NZ711002B2 - New octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors - Google Patents
New octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors Download PDFInfo
- Publication number
- NZ711002B2 NZ711002B2 NZ711002A NZ71100214A NZ711002B2 NZ 711002 B2 NZ711002 B2 NZ 711002B2 NZ 711002 A NZ711002 A NZ 711002A NZ 71100214 A NZ71100214 A NZ 71100214A NZ 711002 B2 NZ711002 B2 NZ 711002B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- substituted
- pyrrolo
- hexahydro
- pyrrole
- trifluoromethoxy
- Prior art date
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- 101700057276 ENPP2 Proteins 0.000 title abstract description 33
- 102100016621 ENPP2 Human genes 0.000 title abstract description 33
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 230000002401 inhibitory effect Effects 0.000 title abstract description 7
- QFCMBRXRVQRSSF-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole Chemical class C1NCC2CNCC21 QFCMBRXRVQRSSF-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- -1 hydroxyhaloalkyl Chemical group 0.000 claims description 286
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- 239000002253 acid Substances 0.000 claims description 47
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 239000011780 sodium chloride Substances 0.000 claims description 36
- 201000010099 disease Diseases 0.000 claims description 34
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000004076 pyridyl group Chemical group 0.000 claims description 28
- 230000000268 renotropic Effects 0.000 claims description 24
- 125000000173 4-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC(F)(F)F)C([H])([H])* 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 230000001684 chronic Effects 0.000 claims description 23
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- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 21
- 125000001188 haloalkyl group Chemical group 0.000 claims description 21
- 230000000069 prophylaxis Effects 0.000 claims description 19
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- 125000001544 thienyl group Chemical group 0.000 claims description 15
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- 125000005938 2,3-dihydro-1H-isoindolyl group Chemical group 0.000 claims description 6
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 6
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- IQCOXMRXONRSKN-IYBDPMFKSA-N (3,5-dichlorophenyl)methyl (3aS,6aR)-2-(4-sulfamoylbenzoyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C1=CC(S(=O)(=O)N)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=C(Cl)C=C(Cl)C=3)C[C@H]2C1 IQCOXMRXONRSKN-IYBDPMFKSA-N 0.000 claims description 5
- YWDOEECQYOCCFX-OKILXGFUSA-N (3,5-dichlorophenyl)methyl (3aS,6aR)-2-(5-aminopyridine-2-carbonyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound N1=CC(N)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=C(Cl)C=C(Cl)C=3)C[C@H]2C1 YWDOEECQYOCCFX-OKILXGFUSA-N 0.000 claims description 5
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- NUEYFOCINLFWLI-HDICACEKSA-N (3,5-dichlorophenyl)methyl (3aS,6aR)-2-(4-methoxycarbonylbenzoyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C1=CC(C(=O)OC)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=C(Cl)C=C(Cl)C=3)C[C@H]2C1 NUEYFOCINLFWLI-HDICACEKSA-N 0.000 claims description 4
- RYUDEAWKWHGLOU-IYBDPMFKSA-N (3,5-dichlorophenyl)methyl (3aS,6aR)-2-(5-acetamidopyridine-2-carbonyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound N1=CC(NC(=O)C)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=C(Cl)C=C(Cl)C=3)C[C@H]2C1 RYUDEAWKWHGLOU-IYBDPMFKSA-N 0.000 claims description 4
- RTBWVTYKABIUSI-CALCHBBNSA-N (3,5-dichlorophenyl)methyl (3aS,6aR)-2-[4-(methylsulfamoyl)benzoyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C1=CC(S(=O)(=O)NC)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=C(Cl)C=C(Cl)C=3)C[C@H]2C1 RTBWVTYKABIUSI-CALCHBBNSA-N 0.000 claims description 4
- TVUCMAULYAOYAB-GASCZTMLSA-N (3,5-dichlorophenyl)methyl (3aS,6aR)-5-(4-sulfamoylphenyl)sulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate Chemical compound C1=CC(S(=O)(=O)N)=CC=C1S(=O)(=O)N1C[C@H]2CN(C(=O)OCC=3C=C(Cl)C=C(Cl)C=3)C[C@H]2C1 TVUCMAULYAOYAB-GASCZTMLSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- GTGZMJOXBTUBFD-IYBDPMFKSA-N (3,5-dichlorophenyl)methyl (3aS,6aR)-2-(4-hydroxybenzoyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C1=CC(O)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=C(Cl)C=C(Cl)C=3)C[C@H]2C1 GTGZMJOXBTUBFD-IYBDPMFKSA-N 0.000 claims description 3
- JFZGBPCPTWEGKG-OKILXGFUSA-N (3,5-dichlorophenyl)methyl (3aS,6aR)-2-(5-hydroxypyridine-2-carbonyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound N1=CC(O)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=C(Cl)C=C(Cl)C=3)C[C@H]2C1 JFZGBPCPTWEGKG-OKILXGFUSA-N 0.000 claims description 3
- TXGFGCRDMPPEGX-BETUJISGSA-N (3,5-dichlorophenyl)methyl (3aS,6aR)-2-(5-sulfamoylthiophene-2-carbonyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound S1C(S(=O)(=O)N)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=C(Cl)C=C(Cl)C=3)C[C@H]2C1 TXGFGCRDMPPEGX-BETUJISGSA-N 0.000 claims description 3
- 125000004702 alkoxy alkyl carbonyl group Chemical group 0.000 claims description 3
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
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- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007374 clinical diagnostic method Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 230000001143 conditioned Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 201000008739 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004410 cyclooctyloxy group Chemical group C1(CCCCCCC1)O* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000856 decreased creatinine clearance Toxicity 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 229940042397 direct acting antivirals Cyclic amines Drugs 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000003511 endothelial Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000006232 ethoxy propyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000003394 haemopoietic Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000002140 halogenating Effects 0.000 description 1
- 230000002440 hepatic Effects 0.000 description 1
- MVFGXYPEQHIKIX-UHFFFAOYSA-M heptane;acetate Chemical compound CC([O-])=O.CCCCCCC MVFGXYPEQHIKIX-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000000642 iatrogenic Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesions Effects 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000000873 masking Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000001394 metastastic Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 1
- XNCXTSXLHGDKTP-UHFFFAOYSA-N methyl 2-amino-3-cyanobenzoate Chemical compound COC(=O)C1=CC=CC(C#N)=C1N XNCXTSXLHGDKTP-UHFFFAOYSA-N 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000002107 myocardial Effects 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 201000009925 nephrosclerosis Diseases 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001991 pathophysiological Effects 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 200000000002 platelet activation Diseases 0.000 description 1
- 229920002496 poly(ether sulfone) Polymers 0.000 description 1
- 229920003208 poly(ethylene sulfide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (NE)-N-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- NKFLEFWUYAUDJV-UHFFFAOYSA-N pyridine-3-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CN=C1 NKFLEFWUYAUDJV-UHFFFAOYSA-N 0.000 description 1
- 125000006513 pyridinyl methyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000033458 reproduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 201000010001 silicosis Diseases 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002522 swelling Effects 0.000 description 1
- 108060007983 swi1 Proteins 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HEFYZXCUGNIOCW-IUCAKERBSA-N tert-butyl (3S,4S)-3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO)C1 HEFYZXCUGNIOCW-IUCAKERBSA-N 0.000 description 1
- FYUVLZRRIRGSTE-RKDXNWHRSA-N tert-butyl (3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C1NC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21 FYUVLZRRIRGSTE-RKDXNWHRSA-N 0.000 description 1
- YPOYYGCFQBSOOE-KBPBESRZSA-N tert-butyl (3aS,6aS)-2-(4-sulfamoylbenzoyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C([C@H]1CN(C[C@@H]1C1)C(=O)OC(C)(C)C)N1C(=O)C1=CC=C(S(N)(=O)=O)C=C1 YPOYYGCFQBSOOE-KBPBESRZSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001732 thrombotic Effects 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 201000006397 traumatic glaucoma Diseases 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 201000011528 vascular disease Diseases 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention provides novel compounds as autotaxin inhibitors having the general formula (I) wherein R1, Y, A, W, R2, m, n, p and q are as described herein, compositions including the compounds and methods of using the compounds.
Description
NEW OCTAHYDRO-PYRROLO[3,4-c]-PYRROLE DERIVATIVES AND ANALOGS
THEREOF AS AUTOTAXIN INHIBITORS
The present invention relates to organic compounds useful for therapy or prophylaxis in a
mammal, and in particular to autotaxin (ATX) inhibitors which are inhibitors of lysophosphatidic
acid (LPA) production and thus modulators of LPA levels and associated signaling, for the
treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions,
conditions of the nervous system, conditions of the respiratory system, vascular and
cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions,
cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
The present invention provides novel compounds of formula (I)
( ) ( )
1 ( ) ( )
wherein
R is substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted
phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted
phenylalkenyl, substituted phenylalkynyl, substituted naphthyl, substituted
naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted
pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted
pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted
thiophenylalkenyl, substituted thiophenylalkynyl, substituted indolyl, substituted
quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindolyl, substituted
1H-indolyl or substituted benzofuranyl wherein substituted cycloalkyl,
substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted
phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted
phenylalkynyl, substituted naphthyl, substituted naphthylalkyl, substituted
naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted
pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted
thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted
thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl,
substituted 2,3-dihydro-1H-isoindolyl, substituted 1H-indolyl and substituted
7 8 9
benzofuranyl are substituted with R , R and R ;
R is substituted phenyl, substituted pyridinyl, substituted pyrrolyl, oxodihydropyridinyl
or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl, substituted
11 12
pyrrolyl and substituted thiophenyl are substituted with R , R and R ;
NN NN
Y is -OC(O)-, -NR C(O)-, -C(O)-, -S(O) -, or ;
A is -N- or CH-;
6 3 4
W is -O-, -S-, -NR -, -C(O)-, -S(O) -, or -CR R -;
R and R are independently selected from H, halogen, alkyl and cycloalkyl;
R and R are independently selected from H, alkyl and cycloalkyl;
7 8 9
R , R and R are independently selected from H, alkyl, hydroxyalkyl, haloalkyl,
hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy,
cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy,
alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl,
pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl,
haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl,
cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted
aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted
aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the
nitrogen atom with one to two substituents independently selected from H, alkyl,
cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are
optionally substituted with one to three substituents independently selected from alkyl,
7 8 9
halogen, haloalkyl, alkoxy and haloalkoxy, wherein at least one of R , R and R is not
R is aminosulfonyl, alkoxycarbonyl, alkylcarbonylamino, alkylsulfonylamino, substituted
amino, carboxy, cyano, hydroxy or tetrazolyl, wherein substituted amino is substituted
on the nitrogen atom with one to two substituents independently selected from H,
alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;
11 12
R and R are independently selected from H, alkyl, cycloalkyl, alkoxy, halogen and
haloalkyl;
m, n, p and q are independently selected from 1 or 2;
or pharmaceutically acceptable salts.
Described are compounds of formula (I’)
( ) ( )
1 ( ) ( )
(I’)
wherein
R is substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted
phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted
phenylalkenyl, substituted phenylalkynyl, substituted naphthyl, substituted
naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted
pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted
pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted
thiophenylalkenyl, substituted thiophenylalkynyl, substituted indolyl, substituted
quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindolyl, substituted
1H-indolyl or substituted benzofuranyl wherein substituted cycloalkyl,
substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted
phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted
phenylalkynyl, substituted naphthyl, substituted naphthylalkyl, substituted
naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted
pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted
thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted
thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl,
substituted 2,3-dihydro-1H-isoindolyl, substituted 1H-indolyl and substituted
7 8 9
benzofuranyl are substituted with R , R and R ;
R is substituted phenyl, substituted pyridinyl, substituted pyrrolyl, oxodihydropyridinyl
or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl, substituted
11 12
pyrrolyl and substituted thiophenyl are substituted with R , R and R ;
NN NN
C(O)-, -C(O)-, -S(O) -, or ;
Y is -OC(O)-, -NR 2
A is -N- or CH-;
6 3 4
W is -O-, -S-, -NR -, -C(O)-, -S(O) -, or -CR R -;
R and R are independently selected from H, halogen, alkyl and cycloalkyl;
R and R are independently selected from H, alkyl and cycloalkyl;
7 8 9
R , R and R are independently selected from H, alkyl, hydroxyalkyl, haloalkyl,
hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy,
cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy,
alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl,
pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl,
haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl,
cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted
aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted
aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the
nitrogen atom with one to two substituents independently selected from H, alkyl,
cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are
optionally substituted with one to three substituents independently selected from alkyl,
7 8 9
halogen, haloalkyl, alkoxy and haloalkoxy, wherein at least one of R , R and R is not
H;
R is substituted aminosulfonyl, alkoxycarbonyl, alkylcarbonylamino, alkylsulfonylamino,
substituted amino, carboxy, cyano, hydroxy or tetrazolyl, wherein substituted amino is
substituted on the nitrogen atom with one to two substituents independently selected
from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;
11 12
R and R are independently selected from H, alkyl, cycloalkyl, alkoxy, halogen and
haloalkyl;
m, n, p and q are independently selected from 1 or 2;
or pharmaceutically acceptable salts.
Autotaxin (ATX) is a secreted enzyme also called ectonucleotide pyrophosphatase /
phosphodiesterase 2 or lysophospholipase D that is important for converting lysophosphatidyl
choline (LPC) to the bioactive signaling molecule lysophosphatidic acid (LPA). It has been
shown that plasma LPA levels are well correlated with ATX activity and hence ATX is believed
to be an important source of extracellular LPA. Early experiments with a prototype ATX
inhibitor have shown that such a compound is able to inhibit the LPA synthesizing activity in
mouse plasma. Work conducted in the 1970s and early 1980s has demonstrated that LPA can
elicit a wide range of cellular responses; including smooth muscle cell contraction, platelet
activation, cell proliferation, chemotaxis and others. LPA mediates its effects via signaling to
several G protein coupled receptors (GPCRs); the first members were originally denoted Edg
(endothelial cell differentiation gene) receptors or ventricular zone gene-1(vzg-1) but are now
called LPA receptors. The prototypic group now consists of LPA1/Edg-2/VZG-1, LPA2/Edg-4,
and LPA3/Edg-7. Recently, three additional LPA receptors LPA4/p2y9/GPR23, LPA5/GPR92
and LPA6/p2Y5 have been described that are more closely related to nucleotide-selective
purinergic receptors than to the prototypic LPA1-3 receptors. The ATX-LPA signaling axis is
involved in a large range of physiological and pathophysiological functions, including, for
example, nervous system function, vascular development, cardiovascular physiology,
reproduction, immune system function, chronic inflammation, tumor metastasis and progression,
organ fibrosis as well as obesity and/or other metabolic diseases such as diabetes mellitus.
Therefore, increased activity of ATX and/or increased levels of LPA, altered LPA receptor
expression and altered responses to LPA may contribute to the initiation, progression and/or
outcome of a number of different pathophysiological conditions related to the ATX/LPA axis.
