ZA200506130B - Phenylacetamides and their use as glucokinase modulators - Google Patents
Phenylacetamides and their use as glucokinase modulators Download PDFInfo
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- ZA200506130B ZA200506130B ZA200506130A ZA200506130A ZA200506130B ZA 200506130 B ZA200506130 B ZA 200506130B ZA 200506130 A ZA200506130 A ZA 200506130A ZA 200506130 A ZA200506130 A ZA 200506130A ZA 200506130 B ZA200506130 B ZA 200506130B
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- ZA
- South Africa
- Prior art keywords
- group
- tetrahydropyran
- propionamide
- compound
- acceptable salt
- Prior art date
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- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical class NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 title description 4
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- 108010021582 Glucokinase Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 81
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- -1 hydroxy, cyano, methoxy Chemical group 0.000 claims description 54
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- 239000001257 hydrogen Substances 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
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- 206010012601 diabetes mellitus Diseases 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 16
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- 125000001424 substituent group Chemical group 0.000 claims description 15
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- 238000000034 method Methods 0.000 claims description 14
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- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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 Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 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
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960003362 carbutamide Drugs 0.000 description 1
- VDTNNGKXZGSZIP-UHFFFAOYSA-N carbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 VDTNNGKXZGSZIP-UHFFFAOYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 125000005744 ethylethenyl group Chemical group [H]\C(*)=C(/[H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960003236 glisoxepide Drugs 0.000 description 1
- ZKUDBRCEOBOWLF-UHFFFAOYSA-N glisoxepide Chemical compound O1C(C)=CC(C(=O)NCCC=2C=CC(=CC=2)S(=O)(=O)NC(=O)NN2CCCCCC2)=N1 ZKUDBRCEOBOWLF-UHFFFAOYSA-N 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- RIGBPMDIGYBTBJ-UHFFFAOYSA-N glycyclamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 RIGBPMDIGYBTBJ-UHFFFAOYSA-N 0.000 description 1
- 229950005514 glycyclamide Drugs 0.000 description 1
- NFRPNQDSKJJQGV-UHFFFAOYSA-N glyhexamide Chemical compound C=1C=C2CCCC2=CC=1S(=O)(=O)NC(=O)NC1CCCCC1 NFRPNQDSKJJQGV-UHFFFAOYSA-N 0.000 description 1
- 229950008290 glyhexamide Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- RGXCTRIQQODGIZ-UHFFFAOYSA-O isodesmosine Chemical compound OC(=O)C(N)CCCC[N+]1=CC(CCC(N)C(O)=O)=CC(CCC(N)C(O)=O)=C1CCCC(N)C(O)=O RGXCTRIQQODGIZ-UHFFFAOYSA-O 0.000 description 1
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- HZIVRQOIUMAXID-UHFFFAOYSA-N oxocane Chemical compound C1CCCOCCC1 HZIVRQOIUMAXID-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- AFOGBLYPWJJVAL-UHFFFAOYSA-N phenbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=CC=C1 AFOGBLYPWJJVAL-UHFFFAOYSA-N 0.000 description 1
- 229950008557 phenbutamide Drugs 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- NNLBRYQGMOYARS-UHFFFAOYSA-N thiane 1-oxide Chemical compound O=S1CCCCC1 NNLBRYQGMOYARS-UHFFFAOYSA-N 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 150000000450 thiocanes Chemical class 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
TRI(CYCLO) SUBSTITUTED AMIDE COMPOUNDS
The- present invention is directed tom tri(cyclo) substitute amide compounds.
In particulaay, the present invention is directed to amide compoumds substituted 1) at the carbonye1 carbon with an ethyl/ethenyl =attached to a phenyl r=ing and an aryl/heterosaryl/heterocyclic ring, and ii) at- the amino with a nitmrogen bearing heteroaryl mring, which are modulators of g-lucokinase and are useful in the prophylact#ic or therapeutic treatment of hyperglycemia and typ -e II diabetes.
Glumcokinase (“GK”) is believed to be important in the t>ody’s regulation of its plasma glu_cose level. GK, found principaally in the liver and pancreas, is one of four hexokinasess that catalyze the initial metabwolism of glucose. Tkae GK pathway is saturated a_t higher glucose levels than the other hexokinase pat-hways (See R.L.
Printz et all.., Annu. Rev. Nutr., 13:463-496(1993)). GK is critical to maintaining the glucose balance in mammals. Animals th at do not express GK_ die soon after birth with diabetes, while animals that overexparess GK have improv—ed glucose tolerance.
Activation: of GK can lead to hyperinsulimemic hypoglycemia. (See, for example,
H.B.T. Ch-ristesen et al., Diabetes, 51:124-0-1246(2002)). Additionally, type I maturity-ownset diabetes of the young is caused by the loss of fitanction mutations in the
GK gene, - suggesting that GK operates as a glucose sensor in humans. (Y. Liang et al., Biochezm. J. 309:167-173(1995)). Thuis, compounds that activate GK increase the- sensitivity— of the GK sensory system and would be useful in thme treatment of hyperglycemia — particularly the hypergls/cemia associated with type II diabetes. It is therefore clesirable to provide novel compounds that activate (GK to treat diabetes.
Int=ernational Patent Publication No. W02001044216 amnd U.S. Patent No. 6,353,111 describe (£)-2,3-disubstituted-_N-heteroarylacrylamili des as GK activators.
Internatiomnal Patent Publication No. W022002014312 and U.S_ Patent Nos. 6,369,232, 6,388,088. , and 6,441,180 describe tetrazolylphenylacetamide » GK activators.
Internatio—nal Patent Publication No. WO=2000058293, Europe=an Patent Application
No. EP 1.69312 and U.S. Patent No. 6,320,050 describe arylesycloalkylpropionamide
GK activators. International Patent Publication No. 20020082209 and U.S. Patent No_. 6,486,184% describe alpha-acyl and alpha~heteroatom-substituteed benzene acetamide
GK activators as anti-diabetic agents. International Patent P-ublication No.
WO02001083478 describes hydantoin-containing GK activateors. International Patent
Publication No. W02001.083465 and U.S. Patent No. 6,388,071 describe alkynylphenyl heteroarormatic GK activators. International ¥Patent Publication No.
W02001085707 and U.S. Patent No. 6,489,485 describe pamra-amine substituted phenylamide GK activateors. International Patent Publication No. W02002046173 and U.S. Patent Nos. 6,4 33,188, 6,441,184, and 6,448,399 Mescribe fused heteroaromatic GK activ-ators. International Patent Publicastion No. W02002048106 and U.S. Patent No. 6,482,951 describe isoindolin-1-one GIK activators. International
Patent Publication No. WW02001085706 describes substitute=d phenylacetamide GK activators for treating type II diabetes. U.S. Patent No. 6,3834,220 describes para-aryl or heteroaryl substituted phenyl GK activators. French Patent No. 2,834,295 describes methods for the purification and crystal structure of human GK.
International Patent Pubslication No. W02003095438, publ ished after the priority date of the present applicatioen, describes N-heteroaryl phenylac etamides and related compounds as GK activators for the treatment of type II di-abetes. U.S. Patent No. 6,610,846 describes the preparation of cycloalkylheteroary=1 propionamides as GK activators. International Patent Publication No. WO020030- 00262 describes vinyl phenyl GK activators. “International Patent Publication No=-. W02003000267 describes aminonicotinate derivatives as GK modulators. Internatiomnal Patent Publication No.
