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

Abstract

Bisphosphonates in combination with growth hormone secretagogues reduce the deleterious effects of osteoporosis in elderly patients.

Description

The present invention is based on a combination of active substances for the treatment and prevention of osteoporosis, a combination of biphosphophate and a substance for growth hormone secretion.

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 X

OR ² O

HO-P-C-P-OH

OH R ¹ OH (X) where r! is selected from the group

(a) alkyl of 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 atom, o

R is hydrogen, hydroxy or chloro, and

R is hydrogen or alkyl of 1 to 4 carbon atoms,

R ⁴ is C 1 -C 4 alkyl, C 1 -C 10 alkyl, and R 6 is aryl, as well as pharmaceutically acceptable salts thereof.

Formula X includes the alkali metal, organic base and also basic amino acid salts of the compounds.

Preferred compounds of formula X are those wherein R 1 is C 1 -C 5 alkyl substituted with amino or pyridyl, preferably at the terminal carbon atom, and R 1 is hydroxy. Preferred salts are alkali metal salts, especially sodium salts.

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

The preparation of biphosphonic acids is known in the literature, examples of which 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,

621 077, 4 624 947, 4 746 654, 4 761 406, 4 922 007, 4 942 157 and 5 227 506; 252,504 and J. Org. Chem., 36, 3843 (1971).

The second component of the combination is growth hormone secretagogues.

Representative agents having this 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; 144 230 and 513 974 and in published international patent applications no. 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

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

The most preferred benzolactam compounds have the structure _štruktt , _Ä1 ,

CH ₃ CH ₃

H I \ /

N - C - CH ₂ - C - NH ₂

N or

Other agents promoting growth hormone release have been described in published international patent application no. WO 94/13696 are spiro compounds which can be represented by formulas I and II

R ² R ⁶ ; R ⁴

R ¹ -C-N-C-A-N. _T ** RR ² R ⁶ R ⁴

R-C-C-C-A-N \

R ⁵ c = o

C = 0

where

R ¹ represents alkyl of 1 to 6 carbon atoms alkyl of 3 to 7 carbon atoms up to 6 carbon atoms, arylalkyl in the alkyl moiety, cycloalkylcarbonyl in the cycloalkyl about alkyl moiety, alkyl-C-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) with C 3 -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 ² = CR ² -, or -OC-, wherein the aryl groups have

The meanings given below and the R group and the alkyl groups may be further substituted by 1 to 9 halogen atoms or S (O) _m R ^2a , 1 to 3 OR ^2a or C (O) OR ^2a groups and the aryl groups are optionally further substituted by a phenyl group , phenoxy, halophenyl, 1 to 3 alkyl groups of 1 to 6 carbon atoms, 1 to 3 halogen atoms, 1 or 2 substituents from -OR, methylenedioxy, -S (O) _m R ² , -CF 3, -OCF 3, nitro, -N ^{(R2) (R2),} -N ^(R2) C (0) ^R2, -C (0) 0R ^2, -C (0) N ^{(R2) (R2),} - S02N ^{(R2) (R2),} -N ^(R2) s (O) 2-aryl-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 there are two alkyl groups of 1 to 6 carbon atoms in one atom, they can optionally be joined to form a ring of 3 to 8 carbon atoms and optionally an oxygen, sulfur or NR ^2a atom,

R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms,

R ^3a and R ^{3 '} are independently selected from hydrogen, halo, C 1 -C 6 alkyl, -OR, cyano, -OCF-j, methylenedioxy, nitro, -S (O) _m R 3, -CF 3; or -C (O) OR ² , provided that when R ^3a and R ^{3 '} are in the ortho position, they may be joined to form an aliphatic or aromatic ring of 5 to 8 carbon atoms, optionally containing 1 or 2 heteroatoms from the group oxygen, sulfur or nitrogen, and R ³ are independently selected from hydrogen, alkyl, optionally substituted, wherein the substituents are selected from 1 to 5 halogen atoms, 1 to 3 substituents from hydroxy, alkanoyloxy of 1 to 10 carbon atoms, or (C 1 -C 6) alkoxy, phenyl, phenoxy, 2-furyl, (C 1 -C 6) alkoxycarbonyl, -S (O) _m -C 1 -C 6 alkyl, or the groups and r 5 taken together may form - ( CH 2) _r L ^a (CH 2) s -, wherein L ^a represents a group -CCR 4 -, -O-, -S (O) m - or - N (R ²⁾ -, wherein ras independently represent an integer of 1 to 3 and R is as defined above, R 6 is H or alkyl of 1 to 6 carbon atoms,

