KR960705575A - Combination of bisphosphonates and growth hormone secretagogues (bisphosphonates and growth hormone secretagogues) - Google Patents

Abstract

Bisphosphonates combined with growth hormone secretagogues reduce the adverse effects of osteoporosis in adult patients.

Description

Combination of bisphosphonates and growth hormone secretagogues

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Claims (29)

A combination useful in treating osteoporosis, comprising bisphosphonate and a growth hormone secretagogue. The combination according to claim 1, wherein the bisphosphonate is a compound of the general formula (X) or a pharmaceutically acceptable salt thereof. Wherein R ¹ is unsubstituted or substituted by NH ₂ , pyridyl, pyrrolidyl or NR ³ N ⁴ wherein R ³ is H or C _1-4 alkyl and R ⁴ is C _1-4 alkyl. substituted C _1-5 alkyl, NR ⁵ (wherein, R ⁵ is a C _1-10 alkyl), SR ⁶ (wherein, R ⁶ is an aryl group) and is selected from the group consisting of C1, R ² is H, OH , Or C1. 3. The composition of claim 1, wherein the bisphosphonate is selected from the group consisting of alendronic acid, etidronate, clodronic acid, pamidronic acid, tiludronic acid, lysedronic acid, 6-amino-1 -hydroxy-hexylidene- -Hydroxy-3- (methylpentylamino) -propylidene-bisphosphonic acid, or a pharmaceutically acceptable salt thereof. 4. The combination according to claim 3, wherein the bisphosphonate is alendronic acid or a pharmaceutically acceptable salt thereof. 2. The combination according to claim 1, wherein the growth hormone secretagogue is a compound of the following general formulas (I) and (II) and pharmaceutically acceptable salts thereof and their respective diastereomers. Wherein, R ¹ is -C ₁ -C ₁₀ alkyl, - aryl, aryl - (C ₁ -C ₆ alkyl), -C ₃ -C ₇ cycloalkyl, - (C ₁ -C ₆ alkyl), -C ₁ -C ₅ alkyl -KC ₁ -C ₅ alkyl, aryl (C ₀ -C ₅ alkyl) - (C ₁ -C ₆ alkyl) and -C ₃ -C ₇ cycloalkyl (C ₀ -C ₅ alkyl) - K- (C ₁ -C ₆ alkyl) wherein, K is O, S (O) m, N (R 2) C (O), C (O) N (R 2), OC (O), C ( _{O) O, -CR 2 = CR} 2 - or -C≡C-, and the aryl group are the same as defined below, R ₂ and alkyl groups having 1 to 9 halogen, S (O) mR _2s (where , R _2s is hydrogen or C _1-6 alkyl, and m is 0, 1 or 2. 1 to 3 OR ₂ or C (O) may be further substituted by OR _2s, aryl groups are phenyl, phenoxy, halophenyl, 1 to 3 C _1-6 alkyl, one to three halogen, or two -OR _{2, methylenedioxy, -S (O) mR 2,} 1 or 2 -CF _3, -OCF _{3, nitro, -N (R 2) (R} 2) -, -N (R 2 _{) C (O) R 2,} -C (O) OR 2, -C (O) N (R 2) (R 2), -SO 2 N (R 2) (R 2), -N (R 2) S (O) ₂ aryl and -N (R ₂ ) SO ₂ R ₂ , and R ₂ is selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl , Two C _1-6 alkyl groups are present at one atom and they may be optionally joined to form a C _3-8 cyclic ring optionally containing oxygen, sulfur or NR _2a , R _3a and R _3b are independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, -OR ₂ , cyano, -OCF ₃ , methylenedioxy, nitro, -S (O) mR, -CF ₃ and -C ) OR < _{2 &gt}; Is selected from, R _3a and R _3b is an ortho arrangement, they may be combined to form a C _5-8 aliphatic or aromatic ring containing optionally one or two heteroatoms selected from oxygen, sulfur and nitrogen, R ₄ And R ₅ are independently selected from the group consisting of hydrogen, C _1-6 alkyl, and substituted C _1-6 alkyl wherein the substituents are selected from the group consisting of 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C _1-10 alkanoyloxy , C _1-6 alkoxy, phenyl, phenoxy, 2-furyl, C _1-6 alkoxycarbonyl and -S (O) m (C _1-6 alkyl) ₄ and R ₅ are together _{- (CH 2) rLa (CH} 2) s- [ wherein, La is _{C (R 2) 2 -,} -O-, -S (O) m- , or N- (R ₂₎ - And r and s are independently 1 to 3 and R ₂ is as defined above, R ₆ is hydrogen or C _1-6 alkyl, A is Wherein x and y are independently 0 to 3, Z is -NR ₂ or 0, and R ₇ and R ₇ a are independently selected from the group consisting of hydrogen, C _1-6 alkyl, -OR ₂ , trifluoromethyl, phenyl And substituted C _1-6 alkyl wherein the substituent is selected from