WO02003015774, published after the priority date of the present application, describes compounds as GK modulators. International Patent Publiczation No. W02003 047626, published after the prioerity date of the present application, describes the use ofa GK activator in combinatiosn with a glucagon antagonist for tre=ating type II diabetes. . International Patent Publication No. W02003055482, pubmlished after the priority date= of the present applicati on, describes amide derivatives as @GK activators. International
Patent Publication No. WO2003080585, published after tine priority date of the present application, describes aminobenzamide derivativess with GK activity for the treatment of diabetes and obesity. International Patent Publication No.
W02003097824, published after the priority date of the peresent application, describes human liver GK crystals and their used for structure-based drug design. International.
Patent Publication No. W(02004002481, published after the priority date of the present application, discloses arylcarbonyl derivatives as GK activators.
Compounds represented by Formula (I): rR} R? ( : Im
RB R* tA H lJ "
LT
R® RY,
RS
® or phamrmaceutically acceptable salts tha ereof, are useful in the prophylactic or therapeutic treatment of hyperglycemia and type II diabetes.
The present invention is directed to a compound of Fommula (I):
R! R2 (CH2 Dn rR? R* iA H ) N 3
T
5h
RE \__/
RE
D or a ph_armmaceutically acceptable salt tkaereof, wherein:
Q is an aryl, a 5- or 6-membere=d heteroaryl, or a 4—8-mmembered heterocyclic ring;
T together with the -N=C- to which it is attached formms a heteroaryl ring, or a heterocyclic ring where the N=C bond is the only site of unsat=uration; _3.
R! and R? each independently are hydrogen, hydroxy, halogen, cyano, nitro, vinyl, ethyny}, methoxy, OCFnHi un, ~N(Coalkyl)(Cosalkyl), CHRO, or C,.zalkyl optionally substituted with 1-5 independent halogen, hydroxy, C3»/ano, methoxy, “N(Co_zalkyl)(Co-zalkyl), SOCHs, or SO,CHj substituents; or R! and R? together form a carbocyclic or heterocyclic ring; or R! and R? may be taken together to represent an oxygen atom attached to the ring via a double bond;
R® and R* each independently are hydrogen, halogen, OCF, Hj, methoxy,
CO,R”’, cyano, nitro, CHO, CONRYR'®, CON(OCH3)CHa, or Ci.palkyl, heteroaryl, or Cs_scycloalkyl optionally substituted with 1-5 independent halogen, hydroxy, cyano, methoxy, -NHCO,CH, or —N(Co.alkyl)(Coalkyl) substituents; or R? and R* together form a 5—8-membered aromatic, heteroaromatic, carbo- cyclic, or heterocyclic ring;
RS and R® each independently are hydrogen, hydroxy, halogen, cyano, nitro,
CO,R’, CHO, COR®, C(OEDR'R?, C(=NOR')R’, CONR’RY, S-K’, SOR’, SOR,
SO,NR'R'?, CH,NR’R', NRR", N(Cosalkyl)SO:R®, NHCORR', or Cyalkyl group,
C.salkenyl group, Cz4alkynyl group, C4alkoxy group, aryl group, or heteroaryl group, wherein any group optionally is substituted with 1-6 ind= ependent halogen, cyano, nitro, hydroxy, Ci-z2alkoxy, ~N(Co-2alkyl)(Co-alkyl), C—_salkyl, CFHa, aryl, heteroaryl, -COC)-2alkyl, —CON(Co-2alkyl)(Co-2alkyl), SCH, SOCH;, SO.CH3, or —S0,N(Cozalkyl)(Coalkyl) substituents; or R® and RS together form a 5-8- membered carbocyclic or heterocyclic ring;
R” and R” each independently are hydrogen, or Calk=yl group, Cpalkenyl group, Cz4alkynyl group, Ca.scycloalkyl group, aryl group, heteroaryl group, or 4—7- membered heterocyclic group, wherein any group optionally iss substituted with 1-6 independent halogen, cyano, nitro, hydroxy, Ci-zalkoxy, “N(Cp-2alkyl)(Co-2alkyl),
C,_,alkyl, Csscycloalkyl, 4—7-membered heterocyclic ring, CIF Hs, aryl, heteroaryl,
CO,H, COC alkyl, —CON(Co-2alkyl)(Co-ralkyl), SOCH3, S O,CHj, or —SO,N(Copzalkyl)(Co-2akkyl) substituents;
RE is C,4alkyl group, C;.alkenyl group, C24alkynyl grxoup, Csscycloalkyl group, aryl group, heteroary] group, or 4-7-membered heterocyclic group, wherein any group optionally is substituted with 1-6 independent haloggen, cyano, nitro, hydroxy, Ci—zalkoxy, ~N(Co-salkyl)(Co-zalkyl), Ci-zalkyl, C3 —cycloalkyl, 4-7- membered heterocyclic ring, CFqHz, aryl, heteroaryl, CO,H_, COCy-salkyl,
~CON(Co_zalkyl)(Co-zalkyl), SCOCH3, SO,CH3, or —SO,N(Coazmalkyl)(Co-zalkyl) substituents;
R’, RY R%, and R'® each independently are hydrogen, or Ci4alkyl group,
Cs.7cycloalkyl group, aryl group, heteroaryl group, or 4-7-memmbered heterocyclic group, wherein any group opticenally is substituted with 1-6 inclependent halogen, cyano, nitro, hydroxy, C;2alko-xy, —N(Co2a1kyl)(Co-2alkyl), C= 1-alkyl, Cs cycloalkyl, 4-7-membered heterocyclic ring, CFnHa a, aryl, heeteroaryl, COC, alkyl, —CON(Co_zalkyl)(Co-alkyl), S«OCH;, SO,CHj, or —SO,N(Co_z=alkyl)(Co-2alkyl) substituents; or R® and R' or = and R!% together form a 6-88-membered heterobicyclic ring system or a- 4-8-membered heterocyclic rirag which optionally is substituted with 1-2 independent Cy-zalkyl, CH,0OCHj3, COCoalkyl, hydroxy, or
SO,CHj; substituents; nis 1,2 or3; mis Oor 1; and the dotted line together with the solid line forms an optional double bond, and
A indicates that the double borad has the (E)-configuration.
If the dotted line together with the solid line forms a si_ngle bond, the carbon atom linking the aryl ring and Q-bearing sidechain to the carb-onyl carbon is a chiral centre. Accordingly, the comp-ound may be present either as a_ racemate, or as a single enantiomer in the (R)- or (S)-c onfiguration. The (R)-enantiom._ers are preferred.
A particular group of compounds which may be menti_oned are compounds of
Formula (I), or pharmaceutically acceptable salts thereof, pro=vided that when Q is an unsubstituted 5- or 6-membered heterocyclic ring containing eone heteroatom selected from O, S and S=0;
T completes a 5- or 6-rmembered heteroaryl ring which is unsubstituted or monosubstituted by halogen, rmethoxy, CO,—Co.salkyl, cyano, nitro, CONHa, CONH-
C1 4alkyl, perfluoroC.zalkyl, or Ciaalkyl optionally monosubmstituted with methoxy or ~NH(Co-alky);
RS and RE each independently are hydrogen, hydroxy, halogen, cyano, nitro,
COC 4alkyl, S-Ciualkyl, S—perfluoroCy alkyl, SO-C; 4all=cyl, SOC) 4alkyl, SO perfluoroCi.qalkyl, SO,NH,, INH,, C).42lkyl, perfluoroC.salk—yl, C,.4alkoxy or perfluoroC,4alkoxy; and mis 0;
then the dotted line together with the solid line must form a do-uble bond.
