AU2005214088B2 - Alkyl carbamate-substituted butyrolactones, process for their preparation, and pharmaceutical compositions containing them - Google Patents
Alkyl carbamate-substituted butyrolactones, process for their preparation, and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- AU2005214088B2 AU2005214088B2 AU2005214088A AU2005214088A AU2005214088B2 AU 2005214088 B2 AU2005214088 B2 AU 2005214088B2 AU 2005214088 A AU2005214088 A AU 2005214088A AU 2005214088 A AU2005214088 A AU 2005214088A AU 2005214088 B2 AU2005214088 B2 AU 2005214088B2
- Authority
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- Australia
- Prior art keywords
- alkyl
- solution
- carbon atoms
- oxygen
- sulphur
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims description 23
- 238000000034 method Methods 0.000 title claims description 14
- 230000008569 process Effects 0.000 title claims description 9
- -1 Alkyl carbamate-substituted butyrolactones Chemical class 0.000 title description 31
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 108
- 239000000203 mixture Substances 0.000 claims description 48
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 26
- 239000001301 oxygen Substances 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 239000005864 Sulphur Substances 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 208000008589 Obesity Diseases 0.000 claims description 11
- 235000020824 obesity Nutrition 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 200000000007 Arterial disease Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 201000001431 Hyperuricemia Diseases 0.000 claims description 2
- 206010022489 Insulin Resistance Diseases 0.000 claims description 2
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 230000002093 peripheral effect Effects 0.000 claims description 2
- 230000017105 transposition Effects 0.000 claims description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 2
- 125000000686 lactone group Chemical group 0.000 claims 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims 1
- 239000000243 solution Substances 0.000 description 144
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 121
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 68
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 54
- 239000002904 solvent Substances 0.000 description 43
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 239000012074 organic phase Substances 0.000 description 35
- 239000004367 Lipase Substances 0.000 description 34
- 102000004882 Lipase Human genes 0.000 description 34
- 108090001060 Lipase Proteins 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
- 229940040461 lipase Drugs 0.000 description 34
- 235000019421 lipase Nutrition 0.000 description 34
- 239000000741 silica gel Substances 0.000 description 33
- 229910002027 silica gel Inorganic materials 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 31
- 235000002639 sodium chloride Nutrition 0.000 description 31
- 239000011780 sodium chloride Substances 0.000 description 30
- 238000012360 testing method Methods 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 235000011152 sodium sulphate Nutrition 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 23
- 239000012299 nitrogen atmosphere Substances 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 102000019280 Pancreatic lipases Human genes 0.000 description 14
- 108050006759 Pancreatic lipases Proteins 0.000 description 14
- 229940116369 pancreatic lipase Drugs 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 239000003112 inhibitor Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 150000002596 lactones Chemical class 0.000 description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 8
- 239000001120 potassium sulphate Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 229910021642 ultra pure water Inorganic materials 0.000 description 8
- 239000012498 ultrapure water Substances 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 230000000269 nucleophilic effect Effects 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 229940043279 diisopropylamine Drugs 0.000 description 6
- 239000013067 intermediate product Substances 0.000 description 6
- ICHTXAXBLUZAOZ-UHFFFAOYSA-N methyl 3-hydroxy-8-phenylmethoxyoctanoate Chemical compound COC(=O)CC(O)CCCCCOCC1=CC=CC=C1 ICHTXAXBLUZAOZ-UHFFFAOYSA-N 0.000 description 6
- 239000004006 olive oil Substances 0.000 description 6
- 235000008390 olive oil Nutrition 0.000 description 6
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000012927 reference suspension Substances 0.000 description 6
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 239000011593 sulfur Substances 0.000 description 6
- YFBSWZQDOOTQOC-UHFFFAOYSA-N 3-hexyl-4-(5-hydroxypentyl)oxetan-2-one Chemical compound CCCCCCC1C(CCCCCO)OC1=O YFBSWZQDOOTQOC-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 125000003158 alcohol group Chemical group 0.000 description 5
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000003925 fat Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 244000215068 Acacia senegal Species 0.000 description 4
- 229920000084 Gum arabic Polymers 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229940086609 Lipase inhibitor Drugs 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000205 acacia gum Substances 0.000 description 4
- 235000010489 acacia gum Nutrition 0.000 description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 239000012086 standard solution Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- YFBSWZQDOOTQOC-STQMWFEESA-N (3s,4s)-3-hexyl-4-(5-hydroxypentyl)oxetan-2-one Chemical compound CCCCCC[C@H]1[C@H](CCCCCO)OC1=O YFBSWZQDOOTQOC-STQMWFEESA-N 0.000 description 3
- XQQUKAGHLDAJGO-UHFFFAOYSA-N 1-(2,6-dihydroxy-4-methoxyphenyl)hexan-1-one Chemical compound CCCCCC(=O)C1=C(O)C=C(OC)C=C1O XQQUKAGHLDAJGO-UHFFFAOYSA-N 0.000 description 3
- MCKUQXMNBVZWAE-UHFFFAOYSA-N 2-hexyl-3-hydroxy-8-phenylmethoxyoctanoic acid Chemical compound CCCCCCC(C(O)=O)C(O)CCCCCOCC1=CC=CC=C1 MCKUQXMNBVZWAE-UHFFFAOYSA-N 0.000 description 3
- VZQVCXYLOZMAMG-UHFFFAOYSA-N 3-hexyl-4-[5-(oxan-2-yloxy)pentyl]oxetan-2-one Chemical compound O1C(=O)C(CCCCCC)C1CCCCCOC1OCCCC1 VZQVCXYLOZMAMG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000002366 lipolytic effect Effects 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 3
- MCKUQXMNBVZWAE-PMACEKPBSA-N (2s,3s)-2-hexyl-3-hydroxy-8-phenylmethoxyoctanoic acid Chemical compound CCCCCC[C@H](C(O)=O)[C@@H](O)CCCCCOCC1=CC=CC=C1 MCKUQXMNBVZWAE-PMACEKPBSA-N 0.000 description 2
- AMEKKFWQRUYAIB-PMACEKPBSA-N (3s,4s)-3-hexyl-4-(5-phenylmethoxypentyl)oxetan-2-one Chemical compound O1C(=O)[C@@H](CCCCCC)[C@@H]1CCCCCOCC1=CC=CC=C1 AMEKKFWQRUYAIB-PMACEKPBSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- ANOOTOPTCJRUPK-UHFFFAOYSA-N 1-iodohexane Chemical compound CCCCCCI ANOOTOPTCJRUPK-UHFFFAOYSA-N 0.000 description 2
- PNBUGOFIKAHZRW-UHFFFAOYSA-N 1-isocyanato-4-phenoxybenzene Chemical compound C1=CC(N=C=O)=CC=C1OC1=CC=CC=C1 PNBUGOFIKAHZRW-UHFFFAOYSA-N 0.000 description 2
- PNEVFNIEFNHCIG-UHFFFAOYSA-N 2-benzyl-3-hydroxy-8-phenylmethoxyoctanoic acid Chemical compound C=1C=CC=CC=1CC(C(O)=O)C(O)CCCCCOCC1=CC=CC=C1 PNEVFNIEFNHCIG-UHFFFAOYSA-N 0.000 description 2
- AAILMCRJANAGRC-UHFFFAOYSA-N 2-hexyl-3-hydroxy-8-(oxan-2-yloxy)octanoic acid Chemical compound CCCCCCC(C(O)=O)C(O)CCCCCOC1CCCCO1 AAILMCRJANAGRC-UHFFFAOYSA-N 0.000 description 2
- JZJUSIIKTZNEPQ-UHFFFAOYSA-N 3-benzyl-4-(5-hydroxypentyl)oxetan-2-one Chemical compound OCCCCCC1OC(=O)C1CC1=CC=CC=C1 JZJUSIIKTZNEPQ-UHFFFAOYSA-N 0.000 description 2
- FVLVUTDPBUXKJP-UHFFFAOYSA-N 4-[5-[tert-butyl(dimethyl)silyl]oxypentyl]-3-hexyloxetan-2-one Chemical compound CCCCCCC1C(CCCCCO[Si](C)(C)C(C)(C)C)OC1=O FVLVUTDPBUXKJP-UHFFFAOYSA-N 0.000 description 2
- NHCIXEPZNPKEAR-UHFFFAOYSA-N 6-(oxan-2-yloxy)hexan-1-ol Chemical compound OCCCCCCOC1CCCCO1 NHCIXEPZNPKEAR-UHFFFAOYSA-N 0.000 description 2
- PRGUNFCZRODZGQ-UHFFFAOYSA-N 6-(oxan-2-yloxy)hexanal Chemical compound O=CCCCCCOC1CCCCO1 PRGUNFCZRODZGQ-UHFFFAOYSA-N 0.000 description 2
- QRPJDVQNRZJLJE-UHFFFAOYSA-N 6-[tert-butyl(dimethyl)silyl]oxyhexanal Chemical compound CC(C)(C)[Si](C)(C)OCCCCCC=O QRPJDVQNRZJLJE-UHFFFAOYSA-N 0.000 description 2
- FMSYZEGXVQMCSX-UHFFFAOYSA-N 6-phenylmethoxyhexan-1-ol Chemical compound OCCCCCCOCC1=CC=CC=C1 FMSYZEGXVQMCSX-UHFFFAOYSA-N 0.000 description 2
- OKBHPVOFRDHZPQ-UHFFFAOYSA-N 6-phenylmethoxyhexanal Chemical compound O=CCCCCCOCC1=CC=CC=C1 OKBHPVOFRDHZPQ-UHFFFAOYSA-N 0.000 description 2
- CFISCCKEXBOEKH-UHFFFAOYSA-N 8-[tert-butyl(dimethyl)silyl]oxy-2-hexyl-3-hydroxyoctanoic acid Chemical compound CCCCCCC(C(O)=O)C(O)CCCCCO[Si](C)(C)C(C)(C)C CFISCCKEXBOEKH-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- 102100035593 POU domain, class 2, transcription factor 1 Human genes 0.000 description 2
- 101710084414 POU domain, class 2, transcription factor 1 Proteins 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
- C07D305/12—Beta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Description
1 ALKYL CARBAMATE-SUBSTITUTED p-LACTONES, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM BACKGROUND OF THE INVENTION 5 The present invention relates to p-lactones (oxetanones) substituted by an unbranched alkyl carbamate side chain, which are suitable for the treatment and/or prophylaxis of obesity and also of associated accompanying and/or concomitant diseases in larger mammals and humans, in particular metabolic syndrome and cardiovascular diseases. Furthermore, the invention relates to 10 pharmaceutical preparations containing these novel compounds and also to processes for the preparation of these compounds. The compounds according to the invention then act as inhibitors of lipase, in particular of pancreatic lipase. Oxetanones substituted by a branched side chain and having an action inhibiting pancreatic lipase are already known from U.S. Patent No. 5,260,310 15 (=EP 444,482). Hexadecanoic acid and hexadecadienoic acid derivatives which inhibit pancreatic lipase and therefore can be used in combating or preventing obesity and hyperlipaemias are already known from U.S. Patent No. 4,598,089 (=EP 129,748). 20 U.S. Patent No. 4,598,089 (=EP 129,748) (WO 03/050154) describes, inter alia, also oxetanones substituted by side chains as substrates for catalytic carbonylation. SUMMARY OF THE INVENTION 25 It was an object of the present invention to provide new lipase-inhibitory compounds. It was also an object of the invention to provide lipase-inhibitory substances suitable for the treatment and/or inhibition of obesity and accompanying and/or concomitant diseases. 30 Another object of the invention was to provide lipase inhibitory compounds which a highly effective mode of action. A further object of the invention was to provide lipase-inhibitory compounds which can be obtained in simple manner.
la These. and other objects have been achieved in accordance with the present invention by providing a compound corresponding to formula 1, O R'2 3 RI -- N,10- (CH2 )n R2 H wherein R 1 is C1-1 8 -alkyl, one or two alkyl-chain carbon atoms of which are 5 optionally replaced by oxygen or sulfur; phenyl-Co.