In accordance with the invention, the compounds of formula (I) or their pharmaceutically
acceptable salts and esters can be used for the treatment or prophylaxis of diseases, disorders or
conditions that are associated with the activity of autotaxin and/or the biological activity of
lysophosphatidic acid (LPA).
The compounds of formula (I) or their pharmaceutically acceptable salts and esters herein
inhibit autotaxin activity and therefore inhibit LPA production and modulate LPA levels and
associated signaling. Autotaxin inhibitors described herein are useful as agents for the treatment
or prevention of diseases or conditions in which ATX activity and/or LPA signaling participates,
is involved in the etiology or pathology of the disease, or is otherwise associated with at least
one symptom of the disease. The ATX-LPA axis has been implicated for example in
angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor
metastasis and progression, ocular conditions, metabolic conditions such as obesity and/or
diabetes mellitus, conditions such as cholestatic or other forms of chronic pruritus as well as
acute and chronic organ transplant rejection.
Objects of the present invention are the compounds of formula (I) and their
aforementioned salts and esters and their use as therapeutically active substances, a process for
the manufacture of the said compounds, intermediates, pharmaceutical compositions,
medicaments containing the said compounds, their pharmaceutically acceptable salts or esters,
the use of the said compounds, salts or esters for the treatment or prophylaxis of disorders or
conditions that are associated with the activity of ATX and/or the biological activity of
lysophosphatidic acid (LPA), particularly in the treatment or prophylaxis of renal conditions,
liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the
respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular
conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and-
chronic organ transplant rejection, and the use of the said compounds, salts or esters for the
production of medicaments for the treatment or prophylaxis of renal conditions, liver conditions,
inflammatory conditions, conditions of the nervous system, conditions of the respiratory system,
vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic
conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant
rejection.
The term “alkenyl” denotes a monovalent linear or branched hydrocarbon group of 2 to 7
carbon atoms with at least one double bond. In particular embodiments, alkenyl has 2 to 4 carbon
atoms with at least one double bond. Examples of alkenyl include ethenyl, propenyl, propenyl,
isopropenyl, n-butenyl and iso-butenyl. Particular alkenyl group is ethenyl.
The term “alkoxy” denotes a group of the formula -O-R’, wherein R’ is an alkyl group.
Examples of alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy
and tert-butoxy. Particular alkoxy group include isopropoxy.
The term “alkoxyalkoxy” denotes an alkoxy group wherein at least one of the hydrogen
atoms of the alkoxy group has been replaced by another alkoxy group. Examples of
alkoxyalkoxy group include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy,
methoxypropoxy and ethoxypropoxy. Particular alkoxyalkoxy groups include methoxymethoxy
and methoxyethoxy.
The term “alkoxyalkoxyalkyl” denotes an alkyl group wherein at least one of the
hydrogen atoms of the alkyl group has been replaced by an alkoxyalkoxy group. Examples of
alkoxyalkoxyalkyl group include methoxymethoxymethyl, ethoxymethoxymethyl,
methoxyethoxymethyl, ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl,
methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl,
methoxypropoxyethyl and ethoxypropoxyethyl.
The term “alkoxyalkyl” denotes an alkyl group wherein at least one of the hydrogen
atoms of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups
include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl,
ethoxypropyl and isopropoxymethyl. Particular alkoxyalkyl group include include
methoxymethyl, methoxyethyl and isopropoxymethyl.
The term “alkoxycarbonyl” denotes a group of the formula -C(O)-R’, wherein R’ is an
alkoxy group. Examples of alkoxycarbonyl groups include groups of the formula -C(O)-R’,
wherein R’ is methoxy or ethoxy. Particular alkoxycarbonyl group include groups of the formula
-C(O)-R’, wherein R’ is methoxy.
The term “alkoxyhaloalkyl” denotes a haloalkyl group wherein at least one of the
hydrogen atoms of the haloalkyl group has been replaced by an alkoxy group. Exemplary
alkoxyalkyl groups include methoxytrifluoroethyl, ethoxytrifluoroethyl, methoxytrifluoropropyl
and ethoxytrifluoropropyl.
The term “alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of
1 to 12 carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more
particular embodiments 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl,
isopropyl, n-butyl, iso-butyl and sec-butyl, pentyl. Particular alkyl groups include methyl, ethyl,
propyl and isopropyl. More particular alkyl group is methyl.
The term “alkylcarbonyl” denotes a group of the formula -C(O)-R’, wherein R’ is an alkyl
group. Examples of alkylcarbonyl groups include groups of the formula -C(O)-R’, wherein R’ is
methyl or ethyl. Particular alkylcarbonyl groups include groups of the formula -C(O)-R’,
wherein R’ is methyl.
The term “alkylcarbonylamino” denotes a group of the formula -NH-C(O)-R’, wherein R’
is an alkyl group. Examples of alkylcarbonylamino groups include groups of the formula -NH-
C(O)-R’, wherein R’ is methyl or ethyl. Particular a alkylcarbonylamino groups include groups
of the formula -NH-C(O)-R’, wherein R’ is methyl.
The term “alkylsulfanyl” denotes a group of the formula -S-R’, wherein R’ is an alkyl
group. Examples of alkylsulfanyl groups include groups of the formula
-S-R’, wherein R’ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Particular
alkylsulfanyl groups include group of the formula -S-R’, wherein R’ is methyl.
The term “alkylsulfinyl” denotes a group of the formula -S(O)-R’, wherein R’ is an alkyl
group. Examples of alkylsulfinyl groups include groups of the formula
-S(O)-R’, wherein R’ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
Particular alkylsulfinyl groups include group of the formula -S(O)-R’, wherein R’ is methyl.
The term “alkylsulfonyl” denotes a group of the formula -S(O) -R’, wherein R’ is an alkyl
group. Examples of alkylsulfonyl groups include groups of the formula
-S(O) -R’, wherein R’ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
Particular alkylsulfonyl groups include group of the formula -S(O) -R’, wherein R’ is methyl.
The term “alkylsulfonylamino” denotes a group of the formula -NH-S(O) -R’, wherein R’
is an alkyl group. Examples of alkylsulfonylamino groups include groups of the formula -NH-
S(O) -R’, wherein R’ is methyl or ethyl. Particular a alkylsulfonylamino groups include groups
of the formula -NH-S(O) -R’, wherein R’ is methyl.
The term “amino” denotes a -NH group.
The term “aminoalkyl” denotes an alkyl group wherein at least one of the hydrogen atoms
of the alkyl group has been replaced by an aminogroup. Examples of aminoalkyl include
aminomethyl, aminoethyl, aminomethyl-ethyl, aminopropyl, aminomethylpropyl and
aminopropyl. Particular examples are aminomethyl and haminoethyl.
The term “aminosulfonyl” denotes a -S(O) -NH group.
The term “carbonyl” denotes a -C(O)- group.
The term “carboxy” denotes a -COOH group.
The term “cyano” denotes a -C ≡N group.
The term “cycloalkoxy” denotes a group of the formula -O-R’, wherein R’ is a cycloalkyl
group. Examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy,
cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. Particular cycloalkoxy group is cyclopropoxy.
The term “cycloalkoxyalkyl” denotes an alkyl group wherein at least one of the hydrogen
atoms of the alkyl group has been replaced by a cycloalkoxy group. Examples of
cycloalkoxyalkyl groups include cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl,
cyclobutoxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxymethyl,
cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl and
cyclooctyloxyethyl.
The term “cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon
group of 3 to 10 ring carbon atoms. In particular embodiments, cycloalkyl denotes a monovalent
saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring
system consisting of two saturated carbocycles having two carbon atoms in common. Examples
for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.
Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl. Particular
monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More
particular monocyclic cycloalkyl group is cyclopropyl.
The term “cycloalkylalkoxy” denotes an alkoxy group wherein at least one of the hydrogen
atoms of the alkoxy group is replaced by a cycloalkyl group. Examples of cycloalkylalkoxy
include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy,
cycloheptylmethoxy and cyclooctylmethoxy.
The term “cycloalkylalkoxyalkyl” denotes an alkyl group wherein at least one of the
hydrogen atoms of the alkyl group is replaced by a cycloalkylalkoxy group. Examples of
cycloalkylalkoxyalkyl include cyclopropylmethoxymethyl, cyclopropylmethoxyethyl,
cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl,
cyclopentylmethoxyethyl, cyclohexylmethoxymethyl, cyclohexylmethoxyethyl,
cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl and
cyclooctylmethoxyethyl.
The term “cycloalkylalkyl” denotes an alkyl group wherein at least one of the hydrogen
atoms of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include
cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl,
cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl,
bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl,
adamentanylmethyl and adamantanylethyl. Particular examples of cycloalkylalkyl are
cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl,
bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl, adamentanylmethyl and
adamantanylethyl. Further particular examples cycloalkylalkyl are cyclohexylmethyl,
cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[2.2.2]octanylmethyl, adamentanylmethyl
and adamantanylethyl.
The term “cycloalkylcarbonyl”of the formula -C(O)-R’, wherein R’ is a cycloalkyl group.
Examples of cycloalkylcarbonyl groups include groups of the formula -C(O)-R’, wherein R’ is
cyclopropyl.
The term “cycloalkylsulfanyl” denotes a group of the formula -S-R’, wherein R’ is a
cycloalkyl group. Examples of cycloalkylsulfanyl groups include groups of the formula -S-R’,
wherein R’ is cyclopropyl.
The term “cycloalkylsulfinyl” denotes a group of the formula -S(O)-R’, wherein R’ is a
cycloalkyl group. Examples of cycloalkylsulfinyl groups include groups of the formula -S(O)-R’,
wherein R’ is cyclopropyl.
The term “cycloalkylsulfonyl” denotes a group of the formula -S(O) -R’, wherein R’ is a
cycloalkyl group. Examples of cycloalkylsulfonyl groups include groups of the formula -S(O) -
R’, wherein R’ is cyclopropyl.
The term “haloalkoxy” denotes an alkoxy group wherein at least one of the hydrogen
atoms of the alkoxy group has been replaced by the same or different halogen atoms. The term
“perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms of the alkoxy group have
been replaced by the same or different halogen atoms. Examples of haloalkoxy include
fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy,
trifluorodimethylethoxy and pentafluoroethoxy. Particular haloalkoxy group is trifluoromethoxy.
The term “haloalkyl” denotes an alkyl group wherein at least one of the hydrogen atoms of
the alkyl group has been replaced by the same or different halogen atoms. The term
“perhaloalkyl” denotes an alkyl group where all hydrogen atoms of the alkyl group have been
replaced by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl,
difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl.
Particular haloalkyl group is trifluoromethyl.
The term “haloalkylsulfanyl” denotes a group of the formula -S-R’, wherein R’ is a
haloalkyl group. Examples of haloalkylsulfanyl groups include groups of the formula -S-R’,
wherein R’ is trifluoromethyl.
The term “haloalkylsulfinyl” denotes a group of the formula -S(O)-R’, wherein R’ is a
haloalkyl group. Examples of haloalkylsulfinyl groups include groups of the formula -S(O)-R’,
wherein R’ is trifluoromethyl.
The term “haloalkylsulfonyl” denotes a group of the formula -S(O)2-R’, wherein R’ is a
haloalkyl group. Examples of haloalkylsulfonyl groups include groups of the formula -S(O) -R’,
wherein R’ is trifluoromethyl.
The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro,
bromo, or iodo. Particular halogens are chloro and fluoro.
The term “hydroxy” denotes a -OH group.
The term “hydroxyalkyl” denotes an alkyl group wherein at least one of the hydrogen
atoms of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl
include hydroxymethyl, hydroxyethyl, hydroxymethyl-ethyl, hydroxypropyl,
hydroxymethylpropyl and dihydroxypropyl. Particular examples are hydroxymethyl and
hydroxyethyl.
The term “hydroxyhaloalkyl” denotes a haloalkyl group wherein at least one of the
hydrogen atoms of the haloalkyl group has been replaced by an hydroxy group. Exemplary
hydroxyhaloalkyl groups include hydroxytrifluoroethyl and hydroxytrifluoropropyl. Particular
hydroxyhaloalkyl groups include hydroxytrifluoroethyl.
The term “naphthylalkenyl” denotes an alkenyl group wherein at least one of the hydrogen
atoms of the alkenyl group has been replaced a naphthynaphthyl. Particular naphthylalkenyl
group is naphytylethenyl.
The term “naphthylalkyl” denotes an alkyl group wherein at least one of the hydrogen
atoms of the alkyl group has been replaced a naphthyl. Particular naphthylalkyl groups are
naphthylmethyl, naphthylethyl and naphthylpropyl.
The term “naphthyloxyalkyl” denotes an alkyl group wherein at least one of the hydrogen
atoms of the alkyl group has been replaced by a naphthyloxy group. Exemplary
naphthyloxyalkyl groups include naphthyloxymethyl, naphthyloxyethyl and naphthyloxypropyl.
The term “phenoxy” denotes a group of the formula -O-R’, wherein R’ is a phenyl.
The term “phenoxyalkyl” denotes an alkyl group wherein at least one of the hydrogen
atoms of the alkyl group has been replaced by a phenoxy group. Exemplary phenoxyalkyl groups
include phenoxymethyl, phenoxyethyl and phenoxypropyl. Particular alkoxyalkyl group is
phenoxymethyl.
The term “phenylalkenyl” denotes an alkenyl group wherein at least one of the hydrogen
atoms of the alkenyl group has been replaced a phenyl. Particular phenylalkenyl group is
phenylethenyl.
The term “phenylalkyl” denotes an alkyl group wherein at least one of the hydrogen atoms
of the alkyl group has been replaced a phenyl. Particular phenylalkyl groups are benzyl,
phenethyl and phenylpropyl. More particular phenylalkyl groups are benzyl and phenethyl.
Further particular phenylalkyl group is benzyl.
The term “phenylalkynyl” denotes an alkynyl group wherein at least one of the hydrogen
atoms of the alkynyl group has been replaced a phenyl. Particular phenylalkynyl group is
phenylethynyl.
The term “phenylcyloalkyl” denotes a cycloalkyl group wherein at least one of the
hydrogen atoms of the cycloalkyl group has been replaced a phenyl. Particular phenylcycloalkyl
group is phenylcyclopropyl.
The term “pyridinylalkenyl” denotes an alkenyl group wherein at least one of the hydrogen
atoms of the alkenyl group has been replaced a pyridinyl. Particular pyridinylalkenyl group is
pyridinylethenyl.
The term “pyridinylalkyl” denotes an alkyl group wherein at least one of the hydrogen
atoms of the alkyl group has been replaced a pyridinyl. Particular pyridinylalkyl groups are
pyridinylmethyl, pyridinylethyl and pyridinylpropyl. More particular pyridinylalkyl group is
pyridinylethyl.
The term “pyridinylalkynyl” denotes an alkynyl group wherein at least one of the hydrogen
atoms of the alkynyl group has been replaced a pyridinyl. Particular pyridinylalkynyl group is
pyridinylethynyl.
The term “thiophenylalkenyl” denotes an alkenyl group wherein at least one of the
hydrogen atoms of the alkenyl group has been replaced a thiophenyl. Particular
thiophenylalkenyl group is thiophenylethenyl.
