SK49796A3 - Compound remedy for osteoporosis treatment, pharmaceutical composition and application thereof - Google Patents

Compound remedy for osteoporosis treatment, pharmaceutical composition and application thereof Download PDF

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Publication number
SK49796A3
SK49796A3 SK49796A SK49796A SK49796A3 SK 49796 A3 SK49796 A3 SK 49796A3 SK 49796 A SK49796 A SK 49796A SK 49796 A SK49796 A SK 49796A SK 49796 A3 SK49796 A3 SK 49796A3
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ch
yl
carbon atoms
alkyl
aryl
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SK49796A
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Slovak (sk)
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Barry J Gertz
Gideon A Rodan
Roy G Smith
Matthew J Wyvratt
Arthur A Patchett
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Merck & Co Inc
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Priority to US25909194A priority
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Priority to PCT/US1994/011912 priority patent/WO1995011029A1/en
Publication of SK49796A3 publication Critical patent/SK49796A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof

Description

- 1 -

A combined preparation for the treatment of osteoporosis, a pharmaceutical composition thereof and its use

Technical field

The invention relates to a combination preparation of bisphosphonates and growth hormone releasing compounds for the treatment and prevention of osteoporosis and to a pharmaceutical composition comprising the combination.

Prior art

Biphosphonates and biphosphonic acids are known to cause bone resorption inhibition, and these properties can be used to treat such resorption disorders as disclosed in U.S. Pat. 4,621,077 (Rosini et al.). Treatment of osteoporosis with calcitonin per se or in combination with human growth hormone is described in Aloia et al., Metabolism, 34 (2), 124-129 (1985). This publication does not report any significant deterioration in the treatment of osteoporosis with a combination of cal-citoin and growth hormone. The effect of growth hormone as the only active agent in the treatment of osteoporosis is described in Aloia et al., J. Clin. Endocrinol. Metab., 54, 992-999, 1976. It is known that certain growth hormone secretagogues or release stimulate the pituitary gland, which is beneficial in children with undergrowth, but also in adults in severe burns, in the treatment of Turner syndrome. , in the suppression of adverse side effects in the administration of glucocorticoids, in the treatment of muscle wasting or in the case of their high load in growth hormone deficient adults, have been described in U.S. Pat. Nos. 3,239,345, 4,036,979, 4,411,890, 5,206,235, 5,284,841, 5,310,737, and 5,317,017, in European Patent Application Publication Nos. 144 230 and 513 974, in International Patent Applications Publication Nos. WO 94/07486, WO 94/13696, and Science, 260, 1640-21643 (June 11, 1993). These publications describe compounds with beneficial effects on growth hormone release. A number of bisphosphonic acids have also been reported in the literature that can be used in the treatment and prevention of bone resorption diseases. Examples of publications in which these compounds are disclosed may be U.S. Pat. 3 251 907, 3 422 137, 3 584 125, 3 940 436, 3 944 599, 3 962 432, 4 054 598, 4 267 108, 4 327 039, 4 407 761, 4 578 376, 4 621 077, 4 624 Nos. 947, 4,746,654, 4,761,406, 4,922,007, 4,942,157, and 5,227,506; 252,504 and in J. Org. Chem., 36, 3843 (1971).

Preparations of bisphosphonic and halobiphosphonic acids are known and described in the literature. Examples of various procedures can be found in the above-mentioned publications, in which it is also reported that the prepared substances can be used to treat calcium or phosphate metabolism disorders, in particular to inhibit bone resorption.

SUMMARY OF THE INVENTION

The present invention provides a combination of active ingredients for the treatment and prevention of osteoporosis, a combination of a bisphosphate and a growth hormone secretagogue. This combination can be used to treat and prevent all bone resorption diseases, particularly in the case of osteoporosis in the elderly.

The first component of said combination is a bisphosphonate, in particular a compound selected from bisphosphonates or bisphosphonic acids of formula XO R2O

HO - P - C - P - OH

OH R 1 OH (X) 3 wherein R 6 is selected from (a) alkyl having 1 to 5 carbon atoms optionally substituted by one of the following groups 1) nh 2. 2) pyridyl, 3) pyrrolidyl, 4) NR 3 R 4, b) NR 5, c) SR ** or d) chlorine, 2 R represents hydrogen, hydroxy or chlorine,

R 7 is hydrogen or alkyl of 1 to 4 carbon atoms, R 4 is alkyl of 1 to 4 carbon atoms, R 1 is alkyl of 1 to 10 carbon atoms, and R 2 is aryl, and the salts thereof are acceptable. pharmaceutical aspect.

Formula X includes salts of said compounds with alkali metals, with organic bases as well as with basic amino acids. Preferred compounds of formula (X) are those in which R5 is alkyl of 1 to 5 carbon atoms substituted with amino or pyridyl, preferably at the terminal carbon atom and R5 is hydroxy. Preferred salts are alkali metal salts, especially sodium salts.

Most preferred bisphosphonates are the following compounds: alendronic acid, etidrononic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1-hydroxyhexylidene biphosphonic acid and 1-hydroxy-3- (methylpentylamino) propylidene biphosphonic acid and pharmaceutically acceptable salts thereof.

The preparation of bisphosphonic acids is known from the literature, examples can be found in U.S. Pat. 3 251 907, 3 422 137, 3 584 125, 3 940 436, 3 944 599, 3 962 432, 4 054 598, 4 267 108, 4 327 039, 4 407 761, 4 578 376, 4 4 621 077, 4 Nos. 624,947, 4,746,654, 4,761,406, 4,922,007, 4,942,157, and 5,227,506; 252,504 and in J. Org. Chem., 36, 3843 (1971).

The second component of said combination is growth hormone secretagogues.

Representative substances having the aforementioned effect have been described in U.S. Pat. Nos. 3,239,345, 4,036,979, 4,411,890, 5,206,235, 5,284,841, 5,310,737 and 5,317,017, in European Patent Nos. 144,230 and 513,974 and in International Patent Application Publication Nos. WO 94/07486, WO 94/08583 and WO 94/13696, and Science 260, 1640-1643, (June 11, 1993). U.S. Pat. No. 5,206,235 are growth hormone secretagogues represented by the general formula

(CH 2) q

wherein the individual general symbols are as defined in the patent specification.

Most preferably, said benzolactam compounds have the structure O CH 3 CH 2 II V /

5 or 5

Other growth hormone release agents have been disclosed in published International Patent Application No. WO 94/13696 are spiro compounds which can be represented by the general formulas I and II C = O C = O i

(II)

R2 R6, R4 R2 R6 R4 R1-C-N-C-A-N. Wherein R 1 is alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl-alkyl of 3 to 7 carbon atoms in the cycloalkyl C 6 to C 5 alkyl, aryl (C 1 -C 5 alkyl) -K- (C 1 -C 5 alkyl), cycloalkyl (C 1 -C 5) alkyl, C 1 -C 5 alkyl, C 1 -C 5 alkyl. alkyl having from 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) with a cycloalkyl moiety of 3 to 7 carbon atoms, wherein K is O, S (O) m, N (R 2) C (O ), C (O) N (R 2), OC (O), C (O) O or -CR = CR -, or -OC-, wherein the aryl groups are as defined below and the R 2 and alkyl groups may be further substituted 1 to 9 halogen atoms or S (O) m R 2a, 1 to 3 groups of OR 2a or C (O) OR 2a, and aryl groups are optionally further substituted with phenyl, phenoxy, halophenyl, 1 to 3 alkyl groups having 1 to 6 atoms coal with 1 to 3 halogen atoms, 1 or 2 substituents from the group -OR, methylenedioxy, -S (O) mR 2, -CF 4, -OCF 8, 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 with -N ( R 2 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, and, optionally, may be joined together to form two alkyl groups having 1 to 6 carbon atoms, a ring having from 3 to 8 carbon atoms and optionally an oxygen, sulfur or NR 2a atom, R 2a is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, R 5a and R 6a are independently selected from hydrogen, halo, alkyl and C1-C6, -OR, cyano, -OCF8, methylenedioxy, nitro, -S (O) mR, -CF3 or -C (O) OR2, where R5 and R6 are ortho , may be linked to form an aliphatic or aromatic ring with from C to 8 carbon atoms or obs containing 1 or 2 heteroatoms from oxygen, sulfur or nitrogen, R 1 and R 4 are independently selected from hydrogen, alkyl optionally substituted, wherein the substituents are selected from 1 to 5 halogen atoms, 1 to 3 substituents from 7 groups hydroxy, alkanoyloxy of 1 to 10 carbon atoms or alkoxy of 1 to 6 carbon atoms, phenyl, phenoxy, 2-furyl, alkoxycarbonyl of 1 to 6 carbon atoms, -S (O) m-alkyl of 1 to 6 atoms carbon, or R * and together may form - (CH2) rLa (CH2) s-, wherein La is -C (R6) 2 '. -O-, -S (O) jn- or -N (R 2) -, wherein ras independently represents an integer of 1 to 3 and R is as defined above, R ** represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, A represents a group R 7 - (CH 2) x - O - (CH 2) y --R 7a or

Z- (CH 2) x C- (CH 2) y -R 7a wherein x and y are independently integers 0 to 3, Z is NR or oxygen, 7 and R and R are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, -OR, trifluoromethyl, phenyl, substituted alkyl of 1-6 carbon atoms in which the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR 2, 1-3 fluoro atoms. -S (O) m R 2, -C (O) OR 2, cycloalkyl of 3 to 7 carbon atoms, -N (R 2) (R 2), -C (O) N (R 2) (R 2), or may be R 'and R 1a independently linked to one or both of the examinations and to the formation of alkylene bridges between the terminal nitrogen atom and the alkyl moiety of R 2 or R 2a, wherein the bridges may contain 1 to 5 carbon atoms, B, D, E and F is independently selected from the group consisting of -C (R ®) (R 6 -R) -, -O-, -C = O-, -S (O) m- or -NR 9 -, and one or two of B, D, E or F may be absent to form a 5, 6 or 7-membered ring, provided that B, D, E and F may be -C (R ®) (R * 9) - or -C = O-len in the case that one of the remaining symbols B, D, E and F simultaneously represents -O-, -S (O) m- or -NR 9 - or Ba D or D and E may together form a group -NMTR · * · 9 - or -CR * ® = N- or B and D or D and E may be taken together to form a group -CR-CR 1 - - provided that one of the remaining symbols B and E or F simultaneously represents - O-, -S (O) n - or -NR 9 -, R 1 and R 0 and R-LU independently represent hydrogen, -R, -OR, - (CH 2) q -aryl, - (CH 2) q C (O OR 2, - (CH 2) q C (O) (CH 2) q -aryl or - (CH 2) q - (1H-tetrazol-5-yl), wherein the aryl moiety is optionally substituted with 1 to 3 halogen atoms, 1 or 2 alkyl with 1 to 8 carbon atoms, 1 to 3 groups -OR or 1 or 2 groups -C (O) OR 2, R 9 represents the group -R 2, - (CH 2 -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) OR2, -H-tetrazol-5-yl, -SO3H, -SO2NHON, -SO2N (R2) aryl or -SO2N (R2) (R2), wherein (CH2) q is optionally substituted with 1 up to 2 alkyl groups having 1 to 4 carbon atoms and R and an aryl moiety optionally being further substituted with 1 to 3 groups -OR a, a, -O (CH 2) q -aryl, 1 to 2 -C (O) OR 2a, 1 to 2 groups -C (O) O (CH 2) q -aryl, 1 to 2 groups -C (O) N (R 2a) (R 2a), 1 to 2 groups -C (O) N (R 2a) (CH 2) q - aryl, 1 to 5 halogen atoms, 1 to 3 alkyl groups C1-4 atoms or 1,2,4-triazolyl, 1H-tetrazol-5-yl, -C (O) NHSO2R2a, 9 -S (O) mR2a, -C (O) NHSO2 (CH2 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 2a) 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, -SO 2 (CH 2) CONH- (CH 2) wNHC (O) R ** where v is an integer from 2 to 6 and R 1 is a biotin, aryl or aryl radical

O is substituted with 1 or 2 OR, 1 or 2 halogen, azido or nitro, m is an integer of 0, 1 or 2, n is an integer of 1 or 2, q is 0, 1, 2, 3 or 4 and G respectively. H, I and J are carbon, nitrogen, sulfur or oxygen atoms, at least one of which is a heteroatom and one of G, H, I or J may be absent to form an S or 6-membered heterocyclic aromatic ring, as well as a salt thereof pharmaceutically acceptable and individual diastereomers.

In the above structural formulas, some terms have the following meanings:

The alkyl groups have the aforementioned length and the straight or branched chain and optionally contain a double or triple bond and optionally a greater number of such bonds. Examples which may be mentioned are methyl, ethyl, propyl, ethynyl, iso-propyl, butyl, sec-butyl, tert-butyl, pentenyl, isopentenyl, hexyl, isohexyl, allyl, propenyl, butenyl, butadienyl and the like.

Alkoxy groups have the above-mentioned straight or branched chain length and optionally contain double or triple bonds. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propyloxy, isobutenyloxy and the like. or 2-hexenyloxy and the like.

The halogen atom can be a fluorine, chlorine, bromine or iodine atom. 10

&Quot; aryl " means phenyl, naphthyl and aromatic radicals containing S- and 6-membered rings with 1-3 heteroatoms or fused bicyclic systems containing 5- or 6-membered rings with 1-3 heteroatoms from nitrogen, sulfur or oxygen. Examples of such heterocyclic aromatic rings include pyridine, thiophene, benzothiophene, tetrazole, indole, N-methylindole, dihydroindole, indazol, N-formylindole, benzimidazole, thiazole, furan, pyrimidine and thiadiazole.

Some of the above groups may occur more than once in the resulting product molecules. In such cases, the meanings of said groups are completely independent of one another.

Preferred growth hormone secretagogue compounds suitable for use in the combination of the present invention may be represented by structural formula V

11

R 3 and D are hydrogen or fluorine, are selected from -O-, -S-, -S (O) m-, N (R 12), NSO 2 (R 2), NSO 2 (CH 2) t -aryl, NC ( 0) R 2), NSO 2 (CH 2) q COOR, NSO 2 (CH 2) q C (O) -N (R 2) (R 2), NSO 2 (CH 2) q C (O) -N (R 2) (CH 2) w OH.

ABOUT

N-SO 2 (CH 2) p C (O) -N (R 2) (CH 2) v /

About OH

N 3 ·

N-NH N-SO 2 (CH 2) q - (/ N = N 'aryl is phenyl or pyridyl, wherein phenyl is optionally substituted with 1 to 2 halogen atoms, R is hydrogen or alkyl of 1 to 4 carbon atoms, m is integer 1 or 2, t is an integer of 0, 1 or 2, q is an integer of 1, 2 or 3, w is an integer of 2, 3, 4, 5 or 6, as well as pharmaceutically acceptable salts thereof. and their individual diastereomers.

Examples of the most preferred growth hormone secretagogues for use in the combination of the present invention include the following compounds: 1 N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3 H -indole-2 3,4 ']) -piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 12) N- [1 (R) - [(1,2- dihydro-1-methanecarbonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; N- [1 (R) - [(1,2-dihydro-l-benzénsulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (indol-3-yl ethyl) -2-amino-2-methylpropanamide, 4) N- [1 (R) - [(3,4-dihydrospiro [2H-1-benzopyran-2,4'-piperidin] -1'-yl) carbonyl ] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 5) N- [1 (R) - [(2-acetyl-1,2,3,4-tetrahydrospiro [ isoquinoline-4,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 6) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-m ethylpropanamide, 7) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] 2-amino-2-methylpropanamidinesylate, 8) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (2 ', 6'-difluorophenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 9) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5-fluorospiro) [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 10) N- [1 (S) - [( 1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethylthio) ethyl] -2-amino-2-methylpropanamide, 13.11) N- [1 (R) - [(1,2-dihydro-l-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2 12) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-cyclohexylpropyl] - 2-amino-2-methylpropanamide, 13) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] - 4 -phenylbutyl] -2-amino-2-methylpropanamide; 14) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3 H -indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro-1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 15) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl) 5-fluorospiro [3H-indole-3,4'-piperidin] -r-yl) carbonyl] -2- (5-fluoro-lH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide. 16) N- [1 (R) - [(1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonyl-spiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 17) N- [1 (R) - [(1,2-dihydro-1,1-dioxospiro [3 H -benzothiophene-3, 4-piperidin] -1 * -yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, and pharmaceutically acceptable salts thereof.

