 3H); 1.87-1.95 (m,
2H); 2.47 (t, J = 10Hz; 2H); 3.48 (q, J = 9.2Hz, 4H).
l procedure for synthesis of hioalkylcarboxylic acid esters (33) (Scheme 8)
To a stirred solution of sodium alkanethiolate (32) (1 eq) in anhydrous DMF (10 mL) at 0°C was
added bromoalkylcarboxylic acid ester (31) (1eq) over 5 min. The reaction mixture was stirred
for 15h at room temperature. The progress of the reaction was red by thin layer
chromatography (TLC). The on mixture was diluted with ethyl acetate (20 mL) and washed
with saturated NaHC03 solution (the aqueous layer was quenched with bleach). The organic
layer was dried over anhydrous NaZSO4 to give the corresponding alkylthioethercrboxylic acid
ester (33) which was purified by silica gel column chromatography using a gradient of hexane
and ethyl acetate and isolated as colorless oil
Example 78
Ethyl 4-(ethylthi0)butan0ate (33a). Colorless oil (6.87g, 100% yield). 1HNMR (400 MHz,
CDC13)C 8 .26 (m, 6H); 1.84-1.92 (m, 2H); 2.40 (t, J = 9.6Hz, 2H); 2.47-2.55 (m, 4H); 4.12
(q, J = 7.2Hz, 2H).
Example 79
Ethyl 2-(ethylthi0)acetate (33b). Colorless oil (5.87g, 90% yield). 1HNMR (400 MHz, CDC13)C
8 1.20-1.29 (m, 6H); 2.63 (q, J = 7.6Hz, 2H); 3.l9(s, 2H); 4.15 (q, J = 7.2Hz, 2H).
Example 80
Ethyl 4-(butylthi0)butan0ate (33c). Colorless oil (14.12g, 100% yield). 1HNMR (400 MHZ,
CDC13): 5 0.89 (t, J = 7.6Hz, 3H); 1.22 (t, J = 7.6Hz, 3H); 1.34-1.36 (m, 2H); 1.48-1.54 (m, 2H);
1.87-1.90 (m, 2H); 2.39 (t, J = 7.6Hz, 2H); 2.44-2.51 (m, 4H); 4.10 (q, J = 7.6Hz, 2H)
Example 81
Ethyl 2-(butylthi0)acetate (33d). Colorless oil (5.80 g, 100% yield). 1HNMR (400 MHz,
CDC13): 8 0.89 (t, J = 6.8Hz, 3H); 1.26 (t, J = 7.2Hz, 3H); 1.36-1.41 (m, 2H); 1.52-1.61 (m, 2H);
2.61 (t, J = 7.6Hz, 2H); 3.18 (s, 2H); 4.15 (q, J = 7.2Hz, 2H)
General procedure for synthesis of alkylthioether ylic acids (14) (Scheme 8)
To a stirred solution of alkylthioethercarboxylic acid ester (33) (0.1 mole, 1 eq) in ethanol (20
rnL) was added 2N aq. NaOH (1.5eq) se into the reaction mixture. The on mixture
was stirred room temperature for 30min (the reaction ss is monitored by TLC). After the
reaction was completed, the reaction mixture was concentrated on a rotavapor and the residue
was cooled in ice bath. A few pieces of crushed ice were introduced into the flask and
neutralized with 1N HCl. The product was extracted with ethyl acetate (20 x 20 rnL). The
combined extracts was dried over Na2S04 and evaporated at 0°C on rotavap. The residue was
d by silica gel column chromatography using hexane as eluents to get the pure
hioether carboxylic acids (14).
Example 82
4-(Ethylthi0)butan0ic acid (14a). Colorless oil (2.01 g, 90% yield). 1HNMR (400 MHz,
CDC13): 8 1.26 (t, J = 7.6Hz, 3H); 1.84-1.92 (m, 2H); 2.40 (t, J = 9.6Hz, 2H); 2.47-2.55 (m, 4H);
10.92 (sbroad, 1H).
Example 83
2-(Butylthi0)acetic acid (14b). Colorless oil (0.77g, 77% yield).1HNMR (400 MHz, CDC13): 8
0.89 (t, J = 7.6Hz, 3H); .43 (m, 2H); 1.54-1.60 (m, 2H); 2.65 (t, J = 7.6Hz, 2H); 3.23 (s,
2H); 10.00 (sbroad, 1H).