The term “thiophenylalkyl” denotes an alkyl group wherein at least one of the hydrogen
atoms of the alkyl group has been replaced a thiophenyl. Particular thiophenylalkyl groups are
thiophenylmethyl, thiophenylethyl and thiophenylpropyl. More particular thiophenylalkyl group
is thiophenylmethyl.
The term “thiophenylalkynyl” denotes an alkynyl group wherein at least one of the
hydrogen atoms of the alkynyl group has been replaced a thiophenyl. Particular
thiophenylalkynyl group is thiophenylethynyl.
The term "pharmaceutically acceptable salts" refers to those salts which retain the
biological effectiveness and properties of the free bases or free acids, which are not biologically
or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular
hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic
acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-
toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition, these salts may be
prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from
an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium,
calcium, magnesium salts and the like. Salts derived from organic bases include, but are not
limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally
occurring substituted amines, cyclic amines and basic ion exchange resins, such as
isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine,
lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular
pharmaceutically acceptable salts of compounds of formula (I) are the sodium and potassium
salts.
"Pharmaceutically acceptable esters" means that compounds of general formula (I) may be
derivatised at functional groups to provide derivatives which are capable of conversion back to
the parent compounds in vivo. Examples of such compounds include physiologically acceptable
and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl
esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of
the compounds of general formula (I), similar to the metabolically labile esters, which are
capable of producing the parent compounds of general formula (I) in vivo, are within the scope
of this invention.
The term “protecting group” (PG) denotes a group which selectively blocks a reactive site
in a multifunctional compound such that a chemical reaction can be carried out selectively at
another unprotected reactive site in the meaning conventionally associated with it in synthetic
chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting
groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups.
Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz),
fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Further particular protecting groups
are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More
particular protecting group is the tert-butoxycarbonyl (Boc) group.
The abbreviation uM means microMolar and is equivalent to the symbol µM.
The abbreviation uL means microliter and is equivalent to the symbol µL.
The abbreviation ug means microgram and is equivalent to the symbol µg.
The compounds of formula (I) can contain several asymmetric centers and can be present
in the form of optically pure enantiomers, mixtures of enantiomers such as, for example,
racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric
racemates or mixtures of diastereoisomeric racemates.
According to the Cahn-Ingold-Prelog Convention the asymmetric carbon atom can be of
the "R" or "S" configuration.
Also an embodiment of the present invention are compounds according to formula (I) as
described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds
according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more
particularly compounds according to formula (I) as described herein.
A further embodiment of the present invention are compounds according to formula (I) as
described herein, wherein R is substituted phenyl, substituted phenylalkyl, substituted
phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl, or substituted
isoquinolyl, wherein substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl,
substituted naphthyl, substituted indolyl, substituted quinolyl and substituted isoquinolyl are
7 8 9
substituted with R , R and R .
A particular embodiment of the present invention are compounds according to formula (I)
1 7 8 9
as described herein, wherein R is phenylalkyl substituted with R , R and R .
In a further embodiment of the present invention are compounds according to formula (I)
as described herein, wherein R is 3,5-dichlorobenzyl, 4-trifluoromethoxybenzyl or 4-
trifluoromethoxyphenylethyl.
The present invention also relates to compounds according to formula (I) as described
herein, wherein R is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and
11 12
substituted pyridinyl are substituted with R , R and R .
A further particular embodiment of the present invention are compounds according to
2 10 11 12
formula (I) as described herein, wherein R is phenyl substituted phenyl with R , R and R .
Another further embodiment of the present invention are compounds according to formula
(I) as described herein, wherein R is 4-aminosulfonylphenyl, 3-fluoroaminosulfonylphenyl,
3-aminosulfonylpyridinyl or 2-aminosulfonylpyridinyl.
Another embodiment of the present invention are compounds according to formula (I) as
described herein, wherein Y is -OC(O)- or -C(O)-.
A more particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein A is -N-.
Also an embodiment of the present invention are compounds according to formula (I) as
described herein, wherein W is -C(O)- or -S(O) -.
Another embodiment of the present invention are compounds according to formula (I) as
described herein, wherein W is -C(O)-.
Another embodiment of the present invention are compounds according to formula (I) as
7 8 9
described herein, wherein R , R and R are independently selected from H, alkoxy, haloalkoxy,
halogen, alkylsulfonyl and phenyl substituted with one halogen, and wherein at least one of R ,
R and R is not H.
A further particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein R is alkoxy, haloalkoxy, halogen or phenyl substituted
with one halogen.
A further particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein R is haloalkoxy or halogen.
A further particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein R is H, halogen or alkylsulfonyl.
A further particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein R is H or halogen.
A further particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein R is H.
A further particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein R is aminosulfonyl.
A further particular embodiment of the present invention are compounds according to
11 12
formula (I) as described herein, wherein R and R are independently selected from H, alkyl
and halogen.
A further particular embodiment of the present invention are compounds according to
11 12
formula (I) as described herein, wherein R and R are independently selected from H and
halogen.
A further particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein m and n are 1.
A further particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein m, n, p and q are 1.
A further particular embodiment of the present invention are compounds according to
formula (I) as described herein, wherein R is 4-aminosulfonylphenyl and of formula (Ia).
( ) ( )
Y N A W
( ) ( )
R q n
(Ia)
Particular examples of compounds of formula (I) as described herein are selected from
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-
(6H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophenecarbonyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
4-{(3aS,8aR)[(E)(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-
d]azepinecarbonyl}-benzenesulfonamide;
(3aS,6aS)(3-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic
acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(6-oxo-1,6-dihydro-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(1-methylsulfamoyl-1H-pyrrolecarbonyl)-hexahydro-pyrrolo[3,4-
c]pyrrolecarboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(1-methylsulfamoyl-1H-pyrrolecarbonyl)-hexahydro-pyrrolo[3,4-
c]pyrrolecarboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(6-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(5-hydroxy-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy benzyl ester;
(3aS,6aS)(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-benzyl ester;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-(1H-tetrazolyl)benzoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
4-((3aR,6aS)((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole
carbonyl)benzoic acid;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
(3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 3-
chloromethanesulfonyl-benzyl ester;
(3aR,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 2-
fluorotrifluoromethoxy-benzyl ester;
(3aR,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-benzyl ester;
(3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-benzyl ester;
4-{(3aR,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-benzenesulfonamide;
4-{(3aR,6aR)[(E)(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-benzenesulfonamide;
4-[(3aR,6aS)(4-isopropoxy-naphthalenecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-
2-carbonyl]-benzenesulfonamide;
4-{(3aR,6aS)[1-(2,2,2-trifluoro-ethoxy)-isoquinolinecarbonyl]-hexahydro-
pyrrolo[3,4-c]pyrrolecarbonyl}-benzenesulfonamide;
4-[(3aR,6aS)(1-Methyltrifluoromethoxy-1H-indolecarbonyl)-hexahydro-
pyrrolo[3,4-c]pyrrolecarbonyl]-benzenesulfonamide;
4-[(3aR,6aS)(4-Isopropoxy-quinolinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carbonyl]-benzenesulfonamide;
4-[(3aS,6aR)(4'-chloro-biphenylcarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carbonyl]-benzenesulfonamide;
4-{(3aS,6aR)[3-(2-fluorotrifluoromethoxy-phenyl)-propionyl]-hexahydro-
pyrrolo[3,4-c]pyrrolecarbonyl}-benzenesulfonamide;
4-{(3aS,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-benzenesulfonamide;
4-((3aR,6aR)(3-(2-fluoro(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-
c]pyrrolecarbonyl)benzenesulfonamide;
(+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-
(6H)-carboxylate;
(-)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-
(6H)-carboxylate;
and pharmaceutically acceptable salts thereof.
Also particular examples of compounds of formula (I) as described herein are selected
from
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-
5(6H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophenecarbonyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
4-{(3aS,8aR)[(E)(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-
d]azepinecarbonyl}-benzenesulfonamide;
(3aS,6aS)(3-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic
acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(6-oxo-1,6-dihydro-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(1-methylsulfamoyl-1H-pyrrolecarbonyl)-hexahydro-pyrrolo[3,4-
c]pyrrolecarboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(1-methylsulfamoyl-1H-pyrrolecarbonyl)-hexahydro-pyrrolo[3,4-
c]pyrrolecarboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(6-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(5-hydroxy-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy benzyl ester;
(3aS,6aS)(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-benzyl ester;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-(1H-tetrazolyl)benzoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
4-((3aR,6aS)((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole
carbonyl)benzoic acid;
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate;
(3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 3-
chloromethanesulfonyl-benzyl ester;
(3aR,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 2-
fluorotrifluoromethoxy-benzyl ester;
(3aR,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-benzyl ester;
(3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-benzyl ester;
4-{(3aR,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-benzenesulfonamide;
4-{(3aR,6aR)[(E)(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-benzenesulfonamide;
4-[(3aR,6aS)(4-isopropoxy-naphthalenecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-
2-carbonyl]-benzenesulfonamide;
4-{(3aR,6aS)[1-(2,2,2-trifluoro-ethoxy)-isoquinolinecarbonyl]-hexahydro-
pyrrolo[3,4-c]pyrrolecarbonyl}-benzenesulfonamide;
4-[(3aR,6aS)(1-Methyltrifluoromethoxy-1H-indolecarbonyl)-hexahydro-
pyrrolo[3,4-c]pyrrolecarbonyl]-benzenesulfonamide;
4-[(3aR,6aS)(4-Isopropoxy-quinolinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carbonyl]-benzenesulfonamide;
4-[(3aS,6aR)(4'-chloro-biphenylcarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carbonyl]-benzenesulfonamide;
4-{(3aS,6aR)[3-(2-fluorotrifluoromethoxy-phenyl)-propionyl]-hexahydro-
pyrrolo[3,4-c]pyrrolecarbonyl}-benzenesulfonamide;
4-{(3aS,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-benzenesulfonamide;
4-((3aR,6aR)(3-(2-fluoro(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-
c]pyrrolecarbonyl)benzenesulfonamide;
(+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-
(6H)-carboxylate;
(-)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-
(6H)-carboxylate;
(3aS,6aS)(2-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic
acid 4-trifluoromethoxy-benzyl ester;
-{(3aR,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-pyridinesulfonic acid amide;
-((3aS,6aS)(4-ethoxyquinolinecarbonyl)octahydropyrrolo[3,4-c]pyrrole
carbonyl)pyridinesulfonamide;
(3aS,6aS)(3-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic
acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester;
(3aS,6aS)(6-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester;
(3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
cyano(2,2-dimethyl-propionylamino)-benzylester;
(3aS,6aS)(2-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic
acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester;
(3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester;and
pharmaceutically acceptable salts thereof.
Further particular examples of compounds of formula (I) as described herein are selected
from
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aS,6aS)(3-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic
acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(6-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-benzyl ester;
4-{(3aR,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-benzenesulfonamide;
and pharmaceutically acceptable salts thereof.
Also further particular examples of compounds of formula (I) as described herein are
selected from
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate;
(3aS,6aS)(3-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic
acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(6-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-benzyl ester;
4-{(3aR,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-benzenesulfonamide;
(3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
carboxylic acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester;
and pharmaceutically acceptable salts thereof. Processes for the manufacture of compounds
of formula (I) as described herein are an object of the invention.
The preparation of compounds of formula (I) of the present invention may be carried out in
sequential or convergent synthetic routes. Syntheses of the invention are shown in the following
general schemes. The skills required for carrying out the reactions and purifications of the
resulting products are known to those persons skilled in the art. In case a mixture of enantiomers
or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be
separated by methods described herein or known to the man skilled in the art such as e.g. (chiral)
chromatography or crystallization. The substituents and indices used in the following description
of the processes have the significance given herein.
Compounds of general formula (I) can be synthesised from amine precursor 1 and
appropriate reagents, using methods well known in the art.
( ) m
HN A W 1
For instance, amine 1 is reacted with a suitable chloroformate ester of formula
R –O–C(O)–Cl (2), or with an imidazolecarboxylate ester of formula (3), leading to a
compound of formula (I) wherein Y is –OC(O)–.
The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran,
N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a
base, e. g., triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate,
potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent
mixture.
Chloroformate esters 2 are commercially available or can be synthesised from the
corresponding alcohol of formula R –OH, by reaction with phosgene or a phosgene equivalent (e.
g., diphosgene, triphosgene), as described in the literature.
Imidazolecarboxylate esters 3 are synthesised from the corresponding alcohols of
formula R –OH, by reaction with 1,1'-carbonyldiimidazole. The reaction is performed at room
temperature, in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile. The
imidazolecarboxylate esters 3 are typically not isolated but directly reacted with amines 1 as
described above.
Alcohols of formula R –OH are commercially available or can be produced by methods
described herein or known in the art.
Alternatively, amine 1 is reacted with a suitable N-(chlorocarbonyl)amine of formula
1 5 5 1
R –N(R )–C(O)–Cl (4), or, in the case where R is H, with an isocyanate of formula R –NCO (5),
leading to compounds of formula (I) wherein Y is –NR C(O)–.
N-(Chlorocarbonyl)amines (4) are synthesised from the corresponding amines of formula
R –N(R )H by reaction with phosgene or a phosgene equivalent, as described in the literature.
Isocyanates 5 are commercially available or can be prepared from the corresponding
amines of formula R –NH , by reaction with phosgene or a phosgene equivalent (e. g.,
diphosgene, triphosgene, 1,1'-carbonyldiimidazole) using conditions described in the literature.
Alternatively, amine 1 is reacted with a suitable carboxylic acid of formula R –COOH (6)
leading to a compound of formula (I), wherein Y is –C(O)–. The reaction is performed in the
presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O-(benzotriazolyl)-
N,N,N’,N’-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazolyl)-N,N,N’,N’-
tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-
dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C
and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-
methylmorpholine and/or 4-(dimethylamino)pyridine.
Amine 1 can also be reacted with suitable acylating reagents such as acyl chlorides of
formula R –COCl (7) to lead to compounds of formula (I) wherein Y is –C(O)–. The reaction is
performed in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, in
the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between
0°C and 80°C.
Carboxylic acids (6) and acyl halides (7) are commercially available or can be prepared as
described herein or in the literature.
Alternatively, amine 1 is reacted with a suitable sulfonyl chloride of formula R –SO Cl (8),
leading to compounds of formula (I) wherein Y is –S(O2)–. The reaction is performed in a
suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,
acetone, water, or mixtures thereof, in the presence of a base, e. g., triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at
temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Sulfonyl chlorides (8) are commercially available or can be synthesised as described herein
or in the literature.
Alternatively, amine 1 is reacted with a suitable chloro-oxadiazole reagent of general
formula 9, or with oxadiazolone reagent 10, leading to a compound of formula (I), wherein Y is
.
R Cl R O
NN NN
9 10
In the case where compounds of formula (I) are produced from amine 1 and chloro-
oxadiazole 9, the reaction is performed in the presence of a base, e. g., potassium carbonate,
triethylamine, or 1,8-diazabicyclo[5.4.0]undecene, in a solvent such as toluene, ethanol, N,N-
dimethylformamide, or 1,4-dioxane at temperatures between 20°C and 150°C.