In the first aspect, the present invention is directed to a compo-und represented by Formula (Ja): . rR" R2 : >
R3 rR4 lo it AA
N
1
Nog J = (Ia) or a pharmaceutically acceptable salt thereof, wherein Q, T, R-R®, mm, and A are as defined above in Formula (I).
In an embodiment of the first aspect, the present invention is directed to a compound represented by Formul a (Ia), or a pharmaceutically acceptable salt thereof, wherein: Q is an aryl.
In another embodiment of the first aspect, the present inventieon is directed to 2 compound represented by Formula (Ia), or a pharmaceutically accepsable salt thereof, wherein Q is a 5- or 6-membered heteroaryl ring.
In another embodiment of the first aspect, the present inventi-on is directed to a compound represented by Formula (Ia), or a pharmaceutically accep table salt thereof, wherein Q is a thienyl, furyl, thia=zolyl, or pyridyl ring.
In another embodiment of the first aspect, the present inventi_on is directed to a compound represented by Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein Q is a 4-8-membered heterocyclic ring.
In another embodiment off the first aspect, the present inventi_on is directed to a compound represented by Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein Q is tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, 21-oxo- tetrahydrothiopyranyl or 1,1-dioxo-tetrahydrothiopyranyl.
In the second aspect, the present invention is directed to a co-mpound represented by Formula (Ib):
R' Rr? >
RB FR
H a og J
RS
(Tb) or a pharmaceutically ac- ceptable salt thereof, wherein (3, T, R!-R® and m are as defined above in Formul_a (I).
In an embodiment of the second aspect, the preseent invention is directed to a compound represented bey Formula (Ib), or a pharmaceutically acceptable salt therseof, wherein: Q is a 5- or 6-mnembered heteroaryl ring.
In another emboadiment of the second aspect, the= present invention is directed to a compound represented by Formula (Ib), or a pharm _aceutically acceptable salt thereof, wherein: Q is a thienyl, furyl, thiazolyl, or pyriiyl ring.
In another embodiment of the second aspect, thes present invention is directed to a compound represented by Formula (Ib), or a pharnmaceutically acceptable salt thereof, wherein: Q is a 4-8-membered heterocyclic rinmg.
Tn another embo diment of the second aspect, thes present invention is direc ted to a compound represented by Formula (Ib), or a pharmaceutically acceptable salt- thereof, wherein: Q is testrahydropyranyl, piperidinyl, testrahydrothiopyranyl, 1-oxeo- tetrahydrothiopyranyl, or 1,1-dioxo-tetrahydrothiopyramnyl.
The molecular weight of the compounds of formula (I) is preferably less than 800, more preferably le ss than 600, most preferably lesss than 500.
In the present inmvention, Q is preferably 2-furyl , 2-thienyl, tetrahydropyra-myl, tetrahydrothiopyranyl, =1-oxo-tetrahydrothiopyranyl, or 1,1-dioxo- tetrahydrothiopyranyl; more preferably 4-tetrahydropymxanyl or 4- tetrahydrothiopyranyl; =most preferably 4-tetrahydropym-anyl.
When Q is a heteroaryl or heterocyclic group it: is preferably linked to the - (CHa) group through a carbon atom.
When Qis a heteroaryl group it preferably does rot have a substituent R! or
R? other than hydrogen at a position adjacent to point of” attachment to the -(CHz)m~ group. .
In the presemt invention, the group of formula 1D, is preferably a moneocyclic heteroaryl group. More prefeerably it is thiazolyl, thiadiazolyl, oxazol yl, isoxazolyl, pyrimidinyl, pyraziny~1, or pyridyl; more preferabMy 2-thiazolyl, 5-[1,2,4]thiadiazolyl, 2-[1,3,4]thiadiazolyl, ~4-pyrimidinyl, 2-pyrazinyl, =3- isoxazolyl, or 2-pyr-idyl; even more preferably 2-thiazol yl, 5-[1,2,4]thiadiazolyl, 4- pyrimidinyl, 2-pyra zinyl, or 2-pyridyl; most preferably —2-thiazolyl, 2-pyrazinyl, or =2- pyridyl.
More preferably the group of formula 1 is 2-thiazolyl, or 2-ypyrazinyl.
Most preferably the group of formula 1) is 2-thiazolsyl and R® is 5-fluoro and R* is hydrogen; or 2-pyrazinyl and R* amnd
R* are hydrogen; especially preferred is 2-thiazolyl where R? is 5-fluoro and R* is hydrogen. :
In the presemt invention, R' and R? are preferably hydrogen.
In the presemnt invention R® and R* are preferably independently selected fromm hydrogen, halogen, and methyl, more preferably R® and_ R* are independently selectzed from hydrogen, flucoro, and methyl.
In the present invention, R? is preferably hydrog=en or halogen; more preferably hydrogen, fluoro, chloro or bromo; even more preferably hydrogen, fluomro, or chloro; most preferably hydrogen or fluoro.
In the present invention, R* is preferably hydrogen , halogen, or methyl; mo:re preferably hydrogen or metinayl.
In the present invention, RS and RS are preferably rot both hydrogen.
In the present invent-ion, R® is preferably CFs, SORR!, SO,R?, SO,NR’R'’,
NHSO,R®, or triazolyl; more preferably SOR, SO;R®, or SO,NR°R!®; most preferably SO;R® or SO;NFR’R'’, especially SO;R®,
In particular R® is S€,C; cycloalkyl, especially S O.cyclopropyl.
In the present invention, RS is preferably hydroger, chloro, fluoro, or trifluoromethyl; more preferably hydrogen.
In the present invenstion, R7,R”, and R® are prefer=ably Ci.alkyl, Cs ;cycloalkyl, heteroaryl, or 4-7-membered heterocyclic greoup; more preferably C1— jalkyl, 4-6-membered hetemrocyclic group, or Cascycloall=<yl; most preferably methyl, ethyl, n-propyl, cyclopropy-1, cyclobutyl, oxetanyl, or tetrezhydrofuryl, and especially methyl, ethyl, n-propyl, cyclopropyl, or cyclobutyl.
When the dotted lin_e together with the solid line f~orms a double bond Rlis preferably Cy-salkyl, or C3_cycloalkyl.
When the dotted lin_e together with the solid linc forms a single bond R® is preferably Cs 4cycloalkyl, especially cyclopropyl.
When R® and/or R® are COR’ or SR’, R’ is prefemrably not hydrogen.
In the present inven tion, R?® and R'? are preferably independently Co4alky® e.g. one of R® and RY is hydrogzen and the other is ethyl, or combine to form a 4-8- membered heterocyclic rings. R® and R'? are preferably n-ot both hydrogen.
In the present invemtion, R® and R'® are preferabwly Co4alkyl.
In the present invenstion, m is preferably O.
In the present invention, n is preferably 2 or 3.
A preferred group cof compounds are compounds »of Formula (I), or pharmaceutically acceptable salts thereof, wherein:
Q is 4-tetrahydropyranyl;
T together with the —N=C— to which it is attached forms a 2-pyrazinyl or 22- thiazolyl ring; .