1 8 -alkyl, the phenyl group of which is optionally substituted one or two times by halogen, trifluoromethyl, nitro, C.e-alkyl, C 1 -- alkoxy, C1.
6 -alkylcarbonyt, C1.ealkoxycarbonyl, phenyl, benzy or phenoxy, and one or two alkyl-chain carbon atoms of which are optionally replaced by oxygen or sulfur; C 3 -. rcycloalkyl-Co 18 -alkyl, one or two alkyl-chain 10 carbon atoms of which are optionally replaced by oxygen or sulfur, or benzoyl; R 2 is C 1
-
1 2 -alkyl, one or two alkyl-chain carbon atoms of which are optionally replaced by oxygen or sulfur; phenyl-C 1
.
1 8 -alkyl, the phenyl group of which is optionally substituted once or twice by halogen, C 1
.
4 -alkyl, C 1
.
4 -alkoxy, benzyl or phenoxy, and one or two alkyl-chain carbon atoms of which are optionally 15 replaced by oxygen or sulfur; or C3- 7 -cycloalkyl-Co.
1 6 -alkyl, one or two alkyl-chain carbon atoms of which are optionally replaced by oxygen or sulfur, and n is a whole number from 2 to 8. It has now been found that a group of alkyl carbamate-substituted b lactones which are unbranched in the alkyl carbamate side chain can act as 20 inhibitors of lipase, in particular of pancreatic lipase. The compounds according to the invention are thus capable of reducing the lipid digestion induced by pancreatic lipase in mammals, particularly humans, with the result that the body has overall fewer usable edible fats available. The compounds according to the invention therefore appear suitable for the treatment and/or prophylaxis of obesity 25 and illnesses associated therewith. The present invention relates to lipase-inhibitory alkyl carbamate substituted p-lactones of the general formula 1, 0 0 0 23I R1 -N 0-- (CH 2 ), R2 H wherein
R
1 is C1-1 8 -alkyl, the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur; phenyl-Co.
1 8-alkyl, the phenyl group of which is optionally substituted 1-2 times by halogen, trifluoromethyl, nitro, C 1 8 -alkyl, C18 alkoxy, C 1
-
6 -alkylcarbonyl, C1- 6 -alkoxycarbonyl, phenyl, benzyl and/or phenoxy and the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur; C 37 -cycloalkyl-Co-1 8 -alkyl, the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur, or benzoyl;
R
2 is C 1 2 -alkyl, the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur; phenyl-Cl- 1 8 -alkyl, the phenyl group of which is optionally substituted 1-2 times by halogen, C 14 -alkyl, C 1 4 -alkoxy, benzyl and/or phenoxy and the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur; or C 37 -cycloalkyl-CO- 1 8 -alkyl, the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur, and n is a whole number from 2 to 8. A further subject of the invention is medicaments containing the compounds of Formula 1. Furthermore, a subject of the invention is a process for the preparation of the compounds of Formula I and intermediate products of this process. Where in the compounds of Formula I or in other compounds described in the context of the present invention substituents are or contain alkyl, these may each be straight-chain or branched. Where substituents in compounds of Formula I stand for halogen, fluorine, chlorine or bromine are suitable. Chlorine is preferred.
R
1 is preferably phenyl-CO- 2 -alkyl, the phenyl group of which is optionally substituted as stated above. Preferred substituents are C14-alkyl, C 1 4-alkoxy and phenoxy. In particular, R 1 may stand for 4-phenoxyphenyl, benzyl, phenylethyl or 4-ethoxybenzyl. 4-phenoxyphenyl is particularly preferred.
R
2 is preferably C 2
-
6 -alkyl, the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur, in particular hexyl. Where R 2 is phenyl
C
118 -alkyl optionally substituted in the phenyl group, phenyl-C 2 4-alkyl is preferred. n is preferably a whole number from 2 to 5.
Compounds of Formula I wherein the substituents of the carbon in the 2 position of the lactone ring and the substituents of the carbon in the 3 position of the lactone ring are in the trans position relative to each other are preferred. Particularly preferred compounds of Formula I are selected from the group consisting of 5-(3-hexyl-4-oxo-oxetan-2-yl)-pentyl-(phenoxyphenyl)-carbamate and 4-(3-hexyl-4-oxo-oxetan-2-yl)-butyl-(phenoxyphenyl)-carbamate, each of which are particularly preferred in their 2S,3S-trans form. Numerous processes for the preparation of p-lactones (oxetanes) are known (cf. e.g: A. Pommier, J.-M. Pons, Synthesis 5 (1993) 441 - 459). According to the invention, the novel compounds of Formula I are obtained by reacting a compound of the general formula 11, 0 23 II HO- (CH 2 )n R2 wherein R2 and n have the above meanings, with a compound of the general formula |||,
R
1 -N C0 III wherein R 1 has the above meaning. The reaction of the alcohol derivative of Formula 11 with an isocyanate compound of Formula Ill can be carried out in known manner, for example in a solvent which is inert under the reaction conditions such as a dipolar-aprotic solvent, in particular a lower-alkyl halide, preferably dichloromethane. Usual reaction temperatures are between approximately -25*C and approximately 50 0 C. Usually the reaction temperature during the addition of the reaction partners is kept between approximately -25*C and 10 C, preferably 0*C, and once they have been completely added is increased to approximately 15 0 C to 50 0 C, preferably room temperature (= RT). In some cases it is beneficial, after a certain reaction time, for example after 2 hours, to add to the reaction mixture a non-nucleophilic base, for example an organic nitrogen base such as in particular diisopropylethylamine (= "Honig's base"), and then to allow it to react further for a certain time, for example another 2 hours, to complete the reaction. Compounds of Formula I can then be isolated from the reaction mixture in known manner and if necessary purified.
Compounds of Formula II can be obtained by cleaving off the alcohol protective group from lactone compounds protected at the alcohol function of the general formula IVa, 0 23 IVa
R
301 -0- (CH 2 )n R2 wherein R2 and n have the above meanings and R 3 0 1 stands for an alcohol protective group, in known manner. Suitable protective groups for alcohol functions and methods for the introduction and cleavage thereof are known for example from McOmie, "Protective Groups in Organic Chemistry", Plenum Press, and Greene, Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience Publication, the newest edition of each. Particularly suitable alcohol protective groups R301 are selected from the group consisting of benzyl, tetrahydropyranyl, methoxymethyl (= MOM), methoxyethoxymethyl (= MEM) and the silyl alcohol protective groups, in particular tert. butyldimethylsilyl and triethylsilyl. Compounds of Formula 11 are novel compounds which are advantageously suitable as intermediate products for the preparation of novel pharmacologically active active substances, for example for the preparation of the compounds of Formula I. Compounds of Formula III are known per se or can be prepared in known manner from known compounds. Compounds of Formula IVa are novel compounds which are advantageously suitable as intermediate products for the preparation of novel pharmacologically active active substances, for example for the preparation of the compounds of Formula 1. Compounds of Formula IVa, in particular the compounds 3-hexyl-4-{5[(tetrahydro-2H pyran-2-yl)oxy]pentyl}oxetan-2-one and 3-hexyl-4-[5(benzyloxy)pentyl}]oxetan-2-one, likewise already exhibit an action inhibiting pancreatic lipase and therefore likewise appear advisable for the treatment and/or prophylaxis of obesity and its accompanying and/or concomitant diseases. The alcohol protective groups R301 can be cleaved off again from compounds of Formula IV in known manner in order to obtain the free alcohol functions. In this manner, compounds of the general formula IV are accessible, 0 23 IV R3--O-(CH 2 )n R wherein R 2 and n have the above meanings and R 3 is hydrogen or an alcohol protective group. Compounds of Formula IVa can be obtained, in a first variant, by cyclising a p-hydroxycarboxylic acid of the general formula V, OH 0
R
301 -0- (CH 2 ) OH V R2 wherein R 2 , R 30 1 and n have the above meanings, in known manner to form a p-lactone. The cyclisation can for example be performed by reacting the compound of Formula IVa with a reagent which together with a carboxylic acid function produces a readily cleavable leaving group, such as with a sulphonic acid derivative, for example with toluene sulphonic acid chloride. Likewise it is also possible, in a compound of Formula IVa in known manner to activate the free alcohol function accordingly, in order to make it accessible to the nucleophilic attack of the optionally activated carboxylic acid function, for example the carboxylate. Compounds of Formula V can be prepared in a first variant by reacting an aldehyde of the general formula VI, 0
R
3 0 1 -0- (CH 2 )n VI H wherein R 30 1 and n have the above meanings, in known manner with a carboxylic acid derivative of the general formula VII, 0 R2 OR 4 wherein R 2 has the above meaning and R 4 is hydrogen or ClA-alkyl. To perform the reaction, a compound of Formula VII may first be - optionally doubly - deprotonated in known manner with a strong non-nucleophilic base such as lithium diisopropylamide (= LDA), and the resulting carbanion can then be reacted with the compound of Formula VI. The compounds of Formula V prepared according to this aforementioned variant as a rule do not have a defined stereochemistry at the carbon atoms bearing the substituents "R 2 " and "p-hydroxy", and are therefore present as "syn/anti mixtures".