A represents a group

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 independently represent integers from 0 to 3,

Z represents an N-R group or an oxygen atom,

R ⁷ and R ^7a are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, -OR, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms, wherein the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR ² , 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 can be of R and R ^{independently} linked to one or both of the greedy-8 us of a to form an alkylene bridge between the terminal nitrogen and the alkyl portion of R? or R ^a, and these bridges may have 1 to 5 carbon atoms,

B, D, E and F are independently selected from -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) - or -C = 0- only 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 can together form a group

CRlO- -N- or -CR ⁹ = N-, or B and D or D and E can be in the form a group -CR = CR -, provided that one of the remaining symbols of B and E or F is simultaneously -0 -, -S (O) _m - or -NR ⁹ -,

Ä 10 2 2

R c and R independently represent hydrogen, -R, -OR, - (CH ₂ ) _q -aryl, - (CH ₂ ) _q -C (O) OR ² , - (CH ₂ ) _q -C (O) ( _{CH2) q} -aryl, or - _{(CH2) q} - (lH-tetrazol-5-yl), wherein the aryl portion is optionally substituted with 1 to 3 halogens, 1 or 2 alkyl groups having 1 to 8 carbon coal lika, 1 up to 3 -OR or 1 or 2 -C (O) OR ² groups,

R ⁹ is -R ² , - (CH ₂ ) _q -aryl, -C (O) R ² ,

-C (O) (CH ₂ ) _q -aryl, -SO ₂ R ² , -SO ₂ (CH ₂ ) _q -aryl,

-C (O) N (R ² ) (R ² ), -C (O) N (R ² ) (CH ₂ ) _q -aryl, -C (O) OR ² ,

-H-tetrazol-5-yl, -SO ₃ H, -SO ₂ NHC = N, -SO ₂ N (R ² ) aryl or -SO ₂ N (R ² ) (R ² ), wherein the group (CH 2) _q is optionally substituted with 1 to 2 alkyl groups of 1 to 4 n

carbon atoms and R, and the aryl moiety is optionally further substituted with 1 to 3 radicals -0R ^ ^a, -0 _{(CH2) q} aryl, 1 to 2 -C (0) 0R ^2, 1 to 2 groups,

-C (0) 0 _(CH2) aryl, 1 to 2 -C (0) N (R ^2a) (R ^2a), 1 to 2 -C (0) N (R ^In) _{(CH2) q} -aryl, 1 to 5 halogen atoms, 1 to 3 alkyl groups having 1 to 4 carbon atoms or substituents from the group

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 NHON,

-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 ) _w NHC (O) R ¹¹ where w is an integer H of 2 to 6 and R ¹ is a biotin, aryl or aryl radical substituted with 1 or 2 OR 1 or 2 halogen atoms, 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 may be absent to form a 5 or 6-membered heterocyclic aromatic ring as well as pharmaceutically acceptable salts thereof, and individual diastereomers.

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

The alkyl groups have the above length and straight or branched chain and optionally contain a double or triple bond and optionally a plurality of such bonds. Examples include methyl, ethyl, propyl, ethynyl, isopropyl, butyl, sec-butyl, tert-butyl, pentenyl, isopentenyl, hexyl, isohexyl, allyl, propenyl, butenyl, butadienyl and the like.

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

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

Aryl refers to phenyl, naphthyl and aromatic radicals containing 5- and 6-membered rings having 1 to 3 heteroatoms or fused bicyclic systems containing 5- or 6-membered rings having 1 to 3 heteroatoms selected from nitrogen, sulfur or oxygen . Examples of such heterocyclic aromatic rings include pyridine, thiophene, benzothiophene, tetrazole, indole, N-methylindole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, furan, pyrimidine and thiadiazole.

Some of the above groups may occur more than once in the molecules of the resulting products. In such cases, the meanings of these groups are quite independent of each other.

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

CH ₂ CH ₂ CH ₂ -;

R ^a is H or F,

D is selected from -O-, -S-, -S (O) _m -, N (R ² ),

NS0 ₂ (R ²⁾ NS02 (CH 2) t aryl, NC (0) R ²⁾ NS02 _{(CH2) q} C00R,

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

N-NH

N-SO ₂ (CH ₂ ) _q - (R)

N = N 'aryl means phenyl or pyridyl, wherein the phenyl is optionally substituted with 1 to 2 halogen atoms, o

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 their individual diastereomers.

Examples of the most preferred growth hormone secretagogues for use in the combination of the invention are the following:

1) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-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.

3) N- [1 (R) - [(1,2-dihydro-1-benzenesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-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-methylpropanamide.

