ZA200304265B - Isoindolin-1-one glucokinase activators. - Google Patents
Isoindolin-1-one glucokinase activators. Download PDFInfo
- Publication number
- ZA200304265B ZA200304265B ZA200304265A ZA200304265A ZA200304265B ZA 200304265 B ZA200304265 B ZA 200304265B ZA 200304265 A ZA200304265 A ZA 200304265A ZA 200304265 A ZA200304265 A ZA 200304265A ZA 200304265 B ZA200304265 B ZA 200304265B
- Authority
- ZA
- South Africa
- Prior art keywords
- isoindol
- propionamide
- dihydro
- cyclohexyl
- oxo
- Prior art date
Links
- 102000030595 Glucokinase Human genes 0.000 title description 22
- 108010021582 Glucokinase Proteins 0.000 title description 22
- 239000012190 activator Substances 0.000 title description 4
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 title description 2
- 229940080818 propionamide Drugs 0.000 claims description 81
- 150000001875 compounds Chemical class 0.000 claims description 79
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
- 229910052799 carbon Inorganic materials 0.000 claims description 38
- 150000001721 carbon Chemical group 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- 229910052757 nitrogen Chemical group 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 18
- -1 benzoimidazolyl Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 125000002950 monocyclic group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000001301 oxygen Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 239000011593 sulfur Substances 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 150000001204 N-oxides Chemical class 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000011321 prophylaxis Methods 0.000 claims description 5
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 5
- GBNHOHZADLLVKN-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(7-fluoro-3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)F)C(=O)NC=1SC=CN=1)C1CCCCC1 GBNHOHZADLLVKN-KRWDZBQOSA-N 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- VPMSFNVPKXVXRA-UHFFFAOYSA-N n-(5-chloro-1,3-thiazol-2-yl)-3-cyclopentyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound S1C(Cl)=CN=C1NC(=O)C(N1C(C2=CC=CC=C2C1)=O)CC1CCCC1 VPMSFNVPKXVXRA-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- CAFYGEUIKNMVSG-SFHVURJKSA-N (2s)-3-cyclohexyl-2-(7-fluoro-3-oxo-1h-isoindol-2-yl)-n-pyrazin-2-ylpropanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)F)C(=O)NC=1N=CC=NC=1)C1CCCCC1 CAFYGEUIKNMVSG-SFHVURJKSA-N 0.000 claims description 3
- 125000005872 benzooxazolyl group Chemical group 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- AVZFDRVTBXTFED-LJQANCHMSA-N (2r)-n-(5-bromopyridin-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound N1=CC(Br)=CC=C1NC(=O)[C@H](N1C(C2=CC=CC=C2C1)=O)CC1CCCCC1 AVZFDRVTBXTFED-LJQANCHMSA-N 0.000 claims description 2
- VEMZDALOYZQAEW-QHCPKHFHSA-N (2s)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)-n-quinolin-2-ylpropanamide Chemical compound C([C@@H](C(NC=1N=C2C=CC=CC2=CC=1)=O)N1C(C2=CC=CC=C2C1)=O)C1CCCCC1 VEMZDALOYZQAEW-QHCPKHFHSA-N 0.000 claims description 2
- FXJNEBZFBPOSTM-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(4-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-pyrimidin-4-ylpropanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)S(=O)(=O)C)C(=O)NC=1N=CN=CC=1)C1CCCCC1 FXJNEBZFBPOSTM-KRWDZBQOSA-N 0.000 claims description 2
- JRASWERIVQXADO-NRFANRHFSA-N (2s)-n-(1h-benzimidazol-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound C([C@@H](C(NC=1NC2=CC=CC=C2N=1)=O)N1C(C2=CC=CC=C2C1)=O)C1CCCCC1 JRASWERIVQXADO-NRFANRHFSA-N 0.000 claims description 2
- PLENEAJJYFHWBP-HNNXBMFYSA-N (2s)-n-cyclohexyl-n-(2-methylpyrimidin-4-yl)-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound O=C([C@@H](N1C(C2=CC=CC=C2C1)=O)C)N(C=1N=C(C)N=CC=1)C1CCCCC1 PLENEAJJYFHWBP-HNNXBMFYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 238000010976 amide bond formation reaction Methods 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 4
- BMJGFYCEVPVPNV-KRWDZBQOSA-N (2s)-2-(7-chloro-3-oxo-1h-isoindol-2-yl)-3-cyclohexyl-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)Cl)C(=O)NC=1SC=CN=1)C1CCCCC1 BMJGFYCEVPVPNV-KRWDZBQOSA-N 0.000 claims 1
- HAZJQNXTVYBGMP-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound O=C([C@H](CC1CCCCC1)N1C(C2=CC=CC=C2C1)=O)NC1=NC=CS1 HAZJQNXTVYBGMP-KRWDZBQOSA-N 0.000 claims 1
- FSHQEAUMFQXYOM-SFHVURJKSA-N (2s)-3-cyclohexyl-2-(7-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-pyrazin-2-ylpropanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)S(=O)(=O)C)C(=O)NC=1N=CC=NC=1)C1CCCCC1 FSHQEAUMFQXYOM-SFHVURJKSA-N 0.000 claims 1
- ABUMTHLKVAXGJG-SFHVURJKSA-N (2s)-3-cyclohexyl-2-(7-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-pyrimidin-4-ylpropanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)S(=O)(=O)C)C(=O)NC=1N=CN=CC=1)C1CCCCC1 ABUMTHLKVAXGJG-SFHVURJKSA-N 0.000 claims 1
- HEMJGYNZNHUXMQ-FQEVSTJZSA-N (2s)-n-(1,3-benzoxazol-2-yl)-3-cyclohexyl-2-(3-oxo-1h-isoindol-2-yl)propanamide Chemical compound C([C@@H](C(NC=1OC2=CC=CC=C2N=1)=O)N1C(C2=CC=CC=C2C1)=O)C1CCCCC1 HEMJGYNZNHUXMQ-FQEVSTJZSA-N 0.000 claims 1
- CRJFRTOZGDAQPG-UHFFFAOYSA-N 3-cycloheptyl-2-(3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C1CCCCCC1CC(N1C(C2=CC=CC=C2C1)=O)C(=O)NC1=NC=CS1 CRJFRTOZGDAQPG-UHFFFAOYSA-N 0.000 claims 1
- PWPUNWJDAFANEV-UHFFFAOYSA-N 3-cyclopentyl-2-(3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C1CCCC1CC(N1C(C2=CC=CC=C2C1)=O)C(=O)NC1=NC=CS1 PWPUNWJDAFANEV-UHFFFAOYSA-N 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 239000002253 acid Substances 0.000 description 13