R! and R? are hydrogen;
R® and R* each independently are hydrogen or flum.oro;
R’ is SO;R®, or SOSNR®R'Y;
RS is hydrogen;
VO 2004/072031 PCT/US2004/003968
R® is a Cs.scycloalkyl group or a 4-6-membered heterocyclic- group, and, in acldition, when the dotted line togeether with the solid line forms a dosuble bond R® may bes a Craalkyl group;
R® and R'° are independeratly Co4alkyl, provided that R® andl R'? are not both hydrogen; mis 0; and the dotted line together with the solid line forms an optional double bond, and
Aa indicates that the double bond Inas the (E)-configuration.
A more preferred group of compounds are compounds of Fostmula (I), or peharmaceutically acceptable salts thereof, wherein:
Q is 4-tetrahydropyranyl;
T together with the -N=C=—to which it is attached forms a 2—pyrazinyl or 2- tahiazolyl ring;
R! and R? are hydrogen;
R3 and R* each independently are hydrogen or fluoro;
R® is SOR’;
RS is hydrogen;
R® is a Cs.scycloalkyl group and, in addition, when the dotte=d line together vith the solid line forms a doubles bond R® may be a C.3alkyl group; m is 0; and the dotted line together with the solid line forms an optional double bond, and
A indicates that the double bond “has the (E)-configuration.
Specific compounds of thme invention which may be mentiored are those described in the Examples, in particular. Examples 1 to 201, and ph=armaceutically acceptable salts thereof.
Specific compounds of time invention which may be mentiored are: (2R)-2-(4-Cyclopropanes. ulfonylphenyl)-N-(5-fluorothiazol—2-y1)-3-
Ctetrahydropyran-4-yl)propionanide; (2R)-2-(4-Cyclopropanes.ulfonyiphenyl)-N-pyrazin-2-yl-3-(-tetrahydropyran-4- w/l)propionamide; (2R)-2-(4-Cyclobutanesu 1fonylphenyl)-N-pyrazin-2-yl-3-(testrahydropyran-4- s/l)propionamide;
WO =2004/072031 PCT/US2004/0039688 (2R)-2-(4-Cyclobutanesulfone yiphenyl)-N-(5-fluorothia=zol-2-yl)-3- (tetmrahydropyran-4-yl)propionamide ; and (E)-N-(5-Fluorothiazol-2-y1) —2-(4-methanesulfonylphemnyl)-3- (tetzrahydropyran-4-yl)acrylamide; or a pharmaceutically acceptable salt thereof.
In particular the compounds= (2R)-2-(4-Cyclopropanesulfonylphenyl)-N-(5 -fluorothimazol-2-yl)-3- (te®rahydropyran-4-yl)propionamides; (2R)-2-(4-Cyclopropanesulfonylphenyl)-N-pyrazin-2-3w/l-3 -(tetrahydropyran-4— yl)—propionamide; and (E)-N-(5 Fluorothiazol-2-yI»-2-(4-methanesulfonylphe=nyl)-3- (te—trahydropyran-4-yl)acrylamide; or a pharmaceutically accep table salt thereof.
While the preferred groups for each variable have generally been listed above separately for each variable, preferred compounds of this inve=ntion include those in which several or each variable in Formula (I) is selected from. the preferred, more preferred, most preferred, especially or particularly listed grovaps for each vazriable. Therefore, this invention 1s intended to include all ¢c-ombinations of pre=ferred, more preferred, most pre ferred, especially and particularly listed groups.
As used herein, unless stated otherwise, “alkyl” as well as other groups ha=ving the prefix “alk” such as, for example, alkoxy, alkanyl, alkenyl, alkynyl, and the like, means carbon chains whick may be linear or branche=d or combinations the=reof, Examples of alkyl groups include methyl, ethyl, propoyl, isopropyl, butyl, sec- an_d tert-butyl, pentyl, hexyl, heptyll and the like. “Alkenyl”, =‘alkynyl” and other like= ter—ms include carbon chains having at least one unsaturated caarbon-carbon bond.
As used herein, for examples, “Cg 4alkyl” is used to me=an an alkyl having 0-4 ca—xbons — that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration. An all<yl having no carbon is hydrogerm when the alkyl is a termiraal group. An alkyl ha_ving no carbon is a direct bond when the alkyl is a bridging (connecting) group.
The terms “cycloalkyl” and. “carbocyclic ring” mean carbocycles containing now heteroatoms, and include mono—, bi-, and tricyclic saturate=d carbocycles, as well a_s fu:sed and bridged systems. Such fused ring systems can inclmnde one ring that is pamtially or fully unsaturated, such as a benzene ring, to form fused ring systems, such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofuse=d ring systems. Exampoles of cycloalkyl and carbocyclic rings include Cascycloallikyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and decahydronaphthaalene, adamantane, indanyli, 1,2,3 J4-tetrahydronaphthalene anc the like.
The term “halogen” includes fluorine, chlorine, bromine, and iodine atomms.
The term “ar~y!”” includes, for example, phenyl and naphthyl.
Unless otherwise stated, the term “heterocyclic ring” includes 4-8-memmbered saturated rings containing one or two heteroatoms chossen from oxygen, sulfur, and nitrogen. The heteroatoms are not directly attached to ©ne another. Examples o f heterocyclic rings imnclude oxetane, tetrahydrofuran, tetorahydropyran, oxepane, oxocane, thietane, tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiocanes, azetidine, pyrrolidimne, piperidine, azepane, azocane, [L ,3]dioxane, oxazolidine , piperazine, and the like. Other examples of heterocyclic rings include the oxid=ised forms of the sulfur— containing rings. Thus, tetrahydrot-hiophene 1-oxide, tetrahydrothiophen_e 1,1-dioxide, tetrahydrothiopyran 1-oxide, and tetrahydrothiopyramn 1,1-dioxide are also considered to be heterocyclic rings.
Unless otherwise stated, the term “heteroaryl” includes 5- or 6-membe-=red heteroaryl rings cosntaining 1-4 heteroatoms chosen from oxygen, sulfur, and nitrogen.
Examples of such “heteroaryl rings are furyl, thienyl, pyrrolyl, pyrazolyl, imidaazolyl, oxazolyl, isoxazol-yl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazoly=], tetrazolyl, pyridinzyl, pyridazinyl, pyrimidinyl, pyrazimnyl, and triazinyl.
The above formulas are shown without a defimitive stereochemistry at. certain positions. The present invention includes all stereois omers (e.g. geometric ismomers, optical isomers, di astereoisomers, etc.) and pharmaceutically acceptable salts thereof, except where specifically drawn or stated otherwise. Further, mixtures of stereoisomers as well as isolated specific stereoisomests are also included, except where specificallyy drawn or stated otherwise. During the course of the synth-etic procedures used t-o prepare such compounds, or in ussing racemization or epimerization prowcedures known to those skilled in the art, the products of stach procedures can bes a mixture of stereoisomers. Wher a tautomer of the compwound of the above formulzas exists, the present invention inclmudes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtimres thereof, except wher—e specifically drawn or stated otherwise. When the compound of the above formulas and pharmaceutically acceptable salts thereof exist i_n the form of solvates or= polymorphic forrmns, the present invention includes amny possible solvates andi polymorphi«c forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologzically acceptable. For example, water, ethanol, prospanol, acetone or the like can be used.
Since the compounds of Formula (I) are intended for pharmaceutical use they are preferatsly provided in substantially pure form, for example at least- 60% pure, more suitabely at least 75% pure, especially at least 98% pure (% are or a weight for weight basi s).