Aldehydes of Formula VI can be prepared by known selective oxidation of primary alcohols of the general formula VIII,
R
30 1 -0- (CH 2 )n -OH VIII wherein R 30 1 and n have the above meanings. The selective oxidation may for example be performed as what is called a "Swern oxidation", with dimethyl sulphoxide (= DMSO) being used as oxidising agent in the presence of an electrophile, for example oxalyl chloride. Furthermore, selective oxidation can also be performed with pyridinium chlorochromate (= PCC) as oxidising agent. Compounds of Formula VIII are known per se or can be prepared in known manner, in particular by known introduction of suitable alcohol protective groups into the corresponding basic terminal diols. Compounds of Formula VII are known per se, or can be prepared in known manner from known compounds. Compounds of Formula V can also be prepared in a second variant by first doubly deprotonating a compound of the general formula IX, OH 0
R
3 0 1 -0- (CH 2 )n OR 4 0 1 IX wherein R 3 0 1 and n have the above meanings and R 4 01 is C1.4-alkyl, in particular methyl, in known manner with a strong non-nucleophilic base such as a lithium-lower alkyl compound, preferably LDA, and then reacting the deprotonated intermediate product with a compound of the general formula X,
R
2 -X X wherein R 2 has the above meaning and X stands for a cleavable leaving group, for example halogen, in particular iodine, bromine or chlorine, preferably iodine, and subsequently cleaving off the ester group R 40 1 in known manner. The deprotonation and the subsequent reaction with a compound of Formula X can be carried out in an organic solvent which is inert under the reaction conditions, such as a cyclic or open chained di-lower alkyl ether, in particular tetrahydrofuran (= THF). In a preferred variant, compounds of Formula V can be obtained at least in diastereomer-enriched form, preferably diastereoselectively, if a suitable complexing agent is added to the reaction mixture before the compound of Formula X is added. Suitable complexing agents are for example tris-(dimethylamino)-phosphine (= HMPT), 1,3-dimethyl- 3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (= DMPH) or 1, 3 -dimethyl-imidazolidin-2-one (= DMEU). DMPH is preferred. The compounds of Formula V under these conditions are preferentially formed in the "anti" configuration. The aforementioned cleavage of the ester group R 40 1 can for example be carried out by saponification with an alkali hydroxide such as lithium hydroxide and in a polar-protic solvent such as ethanol. Compounds of Formula IX can be prepared in a first variant by first deprotonating in known manner a compound of the general formula XI, 0
H
3 C OR 4 0 1 XI wherein R 4 0 1 has the above meaning, with a strong, non-nucleophilic base such as a lithium-lower-alkyl compound, preferably LDA, and then reacting the deprotonated intermediate product with a compound of Formula VI. The deprotonation and the subsequent reaction with a compound of Formula VI can be performed in an organic solvent which is inert under the reaction conditions, such as a di-lower alkyl ether, in particular THF. Operation is usually at low temperatures of between about -80 0 C and -50 0 C. Compounds of Formula XI are known or can be prepared in known manner from known compounds. Compounds of Formula IX can be prepared in a second variant in at least enantiomer-enriched form, preferably enantiomerically pure form, by selectively oxidising a racemic starting compound of Formula IX in known manner to form a p-keto ester of the general Formula XII, O 0
R
3 01-0-(CH 2 )n OR 401 XII wherein R 30 1 , R 40 1 and n have the above meanings, and then selectively reducing the resulting keto ester compound in the presence of a suitable chiral catalyst to form an at least enantiomer-enriched compound of Formula IX. The oxidation of a starting compound of Formula IX can be carried out in an organic solvent which is inert under the reaction conditions such as a lower-alkyl halide, in particular dichloromethane. PCC, for example, is suitable as selective oxidising agent. The enantioselective reduction of a p-keto ester of the general formula XII can be carried out with air excluded in a solvent which is inert under the reaction conditions, such as dimethyl formamide (= DMF) or methanol or in a mixture of the aforementioned solvents. The hydrogenation can be performed at a hydrogen pressure of approximately 2 - 6 bar, preferably approximately 4.0 - 4.5 bar. Suitable reaction temperatures are between approximately 500C and approximately 900C, preferably between approximately 600C and 800C. Suitable chiral hydrogenation catalysts are in particular known complexes of ruthenium-Il with (S)-(-)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (= (S)-(-) BINAP) or of ruthenium-Il with (R)-(+)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (= (R)-(+)-BINAP). Depending on the stereochemistry in the chiral hydrogenation catalyst, a compound of Formula IX which is enriched in each case at least in (S)-isomer or in (R)-isomer can be obtained. Where (S)-(-)-BINAP is used as ligand of the chiral catalyst, as a rule compounds of Formula IX are obtained, wherein the carbon bearing the newly produced alcohol function is in the "S" configuration. Compounds of Formula IVa can also be obtained, in a second variant, by reacting in known manner a silyl-ketene acetal compound of the general formula XIII, R2 0- R 5 S XIII N wherein R2 has the above meaning and R 5 is a silyl group, in particular triethylsilyl, in the manner of a Tandem-Mukaiyama-Aldol lactonisation (cf. e.g. H.W. Yang et al., Tetrahedron 53 No. 48 (1997) 16471-16488) with an aldehyde of Formula VI. The reaction can for example be carried out under a protective gas atmosphere in an organic solvent such as a lower-alkyl halide, in particular dichloromethane, and in the presence of a Lewis acid, in particular a Zn(Il) salt such as Zn(II) chloride. In this reaction variant, as a rule mixtures of compounds of Formula IVa are obtained, the substituents "R 2 " and "R 301 -0-(CH 2 )n-" of which are predominantly in the "trans" configuration relative to one another. Compounds of Formula XIII can be prepared by deprotonating a compound of the general formula XIV, 0 R2 XIV S ' N wherein R 2 has the above meaning, in known manner first with a strong non nucleophilic base, and then reacting the deprotonated intermediate product with a reagent suitable for introducing a silyl protective group. The reaction can be carried out in an organic solvent such as DMF or THF or in a mixture of these solvents. Lithium hexamethyl disilazide for example is suitable as strong non-nucleophilic base. Preferably the reaction is carried out at temperatures between approximately -90'C and -60*C. For example triethylsilyl chloride can be used as reagent suitable for introducing a silyl protective group. Compounds of Formula XIV can be obtained by reacting in known manner a compound of the general formula XV, 0 R2 XV wherein R 2 and X have the above meanings, with 2-mercaptopyridine. The compounds of Formula I contain two chiral carbon atoms, namely the carbon bearing the substituent "R 1
-N-C(O)-(CH
2 )n-" in the 2 position of the lactone ring and the carbon bearing the substituent "-R 2 " in the 3 position of the lactone ring. The compounds can thus be present in a total of four stereoisomeric forms. The present invention comprises both the mixtures of stereoisomers and enantiomers, and also the isomerically pure compounds of Formula 1. Isomerically pure compounds of Formula I are preferred, in particular those in which the aforementioned substituents of the carbon atoms in the 2 position and in the 3 position of the lactone ring are in the "trans" configuration. Usually compounds of Formula I in which the carbon bearing the substituent "R 1
-N-C(O)-(CH
2 )n-" in the 2 position of the lactone ring and the carbon bearing the substituent "-R 2 " in the 3 position of the lactone ring are both in the "S" configuration are particularly preferred. In the reactions described above, the optionally preformed chiral centres in the starting compounds of Formula V are no longer changed to compounds of Formula I in the subsequent reactions, so that depending on the type of starting compounds finally isomerically pure compounds of Formula I or isomer mixtures can be obtained. For the preparation of stereochemically uniform compounds of Formula 1, expediently stereochemically uniform compounds of Formula V are used. If mixtures of isomers of Formula I are obtained, these may if desired be separated off in known manner, for example by chromatography, in particular by HPLC separation on optionally chiral separating materials.
The compounds of Formula I according to the invention are suitable for the inhibition of lipase, in particular for the optionally selective inhibition of pancreatic lipase of larger mammals, particularly humans. Compounds with lipase-inhibiting properties are capable, if supplied to the digestive tract preferably together with fat containing food, of reducing the proportion of edible fats actually digested by the body in the total edible fats ingested. In this manner, fat resorption in mammals, particularly humans, can be reduced. The group of compounds according to the invention thus appears suitable for the treatment and/or prophylaxis of obesity and of associated accompanying and/or concomitant diseases involved therewith. The accompanying diseases of obesity or the concomitant diseases thereof which can each be treated with the compounds according to the invention include in particular metabolic syndrome and cardiovascular diseases. The term "metabolic syndrome" usually covers a complex of clinical pictures which mainly comprise hypertension, in particular arterial hypertension, insulin resistance, in particular Type 11 diabetes mellitus, dyslipoproteinaemia, in particular as hypertriglyceridaemia, accompanied by dyslipoproteinaemia occurring lowered HDL-cholesterol [sic], and also hyperuricaemia, which can lead to gout. The term "cardiovascular diseases" in conjunction with obesity is usually understood to mean coronary heart disease, which can lead to heart failure, cerebrovascular diseases, which may for example be accompanied by an increased risk of strokes, and peripheral occlusive arterial disease. Further accompanying and/or concomitant diseases of obesity may be gall bladder diseases such as formation of gallstones, sleep apnoea syndrome, orthopaedic complications such as osteoarthritis and psychosocial disorders. Description of the pharmacological test methods 1. p-nitrophenyl palmitate test The lipase-inhibiting properties of the compounds of Formula I can be demonstrated e.g. by an in vitro activity test. In this test the inhibition of the lipolytic action of porcine pancreatic lipase with respect to the test substrate p-nitrophenyl palmitate(= pNpp) under the influence of the test substances of Formula I was determined. Therein, the change in the relative absorbance of the investigated solutions caused by the lipolytic release of p-nitrophenol from pNpp was measured. The reagents given below were prepared: A. Substrate solution To prepare a "solution A", 45 mg pNpp was dissolved in 15 ml isopropanol by sonication with ultrasound. To prepare a "solution B", 558 mg Na-deoxycholate dry substance and 67.5 mg gum arabic were dissolved in 135 ml 0.05 M sodium phosphate buffer (pH = 8.0). 15 ml "solution A" was injected into 135 ml ice-cold "solution B" in 8 steps of 1.25 ml with an Eppendorf hand dispenser with stirring at 400 rpm at the highest possible rate. The initial absorbance El when determining the blank reading was less than 0.250 U each time. B. Sodium chloride solution 1% (mN) 10 g sodium chloride (NaCl, p.a.) was dissolved in 1000 ml ultrapure water. C. Lipase standard solution (50 FIP units/ml) 120.8 mg lipase standard LS7 in accordance with the rules of the "F6d6ration Internationale Pharmaceutique" (= FIP) (porcine pancreatic lipase, 36,700 FIP units/g) was dissolved in 50 ml ice-cold sodium chloride solution (B) and filtered through a 0.2 pm syringe filter. 20 ml of the filtrate was diluted with 8 ml sodium chloride solution (B) (corresponding to 50 FIP units/ml). D. Lipase calibration solutions (10 - 20 - 30 - 40 FIP units/ml) In each case 2 - 4 - 6 - 8 ml lipase standard solution (C) was made up to 10 ml with sodium chloride solution (B) and stored in an ice bath. E. Lipase stock solution (40 FIP units/ml) 8 ml lipase standard solution was made up to 10 ml with sodium chloride solution (B) and stored in an ice bath. F. Inhibitor solutions The lipase-inhibitory compounds of Formula I were dissolved in DMSO. A dilution series of 100 - 0.1 nmol/ml was produced from this stock solution. 100 pl of these dilutions was used in the test. The dilutions were adapted such that the maximum residual activity of the lipase was > 90%. G. Performance Measurement was effected at 37 0 C, and the absorbances were measured at a wavelength of 405 nm. The photometric measuring station comprised a photometer and an agitator (from Eppendorf). The photometer was adjusted to 0 U with water. At the start and end of the investigation series, in each case eight blank readings and one lipase calibration series were measured. For the blank readings, in each case 1 ml substrate solution was mixed with 100 pl DMSO, the mixture was shaken for 5 seconds and kept at a controlled temperature for 5 minutes. Then 100 pl sodium chloride solution (B) was added thereto by pipette and the mixture was shaken for a further 5 seconds. After 2 minutes, the increase in absorbance was detected for 4 minutes. The absorbance starting value El when determining the blank readings was in each case less than 0.250 U. For the calibration, 1 ml substrate solution was placed in each of eight cuvettes, mixed with 100 pl DMSO, shaken for 5 seconds and kept at a controlled temperature for 5 minutes. The reaction was started with 100 pl calibration solution. After 2 minutes, the kinetics were detected for 4 minutes. Each concentration was measured twice. For measuring the inhibitor solutions, 1 ml substrate solution was placed in each of eight cuvettes, mixed with 100 pi inhibitor solution, shaken for 5 seconds and then kept at a controlled temperature for 5 minutes. The reaction was started with 100 pl lipase stock solution. After 2 minutes, the kinetics were detected for 4 minutes. The inhibitor solutions and the lipase standard solution were each prepared immediately before the start of the investigation series. To calculate the results, the linear equation, the intercept and the coefficient of determination were determined from the calibration data and the blank reading by means of linear regression in accordance with the following equation: y = mx + b x = lipase units FIP units; y = absorbance in A U/min; m = gradient in (A U/min)/U; b = intercept The unknown activity x of a lipase inhibitor solution was calculated from these data in accordance with the following formula: x = (y - b) / m The following formula was used for the enzymatic residual activity [in %]: % = x *100 / 4 FIP units The measure of the inhibitory effectiveness of the substances of Formula I which was determined was their IC 50 value. To this end, the inhibition values in percent measured for the individual compounds of Formula I were converted into concentrations and were converted into IC5o values using the "PRISM-3" software in accordance with the following algorithm: non-linear curve fit, sigmoidal curve with variable gradient; 100% inhibition as maximum value, 0% inhibition as minimum value were added as constants. The IC 50 value of a test substance having enzyme-inhibitory activity is that concentration of the test substance at which the enzyme is still at 50% residual activity under otherwise identical test conditions. In the above pancreatic lipase activity test, the test substances of Formula I listed in Table 1 below exhibited the IC 50 values given below. The example numbers quoted relate to the preparation examples given below. Table 1: Porcine pancreatic lipase-inhibiting action of the test substances in vitro with respect to pNpp Example IC 50 [nM] No. 1 106 2 47 3 88 6 113 7 107 8 187 9 67 10 177 11 28 13 319 2. Olive oil test The lipase-inhibiting properties of the compounds of Formula I can also be demonstrated by a further in vitro activity test. In a heterogeneous reaction, the inhibition of the lipolytic action of porcine pancreatic lipase was determined under the influence of the test substances of Formula I with respect to the triglycerides contained in the test substrate olive oil. The fatty acids released by the lipase were titrated with sodium hydroxide solution to pH 9.0. The reagents given below were prepared: A. Gum arabic solution 10% (mN) 200 g gum arabic (Acaciae gummi in accordance with the specifications of the German Pharmacopeia (= DAB) / European Pharmacopeia (= Ph.Eur.)) was dissolved in 2000 ml ultrapure water with stirring and if necessary centrifugation. The solution was stored at -20*C in plastic vessels of a capacity of 250 ml. The amount required per day was thawed as required.