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 12
- 239000008103 glucose Substances 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 7
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000001828 Gelatine Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 102000005548 Hexokinase Human genes 0.000 description 3
- 108700040460 Hexokinases Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 230000004153 glucose metabolism Effects 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 101150109586 Gk gene Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000035180 MODY Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 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 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 201000006950 maturity-onset diabetes of the young Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 150000003022 phthalic acids Chemical class 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 150000003557 thiazoles Chemical class 0.000 description 2
- XHWIOENGQYROJH-INIZCTEOSA-N (2s)-2-(4-chloro-3-oxo-1h-isoindol-2-yl)-3-cyclohexyl-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)Cl)C(=O)NC=1SC=CN=1)C1CCCCC1 XHWIOENGQYROJH-INIZCTEOSA-N 0.000 description 1
- GBFOLYLWHXRFRM-SFHVURJKSA-N (2s)-2-(7-chloro-3-oxo-1h-isoindol-2-yl)-3-cyclohexyl-n-pyrazin-2-ylpropanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)Cl)C(=O)NC=1N=CC=NC=1)C1CCCCC1 GBFOLYLWHXRFRM-SFHVURJKSA-N 0.000 description 1
- AESJIZQMLZJCIX-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(4-fluoro-3-oxo-1h-isoindol-2-yl)-n-pyrazin-2-ylpropanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)F)C(=O)NC=1N=CC=NC=1)C1CCCCC1 AESJIZQMLZJCIX-KRWDZBQOSA-N 0.000 description 1
- BVNOVXGXNDLFON-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(4-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-pyrazin-2-ylpropanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)S(=O)(=O)C)C(=O)NC=1N=CC=NC=1)C1CCCCC1 BVNOVXGXNDLFON-KRWDZBQOSA-N 0.000 description 1
- AMYSZDQNPNHAGO-KRWDZBQOSA-N (2s)-3-cyclohexyl-2-(7-methylsulfonyl-3-oxo-1h-isoindol-2-yl)-n-(1,3-thiazol-2-yl)propanamide Chemical compound C([C@H](N1C(=O)C=2C=CC=C(C=2C1)S(=O)(=O)C)C(=O)NC=1SC=CN=1)C1CCCCC1 AMYSZDQNPNHAGO-KRWDZBQOSA-N 0.000 description 1
- JFZLHUCEJYRSNM-HNNXBMFYSA-N (2s)-n-(5-chloro-1,3-thiazol-2-yl)-3-cyclohexyl-2-(4-fluoro-3-oxo-1h-isoindol-2-yl)propanamide Chemical compound C([C@H](N1CC=2C=CC=C(C=2C1=O)F)C(=O)NC=1SC(Cl)=CN=1)C1CCCCC1 JFZLHUCEJYRSNM-HNNXBMFYSA-N 0.000 description 1
- CLICAWXVUGZAHG-INIZCTEOSA-N (2s)-n-(5-chloro-1,3-thiazol-2-yl)-3-cyclohexyl-2-(6-nitro-3-oxo-1h-isoindol-2-yl)propanamide Chemical compound C([C@H](N1C(=O)C2=CC=C(C=C2C1)[N+](=O)[O-])C(=O)NC=1SC(Cl)=CN=1)C1CCCCC1 CLICAWXVUGZAHG-INIZCTEOSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- KTPMVZCGIJJWCD-UHFFFAOYSA-N 1-hydroxypyridin-2-imine Chemical compound ON1C=CC=CC1=N KTPMVZCGIJJWCD-UHFFFAOYSA-N 0.000 description 1
- FFJWPGGBISIFHI-UHFFFAOYSA-N 1-methylnaphthalen-2-amine Chemical compound C1=CC=C2C(C)=C(N)C=CC2=C1 FFJWPGGBISIFHI-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical class O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- ZLOCOQNMVGDMBT-UHFFFAOYSA-N 2-[(5,6-dihydroxy-4-methoxy-2h-pyran-2-yl)oxy]-4-methoxy-2h-pyran-5,6-diol Chemical class O1C(O)=C(O)C(OC)=CC1OC1C=C(OC)C(O)=C(O)O1 ZLOCOQNMVGDMBT-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- ZZOKVYOCRSMTSS-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl carbamate Chemical compound C1=CC=C2C(COC(=O)N)C3=CC=CC=C3C2=C1 ZZOKVYOCRSMTSS-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical class ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000002660 insulin-secreting cell Anatomy 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000004457 myocytus nodalis Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 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
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Isoindolin-l-one Glucokinase Activators
Glucokinase (GK) is one of four hexokinases that are found in mammals [Colowick, S.P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York,
NY, pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic B-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose "homeostasis [Chipkin, S.R., Kelly, K.L., and Ruderman, N.B. in Joslin’s Diabetes (C.R.
Khan and G.C. Wier, eds.), Lea and Febiger, Philadelphia, PA, pages 97-115, 1994].
The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations (<1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (=10-15 mM) levels following a carbohydrate-containing meal [Printz,
R.G., Magnuson, M.A., and Granner, D.K. in Ann. Rev. Nutrition Vol. 13 (R.E. Olson,
D.M. Bier, and D.B. McCormick, eds.), Annual Review, Inc., Palo Alto, CA, pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that
GK functions as a glucose sensor in P-cells and hepatocytes (Meglasson, M.D. and
Matschinsky, F.M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole- body glucose homeostasis. Animals that do not express GK die within days of birth 7 with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E.,
Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in B-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a , glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167- 173, 1995). Additional evidence supporting an important role for GK in the regulation ‘ 5 of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England ]. Med. 338, 226-230, 1998).
