MX2007007578A - Fused pyrazole derivatives and uses thereof in methods of treatment of metabolic-related?disorders - Google Patents
Fused pyrazole derivatives and uses thereof in methods of treatment of metabolic-related?disordersInfo
- Publication number
- MX2007007578A MX2007007578A MXMX/A/2007/007578A MX2007007578A MX2007007578A MX 2007007578 A MX2007007578 A MX 2007007578A MX 2007007578 A MX2007007578 A MX 2007007578A MX 2007007578 A MX2007007578 A MX 2007007578A
- Authority
- MX
- Mexico
- Prior art keywords
- tetrahydro
- diaza
- pentalene
- cyclopropa
- compound according
- Prior art date
Links
- 201000010099 disease Diseases 0.000 title claims abstract description 95
- 150000003217 pyrazoles Chemical class 0.000 title claims abstract description 9
- 230000002503 metabolic Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 586
- 239000000203 mixture Substances 0.000 claims abstract description 121
- 239000011780 sodium chloride Substances 0.000 claims abstract description 77
- 150000003839 salts Chemical class 0.000 claims abstract description 68
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 56
- 239000003112 inhibitor Substances 0.000 claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 39
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 34
- 201000001320 atherosclerosis Diseases 0.000 claims abstract description 33
- 206010022489 Insulin resistance Diseases 0.000 claims abstract description 27
- YYGNTYWPHWGJRM-RUSDCZJESA-N Squalene Natural products C(=C\CC/C(=C\CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)/C)(\CC/C=C(\C)/C)/C YYGNTYWPHWGJRM-RUSDCZJESA-N 0.000 claims abstract description 24
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 claims abstract description 23
- 206010058108 Dyslipidaemia Diseases 0.000 claims abstract description 22
- 206010061227 Lipid metabolism disease Diseases 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- 208000004981 Coronary Disease Diseases 0.000 claims abstract description 19
- 201000008739 coronary artery disease Diseases 0.000 claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 18
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 17
- 230000002194 synthesizing Effects 0.000 claims abstract description 16
- 239000003623 enhancer Substances 0.000 claims abstract description 15
- 230000002708 enhancing Effects 0.000 claims abstract description 15
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 15
- 229940031439 Squalene Drugs 0.000 claims abstract description 12
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims abstract description 10
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims abstract description 10
- 229940058933 biguanide antimalarials Drugs 0.000 claims abstract description 9
- 229940090145 biguanide blood glucose lower drugs Drugs 0.000 claims abstract description 9
- 150000004283 biguanides Chemical class 0.000 claims abstract description 9
- 230000015556 catabolic process Effects 0.000 claims abstract description 8
- 230000003914 insulin secretion Effects 0.000 claims abstract description 8
- 230000035569 catabolism Effects 0.000 claims abstract description 7
- 230000000144 pharmacologic effect Effects 0.000 claims abstract description 7
- 239000003288 aldose reductase inhibitor Substances 0.000 claims abstract description 6
- 229940096700 plain lipid modifying drugs Fibrates Drugs 0.000 claims abstract description 6
- 229940090865 Aldose reductase inhibitors used in diabetes Drugs 0.000 claims abstract description 4
- -1 C-6 haloalkitio Chemical group 0.000 claims description 221
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- YZGJIENQZBJQNS-UHFFFAOYSA-N pentalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=C21 YZGJIENQZBJQNS-UHFFFAOYSA-N 0.000 claims description 66
- 239000012453 solvate Substances 0.000 claims description 61
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 46
- 230000036740 Metabolism Effects 0.000 claims description 44
- 230000004060 metabolic process Effects 0.000 claims description 44
- 230000035786 metabolism Effects 0.000 claims description 44
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 37
- 229910052799 carbon Inorganic materials 0.000 claims description 36
- 239000003814 drug Substances 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 239000008079 hexane Substances 0.000 claims description 32
- 125000004494 ethyl ester group Chemical group 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 26
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 238000002560 therapeutic procedure Methods 0.000 claims description 20
- 150000004677 hydrates Chemical class 0.000 claims description 19
- GUVXZFRDPCKWEM-UHFFFAOYSA-N Pentalene Chemical compound C1=CC2=CC=CC2=C1 GUVXZFRDPCKWEM-UHFFFAOYSA-N 0.000 claims description 18
- 125000002252 acyl group Chemical group 0.000 claims description 18
- 125000004423 acyloxy group Chemical group 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 150000003857 carboxamides Chemical class 0.000 claims description 15
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 15
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 14
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 12
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 12
- 125000005431 alkyl carboxamide group Chemical group 0.000 claims description 12
- 230000000051 modifying Effects 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 125000004749 (C1-C6) haloalkylsulfinyl group Chemical group 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 11
- 125000004422 alkyl sulphonamide group Chemical group 0.000 claims description 11
- 230000003042 antagnostic Effects 0.000 claims description 11
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 11
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 11
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 230000036961 partial Effects 0.000 claims description 11
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
- 239000005557 antagonist Substances 0.000 claims description 10
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims description 10
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 10
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 9
- 208000008589 Obesity Diseases 0.000 claims description 9
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 9
- 125000005432 dialkylcarboxamide group Chemical group 0.000 claims description 9
- 235000020824 obesity Nutrition 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 125000004741 (C1-C6) haloalkylsulfonyl group Chemical group 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 8
- 208000006011 Stroke Diseases 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 201000010874 syndrome Diseases 0.000 claims description 8
- 239000005541 ACE inhibitor Substances 0.000 claims description 7
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 7
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 7
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 7
- 229940090127 blood glucose lowering Alpha glucosidase inhibitors Drugs 0.000 claims description 7
- 125000004440 haloalkylsulfinyl group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 6
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical group [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 6
- ABDMQSFNJPYOLA-UHFFFAOYSA-N NS(=O)(=O)[N+]([O-])=O Chemical compound NS(=O)(=O)[N+]([O-])=O ABDMQSFNJPYOLA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 6
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 6
- 201000010238 heart disease Diseases 0.000 claims description 6
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 6
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 5
- VCFPZFAEWLRVLA-UHFFFAOYSA-N C(C)OC(=O)C=1C2=CC=CC2=CC=1 Chemical compound C(C)OC(=O)C=1C2=CC=CC2=CC=1 VCFPZFAEWLRVLA-UHFFFAOYSA-N 0.000 claims description 5
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 5
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229960001663 sulfanilamide Drugs 0.000 claims description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 102000004316 Oxidoreductases Human genes 0.000 claims description 4
- 108090000854 Oxidoreductases Proteins 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N diguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 101700008793 BNP Proteins 0.000 claims description 3
- 101700018247 BPP Proteins 0.000 claims description 3
- 101700071361 BPP4 Proteins 0.000 claims description 3
- 101700034740 BPP8 Proteins 0.000 claims description 3
- 101710004889 Vejaci Proteins 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- UKQFEWRNKWDNBW-UHFFFAOYSA-N C1C2CC2C2=C(C(=O)O)NN=C21 Chemical compound C1C2CC2C2=C(C(=O)O)NN=C21 UKQFEWRNKWDNBW-UHFFFAOYSA-N 0.000 claims description 2
- DKSPRNJUDCWTID-UHFFFAOYSA-N GTPL5790 Chemical compound C12CC2CC=2C1=NNC=2C=1N=NNN=1 DKSPRNJUDCWTID-UHFFFAOYSA-N 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 4
- QDXQAOGNBCOEQX-UHFFFAOYSA-N 1-methylcyclohexa-1,4-diene Chemical compound CC1=CCC=CC1 QDXQAOGNBCOEQX-UHFFFAOYSA-N 0.000 claims 2
- ZYICRESAGWVMJD-UHFFFAOYSA-N C=1C=CC=CC=1CC(C12)C2CC=2C1=NNC=2C=1N=NNN=1 Chemical compound C=1C=CC=CC=1CC(C12)C2CC=2C1=NNC=2C=1N=NNN=1 ZYICRESAGWVMJD-UHFFFAOYSA-N 0.000 claims 2
- VSBDNNUJQGUHKD-UHFFFAOYSA-N (+/-)-1,1-dimethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene Chemical compound C12C(C)(C)C2CC=2C1=NNC=2C=1N=NNN=1 VSBDNNUJQGUHKD-UHFFFAOYSA-N 0.000 claims 1
- ADDWQSJBENMLJW-UHFFFAOYSA-N C12=NNC(C3=NNN=N3)=C2CC2C1C2C1=CC=CC=C1 Chemical compound C12=NNC(C3=NNN=N3)=C2CC2C1C2C1=CC=CC=C1 ADDWQSJBENMLJW-UHFFFAOYSA-N 0.000 claims 1
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- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- FFXIGVUMVPUWDK-UHFFFAOYSA-N pentanethioamide Chemical compound CCCCC(N)=S FFXIGVUMVPUWDK-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
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- 230000000275 pharmacokinetic Effects 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
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- 230000000291 postprandial Effects 0.000 description 1
- OCFVSFVLVRNXFJ-UHFFFAOYSA-N potassium hydride Inorganic materials [H-].[K+] OCFVSFVLVRNXFJ-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical group 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 229960003611 pramlintide Drugs 0.000 description 1
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- 230000000750 progressive Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000013333 regulation of fatty acid metabolic process Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 230000033458 reproduction Effects 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- VRQDPNKOUPEWOC-UHFFFAOYSA-N spiro[bicyclo[2.2.2]octane-3,3'-piperidine] Chemical compound C1CCNCC21C(CC1)CCC1C2 VRQDPNKOUPEWOC-UHFFFAOYSA-N 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- 125000001174 sulfone group Chemical group 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
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- 229960004084 temocapril Drugs 0.000 description 1
- GSTHGUFEIGVSRH-UHFFFAOYSA-N tert-butyl-dimethyl-[5-(oxiran-2-yl)pent-2-enoxy]silane Chemical compound CC(C)(C)[Si](C)(C)OCC=CCCC1CO1 GSTHGUFEIGVSRH-UHFFFAOYSA-N 0.000 description 1
- ODGCEQLVLXJUCC-UHFFFAOYSA-N tetrafluoroborate Chemical class F[B-](F)(F)F ODGCEQLVLXJUCC-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000001391 thioamide group Chemical group 0.000 description 1
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- 239000000700 tracer Substances 0.000 description 1
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- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Abstract
The present invention relates to certain fused pyrazole derivatives of Formula (Ia), and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists for the RUP25 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of metabolic-related disorders, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, Syndrome-X and the like. In addition, the present invention also provides for the use of the compounds of the invention in combination with other active agents such as those belonging to the class ofα-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers, DP receptor antagonists, and the like.
Description
MERGED PIRAZOL DERIVATIVES AND METHODS OF TREATMENT OF DISORDERS IS RELATED TO THE
M ETABOLISM
Field of the Invention The present invention relates to certain fused pyrazole derivatives, and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example as combatants for the nicotinic acid receptor, RU P25. Also provided by the present invention are pharmaceutical compositions containing one or more compounds of the invention, and methods for using the compounds and compositions of the invention in the treatment of disorders related to metabolism, including dyslipidemia, atherosclerosis, coronary heart disease, resistance to insulin, type 2 diabetes, S hynd X and the like. Additionally, the present invention also relates to the use of the compounds of the invention in combination with other active agents such as those belonging to the class of α-glucosidase inhibitors, aldose net uctase inhibitors, biguanides, HM G- inhibitors. CoA reductase, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers, thiazolidinedione, DP receptor antagonists and the like.
BACKGROUND OF THE INVENTION Compounds of the Invention As Antilynotic Agents Atherosclerosis and stroke are the number one and number three causes of death for both men and women in the United States. Type 2 diabetes is a public health problem that is serious, expanding and growing. High levels of low density lipoprotein (LDL) cholesterol or low levels of high density lipoprotein cholesterol (H DL) are, independently, risk factors for atherosclerosis and associated cardiovascular pathologies. Additionally, the high levels of free fatty acids in the plasma are associated with insulin resistance and type 2 diabetes. A strategy to lower LDL cholesterol, increase HLD cholesterol, and decrease free fatty acids in plasma is to inhibit lipolysis in adipose tissue. This approach involves the regulation of hormone-sensitive lipase, which is the speed limiting enzyme in lipolysis. Lipolytic agents increase the cellular levels of cAMP, which leads to the activation of the hormone-sensitive lipase within the adipocytes. Agents that decrease intracellular cAMP levels, on the other hand, would be antilipolytic. It is also worth noting in passing that an increase in cellular levels of cAMP down regulates adiponectin secretion from adipocytes [Delporte, M L and other Biochem J (2002) July]. Reduced levels of adiponectin in plasma have been associated with disorders related to metabolism, including atherosclerosis, coronary heart disease, insulin resistance and type 2 diabetes [Matsuda, M and others J Biol Chem (2002) July and reviewed there]. Nicotinic acid (niacin, pyridine-3-carboxylic acid) is a water-soluble vitamin required by the human body for health, growth and reproduction; a part of the vitamin B complex. Nicotinic acid is also one of the oldest drugs used to treat dyslipidemia. It is a valuable drug because it favorably affects virtually all the above-mentioned lipid parameters [Goodman and Gilman's Pharmacological Basis of Therapeutics, Harmon JG and Limbird LE editors, Chapter 36, Mahley RW and Bersot TP (2001) pages 971 -1 002]. The benefits of nicotinic acid in the treatment or prevention of atherosclerotic cardiovascular disease have been documented in six large clinical trials [Guyton J R (1,998) Am J Cardiol 82: 1 8U-23U]. Nicotinic acid and related derivatives, such as, the acipimox have been recently analyzed [Lorenzen, A et al. (2001) Molecular Pharmacology 59: 349-357]. The structure and synthesis of additional analogues and derivatives of nicotinic acid are analyzed throughout Merck Index, An Encyclopedia of Chemicals, Drugs and Biologicals, Tenth Edition (1 983), which is incorporated herein by reference in its entirety. Nicotinic acid inhibits the production and release of free fatty acids from adipose tissue, probably through an inhibition of adenylyl cyclase, a decrease in intracellular cAMP levels, and a concomitant decrease in lipase activity. sensitive to the hormone. It is possible that combatants who down regulate the activity of hormone-sensitive lipase that tends to a decrease in plasma free fatty acid levels have a therapeutic value. The consequence of decreasing free fatty acids in the plasma is twofold. First, it will ultimately lower LDL cholesterol levels and increase H-DL cholesterol, independent risk factors, thus reducing the risk of mortality due to cardiovascular incidence after atheroma formation. Second, it will provide an increase in insulin sensitivity in an individual with insulin resistance or type 2 diabetes. Unfortunately, the use of nicotinic acid as a therapeutic agent is partially mimicked by the number of associated adverse side effects. These include flushing, rebound of free fatty acid, and liver toxicity. The rational development of new fighters of the nicotinic acid receptor that have fewer side effects will be valuable, but at the moment it is being prevented by the impossibility of molecularly identifying the nicotinic acid receptor. In addition, other receptors of the same class may exist on the surface of adimites and similarly decrease the activity of the hormone-sensitive lipase by reducing the level of intracellular cAMP but without causing adverse effects such as redness, representing thus promising novel therapeutic objectives. Recent work suggests that nicotinic acid probably acts through the specific GPCR [Lorenzen A, et al. (2001) Molecular Pharmacology 59: 349-357 and reviewed there]. Other work has suggested that the effects of nicotinic acid in macrophages, the spleen and probably the adipocytes are mediated through this specific GCR [Lorenzen A, et al. (2002) Biochemical Pharmacology 64: 645-648 and reviewed there] .
Brief Description of the Invention The present invention is directed to compounds that bind to and activate the RU P25 receptor, and the uses thereof. The term receptor RU P25 of the form used herein includes the human sequences found in Gene Bank Accession No. M_1 77551 for the nucleotide, Gene Bank Accession No. NM_80821 9 for the peptide, and allelic variants that exist naturally, mammalian orthologs, and recombinant mutants thereof. One aspect of the present invention pertains to certain fused pyrazole derivatives as represented by Formula (Ia):
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: X is N and Z is CR7, or X is CR7 and Z is N; Ri and R 4 are each independently selected from the group consisting of H, C 1-6 acyl, C-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C-6 alkyl, C 1-6 alkylamino, C 1-6 alkylcarboxamide, C 1-6 alkylthiocarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylthioureyl, C 1-6 alkylureyl, amino, C 1-6 alkylamino, amino C-6-alkylsulfonyl, C 1-6 alkylthioamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-6 dialkylamino, C 1-6 dialkylcarboxamide, C 1-6 dialkylthiocarboxamide, halogen, Ci- 6 haloalkoxy, d-6 haloalkyl, Ci-6 haloalkylsulfinyl, d-6 haloalkylsulfonyl, C-6 haloalkitio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol; R2 and R3 are each independently selected from the group consisting of H, C1-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, C1-6 alkyl, C -6 alkylamino, C1-6 alkylcarboxamide, C 1-6 alkylthiocarboxamide, C 2-6 alkynyl, C-6 alkylsulfonamide, C 1-6 alkylsufinyl, C 1-6 alkylsulfonyl, C-6 alkyl, C 1-6 alkylthioureyl,
6 alkyl, amino, Ci-6-alkylamido, amino-C 1-6 alkylsulfonyl, C 1-6 alkylthioamido, arylsulfinyl, arylsulfonyl, arylthio, carbamimidoyl, carbo-C 1-6 alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 dilaquilcarboxamide, C1-6 dialkylthiocarboxamide, Ci-6-dialkylamido, C1-6-dialkylthioamido, halogen, C1-6 haloalkoxy, Ci-6 haloalkyl, C1-6 haloalkylsulfinyl , C-. 6 haloalkylsulfonyl, C-6 haloalkitium, heterocyclic, heterocyclic-oxy, heterocyclic sulfonyl, heterocyclic carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C4-7 oxy cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid and thiol; wherein said C1-6 alkyl is optionally substituted by substituents selected from the group consisting of C1-6 acyl, C1-6 acyloxy, C -6 alkoxy, C-6 alkylamino, Ci-6 alkylsufinyl, Ci-6 alkylsulfonyl, C1-6 alkyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, Ci-6 haloalkoxy, Ci-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, nitro, phenoxy and phenyl; or R2 and R3 together with the carbon to which both are bonded form a C3-6 cycloalkyl; R 5 and R 6 are each independently selected from the group consisting of H, C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, d 6 -alkoxy, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylcarboxamide, C -6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, Ci-6 alkylsufinyl, C1-6 alkylsulfonyl, alkyltio, Ci-6 alkyoureoureyl, Ci-6 alkyluretyl, amino, carbo-Ci.6-alkoxy, carboxamide, carboxy , cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, Ci-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, Ci-6 haloalkitium, heterocyclic, hydroxyl, nitro, sulfonamide and thiol; and R7 is carbo-Ci.6-alkoxy, carboxy or tetrazol-5-yl.
In some embodiments, and R4 are in a cis position with respect to each other. Another aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention in combination with a pharmaceutically acceptable carrier. Another aspect of the present invention pertains to pharmaceutical compositions such as those described herein which further comprise one or more agents selected from the group consisting of α-glucosidase inhibitors., aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers , thiazolidinedione and DP receptor antagonists. Another aspect of the present invention pertains to methods of treating a disorder related to metabolism comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. Another aspect of the present invention pertains to methods of reducting the levels of VLDL or LDL in an individual comprising administering to said individual in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition of the invention. same. Another aspect of the present invention pertains to methods of reducing serum triglyceride levels in an individual comprising administering to said individual in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition. of the same. Another aspect of the present invention pertains to methods of reducing serum Lp (a) levels in an individual comprising administering to said individual in need of such treatment a therapeutically effective amount of a compound of the present invention or a composition pharmaceutical company. Another aspect of the present invention pertains to methods of treating a disorder related to metabolism comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of the present invention and a DP receptor antagonist. Another aspect of the present invention pertains to modulation methods of a RU P25 receptor comprising contacting the receptor with a compound of the present invention. Another aspect of the present invention pertains to methods of modulating a RU P25 receptor for the treatment of a disorder related to metabolism in an individual in need of such treatment comprising contacting said receptor with a therapeutically effective amount of the compound of the present invention. . Another aspect of the present invention pertains to compounds in which the compound is a combatant. Another aspect of the present invention pertains to compounds in which the compound is a partial combatant. Another aspect of the present invention pertains to methods of treating atherosclerosis in a human patient comprising administering to the patient a compound of the present invention in an amount that is effective in treating atherosclerosis. Another aspect of the present invention pertains to methods of treating dyslipidemia in a human patient in need of such treatment comprising administering to the patient a compound of the present invention in an amount that is effective to treat dyslipidemia. Another aspect of the present invention pertains to methods for raising H-DL in an individual comprising administering to the individual a therapeutically effective amount of a compound of the present invention. Another aspect of the present invention pertains to compounds of the present invention for use in a method of treating the human or animal body by therapy.
Another aspect of the present invention pertains to compounds of the present invention for use in a method of treating a disorder related to the metabolism of the human or animal body by therapy. Another aspect of the present invention pertains to compounds of the present invention for the manufacture of a medicament to be used in the treatment of a disorder related to metabolism. In some embodiments of the present invention, the disorder related to metabolism is from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity, glucose intolerance, atheromatous disease, hypertension, stroke, Syndrome X, cardiopathy and type 2 diabetes. In some embodiments of the present invention, the disorder related to metabolism is dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance and type 2 diabetes. In some embodiments of the present invention, the disorder related to the Metabolism is dyslipidemia. In some embodiments of the present invention, the disorder related to metabolism is atherosclerosis. In some embodiments of the present invention, the disorder related to metabolism is coronary heart disease. In some embodiments of the present invention, the disorder related to metabolism is insulin resistance. In some embodiments of the present invention, the disorder related to metabolism is type 2 diabetes. Some embodiments of the present invention pertain to methods in which the individual is a mammal. Some embodiments of the present invention pertain to methods in which the mammal is a human. Another aspect of the present invention pertains to methods of producing a pharmaceutical composition comprising the mixture of at least one compound of the present invention and a pharmaceutically acceptable carrier or excipient. This application is related to United States patent application Serial No. 60 / 638,668, filed December 23, 2004, and United States patent application Serial No. 60/676, 521, filed on April 29, 2005, both incorporated herein by reference in their entirety. These and other aspects of the invention presented herein will be described in more detail as the patent presentation progresses.
Detailed Description of the Invention The scientific literature has adopted a number of terms, for reasons of consistency and clarity, the following definitions will be used throughout this patent document. COM BATIENTES will mean halves that interact and activate the receptor, such as the RU P25 receptor and initiate a physiological and pharmacological response characteristic of that receptor. For example, when the halves activate the intracellular response by binding to the receptor, or they improve the binding of GTP to the membranes. ATE ROSC LEROSIS is understood here to include disorders of the arteries of medium and large size that result in the progressive accumulation within the intima of smooth and lipid muscle cells. G RU PO UM I, M ITAD OR RADICAL: The term "Ci.6 aci lo" denotes a C1-6 alkyl radical attached to a carbonyl where the definition of alkyl has the same definition described here; some examples include but are not limited to, acetyl, propionyl, n-butanoyl, / 'so-butanoyl, sec-butanoyl, t-butanoyl (ie, pivaloyl), pentanoyl and the like. The term "C1.6 acyloxy" denotes an acyl radical attached to an oxygen atom where the acyl has the same definition described herein; some examples include but are not limited to acetyloxy, propionyloxy, butanoyloxy, / so-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and the like. The term "C2-6 alqueni lo" denotes a radical containing 2 to 6 carbons where at least one carbon-carbon double bond is present, some modalities are from 2 to 4 carbons, and some modalities have 2 carbons. Both E and Z isomers are comprised by the term "alkenyl". In addition, the term "alq uenil" includes di-enos. Correspondingly, if more than one double bond is present, then all bonds can be E or Z or a mixture of E and Z. Examples of an alkenyl include vinyl, propenyl, allyl, isopropenyl, 2-methyl-propenyl , 1-methyl-propenyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, and the like. The term "Ci-6 alkoxy" denotes an alkyl radical, as defined herein, directly attached to an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, sec-butoxy and the like. The term "C-6 alkyl" denotes a straight or branched carbon radical containing the number of carbons indicated, for example, in some embodiments, alkyl is a "C1.4 alkyl" and the group contains from 1 to 4 carbons. In some embodiments, alkyl contains 1 to 13 carbons, some modalities contain 1 to 2 carbons, some modalities contain 1 carbon. Examples of an alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, sec-butyl and the like. The term "C-i.6 alkylcarboxamide" denotes a d-6 simple alkyl group attached to the nitrogen of an amide group, where alkyl has the same definition found herein. Ci_6 alkylcarboxamide can be represented by the following:
alkyl Examples include, but are not limited to, N-methylcarboxamide, A / -ethylcarboxamide, A / -n-propylcarboxamide, A / -iso-propylcarboxamide, / Vn-butylcarboxamide, / V-sec-butylcarboxamide, N-iso- butylcarboxamide, / Vt-butylcarboxamide and the like. The term "Ci. 6 alkylsulfinyl" denotes a C 1-6 alkyl radical attached to a sulfoxide radical of the formula: -S (O) - wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, iso-butylsulfinyl, t-butyl, and the like. The term "Ci-6 alkylsulfonamide" refers to the group
I rent
where C1-6 alkyl has the same definition described herein. The term "Ci.6 alkylsulfonyl" denotes a Ci-6 alkyl radical attached to a sulfone radical of the formula -S (O) - wherein the alkyl radical has the same definition described herein. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, t-butylsulfonyl, and the like. The term "Ci.6 alkylthio" denotes a C -6 alkyl radical attached to a sulfide group of the formula: -S- where the alkyl radical has the same definition described herein. Examples include, but are not limited to, methylsulfonyl (i.e. CH3S-), ethylsulfanyl, n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, iso-butylsulfanyl, t-butyl, and the like. The term "C ^ -alkylthiocarboxamide" denotes a simple C -6 alkyl group attached to a nitrogen of a thiamide group where the alkyl radical has the same definition described herein. The C 1-6 alkylthiocarboxamide can be represented by the following:
rent
Examples include, but are not limited to, N-methylthiocarboxamide, / V-ethylthiocarboxamide, A / -propylthiocarboxamide, / V-iso-propylthiocarboxamide, / Vn-butylthiocarboxamide, N-sec-butylthiocarboxamide, / V-iso butylthiocarboxamide, γ-butylthiocarboxamide and the like. The term "Ci.6 alkylthioureyl" denotes the group of the formula: -NC (S) N- where one or both nitrogens are substituted by the same or different Ci-6 alkyl groups and alkyl has the same definition described herein. Examples include, but are limited to, CHjNHCCOJNH-, M¾C (0) NCH3-, (CH3) 2N (0) NH-, ((¾> 2N (0) NH-, (< ¾2? (0)? ? ¾-, CH3CH2 HC (0) NH-, CH3CH2 HC (0) NCH3-, and s ¡m ¡| a re s.
The term "Ci-6 alkylurei lo" denotes the group of the formula: -NC (0) N- where one or both nitrogens are substituted by the same or different C1-6 alkyl groups where alkyl has the same definition described herein. Examples of an alkylurethyl include, but are not limited to,
CH3NHC (0) NH-, H2C (0) NCH3-, (CH3) 2N (0) NH-, (CH ^ N ^ NH-, (CH3) _N (0) NCH3-, CH3CH2NHC (0) NH-, CH3CH2NHC (0) NCH3-, and s ¡m ¡| re s.
The term "C2-6 alkynyl" denotes a radical containing 2 to 6 carbons and at least one carbon-carbon triple bond, some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons. Examples of an alkynyl include, but are not limited to, ethynyl, prop-1-innyl, 3-prop-2-ynyl, but-1-ynyl, 1-methyl-prop-2-ynyl, buta-1, 3 -diinyl, and the like. The term "alkynyl" includes di-inas. The term "amino" denotes the group -NH2. The term "C 1.6 alkylamido" denotes the C 1-6 acyl group, as defined herein, attached to an NH group. The C1-6 alkylamido group can be represented by the following formula:
Examples of an alkylamido group include, but are not limited to, -NHCOMe, -NHCOEt, and the like. The term "amino-C-6-alkylsulfonyl" denotes an alkylsulfonyl group, as defined herein, linked to an NH group. The amino-Ci-6-alkylsulfonyl group can be represented by the following formula:
alkyl Examples of an amino-C-6-alkylsulfonyl group include, but are not limited to, -NHS02Me, -NHS02Et, -NHS02 propyl, and the like.
The term "C-i-6 alkylthioamido" denotes the group C 1-6 thioacyl, as defined herein, linked to an NH group. The d-6 alkylthioamido group can be represented by the following formula:
I rent
Examples of the alkylthioamido group include, but are not limited to, -NHCSMe, -NHCSEt, and the like. The term "Ci.6 alkylamino" denotes an alkyl radical attached to an amino radical where the alkyl radical has the same meaning as described herein. Some examples include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino, t-butylamino, and the like. Some embodiments are "Ci-2 alkylamino". The term "aryl" denotes an aromatic ring radical containing from 6 to 10 carbons in the ring. Examples include phenyl and naphthyl. The term "arylsulfinyl" denotes an aryl group attached to a sulfoxide radical of the formula: -S (O) - wherein the aryl radical has the same definition described herein. The term "arylsulfonyl" denotes an aryl group attached to a sulfonyl radical of the formula: -S (0) 2- where the aryl radical has the same definition as described herein. The term "arylthio" denotes an aryl group attached to a thio radical of the formula: -S- where the aryl radical has the same definition described herein. The term "carbamimidoyl" refers to a group of the following chemical formula:
and in some embodiments, one or both hydrogens are replaced by another group. For example, a hydrogen can be replaced by a hydroxyl group to produce an N-hydroxycabamimidoyl group, or a hydrogen can be replaced by an alkyl group to produce V-methylcabamimidoyl, N-ethylcabamimidoyl, / V-propylcabamimidoyl, / V-butylcabamimidoyl, and similar. The term "carbo-C-6-alkoxy" denotes an alkyl ester C-i-6 of a carboxylic acid, wherein the alkyl group is as defined herein. Examples include, but are not limited to, carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy, carbo-iso-butoxy, carbo-t-butoxy, and the like. The term "carboxamide" refers to the group -CONH2. The term "carboxy" or "carboxyl" denotes the group -CQ2H; also called carboxylic acid group. The term "cyano" denotes the group -CN. The term "C3.7 cycloalkyl" denotes a saturated ring radical containing from 3 to 6 carbons; some modalities contain from 3 to 5 carbons; some modalities contain 3 to 4 carbons. Examples include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term "C3-7 cycloalkyloxy" denotes a cycloalkyl radical, as defined herein, directly attached to an oxygen atom. Examples include cyclopropyloxy, cyclobutyloxy, cyclopentoxy, and the like. The term "C2-8 dialkylamino" denotes an amino substituted by two of the same or different alkyl radicals wherein the alkyl radical has the same definition described herein. A C2-8 dialkylamino can be represented by the following groups:
Some embodiments include C2-6 dialkylamino, such as -N (C -3 alkyl) 2. Examples of dialkylamino include but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, and the like. The term "C 1-6 dialkylamido" denotes two alkyl radicals, which are the same or different, attached to an amido group, wherein alkyl has the same definition described herein. A C 1-6 dialkylamido can be represented by the following group:
alkyl where Ci-6 has the same definition described here. Examples of a dialkylamido include, but are not limited to, -N (CH 3) COCH 3 1 -N (CH 3) COCH 2 CH 3, and the like. The term "Ci.6 dialkylthioamido" denotes two alkyl radicals, which are the same or different, attached to a thioamido group, where the alkyl has the same definition described herein. A C-6 dialkylthioamido can be represented by the following group:
where C1-6 has the same definition described here. Examples of a dialkylthioamido include, but are not limited to, N (CH 3) CSCH 3, -N (CH 3) CSCH 2 CH 3, and the like. The term "C 1-6 dialkylcarboxamide" denotes two alkyl radicals, which are the same or different, attached to an amide group, wherein the alkyl has the same definition described herein. A C 1-6 dialkylcarboxamide can be represented by the following group:
uilo alkyl
where C1.6 has the same definition described here. Examples of dialkylcarboxamide include, but are not limited to, N, N-dimethylcarboxamide, / S / -methyl-A / -ethylcarboxamide, N, N-diethylcarboxamide, / V-methyl-A / -isopropylcarboxamide, and the like. The term "Ci.6 dialkylthiocarboxamide" denotes two alkyl radicals, which are the same or different, attached to a thioamide group, wherein the alkyl has the same definition described herein. A d-6 dialkylthiocarboxamide can be represented by the following group:
Examples of dialkylthiocarboxamide include, but are not limited to, / V, / V-d-methylolcarboxamide, A / -methyl- / N / -ethylthiocarboxamide, and the like. The term "Ci.6 haloalkoxy" denotes a haloalkyl, as defined herein, which is attached directly to an oxygen atom. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the like. The term "C-6 haloalkyl" denotes an alkyl group wherein the alkyl is substituted by halogen ranging from one to fully substituted, where a fully substituted haloalkyl can be represented by the formula ChL2h + i where L is a halogen and "h" represents the number of carbon atoms; when more than one halogen is present then the halogens may be the same or different and selected from the group consisting of F, Cl, Br and I; it is understood that the terms "alkyl" and "halogen" have the same definition found herein. In some embodiments, haloalkyl is a "C-haloalkyl" and the group contains from 1 to 4 carbons, some embodiments contain from 1 to 3 carbons, some embodiments contain from 1 to 2 carbons, some embodiments contain 1 carbon. When the haloalkyl is completely substituted by halogen atoms, this group is called here a perhaloalkyl, an example, is an alkyl completely substituted by fluorine atoms and is referred to herein as a "perfluoroalkyl". In some embodiments, the haloalkyl examples include, but are not limited to, difluoromethyl, fluoromethyl, 2,2,2-trifluoro-ethyl, 2,2-difluoro-ethyl, 2-fluoro-ethyl, 1, 2,2- trifluoro-ethyl, 1,2-difluoro-ethyl, 1,1-difluoro-ethyl, 1,1, 2-trifluoro-ethyl, 3,3,3-trifluoro-propyl, 2,2-difluoro-propyl, 3, 3-difluoro-propyl, 3-fluoro-propyl, 2,3,3-trifluoro-propyl, 2,3-difluoro-propyl, 2,2,3,3,3-pentafluoro-propyl, 2,2,3, 3-tetrafluoro-propyl, 2,2,3-trifluoro-propyl, 1, 2,3,3-tetrafluoro-propyl, 1, 2,3-trifluoro-propyl, 3,3-difluoro-propyl, 1, 2, 2,3-tetrafluoro-propyl, 4,4-difluoro-butyl, 3,3-difluoro-butyl, 4,4,4-trifluoro-butyl, 3,3-difluoro-butyl and the like. In some embodiments, examples of perfluoroalkyl include, but are not limited to, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl, and the like. The term "Ci-6 haloalkylsulfyl" denotes a haloalkyl radical attached to a sulfoxide group of the formula: -S (O) - wherein the haloalkyl radical has the same definition described herein. The term "Ci-6 haloalkylsulfonyl" denotes a haloalkyl radical attached to a sulfone group of the formula: -S (0) 2- where the haloalkyl radical has the same definition described herein.
The term "C1 -6 haloalkylthio" denotes a haloalkyl radical attached directly to a sulfur atom where the haloalkyl radical has the same definition as described herein. The term "halogen" or "halo" denotes a fluorine, chlorine, bromine, or iodine group. The term "heteroari lo" denotes an aromatic ring system that may be a single ring, two fused rings or three fused rings where at least one carbon ring is replaced by a heteroatom selected from, but not limited to, the group that consists of O, S and N where the N can optionally be substituted by H, C -4 alkyl or C 1-4 alkyl. Examples of heteroaryl groups include, but are not limited to, pyridyl, benzofuranyl, Pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1 H-bencimidazonilo, isoquinolinyl, quinazolinyl, qui noxalinilo and the like. In some embodiments, the heteroaryl atom is O, S, N H, examples include, but are not limited to, pyrrolyl, indolyl, and the like. The term "Heterocycl ic" denotes a carbon ring nonaromatic (i.e., cycloalkyl or cycloalkenyl as defined herein) wherein one, two or three rbonos ca ring are replaced by a heteroatom selected from, but not limited to, the group consisting of O, S, N, wherein the N can be optionally substituted by H, Ci-4 acyl or C1 -4 alkyl, and the carbon atoms of the ring optionally substituted by oxo or thiooxo thus forming a carbonyl group or thiocarbonyl. The heterocyclic group is a ring containing 3, 4, 5, 6 or 7 members. Examples of a heterocyclic group including uence, but are not limited to aziridine-1 -yl, aziridine-2-yl, azetidine-1 -yl, azetidine-2-yl, azetina-3-yl, piperidine-1 -yl, piperidine-4-yl, morpholine-4-yl, piperazine-1 -yl, piperazine-4-yl, pyrrolidine-1 -yl, pi rrodilina-3-i as [1, 3] dioxolane-2-yl and Similar. The term "heteroarylcarbonyl" denotes a heteroaryl group, as defined herein, that is directly attached to the carbon of a carbonyl group (ie, C = 0). Examples of groups heteroarylcarbonyl include, but are not limited to, pyridyl-carbonyl, benzofuranyl-carbonyl, pyrazinyl-carbonyl, piridanizil-carbonyl, pi rimidinil-carbonyl, triazinyl-carbonyl, quinolinyl-carbonyl, benzoxazolyl-carbonyl, benzothiazolyl-carbonyl, 1 H-benzimidazoyl-carbonyl, isoquinolinyl-carbonyl, quinazolinyl-carbonyl, quinoxalinyl-carbonyl, pyrrole-carbonyl, indolyl-carbonyl, and the like. The term "heterocyclic carbonyl" denotes a heterocyclic group, as defined herein, that is directly attached to the carbon of a carbonyl group (ie, C = 0). In some embodiments, a nitrogen ring of the heterocyclic group is attached to the carbonyl group to form an amide. Examples include, but are limited to,
and similar.
The term "heterocyclic-oxy" refers to a heterocyclic group, as defined herein, that is directly attached to an oxygen atom. Examples include the following:
and similar. The term "heterocyclic ionsulfonyl" denotes a heterocyclic group, as defined herein, with a nitrogen ring where the ring nitrogen is directly attached to a S02 group to form a sulfonamide. Examples include, but are not limited to,
and similar. The term "hydroxyl" denotes the -OH group. The term "C -7 oxo-cycloalkyl" refers to C4-7 cycloalkyl, as defined herein, wherein one of the ring carbons is replaced by a carbonyl. Examples of C4-7 oxo-cycloalkyl include, but are not limited to, 2-oxo-cyclobutyl, 3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl, and the like and represented by the following structures respectively :
The term "nitro" denotes the group -N02. The term "phenoxy" denotes the group C6H50-. The term "fen ilo" denotes the group C6H5-. The term "its lfonamide" denotes the group -S02NH2. The term "sulfonic acid" denotes the group -S03H The term "thiol" denotes the group -SH. The term "C1-6 thioacyl" denotes a C1-6 alkyl radical attached to a thiocarbonyl where the definition of alkyl has the same definition as described herein, some examples include, but are not limited to, -CSCH3, -CSCH2CH3, -CSCH2CH2CH3, and the like. The term COM POSITION shall mean a material comprising at least two compounds or two components; for example, and without limitation, a Pharmaceutical Composition is a Composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The term EF ICACIA DEL COM PU ESTO will mean a measurement of the ability of a compound to inhibit or stimulate receptor functionality, as opposed to the receptor binding affinity. The term RECE CORRECTIVE CONSTITUTIVAM ENTE ACT8VADO means a receptor subject to constitutive activation of the receiver.
The term "CONSTITUTIVE ACTIVATION OF RECE" PTOR will mean stabilization of a receptor in the active state by other means than the receptor's link to its endogenous ligands or a chemical equivalent thereof. The terms CONTACT or CONTACT will mean gathering the two halves indicated, either in an in vitro system or in an in vivo system. Thus, "contacting" an RUP25 receptor with a compound of the invention includes the administration of a compound of the present invention to an individual, for example a human, having an RU P25 receptor, as well as, for example, introducing a compound of the invention in a sample containing a cellular preparation or more purified containing a RU P25 receptor. CORONARY CARDIOPATHY is understood here as encompassing disorders that include a narrowing of the small blood vessels that supply blood and oxygen to the heart. Coronary heart disease usually results from the increase of fatty material and plaque. As the coronary arteries narrow, the flow of blood to the heart can slow down or stop. Coronary heart disease can cause chest pain (stable angina), shortness of breath, heart attack, or other symptoms. DEC RECER is used to refer to a reduction in a measurable quantity and is used as a synonym for the terms "reduce", "decrease", "lower", and "decrease". DIABETES as used herein is intended to encompass the usual diagnosis of DIABETES made from any of the methods including, but not limited to, the following list: symptoms of diabetes (eg, polyuria, polydipsia, polyphagia) more Occasional plasma glucose levels greater than or equal to 200 mg / dl, where occasional glucose in the plasma is defined at any time of the day irrespective of the time of consumption of food or beverages; plasma glucose levels after 8 hours of fasting less than or equal to 1 26 mg / dl; and plasma glucose levels greater than or equal to 200 mg / dl 2 hours after oral administration of 75 g of anhydrous glucose dissolved in water. The phrase DISORDER OF M ETABOLISM OF THE LIPIDS is conceived here to include, but is not limited to, dyslipidemia. The term DISLIPIDEMIA is intended herein to encompass disorders comprising any high level of free fatty acids in the plasma, high level of plasma cholesterol, high level of LDL cholesterol, reduced level of HDL cholesterol, and high level of plasma triglycerides. . The phrase QU IN ECESITA TREATMENT, as used here, refers to an opinion formed by a specialist (for example, doctor, nurse, nurse practitioner, etc. in the case of humans, veterinarian in the case of animals, including to non-human mammals) that an individual or animal requires or will benefit from treatment. This opinion is formed on the basis of a variety of factors that are found in the domain of a specialist's experience, including the knowledge that the individual is ill, or will be ill, as a result of a disease, condition or disorder that it is treatable by the compounds of the invention. In addition, the phrase "in need of treatment" also refers to the "prophylaxis" of an individual that in the opinion formed by the specialist that individual will become ill. In this context, the compounds of the invention are used in a preventive and protective manner. Correspondingly, "in need of treatment" refers to a specialist's opinion that the individual is already sick or ill and the compounds of the present invention can be used to alleviate, inhibit, ameliorate or prevent the disease, condition or disorder . The term IN DIVIDUAL as used herein refers to any animal, including mammals, for example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and in a , humans. The terms I N H IBE or I N HIBIR, in relation to the term "response" will mean that a response is diminished or avoided in the presence of a compound as opposed to in the absence of the compound. RESISTANCE TO INS U LINE as used herein is intended to encompass the usual diagnosis of insulin resistance performed by any of a number of methods, including but not limited to: the intravenous glucose tolerance test or the measurement of fasting insulin level. It is well known that there is an excellent correlation between the elevation of the fasting insulin level and the degree of insulin resistance. Therefore, fasting insulin evasion levels could be used as a surrogate marker of insulin resistance for the purposes of identifying which individuals with normal glucose tolerance (NGT) have insulin resistance. A diagnosis of insulin resistance can also be made using the euglycemic glucose clamp test. The term I NVERSOS combatants will mean halves that link the endogenous form of the receptor or the constitutively activated form of a receptor, and which inhibit the basic intracellular response initiated by the active form of the receptor below the normal base level of activity that is observed in absence of combatants or partial fighters, or decrease the GTP link to the membranes. In some modalities, the basic intracellular response is inhibited in the presence of the reverse fighter in at least 30%, in other modalities, in at least 50%, and still in other modalities, in at least 75%, compared to the response basic in the absence of the reverse combatant. The term LIGANDO will mean an endogenous molecule, which naturally exists specifically for an endogenous receptor, which exists naturally. The phrase DESORREN IS RELATED TO M ETABOLIS MO is conceived here to include, but is not limited to, dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity, glucose intolerance, atheromatous disease, hypertension, stroke, Syndrome X, heart disease and type 2 diabetes. As used herein, the term MODU LAR or MODULATION will mean referring to an increase or decrease in the quantity, quality, response or effect of a particular activity, function or molecule. As used herein, the term "PARTIAL SWITCHING COMB" is a half that activates an intracellular response by binding to a receiver (eg, a RUP25 receiver) but to a lesser extent / extent as compared to a full combatant. The term partial fighter is a relative term since a partial fighter generates a partial response compared to that of a full fighter. It is understood that because new compounds are being discovered over time a compound once described as a complete combatant may subsequently change to a partial combatant based on the discovery of a new complete com batiente. The term "PHARMACEUTICAL POSITION" shall mean a composition for preventing, treating or controlling a disease state or condition comprising at least one active compound, for example, a compound of the present invention including pharmaceutically acceptable salts, pharmaceutically acceptable solvates and / or pharmaceutically hydrates. acceptable thereof, and at least one pharmaceutically acceptable carrier. The term CARRIER or EXCIPIENT
PHARMACEUTICALLY ACCEPTABLE will mean any substantially inert substance used as a diluent or carrier for a compound of the present invention. The phrase "THERAPEUTICALLY EFFECTIVE AMOUNT" as used herein refers to the amount of the active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual or human that is being investigated by the researcher, veterinarian, physician or another clinician, which includes one or more of the following: (1) Prevention of the disease; for example, prevention of the disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or show the pathology or symptomatology of the disease, (2) Inhibition of the disease; for example, inhibiting the disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (ie, stopping the further development of the pathology and / or symptomatology), and (3) ) Improvement of the disease; for example, improvement of the disease, condition or disorder in an individual who is experiencing or showing the pathology or symptomatology of the disease, condition or disorder (ie, reversing the pathology and / or symptomatology).