B. Sodium taurocholate solution 8% (mN) 8 g sodium taurocholate (FIP) was dissolved in 100 ml ultrapure water. C. Buffer solution 60.6 mg tris(hydroxymethyl)aminomethane p.a. (Merck, No. 8382) and 234 mg sodium chloride (p.a.) were dissolved in 100 ml ultrapure water. D. 0.1 N sodium hydroxide solution E. Olive oil emulsion 40 ml olive oil (DAB, room temperature), 330 ml gum arabic solution (A.) and 30 g ice (made from ultrapure water) were emulsified in a suitable mixer for 15 minutes. The emulsion was freshly prepared for the respective day of use. F. Reagent mixture 100 ml sodium taurocholate solution (B.), 400 ml buffer solution (C.) and 450 ml ultrapure water were mixed with stirring. The mixture was prepared freshly each day. 19 ml was required for each measurement. G. Lipase solvent 10.0 g sodium chloride (p.a.), 6.06 g tris(hydroxymethyl)aminomethane (p.a. Merck, No. 8382) and 4.9 g maleic anhydride (p.a.) were dissolved in 900 ml ultrapure water. A pH value of 7.0 was set with 4 N sodium hydroxide solution (p.a.). The solution was made up to 1000.0 ml with ultrapure water. Storage at 5 0 C+/-3 0 C for up to 3 months. H. Inhibitor stock solutions 5 ml of a 0.02 mM stock solution in DMSO was prepared from the inhibitor compounds of Formula I in each case. Then dilutions in a concentration range from 20,000 0.00002 nmol/test were produced from the stock solution. Aliquots of these solutions were used in the test. The dilutions and volumes in the test were adapted such that the maximum residual activity of the lipase was > 90%. 1. Reference suspension (lipase reference standard) Approx. 2500 FIP/Ph.Eur. units lipase reference standard were weighed accurately into a beaker, formed into a paste with some marine sand and a few drops of ice-cold lipase solvent (G.) using a glass rod, and the paste was stirred with 200 ml ice-cold lipase solvent for 15-30 min. in an ice bath. 1 ml of this solution was used in the test. J. Reaction solution 10 ml olive oil emulsion (E.) and 19 ml reagent mixture (F.) were kept at a controlled temperature in a thermostatted reaction vessel at 37.00C +/- 0.1*C. The pH value was pre-adjusted to pH 9.0 with 0.1 mol/l sodium hydroxide solution (D.). K. Lipase inhibitor solution 1 ml lipase reference suspension was incubated with the respective amount of inhibitor solution for 10 minutes in an ice bath. After the incubation period, the lipase inhibitor solution was pipetted into the reaction solution. This started the reaction. The acid released was titrated at 37.0*C +/- 0.50C under pH-stat conditions at pH 9.0 automatically with 0.1 mol/1 sodium hydroxide solution (D.) for at least 5 minutes. The sodium hydroxide consumption between the 1st and the 5th minute was evaluated. The titration was performed twice per inhibitor concentration and the results of both determinations were averaged. Likewise, the titration was carried out without addition of inhibitor solution, in order to determine the activity of the reference suspension. In order to calculate the lipase residual activity in relation to the lipase reference standard in FIP/Ph.Eur units per gramme when using inhibitors, the following equation was used: [(na x mr) / (nr x ma)] x A = lipase units / g n= ml consumption of 0.1 mol/I sodium hydroxide solution / min. upon titration of the lipase inhibitor test suspension nr = ml consumption of 0.1 mol/l sodium hydroxide solution / min. upon titration of the reference suspension m,= weight of the lipase reference standard in the test suspension with inhibitor in mg mr = weight of the lipase reference standard in the reference suspension in mg A = declared activity of the reference standard in the reference suspension in FIP/Ph.Eur units / g standard The result is given in "percent residual activity": Residual activity [%] = lipase-FIP/Ph.Eur units/ g x 100 / desired activity of the reference standard The desired activity of the lipase reference standard according to FIP is 36,700 lipase FIP/Ph.Eur units / g. The measure of the inhibitory effectiveness of the substances of Formula I which was determined corresponding to the manner given above for the pNpp test was their IC5o value. In the above pancreatic lipase activity test, the test substances of Formula I listed in Table 2 below exhibited the IC50 values given below. The example numbers quoted relate to the preparation examples given below. Table 2: Porcine pancreatic lipase-inhibiting action of the test substances in vitro with respect to triglycerides in olive oil Example No. IC 50 [nM] 1 17 15 75 The lipase-inhibiting properties of the compounds of Formula I can also be demonstrated by feeding tests on rats. The compounds of Formula I may be administered in conventional pharmaceutical preparations. The doses to be used may vary individually and will naturally vary according to the type of condition to be treated and the substance used. In general, however, medicinal forms with an active substance content of 10 to 500 mg, in particular 50 to 250 mg, active substance per individual dose are suitable for administration to humans and larger mammals. The compounds may be contained according to the invention, together with conventional pharmaceutical auxiliaries and/or excipients, in solid or liquid pharmaceutical preparations. Examples of solid preparations are preparations which can be administered orally, such as tablets, coated tablets, capsules, powders or granules. These preparations may contain conventional inorganic and/or organic pharmaceutical excipients, such as talcum, lactose or starch, in addition to conventional pharmaceutical auxiliaries, for example lubricants or tablet disintegrating agents. Liquid preparations such as suspensions or emulsions of the active substances may contain the usual diluents such as water, oils and/or suspension agents such as polyethylene glycols and the like. Other auxiliaries may additionally be added, such as preservatives, taste correctives and the like.
The active substances may be mixed and formulated with the pharmaceutical auxiliaries and/or excipients in known manner. For the preparation of solid medicament forms, the active substances may for example be mixed with the auxiliaries and/or excipients in conventional manner and may be wet or dry granulated. The granules or powder may be poured directly into capsules or be pressed into tablet cores in conventional manner. The preparation examples for the preparation of compounds of the general formula I given below are intended to explain the invention further, without limiting its scope. Example 1: trans-(3-hexyl-4-oxo-oxetan-2-yl)-pentyl-(phenoxyphenyl)-carbamate 0 0 H I ji ' A) 18.9 g potassium tert. butylate was added in portions under a nitrogen atmosphere at 0*C to a solution of 41.9 g 1,6-hexanediol in 400 ml dry DMF. After 15 minutes, a solution of 14 ml benzyl bromide in 120 ml dry DMF was added dropwise thereto at 00C. The reaction mixture was stirred for 5 minutes at 0*C and then for 2 hours at room temperature. The precipitate was filtered off and the filtrate was reduced in a vacuum. The residue was taken up in dichloromethane and washed in succession with water and saturated aqueous common salt solution. The organic phase was separated off, dried over sodium sulphate and evaporated in a vacuum. The crude product was flash chromatographed on silica gel with a solvent system consisting of n-hexane/ethyl acetate (= EA) (4:1 v/v), with 19 g oily 6-(benzyloxy)hexan-1-ol being obtained, 'H-NMR (400 MHz, CDC13): ( = 1.33-1.46 (m, 4H), 1.54-1.68 (m, 4H), 3.47 (t, 2H), 3.63 (t, 2H), 4.50 (s, 2H), 7.24-7.37 (m, 5H). B) A solution of 25.1 ml DMSO in 50 ml dry dichloromethane was added dropwise under a nitrogen atmosphere to a solution of 14.8 ml oxalyl chloride in 250 ml dry dichloromethane at -55*C. After three minutes' stirring a solution of 24 g 6-(benzyloxy)hexan-1 -ol in 100 ml dry dichloromethane was slowly added dropwise thereto at this temperature. After 15 minutes, 103 ml triethylamine was added dropwise thereto. Then the reaction mixture was stirred for 10 minutes at -550C and then warmed to room temperature (= RT). It was washed first with water and then with saturated aqueous common salt solution. The organic phase was separated off, dried over sodium sulphate and evaporated in a vacuum. For purification, the crude product was flash chromatographed on silica gel with a solvent system of n-hexane/EA (8:1 v/v), with 15.7 g 6-(benzyloxy)hexanal being obtained, 1 H-NMR (400 MHz, CDCl 3 ): 6 = 1.38-1.46 (m, 2H), 1.59-1.70 (m, 4H), 2.43 (dt, 1H), 3.47 (t, 2H), 4.49 (s, 2H), 7.24-7.36 (m, 5H), 9.76 (t, 1H). C) 104.2 ml of a 1.6-molar solution of butyllithium in n-hexane was added dropwise to a solution of 23.3 ml diisopropylamine in 200 ml THF under a nitrogen atmosphere at -70*C. Once this solution had been warmed to -20*C and had been left for 10 minutes at this temperature, it was again cooled to -700C and 17.5 ml methyl acetate was slowly added dropwise thereto. After 15 minutes' stirring, a solution of 30.16 g 6-(benzyloxy)hexanal in 250 ml THF was added dropwise thereto at this temperature and the mixture was left for 10 minutes at -700C. After slowly warming to -20*C, 150 ml of a saturated ammonium chloride solution was added and the mixture was diluted with ethyl acetate. After separating off the organic phase, the aqueous phase was extracted twice with EA and the combined organic extracts were washed with water and common salt solution. After drying over sodium sulphate, it was reduced in a vacuum and the crude product was flash-chromatographed with a solvent system of n-hexane/EA (9:1 v/v) on silica gel, with 25.6 g 8-benzyloxy-3-hydroxy-octanoic acid-methyl ester being obtained after evaporation in a vacuum, 'H-NMR (400 MHz, DMSO d6): 6 = 1.24-1.40 (m, 6H), 1.53 (m, 2H), 2.29 (dd, J=8.2; 14.7 Hz, 1H), 2.39 (dd, J=4.8; 14.7 Hz, 1H), 3.41 (t, 2H), 3.57 (s, 3H), 3.80 (m, 1H), 4.44 (s, 2H), 4.63 (d, J=5.7 Hz, 1H), 7.24-7.37 (m, 5H). D) 89.4 ml of a 1.6-molar solution of butyllithium in n-hexane was added dropwise to a solution of 14.3 ml diisopropylamine in 100 ml THF under a nitrogen atmosphere at -700C. Once this solution had been warmed to -200 and had been left for 10 minutes at this temperature, it was cooled to -75*C. Then a solution