the group consisting of imidazolyl, phenyl, indolyl, P-hydroxyphenyl, -OR ₂ , 1-3 fluorine, -S (O) mR ₂ , -C ) oR _2, C _{3-7 cycloalkyl, -N (R 2) (R} 2) and _{-C (O) N (R 2} ) ( or selected from the group consisting of R is selected from _2)), R ₇ and R _7a may independently bond with one or both of R ₄ and R ₅ to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R ₇ or R _7a group, comprises; a, B, D, E and F independently represent _{-C (R 8) (R 10} ) - [ wherein, R ₈ and R ₁₀ are independently _{hydrogen, R 2, -OR 2, -} (CH 2 ) q- _{aryl, - (CH 2) qC (} O) oR 2 ( wherein, q may optionally 0,1,2,3 or 4 _{days), - (CH 2) qC} (O) O (CH 2) q-ah Reel and - (CH ₂₎ (day 1H- tetrazol -5-) q- (wherein aryl is from 1 to 3 halo, one or two C _1-8 alkyl, one to three or one or _two -OR the two -C (O) is selected from the group consisting of optionally may be substituted) by an _{OR 2], -O-, C =} O, m- and -NR ₉ -S (O) - [wherein, R ₉ is _{-R 2, - (CH 2)} q- _{aryl, -C (O) R 2,} -C (O) (CH 2) q- _{aryl, -SO 2 R 2, -SO 2} (CH 2) q- aryl, -C (O) N (R 2) (R 2), -C (O) N (R 2) (CH 2) q- _{aryl, -C (O) OR 2,} 1H- tetrazol-5 _{yl, -SO 3 H, -SO 2 NHC≡N} , -SO 2 N (R 2) -SO aryl and is selected from the group consisting of _{2 N (R 2) (R} 2) { wherein, (CH ₂₎ q one or two C _1-4, and may be substituted by alkyl, optionally, R ₂ and aryl is from 1 to 3 -OR _2a -O (CH ₂₎ q- aryl, with one or two -C (O) oR _2a, (R _2a) one or two _{-C (O) O (CH 2} ) q- aryl, with one or two -C (O) N (R _2a), one or two -C (O) N ( R _2a) (CH ₂₎ q- aryl, one to five halogen, one to three C _1-4 alkyl, 1,2,4 Thiazolyl, 1H- _{tetrazol-5-yl, -C (O) NHSO 2 R} 2a:, -S (O) mR 2a, -C (O) NHSO 2 (CH 2) q- aryl, -SO ₂ NHC≡ _{N, -SO 2 NHC (O)} R 2a, -SO 2 NHC (O) (CH 2) q allyl _{-N (R 2) C (O} ) N (R 2a R 2a), -N (R 2) C _{(O) N (R 2a)} (CH 2) q- _{aryl, -N (R 2a) (R} 2a), -N (R 2a) C (O) R 2a, -N (R 2a) C (O) (CH ₂₎ q aryl, -OC (O) N (R 2a) (R 2a) (CH 2a), -OC (O) N (R 2a) (CH 2) q aryl and -SO ₂ (CH ₂₎ qCONH- (CH ₂₎ may optionally be further substituted by wNHC (O) R _11. (wherein, w is 2 to 6, R ₁₁ is aryl turn biotin, with one or two -OR _2, 1, or 2, 3, 4, 5, 6, or 7 membered ring optionally substituted with one or two B, D, E or F to form a 5-, 6- or 7-membered ring (R ₈ (R ₁₀ )) only when one of the remaining B, D, E and F is simultaneously -O-, -S (O) m or -NR ₉ - - or C = O, or B and D, or D and E together are -N = CR ₁₀ - Or F may be simultaneously -CR ₁₀ ═N, and B and D, or D and E together may be -CR ₈ ═CR ₁₀ , and one or both of B and E may be simultaneously -O-, -S O) m-, or -NR ₉ -, and one of G, H, I and J are carbon, nitrogen, and sulfur, or oxygen atom is then one or more hetero atoms in these G, H, I and J are thought optionally 5 or 6 membered heterocyclic aromatic ring. 2. The combination according to claim 1, wherein the growth hormone secretagogue is a compound of the general formula (V) and pharmaceutically acceptable salts thereof and their respective diastereomers. Wherein R < ₁ > is And (R ₂ ), NSO ₂ (R ₂ ), NSO ₂ (CH (CH ₂ ) ₂ ), R ₃ is H or fluorine and D is selected from the group consisting of -O-, -S-, _{2) 1 aryl, NC (O) (R 2} ), NSO 2 (CH 2) qOH, NSO 2 (CH 2) qCOOR 2, NSO 2 (CH 2) qC (O) -N (R 2) (R 2 _{), N-SO 2 (CH} 2) qC (O) -N (R 2) (CH 2) W OH, N-SO 2 (CH 2) qC (O) -N (R 2) (CH 2) W , N-SO ₂ (CH ₂ ) _q C (O) -N (R ₂ ) (CH ₂ ) _W And Wherein aryl is phenyl or pyridyl and phenyl can be substituted by one or two halogens, R ₂ is H or C _1-4 alkyl, m is 1 or 2, t is 0, 1 or 2 , Q is 1, 2 or 3, and w is 2, 3, 4, 5 or 6. The method of claim 1, wherein the growth hormone distribution enhancer is selected from the group consisting of 1) N- [1 (R) - [- 1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (lH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 2) Synthesis of N- [1 (R) - [1,2-dihydro-1 -methanecarbonylspyroh 3H-indole-3,4'- piperidin] (LH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 3) N- [1 (R) - [1,2-dihydro-1-benzenesulfonylpyrazolo [3H-indole-3,4'-piperidine] (LH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 4) Synthesis of N- [1 (R) - [(3,4-dihydro- spiro [2H-1-benzopyran-2,4'- 1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 5) Preparation of N- [1 (R) - [(2-acetyl-1,2,3,4-tetrahydropyrrolo [isoquinoline-4,4'- piperidin] 2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 6) Preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] - (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 7) N- [1 (R) - [1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] (Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide mesylate salt; 8) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] - (2 ', 6'-difluoromethylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 9) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5- fluorospiro [ Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 10) N- [1 (S) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] - (phenylmethylthio) ethyl] -2-amino-2-methylpropanamide; 11) N- [1 (R) - [(1,2-dihydro-1 -methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -Phenylpropyl] -2-amino-2-methylpropanamide; 12) Preparation of N- [1 (R) - [(1,2-dihydro-1 -methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -Cyclohexylpropyl] -2-amino-2-methylpropanamide; 13) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -Phenylbutyl] -2-amino-2-methylpropanamide; 14) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -2 (5-fluoro-lH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 15) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5-fluorospiro- [3H- indole-3,4'-piperidin] ) Carbonyl] -2 - (- 5-fluoro-1 H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 16) Synthesis of N- [1 (R) -1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonylpyrazolo- [3H-indole-3,4'-piperidine] Yl) ethyl] -2-methylpropanamide and 17) N- [1 (R) - [(1, 2-dihydro- Methyl-2- (phenylmethyloxy) ethyl] -2-amino-2-methyl < / RTI > Propanamide, and a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition according to claim 1, wherein the bisphosphonate is alendronic acid or pamidronic acid or a pharmaceutically acceptable salt thereof, wherein the growth hormone secretagogue is N - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H Yl] carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2- methylpropanamide, N- [1 (R) - Carbonyl] -3-phenylpropyl] -2-amino-2 (1 H-indole-2-carbonyl) - < / RTI > methylpropanamide or a pharmaceutically acceptable salt thereof. 3. The method of claim 1 wherein the bisphosphonate is alendronic acid or a pharmaceutically acceptable salt thereof and wherein the growth hormone secretagogue is N- [1 (R) - [(1, 2-dihydro-1-methanesulfonylsulfi [ 3'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2- methylpropanamide or a pharmaceutically acceptable salt thereof Formulation. A pharmaceutical composition for treating osteoporosis, comprising bisphosphonate and a growth hormone secretagogue together with an inert carrier. The composition of claim 1, wherein the bisphosphonate is a compound of formula (X) or a pharmaceutically acceptable salt thereof. Wherein R ¹ is unsubstituted or substituted by NH ₂ , pyridyl, pyrrolidyl or NR ³ N ⁴ wherein R ³ is H or C _1-4 alkyl and R ⁴ is C _1-4 alkyl. substituted C _1-5 alkyl, NR ⁵ (wherein, R ⁵ is a C _1-10 alkyl), SR ⁶ is selected from (wherein, R ⁶ is an aryl group) and the group consisting of C1, R ² is H, OH or C1. 11. The composition of claim 10, wherein the bisphosphonate is selected from the group consisting of alendronic acid, etidronate, claudronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1 -hydroxy-hexylidene-bisphosphonic acid, and 1 -Hydroxy-3- (methylpentylamino) -propylidene-bisphosphonic acid, or a pharmaceutically acceptable salt thereof. 13. The composition of claim 12, wherein the bisphosphonate is alendronate or a pharmaceutically acceptable salt thereof. 