Particularly useful growth hormone secretagogues include: N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide mesylate, 14 N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide, and pharmaceutically acceptable salts thereof.

The preparation of bisphosphonic acids is known from the literature, examples can be found in U.S. Pat. 3 251 907, 3 422 137, 3 584 125, 3 940 436, 3 944 599, 3 962 432, 4 054 598, 4 267 108, 4 327 039, 4 407 761, 4 578 376, 4 621 077, 4 624 Nos. 947, 4,746,654, 4,761,406, 4,922,007, 4,942,157, and 5,227,506; 252,504 and in J. Org. Chem., 36, 3843 (1971).

Representative substances having the aforementioned effect have been described in U.S. Pat. Nos. 3,239,345, 4,036,979, 4,411,890, 5,206,235, 5,284,841, 5,310,737 and 5,317,017, in European Patent Nos. 144,230 and 513,974 and in International Patent Application Publication Nos. WO 94/07486, WO 94/08583 and WO 94/13696, and Science 260, 1640-1643, (June 11, 1993).

The preparation of growth hormone secretagogues of formulas I and II for use in the combination of the invention can be accomplished by a variety of procedures. Details will be given in the following reaction schemes.

The protected amino acid derivatives of Formula 1 are commonly available in a number of cases. L-protecting groups are, for example, BOC or CBZ. Other protected amino acid derivatives of formula I can be prepared by literature procedures. A number of spiropiperidines and spiro-azepine compounds (n = 2) of formulas 2 and 2a are known from the literature, derivatives of which can be formed on the phenyl or heteroaryl moieties using standard procedures such as halogenation, nitration, sulfonylation and the like. The various spiropiperidine and spiroazepine derivatives substituted on the phenyl or heteroaryl moiety can be prepared by the following literature procedures using intermediates which are also substituted on the 15 phenyl or heteroaryl moiety. In the schemes that follow Scheme 1 below, synthetic methods are illustrated on Spiropiperidine Derivatives only, but it is readily apparent that the described conversions are also possible. a variety of higher homologues to produce compounds of Formulas I and II wherein n = 2.

Scheme 1 R2 R6

R2 R6

R · 1 · —J – L COOH CO

The intermediates of formulas 3 and 3a can be synthesized as shown in Scheme 1. Binding of the spiropiperidino derivatives of formulas 2 and 2a to the protected amino acids of formula 1 wherein L is the appropriate protecting group is conveniently carried out in an inert solvent such as dichloromethane in the presence of a coupling agent, for example DCC or EDC and in the presence of HOBT. Binding may also be carried out with another binding agent, for example BOP in an inert solvent such as dichloromethane. Undesirable by-products can be removed and at the same time the intermediates can be purified by silica gel chromatography, typically by flash chromatography according to V. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 43, 2923 (1978), MPLC or preparative TLC.

The conversion of the compounds of formulas 3 and 3a on the intermediates of formulas 4a and 4a can be carried out as shown in Scheme 2 below.

Removal of the benzyloxycarbonyl group can be accomplished by a variety of known methods. For example, it is possible to use catalytic hydrogenation with hydrogen in the presence of a palladium or platinum catalyst in a protic solvent such as methanol. Where catalytic hydrogenation cannot be performed due to the presence of other potentially reactive functional groups, removal of the benzyloxycarbonyl groups can also be achieved by treatment with a hydrogen bromide solution in acetic acid. BOC deprotection can be carried out in a solvent such as methylene chloride or methanol by treatment with a strong acid such as hydrochloric acid or trifluoroacetic acid. Conditions to remove other optional protecting groups can be found in Greene T., Vuts P.G.M., Protective Groups in Organic Synthesis, John Viley and Sons., New York, NY 1991.

R2 R6 1 I R1— | - N-HCO

Scheme 3

R2 R6 O R4 1. · II · __M — η-Δ — M CO R5

r5 or L

R 1 | N-C-A-N

R1— | —N — H CO or

(5) and (5a) R 2 R 6 O

R1-f-N-C-A-N 'CO

r5 or L

(4a) R 3b R 3b (5b) a. (5c) 18

The intermediates of formulas 5a and 5b wherein A is methylene or substituted methylene may be prepared as shown in Scheme 3 by coupling intermediates of formulas 4a and 5a to an amino acid of formula 6 in an inert solvent such as dichloromethane using a coupling agent such as EDC or DCC and in the presence of HOBT. The amino acids of formula 6 are known amino acids or are amino acids which can be readily synthesized by methods analogous to those described in the literature. Binding can also be performed using a BOP-type binding agent in an inert solvent such as dichloromethane. When or when they are hydrogen, amino acids of formula 7 in which L is a protecting group as defined above can be used for the coupling reaction to give intermediates of formulas 5a and 5c. Removal of the protecting group L from these compounds can then be carried out by known procedures.

The compounds of formulas (I) and (II) in which R11 and / or are hydrogen may be further processed into the novel compounds of formulas (I) and (II). wherein X = H or OH), which are substituted at the amino group by the method of Scheme 4. 19

Scheme 4 19

R1 2 3 R 4 (J R 2 R 4 Q I n

-N-C-A-N CO 1

3a

N-C-A-N

CO I

3a

R 5 and / or R 6 = H 1 wherein R 5 and / or R 6 are C 1-6 -alkyl, 2 optionally substituted 3

The reductive amination of compounds I and II by aldehyde treatment can be accomplished under known conditions, for example, 4 reducing agents such as cyanoborohydride and the like in an inert solvent such as methanol or ethanol. A similar transformation can be accomplished through the opening of the epoxide ring. 5a hydrogenation in the presence of a catalyst based on platinum, palladium or nickel base or by chemical treatment

20 Scheme S R2 R6

R 1 | n-H

CO i

R 2 and R 7 are X - (-) - (CH 2) x - (CH 2) y N (8) or / and 7 and O) or

R 1 -J-H-CO 2 N-R 7 -R 4 O-C = N- (CH 2) x - (CH 2) y N /

, 7a \ t

l / V (4a) R 'I, 3b

Compounds of formulas I and II wherein A is N (R 2) - (CH 2) Z C (R 7) (R 7a) -CH 2 y may be prepared according to Scheme 5 by reacting compounds of formulas 4 or 4a with a reaction with an agent of formula 8 wherein X is a leaving group such as chlorine, bromine or iodine or an imidazolyl group. It is also possible to react the compounds of formula 4 and 4a with an isocyanate of formula 9 in an inert solvent such as 1,2-dichloroethane. In the case where R 4 or R 6 in the final product is a hydrogen atom, the reagents of formula 8 and 9 will have a removable protecting group L in the position of the groups R 4 or R 4. 21

The compounds of the formulas I and II for the combination according to the invention can also be prepared as shown in Reaction Schemes 6, 7 and 8.

Protected amino acid derivatives of Formula 10 are commonly available in a number of instances. These are esters in which M is methyl, ethyl or benzyl. Other protected amino acids in the form of esters can be prepared by conventional procedures known in the art. Some of these procedures involve reacting the protected amino acid with diazoalkane and protecting group L, or allowing the amino acid to react with the appropriate alcohol in the presence of a strong acid such as hydrochloric acid or p-toluenesulfonic acid. Synthetic procedures for the preparation of new amino acids will then be further described in Schemes 14, 15 and 16.

Scheme 6 R2 R6

I N-H

hooc-an-r5 (O COOM (10) or HOOC-ANL (7) R2 R6 O R4 r1-j-N-CA-N-R5 COOMCH) R2 R6 O R4 R1— | - N-CA-N-L COOM (113) \ t

The intermediates of Formulas 11 and 11a can be prepared as depicted in Scheme 6 by linking an amine of Formula 10 to amino acids of Formula 6 and / or 7 wherein L is a protecting group as defined in Scheme 3. that a urea-type bond is to be present in the compound of formula 11 or 11a can be introduced by the method shown in Scheme 5.

Scheme 7 R 2 R 6 R 4

COOM

"I '11'1 R1-N-C-A-N-R5

FROM

R1 - | -N-C-A-N-R5 COOH (12) r2 r6 o r4 l1 1

R2 R6 O R4 I I II

Rl- | -N-C-A-N-L COOM (11a) R1-j-N-C-A-N-L COOH (12a)

As shown in Scheme 7, it is possible to convert the esters of formulas 11 or 11a to the acids of formulas 12 or 12a as intermediates by a variety of techniques known in the art. For example, methyl esters and ethyl esters may be subjected to hydrolysis by treatment with lithium hydroxide in a protic solvent such as aqueous methanol. In addition, removal of the benzyl group can also be achieved by a number of substantially reducing processes, including hydrogenation in the presence of a platinum or palladium catalyst, in a protic solvent such as methanol. Allyl esters can be resolved by treatment with tetrakistriphenylphosphine palladium as a catalyst in the presence of 2-ethylhexanoic acid in a variety of solvents such as ethyl acetate and dichloromethane as described in J. Org. Chem., 1982, 42, 587.

The acids of formulas 12 or 12a can be converted to compounds of formulas 5 and 5a or 5b and 5c in the manner described in Scheme 8. 23 Scheme 8

R2 R6 O R4 R1— | —C ~ A " N CO R5 or L

H N

R 2 R 6 O R 4 V 3a. I II i Dx // R 1— | —N-C — A_N " R5 E — f J COOH = là {. t »3d (12) R2 R6 O R4 Rl-N-C-A-N-L COOH (12a) (2)

H N

B 'UG R3a Ds _ / V E-f; h VR3b (2af

r2r69 r4-l-N-C-A-N. CO R 5 or L i

(5b) a. (5c) The binding of the spiropiperidine derivatives of formulas 2 and 2a to the acids of formulas 12 or 12a in which L is an appropriate protecting group can be readily carried out in an inert solvent such as dichloromethane using a coupling reagent such as DCC or EDC dicyclohexylcarbo dimer. the presence of 1-hydroxybenzothiazole, HOBT. However, binding can also be accomplished using a benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate BOP binding agent in an inert solvent such as dichloromethane. Conversion of compounds 5a and 5c to compounds of formulas I and II can be accomplished by deprotection of the protecting group L. In the case where R 4 and / or R 5 is a hydrogen atom, optionally by addition of substituted 24 alkyl groups on the nitrogen atom, one can perform. as shown in Scheme 4 above.

Scheme 9

The preparation of the exygenated spiroindanyl piperidine intermediates is shown in Scheme 9. These are compounds wherein R 6a and a are hydrogen. One proceeds by treating the protected spiroindane derivative of formula 13 with hydroborate followed by oxidative treatment with pyridinium chlorochromate to give the resulting spiroin-danon of formula 14.

Figure 10

Scheme 10 illustrates the conversion of spiroindane derivatives to benzolactam intermediates. The spiroindane derivatives are treated with nitric acid in an inert solvent such as chloroform according to the Schmidt reaction, one of a number of methods described in the literature for this transformation. In this case, a mixture of the two benzolactams is formed. The isomers can be readily separated by chromatography on silica gel. The intermediates obtained can then be deprotected and added to the growth hormone secretion compounds as shown in Schemes 1 and 8 using the intermediates of Formula 2 above.

By alkylation of compounds of formula 15 or 16 with an alkyl halide in a solvent such as dimethylformamide in the presence of sodium hydride, compounds of formula 17 and 18 may be obtained wherein R is alkyl of 1 to 4 carbon atoms as depicted in Scheme 10A .

Other possible transformations of the compounds of general formula and 16 are shown in Schemes 11 and 11A.

Scheme 11

L L L

LAH

(19)

(20) 26

In the case where L represents an appropriate protecting group, for example a benzyl group, the amides can be reduced using lithium aluminum hydride to form general amines.

Formulas 19 and 21. These amines, in which R is hydrogen, can then be alkylated, arylated or acylated, or reacted with substituted sulfonyl halides or isocyanates under known conditions to give compounds 20 and 22 By removing the protecting group L by hydrolysis using palladium as a catalyst, it is possible to obtain intermediates which can be incorporated into the compounds for growth hormone secretion for use in the combination of the invention using the procedures outlined above in Schemes 1 and 8, in which a basic intermediate is used of Formula 2.

Figure 12

(24) 27 Scheme 12 shows a further possible procedure for obtaining the 1,2,3,4-tetrahydrospiro [isoquinoline-4,4'-piperidin] ring system. One proceeds by subjecting the protected spiroindene derivative to ozonolysis followed by treatment with dimethylsulfide to provide the intermediate hemiacetal of formula 24. From this intermediate, the amine of formula 23 is obtained by reductive amination and acylation. meaning.

Figure 13

1) HCl

2) H 2, Pd / C

28

Analogs of formula 26 wherein X and Y are both hydrogen or one is hydrogen and the other is hydroxy or together form an oxygen atom may be prepared by methods known in the art and described in the literature. For example, as shown in Scheme 13, a spiro [2H-1-benzopyran-2,4'-piperidine] analog can be prepared from substituted 2-hydroxyacetophenone and the corresponding protected 4-piperidone by the method of Kabbe H., J., Synthe -sis, 1978, 886-887 and references cited therein. 2-hydroxyacetophenones are commercially available or can be prepared by methods described in the literature, for example, by Chang C. T et al., J. Am. Chem. Soc., 1961, 3414-3417 and Elliot JM et al., J. Med., Chem., 1992, 35, 3973-3976. By deprotection of Protective Groups in Organic Synthesis, Greene TV, PG Vuts, John Viley and Sons, New York, 1991; and Olofson RA et al., J. Org. Chem., 1984, 49, 2081-2082, provides an amine which can then be incorporated into compounds for increased growth hormone secretion as described in Schemes 1 and 8 using the intermediate of Formula 2.

(26)

The ketane function in the compounds of Formula 2 can be reduced to an alcohol function using sodium borohydride, or it can be completely reduced to the methylene group in a known manner. For example, it is possible to reduce the ketone by treatment with sodium borohydride followed by concentrated hydrochloric acid and hydrogenation to obtain compounds of formula 29. The amines of formula 27, 28 or 29 can then be incorporated into growth hormone secretagogues of Schemes 1a8 using 29 intermediate of formula 2 It is also possible to reduce the ketone function frequently after the compound of formula I is formed.

The preparation of chiral hydroxyspiro [2H-1-benzopyran-2,4'-piperidine analogs can be accomplished using optically active agents and crystallization of diastereomeric salts.

Compounds of formula (I) and (II) may be prepared from a variety of substituted natural and synthetic amino acids, for example, formulas 30, 6 and 7, wherein A is - (CH 2) X - C (R 4) (R 6a) - ( CH 2) y. The preparation of a number of these acids has been described in U.S. Pat. 5 206 237.

The preparation of intermediates in racemic form is carried out by conventional methods known in the art, for example, by Villiams R.M., Synthesis of Optically Active Alpha-Amino Acids, Pergamon Press, Oxford, 1989, Vol. 7. R 2 R 6 R 1 —Nv Λ j | co2h (30)

There are a number of methods for partitioning DL-amino acids. One common technique is to separate protected amino or carboxyl protected intermediates or to crystallize salts derived from optically active acids or amines. The amino group of the carboxyl-protected intermediate can be coupled to the optically active acids as described above. Separation of the individual diastereomers by chromatography or crystallization followed by hydrolysis of the chiral amide results in the partitioning of the amino acids. Similarly, amino-protected intermediates can be converted to a mixture of chiral esters and amides. D- and L-amino acids are then obtained by separating this distaeromeric mixture as described above followed by hydrolysis of the individual 30 diastereomers. Enzymatic procedures for the separation of N-acetyl derivatives of DL-amino acid have been described by Vhitesides et al., J. Am. Chem., Soc., 1989, 111, 6354-6364. If it is desired to synthesize intermediates in optically pure form, 1) asymmetric amination of chiral enolates according to J. Am. Chem. Soc., 1986, 108, 6394-6395, 6395-6397 and 6397-6399, 2) asymmetric nucleophilic amination of optically active carbonyl derivatives according to J. Am. Chem. Soc., 1992, 114, 1906 or Tetrahedron Lett., 1987, 28, 32, 3) diastereoselective alkylation of chiral glycine phenol synthons according to J. Am. Chem. Soc., 1991, 113, 9276, or J. Org. Chem., 1989, 54, 3916, 4) diasteroselective nucleophilic addition to chiral electrophilic glycinate syndrome according to J. Am. Chem. Soc., 1986, 108, 1103, 5) asymmetric hydrogenation of prochiral derivatives of dehydroamino acids according to Asymmetry Synthesis, Chiral Catalysis, Morrison J. D., Ed. Academic Press, Orlando, FL, 1985, Vol. 5, and 6) Angew enzymatic synthesis. Chem. Int. Ed. Engl., 1978, 17, 176.