Compounds of the Invention One aspect of the present invention pertains to certain fused pyrazole derivatives as represented by the Formula
(the);
or a pharmaceutically acceptable salt, hydrate or solvate thereof; where X, Z, R1f R2, R3, R, R5 and Re have the same definitions described herein, supra and infra. One aspect of the present invention pertains to certain fused pyrazole derivatives as represented by Formula (Ia), or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: X is N and Z is CR7, or X is CR7 and Z is N; RT and R 4 are each independently selected from the group consisting of H, C-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, Ci- 6 alkyl, C 1-6 alkylamino, C 1-6 alkylcarboxamide, Ci-6 alkylthiocarboxamide, C 2-6 alkynyl, d-6 alkylsulfonamide, C 1-6 alkylsulfinyl, Ci-6 alkylsulfonyl, Ci-6 alkylthio, C-6 alkylthioureyl, C 1-6 alkylureyl, amino, Ci-6-alkylamino, amino- C1-6-alkylsulfonyl, C1-6-alkylthioamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, d-6 dialkylcarboxamide, d-6 dialkylthiocarboxamide, halogen, C- 6 haloalkoxy, Ci-6 haloalkyl, Ci-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkitio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol; R2 and R3 are each independently selected from the group consisting of H, C1-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C -6 alkylamino, Ci-6 alkylcarboxamide, Ci-6 alkylthiocarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsufinyl, 0? -6 alkylsulfonyl, C -, - 6 alkyl, C 6 alkylthioureyl, d. 6 alkyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, d-6-alkylthioamido, arylsulfinyl, arylsulfonyl, arylthio, carbamimidoyl, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 dilaquilcarboxamide, C -6 dialkyltiocarboxamide, C1-6-dialkylamido, C1-6-dialkyltioamido, halogen, C -6 haloalkoxy, C -6 haloalkyl, C1-6 haloalkylsulfinyl , d-6 haloalkylsulfonyl, Ci-6 haloalkitio, heterocyclic, heterocyclic-oxy, heterocyclic sulfonyl, heterocyclic carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C4-oxy cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid and thiol; wherein said C 1-6 alkyl is optionally substituted by substituents selected from the group consisting of C 1-6 acyl, Ci-6 acyloxy, C-6 alkoxy, d-6 alkylamino, Ci-6 alkylsufinyl, C 1-6 alkylsulfonyl, C-6 alkyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, d-6 haloalkoxy, d-6 haloalkylsulfinyl, d-6 haloalkylsulfonyl, C1- 6 haloalkylthio, hydroxyl, nitro, phenoxy and phenyl; R 5 and R 6 are each independently selected from the group consisting of H, Ci-6 acyl, C-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, Ci-6 alkyl, C 1-6 alkylamino, C 1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, Ci-6 alkylsulfonamide, C 1-6 alkylsufinyl, C 1-6 alkylsulfonyl, C 1-6 alkyio, C-6 alkyoureriyl, Ci-6 alkylureyl, amino, carbo-C 1-6 alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C -6 haloalkylsulfonyl, C- 6 haloalkitium, heterocyclic, hydroxyl, nitro, sulfonamide and thiol; and R7 is carbo-C1-6-alkoxy, carboxy or tetrazol-5-yl. It is understood that the present invention encompasses each generic compound and formula, infra and supra, where R ^ and R4 are in cis position with respect to each other. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Vice versa, several features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in a suitable sub-combination. As used herein, "substituted" indicates that at least one hydrogen atom of each chemical group is replaced by a substituent or non-hydrogen group. When a chemical group is "substituted" here it can have up to the full balance of substitution; for example, a methyl group can be substituted by 1, 2 or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4 or 5 substituents, and the like. In some embodiments, the term "substituted" refers to 1, 2, 3, 4, 5 or 6 substituents. In some embodiments, the term "substituted" refers to 1, 2, 3, 4, or 5 substituents. In some embodiments, the term "substituted" refers to 1, 2, 3, or 4 substituents. In some embodiments, the term "substituted" refers to 1, 2, or 3 substituents. In some embodiments, the term "substituted" refers to 1, or 2 substituents. In some embodiments, the term "substituted" refers to 1 substituent. It is understood and appreciated that the compounds of Formula (Ia) may have one or more chiral centers, and therefore may exist as enantiomers and / or diastereomers. The invention is understood to extend and encompass all such enantiomers, diastereomers and mixtures thereof, including but not limited to racemates. Correspondingly, one modality of the present invention pertains to compounds of Formula (Ia) and the formulas used throughout this description which are R-enantiomers. In addition, one embodiment of the present invention pertains to compounds of the Formula ) and the formulas used throughout this description which are S enantiomers. In another embodiment, the compounds of the present invention possess two stereochemical centers and both are R. In another embodiment, the compounds of the present invention possess two stereochemical centers. and both are S. In another embodiment, the compounds of the present invention possess three stereochemical centers where all are R. In another embodiment, the compounds of the present invention possess three stereochemical centers where two are R and the third is S. In another embodiment, the compounds of the present invention possess three stereochemical centers where two are S and the third is R. It is understood that the compounds of Formula (Ia) and the formulas used throughout this description are intended to represent all individual enantiomers and mixtures of the same, unless it is stated or shown otherwise. The compounds of the present invention can exist in various tautomeric forms. For example, it is well appreciated by those skilled in the art that tetrazoles can exist in at least two tautomeric forms and although in certain formulas described herein they represent a form it is understood that all tautomeric forms are encompassed by the present invention; by way of illustration, when X is N and Z is CR7 where R7 is tetrazol-5-yl then two possible tautomers for the tetrazole ring are shown below:
Likewise, it is understood that when X is CR7, where R7 is tetrazol-5-yl, and Z is N that tautomers may also exist for the tetrazole ring. Furthermore, it is well appreciated by those skilled in the art that pyrazole heterocycles can exist in at least two tautomeric forms and although the formulas described herein represent a form it is understood that all tautomeric forms are encompassed by the present invention. By way of illustration, two possible tautomers for the pyrazole ring (when X is N and Z is CR7) are shown below:
Similarly, tautomers may exist for when X is CR7 and Z is N. Furthermore, it is understood that when R7 is a tetrazole-5-yl ring then tautomers may exist for both the piperale ring and the tetrazole ring in combination. It is understood that all tautomers that may exist for the compounds described herein are within the scope of the invention.
It is further understood that tautomeric forms can have corresponding nomenclatures for each tautomer. Accordingly, the present invention includes all tautomers and the different nomenclature designations for all tautomers.
Some embodiments of the present invention pertain to compounds where X is N; Z is CR7; and R7 is carbo-Ci-6-alkoxy or carboxy. Some embodiments of the present invention pertain to compounds where X is N; Z is CR7; and R7 is carboxy. Some modalities can be represented by the Formula (le) as illustrated below:
(Ic) where each variable in the Formula (le) has the same meaning described here, supra and infra. Some embodiments of the present invention pertain to compounds where X is N; Z is CR7; and R7 is tetrazol-5-yl. Some modalities can be represented by the Formula (le) as illustrated below:
where each variable in the Formula (le) has the same meaning described here, supra and infra. Some embodiments of the present invention pertain to compounds wherein X is CR7; R7 is carbo-C1 -6-alkoxy or carboxy; and Z is N. Some embodiments of the present invention pertain to compounds wherein X is CR7; and R7 is carboxy; and Z is N. Some modalities can be represented by the Formula (Ig) as illustrated below:
(Ig)
where each variable in the Formula (Ig) has the same meaning as described here, supra and infra. Some embodiments of the present invention pertain to compounds wherein X is CR7; R7 is tetrazol-5-yl; and Z is N. Some modalities can be represented by the Formula (li) as illustrated below:
where each variable in Formula (li) has the same meaning as described herein, supra and infra. Some embodiments of the present invention pertain to compounds wherein R is H or halogen.
Some embodiments of the present invention pertain to compounds wherein Ri is H. Some embodiments of the present invention pertain to compounds wherein R 4 is H or halogen. Some embodiments of the present invention pertain to compounds wherein R4 is H. Some embodiments of the present invention pertain to compounds where Ri and R are at least H. Some embodiments of the present invention pertain to compounds represented by Formula (Ik) as illustrated below:
where each variable in the Formula (Ik) has the same meaning as described here, supra and infra. Some embodiments of the present invention pertain to compounds wherein R5 is H or halogen. Some embodiments of the present invention pertain to compounds wherein R5 is H. Some embodiments of the present invention pertain to compounds wherein R6 is H or halogen. Some embodiments of the present invention pertain to compounds wherein R6 is H.
Some embodiments of the present invention pertain to compounds wherein R5 and R6 are both H. Some embodiments of the present invention pertain to compounds represented by the Formula (Im) as illustrated below:
(Im) where each variable in the Formula (Im) has the same meaning described here, supra and infra. Some embodiments of the present invention pertain to compounds wherein R1 (R4, R5 and R6 are each H. Some embodiments may be represented by Formula (lo) as illustrated below:
(lo) where each variable in the Formula (lo) has the same meaning described here, supra and infra. Some embodiments of the present invention pertain to compounds wherein R 2 and R 3 are each independently selected from the group consisting of H, C 1-6 alkyl and halogen; wherein said d -6 alkyl is optionally substituted by substituents selected from the group consisting of d -6 acyloxy, C-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfinyl, d-6 alkylsulfonyl, C-6 alkylthio, amino, C3 -7-cycloalkyloxy, C2-6 dialkylamino, C-6 haloalkoxy, C1-6 haloalkylsulfinyl, C-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, phenoxy and phenyl. Some embodiments of the present invention pertain to compounds wherein R2 and R3 together with the carbon to which both are attached form a C3-6 cycloalkyl. Some embodiments of the present invention pertain to compounds wherein R2 is H or Ci-6 alkyl; and R3 is H, C1-6 alkyl and halogen; wherein said C 1-6 alkyl is optionally substituted by substituents selected from the group consisting of C 1-6 acyloxy, C-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, Ci- 6 alkylthio, amino, C 3 -7-cycloalkyloxy, C2-6 dialkylamino, Ci.6 haloalkoxy, C-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, hydroxyl, phenoxy and phenyl. Some embodiments of the present invention pertain to compounds wherein R 2 is H or C 1-6 alkyl; and R3 is H, C2-6 alkenyl, Ci-6 alkyl, C3.7 cycloalkyl, halogen or phenyl; wherein said C- | .6 alkyl is optionally substituted by substituents selected from the group consisting of d-6 alkoxy, Ci-6 alkylthio, hydroxyl, phenoxy and phenyl; or R2 and R3 together with the carbon to which both are attached form a cyclopropyl, cyclopentyl or cyclohexyl group. Some embodiments of the present invention pertain to compounds wherein R 2 is H or CH 3; and R3 is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl, phenoxymethyl, methylsulfanylmethyl, ethoxymethyl, cyclopropyl, 1-but-2-enyl , or allyl; or R2 and R3 together with the carbon to which both are attached form a cyclopropyl, cyclopentyl or cyclohexyl group. Some embodiments of the present invention pertain to compounds wherein R 2 is H or C 1-6 alkyl; and R3 is H, C2-6 alkenyl, C1-6 alkyl, halogen or phenyl; wherein said C -6 alkyl is optionally substituted by substituents selected from the group consisting of d-6alkoxy, hydroxyl, phenoxy and phenyl. Some embodiments of the present invention pertain to compounds wherein R 2 is H or CH 3; and R3 is H, CH3 or benzyl. Some embodiments of the present invention pertain to compounds wherein R 2 is H or CH 3; and R3 is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, / pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl. Some embodiments of the present invention pertain to compounds wherein: X is N, Z is CR7, and R7 is carboxyl; or X is CR7, R7 is carboxyl or tetrazolyl, and Z is N; RL R4, R5 and R6 are each H; R2 is H or CH3; and R3 is H, CH3 or benzyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof. Some embodiments of the present invention pertain to compounds wherein: X is N, Z is CR7, wherein R7 is carboxyl, -C02Et or tetrazol-5-yl; or X is CR7, where R7 is carboxyl, -C02Et or tetrazolyl, and Z is N, R-i, R4, R5 and 6 are each H; R2 is H or CH3; and R3 is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof. Some embodiments of the present invention pertain to compounds wherein: X is N, Z is CR7, where R7 is carboxyl, -C02Et or tetrazol-5-yl; or R-i, R4, R5 and 6 are each H; R2 is H or CH3; and R3 is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof. Some embodiments of the present invention pertain to compounds selected from the group consisting of: 3b, 4,4a, 5-Tetrahydro-2H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-3-carboxylic acid; 1 a, 3,5,5a-Tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Benzyl-1 a, 3, 5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; and 1, 1 -Dimethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; or a pharmaceutically acceptable salt, hydrate or solvate thereof. Some embodiments of the present invention pertain to compounds selected from the group consisting of: 4- (2H-Tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a ] pentalene; 1, 1 -Dimethyl-4- (2H-tetrazol-5-yl) -1 a, 3, 5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; and 1-Benzyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; or a pharmaceutically acceptable salt, hydrate or solvate thereof. Some embodiments of the present invention pertain to compounds wherein the stereochemistry for the two carbons assigned as 3b and 4a, or 1a and 5a are both R. Some embodiments of the present invention pertain to compounds wherein the stereochemistry for the two carbons assigned as 3b and 4a, or 1a and 5a are both S. Some embodiments of the present invention pertain to compounds wherein the stereochemistry for the two carbons assigned as 1a and 5a are both R. Some embodiments of the present invention pertain to compounds where the stereochemistry for carbon assigned as 1a is R and the stereochemistry for the carbon assigned as 5a is S.
Some embodiments of the present invention pertain to compounds where the stereochemistry for the carbon assigned as 1a is S and the stereochemistry for the carbon assigned as 5a is R.
Some embodiments of the present invention pertain to compounds where the stereochemistry for the priority group attached to the carbon assigned as 1 is endo. It is understood that the term "priority group" has the same meaning defined by "The Cahn, Ingold and Pelog System" by the application of sequence rules, for a general revision of the CIP system see R.S. Cahn, C.K. Ingold and V. Prelog, Angew. Chem. Internat. Ed. Eng. 5, 385-415, (1966); and V. Prelog and G. Helmchen, Angew. Chem. Internat. Ed. Eng. 21, 567-583 (1982). Some embodiments of the present invention pertain to compounds where the stereochemistry for the priority group attached to the carbon assigned as 1 is exo. In general, the terminology endo and exo applies to R2 and R3 and can be represented by the following formulas, for example, when X is CR7 and Z is N:
when X is N and Z is CR7
In general, when X is CR7 and Z is N, then the two carbons assigned as 3b and 4a are shown in Formula (lia) below:
It is understood that the compounds of the present invention have the stereochemistry where the Ri and R4 groups are in the cis position with respect to each other. These compounds can generally be represented by the Formula (Me) and the Formula (8ld):
In some embodiments, the carbons assigned as 3b and 4a have the stereochemical designations as represented by Formula (Me):
(lie) In some embodiments, the carbons assigned as 3b and 4a have the stereochemical designations as represented by the Formula (lid):
Similarly, when X is N and Z is CR7, then the two carbons assigned as 1a and 5a are shown in the Formula (lie) below:
(He)
It is understood that the compounds of the present invention have the stereochemistry where the R- ^ and R4 groups are in the cis position with respect to each other. These compounds can generally be represented by Formula (llg) and Formula (8l):
In some embodiments, the carbons assigned as 1a and 5a have the stereochemical designations as represented by Formula (IIg): In some embodiments, the carbons assigned as 1a and 5a have the stereochemical designations as represented by Formula (IIh):
It is understood that the actual designation "R" and "S" for C (3b) and C (4a) in the formulas (Me) and (lid); and C (1a) and C (5a) in the Formulas (llg) and (llh) will vary depending on the different groups present. For example, in some embodiments, when Ri to R6 are all hydrogens then the stereochemistry is defined as shown in Formulas (llj) and (llk):
(nj) (Hk) In some embodiments, when Ri, R2, R4, R5 and R6 are all hydrogens and R3 is a group such that the carbon of the group is directly bonded to C (4) or C (1), then the Stereochemistry is defined as is shown in Formulas (llm) and (Un). Examples for R3 may be selected from methyl, ethyl, / 7-propMo, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl and phenoxymethyl; or R3 may be selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, rj-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl, phenoxymethyl, methylsulfanylmethyl, ethoxymethyl, cyclopropyl, 1 -but-2-. enyl, and allyl:
(Um) (??) It is understood that all other possible stereochemical modalities and designations are encompassed by the invention. Some embodiments of the present invention pertain to compounds as depicted in TABLE 1 below. TABLE 1
In some embodiments, the compounds of the present invention pertain to the compounds of TABLE 2: TABLE 2
fifteen
twenty
In some embodiments, the compounds of the present invention pertain to the compounds of TABLE 3: TABLE 3
Additionally, the compounds of the present invention, for example those compounds found in Tables 1, 2 and 3 including the diastomers and enantiomers thereof, encompass all pharmaceutically acceptable salts, solvates, and particularly hydrates, thereof. It is understood that the present invention encompasses each diastomer, each enantiomer and mixtures thereof of each compound and generic Formulas described herein just as if they were each individually described with the specific stereochemical designation for each chiral carbon. For example, one embodiment of the present invention includes a compound with the stereochemistry (3bS, 4aS) or (1aS, 5aS). One embodiment of the present invention is selected from the group consisting of: (3bS, 4aS) -3b, 4,4a, 5-Tetrahydro-2H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-3- carboxylic acid; (1aS, 5aS) -4- (2H-Tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; and (1aS, 5aS) -1 a, 3,5,5a-Tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid. Similarly, one embodiment of the present invention includes a compound with the stereochemistry (3bR, 4aR) or (1af? 5af?). One embodiment of the present invention is selected from the group consisting of: (3bR, 4af?) - 3b, 4,4a, 5-Tetrahydro-2H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-3 -carboxylic acid; (1aR, 5af?) - 4- (2H-Tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; and (1a, 5af?) - 1 a, 3,5,5a-Tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid. In another example, one embodiment of the present invention includes a compound with endo- (1aR, 5aS) stereochemistry. One embodiment of the present invention is selected from the group consisting of: endo- (1aR, 5aS) -1-methyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- (1af ?, 5aS) -1-lsobutyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- (1af ?, 5aS) -1 -Butyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; e / ido- (1 aR, 5aS) -1-Methyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; endo- (1aR, 5aS) -1-Ethyl-4- (2 H -tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; endo- ^ aR, 5aS) -1-Pentyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- ^ aR, 5aS) -1-Propyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; endo- (1aR, 5aS) -1-Propyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo-aR, 5aS) -1-lsobutyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; endo- (1 af ?, 5aS) -1-Methoxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- (1af ?, 5aS) -1-Ethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; enoO- (1af ?, 5aS) enoO- (1af ?, 5aS) -1-phenyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3 -diaza-cyclopropa [a] pentalene; endo- (1 aR, 5aS) -1-Benzyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; endo- (1af ?, 5aS) -1-Benzyl-1 a, 3, 5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; ethyl ester of endo- ^ aR, 5aS) -1-Benzyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Endo- (1a, 5aS) -1-Phenyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ethyl ester; enoO- (1aR, 5aS) -1-Phenyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- (1af ?, 5aS) -1-Pentyl-4- (2H-tetrazol-5-yl) -1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; endo- (1 af ?, 5aS) -1-Butyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; Endo- (1aR, 5aS) -1-Ethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ethyl ester; Ethyl ester of endo- (1aR, 5aS) -1 -Methyl-1 a, 3, 5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Endo- (1af? 5aS) -1-Pentyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ethyl ester; endo- (1af ?, 5aS) -1-lsopropyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pe includes a compound with the ntalene; enoO- (1a, 5aS) -1-phenoxymethyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; endo- ^ aR, 5aS) -1-lsopropyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; enoO- (1af? 5aS) -1-Vinyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ethyl ester; endo- (1af ?, 5aS) -1-Vinyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- (aR, 5aS) -4- (2H-Tetrazol-5-yl) -1-vinyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; ethyl ester of endo- (1af ?, 5aS) -1-Ethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Endo- (1aR, 5aS) -1-Methoxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ethyl ester; enoO- (1 af ?, 5aS) -1-Methoxymethyl-4- (2H-Tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; ethyl ester of endo- ^ aR, 5aS) -1-Hydroxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- ^ aR, 5aS) -1-Hydroxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; and endo- (1aR, 5aS) - [4- (2H-Tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene-1-yl] -methanol. Another embodiment of the present invention is selected from the group consisting of: endo- (1af ?, 5aS) -1-Methylsulfanimethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a ] pentalene-4-carboxylic acid; embedded image (1 aR, 5aS) -1-Ethoxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- ^ aR, 5aS) -1-Chloropropyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; enoO- (1aft, 5aS) -1-Cyclopropyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; endo- (1 aR, 5aS) -1-Vinyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- ^ aR, 5aS) -4- (2H-Tetrazol-5-yl) -1-vinyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; (1aR, 5aS) -1-Spirocyclopropyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- (1 af ?, 5aS) -1 -espirocyclopropyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; endo- ^ aR, 5aS) - (E) -1-But-2-enyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; enoO- (1 aR, 5aS) - (Z) -1-But-2-enyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-acid carboxylic; endo- ^ aR, 5aS) - (£) -1-Propenyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [ a] pentalene; endo- (1aR, 5aS) - (Z) -1-Propenyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a ] pentalene; endo- ^ aR, 5aS) -1-Methoxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- ^ aR, 5aS) -1-Methoxymethyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; endo- ^ aR, 5aS) -1 - Phenoxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- ^ aR, 5aS) -Espiro [1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-1,1'-cyclopentane] -4-carboxylic acid; endo- (1aR, 5aS) -5- (Spiro- [1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-1,1'-cyclopentane] -4- il) -1 H-tetrazole; endo- (1aR, 5aS) -Espiro [1 a, 3, 5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-1,1'-cyclohexane] -4-carboxylic acid; gum- (1af ?, 5aS) -5- (Spiro- [1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-1, 1'-cyclohexane] -4 -yl) -1 H-tetrazole; enoO- (1 aR, 5aS) -1-Allyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; endo- (1af ?, 5aS) -1-Allyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; and endo- (1af ?, 5aS) -1-cyclopropylmethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid. It is understood that a compound, as described herein, having stereochemistry exo- (1af ?, 5aS), endo- (1aS, 5aR) and exo- (1aS, 5af?) Can be written analogously. In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure: or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure: or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, a compound of the present invention has the structure: or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, a compound of the present invention has the structure:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
QUÍMICA DE LA PRESENT I NVENCIÓN Special procedures for the preparation of the com ponents of the present invention. Some embodiments of the present invention pertain to synthetic processes for the preparation of novel fused pyrazoles of Formula (la). The compounds of the present invention can be readily prepared in accordance with these new processes using a variety of starting materials that are commercially available or are readily prepared by synthetic regimens which will be familiar to those skilled in the art. In the illustrated synthesis described below, unless otherwise stated, the labeled substituents have the same definitions as described herein.
A method that can be used to prepare the compounds of the invention where X is N and Z is C-tetrazol-5-yl uses intermediates derived from the cyclic ketone of Formula (A) as illustrated in Reaction Scheme I below : Scheme I
The compounds of Formula (Ia) can be prepared by reacting a cyclic ketone of Formula (A) with a dialkyloxalate of formula (C (O) OR 10) 2, wherein R 10 is a C 1-6 alkyl, in the presence of a base and a polar solvent such as, but not limited to, Ci-6 alkanol, methanol, ethanol, butanol, pentanol, hexanol, 2-methoxyethanol, isopropanol, THF, DMF and the like to produce ketoester of Formula (B). Suitable bases include alkali metal alkoxides, for example, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, and the like; alkali metal amides (i.e., alkali metal-NRn where Rn is d-6 alkyl or silyl-C-6-alkyl) for example, lithium diisopropylamide, lithium hexamethyldisilacid, sodium hexamethyldisilacid, potassium hexamethyldisilacid and similar bases. The ketoester (B) is reacted with hydrazine, protected or unprotected hydrazine can be used, under conditions suitable for producing pyrazole esters of Formula (C). Optionally, the pyrazole can be protected, for example, with a benzyl group and the like. Subsequently, the ester is converted to amide of Formula (D) using methods known to a person skilled in the art, for example, by treating with ammonia in a polar solvent at a temperature from room temperature to the boiling point of the solvent. The amide (D) is reacted with a dehydrating reagent, such as phosphorus oxychloride, phosphorus pentoxide, thionyl chloride, trifluoroacetic anhydride and the like, either neat or in the presence of a non-protic solvent, such as acetonitrile, DM F , and the like, to produce nitrile (E). The nitrile (E) is reacted with an acid (i.e., N3) or acid equivalent, such as, sodium acid, potassium acid, trimethylsilyl acid (i.e., (CH3) Si N3), and the like to produce Compounds of Formula (Ia) wherein X is N and Z is C-tetrazol-5-yl. In some cases it may be beneficial to exclude the presence of a Lewis acid, for example, AICI3, ZnB r2, and the like, in a suitable solvent, such as DM F and the like. Other compounds of the invention wherein X is N and Z is C-C02H or Z is N and X C02H can be prepared from intermediate C by hydrolysis to the corresponding acids of Formula (Ie) by lithium hydroxide, hydroxide of sodium, potassium hydroxide, potassium trimethylsilanoate or similar. This process is illustrated below for modalities is where X is N and Z is C-C02H.
A similar process can also be illustrated for embodiments of the present invention where X is C-C02H and Z is N.
In a manner similar to that described above in Scheme I, compounds of the present invention, wherein Z is N and X is C-tetrazoyl or C-C02H or C-C02-C- i -6-alkyl, can be prepared using the ketone (F).
Ketone compounds (F) can be prepared by cyclopropanation of the appropriate cyclopentenol by treating with a reagent that generates an appropriate carbene or carbenoid, such as, but not limited to, diiodoethane with diethyl zinc, dibromomethane and sodium hydroxide, and the like. The reagent that generates carbene or carbenoid can be selected with the appropriate substitution to directly introduce R2 and R3 to the ketone (F) or to introduce group (s) (ie, represented by R12 and R1 3) which can be subsequently converted to groups R2 and R3 using methods known in the art. The cyclopentyl alcohol can be oxidized to the cyclic ketone by oxidizing agents such as pyridium chlorochromate, tetrapropylammonium perruthenate, and similar oxidizing agents. This process is illustrated below.
The compounds can be prepared by treating a suitable 1, 2-epoxy-5,6-alkene appropriately substituted with a strong base such as lithium tetramethylpipericide, lithium disopropylamide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane and similar bases for producing Alcohol (M), see Hodson, et al., J. Am. Chem. Soc. 2004, 126, 8664. Subsequently, alcohol can be converted to ketone (L) using an oxidizing agent, such as, but not limited to a, pyridium chlorochromate, tetrapropylammonium perruthenate, and the like.
The chiral (non-racemic) compounds of the invention can be prepared by kinetic hydrolytic resolution of Epoxide (G) using the published method (Schaus, SE; Brandes, BD; Larrow, JF; Tokunga, M; Hansen, KB; Gould, A; E,; Furrow, ME; Jacobsen, ENJ Am. Chem. Soc. 2002, 124, 1307). Alternatively, other substituted (L) Ketones can be prepared by addition of the anion generated by reaction of trimethylsulfoxonium iodide and a suitable base such as sodium hydride, potassium hydride, and the like to an appropriate cyclopentenone.
Another method that can be used to prepare compounds of the present invention, wherein X or Z is C-tetrazol-5-yl, is described herein. This method allows the option of directly introducing the tetrazol-5-yl group without the need of using several steps or an acid reagent. This method is illustrated in the scheme below where X is N and Z is C-tetrazol-yl:
An appropriately substituted Ketone (A) can be converted to Dicetone (O) using Tetrazole (P) in the presence of a base, where PG is a suitable metal cation or protective group. A suitable base to be used in the reaction is one which is soluble in the solvent and can remove a proton from the cyclopentanone, but which does not participate otherwise in the reaction. Strong organic bases are particularly useful, such as DB U, DB N, tetramethylguanidine or alkali or alkaline earth metal bases, such as sodium or magnesium alkoxides, and particularly potassium butoxide. Suitable sterile groups (ie, LG) include groups that can be displaced without affecting the stability of the resulting Tetrazole (P) or Dicetone (O), some examples include esters (d-alkoxy or substituted benzyloxy). Suitable solvents include dimethylformamide (DM F), dimethylacetamide (DMAC), dimethylsulfoxide (DMSO), N-methylpyrrolidinone (N M P), and H M PT as well as tetrahydrofuran (TH F). In the same reaction or as an additional step after isolation, Dicetone (O) is converted to Tetrazole (Q) using hydrazine. The protecting group is subsequently removed to provide compounds of the present invention. A similar process can also be used for embodiments of the present invention wherein X is C-tetrazol-5-yl and Z is N.
The various transformations of organic groups and protective groups used herein may be carried out by a number of procedures other than those described above. References for other synthetic procedures that can be used for the preparation of the intermediates or compounds described herein can be found in, for example, Smith, M. B.; and March, J. , Advanced Organic Chemistry, 5th Edition, Wiley-l nterscience (2001); Larock, R. C., Cromprehensive Organic Transformations, A Guide to Functional Group Preparations, 2nd Edition, VCH Publishers, I nc. (1 999), or Wuts, P.G. M.; Greene, T.W. , Protective Groups in Organic Systhesis, 3rd Edition, John Wiley and Sons, (1 999), the three incorporated herein by reference in their entirety. Racemic mixtures can be broken down into the pure optical enantiomers by known methods, for example, by separating the diastereomeric salts thereof with an optically active acid, and releasing the optically active amine compound by treatment with a base or salt separation. diastereomers with an optically active base and subsequently releasing the acid by treatment with an acid. Another method for decomposing racemates into the pure optical enantiomers is based on chromatography on an optically active chiral matrix or support. Certain racemic compounds of the present invention can thus be decomposed in their optical antipodes, for example, by fractional crystallization of for example d- or 1- (tartrate, mandelate, or camphor sulfonate) salts. The compounds of the present invention can be decomposed by the formation of amides or diastereomeric esters by reaction of the compounds of the present invention with an optically active amine or alcohol, such as, but not limited to, (+) or (-) a-methylbenzylamine, (+) or (-) a-methylbenzylalcohol, and the like, separated by means of fractional recrystallization, chiral chromatography or a similar method, and subsequently hydrolysates. Additional methods for the decomposition of optical isomers known to those skilled in the art can be used and will be apparent to the average worker skilled in the art. Such methods include those discussed by J. Jacques, A. Collet, and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1 981). It is understood that the chemistry described herein is representative and is not intended to be limiting in any way.
Methods and Uses The compounds of the present invention are useful in inhibiting the production of free fatty acids. In addition, the compounds of the present invention are useful in the inhibition of the production of free fatty acids resulting in minor side effects of redness or in some cases not measurable. Redness is a side effect commonly associated with the administration of niacin. The compounds of the present invention usually do not cause vasodilation in doses as high as about 300 mpk measured using methods known in the art, such as the method shown in Example 7. In some embodiments, the compounds of the present invention cause essentially reddening not measurable in an individual compared to an essentially equally effective dose of niacin. In other embodiments, the compounds of the present invention cause less than about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25% , 20%, 15%, 10%, 5%, or 1% of redness measurable in an individual compared to a dose of niacin essentially equally effective. The compounds of the present invention can modulate the activity of the RUP25 receptor. The term "modular" is intended to refer to the ability to increase or decrease the activity of the recipient. In some modalities, the compounds of the invention can be used in modulation methods of a RUP25 receptor by contacting the receptor with one or more of the compounds described herein. In still other embodiments, the compounds of the invention can be used in methods of the modulation method of a RUP25 receptor for the treatment of a disorder related to metabolism in an individual in need of such modulation comprising contacting the receptor with a Therapeutically effective amount of a compound of Formula (Ia). In some embodiments, the compounds of the invention increase the activity of the RUP25 receptor. In other embodiments, the compounds of the invention are fighters of the RUP25 receptor. The term "combatant", as used herein, refers to agents that can stimulate receptor activity (ie, activate), such as the RUP25 receptor. In some embodiments, the compounds of the invention are partial fighters of the RU P25 receptor. Another aspect of the present invention pertains to methods of treating a disorder related to metabolism comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (Ia). Another aspect of the present invention pertains to methods of raising HDL in an individual comprising administering to said individual a therapeutically effective amount of a compound of Formula (Ia). Another aspect of the present invention pertains to compounds of Formula (Ia), described herein, for use in a method of treating a human or animal body by therapy. Another aspect of the present invention pertains to compounds of Formula (la), described herein, for use in a method of treating a disorder related to the metabolism of the human or animal body by therapy. Another aspect of the present invention pertains to compounds of the Formula (la), described herein, for use in a method of treating a disorder related to the metabolism of the human or animal body by therapy where said disorder related to the metabolism is selected from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity, glucose intolerance, atheromatous diseases, hypertension, stroke, Syndrome X, heart disease and type 2 diabetes. Another aspect of the present invention belongs to compounds of Formula (Ia), described herein, for use in a method of treating a disorder related to the metabolism of the human or animal body by therapy where said disorder related to metabolism is selected from the group consisting of dyslipidemia , atherosclerosis, coronary heart disease, insulin resistance and type 2 diabetes. Other aspec The present invention pertains to compounds of Formula (Ia), described herein, for use in a method of treating atherosclerosis of the human or animal body by therapy. Another aspect of the present invention pertains to compounds of Formula (Ia), described herein, for use in a method of raising the H-DL of the human or animal body by therapy. Another aspect of the present invention pertains to uses of the compounds of Formula (Ia), described herein, for the manufacture of a medicament to be used in the treatment of a disorder related to metabolism. Another aspect of the present invention pertains to uses of the compounds of the Formula (la), described herein, for the manufacture of a medicament to be used in the treatment of a disorder related to the metabolism selected from the group consisting of dyslipidemia, atherosclerosis , coronary heart disease, insulin resistance, obesity, glucose intolerance, atheromatous diseases, hypertension, stroke, S syndrome X, heart disease and type 2 diabetes. Another aspect of the present invention pertains to uses of the compounds of the Formula ( the), described herein, for the manufacture of a medicament to be used in the treatment of atherosclerosis. Another aspect of the present invention pertains to uses of the compounds of Formula (Ia), described herein, for the manufacture of a medicament for use in raising HDL in an individual. Some embodiments of the present invention relate to methods of treating disorders related to metabolism. In some modalities, the disorder related to metabolism is from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity, glucose intolerance, atheromatous diseases, hypertension, stroke, S syndrome X, heart disease and diabetes type 2. In some modalities, the disorder related to metabolism is dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance and type 2 diabetes. In some modalities, the disorder related to the metabolism is dyslipidemia. In some modalities the disorder related to metabolism is atherosclerosis. In some modalities, the disorder related to metabolism is coronary heart disease. In some modalities the disorder related to metabolism is insulin resistance. In some embodiments, the disorder related to metabolism is type 2 diabetes. In some embodiments related to methods of the present invention, the individual is a mammal. In other modalities, the mammal is a human. Another aspect of the present invention pertains to methods of producing a pharmaceutical composition comprising mixing or combining a compound of Formula (Ia), described herein, and a pharmaceutically acceptable carrier.
Compositions of the Present Invention Some embodiments of the present invention include pharmaceutical compositions comprising a compound according to Formula (la) in combination with a pharmaceutically acceptable carrier. Some embodiments of the present invention include a method for the production of a pharmaceutical composition comprising the mixture of at least one compound according to any of the embodiments of the compound described herein and a pharmaceutically acceptable carrier. The formulations can be prepared by any suitable method, generally by uniformly mixing the active compounds with liquid carriers or finely divided solids, or both, in the required proportions, and then, if necessary, shaping the resulting mixture into a desired form. . Conventional excipients, such as binding agents, fillers, acceptable wetting agents, lubricants for tabletting, and disintegrating can be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, the oral preparations may be in the form of dry powder which may be reconstituted with water or other suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms can be prepared by dissolving the compound of the invention in an appropriate liquid vehicle and filter by sterilizing the solution before filling and sealing an appropriate vial or vial. These are only a few examples of the many appropriate methods well known in the art for the preparation of dosage forms. A compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art. Suitable pharmaceutically acceptable carriers, other than those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro, A.R., and others). Although it is possible that a compound to be used in the treatment of the present invention can, in an alternative use, be administered as raw or pure chemical, it is preferable, however, to present the compound or "active ingredient" as a pharmaceutical formulation or composition that further comprises a pharmaceutically acceptable carrier. Accordingly, an aspect of the present invention comprises pharmaceutical compositions in combination with at least one compound according to Formula (Ia). The invention provides pharmaceutical formulations comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, together with one or more pharmaceutically acceptable carriers therefor. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not too deleterious to the recipient thereof. Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a patch transdermal The transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption efficiently with minimal degradation of the drug. Generally, transdermal patches comprise an impermeable backcoat layer, a simple pressure sensitive adhesive and a removable protective layer with a release liner. Someone with ordinary skill in the art will understand and appreciate the appropriate techniques for the fabrication of a desired effective transdermal patch based on the manufacturer's needs. The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, can thus be placed in the form of pharmaceutical formulations and unit dosages thereof, and in such a manner can be employed as solids, such as tablets or filled capsules, liquids such as solutions, suspensions, emulsions, elixirs, gel or capsules filled with them, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous). Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active components or printers, and such unit dosage forms contain any suitable effective amount of the active ingredient in proportion to the dosage range. daily scheduled to be used.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch, potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient can also be administered by injection as a composition in which, for example, saline, dextrose or water can be used as a suitable pharmaceutically acceptable carrier. The compounds of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, can be used as active ingredients in pharmaceutical compositions, specifically as combatants / partial combatants of the RU P25 receptor. The term "active ingredient" is defined in the context of a "pharmaceutical composition" and will mean a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient" which would generally be recognized as providing a benefit essentially not pharmaceutical.
The dosage when using the compounds of the present invention can vary within wide limits, and as is customary and is known to physicians, it must be adjusted to the conditions of the individual in each individual case. It depends, for example, on the nature and severity of the disease to be treated, on the condition of the patient, on the compound used or on whether an acute or chronic disease state is treated or on whether other active compounds are administered in addition to the compounds of the present invention. Representative doses of the present invention include, but are not limited to, from about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, of 0.001 mg a about 500 mg, from 0.001 mg to about 250 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg. Multiple doses can be administered during the day, especially when relatively large amounts are considered necessary, for example 2, 3 or 4, doses. Depending on the individual and as deemed appropriate by the patient's physician or specialist it may be necessary to deviate up or down from the dose described here. The amount of active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof, required to be used in the treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated. treated and the age and condition of the patient. Correspondingly, the amount used will ultimately be at the discretion of the physician or clinician in charge. In general, one skilled in the art understands how to extrapolate the in vivo data obtained in one model system to another, for example, an animal to a human model. Usually, animal models include, but are not limited to, rodent diabetes models such as that described in Example 1, infra; the mouse atherosclerosis model as described in Example 2, infra; or the animal atherosclerosis in vivo model as shown in Example 5, infra. In some circumstances, these extrapolations may be based merely on the weight of the animal model compared to another, such as, a mammal and preferably a human. However, more often, these extrapolations are not based on weight differences, but rather incorporate a variety of factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as activity, efficiency, pharmacokinetic profiles and toxicology. of the particular compound employed, if a delivery system of the medicament is used, of whether an agonized or chronic state of the disease is being treated, of whether other compounds are administered in addition to the compounds of the present invention as part of a combination therapy. . The dosage regimen for treating a disease condition with the compounds and / or compositions of this invention is selected in correspondence with a variety of factors, such as those cited above. Thus, the actual dosage regimen can vary considerably and therefore can deviate from a preferred dosage regimen and one skilled in the art will recognize that the dosage and dosing regimen outside these typical ranges can be tested and, where appropriate, they can be used in the methods of this invention. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself can continue to be divided, for example, into a number of discrete, spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, in several, for example, 2, 3 or 4, partial administrations. If appropriate, depending on the behavior of the individual, it may be necessary to deviate upwards or downwards from the indicated daily dose. The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as an active component, a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
To prepare pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carriers can be solids or liquids. Preparations in solid form include powders, tablets, pills, capsules, pills, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binder capacity in suitable proportions and compacted in the desired shape and size. The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 95% of the active compound; however, a manufacturer would know when quantities outside this range are necessary. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, carboxymethylcellulose sodium, a reducing melting wax, cocoa butter, and the like . The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier that provides a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with he . Similarly, capsules and pills are included. Tablets, powders, capsules, pills, and pills can be used as solid forms suitable for oral administration. To prepare suppositories, a wax below melting point, such as a mixture of fatty acid glycerides or cocoa butter, is fused first and the active component is dispersed homogeneously therein, by agitation. The homogeneous fused mixture is then pulverized into molds of suitable size, allowed to cool, and in this way solidify. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams and sprays containing in addition to the active ingredient carriers such as those known in the art as appropriate. The liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, liquid parenteral injection preparations can be formed in aqueous polyethylene glycol solution. Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed, sterile oils are conveniently used as a solvent or suspension medium. For this purpose any soft fixed oil may be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds according to the present invention can thus be formulated for parenteral administration (for example, by injection, for example bolus injection or continuous infusion) and can be presented in unit dose form in ampoules, prefilled syringes, infusion of small volume or multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in the form of powder, obtained by aseptic isolation of sterile solid or by lyophilization from the solution, for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the active component finely divided in water with viscous material, such as natural or synthetic gum, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizers, and the like. For topical administration to the epidermis the compounds according to the invention can be formulated as ointments, creams or lotions, or as a transdermal patch. The ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickeners and / or gelatinizers. The lotions can be formulated with an aqueous or oily base and in general will also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pills comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprising the active ingredient in a suitable liquid carrier. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or atomizer. The formulations can be provided in single or multiple dose form. In the latter case of a dropper or pipette, this can be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of an atomizer, this can be achieved for example by means of a dosing atomizing pump. Administration directly to the respiratory tract can also be achieved by an aerosol formulation in which the active ingredient is provided in a pressurized package with a suitable propellant. If the compounds of the Formula (Ia) or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal sprays or by inhalation, this can be accomplished, for example, by using an atomizer, a nebulizer, a pump nebulizer. , an inhalation device, a metered dose inhaler or a dry powder inhaler. The dosage forms for administering the compounds of Formula (Ia) as an aerosol can be prepared by processes well known to the person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the Formula (Ia) in water, water / alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, enhancers of the absorption, to increase bioavailability, solubilizers, dispersants and others, and if appropriate, customary propellants, for example include carbon dioxide, CFC, such as, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoromethane; and if milar. The aerosol may also conveniently contain a surfactant such as lecithin. The dosage of medication can be controlled by providing a dosing valve. In the formulations designed for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such particle size can be obtained by means known in the art, for example by micronization. When desired, formulations adapted to provide sustained release of the active ingredient can be employed. Alternatively, the active ingredients may be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition can be presented in the form of unit doses for example in capsules or cartridges of, for example, gelatin, or packets of ampoules from which the powder can be administered via an inhaler. The pharmaceutical preparations are preferably in the form of unit dosages. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, such as packed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form itself may be a capsule, tablet, pill or pill, or it may be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions. Such tablets and capsules usually contain about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, or about 0.001 mg to about 250 mg of a compound of Formula (Ia).
