NZ750252B2 - Sulfonamides as gpr40- and gpr120-agonists - Google Patents

Sulfonamides as gpr40- and gpr120-agonists

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Publication number
NZ750252B2
NZ750252B2 NZ750252A NZ75025217A NZ750252B2 NZ 750252 B2 NZ750252 B2 NZ 750252B2 NZ 750252 A NZ750252 A NZ 750252A NZ 75025217 A NZ75025217 A NZ 75025217A NZ 750252 B2 NZ750252 B2 NZ 750252B2
Authority
NZ
New Zealand
Prior art keywords
phenyl
sulfamoyl
heptanoic acid
dimethylphenyl
compound according
Prior art date
Application number
NZ750252A
Other versions
NZ750252A (en
Inventor
Andrea Aramini
Andrea Beccari
Gianluca Bianchini
Pizzol Maria De
Chiara Rossana Maria Liberati
Anna Sirico
Mara Zippoli
Original Assignee
Dompe' Farmaceutici Spa
Filing date
Publication date
Priority claimed from EP16183294.4A external-priority patent/EP3281937A1/en
Application filed by Dompe' Farmaceutici Spa filed Critical Dompe' Farmaceutici Spa
Publication of NZ750252A publication Critical patent/NZ750252A/en
Publication of NZ750252B2 publication Critical patent/NZ750252B2/en

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/4192—1,2,3-Triazoles
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    • A61K31/4196—1,2,4-Triazoles
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    • A61K31/425—Thiazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention relates to compounds acting as agonists of G-protein coupled receptor 120 (GPR120) and/or 40 (GPR40), and having formula (I). Said compounds are useful in the treatment of diseases or disorders modulated by GPR120 and/or GPR40 such as diabetes (particularly type 2 diabetes), impaired oral glucose tolerance, insulin resistance, obesity, obesity related disorders, metabolic syndrome, dyslipidemia, elevated LDL, elevated triglycerides, obesity induced inflammation, osteoporosis and obesity related cardiovascular disorders.

Claims (10)