Scheme 14

Ph (33) 31

For example, alkylation of diphenyloxazinone enolate of Formula 31 according to J. Am. Chem. Soc., 1991, 113, 9276 proceeds well with cinnamyl bromide in the presence of sodium bis (trimethylsilyl) amide to give intermediate 32, which is then converted to the desired (D) -2-amino-5-phenylpentanoic acid 33 by removal of N tert-butyloxycarbonyl by treatment with trifluoroacetic acid and hydrogenation in the presence of a palladium chloride catalyst as described in Scheme 14.

Scheme 15 H 1 NaH / DMF H 1 HO ' Ar-CH2-X co2h co2h (34) (35)

The intermediates of formula 30 which are derivatives of O-benzyl- (D) -serine of formula 34 can be readily prepared from the corresponding substituted benzyl halides and N-protected (D) -serine of formula 34. The protecting group L is preferably BOC or CBZ. Benzylation of compound 34 can be accomplished by a variety of known techniques including deprotonation by treatment with two equivalents of sodium hydride in an inert solvent such as DMF followed by treatment with one equivalent of various benzyl halides according to Synthesis, 1989, 36 as shown in Scheme 15. O-alkyl- (D) Serine derivatives can also be prepared by alkylation according to Scheme 15. Other procedures that could be used to prepare (D) -serine derivatives of Formula 35 include the benzylation of carboxy-protected intermediates derived from Compound 34 by reagents of Formula ArCH 2 OC (= NH) CCl3, the reaction is catalyzed by an acid according to 0. Yonemitsu et al., Chem. Pharm. Bull., 1988, 36, 4244. Alkylation of chiral glycine enolate according to J. Am. 32

Chem. Soc., 1991, 113, 9276, J. Org. Chem., 1989, 54, 3916, by treatment with ArCH3OCl4X, where X is a leaving group, compounds of formula 35 are obtained. In addition, the D, L-O-aryl (alkyl) serines can be prepared and separated by the above processes.

Scheme 16 H -xA H NaWTHF 'Rla-X R' S- ^ V 'L co2h " 1 co2h (36) (37) H [0] | R11N (%) n ° 1 n is CO2H (38) n = 1.2

The alkylation of the N-protected (D) -cysteine of formula 36 is carried out as described for the synthesis of (D) -serine derivatives and will be described in more detail below by treating a compound of formula R 1 and X wherein X is a leaving group such as a halide or mesyloxy group as shown in Scheme 16.

Oxidation of cysteine derivatives of Formula 37 to sulfoxides of Formula 38 wherein n = 1 and sulfones of Formula 38 wherein n = 2 can be accomplished by a variety of oxidizing agents. The sulfide oxidation has been described in detail in Org. Prep. Proced. Int., 1982, 14, 45. Sodium periodate is often used in the case of sulfoxide synthesis according to J. Org. Chem., 1967, 32, 3191, and for the synthesis of sulfones, potassium hydrogen peroxide, OXONE, is often used according to Tetrahedron. Lett., 1981, 22, 1287. 33

It will be appreciated that a variety of substituted amino acids may be included in the growth hormone secretagogues of Schemes 1 and 8 above. Growth hormone secretagogues containing a sulfoxide or sulfone functional group can also be prepared from cysteine compounds using sodium periodate or potassium hydrogen sulfate. Thus, at the last stage of the synthesis, hydrogen peroxide can be used as the oxidizing agent as shown in Scheme 17. Sulfoxide analogs of Formula 40 wherein n = 1 can be separated from the sulfone analogs of Formula 40 wherein n = 2 by preparative thin layer chromatography .

Scheme 17

H CO 0

(39)

H

(40) 34

By deprotection of the amino group, a variety of procedures have been described as described above and in Protective Groups in Organic Synthesis, T. V. Green, John Viley and Sons, NY, 1981.

Compounds of formula (I) wherein a is hydrogen may be further treated by reductive alkylation with an aldehyde as described above or by alkylation, for example by reaction with various epoxides. The products obtained as hydrochlorides or trifluoroacetates are purified in a conventional manner by reverse phase HPLC or recrystallization.

The spiropiperidine derivatives of Formula 41 can be prepared by a variety of techniques including synthetic procedures, which will be described below. (41)

Scheme 18

(42) (43)

The Spiropiperidine Derivatives of Formula 42 wherein L is a protecting group may be synthesized using procedures known in the literature, for example, by H. Ong et al., J. Med. Chem., 1983, 23, 981-986. The nitrogen atom of the indoline ring in the compound of formula 42 wherein L is a protecting group, for example, methyl or benzyl, can be reacted with a variety of electrophilic compounds to provide the spiropiperidine derivatives of the general formula of formula 43 in which it may represent a number of functional groups. For example, the compound of formula 42 can be reacted with isocyanates in an inert solvent such as chloromethane to give urea derivatives by treatment with chloroformate in an inert solvent such as dichloromethane to give the carbates, by obtaining acid chlorides, acid anhydrides or acylimidazoles. amides, sulfonamides can be obtained by treatment with sulfonyl chlorides and sulfamides can be obtained by the action of sulfamyl chlorides. The nitrogen atom of the indoline ring in the compound of formula 42 can also be subjected to reductive alkylation by treatment with aldehydes under known conditions. When the aldehyde used in the reductive amination is protected with a glyoxylic acid of the formula HCOCOOM, where H is a defined protecting group, the M group can be cleaved from the product to form another derivative. In addition, the intermediate of formula 42 can also be reacted with epoxides to form compounds of formula 43 wherein the alkyl or aralkyl group is substituted with a β-hydroxy group. It is also possible to convert the indoline derivatives of formula 42 to compounds of formula 43 wherein R 1 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl by treating the reaction with fluorophenyl or fluoroether aryl reagents. This procedure is detailed in H. Ong et al., J. Med. Chem., 1983, 23, 981-986

(44)

Spiropiperidine Intermediates of Formula 43 wherein L = Me or Bn and wherein is hydrogen and most of the derivatives thereof may be demethylated or debenzylated to form a compound of Formula 44 wherein the hydrogen atom or a number of other functional groups are as depicted in the Scheme 19. In the case of compounds of formula 43 wherein L is methyl, demethylation can be accomplished by a variety of known methods. In the case of demethylation of the compound of formula 43, it can be reacted with cyanide and potassium carbonate in an inert solvent such as dichloromethane to give the cyanide which can be reduced to the compound of formula 44 by refluxing lithium aluminum hydride for refluxing. boiling in a strong acid such as aqueous hydrochloric acid under reflux or by treatment with a Grignard reagent such as methylmagnesium bromide. Demethylation of the compound of Formula 43 can also be accomplished by the ACE-C1 method of R. Olofson et al., J. Org. Chem., 1984, 49, 2795 and the references cited therein. In the case of intermediates of formula 43 in which L is benzyl, the benzyl group can be removed by reducing processes, including hydrogenation in the presence of a platinum or palladium catalyst in a protic solvent such as methanol. Debenzylation of a compound of formula 43 wherein L is a benzyl group can also be accomplished by the ACE-C1 method of R. Olofson et al., J. Org. Chem., 1984.

Spiroheterocyclic compounds of Formula 45 can be prepared by a variety of methods including the synthesis described in Scheme 20. The oxidation of the protected piperidine derivative of Formula 47 can be accomplished by conventional procedures, for example, using the allyl group of Rabjohn N., Org. React., 1976, 24, 261. The resulting allyl alcohol is then treated with thionyl chloride in an inert solvent such as benzene to give the corresponding chloride of formula 48. When D = O or S, alkylation can be carried out in DMF or acetone as a solvent using potassium carbonate as the base and, if D = NR, wherein R 6 is hydrogen, alkyl, aryl, acyl, sulfonyl or carbamate, the reaction is carried out by treatment with sodium hydride as a base in an inert solvent such as THF to form In the case where L is a defined protecting group, the compound of formula 49 can be cyclized by a variety of known procedures.

Scheme 20

For example, cyclization of intermediate 49 can be accomplished by treatment with tributyltin hydride according to Curra DP, Synthesis, 1988, 417 and 489 in an inert solvent such as benzene to afford intermediate 46. The intermediate 46 wherein D = NR 4 can also be prepared as described above in Schemes 18 and 19. 38

Scheme 21

38 L

i N

[ABOUT]

(46) D = S

[° J m

L N

(46) D = S (O) m m = 1.2 In case D represents a sulfur atom, the compound of formula 46 can be oxidized! to a sulfoxide of formula 47 wherein n = 1 to a sulfone of formula 47 wherein n = 2 by a series of oxidizing agents according to scheme 21. For example, sodium periodate is often used in sulfoxide synthesis and OXONE is often used in sulfone synthesis. Removal of the protecting group affords the amine of formula 45 which can be incorporated into the growth hormone release compound according to Schemes 1 and 8 using the intermediate of Formula 2.

The spiropiperidine derivatives of formulas 50 and 51 can be prepared according to Scheme 22.

The phthalimidine derivatives of formula 53 wherein R ** is alkyl, aryl, (CH 2 -aryl or a protecting group are commonly available or can be prepared from the corresponding phthalimides by methods described in the literature, e.g., Bewster et al., J. Chem., 1963, 28, 501 and Mcalees et al., J. Chem Soc., 1977, 2038. The phthalimidine derivatives of Formula 43 can be alkylated in the presence of a base such as potassium hydride or lithium or potassium bis (trimethylsilyl) amide. by treatment of a protected bis-2-haloethylamine wherein L is a defined protecting group such as methyl, benzyl, t-BOC or CBZ and the like and Y is, for example, Cl, Br, I to form a spiropiperidine of formula 54. by the procedures described above to give a compound of formula (50). By reducing the lactam in formula (50) by treatment with a hydride, e.g. of Formula SI 39 Scheme 22

U and Q ^ (50) (51)

It will be appreciated that the order of the reactions in the above schemes is not essential, and that the order of the reactions can be changed by one of ordinary skill in the art so that the reaction proceeds better or that unwanted by-products are avoided.

The utility of the individual growth hormone secretagogues can be demonstrated by known methods, for example, by Smith et al., Science, 260, 1640-1643, as exemplified in FIG. 2. 40

The combination of the bisphosphonate and the growth hormone release compound of the present invention is useful in the treatment or prevention of calcium or phosphate metabolism disorders and related diseases. These diseases can be divided into two groups: 1. Abnormal (ectopic) deposition of calcium salts, predominantly calcium phosphate, associated with pathological tissue hardening and bone deformities. 2. Conditions in which improvement can be achieved by reducing bone resorption. Reduced bone resorption should in this case improve the balance between tissue resorption and formation, reduce bone loss or increase the amount of tissue. Reducing bone resorption can alleviate the pain of areas where osteolytic processes occur and also reduce the incidence and / or size of these areas. Diseases that can be treated or alleviated by the combination of the present invention include osteoporosis including estrogen deficiency, glucocorticoid-induced or age-induced osteoporosis, osteodystrophy, Paget's disease, myositis ossificans, Bechter's disease, malignant hypercalcemia, metastatic malignancy bones, bone disorders, cholelithiasis, kidney or urinary incidence, calcium deposition in arteriosclerosis, arthritis, bursitis, neuritis and tetanus.

Increased bone resorption can also be observed in connection with high calcium and phosphate concentrations in blood plasma, which can also be improved or cured by the combination of the compounds of the invention.

Combination therapy for inhibiting bone resorption, preventing osteoporosis, and accelerating fracture healing can be illustrated by the use of a combination of bisphosphonates and growth hormone secretagogues of the invention. Possible uses of bisphosphonates for this purpose have been summarized, for example, by Hamdy N.A.T., Role of Bisphosphonates in Metabolic Bone Diseases, Trends in Endocrinol. Metab., 4, 19-25, 1993. Biphosphonates for this purpose include alendronate, tiludronate, dimethyl-APD, risedronate, etidronate, YM-175, clodronate, pamidronate, and BM-210995, alendronate being the preferred diphosphonate.

It has been shown that the combination of a bisphosphonate, in particular pamidronate or alendronate, produces unexpected effects in the treatment and prevention of bone resorption diseases when used together with growth hormone secretagogues. Although it is not necessary to be bound by a theoretical explanation of this effect, it is possible to observe the use of said combination of substances with a much higher effect to reduce or suppress bone loss during aging and osteoporosis than would be seen with only one agent from of said combination. Upon administration of a combination of a growth hormone secretagogue and a bisphosphonate, even an increase in bone mass can be observed. This increase in bone tissue is likely due to the formation of this tissue as the growth hormone and IGF-1 levels increase due to the action of growth hormone secretagogue, and as a consequence of decreased bone resorption by the bisphosphonate. This effect of the combination of the two substances could not be predicted from the known state.

A particularly good effect when using the combination according to the invention can be obtained when the combination comprises 4-amino-1-hydroxybutylidene-1,1-bi-phosphonic acid as a bisphosphonate, commonly referred to as alendronic acid. Also preferred is a dosage form comprising 4-amino-1-hydroxybutylidene-1,1-biophosphonic acid monosodium salt trihydrate, alendronate. In parenteral administration, this agent is about five times more potent than pamidronate, 3-amino-1-hydroxypropylidene-1,1-biphosphonic acid, which is currently the most effective diphosphonate supplied for treatment in reducing blood calcium levels during bone cancer. cancerous bone diseases.

4-Amino-1-hydroxybutylidene-1,1-biphosphonic acid and its homologues in which R 1 in the side chain is an N-alkyl group having 1 to 5 carbon atoms, which homologues are 42 terminally substituted with an amino group, can be readily synthesized by U.S. Pat. 4,407,761 and 4,922,007. In addition to mono-, di- and trisodium salts, other pharmaceutically acceptable salts of biphosphonic acids, including ammonium salts, salts with other alkali metals, e.g., potassium salts and alkaline earth metal salts, can be used in combination. , such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine, N-methyl-D-glucamine and salts with amino acids such as arginine, lysine and the like. These salts can be prepared by known methods, for example, U.S. Pat. In the combination according to the invention, the bisphosphonates and growth hormone secretagogues can be administered together or separately. In the case of separate administration, the administration may be simultaneous or administered at different time intervals.

The pharmaceutical compositions of the present invention may be formulated for oral administration, parenteral administration, e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or in the form of an implant, and may be for nasal, vaginal, rectal, sublingual, or oral administration. For example, the topical administration may be a single component of the pharmaceutical composition, but usually the non-toxic pharmaceutically acceptable carriers and excipients suitable for the individual routes of administration will still be present.

The pharmaceutical compositions may be formulated into a dosage form suitable for single administration and may be prepared by known procedures. All these processes essentially involve mixing the active ingredient with a carrier that contains one or more accessory ingredients. Typically, the process involves homogeneous and thorough mixing of the active ingredient with a liquid or finely divided solid carrier with optional subsequent processing of the mixture into the desired shape. The pharmaceutical composition must contain the active ingredients in an amount sufficient to produce the desired 43 effect.

Pharmaceutical compositions suitable for oral administration may be in divided form, for example, as hard or soft capsules, tablets, lozenges or wafers, each containing a predetermined amount of the active ingredient. However, it may also be a dispersible powder or granulate, or a solution or suspension in an aqueous or non-aqueous liquid medium, and may be syrups or elixirs or oil-in-water or water-in-oil emulsions. Formulations for oral administration may be prepared by any known method for the manufacture of pharmaceutical compositions, and may contain sweetening, flavoring, coloring, and preserving agents as excipients to provide a visually acceptable pharmaceutical composition.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredients are mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. These dosage forms may also conveniently contain other excipients such as glidants, for example, magnesium stearate. In the case of capsules, tablets and pills, these dosage forms may also contain buffers.

Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients can also be prepared in a known manner. The excipients used can be, for example: 1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate, 2) granulating and disintegrating agents such as corn starch or alginic acid, 3) binders such as starch, gelatin or acacia and (4) glidants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated in a manner known per se so as to slow down the disintegration of the tablet and thereby absorb the active ingredient in the gastrointestinal tract and to achieve a sustained action over a further period of time. It is also possible to use a material which directly slows down absorption or absorption, for example glyceryl monostearate or glycerol distearate. The tablets may be coated with, for example, the method of U.S. Pat. Nos. 4,256,108, 4,160,452 and 4,265,874 to form tablets which, due to osmotic pressure, can release the active ingredient in a controlled manner. In some cases, the compositions for oral administration may be a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin. It may also be soft gelatin capsules containing the active ingredient as a mixture with water or oil, for example peanut oil, liquid paraffin or olive oil.

Liquid dosage forms for oral administration are, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing conventional inert diluents, for example, water. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying or suspending agents, and sweetening, flavoring and perfuming agents.

Aqueous suspensions generally contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. These excipients include: 1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum, 2) dispersing or wetting agents such as a) naturally occurring phosphatide such as lecithin b) a condensation product of an alkylene oxide and a fatty acid, for example polyoxyethylene stearate; c) a condensation product of ethylene oxide with an aliphatic long-chain al-45 alcohol such as heptadeca-ethyleneoxycethanol; d) a condensation product of ethylene oxide with a partial ester derived from fatty acid and hexitol for example polyoxyethylene sorbitol monooleate; or e) a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitolanhydride, for example polyoxyethylene sorbitan oleate.

The aqueous suspension may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, a coloring agent, or a flavoring or sweetening agent such as sucrose or saccharin.

Suspensions in oil may be formed by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil, or coconut oil, or even in mineral oil, for example, liquid paraffin. Suspensions in oil may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring compounds may also be added for greater oral acceptance of the composition. In addition, this type of composition may contain an antioxidant such as ascorbic acid.

Dispersible powders and granulates are suitable for the preparation of an aqueous suspension. In these compositions, the active ingredient is in admixture with a dispersing agent or wetting agent, a suspending agent, and one or more preservatives. As the dispersing or wetting agent as well as suspending agents, the above-mentioned substances can be used. The compositions may also contain other excipients, for example the above-mentioned sweetening, flavoring and coloring agents.

The pharmaceutical compositions of the invention may also be in the form of a water-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil. A suitable emulsifying agent is, for example, 1) natural gum, for example from acacia or tragacanth, 46 2) optionally occurring phosphatidyl, such as from soy and lecithin, 3) esters or partial esters derived from fatty acids and hexitol anhydrides, such as e.g. sorbitan monooleate; and 4) condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Compositions of this type may also contain plasticizers, preservatives, flavoring agents and coloring agents.

The pharmaceutical compositions may also be in the form of sterile injectable solutions or suspensions or solutions in oil. Suspensions can be obtained by known methods, it is also possible to use known dispersing agents, wetting agents and suspending agents of the above types. The sterile injectable preparation may be a solution or suspension in a non-toxic, suitable diluent or solvent for parenteral administration, for example a solution in 1,3-butanediol. Suitable solvents and vehicles include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can be used. These are in particular synthetic mono- or diglycerides as well as fatty acids, for example oleic acid.

Thus, compositions for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, corn oil, gelatin, and some organic esters such as ethyl oleate. These compositions may also contain adjuvants such as preservatives, wetting agents or emulsifying or dispersing agents. Compositions of this type can be sterilized, for example, by filtration through a bacteria-retaining filter, by addition of sterilizing agents, irradiation, or heating. It is also possible to form a sterile solution by mixing a sterile solid composition and sterile water or other sterile injection medium 47 immediately prior to use.

It is also possible to administer the combination according to the invention rectally in the form of suppositories. These rectal compositions can be prepared by mixing the active ingredient with a suitable, non-irritating vehicle that is solid at ordinary temperatures but becomes liquid at the rectal temperature to release the active ingredient. Suitable bases are, for example, cocoa butter and polyethylene glycols.

Formulations for nasal or sub-nasal administration can also be prepared using standard excipients in a known manner. In the case of topical administration, the combination of the invention may be formulated as liquid or semi-solid compositions such as ointments, oil-in-water emulsions or water-in-oil, creams, jellies or pastes, including toothpaste, may also be solutions or suspensions, e.g. and so on.

In addition, the pharmaceutical compositions of the present invention may additionally contain other active ingredients commonly used in the treatment of the aforementioned pathological conditions. These may be, for example, D2 vitamins and their hydroxylated derivatives, for example 1-hydroxy-vitamin, Ια-hydroxy-vitamin D2, Ια-25-dihydroxyvitamin D ^, Ια-25-dihydroxyvitamin D2, human calciotin, pig or salmon, mitramycin such as are acetylsalicylic acid, indomethacin, naprosyn and timegadine. The dosage of the active ingredients in the compositions of the invention can be varied so that a suitable dosage form is always obtained. The dose used depends on the desired therapeutic effect, the route of administration and the total duration of treatment. Typically, doses of biphosphophate range from 0.001 to 10 mg / kg body weight, preferably 0.01 to 1.0 mg / kg body weight. Dosages of the growth hormone secretagogue compound typically range from 0.0001 to 25 mg / kg per day.

The combination of the invention may be administered intermittently. For the treatment or prophylaxis of bone resorption diseases, a typical dose of biphosphophate for oral administration is 0.001 to 10 mg / kg, and 48 for growth hormone release is 0.0001 to 25 mg / kg, then, if necessary, a maintenance dose of one or both components of about half of the original dose once or twice a week, once or twice a month, once every two or three months, once every six months, once a year or once every other two years. Preferred compounds suitable for use in the combination of the present invention can be prepared by the method set forth in the following examples. A full description of the method for producing growth hormone secretagogues can also be found in U.S. Pat. Nos. 3,239,345, 4,036,979, 4,411,890, 5,206,235, 5,284,841, 5,310,737, and 5,317,017, in European Pat. 144 230 and 513 974 and in International Publication Nos. WO 94/07486, WO 94/08583 and WO 94/13696, as well as Science, 260, 1640-1643, June 11, 1993.

The following examples illustrate the invention, but are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A mixture of 1 mol of 4-aminobutyric acid, 1.5 mol of phosphoric acid and 500 ml of anhydrous chlorobenzene is heated to 100 eC. At this temperature, 1.5 mol of phosphorus trichloride is added under vigorous stirring. The mixture is stirred at 100 ° C for about 3 hours, during which time a solid phase is formed and the mixture is allowed to cool. The solid is filtered off, washed with a small amount of chlorobenzene and then dissolved in water. The solution is then boiled for about one hour, then cooled and decolorized with charcoal. The material was filtered and the product precipitated with excess hot methanol. The crude material thus obtained was refluxed in 20% hydrochloric acid for 8 hours. Hydrochloric acid is distilled off and the residue is recrystallized from water. As the product, 4-amino-1-hydroxybutane-1,1-biphosphonic acid is obtained as a white crystalline powder with the following structure and characteristics: (CHa) 3 NH 3

H 2 O 3 P - C - PO 3 H 2 OH

Elemental analysis C% H% N% P% found 17.88 5.62 4.93 23.94 calculated for product 19.28 5.26 5.64 24.86 calculated for product monohydrate 17.98 5.66 5 , 24, 23.19

Example 2 3-amino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1 - [[2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] 4-yl] methyl] -ΙΗ-1-benzazepin-3 (R) -yl] butanamide

Step A: 3-Amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

A solution of 9.22 g, 45.6 mmol of 3-azido-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (prepared according to Vatthey et al., J. Med. Chem., 28, 1985, 1511-1516) in 30 ml of methanol was hydrogenated at 0.28 MPa in the presence of 1.0 g of 5% platinum on charcoal for 4.5 hours. The filtrate is concentrated and then left at room temperature for 16 hours to form crystals. The product was filtered off and dried in vacuo to give the title compound (4.18 g, 23.7 mmol, 52%). The mother liquor is diluted to 100 ml with methanol, 2 g of activated carbon are added, the mixture is filtered through a pad of celite and the filtrate is concentrated in vacuo to a volume of about 15 ml. This gave a second crop of product (2.02 g, 11.5 mmol). After further treatment of the mother liquor, 0.88 g (5.0 mmol) of product was obtained in 11% yield. Thus, the final product (7.08 g, 40.2 mmol) was obtained in 88% yield. 1 H-NMR (200 MHz, CDCl 3): 1.6 (br s, 2H), 1.80 (m, 1H), 2.55 (m, 2H), 2.88 (m, 1H), 3.42 (dd, 7 Hz, 11 Hz, 1H), 6.98 (d, 18 Hz, 1H), 7.2 (m, 3H), 8.3 (br s, 1H). FAB-MS calcd for C13H16F3O4: 176 found: 177 (M + H, 100%).

Step B: 3 (R) -amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 2.37 g, 13.5 mmol of 3-amino-2,3,4,5- of tetrahydro-1H-1-benzazepin-2-one of step A and 2.02 g, 13.5 mmol of L-tartaric acid are suspended in 40 ml of ethanol. The mixture is heated gently, complete dissolution is achieved by adding 5 ml of distilled water dropwise. The solution was cooled to room temperature and then allowed to stand overnight. The solid which forms in this way is filtered off, washed with a 1: 1 mixture of ethanol and diethyl ether and dried under vacuum to give 1.75 g of crude L-tartrate. The mother liquor is evaporated to dryness in vacuo, the residue is redissolved in 40 ml of water and the pH is adjusted to 10 to 11 by addition of solid potassium carbonate. The mixture is extracted with 6 x 20 ml of chloroform, the extracts are combined, washed with water and saturated sodium chloride solution, dried over potassium carbonate, filtered and the solvent is evaporated off under vacuum to give 1.29 g, 7.33 mmol of material, partially enriched in 3 (R) -amine. The initial amount of 1.75 g of L-tartrate was recrystallized twice from aqueous ethanol to give 1.03 g, 3.17 mmol of purified L-tartrate with optical rotation [.alpha.] D = -212 in 24% yield. (c = 1, water). The purified L-tartrate is dissolved in 20 ml of water and the pH is adjusted to 10 to 11 by the addition of solid potassium carbonate. The mixture is extracted with 5 x 10 ml of chloroform, the extracts are combined, washed with water and saturated sodium chloride solution and then dried over potassium carbonate, filtered and the solvent is evaporated off under vacuum to give 522 mg, 2, of a total yield of 22%. 96 mmol of 3 (S) -amine with optical rotation [α] D = -446 °, (c = 1, chloroform).

The remaining 1.29 g (7.33 mmol) of partially enriched 3 (R) -amine was treated with 1.10 g (7.33 mmol) of D-tartaric acid as described above and the resulting salt was recrystallized twice from aqueous ethanol to give. obtaining 1.20 g of purified D-tartrate with optical rotation [α] D = -214 °, (c = 1, water). The purified D-tartrate was dissolved in 20 mL of water and the free base was isolated as above to give 629 mg, 3.57 mmol of 3 (R) -amine with optical rotation [.alpha.] D +455 " (c = 1, CH 2 OH).

Step C: 2,2-Dimethylbutanedicarboxylic acid 4-methyl ester of 2,2-dimethylsuccinic acid (20 g, 137 mmol) was dissolved in 200 mL of absolute methanol at 0 ° C and 2 mL of concentrated sulfuric acid was added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and stirred at this temperature for 16 hours.

Then, the mixture was evaporated in vacuo to a volume of 50 mL and 200 mL of saturated aqueous sodium bicarbonate solution was added slowly. The mixture was washed three times with hexane and the aqueous layer was separated and cooled in an ice bath. Then the mixture is acidified to pH 2 by slowly adding 6 M hydrochloric acid solution, then extracted eight times with ether. The extracts were combined, washed with saturated brine, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was dried in vacuo at room temperature to give 14.7 g (91.8 mmol) of a viscous oil (67%) which slowly solidified on standing. 52% by weight of 1 H-NMR indicated that the material was a mixture of the product and 15% of the isomeric 2,2-dimethylbutanedicarboxylic acid 1-methyl ester. NMR (200 MHz, CDCl 3): for final product: 1.29 (s, 6H), 2.60 (s, 2H), 3.66 (s, 3H). NMR (200 MHz, CDCl 3): for isomer: 1.28 (s, 6H), 2.63 (s, 2H), 3.68 (s, 3H).

Step D: 3- [Benzyloxycarbonylamino] -3-methylbutanoic acid methyl ester To 14.7 g (91.8 mmol) of 2,2-dimethyl-butanedicarboxylic acid 4-methyl ester from Step C containing 15% of isomeric 1-methyl ester in 150 mL of benzene triethylamine (13 ml, 9.4 g, 93 mmol, 1.01 eq) was added followed by diphenylphosphoryl azide (21.8 ml, 27.8 g, 101 mmol, 1.1 eq). The mixture was refluxed for 45 minutes under nitrogen and 19 ml, 19.9 g, 184 mmol, two equivalents of benzyl alcohol were added and the mixture was refluxed for 16 hours.

The mixture was cooled, filtered and the filtrate evaporated to low volume in vacuo. The residue is redissolved in 250 ml of ethyl acetate, washed once with water, twice with saturated aqueous sodium bicarbonate solution and once with saturated sodium chloride solution. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate evaporated to a small volume in vacuo. The crude product is purified by chromatography on silica using a medium pressure of 4: 1 hexane / ethyl acetate to give the title compound as a pale yellow liquid (18.27 g, 68.9 mmol, 75%). this gives a small amount of pure 3- [benzyloxycarbonylamino] -2,2-dimethylpropanoic acid methyl ester. 1 H-NMR (200 MHz, CDCl 3): for the final product: 1.40 (s, 6H), 2.69 (s, 2H), 3.63 (s, 3H), 5.05 (s, 2H) 5.22 (br s, 1H); 7.32 (s, 5H). 1 H-NMR (200 MHz, CDCl 3): for 3- [benzyloxycarbonylamino] -2,2-dimethylpropanoic acid methyl ester: 1.19 (s, 6H), 3.30 53 (d, 7 Hz, 2H, resonance) was changed to singlet in CD4OD), 3.67 (s, 3H), 5.09 (s, 2H), 5.22 (br s, 1H, resonance not observed in CD3OD), 7.3 ( br s, 5H).

Step E: 3-Benzyloxycarbonylamino-3-methylbutanoic acid

A solution of 18.27 g (68.9 mmol) of methyl 3-benzyloxycarbonylamino-3-methylbutanoate from Step D in 20 mL of methanol was allowed to stand at room temperature and 21 mL, 102 mmol, 1.5 equivalents 2 was added dropwise. M sodium hydroxide solution. The mixture was stirred at room temperature for 16 hours, then transferred to a separatory funnel and washed three times with hexane. The aqueous layer was separated, cooled to 0 ° C and acidified slowly to pH 2 by the dropwise addition of 6 M hydrochloric acid solution. The mixture was extracted 6 times with ether, the extracts combined, washed with 1M hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo to give 17.26 g (68%). 7 mmol of the final product. 1 H-NMR (200 MHz, CDCl 3): 1.42 (s, 6H), 2.77 (s, 2H), 5.06 (s, 2H), 5.2 (br s, 1H). 7.3 (s, 5H).

Step F: 3-Benzyloxycarbonylamino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] butanamide. (43 mmol) of 3 (R) -amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one from step B in 4 ml of methylene chloride was added at room temperature to 400 mg, 1, 60 mmol, 1.1 equivalents of 3-benzyloxycarbonylamino-3-methylbutanoic acid from Step E followed by 760 mg, 1.7 mmol, 1.2 equivalents of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate and 0.50 ml, 380 mg, 2.9 mmol, 2 equivalents of diisopropylethylamine. After 3 hours at room temperature, the mixture is diluted with 30 ml of ethyl acetate and washed with 5% aqueous citric acid solution, then with saturated aqueous sodium bicarbonate solution twice. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with ethyl acetate to give 586 (100% yield). mg, 1.43 mmol of the title product. 1 H-NMR (200 MHz, CDCl 3): 1.38 (s, 3H), 1.39 (s, 3H), 1.82 (m, 1H), 2.52 (s, 2H), 2.5 to 3.0 (m, 3H), 4.51 (m, 1H), 5.07 (br s, 2H), 5.57 (br s, 1H), 6.68 (d, 7 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.1-7.4 (m, 8H), 7.61 (br s, 1H). FAB-MS calc for 409 found 410 (M + H, 100%).