The compounds of the present invention can be converted into "prodrugs". The term "prodrugs" refers to compounds that have been modified with specific chemical groups known in the art and when administered to an individual those groups undergo biotransformation to produce the mature compound. Thus prodrugs can be viewed as compounds of the invention which contain one or more specialized non-toxic protective groups used transiently to alter or eliminate a property of the compound. In general, the "prodrug" approach is used to facilitate oral absorption. A detailed discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of A.C.S Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B Roche, American Pharmaceutical Association and Pergamon Press, 1 987, both are incorporated herein by reference in their entirety.
Terapi a com bi natori a: Although the compounds of the present invention can be administered as the only active pharmaceutical agent (ie, monotherapy), they can also be used in combination with other pharmaceutical agents (ie, combinatorial therapy), such as, for the treatment of the diseases / conditions / disorders described herein. Accordingly, another aspect of the present invention includes methods of treating diseases related to metabolism comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with one or more pharmaceutical agents. additional as described here. Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include anti-obesity agents such as inhibitors of apolipoprotein-B / microsomal triglyceride transfer protein (apo-B / MTP) secretion, MCR-4 fighters, cholescistokinin-A fighters (CCK-A), serotonin and norepinephrine reuptake inhibitors (eg, sibutramide), sympathomimetic agents, ß3 adrenergic receptor fighters, dopamine fighters (eg, bromocriptine), melanocyte-stimulating hormone receptor analogs, cannabinoid receptor 1 antagonists [e.g., S R141 71 6: A / - (piperidin-1 -yl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide], melanin-concentrating hormone antagonists, leptons (OB protein), leptin analogues, leptin receptor fighters, antagonists of galanin, inhibi lipase agonists (such as tetrahydrolipstatin, ie, Orlistat), anorectic agents (such as a bombesin fighter), Neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid receptor combatants or antagonists, orexin receptor antagonists, urocortin agglutinant protein antagonists, glucagon-like peptide-1 receptor combatants, neutrotrophic cialiares factors (such as Axokine ™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati OH), agouti related human proteins (AGRP), ghrelin receptor antagonists, antagonists or inverted histamine 3 receptor fighters, neuridine U receptor fighters, non-adrenergic anorexic agents (e.g., phentermine, Mazindol and the like) and appetite suppressants (for example, bupropion). Other anti-obesity agents, including the agents raised infra, are well known, or will be readily apparent in the light of the instant description, to someone skilled in the art. In some modalities, anti-obesity agents are selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine. In another embodiment, the compounds of the present invention and combinatorial therapies are administered in conjunction with exercise and / or a sensible diet. It is understood that the scope of the combinatorial therapy of the compounds of the present invention with other anti-obesity agents, anorectic agents, appetite suppressants and related agents is not limited to those mentioned above, but includes in principle any combination with any agent Pharmaceutical or combination pharmaceutical nation useful for the treatment of overweight or obese individuals.
Other suitable pharmaceutical agents, in addition to the anti-obesity agents, which may be used in combination with the compounds of the present invention include agents useful in the treatment of concomitant disorders. The treatment of such disorders includes the use of one or more pharmaceutical agents known in the art to belong to the classes of medicaments referred to, but not limited to, the following: sulfonylurea, meglitinide, biguanide, a-glucosidase inhibitor , fighters of the receiver-? peroxisome proliferator-activated (ie, PPAR-?), insulin, insulin analogues, H-MG-CoA-uctase inhibitors, cholesterol-lowering drugs (eg, fibrates including: fenofibrate, bezafibrate, gemfibrozil, clofibrate and similar, bile acid sequestrants including: cholestyramine, colestipol and the like, and niacin), antiplatelet agents (eg, aspirin and adenosine diphosphate receptor antagonists including: clopidogrel, ticlopidine and the like), converting enzyme inhibitors of angiotensin, angiotensin II receptor antagonists and adiponectin. In accordance with one aspect of the present invention, a compound of the present invention can be used in combination with a pharmaceutical agent or agents belonging to one or more of the classes of medicaments cited herein. It is understood that the scope of the combinatorial therapy of the compounds of the present invention with other pharmaceutical agents is not limited to those listed herein, supra or infra, but in principle includes any combination with any pharmaceutical agent or pharmaceutical composition useful for the treatment of diseases, conditions or disorders that are linked to disorders related to metabolism. Some embodiments of the present invention include methods of treating a disease, disorder or condition described herein comprising administering to an individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention in combination with at least one pharmaceutical agent selected from the group consisting of: sulfonylureas, meglitinides, biguanides, a-glucosidase inhibitors, receptor-fighters. activated by peroxisome proliferators (ie, PPA -?), insulin, insulin analogues, HMG-CoA reductase inhibitors, cholesterol-lowering drugs (eg, fibrates including: fenofibrate, bezafibrate, gemfibrozil, clofibrate and similar, bile acid sequestrants including: cholestyramine, colestipol and the like, and niacin), antiplatelet agents (eg, aspirin and adenosine diphosphate receptor antagonists including: clopidogrel, ticlopidine and the like), inhibitors of the enzyme angiotensin, angiotensin II receptor antagonists and adiponectin a. In some embodiments, the pharmaceutical composition further comprises one or more agents selected from the group consisting of a-glucosidase inhibitors, aldose reductase inhibitors, biguanide, inhibitors of the HMG-CoA uctase network, inhibitor of squalene synthesis, fibrate , enhancer of LDL catabolism, angiotensin-converting enzyme inhibitor, insulin secretion enhancer, thiazolidinedione and DP receptor antagonist. One aspect of the present invention encompasses pharmaceutical compositions comprising at least one compound of the present invention, as described herein. In some embodiments, the pharmaceutical composition further comprises one or more agents selected from the group consisting of a-glucosidase inhibitor, aldose reductase inhibitor, biguanide, HMG-CoA reductase inhibitor, squalene synthesis inhibitor, fibrate, LDL catabolism enhancer, angiotensin-converting enzyme inhibitor, enhancer of insulin secretion and thiazolidinedione. Suitable pharmaceutical agents that can be used in conjunction with compounds of the present invention include the α-glucosidase inhibitors. A-glucosidase inhibitors belong to the class of drugs that completely inhibit digestive enzymes such as a-amylase, maltase, a-dextrinase, sucrose, etc. , in the pancreas and or the small intestine. Reversible inhibition by inhibitors of a-glucosidase slows down, otherwise lowers or reduces blood glucose levels by delaying the digestion of starch and sugars. Some representative examples of α-glucosidase inhibitors include acarbose, N- (1,3-dihydroxy-2-propyl) vale-lamina (generic name); voglibose), muglitol, and a-glucosidase inhibitors known in the art. Suitable pharmaceutical agents that can be used in conjunction with the compounds of the present invention include the sulfonylureas. Sulfonylureas (SU) are drugs that promote the secretion of insulin from the pancreatic ß cells by transmitting signals of insulin secretion through SU receptors in cell membranes. Examples of sulfonyl ureas include glyburide, glipizide, glimepiride and other sulfonylureas known in the art. Suitable pharmaceutical agents that can be used in conjunction with the compounds of the present invention include meglitinides. Meglltinides are benzoic acid derivatives that represent a new class of insulin secretagogues. These agents point to postprandial hyperglycaemia and show an efficacy similar to that of sulfonylureas in the reduction of HbAi c. Examples of meglitinides include repaglinide, nateglinide and other meglitinides known in the art. Suitable pharmaceutical agents that can be used in conjunction with the compounds of the present invention include the biguanides. Biguanides represent a class of drugs that stimulate anaerobic glycolysis, increase insulin sensitivity in peripheral tissues, inhibit the absorption of glucose from the intestine, suppress hepatic gluconeogenesis, and inhibit the oxidation of fatty acid. Examples of biguanides include phenformin, metformin, buformin, and biguanides known in the art. Suitable pharmaceutical agents that can be used in conjunction with the compounds of the present invention include the α-glucosidase inhibitors. The a-glucosidase inhibitors completely inhibit the digestive enzymes such as α-amylase, maltase, α-dextrinase, sucrose, etc. in the pancreas and or the small intestine. Reversible inhibition by inhibitors of a-glucosidase slows down, otherwise lowers or reduces blood glucose levels by delaying the digestion of starch and sugars. Representative examples of α-glucosidase inhibitors include acarbose, N- (1,3-dihydroxy-2-propyl) valiolamine (generic name: voglibose), mug lithol, and a-glucosidase inhibitors known in the art. Suitable pharmaceutical agents that can be used in conjunction with the compounds of the present invention include the fighters of the receptor-? activated by peroxisome proliferators (ie, PPAR-?). The fighters of the receiver-? activated by peroxisome proliferators represent a class of compounds that activate the nuclear receptor PPAR-? and therefore they regulate the transcription of the genes responsible for the insulin involved in the control of the production, transportation and utilization of glucose. Agents in the class also facilitate the regulation of fatty acid metabolism. Examples of PPAR- fighters? include rosig litazone, pioglitazone, tesaglitazar, netoglitazone, GW-409544, GW-501 516 and PPAR-? combatants. known in the art. Suitable pharmaceutical agents that can be used in conjunction with the compounds of the present invention include the DP receptor antagonists. DP receptor antagonists include those described in patent applications WO01 / 79169, WO03 / 062200, WO01 / 66520, WO03 / 0228 4, WO03 / 078409, WO2004 / 1 03370, EP 1 305286, WO02 / 094830, and the like. Other representatives of DP antagonist compounds can be found in WO04 / 03370. Examples of compounds that are particularly useful for selectively antagonizing the DP receptor include the following:
The pharmaceutically acceptable salts, solvates and hydrates thereof are included. The compound AB can be synthesized in correspondence with the description presented in WO01 / 66520A1 published on September 3, 2001; the AC compound can be synthesized in correspondence with the description presented in WO03 / 022814A1 published on March 20, 2003, and the compounds AD and AE can be synthesized in correspondence with the description presented in WO03 / 078409 published on September 25, 2003. Suitable pharmaceutical agents that can be used in conjunction with compounds of the present invention include the HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors are agents also called Statin compounds that belong to a class of drugs that lower blood cholesterol levels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA) reductase. HMG-CoA reductase is the speed limiting enzyme in cholesterol biosynthesis. Statins reduce serum concentrations of LDL by upregulating the activity of LDL receptors and are responsible for eliminating LDL from the blood. Some representative examples of the Statin compounds include rosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, pitavastatin,
"superstatin" of BMS, and the HMG-CoA reductase inhibitors known in the art.
Suitable pharmaceutical agents that can be used in conjunction with the compounds of the present invention include the inhibitors (ACE) of the angiotensin-converting enzyme. Angiotensin-converting enzyme inhibitors belong to the class of drugs that partially regulate blood glucose levels, in addition to reducing blood pressure by inhibiting angiotensin-converting enzymes. Examples of angiotensin converting enzyme inhibitors include captopril, enalapril, alacepril, delapril; ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril, perindopril, quinapril, espirapril, temocapril, trandolapril, and angiotensin-converting enzyme inhibitors known in the art. Suitable pharmaceutical agents that can be used in conjunction with the compounds of the present invention include angiotensin I I receptor antagonists. Antagonists of angiotensin I I receptors point to subtype 1 of angiotensin I I receptors (ie, ATI) and demonstrate their beneficial effect in hypertension. Examples of angiotensin I I receptor antagonists include losartan (and the potassium salt form), and angiotensin I I receptor antagonists known in the art. Other treatments for one or more of the diseases cited herein include the use of one or more pharmaceutical agents known in the art to belong to the classes of drugs referred to, but not limited to, the following: amylin fighters (e.g., pramlintide) ), insulin secretagogues (eg, GLP-1 fighters, exendin-4, insulinotropin (N N221 1), dipeptyl peptidase inhibitors (eg, NVP-DPP-728), the inhibitors of acyl CoA cholesterol acetyltransferase ( for example, Ezetimibe, eflucimibe, and other similar compounds), cholesterol absorption inhibitors (e.g., ezetimibe, pamaqueside and other similar compounds), inhibitors of the cholesterol ester transfer protein (e.g., CP-529414, JTT- 705, CETi-1, torcetrapiba and other similar compounds), inhibitors of the microsomal triglyceride transfer protein (e.g., implitapide, and other similar compounds), modulating s of cholesterol (for example, NO-1 886, and other similar compounds), bile acid modulators (for example, GT1 03-279 and other similar compounds), inhibitors of squalene synthesis and 1 1 p-HSD1 inhibitors. Inhibitors of squalene synthesis belong to a class of drugs that lower the level of blood cholesterol by inhibiting the synthesis of squalene. Examples of squalene synthesis inhibitors include (S) -a- [Bis [2,2-dimethyl-1-oxopropoxy) methoxy] phosphinyl] -3-phenoxybenzenebutanesulfonic acid, mono potassium salt (BMS-1 88494) and the squalene synthesis inhibitors known in the art. According to the present invention, the combination can be used by mixing the respective active components, either all together or independently with a carrier, excipient, binder, diluent, etc. , pharmaceutically accepted, as described hereinbefore, and administering the mixture or mixtures either orally or non-orally in the form of a pharmaceutical composition. When a compound of the present invention is administered as a combinatorial therapy with another active compound, the therapeutic agents can be formulated as separate pharmaceutical compositions delivered at the same time or at different times or the therapeutic agents can be delivered as a single composition. According to the present invention, the combination of a compound of the present invention and a pharmaceutical agent can be prepared by mixing the respective active components, either all together or independently with a carrier, excipient, binder, or diluent, etc. , pharmaceutically accepted, as described hereinbefore, and administering the mixture or mixtures either orally or non-orally in the form of a composition. When a compound of the present invention is administered as a combinatorial therapy with another active compound, the therapeutic agents can be formulated as separate pharmaceutical compositions delivered at the same time or at different times, or the therapeutic agents can be delivered as separate separate compositions. .MARKED COMPOUNDS AND TEST METHODS Another objective of the present invention relates to the radiolabelled compounds of Formula (Ia) and the formulas related thereto which are useful not only in radioimaging but also in assays, both in vitro and in vitro. vivo, to locate and quantitate RUP25 in tissue samples, including humans, and to identify ligands of the RUP25 receptor by inhibiting the binding of a radiolabeled compound. It is also an object of this invention to include new RUP25 assays comprising these radiolabelled compounds. The present invention comprises isotopically-labeled compounds of Formula (Ia) and any subgenre thereof, such as, but not limited to, Formulas (la) to (lo). The "isotopically" or "radiolabelled" compounds are those which are identical to the compounds described herein, except for the fact that one or more atoms are replaced or replaced by an atom having an atomic mass or a different mass number of the atomic mass or the atomic number typically found in nature (that is, as naturally exits). Suitable radionuclides that can be incorporated into compounds of the present invention include, but are not limited to, 2H (also written as D by deuterium), 3H (also written as T by tritium),
1 1 C > 1 3C i 1 C 1 3 N > 1 5 N) 1 5Q j 1 23l, 2 l, 25l and 1 31 L. The radionuclide that is incorporated into the radiolabeled instant compounds will depend on the specific application of that radiolabeled compound. For example, for RUP25 tagging and competition assays in vitro, compounds that incorporate 3H, 4C, 82Br, 1 25l, 3 l, or 35S will generally be the most useful. For radio-imagery applications C, 1 8F, 1 25l, 1 23l, 1, 13, 75Br, 76B r or 77Br will usually be the most useful. It is understood that "radiolabelled" or "labeled compound" is a compound of the present invention that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from the group consisting of 3H, 14C, 25l, 35S and 82Br. Certain isotopically-labeled compounds of the present invention are useful in compound and / or substrate tissue distribution assays. In some embodiments the 3 H radionuclide and / or the 1 4 C isotopes are useful in these studies. In addition, replacement with heavier isotopes such as deuterium (ie, 2H) can produce certain therapeutic advantages resulting from their greater metabolic stability (eg, increased in vivo half-life or reduced dose requirements) and thus So much can be preferred in certain circumstances. The isotopically-labeled compounds of the present invention can generally be prepared following procedures analogous to those described above in Schemes supra and Examples infra, substituting an isotopically labeled reagent for an isotopically unlabeled reagent. Other synthetic methods that are useful are discussed infra. Furthermore, it should be understood that all the atoms represented in the compounds of the invention can be the isotope that most often exists in said atoms or the radioisotope or radioactive non-radioactive isotope. The synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the invention and are well known in the art. These synthetic methods, for example, that incorporate levels of tritium activity to target molecules, and are as follows: A. Catalytic Reduction with Tritium Gas - This procedure usually results in products of high specific activity and requires halogenated precursors. or not saturated. B. Reduction with Sodium Borohydride [3H] - This process is quite cheap and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, and others. C. Reduction with Lithium Aluminum Hydride [3H] - This procedure offers products with specific, almost theoretical activities. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, and others. D. Marking by Tritium Gas Exposure - This procedure involves the exposure of precursors containing interchangeable protons to tritium gas in the presence of an appropriate catalyst.
E. N-Methylation using Methyl Iodine [3 H] - This procedure is generally used to prepare O-methyl or N-methyl (3 H) products by treating the appropriate precursors with high specific activity (3 H) methyl iodine. This method usually allows a higher specific activity, such as, for example, about 70-90 Ci / mmol. Synthetic methods for incorporating 1 251 activity levels into target molecules include: A. Sandmeyer reactions and the like - This process transforms an aryl or heteroaryl amine into a diazonium salt, such as a tetrafluoroborate salt, and subsequently into a 25l labeled compound using Na1 25l. A procedure represented was reported by Zhu, D.-G. and collaborators in J. Org. Chem. 2002, 67, 943-948. B. Ortho 125Podolization - This procedure allows the incorporation of 1 25l in the ortho position of a phenol as reported by Collier, T. L. and collaborators in J. Labeled Compd Radiopharm. 1999, 42, S264-S266. C. Interchange of aryl and heteroaryl bromide with 1 25l - This method is usually a two-step process. The first step is the conversion of the aryl bromide or heteroaryl to the corresponding tri-alkyltin intermediate using, for example, a catalyzed reaction of Pd [ie Pd (Ph3P) 4] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltin halide or hexaalkyldistane [e.g., (CH3) 3S nS n (CH3) 3]. A represented procedure was reported by Bas, M.-D. and collaborators in J. Labeled Compd Radiopharm. 2001, 44, S280-S282. A radiolabelled RUP25 compound of Formula (Ia) can be used in a detection assay to identify / evaluate compounds. In general terms, the ability of a newly synthesized or identified compound (ie, test compound) to reduce the binding of the "radiolabelled" compound of Formula (Ia) to the RU P25 receptor can be evaluated. Accordingly, the ability of a test compound to compete with the "radiolabeled" compound of the Formula (la) at the binding to the RU P25 receptor is directly correlated with its binding affinity. The labeled compounds of the present invention bind to the RU P25 receptor. In one embodiment the labeled compound has an I C50 less than about 500 μ? , in another embodiment, the labeled compound has an IC50 of about 1 00 μ? , and still in another embodiment, the labeled compound has an IC50 less than about 1.0 μ? , and still in another embodiment, the labeled compound has an I C50 less than about 1 μ? , and even in another modality, the labeled inhibitor has an IC50 less than about 0.1 μ? . Other uses of the receptors and methods described will be apparent to those in the art based, inter alia, on a review of this disclosure. As will be recognized, the steps of the methods of the present invention do not need to be executed a particular number of times or in any particular sequence. Other objectives, advantages, and novel features of this invention will be apparent to those skilled in the art when examining the following examples thereof, which are intended to be illustrative and not limiting. EXAMPLES The following examples are offered for illustrative purposes and not as a means of limitation. One of ordinary skill in the art would be able to design tests and equivalent methods based on the descriptions contained herein, all of which form a part of the present invention.
Example 1 MODELS OF DIEBETES OF RODENTS Rodent models of type 2 diabetes associated with obesity and insulin resistance have been developed. Genetic models such as db / db and ob / ob have been developed [see Diabetes (1 982) 31: 1-6] in mice and fa / fa in zucker rats to understand the pathological physiology of the disease and to test candidates for therapeutic compounds [Diabetes (1 983) 32: 830-838; Annu Rep Sankyo Res Lab (1 994) 46: 1-57]. The homozygous animals, C57 BL / KsJ-db / db mice developed by the Jackson Laboratory, are obese, hyperglycemic, hyperinsulinemic, and insulin resistant [J Clin I nvest (1990) 85: 962-967], whereas the heterozygotes They are thin and normoglycemic. In the d b / db model, mice progressively develop insulinopenia with age, a trait commonly observed in late stages of human type 2 diabetes when sugar levels are insufficiently controlled. Because this model resembles that of human diabetes of type 2, the compounds of the present invention are tested for activities including, but not limited to, the reduction of plasma glucose and triglycerides. Zucker rats (fa / fa) are extremely obese, hyperinsulinemic, and insulin resistant. { Coleman, Diabetes (1 982) 31: 1; E Shafrir in Diabetes Mellitus, H Rifkin and D Porte, Jr, Eds [Elsevier Science Publishing Co., New York, ed. 4, (1990), pp. 299-340]} , and the fa / fa mutation could be the rat equivalent of the murine db mutation [Friedman et al., Cell (1992) 69:21 7-220; Truett et al., Proc Nati Acad Sci USA (1 991) 88: 7806]. Tubby (tub / tub) mice are characterized by obesity, moderate insulin resistance, and hyperinsulinemia without significant hyperglycaemia [Coleman et al., Heredity (1990) 81: 424]. The present invention comprises the use of the compounds of the invention to reduce insulin resistance and hyperglycemia in one or all of the above models of diabetes in rodents, in humans with type 2 diabetes or other preferred disorders related to metabolism or disorders of lipid metabolism previously described, or in models based on other mammals. Glucose levels in plasma and insulin will be analyzed, as well as other factors, including, but not limited to, free fatty acids in plasma and triglycerides. Live Assay for the Anti-H Activity of the Compounds of the Invention Obese diabetic mice genetically altered (db / db) (males, 7-9 nine weeks of age) are caged (7-9 mice per cage) ) under standard laboratory conditions at 22 ° C and relative humidity of 50%, and maintained with a food diet Purine for rodents and water ad Ubitum. Before the treatment, blood samples are collected from the tail vein of each animal and blood glucose concentrations are determined using One Touch Basic Glucose Monitor System (Lifescan). Mice that have plasma glucose levels between 250 and 500 mg / dl are used. Each treatment group consists of seven mice that are distributed in such a way that the average glucose levels are equivalent in each group at the beginning of the study. The db / db mice are dosed by micro-osmotic pumps, inserted using isoflurane anesthesia, to administer the compounds of the invention, saline compounds, or a compound relevant to the mice subcutaneously (s.c.). Blood samples are then collected from the tail vein at intervals and examined for blood glucose concentrations. The significant differences between the groups are evaluated (comparing those treated with the compounds of the invention with those treated with saline compounds) using the t-Student test.
EXAMPLE 2 MODEL OF MOUSE ATHEROSCLEROSIS Adiponectin deficient mice generated by elimination of the adiponectin gene have been shown to be predisposed to atherosclerosis and insulin resistance. Mice are also an appropriate model for ischemic heart disease [Matsuda, M et al. J Biol Chem (2002) Julio, and reference cited in the same, whose descriptions are incorporated here as a reference in its entirety]. Mice si n Adiponectin are caged (7-9 mice / cage) under standard laboratory conditions at 22 ° C and 50% relative humidity. The mice are dosed by micro-osmotic pumps, inserted using isoflurane anesthesia, to administer the compounds of the invention, saline compounds, or a compound irrelevant to mice subcutaneously (s.c.). Neointimal thickening and ischemic heart disease are determined for different groups of mice sacrificed at different time intervals. Significant differences between groups (comparing those treated with the compounds of the invention with those treated with saline solutions) are evaluated using the t-Student test.
EXAMPLE 3 In Vitro Biological Activity A modified Mod Pita ™ modified adenyl cyclase kit (New England N uclear; Cat. No. SM P004A) was used for the direct identification of candidate compounds as hRUP25 combatants in correspondence with the following protocol. The term h U P25 includes the human sequences found in Gene Bank Accession No. N M_1 77551 for the nucleotide and in Genebank Accession No. NP 80821 9 for the polypeptide, and the allelic variants that exist in a natural, mammalian orthologs, and recombinant mutants thereof. CHO cells stably transfected with an expression vector encoding hRU P25 and cultured under permissive conditions of cell surface expression of the encoded RUP25 h receptor were harvested from the flasks through non-enzymatic means. The cells were washed in PBS and resuspended in the manufacturer's Assay Buffer. Live cells were counted using a hemacytometer and Trypan blue exclusion, and the cell concentration was adjusted to 2x1 06 cel / ml. cAMP and the standard Detection Buffer (comprising 2 pCi of tracer [1 25l] -cAM P (1 00 μ?) per 1 1 ml of Detection Buffer) were prepared and maintained in accordance with the manufacturer's instructions. The candidate compounds identified according to the above (if they were frozen, thawed at room temperature) were added to their respective cavities (preferably 96-well plate cavities) in increasing concentrations (3 μ? / Well, 1 2 μ? Of final assay concentration). ). To these cavities, 1 00,000 cells were added in 50 μ? of Test Size and the mixture was then incubated for 30 minutes at room temperature, with gentle agitation. After the incubation, 1 00 μ was added to each cavity. of Detection Buffer, after incubation for 2 to 24 hours. The plates were counted in a Wallac M icroBeta ™ plate reader using "Prot. # 31" (following the manufacturer's instructions). Certain compounds of the invention have an EC50 in the cAM P Whole Cell method of about 25 μ? or less.
Example 4: In Vitro Biological Activity 35S-GTPyS Binding Assay: Ovarian Cells (CHO) -K1 Prepared Membranes
Chinese hamster stably expressing the niacin receptor or vector control (7pg / assay) were diluted in the assay buffer (1 00 mM HEPES, 1 00mM NaCl and 1 0mM MgCl 2, pH 7.4) in Wallac Scintistrip plates and preincubated with test compounds diluted in assay buffer containing 40 μ? G DP (final [GDP] was 1 0 μ?) D uring ~ 10 minutes before the addition of 35S-GTPyS at 0.3 nM. To avoid possible precipitation of the compound, all compounds were first prepared in 100% DMSO and then diluted with assay buffer resulting in a final concentration of 3% DMSO in the assay. It was allowed to continue the link for one hour before centrifugation of the plates at 4000 rpm for 15 minutes at room temperature and after counting in a TopCount scintillation counter. The non-linear regression analysis of the bond curves in the GraphPad Prism was performed. Preparation of the membrane Materials: Culture medium of CHO-K1 cells: Modified Cell Culture Medium of Kaighn F-12 with 10% FBS, 2 mM L-Glutamine, 1mM Sodium Pyruvate and 400 pg / mL G418 Buffer of Membrane Scraping: 20 mM HEPES 10 mM EDTA, pH 7.4
Membrane Wash Buffer: 20 mM HEPES 0.1 mM EDTA, pH 7.4
Protease Inhibitor Cocktail: P-8340, (Sigma, St. Louis, MO) Procedure: o Aspirate out cell culture media from the 15 cm2 plates, rinse with 5 mL of cold PBS and aspirate. o Add 5 mL of Membrane Scraper Buffer and scrape the cells. Transfer the scraping to a 50 mL centrifuge tube. Add 50 pL of Protease Inhibitor Cocktail. o Rotate at 20,000 rpm for 17 minutes at 4 ° C. o Aspirate out the supernatant and resuspend the pellet in 30 ml_ of Membrane Wash Buffer. Add 50 pL of
Protease inhibitor cocktail. o Rotate at 20,000 rpm for 17 minutes at 4 ° C. o Aspirate the supernatant out of the pellet of the membrane. The pellet can be frozen at -80 ° C for later use or can be used immediately.
Assay Materials: Guanosine 5'-sodium diphosphate salt (GDP, Sigma-Aldrich Catalog # 87127) Guanosine 5 '- [Y35S] thiotriphosphate, triethylammonium salt (- [35S] GTPYS,
Amersham Biosciences Catalog # SJ1320, ~ 1 OOOCi / mmol) 96-well scintillation plates (Perkin-Elmer # 1450-501) Linker Buffer: 20 mM HEPES, pH 7.4 100 mM 10 mM NaCl MgCI2 GDP Buffer: binding buffer plus GDP, which ranges from 0.4 to 40 μ ?, prepared fresh before the test
Procedure: (total assay volume = 100 μ cavities) 25 pL of GDP buffer with or without compounds (final GDP 10 μ? - in this way employing 40 μ? Of broth) 50 μL of membrane in the binding buffer (0.4 mg protein / mL) 25 pL of [S] GTPyS in the binding buffer. This is done by adding 5 μ? of broth of [35S] GTPYS in 10 ml_ of the binding buffer (This buffer does not have GDP) or Melt the plates of the compound to be examined (development plates with 5 pL of the compound at 2mM in 100% DMSO) or Dilute the 2mM of compounds 1:50 with 245 μ? _ GDP of buffer at 40 μ? in 2% DMSO. Melt the pellet of membrane frozen in ice. o Homogenize the membranes briefly until they are in suspension using a POLYTRON PT3100 (probe PT-DA 3007/2 configured at 7000 rpm). Determine the protein concentration of the membrane using the Bradford assay. Dilute the membrane to a protein concentration of 0.40 mg / ml in the Linkage Buffer. (Note: the final concentration of the assay is 20 pg / cavity). or Add 25 μl of compounds in the GDP buffer per well to the scintillation plate. or Add 50 μm of membranes per well to the scintillation plate. o Pre-incubate for 5-10 minutes at room temperature. or Add 25 μ? _ of [35S] GTPyS diluted. Incubate in a shaker
(Lab-Line # 1314, shaken to a setting of 4) for 60 minutes at room temperature, or The test is stopped by rotating the plates sealed with the plate covers at 2500 rpm for 20 minutes at 22 ° C or Read the counter of scintillation TopCount NXT - protocol 35S. Some compounds of the invention have an EC50 in the in vitro functional binding assay GTPyS within the range of about 10-100 μ ?. More advantageous compounds of the invention have an EC50 value in this assay within the range of about 1-10 μ ?. Even more advantageous compounds have an EC50 value in this assay of less than about 1 μ ?.
EXAMPLE 5 In Vivo Animal Model An utility of the compound of the present invention as a medical agent in the prophylaxis and treatment of a high total cholesterol / HDL cholesterol ratio and conditions related thereto is demonstrated by the activity of the compound in the decrease in the proportion of total cholesterol with respect to HDL cholesterol, in the elevation of HDL cholesterol, or in the protection against atherosclerosis in a pig model in vivo. Pigs are used as an animal model because they reflect human physiology, especially lipid metabolism, more closely than most other animal models. An illustrative model of in vivo pig not designed to be limiting is presented here. A Yorkshire albino pigs (body weight 25.5 + 4 kg) are fed a diet rich in saturated fatty acid and high in cholesterol (SFA-CHO) for 50 days (1 kg of food 35 kg "1 of weight of the pig), composed of normal food supplemented with 2% cholesterol and 20% tallow of cattle [Royo T., and others, European Journal of Clinical Investigation (2000) 30: 843-52; whose description is incorporated here as a reference in its entirety]. The ratio of saturated fatty acid to unsaturated fatty acid is modified from 0.6 in the normal food for pigs to 1.12 in the SFA-CHO diet. The animals are divided into two groups, one group (n = 8) fed with the SFA-CHO diet and treated with placebo and one group (n = 8) fed with the SFA-CHO diet and treated with the compound (3.0 mg kg "1 The control animals are fed a standard meal for a period of 50 days, blood samples are collected at the beginning (2 days after receipt of the animals), and 50 days after starting the diet. lipids in the blood Animals are sacrificed and necropsed Alternatively, the foregoing analysis comprises a plurality of groups each treated with a different dose of the compound, said preferred doses are selected from the group consisting of: 0.1 mg kg "1, 0.3 mg kg "1, 1.0 mg kg" 1, 3.0 mg kg'1, 10 mg kg "1, 30 mg kg" 1 and 100 mg kg "1. Alternatively, the preceding analysis is carried out at different times. preferred are selected from the group consisting of 10 weeks, 20 weeks, 30 weeks , 40 weeks, and 50 weeks.
HDL cholesterol The blood is collected in trisodium citrate (3.8%, 1:10). The plasma is obtained after centrifugation (1 200 g 1 5 min) and processed immediately. Total cholesterol, H DL cholesterol, and LDL cholesterol are measured using the Kodak Ektachem DT System automatic analyzer (Eastman Kodak Company, Rochester, NY, USA). Samples with parameters estimated above the range are diluted with the solution supplied by the manufacturer and then retested. The ratio of total cholesterol / cholesterol H DL is determined. A comparison of the level of cholesterol H DL between the groups is made. A comparison of the ratio of total cholesterol / HLD cholesterol between the groups is made. The elevation of the cholesterol H DL or the reduction of the ratio of total cholesterol / cholesterol H DL in the administration of the compound is taken as indicative of the compound having the aforementioned utility.
Atherosclerosis The thoracic and abdominal aortas are removed intact, opened longitudinally along the ventral surface, and fixed in neutral buffered formalin after excision of the samples from the standard sites in the thoracic and abdominal aorta for histological examination and studies. of the composition and synthesis of the positive. After fixation, the complete aortas are stained with Sudan IV and crushed, and digital images are obtained with a TV camera connected to a computerized image analysis system (I mage Pro Plus, Media Cybernetics, Silver Spring, MD) to determine the percentage of aortic surface involved in atherosclerotic lesions [Gerrity RG et al., Diabetes (2001) 50: 1 654-65; Cornhill JF et al., Arteriesclerosis, Thrombosis, and Vascular Biology (1985) 5: 415-26; whose descriptions are incorporated here as a reference in their entirety]. A comparison of the percentage of aortic surface involved in atherosclerotic lesions between the groups is made.
The reduction in the percentage of aortic surface involved in atherosclerotic lesions when administering the compound is taken as indicative of the compound having the utility mentioned above.
EXAMPLE 6 Receptor Linkage Assay In addition to the methods described herein, another means for evaluating a test compound is to determine the binding affinities to the RU P25 receptor. This type of assay usually requires a radiolabelled ligand to the RUP25 receptor. If known ligands for the RUP25 receptor and radiolabel thereof are not used, the compounds of Formula (Ia) can be labeled with a radioisotope and used in an assay to evaluate the affinity of a test compound with the RUP25 receptor. A radiolabeled RU P25 compound of Formula (Ia) can be employed in a screening assay to identify / evaluate the compounds. In general terms, the ability of a newly synthesized or identified compound (ie, test compound) to reduce the binding of the "radiolabelled compound of Formula (Ia)" to the RUP25 receptor can be evaluated. Correspondingly, the ability to compete with the "radiolabelled compound of Formula (Ia)" or radiolabeled ligand RUP25 for the binding to the RUP25 receptor is directly related to its binding affinity of the test compound to the RUP25 receptor.
TEST PROTOCOL FOR THE DETERMINATION OF THE LINK TO THE RECEIVER FOR RUP25: A. PREPARATION OF RUP25 RECEPTOR 293 cells (human kidney, ATCC), temporarily transferred with 10 ug of the human RUP25 receptor and 60 pL of Lipofectamine (by 15-cm plates ), are cultured on the plate for 24 hours (75% confluence) with a change of media and withdrawals with 10 ml / plate of Hepes-EDTA buffer (20mM Hepes + 10mM EDTA, pH 7.4). The cells are centrifuged in a Beckman Coulter centrifuge for 20 minutes at 17,000 rpm (rotor JA-25.50). Subsequently, the pellet is resuspended in 20 mM Hepes + 1mM EDTA, pH 7.4 and homogenized with a 50-ml Dounce homogenizer and centrifuged again. After the supernatant is removed, the pellets are stored at -80 ° C, until used in the binding assay. When used in the assay, the membranes are thawed on ice for 20 minutes and then 10 mL of incubation buffer (20 m Hepes, 1 mM MgCl 2, 100 mM NaCl, pH 7.4) is added. The membranes are swirled to resuspend the pellet of the crude membrane and homogenized with a Polytron Bri nkmann PT-31 00 homogenizer for 1 5 seconds set to 6. The protein concentration of the membrane is determined using the Bradford BRL protein assay.
B. LINK TEST For the total laceration, a total volume of 50 pL of suitably diluted membranes (diluted in assay buffer containing 50mM Tris HCl (pH 7.4), 1mM MgCl2, and 1mM EDTA; 5-50ug of protein) is added to the 96-well polypropylene microtiter plates followed by the addition of 1 00 pL assay buffer and 50 pL of RU P25 radiolabeled ligand. For a non-specific binding, 50 pL of assay buffer is added instead of 1000 pL and another 50 pL of 10 p M M RU P25 cold are added before 50 pL of radiolabelled ligand RUP25 is added. Then the plates are incubated at room temperature for 60-1 20 minutes. The binding reaction is terminated by filtering the assay plates through a Microplate Devices GF / CU nifilter filtration plate with a Brandell 96-well plate harvester followed by washing with 50mM cold Tris HCI, pH 7.4 containing 0.9% NaCl . Then, the bottoms of the filtration plate are sealed, 50 pL of Optiphase Its permix are added to each cavity, the caps of the plates are sealed, and the plates are counted in a Tril ux M icroBeta scintillation counter. For competition studies of the compound, instead of adding 1 00 μ? _ Of the assay buffer, 1 00 ask! Properly diluted test compound is added to the appropriate wells followed by the addition of 50 μl of RU P25 radiolabelled ligand.
C. Calculations The test compounds are initially tested at 1 and 0.1 μ? and then in a range of chosen concentrations such that the average dose could cause about 50% inhibition of a link to Ligando Radio-RU P25 (ie, IC50). The specific binding in the absence of the test compound (B0) is the difference of the total bond (BT) minus the non-specific binding (NSB) and similarly the specific binding (in the presence of the test compound) (B) is the difference of the displacement link (BD) minus the non-specific link (N SB). IC50 is determined from an inhibition response curve, interlogarithmic graphical representation of% B / B0 against the concentration of the test compound. K¡ is calculated by the transformation Prustoff and Cheng: K, = IC50 / (1 + [L] / Kd) where [L] is the concentration of a Ligand of Radio-RU P25 used in the test and Kd is the constant of dissociation of a Ligando Radio RU P25 determined independently in the same link conditions.
D. ALTERNATIVE LINK TEST PROCEDURE Competency test of the H-nicotinic acid bond. CHO-KI cells that stably express the niacin receptor were used to make membrane for linkage analysis. Cells were grown up to -80% confluence in culture medium (modified medium of Kaighn F-12 (ATCC, # 30-2004) containing 10% FBS (GIBCO, # 10438-026), 1mg / ml of G418 (GIBCO, # 10131-027) and 1X of Pen-Strep (Sigma P-0871), harvested by scraping, and centrifuged at 12,000 X g, 4o Celsius, 10 minutes.The pellets of cells were resuspended in harvest buffer ( 20 m HEPES, 10 mM EDTA, pH 7.4) and homogenized with bursts 4 x 10 seconds in a 12 mm Polytron homogenizer, set to 5. The lysate was centrifuged at 2000 X g, 4o, 10 minutes to remove the cells and nuclei Unused, and the resulting supernatant centrifuged at 39,000 X g, 4o, 45 minutes to form pellets of membranes The resulting pellet was resuspended in wash buffer (20 mM HEPES, 0.1 mM EDTA, pH 7.4), homogenized with bursts 3 X 10 seconds of a 12 mm Polytron, set to 4, and recentrifuged at 39,000 X g, 4o, 45 minutes The resulting pellet was resuspended in buffer n washing and stored in liquid nitrogen before use. The concentration of membrane proteins in that preparation was determined using the Pierce BCA protein assay, with BSA as a standard. The equilibrium bond of 3H-nicotinic acid was made in 96-well polypropylene plates. The reactions contained 140 pL of membranes diluted in assay buffer (20 mM HEPES, pH 7.4, 1 mM MgCl 2, and 0.01% CHAPS).; 15-30 membrane protein / assay), 20 μl of test compounds diluted in assay buffer (the broths of the compounds were in 100% DMSO, the final concentration of DMSO in the assay was 0.25%), and 40 μ? _ 250 nM tritiated niacin ([5,6-3 H] -nicotinic acid: American Radiolabeled Chemicals, Inc., 20 μ? in ethanol, the final concentration of ethanol in each assay was 1.5%). The non-specific binding was determined in the presence of 250 μ? _ Of unlabeled nicotinic acid. After mixing for 3-4 hours at room temperature, the reactions were filtered through GF / C Packard Unifilter plates using a Packard Harvester, and washed with 8 X 200 μl of ice-cold binding buffer. The plates were dried overnight and their backs sealed using PerkinElmer adhesive tape designed for GF / C plates. 40 pL of PerkinELmer scintillation fluid Microscint-20 were added to each cavity, the sealed top parts, and the plates analyzed in a TopCount Packard scintillation counter. The calculations were performed as in C mentioned above. Certain compounds of the invention have an EC5o in the competition assay of the 3H-nicotinic acid linkage in the range of about 10 to about 100 μ ?. More advantageous compounds of the invention have an EC50 value in this assay within the range of about 1 to about 10 μ ?.
Even more advantageous compounds have an EC50 value in this assay of less than about 1 μ ?.