In the case where compounds of formula (I) are produced from amine 1 and oxadiazolone
, the reaction is performed in the presence of a coupling agent, e. g. benzotriazolyl-oxy-tris-
(dimethylamino)-phosphonium hexafluorophosphate and a base, e. g., diisopropylethylamine or
4-methylmorpholine, in a solvent such as N,N-dimethylformamide, at temperatures between
20°C and 100°C as described in the literature.
Oxadiazolones 10 are commercially available or can be produced as described in the
literature.
Chloro-oxadiazoles 9 are commercially available or can be produced from the
corresponding oxadiazolones, by reaction with a suitable halogenating reagent, e. g. phosphorus
oxychloride and/or phosphorus pentachloride, at temperatures between 60°C and 120°C.
Alternatively, amine 1 is reacted with a suitable halo-thiadiazole reagent of general
formula 11 (X = Cl or Br), or with thiadiazolethione reagent 12, leading to compounds of (I)
wherein Y is .
R X R S
NN NN
11 12
In the case where compounds of formula (I) are produced from amine 1 and halo-
thiadiazole 11, the reaction is performed in the presence of a base, e. g. potassium carbonate,
triethylamine or 1,8-diazabicyclo[5.4.0]undecene, in a solvent such as toluene, ethanol, N,N-
dimethylformamide or 1,4-dioxane, at temperatures between 20°C and 150°C.
In the case where compounds of formula (I) are produced from amine 1 and
thiadiazolethione 12, the reaction is performed in a solvent such as ethanol or N,N-
dimethylformamide at temperatures between 20°C and 100°C as described in the literature.
Thiadiazolethiones 12 are commercially available or can be produced as described in the
literature.
Halo-thiadiazoles 11 are commercially available or can be produced as described in the
literature.
Amines of general formula 1 are synthesised from suitably protected precursors 13.
( ) m
PG N A W 13
Suitable protective groups (PG) are tert-butoxycarbonyl, benzyloxycarbonyl and
substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl. The deprotection of
intermediates 13 can be performed using methods and reagents known in the art.
For instance, in the case where PG is optionally substituted benzyloxycarbonyl, the
deprotection may be performed by hydrogenation at pressures between 1 bar and 100 bar, in the
presence of a suitable catalyst such as palladium on activated charcoal, at temperatures between
°C and 150°C in solvents such as methanol or ethanol.
Alternatively, in the case where PG is tert-butoxycarbonyl, the deprotection may be
performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoroacetic acid, in a
solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane at temperatures between 0°C
and 30°C.
Intermediates 13, wherein A is N are represented by general structure 13A.
( ) m
PG N N W 13A
PG is a suitable protective group, e. g., tert-butoxycarbonyl, benzyloxycarbonyl and
substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
Intermediates 13A can be produced from amine precursors of general formula 14 by
reaction with appropriate reagents, using methods known in the art.
( ) m
PG N 14
3 4 2
For instance, 14 is reacted with alkylating agents of general formula X–CR R –R (15)
where X is a leaving group such as Cl, Br, I, or OSO CH , leading to 13A, wherein W is
–CR R –. This reaction is performed in a solvent such as tetrahydrofuran or N,N-
dimethylformamide, in the presence of a base, e. g. triethylamine or potassium carbonate, at
temperatures between 0°C and 100°C.
3 4 4
Alternatively, for compounds of formula 13A, wherein W is –CR R –, R is hydrogen,
alkyl or cycloalkyl, and R is H, amine 14 is reacted with aldehydes or ketones of general
formula R –C(O)–R (16) in a reductive amination reaction, leading to 13A. This reaction is
performed in the presence of a suitable reducing agent, e. g., sodium borohydride or sodium
triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-
dichloroethane or mixtures thereof, at temperatures between 0°C and 50°C.
Alternatively, amine 14 is reacted with a suitable carboxylic acid of formula R –COOH
(17), leading to compounds of formula 13A, wherein W is –C(O)–. The reaction is performed in
the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N’-
dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O-
(benzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-
1-yl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-
phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran,
N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -
40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine,
4-methylmorpholine and/or 4-(dimethylamino)pyridine.
Alternatively, amine 14 is reacted with a suitable sulfonyl chloride of formula
R –SO Cl (18), leading to compounds of formula 13A, wherein W is –S(O )–. The reaction is
performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-
dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e.
g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium
carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Amines 14, alkylating agents 15, aldehydes/ketones 16, carboxylic acids 17, sulfonyl
chlorides 18, and amines 22 are commercially available or can be synthesised as described in the
literature or in the experimental section.
Intermediates 13 wherein A is C–H are represented by general formula 13B, wherein PG is
a suitable protective group, e. g tert-butoxycarbonyl, benzyloxycarbonyl and substituted
benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
( ) m
PG N W 13B
Compound 13B, wherein W is –NR –, is produced from ketone 19 by reaction with an
amine of formula HN(R )R (20) in the presence of a suitable reducing agent, e. g. sodium
borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid,
tetrahydrofuran, 1,2-dichloroethane, or mixtures thereof, at temperatures between 0°C and 50°C.
PG N O 19
Ketones 19 and amines 20 are commercially available or can be prepared as described in
the literature.
Compound 13B, wherein W is –O– or –S–, is produced from alcohol 21 using methods and
reagents known in the art.
( ) m
PG N OH 21
For instance, alcohol 24 is reacted at room temperature with phenol HO–R or thiophenol
HS–R in the presence of triphenylphosphine and an dialkylazodicarboxylate, e. g.
diisopropylazodicarboxylate or diethylazodicarboxylate, in a solvent such as toluene,
dichloromethane, or tetrahydrofuran, leading to 13B, wherein W is –O– or –S–.
Alternatively, conversion of alcohol 21 to the corresponding methanesulfonate using
methanesulfonyl chloride in the presence of a base, e. g. triethylamine, in a solvent such as
dichloromethane or tetrahydrofuran, at temperatures between –20°C and +30°C, and treatment of
the methanesulfonate intermediate with phenol HO–R or thiophenol HS–R in the presence of a
base, e. g., potassium carbonate, in a solvent such as N,N-dimethylformamide or acetonitrile, at
temperatures between 20°C and 100°C, leads to 13B, wherein W is –O– or –S–.
Compound 13B, wherein W is –SO –, is produced from compound 13B, wherein W is –S–,
by oxidation with a suitable reagent, e. g., hydrogen peroxide or 3-chloroperbenzoic acid, in a
solvent such as formic acid, acetic acid, or dichloromethane, at temperatures between 0°C and
50°C.
Alcohols 21 are produced from ketones 19 using a suitable reducing agent, e. g., sodium
borohydride, in a solvent such as methanol, at temperatures between 0°C and 50°C.
Compounds of formula (I), wherein A is N can be produced from amine precursors of
general formula 22 by reaction with appropriate reagents, using methods known in the art.
( ) m
Y N NH 22
For instance, an amine of formula 22 is reacted with alkylating agents of general formula
3 4 2
X–CR R –R (15) where X is a leaving group such as Cl, Br, I, or OSO CH , leading to
compounds of formula (I), wherein A is N and W is –CR R –. This reaction is performed in a
solvent such as tetrahydrofuran or N,N-dimethylformamide, in the presence of a base, e. g.,
triethylamine or potassium carbonate, at temperatures between 0°C and 100°C.
Alternatively, an amine of formula 22 is reacted with aldehydes or ketones of general
formula R –C(O)–R (16) in a reductive amination reaction, leading to compounds of formula (I)
3 4 4 3
wherein A is N, W is –CR R –, R is hydrogen, alkyl or cycloalkyl, and R is H. This reaction is
performed in the presence of a suitable reducing agent, e. g. sodium borohydride or sodium
triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-
dichloroethane or mixtures thereof, at temperatures between 0°C and 50°C.
Alternatively, amine 22 is reacted with a suitable carboxylic acid of formula R –COOH
(17), leading to compounds of formula (I) wherein A is N and W is –C(O)–. The reaction is
performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N’-
dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O-
(benzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-
1-yl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-
phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran,
N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -
40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine,
4-methylmorpholine and/or 4-(dimethylamino)pyridine.
Alternatively, amine 22 is reacted with a suitable sulfonyl chloride of formula
R –SO Cl (18), leading to (I) wherein A is N and W is –S(O )–. The reaction is performed in a
suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,
acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at
temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Amines 22 can be synthesised from their tert-butyl carbamate derivatives of formula 23 by
carbamate deprotection. The deprotection may be performed in the presence of a suitable acid, e.
g, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2-propanol,
dichloromethane, or 1,4-dioxane, at temperatures between 0°C and 30°C.
Y N N 23
tert-Butyl carbamates 23 can be synthesised from amine precursors of formula
24 and appropriate reagents, using methods well known in the art.
( ) m
N 24
For instance, an amine of formula 24 is reacted with a suitable chloroformate ester of
formula R –O–C(O)–Cl (2), or with an imidazolecarboxylate ester of formula (3), leading to
compounds of formula 23, wherein Y is –OC(O)–. The reaction is performed in a suitable
solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone,
water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine,
pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and
the boiling point of the solvent or solvent mixture.
Alternatively, an amine of formula 24 is reacted with a suitable N-(chlorocarbonyl)amine
of formula R –N(R )–C(O)–Cl (4) leading to compounds of formula 23, wherein Y is –
NR C(O)–, or with an isocyanate of formula R –NCO (5) leading to compounds of formula 23,
wherein Y is –NR C(O)– and R is H.
Alternatively, amine 24 is reacted with a suitable carboxylic acid of formula R –COOH (6)
leading to compounds of formula 23, wherein Y is –C(O)–. The reaction is performed in the
presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O-(benzotriazolyl)-
N,N,N’,N’-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazolyl)-N,N,N’,N’-
tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-
dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C
and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-
methylmorpholine and/or 4-(dimethylamino)pyridine.
Amine 24 can also be reacted with suitable acylating reagents, such as acyl chlorides of
formula R –COCl (7) to provide compounds of formula 23, wherein Y is –C(O)–. The reaction
is performed in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide,
in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between
0°C and 80°C.
Alternatively, amine 24 is reacted with a suitable sulfonyl chloride, of formula R –SO Cl
(8), leading to compounds of formula 23, wherein Y is –S(O )–. The reaction is performed in a
suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,
acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at
temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Alternatively, amine 24 is reacted with a suitable chloro-oxadiazole reagent of general
formula 9, or with oxadiazolone reagent 10, leading to compounds of formula 23, wherein Y is
In the case where 23 is produced from amine 24 and chloro-oxadiazole 9, the reaction is
performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8-
diazabicyclo[5.4.0]undecene, in a solvent such as toluene, ethanol, N,N-dimethylformamide,
or 1,4-dioxane, at temperatures between 20°C and 150°C.
In the case where 23 is produced from amine 24 and oxadiazolone 10, the reaction is
performed in the presence of a coupling agent, e. g., benzotriazolyl-oxy-tris-(dimethylamino)-
phosphonium hexafluorophosphate, and a base, e. g. diisopropylethylamine or 4-
methylmorpholine, in a solvent such as N,N-dimethylformamide, at temperatures between 20°C
and 100°C, as described in the literature).
Alternatively, amine 24 is reacted with a suitable halo-thiadiazole reagent of general
formula 11 (X is Cl or Br), or with thiadiazolethione reagent 12, leading to compounds of
formula 23, wherein Y is .
In the case where 23 is produced from amine 24 and halo-thiadiazole 11, the reaction is
performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8-
diazabicyclo[5.4.0]undecene, in a solvent such as toluene, ethanol, N,N-dimethylformamide,
or 1,4-dioxane, at temperatures between 20°C and 150°C.
In the case where 23 is produced from amine 24 and thiadiazolethione 12, the reaction is
performed in a solvent such as ethanol or N,N-dimethylformamide, at temperatures between
°C and 100°C, as described in the literature.
Alternatively, amine 24 is acylated with a haloalkanoyl halide, e. g., bromoacetyl chloride,
in the presence of a base, e. g. triethylamine, in a solvent such as dichloromethane or
tetrahydrofuran, at temperatures between –78°C and +20°C, leading to the corresponding
haloalkanamide intermediate, which in the presence of a base, e. g. potassium carbonate or
caesium carbonate, in a solvent such as N,N-dimethylformamide undergoes a nucleophilic
substitution reaction with a substituted phenol, leading to compounds of formula 28, wherein Y
is –C(O)– and R is substituted phenoxyalkyl.
Amines of formula 24 are commercially available or can be produced as described in the
literature or in the experimental section.
Also an embodiment of the present invention is a process to prepare a compound of
formula (I) as defined above comprising the reaction of a compound of formula (II) in the
presence of a compound of formula (III);
p m N p m
( ) ( ) ( ) ( )
(III)
A W A W
HN Y N
( ) ( ) 1 ( ) ( )
q n q n
(II)
wherein R , R , A, W, m, n, p and q are as defined above, Y is -OC(O)-.
In particular, in the presence of a coupling agent such as O-(7-azabenzotriazolyl)-
N,N,N’,N’-tetramethyluronium hexafluoro-phosphate, in a solvent such as N,N-
dimethylformamide, in the presence of a base such as 4-methylmorpholine and at a temperature
comprised between -78°C and reflux, particularly between -10°C and room temperature.
Also an object of the present invention is a compound according to formula (I) as
described herein for use as a therapeutically active substance.
Likewise an object of the present invention is a pharmaceutical composition comprising a
compound according to formula (I) as described herein and a therapeutically inert carrier.
Described is the use of a compound according to formula (I’) as described herein for the
treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions,
conditions of the nervous system, conditions of the respiratory system, vascular and
cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions,
cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
Renal conditions include, but are not limited to, acute kidney injury and chronic renal
disease with and without proteinuria including end-stage renal disease (ESRD). In more detail,
this includes decreased creatinine clearance and decreased glomerular filtration rate, micro-
albuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of reticulated
mesangial matrix with or without significant hypercellularity (particularly diabetic nephropathy
and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic
microangiopathies), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such
as ischemic retraction, reduced renal blood flow and renal arteriopathy), swelling and
proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents)
like in glomerular nephritis entities, focal segmental glomerular sclerosis, IgA nephropathy,
vasculitides / systemic diseases as well as acute and chronic kidney transplant rejection.
Liver conditions include, but are not limited to, liver cirrhosis, hepatic congestion,
cholestatic liver disease including pruritus, nonalcoholic steatohepatitis and acute and chronic
liver transplant rejection.
Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, multiple
sclerosis, systemic lupus erythematodes, inflammatory bowel disease, abnormal evacuation
disorder and the like as well as inflammatory airways diseases such as idiopathic pulmonary
fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic asthma bronchiale.
Further conditions of the respiratory system include, but are not limited to, other diffuse
parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis,
occupational and/or environmental induced fibrosis, systemic diseases and vasculitides,
granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease,
alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited
diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage
disorders, familial interstitial lung disease), radiation induced fibrosis, silicosis, asbestos induced
pulmonary fibrosis or acute respiratory distress syndrome (ARDS).