[a] p = + 137 " (c = 1, chloroform).

Step G: 5-Phenyltetrazole 3.3 g, 24.3 mmol, 0.5 equivalents of zinc chloride is added to 15 mL of Ν, Ν-dimethylformamide in small portions, keeping the temperature below 60 ° C. The zinc chloride suspension was then cooled to room temperature and benzonitrile (5.0 g, 48.5 mmol, 1.0 equivalent) was added followed by sodium azide (3.2 g, 48.5 mmol, 1.0 equivalent). The heterogeneous mixture was heated to 115 ° C for 18 hours with stirring. Then the mixture is cooled to room temperature, 30 ml of water are added and the mixture is acidified by the addition of 5.1 ml of concentrated hydrochloric acid. The mixture is then cooled to 0 DEG C. and left to stand for 1 hour, then filtered, the filter cake is washed with 15 ml of cold 0.1 M hydrochloric acid and then dried under vacuum at 60 DEG C. 6.38 g (43.7 mmol) of the title compound are obtained in 90% yield.

Step H: 5-Phenyl-2-trityltetrazole To a suspension of 5-phenyltetrazole (5.0 g, 34.2 mmol) in acetone (55 mL) was added triethylamine (5.0 mL, 3.6 g, 35.6 mmol, 1.04 eq) . After 15 minutes, a solution of 10.0 g (55%), 35.9 mmol, 1.05 equivalents of triphenylmethyl chloride in 20 mL of tetrahydrofuran was added and the mixture was stirred at room temperature for 1 hour. Then 75 ml of water was added slowly and the mixture was stirred at room temperature for 1 hour. The product is filtered off, washed with 75 ml of water and dried under vacuum at 60 DEG C. to give 13.3 g (34.2 mmol) of product in 100% yield.

Step I: N-Triphenylmethyl-5- [2- (4'-methyl-biphen-4-yl) -tetrazole

A solution of 6.3 g (46.2 mmol) of 0.6 equivalents of zinc chloride in 35 mL of tetrahydrofuran is dried over a molecular sieve. 30.0 g, 77.3 mmol, 1.0 equivalents of 5-phenyl-2-trityl-tetrazole are dissolved in 300 mL of anhydrous tetrahydrofuran and the solution is gently stirred and degassed three times during the stirring so that the pressure drop alternates. nitrogen purge. Thereafter, the solution is cooled to -15 ° C with stirring, and 50.5 ml, 80.0 mmol, 1.05 equivalents of a 1.5 M solution of n-butyllithium in hexane are slowly added to keep the temperature below -5 ° C. . The solution is then kept at -5 to 15 ° C for 1.5 hours, then the dried zinc chloride solution prepared above is added and the mixture is allowed to warm to room temperature. In a separate vessel, 20.17 g, 92.5 mmol, 1.2 equivalents of 4-iodotoluene and 1.5 g, 2.3 mmol, 0.03 equivalents of bis- (triphenylphosphine) nickel chloride are dissolved in 60 mL of tetrahydrofuran solution is degassed and allowed to stand under nitrogen. Then the mixture was cooled to 5 ° C and 1.5 ml of a 3.0M solution of phenylmagnesium chloride in 4.5 mmol, 0.06 equivalent of tetrahydrofuran was added to maintain the temperature below 10 eC. The solution was then allowed to warm to room temperature and a solution of the aryl zinc compound was added under nitrogen. The reaction mixture was vigorously stirred at room temperature for 8 hours and then quenched by the slow addition of a solution of 10 mL, 1.6 mmol, 0.02 equivalents of glacial acetic acid in 60 mL of tetrahydrofuran, the addition being maintained at a lower temperature. than 40 eC. 56

Then the mixture is stirred for 30 minutes, then 150 ml of 80% saturated sodium chloride solution are added, and then the reaction mixture is extracted for 30 minutes to separate the two layers. The organic layer is separated, then washed with 150 ml of an aqueous solution of sodium chloride saturated to 80% and adjusted to a pH above 10 by addition of ammonium hydroxide. The organic phase is separated and evaporated in vacuo to a volume of about 50 ml, then 250 ml of acetonitrile are added. The mixture was evaporated again in vacuo to a volume of 50 mL and acetonitrile was added to a final volume of 150 mL. The resulting suspension is stirred for 1 hour at 5 ° C, then filtered and washed with 50 ml of cold acetonitrile followed by 150 ml of distilled water. The filter cake is air dried to a free-flowing powder which is then further dried for 12 hours under vacuum at 50 ° C to yield 30.0 g (62.8 mmol) of the title product in 81% yield. 1 H-NMR (200 MHz, CDCl 3): 2.28 (s, 3H), 6.9 to 7.05 (m, 10H), 7.2 to 7.5 (m, 12H), 7.9 (m , 1H).

Step J: N-triphenylmethyl-5- [2- (4'-bromomethylbiphen-4-yl)] - tetrazole

A solution of 3.15 g (6.6 mmol) of N-triphenylmethyl-5- [2- (4'-methyl-biphen-4-yl)] tetrazole from Step I in 25 mL of methylene chloride is mixed with 1.29 g, 7% by weight. 25 mmol, 1.1 equivalents of N-bromosuccinimide, 80 mg, 0.5 mmol, 0.07 equivalents of AIBN, 200 mg of sodium acetate and 200 mg of acetic acid. The mixture is refluxed for 2 to 16 hours, then cooled and washed with saturated aqueous sodium bicarbonate solution. The organic layer was removed, dried over sodium sulfate, filtered and evaporated to low volume by distillation at atmospheric pressure. Methyl tert-butyl ether is then added and distillation is carried out until all methylene chloride is removed and the total volume is reduced to about 12 ml, then 12 ml of hexanes are added. The mixture was allowed to stand at room temperature for 2 hours, filtered, washed with hexanes and dried under vacuum at 50 ° C to give 5.81 g (5.04 mmol) of product in 76% yield. 1 H-NMR (200 MHz, CDCl 3): 4.38 (s, 2H), 6.9 to 8.0 (m, 23H, spectrum showing approximately 1% starting material and 7% dibrominated derivative).

Step K: 3-Benzyloxycarbonylamino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1 - [[2 '- (N-triphenylmethyl) tetrazol-5-yl] - [ 1,1'-biphenyl] -4-yl] methyl-1H-1-benzazepin-3 (R) -yl] butanamide To a solution of the intermediate of step F (437 mg, 1.07 mmol) in anhydrous dimethylformamide (2 mL) at room temperature sodium hydride (55 mg, 60% dispersion of sodium hydride, i.e. 33 mg, 1.38 mmol, 1.3 equivalents of sodium hydride) was added under nitrogen. After 15 minutes, a solution of 715 mg, 1.28 mmol, 1.2 equivalents of N-triphenylmethyl-5- [2- (4'-bromomethylbenzen-4-yl) tetrazole from step J in 1.5 mL anhydrous is added. DMF and the mixture was stirred for 90 minutes.

The reaction mixture was poured into 100 ml of ethyl acetate and washed twice with water and then with saturated aqueous sodium chloride solution. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The product was purified by flash chromatography on silica, eluting with a 1: 1 mixture of ethyl acetate and hexane to give the product (902 mg, 1.02 mmol, 95%). 1 H-NMR (200 MHz, CDCl 3): 1.38 (s, 3H), 1.39 (s, 3H), 1.60 (m, 1H), 2.2-2.5 (m, 5H), 4.44 (m, 1H), 4.67 (d, 14 Hz, 1H), 5.06 (s, 2H), 5.12 (d, 14 Hz, 1H), 5.63 (br s, 1H) ), 6.65 (d, 8 Hz, 1H), 6.9-7.5 (m, 31H), 7.85 (m, 1H).

Step L: 3-amino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1 - [[2 '- (1H-tetrazol-5-yl) [1,1'- biphenyl] -4-yl] methyl] -1H-1-benzazepin-3 (R) -yl] butanamidine trifluoroacetate

A solution of 902 mg (1.02 mmol) of the intermediate from Step H in 5 mL of 58 mL of methanol was hydrogenated at room temperature and 0.1 MPa over 160 mg of 20% palladium hydroxide on charcoal for 14 hours. The mixture was then filtered through a pad of celite and evaporated in vacuo. The residue was purified by reverse phase HPLC using C-18, eluting with methanol with 0.1% aqueous trifluoroacetic acid, using a linear gradient, increasing 60% methanol to 80% methanol over 10 minutes, giving a 10% yield. 568 mg (0.91 mmol) of the title compound were obtained in 89% yield. 1 H-NMR (200 MHz, CDCl 3): 1.33 (s, 3H), 1.37 (s, 3H), 2.00-2.6 (m, 6H), 4.35 (dd, 7 Hz, 11 Hz, 1H), 4.86 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.00 (d, 8 Hz, 2H), 7.15-7.35 ( m, 6H), 7.45-7.70 (m, 4H). Calcd for FAB-MS: 509 found 510 (M + H, 100%).

Example 3 3 - [(1 '- (R) -Hydroxypropyl) amino] -3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1 - [[2' - (1H-tetrazole- 5-yl) - [1,1'-biphenyl] -4-yl] methyl] -lH-l-benzazepin-3 (R) -yl] butanamide

Step A: 3 - [(2 (R) -benzyloxypropyl) amino] -3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1 - [[2 '- (1H-tetrazole- 5-yl- [1,1'-biphenyl] -4-yl] methyl] -1-benzazepin-3 (R) -yl] butanamide trifluoroacetate The resulting product is prepared from 3-amino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-l - [[2 '- (lH-tetrazol-5-yl) [1,1'-bis - phenyl] -4-yl] methyl] -1H-1-benzazepin-3 (R) -yl] -butanamide trifluoroacetate from Example 1az (R) -2-benzyloxypropanol (prepared from ethyl-D-lactate according to Hanessian and Kloss, Tetrahedron Lett., 26, 1261 to 1264, 1985) by the method of Example 86, step A in US Patent No. 5,206,235. 1 H-NMR (200 MHz, CD 3 OD): 1.25 (d, 6 Hz, 3H), 1.35 (s, 6H), 2.11 (m, 1H); 2.32 (m, 1H); 2.5-2.7 (m, 4H); 2.95 (m, 1H); 3.17 (m, 1H); , 80 (m, 1H), 4.40 (m, 1H), 4.44 (d, 11 Hz, 59 1Η), 4.64 (d, 11 Hz, 1H), 4.90 (d, 15 Hz (1H), 5.02 (d, 15 Hz, 1H), 6.99 (d, 8 Hz, 2H), 7.1-7.7 (m, 15H). FAB-MS calc for C18H14N3O4: 657 found 658 (M + H, 100%).

Step B: 3 - [(2 (R) -Hydroxypropyl) amino] -3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1 - [[2 '- (1H-tetrazole- 5-yl) - [1,1'-biphenyl] -4-yl] methyl] -1H-1-benzazepin-3 (R) -yl] -butanarboxylic acid trifluoroacetate The resulting product is prepared from the intermediate prepared in Step A by according to U.S. Pat. 5,206,235, Example 86, Step B. 1 H-NMR (200 MHz, CD 3 OD): 1.22 (d, 6 Hz, 3H), 1.37 (s, 3H), 1.39 (s, 3H), 2.10 (m, 1H), 2.31 (m, 1H), 2.45-2.70 (m, 4H), 2.81 (dd, 10 Hz, 12 Hz, 1H), 3.08 ( dd, 4 Hz, 12 Hz, 1H), 3.92 (m, 1H), 4.36 (dd, 7 Hz, 11 Hz, 1H), 4.93 (d, 15 Hz, 1H), 5.17 (d, 15 Hz, 1H), 7.04 (d, 8Hz, 2H), 7.19 (d, 8Hz, 2H), 7.20-35 (m, 4H), 7.54 (m (2H), 7.65 (m, 2H). FAB-MS for C 32 H 37 N 7 O 3 calculated 567 found 568 (M + H, 45%).

Example 4 (procedure 1) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide

Step A: 1,2-Dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine] hydrochloride To a solution of 1.20 g, 5.8 mmol of 1'-methyl-1,2-dihydrospiro [3 H- indole-3,4'-piperidine] (prepared by H. Ong et al., J. Med. Chem., 23, 981-986, 1983) in 20 ml of anhydrous dichloromethane is added 0.90 at 0 ° C. triethylamine (6.4 mL) and methanesulfonyl chloride (0.49 mL, 6.35 mmol) and stirred for 30 min. The reaction mixture was then poured into 15 mL of saturated aqueous sodium bicarbonate solution and the resulting mixture was extracted with 2 x 10 mL of dichloromethane. Combine the organic extracts, wash with 20 mL of saturated sodium chloride solution, dry over anhydrous potassium carbonate, filter and evaporate the solvent under reduced pressure to give 1.44 g of the methanesulfonamide derivative as a pale yellow oil which is used for the next reaction. without further purification. To a solution of the above crude product in 20 mL of anhydrous 1,2-dichloroethane was added 1.0 mL, 9.30 mmol of 1-chloroethyl chloroformate at 0 ° C, then the mixture was stirred at room temperature for 30 minutes and one more time. 1 hour under reflux. Then the reaction mixture was evaporated to about 1/3 of its volume, diluted with 20 ml of anhydrous methanol and refluxed for 1.5 hours. The reaction mixture was then cooled to room temperature and evaporated to approximately half its volume. The precipitate formed is filtered off and washed with a small amount of cold methanol. 1.0 g of piperidine hydrochloride is obtained in the form of a white solid. The filtrate was evaporated to low volume and a small volume of methanol was added followed by ether. The precipitated material is filtered again, washed with cold methanol and dried. 0.49 g of the desired product is obtained. A total of 1.49 g of product is obtained in 0% yield. 1 H-NMR (200 MHz, CDCl 3): 7.43-7.20 (m, 3H), 7.10 (dd, 1H), 3.98 (bs, 2H), 3.55-3.40 (bd) 2H), 3.35-3.10 (m, 2H), 2.99 (s, 3H), 2.15 (t, 2H), 2.00 (t, 2H).