of 18.0 g 8-benzyloxy-3-hydroxy-octanoic acid-methyl ester in 15 ml THF was added slowly thereto and the mixture was warmed to -45*C over 2.5 hours. After cooling again to -70'C, 13.0 ml HMPT in 10 ml THF was added dropwise thereto and the mixture was stirred for 30 minutes. Then 30.4 g n-hexyl iodide was added thereto at -70*C over a period of 30 minutes. This reaction mixture was warmed overnight to 10C. For working-up, it was washed in succession with dilute aqueous potassium hydrogen sulphate solution and three times with water. Then the organic phase was dried over sodium sulphate and evaporated at reduced pressure. This test was repeated with 18.0 g 8-benzyloxy-3-hydroxy octanoic acid-methyl ester. A total of 75 g crude product was obtained, which was flash-chromatographed with a solvent system of n-hexane/EA (9:1 v/v), the composition of which was continuously changed to 3:1, on silica gel. 23.7 g diastereomerically pure 8-benzyloxy-3-hydroxy-octanoic acid methyl ester was obtained. E) 25.33 g 8-benzyloxy-2-hexyl-3-hydroxy-octanoic acid methyl ester was dissolved in 180 ml ethanol and a solution of 5.2 g lithium hydroxide hydrate in 60 ml water was added thereto. This reaction mixture was stirred for 48 hours at RT. Then it was set to pH 6 with aqueous potassium hydrogen sulphate solution and evaporated at reduced pressure. The residue was taken up with EA, and washed in succession with aqueous potassium hydrogen sulphate solution, water and saturated aqueous common salt solution. The organic phase was separated off, dried over sodium sulphate, evaporated in a vacuum and finally dried for 4 hours in an oil pump vacuum. 23.9 g 8-benzyloxy-2-hexyl-3-hydroxy-octanoic acid was obtained, IR: 2928, 2856, 1706, 1454, 1100 cm 1 . F) 23.9 g 8-benzyloxy-2-hexyl-3-hydroxy-octanoic acid was dissolved in 100 ml pyridine under a nitrogen atmosphere and 13.3 g benzenesulphonic acid chloride was added thereto at -20*C. This reaction mixture was left to stand for 18 hours at 4 0 C. Then it was taken up with EA, the organic phase was washed in succession three times with water, dilute aqueous citric acid solution and saturated common salt solution, dried over sodium sulphate and evaporated at reduced pressure. This test was repeated with 5.76 g 8-benzyloxy-2-hexyl-3 hydroxy-octanoic acid. A total of 30 g crude product was obtained which was flash-chromatographed with a solvent system consisting of n-hexane/EA (3:1 v/v) on silica gel, with a total of 21.4 g 4-[5-(benzyloxy)pentyl]-3-hexyl-oxetan-2-one being obtained as pure trans product, IR: 2929, 2857, 1818, 1455, 1117 cm 1 . G) 10.0 g of the product obtained above was dissolved in 200 ml EA and 1.0 g of a 10%-strength Pd/C catalyst was added thereto. Then it was hydrogenated for 4 hours at 2.5 bar hydrogen pressure. Once the catalyst had been filtered off, the organic phase was evaporated in a vacuum and 7.1 g 3-hexyl-4-(5 hydroxypentyl)-oxetan-2-one was obtained as pure trans product, 1 H-NMR (400 MHz, CDC 3 ): 6 = 0.89 (t, 3H), 1.2-1.9 (m, 18H), 3.17 (m, 1H), 3.66 (t, 2H), 4.22 (m, 1H).
H) A solution of 5.5 g 3-hexyl-4-(5-hydroxypentyl)-oxetan-2-one in 25 ml dichloromethane was added dropwise under a nitrogen atmosphere to a solution of 5.8 g 4-phenoxyphenyl isocyanate in 50 ml dichloromethane at 00C and was left for 5 minutes at 0*C. Then it was stirred for 2 hours at RT and 0.4 ml diisopropylethylamine (= "HOnig's base") was additionally added to complete the reaction. After stirring overnight, the reaction mixture was washed first with water, then with saturated aqueous common salt solution. Then the organic phase was dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash-chromatographed on silica gel, with initially pure n-hexane, to which a continuously increasing proportion of EA was added, being used as mobile solvent. After evaporating the product fractions in a vacuum, a solid residue was obtained which was recrystallised from n-hexane/EA. 7.1 g of the title compound was obtained as pure trans product , mp. 63.1-66.3*C; 1 H-NMR (400 MHz, CDC 3 ): 6 = 0.89 (t, 3H), 1.2-1.9 (m, 18H), 3.17 (m, 1H), 4.17 (t, 2H), 4.22 (m, 1H), 6.55 (s, br, 1H), 6.96-7.00 (m, 4H), 7.07 (dt, 1H), 7.28-7.37 (m, 4H). Example 2: cis/trans-5-(3-hexyl-4-oxo-oxetan-2-yl)pentyl-phenyl carbamate 00 A) 16.3 g imidazole was added to a solution of 20.9 g 1,6-hexanediol in 300 ml DMF. A solution of 17.8 g tert. butyldimethylsilyl chloride in 120 ml DMF was added dropwise thereto at RT. Then it was stirred for 20 hours. Water was added thereto and the aqueous phase was extracted several times with EA. The combined organic phases were washed in succession with water and with saturated aqueous common salt solution, dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash-chromatographed with a solvent system consisting of n-hexane/EA (9:1 v/v) on silica gel. 17.4 g 6-{[tert. butyl(dimethyl)silyl]oxy}hexan-1-ol was obtained, 1 H-NMR (400 MHz, CDC 3 ): 6 = 0.05 (s, 6H), 0.89 (s, 9H), 1.37 (m, 4H), 1.55 (m, 4H), 3.61 (t, 2H), 3.64 (t, 2H). B) A solution of 15.9 ml DMSO in 75 ml dry dichloromethane was added dropwise under a nitrogen atmosphere to a solution of 9.4 ml oxalyl chloride in 250 ml dry dichloromethane at -550C. After three minutes' stirring, a solution of 17 g 6-{[tert.
butyl(dimethyl)silyl]oxy}hexan-1-ol in 150 ml dry dichloromethane was slowly added dropwise thereto at this temperature. After 15 minutes, 65.9 ml triethylamine was added dropwise. The reaction mixture was then stirred for 15 minutes at -55*C and then warmed to RT. The organic phase was washed in succession with water and with saturated aqueous common salt solution. The organic phase was separated off, dried over sodium sulphate, filtered off and evaporated in a vacuum. The remaining residue was flash-chromatographed with a solvent system of n-hexane/EA (9:1 v/v) on silica gel, with 14.9 g 6-{[tert. butyl(dimethyl)silyl]oxy}hexanal being obtained, 1 H-NMR (400 MHz, CDCl 3 ): 6 = 0.04 (s, 6H), 0.89 (s, 9H), 1.38 (m, 2H), 1.54 (m, 2H), 1.65 (m, 2H), 2.43 (dd, J=1.8; 7.3 Hz, 1H), 3.61 (t, 2H), 9.77 (t, J=1.8 Hz, 1H). C) 113.4 ml of a 1.6 molar solution of n-butyllithium in n-hexane was added dropwise to a solution of 25.5 ml diisopropylamine in 300 ml THF at -70*C. Once this solution had been warmed to OC and had been left for 10 minutes at this temperature, it was cooled to -50 0 C and a solution of 14.2 ml octanoic acid in 150 ml THF was slowly added dropwise thereto at this temperature. After 15 minutes' stirring at this temperature, it was stirred for 1 hour at room temperature. Then it was cooled to -78 0 C and a solution of 19 g 6-{[tert. butyl(dimethyl)silyl]oxy}hexanal in 150 ml THF was added dropwise thereto such that the temperature did not exceed -60*C. After three hours' stirring at -78*C, it was warmed to room temperature. Then 150 ml of a saturated aqueous ammonium chloride solution was added thereto and the mixture was extracted several times with EA. The combined organic phases were washed in succession with water and saturated aqueous common salt solution, dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash chromatographed with a solvent system consisting of n-hexane/EA (4:1 v/v) on silica gel. Evaporating the product fractions in a vacuum yielded 28.5 g 8-{[tert. butyl(dimethyl)silyl]oxy}-2-hexyl-3-hydroxy-octanoic acid as syn/anti mixture, 1 H-NMR (400 MHz, CDCl 3 ; selected signals): 6 = 0.05 (s, 6H), 0.88 (t, 3H), 0.89 (s, 9H), 2.47 (m, 1H), 3.61 (t, 2H), 3.72 and 3.85 (m, 1H). D) 49 ml pyridine was added at 00C under a nitrogen atmosphere to a solution of 7.6 ml freshly distilled benzenesulphonic acid chloride in 100 ml dichloromethane. Then a solution of 11.1 g 8-{[tert. butyl(dimethyl)silyl]oxy}-2 hexyl-3-hydroxy-octanoic acid in 100 ml dichloromethane was added dropwise thereto at this temperature. This reaction mixture was left for 20 hours at 40C. Then the organic phase was washed in succession with water and saturated aqueous common salt solution, dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash-chromatographed on silica gel, with pure n-hexane, to which a continuously increasing proportion of EA was added, being used as mobile solvent. 4.0 g 4-(5-{{tert. butyl(dimethyl)silyl]oxy}pentyl)-3 hexyl-oxetan-2-one was obtained as trans/cis mixture (7:1), 'H-NMR (400 MHz, CDCl 3 ): 6 = 0.05 (s, 6H), 0.89 (t, 3H), 0.89 (s, 9H), 3.16 (m, 1H), 3.61 (t, 2H), 4.21 (m, 1 H) (selected signals for trans-isomer); 3.60 (m, 1 H), 4.52 (m, 1 H) (selected signals for cis-isomer). E) A solution of 10.97 g tetrabutylammonium fluoride trihydrate in 40 ml THF was added dropwise to a solution of 3.1 g 4-(5-{[tert. butyl(dimethyl)-silyl]oxy}pentyl) 3-hexyl-oxetan-2-one in 40 ml THF under a nitrogen atmosphere at 0*C and stirred first for 1 hour at this temperature and then for 1 hour at RT. Then the reaction mixture was diluted with EA and the organic phase was washed in succession with water and saturated aqueous common salt solution. The organic phase was dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash-chromatographed on silica gel with a solvent system consisting of n-hexane/EA (9:1 v/v). Evaporating the product fractions in a vacuum yielded 1.9 g 3-hexyl-4-(5-hydroxypentyl)-oxetan-2-one as trans/cis mixture (8:1), 1 H-NMR (400 MHz, CDC13): trans: 6 = 3.17 (m, 1H), 4.22 (m, 1H); cis: 6 = 3.6 (m, 1H), 4.53 (m, 1H) (characteristic signals of the protons of B-lactone). F) A solution of 0.3 g 3-hexyl-4-(5-hydroxypentyl)-oxetan-2-one in 5 ml dichloromethane was added dropwise under a nitrogen atmosphere to a solution of 0.45 g phenyl isocyanate in 5 ml dichloromethane at 0*C. Then the solution was stirred for 5 minutes at 0*C and then for 1 hour at RT. For working-up, the organic phase was washed in succession with water and with saturated aqueous common salt solution, dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash-chromatographed on silica gel with a solvent system consisting of n-hexane/EA (9:1 v/v). 0.4 g 5-(3-hexyl-4-oxo-oxetan- 2 yl)pentyl-phenyl carbamate was obtained as trans/cis mixture, 1 H-NMR (400 MHz, CDC13) trans: 6 = 3.17 (m, IH), 4.22 (m, 1H); cis: 6 = 3.60 (m, 1H), 4.53 (m, 1 H) (characteristic signals of the protons of F lactone); IR: 3331, 2931, 2859, 1818, 1732, 1600, 1540 cm 1
.