While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in B-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
This invention provides a compound comprising an amide of the formula:
R} iy ~
N
\ °o J Ro wherein A is unsubstituted phenyl or phenyl which is mono- or di-substituted with halo or mono-substituted with lower alkyl sulfonyl, lower alkyl thio or nitro;
R! is cycloalkyl having from 3 to 9 carbon atoms or lower alkyl having from 2 to 4 carbon atoms;
R? is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six- membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, which ring may be monocyclic or fused with phenyl at two of its ring carbons, said monosubstituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom With a substituent selected from the group consisting of halo,
lower alkyl, nitro, cyano, perfluoro-lower alkyl; hydroxy, -(CH,),-OR’, -(CHy)n-C(O)-
OR’, -(CH3)a-C(0)-NH-R?, -C(O)C(0)-OR?, or -(CH;),-NHR* where R® is hydrogen ‘ or lower alkyl; and nis 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salts or N-oxides thereof.
Preferably R? is a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown in formula I, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom. This ring may be monocyclic or may be fused with phenyl at two of its ring carbons. In accordance with an embodiment of this invention, the adjacent nitrogen in the nitrogen containing heteroaromatic rings may be in the form of an N- oxide where the nitrogen adjacent to the ring carbon atom is converted to an N-oxide.
On the other hand, compounds of formula I can be in the form of pharmaceutically acceptable salts.
The compounds of formula I have been found to activate glucokinase in vitro.
Glucokinase activators are useful for increasing insulin secretion in the treatment of type II diabetes.
The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier and/or adjuvant.
Furthermore, the present invention relates to the use of such compounds as therapeutic active substances as well as to their use for the preparation of medicaments for the treatment or prophylaxis of type II diabetes. The present invention further relates to processes for the preparation of the compounds of formula I. In addition, the present invention relates to a method for the prophylactic or therapeutic treatment of type II diabetes, which method comprises administering a compound of formula I to a human being or an animal.
In more detail, this invention provides a compound comprising an amide of the formula I above or an N-oxide of the amide of formula I above, as well as pharmaceutically acceptable salts thereof.
In the compound of formula I, the “+” illustrates the asymmetric carbon atom in this compound. The compound of formula I may be present as a racemate at the . asymmetric carbon shown. However, the “S” enantiomers, where the amide is in the "S"configuration at the asymmetric carbon, is preferred. When the phenyl ring A is ‘ 5 monosubstituted with lower alkyl sulfonyl, nitro or lower alkyl thio, it is preferred that it is substituted at the 5- or 6-position as indicated in formula I. Thus, when A is phenyl substituted with nitro, it is preferred that this substitution be at positions 5 or 6 such as 5-nitro phenyl and 6 nitro phenyl.
In one embodiment of formula I, the R? ring as described above is a single, or monocyclic (unfused) ring. When R? is a monocyclic ring, it is preferably substituted or unsubstituted pyridine. In another embodiment of formula I, the R? ring as described above is a bicyclic ring, i.e. is fused with a phenyl.
As used throughout this application, the term “lower alkyl” includes both straight chain and branched chain alkyl groups having from 1 to 10 and preferably 3 to 9 carbon atoms, such as propyl, isopropyl, heptyl, and especially 2 to 4 carbon atoms.
As used herein, the term "cycloalkyl" signifies a 3- to 9-membered cycloalkyl ring, preferably 5- to 8-membered, for example cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
As used herein, “perfluoro-lower alkyl” means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro. Among the preferred perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc.
As used herein, "lower alkyl thio" means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in a thio group.
As used herein, "lower alkyl sulfonyl" means a lower alkyl group as defined above bound to the res: of the molecule through the sulfur atom in a sulfonyl group.
As used herein, the term “halogen” is used interchangeably with the word "halo”, and, unless otherwise stated, designates all four halogens, i.e. fluorine, chlorine, bromine, and iodine.
As used Joven, the term "N-oxide" means a negatively charged oxygen atom which is covalently linked to a nitrogen which is positively charged in a heteroaromatic . ring.
As used herein, "heteroaromatic ring" means a five or six membered unsaturated carbacyclic ring where one or more carbon is replaced by a heteroatom such as oxygen, nitrogen, or sulfur. The heteroaromatic ring may be a single cycle or may be bicyclic, i.e. formed by the fusion of two rings.
The heteroaromatic ring defined by R’ can be an unsubstituted or mono- substituted five- or six-membered heteroaromatic ring having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur and connected by a ring carbon to the amine of the amide group shown. At least one heteroatom is nitrogen and is adjacent to the connecting ring carbon atom. If present, the other heteroatoms can be sulfur, oxygen or nitrogen. The ring defined by R? may be a single cycle. Such heteroaromatic rings include, for example, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, and imidazolyl. A preferred heteroaromatic ring is pyridinyl. The ring defined by R? may be a bicyclic, i.e. may be fused with phenyl at two of its free ring carbons. Examples of such rings are benzimidazolyl, benzothiazolyl, quinolynyl, benzooxazolyl, and so forth. The ring defined by R? is connected via a ring carbon atom to the amide group to form the amides of formula I. The ring carbon atom of the heteroaromatic ring which is connected via the amide linkage to form the compound of formula I cannot contain any substituent. When R’ is an unsubstituted or mono-substituted five-membered heteroaromatic ring, the preferred rings are those which contain a nitrogen heteroatom adjacent to the connecting ring carbon and a second heteroatom adjacent to the connecting ring carbon. ™
As used herein, -C(O)OR’ represents § and so forth.
The term “pharmaceutically acceptable salts” as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term “pharmaceutically acceptable salts” also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques. : Also part of this invention are prodrugs of the compound of formula I. By prodrug is meant a metabolic precursor of a drug which when administered to a patient ' 5 breaks down into the drug and acceptable by-products. Compounds of this invention may be made into any conventional prodrug. One particular prodrug of this invention are the N-oxides as described above. Any individual compound of this invention may be obtained as a prodrug in general.
During the course of the reactions provided below in the Reaction Scheme and discussion, the various functional groups such as the free carboxylic acid or hydroxy groups may be protected via conventional hydrolyzable ester or ether protecting groups.
As used herein, the term “hydrolyzable ester or ether protecting groups” designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective carboxyl or hydroxyl group. Exemplary ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxylic acid. Among the activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Examples of anhydrides are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxylic acid anhydrides, e.g. succinic anhydride as well as chloro formates e.g. trichloro, ethylchloro formate being preferred. A suitable ether protecting group for alcohols are, for example, the tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy-2H-pyranyl ethers.