The invention also encompasses a phmarmaceutical composition that is comprised of a compound of Formula (I), or 2a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
Preferably the composition is comprmsed of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compouned of Formula (I) as describeed above, or a pharmaceutically acceptable salt thereof.
Moreover, within this preferred embodiment, the invention enczompasses a pharmaceuttical composition for the prophylaaxis or treatment of hyperglycemia and diabetes by the activation of GK, comprising a pharmaceutically acceptable carrier and a non-t oxic therapeutically effective am-ount of compound of Formula (I) as described a_bove, or a pharmaceutically acceptable salt thereof.
The= invention also provides the use ©f a compound of Formula. (D,ora pharmaceutically acceptable salt thereof as &a pharmaceutical.
The compounds and compositions off the present invention are effective for treating hyperglycemia in mammals such as. for example, hurnans.
Thes invention also provides a methoed of prophylactic or therapmeutic treatment of a conditi on where activation of GK is deszirable comprising a step of administering an effective amount of a compound of Form ula (I), or a pharmaceutically acceptable salt thereof".
The= invention also provides a metho=d of prophylactic or therapeutic treatment of hyperglycemia or diabetes comprising a sstep of administering an efFective amount of a compound of Formula (I), or a pharmac=eutically acceptable salt thereof.
Thes invention also provides a method of prevention of diabetes in a human demonstrat-ing pre-diabetic hyperglycemia oer impaired glucose tolerance comprising a step of administering an effective prophylactic amount of a compound. of Formula (I), or a pharmaceutically acceptable salt thereo=f.
The invention also provides the use of 2 compomund of Formula (I), or a— pharmaceutically acceptable salt thereof, as a GK activator.The inventicon also provides the use of a compound of Formula (I), or aa pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of hyperglycemia oer diabetes.
The inventi-on also provides the use of 2 compound of Formula (I), or & pharmaceutically acceptable salt thereof, for the preve=ntion of diabetes in 2a hvmman demonstrating pre- diabetic hyperglycemia or impairecd glucose tolerance.
The inventi_on also provides the use of a compwound of Formula D,ora pharmaceutically as.cceptable sait thereof, in the manuffacture of a medicament for the activation of GK.
The invention also provides the use of a comp=ound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manu—facture of a medicament for the prophylactic or therapeutic treatment of hyperglycemia or diabetes.
The invention also provides the use of a compound of Formula (I), or a pharmaceutically sacceptable salt thereof, in the manufacture of a medicament for the prevention of diab-etes in a human demonstrating pre—diabetic hyperglycemia or impaired glucose tolerance.
The compounds and compositions of the preseent invention may be optionally employed in comi>ination with one or more other antm-diabetic agents or anti- hyperglycemic ageents, which include, for example, smlfonylureas (e.g. glyburide, glimepiride, glipy-¥ide, glipizide, chlorpropamide, gliaclazide, glisoxepid, acetohexamide, gllibornuride, tolbutamide, tolazamid e, carbutamide, gliquidomne, glyhexamide, phenbutamide, tolcyclamide, etc.), bigmuanides (e.g. metformin, phenformin, bufommin, etc.), glucagon antagonists (e -g a peptide or non-peptide glucagon antagonist), glucosidase inhibitors (e.g. acamrbose, miglitol, etc.), insulin secetagogues, insmilin sensitizers (e.g. troglitazone, rOsiglitazone, pioglitazone, etc.) and the like; or armti-obesity agents (e.g. sibutramine, orlistat, etc.) and the likze. The compounds and ceompositions of the present inventiosn and the other anti-diatoetic agents or anti-hypoerglycemic agents may be adminiss tered simultaneously, sequentially or se=parately.
The term ‘pharmaceutically acceptable salis’™ refers to salts prepared from pharmaceutically acceptable non-toxic bases or acidss. When the compound of the present invention _ is acidic, its corresponding salt car be conveniently prepar—ed from pharmaceutically acceptable non-toxic bases, including inorgaric bases and organic bases. Salts derived from such_ inorganic bases include aluminwm, ammonium, calcium, cupric, cuprous, ferric, ferrous, lithium, magnesium, rnanganic, manganous, potassium, sodium, zinc and the like salts. Particularly preferr=ed are the ammonium, calcium, magnesium, potassiurm and sodium salts. Salts deriveed from pharmaceutically acceptable organic non-toxic bases include s=alts of primary, secondary, and tertiary amines _, as well as cyclic amines and stabstituted amines such ass naturally occurring and synt-hetic amines. Other pharmaceutically acceptable oxganic non-toxic bases from which salts can be formed incluce, for example, axginine, betaine, caffeine, chosline, N’,N ’.dibenzylethylenedizamine, diethylamine, 2- d jethylaminoethanol, 2-dimetimylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiper-idine, glucamine, glucosamine, histidine, isopropylamine, lysine, methy_Iglucamine, morpholine, pipera=ine, piperidine, polyamine resins, procaine, pusrines, theobromine, triethylamire, trimethylamine, tx-ipropylamine, tromethamine and the like.
When the compound of the present invention is basic, Hts corresponding salt c an be conveniently prepared #rom pharmaceutically acceptable non-toxic acids, imcluding inorganic and organic acids. Such acids include, for example, acetic, be enzenesulfonic, benzoic, cammaphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitrics, pamoic, pantothenic, phosphomric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly prefe=tred are citric, a ydrobromic, hydrochloric, maleic, phosphoric, sulfuric, methmanesulfonic, and tartaric acids.
The pharmaceutical co mpositions of the present inven®ion comprise a compound of Formula (I), or zm pharmaceutically acceptable samlt thereof, as an active imgredient, a pharmaceutically~ acceptable carrier and optionally other therapeutic imgredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (Cincluding subcutaneous, intramuscular, and jmtravenous) administration, ass well as administration through _ inhaling, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
The pharmaceutical compositiz ons may be conveniently preserated in unit dosage form and prepared by any of the methods well known in the art of poharmacy.
T be pharmaceutical compositionss according to the invention are preferably adapted for oral administration.
Ir practice, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, of this invention can be conribined as the active ingmredient in intimate admixtur-e with a pharmaceutical carrier zccording to conventiormal pharmaceutical compounding techniques. The carrier mzay take a wide variety of forms depending cn the form of preparation desired for admirnistration, e.g. oral or parenteral (including intravenous). Thus, the pharmaceutical ccompositions of the present invention can b- € presentecd as discrete units suitable for or-al administration such as capsules, cachets or tablets ezach containing a predetermined amount of the active ingredient. Further, thae composistions can be presented as a powdller, as granules, as a solution, as a suspensieon in an aquaeous liquid, as a non-aqueous liequid, as an oil-in-water emulsion, or as a water-in—oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula (ID), or a pharmaceutically acceptable salt thereof, amay also be administered by comtrolled release means amnd/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. Ira general, ssuch methods include a step of beringing into associatior the active ingredie—mt with the carrier that constitutes one or more necessary ingrediendts. In general, the compositions are prepared by uniformly =and intimately admixing the active ingredie=nt with liqu_id carriers or finely divided solic carriers or both. The mproduct can then be convenie=ntly shaped into the desired pressentation.
Thus, the pharmaceutical compos-itions of this invention may include a pharmace=utically acceptable carrier and & compound of Formula- (I), or a pharmace=utically acceptable salt thereof. The compounds of Fommula (I), or pharmace=utically acceptable salts thereof, can also be included ir pharmaceutical composit=ions in combination with one or more other therapeutically active compourmds.”