Conditions of the nervous system include, but are not limited to, neuropathic pain,
schizophrenia, neuro-inflammation (e.g. astrogliosis), peripheral and/or autonomic (diabetic)
neuropathies and the like.
Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular
disease as well as thrombotic microangiopathies, proliferative arteriopathy (such as swollen
myointimal cells surrounded by mucinous extracellular matrix and nodular thickening),
atherosclerosis, decreased vascular compliance (such as stiffness, reduced ventricular
compliance and reduced vascular compliance), endothelial dysfunction and the like.
Cardiovascular conditions include, but are not limited to, acute coronary syndrome,
coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac
arrhythmia such as atrial fibrillation, stroke and other vascular damage.
Fibrotic diseases include, but are not limited to myocardial and vascular fibrosis, renal
fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulating
peritonitis.
In a particular embodiment, the compounds of formula (I) or their pharmaceutically
acceptable salts and esters can be used for the treatment or prophylaxis of organ or skin fibrosis.
In another embodiment, the fibrotic disease is renal tubulo-interstitial fibrosis or
glomerulosclerosis.
In another embodiment, the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or
liver cirrhosis.
In another embodiment, the fibrotic disease is idiopathic pulmonary fibrosis.
Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer,
lung cancer, prostate cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers
and progression and metastatic aggressiveness thereof.
Ocular conditions include, but are not limited to, proliferative and non-proliferative
(diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema,
central arterial /venous occlusion, traumatic injury, glaucoma and the like.
Metabolic conditions include, but are not limited to, obesity and diabetes.
In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable
salts and esters can be used for the treatment or prophylaxis of cholestatic or non-cholestatic
chronic pruritus.
Also described is the use of a compound according to formula (I’) as described herein for
the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions,
conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant
rejection.
Also described is the use of a compound according to formula (I’) as described herein for
the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
A particular embodiment of the present invention is a compound according to formula (I)
as described herein for the treatment or prophylaxis of renal conditions, liver conditions,
inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and
chronic organ transplant rejection.
A particular embodiment of the present invention is a compound according to formula (I)
as described herein for the treatment or prophylaxis of renal conditions, liver conditions and
fibrotic diseases.
The present invention also relates to the use of a compound according to formula (I) as
described herein for the preparation of a medicament for the treatment or prophylaxis of renal
conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic
diseases and acute and chronic organ transplant rejection.
The present invention also relates to the use of a compound according to formula (I) as
described herein for the preparation of a medicament for the treatment or prophylaxis of renal
conditions, liver conditions and fibrotic diseases.
Also described is a method for the treatment or prophylaxis of renal conditions, liver
conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and
acute and chronic organ transplant rejection, which method comprises administering an effective
amount of a compound according to formula (I’) as described herein.
Also described is a method for the treatment or prophylaxis of renal conditions, liver
conditions and fibrotic diseases, which method comprises administering an effective amount of a
compound according to formula (I’) as described herein.
In a particular embodiment, the renal condition is selected from the group consisting of
acute kidney injury, chronic kidney disease, diabetic nephropathy, acute kidney transplant
rejection and chronic allograft nephropathy.
In another particular embodiment, the renal condition is acute kidney injury.
In another particular embodiment, the renal condition is chronic kidney disease.
In a further particular embodiment, the renal condition is diabetic nephropathy.
In another particular embodiment, the renal condition is acute kidney transplant rejection.
In another particular embodiment, the renal condition is chronic allograft nephropathy.
In a particular embodiment, the liver condition is acute and chronic liver transplant
rejection
In a particular embodiment, the inflammatory condition is arthritis.
In a particular embodiment, the condition of the nervous system is neuropathic pain.
In another embodiment, the fibrotic disease is encapsulating peritonitis
In another embodiment, the fibrotic disease is idiopathic pulmonary fibrosis.
In another embodiment, the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or
liver cirrhosis.
Also an embodiment of the present invention are compounds of formula (I) as described
herein, when manufactured according to any one of the described processes.
Assay procedures
PRODUCTION OF HUMAN FULL LENGTH ATX, WITH AND WITHOUT HIS TAG
Autotaxin (ATX - ENPP2) cloning: cDNA was prepared from commercial human
hematopoietic cells total RNA and used as template in overlapping PCR to generate a full length
human ENPP2 ORF with or without a 3’-6xHis tag. These full length inserts were cloned into
the pcDNA3.1V5-His TOPO (Invitrogen) vector. The DNA sequences of several single clones
were verified. The DNA from a correct full length clone was used to transfect Hek293 cells for
verification of protein expression. The sequence of the encoded ENPP2 conforms to Swissprot
entry Q13822, with or without the additional C-terminal 6xHis tag.
ATX Fermentation: Recombinant protein was produced by large-scale transient transfection in
L controlled stirred tank bioreactors (Sartorius). During cell growth and transfection,
temperature, stirrer speed, pH and dissolved oxygen concentration were maintained at 37°C, 120
rpm, 7.1 and 30% DO, respectively. FreeStyle 293-F cells (Invitrogen) were cultivated in
suspension in FreeStyle 293 medium (Invitrogen) and transfected at ca. 1-1.5 x 10E6 cells/mL
with above plasmid DNAs using X-tremeGENE Ro-1539 (commercial product, Roche
Diagnostics) as complexing agent. Cells were fed a concentrated nutrient solution (J Immunol
Methods 194 (1996), 19, 1-199 (page 193)) and induced by sodium butyrate (2 mM) at 72 h
post-transfection and harvested at 96 h post-transfection. Expression was analyzed by Western
Blot, enzymatic assay and/or analytical IMAC chromatography. After cooling the cell
suspension to 4°C in a flow-through heat exchanger, cell separation and sterile filtration of
supernatant was performed by filtration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2
XLG (Sartorius) filter units. The supernatant was stored at 4°C prior to purification.
ATX Purification: 20 liter of culture supernatant were conditioned for ultrafiltration by adding
Brij 35 to a final concentration of 0.02% and by adjusting the pH to 7.0 using 1 M HCl. Then the
supernatant was first microfiltred through a 0.2 μm Ultran-Pilot Open Channel PES filter
(Whatman) and afterwards concentrated to 1 liter through an Ultran-Pilot Screen Channel PES
filter with 30 kDa MWCO (Whatman). Prior to IMAC chromatography, NiSO was added to a
final concentration of 1 mM. The cleared supernatant was then applied to a HisTrap column (GE
Healthcare) previously equilibrated in 50 mM Na HPO pH 7.0, 0.5 M NaCl, 10% glycerol,
0.3% CHAPS, 0.02% NaN . The column was washed stepwise with the same buffer containing
mM , 40 mM and 50 mM imidazole, respectively. The protein was subsequently eluted using
a linear gradient to 0.5 M imidazole in 15 column volumes. ATX containing fractions were
pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane.
The protein was further purified by size exclusion chromatography on Superdex S-200 prep
grade (XK 26/100) (GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% glycerol,
0.3% CHAPS, 0.02% NaN . Final yield of protein after purification was 5-10 mg ATX per liter
of culture supernatant. The protein was stored at -80°C.
HUMAN ATX ENZYME INHIBITION ASSAY
ATX inhibition was measured by a fluorescence quenching assay using a specifically labeled
substrate analogue (MR121 substrate). To obtain this MR121 substrate, BOC and TBS protected
6-amino-hexanoic acid (R)({2-[3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-
propionylamino]-ethoxy}-hydroxy-phosphoryloxy)hydroxy-propyl ester (Ferguson et al., Org
Lett 2006, 8 (10), 2023) was labeled with MR121 fluorophore (CAS 1853081, 1-(3-
carboxypropyl)ethyl-1,2,3,4,8,9,10,11-octahydro-dipyrido[3,2-b:2’,3’-i]phenoxazinium)
on the free amine of the ethanolamine side and then, after deprotection, subsequently with
tryptophan on the side of the aminohexanoic acid.
Assay working solutions were made as follows:
Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 0.01%
Triton-X-100, pH 8.0;
ATX solution: ATX (human His-tagged) stock solution (1.08 mg/mL in 20mM bicine, pH 8.5,
0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN ), diluted to 1.4 – 2.5x final
concentration in assay buffer;
MR121 substrate solution: MR121 substrate stock solution (800 µM MR121 substrate in DMSO),
diluted to 2 – 5x final concentration in assay buffer.
Test compounds (10 mM stock in DMSO, 8 µL) were obtained in 384 well sample plates
(Corning Costar #3655) and diluted with 8 µL DMSO. Row-wise serial dilutions were made by
transferring 8 µL cpd solution to the next row up to row O. The compound and control solutions
were mixed five times and 2 µL were transferred to 384 well assay plates (Corning Costar #
3702). Then, 15 µL of 41.7 nM ATX solution was added (30 nM final concentration), mixed five
times and then incubated for 15 minutes at 30°C. 10 µL of MR121 substrate solution was added
(1µM final concentration), mixed 30 times and then incubated for 15 minutes at 30 °C.
Fluorescence was then measured every 2 minutes for 1 hour (Perkin Elmer plate: vision
multimode reader); light intensity: 2.5%; exp. time: 1.4 sec, Filter: Fluo_630/690 nm) and IC
values were calculated from these readouts.
IC values for the examples of this invention are given in the table below:
Example IC50 (µM) Example IC50 (µM) Example IC50 (µM)
1 1.156 1.01 0.293 1.02 0.444
Example IC50 (µM) Example IC50 (µM) Example IC50 (µM)
1.03 0.007 1.19 0.004 7.02 0.003
1.04 0.008 1.20 0.019 7.03 0.004
1.05 0.004 1.21 0.118 8 0.0085
1.06 0.255 1.22 0.007 8.01 0.0075
1.07 6.108 1.23 0.004 8.02 0.014
1.08 1.1995 1.24 0.012 8.03 0.0055
1.09 0.118 1.25 0.002 8.04 0.1665
1.10 0.002 1.26 0.01 8.05 0.093
1.11 0.001 2 0.342 8.06 0.003
1.12 0.44 2.01 1.5 8.07 0.001
1.13 0.001 3 0.031 8.08 0.0015
1.14 0.064 4 0.573 8.09 0.001
1.15 0.0585 5 1.3445 9A 0.004
1.16 0.001 6 0.6225 9B 0.005
1.17 0.025 7 0.0145
1.18 0.013 7.01 0.001
Compounds of formula (I) and their pharmaceutically acceptable salts or esters thereof as
described herein have IC values between 0.00001 μM and 1000 μM, particular compounds
have IC values between 0.0005 μM and 500 μM, further particular compounds have IC
50 50
values between 0.0005 μM and 50 μM, more particular compounds have IC values between
0.0005 μM and 5 μM. These results have been obtained by using the enzymatic assay described
above.
The compounds of formula (I) and their pharmaceutically acceptable salts can be used as
medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations
can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées,
hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of
nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also
be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection
solutions).
The compounds of formula (I) and their pharmaceutically acceptable salts can be processed
with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated
tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic
acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard
gelatin capsules.
Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats,
semi-solid substances and liquid polyols, etc.
Suitable adjuvants for the production of solutions and syrups are, for example, water,
polyols, saccharose, invert sugar, glucose, etc.
Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols,
glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats,
semi-solid or liquid polyols, etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers,
viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants,
flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable substances.
The dosage can vary in wide limits and will, of course, be fitted to the individual
requirements in each particular case. In general, in the case of oral administration a daily dosage
of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body
weight (e.g. about 300 mg per person), divided preferably into 1-3 individual doses, which can
consist, for example, of the same amounts, should it be appropriate. It will, however, be clear
that the upper limit given herein can be exceeded when this is shown to be indicated.
The invention is illustrated hereinafter by Examples, which have no limiting character.
In case the preparative examples are obtained as a mixture of enantiomers, the pure
enantiomers can be obtained by methods described herein or by methods known to those skilled
in the art, such as e.g. chiral chromatography or crystallization.
Examples
All examples and intermediates were prepared under nitrogen atmosphere if not specified
otherwise.
Abbreviations: aq. = aqueous; CAS-RN = Chemical Abstracts Service Registry Number; HPLC
= high performance liquid chromatography; MS = mass spectrum; sat. = saturated
Example 1
(3aR,6aS)-3,5-Dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate
O N S
To a solution of (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate hydrochloride (intermediate 1; 40 mg, 114 µmol), 4-methylmorpholine (57.5 mg,
569 µmol) and 4-(N-methylsulfamoyl)benzoic acid (24.5 mg, 114 µmol) in N,N-
dimethylformamide (2 mL) was added O-(7-azabenzotriazolyl)-N,N,N’,N’-
tetramethyluronium hexafluoro-phosphate (43.3 mg, 114 µmol) at 0°C, then the reaction mixture
was allowed to reach room temperature over 16 h. After partitioning between ethyl acetate and
aq. sat. sodium hydrogen carbonate solution the organic layer was washed with water and brine,
dried over magnesium sulfate filtered and evaporated. Chromatography (silica gel; ethyl
acetate–methanol gradient) afforded the title compound (58 mg, 99%). White foam, MS: 512.3
(M+H) .
The following examples were prepared according to example 1, replacing (3aR,6aS)-3,5-
dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride by the
appropriate amine and 4-(N-methylsulfamoyl)benzoic acid by the appropriate carboxylic acid.