Others are aroylmethylethers such as benzyl, benzhydryl or trityl ethers or o-lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethylsilylether.
Similarly, the term “amino protecting group” designates any conventional amino protecting group which can be cleaved to yield the free amino group. The preferred protecting groups are the conventional amino protecting groups utilized in peptide synthesis. Especially preferred are those amino protecting groups which are cleavable _ under mildly acidic conditions from about pH 2 to 3. Particularly preferred amino protecting groups are t-butyl carbamate (BOC), benzyl carbamate (CBZ), and 9- fluorenylmethyl carbamate (FMOC).
In a preferred compound of formula I, R' is cycloalkyl having from 5 to 8 carbon atoms, and R? is an unsubstituted or mono-substituted five- or six-membered ] heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 2 heteroatoms selected , 5 from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, which ring may be a single cycle, or may be fused with a phenyl at two of its ring carbons, said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of halo or lower alkyl (Formula AB). R?as described in Formula AB may be a monocyclic ring (Formula A), or may be a bicyclic ring through fusion with phenyl (Formula B). In compounds of formula A, it is particularly preferred that R? is substituted or unsubstituted pyridine. It is also preferred that R' is cyclohexyl. Phenyl A is preferably unsubstituted.
In a preferred compound of Formula I, R' is cyclohexyl and R?is a monocyclic ring (Formula A-1). Itis preferred in compounds of Formula A-1 that phenyl A is unsubstituted. It is particularly preferred that R? is substituted or unsubstituted pyridine.
In one embodiment of Formula A-1, R? is unsubstituted pyridine, and in another
R?is a mono-substituted pyridine. Preferably, the substituent is halo such as bromo, fluoro or chloro or lower alkyl such as methyl.
In one embodiment of Formula A-1, R? is a mono-substituted pyrimidine.
Preferably, the substituent is lower alkyl, such as methyl, and phenyl A is unsubstituted.
R* may also be an unsubstituted pyrimidine of Formula A-1. Preferably, phenyl A is unsubstituted or substituted with lower alkyl sulfonyl at the 4 or 7 position.
In one embodiment of Formula A-1, R? is unsubstituted thiazole. In preferred such compounds, A is phenyl unsubstituted, or substituted with chloro at positions 5 and 6, or substituted with nitro at positions 5 or 6, or substituted with halo or lower alkyl sulfonyl at positions 4 or 7.
In one embodiment of Formula A-1, R? is a mono-substituted thiazole.
Preferably, the substituent is halo, and A is phenyl unsubstituted, or substituted with chloro at positions 5 and 6, or substituted with nitro at positions 5 or 6, or substituted with halo or lower alkyl sulfonyl at positions 4 or 7.
In one embodiment of Formula A-1, R? is an unsubstituted pyrazine. A is preferably phenyl unsubstituted, or substituted with halo or lower alkyl sulfonyl at positions 4or7.
In one embodiment of Formula A-1 where R' is cylohexyl and R is a monocyclic ring, R? is unsubstituted imidazole, and phenyl and A is preferably unsubstituted phenyl.
In another embodiment of Formula I or of Formula A, phenyl A is unsubstituted,
R%is a monocyclic ring, and it is preferable that R* is substituted or unsubstituted thiazole. (Formula A-2). In some compounds of Formula A-2, R! is cyclopentyl, in others, R! is cycloheptyl, and in others, R' is cyclooctyl.
In a preferred compound of Formula I where R? is a bicyclic heteroaromatic ring through fusion with phenyl at two of its ring carbons and R' is cyclohexyl (Formula B- 1). In compounds of Formula B-1, it is preferred that phenyl A is unsubstituted. It is further preferred that R? is benzthiazole, benzimidazole, benzoxazole, or quinoline, all preferably unsubstituted.
In one preferable embodiment of the present invention, A is unsubstituted phenyl or phenyl which may be substituted with fluoro, lower alkyl sulfonyl or lower alkyl thio at position 4 or 7, or with chloro at position 5 or 6 or 5 and 6, or with bromo or nitro at * position 5 or 6. In another preferable embodiment, A is unsubstituted phenyl or phenyl which may be mono- or di-substituted with halo or mono-substituted with lower alkyl sulfonyl or nitro. Most preferably, A is unsubstituted phenyl or phenyl monosubstituted by halo, preferably by fluoro.
In one preferable embodiment of the present invention, R' is cycloalkyl having from 3 to 9, preferably from 5 to 8 carbon atoms. Most preferable residues R' are cyclopentyl or cyclohexyl.
In one preferable embodiment of the present invention, R? is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains 1 or 2 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, which ring is 2 monocyclic ring or fused with phenyl at two of its ring carbons, said mono- . substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected . 5 from the group consisting of halo or lower alkyl. In another preferable embodiment, R? is a heteroaromatic ring selected from thiazolyl, quinolinyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, benzoimidazolyl, benzothiazolyl or benzooxazolyl, said heteroaromatic ring being optionally monosubstituted by halo, preferably chloro or bromo, or lower alkyl, preferably methyl. More preferable heteroaromatic rings residues
RZ are selected from thiazolyl, pyrimidyl, pyrazinyl or pyridyl, said heteroaromatic ring being optionally monosubstituted by halo, preferably brome or chloro, or lower alkyl, preferably methyl. Most preferable residue R? is an unsubstituted heteroaromatic ring selected from thiazolyl, pyrimidyl, pyrazinyl or pyridyl or a monosubstituted heteroaromatic ring selected from thiazolyl substituted by chloro or pyridyl substituted by chloro, bromo or lower alkyl, preferably methyl.
