Triazole Derivatives with better Properties of receptor activity and bioavailability of ghrelin Receptor Antagonists of growth hormone Secretagogue

摘要

According to formula (1), ghrelina like binding, as a growth hormone secretion receptor, has high receptor activity and bioavailability and can be used to treat or prevent physiological and / or pathological conditions in mammals (preferably humans), They are through GHS receivers. The product also provides antagonists and stimulants for GHS receivers, which can be used to modulate GHS receivers and help to deal with the above conditions, including alcoholism, drug abuse, stunting, Kakha, short-term regulation, etc.Medium and / or long term energy balance; short, medium and / or long term (stimulation and / or inhibition) food intake; beneficial food intake; getting rich; fat and / or obesity; weight gain and / or weight loss; diabetes, type 1 diabetes, type 2 diabetes; cell proliferation Tumor, inflammation, inflammation, gastric obstructionpostoperative obstruction and / or gastrectomy (replacement therapy with ghrelin). Claim 1: Use of a compound characterized in that it has the formula (1) wherein: (A) R1 and R2 are independently selected from each other from the group consisting of hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkyl sulfonyl groups which are optionally substituted in the group, alkyl, arylalkyl, cycloalkyl, aryl alkyl heteroarylalkyl,heterocyclyl and / or heterocyclylalkyl with up to 3 substituents independently selected from the group consisting of halogen, -F, -Cl, -Br, -I, -N3, -CN, -NR7R8, -NR11R12, -OH, -NO2 , alkyl, aryl, heteroaryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O-cycloalkylalkyl , -C (O) O-aryl, -C (O) O-arylalkyl, -C (O) O-heteroaryl, -C (O) O-heteroarylalkyl, -C (O) O-heterocyclyl, -C (O ) O-heterocyclylalkyl, -C (O) NR9R10, -C (S) NR9R10;one of the radicals R3 and R4 is a hydrogen atom, where the other radical is selected from the group consisting of hydrogen atom, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl, alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl -CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, -alkyl-CO-heterocyclylalkyl, -alkyl-C (O) O-aryl, -alkyl-C (O) O-arylalkyl, -alkyl -C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl-C (O) O-heterocyclyl,-alkyl-C (O) O-heterocyclylalkyl, -alkyl-CO-NH2, -alkyl-CO-OH, -alkyl-NH2, -alkyl-NH-C (NH) -NH2, alkylsulfonyl, arylsulfonyl, arylalkyl sulfonyl, alkyl- S-alkyl, alkyl-SH which are optionally substituted in the aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl group group with up to 3 substituents independently selected from the group consisting of halogen, -F, -Cl, - Br, -I, -N3, -CN, -NR7R8, -OH, -NO2, alkyl, aryl, arylalkyl, -O-alkyl, -O-CF3, -O-aryl, -O-arylalkyl;R5 is selected from the group consisting of -C (S) alkyl, -C (S) -cycloalkyl, -C (S) -cycloalkylalkyl, -C (S) -aryl, -C (S) -arylalkyl, -C (S) -heteroaryl, -C (S) -heteroarylalkyl, -C (S) -heterocyclyl, -C (S) -heterocyclylalkyl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O-cycloalkylalkyl, -C (O) O-aryl, -C (O) O-arylalkyl, -C (O) O-heteroaryl, -C (O) O-heteroarylalkyl, -C (O) O- heterocyclyl, -C (O) O-heterocyclylalkyl, -C (O) NR9R10, -C (S) NR9R10;Alternative alternatives include: asphalt, cyclopropyl, cyclopropyl, cyclopropyl, arilo, isopropyl, isopropyl and / or isopropyl allyl, with up to three alternatives selected from the following groups: halogen, F, Cl, Br, I, N3, CN, CF3, n7r8, oh, NO2, -NH2, tar, arilo, arilalquilo, o-tar, o-arilo, o-arilalquilo rdque;R6 was selected from the following groups: hydrogen, tar, cyclopentanediol, cyclohexaclquilo and rdqoe;R7 and R8 are independently selected from the following groups: uranium chloride; hydrogen atom; tar; cyclopentadiene; cyclopentadienediene; cyclopentadienediene; cyclopentadienediene;R9 