11. The composition of claim 10, wherein the growth hormone secretagogue is a compound of the following general formulas (I) and (II) and pharmaceutically acceptable salts thereof and their respective diastereomers. Wherein, R ¹ is -C ₁ -C ₁₀ alkyl, - aryl, aryl - (C ₁ -C ₆ alkyl), -C ₃ -C ₇ cycloalkyl, - (C ₁ -C ₆ alkyl), -C ₁ -C ₅ alkyl -KC ₁ -C ₅ alkyl, aryl (C ₀ -C ₅ alkyl) -K- (C ₁ -C ₅ alkyl) and -C ₃ -C ₇ cycloalkyl (C ₀ -C ₅ alkyl) -K- (C ₁ -C ₅ alkyl) wherein, K is O, S (O) m, n (R 2) C (O), C (O) N (R 2), OC (O), C _{(O) O, -CR 2 =} CR 2 - or -C≡C-, and the aryl group are the same as defined below, R ₂ and alkyl groups having 1 to 9 halogen, S (O) mR _2a ( Wherein R _2a is hydrogen or C _1-6 alkyl, and m is 0, 1 or 2. Wherein the aryl group is optionally substituted with one to three OR _2a or C (O) OR _{2a wherein the} aryl group is optionally substituted with one or more substituents selected from the group consisting of phenyl, phenoxy, halophenyl, 1 to 3 C _1-6 alkyl, or two -OR _{2, methylenedioxy, -S (O) mR 2,} 1 or 2 -CF _3, -OCF _{3, nitro, -N (R 2) (R} 2) -, -N (R 2 _{) C (O) R 2,} -C (O) OR 2, -C (O) N (R 2) (R 2), -SO 2 N (R 2) (R 2), -N (R 2) S (O) ₂ aryl and -N (R ₂ ) SO ₂ R ₂ , and R ₂ is selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl And two C _1-6 alkyl groups are present at one atom and they may optionally be joined to form a C _3-8 cyclic ring optionally containing oxygen, sulfur or NR _2a , R _3a and R _3b are independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, -OR ₂ , cyano, -OCF ₃ , methylenedioxy, nitro, -S (O) mR, -CF ₃ and -C ) OR < ₂ > R _3a and R _3b are ortho arrangements which may combine to form a C _5-8 aliphatic or aromatic ring optionally containing one or two heteroatoms selected from oxygen, sulfur and nitrogen and R ₄ And R ₅ are independently selected from the group consisting of hydrogen, C _1-6 alkyl, and substituted C _1-6 alkyl wherein the substituents are selected from the group consisting of 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C _1-10 alkanoyloxy , C _1-6 alkoxy, phenyl, phenoxy, 2-furyl, C _1-6 alkoxycarbonyl and -S (O) m (C _1-6 alkyl) ₄ and R ₅ are together _{- (CH 2) rLa (CH} 2) s- [ wherein, La is _{C (R 2) 2 -,} -O-, -S (O) m- , or N- (R ₂₎ - And r and s are independently 1 to 3 and R ₂ is as defined above, R ₆ is hydrogen or C _1-6 alkyl, A is Wherein x and y are independently 0 to 3, Z is -NR ₂ or 0, and R ₇ and R ₇ a are independently selected from the group consisting of hydrogen, C _1-6 alkyl, -OR ₂ , trifluoromethyl, phenyl And substituted C _1-6 alkyl wherein the substituent is selected from the group consisting of imidazolyl, phenyl, indolyl, P-hydroxyphenyl, -OR ₂ , 1-3 fluorine, -S (O) mR ₂ , -C ) oR _2, C _{3-7 cycloalkyl, -N (R 2) (R} 2) and _{-C (O) N (R 2} ) ( or selected from the group consisting of R is selected from _2)), R ₇ and R _7a may independently bond with one or both of R ₄ and R ₅ to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R ₇ or R _7a group, comprises; a, B, D, E and F independently represent _{-C (R 8) (R 10} ) - [ wherein, R ₈ and R ₁₀ are independently _{hydrogen, R 2, -OR 2, -} (CH 2 ) q- _{aryl, - (CH 2) qC (} O) oR 2 ( wherein, q may optionally 0,1,2,3 or 4 _{days), - (CH 2) qC} (O) O (CH 2) q-ah Reel and - (CH ₂ - (1H- tetrazol-5-yl) (wherein aryl is from 1 to 3 halo, one or two C _1-8 alkyl, one to three or one or two -OR ₂ -C (O) is selected from the group consisting of optionally may be substituted) by an _{OR 2], -O-, C =} O, -S (O) m- and -NR ₉ - [wherein, R ₉ is - _{R 2, - (CH 2)} q- _{aryl, -C (O) R 2,} -C (O) (CH 2) q- _{aryl, -SO 2 R 2, -SO 2} (CH 2) q- aryl, _{-C (O) N (R 2} ) (R 2), -C (O) N (R 2) (CH 2) q- _{aryl, -C (O) OR 2,} 1H- tetrazol-5-yl, _{-SO 3 H, -SO 2 NHC≡N,} -SO 2 N (R 2) is selected from aryl and -SO ₂ N (R ₂₎ group consisting of (R ₂₎ {wherein, (CH ₂₎ q is 1, Or two C _1-4 alkyl; R ₂ and aryl are optionally substituted with one to three -OR _2a -O (CH ₂ ) q -aryl, one or two -C (O) OR _2a , one or two _{-C (O) O (CH 2} ) q- aryl, with one or two _{-C (O) N (R 2a} ) (R 2a), 1 or 2 -C (O) N (R _2a (CH ₂ ) q -aryl, 1 