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

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-indol-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 .

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 [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro-1H-indole) -3-yl) ethyl] -2-amino-2-methylpropanamide.

15) N- [1 (R) - [(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro) -lHindol-3-yl) ethyl] -2-amino-2-methylpropanamide.

16) N- [1 (R) - [(1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- ( 1H-indol-3-y1) 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 of these compounds.

Particularly suitable growth hormone secretagogues include:

N- [1 (R) - [(1,2-Dihydro-l-methanesulfonylspiro [3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2 -metylpropánamidmesylát.

N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2- methylpropanamide, and pharmaceutically acceptable salts thereof.

The preparation of biphosphonic acids is known in the literature, examples of which 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,

054 598, 4 267 108, 4 327 039, 4 407 761, 4 578 376

(+420) 621 077, 4 624 947, 4 746 654, 4 761 406, 4 922 007,

942,157 and 5,227,506; 252,504 and J. Org. Chem., 36, 3843 (1971).

Representative agents having this effect have been described in U.S. Pat. 3,239,345, 4,036,979, 4,411,890,

206 235, 5 284 841, 5 310 737 and 5 317 017; 144 230 and 513 974 and in published international patent applications no. 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.

Protected amino acid derivatives of formula 1 are commercially available in a number of cases. The L-protecting group is, for example, BOC or CBZ. Other protected amino acid derivatives of formula 1 can be prepared by methods known in the literature. A variety of spiropiperidines and spiroazepine compounds (n = 2) of formulas 2 and 2a are known in the literature and can be derivatives of the phenyl or heteroaryl moieties using standard procedures such as halogenation, nitration, sulfonylation and the like. Various spiropiperidine and spiroazepine derivatives substituted on the phenyl or heteroaryl moieties may be prepared by the following literature procedures using intermediates which are also substituted on the phenyl or heteroaryl moiety. In the schemes that follow Scheme 1, the synthetic methods are illustrated only on spiropiperidine derivatives, however, it will be understood that the described transformations can also be carried out on a number of higher homologues to give compounds of formulas I and II in which n = 2.

Scheme 1

R ¹ —I — N-L

R ² R ⁶

R ³ · —j — ““ L COOH (C

H

_R 3b (2a)

R ² R ⁶

Λ - jf-N-L

The intermediates of formulas 3 and 3a can be synthesized as shown in Scheme 1. The coupling of the spiropiperidine derivatives of formulas 2 and 2a to the protected amino acids of formula 1 wherein L is the appropriate protecting group readily takes place in an inert solvent such as dichloromethane in the presence an agent facilitating binding, such as DCC or EDC, and in the presence of HOBT. The coupling may also be effected by another coupling agent, for example BOP in an inert solvent such as dichloromethane. Unwanted by-products can be removed and at the same time the intermediates can be purified by silica gel chromatography, usually 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 into the intermediate of formulas 4a and 4a can be carried out as shown in the following Scheme 2.

Removal of the benzyloxycarbonyl group can be accomplished by a number 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 solution of hydrogen bromide in acetic acid. Removal of the BOC protecting groups may 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 for deprotection of other optionally present protecting groups can be found in Greene T., Vuts P. G. M., Protective Groups in Organic Synthesis, John Viley & Sons., New York, NY 1991.

R ^J

R ² R ⁶

Scheme 3 l ² R ⁶ O

N-C-A-N5 or L

N-H

WHAT

WHAT

, 3a

HOOC-A-N-L

R ^J

R ² R ⁶ O j

-A-C-A-N;

or L

WHAT

WHAT

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 the general formula (6) are known amino acids or are easily synthesized by processes analogous to the known compounds or described in the literature. Coupling may also be accomplished using a BOP-type coupling agent in an inert solvent such as dichloromethane.

When or R 8 is 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 accomplished by known methods.

Compounds of formulas I and II in which R ^ and / or R ^ are hydrogen atoms may be further elaborated to novel compounds of formulas I and II (the preferred side chain of R ⁷ is CH ₂ -CH (OH) -CH ₂ X, wherein X = H or OH), which are substituted on the amino group by the method of Scheme 4.

Scheme 4

R ² R ⁶ Q r ¹ —j — nc ^- a — n, CO

R ² R ⁶ QI II

N-C-A-N

WHAT

Although R ⁴ and / or R 6 are C 1-6 -alkyl, optionally substituted reductive amination of compounds I and II with an aldehyde may be carried out under known conditions, for example by catalytic hydrogenation with hydrogen in the presence of a platinum, palladium or nickel catalyst or chemical treatment. reducing agents such as sodium cyanoborohydride and the like in an inert solvent such as methanol or ethanol. A similar transformation can be accomplished through the opening of the epoxy ring.

