Title of Invention

"COMPOUNDS AS GLUCAGON RECEPTOR ANTAGONISTS"

Abstract

The present invention discloses novel compounds of Formula I, or pharmaceutically acceptable salts thereof, which have glucagons receptor antagonist or inverse agonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I as well as methods of using them to treat diabetic and other glucagons related metabolic disorders, and the like.

Full Text

The invention relates to compounds that are antagonists or inverse agonists of the glucagon receptor, and to pharmaccutial compositions in the treatment of the human or animal body...................... WE CLAIM: 1. A compound structurally represented by Formula 1 (Formula Removed) (I) or a pharmaceutically acceptable salt thereof wherein: Rl and R2 are independently -H or -halogen; R3 is ~(C1-C8) alkyl(optionally substituted with 1 to 3 halogens), -(C3-C7)cycloalkyl, -(C1-C6)alkvl-(C3-C7)cycloalkyl, or -(C3-C7)cycloalkyl-(C1-C6)alkyl(optionally substituted with 1 to 3 halogens); R4 and R5 are independently -H, -halogen, -hydroxy, hydroxymethyl, -CN, -(C1-C7) alkoxy, -(C2- C7)alkenyl, or -(C1-C6)alkyl (optionally substituted with 1 to 3 halogens); R6 is (Formula Removed) wherein the zig-zag mark shows the point of attachment to the parent molecule; R7 and R8 are independently -H, -halogen, -(C1-C6)alkyl(optionally substituted with 1 to 3 halogens), -(C1-C6)alkoxy, -(C3-C7)cyeloalkyl, -C(O)R10) -COOR10, -OC(O)R10,-OS(O)2R10, -SR10, - S(O)R10, -S(O);R10, or -O(C2-C7)alkenyl; R9 is independently -II, -halogen, -CN, -(G-G)cycloalkyl, -C(O)R10, -COOR10, -OC(O)R10, -OS(O)2R10, -SR10, -S(O)Rl0, -S(O)2R10, or -O(C2-C7)alkenyl, -(C1-C3)alkoxy(optionallv substituted with 1 to 3 halogens), or -(C1-C6) alkyl (optionally substituted with 1 to 3 halogens); and R10 is independently at each occurrence -hydrogen, or -(C1-C6) alkyl(optionallv substituted with 1 to 3 halogens). 2. The compound as claimed in claim 1, or a pharmaceuticallv acceptable salt thereof, wherein Rl and R2 are -H; R3 is -(C1-C8) alkyl(optionallv substituted with 1 to 3 halogens), -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, or -(C3-C6)cycloalkyl-(C1- C6)alkyl(optionally substituted with 1 to 3 halogens); R4 and R5 are independently -H, -halogen, or -(C1-C6)alkyl (optionally substituted with 1 to 3 halogens); R6 is (Formula Removed) wherein the zig-zag mark shows the point of attachment to the parent molecule; R7 and R8 are independently -H, -halogen, -(C1-C3)alkyl(optionally substituted with 1 to 3 halogens), or -(C1-C3alkoxy; and R9 is independently -H, -halogen, or -(C1-C6) alkvl (optionally substituted with 1 to 3 halogens). 3. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein Rl and R2 are -H; R3 is -(C1-C8) alkyl(optionally substituted with 1 to 3 halogens), -(C3-C6)cycloalkyl, -( C1-C6)alkyl-(C3-C6)cycloalkyl, or -(C3-C6,)cyeloalkyl-( C1-C6)alkyl(optionallv substituted with 1 to 3 halogens); R4 and R5 are independently -H, -halogen, or -CH-, (optionally substituted with 1 to 3 halogens); R6 is (Formula Removed) wherein the zig-zag mark shows the point of attachment to the parent molecule; R7 and R8 are independently -I I, or -halogen; and R9 is independently -(G-G) alkyl (optionally substituted with 1 to 3 halogens). 4. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein Rl and R2 are -H; R3 is -(C4-C8) alkyl(optionally substituted with 1 to 3 halogens), -(C3,-C6)cycloalkvl, -(C1-C6)alkvl-(C3-C6)cycloalkyl, or -(C3-C6)evcloalkyl-(C1- C6,)alkyl(optionally substituted with 1 to 3 halogens); R4 and R5 are -CH3; (optionally substituted with 1 to 3 halogens) and each occupies a position adjacent to R6 on the phenyl ring to which R6 is attached; R6 is (Formula Removed) wherein the zig-zag mark shows the point of attachment to the parent molecule; R7 and R8 are -H; and R9 is independently -(G-G,) alkyl (optionally substituted with 1 to 3 halogens). 5. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein Rl and R2 are independently hydrogen or halogen; R3 is methyl, ethyl, propyl, isopropyl, butyl, pentvl, hexyl, heptyl, octyl, 3,3-dimethylbutyl, 2-methylpropyl, 3 -methyl-butyl, tertbutyl, 4-methylpentyl, 2,2-dimethvlpropyl, 3,3,3- trifluoropropyl, 4,4,4-trifluorbutyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexvl; R4 and R5 are independently hydrogen, methyl, ethyl, tertbutyl, cyclohexvl, pentvl, isopropoxy, chloro, t'luoro, bromo, hvdoxv, trifluoromethyl - CN, methoxy, hydroxymethyl, 4-methylpentyloxy, or pentvloxy; R7 and R8 are independently hydrogen, fluoro, chloro, methyl, ethyl, pentyl, isopropyl, tertbutyl, trifluoromethyl, acetyl, 2-methylpropvl, methoxy, cyclohexyl, or Irifluormethoxv; and R9 is hydrogen, bromo, fluoro, methyl, tertbutyl, trifluoromethyl, or isopropyl. 6. The compound as claimed in claim 1, selected from the group consisting of formulae XI to XII (Table Removed) or a pharmaceutically acceptable salt thereof. 7. The compound as calimed in claim 1 selected from the group consisting of: (R3)-5-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide; (±)-5-[ 1 -(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-propyl]-thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide; (±)-5-[l-(4'-tert-Butyl-2,6-dimothyl-biphenyl-4-ylsulfanyl)butyl]-thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide; (+)-5-[1-(4!-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-pentyl]-thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide; (±)-5-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide; ((±)-5-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-3,3-dimethyl-butyl]-thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide; (±)-5-[l-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-2,2-dimethyl-propyl]-thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide; (±)-5-[l-(2,5-Dimethyl-4,-trifluoromethyl-biphenyl-4-ylsulfanyl)-butyl]- thiophene-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide; (±)-5-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl- propyl]-thiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl)-amide; (±)-541-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-2,2-dimethyl-propy]]-thiophene-2-carboxvlic acid (lH-tetrazol-5-ylmethyl)-amide; (±)-5-[l-(2,6-Dimethyl-4'-trifluoromethyl-bipbenyl-4-ylsulfanyl)-3-methyl-butyl]-thiophene-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide; (±)-5-[l-(2,6-Dimelhyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3,3-dimethyl-butyl]-thiophene-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide; (±)-5-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-pentyl]- thiophene-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide; 5-[l-(4'-tert-Butyl-2,6-dimethyl-biphhenyl-4-ylsulfanyl)-2,2-dimethyl-propyl]- tbiophene-2-earboxylie acid (2H-tetrazol-5-vlmetbyl)-amide (Isomer 1); 5-[l-(4'-tert-Butyl-2,5-dimethyl-biphenyl-4-ylsulfanyl)-2,2-dimethyl-propyl]- thiopbene-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide (Isomer T); 5-[1-(4,-tert-Butyl-2H-dimethyl-biphenyl-4-ylsulfanyl)-propyl]-thiophene-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide (Isomer 1); 5-[l-(4'-tert-Butyl-2,6-dimethyl-bipbenyl-4-ylsulfanyl)-propyl]-thiophone-2- carboxylic-add (2H-tetrazol-5-ylmetbyl)-amide (Isomer 2); 5-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-butyl]-thiophene-2-carboxvlic acid (lH-tetrazol-5-ylmethyl)-amide (Isomer 1); 5-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-butyl]-thiophene-2- carboxylic acid (1H-tetrazol-5-ylmethyl)-amide (Isomer 2); 5-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carboxvlic acid (1H-terrazol-5-ylmethyl)-amide (Isomer 1); 5-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide (Isomer 2); 5-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-2,2-dimethyl- propyl]-thiophene-2-carboxylic acid (lH-tetrazol-5-vlmethyl)-amideb (Isomer 1); 5-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-2,2-dimethyl- propyl]-thiophene-2-carboxvlic acid (1H-tetrazol-5-vlmethyl)-amideb (Isomer 2); 5-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]- tbiophene-2-carboxylic acid (lH-tetrazol-5-ylmethyl)-amide (Isomer 1); 5-[l-(2,6-Dimetbyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]- thiophene-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide (Isomer 2); 5-[l-(2,6-Dimethyl-4'-trifluorometbyI-bipbenyl-4-ylsulfanyl)-3,3-dimethyl-butyl]-thiophene-2-carboxylic acid (II I-tetrazol-5-ylmetbvl)-amide (Isomer 1); 5-[l -(2,6-Dimethyl-4'-trifluorometthyl-biphenyl-4-ylsulfanyl)-3,3-dimethyl-butyl]- thiophene-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide (Isomer 2); 5-[l-(2,6-Dimethyl-4'-trifluorometby]-biphonyl-4-ylsulfanyl)-pentyl]-thiophene-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide (Isomer 1); and 5-[l-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanvl)-pontyl]-thiophone-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide (Isomer 2); or a pharmaceutically acceptable salt thereof. 8. A pharmaceutical composition comprising a compound of any of claims 1-7 and a pharmaceutically acceptable carrier. 9. A compound or a salt thereof, as claimed in anv one of claims 1-7 for use in treating a diabetic or other glucagon related metabolic disorder for the manufacture of a medicament thereof.