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(3aR,6aS)-3,5-
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-
dichlorobenzyl
hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-
hexahydropyrrolo[3,4-
2(1H)-carboxylate
c]pyrrole-2(1H)- 436.2
1.01
Cl +
carboxylate (M+H)
hydrochloride
(intermediate 1) / 5-
HO N O
H Cl
hydroxypicolinic acid
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-
(3aR,6aS)-3,5-
hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
dichlorobenzyl
carboxylate
hexahydropyrrolo[3,4-
c]pyrrole-2(1H)- 435.2
1.02
carboxylate (M+H)
hydrochloride
HO N O
(intermediate 1) / 4-
O hydroxybenzoic acid
(3aS,7aS)-3,5-
trans-3,5-dichlorobenzyl 2-(4-
dichlorobenzyl
sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-
hexahydro-1H-
c]pyridine-5(6H)-carboxylate
pyrrolo[3,4-
512.5
1.03 c]pyridine-5(6H)-
(M+H)
carboxylate
hydrochloride
S (intermediate 1.1) / 4-
H NH
sulfamoylbenzoic acid
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(3aR,6aS)-3,5-
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophene-
dichlorobenzyl
2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
hexahydropyrrolo[3,4-
carboxylate
c]pyrrole-2(1H)-
504.3
1.04 carboxylate
(M+H)
hydrochloride
(intermediate 1) / 5-
sulfamoylthiophene
carboxylic acid
(3aR,6aS)-3,5-
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-
dichlorobenzyl
sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
hexahydropyrrolo[3,4-
2(1H)-carboxylate
O c]pyrrole-2(1H)- 498.3
1.05
carboxylate (M+H)
hydrochloride
Cl H (intermediate 1) / 4-
sulfamoylbenzoic acid
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-
(3aR,6aS)-3,5-
aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
dichlorobenzyl
carboxylate
hexahydropyrrolo[3,4-
c]pyrrole-2(1H)- 434.4
1.06
carboxylate (M+H)
hydrochloride
H N N O
(intermediate 1) / 4-
H Cl
aminobenzoic acid
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(3aR,6aS)-3,5-
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-
dichlorobenzyl
aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
hexahydropyrrolo[3,4-
carboxylate
c]pyrrole-2(1H)-
435.4
1.07 carboxylate
N H +
(M+H)
hydrochloride
(intermediate 1) /5-
aminopicolinic acid
hydrochloride
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-
(3aR,6aS)-3,5-
cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
dichlorobenzyl
carboxylate
hexahydropyrrolo[3,4-
c]pyrrole-2(1H)- 444.2
1.08
carboxylate (M+H)
hydrochloride
(intermediate 1) / 4-
H Cl
cyanobenzoic acid
(3aR,6aS)-3,5-
(3aR,6aS)-3,5-dichlorobenzyl 5-(4-
dichlorobenzyl
(methoxycarbonyl)benzoyl) hexahydropyrrolo[3,4-
hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate
c]pyrrole-2(1H)-
O 477.2
1.09 carboxylate
(M+H)
hydrochloride
(intermediate 1) / 4-
Cl H
(methoxycarbonyl)-
benzoic acid
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(E)((3aR,8aS)-
4-{(3aS,8aR)[(E)(4-trifluoromethoxy-phenyl)-
octahydropyrrolo[3,4-
acryloyl]-octahydro-pyrrolo[3,4-d]azepinecarbonyl}-
d]azepin-6(7H)-yl)
benzenesulfonamide
538.5
1.10 (trifluoromethoxy)phe
(M+H)
O nyl)propenone
hydrochloride
H N H
(intermediate 2) / 4-
sulfamoylbenzoic acid
(3aS,6aS)-hexahydro-
pyrrolo[3,4-c]pyrrole-
(3aS,6aS)(3-fluorosulfamoyl-benzoyl)-hexahydro-
2-carboxylic acid 4-
pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-
trifluoromethoxy-benzyl ester
benzyl ester
532.5
1.11 hydrochloride
(M+H)
(intermediate 1.2) / 3-
S N O fluorosulfamoyl-
benzoic acid (CAS-
2446069)
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(3aS,6aS)-hexahydro-
pyrrolo[3,4-c]pyrrole-
(3aS,6aS)(6-oxo-1,6-dihydro-pyridinecarbonyl)-
2-carboxylic acid 4-
hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-
trifluoromethoxy-benzyl ester
benzyl ester 452.5
1.12
F hydrochloride (M+H)
HN N
(intermediate 1.2) / 6-
O N O
oxo-1,6-
dihydropyridine
carboxylic acid
(3aS,6aS)-hexahydro-
pyrrolo[3,4-c]pyrrole-
(3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-
2-carboxylic acid 4-
hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-
trifluoromethoxy-benzyl ester
benzyl ester 515.5
1.13
hydrochloride (M+H)
(intermediate 1.2) / 5-
sulfamoylpicolinic
acid (CAS-RN
13086779)
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(3aS,6aS)-hexahydro-
pyrrolo[3,4-c]pyrrole-
2-carboxylic acid 4-
(3aS,6aS)(1-methylsulfamoyl-1H-pyrrole
trifluoromethoxy-
carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic
benzyl ester
acid 4-trifluoromethoxy-benzyl ester
O hydrochloride 517.5
1.14
F (intermediate 1.2) / 1- (M+H)
methylsulfamoyl-
1H-pyrrole
carboxylic acid (CAS-
8782183)
(3aS,6aS)-hexahydro-
pyrrolo[3,4-c]pyrrole-
(3aS,6aS)(1-methylsulfamoyl-1H-pyrrole
2-carboxylic acid 4-
carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic
trifluoromethoxy-
acid 4-trifluoromethoxy-benzyl ester
benzyl ester
517.5
1.15 hydrochloride
(M+H)
(intermediate 1.2) / 1-
methylsulfamoyl-
1H-pyrrole
carboxylic acid (CAS-
RN 3069369)
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(3aS,6aS)-hexahydro-
pyrrolo[3,4-c]pyrrole-
(3aS,6aS)(6-sulfamoyl-pyridinecarbonyl)-
2-carboxylic acid 4-
hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
trifluoromethoxy-
trifluoromethoxy-benzyl ester
benzyl ester 515.6
1.16
hydrochloride (M+H)
(intermediate 1.2) / 6-
sulfamoylnicotinic
acid (CAS-RN
2851350)
(3aS,6aS)-hexahydro-
(3aS,6aS)(5-hydroxy-pyridinecarbonyl)-
pyrrolo[3,4-c]pyrrole-
hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
2-carboxylic acid 4-
trifluoromethoxy-benzyl ester
trifluoromethoxy- 452.4
1.17
benzyl ester (M+H)
hydrochloride
HO N O
H (intermediate 1.2) / 5-
hydroxypicolinic acid
(3aS,6aS)-hexahydro-
(3aS,6aS)(4-hydroxy-benzoyl)-hexahydro-
pyrrolo[3,4-c]pyrrole-
pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
2-carboxylic acid 4-
trifluoromethoxy-benzyl ester
trifluoromethoxy- 451.4
1.18
benzyl ester (M+H)
hydrochloride
(intermediate 1.2) / 4-
hydroxybenzoic acid
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(3aS,6aS)(2-fluorosulfamoyl-benzoyl)-
hexahydro-pyrrolo[3,4-c]pyrrole
(3aS,6aS)-hexahydro-pyrrolo[3,4-
carboxylic acid 4-trifluoromethoxy-benzyl
c]pyrrolecarboxylic acid 4-
ester
trifluoromethoxy-benzyl ester 530.3
1.19
hydrochloride (intermediate 1.2) / (M-H)
2-fluorosulfamoylbenzoic acid
(CAS-RN 7149680)
1-((3aS,6aS)-
-{(3aR,6aR)[3-(4-trifluoromethoxy-
hexahydropyrrolo[3,4-c]pyrrol-
phenyl)-propionyl]-hexahydro-pyrrolo[3,4-
2(1H)-yl)(4-
c]pyrrolecarbonyl}-pyridinesulfonic
(trifluoromethoxy)phenyl)propan- 513.3
acid amide
1.20
1-one dihydrochloride (M+H)
(intermediate 2.2) / 6-
sulfamoylnicotinic acid (CAS-RN
2851350)
-((3aS,6aS)(4-ethoxyquinoline
(4-ethoxyquinolin
carbonyl)octahydropyrrolo[3,4-c]pyrrole
yl)((3aS,6aS)-
carbonyl)pyridinesulfonamide
hexahydropyrrolo[3,4-c]pyrrol-
496.2
1.21 2(1H)-yl)methanone
(M+H)
hydrochloride (intermediate 2.1) /
6-sulfamoylnicotinic acid (CAS-
RN 2851350)
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(3aS,6aS)(3-fluorosulfamoyl-benzoyl)-
(3aS,6aS)cyano
hexahydro-pyrrolo[3,4-c]pyrrole
pivalamidobenzyl
carboxylic acid 4-cyano(2,2-dimethyl-
hexahydropyrrolo[3,4-c]pyrrole-
propionylamino)-benzyl ester
570.3
1.22 2(1H)-carboxylate hydrochloride
(M-H)
(intermediate 1.3) / 3-fluoro
sulfamoylbenzoic acid (CAS-RN
2446069)
(3aS,6aS)(6-sulfamoyl-pyridine
carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole- (3aS,6aS)cyano
2-carboxylic acid 4-cyano(2,2-dimethyl- pivalamidobenzyl
propionylamino)-benzyl ester hexahydropyrrolo[3,4-c]pyrrole-
553.3
1.23 2(1H)-carboxylate hydrochloride
(M-H)
(intermediate 1.3) / 6-
sulfamoylnicotinic acid (CAS-RN
2851350)
(3aS,6aS)(4-sulfamoyl-benzoyl)-
hexahydro-pyrrolo[3,4-c]pyrrole
(3aS,6aS)cyano
carboxylic acid 4-cyano(2,2-dimethyl-
pivalamidobenzyl
propionylamino)-benzylester
hexahydropyrrolo[3,4-c]pyrrole- 552.3
1.24
2(1H)-carboxylate hydrochloride (M-H)
(intermediate 1.3) / 4-
sulfamoylbenzoic acid
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
(3aS,6aS)(2-fluorosulfamoyl-benzoyl)-
(3aS,6aS)cyano
hexahydro-pyrrolo[3,4-c]pyrrole
pivalamidobenzyl
carboxylic acid 4-cyano(2,2-dimethyl-
hexahydropyrrolo[3,4-c]pyrrole-
propionylamino)-benzyl ester
570.4
1.25 2(1H)-carboxylate hydrochloride
(M-H)
(intermediate 1.3) / 2-fluoro
sulfamoylbenzoic acid (CAS-RN
7149680)
(3aS,6aS)(5-sulfamoyl-pyridine
carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole- (3aS,6aS)cyano
2-carboxylic acid 4-cyano(2,2-dimethyl- pivalamidobenzyl
propionylamino)-benzyl ester hexahydropyrrolo[3,4-c]pyrrole-
553.3
1.26 2(1H)-carboxylate hydrochloride
(M-H)
(intermediate 1.3) / 5-
sulfamoylpicolinic acid (CAS-RN
13086779)
Example 2
(3aR,6aS)-3,5-Dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate
N N O
H Cl
Acetyl chloride (8.7 mg, 110 µmol) was added at 0°C to a suspension of (3aR,6aS)-3,5-
dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (example
1.06; 40 mg, 92.1 µmol) and triethylamine (28.0 mg, 276 µmol) in dichloromethane (1 mL). The
ice bath was removed, then after 90 min another portion of acetyl chloride (5.8 mg, 73 µmol)
was added, then after another 2 h the reaction mixture was partitioned between dichloromethane
and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated.
Chromatography (silica gel; ethyl acetate–methanol gradient) produced the title compound (27
mg, 61%). White foam, MS: 476.4 (M+H) .
Example 2.1
(3aR,6aS)-3,5-Dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-
2(1H)-carboxylate
The title compound was produced in analogy to example 2, replacing (3aR,6aS)-3,5-
dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate by
(3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate (example 1.07). White solid, MS: 477.4 (M+H) .
Example 3
(3aR,6aS)-3,5-Dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate
Cl H
To a suspension of (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate hydrochloride (intermediate 1; 50 mg, 142 µmol) and pyridine (112 mg, 1.42 mmol)
in tetrahydrofuran (1 mL) was added a solution of 4-sulfamoylbenzenesulfonyl chloride (32.7
mg, 128 µmol) in tetrahydrofuran (1 mL) at 0°C, then the reaction mixture was stirred at room
temperature for 16 h. After partitioning between ethyl acetate and sat. aq. sodium
hydrogencarbonate solution, the organic layer was washed with brine, dried over magnesium
sulfate, filtered, and evaporated. The residue was triturated in ethyl acetate to produce the title
compound (45 mg, 59%). Light yellow solid, MS: 532.1 (M–H) .
Example 4
(3aR,6aS)-3,5-Dichlorobenzyl 5-(4-(1H-tetrazolyl)benzoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate
H Cl
To a solution of (3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate (example 1.08; 83 mg, 187 µmol) in 2-propanol (4 mL) and water
(5 mL) was added sodium azide (24.3 mg, 374 µmol) and zinc bromide (21.0 mg, 93.4 µmol).
The reaction mixture was heated at 80°C for 16 h, then another portion of sodium azide (24.3 mg,
374 µmol) and zinc bromide (21.0 mg, 93.4 µmol) was added, then after another 14 h the
reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed
with water and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography
(silica gel; gradient dichloromethane to dichloromethane/methanol 4:1) afforded the title
compound (46 mg, 51%). White foam, MS: 487.4 (M+H)+.
Example 5
4-((3aR,6aS)((3,5-Dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole
carbonyl)benzoic acid
H Cl
To a solution of (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydro-
pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (example 1.09; 82 mg, 172 µmol) in tetrahydrofuran
(1.5 mL) was added 2 M aq. sodium hydroxide solution (515 µl, 1.03 mmol). The reaction
mixture was stirred at room temperature for 2 h, then heated at 50°C for 3 h, then partitioned
between ethyl acetate and 1 M aq. hydrochloric acid solution. The organic layer was washed
with water and brine, dried over magnesium sulfate, filtered, and evaporated to afford the title
compound (74 mg, 93%). White solid, MS: 463.6 (M–H) .
Example 6
(3aR,6aS)-3,5-Dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-
c]pyrrole-2(1H)-carboxylate
H Cl
Step 1: (3aR,6aS)-3,5-Dichlorobenzyl 5-(5-(N-(methylsulfonyl)methylsulfonamido)-
picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
A solution of methanesulfonyl chloride (21 mg, 184 µmol) in dichloromethane (0.5 mL) was
added dropwise at 0°C to a solution of (3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)-
hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (example 1.07; 40 mg, 91.9 µmol) and
triethylamine (27.9 mg, 276 µmol) in dichloromethane (1 mL). The ice bath was removed, then
after 18 h the reaction mixture was partitioned between dichloromethane and water. The organic
layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated.
Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq.
ammonia solution 95:5:0.25) produced the title compound (42 mg, 77%). White foam, MS:
591.4 (M+H) .
Step 2: (3aR,6aS)-3,5-Dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydro-
pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
To a solution of (3aR,6aS)-3,5-dichlorobenzyl 5-(5-(N-(methylsulfonyl)methylsulfonamido)-
picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (36 mg, 60.9 µmol) in
tetrahydrofuran (0.5 mL) was added 1 M aq. sodium hydroxide solution (122 µl, 122 µmol), then
after 1 h the reaction mixture was partitioned between ethyl acetate and sat. aq. ammonium
chloride solution. The organic layer was washed with water and brine, dried over magnesium
sulfate, filtered, and evaporated to afford the title compound (29 mg, 93%). White foam, MS:
513.4 (M+H) .
Example 7
(3aS,6aS)(4-Sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 3-
chloromethanesulfonyl-benzyl ester
To a solution of (3-chloro(methylsulfonyl)phenyl)methanol (intermediate 5; 23.3 mg, 105
µmol) in acetonitrile (4 ml) was added N,N'-carbonyldiimidazole (18.0 mg, 111 µmol) at room
temperature, then after 2 h triethylamine (53.4 mg, 527 µmol) and 4-((3aR,6aR)-
octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide hydrochloride (intermediate 4;
mg, 105 µmol) were added and the reaction mixture was heated at reflux for 15 h. After
cooling the reaction mixture was partitioned between ethyl acetate and sat. aq. ammonium
chloride solution. The aqueous layer was back-extracted with ethyl acetate, then the combined
organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated.
The residue was triturated in tert-butyl methyl ether to afford the title compound (26 mg, 46%).
White solid, MS: 542.5 (M+H) .
The following examples were prepared according to example 7, replacing 4-((3aR,6aR)-
octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide hydrochloride by the
appropriate amine and (3-chloro(methylsulfonyl)phenyl)methanol by the appropriate alcohol.