to 5 halogens, 1 to 3 C _1-4 alkyls, 1,2,4-triazoles Reel, 1H- _{tetrazol-5-yl, -C (O) NHSO 2 R} 2a, -S (O) mR 2a, -C (O) NHSO 2 (CH 2) q- aryl, -SO ₂ NHC≡N _{, -SO 2 NHC (O) R} 2a, -SO 2 NHC (O) (CH 2) q aryl _{-N (R 2) C (O} ) N (R 2a R 2a), -N (R 2) C ( _{O) N (R 2a) (} CH 2) q- _{aryl, -N (R 2a) (R} 2a), -N (R 2a) C (O) R 2a, -N (R 2a) C (O) ( CH ₂₎ q aryl, -OC (O) N (R 2a) (R 2a), -OC (O) N (R 2a) (CH 2) q aryl and _{-SO 2 (CH 2) qCONH- (} CH 2 ) wNHC (O) R ₁₁ , wherein w is 2 to 6 and R ₁₁ is biotinyl or aryl, or one or two -OR ₂ , one or two halogens, Or nitro; and one or two of B, D, E or F may be optionally absent to provide a 5, 6 or 7 membered ring, and B, D , E and F, the remaining B, D, E and F at the same time one of -O-, -S (O) m or -NR ₉ - -C (R ₈₎ only if the (R ₁₀₎ - or C = O Or B and D, or D and E taken together are -N = CR ₁₀ - or -CR _{1 0} = N- may be a, B and D, or D and E are -CR ₈ = CR ₁₀ may be one, or one of F B and E together are simultaneously -O-, -S (O) m- or - NR ₉ - and, G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms and then, one of them at least is a hetero atom is one of G, H, I and J are thought optionally a 5 or 6-membered heteroaryl To form a cyclic aromatic ring. 11. The composition according to claim 10, wherein the growth hormone secretagogue is a compound of formula (V) and pharmaceutically acceptable salts thereof and their respective diastereomers. Wherein R < ₁ > is And (R ₂ ), NSO ₂ (R ₂ ), NSO ₂ (CH (CH ₂ ) ₂ ), R ₃ is H or fluorine and D is selected from the group consisting of -O-, -S-, _{2) 1 aryl, NC (O) (R 2} ), NSO 2 (CH 2) qOH, NSO 2 (CH 2) qCOOR 2, NSO 2 (CH 2) qC (O) -N (R 2) (R 2 _{), N-SO 2 (CH} 2) qC (O) -N (R 2) (CH 2) W OH, N-SO 2 (CH 2 qC (O) -N (R 2) (CH 2) W , N-SO ₂ (CH ₂ ) _q C (O) -N (R ₂ ) (CH ₂ ) _W And Wherein aryl is phenyl or pyridyl and phenyl can be substituted by one or two halogens, R ₂ is H or C _1-4 alkyl, m is 1 or 2, t is 0, 1 or 2 , Q is 1, 2 or 3, and w is 2, 3, 4, 5 or 6. 11. The method of claim 10, wherein the growth hormone secretagogue is selected from the group consisting of 1) N- [1 (R) - [- 1, 2-dihydro- 1- methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (lH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 2) Preparation of N- [1 (R) - [1,2-dihydro-1 -methanecarbonyls pyrrolo [3H-indole-3,4'-piperidin] (LH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 3) N- [1 (R) - [1,2-dihydro-1-benzenesulfonylpyrazolo [3H-indole-3,4'-piperidine] (LH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 4) Synthesis of N- [1 (R) - [(3,4-dihydro- spiro [2H-1-benzopyran-2,4'- 1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 5) Preparation of N- [1 (R) - [(2-acetyl-1,2,3,4-tetrahydropyrrolo [isoquinoline-4,4'- piperidin] 2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 6) Preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] - (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 7) N- [1 (R) - [1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] (Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide mesylate salt; 8) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] - (2 ', 6'-difluoromethylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 9) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5- fluorospiro [ Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 10) N- [1 (S) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] - (phenylmethylthio) ethyl] -2-amino-2-methylpropanamide; 11) N- [1 (R) - [(1,2-dihydro-1 -methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -Phenylpropyl] -2-amino-2-methylpropanamide; 12) Preparation of N- [1 (R) - [(1,2-dihydro-1 -methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -Cyclohexylpropyl] -2-amino-2-methylpropanamide; 13) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -Phenylbutyl] -2-amino-2-methylpropanamide; 14) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -2 (5-fluoro-lH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 15) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5-fluorospiro- [3H- indole-3,4'-piperidin] ) Carbonyl] -2 - (- 5-fluoro-1 H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 16) Synthesis of N- [1 (R) -1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonylpyrazolo- [3H-indole-3,4'-piperidine] Yl) ethyl] -2-methylpropanamide and 17) N- [1 (R) - [(1, 2-dihydro- Methyl-2- (phenylmethyloxy) ethyl] -2-amino-2-methyl < / RTI > Propanamide, and a pharmaceutically acceptable salt thereof. 