Preferable compounds in accordance with the present inevntion are selected from the group consisting of: (8)-3-cyclohexyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl- propionamide, (8)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl- propionamide, (8)-3-cyclohexyl-2-(7-fluoro-1-o0x0-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl- propionamide, (8)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl- propionamide, (8)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3dihydro-isoindol-2-yl)-N-pyridin-2-yl- propionamide, (R)-N-(5-bromo-pyridin-2-yl)-3-cyclohexyl-2-(1-0xo-1,3-dihydro-isoindol-2-yl)- propionamide,
(S)-3-cyclohexyl-2-(1-0xo0-1,3-dihydro-isoindol-2-y1)-N-5-chloro-pyridin-2-yl- propionamide, (S)-3-cyclohexyl-2-(1-o0xo0-1,3-dihydro-isoindol-2-yl)-N-4-methyl-pyridin-2-yl- propionamide, (8)-3-cyclohexyl-2-(1-o0xo-1,3-dihydro-isoindol-2-yl)-N-5-methyl-pyridin-2-yl- propionamide, 3-cyclohexyl-2-(1-o0x0-1,3-dihydro-isoindol-2-yl)-N-pyrimidin-4-yl- propionamide, (8)-3-cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N- pyrimidin-4-yl-propionamide, (S)- 3-cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N- pyrimidin-4-yl-propionamide, (S)-N-3-cyclohexyl-N-(2-methyl-pyrimidin-4-yl)-2-(1-oxo-1,3-dihydro-isoindol- 2-yl)-propionamide, (S)-3-cyclohexyl-2-(1-0xo0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (R)-3-cyclohexyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (S)-3-cyclohexyl-2-(5,6-dichloro-1-o0xo0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2- yl-propionamide, (S)-3-cyclohexyl-2-(4-chloro-1-oxo0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (8)-3-cyclohexyl-2-(7-fluoro-1-o0xo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide,
(S)-3-cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N- thiazol-2-yl-propionamide, (§)-3-cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-y1)-N- thiazol-2-yl-propionamide, (8)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl — propionamide, (8)-3-cyclohexyl-2-(6-nitro-1-oxo0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (8)-N-(5-chloro-thiazol-2-y1)-3-cyclohexyl-2-(1-o0xo-1,3-dihydro-isoindol-2-yl) propionamide, (S)-N-(5-bromo-thiazol-2-yl)-3-cyclohexyl-2-(1-o0xo-1,3-dihydro-isoindol-2-yl)- propionamide, (8)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2-(5,6-dichloro-1-o0xo-1,3-dihydro- isoindol-2-yl)-propionamide, (S)-N-(5-bromo-thiazol-2-yl)-3-cyclohexyl--2-(5,6-dichloro-1-o0xo-1,3-dihydro- isoindol-2-yl)-propionamide, (8)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydro- isoindol-2-yl)-propionamide, (8)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2-(7-chloro-1-0x0-1,3-dihydro- isoindol-2-yl)-propionamide, (S)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydro- isoindol-2-yl)-propionamide, (8)-N-(5-chloro-thiazol-2-y1)-3-cyclohexyl-2- (6-nitro-1-oxo-1,3-dihydro- isoindol-2-yl)-propionamide, (8)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro- isoindol-2-yl)-propionamide,
(S)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro- isoindol-2-yl)-propionamide, (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3dihydro-isoindol-2-yl)-N- pyrazin-2-yl- propionamide, (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl- propionamide, (S)-3-cyclohexyl-2-(4-methylsulfonyl-1-o0xo-1,3-dihydro-isoindol-2-yl)-N- pyrazin-2-yl-propionamide, (S)-3-cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N- pyrazin-2-yl-propionamide, (S)-3-cyclohexyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl- propionamide, (S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl- propionamide, (8)-3-cyclohexyl-N-(1H-imidazol-2-yl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl) propionamide, 3-cyclopentyl-2-(1-oxo0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide,
N-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)- propionamide, 3-cycloheptyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide,
N-(5-chloro-thiazol-2-yl)-3-cycloheptyl-2-(1-oxo-1,3-dihydro-isoindol-2-y1)- propionamide, 3-cyclooctyl-2-(1-ox0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide, (8)-N-benzothiazol-2-yl-3-cyclohexyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)- propionamide, (S)-N-(1H-benzoimidazol-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2- yl)-propionamide,
(S)-N-benzooxazol-2-yl-3-cyclohexyl-2-(1-o0xo-1,3-dihydro-isoindol-2-yl)- propionamide, (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-quinolin-2-yl- propionamide, (S)-3-Cyclobexyl-2-(7-chloro-1-o0x0-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl- propionamide, (S)-3-cyclohexyl-2-(1-o0x0-1,3-dihydro-isoindol-2-yl)-N-(1-oxy-pyridin-2-yl)- propionamide, and (S)-3-cyclohexyl-2-(7-chloro- 1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide.
Most preferable compounds in accordance with the present inevntion are selected from the group consisting of: 3-Cyclohexyl-2-(1-o0x0-1,3-dihydro-isoindol-2-y1)-N-pyrimidin-4-yl- propionamide,
N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)- propionamide, (S)-3-Cyclohexyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)-N-5-chloro-pyridin-2-yl- propionamide, (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3dihydro-isoindol-2-yl)-N- pyrazin-2-yl- propionamide, (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (S)-3-Cyclohexyl-2-(1-o0xo0-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl- propionamide, (8S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl- propionamide,
(8)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yi- propionamide, (S)-3-Cyclohexyl-2-(1-o0xo0-1,3-dihydro-isoindol-2-yl)-N-5-methyl-pyridin-2-yl- propionamide, and (R)-N-(5-Bromo-pyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2- yl)-propionamide.
The compounds of this invention can be prepared by the following Reaction
Schemes where phenyl A, R}, R? and R® are as in formula I.
Reaction Schemes
Scheme 1
A o 1
R 0 1 2 rR i OH —
HH — N H,N-R? N q oO OH o oJ 0g Ww 1 2 3 I
B
Rl R! Rl
H on NHR? + —_— N N
OY 0 lo] S lo lo} 1 2 3 I
Scheme 2 : . o
R R
OH - H
OH H
Rb Rb 0) 0] 4 1’
Ra = halo, Rb = H or halo
Ra = Nitro, Rb = H
Ra = lower alkyl thio, lower alkyl sulfonyl, Rb =H
Scheme 3 ® A —_————— OH
XX H Be
N 2 oY 0 2
The compounds of this invention may be obtained by reacting substituted ortho- 5 . phenylene dialdehyde 1 or 1', with amino acid derivative 2 or 2' in a suitable solvent such as acetonitrile, to obtain carboxylic acid derivative 3 or 3'. 3 or 3' may then be coupled with a suitable heteroaromatic amine H,N-R? under conventional reaction conditions for amide bond formation to obtain the compounds of formula I.