Scheme 5

R ² R ⁶

R ¹ —N — H CO

_R 2a _r 7 N - (CH ₂ ) _x - | - (CH ₂ ) y N

R ⁴

R ^7a (I) or

O = C = N- (CH ₂₎ or (9), -) - (CH ₂₎ y N (II), 7

The compounds of the formula Ia 11 wherein A is N ^(R2) - (CH2) _Z-C (R ⁷⁾ (R ⁷⁾ -CH 2) y can be prepared according to Scheme 5 in a way that the compound of formula 4, or 4a are reacted with a reagent of formula 8 wherein X is a readily cleavable group such as a chlorine, bromine or iodine atom 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, for example 1,2-dichloroethane. When R ⁴ or R ³ in the resulting product is a hydrogen atom, the reagents of formula 8 and 9 will have a removable protecting group L at the R ⁴ or R ^{3 position} .

The compounds of formula (I) and (II) for the combination according to the invention may also be prepared as outlined in reaction schemes 6, 7 and 8.

Protected amino acid derivatives of formula 10 are commercially available in a number of cases. 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 well known in the art. Some of these processes involve reacting the protected amino acid with a diazoalkane and removing the protecting group L or reacting the amino acid with an appropriate alcohol in the presence of a strong acid such as hydrochloric acid or p-toluenesulfonic acid. Synthetic procedures for preparing new amino acids will then be further described in Schemes 14, 15 and 16.

Scheme 6

R ⁴ R ² R ⁶ HOOC-anr ⁵ 1 (6) _{R1- N- H} COOM ₊ or R ⁴ (10) HOOC-A-N-L (7)

R ² R ⁶ OR ⁴ _R 1 -cn-r ⁵

COOM (10)

R ² R ⁶

ABOUT

II

N-C-A-N-L

COOM (11 a)

Intermediate of general formulas 11 and prepare as shown in Scheme 6 of formula 10 for amino acids of formula 6 and / or

L is a protecting group as defined in Scheme 3 above

11a is possible by coupling of amine 7 in which

11a, a urea-type bond is to be present and can be introduced as shown in Scheme 5.

Scheme 7

R ² R ⁶ 0 R ⁴ R ¹ —j — NCA-N- R ⁵

COOM

FROM

R ² R ⁶ Q

NCANR ⁵

COOH (12) r ² r ⁶ o R ⁴ _r 1 -? -? -? -? - L

COOM (12a)

R ² R ⁶ OR ⁴ R ¹ - | - N-CA-N-L

COOH (11a)

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 through a variety of procedures known in the art. For example, methyl and ethyl esters can be hydrolyzed by treatment with lithium hydroxide in a protic solvent, for example aqueous methanol. In addition, the 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, the reaction being carried out in a protic solvent such as methanol. The allyl esters can be cleaved by treating 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 as described in Scheme 8.

Scheme 8

R ^J

R ² R ⁶ OR ⁴ , ^1- j-N-CAN

CO R ⁵ or L, 3a

R ² R ⁶ OR ⁴ . II i

J-N-C-A-N-L

COOH (11a)

H

N

B □ x

K, / (2a) ', 3b

R ² R 9 9 _r 4

R ¹ - (- NCAN.

CO R ⁵ or L

(5b) a. (5c)

The coupling 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 readily be carried out in an inert solvent such as dichloromethane using a coupling agent such as dicyclohexylcarbodimide DCC or EDC in the presence of 1-hydroxybenzothiazole. HOBT. However, the coupling may also be performed using a benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) coupling agent in an inert solvent such as dichloromethane. Conversion of compounds 5a and 5c to compounds of formulas I and II may be accomplished by deprotection of L. If R ⁴ and / or R 8 is hydrogen, optionally by addition of substituted alkyl groups at the nitrogen atom such as is shown above in Scheme 4.

Scheme 9

L

(13)

1.9 PCB

L

Preparation exygenovaných spiroindanyl intermediates is outlined in Scheme 9, it is a compound, wherein R @ ^a and R ^^ are hydrogen. The protected spiroindan derivative of formula 13 is treated with hydroborate followed by oxidative treatment with pyridinium chlorochromate to give the resulting spiroindanone of formula 14.