Step B: N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2 - [(1,1-dimethylethoxy) carbonyl] -amino-2-methylpropanamide To 0.35 g, 1.15 mmol of 2 (R) -2 - [(1,1-dimethylethoxy) xylene] 1,2-dihydro-1-methanesulfonylspiro [3H-indole-3-yl] -carbonylamino-3- [2- (phenylmethyloxy) ethyl] -1-propanoic acid in 13 ml of dichloromethane is added. N-methylmorpholine, 0.18 ml, 1.63 mmol of N-methylmorpholine and 0.159 g, 1.18 nmol of 1-hydroxybenztriazole, HOBT and stirred for 15 minutes. EDC (0.31 g, 1.62 mol) was added and the mixture was stirred for 1 h. 60 microliters of N-methylmorpholine are then added and the mixture is stirred for another 45 minutes. The mixture is poured into 5 ml of water and the organic layer is separated and then washed with 5 ml of 0.5 M aqueous hydrochloric acid solution and 5 ml of saturated aqueous sodium bicarbonate solution. The organic extracts were combined, dried over anhydrous magnesium sulfate, and evaporated to give 0.627 g of the product as a yellow foam which was used for the next reaction without further purification. To the above product (0.627 g, 1.07 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (1.0 ml) and the mixture was stirred at room temperature for 75 minutes. Then trifluoroacetic acid (1.00 ml) was added and the mixture was stirred for 10 minutes. The reaction mixture was concentrated, diluted with 5.0 mL of dichloromethane and carefully basified by pouring into 10 mL of 10% aqueous sodium carbonate. The organic layer was separated and the aqueous layer was further extracted with 2 x 15 mL of dichloromethane. The organic extracts were combined, washed with 5 ml of water, dried over potassium carbonate, filtered and evaporated to give 0.486 g of the resulting amine as a pale yellow foam which was used without further purification. To the 0.486 g, 1.01 mmol of the above amine and 10 mL of dichloromethane was added 2 - [(1,1-dimethylethoxy) carbonyl] amino-2-methylpropanoic acid (0.273 g, 1.28 mmol), 0.173 g, 1. 28 mmol of 1-hydroxybenzotriazole, HOBT and 0.245 g, 1.28 mol of EDC and stirred overnight at room temperature. Then the reaction mixture is poured into 5.0 ml of water and the organic layer is separated. The aqueous layer was back-extracted with 5 mL of dichloromethane. The organic extracts were combined, washed with 5.0 mL of 0.5 M aqueous hydrochloric acid solution, 5 mL of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated to give 0.751 g of the crude product as a yellow foam. A solution of this crude product in dichloromethane was chromatographed on 25 g of silica gel, eluting with hexanes: acetone: dichloromethane (70: 25: 5) followed by hexanes: acetone: dichloromethane (65: 30: 5). 0.63 g of the title compound is obtained in the form of a white solid. 1 H-NMR (400 MHz, CDCl 3): compound exists as a mixture of rotamers in a 3: 2 ratio: 7.40-7.10 (m, 6H), 7.06 (d, 1 / 3H), 7.02 ( t, 1 / 3H), 6.90 (t, 1 / 3H), 6.55 (d, 1 / 3H), 5.15 (m, 1H), 4.95 (bs, 1H), 4.63 (bd, 1 / 3H), 4.57-4.40 (m, 2H / 3H), 4.10 (bd, 1 / 3H), 4.00 (bd, 1 / 3H), 3.82 ( t, 1H), 3.78-3.62 (m, 2H), 3.60-3.50 (m, 1H), 3.04 (q, 1H), 2.87 (s, 1H), 2 , 86 (s, 2H), 2.80-2.60 (m, 1H), 1.90 (bs, 1H), 2.85-2.75 (m, 1H), 1.82-1.60 (m, 3H), 1.55-1.45 (m, 1H), 1.45 (s, 4H), 1.42 (s, 2H), 1.39 (s, 9H).

Step C: N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3 H -indole-3,4 * -piperidin] -1 * -yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide hydrochloride To 0.637 g (0.101 mmol) of intermediate B in 5 mL of dichloromethane was added 2.5 mL of trifluoroacetic acid and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated to an oil, treated with 10 mL of ethyl acetate and washed with 8 mL of 10% aqueous sodium carbonate. The aqueous layer was further extracted with 5 mL of ethyl acetate. The organic extracts are combined, washed with 10 ml of water, dried over magnesium sulfate, filtered and evaporated to give 0.512 g of the free base as a white foam. To 0.512 g of this free base in 5 ml of ethyl acetate was added 0.2 ml of a saturated solution of hydrochloric acid in ethyl acetate at 0 ° C and the mixture was stirred for 1.5 hours. The resulting white precipitate was filtered off under nitrogen, washed with ether and dried to give 0.50 g of product as a white solid. 1 H-NMR (400 MHz, CD 3 OD): compound exists as a 3: 2 mixture of rotamers: 7.40-7.28 (m, 4H), 7.25-7.17 (m, 63 2,) , 7.08 (ΐ, 1 / 3Η), 7.00 (t, 1 / 3Η), 6.80 (d, 1 / 3Η), 5.16 (ddd, 1Η), 4.60-4.42 (m, 3H), 4.05 (t, 1H), 3.90 (bs, 2H), 3.83-3.70 (m, 2H), 3.30-3.15 (m, 1H), 2.97 (s, 1H), 2.95 (s, 2H), 2.90-2.78 (m, 1H), 1.96 (t, 1 / 3H), 1.85-1.65 ( m, 4H), 1.63 (s, 2H), 1.60 (s, 4H).

Example 5 (procedure 2) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ) ethyl] -2-amino-2-methylpropanamide

Step A: 2 (R) - [[[2- (1,1-Dimethylethoxy) carbonyl] amino] -2,2-dimethyl-1-oxoethyl] amino-2- (phenylmethoxy) ethyl] -1-allyl ester The resulting product is prepared from 2 (R) -2 - [(1,1-dimethylethoxy) carbonyl] amino] -3- (phenylmethoxy) ethylpropanoic acid and allyl alcohol, the reaction is carried out in methylene chloride in the presence of EDC and DMAP. 1 H-NMR (400 MHz, CDCl 3): 7.25 (s, 5H), 5.8 (m, 1H), 5.2 (dd, 2H), 5.0 (bs, 1H), 4.7 ( m, 1H), 4.6 (m, 2H), 4.4 (dd, 2H), 3.9 (dd, 1H), 3.6 (dd, 1H), 1.45 (d, 6H), 1.39 (s, 9H).

Step B: 2 (R) - [[2- (1,1-Dimethylethoxy) carbonyl] amino] -2,2-dimethyl-1-oxoethyl] amino-2- (phenylmethoxy) ethyl] -1-propanoic acid K of a crude solution of 6.7 g, 15.9 mmol of crude intermediate product obtained in Step A, 1.8 g, 0.1 equivalents of tetrakis (triphenylphosphine) palladium and 1.25 g, 0.3 equivalents of triphenylphosphine is added to 35 ml 0.5 M solution of potassium 2-ethylhexanate in ethyl acetate. The reaction mixture was stirred under nitrogen at room temperature for 1 hour, then diluted with 100 mL of ether and poured into water / ice. The organic layer was separated and the aqueous layer was acidified with 20% citric acid and then extracted with ethyl acetate. The organic extracts are combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give the title compound as a solid. 1 H-NMR (400 MHz, CD 3 OD): 7.3 (s, 5H), 4.7 (m, 1H), 4.5 (s, 2H), 4.0 (m, 1H), 3.6 ( m, 1H), 1.4 (d, 6H), 1.3 (s, 9H).

Step C: N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2 - [(1,1-dimethylethoxy) carbonyl] amino-2-methylpropanamide To a solution of 1.0 g, 3.44 mmol of 1-methanesulfonylspiro [indoline-3,4'-piperidine] hydrochloride, 1.44 g, 3.78 mmol of 2 (R) - [[2- (1,1-dimethylethoxy) carbonyl] amino] -2,2-dimethyl-1-oxoethyl] amino-2- (phenylmethoxy) ethyl] - 1-propanoic acid, 0.58 ml, 5.20 mmol of N-methylmorpholine and 0.58 g, 3.78 mmol of 1-hydroxybenzothiazole, HOBT in 50 ml of dichloromethane are added 1.03 g, 5.20 mmol of EDC and the mixture is stirred for 16 hours. hours at room temperature. The reaction mixture was diluted with an additional 50 mL of dichloromethane and washed with 50 mL of aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The crude oily residue was flash chromatographed on 50 g silica gel to give 2.148 g (90%) of the desired product as a colorless foam. 1 H-NMR (400 MHz, CDCl 3): compound exists as a 3: 2 mixture of rotamers: 7.40-7.10 (m, 6H), 7.06 (d, 1 / 3H), 7.02 ( t, 1 / 3H), 6.90 (t, 1 / 3H), 6.55 (d, 1 / 3H), 5.15 (m, 1H), 4.95 (bs, 1H), 4.63 (bd, 1 / 3H), 4.57-4.40 (m, 2H / 3H), 4.10 (bd, 1 / 3H), 4.00 (bd, 1 / 3H), 3.82 ( t, 1H), 3.78-3.62 (m, 2H), 3.60-3.50 (m, 1H), 3.04 (q, 1H), 2.87 (s, 1H), 2 , 86 (s, 2H), 2.80-2.60 (m, 1H), 1.90 (bs, 1H), 2.85-2.75 (m, 1H), 1.82-1.60 (m, 3H), 1.55-1.45 (m, 1H). 1.45 (s, 4H), 1.42 (s, 2H), 1.39 (s, 9H). 65

Step D: N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide hydrochloride To a solution of the intermediate (2.148 g, 3.41 mmol) in Step C (10 mL) was added trifluoroacetic acid (5 mL) and the mixture was stirred for 1 h. The reaction mixture was concentrated and basified by the addition of 100 ml of 5% aqueous sodium carbonate solution, then extracted with dichloromethane (3.times.50 ml). The organic extracts are combined, washed with 50 ml of saturated sodium chloride solution, dried over anhydrous potassium carbonate, filtered and evaporated to a colorless foam. To a solution of this foam in 25 mL of ethyl acetate was added 4 mL of a 1 M solution of hydrochloric acid in ethyl acetate at 0 ° C. The precipitate formed is filtered off and washed first with ethyl acetate and then with a 1: 1 mixture of ethyl acetate and ether and dried to give 1.79 g of the title product as a colorless solid (93%). 1 H-NMR (400 MHz, CD 3 OD): compound exists as a 3: 2 mixture of rotamers: 7.40-7.28 (m, 4H), 7.25-7.17 (m, 2H), 7.08 (t, 1 / 3H), 7.00 (t, 1 / 3H), 6.80 (d, 1 / 3H), 5.16 (ddd, 1H), 4.60-4.42 ( m, 3H), 4.05 (t, 1H), 3.90 (bs, 2H), 3.83-3.70 (m, 2H), 3.30-3.15 (m, 1H), 2 , 97 (s, 1H), 2.95 (s, 2H), 2.90-2.78 (m, 1H), 1.96 (t, 1 / 3H), 1.85-1.65 (m) , 4H), 1.63 (s, 2H), 1.60 (s, 4H).

Example 6 N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3 H -indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino -2-methyl-propánamidhydrochlorid

Step A: N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2- [(1,1-dimethylethoxy) carbonyl] amino-2-methylpropanamide 66 The resulting product can be prepared from 2 (R) -2 - [(1,1-dimethylethoxy) carbonyl] amino-4-phenyl-1 -butanoic and 1,2-dihydro-1-methylsulfonylspiro [3H-indole-3,4'-piperidine] hydrochloride using the binding procedure of Example 18, step B. The crude product is purified on silica gel using 5% acetone in methylene chloride . 1 H-NMR (400 MHz, CDCl 3): 7.2 (m, 9H), 4.9 (m, 1H), 4.5 (m, 1H), 3.8 (m, 2H), 2.0 ( m, 2H), 1.7 (m, 4H), 1.5 (s, 6H), 1.4 (s, 9H).

Step B: N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3 H -indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] - 2-amino-2-methylpropanamide hydrochloride

The product can be prepared from the intermediate of Step A by deprotection as described in Step C of Example 18. 1 H-NMR (400 MHz, CD 3 OD): 7.2 (m, 9H), 4.5 (m, 1H), 3 9 (m, 2H); 3.5 (m, 2H); 3.2 (m, 2H); 2.9 (s, 3H); 2.7 (m, 4H); 4H), 1.6 (s, 6H).

Example 7

Combination Treatment Using N- [1 (R) - [(1,2-Dihydro-1-methanesulfonyl-spiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] - 2-amino-2-methylpropanamide and pamidronate. Experiments in 9-week-old female rats The purpose of these experiments was to evaluate the effect of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3 H -indole-3,4 * -piperidine] -1 ') -yl) -carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide alone and in combination with pamidronate, 3-amino-1-hydroxypropylidene-1,1-biphosphonic acid for bone in older rat females. The experiments lasted 9 weeks. The propanamide derivative was administered once a day 7 days a week. Pamidronate was given once a week, the first day of the week. the propanamide derivative was administered by the esophageal probe. Control group 67 was administered only distilled water in which the corresponding derivative was also dissolved as in the vehicle, the propanediate derivative was administered in a volume of 5 ml / kg, pamidronate in a volume of 1 ml / kg. Female Sprague-Dawley Cr1: CD® (SD) BR rats were used for the experiments, the approximate female age at the start of the experiment was greater than 18 months and the mean weight at the start of the experiment was 300-400 g. No substances known to interfere with the course of the experiment were present in feed and water. No such substances were found in the cage material either, the rats were housed individually in wire and stainless steel cages. The litter was also free of interfering substances. Dosage code for batch number of male animals female control 1 01 0 7 control 2 distilled water 07 0 8 N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4 ' -piperidine] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide (50 mg / kg / day) 15 0 11 pamidronate (120 µg / kg / once weekly) 25 0 10 N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino -2-methyl-propanamide + pamidronate (50 mg / kg / day + 120 μg / kg / once weekly) 35 12 68

Hormone analysis

Day 1: Administration of active substances. Blood was collected in approximately 1.5 ml of sinus orbitalis rats of all groups fed with conventional GH (growth hormone) feed, blood collection was performed 15 minutes after administration of distilled water in the control groups and in the treatment groups. substances individually or in combination. Weeks 2X and 9: Blood was collected at approximately 1.5 ml in the same manner for all groups except for growth hormone control group 1, blood was collected 15 minutes after administration of distilled water in control group 2 and the propanamide treated groups derivative as such or in combination. In addition, a blood sample was taken from as much hollow vein as possible after sacrificing animals for IGF-1 measurement. x Only for control group 1.

Determination of Growth Hormone Level, Day 1 Control 1 Control 2 pamidronate N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine ] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide + pamidronate 10 ng / ml 10 ng / ml 5 ng / ml 85 ng / ml 48 ng / ml

Bone Tissue Labeling All rats were given bone marrow 69, oxytetracycline and calcein, oxytetracycline for 9 days and calcein 2 days prior to sacrifice.

Oxytetracycline was injected subcutaneously at two doses over a period of S hours, 25 mg per kg of body weight was administered at each dose, calcein was administered intraperitoneally at a single dose of 15 mg / kg. Effect on osteoblast surface treatment method osteoblast surface in%

± SEM control 2 N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine] -1'-yl) -2-amino-2-methylpropanamide \ t carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide + pamidronate 3.51 (0.63) 3.91 (0.73) 0.80 (0.26) 3.05 (0.36) )

As can be seen from these results, growth hormone secretagogues can restore bone formation that has been suppressed by pamidronate to control levels. In addition, no difference in the surface of osteoblasts (bone resorption) was observed as a result of treatment with growth hormone secretagogues. The results observed are representative of the unexpected beneficial effects that can be achieved with the combination of the compounds of the invention.

The invention has been described and, in individual cases, illustrated in various specific embodiments. However, it is quite clear that a number of changes, modifications, could be proposed

And adjusting said procedures without departing from the spirit and scope of the invention. For example, it would be possible to administer dosages other than the dosages indicated, for example, as a result of another reaction of the treated mammal to said agents in some indications for the combination of the invention. The specific pharmacological effects could vary depending on the particular substances used or also on the selected type of pharmaceutical composition or depending on the mode of administration. All such modifications and expected changes are within the scope of the invention.