T he pharmaceutical compositions- of this invention inclucde a pharmaceutically acceptable liposomal formulation containming a compound of Formmula (I) or a pharmaceutically acceptable salt thereof.
T he pharmaceutical carrier employed can be, for exampLe, a solid, liquid, or- gas. Bxacsuoples of solid carriers include I=actose, terra alba, sucrose, tale, gelatin, agamr, pectin, acoacia, magnesium stearate, and satearic acid. Examples c>fliquid carriers are
Claims (40)
- PCT/US2004/003968 “WVHAT IS CLAIMED IS:I. A compound of Formula (I): R' R? (CH2)m aH RK lb 5 MX J! RE 6) or a pharmaceutically acceptable salt thereof, wherein: Qs an aryl, a 5- or 6—membered heteroaryl, or a 4-8-membered heterocyclic mring; T together with the —~=C- to which it is attached forms a heteroaryl ring, or am heterocyclic ring where the NIJ=C bond is the only site of unsatur-ation; R! and R? each independently are hydrogen, hydroxy, halogen, cyano, nitro, v=inyl, ethynyl, methoxy, OCE Hs, —N(Co4alkyl)(Cosalkyl), CHO, or C 1-2alkyl osptionally substituted with 1- 5 independent halogen, hydroxy, cyano, methoxy, —_N(Co_zalkyl)(Co_zalkyl), SO=CH3, or SO,CHj substituents; or R ' and R? together form a carbocyclic or heterocyclic ri-ng; or R! and R? may be taken together to represent an owxygen atom attached to the ring via a double bond; R? and R* each indepe=ndently are hydrogen, halogen, OCF,Hi_,, methoxy, C0,R”’, cyano, nitro, CHO, CCONR*’R'®, CON(OCH;3)CHj, or <Ci.zalkyl, heteroaryl, wor(C3.scycloalkyl optionally sub stituted with 1-5 independent halogen, hydroxy, cyano, methoxy, -NHCO,CH;, or ~M(Co-2alkyl)(Coralkyl) substituents; or R® and R* together form a S-8-membered aromattic, heteroaromatic, carbocyclic, or heterocyclic ring; R® is SO,Cs4cycloalk=yl; R® is hydrogen, hydro-xy, halogen, cyano, nitro, CO,R’, CHO, CORS®, C(OH)R_'R?, (=(=NOR)R?, CONR’R", SR=’, SOR?, SOR? -94 - AMENDED SHEETC, alkenyl gromup, C,4alkynyl group, C14alkoxy group, aryl group, or heteroar=yl group, wherein . any group optionally is substitute} with 1-6 independent halogen, cyano, nitro, hydroxy, Cialkoxy, —N(Co_2alkyl)( Co-2alkyl), C_zalkyl, CF,Hz un, aryl, heteroaryl, -CCOC1_zalkyl, —CON(Co-2alkyl)(Co-2amlkyl), SCHj, SOCH3, SO,CHL3, or —SO;N(Co_palk=yl)(Co-2alkyl) substituents; or R® a—nd RS together form a 5-8- membered carbocyclic or heterocyclic ring; R’ and R” each independently are hydrogeen, or Cialkyl group, C,4allkenyl group, Cp4alk=ynyl group, C,.scycloalkyl group, amxyl group, heteroaryl group, or 4-7- membered heterocyclic group, wherein any group optionally is substituted with 1-6 independent h_alogen, cyano, nitro, hydroxy, Ci_2- alkoxy, ~N(Co-zalky)(Coallyl), C1_alkyl, Cs_—~cycloalkyl, 4-7 membered heterocyclic ring, CFuHs-x, aryl, heteeroaryl, CO,H, -COC 1.zalkyl, ~CON(Co-2alkyl)(Co-2alk sl), SOCH;, SO,CHj, or —SO;N(Cq2al kyl)(Co-zalkyl) substituents; RE is C4alkyl group, Cz salkenyl group, C,4alkynyl group, Cscycloamlkyl group, aryl gr-oup, heteroaryl group, or 4-7-menmbered heterocyclic group, wheerein any group optionally is substituted with 1-6 inde=pendent halogen, cyano, nitro, hydroxy, Ci-malkoxy, —~N(Co-zalkyl)(Co-zalkyl), eC, alkyl, Cs cycloalkyl, 4—77- membered he=terocyclic ring, CF Hz», aryl, heteroaryl, CO-H, COC-2alkyl, —CON(Co-2alky1)(Co-zalkyl), SOCH3, SO,CHa, wor —SO;N(Co-2alkyl)(Co-zalky1) substituents; R°, RY, R®, and R'® each independently are hydrogen, or C, alkyl group,Cs.scycloalkyws1 group, aryl group, heteroaryl group, or 4-7-membered heteroc=yclic. group, where=in any group optionally is substituted with 1-6 independent halomgen, cyano, nitro, hydroxy, C;_zalkoxy, ~N(Co—alky1)(Co-2alkyl), Ci-2alkyl, Cs scycloalkyl, <4-7-membered heterocyclic ring, CF,Hjy, aryl, heteroaryl, COCzalkyl, —CON(Co-22 Tkyl)(Cozalkyl), SOCHs, SO.CHj, or —SO,N(Copalkyl)(Co-zalk yl) substituents; or R® and R' or R® and R'® together form a 6-8-membered heterobicyclHc ring system or a 4-8-membered “heterocyclic ring which optio-nally is substituted vwith 1-2 independent C,»alkyl, CHE,0CHS, COCo-alkyl, hydroxy, or SO,CH; sub stituents; nis M,2o0r3; mis Oorl; and the dotted line together wit the solid line forms an opstional double bond, and A inadicates that the double bond ha_s the (E)-configuration.
- 2. A compound according to claim 1, or a pharmaceu—tically acceptable s=alt theresof, wherein the dotted line tog=ether with the solid line foerms a double bond.
- 3. A compound according toclaim 1, ora pharmaceutically acceptable s-alt theresof, wherein the dotted line togzether with the solid line fosrms a single bond.
- 4. A compound according to claim 3, or a pharmaceumtically acceptable szalt thereeof, wherein the dotted line together with the solid line forms a single bond, and the mabsolute configuration at the asymmetric centre a to the ammide carbonyl cartoon is®.
- 5. A compound according to any one of the precedinzg claims, wherein n= is 0.
- 6. The compound accordirag to any one of the preced—ing claims, or a phar-maceutically acceptable salt thereof, wherein Q is thieny—1, furyl, thiazolyl, pyri-dyl, tetrahydropyranyl, piperidtinyl, tetrahydrothiopyrany-1, 1-oxo- tetramhydrothiopyranyl or 1,1-dioxcom-tetrahydrothiopyranyl.
- 7. A compound according to claim 6, or a pharmacewatically acceptable ssalt therweof, wherein Q is 4-tetrahydrogoyranyl.
- 8. The compound accordirag to any one of the preced—ing claims, or a phar-maceutically acceptable salt tiaereof, wherein the group of formula 1S is thmiazolyl, thiadiazolyl, oxazolyl,. isoxazolyl, pyrimidinyl, p=yrazinyl, or pyridyB.
- 9. A compound according to claim 8, or a pharmaceutically acceptable salt thereeof, wherein the group of fornmulaPCT/US2004/0039689. A compound according to claim 8, or a pharmaceutically acceptable salt tihereof, wherein the group of formula 1S iss 2-pyrazinyl or 2-thiazolyl.