Example 7: Reddening via Doppler Laser Procedure - male C57B16 mice (~ 25g) are anesthetized using 10mg / ml / kg Nembutal sodium. If they have to be administered antagonists these are injected in conjunction with Nembutal anesthesia. After 10 minutes the animal is placed under the laser and the ear is bent back to expose the abdominal part. The laser is placed in the center of the ear and focused at an intensity of 8.4-9.0 V (usually ~ 4.5cm above the ear). The acquisition of the data is initiated with an image format of 15 by 15, auto interval, 60 images and a time delay of 20 seconds with an average resolution. The test compounds are administered after the 10th image by injection into the peritoneal space. The images 1-10 are considered the baseline of the animal and the information is normalized with respect to an average of average intensities of the baseline. Materials and Methods - Pirimed Pimll Droppler Laser; Niacin (Sigma); Nembutal (Abbot laboratories)
Example 8: Inhibition of free fatty acid production, in vivo, in catheterized Sprague-Dalv male rats. Non-esterified free fatty acid (NEFA) assays are performed on serum derived from live rats, which move freely. Jugular vein catheters are surgically implanted within the jugular veins and animals are allowed to recover at least 48 hours after surgery. The feed is removed to the animals approximately 1 6 hours before the test. An extraction of -200 μ? Blood is extradited from the catheter and represents the serum sample N E FA basic. Drug is administered intratracheally (I P) at various concentrations to individual rats and then extractions of -200 μ? of blood are removed from the catheter at the scheduled times to continue the analysis of N EFA. N EFA tests are performed according to the manufacturer's specifications (Wako Chemicals, USA, NEFA C) and free fatty acid concentrations are determined through regression analysis of a known standard curve (range of known free fatty acids) . The data is analyzed using Excel and PrismGraph.
Example 9 Synthesis of Selected Compounds of the Invention. The compounds of the invention and their syntheses are illustrated in more detail by the following examples. The following examples are provided to continue defining the invention without, however, limiting the invention to the particularities of these examples. The compounds described herein, supra and infra, are named according to CS Chem Draw Ultra Version 7.0.1 or AutoNorm 2000. In certain circumstances common names are used and it is understood that those common names would be recognized by those skilled in the art. . In general, for the Examples provided below, the standard designation "(±)" directly preceding the chemical name is used to indicate a racemic mixture. The chemical structures shown in the examples are present for illustrative purposes only and are not intended to be limiting unless the chemical name for the example states otherwise. What is it ?: Proton nuclear magnetic resonance spectra
(1 HNMR) were collected in a Varian Mercury Vx-400 equipped with a 4-core and z-gradient self-switching probe or a Bruker Avance-400 equipped with a QN P (Assisted Nucleus Probe) or a BBI (Inverse of Broadband) and gradient z. Chemical changes are given in part by millions (ppm) with the residual solvent signal used as a reference. The abbreviations N M R are used as follows: s = singlet, d = doublet, dd = doublet of doublet, dt = doublet of tri plete, t = triplet, q = quatrain, m = multiplet, br = broad. Microwave radiations were made using the Emyrs Synthesizer (Personal Chemistry). Thin layer chromatography (TLC) was performed on silica gel 60 F254 (Merck), preparatory thin layer chromatography (prep TLC) was performed on plates of 60 To 1 mm of PK6F silica gel (Whatman), and column chromatography on a silica gel column was performed using Kieselgel 60, 0.063-0.200 mm ( Merck). The evaporation was carried out under vacuum in a Buchi rotary evaporator. Celite 545 ® was used during palladium filtrations. LCMS Specifications: 1) PC: HPLC Pumps: LC-10AD VP, Shimadzu Inc.; HPLC system controller: SCL-10A VP, Shimadzu Inc; UV detector: SPD-10A VP, Shimadzu Inc; Sampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Ion Turbo Spray source, AB / MDS Sciex; Software: Analyst 1.2.2) Mac: HPLC Pumps: LC-8A VP, Shimadzu Inc; HPLC system controller: SCL-10A VP, Shimadzu Inc. UV detector: SPD-10A VP, Shimadzu Inc; Automatic Dispenser: 215 Liquid Handler, Gilson Inc; Mass spectrometer: API 150EX with Ion Turbo Spray source, AB / MDS Sciex; Software: Masschrom 1.5.2.
Example 9.1: Preparation of (1aft.5a /?) - (+) - 4- (2H-TetrazoB-5-yl) -1a, 3,5.5a-tetrahydro-1 H-2,3-diaza-cyclopropaphapentalene (Compound 4) . Step A: Preparation of biciclor3.1.01hexan-2-oi.
LiTMP was generated by addition of n-BuLi (2.5M in hexanes, 143 mL, 358 mmol) to a stirred solution of TMP (50.7 g, 359 mmol) in α-BuOMe (1.0L) at -78 ° C. The clear yellow LiTMP solution was heated slowly at 0 ° C for 45 min. To a stirred solution of (7? -2-but-3-en-l-oxirane (17.6 g, 179 mmol, Schaus, SE, et al., J. Am. Chem. Soc. 2002, 124, 1307) in f -BuOMe (500ml_) at 0 ° C the LiTMP solution was added dropwise with a cannula for 50 min.The resulting mixture was stirred at room temperature for 18 hours then cooled with MeOH (40 mL) .The reaction was concentrated to a Total volume of 600 mL and the solution was washed with HCI (1 / V aqueous, 3 x 350 mL) and brine (300 mL) .The organics were dried in MgSO4, filtered, and concentrated (90 mmHg, bath temperature a 25 ° C) to produce bicyclo [3.1.0] hexan-2-ol as light yellow oil The spectral data for the bicyclo [3.1.0] hexan-2-ol were similar to the data reported in the literature, Hodgson, DM, Chung, YK, Paris, J.-MJ Am. Chem. Soc. 2004, 126, 8664.
Step B: Preparation of Biciclor3.1.OIhexan-2-one.
TPAP (1.88 g, 5.35 mmol) was added to a stirred solution of bicyclo [3.1.0] hexan-2-ol (10.5 g, 107 mmol), NMO (25.1 g, 214 mmol), and pulverized 4 HA (20 g). in CH2CI2 (500 mL) at room temperature. The mixture was stirred for 2.5 h and filtered through silica gel (80 cm x 12 cm) and eluted with Et 2 O / CH 2 Cl 2 (1: 1). The organic solvent was carefully evaporated under vacuum (100 mmHg, bath temperature at 25 ° C) to produce bicyclo [3. .0] hexan-2-one. The spectral data were similar to those previously reported for rac-bicyclo [3.1.0] hexan-2-one (Newman-Evans, R.H., Simon, R.J., Carpenter, B.K., J. Org.Chem, 1990, 55, 695).
Step C. Preparation of ethyl ester of 1a, 2,5,5a-Tetrahydro-1IH-2,3-diaza-cycloproparalpentalene-4-carboxylic acid.
To a solution of bicyclo [3.1.0] hexan-2-one (9.24 g, 96.1 mmol) and diethyl oxalate (14.7 g, 101 mmol) in EtOH (250 mL) at room temperature under N2 was added a solution of KOt- Bu in THF (106 mL of a 1M solution, 106 mmol). The reaction was stirred for 3.5 h at which time hydrazine hydrochloride (7.90 g, 115 mmol) in H20 (40 mL) was added. The reaction mixture was stirred for 20 h at room temperature and acidified to pH ~ 3 by the addition of HCL (6? / Ac). The volatiles were removed in vacuo and the resulting solid was diluted with EtOAc (500 mL) and H20 (500 mL). The layers were separated and the aqueous phase was extracted with EtOAc (300 mL). The combined organics were washed with brine (400 mL), dried in MgSO, filtered, and concentrated to a crude oil that was determined to be approximately 75-80% pure pure (weight / weight) per 1 H NMR. The title compound was used directly in the next reaction (aminolysis) without further purification.1H NMR (400 MHz, CDCl 3): (510.55 (1H, bs), 4.32 (2H, q, J = 6.8 Hz), 2.96 (1H , dd, J = 16.8, 6.0 Hz), 2.80 (1H, d, J = 17.2 Hz), 2.23-2.13 (2H, m), 1.35 (3H, t, J = 7.2 Hz), 1.15 (1H, m) 0.34 (1H, m) 13CAPT NMR (partial) (100 MHz, CDCI3): d up: 127.4, 61.2, 26.8, 16.8, down: 23.0, 15.4, 14.5 HPLC / MS: Discovery® C18 column ( 5μ, 50x 2.1 mm), 5% v / v CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient at 99% v / v CH3CN in H20, 0.75 mL / min, tr = 1.62 min, ESI + = 193.1 (M + H).
Step D: Preparation of 1a, 2,5,5a-Tetrahydro-1H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid amide.
To a solution of ester from Step C (14.2 g, 73.9 mmol) in dioxane (140 ml_) was added ammonium hydroxide (28% NH3 in H20, 750 ml_). The mixture was placed in a 1000 ml Pyrex flask and shaken on a shaker plate for 22 h at room temperature. The mixture was concentrated in vacuo to a total volume of 100 mL at which time a light yellow precipitate was evident. The mixture was filtered and the solid was washed with H20 (2 x 100 mL). Subsequent drying of the solid under vacuum produced amide of 1a, 2, 5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid. [HPLC / MS: Column Discovery® C18 (5μ, 50 x 2.1 mm), 5% v / v CH3CN (containing 1% v / V TFA) in H20 (containing 1% v / v TFA) gradient at 99% v / v CH3CN in H20, 0.75 mL / min, fr = 1.09 min, ESI + = 164.0 (M + H)] as a white solid.
Step E: Preparation of 2-Benzyl-1a.2.5.5a-tetrahydro-1 H-2,3-d i aza-cyclic propatal petalene-4-carbonitri
The amide from Step D (9.38 g, 57.9 mmol was partially dissolved in dioxane (150 mL) and NaOH (5N aq, 23.0 mL, 115 mmol) was added followed by benzyl bromide (10.3 g, 60.2 mmol). The mixture was acidified to pH = 2 by the addition of HCl (6? / aq.) and concentrated to dryness in vacuo, and the resulting light yellow solid was washed with water. NaHC03 (sat, ac, 100mL) and H20 (100 mL) The subsequent drying of the solid under vacuum produced the benzylated product, 2-benzyl-1 a, 2,5,5a-tetrahydro-1 H-2,3-amide. -diaza-cyclopropa [a] pentalene-4-carboxylic acid as a white solid.
A flask equipped with a drying tube under N2 atmosphere was charged with (50ml_) DMF anhydride. The flask was cooled to 0 ° C and thionyl chloride (4.84 mL, 66.5 mmol) was added dropwise over 2 minutes. After stirring for another 10 minutes, an amide suspension of 2-benzyl-1 a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid was added ( 14.0 g, 55.3 mmol) in DMF (90 mL) for 5 minutes using an additional funnel. The mixture was slowly warmed to room temperature and stirred for 20 minutes at which time additional thionyl chloride (3.05 mL, 41.9 mmol) was added as a pre-mixed solution in DMF (20 mL). The reaction was stirred for another 20 minutes and a second pre-mixed solution of thionyl chloride (6.0 mL, 82.5 mmol) in DMF (20 mL) was added. The reaction was stirred for another 15 minutes and NaHCO3 (sat aq, 50 mL) was added followed by H2O (100 mL). The mixture was stirred for 10 minutes and concentrated to almost dryness under vacuum. The residue was diluted with EtOAc (350 mL) and H20 (250 mL). The layers were separated and the aqueous phase was extracted with EtOAc (250 mL). The combined organics were washed with NaHCO3 (sat aq, 400 mL), and brine (400 mL), dried on MgSO4, filtered, and concentrated to yield 2-benzyl-1 a, 2.5.5 a-tetrahydro-1 H- 2,3-diaza-cyclopropa [a] pentalene-4-carbonitrile as a brown solid. H NMR (400 MHz, CDCl 3): (57.37 (3H, m), 7.25 (2H, m), 5.31 (1H, d, J = 14.8 Hz), 5.24 (1H, d, J = 14.8 Hz), 2.86 ( 1H, dd, J = 16.4, 6.4 Hz), 2.72 (1H, d, J = 16.0 Hz), 2.19 (1H, m), 1.87 (1H, m), 1.07 (1H, m), 0.32 (1H, m ) 13CAPT NMR (100 MHz, CDCI3): d up: 154.4, 135.3, 130.0, 118.9, 114.3, 55.9, 26.2, 16.9, down: 129.2, 128.6, 128.1, 24.2, 14.4 HPLC / MS: Column Discovery ® C18 (5μ, 50 x 2.1 mm), 5% v / v CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient to 99% v / v CH3CN in H20, 0.75 mL / min, tr = 2.23 min, ESf = 236.1 (M + H).
Step F: Preparation of 2-Benzyl-4- (2H-tetrazol-5-yl) -1a.2.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene.
To a solution of 2-Benzyl-1a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carbonitrile (11.1 g, 47.2 mmol) in DMF (125 mL) ZnBr2 (18.4 g, 70.6 mmol) was added followed by NaN3 (12.2 g, 188 mmol). The mixture was heated to 120 ° C and stirred for 18 h. in an N2 atmosphere. The reaction was cooled to room temperature and the DMF was removed in vacuo. The crude residue was diluted with EtOAc (200 mL) and HCl (3N aq, -100 mL) and stirred for 10 minutes. The layers were separated and the aqueous phase was extracted with EtOAc (150 mL). The combined organics were washed with NaOH (1M aq, 2 x 250 mL), and the organic strata were separated. The basic aqueous phase was acidified with 6N HCl to pH ~ 2 and extracted with EtOAc (2 x 250 mL). The extracts were washed with brine (150 mL), dried over MgSO4, filtered and concentrated to produce 2-benzyl-4- (2H-tetrazol-5-yl) -1a, 2,5,5a-tetrahydro-1 H-2. , 3-diaza-cyclopropa [a] pentalene as a light brown solid. 1 H NMR (400 MHz, MeOD): d 7.33 (5H, m), 5.42 (1H, d, J = 14.8 Hz), 5.35 (1H, d, J = 15.2), 3.01 (1H, dd, J = 16.4, 6.4 Hz), 2.88 (1H, d, J = 17.6 Hz), 2.28 (1H, m), 2.11 (1H, m), 1.14 (1H, m), 0.33 (1H, m). HPLC / MS: Alltech® Prevail C18 column (5μ, 50 x 4.6 mm), 5% v / v CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient at 99% v / v CH3CN in H20, 3.5 mL / min, fr = 2.14 min, ESI + = 279.3 (M + H).
Step G: Preparation of MaR.5aR) -4- (2H-Tetrazol-5-in-1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene (Compound 4)
The air was bubbled through the stirring solution of 2-benzyl-4- (2H-tetrazol-5-yl) -1a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene (10.4 g, 37.4 mmol) and KOt-Bu (374 mL of a 1M solution in THF, 374 mmol) in DMSO (300 mL) for 20 hours at room temperature. The remaining THF was removed under vacuum and the reaction was acidified to pH = 2 by the addition of HCL (3M aq). The mixture was concentrated in vacuo until almost dried. The residue was dissolved in HCl (1N aq, 250 mL) and extracted with EtOAc (5x250 mL). The organics were dried in filtered MgSO4) and concentrated. The product was purified and converted to the ammonium salt by charging material (as a solution in MeOH) onto a column containing Bondesil SCX SPE resin (~ 250 g). The column was rinsed with MeOH (200 mL) to remove detached impurities. The product was eluted using 2N NH3 / MeOH (approximately 200 mL). Concentration of the basic eluent produced the ammonium salt of Compound 4 as a white solid. 1 H NMR (400 MHz, MeOD): d 3.02 (1 H, dd, J = 16.4, 6.0 Hz), 2.90 (1 H, d, J = 16.0 Hz), 2.19 (2 H, m), 1.17 (1 H, m), 0.33 (1H, m). HPLC / MS: Discovery® C18 column (5μ, 50 x 2.1 mm), 5% v / v CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient at 99% v / v CH3CN in H20, 0.75 mL / min, fr = 1.21 min, ESI + = 189.0 (M + H), [a] 25D + 35.7 (c 0.39, MeOH).
Example 9.2: Preparation of (±) -1, 1-Dimethyl-4- (2H-tetrazoB-5-yl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropapha-1 -pentalene ( Compound 7) Step A: (±) -2- (4-Methylpent-3-enyl) oxirane.
2- (But-3-enyl) oxirane (I.OOOg, 10 mmol) and 2-methylbut-2-ene (10 g, 102 mmol) were stirred at room temperature for 24 h. in a scintillation vial sealed with Zhan catalyst (0.057g, 0.086 mmol). The solvent was removed under reduced pressure and the residue purified by column chromatography (0-10% EtOAc / n-hexane / silica) to yield 2- (4-methylpent-3-enyl) oxirane as a colorless oil. H NMR (CDCl 3): 55.2-5.1 (m, 1H), 2.95-2.88 (m, 1H), 2.75 (dd, 1H, J, = 5.0, J2 = 4.1), 2.48 (dd, 1H, J, = 5.0 , J2 = 2.8), 2.15 (2H, q, J = 7.4), 1.70 (s, 3H), 1.63 (s, 3H), 1.60-1.50 (m, 2H).
Step B: Preparation of (±) -6,6-Dimethyl-bicichlor3.1.OThexan-2-ol
2,2,6,6-Tetramethylpiperidine (9.70 g, 69 mmol) was absorbed in MTBE (100 ml_) and cooled to -78 ° C. N-Butyllithium (43 ml_, 1.6 M in n-hexane, 69 mmol) was carefully added and the resulting solution allowed to stir at -78 ° C for 30 minutes. The pale yellow solution was added through a cannula to a cooled (0 ° C) solution of 2- (4-methyl-pent-3-enyl) -oxirane (4.33 g, 34.3 mmol) in MTBE (30 mL) during 30 minutes, allowed to warm slowly to room temperature and stirred under argon for 18 hours. Then the solution was added to the aqueous hydrochloric acid (50 mL) 1 M and extracted into additional MTBE (200 mL). The diluent was removed under reduced pressure and the resulting oil purified by column chromatography (0-40% EtOAc / n-hexane, silica). (±) -6,6-Dimethyl-bicyclo [3.1.0] hexan-2-ol was obtained in the form of a yellow oil. 1 H NMR (CDCl 3): d 4.15-4.10 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 1H), 1.62 (br s, OH) , 1.56 (ddd, 1H, = 12.9, J2 = 9.5, J3 = 2.9), 1.48 (br s, 1H), 1.14 (dd, 1H, J, = 6.3, J2 = 1.2), 0.99 (s, 3H), 0.93 (s, 3H).
Step C: Preparation of (±) -6,6-Dimethyl-bicichlor3.1.OIhexan-2-one.
A cooled solution (0 ° C) of N-methylmorpholine N-oxide
(3.11 g, 26.5 mmol) and tetrapropylammonium perretenate (VII) (0.280 g, 0.796 mmol) in DCM (40 mL) was prepared containing molecular sieves of 4A (ca 0.3 g). A solution of (±) -6,6-dimethyl-bicyclo [3.1.0] hexan-2-ol (1.67 g, 13.3 mmol) in DCM (10 mL) was added dropwise and the solution allowed to warm to Room temperature and stirred for 1 hour under argon. The solution was filtered through a plug of silica, the solvent removed under reduced pressure and the resulting oil purified by column chromatography (0-100% DCM / n-hexane, silica). 6,6-Dimethyl-bicyclo [3.1.0] hexan-2-one was obtained in the form of a brown oil. 1H NMR (CDCl 3): 52.35-2.15 (m, 2H), 2.10-2.00 (m, 1H), 1.97-1.85 (m, 2H), 1.66 (d, 1H, J = 4.7), 1.16 (s, 3H) , 1.12 (s, 3H).
Step D: Preparation of ethyl ester of (±) -1,1-Dimethyl-1a.3.5,5a-tetrahydro-H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid
(±) -6,6-Dimethyl-cyclo [3.1.0] hexan-2-one (1.49 g, 12.0 mmol), diethyl oxalate (2.46 g, 16.8 mmol) and potassium-butoxide ( 18.0 ml_, 1 M in THF, 18.0 mmol) were stirred in ethanol (40 ml_) at room temperature for 2 hours. The desired ethyl ester (6,6-dimethyl-2-ol-bicyclo [3.1.0] hex-3-yl) -oxi-acetic acid was observed by LC S (m / z (ES "): 247 [M + Na] +), 225 [+ H] +) but not isolated.hydrazine monohydrochloride (0.168 g, 24.4 mmol) in water (2.0 ml_) was added and the solution heated at 80 ° C for 18 hours. it was removed under reduced pressure and the resulting oil purified in 0.1M aqueous hydrochloric acid (30 mL) and extracted in DCM (200 mL) The solvent was removed under reduced pressure and the residue purified by column chromatography (0-50%). EtOAc / rj-hexane, silica) to produce ethyl ester of (±) -1,1-di methyl 1-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene -4-carboxylic acid in the form of pale yellow oil which solidified once standing, miz (ES +): 243 [M + Na] +, 221 [M + H] +, 175 [M-OEt] +; 1H NMR (CD3OD): 54.4-4.3 (m, 2H, OCH2), 2.90 (dd, 1H, J, = 17.5, J2 = 6.9), 2.65 (d, 1H, J = 17.5), 2.1-2.0 (m, 1H) , 1.95 (t, 1H, J = 12.9), 1.37 (td, J, = 7.1, J2 = 2.0), 1.13 (s, 3H, exo-CHa) 0.74 (d, 3H, J = 2.0, entfo-CHs).
Step E: Amide preparation of (±) -1,1-Dimethyl-1a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid
Ethyl ester of (±) -1, 1-Dimethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid (1280g, 5.81 mmol) was absorbed in 7M metabolic ammonium (60 mL) in a sealed flask and heated at 100 ° C for 18 hours. The resulting suspension was collected by vacuum filtration to yield 1,1-dimethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid amide as creamy solid. The solvent was removed from the mother liquor and the residue purified by the HPLC preparation to further produce amide of (±) -1, 1-dimethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza -cyclopropa [a] pentalene-4-carboxylic acid as a creamy solid. m / z (ES +): 192 [M + H] +, 175 [M-NH 2] +; 1H NMR (CD30D): d 2.9-2.65 (m, 1H), 2.55 (t, 1H, J = 19.9), 2.0-1.8 (m, 2H), 1.03 (s, 3H), 0.63 (s, 3H).
Step F: Preparation of (±) -1. 1 -Dimethyl-1 a.3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carbon ityl.
Amide of (±) -1, 1 -Dimethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid (0.532 g, 2.79 mmol) was Absorbed in THF (50mL) and trifluoroacetic anhydride (0.936 g, 4.46 mmol) was added. The resulting solution was stirred at room temperature under argon for 1 hour. Ethyl acetate (50 mL) was added and the solvent was removed under reduced pressure. The resulting pale yellow oil was taken up in DCM (100 mL), washed with saturated aqueous sodium bicarbonate solution (40 mL) and the solvent removed under reduced pressure. The resulting white solid was absorbed as suspension in DCM (20 μL) and filtered to yield (±) -1, 1-dimethyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid as a grayish white solid, m / z (ES +): 1 74 [M + H] +.
Step G: Preparation of (± M. 1 -Dimethyl-4- (2H-tetrazol-5-m-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropafalpentalene (Compound 7).
(±) -1, 1-Dimethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carbonitrile (0.184 g, 1.06 mmol) was absorbed in 1 , 4-dioxane (10 mL) with zinc dibromide (0.5 g, 2.22 mmol) and sodium acid (0.300 g, 4.62 mmol) in a glass tube with thick walls. The resulting solution was heated under microwave radiation at 200 ° C for 1 hour. The solution was poured into 1M aqueous hydrochloric acid (10 mL) and extracted into ethyl acetate (50 mL). The solvent was removed under reduced pressure and the resulting oil purified by the HPLC preparation to yield (±) -1, 1 -dimethyl-4- (2H-tetrazol-5-yl) -1 a, 3.5.5a- tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene as a white solid, m / z (ES +): 217 [M + H] +, 189 [M-N 2 + H] +; 1H NMR (CD30D): d 2.87 (dd, 1H, J, = 16.5, J2 = 5.6), 2.67 (dd, 1H, J, = 16.5, J2 = 0.8), 2.1-2.0 (m, 2H), 1.08 ( s, 3H), 0.69 (s, 3H).
Example 9.3: Preparation of (±) -1,1-dimethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropaphapentalene-4-carboxylic acid. (Compound 6).
Ethyl ester of (±) -1, 1 -Dimethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid (0.0390 g, 0.177 mmol) was stirred for 18 hours at room temperature in a solution of 1: 5: 1 methanol: THF: 1 M aqueous lithium hydroxide (14 mL).
The solvent was removed under reduced pressure, the residue was taken up in 1M aqueous hydrochloric acid (5mL) and extracted into ethyl acetate (40 ml). The solvent was removed under reduced pressure and the residue purified by the HPLC preparation to yield a white solid. m / z (ES +): 215 [M + Na] +, 193 [M + H] +, 175 [M-OH] +; 1H NMR (CD3CN): 62.91 (dd, 1H, J ^ = 17.4, J2 = 6.8), 2.66 (d, 1H, J = 17.4), 2.11 (dd, 1H, Jn = 6.3, J2 = 1.2), 2.05- 1.95 (m, 1H), 1.19 (s, 3H, exo-CHg) 0.77 (d, 3H, J = 2.0, endo-C).
Example 9.4: Preparation of (±) exo-1-Benzyl-4- (2H-tetrazoll-5-y1) -1a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparapentalene (Compound 8). Compound 8 was synthesized in a manner similar to that described in Example 9.2 starting with ('E) -2- (5-phenyl-pent-3-enyl) -oxirane. Intermediates were characterized as shown below for the respective steps. Step A: (±) exo-6-Benzyl-bicichlor3.1.01hexan-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.2, Step B. 1 H NMR (CDCl 3): d7.35-7.25 (m, 2H), 7.25-7.15 (m, 3H), 4.25 (d, 1H, J = 4.7), 2.54 (d, 2H, J = 6.9), 2.00-1.85 (m, 1H), 1.74 (dd, 1H, J1 = 12.5, J2 = 8.0), 1.65-1.50 (m, 1H) , 1.45-1.35 (m, 1H), 1.35-1.30 (m, 1H), 0.71 (septet, 1H, J = 3.3). Contains 15% (±) endo-6-benzyl-bicyclo [3.1.0] hexan-2-ol.
Step B: (±) exo-6-Benzyl-bicichlor3.1.01hexan-2-one
The title compound was prepared in a manner similar to that described in Example 9.2, Step C. 1 H NMR (CDCl 3): 57.35-7.28 (m, 2H), 7.25-7.20 (m, 3H), 2.78 (dd, 1H, J, = 14.9, J2 = 6.1), 2.60 (dd, 1H, J, = 14.9, J2 = 7.2), 2.20-2.10 (m, 1H), 2.10-2.00 (m, 4H), 1.74 (dd, 1H, J-, = 5.2, J2 = 2.4), 1.65-1.55 (m, 1H). It contains 15% of (±) in / o-6-benzyl-bicyclo [3.1.0] hexan-2-one.
Step C: ethyl ester of (±) exo-1-Benzyl-1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropaal-pentalene-4-carboxylic acid
The title compound was prepared in a manner similar to that described in Example 9.2, Step C.
1H NMR (CD30D): d 7.35-7.10 (m, 5H), 4.31 (q, 2H, J = 7.1, OCH), 2.97 (dd, 1H, J, = 17.2, J2 = 6.2), 2.90-2.75 ( m, 2H), 2.59 (dd, 1H, = 15.0, J2 = 7.5), 2.20-2.15 (m, 1H), 2.15-2.05 (m, 1H), 1.34 (t, 3H, J = 7.1), 1.00 ( septet, 1H, J = 3.5). It contains 15% ethyl ester of (±) -endo- 1 -benzyl 1-1, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid. MS (m / z (ES +): 305 [M + Na] +, 283 [M + H] +, 237 [M-OEt] +.
Step D: Amide of (±) exo-1-Benzyl-1a.3,5.5a-tetrahydro-1 H ° 2,3-diaza-cycloproparalpentalene-4-carboxylic acid
The title compound was prepared in a manner similar to that described in Example 9.2, Step E. 1 H NMR (CD30D): 67.4-7.1 (m, 5H), 2.95 (dd, 1H, J1 = 16.5, J2 = 5.4), 2.87 (d, 1H, J = 15.6), 2.8-2.6 (m, 2H), 2.25-2.15 (m, 2H), 1.05-0.90 (m, 1H). It contains 15% amide (±) -endo-1 -benzyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid. MS (m / z (ES +): 276 [M + Na] \ 254 [M + H] +, 237 [M-NH2] +.
Step E: (±) -exo-1-Benzyl-1 a.3.5.5a-tetrahydro-1 H-2, 3-diaza-cycloproparalpentalene-4-carbonitrile.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS (m / z (ES +): 236 [M + H] + Contains 15% (t endo-'i -benzyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carbonitrile.
Step F: (±) exo-1-Benzyl-4- (2H-tetrazol-5-ih-1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropapha1pentalene (Compound 8)
described in Example 9.2, Step G. 1H NMR (CD30D): d7.6-7.5 (m, 4H), 7.5-7.4 (m, 1H), 3.29 (dd, 1H, J1 = 16.2, J2 = 6.0), 3.18 (d, 1H, J = 16.2), 3.01 (dd, 1H, J1 = 14.7, J2 = 6.6), 2.90 (dd, 1H, J1 = 14.7, J2 = 7.4), 2.55-2.45 (m, 2H). 1.35-1.25 (m, 1H). MS m / z (ES +): 301 [M + H] +, 279 [M + H] +, 251 [M-N 2 + H] +.
Example 9.5: Preparation of (±) -exo-1-Benzyl-1 a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropaf alpentalene-4-carboxylic acid
(Compound 5)
Compound 5 was synthesized from the ethyl ester of (±) -exo-1-Benzyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid using a method similar to that described in Example 9.3. MS m / z (ES +): 277 [M + Na]? 255 [M + H] +, 237 [M-OH] +; 1H NMR (CD3CN): 57.3-7.1 (m, 5H), 2.83 (dd, 1H, = 17.0, J2 = 5.8), 2.66 (d, 1H, J = 17.0), 2.57 (dd, 2H, J, = 7.0 , J2 = 4.2), 2.05-1.95 (m, 2H), 0.82 (septet, 1H, J = 3.5). It contains 15% (±) -endo-1-benzyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid.
Example 9.6: Preparation of (±) -3b, 4,4a, 5-Tetrahydro-2H-cyclopropaf3.4Tciclopentan .2-c1pyrazol-3-carboxylic acid.
(Compound 1). Step A: Biciclof3.1.Olhexane-3-one.
To a solution of cyclopenen-4-ol (5.0 g, 59.5 mmol) and Et2Zn (12.4 mL_, 121 mmol) in DCM (25 mL_) under N2 atmosphere at 0 ° C was added CH2I2 (9.76 mL_, 121 mmol) for 30 minutes. min using a syringe pump. The reaction was slowly warmed to room temperature and stirred overnight at which time the mixture was opened to the air and slowly cooled by the addition of diluted HCL (50 mL). The mixture was diluted with EtOAc (100 mL) and filtered. The organic layer was separated, washed with H20 (100 mL) and brine (100 mL). The organics were dried on MgSO4, filtered, and concentrated to an oil which was purified by chromatography on silica gel (10% EtOAc in hexanes gradient to 30% EtOAc in hexanes) to yield the cyclopropyl alcohol as light oil. The alcohol (above) was dissolved in DCM (250 mL) and then treated with basic alumina (10 g) and PCC (15.2 g, 70.6 mmol) at room temperature. After stirring for 18 hours the solution was filtered through a pad of celite on silica gel using DCM / Et20 (3: 1) as eluent. The solvent was removed under vacuum (250 mbar, at bath temperature 20 ° C) and the product was purified by bulb to bulb distillation at reduced pressure (100 mbar) to produce the acetone in the form of a clear oil. 1H NMR (CDCl 3, 400 MHz): d2.60 (2H, m), 2.16 (2H, d, J = 20.0 Hz), 1.54 (2H, m), 0.90 (1H, dt, J = 6.0, 1.6 Hz) , -0.05 (1H, dt, J = 6.0, 4.0 Hz).
Step B: Preparation of ethyl ester of (±) - 3b.4,4a.5-Tetrahydro-1 H-cyclopropar3.41cyclopentaH, 2-c1pyrazole-3-carboxylic acid.
The title ester was prepared in a manner similar to that described in Example 9.1, Step C using bicyclo [3.1.0] hexane-3-one.
Step C: Preparation of (±) -3b.4.4a.5-Tetrahydro-2H-cyclopropaf3,41cyclopentari, 2-c1pyrazole-3-carboxylic acid (Compound 1).
To a solution of ester (43 mg, 0.23 mmol) in THF (2 mL) and H20 (1 mL) was added LiOHH20 (38 mg, 0.90 mmol) at room temperature. The reaction was heated at 55 ° C for 1.5 h. After cooling to room temperature the mixture was acidified to pH = 1 with HCL (6? /, Ac). Purification by reverse phase HPLC column Phenomenex® Luna C18 (10 μ, 250 x 21.2 mm), 5% (v / v) CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) 95% H20 gradient, 20 ml / min,? = 214 nm] produced the fatty acid as a white solid after lyophilization. HPLC / MS: Alltech® Prevail C18 column (5μ, 50 x 4.6 mm), 5% v / v CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient at 99% v / v CH3CN in H20, 3.5 mL / min, tr = 1.24 min, ESI + = 165.0 (M + H).
Example 9.7: Preparation of (±) -4- (2H-tetrazol-5-in-1 a.3.5.5a tetrahydro-1 H-2,3-diaza-cyclopropara-1-pentalene (Compound 2).
Compound 2 was prepared in a manner similar to that described in Example 9.1 using racemic 2-but-3-enyl-oxirane.
To a solution of the corresponding (±) -ester (50 mg, 0.26 mmol) in dioxane (1 ml_) was added NaOH (1 μg / ac, 2 ml_) at room temperature. The reaction was stirred overnight and acidified to pH = 1 with HCL (6N, ac). Purification by reverse phase HPLC column Phenomenex® Luna C18 (10 μ, 250 x 21.2 mm), 5% (v / v) CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) 95% H20 gradient, 20 ml / min,? = 214 nm] produced the free acid as a white solid after lyophilization. HPLC / MS: Discovery® C18 column (5μ, 50 x 2.1 mm), 5% v / v CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient at 99% v / v CH3CN in H20, 0.75 mL / min, tr = 1.09 min, EST = 164.1 (M + H).
Example 9.9: Preparation of intermediates (±) -6,6-dicioruro-espirofbiciclof3.1.01hexano-2,2 * -M, 31dioxolano1.
To a solution of 4-dioxy-spiro [4.4] non-6-ene (25.23 g, 0.20 mol) in CHCL3 (200 mL) and CH2CI2 (200 mL_) was added triethylbenzylammonium chloride (100 mg) and 50% strength. NaOH solution (200 mL) at room temperature. This solution was vigorously stirred at 45 ° C for 3 days. The reaction mixture was diluted with H20 (300 mL) and extracted with CHCl3 (2x 150 mL). The combined organic layer was concentrated in vacuo and the residue was purified by Si02 column chromatography (0-50% CH2CL2 in Hexanes) to the title compounds as a colorless liquid. 1H NMR (400 MHz, CDCl 3): d4.06-3.93 (m, 4H), 2.25-2.01 (m, 5H), 1.89-1.83 (m, 1H).
Example 9.10: Preparation of Intermediates (±) -exo-6-chloro-espirorbicichlor3.1.01hexane-2,2 -ri, 3Td -oxalano1 and (±) -endo-6-chloro-is pyrobicyclo3.1.01 hexane-2.2'- f1, 31-dioxolanol.
To a solution of (±) -6,6-dichloro-spiro [bicyclo [3.1.0] hexane-2.2 '- [1,3] dioxolane] (17.0 g, 81 mmol) and KOH (28.0 g, 0.5 mol) in EtOH (200 mL) was added Zn (62.8 g, 0.96 mol) at room temperature. The reaction mixture was heated to 80 ° C by vigorous stirring overnight. After cooling the reaction mixture to room temperature, it was filtered through the celite pad and the filtrate was treated with acetic anhydride (47.27 mL, 0.5 mol) in an ice bath. After concentrating in vacuo, the residue was extracted into hexanes (300 mL) and washed with H20 (2x 150 mL) and brine (150 mL). Column chromatography Si02 (20-70% CH2Cl2 in Hexanes) yielded exo-chloride and endo-chloride. Exo-chloride: 1 H NMR (400 MHz, CDCl 3): 54.07-3.90 (m, 4H), 2.94 (t, 1H, J = 1.9 Hz), 1.95-1.90 (m, 2H), 1.88-1.74 (m, 2H ), 1.68-1.62 (m, 1H), 1.45-1.36 (m, 1H). Endo-chloride: 1 H NMR (400 MHz, CDCl 3): 54.02-3.91 (m, 4H),
3. 42 (t, 1H, J = 7.5 Hz), 2.22-2.12 (m, 1H), 2.05-1.74 (m, 5H).
Example 9.11: Preparation of (±) -endo-6-chloro-exo-6-rnetyl-espirorbiciclof 3.1.01 hexane 0-2.2 '-f1.31dioxalano1 intermediate
To a solution of (±) -6,6-dichloro-spiro [bicyclo [3.1.0] hexane-2.2 '- [1, 3] dioxolane] (6.50 g, 31.1 mmol) in 140 mL of THF was added dropwise to drop t-butyl lithium (37.32 mmol, 21.95 mL of 1.7 M solution in pentane) at -100 ° C. After 20 min, methyl iodide (2.33 mL, 37.32 mmol) was added dropwise to the solution and heated slowly to room temperature. The product was extracted to n-Hexane. The solvent was removed under reduced pressure. Column chromatography Si02 (0-20% EtOAc / n-hexane) afforded the title compound as an oil. 1 H NMR (400 MHz, CDCl 3): 64.01-3.91 (m, 4H), 2.20-2.07 (m, 2H), 1.96-1.82 (m, 2H), 1.63 (dd, 1H, J1 = 6.8 Hz, J2 = 5.3 Hz), 1.61 (s, 3H), 1.54 (dd, 1H, J1 = 7.6 Hz, J2 = 1.0 Hz).
Example 9.12: Preparation of intermediate (±) -6-methylene-espirorbic-chloro3.1.0lhexane-2,2'-ri, 31dioxalano1
A solution of (±) -6-chloro-6-methyl-spiro [bicyclo [3.1.0] hexane-2.2 '- [1, 3] dioxolane] (2.50 g, 13.25 mmol) in DMSO (40 mL) was added a KO'Bu solution (15.9 mL of 1.0M in THF). The solution was heated at 60 ° C overnight. After cooling the reaction mixture to room temperature, the product was extracted into n-Hexane. The solvent was removed under reduced pressure. SiO2 column chromatography (14-25% EtOAc / n-hexane) afforded the title compound as an oil. 1 H NMR (400 MHz, CDCl 3): 65.55 (s, 1 H), 5.42 (t, 1 H, J = 1.0 Hz), 4.08-3.91 (m, 4H), 2.07-1.97 (m, 2H), 1.90-1.84 ( m, 2H), 1.65-1.54 (m, 2H).
Example 9.12a: Preparation of (±) -6-spirocyclopropyl-spiro-bichloro-3,1.0-hexane-2,2-di, intermediate-3-dioxalanol
To a solution of (±) -6-methylene-spiro [bicyclo [3.1.OJhexane-2.2 '- [1, 3] dioxolane] (1.52 g, 10 mmol) in Et20 (20 ml_) and CH2N2 (~5 mmol) in Et20 was added Pd (OAc) 2 (-20 mg). An additional CH2N2 (-45 mmol) in Et20 was added dropwise to the solution for 1 hour at room temperature. After concentration, column chromatography Si02 (50-90% CH2Cl2 in Hexanes) yielded the product (±) -6-spirocyclopropyl-spiro [bicyclo [3.1.0] hexane-2.2 '- [1,3] dioxolane] . 1 H NMR (400 MHz, CDCl 3): d4.02-3.94 (m, 1H), 3.92-2.86 (m, 3H), 1.96-1.89 (m, 1H), 1.75-1.62 (m, 5H), 0.82-0.86 (m, 2H), 0.79-0.76 (m, 1H), 0.73-0.70 (m, 1H).
Example 9.13: Preparation of substitute endo-intermediates. General Scheme of the Reaction: R3 = H or CH3 R2 = electriephile R3 = H or CH3
To a solution of 4,4'-di-tert-butyl-biphenyl (5 eq.) In THF was added lithium wire (5 eq.) Cut into small portions at room temperature. The solution was stirred vigorously at 0 ° C for 6 hours and cooled to -78 ° C. (±) -Endo or exo mono-chloride (1 eq.) Dissolved in THF was added to the dark green solution. After 10 min, the electromyl (5 eq.) Was added dropwise to the solution, it was slowly warmed to room temperature, and the resulting solution was poured rapidly into a mixture of saturated hexane / saturated NH4CI solution vigorously in bath frozen. The separated organic layer was concentrated and the Si02 column chromatography produced the endo-substituted product.
Example 9.13a: (±) -exo-6-Methyl-espyrorbicclor3.1.Olhexane-2,2 -? , 31-dioxalanol.
1 H NMR (400 MHz, CDCl 3): d4.05-3.87 (m, 4H), 1.90-1.80 (m, 1H), 1.76 (dd, 1H, J1 = 12.3 Hz, J2 = 8.0 Hz), 1.61 (dd, 1H, J1 = 13.8 Hz, J2 = 8.4 Hz), 1.45 (ddd, 1H, J1 = 13.8 Hz, J2 = 11.8 Hz, J3 = 8.2 Hz), 1.18-1.14 (m, 1H), 1.10 (ddd, 1H, J1 = 6.1 Hz, J2 = 2.9 Hz, J3 = 1.1 Hz), 1.00 (d, 3H, J = 6.0 Hz), 0.88 (qdd, 1H, J1 = 6.0 Hz, J2 = 3.0 Hz, J3 = 3.0 Hz).
Example 9.13b: (±) -endo-6-Methyl-espirorbiciclof3.1.0 Thexano-2,2-G1, 31dioxalano1.
1 H NMR (400 MHz, CDCl 3): 63.98-3.88 (m, 4H), 2.10-2.00 (m, 1H), 1.91 (dd, 1H, J1 = 14.3 Hz, J2 = 10.7 Hz), 1.69 (ddd, 1H, J1 = 13.2 Hz, J2 = 9.3 Hz, J3 = 1.4 Hz), 1.59-1.45 (m, 2H), 1.38 (ddd, 1H, J1 = 8.6 Hz, J2 = 6.5 Hz, J3 = 1.3 Hz), 1.15 (d , 3H, J = 6.6 Hz), 0.97 (qdd, 1H, J1 = 6.6 Hz, J2 = 7.5 Hz, J3 = 7.5 Hz).
Example 9.13c: (±) -endo-6-ethyl-espirorbiciclor3.1.01hexano-2.2 -? , 31-dioxalanol
1 H NMR (400 MHz, CDCl 3): 63.99-3.88 (m, 4H), 2.09-1.91 (m, 2H), 1.73-1.50 (m, 4H), 1.45-1.35 (m, 2H), 1.15 (t, 3H , J = 7.4 Hz), 0.78 (qdd, 1H, J1 = 7.4 Hz, J2 = 7.5 Hz, J3 = 7.4 Hz).
Example 9.13d: (±) -endo-6-Formyl-espirorbiciclor3.1.Olhexane-2.2'-M.31dioxalanol.