Claims (27)

1. A combination preparation for treating or preventing osteoporosis comprising a bisphosphonate and a growth hormone secretagogue.
Combination preparation according to claim 1, characterized in that it contains a bisphosphonate of general formula XO R2 O (X) HO - P - C - P - OH 1,1 OH R1 OH where R * is selected from a) alkyl with 1 up to S carbon atoms optionally substituted by one of the following groups 1), 2, 2) pyridyl, 3) pyrrolidyl, 4) NR 1 R 2, b) NR 5, c) SR 6, or d) chlorine, R is hydrogen, hydroxy or chloro, R is hydrogen or alkyl of 1 to 4 carbon atoms, R 2 is alkyl of 1 to 4 carbon atoms, R 1 is alkyl of 1 to 10 carbon atoms, and R 1 is aryl, as well as the pharmaceutically acceptable salts of these compounds. A combination preparation according to claim 1, characterized in that the bisphosphonate is selected from the group consisting of alendronic acid, etidronic acid, clodronic acid, pamidronic acid, tiludonic acid, risedronic acid, 6-amino-1-hydroxyhexylidene biphosphonic acid, 1-hydroxy -3- (methylpentylamino) propylidene biphosphonic acid or from pharmaceutically acceptable salts thereof.
3 · N-NH N-SO 2 (CH 2) n - | N = N 'aryl is phenyl or pyridyl, wherein phenyl is optionally substituted with 1 to 2 halogen atoms, R is hydrogen or alkyl of 1 to 4 carbon atoms, m is an integer of 1 or 2, t is an integer of 0, 1, or 2, q is an integer of 1, 2 or 3, w is an integer of 2, 3, 4, 5 or 6, as well as the pharmaceutically acceptable salts thereof and the individual diastereomers thereof.
Combination preparation according to claim 3, characterized in that it contains alendronic acid or a pharmaceutically acceptable salt thereof as a bisphosphonate.
5. Combination preparation according to claim 1, characterized in that it contains, as a growth hormone secretagogue, an amide derivative of the formula I or II R4 R4 R6 R4 'in R1-C' N 'C - 0 and Nn R5 R2 R6 R ^ N-C-C-A-N. = C = 0 c = o
wherein R 1 is alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl-alkyl of 3 to 7 carbon atoms in cycloalkyl of up to 6 carbon atoms in the alkyl moiety, alkyl-K-alkyl of 1 to 5 carbon atoms in each alkyl moiety, aryl (alkyl of 1 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms), cycloalkyl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms); 5 carbon atoms) with a cycloalkyl moiety of 3 to 7 carbon atoms, wherein K is O, S (O) m, N (R 2) C (O), C (O) N (R 2), OC (O), C (O) O or 73 2 -CR-CR-, or -OC-, wherein the aryl groups are as defined below and the R 2 and alkyl groups may be further substituted with 1 to 9 halogen atoms or S (O) m R 2a, 1 up to 3 OR 2a or C (O) OR 2a and aryl groups are optionally further substituted with phenyl, phenoxy, halo-phenyl, 1 to 3 carbon atoms, 1 to 3 h atoms logene, 1 or 2 substituents from -OR 2, methylenedioxy, -S (O) mR 2, -CF 1, -OCF 8, 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, R is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms and, if two alkyl groups of 1 to 6 carbon atoms are present on one atom, may optionally be joined to form a ring containing 3 to 8 carbon atoms. carbon atoms and optionally oxygen, sulfur or NR 2a, R 2a is hydrogen or alkyl of 1 to 6 carbon atoms, R 5a and R 6c are independently selected from hydrogen, halo, alkyl of 1 to 6 carbon atoms, -OR, cyano, -OCF 3, methylenedioxy, nitro, -S (O) mR, -CF 3, or -C (O) OR 2, wherein when R 4 and R 6 are in the ortho position, they may be joined to form an aliphatic or aromatic ring having from C to 8 carbon atoms, optionally containing 1 or 4 carbon atoms; 2 heteroatoms from the group oxygen, sulfur or nitrogen, R 1 and R 4 are independently selected from hydrogen, alkyl optionally substituted, wherein the substituents are selected from 1 to 5 halogen atoms, 1 to 3 hydroxyl groups, alkanoyloxy groups C 1 -C 10 or C 1 -C 6 alkoxy, phenyl, phenoxy, 2-furyl, C 1 -C 6 alkoxycarbonyl, -S (O) m -alkyl of 1-6 carbon atoms, or R 1 and R 2 together form - (CH 2) r L a (CH 2) g -, wherein La represents 74 -C (R 6) 2 --O-, -S (O) m - or -N (R 2) - wherein ras independently represents an integer from 1 to 3 and R 2 is as defined above, R 1 is hydrogen or alkyl of 1 to 6 carbon atoms, A is R 7 - (CH 2) X C - (CH 2) y --R 7a or Z- (CH 2) X - c - (CH 2) y - R 7a wherein x and y are independently integers 0 to 3, Z is N-R a or oxygen, R 7 and R 7a are independently selected from o is hydrogen, alkyl of 1 to 6 carbon atoms, -OR, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from imidazolyl, phenyl, 0 indolyl, p-hydroxyphenyl, -OR, 1 to 3 fluorine atoms. -S (O) m R 2, -C (O) OR 2, cycloalkyl of 3 to 7 carbon atoms, -N (R 2) (R 2), -C (O) N (R 2) (R 2), or R 7 and R 7a independently linked to one or both of R 4 and R 6 to form alkylene bridges between the nitrogen end atom and the alkyl moiety of R 7 or R 7a, wherein the bridges may contain 1 to 5 carbon atoms, B, D, E and F are independently selected from the group -C (R ®) (R 4 ') -, -O-, -C = O-, -S (O) m - or -NR 4 -, and one or two of B, D, E or F may be absent to form an S, 6 or 7-membered ring, provided that B, D, E, and F may be -C (R ®) (R * ®) - or -C = O- in only 75 cases that one of the remaining symbols B, D, E and F simultaneously represents -O-, -S (O) m- or -NR 9 - or B and D or D and E may together form an -N = CR 4 · - or -CR 1 R 4 = N- or B and D or D and E may together form a group -CR 1 CR 1 O-, provided that one of the remaining symbols B and E or F simultaneously represents -O-, -S (O) m- or -NR 9 -, R ® and R 1 '' independently represent hydrogen, -R 2, -OR 2, - (CH 2) q -aryl, - (CH 2) q C (O) OR 2, - (CH 2) q C (O) (CH 2) q -aryl or - (CH 2) q - (1H-tetrazol-5-yl) wherein the aryl moiety is optionally substituted with 1 to 3 halogen atoms, 1 or 2 alkyl groups with 1 up to 8 carbon atoms, 1 to 3 groups -OR or 1 or 2 groups -C (O) OR 2, R 9 represents a group -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, -H-tetrazol-5-yl, -SO 3 H, -SO 2 NHC 5 N, -SO 2 N (R 2) -aryl or -SO 2 N (R 2) (R 2), wherein (CH 2) q is optionally substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms and R 2 and the aryl moiety optionally further substituted with 1 to 3 groups -OR 2 a, -O (CH 2) q -aryl, 1 to 2 groups -C (O) OR 2a, 1 to 2 -C (O) O (CH2) q-aryl, 1-2 (-C (O) N (R2a) (R2a), 1-2 (-C (O) N (R2a) (CH2) q-aryl groups With 1 to 5 halogen atoms, 1 to 3 carbon atoms with 1 to 4 carbon atoms or substituents of 1,2,4-triazolyl, 1H-tetrazol-5-yl, -C (O) NHSO 2 R 2a, -S (0) 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 2a) 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, -SO 2 (CH 2) CONH- (CH 2) ^ HC (O) R11, wherein v is an integer from 2 to 6 and RA is a biotin, aryl or aryl radical substituted with 1 or 2 OR2, 1 or 2 and halogen, azido or nitro. 76 m is an integer of 0, 1 or 2, n is an integer of 1 or 2, q is 0, 1, 2, 3 or 4, and G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms, at least one of which is a heteroatom and one of G, H, I or J may be absent to form an S or 6-membered heterocyclic aromatic ring, as well as pharmaceutically acceptable salts thereof and individual diastereomers.
Combination preparation according to claim 1, characterized in that it contains a compound of the formula V as a growth hormone secretagogue.
N
(V) wherein R 1 is selected from the group
· CH2OCH2. H F H
77 77 R 3 and D are hydrogen or fluoro, are selected from -O-, -S-, -S (O) m-, N (R 12), NSO 2 (R 2), NSO 2 (CH 2) t -aryl, NC (O) R 2), NSO 2 (CH 2) q OH, NSO 2 (CH 2) q COOR, NSO 2 (CH 2) q C (O) -N (R 2) (R 2), N-SO 2 (CH 2) -C (O) -N ( R 2) (CH 2) w0h. ABOUT
OH N * SO 2 (CH 2) q C (O) -N (R 2) (CH 2) w -N
Combination preparation according to claim 1, characterized in that it contains 1 N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-2,3,4-dihydro-1-methanesulfonylspiro [3,4H] -indole-2,3,4-dihydro-1-methanesulfonylspiro [3H-indole-2,3,4] -benzene). 1-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 78 2) N- [1 (R) - [(1,2 -dihydro-1-methanecarbonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; ) N- [1 (R) - [(1,2-dihydro-1-benzenesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indole-3- yl) ethyl] -2-amino-2-methylpropanamide, 4) N- [1 (R) - [(3,4-dihydrospiro [2H-1-benzopyran-2,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 5) N- [1 (R) - [(2-acetyl-1,2,3,4-tetrahydrospiro- [isoquinoline-4,4'-piperidin] -1 * -yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 6) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 7 ) N- [1 (R) - [(1,2-Dihydro-l-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2- amino-2-methylpropanamide mesylate, 8) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (2 ', 6'-difluorophenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 9) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5-fluorospiro [3H- indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 10) N- [1 (S) - [(1,2 -dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethylthio) -ethyl] -2-amino-2-methylpropanamide; 1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide, 12) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-cyclohexylpropyl] -2-amino -2-methylpropanamide; 13) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -4- phenylbutyl] -2-amino-2-methylpropanamide; 14) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3 H -indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro-1H-indol-3-yl) ethyl] -2-amino-2-methylpropanoinide, 15) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl) -5-fluorospiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro-1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide 16) N- [1 (R) - [(1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonyl-spiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] - 2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 17) N- [1 (R) - [(1,2-dihydro-1,1-dioxospiro [3H-benzothiophene- 3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, and pharmaceutically acceptable salts thereof.
Combination preparation according to claim 1, characterized in that it contains alendronic acid or pamidronic acid or one of its pharmaceutically acceptable salts as a bisphosphonate and contains N- [1 (R) - [(I)] as growth hormone secretagogue. 2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, N- [1 ( R) - [(1,2-dihydro-1-methanesulfonylspiro [3 H -indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide, or a pharmaceutically acceptable salt thereof.
Combination preparation according to claim 1, characterized in that it contains alendronic acid or a pharmaceutically acceptable salt thereof as a bisphosphonate and comprises N- [1 (R) - [(1,2-dihydro-1- methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition for the treatment or prevention of osteoporosis, characterized in that it comprises as active ingredients a bisphosphonate and a growth hormone secretagogue together with an inert carrier.
11. A pharmaceutical composition according to claim 10 wherein the bisphosphonate comprises a compound of formula (X) wherein R10 is selected from (a) alkyl having from 1 to 5 carbon atoms, optionally substituted with any of the following groups D, n, 2, 2 pyridyl, 3) pyrrolidyl, 4) NR 3 R 4, b) NR 5, c) SR 6, or d) chlorine, OR represents hydrogen, hydroxy or chlorine, OR represents hydrogen or alkyl of 1 to 4 carbon atoms, R 4 represents alkyl with C 1 -C 4, R 5 is C 1 -C 10 alkyl, and R 5 is a pharmaceutically acceptable pharmaceutically acceptable salt thereof.
Pharmaceutical composition according to claim 10, characterized in that the bisphosphonate is selected from the group consisting of alendic acid, etidronic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1-hydroxyhexylidene-bisphosphonic acid, 1-hydroxy-3- ( methylpentylamino) propylidene biphosphonic acid or pharmaceutically acceptable salts thereof.
Pharmaceutical composition according to claim 12, characterized in that it contains alendronic acid or a pharmaceutically acceptable salt thereof as a bisphosphonate.
14. The pharmaceutical composition of claim 10, wherein the growth hormone secretagogue comprises an amide derivative of Formula I or II.
wherein R 6 is alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl-alkyl of 3 to 7 carbon atoms in cycloalkyl of up to 6 carbon atoms in the alkyl moiety, alkyl-K-alkyl with 1 to 5 carbon atoms in each alkyl moiety, aryl (alkyl having 1 to 5 carbon atoms), -K- (alkyl of 1 to 5 carbon atoms), cycloalkyl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 C to C 7 -C 7 cycloalkyl, wherein K is O, S (O) m, N (R 2) C (O). C (O) N (R 2), OC (O), C (O) O or -CR = CR -, or -C = C-, wherein the aryl groups are as defined below and the R 2 and alkyl groups may be further substituted 1 to 9 halogen atoms or S (O) m R 2a, 1 to 3 OR 2a or C (O) OR 2a, and aryl groups are optionally further substituted with phenyl, phenoxy, halophenyl, 1-3 alkyl groups with 1 to 6 carbon atoms , 1 to 3 halogen atoms, 1 or 2 substituents from -OR 2, methylenedioxy, -S (O) mR 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 is SO, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms and, if two alkyl groups having 1 to 6 carbon atoms are present on one atom, may form together a ring containing from 3 to 8 carbon atoms and optionally an oxygen, sulfur, or carbon atom NR 2a, R 2a is hydrogen or alkyl of 1 to 6 carbon atoms, R 5a and R 6k are independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, -OR 2, cyano, -OCF-j, methylenedioxy , nitro, -S (O) m R, -CF 8 or -C (O) OR 2, wherein when R 4 and R 6 are in the ortho position, they may be linked to form an aliphatic or aromatic ring with from S to 8 atoms carbon, optionally containing 1 or 2 heteroatoms from oxygen, sulfur or nitrogen, R 1 and R 4 are independently selected from hydrogen, alkyl optionally substituted, wherein the substituents are selected from 1 to 5 halogen atoms, 1 to 3 substituents hydroxy, alkanoyloxy of 1 to 10 carbon atoms or alkoxy of 1 to 6 carbon atoms, phenyl, phenoxy, 2-furyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety, -S (O) m-alkyl of 1 to 6 carbon atoms or R 6 and R 6 together may form - (CH 2) r 1a (C H 2) s-, wherein La is -C (R 2) 2 -, -O-, -S (O) m - or -N (R 2) -, wherein ras independently represents an integer of 1 to 3 and R 2 is as defined above; R6 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, A represents a group R7 - (CH3J-O- (CH2) y - R7a, or 84 or - Z- (CH2) xC- (CH2) y-i7a where where x and y independently represent integers from 0 to 3, Z is N-R 2 or oxygen, and R 6a are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, -OR, trifluoromethyl, phenyl, substituted alkyl of 1 to 6; 6 carbon atoms in which the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR 2, 1 to 3 fluorine atoms. -S (O) mR 2, -C (O) OR 2, cycloalkyl of 3 to 7 carbon atoms, -N (R 2) (R 2), -C (O) N (R 2) (R 2), or R 2 and R 2a may be independently linked to one or both of R4 and R ** to form alkylene bridges between the nitrogen end atom and the alkyl moiety of R 1 or R 2a, wherein the bridges may contain 1 to 5 carbon atoms, B, D, E and F and independently selected from the group consisting of -C (R ®) (R 6 ') -, -O-, -C = O-, -S (O) m - or -NR 9 -, and one or two of B, D, E or F may be absent to form an S, 6 or 7-membered ring, provided that B, D, E and F may be -C (R ®) (R * ®) - or -C = O- only in if one of the remaining symbols B, D, E and F simultaneously represents -O-, -S (O) m- or -NR 9 - or Ba D or D and E together may form -N = CR 10 - or -CR 10 = N- or B and D or D and E may be taken together to form a group -CR 1 CR 1 R 1 -, provided that one of the remaining symbols B and E or F simultaneously represents -0- , -S (O) m- or -NR 9 -, R ® and R * ® independently represent hydrogen, -R 2, -OR 2, - (CH 2) q -aryl, - (CH 2) q C (O) OR 2, - ( CH 2) q C (O) (CH 2) q - aryl or - (CH 2) q - (1H-tetrazol-5-yl), wherein the aryl moiety is optionally substituted with 1 to 3 halogens-85 nu, 1 or 2 alkyl groups with 1 to 8 carbon atoms, 1 to 3 groups -OR or 1 or 2 groups -C (O) OR 2, R 6 represents a group -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) OR2, -H-tetrazol-5-yl, -SO3H, -SO2NHON, -SO2N (R2) aryl or -SO2N (R2) (R2), wherein (CH2) q is optionally substituted with 1-2; the alkyl groups having 1 to 4 carbon atoms and R * and the aryl moiety are optionally further substituted with 1 to 3 groups -OR 1 and -O (CH 2) q -aryl, 1 to 2 -C (O) OR 2a, 1 to 2 2 groups -C (O) O (CH 2) q -aryl, 1 to 2 groups -C (O) N (R 2a) (R 2a), 1 to 2 groups -C (O) N (R 2a) (CH 2) q - aryl, 1 to 5 halogen atoms, 1 to 3 alkyls C 1 -C 4 groups or substituents of 1,2,4-triazolyl, 1H-tetrazol-5-yl, -C (O) NHSO 2 R 2a, -S (O) m R 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 2a) 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, -SO 2 (CH 2) CONH- (CH 2) wNHC (O) R 1: L where w is an integer of 2 to 6 and RA is a biotin, aryl or aryl O radical substituted with 1 or 2 OR, 1 or 2 halogen, azido or nitro, m being an integer of 0, 1 or 2, n being an integer of 1, or 2, q is 0, 1, 2, 3 or 4, and G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms, at least one of which is a heteroatom and one of G, H, I or J may be absent to form a 5 or 6-membered heterocyclic aromatic ring, as well as pharmaceutically acceptable salts thereof. and diastereomers. 86