11. The method of claim 10, wherein the bisphosphonate is alendronic acid or a pharmaceutically acceptable salt thereof, wherein the growth hormone secretagogue is N- [1 (R) - [(1,2- (R) -2-amino-2-methylpropanamide, < RTI ID = 0.0 & - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] 2-methylpropanamide or a pharmaceutically acceptable salt thereof. 11. The method of claim 10, wherein the bisphosphonate is alendronic acid or a pharmaceutically acceptable salt thereof, wherein the growth hormone secretagogue is N- [1 (R) - [(1,2- 3'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2- methylpropanamide or a pharmaceutically acceptable salt thereof Composition. A method for treating osteoporosis, comprising administering to a patient in need of such treatment an effective amount of a combination of a bisphosphonate and a growth hormone secretagogue. 20. The method of claim 19, wherein the bisphosphonate is a compound of formula (X) or a pharmaceutically acceptable salt thereof. Wherein R ¹ is unsubstituted or substituted by NH ₂ , pyridyl, pyrrolidyl or NR ³ N ⁴ wherein R ³ is H or C _1-4 alkyl and R ⁴ is C _1-4 alkyl. substituted C _1-5 alkyl, NR ⁵ (wherein, R ⁵ is a C _1-10 alkyl), SR ⁶ is selected from (wherein, R ⁶ is an aryl group) and the group consisting of C1, R ² is H, OH or C1. 20. The composition of claim 19, wherein the bisphosphonate is selected from the group consisting of alendronic acid, etronic acid, claudronic acid, pamidronic acid, tiludronic acid, lysedronic acid, 6-amino-1-hydroxy-hexylidene-bisphosphonic acid, and 1 -Hydroxy-3- (methylpentylamino) -propylidene-bisphosphonic acid or a pharmaceutically acceptable salt thereof. 22. The method of claim 21, wherein the bisphosphonate is alendronate or a pharmaceutically acceptable salt thereof 20. The method according to claim 19, wherein the growth hormone secretagogue is a compound of the following general formulas (I) and (II), and pharmaceutically acceptable salts thereof and their respective diastereomers. Wherein, R ¹ is -C ₁ -C ₁₀ alkyl, - aryl, aryl - (C ₁ -C ₆ alkyl), -C ₃ -C ₇ cycloalkyl, - (C ₁ -C ₆ alkyl), -C ₁ -C ₅ alkyl -KC ₁ -C ₅ alkyl, aryl (C ₀ -C ₅ alkyl) -K- (C ₁ -C ₅ alkyl) and -C ₃ -C ₇ cycloalkyl (C ₀ -C ₅ alkyl) -K- (C ₁ -C ₅ alkyl) wherein, K is O, S (O) m, N (R 2) C (O), C (O) N (R 2), OC (O), C _{(O) O, -CR 2 =} CR 2 - or -C≡C-, and the aryl group are the same as defined below, R ₂ and alkyl groups having 1 to 9 halogen, S (O) mR _2a ( Wherein R _2a is hydrogen or C _1-6 alkyl, and m is 0, 1 or 2. Wherein the aryl group is optionally substituted with one to three OR _2a or C (O) OR _{2a wherein the} aryl group is optionally substituted with one or more substituents selected from the group consisting of phenyl, phenoxy, halophenyl, 1 to 3 C _1-6 alkyl, or two -OR _{2, methylenedioxy, -S (O) mR 2,} 1 or 2 -CF _3, -OCF _{3, nitro, -N (R 2) (R} 2) -, -N (R 2 _{) C (O) R 2,} -C (O) OR 2, -C (O) N (R 2) (R 2), -SO 2 N (R 2) (R 2), -N (R 2) S (O) ₂ aryl and -N (R ₂ ) SO ₂ R ₂ , and R ₂ is selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl And two C _1-6 alkyl groups are present at one atom and they may optionally be joined to form a C _3-8 cyclic ring optionally containing oxygen, sulfur or NR _2a , R _3a and R _3b are independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, -OR ₂ , cyano, -OCF ₃ , methylenedioxy, nitro, -S (O) mR, -CF ₃ and -C ) OR < ₂ > R _3a and R _3b are ortho arrangements which may combine to form a C _5-8 aliphatic or aromatic ring optionally containing one or two heteroatoms selected