Example 3: cis/trans-5-(3-hexyl-4-oxo-oxetan-2-yl)pentyl-isopropyl carbamate 0 0 H N0 A) 12.4 ml 3,4-dihydro-2H-pyran and 0.7 g p-toluenesulphonic acid were added under a nitrogen atmosphere to a solution of 22.8 g 1,6-hexanediol in 400 ml THF at 0*C. After stirring for 45 minutes at 0 0 C, it was allowed to warm to RT. Then a further 6.2 ml 3,4-dihydro-2H-pyran was added thereto and stirred for another hour at RT. It was evaporated in a vacuum, the remaining residue was taken up with dichloromethane, the organic phase was washed in succession with saturated aqueous sodium hydrogen carbonate solution, water and saturated common salt solution and dried over sodium sulphate. Evaporation in a vacuum and flash chromatography of the remaining residue on silica gel with a solvent system which initially consisted of n-hexane/EA (9:1 v/v) and was varied by a continuously increased proportion of EA yielded 18.3 g 6-[(tetrahydro-2H pyran-2-yl)oxy]hexan-1-ol, 1 H-NMR (400 MHz, CDC 3 ): 6 = 1.34-1.47 (m, 4H), 1.48-1.65 (m, 8H), 1.71 (m, 1H), 1.83 (m, 1H), 3.40 (dt, J=6.6; 9.6 Hz, 1H), 3.50 (m, 1H), 3.65 (t, J=6.5 Hz, 2H), 3.74 (dt, J=6.8; 9.6 Hz, 1H), 3.87 (m, 1H), 4.57 (dd, J=2.7; 4.2 Hz, 1H). B) A solution of 19.7 ml DMSO in 75 ml dry dichloromethane was added dropwise under a nitrogen atmosphere to a solution of 11.6 ml oxalyl chloride in 250 ml dry dichloromethane at -55*C. After five minutes' stirring, a solution of 18.3 g 6-[(tetrahydro-2H-pyran-2-yl)oxy]hexan-1 -ol in 150 ml dry dichloromethane was slowly added dropwise thereto at this temperature. After 15 minutes, 81.5 ml triethylamine was added dropwise thereto. Then the reaction mixture was stirred for 15 minutes at -55'C and then thawed to RT. The organic phase was washed first with water and then with saturated aqueous common salt solution, was separated from the aqueous phase and was dried over sodium sulphate. The drying agent was filtered off, the mixture was evaporated in a vacuum and the remaining residue was flash-chromatographed on silica gel with a solvent system consisting of n-hexane/EA (9:1 v/v), the content of EA of which was continuously increased. 14.1 g 6-[(tetrahydro-2H-pyran-2-yl)oxy]hexanal was obtained, 'H-NMR (400 MHz, CDCl 3 ): 6 = 1.37-1.47 (m, 2H), 1.48-1.75 (m, 9H), 1.77-1.89 (m, 1H), 2.44 (dt, J=1.8; 7.3 Hz, 2H), 3.39 (dt, J=6.4; 9.7 Hz, 1H), 3.50 (m, 1H), 3.74 (dt, J=6.7; 9.7 Hz, 1H), 3.86 (m, 1H), 4.56 (dd, J=2.8; 4.4 Hz, 1H), 9.77 (t, 1.8 Hz, 1H). C) 96.1 ml of a 1.6 molar solution of n-butyllithium in n-hexane was added dropwise to a solution of 21.6 ml diisopropylamine in 250 ml THF under a nitrogen atmosphere at -70'C. Once this solution had been warmed to 0*C and had been left at this temperature for 10 minutes, it was cooled to -50'C and a solution of 12.1 ml octanoic acid in 125 ml THF was slowly added dropwise at this temperature. After 15 minutes' stirring at this temperature, it was stirred for 1 hour at RT. Then it was cooled to -78 0 C and a solution of 14 g 6-[(tetrahydro-2H pyran-2-yl)oxy]hexanal in 125 ml THF was added dropwise thereto. After three hours' stirring at -780C, it was warmed to RT. Then 150 ml of a saturated aqueous ammonium chloride solution was added thereto and the mixture was extracted several times with EA. The combined organic phases were washed in succession with water and with saturated aqueous common salt solution, dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash-chromatographed on silica gel with a solvent system consisting of n-hexane/EA (4:1 v/v), the proportion of EA being continuously increased. Evaporating the product fractions in a vacuum yielded 16.2 g 2-hexyl-3-hydroxy 8-[(tetrahydro-2H-pyran-2-yl)oxy]octanoic acid as syn/anti mixture, 'H-NMR (400 MHz, CDC13): 6 = 0.88 (m, 3H), 1.25-1.89 (m, 25H), 2.47 (m, 1 H), 3.40 (dt, 1 H), 3.51 (m, 1H), 3.73 (m, 1H), 3.86 (m, 1H), 4.57 (m, 1H). D) 50 ml pyridine was added under a nitrogen atmosphere to a solution of 12 ml freshly distilled benzenesulphonic acid chloride in 150 ml dichloromethane at 00C. Then a solution of 16.2 g 2-hexyl-3-hydroxy-8-[(tetrahydro-2H-pyran-2 yl)oxy]octanoic acid in 100 ml dichloromethane was added dropwise thereto at this temperature. This reaction mixture was left for 20 hours at 4*C. Then the organic phase was washed in succession with water and saturated aqueous common salt solution, dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash-chromatographed on silica gel, with pure n-hexane, to which a continuously increasing proportion of EA (up to 8:2 v/v) had been added, being used as mobile solvent. 10.0 g 3-hexyl-4-{5[(tetrahydro-2H pyran-2-yl)oxy]pentyl}oxetan-2-one was obtained as diastereomer mixture (2:1), 'H-NMR (400 MHz, CDC1 3 ) trans: 6 = 3.16 (m, 1H), 4.21 (m, 1H); cis: 6 = 3.59 (m, 1 H), 4.53 (m, 1 H) (characteristic signals of the protons of B-lactone), IR: 1822, 1465, 1077 cm- 1 E) 1.89 g 3-hexyl-4-{5[(tetra hyd ro-2H-pyran-2-yl)oxy]pentyl}oxetan-2-one was dissolved in 58 ml ethanol and 1.46 g pyridinium-p-toluenesulphonate was added thereto. It was stirred for 4 hours at 50 0 C and then a further 1.46 g pyridinium-p toluenesulphonate was added thereto. This reaction mixture was stirred for 1 hour at 50*C and then for 20 hours at RT. The precipitate was filtered off, the filtrate was evaporated in a vacuum and the remaining residue was flash chromatographed on silica gel with a solvent system consisting of n-hexane/EA (9:1 v/v), the proportion of EA of which was continuously increased. Evaporation of the product fractions yielded 1.0 g cis/trans-3-hexyl-4-(5-hydroxypentyl) oxetan-2-one, which was used without further purification directly for the next reaction. F) A solution of 0.3 g 3-hexyl-4-(5-hydroxypentyl)-oxetan-2-one in 5 ml dichloromethane was added dropwise under a nitrogen atmosphere to a solution of 0.4 g isopropyl isocyanate in 5 ml dichloromethane at 0*C. Then the solution was stirred for 5 minutes at 0 0 C and then for 1 hour at RT. 0.2 ml diisopropylethylamine was added thereto and the mixture was stirred for a further 2 hours at 50 0 C. It was washed with water and saturated aqueous common salt solution, dried over sodium sulphate and was evaporated in a vacuum. The remaining residue was flash-chromatographed with a solvent system of n-hexane/EA (9:1 v/v), the proportion of EE of which was continuously increased to 100%, on silica gel. 0.1 g 5-(3-hexyl-4-oxo-oxetan-2-yl)pentyl-isopropy carbamate was obtained as trans/cis mixture (2:1), 1 H-NMR (400 MHz, CDCl 3 ): trans: 6 = 3.16 (m, 1H), 4.21 (m, 1H); cis: 6 = 3.60 (m, 1H), 4.52 (m, 1H) (characteristic signals of the protons of B-lactone); IR: 3321, 2930, 1813, 1687, 1538, 1468 cm'. Example 4: trans-5-(3-hexyl-4-oxo-oxetan-2-yl)-butyl-benzyl carbamate 0 0 0 H A) 94.0 ml triethylamine was added to 50.0 g 2-mercaptopyridine, dissolved in 1 I dichloromethane, at 0 0 C under a nitrogen atmosphere. 73.2 g octanoyl chloride in 200 ml dichloromethane was added thereto within 10 minutes. After removal of the cooling, it was stirred for 90 minutes at RT and then 600 ml water was added thereto. Once the organic phase had been separated off, the aqueous phase was extracted three times with 200 ml dichloromethane each time. The combined organic phases were dried over magnesium sulphate and then evaporated in a vacuum. The remaining residue was flash-chromatographed on silica gel with n-pentane/diethyl ether (1:1 v/v). 