Ex. Systematic Name Amine / Alcohol MS, m/e
4-((3aR,6aS)-
(3aR,6aS)(4-sulfamoyl-benzoyl)-hexahydro-
octahydropyrrolo[3,4-
pyrrolo[3,4-c]pyrrolecarboxylic acid 2-fluoro
c]pyrrolecarbonyl)-
trifluoromethoxy-benzyl ester
benzenesulfonamide
532.5
7.01 hydrochloride
H (M+H)
(intermediate 4.1) / (2-
N O fluoro(trifluoro-
methoxy)-
phenyl)methanol
4-((3aR,6aS)-
(3aR,6aS)(4-sulfamoyl-benzoyl)-hexahydro-
octahydropyrrolo[3,4-
pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
c]pyrrolecarbonyl)-
trifluoromethoxy-benzyl ester
benzenesulfonamide 514.6
7.02
H hydrochloride (M+H)
(intermediate 4.1) / (4-
O (trifluoromethoxy)-
phenyl)methanol
4-((3aR,6aR)-
(3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-
octahydropyrrolo[3,4-
pyrrolo[3,4-c]pyrrolecarboxylic acid 4-
c]pyrrolecarbonyl)-
trifluoromethoxy-benzyl ester
benzenesulfonamide 514.5
7.03
hydrochloride (M+H)
(intermediate 4) / (4-
O (trifluoromethoxy)-
phenyl)methanol
Example 8
4-{(3aR,6aR)[3-(4-Trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-
c]pyrrolecarbonyl}-benzenesulfonamide
To a white suspension of 4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole
carbonyl)benzenesulfonamide hydrochloride (intermediate 4; 40 mg, 121 µmol), N-
methylmorpholine (61.0 mg, 603 µmol) and 3-(4-(trifluoromethoxy)phenyl)propanoic acid (28.2
mg, 121 µmol) in N,N-dimethylformamide (5 ml) was added O-(7-azabenzotriazolyl)-
N,N,N’,N’-tetramethyluronium hexafluoro-phosphate (45.8 mg, 121 µmol) at 0°C, and the ice
bath was removed after 15 min. After 16 h, the reaction mixture was partitioned between
dichloromethane and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed
with sat. aq. ammonium chloride solution and brine, dried over magnesium sulfate, filtered and
evaporated. After trituration in tert-butyl methyl ether the precipitate was collected by filtration
to afford the title compound (44 mg, 71%). White solid, MS: 512.5 (M+H) .
The following examples were produced in analogy to example 8, replacing 4-((3aR,6aR)-
octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide hydrochloride by the
appropriate amine and 3-(4-(trifluoromethoxy)phenyl)propanoic acid by the appropriate
carboxylic acid.
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
4-((3aR,6aR)-
4-{(3aR,6aR)[(E)(4-trifluoromethoxy-
octahydropyrrolo[3,4-
phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-
c]pyrrolecarbonyl)-
2-carbonyl}-benzenesulfonamide
benzenesulfonamide 510.5
8.01
H hydrochloride (M+H)
(intermediate 4) / (E)
O (4-(trifluoromethoxy)-
phenyl)acrylic acid
4-((3aR,6aS)-
4-[(3aR,6aS)(4-isopropoxy-naphthalene
octahydropyrrolo[3,4-
carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
c]pyrrolecarbonyl)-
carbonyl]-benzenesulfonamide
benzenesulfonamide
508.4
8.02 O hydrochloride
(M+H)
(intermediate 4.1) / 4-
isopropoxynaphthoic
H NH
2 acid (CAS-RN
13688654)
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
4-((3aR,6aS)-
octahydropyrrolo[3,4-
4-{(3aR,6aS)[1-(2,2,2-trifluoro-ethoxy)-
c]pyrrolecarbonyl)-
isoquinolinecarbonyl]-hexahydro-pyrrolo[3,4-
benzenesulfonamide
c]pyrrolecarbonyl}-benzenesulfonamide
hydrochloride
549.6
8.03 (intermediate 4.1) / 1-
(M+H)
(2,2,2-trifluoroethoxy)-
N isoquinoline
H N NO
O carboxylic acid (CAS-
10969824)
4-((3aR,6aS)-
octahydropyrrolo[3,4-
4-[(3aR,6aS)(1-Methyltrifluoromethoxy-1H-
c]pyrrolecarbonyl)-
indolecarbonyl)-hexahydro-pyrrolo[3,4-
benzenesulfonamide
c]pyrrolecarbonyl]-benzenesulfonamide
hydrochloride
F 537.5
8.04 (intermediate 4.1) / 1-
(M+H)
methyl(trifluoro-
methoxy)-1H-indole
carboxylic acid (CAS-
12571221)
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
4-((3aR,6aS)-
4-[(3aR,6aS)(4-Isopropoxy-quinoline
octahydropyrrolo[3,4-
carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole
c]pyrrolecarbonyl)-
carbonyl]-benzenesulfonamide
benzenesulfonamide
509.6
8.05 O hydrochloride
(M+H)
(intermediate 4.1) / 4-
isopropoxyquinoline
N NH
carboxylic acid (CAS-
RN 14065532)
4-((3aR,6aS)-
octahydropyrrolo[3,4-
4-[(3aS,6aR)(4'-chloro-biphenylcarbonyl)-
c]pyrrolecarbonyl)-
hexahydro-pyrrolo[3,4-c]pyrrolecarbonyl]-
benzenesulfonamide
benzenesulfonamide
hydrochloride 510.5
8.06
H NH (intermediate 4.1) / 4'- (M+H)
O chlorobiphenyl
carboxylic acid (CAS-
57484)
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
4-((3aR,6aS)-
octahydropyrrolo[3,4-
4-{(3aS,6aR)[3-(2-fluorotrifluoromethoxy- c]pyrrolecarbonyl)-
phenyl)-propionyl]-hexahydro-pyrrolo[3,4- benzenesulfonamide
c]pyrrolecarbonyl}-benzenesulfonamide hydrochloride
530.3
8.07 (intermediate 4.1) / 3-
(M+H)
N F O
(2-fluoro(trifluoro-
methoxy)phenyl)-
propanoic acid (CAS-
12402572)
4-((3aR,6aS)-
4-{(3aS,6aR)[3-(4-trifluoromethoxy-phenyl)-
octahydropyrrolo[3,4-
propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole
c]pyrrolecarbonyl)-
carbonyl}-benzenesulfonamide
benzenesulfonamide 512.3
8.08
hydrochloride (M+H)
(intermediate 4.1) / 3-
(4-(trifluoromethoxy)-
phenyl)propanoic acid
Amine / Carboxylic
Ex. Systematic Name MS, m/e
acid
4-((3aR,6aR)-
octahydropyrrolo[3,4-
4-((3aR,6aR)(3-(2-fluoro c]pyrrolecarbonyl)-
(trifluoromethoxy)phenyl)propanoyl)octahydropyrr benzenesulfonamide
olo[3,4-c]pyrrolecarbonyl)benzenesulfonamide hydrochloride
530.5
8.09 (intermediate 4) / 3-(2-
(M+H)
N F O
fluoro(trifluoro-
methoxy)phenyl)-
propanoic acid (CAS-
12402572)
Examples 9A and 9B
(–)-trans-3,5-Dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-
(6H)-carboxylate and (+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-
pyrrolo[3,4-c]pyridine-5(6H)-carboxylate
H NH
H NH
The racemate, trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-
c]pyridine-5(6H)-carboxylate (example 1.03; 60 mg, 117 µmol) was separated by preparative
HPLC using a Reprosil Chiral-NR column as the stationary phase and heptane/ethanol 3:2 as the
mobile phase. This produced the faster eluting (–)-enantiomer (example 9A; 23 mg, 38%; white
solid, MS: 512.4 (M+H) ), and the slower eluting (+)-enantiomer (example 9B; 22 mg, 36%;
orange foam, MS: 512.4 (M+H) ).
Intermediates
Intermediate 1
(3aR,6aS)-3,5-Dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
hydrochloride
Step 1: (3aR,6aS)tert-Butyl 5-(3,5-dichlorobenzyl) tetrahydropyrrolo[3,4-c]pyrrole-
2,5(1H,3H)-dicarboxylate
To a light brown solution of (3,5-dichlorophenyl)methanol (425 mg, 2.35 mmol) in
dichloromethane (7 mL) was added N,N'-carbonyldiimidazole (401 mg, 2.47 mmol). The
solution was stirred at room temperature for 3 h, then (3aR,6aS)-tert-butyl
hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (CAS-RN 2502751; 526 mg, 2.35 mmol)
was added, then after 15 h the reaction mixture was partitioned between 1 M aq. hydrochloric
acid solution and dichloromethane. The organic layer was washed with brine, dried over
magnesium sulfate, filtered and evaporated to afford the title compound (972 mg, 99%). Light
brown viscous oil, MS: 359.2 (M–C(CH ) +H) .
Step 2: (3aR,6aS)-3,5-Dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
hydrochloride
To a solution of (3aR,6aS)tert-butyl 5-(3,5-dichlorobenzyl) tetrahydropyrrolo[3,4-c]pyrrole-
2,5(1H,3H)-dicarboxylate (962 mg, 2.32 mmol) in 2-propanol (4 mL) was added hydrochloric
acid (5–6 M in 2-propanol) (11.6 mL, 57.9 mmol), then after 3 h the reaction mixture was
evaporated. The residue taken up in ethyl acetate and a few drops of ethanol, then the precipitate
was collected by filtration to produce the title compound (738 mg, 91%). White solid, MS: 315.3
(M+H) .
The following intermediates were prepared according to intermediate 1, replacing (3aR,6aS)-
tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate by the appropriate amine and (3,5-
dichlorophenyl)methanol by the appropriate alcohol.
No. Systematic Name Amine Alcohol MS, m/e
trans-tert-butyl
trans-3,5-dichlorobenzyl
hexahydro-1H- (3,5-
hexahydro-1H-pyrrolo[3,4- 329.4
1.1 pyrrolo[3,4-c]pyridine- dichlorophenyl)-
c]pyridine-5(6H)- (M+H)
2(3H)-carboxylate (CAS- methanol
carboxylate hydrochloride
RN 12510145)
(3aR,6aR)-tert-butyl
(3aS,6aS)-hexahydro-
(4-(trifluoro-
pyrrolo[3,4-c]pyrrole hexahydropyrrolo[3,4-
methoxy)- 331.5
1.2 carboxylic acid 4- c]pyrrole-2(1H)-
phenyl)- (M+H)
trifluoromethoxy-benzyl carboxylate (intermediate
methanol
ester hydrochloride 3.1)
Intermediate 2
(E)((3aR,8aS)-Octahydropyrrolo[3,4-d]azepin-6(7H)-yl)(4-(trifluoromethoxy)-
phenyl)propenone hydrochloride
Step 1: (3aR,8aS)-tert-butyl 6-((E)(4-(trifluoromethoxy)phenyl)acryloyl)octahydro-
pyrrolo[3,4-d]azepine-2(1H)-carboxylate
To a solution of (3aR,8aS)-tert-butyl octahydropyrrolo[3,4-d]azepine-2(1H)-carboxylate
hydrochloride (CAS-RN 12510136; 1.5 g, 5.42 mmol), 4-methylmorpholine (2.19 g, 21.7
mmol) and (E)(4-(trifluoromethoxy)phenyl)acrylic acid (1.26 g, 5.42 mmol) in N,N-
dimethylformamide (30 ml) was added O-(7-azabenzotriazolyl)-N,N,N’,N’-
tetramethyluronium hexafluoro-phosphate (2.06 g, 5.42 mmol) at 0°C. After 60 min the ice bath
was removed, then after 16 h the reaction mixture was partitioned between ethyl acetate and sat.
aq. sodium hydrogencarbonate solution. The organic layer was washed with sat. aq. ammonium
chloride solution, water, and brine, dried over magnesium sulfate, filtered, and evaporated. The
residue was triturated in heptane/ethyl acetate 9:1 to produce the title compound (2.20 g, 89%).
White solid, MS: 399.5 (M – isobutene + H) .
Step 2: (E)((3aR,8aS)-Octahydropyrrolo[3,4-d]azepin-6(7H)-yl)(4-(trifluoromethoxy)-
phenyl)propenone hydrochloride
The title compound was produced in analogy to intermediate 1, step 2 from (3aR,8aS)-tert-butyl
6-((E)(4-(trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo[3,4-d]azepine-2(1H)-
carboxylate. White solid, MS: 355.5 (M+H) .
The following intermediates were prepared according to intermediate 2, replacing (3aR,8aS)-
tert-butyl octahydropyrrolo[3,4-d]azepine-2(1H)-carboxylate hydrochloride by the appropriate
amine and (E)(4-(trifluoromethoxy)phenyl)acrylic acid by the appropriate carboxylic acid.
No. Systematic Name Amine Carboxylic acid MS, m/e
(4-ethoxyquinolin (3aR,6aR)-tert-butyl 4-ethoxy-
yl)((3aS,6aS)-hexa- hexahydropyrrolo[3,4- quinoline
312.2
2.1 hydropyrrolo[3,4-c]pyrrol- c]pyrrole-2(1H)- carboxylic acid
(M+H)
2(1H)-yl)methanone carboxylate (intermediate (CAS-RN
hydrochloride 3.1) 406097)
1-((3aS,6aS)-hexahydro- (3aR,6aR)-tert-butyl
3-(4-(trifluoro-
pyrrolo[3,4-c]pyrrol- hexahydropyrrolo[3,4-
methoxy)- 329.5
2.2 2(1H)-yl)(4-(trifluoro- c]pyrrole-2(1H)-
phenyl)- (M+H)
methoxy)phenyl)propan carboxylate (intermediate
propanoic acid
one dihydrochloride 3.1)
Intermediate 3
(3aS,6aS)-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
Step 1: (3R,4R)-tert-Butyl 3,4-bis((methylsulfonyloxy)methyl)pyrrolidinecarboxylate
To a solution of (3R,4R)-tert-butyl 3,4-bis(hydroxymethyl)pyrrolidinecarboxylate (CAS-RN
8952456; 2.97 g, 12.8 mmol) and N,N-diisopropylethylamine (9.96 g, 77.0 mmol) in
dichloromethane (70 ml) was added a solution of methanesulfonyl chloride (4.41 g, 38.5 mmol)
in dichloromethane (5 ml) dropwise at 0°C, then after 1 h the reaction mixture was treated with
sat. aq. ammonium chloride and extracted with ethyl acetate. The organic layer was washed with
sat. aq. sodium hydrogencarbonate solution and brine, dried over magnesium sulfate, filtered,
and evaporated. Chromatography (silica gel; heptane–ethyl acetate gradient) produced the title
compound (4.22 g, 85%). Light yellow oil, MS: 332.4 (M – isobutene + H) .
Step 2: (3aS,6aS)-tert-Butyl 5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
To a solution of (3R,4R)-tert-butyl 3,4-bis((methylsulfonyloxy)methyl)pyrrolidinecarboxylate
(4.22 g, 10.9 mmol) in acetonitrile (100 ml) was added potassium carbonate (15.1 g, 109 mmol)
and phenylmethanamine (3.5 g, 32.7 mmol). The reaction mixture was heated at 95°C for 45 h,
then cooled to room temperature and partitioned between ethyl acetate and water. The organic
layer was washed with sat. aq. ammonium chloride solution, sat. aq. sodium hydrogencarbonate
solution, and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography
(silica gel; ethyl acetate – methanol gradient) produced the title compound (2.23 g 68%). Light
yellow solid, MS: 303.5 (M+H) .