1 H NMR (400 MHz, CDCl 3): 59.60 (d, 1 H, J = 6.3 Hz), 4.05-3.93 (m, 4 H), 2.34-2.19 (m, 2 H), 2.15-2.06 (m, 3 H), 1.91- 1.76 (m, 2H).
Example 9.13e: (±) -exo-6-Formyl-espirorbiciclor3.1.01hexane-2,2-f 1, 31-dioxalanol.
1 H NMR (400 MHz, CDCl 3): d 9.27 (d, 1 H, J = 4.0 Hz), 4.08-4.02 (m, 1 H), 3.99-3.91 (m, 3 H), 2.13-1.99 (m, 4 H), 1.90 (dd, 1H, J1 = 12.7 Hz, J2 = 8.0 Hz), 1.72 (dd, 1H, J1 = 14.0 Hz, J2 = 8.7 Hz), 1.59-1.50 (m, 1H).
Example 9.14: Preparation of intermediate (±) -endo-6 ° vSnil- espirorbiciclor3.1.01hexane-2,2'-ri, 31dioxalano1.
To a solution of methyltriphenylphosphonium bromide (2.55 g, 7.14 mmol) in 40 mL of THF was added n-butyl lithium (7.14 mmol, 4.46 mL of 1.6 M solution in hexane) at room temperature. After 2 h, a solution of enoO-6-formyl-spiro [bicyclo [3.1.Ojhexane-2,2 '- [1,3] dioxolane] (1.0 g, 5.95 mmol) in 8 mL of THF was added to the reaction mixture at room temperature and was stirred overnight. The product was extracted to n-Hexane. The solvent was removed under reduced pressure. Column chromatography of Si02 (0-20% EtOAc / n-hexane) afforded the title compound as an oil. 1 H NMR (400 MHz, CDCl 3): 55.87 (ddd, 1 H, J, = 17.0 Hz, J2 = 10.2 Hz, J3 = 8.6 Hz), 5.30 (ddd, 1H, J, = 17.0 Hz, J2 = 2.0 Hz, J3 = 1.0 Hz), 5.18 (ddd, 1H, J, = 10.2 Hz, J2 = 2.0 Hz, J3 = 1.0 Hz), 4.00-3.88 (m, 4H), 2.12-2.02 (m, 1H), 1.90 (dd, 1H, J, = 14.5 Hz, J2 = 10.3 Hz), 1.80-1.56 (m, 5H).
Example 9.14a: Preparation of (±) -exo-6-Vinyl-espirorbiciclor3.1.01hexano-2.2'-ri, intermediate 31dioxolano1.
The title compound was prepared in a similar manner described in Example 9.14. 1 H NMR (400 MHz, CDCl 3): 55.35 (ddd, 1 H, J, = 17.0 Hz, J2 = 10.2 Hz, J3 = 8.6 Hz), 5.05 (ddd, 1H, J1 = 17.0 Hz, J2 = 1.5 Hz, J3 = 0.4 Hz), 4.96 (dd, 1H, J, = 10.3 Hz, J2 = 1.6 Hz), 4.06-4.00 (m, 1H), 3.99-3.88 (m, 3H), 1.98-1.88 (m, 1H), 1.84 (dd, 1H, J, = 12.1 Hz, J2 = 8.1 Hz), 1.66 (dd, 1H, J, = 14.2 Hz, J2 = 8.8 Hz), 1.56-1.43 (m, 4H).
Example 9.14b: Preparation of intermediate (±) -endo-6- (1 -propenyl) -spirorbiciclof3.1.01hexane-2,2'-ri, 31-dioxolane.
The title compound was prepared in a manner similar to that described in Example 9.14. 1 H NMR (400 MHz, CDC13): 55.75-5.68 (m, 1H), 5.52-5.47 (m, 1H), 3.99-3.88 (m, 4H), 2.06-1.96 (m, 1H), 1.89-1.70 (m , 5H), 1.68-1.52 (m, 4H).
Example 9.14c: Preparation of intermediate (±) -endo-6-cyclodopropyl spiro rbicichlor3.1.01hexane-2,2'-N.31 dioxolane1
The title compound was prepared in a manner similar to that described in Example 9.12a. 1 H NMR (400 MHz, CDCl 3): 54.02-3.88 (m, 4H), 2.09-1.99 (m, 1H), 1.91-1.50 (m, 3H), 1.48-1.39 (m, 2H), 1.22-1.17 (m , 1H), 0.78-0.71 (m, 1H), 0.65-0.52 (m, 2H), 0.33-0.26 (m, 2H).
Example 9.15: Preparation of ketone intermediates General Reaction Scheme:
A solution of the ketone protected in acetone / H20 (4/1) was treated with a catalytic amount of TsOH at room temperature. The solution was stirred overnight. The acetone was removed in vacuo and the product was extracted with hexanes (3x). The combined organic layer was washed with a 5% NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo to yield the ketone product.
Example 9.15a: f ±) -exo-6-Methyl-bicichlor3.1, 01hexan-2-one.
1H NMR (400 MHz, CDCl 3): d2.14-1.98 (m, 4H), 1.85 (q, 1H, J = 4.8 Hz), 1.52 (dd, 1H, J, = 5.0 Hz, J2 = 2.5 Hz), 1.36-1.30 (m, 1H), 1.12 (d, 3H, J = 6.0Hz).
Example 9.15b: (±) -enoO-6-Methyl-bicichlor3.1.01hexan-2-one
1 H NMR (400 MHz, CDCl 3): 52.32-2.21 (m, 2H), 2.13-2.08 (m, 1H), 1.97-1.84 (m, 3H), 1.55-1.48 (m, 1H), 1.15 (d, 3H , J = 6.6 Hz).
Example 9.15c: (±) -enoO-6-Ethyl-bicyclo3. .01hexan-2-one
1 H NMR (400 MHz, CDCl 3): 52.34-2.20 (m, 2 H), 2.15 (q, 1 H, J = 6.0 Hz), 2.00-1.87 (m, 3 H), 1.48-1.36 (m, 3 H), 1.04 ( t, 3H, J = 6.5 Hz).
Example 9.15d: (±) -endo-6-Vini l-biciclor3.1.OIhexan-2-one.
1 H NMR (400 MHz, CDCl 3): 65.67 (ddd, 1 H, J, = 17.0 Hz, J2 = 10.3 Hz, J3 = 8.5 Hz), 5.37 (dt, 1H, J -, = 17.0 Hz, J2 = 1.4 Hz) , 5.27 (dt, 1H, 10.3 Hz, J2 = 1.5 Hz), 2.32-2.21 (m, 3H), 2.20-2.14 (m, 1H), 2.10- 2.07 (m, 1H), 2.03-1.93 (m, 2H ).
Example 9.15e: (±) -6-spirocyclopropyl-bicyclo3.1.01hexan-2-one.
1 H NMR (400 MHz, CDCl 3): 52.33 (t, 1 H, J = 5.0 Hz), 2.26-2.04 (m, 4 H), 1.99-1.91 (m, 1 H), 1.03 (t, 2 H, J = 7.2 Hz) , 0.88-0.78 (m, 2H).
Example 9.15f: (±) -exo-6-Vinyl-biccof3.1.01hexan-2-one.
1 H NMR (400 MHz, CDC13): < 55.35 (ddd, 1H, J, = 17.0 Hz, J2 = 10.2 Hz, J3 = 8.5 Hz), 5.15 (ddd, 1H, J, = 17.0 Hz, J2 = 1.2 Hz, J3 = 0.4 Hz), 4.99 (dd, 1H, J, = 10.2 Hz, J2 = 1.1 Hz), 2.20-2.05 (m, 5Hj, 1.95-1.91 (m, 1H), 1.83 (q, 1H, Jn = 2.5 Hz).
Example 9.15g: (±) -in o-6- (1-propenyl) -biciclof3. .01hexan-2-one.
1 H N R (400 MHz, CDCl 3): 55.82-5.75 (m, 1H), 5.33-5.26 (m, 1H), 2.30-1.89 (m, 7H), 1.76-1.70 (m, 3H).
Example 9.15 h: (±) -in / o-6-cyclopropyl-bicichlor3.1.0 Thexan-2-one. Acetone /? T?
1 H NMR (400 MHz, CDC13): (52.32-2.09 (m, 5H), 1.86-1.82 (m, 1H), 1.16-1.09 (m, 1H), 0.71-0.65 (m, 1H), 0.61-0.56 ( m, 2H), 0.39-0.29 (m, 2H).
Example 9.16: Preparation of yl ester) -exo-1-methyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1-phenylene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS m / z (ES +): 207.2 [M + H] \ 229.4 [M + Na] +; 1 H NMR (400 MHz, CDCl 3): 54.37-4.31 (m, 2H), 2.97 (dd, 1H, Ji = 17.1 Hz, J2 = 5.7 Hz), 2.86 (d, 1H, J = 17.1 Hz), 2.01-1.97 (m, 2H), 1.36 (t, 3H, J = 7.1 Hz), 1.13 (d, 3H, J = 6.1 Hz), 0.78-0.72 (m, 1H).
Example 9.17: Preparation of ±) -exo-1-methyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid
The title compound was prepared in a manner similar to that described in Example 9.3. MS m / z (ES *): 179.1 [M + Hf, 201.5 [M + Na] +; 1H NMR (400 MHz, CDCl 3): d3.02 (dd, 1H, J, = 18.5 Hz, J2 = 6.3 Hz), 2.91 (d, 1H, J = 18.5 Hz), 2.09 (dd, 1H, = 5.6 Hz , J2 = 2.2 Hz), 1.78 (dd, 1H, J, = 9.7 Hz, J2 = 5.9 Hz), 1.17 (d, 3H, J = 6.0 Hz), 0.74 (qdd, 1H, J1 = 6.0 Hz, J2 = 3.0 Hz, J3 = 3.0 Hz).
Example 9.18: Preparation of (±) -exo-1-methyl-4- (2H-tetrazol-5-yl) -1 a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropaxy-1 -pentalene. Step A: Preparation of amide of (±) -exo-1-methyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparaTpentalene-4-acid
The title compound was prepared in a manner similar to that described in Example 9.1, Step D. MS m / z (ES *): 178.1 [M + H] +, 200.1 [M + Na] +; 1H NMR (400 MHz, DMSO-d6): d2.84 (dd, 1H, J, = 18.0 Hz, J2 = 6.4 Hz), 2.69 (d, 1H, J = 18.0 Hz), 1.97 (dd, 1H, J , = 5.8 Hz, J2 = 2.3 Hz), 1.68 (dd, 1H, J, = 9.5 Hz, J2 = 6.0 Hz), 1.08 (d, 3H, J = 6.0 Hz), 0.63 (qdd, 1H, J-, = 6.0 Hz, J2 = 3.0 Hz, J3 = 3.0 Hz).
Step B: Preparation of (±) -exo-1-methyl-1a.3.5.5a-tetrahydro-1H-2,3-diaza-cyclopropaphapentalene-4-carbonitriio.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS m / z (ES +): 160.2 [M + H] +, 319.1 [2M + H] +; 1H NMR (400 MHz, DMSO-d6): 52.80 (dd, 1H, J, = 15.9 Hz, J2 = 4.4 Hz), 2.71 (d, 1H, J = 15.9 Hz), 2.04-1.97 (m, 2H), 1.05 (d, 3H, J = 6.1 Hz), 0.72-0.65 (m, 1H).
Step C: Preparation of (±) -exo-1-methyl-4- (2H-tetrazoS-5-yl) -1 a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropafalpentalene.
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS m / z (ES +): 203.5 [+ H] +, 225.4 [+ Na] +; H NMR (400 MHz, DMSO-d6): 52.89 (ddd, 1H, J, = 16.2 Hz, J2 = 4.7 Hz, J3 = 1.6 Hz), 2.81 (d, 1H, J = 16.2 Hz), 2.02-1.98 ( m, 2H), 1.08 (d, 3H, J = 6.1 Hz), 0.70 (qdd, 1H, J, = 6.1 Hz, J2 = 3.0 Hz, J3 = 3.0 Hz).
Example 9.19: Preparation of ethyl ester of (±) -endo-1-methyl-1 a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparaTypentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS m / z (ES +): 207.1 [M + H] +, 229.2 [M + Na] +; 1 H NMR (400 MHz, CDCl 3): 54.37-4.30 (m, 2H), 2.92 (dd, 1H, J, = 17.5 Hz, J2 = 6.8 Hz), 2.65 (d, 1H, J = 17.5 Hz), 2.33 ( t, 1H, J = 6.8 Hz), 2.33 (dd, 1H, J, = 15.0 Hz, J2 = 6.8 Hz), 1.38 (t, 3H, J = 7.1 Hz), 1.39-1.30 (m, 1H), 0.71 (d, 3H, J = 6.5 Hz).
Example 9.20: Preparation of (±) -endo-1-methyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropaphapentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS m / z (ES *): 179.1 [M + H] +, 357.1 [2M + H] +; 1H NMR (400 MHz, CD3OD): 52.89 (dd, 1H, J, = 17.3 Hz, J2 = 6.7 Hz), 2.64 (d, 1H, J = 17.2 Hz), 2.30-2.18 (m, 2H)), 1.34 (qdd, 1H, J, = 6.4 Hz, J2 = 7.0 Hz, J3 = 7.0 Hz) .0.69 (d, 3H, J = 6.4 Hz).
Example 9.21: Preparation of ± -endo-1-methyl-4- (2H-tetrazoi-5-yl> -1 a.3.5.5a-tetrahydro-1 H-2.3-diaza-cyclopropara-1-pentalene Step A: Preparation of amide of (±) -e /? do-1-methyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopentylpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step E. MS m / z (ES +): 178.1 [M + H] +, 355.2 [2M + H] +; H NMR (400 MHz, CD3OD): 62.88 (dd, 1H, = 16.5 Hz, J2 = 4.8 Hz), 2.66 (d, 1H, J = 16.8 Hz), 2.30-2.22 (m, 2H)), 1.32 (qdd , 1H, J, = 6.4 Hz, J2 = 7.0 Hz, J3 = 7.0 Hz) .0.69 (d, 3H, J = 6.4 Hz).
Step B: Preparation of (±) -endO-1-methyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carbonitrile.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS m / z (ES *): 160.1 [M + H] +, 319.4 [2M + H] +; 1H NMR (400 MHz, CD3OD): 62.84 (dd, 1H, J, = 16.6 Hz, J2 = 6.7 Hz), 2.59 (d, 1H, J = 16.6 Hz), 2.36-2.27 (m, 2H)), 1.39 (qdd, 1H, Ü! = 6.4 Hz, J2 = 7.0 Hz, J3 = 7.0 Hz). 0.69 (d, 3H, J = 6.4 Hz).
Step C: Preparation of (±) -endo-1-methyl-4- (2H-tetrazol-5-yl> -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS m / z (ES +): 203.4 [M + H] +, 405.4 [2M + H] +; H NMR (400 MHz, CDCl 3): 53.18 (dd, 1H, J, = 17.3 Hz, J2 = 6.5 Hz), 2.95 (d, 1H, J = 17.4 Hz), 2.60-2.53 (m, 2H)), 1.67 (qdd, 1H, J, = 6.5 Hz, J2 = 7.0 Hz, J3 = 7.0 Hz). 0.82 (d, 3H, J = 6.5 Hz).
Example 9.22: Preparation of ethyl ester of (±) -enoO-1 ° ethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropafalpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS m / z (ES +): 221.3 [M + H] +, 243.3 [M + Na] +; 1 H NMR (400 MHz, CDCl 3): 64.38-4.30 (m, 2H), 2.92 (dd, 1H, JT = 17.5 Hz, J2 = 6.9 Hz), 2.65 (d, 1H, J = 17.5 Hz), 2.35 (ddd , 1H, = 7.6 Hz, J2 = 6.2 Hz, J3 = 1.3 Hz), 2.21 (dd, 1H, J = 14.4 Hz, J2 = 6.7 Hz), 1.37 (t, 3H, J = 7.1 Hz), 1.23-1.17 (m, 1H), 1.11-1.01 (m, 1H), 0.91-0.83 (m, 4H).
Example 9.23: Preparation of (±) -endo-1-ethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS m / z (ES +): 193.0 [+ H] +, 215.0 [M + Na] +; 1 H NMR (400 MHz, DMSO-d 6): < 52.80 (dd, 1H, J1 = 17.2 Hz, J2 = 6.8 Hz), 2.49 (d, 1H, J = 17.2 Hz), 2.24 (ddd, 1H, J, = 7.6 Hz, J2 = 6.2 Hz, J3 = 1.0 Hz ), 2.15 (dd, 1H, = 14.4 Hz, J2 = 6.4Hz), 1.18-1.11 (m, 1H), 1.03-0.93 (m, 1H), 0.81 (t, 3H, J = 6.9 Hz), 0.77- 0.68 (m, 1H).
Example 9.24: Preparation of (±) -e? OO-1-ethyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene . Step A: Preparation of amide of (±) -in < / o-1-ethyl-1 a.3,5, 5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.1, Step D. MS m / z (ES +): 192.0 [M + H] +, 383.2 [2M + H] +.
Step B: Preparation of (±) -endo-1-ethyl-1a.3,5.5a-tetrahydro-1H-2,3-diaza-cyclopropara1pentalene-4-carbonitrile.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS m / z (ES +): 174.1 [M + H] +, 347.4 [2M + H] +.
Step C: Preparation of (± ¾-enc / o-1-ethyl-4- (2H-tetrazoi-5-yl)
1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene.
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS m / z (ES +): 217.1 | M + H] +, 433.1 [2M + H] +; 1H NMR (400 MHz, CD3OD): 52.91 (dd, 2H, J ^ = 14.6 Hz, J2 = 6.1 Hz), 2.07-2.03 (m, 1H), 1.88-1.79 (m, 1H), 1.66-1.57 (m , 1H), 1.17 (dd, 1H, J, = 7.7 Hz, J2 = 4.7 Hz), 1.09 (t, 3H, J = 7.4 Hz), 0.56 (dd, 1H, J, = 4.2 Hz, J2 = 3.2 Hz ).
Example 9.25: Preparation of (±) -endo-1-vinyl-1 a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid ethyl ester.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS m / z (ES *): 219.2 [M + H] +, 241.1 [M + Na] +; 1 H NMR (400 MHz, CDCl 3): 55.31-5.23 (m, 1H), 5.05-4.95 (m, 1H) 54.39-4.31 (m, 2H), 2.99 (dd, 1H, J, = 17.5 Hz, J2 = 6.7 Hz), 2.76 (d, 1H, J = 17.5 Hz), 2.60 (ddd, 1H, J, = 7.6 Hz, J2 = 6.0 Hz, J3 = 1.2 Hz), 2.42 (dd, 1H, J-, = 15.0 Hz , J2 = 6.0 Hz), 1.99 (ddd, 1H, J-, = 8.0 Hz, J2 = 8.0 Hz, J3 = 8.0 Hz), 1.37 (t, 3H, J = 7.1 Hz).
Example 9.26: Preparation of (±) -encfo-1-vinyl-1 a.3.5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropaalpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS m / z (ES *): 191.2 [M + H] \ 381.3 [2M + H] +; 1H NMR (400 MHz, DMSO-d6): d5.25 (dd, 1H, J, = 16.9 Hz, J2 = 2.3 Hz), 4.99 (dd, 1H, J, = 10.4 Hz, J2 = 2.4 Hz), 4.85 (ddd, 1H, JT = 16.9 Hz, J2 = 10.4 Hz, J3 = 9.2 Hz), 2.88 (dd, 1H, J-, = 17.3 Hz, J2 = 6.6 Hz), 2.57-2.50 (m, 2H), 2.39 (dd, 1H, Ji = 14.5 Hz, J2 = 6.2 Hz), 1.94 (ddd, 1H, J, = 8.4 Hz, J2 = 8.4 Hz, J3 = 8.4 Hz).
Example 9.27: Preparation of Step A: Preparation of amide of ±) -endO-1-vinyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropapha-1-phenylene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.1, Step D. MS m / z (ES *): 190.2 [M + H] +, 379.2 [2M + H] +; 1H NMR (400 MHz, DMSO-d6): 55.25 (dd, 1H, J, = 16.9 Hz, J2 = 2.3 Hz), 4.98 (dd, 1H, J, = 10.4 Hz, J2 = 2.4 Hz), 4.90-4.81 (m, 1H), 2.88 (bd, 1H, J = 13.6 Hz), 2.64-2.49 (m, 2H), 2.40 (dd, 1H, J, = 13.7 Hz, J2 = 6.9 Hz), 1.92 (ddd, 1H , J1 = 8.4 Hz, J2 = 8.4 Hz, J3 = 8.4 Hz).
Step B: Preparation of (±) -endo-1-Vinyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carbonitrile.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS m / z (ES +): 172.3 [M + H] +, 343.3 [2M + H] +; 1 H NMR (400 MHz, CDCl 3): 55.30 (dd, 1 H, = 16.9 Hz, J2 = 2.0 Hz), 5.08 (dd, 1H, J, = 10.4 Hz, J2 = 2.0 Hz), 4.93 (ddd, 1H, JT = 16.9 Hz, J2 = 10.4 Hz, J3 = 8.5 Hz), 2.96 (dd, 1H, J, = 16.9 Hz, J2 = 6.7 Hz), 2.73 (d, 1H, J = 16.9 Hz), 2.60-2.49 (m , 2H), 2.03 (ddd, 1H, Ji = 8.3 Hz, J2 = 8.3 Hz, J3 = 8.3 Hz).
Step C: Preparation of (±) -endo-4- (2H-tetrazol-5-in-1-vinyl-la, 3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene.
The title compound was prepared in a manner similar to that described in Example 9.1, Step F. MS m / z (ES +): 215.2 [M + H] 429.3 [2M + H] +; H NMR (400 MHz, CD3OD): 55.30-5.25 (m, 1H), 5.07-4.99 (m, 2H), 3.05 (dd, 1H, J, = 16.6 Hz, J2 = 6.6 Hz), 2.82 (d, 1H , J = 16.6 Hz), 2.62 (dd, 1H, J = 7.5 Hz, J, = 6.1 Hz), 2.55 (dd, 1H, J-, = 13.5 Hz, J2 = 7.0 Hz), 2.06-2.00 (m, 1 HOUR).
Example 9.28: Preparation of (±) -endo-1-Benzyl-4- (2H-tetrazol-5-yl) -1a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropapha1pentalene.
The title compound was obtained by HPLC purification from the mixture of diastereomers as described in Example 9.4, Step F. MS: m / z (ES +): 301 [M + Na] +, 279 [M + H ] \ 251 [M-N2 + H] +; 1H NMR (CD3OD): 67.2-7.05 (m, 2H), 7.03 (t, 1H, J = 6.8), 6.97 (d, 2H, J = 7.4), 3.0-2.8 (m, 1H), 2.77 (d, 1H, J = 16.7), 2.5-2.3 (m, 3H), 2.02 (dd, 1H, J, = 14.5, J2 = 8.9), 1.55-1.45 (m, 1H).
Example 9.29: Preparation of ethyl ester of f ± -exo-1-Propyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparapentalene-4-carboxylic acid. Step A: Preparation of (±) -exo-6-Propyl-bicichlor3.1.01hexan-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.2, Step B.1H NMR (CDCI3): 54.21 (d, 1H, J = 4.8), 1.95-1.80 (m, 1H), 1.67 (dd, 1H, J, = 12.5, J2 = 8.2), 1.53 (dd, 1H, J, = 14.2, J2 = 8.3), 1.48-1.28 (m, 4H), 1.20-1.05 (m, 3H), 0.88 (t, 3H, J = 7.3), 0.37 (septet, 1H, J = 3.3). Contains ca 30% (±) endo-6-n-propyl-bicyclo [3.1.0] hexan-2-ol.
Step B: Preparation of (±) -exo-6-Propyl-biciclor3.1.OIhexan-2-one.
The title compound was prepared in a manner similar to that described in Example 9.2, Step C. 1 H NMR (CDCl 3): 62.15-1.95 (m, 4H), 1.9-1.8 (m, 1H), 1.53 (d, 1H, J = 5.0), 1.50-1.35 (m, 2H), 1.35-1.25 (m, 3H), 0.91 (t, 3H, J = 7.3). Contains ca 30% (±) endo-6-n-propyl-bicyclo [3.1.0] hexan-2-one.
Step C: Preparation of (±) -exo-1-Propyl-1a.3,5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid ethyl ester.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS: m / z (ES +): 257 [M + Na] +, 235 [M + H] \ 189 [M-OEt] +; 1H NMR (CDCl3): d4.25 (q, 2H, J = 7.1, OCH2), 2.86 (dd, 1H, J, = 17.1, J2 = 6.2), 2.74 (d, 1H, J = 17.1), 1.95- 1.90 (m, 1H), 1.87-1.80 (m, 1H), 1.40-1.10 (m, 7H, including 1.27 (t, 3H, J = 7.2)), 0.85 (t, 3H, J = 7.2), 0.60 ( septet, 1H, J = 3.4). It contains ca 30% (±) -endo-1-n-propyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-ethyl ester carboxylic acid.
Example 9.30: Preparation of (±) -exo-1-Propyl-1a.3.5.5a- tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid
The title compound was prepared in a manner similar to that described in Example 9.3. MS: m / z (ES +): 229 [M + Na] +, 207 [M + H] +, 189 [M-OH] +; 1H NMR (CD3OD): 62.95-2.85 (m, 1H), 2.79 (d, 1H, J = 16.8), 2.00-1.90 (m, 2H), 1.47 (m, 2H, J = 7.1), 1.40-1.25 ( m, 2H), 0.96 (t, 3H, J = 7.3), 0.63 (m, 1H, J = 3.4).
Example 9.31: Preparation of (±) -exo-1-Propyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene. Step A: Preparation of amide of (±) -exo-1-Propyl-1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step E. MS: m / z (ES +): 206 [M + H] +, 189 [M-NH 2] +; 1H NMR (CD3OD): 52.92 (dd, 1H, J, = 16.4, J2 = 5.8), 2.82 (d, 1H, J = 16.5), 2.05-1.90 (m, 2H), 1.47 (pente, 2H, J = 7.1), 1.38-1.28 (m, 2H), 0.96 (t, 3H, J = 7.3), 0.66 (septet, 1H.J = 3.3).
Step B: Preparation of (±) -exo-1-propyl-1a.3,5.5a-tetrahydro-1 H- 2,3-diaza-cyclopropara1pentalene-4-carbonitrile
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS: m / z (ES +): 188 [M + H] +; 1H NMR (CD3OD): .52.88 (dd, 1H, J ^ = 16.3, J2 = 6.0), 2.76 (d, 1H, J = 16.2), 2.1-2.0 (m, 2H), 1.47 (pente, 2H, J = 7.3), 1.40-1.28 (m, 2H), 0.96 (t, 3H, J = 7.3), 0.71 (septet, 1H, J = 3.3).
Step C: Preparation of (±) -exo-1-propyl-4- (2H-tetrazol-5-in-1 a.3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparal entalene.
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS: m / z (ES +): 231 [M + H] +, 203 [M-N 2 + H] +; 1H NMR (CD3OD): 63.00 (dd, 1H, J, = 10.1, J2 = 6.1), 2.91 (d, 1H, J = 16.2), 2.07 (m, 2H), 1.50 (sextet, 2H, J = 7.3) , 1.35 (septet, 2H, J = 7.0), 0.99 (t, 3H, J = 6.1), 0.74 (septet, 1H, J = 3.3).
Example 9.32: Preparation of (±) -endO-1-Propyl-1a.3,5.5a-tetrahydro-1 H-2,3-diaza-cycloproparal entalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3 using the mixture of diastereomers described in Example 9.29, Step C. MS: m / z (ES +): 229 [M + Na] +, 207 [M + H] +, 189 [M-OH] +.
Example 9.33: Preparation of (±) -endO-1-Propyl-4- (2H-tetrazol-5-yl) -1 a.3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene. Step A: Preparation of amide of (±) -encfo-1-Propyl-1 a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step E. MS: m / z (ES +): 206 [M + H] \ 189 [M-NH2] +; 1H NMR (CDCl 3): d6.45 (br s, 1H), 5.95 (br s, 1H), 2.93 (dd, 1H, Jn = 16.6, J2 = 6.6), 2.68 (d, 1H, J = 16.6;, 2.4-2.3 (m, 2H), 1.4-1.2 (m, 3H), 1.15-1.00 (m, 1H), 0.88-0.78 (m, 4H).
Step B: Preparation of (±) -endo- "\ -propyl-1 a, 3,5,5a-tetrahydro-1 H- 2,3-diaza-cycloproparalpentalene-4-carbonitrile
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS: m / z (ES +): 188 [M + H] +; 1H NMR (CD3OD): 52.85 (dd, 1H,? = 16.6, J2 = 6.6), 2.60 (d, 1H, J = 16.6, 2.4-2.3 (m, 2H), 1.45-1.20 (m, 3H), 1.15 -1.05 (m, 1H), 0.90-0.80 (m, 3H), 0.78-0.65 (m, 1H).
Step C: Preparation of (±) -endO-1-Propyl-4- (2H-tetrazoi-5-yl) -1 a.3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene.
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS: m / z (ES +): 231 [M + H] +, 203 [M-N 2 + H] +; 1H NMR (CD3OD): 52.97 (dd, 1H, J, = 10.2, J2 = 6.4), 2.72 (d, 1H, J = I8.3), 2.40-2.34 (m, 2H), 1.42-1.28 (m, 3H), 1.20-1.11 (m, 1H), 0.86-0.77 (m, 4H including 0.85 (t, 3H, J = 7.4)).
Example 9.34: Preparation of (±) -exo-1-Butyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid ethyl ester. Step A: Preparation of (±) - (E) -2- (Oct-3-enyl) oxirane.
2- (But-3-enyl) oxirane (1,000 g, 10.2 mmol) and hex-1-ene (9.12 g, 102 mmol) were stirred at room temperature for 24 hr in a scintillation flask sealed with Zhan catalyst 1 (0.057). g, 0.086mmol). The solvent was removed under reduced pressure and the residue was purified by column chromatography (0-10% EtOAc / n-hexane / silica) to yield (±) - (E) -2- (oct-3-enyl) oxirane in form of colorless oil. 1 H NMR (CDCl 3): 55.5-5.4 (m, 2 H), 3.0-2.9 (m, 1 H), 2.8-2.7 (m, 1 H), 2.5-2.45 (m, 1 H), 2.2-2.1 (m, 2 H) , 1.99 (q, 2H, J = 5.7), 1.65-1.55 (m, 2H), 1.35-1.25 (m, 4H), 0.95-0.85 (m, 3H).
Contains ca 20% (E) -2- (oct-3-enyl) oxirane.
Step B: Preparation of (±) -exo-6-Butyl-bicichlor3.1.01hexan-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.2, Step B. H NMR (CDCl 3): 54.21 (d, 1H, J = 4.8), 1.95-1.80 (m, 1H), 1.69 (dd, 1H, = 12.6, J2 = 8.0), 1.54 (dd, 1H, J, = II.6, J2 = 5.7), 1.48-1.25 (m, 6H), 1.25-1.05 (m, 3H), 0.95-0.85 ( m, 3H), 0.36 (septet, 1H, J = 3.3). Contains ca 20% (±) -endo-6-n-butyl-bicyclo [3.1.0] hexan-2-ol.
Step C: Preparation of (±) -exo-6-Butyl-bicichlor3.1.OIhexan-2-one.
The title compound was prepared in a manner similar to that described in Example 9.2, Step C. 1 H NMR (CDCl 3): 52.15-1.95 (m, 4H), 1.9-1.8 (m, 1H), 1.54 (t, 1H, J = 2.4), 1.45-1.20 (m, 7H), 0.95-0.85 (m, 3H). Contains ca 20% (±) -endo-6-n-butyl-bicyclo [3.1.Ojhexan-2-one.
Step D: Preparation of (±) -exo-1-Butyl-1a.3.5.5a- tetrahydro-1 H-2,3-diaza-cycloproparal entalene-4-acid ethyl ester
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS: m / z (ES +): 249 [M + H] +, 203 [M-OEt] +; 1 H NMR (CDCl 3): 54.30 (q, 2H, J = 7.2, OCH2), 2.91 (dd, 1H, J, = 17.0, J2 = 6.2), 2.79 (d, 1H, J = 17.0), 1.98-1.93 ( m, 1H), 1.89 (dd, 1H, = 9.8, J2 = 6.0), 1.45-1.10 (m, 9H, including 1.32 (t, 3H, J = 7.1)), 0.87 (t, 3H, J = 6.8) , 0.70-0.60 (m, 1H). Contains ca 30% ethyl ester of (±) -endo-1-n-butyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid .
Example 9.35: Preparation of (±) -exo-1-Butyl-1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid
The title compound was prepared in a manner similar to that described in Example 9.3. MS: m / z (ES +): 221 [M + H] +, 203 [M-OH] +; H NMR (CD3OD): 62.95-2.85 (m, 1H), 2.78 (d, 1H, J = 16.9), 2.00-1.90 (m, 2H), 1.5-1.25 (m, 6H), 0.93 (t, 3H, J = 7.0), 0.62 (septet, 1H, J = 3.3).
Example 9.36: Preparation of f ± -exo-1-Butyl-4- (2H-tetrazo »-5-yl) -1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene. Step A: Preparation of amide of (±) -exo-1 -Butyl-1 a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropapha1pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step E. MS: m / z (ES +): 220 [M + H] +, 203 [M-NH 2] +; 1H NMR (CD3OD): 52.92 (dd, 1H, J, = 16.4, J2 = 5.9), 2.82 (d, 1H, J = 16.0), 2.05-1.90 (m, 2H), 1.50-1.30 (m, 6H) , 0.93 (t, 3H, J = 7.0), 0.65 (septet, 1H, J = 3.3).
Step B: Preparation of (±) -exo-1-Butyl-1a, 3,5,5a-tetrahydro-IH-2,3-diaza-cyclopropara-1-phenylene-4-carbonitrile.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS: m / z (ES +): 202 [M + H] +; 1H NMR (CD3OD): 62.89 (dd, 1H, = 16.3, J2 = 6.0), 2.76 (d, 1H, J = 16.2), 2.1-2.0 (m, 2H), 1.50-1.30 (m, 6H), 0.93 (t, 3H, J = 7.0), 0.70 (septet, 1 H, J = 3.3).
Step C: Preparation of (±) -exo-1-Butyl-4- (2H-tetrazol-5-n-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene.
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS: m / z (ES +): 245 [M + H] +, 217 [M-N 2 + H] +; 1H NMR (CD3OD): 62.99 (dd, 1H, = 10.2, J2 = 6.0), 2.90 (d, 1H, J = 16.2), 2.10-2.00 (m, 2H), 1.49-1.32 (m, 6H), 0.93 (t, 3H, J = 7.0), 0.72 (septet, 1H, J = 3.3).
Example 9.37: Preparation of (±) -enoO-1 -Butyl-1 a, 3.5.5a-tetrahydro-1H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3 using the mixture of diastereomers described in Example 9.34, Step D. MS: m / z (ES +): 221 [M + H] +, 203
[-OH] +.
Example 9.38: Preparation of (±) -endo-1 -Butyl-4- (2H-tetrazole ° 5 il) -1 a.3.5.5a-tetrahydro-1 H-2.3-diaza-cyclopentylpentalene. Step A: Preparation of amide of (±) -oenoO-1-n-Butyl-1 a.3.5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropapha1pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step E using the mixture of diastereomers described in Example 9.36, Step D. MS: m / z (ES +): 220 [M + H] +, 203 [M-NH2] +; 1H NMR (CD3OD): 52.87 (dd, 1H, J, = 16.7, J2 = 6.3), 2.66 (d, 1H, J = 16.7), 2.35-2.20 (m, 2H), 1.35-1.15 (m, 5H) , 1.15-1.05 (m, 1H), 0.85-0.70 (m, 4H).
Step B: Preparation of (±) -en or-1 -Butil-1 a. 3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropapha1pentalene-4-carbonitrile.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS: m / z (ES +): 202 [M + H] +; H NMR (CD3OD): 52.86 (dd, 1H, J, = 16.5, J2 = 6.5), 2.60 (d, 1H, J = 16.4), 2.4-2.3 (m, 2H), 1.4-1.1 (m, 6H) , 0.85-0.79 (m, 3H), 0.78-0.68 (m, 1H).
Step C: Preparation of (±) -endo-1-Butyl-4- (2H-tetrazofl-5-yl) -1a, 3.5.5a-tetrahydro-1H-2,3-diaza-cyclopropaphapentalene
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS: m / z (ES +): 245 [M + H] +, 217 [M-N 2 + H] +; 1H NMR (CD3OD): d2.97 (dd, 1H, J, = 10.0, J2 = 6.4), 2.78 (d, 1H, J = 16.6), 2.38 (pente, 2H, J = 5.4), 1.40-1.14 ( m, 6H), 0.85-0.79 (m, 3H), 0.88-0.79 (m, 4H including 0.81 (t, 3H, J = 7.2)).
Example 9.39: Preparation of (±) -endo-1-Pentyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid ethyl ester. Step A: Preparation of (±) -endo-6-n-Pentil-biciclor3.1.OIhexan-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.2, Step B. 1 H NMR (CDCl 3): 64.17 (dd, 1H, J-, = 5.0, J2 = 1.0), 2.15-2.00 (m, 1H ), 1.80-1.45 (m, 3H), 1.40-1.25 (m, 8H), 1.22-1.15 (m, 3H), 0.95-0.85 (m, 3H), 0.75 (penteto, 1H, J = 8.4).
Step B: Preparation of (±) -endo-6-Pentil-biciclor3.1.OIhexan-2-one.
The title compound was prepared in a manner similar to that described in Example 9.2, Step C. H NMR (CDCl 3): 62.35-2.20 (m, 2H), 2.14 (dd, 1H, J, = 11.8, J2 = 5.9) , 2.05-1.85 (m, 3H), 1.50-1.20 (m, 9H), 0.95-0.85 (m, 3H).
Step C: Preparation of ethyl ester of (±) -encro-1-Pentil-1 a.3, 5, 5a tetrahydro-1 H-2,3-diaza-cyclopropapha1pentalene-4-carboxylic acid
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS: m / z (ES +): 263 [M + H] +, 217 [M-OEt] +; 1H NMR (CDCl 3): 64.40-4.30 (m, 2H), 2.91 (dd, 1H, J, = 17.5, J2 = 6.8), 2.66 (d, 1H, J = 17.5), 2.33 (ddd, 1H, Jn = 7.7, J2 = 6.2, J3 = 1.2), 2.20 (dd, 1H, J, = I4.6, J2 = 6.5), 1.35-1.15 (m, 10H), 1.10-0.95 (m, 1H), 0.87 (t , 3H, J = 6.9).
Example 9.40: Preparation of (±) -endo-1-Pentyl-3.5.5.5a-tetrahydro-1 H -2, 3-d aza-c or the pro-para-p-pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS: m / z (ES +): 235 [M + H] +, 217 [M-OH] +; 1H NMR (CD3OD): S2.86 (dd, 1H, J, = 17.2, J2 = 6.7), 2.40 (d, 1H, J = 17.2), 2.33-2.28 (m, 1H), 2.28-2.20 (m, 1H), 1.40-1.15 (m, 7H), 1.13-1.05 (m, 1H), 0.88-0.82 (m, 3H), 0.82-0.73 (m, 1H).
Example 9.41: Preparation of (±) -endo-Pentyl-4- (2H-tetrazol-5-ih-1 a.3.5.5a-tetrahydro-IH-2,3-diaza-cycloproparalpentalene Step A: Preparation of amide of (±) -endO-1-Pentyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step E. MS: m / z (ES +): 234 [M + H] +, 217 [M-NH 2] +; 1H NMR (CD3OD): 52.89 (dd, 1H, J, = 16.8, J2 = 6.2), 2.67 (d, 1H, J = 16.8), 2.35-2.25 (m, 2H), 1.40-1.15 (m, 7H) , 1.15-1.05 (m, 1H), 0.90-0.70 (m, 4H).
Step B: Preparation of (±) -e / 7do-1-Pentyl-1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carbonitrile.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS: m / z (ES +): 216 [M + H] +.
Step C: Preparation of (±) -enoO-1-Pentyl-4- (2H-tetrazol-5-yl) -1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene.
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS: m / z (ES +): 260 [M + H] \ 232 [M-N2 + H] +; 1H NMR (CD3OD): 52.96 (dd, 1H, J, = 16.5, J2 = 6.4), 2.75 (d, 1H, J = 16.5), 2.40-2.33 (m, 2H), 1.40-1.12 (m, 8H ), 0.86-0.78 (m, 4H).
Example 9.42: Preparation of (±) -exo-1-lsopropyl-1a ethyl ester, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparapentalene-4-carboxylic acid. Step A: Preparation of (±) -exo-6-lsopropyl-bicichlor3.1.OIhexan-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.2, Step B.1H NMR (CDCI3): 54.19 (d, 1H, J = 4.8), 1.94-1.85 (m, 2H), 1.65 (dd, 1H, J, = 12.5, J2 = 8.2), 1.53 (dd, 1H, J, = 14.2, J2 = 8.4), 1.36-1.26 (m, 1H), 1.22-1.20 (m, 1H), 1.14-1.12 ( m, 1H), 0.95-0.87 (m, 7H), 0.37 (m, 1H).
Step B: Preparation of (±) -exo-6-lsopropyl-biciclor3.1.OIhexan-2-one
The title compound was prepared in a manner similar to that described in Example 9.2, Step C. 1 H NMR (CDCl 3): 52.07-1.93 (m, 4H), 1.86-1.84 (m, 1H), 1.53 (d, 1H, J = 5.2), 1.05-1.02 (m, 2H), 0.98 (d, 3H, J = 5.1), 0.93 (d, 3H, J = 5.7).
Step C; Preparation of (±) -exo-1-lsopropyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid ethyl ester. The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS: m / z (ES +): 235 [M + H] +, 189 [M-OEt] +; H NMR (CDCl 3): 54.33 (q, 2H, J = 5.9), 2.90 (dd, 1H, J, = 17.1, J2 = 5.3), 2.77 (d, 1H, J = 17.1), 1.91-1.89 (m, 1H), 1.30 (t, 3H, J = 10.1), 1.24-1.19 (m, 1H), 1.06-1.03 (m, 1H), 0.97 (d, 6H, J = 11.5), 0.45 (m, 1H).
Example 9.43: Preparation of (±) -exo-1-lsopropyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropapha1-entalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS: m / z (ES +): 207 [M + H] \ 189 [M-OH] +; H NMR (CD3OD): 52.95-2.93 (m, 1H), 2.90 (d, 1H, J = 16.7), 2.00 (m, 2H), 1.08-1.03 (m, 7H (including d, 6H, J = 12.4) ), 0.43 (septet, 1H, J = 4.1).
Example 9.44: Preparation of (±) -exo-1-lsopropyl-4- (2H-tetrazol-5-ih-1 a.3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropafal entalene.