101.6 g thiooctanoic acid-S pyridin-2-yi ester was obtained, 'H-NMR (400 MHz, CDC 3 ): 6 = 0.88 (t, J=6.9 Hz, 3H), 1.23-1.40 (m, 8H), 1.69-1.76 (m, 2H), 2.70 (t, J=7.5 Hz, 2H), 7.28 (ddd, J=7.5; 4.8; 1.1 Hz, 1H), 7.61 (dt, J=0.8; 7.8 Hz, 1H), 7.73 (dt, J=1.9; 7.7 Hz, 1H), 8.62 (ddd, J= 4.8; 1.8; 0.7 Hz, 1 H). B) 97.6 ml of a lithium hexamethyl disilazide solution (1 M in THF) in 420 ml THF was cooled to -10OC under a nitrogen atmosphere, 12.6 ml DMF and 22.7 ml triethylamine were added thereto in succession and the mixture was stirred for 10 minutes. Then 24.5 g triethylsilyl chloride in 50 ml THF was added thereto and the reaction mixture was cooled to -78*C. Then 19.3 g thiooctanoic acid-S pyridin-2-yl ester in 50 ml THF was slowly added dropwise thereto and the mixture was stirred for 1 hour at -780C. After removal of the cooling, the reaction mixture was warmed to 10*C within one hour and 800 ml water was added thereto. After multiple extractions with diethyl ether, the organic phase was dried over magnesium sulphate and evaporated in a vacuum. The remaining residue was quickly flash-chromatographed on silica gel with a solvent system consisting of n-pentane/diethyl ether (9:1 v/v). Evaporating the product fractions yielded 25.6 g 2-({(1 E)-1 -[(triethylsilyl)oxy]oct-1 -en-1 -yl}thio)pyridine, 1 H-NMR (400 MHz, CDCl 3 ): 6 = 0.60-0.69 (m, 6H), 0.84-0.91 (m, 12H), 1.24-1.43 (m, 8H), 2.18 (q, J=7.2 Hz, 2H), 5.38 (t, J=7.3 Hz, 1H), 6.99 (ddd, J=7.4; 4.9; 1.0 Hz, 1H), 7.34 (dt, J=1.0; 8.1 Hz, 1 H), 7.54 (ddd, J=8.1; 7.4; 1.9; Hz, 1 H), 8.42 (ddd, J= 4.9; 1.9; 0.9 Hz, 1H). C) 37.9 g 5-{[tert. butyl(dimethyl)silyl]oxy}pentanal (for preparation see Example 2B)) was added to a suspension of 34.0 g anhydrous zinc chloride in 800 ml dichloromethane at RT and under a nitrogen atmosphere and the mixture was stirred for 15 minutes. Then 55.9 g 2-({(1 E)-1 -[(triethylsilyl)oxy]oct-1 -en-1 yl}thio)pyridine was added thereto and the reaction mixture was stirred for 40 hours at RT. Then saturated aqueous sodium hydrogen carbonate solution was added thereto, the phases were separated and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulphate and evaporated in a vacuum to a volume of approx. 500 ml. 47.7 g copper dibromide was added to this solution and it was stirred for 90 minutes at RT. Then the resulting suspension was filtered over silica gel, rinsing being performed with dichloromethane. Evaporation in a vacuum and flash chromatography of the remaining residue on silica gel with a solvent system consisting of n-pentane/diethyl ether (33:1 v/v) yielded 17.8 g 4-(5-{[tert. butyl(dimethyl)silyl]oxy}butyl)-3-hexyl-oxetan-2-one as pure trans product, 1 H-NMR (400 MHz, CDC 3 ): 6 = 0.04 (s, 6H), 0.85-0.90 (m, 12H), 1.22 1.92 (m, 16H), 3.16 (ddd, J=8.8; 6.5; 3.9 Hz, 1H), 4.21 (ddd, J=7.2; 6.1; 4.0 Hz, 1 H). D) 17.8 g of the compound obtained above was dissolved in 200 ml THF in a PET vessel, 10 ml HF/pyridine complex was added thereto and the mixture was then stirred overnight at RT. Then the reaction mixture was filtered over silica gel and rinsed with diethyl ether. The solvent was evaporated in a vacuum and the remaining residue was flash-chromatographed with a solvent system consisting of n-pentane/diethyl ether (1:1 v/v) on silica gel. Drying the product fractions yielded 10.6 g 3-hexyl-4-(5-hydroxybutyl)-oxetan-2-one as pure trans product, 'H-NMR (400 MHz, CDCl 3 ): 6 = 0.89 (t, J=6.3 Hz, 3H), 1.29-1.93 (m, 16H), 2.14 (s br, 1H), 3.19 (ddd, J=8.6; 6.6; 3.9 Hz, 1H), 3.65 (t, J=6.3 Hz, 2H), 4.24 (ddd, J=7.4; 5.6; 4.0 Hz, 1H). E) A solution of 0.3 g 3-hexyl-4-(5-hydroxybutyl)-oxetan-2-one in 5 ml dichloromethane was added dropwise to a solution of 0.26 g benzyl isocyanate in 5 ml dichloromethane under a nitrogen atmosphere at 0*C. The mixture was then stirred for 10 minutes at 0*C and then for 20 hours at RT. The organic phase was washed in succession with water and saturated aqueous common salt solution, dried over sodium sulphate and was evaporated in a vacuum. The remaining residue was flash-chromatographed with a solvent system consisting of n-hexane/EA (3:2 v/v) on silica gel and the combined product fractions were then recrystallised from a mixture of n-hexane/EA. 0.4 g of the title compound was obtained as a pure trans product, m.p. 50.9-52.50C; 1 H-NMR (400 MHz, CDC1 3 ): 6 = 0.89 (t, 3H), 3.17 (m, 1H), 4.12 (t, 2H), 4.20 (m, 1H), 4.36 (d, 2H), 4.94 (s br, 1H), 7.23-7.37 (m, 5).
Example 5 trans-5-(3-benzyl-4-oxo-oxetan-2-yl)pentyl-(4-acetyl phenyl)carbamate 0 0 N Y 0 -,- 0 0 A) 13.7 ml of a 1.6 M n-butyllithium solution in n-hexane was added dropwise to a solution of 2.2 g diisopropylamine in 15 ml THF at -60*C. It was allowed to thaw to -40 0 C for 30 minutes and was then cooled to -75 0 C. A solution of 2.8 g 8-benzyloxy-3-hydroxy-octanoic acid-methyl ester (for preparation see Example 1 C)) was added dropwise to this reaction mixture slowly and then was stirred at -55 0 C for 3 hours. It was cooled to -75*C, 2 ml HMPT was added and the mixture was stirred again for 30 minutes. Then 3.42 g benzyl bromide, dissolved in 3 ml THF, was slowly added dropwise and the mixture was warmed to RT over a period of 20 hours. It was taken up with EA and the organic phase was washed in succession with water, aqueous potassium hydrogen sulphate solution and once again water, and then dried over sodium sulphate. The remaining residue was flash-chromatographed with a mixture of n-hexane/EA (9:1 v/v, changed continuously to 3:1 v/v), on silica gel. Drying of the product fractions yielded 2.7 g diastereomerically pure 2-benzyl-8-(benzyloxy)-3-hydroxy-octanoic acid methyl ester, 1 H-NMR (200 MHz, CDC13): 6 = 1.2-1.7 (m, 8H), 2,57 (d, 1H), 2.72 (ddd, 1H), 2.90-3.10 (m, 2H), 3.45 (t, 2H), 3.61 (s, 3H), 4.49 (s, 2H). B) A solution of 1.83 g lithium hydroxide in 30 ml water was added to a solution of 10.8 g 2-benzyl-8-(benzyloxy)-3-hydroxy-octanoic acid methyl ester in 90 ml ethanol. Once this reaction mixture had been stirred for 18 hours at RT, 1 M citric acid was added thereto and excess solvent was evaporated in a vacuum. The remaining residue was taken up in EA, the organic phase was washed in succession with aqueous potassium hydrogen sulphate solution and water and finally dried over sodium sulphate. Evaporating in a vacuum yielded a solid residue which was recrystallised from n-hexane/EA (1:1 v/v). 9.31 g diastereomerically pure 2-benzyl-8-(benzyloxy)-3-hydroxy-octanoic acid was obtained, mp. 66-67OC; IR: 3233, 2932, 2849, 1706, 1454, 1125 cm 1 . C) 9.31 g 2-benzyl-8-(benzyloxy)-3-hydroxy-octanoic acid was dissolved in 52 ml pyridine under a nitrogen atmosphere and 5.1 g benzenesulphonic acid chloride was added thereto at -20*C. Then it was stirred for 2 hours at 00C and then for 48 hours at 4*C. The reaction mixture was diluted with diethyl ether, was washed in succession three times with water and once each with 1 M citric acid and water and the organic phase was dried over sodium sulphate. The solvent was evaporated in a vacuum and the remaining residue was then flash chromatographed on silica gel with a solvent system consisting of n-hexane/EA (initially 9:1 v/v, then continuously changing to 3:1 v/v). Drying the product fractions yielded 7.2 g trans-3-benzyl-4-[5-(benzyloxy)pentyl]oxetan-2-one, IR: 2933, 2858, 1816, 1454, 1114 cm 1 . D) 7.1 g of the product obtained above was dissolved in 200 ml EA and 0.7 g of a 10%-strength Pd/C catalyst was added thereto. Then it was hydrogenated for 5 hours at 2.5 bar hydrogen pressure. After filtering off the catalyst, it was evaporated in a vacuum. 4.9 g 3-benzyl-4-(5-hydroxypentyl)oxetan-2-one was obtained, 1 H-NMR (400 MHz, CDCl 3 ): 6 = 1.08-1.34 (m, 5H), 1.47 (m, 2H), 1.62 (m, 1H), 1.80 (m, 1H), 3.00 (dd, J=9.4; 14.3 Hz, 1H), 3.18 (dd, J=5.7; 14.3 Hz, 1H), 3.46 (m, 1H), 3.58 (t, 2H), 4.28 (m, 1H), 7.19 (m, 2H), 7.26 (m, 1H), 7.32 (m, 2H). E) A solution of 0.3 g 3-benzyl-4-(5-hydroxypentyl)-oxetan-2-one in 5 ml dichloromethane was added under a nitrogen atmosphere to a solution of 0.29 g 4-acetylphenyl isocyanate in 10 ml dichloromethane at 00C. It was then stirred for 30 minutes at 0*C and then for 2 hours at RT. 0.21 ml of diisopropyl ethylamine was added and the mixture was stirred for 2 days at RT. Then it was taken up with dichloromethane, the organic phase was washed in succession with water and saturated aqueous common salt solution, dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash chromatographed on silica gel with a solvent system consisting of n-hexane/EA (3:2 v/v). Drying of the product fractions yielded 0.4 g of the title compound, m.p. 104-106OC; 1 H-NMR (400 MHz, CDC 3 ): 6 = 1.1-1.4 (m, 4H), 1.54-1.68 (m, 3H), 1.80 (m, 1H), 2.56 (s, 3H), 3.00 (dd, J=9.5; 14.3 Hz, 1H), 3.18 (dd, J=5.7; 14.3 Hz, 1H), 3.47 (m, 1H), 4.12 (t, 2H), 4.28 (m, 1H), 6.84 (s br, 1H), 7.19 ("d", 2H), 7.25 (m, 1H), 7.32 ("t", 2H), 7.48 (d, 2H), 7.93 ("d", 2H).