Documents:

3841-DELNP-2008-Abstract-(27-03-2012).pdf

3841-DELNP-2008-Assignment-(27-03-2012).pdf

3841-DELNP-2008-Claims-(10-07-2012).pdf

3841-DELNP-2008-Claims-(27-03-2012).pdf

3841-DELNP-2008-Correspondence Others-(10-07-2012).pdf

3841-delnp-2008-Correspondence Others-(19-10-2011).pdf

3841-DELNP-2008-Correspondence Others-(27-03-2012).pdf

3841-delnp-2008-correspondence-others (12-05-2008).pdf

3841-delnp-2008-Form-1 (06-05-2008).pdf

3841-DELNP-2008-Form-1-(27-03-2012).pdf

3841-delnp-2008-Form-13 (12-05-2008).pdf

3841-delnp-2008-form-18 (12-05-2008).pdf

3841-DELNP-2008-Form-2-(27-03-2012).pdf

3841-delnp-2008-Form-3 (03-10-2008).pdf

3841-DELNP-2008-Form-3-(27-03-2012).pdf

3841-delnp-2008-GPA (06-05-2008).pdf

3841-DELNP-2008-GPA-(10-07-2012).pdf

3841-delnp-2008-GPA-(19-10-2011).pdf

3841-DELNP-2008-Petition-137-(27-03-2012).pdf

Form-1.pdf

Form-3.pdf

Form-5.pdf