(±) -exo-6-lsopropyl-bicyclo [3.1.0] hexan-2-one (0.200 g, 1.45 mmol) and ethyl ester of 1 H-tetrazole-5-carboxylic acid and sodium salt (0.238mg, 1.45 mmol) were dissolved in DMF (5 mL) and cooled to
0 ° C. Potassium tert-butoxide (1.0M in THF, 3.20 mL, 3.20 mmol) was added slowly and the resulting solution was stirred at 0 ° C for 1 hour. Then hydrochloric acid (3.0 N, 1.00 mL, 2.90 mmol) was added slowly, followed by the dropwise addition of hydrazine monohydrate (0.080 mL, 1.67 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The DMF was removed under reduced pressure and the reaction mixture was dissolved in DMSO (5 mL) and purified by HPLC to yield (±) -exo-1-isopropyl-4- (2H-tetrazol-5-yl) -1 a 3, 5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene as a off-white solid. MS: m / z (ES +): 231 [M + H] +, 203 [M-N 2 + H] +; 1H NMR (CD3OD): 62.83 (dd, 1H, J, = 14.6, J2 = 5.6), 2.65 (d, 1H, J = 16.1), 1.95-1.86 (m, 2H), 0.81-0.88 (m, 7H ( including d, 6H, J = 12.9)), 0.31 (septet, 1H, J = 3.3).
Example 9.45: Preparation of (±) -exo-l-lsobutyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid ethyl ester. Step A: Preparation of (±) exo-6-lsobutyl-bicyclo3.1.01hexan-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.2, Step B. 1 H NMR (CDCl 3): < 54.22 (m, 1H), 1.95-1.80 (m, 1H), 1.72-1.45 (m, 4H,), 1.40-1.20 (m, 1H), 1.20-1.16 (m, 1H), 1.15-1.00 (m, 2H), 0.97-0.83 (m, 6H), 0.37 (septet, 1H). Contains ca 30% (±) endo-6-isobutyl-bicyclo [3.1.0] hexan-2-ol.
Step B: Preparation of (±) exo-6-lsobutyl-biciclor3.1.OIhexan-2-one
The title compound was prepared in a manner similar to that described in Example 9.2, Step C. 1 H NMR (CDCl 3): 62.13-1.97 (m, 4H), 1.88-1.82 (m, 1H), 1.74-1.66 (m, 1H), 1.55-1.51 (d, 1H, J = 5.1), 1.32-1.23 (m.2H), 1.15-1.07 (m, 1H), 0.95 (d, 3H, J = 2.5), 0.92 (d, 3H) , J = 2.5). Contains ca 30% (±) endo-6-isobutyl-bicyclo [3.1.0] hexan-2-one.
Step C: Preparation of (±) -exo-1-lsobutyl-1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid ethyl ester.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS: m / z (ES +): 249 [M + H] \ 203 [M-Oet] +; H NMR (CDCl 3): 54.30 (q, 2H, J = 7.1), 2.91 (dd, 1H, J, = 17.0, J2 = 6.2), 2.77 (d, 1H, J = 17.0), 1.98-1.93 (m, 2H), 1.59-1.49 (m, 1H), 1.43-1.34 (t, 3H, J = 6.9), 1.24-1.15 (m, 1H), 0.85 (m, 7H), 0.64-0.57 (m, 1H). Contains ca 30% ethyl ester of (±) -endo-1-lsobutyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid.
Example 9.46: Preparation of (±) -exo-1-lsobutyl-1 a.3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropafalpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS: m / z (ES +): 221 [M + H] \ 203 [M-OH] +; H NMR (CD3OD): 62.95-2.90 (m, 1H), 2.80 (d, 1H, J = 16.9), 1.96 (m, 2H), 1.78-1.72 (m, 1H), 1.26-1.23 (m, 2H) , 0.98-0.94 (m, 6H), 0.62 (septet, 1H, J = 3.3).
Example 9.47: Preparation of (± -exo-l-isobutyl-4- (2H-tetrazol-5-yl) 1 a, 3,5,5a-tetrahydro-IH-2,3-diaza-cyclopropafalpentalene.
The title compound was prepared in a manner similar to that described in Example 9.44. MS: m / z (ES +): 245 [M + H] +, 217 [M-N 2 + H] +; 1H NMR (CD3OD): 52.99 (dd, 1H, J, = 16.2, J2 = 5.6), 2.91 (d, 1H, J = 16.0), 2.10-2.00 (m, 2H), 1.78-1.71 (m, 1 H ), 1.30-1.23 (m, 2H), 0.96 (m, 6H), 0.73 (septet, 1H, J = 3.2).
Example 9.48: Preparation of (±) -endo-1-lsobutyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-ciclo ropara1 entaleno-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3 using the mixture of diastereomers described in Example 9.45, Step C. MS: m / z (ES +): 221 [M + H] +, 203 [M -OH] +; 1H NMR (CD3OD): d2.94-2.88 (dd, 1H, J = 6.7), 2.65 (d, 1H, J = 17.5), 2.35-2.24 (m, 2H), 1.63-1.54 (m, 1H), 1.34-1.27 (m, 1H), 1.07-0.98 (m, 1H), 0.90 (d, 3H, J = 6.6), 0.84 (d, 3H, J = 6.6), 0.66 (septet, 1H, J = 3.1) .
Example 9.49: Preparation of (±) -endo-l-lsobutyl-4- (2H-tetrazol-5-yl) -la.3.5.5a-tetrahydro-IH-2,3-diaza-cyclopropara1-entalene.
The title compound was prepared in a manner similar to that described in Example 9.44 using the mixture of diastereomers described in Example 9.45, Step B. MS: m / z (ES +): 245 [M + H] +, 217 [M -N2 + H] +; 1H NMR (CD3OD): 62.84 (dd, 1H, Ji = 16.5, J2 = 6.6), 2.62 (d, 1H, J = 16.6), 2.38 (m, 2H), 1.50-1.43 (m, 1H), 1.22- 1.18 (m, 1H), 1.00-0.94 (m, 1H), 0.76 (d, 3H, J = 6.6), 0.70 (d, 3H, J = 6.6), 0.59-0.52 (m, 1H)
Example 9.50: Preparation of (±) -endo-1-Phenyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-IH-2,3-diazocyclopropane-1 -pentalene. Step A: Preparation of (Z) -Ethyl 5-phenylpent-4-enoate.
3-Etoxycarbonylpropyltriethylphosphonium bromide (5.488 g, 12.00mmol), benzaldehyde (3.820g, 36.00mmol) and potassium tert-butoxide (4.040g, 36.00mmol) were absorbed in MTBE (300mL) at room temperature and stirred overnight . The reaction mixture was washed with water (IxIOOmL) and the aqueous phase was extracted with MTBE (3x100mL). The solvent was extracted from the combined organic phase under reduced pressure and the resulting oil was purified by column chromatography (0-10% EtOAc / n-hexane, silica) to yield (Z) -ethyl 5-phenylpent-4-enoate in pale yellow oil shape. 1 H NMR (CDCl 3): d7.36-7.31 (m, 2H), 7.28-7.21 (m, 3H), 6.47 (d, 1H, J = 11.6, Ph-CH), 5.63 (dt, 1H, J1 = 11.6 , J2 = 7.2), 4.14 (q, 2H, J = 7.2), 2.66 (dq, 2H, J, = 7.3, J2 = 1.7), 2.43 (t, 2H, J = 7.6), 1.24 (t, 3H, J = 7.1). Contains ca. 33% (E) -ethyl 5-phenylpent-4-enoate
Step B: Preparation of (Z) -5-Fenilpent-4-enal.
The (Z) -Ethyl 5-phenylpent-4-enoate (1600g, 7.833mmol) was absorbed in dichloromethane (100mL) under N2 and cooled to -78 ° C. DIBAL (1M in hexanes, 9mL, 9.0 mmol) was added and the reaction mixture was stirred at -78 ° C for 3 hours. The excess DIBAL was cooled by the slow addition of methanol (25mL). The resulting solution was poured into a saturated solution of sodium / potassium tartarate (400mL). More hexane (150 mL) was added and the mixture was stirred at room temperature overnight. The organic phase was collected and the solvent was extracted under reduced pressure. The resulting oil was purified by column chromatography (0-20% EtOAc / n-hexane, silica) to yield (Z) -5-phenylpent-4-enal as a pale yellow oil. 1 H NMR (CDCl 3): 59.77 (s, 1H), 7.36-7.29 (m, 2H), 7.25-7.21 (m, 3H), 6.49 (d, 1H, J = 11.5), 5.62 (dt, 1H, J, = II.6, J2 = 7.2, Ph-CHCH), 2.70-2.62 (m, 2H), 2.60-2.55 (m, 2H). Contains ca. 16% (E) -5-phenylpent-4-enal.
Step C: Preparation of (Z) -2- (4-Phenylbut-3-enyl) oxirane.
(Z) -5-Fenilpent-4-enal (0.475g, 2.97mmol) and dibromomethane (0.626g, 3.60mmol) were absorbed in THF (20mL) and cooled to -78 ° C under argon n-butyl lithium (1.6M in hexane, 2.0mL, 3.20mmol) were added dropwise for 5 minutes. The resulting mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into saturated aqueous NH4CI (20mL), extracted with MTBE (2 x 30mL) and the solvent was removed under reduced pressure. The resulting oil was purified by column chromatography (0-20% EtOAc / n-hexane, silica) to yield fZ,) - 2- (4-Phenylbut-3-enyl) -oxitan as pale yellow oil . HNMR (CDCI3): 57.32-7.27 (m, 2H), 7.25-7.19 (m, 3H), 6.47 (d, 1H, J = 11.7), 5.68 (J, = II.6, J2 = 7.3), 2.97- 2.93 (m, 1H), 2.77-2.74 (m, 1H), 2.55-2.52 (m, 1 H), 2.53-2.48 (m, Z), 1.76-1.67 (m, 2H). Contains ca. 18% (E) -2- (4-phenylbut-3-ene) oxirane.
Step D: Preparation of (±) -endo-6-Fenilbiciclof3.1.01hexan-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.2, Step B. 1 H NMR (CDCl 3): 67.31-7.17 (m, 5H), 4.20 (d, 1H, J = 5.2), 2.20 (t, 1H, J = 8.6), 2.13-2.03 (m, 2H), 1.92-1.79 (m, 2H), 1.78-1.63 (m, 2H), 0.51-0.40 (m, 1H, Ph-CH).
Step E: Preparation of (±) -endo-6-Phenylbicyclo3.1.Olhexan-2-one.
The title compound was prepared in a manner similar to that described in Example 9.2, Step C. 1 H NMR (CDCl 3): 67.32-7.24 (m, 5H), 2.80 (t, 1H, J = 8.6), 2.45-2.36 ( m, 1H), 2.32-2.15 (m, 2H), 2.08-1.82 (m, 2H), 0.98-0.86 (m, 1H, Ph-CH)
Step F: Preparation of (±) -endo-l-Phenyl-4- (2H-tetrazoi-5-y-1 a, 3,5,5a-tetrahydro-IH-2,3-diazocyclopropane-pentalene)
The title compound was prepared in a manner similar to that described in Example 9.44. MS: m / z (ES +): 265 [M + H] +, 237 [M-N 2 + H] +; H NMR (CD3OD): 67.50-6.90 (m, 5H), 3.05-2.96 (dd, 1H, J, = 16.4, J2 = 6.3), 2.84-2.76 (m, 1H), 2.76-2.67 (m, 1H) , 2.64 (t, 1H, J = 8.1), 1.40-1.25 (m, 1H).
Example 9.51: Preparation of (±) -exo-1-phenoxymethyl-4- (2H-tetrazol-5-yl) -1 a.2.5.5a-tetrahydro-IH-2,3-diaza-cyclopropafalpentalene. Step A: tert-Butyl-dimethyl- (5-oxiranyl-pent-2-enyloxy) -sitan.
The title compound was prepared in a manner similar to that described in Example 9.2, Step A. 1 H NMR (400 MHz, CDCl 3): 65.65 (1H, dt, J = 15.3.6.2 Hz), 5.57 (1H, dt, J = 15.3.4.9 Hz), 4.11 (2H, m), 2.91 (1H, m), 2.73 (1H, m), 2.46 (1H, dd, J = 5.0, 2.7 Hz), 2.19 (2H, m), 1.61 (2H, m), 0.89 (9H, s), 0.05 (6H, s).
Step B: Preparation of (±) -exo-6- (tert-Butyl-dimethyl silanyloxymethyl) -bicyclo3.1.OIhexan-2-ol
LiTMP was generated by the addition of n-BuLi (2.5 M in hexanes, 51 mL, 124 mmol) to a stirred solution of TMP (17.5 g, 124 mmol) in t-BuOMe (400 mL) at -78 ° C. The light yellow solution of LiTMP was slowly heated to 0 ° C. To a stirred solution of tert-butyl-dimethyl- (5-oxiranyl-pent-2-enyloxy) -silane (15.0 g, 62 mmol) in f-BuOMe (200 mL) at 0 ° C was added the LiTMP drop solution Drops via a cannula. The resulting mixture was stirred at room temperature for 18 hours, and then cooled with MeOH (20 mL). The reaction was concentrated to a total volume of 300 mL and the solution was washed with NH 4 Cl (sat., Ac, 3 x 150 mL) and brine (150 mL). The organics were dried over MgSO4, filtered, concentrated and purified on a column of silica gel, (5% EtOAc in hexane, gradient to 30% EtOAc in hexane) to yield the title compound as a light yellow oil. 1 H NMR (400 MHz, CDCl 3): 54.25 (1 H, d, J = 4.8 Hz), 3.49 (1 H, dd, J = 10.8, 6.2 Hz), 3.44 (1 H, dd, J = 10.8, 6.4 Hz), 1.93 (1H, m), 1.72 (1H, dd, J = 12.6, 8.1 Hz), 1.57 (1H, dd, J = 14.5, 8.4 Hz), 1.38-1.24 (4H, m), 0.89 (9H, s), 0.71 (1H, m), 0.04 (6H, s).
Step C: Preparation of (±) -exo-6- (tert-Butyl-domethyl-silanyloxymethyl) -bicyclo3.1.Ohexan-2-one.
TPAP (0.181 g, 0.52 mmol) was added to a stirring solution of (±) -exo-6- (tert-Butyl-dimethyl-silanyloxymethyl) -bicyclo [3.1.0] hexan-2-ol (2.5 g), 10.3 mmol), NMO (2.4 g, 20.6 mmol), and 4Á MS (3 g) in CH2Cl2 (50 mL) at room temperature. The mixture was stirred for 3 h, filtered through celite, poured onto silica gel and eluted with Et20 / CH2CI2 (1: 1). The organic solvent was evaporated in vacuo to yield the title compound. 1 H NMR (400 MHz, CDCl 3): 63.69 (1H, dd, J = 10.8, 4.8 Hz), 3.58 (1H, dd, J = 10.8, 5.3 Hz), 2.15 (1H, m), 2.05 (4H, m) , 1.72 (1H, m), 1.51 (1H, m), 0.87 (9H, s), 0.04 (6H, s).
Step D: Preparation of (±) -exo-1-Hydroxymethyl-1 a.3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid ethyl ester.
To a solution of ketone (2.2 g, 9.2 mmol) and diethyl oxalate (1.35 g, 9.2 mmol) in EtOH (35 ml_) at room temperature under N2 was added a solution of KOt-Bu in THF (10.1 ml_ of a solution of 1M, 10.1 mmol). The reaction was stirred for 4 hours at which time hydrazine hydrochloride (0.756 g, 11 mmol) in H20 (4 mL) was added. The reaction mixture was stirred for 20 hours at room temperature and acidified to pH ~ 3 by the addition of HCl (6 [mu] / ac). The volatiles were removed in vacuo and the resulting solid was diluted with EtOAc (50 mL) and H20 (50 mL). The layers were separated and the aqueous phase was extracted again with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to yield the title compound. The compound was used directly in the next reaction without further purification.1H NMR (400 MHz, CDCl3): 54.23 (2H, q, J = 7.1 Hz), 3.41 (IH, dd, J = 11.4, 5.9 Hz), 3.28 ( 1H, dd, J = 11.4, 6.8 Hz), 2.84 (1H, dd, J = 16.9, 6.2 Hz), 2.69 (1H, d, J = 16.9 Hz), 2.05 (2H, m), 1.26 (3H, t , J = 7.1 Hz), 0.78 (1H, m). HPLC / MS: Column Alltech® Prevail C18 (5μ, 50 x 4.6 mm), 5% v / v CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99% v / v of CH3CN in H20, 3.5 mL / min, tt = 1.54 min, EST = 223.2 (M + H).
Step E: Preparation of 1-hydroxymethyl-1 a, 2, 5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid amide
To a solution of ester (5.3 g, 23.9 mmol) in dioxane (80 mL) was added ammonium hydroxide (28% NH3 in H20, 400 mL). The mixture was placed in a 500 mL pyrex bottle and shaken on a shaker plate for 22 hours at room temperature. The mixture was concentrated in vacuo to a total volume of 100 mL at which time a light yellow precipitate became evident. The mixture was filtered and the solid was washed with H20. Subsequent drying of the solid afforded the title compound as a white solid. The compound was used directly in the next reaction without further purification. 1 H NMR (400 MHz, DMSO-d 6): 57.29 (1 H, bs), 7.12 (1 H, s), 4.62 (1 H, bs), 3.39 (1 H, dd, J = 11.4, 6.0 Hz), 3.28 (1 H, dd, J = 16.4, 5.3 Hz), 2.82 (1H, dd, J = 16.4, 5.3 Hz), 2.73 (1H, d, J = 17.8), 2.03 (2H, m), 1.75 (1H, s), 0.76 (1H, m). HPLC / MS: Column Alltech® Prevail C18 (5μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99 % v / v of CH3CN in H20, 3.5 mL / min, tr = 1.49 min, ESI + = 194.0 (M + H).
Step F: Preparation of amide of (±) -exo-2-Benzyl-1-hydroxyinethyl-1 a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid.
The amide was partially dissolved in dioxane (60 ml_) and NaOH (5N aq, 10.0 mL, 50.0 mmol) was added followed by benzyl bromide (4.25 g, 24.9 mmol). The mixture was slowly rinsed and the reaction was stirred for 20 hours at room temperature. The mixture was acidified to pH ~ 2 by the addition of HCl (6N, aq) and concentrated to dryness in vacuo. The resulting residue was dissolved in EtOAc and washed with NaHCO3 (sat aq, 50 mL) and H20 (50 mL). The residue was purified on a column of silica gel (40% EtOAc in hexane, gradient at 75% EtOAc in hexane) to yield the benzylated product. 1 H NMR (400 MHz, CDCl 3): 57.38 (3H, m), 7.26 (2H, m), 6.64 (1H, bs), 5.30 (1H, d, J = 15.0 Hz), 5.23 (1H, d, J = 15.0 Hz), 3.55 (1H, m), 3.19 (1H, m), 2.96 (1H, dd, J = 16.6, 6.2 Hz), 2.88 (1H, d, J = 16.6 Hz), 2.07 (1H, m) , 1.76 (1H, m), 1.05 (1H, bs), 0.90 (1H, m). HPLC / MS: Column Alltech® Prevail C18 (5μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99 % v / v of CH3CN in H20, 3.5 mL / min, tr = 1.81 min, ESI + = 284.2 (M + H).
Step G: Preparation of (±) -exo-2-Benzyl-1-chloromethyl-1 a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carbonitrile.
A flask loaded with anhydrous DMF (4 mL) under N2 atmosphere was cooled to 0 ° C and thionyl chloride was added dropwise (0.77 mL, 10.6 mmol). After stirring for 5 minutes, a suspension of the amide (1.0 g, 3.5 mmol) in DMF (4 mL) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 20 hours, and NaHCO 3 (sat aq, 10 mL) was added followed by H 2 O (15 mL). The mixture was stirred for 10 minutes and concentrated until almost dry in vacuo. The residue was dissolved with EtOAc (20 mL) and H20 (20 mL). The layers were separated and the aqueous phase was extracted again with EtOAc (20 mL). The combined organics were washed with NaHCO 3 (sat aq, 30 mL), and brine (30 mL), dried over MgSO 4, filtered, and concentrated to yield the title compound as a brown oil. The compound was used directly in the next reaction without further purification. 1 H NMR (400 MHz, CDCl 3): 57.38 (3H, m), 7.31 (2H, m), 5.30 (1H, d, J = 14.8), 5.26 (1H, d, J = 14.8 Hz), 3.47 (1H, dd, J = 11.4.6.6 Hz), 3.22 (1H, dd, J = 11.4, 8.1 Hz), 2.89 (1H, dd, J = 16.5, 6.4 Hz), 2.79 (1H, d, J = 16.5 Hz), 2.20 (1H, m), 1.92 (1H, m), 1.09 (1H, m). HPLC / MS: Column of Alltech® Prevail C18 (5μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient a 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 3.02 min, EST = 284.4 (M + H).
Step H: Preparation of (±) -exo-2-Benzyl-1-phenoxymethyl-1a, 2,5.5a-tetrahydro-1H-2,3-diaza-cyclopropaxy-1 -pentalene-4-carbonitrile.
Nitrile (0.300 g, 1.06 mmol), phenol (0.141 g, 1.5 mmol), and K2C03 (0.277 g, 2.0 10 mmol) were dissolved in D F (6 ml_). The reaction vessel was sealed and heated in a microwave reactor at 120 ° C for 40 minutes. After cooling to room temperature, the reaction mixture was taken up in ethyl acetate and washed once with water, once with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC: Phenomenex® Luna C18 column (10μ, 250 x 21.2 mm), 5% (v / v) CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v of TFA) 95% gradient of H20, 20 ml / min,? = 214 nm to produce the title compound as a white solid after lyophilization. HPLC / MS: Column Alltech® Prevail C18 (5μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H2Q (containing 1% v / v of TFA) gradient to 99 % v / v of CH3CN in H20, 3.5 mL / min, tr = 3.50 min, ESI + = 342.3 (M + H).
Step I: Preparation of (±) -exo-2-Benzyl-1-phenoxymethyl-4- (2H-tetrazol-5-n-1a, 2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropaphappentalene .
Nitrile (0.30 g, 0.88 mmol), 2nBr2 (0.400 g, 1.76 mmol), and NaN3 (0.345 g, 5.31 mmol) were dissolved in DMF (5 mL). The reaction vessel was sealed and heated in a microwave reactor at 190 ° C for 15 minutes. After cooling to room temperature, the reaction mixture was acidified by the addition of HCl (1N, aq) and purified by reverse phase HPLC: Phenomenex® Luna C18 column (10μ, 250 x 21.2 mm), 5% (v. / v) of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 95% H20, 20 ml / min,? = 214 nm to produce the title compound as a white solid after lyophilization. HPLC / MS: Column Alltech® Prevail C18 (5μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99 % v / v of CH3CN in H20, 3.5 mL / min, tr = 2.71 min, ESI * = 384.9 (M + H).
Step J: Preparation of (±) -exo-l-phenoxymethyl-4- (2H-tetrazol-5-yl) -1 a.2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene.
Air was bubbled through a stirred solution of the protected compound (0.150 g, 0.39 mmol) KOf-Bu (4.0 mL of a solution of 1 M in THF, 4.0 mmol) in DMSO (4 mL) for 2 hours at room temperature . The remaining THF was removed in vacuo and the reaction mixture was diluted with EtOAc (20 mL) and H20 (20 mL). The strata were separated and the organic layer was washed with brine, dried over MgSO4, concentrated, and purified by reverse phase HPLC: Phenomenex® Luna C18 column (10 μ, 250 x 21.2 mm), 5% (v / v) CH3CN (containing 1% v / v TFA) in HzO (containing 1% v / v of TFA) 95% gradient of H20, 20 ml / min,? = 214 nm to produce the title compound as a white solid after lyophilization. 1 H NMR (400 MHz, DMSO-d 6): 57.28 (2H, m), 6.94 (3H, m), 4.06 (1H, dd, J = 10.5, 6.1 Hz), 3.83 (1H, dd, J = 10.4, 7.9 Hz), 2.98 (1H, dd, J = 16.3, 6.1 Hz), 2.88 (1H, d, J = 16.6 Hz), 2.40 (1H, m), 2.34 (1H, m), 1.21 (1H, m). HPLC / MS: Column Alltech® Prevail C18 (5μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99 % v / v of CH3CN in H20, 3.5 mL / min, tr = 2.08 min, ESI + = 295.4 (M + H).
Example 9.52: Preparation of f ±) -exo-1-methoxymethyl-1 a, 3.5.5a-tetrahydro-1H-2,3-diaza-cyclopropaphapentalene-4-carboxylic acid. Step A: Preparation of (±) -exo-2-Benzyl-1-hydroxymethyl-1a.2.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropaf alpentalene-4-carboxylic acid ethyl ester.
The ester (1.5 g, 6.75 mmol) was dissolved in DMF (20 ml_) and K2C03 (1.84 g, 13.5 mmol) was added followed by benzyl bromide (1.73 g, 10.1 mmol). The reaction was stirred for 20 hours at room temperature. The mixture was dissolved with EtOAc and washed with water and brine, dried over MgSO4 and concentrated until dried in vacuo. The residue was purified on a column of silica gel (40% EtOAc in hexane, gradient at 75% EtOAc in hexane) to yield the benzylated product as a white solid. 1 H NMR (400 MHz, CDCl 3): d7.38 (3H, m), 7.30 (2H, m), 5.42 (1H, d, J = 14.9 Hz), 5.29 (1H, d, J = 14.9 Hz), 4.36 (2H, q, J = 7.1 Hz), 3.14 (1H, m), 2.91 (1H, dd, J = 16.7, 6.3 Hz), 2.82 (1H, d, J = 16.7 Hz), 2.03 (1H, m) , 1.67 (1H, m), 1.37 (3H, t, J = 7.1 Hz), 0.85 (1H, m).
HPLC / MS. Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 2.11 min, EST = 313.2 (M + H).
Step B: Preparation of (±) -exo-2-Benzyl-1-methoxymethyl-a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparal entalene-4-carboxylic acid ethyl ester.
To a solution of the alcohol (0.350 g, 1.1 mmol) in DMF (5 mL) was added NaH (60% dispersion, 0.088 g, 2.2 mmol) at 0 ° C under N2. The mixture was stirred for 10 minutes and Mel (0.239g, 1.7 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours, and cooled with water. The mixture was extracted with EtOAc (2x10 mL) and the combined organic layers were washed with water (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified on a column of silica gel, eluting with hexane: EtOAc (6: 4) to yield the title compound. HPLC / MS: Column Alltech® Prevail C18 (5μ 50 x 4.6 mm), 5% v / v CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient to 99% v / v of CH3CN in H20, 3.5 mL / min, tT = 2.65 min, ESI * = 327.4 (M + H).
Step C: Preparation of (±) -exo-1-methoxymethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid.
Air was bubbled through a stirring solution of the ester (0.075 g, 0.23 mmol) and Oi-Bu (2.3 mL of a solution of 1 M in THF, 2.3 mmol) in DMSO (2.5 mL) for one hour at room temperature. . The remaining THF was removed in vacuo and the reaction was acidified by the addition of HCl (3M aq.) And purified by reverse phase HPLC: Phenomenex® Luna C18 column (10 μ 250 x 21.2 mm), 5% (v / v) ) of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 95% of H20, 20 ml / min,? = 214nm to produce the title compound as a white solid after lyophilization. 1 H NMR (400 MHz, DMSO-d 6): O 13.0 (1 H, bs), 3.31 (1 H, dd, J = 16.7.6.4 Hz), 3.24 (3 H, s), 3.22 (1 H, dd, J = 10.5 , 7.2 Hz), 2.84 (1H, dd, J = 16.9, 6.2 Hz), 2.69 (1H, d, J = 14.8 Hz), 2.09 (1H, m), 2.04 (1H, m), 0.84 (1H, m ). HPLC / MS: Column Alltech® Prevail C18 (5μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99 % v / v of CH3CN in H20, 3.5 mL / min, tr = 1.36 min, EST = 208.9 (M + H).
Example 9.53: Preparation of (1a?, 5a /?) - (+) - 4- (2H-TetrazoD-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropapy1pentalene .
1eq 1eq PROCEDURE: Ketone was dissolved in DMF. Then Tetrazol was added to the solution. The resulting suspension was cooled to 0 ° C. A solution of Potassium-t-Butoxide in DMF was slowly added to the mixture maintaining the temperature at < 10 ° C. The mixture was stirred at 0 ° C for 1 hour. Then a solution of 2N HCl was slowly added, followed by the dropwise addition of hydrazine hydrate (64% hydrazine). The reaction mixture was allowed to stand to warm to room temperature overnight. ELABORATION: DMF was extracted and the residue was partitioned with waterExtract (7X) with E. The organic elements were dried in MgSO4, filtered, concentrated in vacuo. The crude product was purified on a reverse phase column (25% CH3CN + 0.1% TFA, 75% water + 0.1% TFA, wavelength = 265 nm) (duration of 10 minutes). Separate isomers in SFC (AS (21x250mm), 30% MeOH + 0.1% TFA). Repurify in reverse phase column (25% CH3CN + 0.1% TFA, 75% water + 0.1% TFA, wavelength = 265 nm) (duration of 10 minutes) to eliminate the yellow color. The white solid was dissolved in hot water and allowed to crystallize to produce pure white / colorless crystals.
Example 9.54: Preparation of (+) - endo-1-methyl-1 a.2.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid and exo-1-methyl-1a, 2,5, 5a-tetrahydro-1H-2,3-diaza-cyclopropaph to the pentalene-4-carboxylic acid ico-Step A: Preparation of (/) -5- (chloromethyl) tetrahydrofurano-2-ol.
To a solution of (f?) - 5- (chloromethyl) dihydrofuran-2 (3H) -one
(6.69 g, 49.7 mmol, see Movassaghi, M, Jacobsen, ENJ Am. Chem. Soc. 2002, 124, 245 for the preparation) in DCM (150 ml_) under N2 at -78 ° C was added diisobutylaluminum hydride ( 1MDCM, 62.1 ml, 62.1 mmol) for 15 minutes. The mixture was stirred at -78 ° C for 30 minutes at which time MeOH (~ 10 mL) was added and the mixture was removed from the cooling. Rochelle salt (150 mL sat. Aqueous) was added and the mixture was stirred for 1 hour while heating to room temperature. The organic phase was removed and the aqueous phase was extracted with EtOAc (2x). The combined organics were dried over MgSO4, filtered, and concentrated to yield (f?) - 5-chloromethyltetrahydrofuran-2-ol (6.65 g, 48.7 mmol, 98% yield), a clear oil, as a mixture of epimers (1.25: 1). 1 H NMR (400 MHz, CDCl 3): Major Epimer: 55.62 (1H, m), 4.48 (1H, dq, J = 7.6, 5.6 Hz), 3.67 (1H, dd, J = 10.8, 5.6 Hz), 3.61 (1H , dd, J = 11.2, 6.0 Hz), 2.65 (1H, m), 2.24 (1H, dq, J = 12.4, 8.0 Hz), 2.10-1.72 (3H, m). Minor epimer: 55.30 (1H, m), 4.29 (1H, m), 3.53 (2H, m), 2.65 (1H, m), 2.10-1.72 (4H, m).
Step B: Preparation of cis / trans- (?) - 2- (pent-3-enyl) oxirane.
To a suspension of ethyl triphenylphosphonium bromide (5.57 g, 15.0 mmol) in THF (15 ml_) at 0 ° C was added lithium bis (trimethylsilyl) amide 1M THF (15.0 ml, 15.0 mmol). The solution was stirred for 0.5 hour at which point the (R) -5- (chloromethyl) tetrahydrofuran-2-ol (1.00 g, 7.32 mmol) was added at 0 ° C as a solution in THF (15 ml_). The resulting solution was allowed to warm to room temperature and stirred overnight. The mixture was cooled with H20 and extracted with Et20 (2x), dried over MgSO4, filtered, and concentrated. The mixture was purified by chromatography on silica gel (1% Et20 in gradient of pentane at 5% Et20 in pentane) to produce (γ) -2- (pent-3-enyl) oxirane, a clear oil, in the form of a mixture. inseparable from olefin isomers (cis: trans = 2.3: 1). 1 H NMR (400 MHz, CDCl 3): d5.55-5.26 (2H, m), 2.93 (1H, m), 2.76 (1H, m), 2.49 (from the cis isomer, 0.7H, dd, J = 6.0 , 2.8 Hz), 2.48 (from the trans isomer, 0.3H, dd, J = 6.0, 2.8 Hz), 2.21 (from the cis isomer, 1.4H, q, J = 7.6 Hz), 2.14 (from the trans isomer, 0.6H, m), 1.67-1.56 (5H, m).
Step C: Preparation of (1S; 2S.5?, 6S) -6-methylbicyclo3.1.Olhexan-2-ol vrIS.2S.5ft.e /?) - 6-methylbicyclo3.1.0Thexan-2-ol .
Intramolecular cyclopropanation () -2- (pent-3-enyl) oxirane
(980 mg, 8.74 mmol) was carried out in the manner described above in Example 9.1, Step A to produce
(IS, 2S, 5R, 6S) -6-methylbicyclo [3.1.0] hexan-2-ol and (IS, 2S, 5R, 6R) -6-methylbicyclo [3.1.0] hexan-2-ol in the form of inseparable mixture after chromatography on silica gel. (S, 2S, 5R, 6S) -6-methylbicyclo [3.A.0] hexan-2-o /; 1 H NMR (400 MHz, CDCl 3): 64.15 (1H, d, J = 4.8 Hz), 2.08 (1H, m),
1. 75-1.25 (5H, m), 0.90 (5H, m). (IS; 2S, 5fl, 6 /?) - 6-methylbicyclo [3.1.0] hexan-2-ol: 1H NMR (400 MHz, CDCl 3): O4.21 (1H, d, J = 4.8 Hz), 1.88 (1H, m), 1.75-1.25 (4H, m), 1.15 (1H, m), 1.07 (1H, m), 0.96 (3H, d, J = 6.0 Hz), 0.41 (1H, m).
Step D: Preparation of (1S; 5R) -6-methylbicyclof3.1.OThexan-2-one.
Oxidation of (IS, 2S, 5R, 6S) -6-methylbicyclo [3.1.0] hexan-2-ol / (IS, 2S, 5R, 6R) -6-methylbicyclo [3.1.0] hexan-2-ol (658 mg, 5.87 mmol) was carried out in the manner described above in Example 9.1, Step B to yield (1S, 5R) -6-methylbicyclo [3.1.0] hexan-2-one. The spectral data was identical to that of (±) - (1S, 5R) -6-methylbicyclo [3.1.0] hexan-2-one (as shown above).
Step E: Preparation of ethyl ester of (IR.IaR, 5aS) -1-methyl-1 a.2,5.5a-tetrahydro-IH-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid and ethyl ester of acid ( 1S.laR, 5aS) -1-methyl-1a.2.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparapentalene-4-carboxylic acid.
The preparation of the endo-methyl pyrazole enantiopure derivative and the exo-methyl pyrazole derivative was performed in the manner described above in Example 9.1, Step C (for racemic variants). The separation of the isomers was carried out by reverse phase HPLC: Phenomenex® Luna C18 column (10 μ, 250 x 100 mm), 5% (v / v) of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient at 50% H20, 60 ml / min,? = 254 nm to produce the enafo-methyl-pyrazole followed by e-methyl-pyrazole.
Step F: Preparation of (1 R, 1aR.5aS) -1-methyl-1a, 2.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid.
The hydrolysis of the ester was performed as shown above in Example 9.3 to produce the corresponding acid [a] 25D + 67.6 (c 0.524, MeOH). The spectral data were identical to those of the racemic material.
Step G: Preparation of (1S, 1aR, 5aS) - methyl-1a.2.5.5a-tetra idro-1 H-2.3-diaza-cyclopropara1pentalene-4-carboxylic acid.
The hydrolysis of the ester was performed as shown above in Example 9.3 to produce the corresponding acid. The spectral data were identical to those of the racemic material.
Example 9.55: Preparation of -enco-1-methyl-1 a, 2,5,5a-tetrahydro-H-2,3-diaza-cyclopropara-1-phenylene-4-carboxylic acid and exo-1-methyl-1a, 2,5,5a-tetrahydro- 1 H-2.3-diaza-cyclopropara1pentalene-4-carboxylic acid.
The above compounds were prepared in the form of pure enantiomers by the synthetic route identical to that described above in Example 9.3 using (S) -5- (chloromethyl) dihydrofuran-2 (3H) -one as the starting lactone (see Movassaghi, M Jacobsen, ENJ Am. Chem. Soc. 2002, 724.245 for the preparation). Rotation data for the endo-methyl compound: [a] 25D-93.0 (c 0.552, MeOH).
Example 9.56: Preparation of enoO-1-ethyl-1 a.2.5.5a-tetrah id ro-IH-2,3-diaza-cycloproparaTypentalene-4-carboxylic acid and exo-1-ethyl-1a, 2.5.5a -tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid. Step A: Preparation of (?) - 4- (hex-3-inin-2,2-dimethyl-1,3-dioxolane.
To a cooled flask -78 ° C under N2 was added 2-butyne gas via a syringe until approximately -3 ml_ of liquid had condensed in the flask. Then THF (120 ml_) was added followed by DMPU (18.9 ml, 156 mmol). The flask was purged with N2 and n-butyllithium (2.5M hexanes, 18.7 ml, 46.9 mmol) was added via syringe for 5 minutes and stirred for another 15 minutes at which time it was added (f?) - 4- ( 2-iodoethyl) -2,2-dimethyl-l, 3-dioxolane (10.0 g, 39.1 mmol) as a solution in THF (30 ml_) [the preparation of (R) -4- (2-iodoethyl) -2 , Enantiopure 2-dimethyl-l, 3-dioxolane from commercially available (R) -2- (2,2-dimethyl-l, 3-dioxolane-4-yl) ethanol was made using the procedure described by: Taber. D. F .; Xu, M .; Hartnett, J.C. J. Am. Chem. Soc. 2002,124, 13121]. The reaction was slowly warmed to room temperature and stirred a total of 3 hours. The mixture was cooled with saturated NH4CI, and extracted with Et20 (2x). The organic elements were washed with H20, and brine, dried in MgSO4, filtered, and concentrated. The material was purified by chromatography on silica gel (5% EtOAc in hexanes gradient to 15% EtOAc in hexanes) to yield (R) -4- (hex-3-ynyl) -2,2-dimethyl-1, 3 -dioxolane in the form of clear oil. 1H NMR (400 MHz, CDCl 3): d4.19 (1H, m), 4.08 (1H, dd, J = 8.0, 6.0 Hz), 3.58 (1H, dd, J = 7.6, 6.8 Hz), 2.26 (2H, m), 2.15 (2H, qt, J = 5.2, 2.4 Hz), 1.81 (1H, m), 1.68 (1H, m), 1.40 (3H, s), 1.36 (3H, s), 1.11 (3H, t , J = 7.6 Hz).
Step B: Preparation of (R.Z) -4- (hex-3-eniQ-2,2-dimethyl-1,3-dioxolane.
To a solution of (f?) -4- (hex-3-ynyl) -2,2-dimethyl-l, 3-dioxolane (6.49 g, 35.6 mmol) in hexanes (100 mL) was added 5% palladium on BaSO4 (1.14 g), and quinoline (freshly distilled from Zn powder, 0.631 ml, 5.34 mmol). Then the flask was purged with H2 and stirred under an atmosphere of H2 for 2 hours. The reaction mixture was filtered through celite and washed sequentially with 1 HCl (2x) and brine. The organic elements were dried in MgSO4, filtered, and concentrated to produce (R, Z) -4- (hex-3-enyl) -2,2-dimethyl-l, 3-dioxolane which was used without further purification. This material contained approximately 7% of the trans olefin isomer which was carried through the synthetic route in the form of a mixture (the data for the minor isomers are not shown) eventually producing the corresponding pyrazolyl exo-ethyl acid derivative after separation by reverse phase HPLC (vide-frame). H NMR (400 MHz, CDCl 3): 65.40 (1H, m), 5.31 (1H, m), 4.06 (2H, m), 3.52 (1H, t, J = 4.8 Hz), 2.09 (4H, m), 1.71. (1H, m), 1.54 (1H, m), 1.41 (3H, s), 1.35 (3H, s), 0.96 (3H, t, J = Hz).
Step C: Preparation of (/? Z) -oct-5-ene-1, 2-diol.
The (ft, Z) -4- (hex-3-enyl) -2,2-dimethyl-1,3-d-oxolane (5.95g, 32.3 mmol) was stirred in 80% aq. AcOH (50 ml_) for 20 hours. The mixture was concentrated in vacuo and purified by chromatography on silica gel (40% EtOAc in hexanes gradient to 70% EtOAc in hexanes) to yield (R, Z) -oct-5-ene- "2-diol. in the form of clear oil. 1 H NMR (400 MHz, CDCl 3): 65.45 (1H, m), 5.36 (1H, m), 3.75 (1H, m), 3.67 (1H, dd, J = 10.8, 2.8 Hz), 3.45 (1H, dd, J = 11.2, 7.6 Hz), 2.16 (2H, m), 2.04 (2H, m), 1.50 (2H, m), 0.96 (3H, t, J = 7.6 Hz).
Step D: Preparation of (/?.Z)-2-(hex-3-enil)oxirano.
To a solution of (R, Z) -oct-5-ene-1, 2-diol (8.50 g, 58.9 mmol) in THF (230 ml_) at 0 ° C was added NaH (60% dispersion in mineral oil, 7.06 g, 177 mmol) (7.06 g as dispersion). The mixture was heated to room temperature and stirred for 40 minutes. The reaction was cooled to 0 ° C and triisopropylbenzenesulfonyl chloride (20.7 g, 61.8 mmol) was added. The reaction was warmed to room temperature, stirred for 1 hour, cooled with H20 and extracted with Et20. The organics were washed with brine, dried in MgSO4, filtered, and concentrated. Purification by chromatography on silica gel (2% Et20 in pentane gradient to 8% Et20 in pentane) yielded (R, Z) -2- (hex-3-enyl) oxirane. It was determined that a slight racemization occurred in this step (98% ee to 84% ee). To ensure optical purity, the enantio-enriched product was further stirred using Jacobsen's hydrolytic kinetic resolution (HKR, Step E). 1 H NMR (400 MHz, CDCl 3): 05.41 (1H, m). 5.35 (1H, m), 2.93 (1H, m), 2.75 (1H, dd, J = 5.2, 4.4 Hz), 2.49 (1H, dd, J = 5.2, 2.8 Hz), 2.20 (2H, q, J = 6.8 Hz), 2.06 (2H, quin, 7.6 Hz), 1.59 (2H, m), 0.97 (3H, t, J = 7.6 Hz).
Step E: Preparation of (ff, Z) -2- (hex-3-enyl) oxirane.
To a flask containing (R, Z) -2- (hex-3-enyl) oxirane enantio-enriched (5.04 g, 39.9 mmol) and THF (0.4 ml_) at 0 ° C was added sequentially the catalyst (fi, f ?) - Co-Salt (150 mg, 0.248 mmol), AcOH (60.0 mg, 1.00 mmol), and H20 (130 mg, 7.22 mmol). The mixture was warmed to room temperature and stirred for 20 h. Purification by chromatography on silica gel (2% Et20 in pentane gradient to 10% Et20 in pentane) afforded (R, Z) -2- (hex-3-enyl) oxirane enantiopure.
Step F: Preparation of (1S: 2S.5R.6S) -6-ethylbicyclo3.1.01hexan-2-ol.
The intramolecular cyclopropanation of (f?, Z) -2- (hex-3-enyl) oxirane (3.00 g, 23.8 mmol) was performed as described above in Example 9.1, Step A to produce (7S, 2S, 5R, 6Sj-6-ethylbicyclo [3.1.0] hexan-2-ol as a clear oil. ?? NMR (400 MHz, CDCl 3): 54.18 (1H, m), 2.08 (1H, m), 1.79- 1.51 (4H, m), 1.40 (2H, m), 1.20 (2H, m), 0.96 (3H, t, J = 7.6 Hz), 0.74 (1H, m).