Claims
1. A compound of formula (I): A (X)n NH S(O)2 R3 R2 and pharmaceutically acceptable salts thereof, wherein: A is a mono or di-carbocyclic residue, optionally partially or totally unsaturated, consisting of carbon atoms and optionally one or more heteroatoms selected from N, S or O; R1, R2, R3 are independently selected from the group consisting of –H, -halogen, - CF3, -CN, -CH2CN, -OMe, -OCF3, -OH, phenyl, -OPh, -OCH2Ph, -OCH2OMe, - OCH2CN -NO2, -NR’R”, linear or ed C1-C6 alkyl, -O(CH2)p-S(O)2Me and a fivemembered ring heterocycle; wherein R’ and R” are ndently –H or C1-C4 alkyl; n phenyl and the five-membered ring heterocycle are independently unsubstituted or substituted with a group ed from the group consisting of linear or branched C1-C4 alkyl, halogen, -OMe and –OH; p is 1 to 4; X is –CH2 or –C(O); n is 0, 1or 2; wherein when n is 2, X can be the same or different; R4 is –Y–C(O)OH, wherein Y is a straight chain C4-C18 hydrocarbon, saturated or unsaturated, preferably having from 6 to 10 carbon atoms; R4 is in position meta or para on the aromatic ring; wherein when A is phenyl, n is 0, Y is a C4 hydrocarbon, at least one of said R1, R2, R3 is not hydrogen; wherein when A is , n is 0, Y is a C4 hydrocarbon, R1 and R2 are hydrogen, R3 is not Cl in position para on the aromatic ring.
2. A compound according to claim 1, wherein A is phenyl, naphthyl, biphenyl or a saturated or unsaturated five-membered ring heterocycle having five ring atoms wherein 1, 2, 3 or 4 ring atoms are independently selected from N, O and S.
3. A compound according to claim 1 or 2, wherein the five-membered ring heterocycle is selected from the group consisting of l, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, azolyl, isoxazolyl, triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, and benzimidazole, ally partially saturated.
4. A compound according to anyone of claims 1 to 3, wherein R1, R2, R3 are independently selected from the group consisting of –H, -halogen, -CF3, -OMe, -OH, phenyl, -OPh, -OCH2Ph, -OCH2OMe, -OCH2CN -NO2, -NH2, -NMe2, linear or branched C1-C6 alkyl and -O(CH2)p-S(O)2Me.
5. A compound according to anyone of claims 1 to 4, wherein n is 0 or 1.
6. A compound according to anyone of claims 1 to 5, wherein R4 is in on meta on the aromatic ring.
7. A compound according to anyone of claims 1 to 6 selected from: 7-(3-(N-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (1); 7-(3-(N-(2,4,6-trimethylbenzyl)sulfamoyl)phenyl)heptanoic acid (2); 7-(3-(N-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (3); 7-(3-(N-(4-chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (4); 7-(3-(N-(4-(dimethylamino)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (5); 7-(3-(N-(2,6-dimethyl(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid (6); 7-(3-(N-(4-bromo-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (7); 7-(3-(N-(4-methoxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (8); 7-(3-(N-(6-fluoromethyl-[1,1'-biphenyl]yl)sulfamoyl)phenyl)heptanoic acid (9); N-(5-fluoromethyl-[1,1'-biphenyl]yl)sulfamoyl)phenyl)heptanoic acid (10); 6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoic acid (11); 7-(3-(N-(3,5-dimethyl-1H-pyrazolyl)sulfamoyl)phenyl)heptanoic acid (12); 7-(3-(N-(2,4-dimethylthiazolyl)sulfamoyl)phenyl)heptanoic acid (13); 7-(3-(N-(4,5-dimethylthiazolyl)sulfamoyl)phenyl)heptanoic acid (14); 7-(3-(N-(4,5-dimethyloxazolyl)sulfamoyl)phenyl)heptanoic acid (15); 7-(3-(N-(5-phenyl-1,2,4-thiadiazolyl)sulfamoyl)phenyl)heptanoic acid (16); N-(3-methyl-1,2,4-thiadiazolyl)sulfamoyl)phenyl)heptanoic acid (17); 7-(3-(N-(5-methyl-1,3,4-thiadiazolyl)sulfamoyl)phenyl)heptanoic acid (18); 7-(3-(N-(3,5-dimethylisoxazolyl)sulfamoyl)phenyl)heptanoic acid (19); 7-(3-(N-(5-methyl-4H-1,2,4-triazolyl)sulfamoyl)phenyl)heptanoic acid (20); 7-(3-(N-(3,5-dimethyl-4H-1,2,4-triazolyl)sulfamoyl)phenyl)heptanoic acid (21); 7-(3-(N-(3-phenylisothiazolyl)sulfamoyl)phenyl)heptanoic acid (22); 7-{3-[(5-hydroxynaphthalenyl)sulfamoyl]phenyl}heptanoic acid (23); 7-{3-[(4-fluoro-2,6-dimethylbenzoyl)sulfamoyl]phenyl}heptanoic acid (24); 7-{4-[(4-fluoro-2,6-dimethylphenyl)sulfamoyl]phenyl}heptanoic acid (25); 7-(3-(N-(2-ethyl-2H-1,2,3-triazolyl)sulfamoyl)phenyl)heptanoic acid (26); N-(2-methyl-2H-tetrazolyl)sulfamoyl)phenyl)heptanoic acid (27); N-(4-methyl-4,5-dihydrooxazolyl)sulfamoyl)phenyl)heptanoic acid (28); 7-(3-(N-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2yl)sulfamoyl)phenyl) heptanoic acid (29); 7-(3-(N-(3-phenylisothiazolyl)sulfamoyl)phenyl)heptanoic acid (30); 7-(3-(N-(4-hydroxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (31); 7-(3-(N-(3,5-dimethyl-[1,1'-biphenyl]yl)sulfamoyl)phenyl)heptanoic acid (32); 7-(3-(N-(2,6-dimethylphenoxyphenyl)sulfamoyl)phenyl)heptanoic acid (33); 7-(3-(N-(4-(benzyloxy)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (34); 7-(3-(N-(2,6-dimethyl(3(methylsulfonyl)propoxy)phenyl)sulfamoyl)phenyl)heptanoic acid (35).
8. A compound according to claim 7 selected from: 7-(3-(N-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (1); 7-(3-(N-(2,4,6-trimethylbenzyl)sulfamoyl)phenyl)heptanoic acid (2); 7-(3-(N-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (3); 7-(3-(N-(4-chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (4); 7-(3-(N-(2,6-dimethyl(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid (6); 7-(3-(N-(4-bromo-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid (7) 7-(3-(N-(6-fluoromethyl-[1,1'-biphenyl]yl)sulfamoyl)phenyl)heptanoic acid (9); 7-(3-(N-(5-fluoromethyl-[1,1'-biphenyl]yl)sulfamoyl)phenyl)heptanoic acid (10); 6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoic acid (11); 7-(3-(N-(2,6-dimethylphenoxyphenyl)sulfamoyl)phenyl)heptanoic acid (33).
9. A compound according to anyone of claims 1 to 8, for use as a medicament.
10. A compound for use according to claim 9, in the tion and/or treatment of a disease or disorder modulated by GPR
NZ750252A 2017-08-07 Sulfonamides as gpr40- and gpr120-agonists NZ750252B2 (en)

Applications Claiming Priority (2)

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EP16183294.4A EP3281937A1 (en) 2016-08-09 2016-08-09 Sulfonamides as gpr40- and gpr120-agonists
PCT/EP2017/069958 WO2018029150A1 (en) 2016-08-09 2017-08-07 Sulfonamides as gpr40- and gpr120-agonists

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NZ750252A NZ750252A (en) 2023-12-22
NZ750252B2 true NZ750252B2 (en) 2024-03-26

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