from oxygen, sulfur and nitrogen and R ₄ And R ₅ are independently selected from the group consisting of hydrogen, C _1-6 alkyl, and substituted C _1-6 alkyl wherein the substituents are selected from the group consisting of 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C _1-10 alkanoyloxy , C _1-6 alkoxy, phenyl, phenoxy, 2-furyl, C _1-6 alkoxycarbonyl and -S (O) m (C _1-6 alkyl) ₄ and R ₅ are together _{- (CH 2) rLa (CH} 2) s- [ wherein, La is _{C (R 2) 2 -,} -O-, -S (O) m- , or N- (R ₂₎ - And r and s are independently 1 to 3 and R ₂ is as defined above, R ₆ is hydrogen or C _1-6 alkyl, A is Wherein x and y are independently 0 to 3, Z is -NR ₂ or 0, and R ₇ and R ₇ a are independently selected from the group consisting of hydrogen, C _1-6 alkyl, -OR ₂ , trifluoromethyl, phenyl And substituted C _1-6 alkyl wherein the substituent is selected from the group consisting of imidazolyl, phenyl, indolyl, P-hydroxyphenyl, -OR ₂ , 1-3 fluorine, -S (O) mR ₂ , -C ) oR _2, C _{3-7 cycloalkyl, -N (R 2) (R} 2) and _{-C (O) N (R 2} ) or selected from the group consisting of is selected from the _{7 (R 2)), R} 7 and R _7a is independently selected from R ₄ and R ₅ are one or a combination with the these two to form an alkylene bridge between the alkyl portion of the terminal nitrogen with R ₇ or R _7a groups of the, cross-linking from 1 to 5 carbon atoms and characters contain], B, D, E and F independently represent _{-C (R 8) (R 10} ) - [ wherein, R ₈ and R ₁₀ are independently _{hydrogen, R 2, -OR 2, -} (CH ₂₎ q- _{aryl, - (CH 2) qC (} O) oR 2 ( wherein, q is an optionally 0,1,2,3 or a 4 _{days), - (CH 2) qC} (O) O (CH 2 ) q- Reel and - (CH ₂ - (1H- tetrazol-5-yl) (wherein aryl is from 1 to 3 halo, one or two C _1-8 alkyl, one to three or one or two -OR ₂ -C (O) is selected from the group consisting of optionally may be substituted) by an _{OR 2], -O-, C =} O, -S (O) m- and -NR ₉ - [wherein, R ₉ is - _{R 2, - (CH 2)} q- _{aryl, -C (O) R 2,} -C (O) (CH 2) q- _{aryl, -SO 2 R 2, -SO 2} (CH 2) Q- aryl, _{-C (O) N (R 2} ) (R 2), -C (O) N (R 2) (CH 2) q- _{aryl, -C (O) OR 2,} 1H- tetrazol-5-yl, _{-SO 3 H, -SO 2 NHC≡N,} -SO 2 N (R 2) is selected from aryl and -SO ₂ N (R ₂₎ group consisting of (R ₂₎ {wherein, (CH ₂₎ q is 1, Or two C _1-4 alkyl; R ₂ and aryl are optionally substituted with one to three -OR _2a -O (CH ₂ ) q -aryl, one or two -C (O) OR _2a , one or two _{-C (O) O (CH 2} ) q- aryl, with one or two _{-C (O) N (R 2a} ) (R 2a), 1 or 2 -C (O) N (R _2a ) (CH ₂₎ q- aryl, one to five halogen, one to three C _1-4 alkyl, 1,2,4-triazole Reel, 1H- _{tetrazol-5-yl, -C (O) NHSO 2 R} 2a, -S (O) mR 2a, -C (O) NHSO 2 (CH 2) q- aryl, -SO ₂ NHC≡N _{, -SO 2 NHC (O) R} 2a, -SO 2 NHC (O) (CH 2) q aryl _{-N (R 2) C (O} ) N (R 2a R 2a), -N (R 2) C ( _{O) N (R 2a) (} CH 2) q- _{aryl, -N (R 2a) (R} 2a), -N (R 2a) C (O) R 2a, -N (R 2a) C (O) ( CH ₂₎ q aryl, -OC (O) N (R 2a) (R 2a), -OC (O) N (R 2a) (CH 2) q aryl and _{-SO 2 (CH 2) qCONH- (} CH 2 ) wNHC (O) R ₁₁ , wherein w is 2 to 6 and R ₁₁ is biotin or aryl, or one or two -OR ₂ , one or two halogens, Or B may be optionally absent to provide a 5, 6 or 7 membered ring, and B, D, E or F may be optionally absent, D, E and F, the remaining B, D, E and F at the same time one of -O-, -S (O) m or -NR ₉ - -C (R ₈₎ only if the (R ₁₀₎ - or C = O may be a, B and D, or D and E together are -N = CR ₁₀ - or -CR ₁₀ = N- may be a, B and D, or D and E are -CR ₈ = CR ₁₀ may be one, or one of F B and E together are simultaneously -O-, -S (O) m- or - NR ₉ - and, G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms and then, one of them at least is a hetero atom is one of G, H, I and J are thought optionally a 5 or 6-membered heteroaryl To form a cyclic aromatic ring. 20. The method of claim 19, wherein the growth hormone secretagogue is a compound of formula (V): < EMI ID = 25.1 > Wherein R < ₁ > is And (R ₂ ), NSO ₂ (R ₂ ), NSO ₂ (CH (CH ₂ ) ₂ ), R ₃ is H or fluorine and D is selected from the group consisting of -O-, -S-, _{2) 1 aryl, NC (O) (R 2} ), NSO 2 (CH 2) qOH, NSO 2 (CH 2) qCOOR 2, NSO 2 (CH 2) qC (O) -N (R 2) (R 2 _{), N-SO 2 (CH} 2) qC (O) -N (R 2) (CH 2) W OH, N-SO 2 (CH 2 qC (O) -N (R 2) (CH 2) W , N-SO ₂ (CH ₂ ) _q C (O) -N (R ₂ ) (CH ₂ ) _W And Wherein aryl is phenyl or pyridyl and phenyl can be substituted by one or two halogens, R ₂ is H or C _1-4 alkyl, m is 1 or 2, t is 0, 1 or 2 , Q is 1, 2 or 3, and w is 2, 3, 4, 5 or 6. 