Step G: Preparation of (IS.5R.6S) -6-ethylbicyclo3.1.Olhexan-2-one.
Oxidation of (IS, 2S; 5R, 6S) -6-ethylbicyclo [3.1.0] hexan-2-ol (1.75 g, 13.9 mmol) was performed in the manner described above in Example 9.1, Step B to produce ( IS, 5R, 6S) -6-ethyl-bicyclo [3.1.0] hexan-2-one in the form of a clear oil. The spectral data were identical to those of (±) - (1S, 5R, 6S) -6-ethylbicyclo [3.1.0] hexan-2-one.
Step H: Preparation of l IR.IaR.5aS) -1-ethyl-1 a.2.5.5a-tetrah5dro-1 H-2,3-diaza-cidopropara1pentalene-4-carboxylic acid.
3) LiOH / H20, dioxane
The preparation of the pyroizol derivative of enoO-ethyl enantipuro from the corresponding ketone was performed in a manner similar to that of the racemic endo-ethyl pyramizole compound in Example 9.54, Steps E and F. The spectral data were identical.
Step I: Preparation of (1S.1 aR, 5aS) -1-ethyl-1 a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid.
The pyramizole derivative of exo-ethyl enantiopure was isolated by inverted-phase HPLC as a minor impurity of the previous synthetic route.
Example 9.57: Preparation of (±) -endo-1-methylsulfanylmethyl-1 a.2.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid. Step A: Preparation of ± -endo-espirorbiciclof3.1.01hexano-2,2'-N, 31dioxolano1-6-il methyl exogenous goal.
To a solution of (±) -endo-spiro [bicyclo [3.1.0] hexane-2,2 '- [1,3] dioxolane] -6-ylmethanol (350 mg, 2.06 mmol) in DCM (12 ml_) under N2 was added Et3N (561 μ ?, 4.11 mmol). The flask was cooled to 0 ° C and metasulfonyl chloride was added dropwise (318 μ ?, 4.11 mmol). After stirring for 5 minutes, the flask was heated to room temperature and stirred for 1 hour (reaction almost complete by TLC). The DCM was evaporated and the mixture was cooled with H20. The mixture was extracted with EtOAc (2x) and the combined extracts were dried over MgSO4, filtered, and concentrated to yield (±) - (IR, 5R, 6S) -spiro [bicyclo [3.1.0] hexane-2 methanesulfonate, 2 '- [1,3] dioxolane] -6-ylmethyl. 1 H NMR (400 MHz, CDCl 3): d 4,63 (1H, dd, J = 11.2, 6.3 Hz), 4.34 (1H, dd, J = 11.2, 9.3 Hz), 4.01-3.85 (4H, m), 3.04 ( 3H, s), 2.11 (2H, m), 1.89 (1H, m), 1.78 (1H, m), 1.70 (1H, m), 1.63 (1H, m), 1.35 (1H, m). The material was used immediately in the next reaction without further purification.
Step B: Preparation of (±) -endo-6- (methylthiomethyl) is irorbicyclo3.1.01hexane-2,2'-N, dioxolane1.
To a crude (±) -endo-spiro [bicyclo [3.1.0] hexane-2,2 '[l, 3] dioxolane] -6-ylmethyl methanesulfonate solution (250 mg, 1.01 mmol) in DMF (5.0 mL ) sodium thiomethoxide (176 mg, 2.52 mmol) was added. The solution became quite viscous initially and was stirred at room temperature overnight. The mixture was partitioned between EtOAc and H20. The layers were separated and the aqueous phase was extracted again with EtOAc. The combined organic elements were dried in MgSO4, filtered, and concentrated. Purification by chromatography on silica gel (3% EtOAc in hexanes gradient to 12% EtOAc in hexanes) yielded (±) -endo-6- (methylthiomethyl) spiro- [bicyclo [3.1.0] hexane-2,2 '- [l, 3] dioxolane] in the form of a clear oil. 1 H NMR (400 MHz, CDCl 3): 63.99-3.87 (4H, m), 2.87 (1H, dd, J = 13.5, 5.4 Hz), 2.54 (1H, dd, J = 13.4, 8.8 Hz), 2.19 (3H, s), 2.14-1.96 (2H, m), 1.80 (1H, m), 1.68-1.53 (3H, m), 1.18 (1H, qd, J = 8.6, 5.4 Hz).
Step Cj Preparation of (±) -endo-6- (methylthiomethyl) -biciclof3.1.OIhexan-2-one.
To a solution of (±) -endo-6- (methylthiomethyl) spiro [bi-cycle [3. .0] hexane-2,2 '- [1,3] dioxolane] (190 mg, 0.949 mmol) in Acetone / H20 (4: 1.5 mL) was added p-toluenesulfonic acid monohydrate (9.02 mg, 47.4 pmol ). Agitated at room temperature for 2 hours. Concentrate in vacuo to extract the acetone. Extracted with EtOAc (2x) and washing the organic elements with brine. Drying in filtered MgS04l, concentrated to yield (±) -endo-6-methylsulfanylmethyl-bicyclo [3.1.0] hexan-2-one as a clear oil. 1 H NMR (400 MHz, CDCl 3): 52.63 (1H, dd, J = 13.6, 6.5 Hz), 2.53 (1H, dd, J = 13.6, 8.6 Hz), 2.32 (2H, m), 2.24 (1H, m) , 2.17 (3H, s), 1.99 (3H, m), 1.75 (1H, m).
Step D: Preparation of (±) -endo-1-methylthiomethyl) -1 a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparapentalene-4-carboxylic acid ethyl ester.
The (±) -endo-6- (methylthiomethyl) bicyclo [3.1.0] hexan-2-one (52.0 mg, 0.333 mmol) was converted to the corresponding ethyl ester of endo-1-methyl Isulfanilmeti 1-1 a, 2 , 5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid described above in Example 9.1, Step C. 1 H NMR (400 MHz, CDCl 3): 511.2-9.4 (1H , bs), 4.34 (2H, m), 2.96 (1H, dd, J = 17.7, 6.8 Hz), 2.75 (1H, d, J = 17.7 Hz), 2.50 (1H, m), 2.32 (1H, m) , 2.15 (2H, m), 2.08 (3H, s), 1.57 (1H, m), 1.37 (3H, t, J = 7.1 Hz). HPLC / MS: Column Alltech® Prevail C18 (5μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99 % v / v of CH3CN in H20, 3.5 mL / min, tr = 2.29 min, ESI + = 253.3 (M + H).
Step E: Preparation of (± -endo-1 - (methylthiomethyl) -l a.2.5.5a- tetrahydro-IH-2,3-diaza-cyclopropapha1-entalene-4-carboxylic acid.
The ester hydrolysis of the ethyl ester of endo-l- (methylthiomethyl) -1 a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid (34.0 mg, 0.135 mmol) was performed in the manner described above in Example 9.3 to produce endo-1- (methylthiomethyl) -la2,5,5a-tetrahydro-IH-2,3-diazacyclopropa [a] pentalene-4-carboxylic acid as a white solid after lyophilization. 1 H NMR (400 MHz, d 6 -DMSO): 613.6-12.1 (1H, bs), 2.82 (1H, dd, J = 17.4, 6.8 Hz), 2.57 (1H, d, J = 17.4 Hz), 2.40 (1H, m), 2.23 (1H, m), 2.08 (1H, dd, J = 13.4, 7.1 Hz), 1.99 (4H, m), 1.48 (1H, m). HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient a 99% v / v of CH3CN in HO, 3.5 mL / min, tT = 1.59 min, ESf = 225.3 (M + H).
Example 9.58: Preparation of (±) -exo-1-ethoxymethyl-1 a, 2,5, 5a-tetrahydro-IH-2,3-diaza-cycloproparalpentalene-4-carboxylic acid and (±) -in o-ethoxymethyl-1a, 2.5.5a-tetrahydro-IH-2,3-diaza-cyclopro-a-p -pentalene-4-carboxylic acid.
Step A: Preparation of cis and trans (±) -2- (5-ethoxy-pent-3-enyl) -oxirane.
The cross-metathesis of (±) -2- (but-3-enyl) oxirane (3.80 g, 38.7 mmol) with ethyl allyl ether (10.0 g, 116 mmol) was performed in the manner described above in Example 9.2, Step A to produce (±) -2- (5-ethoxypent-3-enyl) oxirane as an inseparable mixture of olefin isomers (trans: cis = 10: 1) after chromatography on silica gel. 1 H NMR (400 MHz, CDCl 3): trans isomer: 65.73 (1H, m), 5.63 (1H, m), 3.91 (2H, m), 3.48 (2H, q, J = 7.0 Hz), 2.93 (1H, m ), 2.75 (1H, m), 2.48 (1H, dd, J = 5.0, 2.7 Hz), 2.22 (2H, m), 1.63 (2H, m), 1.21 (3H, t, J = 7.0 Hz), isomer cis: d5.62 (2H, m), 4.04 (2H, m), 3.48 (2H, q, J = 7.0 Hz), 2.93 (1H, m), 2.75 (1H, m), 2.49 (1H, m) , 2.22 (2H, m), 1.63 (2H, m), 1.22 (3H, t, 7 = 7.0 Hz).
Step B: Preparation of ±) -exo-6- (ethoxymethyl) bicichlor3.1.Olhexan-2-ol and i +) - enc / o-e- (ethoxymethyl) bicichlor3.1.0lhexan-2-ol.
The intramolecular cyclopropanation of (±) -2- (5-ethoxypent-3-enyl) oxirane (3.34 g, 23.6 mmol) was performed in the manner described above in Example 9.1, Step A to produce (±) -exo-6 - (ethoxymethyl) -bicyclo [3.1.0] hexan-2-ol / (±) -endo-6- (ethoxymethyl) bicyclo [3.1.0] hexan-2-ol (ratio rel. 10: 1) in the form of a clear oil 1H NMR (400 MHz, CDCl 3): d4.29 (1H, m), 3.47 (2H, q, J = 7.1 Hz), 3.24 (2H, m), 1.94 (1H, m), 1.75 (1H, dd, J = 12.6, 8.1 Hz), 1.56 (1H, m), 1.40-1.28 (4H, m), 1.20 (3H, t, J = 7.1 Hz), 0.78 (1H, m).
Step C: Preparation of (±) -exo-6- (ethoxymethyl) bicyclo3.1.Olhexan-2-one.
Oxidation of (±) -endo-6- (ethoxymethyl) bicyclo [3.1.0] hexan-2-ol / (±) -exo-6- (ethoxymethyl) bicyclo [3.1.0] hexan-2-ol (290 mg, 1.86 mmol) was carried out in the manner described above in Example 9.1, Step B to produce (±) -6- (ethoxymethyl) bicyclo [3.1.0] hexan-2-one as a clear oil, (exo isomer ). 1 H NMR (400 MHz, CDCl 3): 63.46 (3H, m), (1H, dd, J = 10.4, 6.7 Hz), 2.19-2.01 (5H, m), 1.70 (1H, dd, J = 5.2, 2.6Hz ), 1.59 (1H, m), 1.20 (3H, t, J = 7.0Hz).
Step D: Preparation of (±) -exo-1-ethoxymethyl-1 a.2.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid and (±) -endo-ethoxymethyl 1- 1 a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid.
The preparation of the pyrazole (±) -exo-ethoxymethyl pyrazole / (±) -endo-ethoxymethyl acid derivatives was prepared in the manner described above in Example 9.56, Step H. The separation of the isomers was performed by HPLC of reverse phase: Phenomenex® Luna C18 column (10 μ, 250 x 50 mm), 5% (v / v) of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient at 50% H20, 60 ml / min,? = 254 nm to produce the endo-methyl-pyrazole followed by the exo-methyl-pyrazole obtained as white solids after lyophilization. (±) -exo-1-ethoxymethyl-a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid: 1 H NMR (400 MHz, CDCl 3): 613.50 -12.03 (1H, bs), 3.42 (2H, q, J = 7.0 Hz), 3.35 (1H, dd, J = 10.5, 6.2), 3.23 (1H, dd, J = 10.5, 7.3 Hz), 2.84 (1H , dd, J = 16.9, 6.2 Hz), 2.69 (1H, d, J = 17.0 Hz), 2.09 (1H, m), 2.03 (1H, m), 1.11 (3H, t, J = 7.0 Hz), 0.83 (1H, m). HPLC / MS: Column Alltech® Prevail CI8 (5μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99 % v / v of CH3CN in H20, 3.5 mL / min, tr = 1.56 min, EST = 223.2 (M + H).
(±) -endo-1-ethoxymethyl-1 a, 2,5,5a-tetrahydro-1 H-2,3 ° diaza-cyclopropa [a] pentaiene-4-carboxylic acid: H NMR (400 MHz, CDCl 3): 53.30-3.15 (2H, m), 3.01 (1H, dd, J = 10.7, 6.8 Hz), 2.91 (1H, dd, J = 10.7, 7.6 Hz), 2.80 (1H, dd, J = 17.3, 6.8 Hz) , 2.57 (1H, d, J = 17.3 Hz), 2.35 (1H, m), 2.24 (1H, m), 1.45 1 = (1H, m), 1.10 (1H, m), 1.00 (3H, t, J = 7.0 Hz). HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient a 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 1.42 min, EST = 223.2 (M + H).
Example 9.59: Preparation of acid ethyl ester (±) -endo- "\ -cyclopropyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS m / z (ES +): 233.4 [M + H] \ 255.4 [M + Na] +; H NMR (400 MHz, CDCI3): 64.37-4.31 (m, 2H), 2.98 (dd, IH, JT = 17.4Hz, J2 = 6.4Hz), 2.88 (d, 1H, J = 17.4 Hz), 2.37-2.34 (m, 1H), 2.24-2.18 (m, 1H), 1.37 (t, 3H, J = 7.2 Hz), 0.74 (q, 1H, J = 8.4Hz), 0.49-0.43 (m, 1H), 0.32- 0.25 (m, 1H), 0.24-0.17 (m, 2H), -0.02- -0.12 (m, 1H).
Example 9.60: Preparation of acid (D-endo-cyclopropyl-1 a.3,5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara-Tetralene-4 ° carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS m / z (ES +): 205.3 [M + H] +; H NMR (400 MHz, CDCl 3): < 53.06 (dd, 1H, J, = 18.9 Hz, J2 = 5.9 Hz), 2.99 (d, 1H, J = 18.7 Hz), 2.43 (t, 1H, J = 8.2 Hz), 2.05 (q, 1H, J = 6.1 Hz), 0.85 (q, 1H, J = 8.3 Hz), 0.55-0.50 (m, 1H), 0.41-0.36 (m, 1H), 0.29-0.21 (m, 2H), 0.08-0.00 (m, 1H ).
Example 9.61: Preparation of (±) -endo-1-cyclopropyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropafalpentalene. Step A: Preparation of amide of (±) -endo-1-cyclopropyl-1 a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropara1pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.1, Step D. MS m / z (ES *): 204.5 [M + H] +, 226.4 [M + Na] +; 1H NMR (400 MHz, CD3OD): d2.99 (dd, 1H, = 16.7 Hz, J2 = 5.9 Hz), 2.93 (d, 1H, J = 16.6 Hz), 2.37-2.29 (m, 2H), 0.80 ( q, 1H, J = 8.2 Hz), 0.54-0.48 (m, 1 H), 0.33-0.25 (m, 2H), 0.22-0.18 (m, 1H), 0.01- -0.05 (m, 1H).
Step B: Preparation of (±) -endo-1-propyl-1 a, 3, 5,5a-tetrahydro-1 H-2,3-diaza-cyclopropaphalpentalene-4-carbonitrile cycle.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS m / z (ES +) \ 186.1 [M + H] +, 371.2 [2M + H] +; 1H NMR (400 MHz, CD3OD): 52.96 (dd, 1H, J-, = 16.5 Hz, J2 = 6.2 Hz), 2.86 (d, 1H, J = 16.4 Hz), 2.41-2.35 (m, 2H), 0.87 (q, 1H, J = 8.2 Hz), 0.57-0.52 (m, 1H), 0.34-0.27 (m, 2H), 0.22-0.18 (m, 1H), -0.02- -0.11 (m, 1H)
Step C: Preparation of (±) -endo-1-cyclopropyl-4- (2H-tetrazo8-5-yl) i-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene.
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS m / z (ES +): 229.3 [M + H] +, 251.2 [M + Na] +; 1H NMR (400 MHz, CD3OD): d2.99 (dd, 2H, J, = 16.7 Hz, J2 = 6.0 Hz), 2.92 (d, 1H, J = 16.7 Hz), 2.36-2.29 (m, 2H), 0.80 (q, 1H, J = 8.3 Hz), 0.53-0.47 (m, 1H), 0.32-0.24 (m, 2H), 0.21-0.17 (m, 1H), 0.01- -0.07 (m, 1H).
Example 9.62: Preparation of (±) -exo-1-vinyl-1 a.3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid ethyl ester.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS m / z (ES +): 219.3 [M + H] +, 241.1 [M + Na] +; 1H NMR (400 MHz, CDCl 3): d5.53-5.44 (m, 1H), 5.04 (dd, 1H, J, = 17.1Hz, J2 = 1.0 Hz), 4.94 (dd, 1H, J, = 10.34 Hz, J2 = 1.4 Hz), 4.33 (q, 2H, J = 7.2 Hz), 3.02 (dd, 1H, J, = 17.3 Hz, J2 = 6.1 Hz), 2.90 (d, 1H, J = 17.3 Hz), 2.34- 2.30 (m, 1H), 2.21-2.17 (m, 1H), 1.35 (t, 3H, J = 7.2Hz), 1.33-1.29 (m, 1H).
Example 9.63: Preparation of (±) -exo-1-Vinyl-1a.3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS m / z (ES +): 191.3 [M + H] +; H NMR (400 MHz, DMSO-de): 65.57-5.48 (m, 1H), 5.13 (dd, 1H, J, = 17.1 Hz, J2 = 1.6 Hz), 4.97 (dd, 1H, J, = 10.3 Hz, J2 = 1.7 Hz), 2.98 (dd, 1H, J-, = 18.2 Hz, J2 = 6.3 Hz), 2.80 (d, 1H, J = 18.2 Hz), 2.36 (dd, 1H, = 6.1 Hz, J2 = 2.6 Hz), 2.07-2.03 (m, 1H), 1.37 (dt, IH, J, = 8.8Hz, J2 = 3.1Hz).
Example 9.64: Preparation of (±) -exo-4- (2H-tetrazol-5-yl) -1-vinyl-1a.3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropapha1pentalene. Step A: Preparation of acid amide (±) -exo-1-Vinyl-1a.3,5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara-Tetralene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.1, Step D. MS m / z (ES +): 190.3 [M + H] +, 379.2 [2M + H] +; 1 H NMR (400 MHz, DMSO-d 6): 65.58-5.49 (m, 1H), 5.09 (dd, 1H, J, = 17.1 Hz, J2 = 1.6 Hz), 4.94 (dd, 1H, J, = 10.3 Hz, J2 = 1.6 Hz), 2.94 (dd, 1H, J, = 17.1 Hz, J2 = 6.1 Hz), 2.78 (d, 1H, J = 17.1 Hz), 2.29 (dd, 1H, J, = 5.8 Hz, J2 = 2.1 Hz), 2.25-2.21 (m, 1H), 1.26-1.23 (m, 1H).
Step B: Preparation of (±) -exo-1-Vinyl-1a, 3.5.5a-tetrahydro-1 H-23-diaza-cycloproparalpentalene-4-carbonitrile.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS m / z (ES +): 172.3 [M + H] +, 343.1 [2M + H] +; 1 H NMR (400 MHz, CDCl 3): 55.52-5.43 (m, 1H), 5.09 (dd, 1H, J, = 17.0 Hz, J2 = 0.6 Hz), 5.00 (dd, 1H, J, = 10.3 Hz, J2 = 1.2 Hz), 2.99 (dd, 1H, J, = 16.7 Hz, J2 = 6.3 Hz), 2.88 (d, 1H, J = 16.7 Hz), 2.34-2.28 (m, 2H), 1.39-1.36 (m, 1H ).
Step C: Preparation of (±) -exo-4- (2H-tetrazol-5-yl) -1-Vinyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene .
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS m / z (ES +): 215.3 [M + H] +, 429.4 [2M + H] +; 1H NMR (400 MHz, CD3OD): 55.62-5.53 (m, 1H), 5.12 (d, 1H, J = 17.1 Hz), 4.99 (d, 1H, J = 10.4 Hz), 3.14-3.08 (m, 1H) , 3.02 (d, 1H, J = 16.5 Hz), 2.38 (s, 1H), 2.07-2.04 (m, 1H), 1.42-1.39 (m, 1H).
Example 9.65: Preparation of (±) -1-spirocyclopropyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid ethyl ester.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS m / z (ES +): 219.4 [M + H] +, 241.2 [M + Na] +; 1 H NMR (400 MHz, CDCl 3): 64.37-4.31 (m, 2H), 2.97 (dd, 1H, J, = 17.0 Hz, J2 = 6.1 Hz), 2.70 (d, 1H, J = 17.0 Hz), 2.58 ( d, 1H, J = 5.5 Hz), 2.52 (t, 1H, J = 5.8 Hz), 1.37 (t, 3H, J = 7.1 Hz), 1.07-1.02 (m, 1H), 0.98-0.93 (m, 1H ), 0.53-0.46 (m, 2H).
Example 9.66: Preparation of (±) -1-spirocyclopropyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparapentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS m / z (ES +): 191.3 [M + H] +, 213.2 [M + Na] +; 1H NMR (400 MHz, CD3OD): 63.03 (dd, 1H, J, = 18.1 Hz, J2 = 6.1 Hz), 2.78 (d, 1H, J = 17.8 Hz), 2.63 (d, 1H, J = 5.7 Hz) , 2.34 (t, 1H, J = 5.7 Hz), 1.12-1.03 (m, 2H), 0.68-0.63 (m, 1H), 0.54-0.49 (m, 1H).
Example 9.67: Preparation of f ±) -1-spirocyclopropyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropaTal pe nt aleño. Step A: Preparation of (±) -1-spirocyclopropyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1-pentalene-4-carboxylic acid amide.
The title compound was prepared in a manner similar to that described in Example 9.1, Step D. MS m / z (ES +): 190.2 [M + H] +, 379.3 [2M + H] +; H NMR (400 MHz, DMSO-d6): 52.90 (dd, 1H, = 16.2 Hz, J2 = 5.4 Hz), 2.66 (d, 1H, J = 16.4 Hz), 2.54 (2H, superimposed with DMSO), 1.07- 1.03 (m, 1H), 0.99-0.95 (m, 1H), 0.55- 0.50 (m, 1H), 0.39-0.34 (m, 1H).
Step B: Preparation of (±) -1-spirocyclopropyl-1a.3.5.5a-tetrahydro-1 H-2, 3-d aza-cyclopropara1pentalene-4-carbonyl group.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS m / z (ES +): 172.3 [M + H] +, 343.4 [2M + H] +; 1 H NMR (400 MHz, CDCl 3): d 2.93 (dt, 1H, Ji = 16.4Hz, J2 = 3.0 Hz), 2.68 (d, 1H, J = 16.3 Hz), 2.61 (d, 2H, J = 3.0Hz) , 1.12-1.08 (m, 1H), 1.02-0.98 (m, 1H), 0.57-0.53 (m, 1H), 0.51-0.46 (m, 1 H).
Step C: Preparation of (±) -1-spirocydopropyl-4- (2H-tetrazoB-5-yl) - a.3,5.5a-tetrahydro-IH-2,3-diaza-cycloproparalpentalene
The title compound was prepared in a manner similar to that described in Example 9.2, Step G. MS m / z (ES +): 215.2 [M + H] +, 429.2 [2M + H] +; 1H NMR (400 MHz, MeOD): d3.06 (dd, 1H, J-, = 16.1 Hz, J2 = 6.1 Hz), 2.85 (d, 1H, J = 16.1 Hz), 2.68 (t, 1H, J = 5.8 Hz), 2.64 (d, 1H, J = 5.4 Hz), 1.11 (quintet, 1H, J = 4.4 Hz), 1.03 (q, 1H, J = 4.0 Hz), 0.61 (q, 1H, J = 4.6 Hz) ), 0.49 (q, 1H, J = 4.3 Hz).
Example 9.68: Preparation of (±) -endo-'\ - propenyl-a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1-pentalene-4-carboxylic acid ethyl ester.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS m / z (ES +): 233.4 [M + H] \ 255.3 [M + Na] +;
Example 9.69: Preparation of α ±) -er? OO-1-propenyl-3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS m / z (ES +): 205.2 [M + H] +;
Example 9.70: Preparation of ±) -in o-1-propenyl-4- (2H-te¾razol-5-γ-1 a.3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene.
Step A: Preparation of ftJ-eneO-l-propenyl 1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara-Tetralene-4-carboxylic acid amide.
The title compound was prepared in a manner similar to that described in Example 9.2, Step E. MS m / z (ES +): 204.1 [M + H] +;
Step B: Preparation of (±) -endo-1-propenyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropaFalpentalene-4-carbonitrile.
The title compound was prepared in a manner similar to that described in Example 9.2, Step F. MS m / z (ES +): 186.1 [+ H] +, 371.1 [2M + H] +;
Step C: Preparation of i ±) -endO-1-propenyl -4- (2H-tetrazol-5-iD-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene The compound of The titer was prepared as an isomeric mixture (1.7: 1) in a manner similar to that described in Example 9.2, Step G. MS m / z (ES *): 229.4 [M + H] +, 457.3 [2M + H] + Major isomer: 1H NMR (400 MHz, MeOD): 55.59-5.51 (m, 1H), 4.69-4.62 (m, 1H), 3.02 (dd, 1H, J, = 6.5 Hz, J2 = 4.0 Hz), 2.78 (d, 1H, J = 16.5 Hz), 2.64-2.55 (m, 2H), 2.15 (q, 1H, J = 8.0 Hz), 1.76 (dd, 3H, J, = 6.8 Hz, J2 = 1.6 Hz). Minor Isomer: 1H NMR (400 MHz, MeOD): 55.79-5.71 (m, 1H), 4.75-4.69 (m, 1H), 3.06 (dd, 1H, J, = 6.5 Hz, J2 = 4.0 Hz), 2.83 ( d, 1H, J = 16.5 Hz), 2.58-2.49 (m, 2H), 2.00 (q, 1H, J = 8.0 Hz), 1.55 (dd, 3H, J1 = 6.5 Hz, J2 = 1.5 Hz).
Example 9.71: Preparation of 1-methoxymethyl-1a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara-Tetralene-4-carboxylic acid. Step A: Preparation of espirorbiciclof3.1.0 Thexano-2,2'-G? | 31d i oxolanol-6-il methane I.
NaBH4 (90 mg, 2.38 mmol) was dissolved in MeOH (2 ml_) and added dropwise to a solution of aldehyde (400 mg, 2.38 mmol) dissolved in MeOH (8 ml_). The reaction was stirred at room temperature for 10 minutes and then cooled with 10% NaOH. The mixture was extracted with ether, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (50% EtOAc / n-hexane / silica) to yield 200 mg of the title compound. 1H NMR (400 MHz, CDCl 3): d4.07-3.88 (5H, m), 3.64 (1H, ddd, J = 12.5, 10.4.2.2 Hz), 2.79 (1H, dd, J = 11.0, 2.2 Hz), 2.18-2.05 (2H, m), 1.82-1.60 (4H, m), 1.40-1.30 (1H, m).
Step Bj Preparation of 6-endo- (methoxymethyl) espirorbicichlor3.1.01hexane-2,2'-N, 31-dioxolane1.
The title compound was prepared in a manner similar to that described in Example 9.52, Step B. 1 H NMR (400 MHz, CDCl 3): 54.00-3.82 (4H, m), 3.77 (1H, dd, J = 10.5, 5.4) , 3.44 (1H, dd, J = 10.5, 8.5 Hz), 3.40 (3H, s), 2.16-2.04 (1H, m), 2.04-1.96 (1H, m) 1.87-1.79 (1H, m), 1.72- 1.65 (1H, m), 1.64-1.54 (2H, m), 1.28-1.15 (IH.m).
Step C: Preparation of 6-enfo-methoxymethyl-bicichlor3.1.01he¾an-2-one.
The title compound was prepared in a manner similar to that described in Example 9.15. 1 H NMR (400 MHz, CDCl 3): 53.55 (1H, dd, J = 10.8, 6.4 Hz), 3.45 (1H, dd, J = 10.8, 8.5 Hz), 3.37 (3H, s), 2.36-2.23 (3H, m), 2.05-1.98 (3H, m), 1.82-1.73 (1H, m).
Step D: Preparation of ethyl ester of 1-endo-methoxomethyl-1 a.2.5.5a-tetrahydro-1 H-2,3-diaza-cicioproparalpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.51, Step D. HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 1.84 min, EST = 236.9 (M + H).
Step E: Preparation of 1-Cromo-methoxymethyl-1a, 2.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1-phenylene-4-carboxylic acid.
To a solution of ester (0.090 g, 0.38 mmol) in dioxane was added 1 M of lithium hydroxide aq. (1.0 ml, 1.0 mmol). The solution was stirred overnight at room temperature and acidified by the addition of 1N HCL. The mixture was concentrated and purified by reverse phase HPLC: Phenomenex® Luna C18 column (10 μ, 250 x 21.2 mm), 5% (v / v) CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v of TFA) 95% gradient of H20, 20 ml / min,? = 214 nm to produce the title compound as a white solid after lyophilization. HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient a 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 1.17 min, ESI + = 209.1 (M + H).
Example 9.72: Preparation of 1-ene-methoxymethyl-4- (IH-tetrazol-5-yl) -1a, 2.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1-pentalene.
The title compound was prepared in a manner similar to that described in Example 9.2, Steps E, F, and G. HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99% v / v of CH3CN in H20, 3.5 mL / min, tT = 1-27 min, EST = 233.0 (M + H).
Example 9.73: Preparation of 1-ene-phenoxymethyl-1 a.2, 5,5a-tetrahydro-1 H-2,3-diaza-c »clopropara-1-phenylene-4-carboxylic acid. Step Aj Preparation of 6-endo- (phenoxymethyl) espirorbicichlor3.1.01hexane-2.2'-ri.31dioxolane).
Alcohol (170 mg, 1.0 mmol), phenol (141.2 mg, 1.5 mmol), PyPh2P (395 mg, 1.5 mmol), and DtBAD (345 mg, 1.5 mmol) were dissolved in THF (5 mL) and stirred at room temperature. overnight. HCI 1N was added to the reaction mixture and extracted with ether (3X). The combined organic layers were washed with brine, dried in MgSO4, and concentrated. The residue was purified by column chromatography (0-25% EtOAc / n-hexane / silica) to yield the title compound. 1 H NMR (400 MHz, CDCl 3): 67.31-7.25 (2H, m), 6.99-6.92 (3H, m), 4.41 (1H, dd, J = 10.6, 5.2 Hz), 4.03-3.89 (5H, m), 2.18-2.08 (1H, m), 2.08-1.99 (1H, m), 1.92-1.84 (1H, m), 1.81-1.75 (1H, m), 1.70-1.63 (1H, m), 1.63-1.56 (1H , m), 1.44-1.35 (1H, m).
Step B: Preparation of 6-endo-phenoxymethyl-bicyclo3.1.Ohexan-2-one.
The title compound was prepared in a manner similar to that described in Example 9.15 1 H NMR (400 MHz, CDCl 3): 57.32-7.25 (2H, m), 7.00-6.94 (1H, m), 6.92-6.88 (2H, m ), 4.19 (1H, dd, J = 10.6, 6.1 Hz), 3.96 (1H, dd, J = 10.6, 8.9 Hz), 2.38-2.32 (3H, m), 2.13-1.94 (4H, m) .25
Step C: Preparation of 1-endO-phenoxymethyl-1 a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid ethyl ester.
The title compound was prepared in a manner similar to that described in Example 9.51, Step D. H NMR (400 MHz, CDCl 3): 57.27-7.21 (2H, m), 6.91 (1H, t, J = 7.3 Hz), 6.83-6.79 (2H, m), 4.39-4.25 (2H, m), 3.88-3.82 (1H, m), 3.48 (1H, dd, J = 10.4, 8.3 Hz), 3.02 (1H, dd, J = 17.8 , 6.8 Hz), 2.84 (IH.d, 17.8 Hz), 2.61-2.56 (IH, m), 2.50-2.43 (IH, m), 1.85-1.76 (IH, m), 1.35 (3H, t, J = 7.1 Hz). HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient a 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 2.56 min, EST = 299.1 (M + H).
Step D: Preparation of 1-cyphenoxymethyl-1a.2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1-pentalene-4-carboxylic acid
To a solution of ester (0.025 g, 0.084 mmol) in dioxane was added 1 M aq. Lithium hydroxide. (0.23 mL, 0.23 mmol). The solution was stirred at 60 ° C for 3 hours and acidified by the addition of 1N HCl. The mixture was concentrated and purified by reverse phase HPLC: Phenomenex® Luna C18 column (10 μ, 250 x 21.2 mm), 5% (v / v) CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v of TFA) 95% gradient of H20, 20 ml / min,? = 214 nm to produce the title compound as a white solid after lyophilization. HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient a 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 2.01 min, ESI + = 271.0 (M + H)
Example 9.74: Preparation of 1-endo-phenoxymethyl-4- (1 H-tetrazol-5-yl) -1a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene.
The title compound was prepared in a manner similar to that described in Example 9.2, Steps E, F, and G. HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v CH3CN (containing 1% v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 1.96 min, EST = 295.3 (M + H)
Example 9.75: Preparation of 1-exo-methylsulfanillmethyl-1 a, 2.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1-pentalene-4-carboxylic acid. Step A: Preparation of 2- (5-methylsulfanyl-pent-3-enyl) -oxirane
Epoxide (5.57 g, 56.7 mmol) and allylmethyl sulfide (I.OOOg, 11.3 mmol) were stirred at 20 ° C for 24 hours with Zhan 1 catalyst (MW = 661.07, 0.150 g, 0.23 mmol, ex ZannanPharma). The solvent was removed under reduced pressure. The residual oil was purified by column chromatography (0-10% EtOAc / n-hexane / silica) to yield the title compound as an oil.1H NMR (400 MHz, CDCl 3): 55.60-5.43 (2H, m), 3.07 (2H, d, J = 7.2 Hz), 2.96-2.91 (1H, m), 2.78-2.74 (1H, m), 2.49 (1H, dd, J = 5.0, 2.7 Hz), 2.28-2.19 (2H, m), 2.02 (3H, s), 1.70-1.57 (2H, m).
Step B: Preparation of (±) -exo-6-methylsulfanylmethyl-bicichlor3.1.01hexan-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.51, Step B. 1 H NMR (400 MHz, CDCl 3): d4.28 (1H, t, J = 5.0 Hz), 2.41 (2H, d, J = 7.0 Hz), 2.14 (3H, s), 2.00-1.89 (1H, m), 1.75 (1H, dd, 12.7, 8.1 Hz), 1.58 (1H, dd, J = 14.6, 8.6 Hz), 1.40-1.28 (4H, m), 0.72-0.66 (IH, m).
Step Preparation of f ±) -6-exo-methylsulfanylmethyl-bicichlor3.1.01hexan-2-one.
The title compound was prepared in a manner similar to that described in Example 9.51, Step C. 1 H NMR (400 MHz, CDCl 3): 02.65 (1H, dd, J = 13.5, 5.8 Hz), 2.38 (1H, dd, J = 13.5, 7.7 Hz), 2.18 (3H, s), 2.16-2.03 (4H, m), 2.00 (1H, dd, J = 9.1, 5.1 Hz), 1.78 1H, dd, J = 5.3, 2.5 Hz), 1.56-1.51 (1H, m).
Step D: Preparation of ethyl ester of (±) -1-exo-methylsulfanylmethyl-1a.2.5.5a-tetrahydro-1 H-2,3-diaza-ci or pro-patal p-naphthalene-4-carboxylic acid.
H20 The title compound was prepared in a manner similar to that described in Example 9.51, Step D. HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v CH3CN (containing 1 % v / v of TFA) in H20 (containing 1% v / v of TFA) gradient to 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 2.35 min, ESI + = 253.1 (M + H).
Step E: Preparation of (±) -endo-1-methylsulfanylmethyl-1 a, 2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropafalpentalene-4 ° carboxylic acid.
To a solution of ester (40mg, 159 pmol) in dioxane was added 1M of lithium hydroxide ac (428 μ ?, 428 pmol). The solution was stirred at room temperature overnight and acidified by the addition of 1N HCl. The mixture was concentrated and purified by reverse phase HPLC: Phenomenex® Luna C18 column (10 μ, 250 x 21.2 mm), 5% (v / v) CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v of TFA) 95% gradient of H20, 20 ml / min,? = 214 nm to produce the title compound as a white solid after lyophilization. 1 H NMR (400 MHz, CD 3 OD): 62.94 (1 H, dd, J = 16.9, 5.9 Hz), 2.82 (1 H, d, 16.8 Hz), 2.53 (2 H, d, J = 7.0 Hz), 2.14 (3 H, s ), 2.16-2.08 (2H, m), 0.92-0.86 (1H, m). HPLC / MS: Column Alltech® Prevail C18 (5 μ, 50 x 4.6 mm), 5% v / v of CH3CN (containing 1% v / v TFA) in H20 (containing 1% v / v TFA) gradient a 99% v / v of CH3CN in H20, 3.5 mL / min, tr = 1.64 min, ESI + = 225.2 (M + H).
Example 9.76: Preparation of acid (±) -spiroH a.3, 5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-1, r-cyclopentane-4-carboxylic acid. Step A: Preparation of (±) -spiro-rbiciclof3.1.OIhexane-6-1 '-cyclopentaneT-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.2, Steps A and B.1H NMR (CDCl 3): 54.11 (d, 1H, J = 4.8), 2.05-1.98 (m, 1H), 1.69- 1.46 (m, 8H), 1.40-1.26 (m, 5H).
Step B: Preparation of (±) -spiro-rbiciclof3.1.0 Thexano-6-1'-cyclopentanol-2-one
The title compound was prepared in a manner similar to that described in Example 9.2, Step C. 1 H NMR (CDCl 3): 52.23-2.11 (m, 2H), 2.02-1.90 (m, 3H), 1.77-1.73 (m, 3H), 1.70-1.50 (m, 5H), 1.48-1.24 (m, 1H).
Step C: Preparation of ethyl ester of (±) -espirof 1 a.3.5.5a- tetrahydro-1 H-2,3-diaza-cycloproparaTypentalene-1, 1'-cyclopentanol-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS: m / z (ES +): 247 [M + H] +, 201 [M-OEt] +
Step D: Preparation of (±) -spiroH a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-1,1'-cyclopentanol-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS: m / z (ES *): 219 [M + H] +, 201 [M-OH] +. 1H NMR (CD3OD): 62.94 (dd, 1H, J, = 17.1, J2 = 2.1), 2.72 (d, 1H, J = 17.1, 2.17 (s, 2H), 1.78-1.53 (m, 6H), 1.34- 1.24 (m, 1H), 0.94-0.84 (m, 1H).
Example 9.77: Preparation of (±) -5- (spiro-f la, 3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropafalpentalene-1,1'-cyclopentano1-4-yl) -1 H-tetrazole.
The title compound was prepared in a manner similar to that described in Example 9.44. MS: m / z (ES *): 243 [M + H] +, 215 [M-N 2 + H] +. 1 H NMR (CD 3 OD): 52.88 (dd, 1 H, = 12.3, J 2 = 6.1), 2.72 ( d, 1H, J = 16.6), 2.18-2.07 (m, 2H), 1.63-1.40 (m, 6H), 1.28-1.13 (m, 1H), 0.83-0.71 (m, 1H).
Example 9.78: Preparation of (±) -spiroH a.3, 5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1-pentalene-1,1'-cyclohexanol-4-carboxylic acid. Step A: Preparation of (±) -spiro-f biciclof 3.1.01hexane-6-1 '-cyclohexanol-2-ol.
The title compound was prepared in a manner similar to that described in Example 9.2, Steps A and B. 1 H NMR (CDCl 3): 64.14 (br s, 1 H), 2.05-2.00 (m, 1 H), 2.0-1.1 (m 15H).
Step B: Preparation of (±) -spiro-rbiciclof3.1.01hexane-6-1 '-cyclohexanol-2-one
The title compound was prepared in a manner similar to that described in Example 9.2, Step C.1H NMR (CDCI3): 52.39-2.28 (m, 1H), 2.28-2.14 (m, 1H), 2.10-1.99 (m, 2H), 1.97-1.82 (m, 2H), 1.64 (d, 1H, J = 5.2), 1.60-1.44 (m, 7H), 1.33-1.25 (m, 2H).
Step C: Preparation of ethyl ester of (±) -espirof 1 a, 3, 5.5a-tetrahydro-1 H-2,3-diaza-cyclopro-aralpentalene-1,1'-hexanol-4-carboxylic acid cycle.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS: m / z (ES +): 283 [M + Naf, 261 [M + H] +, 215 [M-OEt] + . H NMR (CDCl 3): 65.30 (br s, 1H, NH), 4.41-4.27 (m, 2H), 2.89 (dd, 1H, J1 = 17.5, J2 = 6.9), 2.64 (d, 1H, J = 17.5) , 2.08 (d, 1H, J = 6.1), 1.98 (t, 1H, J = 6.3), 1.62-1.42 (m, 4H), 1.40-1.25 (m, 7H, including 1.36 (t, 3H, J = 7.1 ), 1.10-0.90 (m, 2H).
Step D: Preparation of acid (±) -espirof1 a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-1,1'-cyclohexanol-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS: m / z (ES +): 255 [M + Na] +, 233 [M + H] +. 1H NMR (CDCl 3): d2.70 (dd, 1H, J-, = 18.5, J2 = 7.0), 2.46-2.40 (m, 2H), 1.90 (d, 1H, J = 6.2), 1.60 (t, 1H , J = 6.5), 1.40-1.15 (m, 7H), 1.10-0.88 (m, 2H).
Example 9.79: Preparation of (±) -5- (spiro-H a.3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-1, 1'-cyclohexane1-4-il¾-1 H- tetrazole
The title compound was prepared in a manner similar to that described in Example 9.44. MS: m / z (ES +): 279 [M + Na] +, 257 [M + H] +, 229 [M-N 2 + H] +. 1 H NMR (CD 3 OD): 53.20-2.90 (m, 1H), 2.75 (dd, 1H, JT = 16.5, J2 = 1.0), 2.15-2.08 (m, 2H), 1.67-1.40 (m, 6H), 1.40-1.24 (m, 2H), 1.21-1.12 (m, 1H) , 1.07-0.98 (m, 1H).
Example 9.80: Preparation of (±) -exo-1-allyl-1 a, 2.5, 5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid.
Step A: Preparation of cyclobutyldiphenylisulfonium trifluoromethanesulfonate.