- 10. A compound according to claim 9, or a pharmaceuticall y acceptable salt thereof, wherein the group of formula J ) is 2-thiazolyl, R® is 5-fluoro and R* is hydrogen.
- 11. A compound according to any one of the preceding claimms, or a pknarmaceutically acceptable salt thereof, wherein R? and R* are independently selected fr-om hydrogen, halogen, and methyl.
- 12. A compound according to any one of the preceding claimms, or a pharmaceutically acceptable salt thereof, wherein R® is C)4alkyl or =C;_scycloalkyl.
- 13. A compound according to any one of the preceding clair=ns, or a plaarmaceutically acceptable salt thereof, wherein R® is hydrogen.
- 14. A compound selected from: 2-(4-Cyclopropanesulfonylphenyl)-3-(tetrahydropyran-4-yl)—AN-thiazol-2- yl propionamide; 2-(4-Cyclopropanesulfonylphenyl)-N-(5-fluorothiazol-2-yl)- 3-(tetrahydropyran-4- yl )propionamide;-97.- AMENDED SHEETPCT/USZ22004/0039682-(4-Cyclo-propanesulfonylphenyl)-N-(3-mesthyl-[ 1,2,4]thiadiazol-5 -y1)-3- (tetrahydropyran-4&-yl)propionamide;2-(4-Cyclo propanesulfonylphenyl)-N-pyrazi n-2-yl-3-(tetrahydropyrara-4- yl)propionamide;2-(4-Cyclo propanesulfonylphenyl)-3-(tetrah_ydropyran-4-yl)-N-[1 ,2,4 Jthiadiazol- 5-ylpropionamidez(E)-2-(4-C—yclopropanesulfonylphenyl)-3-(te trahydropyran-4-yl)-N-thznazol-2- ylacrylamide;2-(4-Cyclo propanesulfonylphenyl)-N-(5-formmylthiazol-2-yl)-3-(tetrah ydropyran- 4-yl)propiocnamide=;(2R)-2-(4- Cyclopropanesulfonylphenyl)-N-€ 5-fluorothiazol-2-yl1)-3- (tetrahydropyran-4&-yl)propionamide;(2R)-2~(4- Cyclopropanesulfonylphenyl)-3-( tetrahydropyran-4-yl)-N- [1,2,4]thiadiazol-5 -ylpropionamide;(2R)-2-(4-Cyclopropanesulfonylphenyl)-N-pe yrazin-2-yl-3-(tetrahydro_pyran-4- yl)propionamide;(2R)-2-(4- Cyclopropanesulfonylphenyl)-N-(5-fluoropyridin-2-yl)-3- (tetrahydropyran-4&-yl)propionamide;(2R)-2-(4-Cyclopropanesulfonylphenyl)-3-(t-etrahydropyran-4-yl)-¥ -thhiazol-2- ylpropionamide;(2R)-2-(4-Cyclopropanesulfonylphenyl)-N-(3-methyl-[1,2,4]thiadiazo 1-5 -yl)-3- (tetrahydropyran-4--yl)propionamide;(2R)-2-(4-Cyclobutanesulfonylphenyl)-N-py- razin-2-yl-3-(tetrahydrop —yran-4- yl)propionamide;(2R)-2-(4-Cyclobutanesulfonylphenyl)-N-py—rimidin-4-yl-3-(tetrahydrcpyran-4- yl)propionamide;(2R)-2-(4-Cyclobutanesulfonylphenyl)-N-isomxazol-3-yl-3-(tetrahydrooyran-4- yl)propionamide;(2R)-2-(4-Cyclobutanesulfonylphenyl)-N-(1 —methyl-1 H-pyrazol-3-yl}—3- (tetrahydropyran-4--yl)propionamide;-98- AMENDED SHE.ETP=CT/US2004/003968 (2R)-2-(A-Cyclobutanesulfonylphenyl)-N"~(5-fluorothiazol-2-y~1)-3- (tetrahydropyrarm-4-yl)propionamide; (E)-2-(4—Cyclopropanesulfonylphenyl)--(5-fluoropyridin-2-_yl)-3- (tetrahydropyrama-4-yl)acrylamide; (E)-2-(4- Cyclopropanesulfonylphenyl)-N"-(5-fluorothiazol-2-y~1)-3- (tetrahydropyran.-4-yl)acrylamide; N-(5-Cyamnothiazol-2-yl)-2-(4-cyclopropa nesulfonylphenyl)-3—(tetrahydropyran-4- yl)propionamide ; 2-(4-Cyclopropylmethanesulfonylphenyl®-3-(tetrahydropyran- 4-yl)-N-thiazol-2- ylpropionamide; and 2-(4-CycMobutanesulfonylphenyl)-3-(tetra_hydropyran-4-yl)-N-wthiazol-2- ylpropionamide; or a pharmaceutically acceptable salt thereof.
- 15. A compound selected from: 2-(4-Cycl_opropanesulfonylphenyl)-3-(tetr—ahydropyran-4-yl)-»"-thiazol-2- ylpropionamide; 2-(4-Cycl_opropanesulfonylphenyl)-N-(5-fluorothiazol-2-yl)-3- (tetrahydropyran-4- ylpropionamide;. 2-(4-Cycl opropanesulfonylphenyl)-N-(3-rmethyl-[1,2,4]thiadia=z0l-5-yl)-3- (tetrahydropyran—4-yl)propionamide; 2-(4-Cycl-opropanesulfonylphenyl)-N-pyraxzin-2-yl-3-(tetrahydr—opyran-4- yl)propionamide; 2-(4-Cycleopropanesulfonylphenyl)-3-(tetrahydropyran-4-yl)-N—[1,2,4]thiadiazol- 5-ylpropionamide=; (E)-2-(4-Cyclopropanesulfonylpheny!)-3-Ctetrahydropyran-4-y l)-N-thiazol-2- ylacrylamide; (2R)-2-(4 -Cyclopropanesulfonylphenyl)-V-(5-fluorothiazol-2-=yl)-3- (tetrahydropyran--4-yl)propionamide; (2R)-2-(4- -Cyclopropanesulfonylphenyl)-3 —(tetrahydropyran-4-s1)-N- [1,2,4]thiadiazol-35-ylpropionamide; - 99. AMENDED SHEETPCT/US2004/0m03968 (2R)-2-(4-Cyclopropanes- ulfonylphenyl)-N-pyrazin-2--yl-3-(tctrahydropyran—4- yl)propionamide; (2R)-2-(4-Cyclopropanes ulfonylphenyl)-N-(5-fluoropsyridin-2-yl)-3- (tetrahydropyran-4-yl)propionamraide; (2R)-2-(4-Cyclopropanes ulfonylphenyl)-3-(tetrahydro—pyran-4-yl)-N-thiazol—2- ylpropionamide; (2R)-2-(4-Cyclopropanesulfonylphenyl)-N-(3-methyl-[ 1,2,4]thiadiazol-5-yl) -3- (tetrahydropyran-4-yl)propionammide; (2R)-2-(4-Cyclobutanesu Rfonylphenyl)-N-pyrazin-2-yl -3-(tetrahydropyran-4— yl)propionamide; (2R)-2-(4-Cyclobutanesuk fonylphenyl)-N-(5-fluorothiamzol-2-yl)-3- (tetrahydropyran-4-yl)propionam ide; (E)-2-(4-Cyclopropanesu X fonylphenyl)-N-(5-fluorothiaazol-2-yl)-3- (tetrahydropyran-4-yl)acrylamides; and 2-(4-Cyclobutanesulfonyl phenyl)-3-(tetrahydropyran-<3-yl)-N-thiazol-2- ylpropionamide; or a pharmaceutically acceeptable salt thereof.