20. The method of claim 19 wherein the growth hormone secretagogue is selected from the group consisting of 1) N- [1 (R) - [- 1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (lH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 2) Preparation of N- [1 (R) - [1,2-dihydro-1 -methanecarbonyls pyrrolo [3H-indole-3,4'-piperidin] (LH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 3) N- [1 (R) - [1,2-dihydro-1-benzenesulfonylpyrazolo [3H-indole-3,4'-piperidine] (LH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 4) Synthesis of N- [1 (R) - [(3,4-dihydro- spiro [2H-1-benzopyran-2,4'- 1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 5) Preparation of N- [1 (R) - [(2-acetyl-1,2,3,4-tetrahydropyrrolo [isoquinoline-4,4'- piperidin] 2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 6) Preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] - (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 7) N- [1 (R) - [1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] (Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide mesylate salt; 8) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] - (2 ', 6'-difluoromethylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 9) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5- fluorospiro [ Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 10) N- [1 (S) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] - (phenylmethylthio) ethyl] -2-amino-2-methylpropanamide; 11) N- [1 (R) - [(1,2-dihydro-1 -methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -Phenylpropyl] -2-amino-2-methylpropanamide; 12) Preparation of N- [1 (R) - [(1,2-dihydro-1 -methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -Cyclohexylpropyl] -2-amino-2-methylpropanamide; 13) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -Phenylbutyl] -2-amino-2-methylpropanamide; 14) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -2 (5-fluoro-lH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 15) Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5-fluorospiro- [3H- indole-3,4'-piperidin] ) Carbonyl] -2 - (- 5-fluoro-1 H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 16) Synthesis of N- [1 (R) -1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonylpyrazolo- [3H-indole-3,4'-piperidine] Yl) ethyl] -2-methylpropanamide and 17) N- [1 (R) - [(1, 2-dihydro- Methyl-2- (phenylmethyloxy) ethyl] -2-amino-2-methyl < / RTI > Propanamide, and a pharmaceutically acceptable salt thereof. 20. The method according to claim 19, wherein the bisphosphonate is administered in an amount of 0.001 to 10 mg / kg of body weight and the growth hormone secretagogue is administered in a dose of 0.0001 to 25 mg / kg of body weight. 27. The method of claim 26, wherein the bisphosphonate is administered at 0.01 to 1.0 mg / kg body weight. 20. The method of claim 19 wherein the bisphosphonate is alendronic acid or pamidronic acid or a pharmaceutically acceptable salt thereof, wherein the growth hormone secretagogue is N- [1 (R) - [(1, 2-dihydro- (Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, N- [2-methoxyphenylsulfanyl] 1-yl) carbonyl] -3-phenylpropyl] - (2-hydroxy-1- 2-amino-2-methylpropanamide or a pharmaceutically acceptable salt thereof. 20. The method of claim 19, wherein the bisphosphonate is alendronate or a pharmaceutically acceptable salt thereof, wherein the growth hormone secretagogue is N- [1 (R) - [(1, 2-dihydro-1-methanesulfonylsulfi [ 3'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2- methylpropanamide or a pharmaceutically acceptable salt thereof Way. ※ Note: It is disclosed by the contents of the first application.