Scheme 10

Scheme 10 shows the conversion of spiroindan derivatives to benzolactam intermediates. The spiroindan derivatives are treated with hydrochloric acid in an inert solvent, for example in the chloroform of the Schmidt reaction, one of a number of methods reported in the literature for this transformation. In this case, a mixture of two benzolactams is formed. Isomers can be readily separated by silica gel chromatography. The resulting intermediates can then be deprotected and incorporated into growth hormone secretion compounds as shown in Schemes 1 and 8 above using intermediates of Formula 2.

Alkylation of compounds of Formula 15 or 16 with an alkyl halide in a solvent such as dimethylformamide in the presence of sodium hydride provides compounds of Formula 17 and 18 wherein R is C 1 -C 4 alkyl as shown in Scheme 10A.

Scheme 10A

L L or 16

(17)

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

formulas

Scheme 11

V L L

(19)

L

Scheme 11A L .N.

LAH Γ 1

N

H (21)

N

R ⁹ (22)

When L is an appropriate protecting group, for example benzyl, the amides can be reduced using lithium aluminum hydride to form amines of general

The amines in which R is a hydrogen atom can then be alkylated, arylated or acylated or reacted with substituted sulfonyl halides or isocyanates under known conditions to give compounds of formulas 20 and 22. protecting group L by hydrolysis using palladium as catalyst, intermediates can be obtained that can be incorporated into growth hormone secretion compounds for use in combination with the invention using the procedures illustrated in Schemes 1 and 8 above, employing a basic intermediate of formula second

Scheme 12

2) NaBH ₃ CN from R ⁹ , N (25)

Scheme 12 depicts another possible process for obtaining a 1,2,3,4-tetrahydrospiro [isoquinoline-4,4'-piperidine] ring system. The protected spiroindene derivative is subjected to ozonolysis followed by treatment with dimethylsulfide to give the hemiacetal of formula (24) as an intermediate. The amine of formula (25) is then obtained by reductive amination and acylation.

Scheme 13

1) HCl

2) H2, Pd / C

Analogues of formula 26 in which X and Y are both hydrogen or one of which is hydrogen and the other hydroxy or together form an oxygen atom can be prepared by methods known 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 according to the method of Kabbe H., J., Synthesis, 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. Deprotection according to Protective Groups in Organic Synthesis, Greene TV, Vuts PG, 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 enhanced growth hormone secretion by the method described in Schemes 1 and 8 using the intermediate of Formula 2.

The ketane function in the compounds of Formula 2 can be reduced to the alcohol function using sodium borohydride or can be completely reduced to the methylene group in a known manner. For example, compounds of formula 29 can be obtained by reduction of the ketone with sodium borohydride followed by concentrated hydrochloric acid and hydrogenation. The amines of formula 27, 28 or 29 can then be incorporated into growth hormone secretagogues according to Scheme 1 and 8 using an intermediate of formula 2. The ketone function can also often be reduced only after the formation of the compound of formula I.

The preparation of chiral hydroxyspiro [2H-1-benzopyran-2,4'-piperidine] analogs can be accomplished using optically active reagents 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 of formula 30, 6 and 7, wherein A is - (CH ₂ ) _X -C (R ² ) (R ^2a ) - ( _CH2) y-. The preparation of a number of these acids has been described in U.S. Pat. 5,206,237.

The preparation of the intermediates in racemic form is accomplished by conventional procedures well known in the art, for example according to Villiams R. M., Synthesis of Optically Active Alpha-Amino Acids, Pergamon Press, Oxford, 1989, Vol. 7th

R ² R ⁶

IX H co ₂ hrs (30)

There are a number of methods for separating DL-amino acids. One common procedure 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 carboxy-protected intermediate can be linked to the optically active acids as described above. Separation of the individual diastereomers by chromatographic method or crystallization followed by hydrolysis of the chiral amide results in separation of the separated amino acids. Similarly, amino-protected intermediates can be converted to a mixture of chiral esters and amides. Separation of this distaereomeric mixture as described above followed by hydrolysis of the individual diastereomers yields D- and L-amino acids. Enzymatic procedures for the separation of N-acetyl derivatives of the DL-amino acid have been described in Vhitesides et al., J. Am. Chem., Soc., 1989, 111, 6354-6364.

If it is desired to synthesize the intermediates in optically pure form, one may proceed by 1) asymmetric amination of the chiral enolates according to J. Am. Chem. Soc., 1986, 108, 6394-6395, 6395-6397 and 6397-63399, 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 glycineenolate synthons according to J. Am. Chem. Soc., 1991, 113, 9276, or J. Org. Chem., 1989, 54, 3916, 4) diasteroselective nucleophilic addition to the chiral electrophilic glycinate syndrome of J. Am. Chem. Soc., 1986, 108, 1103, 5) asymmetric hydrogenation of prochiral dehydroamino acid derivatives according to Asymmetric Synthesis, Chiral Catalysis, Morrison J. D., Ed. Academic Press, Orlando, FL, 1985, Vol. 5, and 6) the enzymatic synthesis of Angew. Chem. Int. Ed. Engl., 1978, 17,176.