- 16. A compound selected. from: (2R)-2-(4-Cyclobutanesul fonylphenyl)-N-pyrazin-2-yl—3-(tetrahydropyran-4— yl)propionamide; and (2R)-2-(4-Cyclobutanesul fonylphenyl)-N-(5-fluorothia=zol-2-yl)-3- (tetrahydropyran-4-yl)propionamide; or a pharmaceutically acceptable salt thereof.
- 17. (2R)-2-(4-Cycloproparesulfonylphenyl)-N-(5-fluoreothiazol-2-yl)-3- tetrahydropyran-4-yl)propionami_de, or a pharmaceutically acceptable salt thereof.
- 18. (2R)-2-(4-Cyclopropamesulfonylphenyl)-N-pyrazin -2-yl-3-(tetrahydropyr—an- .yl)propionamide, or a pharmace=utically acceptable salt thereof. - 100 - AMENDED SHEETPCT/US2004/00m3968
- 19. A compound of FormuRa(I): RR? ( CH2)m RB RR la H N 2 5K RS NE = ty or a pharmaceutically acceptable salt thereof, wherein : Q is 4-tetrahydropyranyl; T together with the -N=C— t=o which it is attached forrmns a 2-pyrazinyl or 2- thiazoL vy! ring; R! and R? are hydrogen; R? and R* each independentR y are hydrogen or fluoro; R® is SO,C;ucycloalkyl; R® is hydrogen; m is 0; and the dotted line together with the solid line forms an op~tional double bond, and 4 indicat es that the double bond has tine (£)-configuration.
- 20. A pharmaceutical composition comprising a compmound according to any of claims [to 19, or a pharmaceutically acceptable salt thereof, a_nd a pharmaceutically acceptable carrier.
- 21. A process for the preparation of a compound of Fcormula (Ia) - 101 - AMENDED SHEET“PCT/US2004/003968 rR R? (CHz R® R* an N 1A > AJ R® (Ta) said process comprising a step of the condensation of a compound ofS Formula (IV): R™ R? (CH2)m a OH 0] RS Iv R% with a compound of Formula (V)= rE R* HoN ~ CJ Vv wherein Q, T, R'to RS, m and A are as defined in claim I.
- 22. A process for the preparation of a compound of Formula -(Ib) -102 - AMENJDED SHEETPCT/US2004/0039658 rR R2 (CH2)m RS R* H " T Sn RE (Ith) said proce=ss comprising a step of the= condensation of a compound of Formula (VID): R" Rr? () (CH2)m OH RS le) 6 R VIII with a compound of Formula (V): RS R* HN LA J \'% wheerein Q, T, R'to R® and m are as defined in claim 1.
- 23. A compound of formula IV): -103 - AMENDED SHEETPCT /US2004/003968 R’ RZ (CE2)m a OH ©) R® v RS whaerein Q is 4-tetrahydropyranyl; R! and R? are hydrogen; R® is SO,Cs cycloalkyl; R® is hydrogen; m ms 0; and A indicates that the double bond has thee (£)-configuration.
- 24. A compound of Formula (IV) which is: (E)-2-(4-Cyclopropanesulfonylphenyl)—3-(tetrahydropyran-4-ylhaecrylic acid.
- 25. A compound of formula (VIII): Rr? R? (CH2) m OH 0) RS 6 R VIII Q iss 4-tetrahydropyranyl; -104 - AMENDED SHEETPCT/U=S2004/003968 R' and R? amare hydrogen; R’isis SO=C3 4cycloalkyl; R®is hydro _gen; and mis 0.
- 26. A comppound of Formula (VIII) selectecq from: 2-(4-Cycloporopanesulfonylphenyl)-3-(tetratmydropyran-4-yl)propion=ic acid; 2-(4-Cycloboutanesulfonylphenyl)-3-(tetrahy—dropyran-4-yl)propionic= acid; (2R)-2-(4-Cyclopropanesulfonylphenyl)-3-( tetrahydropyran-4-yl)prcopionic acid; and (2R)-2-(4-Cyclobutanesulfonylphenyl)-3-(t<etrahydropyran-4-yl)pro—pionic acid.
- 27. 5-Fluomothiazol-2-ylamine or an amide or acid addition salt ther—eof.
- 28. Use of acompound according to any orme of claims 1 t0 19, ora pharmaceutically a_cceptable salt thereof in the manufacture of a preparatiorm for prophylactic or the rapeutic treatment of a condition where activation of GK is desirable.
- 29. Use of acompound according to any orme of claims 1 to 19, or a pharmaceutically acceptable salt thereof in the manufacture of a preparatiorm for prophylactic or the rapeutic treatment of hyperglyce mia or diabetes.
- 30. Use according to claim 29 wherein the preparation is administramble in combination with One or more other anti-hyperglycesmic agents or anti-diabetic agents.
- 31. Use of acompound according to any ome of claims 1 to 19, or a pharmaceutically acceptable salt thereof in the manufacture of a preparationm for prevention of diabetes in a human demonstrating pr—e-diabetic hyperglycemi a or impaired glucose tolerance. - 105 - AMENDED SHESET }PCT/US200 4/003968
- 32. A substarce or composition for use in a me=thod of prophylactic or thzerapeutic treatment of a conditi on where activation of GK is desi rable, said substance or composition compris&ng a compound according to any one of claims I to 19, oraa pharmaceutically acceptable salt thereof, and said mettmod comprising a step of administering an effeective amount of said substance or composition.
- 33. A substarmce or composition for use in a me=thod of prophylactic or therapeutic treatment of hyperglycemia or diabetes, said substance or composition comprisirag a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and said mettod comprising a step of administering an effective amount of said substance or composition.
- 34. A substan _ce or composition for use in a me thod of prevention or treatment according to claim 33 wherein said substance or compamsition is administered in combination with one= or more other anti-hyperglycemi< agents or anti-diabetic azgents.
- 35. A substan ce or composition for use in a method of prevention of diabmetes in a human demonstrating pre-diabetic hyperglycemia or inapaired glucose tolerance, said substance or composistion comprising a compound acco rding to any one of claims | to 19, or a pharmaceutically acceptable salt thereof, and said rmethod comprising a step of administering an effective amount of said substance or «composition.
- 36. A comppound according to any one of claims 1 to 19, 23 to 325, substantially as hereirx. described with reference to and as illustrated in any of the examples.
- 37. A composition according to claim 20, substantially as herein described with reference to and zs illustrated in any of the exampl es.
- 38. A processs according to claim 21 or claim 22, substantially as herein described with referen_ce to and as illustrated in any of tJhe examples. - 106 - AMENDED SHEETPCT/US20804/003968
- 39. Use acc ording to any one of claims 28 to 31, substantially as hemrein described with reference to and as illustrated in any o=f the examples.
- 40. A substzance or composition for use in a method of prevention omr treatment according to any one o fclaims 32 to 35, substantially as herein described with reference to and as illustrated in any of the examples. - 107 - AMENDED SHEE=T
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US44668303P | 2003-02-11 | 2003-02-11 |
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| CN113527225B (en) * | 2021-07-15 | 2022-11-18 | 南昌大学 | Acylyl thiadiazole derivative and preparation method and application thereof |
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