and R10 are selected independently from a group consisting of hydrogen, tar, cyclopropene, isopropene, arilo, isopropene, arilalquilo, isopropene and isopropene.R11 is un ldqoe; hydrogen atom and rdqoe;R12 is selected independently from the following groups: namely ldque; - C (o) h, - C (o) - tar; - C (o) - cyclopropenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propenyl propeneo (B) R1 se selecciona en forma independiente entre el grupo que consiste en 26ldquo tomo de hidr geno alquilo alquenilo alquinilo cicloalquilo cicloalquilalquilo arilo heteroarilo arilalquilo heteroarilalquilo heterociclilo heterociclilalquilo alquilsulfonilo arilsulfonilo arilalquilsulfonilo 26rdquo que est n opcionalmente sustituidos en el grupo alquilo cicloalquilo cicloalquilalquilo arilo heteroarilo arilalquilo -O-aryl, -O-arylalkyl;R2 is un ldque, a group of lessors and rdque,which is substituted with up to 2 substituents independently selected from the group consisting of aryl, heteroaryl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O-cycloalkylalkyl, -C (O) O-aryl, -C (O) O-arylalkyl, -C (O) O-heteroaryl, -C (O) O-heteroarylalkyl, -C (O) O-heterocyclyl, -C (O) O- heterocyclylalkyl, -C (O) NR9R10, -NR11R12,and in the case of aryl and heteroaryl, the alkyl group must also be substituted with -NR11R12; one of the radicals R3 and R4 is a hydrogen atom, where the other radical is selected from the group consisting of hydrogen atom, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl, alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl -CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, -alkyl-CO-heterocyclylalkyl, -alkyl-C (O) O-aryl, -alkyl-C (O) O-arylalkyl,-alkyl-C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl-C (O) O-heterocyclyl, -alkyl-C (O) O-heterocyclylalkyl, -alkyl-CO-NH2 , -alkyl-CO-OH, -alkyl-NH2, -alkyl-NHC (NH) -NH2, alkylsulfonyl, arylsulfonyl, arylalkyl sulfonyl, alkyl-S-alkyl, alkyl-SH which are optionally substituted in the aryl, heteroaryl, arylalkyl group , heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl with up to 3 substituents independently selected from the group consisting of halogen, - F, -Cl, -Br, -I, -N3, -CN, -NR7R8, -OH, -NO2 , alkyl, aryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl;R5 was selected from the following groups: hydrogen, tar, cyclopentadiene, cyclopentadiene, cyclopentadiene, arilalquilo, isopropyl, allyl, allyl, allyl, CO cyclo cyclo cyclo, CO Arlo, Co arilalquilo, CO hetero, CO allyl, CO allyl -Co-dcp-hc * (r9r10) - nh2-co-ch2-c * (r9r10) - nh2-co-c * (r9r10) - ch2-nh2, aquilsulfonilo, arilsulfonilo, arilalquilsulfonilo rdqoe; these substitutes can be replaced by the following three independent substitutes: halogen F, Cl, Br, N3, CN, n7r8, O2,1. Tar, arilo, arilacilo, altar, arilacilo, and rdqou;R6 was selected from the following groups: hydrogen, tar, cyclopentanediol, cyclohexaclquilo and rdqoe;R7 and R8 are selected independently from the following groups: hydrogen atom, tar, cyclopentyl atom, cyclomethylclalquilo and rdqoe;R9 and R10 are selected independently from the following groups: hydrogen atom, tar, natural amino acid transverse chain, non natural amino acid transverse chain and rdqoe;R11 is un ldqoe; hydrogen atom and rdqoe;R12 is independently selected from the group consisting of -C (O) H, -C (O) -alkyl; -C (O) -cycloalkyl, -C (O) -cycloalkylalkyl, -C (O) -aryl, -C (O) -arylalkyl, -C (O) -heteroaryl, -C (O) -heteroarylalkyl, -C (O) -heterocyclyl, -C (O) -heterocyclylalkyl;In the case of (a) and (b) m, it is 0, 1 or 2; and * refers to the carbon atom in the form of R or s at the time of operation; drugs used to treat or prevent the physiological and / or pathophysiological clinical states of mammals, which are in the middle stage of GHS receptor.