Step 3: (3aS,6aS)-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
To a solution of (3aS,6aS)-tert-butyl 5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
(2.22 g, 7.34 mmol, Eq: 1.00) in methanol (20 mL) was added palladium (10% on carbon, 220
mg, 7.34 mmol), and the reaction mixture was stirred under a hydrogen atmosphere (1 bar) at
room temperature for 24 h, then insoluble material was removed by filtration through
diatomaceous earth. The filtrate was concentrated to produce the title compound (1.60 g, 100%).
White waxy solid, MS: 213.5 (M+H) .
Intermediate 3.1
(3aR,6aR)-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
The title compound was produced in analogy to intermediate 3, replacing (3R,4R)-tert-butyl 3,4-
bis(hydroxymethyl)pyrrolidinecarboxylate by (3S,4S)- tert-butyl 3,4-
bis(hydroxymethyl)pyrrolidinecarboxylate (CAS-RN 8952454). White waxy solid, MS:
213.3 (M+H) .
Intermediate 4
4-((3aR,6aR)-Octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide
hydrochloride
Step 1: (3aS,6aS)-tert-Butyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate
To a solution of (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
(intermediate 3; 206 mg, 970 µmol), N-methylmorpholine (294 mg, 2.91 mmol) and 4-
sulfamoylbenzoic acid (203 mg, 970 µmol) in N,N-dimethylformamide (10 ml) was added O-(7-
azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate (369 mg, 970 µmol)
at 0°C, then after 10 min the ice-bath was removed. After 16 h the reaction mixture was
partitioned between dichloromethane and sat. aq. sodium hydrogencarbonate solution. The
organic layer was washed with sat. aq. ammonium chloride solution and brine, dried over
magnesium sulfate, filtered and evaporated. After trituration in tert-butyl methyl ether the
precipitate was collected by filtration to afford the title compound (348 mg, 91%). Light yellow
solid, MS: 396.6 (M+H) .
Step 2: 4-((3aR,6aR)-Octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide
hydrochloride (intermediate 4)
The title compound was produced in analogy to intermediate 1, step 2 from (3aS,6aS)-tert-butyl
-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. Light yellow solid,
MS: 296.5 (M+H) .
Intermediate 5
(3-Chloro(methylsulfonyl)phenyl)methanol
To a solution of 3-chloro(methylsulfonyl)benzoic acid (CAS-RN 1511041; 500 mg, 2.13
mmol) in tetrahydrofuran (5 mL) was added slowly borane-tetrahydrofuran complex solution (1
M solution in tetrahydrofuran, 5.33 mL, 5.33 mmol) at 0°C, then after 3 h the ice-bath was
removed and the rection mixture was stirred at room temperature overnight. The reaction
mixture was then carefully treated with methanol (3 mL) and evaporated. The residue was
partitioned between ethyl acetate and water. The organic layer was washed with brine, dried
over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane–ethyl
acetate gradient afforded the title compound (428 mg, 91%). White solid, MS: 221.3 (M+H) .
Intermediate 6
N-(5-Cyano(hydroxymethyl)phenyl)pivalamide
Step 1: Methyl 4-cyanopivalamidobenzoate
To a solution of methyl 2-aminocyanobenzoate (CAS-RN 1598473; 776 mg, 4.4 mmol)
in pyridine (6 mL) was added pivaloyl chloride (637 mg, 5.29 mmol) dropwise at 0°C, then after
2 h the reacion mixture was partitioned between 1 M aq. hydrochloric acid solution and ethyl
acetate/2-methyltetrahydrofuran. The organic layer was washed with water, 2 M aq. sodium
carbonate solution, and brine, dried over magnesium sulfate, filtered, and evaporated. The
residue was triturated in ethyl acetate to afford the title compound (819 mg). The mother liquor
was evaporated and triturated in tert-butyl methyl ether to produce a second crop of product (148
mg). Combined yield: 967 mg (84%). White solid, MS: 261.1 (M–H) .
N-(5-cyano(hydroxymethyl)phenyl)pivalamide
A suspension of calcium chloride (592 mg, 5.33 mmol) in ethanol (15 mL) was added at room
temperature to a solution of methyl 4-cyanopivalamidobenzoate (694 mg, 2.67 mmol) in
tetrahydrofuran (15 mL), then sodium borohydride (403 mg, 10.7 mmol) was added. After 2 h
the reaction mixture was poured upon ice water and sat. ammonium chloride solution and
extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium
sulfate, filtered, and evaporated. The residue was triturated in tert-butyl methyl ether to produce
the title compound (293 mg). The mother liquour was evaporated and purified by
chromatography (dichloromethane–methanol gradient) to produce another crop of product (240
mg). Combined yield: 533 mg; (86%). White solid, MS: 231.1 (M–H).
Claims (35)
1. Compounds of formula (I) ( ) ( ) 1 ( ) ( ) wherein 5 R is substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted naphthyl, substituted naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted 10 pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindolyl, substituted 1H-indolyl or substituted benzofuranyl wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted 15 phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted naphthyl, substituted naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted 20 thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindolyl, substituted 1H-indolyl and substituted 7 8 9 benzofuranyl are substituted with R , R and R ; R is substituted phenyl, substituted pyridinyl, substituted pyrrolyl, oxodihydropyridinyl or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl, substituted 10 11 12 25 pyrrolyl and substituted thiophenyl are substituted with R , R and R ; NN NN Y is -OC(O)-, -NR C(O)-, -C(O)-, -S(O) -, or ; A is -N- or CH-; 6 3 4 W is -O-, -S-, -NR -, -C(O)-, -S(O) -, or -CR R -; R and R are independently selected from H, halogen, alkyl and cycloalkyl; R and R are independently selected from H, alkyl and cycloalkyl; 7 8 9 5 R , R and R are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl, 10 haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, 15 cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, 7 8 9 halogen, haloalkyl, alkoxy and haloalkoxy, wherein at least one of R , R and R is not 20 R is aminosulfonyl, alkoxycarbonyl, alkylcarbonylamino, alkylsulfonylamino, substituted amino, carboxy, cyano, hydroxy or tetrazolyl, wherein substituted amino is substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl; 11 12 R and R are independently selected from H, alkyl, cycloalkyl, alkoxy, halogen and 25 haloalkyl; m, n, p and q are independently selected from 1 or 2; or pharmaceutically acceptable salts.
2. A compound according to claim 1, wherein R is substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl, or substituted isoquinolyl, wherein substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, 7 8 9 5 substituted quinolyl and substituted isoquinolyl are substituted with R , R and R . 1 7 8
3. A compound according to claim 1 or 2, wherein R is phenylalkyl substituted with R , R and R .
4. A compound according to any one of claims 1 to 3, wherein R is 3,5-dichlorobenzyl, 4- trifluoromethoxybenzyl or 4-trifluoromethoxyphenylethyl. 10
5. A compound according to any one of claims 1 to 4, wherein R is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted 10 11 12 with R , R and R .
6. A compound according to any one of claims 1 to 5, wherein R is phenyl substituted with 10 11 12 R , R and R . 15
7. A compound according to any one of claims 1 to 5, wherein R is 4-aminosulfonylphenyl, 3-fluoroaminosulfonylphenyl, 3-aminosulfonylpyridinyl or 2-aminosulfonylpyridin- 5-yl.
8. A compound according to any one of claims 1 to 7, wherein Y is -OC(O)- or -C(O)-.
9. A compound according to any one of claims 1 to 8, wherein A is -N-. 20
10. A compound according to any one of claims 1 to 9, wherein W is -C(O)- or -S(O) -.
11. A compound according to any one of claims 1 to 10, wherein W is -C(O)-. 7 8 9
12. A compound according to any one of claims 1 to 11, wherein R , R and R are independently selected from H, alkoxy, haloalkoxy, halogen, alkylsulfonyl and phenyl 7 8 9 substituted with one halogen, and wherein at least one of R , R and R is not H. 25
13. A compound according to any one of claims 1 to 12, wherein R is alkoxy, haloalkoxy, halogen or phenyl substituted with one halogen.
14. A compound according to any one of claims 1 to 13, wherein R is haloalkoxy or halogen.
15. A compound according to any one of claims 1 to 14, wherein R is H, halogen or alkylsulfonyl.
16. A compound according to any one of claims 1 to 15, wherein R is H or halogen. 5
17. A compound according to any one of claims 1 to 16, wherein R is H.
18. A compound according to any one of claims 1 to 17, wherein R is aminosulfonyl. 11 12
19. A compound according to any one of claims 1 to 18, wherein R and R are independently selected from H, alkyl and halogen. 11 12
20. A compound according to any one of claims 1 to 19, wherein R and R are 10 independently selected from H and halogen.
21. A compound according to any one of claims 1 to 20, wherein m and n are1.
22. A compound according to any one of claims 1 to 21, wherein m, n, p and q are1.
23. A compound according to any one of claims 1 to 22 of formula (Ia). ( ) ( ) Y N A W ( ) ( ) R q n (Ia) 15
24. A compound according to any one of claims 1 to 23, selected from (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate; trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine- 5(6H)-carboxylate; 5 (3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophenecarbonyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- 10 carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate; 15 (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate; 4-{(3aS,8aR)[(E)(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4- d]azepinecarbonyl}-benzenesulfonamide; (3aS,6aS)(3-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic 20 acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)(6-oxo-1,6-dihydro-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carboxylic acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carboxylic acid 4-trifluoromethoxy-benzyl ester; 25 (3aS,6aS)(1-methylsulfamoyl-1H-pyrrolecarbonyl)-hexahydro-pyrrolo[3,4- c]pyrrolecarboxylic acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)(1-methylsulfamoyl-1H-pyrrolecarbonyl)-hexahydro-pyrrolo[3,4- c]pyrrolecarboxylic acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)(6-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carboxylic acid 4-trifluoromethoxy-benzyl ester; 5 (3aS,6aS)(5-hydroxy-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carboxylic acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4- trifluoromethoxy-benzyl ester; (3aR,6aS)-3,5-dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole- 10 2(1H)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate; 15 (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(1H-tetrazolyl)benzoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate; 4-((3aR,6aS)((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole carbonyl)benzoic acid; (3aR,6aS)-3,5-dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4- 20 c]pyrrole-2(1H)-carboxylate; (3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 3- chloromethanesulfonyl-benzyl ester; (3aR,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 2- fluorotrifluoromethoxy-benzyl ester; 25 (3aR,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4- trifluoromethoxy-benzyl ester; (3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4- trifluoromethoxy-benzyl ester; 4-{(3aR,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4- c]pyrrolecarbonyl}-benzenesulfonamide; 5 4-{(3aR,6aR)[(E)(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4- c]pyrrolecarbonyl}-benzenesulfonamide; 4-[(3aR,6aS)(4-isopropoxy-naphthalenecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole- 2-carbonyl]-benzenesulfonamide; 4-{(3aR,6aS)[1-(2,2,2-trifluoro-ethoxy)-isoquinolinecarbonyl]-hexahydro- 10 pyrrolo[3,4-c]pyrrolecarbonyl}-benzenesulfonamide; 4-[(3aR,6aS)(1-Methyltrifluoromethoxy-1H-indolecarbonyl)-hexahydro- pyrrolo[3,4-c]pyrrolecarbonyl]-benzenesulfonamide; 4-[(3aR,6aS)(4-Isopropoxy-quinolinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carbonyl]-benzenesulfonamide; 15 4-[(3aS,6aR)(4'-chloro-biphenylcarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carbonyl]-benzenesulfonamide; 4-{(3aS,6aR)[3-(2-fluorotrifluoromethoxy-phenyl)-propionyl]-hexahydro- pyrrolo[3,4-c]pyrrolecarbonyl}-benzenesulfonamide; 4-{(3aS,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4- 20 c]pyrrolecarbonyl}-benzenesulfonamide; 4-((3aR,6aR)(3-(2-fluoro(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4- c]pyrrolecarbonyl)benzenesulfonamide; (+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine- 5(6H)-carboxylate; 25 (-)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine- 5(6H)-carboxylate; (3aS,6aS)(2-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-trifluoromethoxy-benzyl ester; 5-{(3aR,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4- c]pyrrolecarbonyl}-pyridinesulfonic acid amide; 5 5-((3aS,6aS)(4-ethoxyquinolinecarbonyl)octahydropyrrolo[3,4-c]pyrrole carbonyl)pyridinesulfonamide; (3aS,6aS)(3-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester; (3aS,6aS)(6-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole 10 carboxylic acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester; (3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4- cyano(2,2-dimethyl-propionylamino)-benzylester; (3aS,6aS)(2-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester; 15 (3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carboxylic acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester; and pharmaceutically acceptable salts thereof.
25. A compound according to any one of claims 1 to 24, selected from (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole- 20 2(1H)-carboxylate; (3aS,6aS)(3-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carboxylic acid 4-trifluoromethoxy-benzyl ester; 25 (3aS,6aS)(6-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carboxylic acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4- trifluoromethoxy-benzyl ester; 4-{(3aR,6aR)[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4- c]pyrrolecarbonyl}-benzenesulfonamide; 5 (3aS,6aS)(5-sulfamoyl-pyridinecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole carboxylic acid 4-cyano(2,2-dimethyl-propionylamino)-benzyl ester; (3aS,6aS)(2-fluorosulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4-trifluoromethoxy-benzyl ester; and pharmaceutically acceptable salts thereof. 10
26. A compound according to any one of claims 1 to 25, which is (3aS,6aS)(2-fluoro sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrolecarboxylic acid 4- trifluoromethoxy-benzyl ester.
27. A process to prepare a compound according to any one of claims 1 to 26 comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), 15 wherein R , R , A, W, m, n, p and q are as defined above, Y is -OC(O)- p m N p m ( ) ( ) ( ) ( ) (III) A W A W HN Y N ( ) ( ) 1 ( ) ( ) q n q n (II)
28. A compound according to any one of claims 1 to 26 for use as therapeutically active substance.
29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 26 and a therapeutically inert carrier.
30. A compound according to any one of claims 1 to 26 for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
31. The use of a compound according to any one of claims 1 to 26 for the preparation of a 5 medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
32. The compound according to any one of claims 1 to 26, 28 and 30 substantially as herein described with reference to any example thereof. 10
33. The process according to claim 27 substantially as herein described with reference to any example thereof.
34. The pharmaceutical composition according to claim 29 substantially as herein described with reference to any example thereof.
35. The use according to claim 31 substantially as herein described with reference to any 15 example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP13158724.8 | 2013-03-12 | ||
EP13158724 | 2013-03-12 | ||
PCT/EP2014/054631 WO2014139978A1 (en) | 2013-03-12 | 2014-03-11 | New octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors |
Publications (2)
Publication Number | Publication Date |
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NZ711002A NZ711002A (en) | 2020-09-25 |
NZ711002B2 true NZ711002B2 (en) | 2021-01-06 |
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