Compounds of formula I where phenyl A is substituted with halo (obtained from a halo phthalic acid) or nitro are obtained as described in Scheme 2 above where 4 is a suitable commercially available substituted phthalic acid. The substituted ortho- phenylene dialdehydes 1 or 1' may be prepared by reduction of the phthalic acids 4 to the diol intermediates followed by oxidation to provide 1'.
Compounds of formula I where phenyl A is substituted with lower alkyl sulfonyl may be prepared starting from a phthalic acid 4 where Ra is fluoro and Rb is hydrogen by a multistep sequence: a) conversion to the corresponding dimethyl ester with sulfuric acid in methanol b) nucleophilic displacement of fluoride with with sodium thiomethoxide in a suitable solvent such as dimethylsulfoxide to provide 4 when Ra is lower alkyl thio, c) reduction of the resulting phthalic acid 4 when Ra is lower alkyl thio to the diols followed by oxidation to the corresponding ortho-phenylene dialdehyde 1 when Ra is lower alkyl thio d) reaction of the ortho-phenylene dialdehyde 1 when Ra is lower alkyl thio an amino acid 2 in refluxing acetonitrile to give a mixture of the lower alkyl thio, lower alkyl thio carboxylic acid isomers 3 and e) coupling with HN — R? to provide compounds of formula I where Ra is lower alkyl thio.
Compounds of formula I where Ra is lower alkyl sulfonyl and Rb is hydrogen, can be obtained by first oxidizing the lower alkyl isomers of step (d) above with hydrogen peroxide to form the lower alkyl sulfonyl carboxylic acid of formula 3 (Ra is lower alkyl sulfonyl, Rb is hydrogen and then coupling the resulting carboxylic acid of formula 3 with H,N - R%to provide the compound of formula I where Ra is lower alkyl sulfonyl.
Compounds of formula I where R' is C; - Cy cycloalkyl or C; - Cy alkyl (in R, S, or racemic form) are obtained as described above where 2 or 2' is a suitable commercially available amino acid. Amino acid 2 or 2' may also be obtained according to Scheme 3 from 5. 5 is prepared according to the literature procedure (see O'Donnell, M.].; Polt,
R.L. J. Org. Chem. 1982, 47, 2663-2666) and may be reacted under basic conditions with a suitable alkyl halide reagent substituted with the desired R' to obtain, after acidic hydrolysis, any amino acid 2. The alkyl halide reagent may be obtained commercially or made using conventional methods.
Compounds of formula I where R? is as described in formula I may be obtained by coupling the desired heteroaromatic amine (which is commercially available or can be made by conventional methods) to carboxylic acid derivative 3 or 3' under conventional conditions for reacting an amine with an acid. The N-oxide heteroaromatic amine (for example 2-aminopyridine-N-oxide) may be coupled to 3 or 3, or the corresponding compound of Formula I may be oxidized at an unsubstituted R? ring by known methods to obtain an N-oxide.
If it is desired to produce the R or the S isomer of the compound of formula I, this compound can be separated into these isomers by conventional physical or chemical means. One physical means of separation involves resolution of the enantiomeric pairs of compounds of formula 1 using a high performance liquid chromatography instrument equiped with a chromatographic column loaded with a chiral agent. Among the preferred chemical means is to react the intermediate carboxylic acid 3 or 3° with an optically active base. Any conventional optically active base can be utilized to carry out this resolution. Among the preferred optically active bases are the optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha-methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction.
In the resolution step, 3 or 3’ is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of 3 or 3’. In the formation of these salts, temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure. The R and § salts can be separated by any conventional method such as fractional crystallization. After crystallization, each of the salts can be converted to the respective 3 or 3’ in the R and S configuration by hydrolysis with an acid. Among the preferred acids are dilute aqueous acids , i.e., from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid. The configuration of 3 or 3’ which is produced by this method of resolution is carried through the entire reaction scheme to produce the desired R or S isomer of formula I or II. The separation of R and
S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl ester derivatives of 3 or 3’ (see for example, Ahmar, M.; Girard, C.; Bloch, R,
Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. The ester and the acid can be separated by any conventional method of separating an acid from an ester. Another preferred method of resolution of racemates of the compounds 3 or 3’ is via the formation of corresponding diastereomeric esters or amides. These diastereomeric esters or amides can be prepared by coupling the carboxylic acids 3 or 3’ with a chiral alcohol or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine. The corresponding diastereomers of the derivatives of carboxylic acids 3 or 3’ can then be separated using any conventional separation methods, such as HPLC. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R or S isomers. The hydrolysis reaction can be carried out using conventional known methods to hydrolyze an ester or an amide without racemization.
On the basis of their capability of activating glucokinase, the compounds of above formula I can be used as medicaments for the treatment of type II diabetes. Therefore, as mentioned earlier, medicaments containing a compound of formula I are also an object of the present invention, as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula I and, if desired, one or more other therapeutically valuable substances into a galenical administration form, e.g. by combining a compound of formula I with a pharmaceutically acceptable carrier and/or adjuvant.
The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragées, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally, using for example injectable solutions. Furthermore, administration can be carried out sublingually or as an aerosol, for example in the form of a spray. For the preparation of tablets, coated tablets, dragées or hard gelatine capsules the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragées or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc.; according to the nature of the active ingredients it may however be the case that no excipient is needed at all for soft gelatine capsules. For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose. For injectable solutions, excipients which may be used include
Claims (34)
1. A compound comprising an amide of the formula: R! H aN 2 © 0 AI wherein A is unsubstituted phenyl or phenyl which may be mono- or di-substituted with halo or mono-substituted with lower alkyl sulfonyl, lower alkyl thio or nitro; R' is cycloalkyl having from 3 to 9 carbon atoms or lower alkyl having from 2 to 4 carbon atoms; R? is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six- membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, which ring is monocyclic ring or fused with phenyl at two of its ring carbons, said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of halo, lower alkyl, nitro, cyano, perfluoro-lower alkyl; hydroxy, -(CH,),-OR?, - (CHz),-C(0)-OR?, -(CHy),-C(0)-NH-R?, -C(0)C(0)-OR?, or -(CHy),-NHR* R® is hydrogen or lower alkyl; and nis0,1,2,3 0r4; or a pharmaceutically acceptable salts or N-oxides thereof. :
2. A compound according to claim 1, wherein said compound is said amide or a pharmaceutically acceptable salts thereof.
3. A compound according to claim 2, wherein A is unsubstituted phenyl or phenyl which may be substituted with fluoro, lower alkyl sulfonyl or lower alkyl thio at position 4 or 7, or with chloro at position 5 or 6 or 5 and 6, or with bromo or nitro at position 5 or 6.