A solution of cyclobutanol (1.00 g, 13.9 mmol) in 25 ml of DCM was cooled to -20 ° C and dry pyridine (1.35 ml, 16.6 mmol) was added, followed by trifluoromethanesulfonic anhydride (2.33 ml)., 13.9 mmol) (in 5 ml of DCM). The solution was allowed to warm to room temperature for one hour. Pentane (40 ml_) was added and the resulting mixture was stirred and filtered. The filtrate was concentrated under reduced pressure with a bath at room temperature until all the volatile solvents were removed. The residual oil was frozen at -20 ° C and diphenylsulphan (10.2 ml, 61.0 mmol) was added. The mixture was stirred at 25 ° C for 20 hours, heated at 45 ° C for 30 minutes and cooled to room temperature. Pentane was added, the solution was stirred and the resulting solid was collected by vacuum filtration to yield cyclobutyldiphenylisulfonium trifluoromethanesulfonate (1.82 g, 4.86 mmol, 35.0%). MS: m / z (ES +): 241 [C16H17S] +. H NMR (D6-DMSO): 68.10 (dt, 4H, J, = 7.8, J2 = 3.1), 7.84-7.72 (m, 6H), 5.90-5.78 (m, 1H), 5.15 (ddd, 2H, = 14.9 , J2 = 10.3, J3 = 1.4), 4.48 (t, 2H, J = 14.2), 2.45 (dd, 2H, J, = 13.8, J2 = 7.1).
Step B: Preparation of (±) -exo-6-allyl-biciclof3.1.0 Thexan-2-one.
A solution of cyclobutyldiphenylsulfonium trifluoromethanesulfonate (1820 g, 4.86 mmol) in 30 ml of THF was frozen at -78 ° C and 1.7M t-butyllithium in pentane (2,700 ml, 4.59 mmol) was added dropwise. After 30 minutes, cyclopent-2-enone (0.190 ml, 2.35 mmol) in THF (3 ml_) was added and the solution was stirred at -78 ° C for 2 hours. The reaction was cooled by the addition of sat. NaHCO 3. and heated to room temperature. The product was extracted into DCM, the solvent was removed under reduced pressure and purified by column chromatography (EtOAc / n-hexane / 0-20% silica) to yield (±) -exo-6-allyl-bicyclo [3.1. 0] hexan-2-one as a colorless oil (0.178 g, 1.31 mmol, 55.6%). Contains ca 50% ±) -enoO-6-allyl-bicyclo [3.1.0] hexan-2-one. H NMR (CDCl 3): d5.95-5.75 (m, 1H), 5.20-5.00 (m, 2H), 2.38-2.20 (m, 1H), 2.20-1.90 (m, 5H), 1.65-1.50 (m, 2H), 1.40-1.32 (m, 2H).
Step C: Preparation of ethyl ester of (±) -exo-1-a to I i I-1 a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4-carboxylic acid ester.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS: m / z (ES +): 255 [M + Na] +, 233 [M + H] +, 187 [M-OEt ] +. 1H NMR (CDCl 3): d5.91-5.81 (m, 1H), 5.02 (dd, 1H, J, = 17.2, J2 = 1.6), 4.92 (dd, 1H, J, = 10.3, J2 = 1.6), 4.34 (q, 2H, J = 7.1), 2.97 (dd, 1H, J, = 17.1, J2 = 6.3), 2.86 (d, 1H, J = 17.1), 2.22-2.14 (m, 2H), 2.11-2.00 ( m, 2H), 1.36 (t, 3H, J = 7.1), 0.80 (septet, 1H, J = 3.4).
Step D: Preparation of (±) -exo-1-allyl-1 a, 3,5,5a-tetrahydro-1 H ~ 2,3-diaza-cyclopropara-1-pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3 MS: m / z (ES +): 227 [M + Na] +, 205 [M + H] \ 187 [M-OH] +. 1H NMR (CD3CN): d6.00-5.88 (m, 1H), 5.13 (dq, 1H, J-, = 17.2, J2 = 1.7), 5.03 (dq, 1H, J-, = 10.3, J2 = 2.1) , 2.92 (dd, 1H, J, = 16.8, J2 = 5.8), 2.78 (d, 1H, J = 17.0), 2.3-2.0 (m, 4H), 0.71 (septet, 1H, J = 3.4).
Example 9.81: Preparation of (±) -exo-l-allyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene.
The title compound was prepared in a manner similar to that described in Example 9.44. MS: m / z (ES +): 251 [M + Na], 229 [M + H] +, 201 [M-N 2 + H] +. H NMR (CD3CN): 55.98-5.84 (m, 1H, CH = CH2), 5.12 (ddd, 1H, JT = 17.2, J2 = 3.6, J3 = 1.7, CH = CHH), 5.01 (d, 1H, ddd, 1H, = 10.2, J2 = 3.3, J3 = 1.4, CH = CHH), 2.98 (ddd, 1H, J, = 16.3, J2 = 4.8, J3 = 1 6), 2.88 (d, 1H, J = 16.3), 2.14-2.04 (m, 2H), 0.80 (septet, 1H, J = 3.4).
Example 9.82: Acid preparation of (±) -enco-1-allyl-1 a, 2,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1-pentalene-4-carboxylic acid. Step A: Preparation of ethyl ester of (±) -oeno-1-allyl-3,5,5a-tetrahydro-1 H-2,3-diaza-cycloproparalpentalene-4 ° carboxylic acid ester.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D using the mixture of diastereomers described in Example 9.80, Step B. MS: m / z (ES *): 255 [M + Na] + , 233 [M + H] +, 187 [-OEt] +. 1H NMR (CDCl 3): 65.84-5.74 (m, 1H), 5.00 (dd, 1H, J, = 17.2, J2 = 1.7), 4.95 (dd, 1H, J, = 10.2, J2 = 1.5), 4.39-4.31 (m, 2H), 2.95 (dd, 1H, J, = 17.5, J2 = 6.9), 2.70 (d, 1H, J = 17.5), 2.44 (t, 1H, J = 7.6), 2.31 (dd, 1H, J, = 14.5, J2 = 6.5.), 1.79-1.66 (m, 2H), 1.42-1.33 (m, 4H, including 1.37 (t, 3H, J = 7.1)).
Step B: Preparation of acid (±) -enoO-1-allyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopentylpentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS: m / z (ES *): 227 [M + Na] +, 205 [M + H] \ 187 [M-OH] +. 1H NMR (CD3CN): 55.68-5.56 (m, 1H), 4.81 (dq, 1 H, Ji = 15.5, J2 = 1.7), 5.03 (dq, 1H, J, = 10.2, J2 = 1.4), 2.68 (dd) , 1H, J, = 17.4, J2 = 6.8), 2.43 (d, 1H, J = 17.3), 2.17-2.12 (m, 1H), 2.10-2.03 (m, 1H), 1.61-1.50 (m, 1H) , 1.45-1.36 (m, 1H), 1.13 (penteto, 1H, J = 7.8).
Example 9.83: Preparation of (±) -endo- -alyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene
The title compound was prepared in a manner similar to that described in Example 9.44 using the mixture of diastereomers described in Example 9.80, Step B. MS: m / z (ES +): 251 [M + Na] +, 229 [M + H] \ 201 [M-N2 + H] +. H NMR (CD3CN): 55.77-5.68 (m, 1H), 4.92-4.80 (m, 2H), 2.88 (dd, 1H, J, = 16.7, J2 = 6.8), 2.64 (d, 1H, J = 16.7) , 2.37-2.30 (m, 1H), 2.30-2.23 (m, 1H), 1.75-1.67 (m, 1H), 1.55-1.476 (m, 1H), 1.29 (penteto, 1H, J = 7.9).
Example 9.84: Preparation of (±) -exo-4-methyl-3b.4.4a, 5-tetrahydro-1 H -propalene cycle, 41-cyclopentaH, 2-cTpirazol-3-carboxylic acid. Step A: Preparation of ethyl ester of (±) -exo-4-methyl-3b.4,4a, 5-tetrahydro-1 H-cyclopropar3.41cyclopentaH, 2-clpirazole-3-carboxylic acid
The title compound was prepared in a manner similar to that described in Example 9.2, Step D from a 1: 1 mixture of 6-exo-methylbicyclo [3.1.0] hexane-3-one and 6-endo-methylbicyclo [ 3.1.0] hexane-3-one (see PS Mariano, E. Bay, DG Watson, T. Rose, and C. Bracken, J. Org. Chem. 1980, 45, 1753; J. Nishimura, N. Kawa, J. Furukawa, Tetrahedron, 1969, 25, 2647). MS: m / z (ES +): 229 [M + Na] +, 207 [M + H] +, 161 [M-OEt] +. 1H NMR (CDC13): d4.39 (t, 2H, J = 7.2), 2.96 (dd, 1H, J, = 16.9, J2 = 6.6), 2.82 (d, 1H, J = 16.8), 2.03-2.01 ( m, 1H), 1.89-1.85 (m, 1H), 1.40 (t, 3H, J = 7.2), 1.14 (d, 3H, J = 6.1), 0.69-0.64 (m, 1H).
Step B: Preparation of acid (±) -exo-4-methyl-3b, 4,4a, 5-tetrahydro-1 H-cyclopropar3,4TcyclopentaH, 2-c1pyrazole-3-carboxylic acid
The title compound was isolated during the reaction described in Example 9.84, Step A. MS: m / z (ES +): 179 [M + H] +, 161 [M-OH] +. H NMR (CD3CN): 62.90 (dd, 1H, J, = 16.5, J2 = 6.6), 2.74 (d, 1H, J = 16.0), 2.02-1.99 (m, 1H), 1.88-1.78 (m, 1H) , 1.13 (d, 3H, J = 6.1), 0.62-0.55 (m, 1H).
Example 9.85: Preparation of (±) -encfo-4-methyl-3b, 4.4a, 5-tetrahydro-1 H-cyclopropay3,41cyclopentari, 2-clirazole-3-carboxylic acid. Step A: Preparation of ethyl ester of (±) -encro-4-methyl-3b, 4,4a, 5-tetrahydro-IH-cyclopropar3,41cyclopentaN.2-c1pyrazol-3- acid
The title compound was prepared in a manner similar to that described in Example 9.2, Step D using the mixture of diastereomers described in Example 9.84, Step A. MS: m / z (ES +): 229 [M + Na] +, 207 [M + H] +, 161 [M-OEt] +.
Step B: Preparation of acid (±) -endo-4-methyl-3b, 4,4a, 5-tetrahydro-1 H-cyclopropaf3,41cyclopentari, 2-c1pyrazido-3-carboxylic acid
The title compound was isolated during the reaction described in Example 9.85, Step A. MS: m / z (ES +): 179 [M + H] \ 161 | M-OH] +. 1H NMR (CD3CN): 52.83 (dd, 1H, J, = 16.8, J2 = 6.9), 2.55 (d, 1H, J = 16.9), 2.29 (t, 1H, J = 6.9), 2.10 (dd, 1H, J, = 14.4, J2 = 6.6), 1.37-1.31 (m, 1H), 0.61 (d, 3H, J = 6.4).
Example 9.86: Preparation of (±) -endo-7-cyclopropylmethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropara1pentalene-4 ° carboxylic acid.
Step A: Preparation of 4- (2-Iodo-etin-2,2-dimethyl-H .3-thioxolane
Triphenylphosphine (172 mmol, 45 g) and imidazole (172 mmol, 12 g) were dissolved in THF / acetonitrile (3: 1, 300 ml). The mixture was cooled in an ice bath, and iodine (172 mmol, 44 g) was added in four portions and stirred vigorously for 20 minutes. The resulting pulp was heated to 20 ° C and then cooled to 0 ° C. (±) -2- (2,2-Dimethyl- [1, 3] dioxolane-4-yl) -ethanol (156 mmol, 25 g) was added dropwise to the reaction mixture for 15 minutes. The mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with a 5% sodium bicarbonate solution and extracted with hexane. The combined organic layer was dried with MgSO4 and concentrated. Chromatography on silica gel yielded 4- (2-iodo-ethyl) -2,2-dimethyl- [1, 3] dioxolane as a clear oil; 1H NMR (400 MHz, CDC13): 64.18-4.12 (m, 1H), 4.06 (dd, 1H, J, = 8.0 Hz, J2 = 6.1 Hz), 3.55 (dd, 1H, J, = 8.0 Hz, J2 = 6.5 Hz), 3.28-3.17 (m, 2H), 2.11 -1.98 (m, 2H), 1.38 (s, 3H), 1.33 (s, 3H).
Step B: Preparation of r4- (2.2-Dimethyl-H3-thioxolane-4-iB-but-1-ynyl-trimethyl-silane.
To a solution of TMS-acetylene (72 mmol, 7.1 g) in 150 ml anhydrous THF and DMPU (27 ml, 222 mmol) was slowly added 2.5 M (78 mmol, 31 ml) BuLi in Hexane at -78 ° C and then added 4- (2-Iodo-ethyl) -2,2-dimethyl- [1,3] dioxolane to the mixture. It was stirred at -78 ° C for 15 minutes and heated slowly to room temperature. The reaction mixture was cooled with sat. NH 4 Cl. and extracted by EtOAc. The combined organic layer was washed with H20 and brine, dried by MgSO4 and concentrated. Chromatography on silica gel (2-10% EtOAc / Hexane) yielded 4- (2,2-Dimethyl- [1,3] dioxolane-4-yl) -but-1-ynyl] -trimethyl-silane in the form of a clear oil; 1H NMR (400 MHz, CDC13): d4.19-4.12 (m, 1H), 4.07 (dd, 1H, JT = 8.0 Hz, J2 = 6.0 Hz), 3.57 (dd, 1H, J, = 8.0 Hz, J2 = 6.9 Hz), 2.39-2.26 (m, 2H), 1.86-1.79 (m, 1H), 1.76-1.68 (m, 1H), 1.39 (s, 3H), 1.34 (s, 3H), 0.13 (s, 9H).
Step C: Preparation of 4-But-3-inyl-2,2-dimethyl-f 1.31dioxolane To a solution of 4- (2,2-Dimethyl- [1,3] dioxolane-4-yl) -but-1 -inyl] -trimethyl-silane (44 mmol, 10.0 g) in 40 ml of methanol, K2C03 (49 mmol, 6.7 g,) was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, diluted with a solution of NH 4 Cl and extracted with EtOAc. The combined organic layer was dried with MgSO4 and concentrated. Chromatography on silica gel (4-12% EtOAc / Hexane) gave 4-But-3-ynyl-2,2-dimethyl- [1, 3] dioxolane as light oil; 1 H NMR (400 MHz, CDCl 3): 64.21-4.15 (m, 1H), 4.05 (dd, 1H, J, = 8.0 Hz, J2 = 6.0 Hz), 3.55 (dd, 1H, J, = 8.0 Hz, J2 = 6.9 Hz), 2.31-2.26 (m, 2H), 1.94 (t, 1H, J = 2.6 Hz), 1.84-1.75 (m, 1H), 1.73-1.68 (m, 1H), 1.38 (s, 3H), 1.33 (s, 3H).
Step D: Preparation of 4- (5-Cyclopropyl-pent-3-ynyl) -2,2-dimethyl-1,3-dioxolane.
To a solution of 4-But-3-inyl-2,2-dimethyl- [1, 3] dioxolane (6 mmol, 1.0 g) in 40 ml of anhydrous THF and anhydrous DMPU (26 mmol, 3 g) was added an 2.5M BuLi solution in hexane (9.01 mmol, 3.6 ml_) at -78 ° C. It was stirred at -78 ° C for 15 minutes and heated slowly to room temperature. The reaction mixture was cooled with sat. NH 4 Cl. and extracted by EtOAc. The combined organic layer was washed with H20 and brine, dried by MgSO4 and concentrated. Chromatography on silica gel (2~10% EtOAc / Hexane) gave 4- (5-Cyclopropyl-pent-3-ynyl) -2,2-dimethyl- [1,3] dioxolane as a clear oil; 1H NMR (400 MHz, CDCl 3): 64.22-5.15 (m, 1H, 4.07 (dd, 1H, = 8.0 Hz, J2 = 6.0 Hz), 3.57 (dd, 1H, JT = 7.9 Hz, J2 = 7.1 Hz), 2.29-2.23 (m, 2H), 2.20-2.16 (m, 2H), 1.83-1.77 (m, 1Hj, 1.72-1.65 (m, H, 1.40 (s, 3H), 1.35 (s, 3H), 0.91- 0.86 (m, 1Hj, 0.46-0.41 (m, 2H), 0.21-0.17 (m, 2H).
Step E: Preparation of 4- (5-Cyclopropyl-pent-3-enyl) -2,2-dimethyl-1,3-dioxolane.
Hexane
To a solution of 4- (5-Cyclopropyl-pent-3-ynyl) -2,2-dimethyl- [1, 3] dioxolane (1.92 mmol, 0.40 g) in hexane (5 mL) was added quinoline (0.192 mmol, 24.8 mg), followed by an addition of 5% Pd on BaSO4 (0.384 mmol). It was stirred at room temperature under H2 atmosphere for 4 hours. The TLC showed that the reaction had been completed. Filtered through celite and concentrated. Diluted with hexane, washed with NH 4 Cl, brine and dried in MgSO 4.
Chromatography on silica gel (2-7% EtOAc / Hexane) yielded 4- (5-Cyclopropyl-pent-3-enyl) -2,2-dimethyl- [1, 3] dioxolane as a clear oil . H NMR (400 MHz, CDCl 3): 65.52-5.45 (m, 1), 5.40-5.34 (m, IH), 4.11-4.04 (m, 1H), 4.02 (dd, 1H, J1 = 8.0 Hz, J2 = 6.0 Hz), 3.51 (t, 1H, J = 7.5 Hz), 2.17-2.04 (m, 2H), 1.97 (t, 2H, J = 7.0 Hz), 1.74-1.66 (m, 1Hj, 1.58-1.49 (m, 1HJ, 1.41 (s, 3H), 1.35 (s, 3H), 0.73-0.68 (m, ^ H), 0.43-0.39 (m, 2H), 0.08-0.04 (m, 2H).
Step F: Preparation of 7-Cyclopropyl-hepta-5-ene-1,2-diol
4- (5-Cyclopropyl-pent-3-enyl) -2,2-dimethyl- [1, 3] dioxolane (0.30 g, 1.4 mmol) in 80% AcOH (5 mL) was stirred overnight at room temperature. It was concentrated and purified by chromatography on silica gel (70 ~ 90% EtOAc in hexanes) to collect 7-Cyclopropyl-hepta-5-ene-1,2-diol as a clear oil. 1 H NMR (400 MHz, CDCl 3): 65.52-5.47 (m, 1H), 5.41-5.35 (m, 1H), 3.77-3.71 (m, 1H), 3.66 (d, 1H, J = 11.2 Hz), 3.46 ( dd, 1H, J, = 11.2 Hz, J2 = 7.7 Hz), 2.19-2.10 (m, 2H), 1.97 (t, 2H, J = 7.1 Hz), 1.53-1.46 (m, 2H), 0.74-0.68 ( m, 1H), 0.44-0.39 (m, 2H), 0.08-0.04 (m, 2H).
Step G: Preparation of 2- (4-Cyclopropyl-but-2-enyl) -oxiran
To a solution of 7-cyclopropyl-hepta-5-ene-1,2-diol (1.45g, 9.28 mmol) in THF (30 mL) was added 60% sodium hydride (1.1 g, 27.84 mmol) at 0 °. C. The mixture was slowly warmed to room temperature and stirred for I hour. Trislm (3.41g, 10.2 mmol) was added in one portion at 0 ° C, followed by stirring at room temperature for 1.5 hour. The mixture was cooled with water and extracted with Et20. The organic elements were washed with brine, dried in MgSO4, filtered, and concentrated. Purification by chromatography on silica gel (7% EtOAc in hexanes gradient to 14% EtOAc in hexanes) gave 2- (4-Cyclopropyl-but-2-enyl) -oxirane as a clear oil; 1 H NMR (400 MHz, CDCl 3): 65.54-5.48 (m, 1H), 5.44-5.37 (m, 1H), 2.94-2.91 (m, 1H), 2.75 (dd, 1H, = 4.9 Hz, J2 = 4.1 Hz ), 2.48 (dd, 1H, J, = 5.0 Hz, J2 = 2.7 Hz), 2.19 (q, 2H, J = 7.3 Hz), 1.98 (t, 2H, J = 7.0 Hz), 1.62-1.56 (m, 2H), 0.75-0.66 (m, 1H), 0.44-0.39 (m, 2H), 0.09-0.05 (m, 2H).
Step H: Preparation of 6-Cyclopropylmethyl-bicichlor3.1.01hexan-2-ol.
To a solution of tetramethylpiperidine (0.624 ml, 3.7 mmol) in
MTBE (5 mL) was added n-butyllithium 2.5M hexanes (1.5 mL, 3.7 mmol) at -78 ° C. The solution was slowly warmed to about 0 ° C and added via canula to a solution of 2- (4-cyclopropyl-but-2-enyl) -oxirane (0.288 g, 1898 mmol) in MTBE (2 mL) for 10 minutes at 0 ° C. The mixture was allowed to warm to room temperature, stirred overnight, washed with 1N HCl (2X), and brine. The organics were dried over MgSO4, filtered, and concentrated to yield 6-cyclopropylmethyl-bicyclo [3.1.0] hexan-2-ol as a clear oil; HN (400 MHz, CDCl 3): d4.19 (d, 1H, J = 5.5 Hz), 2.15-2.06 (m, 1H), 1.75 (dd, 1H, JT = 11.0 Hz, J2 = 9.7 Hz), 1.69- 1.52 (m, 4H), 1.42 (dd, 1H, J, = 8.1 Hz, J2 = 6.2 Hz), 0.98-0.87 (m, 2H), 0.75-0.68 (m, 1H), 0.46-0.41 (m, 2H ), 0.03 (dd, 2H3 J1 = 9.1 Hz, J2 = 4.7 Hz).
Step I: Preparation of 6-Cyclopropylmethyl-bicyclo3.1.Ohexan-2-one.
To a solution of 6-cyclopropylmethyl-bicyclo [3.1.0] hexan-2-ol (220 mg, 1.45 mmol) in 10 mL of DCM was added sequentially Molecular sieves of 4A (200 mg), NMO (N-Methyl morpholine N) -oxide) (339 mg, 2.90 mmol), TPAP marker (25,448 mg, 0.0725 mmol). The mixture was stirred overnight at room temperature and passed through silica gel (3: 1 DCM: Et20) to yield 6-cyclopropylmethyl-bicyclo [3.1.0] hexan-2-one as a clear oil; 1 H NMR (400 MHz, CDCl 3): 52.32-2.21 (m, 2H), 2.16 (dd, 1H, Ji = 13.4 Hz, J2 = 5.4 Hz), 1.97-1.86 (m, 3H), 1.61-1.53 (m, 1H), 1.38-1.28 (m, 2H), 0.82-0.73 (m, 1H), 0.49-0.44 (m, 2H), 0.09-0.05 (m, 2H).
Step J: Preparation of ethyl ester of (±) -endo-1-cyclopropylmethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropaphapentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.2, Step D. MS m / z (ES +): 247.3 [M + H] +, 269.1 [M + Na] +; 1 H NMR (400 MHz, CDCl 3): 54.38-4.29 (m, 2H), 2.93 (dd, 1H, JT = 17.4 Hz, J2 = 6.8 Hz), 2.65 (d, 1H, J = 17.4 Hz), 2.40 (t , 1H, J = 6.9 Hz), 2.23 (dd, 1H, J, = 14.0 Hz, J2 = 6.7 Hz), 1.40-1.35 (m, 1H), 1.37 (t, 3H, J = 7.1 Hz), 1.03- 0.96 (m, 1H), 0.78-0.64 (m, 2H), 0.39- 0.32 (m, 2H), -0.02- -0.12 (m, 2H).
Step K: Preparation of (±) -encfo-1-cyclopropylmethyl acid 1 a, 3.5.5a-tetrahydro-1 H-2,3-diaza-cyclopropara-1 -pentalene-4-carboxylic acid.
The title compound was prepared in a manner similar to that described in Example 9.3. MS m / z (ES +) \ 219.3 [M + H] +; 1H NMR (400 MHz, CD3OD): 52.95 (dd, 1H, = 18.5 Hz, J2 = 6.9 Hz), 2.69 (d, 1H, J = 18.5 Hz), 2.40 (t, 1H, J = 6.9 Hz), 2.17 (dd, 1H, J, = 14.0 Hz, J2 = 6.7 Hz), 1.47-1.42 (m, 1 H), 1.15-1.08 (m, 1H), 0.86-0.79 (m, 1H), 0.76-0.68 (m , 1H), 0.44- 0.36 (m, 2H), 0.02-0.11 (m, 2H). Throughout this application several publications, patents and published patent applications have been cited. The descriptions of these publications, patents and published patent applications referred to in this application are hereby incorporated by reference in their entirety to the present disclosure. The modifications and extensions of the described inventions that are within the scope of the knowledge of the specialist are comprised within the above descriptions and the claims that follow. Although a variety of expression vectors are available to those skilled in the art, for the purpose of utilizing both endogenous and non-endogenous human GPCRs, the pCMV vector is most preferred to be used. This vector was deposited at the American Type Culture Collection (ATCC) on October 13, 1998 (10801 University Blvd., Manassas, VA 20110-2209, USA) in accordance with the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure. The DNA was tested by the ATCC and considered viable. The ATCC has assigned the following deposit number to the pCMV: ATCC # 203351.
Claims (83)
- CLAIMS 1. A compound of Formula (la)(the)or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: X is N and Z is CR7, or X is CR7 and Z is N; Ri and R4 are each independently selected from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, C1-6 alkylamino, C-6 alkylcarboxamide, C 1-6 alkylthiocarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C-6 alkylthio, C 1-6 alkylthioureyl, C 1-6 alkylureyl, amino, C 1-6 alkylamino, amino- C 1-6 alkylsulfonyl, C ^ e-alkylthioamino, carbo-C-6-alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-6 dialkylamino, C 1-6 dialkylcarboxamide, d-6 dialkylthiocarboxamide, halogen, C- 6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C-6 haloalkitio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol; R2 and R3 are each independently selected from the group consisting of H, C -6 acyl, Ci-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, C1-6 alkyl, Ci-6 alkylamino, Ci-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, Ci-6 alkylsufinyl, d-6 alkylsulfonyl, Ci-6alkitium, Ci-6alkylthioureryl, Ci. 6-alkyl, C 1-6-alkylamido, C 1-6 -alkylsulfonyl, C-6-alkylthioamido, arylsulfinyl, arylsulfonyl, arylthio, carbamimidoyl, carbo-C-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7-cycloalkyloxy, C2-6 dialkylamino, C1-6-dilaquilcarboxamide, C1-6-dialkylthiocarboxamide, Ci-6-dialkylamido, C-6-dialkylthioamido, halogen, C-6 haloalkoxy, C-6 haloalkyl, C -6 haloalkylsulfinyl , C1. 6 haloalkylsulfonyl, Ci-6 haloalkitio, heterocyclic, heterocyclic-oxy, heterocyclic sulfonyl, heterocyclic carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C4-oxy cycloalkyl, phenoxy, phenyl, sulfonamide, sulphonic acid and thiol; wherein said 0? -6 alkyl is optionally substituted by substituents selected from the group consisting of C-6 acyl, C 1-6 acyloxy, C 1-6 alkoxy, Ci- 6 alkylamino, C 1-6 alkylsufinyl, C 1-6 alkylsulfonyl, Ci- 6 6 -alkyl, amino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, Ci-6 haloalkoxy, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1 -6 haloalkylthio, hydroxyl, nitro, phenoxy and phenyl; or R2 and R3 together with the carbon to which both are bonded form a C3-6 cycloalkyl; R5 and R6 are each independently selected from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C -6 alkoxy, Ci-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, Ci-6 alkylthiocarboxamide, C2-6 alkynyl, Ci-6 alkylsulfonamide, C 1-6 alkylsufinyl, C 1-6 alkylsulfonyl, Ci-6 alkythio, d-6 alkyioureriyl, C 1-6 alkylureyl, amino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C -6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, d-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1- 6 haloalkitium, heterocyclic, hydroxyl, nitro, sulfonamide and thiol; and R7 is carbo-C-6-alkoxy, carboxy or tetrazol-5-yl.
- 2. The compound according to claim 1 wherein: R2 and R3 are each independently selected from the group consisting of H, Ci-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, C-6 alkoxy, Ci-6 alkyl, C 1-6 alkylamino, Ci-6 alkylcarboxamide, C-6 alkylthiocarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, Ci-6 alkisulfinyl, Ci-6 alkylsulfonyl, C 1-6 alkyio, C 1-6 alkyoureriyl, C 1-6 alkylureyl, amino, C-6-alkylamide, amino-C 1-6 alkylsulfonyl, C-6 alkylthioamide, arylsulfinyl, arylsulfonyl, arithium, carbamimidoyl, carbo-C 1-6 alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 dilaquilcarboxamide, C1-6 dialkylthiocarboxamide, Ci-6-dialkylamide, C1-6-d-alkylthioamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl , 6-haloalkylsulfonyl, C-6 haloalkitium, heterocyclic, heterocyclic-oxy, heterocyclic sulfonyl, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C 4-7 oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid and thiol; wherein said C-6 alkyl is optionally substituted by substituents selected from the group consisting of C 1-6 acyl, C-6 acycloxy, C 1-6 alkoxy, Ci- 6 alkylamino, C 1-6 alkylsulfinyl, d-6 alkylsulfonyl, C 1-6 alkyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 haloalkoxy, C -6 haloalkylsulfinyl, C -6 haloalkylsulfonyl, C- 6 haloalkitium, hydroxyl, nitro, phenoxy and phenyl.
- 3. The compound according to any of claims 1 or 2, provided that and R4 are in cis position with respect to each other.
- 4. The compound according to any of claims 1 to 3, wherein X is N; Z is CR; and R7 is carbo-C !. 6-alkoxy or carboxy.
- 5. The compound according to any of claims 1 to 3, wherein X is N; Z is CR7; and R7 is carboxy.
- 6. The compound according to any of claims 1 to 3, wherein X is N; Z is CR7; and R7 is tetrazol-5-yl.
- 7. The compound according to any of claims 1 to 3, wherein X is CR; R7 is carbo-C-6-alkoxy or carboxy; and Z is N.
- 8. The compound according to any of claims 1 to 3, wherein X is CR7; R7 is carboxy; and Z is N.
- The compound according to any of claims 1 to 3, wherein X is CR7; R7 is tetrazol-5-yl; and Z is N.
- 10. The compound according to any of claims 1 to 9, wherein R, is H or halogen.
- 11. The compound according to any one of claims 1 to 9, wherein it is H.
- 12. The compound according to any of claims 1 to 11, wherein R4 is H or halogen.
- 13. The compound according to any of claims 1 to 11, wherein R4 is H.
- 14. The compound according to any of claims 1 to 9, wherein R and R4 are both H.
- 15. The compound of according to any of claims 1 to 14, wherein R5 is H or halogen.
- 16. The compound according to any of claims 1 to 14, wherein R5 is H.
- 17. The compound according to any of claims 1 to 16, wherein R6 is H or halogen.
- 18. The compound according to any of claims 1 to 16, wherein R6 is H.
- 19. The compound according to any of claims 1 to 14, wherein R5 and R6 are both H.
- 20. The compound of according to any of claims 1 to 9, wherein R- ?, R4, R5 and R6 are each H.
- 21. The compound according to any of claims 1 to 20, wherein R2 and R3 are each selected independently of the group consisting of H, C 1-6 alkyl and halogen; wherein said C 1-6 alkyl is optionally substituted with substituents selected from the group consisting of C-6 acyloxy, Ci-6 alkoxy, C 1-6 alkylamino, Ci-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkyio, amino, C 3 -7-cycloalkyloxy, C2-6 dialkylamino, C-6 haloalkoxy, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkitio, hydroxyl, phenoxy and phenyl.
- 22. The compound according to any of claims 1 to 20, wherein R2 is H or C1-6 alkyl; and R 3 is H, C-6 alkyl or halogen, wherein said d-6 alkyl is optionally substituted with substituents selected from the group consisting of Ci-6 acyloxy, Ci-6 alkoxy C 1-6 alkylamino, C 1-6 alkisulfinyl, C 1 - 6 alkylsulfonyl, C -6 alkyio, amino, C3-7 cycloalkyloxy, C2-6 dialkylamino, d-6 haloalkoxy, C1-6 haloalkylsulfinyl, Ci-6 haloalkylsulfonyl, C -6 haloalkitio, hydroxyl, phenoxy and phenyl.
- 23. The compound according to any of claims 1 to 20, wherein R2 is H, or d-6 alkyl; and R3 is H, C2-6 alkenyl, C -6 alkyl, C3-7 cycloalkyl, halogen or phenyl; wherein said d-6 alkyl is optionally substituted with substituents selected from the group consisting of d-6 alkoxy, C 1-6 alkylthio, hydroxyl, phenoxy and phenyl; or R2 and R3 together with the carbon to which both are bound form a cyclopropyl, cyclopentyl or cyclohexyl group.
- 24. The compound according to any of claims 1 to 20, wherein R2 is H or C1-6 alkyl, and R3 is H, C2-6 alkenyl, d-6 alkyl, halogen or phenyl; wherein said d-6 alkyl is optionally substituted with substituents selected from the group consisting of C 1-6 alkoxy, hydroxyl, phenoxy and phenyl.
- 25. The compound according to any of claims 1 to 20, wherein R2 is H or CH3; and R3 is H, CH3 or benzyl.
- 26. The compound according to any of claims 1 to 20, wherein R2 is H or CH3; and R3 is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl, phenoxymethyl.
- 27. The compound according to any of claims 1 to 20, wherein R2 is H or CH3; and R3 is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl, phenoxymethyl, methylsulfanimethyl, ethoxymethyl, cyclopropyl, 1-but-2-enyl , or allyl; or R2 and R3 together with the carbon to which both are bonded form a cyclopropyl, cyclopentyl or cyclohexyl group.
- 28. The compound according to any of claims 1 to 3, wherein: X is N, Z is CR7, wherein R7 is carboxyl, -C02Et or tetrazol-5-yl; or X is CR7, where R7 is carboxyl, -C02Et or tetrazolyl, and Z is N; R R4, R5 and R6 are each H; R2, is H or CH3; and R3 is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
- 29. The compound according to any one of claims 1 to 3, wherein: X is N, Z is CR7, wherein R7 is carboxyl, -C02Et or tetrazol-5-yl; R- \, R4l R5 and R6 are each H; R2, is H or CH3; and R3 is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof. 30. The compound according to any of claims 1 to 3, wherein: X is N, Z is CR7. wherein R7 is carboxyl, or X is CR7, R7 is carboxyl or tetrazol-5-yl, and Z is N; R ,, R4) R5 and R6 are each H; R2 is H or CH3; and R3 is H, CH3 or benzyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof. 31. The compound according to any of claims 1 to 3, having the structure:
- 25
- or a pharmaceutically acceptable salt, solvate or hydrate thereof. 32. The compound according to any of claims 1 to 3, having the structure:
- or a pharmaceutically acceptable salt, solvate or hydrate smos.
- 33. The compound according to any one of claims 1 to 3, selected from the group consisting of: 3b, 4,4a, 5-Tetrahydro-2H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole- 3-carboxylic; 1 a, 3,5,5a-Tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; and 4- (2H-Tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
- 34. The compound according to claim 33, wherein the stereochemistry for the two carbons assigned as 3b and 4a, or 1a and 5a are both R.
- 35. The compound according to any of claims 1 to 3, selected from group consisting of: 1-Benzyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1, 1-Dimethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1, 1-Dimethyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; and 1-Benzyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
- 36. The compound according to any of claims 1 to 3, selected from the group consisting of: 1-methyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic; 1-lsobutyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Butyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Pentyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; acid-Propyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cycle p clothing [a] pen tale - 4-carboxy Mico; 1-Methoxymethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Ethyl-1a, 3r5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Benzyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Ethyl ester 1-Benzyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Ethyl 1,1-dimethyl-1-a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ester; Ethyl 1-phenyl-1-a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ester; 1-Phenyl-1a, 3,5,5a-tetrahydro-1H-2,3-diazacyclopropa [a] pentalene-4-carboxylic acid; Ethyl ester of 1-Ethyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Ethyl ester of 1-methyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Ethyl ester of 1 -Pentyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-lsopropyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Ethyl ester of 1-vinyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Vinyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Ethyl 1-ethyl-a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ester; Ethyl 1-methoxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ester; 1-Hydroxymethyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid ethyl ester; and 1-Hydroxymethyl-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
- 37. The compound according to any of claims 1 to 3, selected from the group consisting of: 1 -M eti I its lf indigo metí 1-1 a, 3,5,5a-tetrahidro-1 H-2 , 3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Ethoxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Cyclopropyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Spirocyclopropyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; (E) -1-Propene 1-1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; (Z) -1-Propenyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; 1-Phenoxymethyl-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; Spiro acid [1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-1,1'-cyclopentane] -4-carboxylic acid; Spiro acid [1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-1,1'-cyclohexane] -4-carboxylic acid; 1-Al i 1-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; and 4-Methyl-3b, 4,4a, 5-tetrahydro-2H-cyclopropa [3,4] cyclopenta [1, 2] pyrazole-3-carboxylic acid; 1-Cyclopropyl methyl 1-1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-4-carboxylic acid; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
- 38. The compound according to any one of Claims 1 to 3, selected from the group consisting of: 1- ethyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro- 1 H-2,3-diaza cyclopropa [a] pentalene; 1-Ethyl-4- (2H-tetrazol-5-yl) -1 a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; 1-Propyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diazacyclopropa [a] pentalene; 1-lsobutyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; 1-Phenyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; 1-Benzyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diazacyclopropa [a] pentalene; 1-Pentyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; 1-Butyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; 1-lsopropyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; 1-Phenoxymethyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; 4- (2H-tetrazol-5-yl) -1-vinyl-1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene;1-Methoxymethyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; and [4- (2H-Tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-1-yl] -methanol; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
- 39. The compound according to any of claims 1 to 3, selected from the group consisting of: 1-Cyclopropyl-4- (2H-tetrazol-5-yl) -a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; 1-Spray it with pro-pil-4- (2H-tetrazol-5-yl) -1 a, 3,5, 5a-tetrah id ro-1 H-2,3-diaza-cyclopropa [a] pentalene; ('E -1-Propenyl-4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa [a] pentalene; CZ-1-Propenyl- 4- (2H-tetrazol-5-yl) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene; 5- (Spiro- [1 a, 3,5, 5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-, 1'-cyclopentane] -4-yl) -1 H-tetrazole; 5- (Spiro- [1a, 3,5,5a- tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene-1, 1 '-hexane] -4-yl) -1 H-tetrazole, and 1-Allyl-4- (2H-tetrazole-5 il) -1a, 3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa [a] pentalene, or a pharmaceutically acceptable salt, solvate or hydrate thereof 40.
- The compound according to any of claims 35 to 39, wherein the stereochemistry for the carbon assigned as 1 a is R and the stereochemistry for the carbon assigned as 5a is S.
- The compound according to any of claims 31 to 40, wherein the stereochemistry for the priority group attached to the carbon assigned as 1 is endo
- 42. The compound according to any of claims 31 to 40, wherein the stereochemistry for the priority group attached to the carbon assigned as 1 is exo.
- 43. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 44. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 45. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 46. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 47. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 48. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 49. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 50. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 51 A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 52. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 53. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 54. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 55. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 56. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates d thereof.
- 58. A compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, hydrates and solvates thereof.
- 59. A pharmaceutical composition comprising a compound according to any of claims 1 to 58, in combination with a pharmaceutically acceptable carrier.
- 60. A pharmaceutical composition according to claim 59 further comprising an agent selected from the group consisting of a-glucosidase inhibitor, aldose reductase inhibitor, HM G-CoA reductase inhibitor, biguanide, synthesis inhibitor of squalene, fibrate, LDL catabolism enhancer, angiotensin-converting enzyme inhibitor, insulin secretion enhancer, thiazolidinedione and DP receptor antagonist.
- 61 A method for the treatment of a disorder related to metabolism comprising the administration to an individual in need of such treatment of a therapeutically effective amount of a compound according to any of claims 1 to 58 or a pharmaceutical composition in accordance with claim 59.
- 62. A method for the treatment of a disorder related to metabolism comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any of claims 1 to 58 and an antagonist. of the DP receiver.
- 63. The method according to claim 62, wherein said DP receptor antagonist is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate or hydrate thereof.
- 64. A method of modulating an RUP25 receptor comprising contacting said receptor with a compound according to any of claims 1 to 58.
- 65. A modulation method of a RU P25 receptor for the treatment of an individual in need of that. modulation comprising contacting said receptor with a therapeutically effective amount of a compound according to any of claims 1 to 58.
- 66. The method according to claim 64 or 65, wherein said compound is a combatant.
- 67. The method according to claim 66, wherein said combatant is a partial combatant.
- 68. A method for the treatment of atherosclerosis in a human patient in need of such treatment comprising the administration to said patient of a compound according to any of claims 1 to 58 in an amount that is effective to treat atherosclerosis.
- 69. A method for the treatment of dyslipidemia in a human patient in need of such treatment comprising administering to said patient a compound according to any of claims 1 to 58 in an amount that is effective to treat dyslipidemia .
- 70. A method of raising HDL in an individual comprising administering to said individual a therapeutically effective amount of a compound according to any of claims 1 to 58.
- 71. The method according to any of claims 61 to 63 and 65 to 70, wherein said individual is a mammal.
- 72. The method according to claim 71, wherein said mammal is a human.
- 73. A compound according to any of claims 1 to 58, for use in a method of treating the human or animal body by therapy.
- 74. A compound according to any of claims 1 to 58, for use in a method of treating a disorder related to the metabolism of the human or animal body by therapy.
- 75. A compound according to any of claims 1 to 58, to be used in a method of treating a disorder related to the metabolism of the human or animal body by therapy where said disorder related to metabolism is selected from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity , glucose intolerance, atheromatous disease, hypertension, stroke, Syndrome X, heart disease and type 2 diabetes.
- 76. A compound according to any of claims 1 to 58, to be used in a method of treatment of a disorder related to the metabolism of the human or animal body by therapy where said disorder related to metabolism is selected from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance and type 2 diabetes.
- 77. A compound according to any of Claims 1 to 58, to be used in a method of treating atherosclerosis of the human or animal body through therapy.
- 78. A compound according to any one of claims 1 to 58, for use in the H DL elevation method of the human or animal body by therapy.
- 79. Use of a compound according to one of claims 1 to 58, for the manufacture of a medicament for use in the treatment of a disorder related to metabolism.
- 80. Use of a compound according to one of claims 1 to 58, for the manufacture of a medicament for use in the treatment of a disorder related to the metabolism selected from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity, glucose intolerance, atheromatous disease, hypertension, stroke, Syndrome X, heart disease and type 2 diabetes.
- 81. Use of a compound according to one of claims 1 to 58, for the manufacture of a medicament for use in the treatment of atherosclerosis.
- 82. Use of a compound according to one of claims 1 to 58, for the manufacture of a medicament to be used in the treatment in raising HDL in an individual.
- 83. A method of producing a pharmaceutical composition comprising the mixture of a compound according to any of claims 1 to 58, and a pharmaceutically acceptable carrier.RE SUM IN The present invention relates to certain fused pyrazole derivatives of Formula (Ia), and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example as combatants for the R UP25 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods for using the compounds and compositions of the invention in the treatment of disorders related to metabolism, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, S syndrome X and the like. Additionally, the present invention is also provided for the use of the compounds of the invention in combination with other active agents such as those belonging to the class of α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG- inhibitors. CoA reductase, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers, DP receptor antagonists and the like.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/638,668 | 2004-12-23 | ||
| US60/676,521 | 2005-04-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2007007578A true MX2007007578A (en) | 2008-10-03 |
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