Scheme 14

every ₂ h (33)

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

Scheme 15

H

HO ^ V ^ L every ₂ h (34)

NaH / DMF

_Ar-CH2-X

(35)

Intermediates of formula 30, which are derivatives of O-benzyl- (D) -serine 34, can be readily prepared from the corresponding substituted benzyl halides and N-protected (D) -serine 34. Preferably, L is BOC or CBZ. Benzylation of compound 34 can be accomplished by a variety of known procedures including deprotonation by treatment with two equivalents of sodium hydride in an inert solvent such as DMF followed by 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 the (D) -serine derivatives of Formula 35 include benzylation of carboxy-protected intermediates derived from compound 34 by reaction reagents of formula ArCH 2 OC (= NH) CCl 3, the reaction is catalyzed by the acid of 0. Yonemitsu et al., Chem. Pharm. Bull., 1988, 36, 4244. By alkylation of chiral glycinoenolates according to J. Am.

Chem. Soc., 1991, 113, 9276; J. Org. Chem., 1989, 54, 3916, by treatment with ArCl 3 OCl 2 X, where X is a leaving group, compounds of Formula 35 are obtained. In addition, D, L-O-aryl (alkyl) serines can be prepared and separated by the above procedures.

Scheme 16

H

(36)

NaH / THF

RLA-X

R ^la \

H

I

N.

[ABOUT]

R ^la \

s' γ t co ₂ h

H i

Ns, [° 1n CO ₂ H (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, which will be described in more detail below by the action of a compound of formula R 1 ^and -X where X is a leaving group, e.g. or a mesyloxy group as shown in Scheme 16.

Oxidation of the cysteine derivatives of formula 37 to sulfoxides of formula 38 in which n = 1 and to sulfones of formula 38 in which n = 2 can be accomplished by the action of a variety of oxidizing agents. Oxidation of sulfides has been described in detail in Org. Prep. Proced. Int., 1982, 14, 45. Sodium periodate is frequently used in the synthesis of sulfoxides as reported

J. Org. Chem., 1967, 32, 3191 and potassium hydrogen sulphate, OXONE, according to Tetrahedron, is often used for sulfone synthesis. Lett., 1981, 22, 1287.

Obviously, according to Schemes 1 and 8 above, a variety of substituted amino acids can be incorporated into growth hormone secretagogues. Growth hormone secretion-promoting compounds containing a sulfoxide or sulfone functional group can also be prepared from cysteine compounds using sodium periodate or potassium hydrogen sulfate. Thus, hydrogen peroxide can be used as the oxidizing agent in the last step of the synthesis, as shown in Scheme 17. Sulfoxide analogues of formula 40 in which n = 1 can be separated from sulfone analogues of formula 40 in which n = 2 by preparative thin layer chromatography .

Scheme 17

TFA

SJ [| NH ₂ TFA CO

(39)

(40)

Removal of the amino protecting groups can accomplish a variety of procedures described above and in Protective Groups in Organic Synthesis, T.V. Green, John Viley and Sons, NY, 1981.

Compounds of formula I in which R 1 and R 2 are hydrogen may be further processed by reductive alkylation by treatment 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 by conventional HPLC reversed phase HPLC or recrystallization.

The spiropiperidine derivatives of formula 41 may be prepared by a variety of procedures including synthetic procedures as described hereinafter.

(41)

Scheme 18

(42)

The spiropiperidine derivatives of formula 42 wherein L is a protecting group can be synthesized using procedures known in the literature, for example, according to the method of H. Ong et al., J. Med. Chem., 1983, 23, 981-986. The nitrogen atom of the indoline ring in a compound of Formula 42 wherein L is a protecting group, such as a methyl or benzyl group, can be reacted with a variety of electrophile materials to provide spiropiperidine derivatives of formula 43 in which it may mean a variety of functional groups. For example, the compound of formula 42 may be reacted with isocyanates in an inert solvent such as chloromethane to give urea derivatives by treatment with a chloroformate in an inert solvent such as dichloromethane to give carbamates, treatment with acid chlorides, acid anhydrides or acylimidazoles to provide amides, sulfonyl chloride sulfonamides can be obtained and sulfamides can be obtained by treatment with 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 M is a defined protecting group, the M group can be cleaved from the product to form another derivative. In addition, it is also possible to react the intermediate of formula 42 with epoxides to form compounds of formula 43 in which R 1 represents an alkyl or aralkyl group substituted with a β-hydroxy group. The indoline derivatives of Formula 42 can also be converted to compounds of Formula 43 wherein R 1 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl by carrying out the reaction with fluorophenyl or fluoroeteroaryl reagents. This procedure is described in detail in H. Ong et al., J. Med. Chem., 1983, 23, 981-986.