4. A compound according to any of claims 1 to 3, wherein the amide is in the S configuration at the asymmetric carbon shown.
5. A compound according to any of claims 1, 2 or 4, wherein A is unsubstituted phenyl or phenyl which may be mono- or di-substituted with halo or mono-substituted with lower alkyl sulfonyl or nitro.
6. A compound according to any of claims 1, 2 or 4, wherein A is unsubstituted phenyl or phenyl monosubstituted by halo.
7. A compound according to any of claims 1 to 6, wherein R' is cycloalkyl having from 3 to 9 carbon atoms.
8. A compound according to any of claims 1 to 6, wherein R' is cyclopentyl or cyclohexyl.
9. A compound according to any of claims 1 to 8, wherein R? is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains 1 or 2 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, which ring is a monocyclic ring or fused with phenyl at two of its ring carbons, said mono- substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of halo or lower alkyl.
10. A compound according to any of claims 1 to 8, wherein R? is a heteroaromatic ring selected from thiazolyl, quinolinyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, benzoimidazolyl, benzothiazolyl or benzooxazolyl, said heteroaromatic ring being optionally monosubstituted by halo or lower alkyl. } ;
11. A compound according to any of claims 1 to 8, wherein R? is a heteroaromatic ring selected from thiazolyl, pyrimidyl, pyrazinyl or pyridyl, said heteroaromatic ring being optionally monosubstituted by halo or lower alkyl.
12. A compound according to any of claims 1 to 8, wherein R? is an unsubstituted heteroaromatic ring selected from thiazolyl, pyrimidyl, pyrazinyl or pyridyl or a monosubstituted heteroaromatic ring selected from thiazolyl substituted by chloro or pyridyl substituted by chloro, bromo or lower alkyl.
13. A compound according to claim 1, wherein A is unsubstituted phenyl or phenyl which may be mono- or di-substituted with halo or mono-substituted with lower alkyl sulfonyl or nitro; R' is cycloalkyl having from 5 to 8 carbon atoms; R? is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six- membered heteroaromatic ring contains 1 or 2 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, which ring is a monocyclic ring or fused with phenyl at two of its ring carbons, said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of halo or lower alkyl.
14. A compound of any of claims 1 to 13 selected from the group consisting of: (8)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl-propionamide, (8)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yi- propionamide, (8)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl- propionamide, (8)-3-cyclohexyl-2-(4-chloro-1-oxo0-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl- propionamide, (8)-3-cyclohexyl-2-(7-chloro-1-oxo-1,3dihydro-isoindol-2-yl)-N-pyridin-2-yl- propionamide, ,
(R)-N-(5-bromo-pyridin-2-y1)-3-cyclohexyl-2-(1-ox0-1,3-dihydro-isoindol-2-yl)- propionamide, (S)-3-cyclohexyl-2-(1-ox0-1,3-dihydro-isoindol-2-yl)-N-5-chloro-pyridin-2-yl- propionamide,
(S)-3-cyclohexyl-2-(1-oxo0-1,3-dihydro-isoindol-2-yl)-N-4-methyl-pyridin-2-yl- propionamide, (S)-3-cyclohexyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)-N-5-methyl-pyridin-2-yl- propionamide, 3-cyclohexyl-2-(1-ox0-1,3-dihydro-isoindol-2-yl)-N-pyrimidin-4-yl-propionamide,
(S)-3-cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrimidin- 4-yl-propionamide,
(S)- 3-cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrimidin- 4-yl-propionamide, (S)-N-3-cyclohexyl-N-(2-methyl-pyrimidin-4-yl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-
propionamide, (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide, (R)-3-cyclohexyl-2-(1-0xo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide,
" (8)-3-cyclohexyl-2-(5,6-dichloro-1-o0xo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide,
(S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (8)-3-cyclohexyl-2-(7-fluoro-1-o0xo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-
propionamide, (8)-3-cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, :
(S8)-3-cyclohexyl-2-(7-methylsulfonyl- 1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (8)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl — propionamide,
(S)-3-cyclohexyl-2-(6-nitro-1-o0xo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (8)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2-(1-o0x0-1,3-dihydro-isoindol-2-yl) propionamide, (S)-N-(5-bromo-thiazol-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-y1)-
propionamide, (8)-N-(5-chloro-thiazol-2-y1)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydro- isoindol-2-yl)-propionamide, (§)-N-(5-bromo-thiazol-2-yl)-3-cyclohexyl--2-(5,6-dichloro-1-ox0-1,3-dihydro- isoindol-2-yl)-propionamide,
(S)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2- (4-chloro-1-0xo0-1,3-dihydro-isoindol-2- yl)-propionamide,
(8)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2- (7-chloro-1-oxo-1,3-dihydro-isoindol-2- yl)-propionamide, (8)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2-(5-nitro-1-0xo-1,3-dihydro-isoindol-2-
yl)-propionamide, (8)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2- (6-nitro- 1-0xo0-1,3-dihydro-isoindol-2- yl)-propionamide, (8)-N-(5-chloro-thiazol-2-y1)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2- yl)-propionamide,
(8)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2- yl)-propionamide,
(S)-3-cyclohexyl-2-(4-fluoro-1-ox0-1,3dihydro-isoindol-2-yl)-N- pyrazin-2-yl- propionamide, (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl- propionamide,
(S)-3-cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2- yl-propionamide, (8)-3-cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2- yl-propionamide, (S)-3-cyclohexyl-2-(1-0xo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide,
(S)-3-cyclohexyl-2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yi- propionamide, (S)-3-cyclohexyl-N-(1H-imidazol-2-yl)-2-(1-0x0-1,3-dihydro-isoindol-2-yl) propionamide, 3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide,
N-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)- propionamide, 3-cycloheptyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide, N-(5-chloro-thiazol-2-yl)-3-cycloheptyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)- propionamide,
3-cyclooctyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide, (8)-N-benzothiazol-2-yl-3-cyclohexyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)- propionamide, (S)-N-(1H-benzoimidazol-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)- propionamide,
(S)-N-benzooxazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)- propionamide,
(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-quinolin-2-yl-propionamide, (8)-3-Cyclohexyl-2-(7-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl- propionamide, (S)-3-cyclohexyl-2-(1-0xo-1,3-dihydro-isoindol-2-yl)-N-(1-oxy-pyridin-2-yl)- propionamide, and (S)-3-cyclohexyl-2-(7-chloro-1-oxo0-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide.