Example 6: (2S, 3S)-5-(3-hexyl-4-oxo-oxetan-2-yl)-pentyl-(4-phenoxyphenyl)-carbamate 0 0 Z 11 0 A) First 14.9 g pyridinium chlorochromate and then some Celite@ was added to a solution of 17.7 g 8-benzyloxy-3-hydroxy-octanoic acid methyl ester (for preparation see Example 1C)) in 350 ml dichloromethane. It was stirred overnight at RT, a further 15.0 g pyridinium chlorochromate was added and the mixture was heated to boiling for 10 minutes under reflux cooling. Then it was again stirred overnight at RT, then 400 ml diethyl ether was added and it was filtered over Celite@. The filtrate was evaporated in a vacuum and the remaining residue was flash-chromatographed with a solvent system consisting of n-heptane/EA (2:1 v/v) on silica gel. Drying the product fractions yielded 13.0 g 8-benzyloxy-3-oxo-octanoic acid methyl ester. B) 0.106 g benzene ruthenium(lI) chloride dimer was added under an argon atmosphere to 0.26 g (S)-(-)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl. 8 ml DMF, which had previously been purified by freezing and thawing three times, was added thereto. The resulting reaction mixture was heated for 15 minutes to 1150C and after cooling to RT was evaporated in a vacuum at 65 0 C. A solution of 13 g 8-benzyloxy-3-oxo-octanoic acid methyl ester in 35 ml methanol was added to the remaining brown solids and the reaction solution was then transferred into an autoclave using a syringe. The solution was hydrogenated at 700C for 6 hours at a hydrogen pressure of 4.2 bar, then evaporated in a vacuum and the remaining residue was flash-chromatographed with a solvent system consisting of n-heptane/EA (2:1 v/v) on silica gel. Drying the product fractions yielded 10.7 g (S)-8-benzyloxy-3-hydroxy-octanoic acid methyl ester as a slightly yellowish oil. The enantiomeric purity was determined using a Chiralpak AD-H column from Daicel. A solvent system consisting of n-heptane/isopropanol (9:1 v/v) was used as mobile phase; the flow rate was 1 ml/min. Under these conditions, a retention time of 32.297 minutes was measured. C) 48 ml of a 1.6 molar solution of n-butyllithium in n-hexane was added dropwise to a solution of 7.7 g diisopropylamine in 60 ml THF at -60*C. It was allowed to thaw to -40 0 C for 30 minutes and was then cooled to -78 0 C. A solution of 9.8 g (S)-8-benzyloxy-3-hydroxy-octanoic acid methyl ester in 10 ml THF was slowly added dropwise to the resulting reaction mixture and the mixture was warmed to -400C for 3 hours. Then it was cooled again to -75*C and first 8 ml DMPH, dissolved in 8 ml THF, and then 14.8 g n-hexyl iodide were added dropwise thereto. The resulting reaction mixture was left to thaw to RT overnight, diluted with EA and the organic phase was washed in succession with water, dilute aqueous potassium hydrogen sulphate solution and saturated aqueous common salt solution. The organic phase was dried over sodium sulphate, evaporated in a vacuum and the remaining residue was flash-chromatographed on silica gel with a solvent system consisting of n-hexane/EA (9:1 v/v), to which EA was added gradually up to a composition of 3:1 (v/v). Drying the product fractions yielded 4.0 g (S,S)-8-benzyloxy-2-hexyl-3-hydroxy-octanoic acid methyl ester, [a]D = -12.60* (c = 25.7 mg in 2 ml methanol); IR: 2928, 2856, 1733, 1454,1164, 1100 cm~ 1 . D) 5.5 g (S,S)-8-benzyloxy-2-hexyl-3-hydroxy-octanoic acid methyl ester was dissolved in 40 ml ethanol, 0.97 g lithium hydroxide hydrate in 13 ml water was added thereto and the mixture was stirred for 24 hours at RT. Then dilute aqueous potassium hydrogen sulphate solution was added thereto and excess solvent was evaporated in a vacuum. It was taken up with EA, the organic phase was washed in succession with dilute aqueous potassium hydrogen sulphate solution and water, it was separated off from the aqueous phase and dried over sodium sulphate. After evaporating in a vacuum and drying in an oil pump vacuum, 5.4 g (S,S)-8-benzyloxy-2-hexyl-3-hydroxyoctanoic acid was obtained as a slightly yellowish oil, which was used without further purification for the next reaction, [a]D = -14.23* (c = 21.5 mg in 2 ml methanol); IR: 2928, 2856, 1706, 1454, 1100 cm~ 1 . E) 5.4 g (S,S)-8-benzyloxy-2-hexyl-3-hydroxy-octanoic acid was dissolved in 30 ml pyridine and 2.99 g benzenesulphonic acid chloride was added thereto at -20*C. The mixture was warmed to OC within 2 hours and then left for 48 hours at 40C. It was diluted with diethyl ether and the organic phase was washed in succession three times with ice-cold water, 0.5 M citric acid and saturated aqueous common salt solution. The organic phase was dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash-chromatographed with a solvent system consisting of n-hexane/EA (initially 9:1 v/v, then continuously changing to 3:1 v/v), on silica gel. Drying the product fractions yielded 2.6 g (S,S)-4-[5 (benzyloxy)pentyl]-3-hexyl-oxetan-2-one, [C]D = -23.21o (c = 16.6 mg in 2 ml chloroform), IR: 2929, 2857, 1818, 1455, 1117 cm- 1
.
F) 2.5 g (S,S)-4-[5-(benzyloxy)pentyl]-3-hexyl-oxetan-2-one was dissolved in 100 ml EA and 0.25 g of a 10%-strength Pd/C catalyst was added thereto. Then it was hydrogenated at a hydrogen pressure of 2.5 bar for 5 hours. The catalyst was filtered off, excess solvent was evaporated in a vacuum and it was then dried in an oil pump vacuum. 1.86 g (S,S)-4-[5-hydroxypentyl]-3-hexyl-oxetan-2-one was obtained as oil, [a]D = -37.5 (c = 1 in EA). G) A solution of 0.6 g (S,S)-4-[5-hydroxypentyl]-3-hexyl-oxetan-2-one in 10 ml dichloromethane was added dropwise to a solution of 0.78 g 4-phenoxyphenyl isocyanate in 10 ml dichloromethane at 00C under a nitrogen atmosphere. The mixture was then stirred for 15 minutes at 00C and then for 2 hours at RT. 0.43 ml diisopropylethylamine was added and the mixture was stirred for 2 days at RT. Then it was taken up with dichloromethane, the organic phase was washed in succession with water and saturated aqueous common salt solution, dried over sodium sulphate and evaporated in a vacuum. The remaining residue was flash-chromatographed with a solvent system consisting of n-hexane/EA (4:1 v/v) on silica gel. Drying of the product fractions yielded 0.74 g of the title compound, m.p. 73-74OC; [a]D = -21.50 (c = 1 in EA); 'H-NMR (400 MHz, CDCl 3 ): 6 = 0.89 (t, 3H), 1.2-1.9 (m, 18H), 3.18 (m, 1H), 4.17 (t, 2H), 4.22 (m, 1H), 6.55 (s, br, 1H), 6.96-7.00 (m, 4H), 7.07 ("t", 1H), 7.28-7.37 (m, 4H). The compounds of Formula I listed in Table 3 below can also be prepared according to the processes described in the examples above or according to processes analogous thereto: Table 3: Further compounds of Formula I Ex. R 1 R 2 n trans: No. cis 7 phenyl n-hexyl 3 cis 8 benzyl n-hexyl 5 3: 1 9 4-ethoxyphenyl n-hexyl 5 3: 1 10 benzoyl n-hexyl 5 3: 1 11 phenylethyl n-hexyl 5 6: 1 12 n-butyl n-hexyl 5 2: 1 13 3,4-dichlorophenyl n-hexyl 5 12: 1 14 4-fluorophenyl n-hexyl 5 3.5: 1 15 4-phenoxyphenyl n-hexyl 4 trans 16 2-isopropylphenyl n-hexyl 4 trans 17 2-nitrophenyl n-hexyl 4 trans 18 4-benzylphenyl n-hexyl 4 trans 19 2-ethyloxycarbonylphenyl benzyl 5 trans 20 octadecanyl n-hexyl 4 trans 21 2-trifluoromethylphenyl n-hexyl 4 trans 22 4-heptyloxyphenyl n-hexyl 4 trans 23 2,5-dimethoxyphenyl -benzyl 5 trans All the compounds listed in Table 3 are racemic.
34 EXAMPLE I Capsules containing trans-(3-hexyl-4-oxo-oxetan-2-yl)-pentyl-(4-phenoxyphenyl) carbamate: 5 Capsules with the following composition per capsule were produced: trans-(3-hexyl-4-oxo-oxeta n-2-yl)-pentyt-(4- phe noxyp h enyl)-carba mate 20 mg Corn starch 60 mg Lactose 300 mg EA q.s. 10 The active substance, the corn starch and the lactose were processed into a homogeneous pasty mixture using EA. The paste was ground and the resulting granules were placed on a suitable tray and dried at 45"C in order to remove the solvent, The dried granules were passed through a crusher and mixed in a mixer 15 with the further following auxiliaries: Talcum 5 mg Magnesium stearate 5mg Corn starch 9 mg and then poured into 400 mg capsules (= capsule size 0). 20 The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention 25 may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.
Claims (10)
1. A compound corresponding to formula I 0 R1 -- N 0- (CH 2 )n R2 H 5 wherein R 1 is C-1 8 -alkyl, one or two alkyl-chain carbon atoms of which are optionally replaced by oxygen or sulphur; phenyl-Co- 1 -alkyl the phenyl group of which is optionally substituted one or two times by halogen, trifluoromethyl, nitro, C1- 8 alkyl, C1-i-alkoxy, C 1 . 6 -alkylcarbonyl, C-alkoxycarbonyl, phenyl, benzyl or 10 phenoxy, and one or two alkyl-chain carbon atoms of which are optionally replaced by oxygen or sulphur; C3. 7 -cycloalkyl-Co- 15 -alky, one or two alkyl chain carbon atoms of which are optionally replaced by oxygen or sulphur, or benzoyl; R 2 is C 1 - 12 -alkyl one or two alkyl-chain carbon atoms of which are optionally 15 replaced by oxygen or sulphur; phenyl-C 1 - 1 8 -alkyl, the phenyl group of which is optionally substituted once or twice by halogen, C 4 -alkyl, Cw- 4 -alkoxy, benzyl or phenoxy, and one or two alkyl-chain carbon atoms of which are optionally replaced by oxygen or sulphur; or C3-7-cycloalkyl-Co. 1 8 -alkyl, one or two alkyl-chain carbon atoms of which are optionally replaced by oxygen or 20 sulphur; and n is a whole number from 2 to 8.
2. A compound according to claim 1, wherein R 1 is phenyl-CO 2 -alkyl, the phenyl group of which is optionally substituted by C 1 1 4 -alkyl, C 1 4 -alkoxy or phenoxy.
3. A compound according to claim 1, wherein R 2 is C 2 - 6 -alkyl, the alkyl-chain 25 carbon atoms of which are optionally replaced 1 or 2 times by at least one of oxygen and sulphur.
4. A compound according to claim 1, wherein n is a whole number from 2 to 5. 36
5. A compound according to claim 1, selected from the group consisting of: 5-(3-hexyl4-oxo-oxetan-2-yl)-pentyl-(ph enoxyphenyl)-carbam ate and 4-(3-hexyl4-oxo-oxetan-2-yl)-butyl-(ph enoxyphenyl)-carbam ate.
6. A compound according to claim 1, wherein the substituents of the carbon in 5 the 2-position of the lactone ring and the substituents of the carbon in the 3-position of the lactone ring adopt the trans position relative to one another.
7. A composition of matter comprising a pharmacologically effective amount of a compound according to claim 1 and at lest one pharmaceutical carrier, auxiliary or excipient. 10
8. A method of treating or inhibiting obesity or an obesity-associated condition selected from the group consisting of metabolic syndromes and cardiovascular diseases in a patient in need thereof, said method comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1.
9. A method according to claim 8, wherein a metabolic syndrome selected from 15 the group consisting of hypertension, insulin resistance, Type 11 diabetes mellitus, dyslipoproteinaemia and hyperuricaemia, or a cardiovascular disease selected from the group consisting of coronary heart disease, cerebrovascular disease and peripheral occlusive arterial disease, is treated.
10. A process for the preparation of a compound corresponding to formula 1, 20 0 0 23 3I RI - 1 - 0- (CH 2 )n R2 H wherein R1 is CI- 1 8 -alkyl, the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur; phenyl-Co 18 -alkyl, the phenyl group of which 25 is optionally substituted 1-2 times by halogen, trifluoromethyl, nitro, C 1 8 -alkyl, C 18 -alkoxy, C-1 6 -alkylcarbonyl, C 6 -alkoxycarbonyl, phenyl, benzyl and/or 37 phenoxy and the alkyl-chain carbon atoms of which are optionally replaced 1 2 times by oxygen and/or sulphur; C 3 - 7 -cycloalkyl-Co18-alkyl, the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur, or benzoyl; 5 R 2 is C 1 - 12 -alkyl, the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur; phenyl-C 1 -1 8 -alkyl, the phenyl group of which is optionally substituted 1-2 times by halogen, C 1 . 4 -alkyl, C 1 4 -alkoxy, benzyl and/or phenoxy and the alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur; or C 3 -7-cycloalkyl-Co- 1 8 -alkyl, the 10 alkyl-chain carbon atoms of which are optionally replaced 1-2 times by oxygen and/or sulphur; and n is a whole number from 2 to 8; said method comprising reacting a compound corresponding to formula II, O II HO- (CH 2 )n R2 15 wherein R 2 and n have the above meanings, with a compound corresponding to formula ill, R 1 -N=C=O iII wherein R 1 has the above meaning. 20 SOLVAY PHARMACEUTICALS GMBH 25 WATERMARK PATENT AND TRADE MARKS ATTORNEYS P27636AU00
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