Scheme 19

(44)

Spiropiperidine intermediates of formula 43 wherein L = Me or Bn and where hydrogen and most of the derivatives thereof may be subjected to demethylation or debenzylation to give a compound of formula 44 wherein R 1 represents a hydrogen atom or a number of other functional groups as shown In the case of compounds of formula 43 wherein L is methyl, the demethylation can be carried out by a variety of known methods. In the case of demethylation of 43, it can be reacted with cyanogen bromide and potassium carbonate in an inert solvent such as dichloromethane to form a cyanide which can be reduced to 44 with lithium aluminum hydride at reflux in tetrahydrofuran under reflux. an acid such as aqueous hydrochloric acid at reflux or under the action of 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 may be removed by reduction procedures 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 in which L is a benzyl group may also be accomplished by the ACE-C1 method of R. Olofson et al., J. Org. Chem., 1984.

The spiroheterocyclic compounds of Formula 45 can be prepared by a variety of procedures including the synthesis described in Scheme 20. 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, the alkylation can be carried out in DMF or acetone as a solvent using potassium carbonate as the base and when D = NR 6, where 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 a cyclization 49. When L is a defined protecting group, the compound of formula 49 can be cyclized by a variety of known procedures.

Scheme 20 (47)

1) SeO ₂

SOCI ₂

For example, cyclization of intermediate 49 can be accomplished by treatment with tributyltin hydride according to Curra D.

P., Synthesis, 1988, an example of benzene at 46 in which D = NR ⁹ ,

417 and 489 in an inert solvent to give intermediate 46. The intermediate can also be prepared as described in Schemes 18 and 19.

Scheme 21

L i

N

(46) D = S (O) [ _m] (46) D = S (O) _m m = 1.2

When D is a sulfur atom, the compound of formula 46 can be oxidized to the sulfoxide of formula 47 wherein n = 1 to the sulfone of formula 47 wherein n = 2 by a series of oxidizing agents according to Scheme 21. For example, periodate is often used in sulfoxide synthesis. sodium and sulfone synthesis often uses OXONE. Removal of the protecting group yields an amine of Formula 45, which can be incorporated into the growth hormone releasing compound by the method of Schemes 1 and 8 using the intermediate of Formula 2.

The spiropiperidine derivatives of formulas 50 and 51 may be prepared by the method of Scheme 22.

The phthalimidine derivatives of formula (53) wherein R ¹¹ is alkyl, aryl, (C 1-6 -aryl, or a protecting group are commercially available or can be prepared from the corresponding phthalimides by methods described in the literature, for example, in Bevster et al., J. Org. 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 with a protected bis-2-haloethylamine in which 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 give spiropiperidine of formula 54. by reduction of the lactam in formula 50 with a hydride, for example, l39 thium aluminum hydride of formula 51.

it is then possible to obtain the compound of Scheme 22

(50)

⁽⁵⁴⁾ (50) < ⁵⁰ )

Obviously, the order of reactions in the above schemes is not essential and the order of reactions can be varied by one of ordinary skill in the art so that the reaction proceeds better or avoids formation of unwanted by-products.

The usefulness of individual growth hormone secretagogues can be demonstrated by known procedures, for example, by the method of Smith et al., Science, 260, 1640-1643, as explained, for example, in the text of FIG.

Second

The combination of a bisphosphonate and a growth hormone releasing compound of the invention is useful in the treatment or prevention of disorders of calcium or phosphate metabolism and related diseases. These diseases can be divided into two groups:

Abnormal (ectopic) deposition of calcium salts, predominantly calcium phosphate, associated with pathological tissue hardening and bone deformation.

2. Conditions where improvement can be achieved by reducing bone resorption. In this case, reduced bone resorption should improve the balance between tissue resorption and formation, reduce bone loss or increase the amount of bone tissue. Reducing bone resorption can reduce the pain of areas where osteolytic processes occur and also reduce the incidence and / or size of these areas.