Example 84
2-(Ethylthi0)acetic acid (14c). Colorless oil , 85% yield). 1HNMR (400 MHz, CDC13): 8
1.26 (t, J = 7.6Hz, 3H); 2.65 (q, J = 7.6Hz, 2H); 3.22 (s, 2H); 10.92 (sbroad, 1H).
Example 85
4-(Butylthi0)butan0ic acid (14d). Colorless oil (3.64g, 80% . 1HNMR (400 MHz,
CDC13)C 8 0.89 (t, J = 7.6Hz, 3H); 1.35-1.41 (m, 2H); 1.50-1.56 (m, 2H); 1.88-1.93 (m, 2H);
2.47-2.50 (m, 4H); 2.55 (t, J = 7.2Hz, 2H); 10.89 (sbroad, 1H).
Example 86
In vitro pharmacology results:
The monoamine transporters inhibitory ties of selected cycloalkylmethylamines of Formula
(I) are reported herein. The compounds were evaluated using well established radioligand
binding assays protocols (Galli, A. et al., J. Exp. Biol. 1995, 198, 2197-2212; Giros, B. et al.,
Trends Pharmcol. Sci. 1993, 14, 43-49; Gu, H. et al., J. Biol. Chem. 1994, 269(10), 7124-7130;
an, L. P. et al, Am. J. Physiol., 1998, 275(6 Pt 1), C1621-1629; Wolf, W. A. et al., J.
Biol. Chem. 1992, 267(29), 20820-20825). The human recombinant transporter proteins
dopamine (DAT), norepinephrine (NET) and serotonin (SERT) were selected for the in vitro
assays. The igand binding assays were carried out at 11 different test concentrations 0.1
nM to 1 11M.
The assays were carried out in duplicates and the quantitative data are reported as Ki in the Table 1.
DAT NET SERT
Example Compound
K1 (nM)_ K1 (nM)_ K1 (nM).
29 I___—
32 I___—
WO 02195 PCT/U82012/072283
54 130 23.93 17.07 14.84
Claims (17)
1. A compound of structural Formula (I): 5 or pharmaceutically acceptable salt thereof, wherein: n is 1; SP is a spacer of butylene; X is O or S; R1 and R2 are independently H, C1-6 alkoxy, or halogen; 10 R3 is C1-6 alkyl; R4 is H; R5 is C1-6 alkyl; optionally R1, R2, R3, R4, and R5 is tuted with 2H (deuterium); and “*” s a carbon capable of being optically active. 15
2. The compound according to Claim 1, wherein R1 and R2 are independently C1-6 alkoxy or halogen.
3. The compound according to Claim 1, wherein R3 is isobutyl.
4. The compound according to Claim 1, wherein X=O.
5. The compound according to Claim 1, which is 20 .
6. The nd according to Claim 1, wherein R1 is H and R2 is halogen or alkoxy.
7. The compound according to Claim 1, wherein R5 is ethyl.
8. The compound according to Claim 1, which is at least about in 95% enantiomeric excess in R-form over S-form.
9. The compound according to Claim 8, which is optical pure R-form. 5
10. The compound according to Claim 1, which is at least about in 95% enantiomeric excess in S-form over R-form.
11. The compound according to Claim 10, which is optical pure .
12. A pharmaceutical composition comprising the compound of any one of Claims 1 to 11 and a pharmaceutically acceptable vehicle. 10
13. Use of the compound of any one of Claims 1 to 11 in the preparation of a medicament for treating or preventing y in a mammal t.
14. Use of the compound of any one of Claims 1 to 11 in the preparation of a medicament for treating or preventing depression in a mammal patient.
15. A compound of structural Formula (I) according to any one of claims 1 to 11, 15 substantially as herein bed with reference to any one or more of the examples but excluding comparative examples.
16. A pharmaceutical composition according to claim 12, ntially as herein described with reference to any one or more of the examples but excluding comparative 20
17. Use of a compound according to claim 13 or claim 14, substantially as herein bed with reference to any one or more of the examples but excluding comparative examples.
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US61/582,201 | 2011-12-30 | ||
PCT/US2012/072283 WO2013102195A1 (en) | 2011-12-30 | 2012-12-31 | Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives |
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NZ627327B2 true NZ627327B2 (en) | 2016-11-01 |
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