15. The pharmaceutical composition of claim 10, wherein the growth hormone secretagogue comprises a compound of Formula (C) and (V).
(V) where R ^ is selected from the group
-CH2CH2CH2-.
-CH2OCH2-.
F t CH 2 CH 2 CH 2 -; R1 is hydrogen or fluorine; D is selected from -O-, -S-, -S (O) m-, N (R2), NS02 (R2) NS02 (CH2) t-aryl, NC (0 R2), NS02 (CH2) qOH, NS02 (CH2) qC00R, NS02 (CH2) qC (O) -N (R2) (R2), N-SO2 (CH2) qC (O) -N (R2) (CH2) ) w0h. 87
About OH
N 3 'N-SO 2 (CH 2) q C (O) -N (R 2) (CH 2) w -NN-NH N -SO 2 (CH 2) q - ^ | N = N 'aryl means phenyl or pyridyl, wherein phenyl is optionally substituted with 1 to 2 halogen atoms, R is hydrogen or alkyl of 1 to 4 carbon atoms, m is an integer of 1 or 2, t is an integer of 0.1; or 2, q is an integer of 1, 2 or 3, v is an integer of 2, 3, 4, 5 or 6, as well as the pharmaceutically acceptable pharmaceutically acceptable salts and salts thereof.
Pharmaceutical composition according to claim 10, characterized in that it contains 1) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3] - [1,2-dihydro-1-methanesulfonylspiro] 4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 2) N- [1 (R) - [( , 2-dihydro-l-metánkarbonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (lH-indol-3-yl) ethyl] -2-amino-2-methylpropanamide , 88 3) N- [1 (R) - [(1,2-dihydro-1-benzenesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indole 3-yl) ethyl] -2-amino-2-methylpropanamide; 4) N- [1 (R) - [(3,4-dihydrospiro [2H-1-benzopyran-2,4'-piperidine] -1 ') 5-N- [1 (R) - [(2-acetyl-1,2,3, -benzyl) -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 4-tetrahydrospiro [isoquinoline-4,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2- methyl lpropanamide, 7) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide mesylate, 8) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3 H -indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (2 ', 6'-difluorophenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 9) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl- 5-fluorospiro [3 H -indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 10) N- [1 (S) - [(1,2-dihydro-l-raetánsulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethylthio) ethyl] -2-amino-2-methylpropanamide. 11) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino -2-methylpropananide, 89 12) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1 * -yl) carbonyl] -3- cyclohexylpropyl] -2-amino-2-methylpropanamide, 13) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) -one; arbyl] -4-phenylbutyl] -2-amino-2-methylpropanamide, 14) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3 H -indole-3,4'-piperidine] -) 1'-yl) carbonyl] -2- (5-fluoro-1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 15) N- [1 (R) - [(1,2- dihydro-5-methanesulfonyl-fluorospiro [3H-indole-3,4'-piperidin] -r-yl) carbonyl] -2- (5-fluoro-lH-indol-3-yl) ethyl] -2-amino -2-methylpropanamide, 16) N- [1 (R) - [(1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonyl-spiro [3H-indole-3,4'-piperidine] -1'-yl] carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanoinide, 17) N- [1 (R) - [(1,2-dihydro-1,1-dioxospiro [ 3 H -benzothiophene-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, and pharmaceutically acceptable salts thereof.
Pharmaceutical composition according to claim 10, characterized in that it contains alendronic acid or pamidronic acid or one of its pharmaceutically acceptable salts as a bisphosphonate and contains N- [1 (R) - [(1,2 -dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 90 N- [1 (R ) - [(1,2-dihydro-l-methanesulfonyl £ onylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2-methyl-propanamide or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition according to claim 10, characterized in that it contains alendronic acid or a pharmaceutically acceptable salt thereof as a bisphosphonate and comprises N- [1 (R) - [(1,2-dihydro-1- methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide or a pharmaceutically acceptable salt thereof.
Use of a bisphosphonate and a growth hormone secretagogue for the manufacture of pharmaceutical compositions for the treatment of osteoporosis.
Use according to claim 19, characterized in that the bisphosphonate of the general formula XO R 2 O HO - P - C - P - OH (X) OH R 1 OH is administered as component of the combined preparation to sick patients. C 1 -C 5 alkyl optionally substituted by one of the following groups 1) n 2, 2) pyridyl, 3) pyrrolidyl, 4) NR 3 R 4, 91 b) NR 5, c) SR 5 or d) chlorine, R 2 represents hydrogen, hydroxy or chloro, R 5 is hydrogen or alkyl of 1 to 4 carbon atoms, R 1 is alkyl of 1 to 4 carbon atoms, R 5 is alkyl of 1 to 10 carbon atoms, and R 5 is aryl, as well as salts thereof, pharmaceutical aspect.
Use according to claim 19, characterized in that the alendronic acid, etidronic acid, clodronic acid, pamidroic acid, tiludronic acid, risedronic acid, 6-amino-1-hydroxyhexylidene-biphosphonic acid, l-hydroxy-1-hydroxyhexylidene-biphosphonic acid, 1-hydroxy -3- (methylpentylamino) propylidene biphosphonic acid or pharmaceutically acceptable salts thereof.
Use according to claim 19, characterized in that alendronic acid or a pharmaceutically acceptable salt thereof is administered to the patient as a component of the combination preparation.
Use according to claim 19, characterized in that the growth hormone secretagogue of formula (I) or (II) R 2 R 6 R f R 2 R 6 -O-NCA - No R r 1 - C- is administered to the patient as a component of the combined preparation. Ň " CA — Nn II O c = oc = o
Wherein C 1 -C 10 alkyl, C 1 -C 6 arylalkyl, C 3 -C 7 cycloalkyl C 1 -C 6 alkyl, C 1 -C 6 alkyl-C 1-6 alkyl. 5 carbon atoms in each alkyl moiety, aryl (alkyl of 1 to 5 carbon atoms), - C (alkyl of 1 to 5 carbon atoms), cycloalkyl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) carbon atoms) having a C 3 -C 7 cycloalkyl moiety wherein K is O, S (O) m, N (R 2) C (O), C (O) N (R 2), OC (O), C (O) O or -CR (R) R (1) -, or -OC-, wherein the aryl groups are as defined below and R 2 and alkyl groups may be further substituted with 1 to 9 halogen atoms or S (O) m R 2a, 1 to 3 groups OR 2a or C (O) OR 2a and aryl groups are optionally further substituted with phenyl, phenoxy, halophenyl, 1-3 alkyl groups with 1 to 6 carbon atoms, 1 to 3 halogen atoms u, 1 or 2 substituents from -OR 2, methylenedioxy, -S (O) mR 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, R is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms and, if two alkyl groups of 1 to 6 carbon atoms are present on one atom, may optionally be joined to form a ring containing 3 to 8 carbon atoms. carbon atoms and optionally oxygen, sulfur or NR 2a, R 2a is hydrogen or alkyl of 1 to 6 carbon atoms, R 5a and R 6 are independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, -OR 2 , cyano, -OCF 3, methylenedioxy, nitro, -S (O) mR, -CF 3 or -C (O) OR 2, wherein when R 4 and R 6 are in the ortho position, they may be joined to form an aliphatic or an aromatic ring having from about 5 to about 8 carbon atoms, optionally containing from about 1 to about 10 carbon atoms or 2 heteroatoms from oxygen, sulfur or nitrogen, R 6a is independently selected from hydrogen, alkyl optionally substituted, wherein the substituents are selected from 1 to 5 halogen atoms, 1 to 3 hydroxy substituents, alkanoyloxy having 1 C 1 -C 10 or C 1 -C 6 alkoxy, phenyl, phenoxy, 2-furyl, C 1 -C 6 alkoxycarbonyl, -S (O) m -alkyl of 1-6 carbon atoms or R And R 1 together form - (CH 2) r L a (CH 2) s -, wherein La is -C (R 4) 2 -. -O-, -S (O) m- or -N (R 2) -, wherein ras independently represents an integer of 1 to 3 and R is as defined above, R 1 represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, A R 7 - (CH 2) -O- (CH 2) y -R 7a or - Z- (CH 2) x C (CH 2) y R 7a where x and y are independently integers 0 to 3, Z is NR or oxygen, R 7 and R 7a are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, -OR, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, - OR, 1 to 3 fluorine atoms. -S (O) m R 4, -C (O) OR 3, cycloalkyl having 3 to 7 carbon atoms, 94 k, -N (R 2) (R 2), -C (O) N (R 2) (R 2), or R 1 and R 2a are independently linked to one or both of R 4 and R 6 to form alkylene bridges between the nitrogen end atom and the alkyl moiety of R 1 or R 6a, wherein the bridges may contain 1 to 5 carbon atoms, B , D, E and F are independently selected from -C (R ®) (R 10) -, -O-, -C = O-, -S (O) m - or -NR 9 -, and one or two of the symbols B, D, E or F may be absent to form a 5, 6 or 7-membered ring, provided that B, D, E and F may be -C (R ®) (R 6 ') - or -C = Only if one of the remaining symbols B, D, E and F simultaneously represents -O-, or -NR 9 - or Ba D or D and E may together form a group -N = CR * ® - or -CR * ® = N- or B and D or D and E may together form a group -CR ® = CR * ® - provided that one of the remaining symbols B and E or F simultaneously represents -0- , -S (O) m- or -NR 9 -, R ®, and R 5 '' ® independently represent hydrogen, -R 2, -OR 2, - (CH 2) q -axyl, - (CH 2) q C (O) OR 2, - (CH 2) q C (O) (CH 2) q - aryl or - (CH 2) q - (1H-tetrazol-5-yl), wherein the aryl moiety is optionally substituted with 1 to 3 halogen atoms, 1 or 2 alkyl groups with 1 up to 8 carbon atoms, 1 to 3 groups -OR or 1 or 2 groups -C (O) OR 2, R 9 represents a group -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) O 2 R 2, -H-tetrazol-5-yl, -SO 3 H, -SO 2 NH, -SO 2 N (R 2) aryl or -SO 2 N (R 2) (R 2), wherein the (CH 2) group is optionally substituted with 1 to 12 alkyl groups with C 1-4 alkyl and R and aryl are optionally further substituted with 1 to 3 -OR 6 and -O (CH 2) q -aryl, 1 to 2 -C (O) OR 2a groups, 1 to 2 -C groups ( 0) O (CH 2) q -aryl, 1 to 2 groups -C (O) N (R 2a) (R 2a), 1-2 groups -C (O) N (R 2a) (CH 2) q -aryl, 1 to 5 halogen atoms, 1-3 alkyl C 1 -C 4 or 95 substituents of 1,2,4-triazolyl, 1H-tetrazol-5-yl, -C (O) NHSO 2 R 2a, -S (O) m R 2a, -C (O) NHSO 2 ( CH 2) q-aryl, -SO 2 NHC 5 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 2a) 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, -SO 2 (CH 2) CONH- (CH 2) wNHC (O) R 11, wherein w is an integer ¥ ** -J is 2-6 and R is a biotin, aryl or aryl radical substituted by 1 or 2 OR 2, 1 or 2 halogen, azido or nitro, m is an integer of 0, 1 or 2, n is an integer of 1 or 2, q is optionally 0, 1, 2, 3 or 4 and G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms, at least one of which is a heteroatom and one of G, H, I or J can be missing! to form a 5 or 6-membered heterocyclic aromatic ring, as well as pharmaceutically acceptable salts thereof and individual diastereomers.
Use according to claim 19, characterized in that the compound of formula (V) is administered to the patient as a component of the combination preparation.
wherein R - * - is selected from (V) 96 (y) - CH 2 CH 2 -, - (CH 2 CH 2 CH 2) 2 --CH 2 OCH 2 -.
f - CH 2 CH 2 CH 2 · MR · 38, represents hydrogen or fluorine, D is selected from -O-, -S-, -S (O) m-, N (R2), NS02 (R2), NS02 (CH 2) t -aryl, NC (O) R 2), NSO 2 (CH 2) q OH, NSO 2 (CH 2) q COOR, NSO 2 (CH 2) q C (O) -N (R 2) (R 2), N-SO 2 (CH 2) q C (0) -N (R 2) (CH 2) w0h. 0
N-SO 2 (CH 2) q C (O) -N (R 2) (CH 2) w N-NH N-SO 2 (CH 2) q —f | N = NII 97 97 ♦ 4 λ «aryl means phenyl or pyridyl, where phenyl is optionally substituted with 1 to 2 halogen atoms, represents hydrogen or alkyl having 1 to 4 carbon atoms, m represents an integer of 1 or 2, t represents an integer of 0 , 1 or 2, q is an integer of 1, 2 or 3, w is an integer of 2, 3, 4, S or 6, as well as the pharmaceutically acceptable salts thereof, and their individual diastereomers.
Use according to claim 19, characterized in that 1) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4] -benzenesulfonyl-spiro [3,4-d] indole-3,4-dihydro-1 1-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 2) N- [1 (R) - [(1,2 -dihydro-1-methanecarbonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; ) N- [1 (R) - [(1,2-dihydro-1-benzenesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indole-3- yl) ethyl] -2-amino-2-methylpropanamide, 4) N- [1 (R) - [(3,4-dihydrospiro [2H-1-benzopyran-2,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 5) N- [1 (R) - [(2-acetyl-1,2,3,4-tetrahydrospiro- [isoquinoline-4,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 6) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 98 98 * «E 7) N- [ 1 (R) - [(1,2-Dihydro-l-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2 -methylpropanamide mesylate, 8) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3 H -indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (2 ') , 6'-difluorophenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 9) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5-fluorospiro [3 H -indole-3 4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 10) N- [1 (S) - [(1,2-dihydro- 1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethylthio) ethyl] -2-amino-2-methylpropanamide, 11) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1 * -yl) carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide; [1 (R) - [(1,2-dihydro-l-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-cyclohexylpropyl] -2-amino-2-methylpropanamide 13) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -4-phenylbutyl] -2- amine o-2-methylpropanamide, 14) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro-1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide, 15) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5-fluorospiro [ 3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro-1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; - [l (R) - [(1,2-dihydro-l- (2-ethoxycarbonyl) methylsulfonyl-spiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1 H -indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 17) N- [1 (R) - [(1,2-dihydro-1,1-dioxospiro [3 H -benzothiophene-3,4 ') -piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, | and pharmaceutically acceptable salts thereof.
Use according to claim 19, characterized in that alendronic acid or pamidronic acid or a pharmaceutically acceptable salt thereof is administered as the bisphosphonate. and as a growth hormone secretagogue, N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] - 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, 4 N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3 H -indole-3,4'-piperidine] -1 -yl) carbonyl] -3-phenylpropyl] -2-amino-2-methyl- propanamide, or pharmaceutically acceptable salts thereof.
Use according to claim 19, characterized in that alendronic acid or a pharmaceutically acceptable salt thereof is administered as the bisphosphonate and the N- [1 (R) - [(1,2-dihydro - 1-methanesulfonylspiro [3 H -indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide or a pharmaceutically acceptable salt thereof.
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BG100517A (en) 1996-11-29
AU8083694A (en) 1995-05-08
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EP0813414A4 (en) 1999-07-21
LV11432A (en) 1996-08-20
EP0813414A1 (en) 1997-12-29
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KR960705575A (en) 1996-11-08
HUT75224A (en) 1997-04-28
FI961681D0 (en)
CA2173333A1 (en) 1995-04-27
CN1136278A (en) 1996-11-20
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FI961681A (en) 1996-06-12
NO961536D0 (en) 1996-04-18
LV11432B (en) 1996-12-20

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