15. A compound of any of claims 1 to 13 selected from the group consisting of: 3-Cyclohexyl-2-(1-ox0-1,3-dihydro-isoindol-2-yl)-N-pyrimidin-4-yl-propionamide, N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-(1-oxo- 1,3-dihydro-isoindol-2-yl)- propionamide, (S)-3-Cyclohexyl-2-(1-ox0-1,3-dihydro-isoindol-2-yl)-N-5-chloro-pyridin-2-yl- propionamide, (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3dihydro-isoindol-2-yl)-N- pyrazin-2-yl- propionamide, (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl- propionamide, (8)-3-Cyclohexyl-2-(1-0x0-1,3-dihydro-isoindol-2-y1)-N-pyrazin-2-yl-propionamide, (8)-3-Cyclohexyl-2-(1-o0x0-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl-propionamide, (8)-3-cyclohexyl-2-(1-0x0-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide, (8)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-y1)-N-5-methyl-pyridin-2-yl- propionamide, and (R)-N-(5-Bromo-pyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)- propionamide.
-68- PCT/EP01/14404
16. A pharmaceutical composition comprising a compound of any of claims 1 to and a pharmaceutically acceptable carrier and/or adjuvant.
17. A process for the preparation of a pharmaceutical composition of claim 16 comprising combining a compound of formula I according to any one of claims 1 to 15 with a pharmaceutically acceptable carrier and/or adjuvant.
18. The compounds according to any of claims 1 to 15 for use as a therapeutic active substance.
19. The use of the compounds according to any of claims 1 to 15 for the treatment or prophylaxis of type II diabetes.
20. The use of a compound according to any of claims 1 to 15 for the preparation of a medicament for the treatment or prophylaxis of type II diabetes.
21. A method for the prophylactic treatment of type II diabetes, which method comprises administering a compound of any of claims 1 to 15 to a human being or an animal.
22. A process for the preparation of a compound according to any of claims 1 to 15, said process comprising: coupling a compound of the formula 3; 1 (0 H 0 0 3 wherein A and R! are as defined in claim 1; with a suitable heteroaromatic amine of the formula H,N-R? AMENDED SHEET
-69- ~ PCT/EP01/14404 wherein R? is as defined in claim 1; under conventional reaction conditions for amide bond formation to obtain a compound of formula I; = BR H N o] 0 Rr I wherein *, A, R! and R? are as defined in claim 1.
23. A compound prepared by the process according to claim 22.
24. Use of a compound according to any of claims 1 to 15 in the manufacture of a preparation for use in a method of treatment or prevention.
25. A substance or composition for use in a method of treatment or prevention, said substance or composition comprising a compound according to any of claims 1 to 15, and said method comprising administering said substance or composition.
26. A substance or composition for use in a method for the treatment or prophylaxis of type II diabetes, said substance or composition comprising a compound according to any of claims 1 to 15, and said method comprising administering said substance or composition.
27. The invention as hereinbefore defined.
28. A compound according to any one of claims 1 to 15, 18 or 23, substantially : as herein described and illustrated.
29. A composition according to claim 16, substantially as herein described and AMENDED SHEET
-70- PCT/EP01/14404 illustrated.
30. A process according to claim 17 or claim 22, substantially as herein described and illustrated.
31. Use according to any one of claims 19, 20 or 24, substantially as herein described and illustrated.
32. A method according to claim 21, substantially as herein described and illustrated.
33. A substance or composition for use in a method of treatment or prevention according to claim 25 or claim 26, substantially as herein described and illustrated.
34. A new compound, a new composition, a new process for the preparation of a compound, a new use of a compound as claimed in any one of claims 1 to 15, a new non-therapeutic method of treatment, or a substance or composition for a new use in a method of treatment or prevention, substantially as herein described. : AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US22527300P | 2000-12-13 | 2000-12-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200304265B true ZA200304265B (en) | 2004-08-30 |
Family
ID=34115101
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200304265A ZA200304265B (en) | 2000-12-13 | 2003-05-30 | Isoindolin-1-one glucokinase activators. |
Country Status (1)
Country | Link |
---|---|
ZA (1) | ZA200304265B (en) |
-
2003
- 2003-05-30 ZA ZA200304265A patent/ZA200304265B/en unknown
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1349856B1 (en) | Isoindolin-1-one glucokinase activators | |
AU2002238415A1 (en) | Isoindolin-1-one glucokinase activators | |
EP1282612B1 (en) | Alkynyl phenyl heteroaromatic glucokinase activators | |
JP3971189B2 (en) | p-Amino-substituted phenylamide glucokinase activator | |
ZA200203829B (en) | Trans olefinic glucokinase activators. | |
US6608218B2 (en) | α-acyl- and α-heteroatom-substituted benzene acetamide glucokinase activators | |
AU2001265914A1 (en) | Para-amine substituted phenylamide glucokinase activators | |
AU2001270494A1 (en) | Alkynyl phenyl heteroaromatic glucokinase activators | |
WO2004063194A1 (en) | Heteroaryl compounds | |
ZA200208367B (en) | Substituted phenylacetamides and their use as glucokinase activators. | |
US20010051731A1 (en) | Para-amine substituted phenylamide glucokinase activators | |
ZA200304265B (en) | Isoindolin-1-one glucokinase activators. |