Dipeptide compounds that are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis

摘要

The compounds of formula described and the pharmaceutically-acceptable salts thereof, where the substituents are as defined below, which are growth hormone secretagogues and which increase the level of endogenous growth hormone. The compounds of this formula are useful for the treatment and prevention of osteoporosis, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds described are also useful in treating osteoporosis when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful thereof. Further disclosed, pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound described and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. Wherein e is 0 or 1; n and w are each independently 0, 1 or 2; provided that w and n cannot both be 0 at the same time; Y is oxygen or sulfur; R1 is hydrogen, -CN, -(CH2)qN(X6)C(O)X6, -(CH2)qN(X6)C(O)(CH2)t-A1, -(CH2)qN(X6)SO2(CH2)t-A1, -CH2)qN(X6)SO2X6, -(CH2)qN(X6)C(O)N(X6)(CH2)t-A1, -(CH2)qN(X6)C(O)N(X6)(X6)-, -(CH2)qC(O)N(X6)(X6), -(CH2)qC(O)N(X6)(CH2)t-A1, -(CH2)qC(O)OX6, -(CH2)qC(O)O(CH2)t-A1, -(CH2)qOX6, -(CH2)qOC(O)X6, -(CH2)qOC(O)(CH2)t-A1, -(CH2)qOC(O)N(X6)(CH2)t-A1, -(CH2)qOC(O)(X6)(X6), -(CH2)qC(O)X6, -(CH2)qC(O)(CH2)q-A1, -(CH2)qN(X6)C(O)OX6, -(CH2)qN(X6)SO2N(X6)(X6), -(CH2)qS(O)mX6, -(CH2)qS(O)m(CH2)t-A1, -C1-10alkyl, -(CH2)t-A1, -(CH2)q-C3-7Cycloalkyl, -(CH2)q-Y-C1-6alkyl, -(CH2)q-Y-(CH2)t-A1 or -(CH2)q-Y-(CH2)t-C3-7Cycloalkyl; R2 is hydrogen, C1-8alkyl, -C0-3alkyl-C3-8Cycloalkyl, -C1-4alkyl-A1 or A1; R3 is A1, C1-10alkyl, -C1-6alkyl-A1, -C1-6alkyl-C3-7cycloalkyl, -C1-5alkyl-X-C1-5alkyl, -C1-5alkyl-X-C0-5alkyl-A1 or -C1-5alkyl-X-C1-5alkyl-C3-7cycloalkyl; R4 is hydrogen, C1-6alkyl or C3-7cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form C5-7cycloalkyl, C5-7cycloalkenyl X4 is hydrogen or C1-6alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring; R6 is a bond or is where a and b are independently 0, 1, 2 or 3; R7 and R8 are independently hydrogen or optionally substituted C1-6alkyl; where the optionally substituted C1-6alkyl in the definition of R7 and R8 is optionally independently substituted with A1, -C(O)O-C1-6alkyl, -S(O)mC1-6alkyl.