Diseases treatable or ameliorated by the combination of the invention include osteoporosis including estrogen deficiency, osteoporosis from glucocorticoid-induced immobilization or age, osteodystrophy, Paget's disease, myositis ossificans, Bechter's disease, malignant hypercalcemia, malignant hypercalcemia bone diseases, cholelithiasis, kidney or urinary stones, calcium deposition in arteriosclerosis, arthritis, bursitis, neuritis and tetany.

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

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

The combination of bisphosphonate, especially pamidronate or alendronate, has been shown to produce unexpected effects in the treatment and prevention of diseases in which bone resorption occurs when used in conjunction with growth hormone secretagogues. Although there is no need to be bound by any theoretical explanation for this effect, a much higher effect on reducing or suppressing bone loss during aging and osteoporosis is observed with the combination of agents than would be seen with only one of of said combination. An increase in bone mass is even observed after administration of a combination of a growth hormone secretagogue and a bisphosphonate. This increase in the amount of bone tissue is likely to be due to the formation of this tissue by increasing the levels of growth hormone and IGF-1 due to the action of the substance on growth hormone secretion, and at the same time due to decreased bone resorption by biphosphonate. This effect of the combination of both substances could not be predicted from the known state.

A particularly good effect with the combination according to the invention can be achieved if the combination contains 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, which is commonly referred to as alendric acid, as the bisphosphonate. Also preferred is a dosage form comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate, alendronate. When administered parenterally, it is approximately five times more potent than pamidronate, 3-amino-1-hydroxypropylidene-1,1-biphosphonic acid, which is currently the most effective diphosphonate supplied for the treatment of cancer bone in reducing blood calcium levels during cancerous bone diseases. diseases.

4-Amino-1-hydroxybutylidene-1,1-biphosphonic acid and its homologues in which R ¹ in the side chain represents an N-alkyl group having 1 to 5 carbon atoms, these homologues being terminally substituted with an amino group, can be readily synthesized by according to U.S. Pat. 4,407,761 and 4,922,007. In addition to the mono-, di- and trisodium salts, other pharmaceutically acceptable salts of biphosphonic acids, including ammonium salts, salts with other alkali metals such as potassium salts and alkaline earth metal salts may be used in the combination of the invention. such as calcium and magnesium salts, further 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 according to U.S. Pat. 4,922,077.

In the combination of the invention, the bisphosphonates and growth hormone secretagogue compounds may be administered together or separately. In the case of separate administration, it may be simultaneous or at different time intervals.

The pharmaceutical compositions containing the compounds may be formulated for oral administration, parenteral administration, for example in the form of intramuscular, intraperitoneal, intravenous or subcutaneous injections, or in the form of an implant, nasal, vaginal, rectal, sublingual or For example, in the case of topical administration, the active ingredient may form a single component of the pharmaceutical composition, but usually the dosage form will still contain conventional non-toxic pharmaceutically acceptable carriers and excipients suitable for each mode of administration.

The pharmaceutical compositions may be formulated to contain a dosage suitable for single administration and may be prepared by known methods. Essentially, all of these methods involve admixing the active ingredient with a carrier which comprises one or more accessory ingredients. Usually, the process consists in homogeneously and thoroughly mixing the active ingredient with a liquid or finely divided solid carrier, optionally with subsequent processing of the mixture to the desired shape. The pharmaceutical composition must contain the active ingredients in an amount sufficient to produce the desired effect.

Pharmaceutical compositions suitable for oral administration may be presented in divided form, for example 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, or may be syrups or elixirs or oil-in-water or water-in-oil emulsions. Formulations for oral administration may be prepared by any known means for the manufacture of pharmaceutical compositions and may contain, as excipients, sweetening, flavoring, coloring and preservative agents 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 admixed 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 may also be prepared in a manner known per se. For example, the excipients used may be 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 gum, and 4) glidants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated in a known manner so as to slow down the disintegration of the tablet and thereby absorb the active ingredient in the digestive tract and achieve a sustained action over a further period of time. It is also possible to use a material which directly inhibits absorption or absorption, for example glyceryl monostearate or glyceryl distearate. Tablets may be coated, for example, by the method of U.S. Pat. 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, for example calcium carbonate, calcium phosphate or kaolin. They may also be soft gelatin capsules containing the active ingredient as a mixture with water or an oil, for example arachis 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, such as 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 usually contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions.

The following ingredients may be mentioned:

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 such as polyoxyethylene stearate;

(c) the condensation product of a long-chain aliphatic α145 alcohol, for example heptadecaethyleneoxycetanol,

d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol, for example polyoxyethylene sorbitol monooleate; or

e) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and 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 or flavoring or sweetening agents, such as sucrose or saccharin.

Suspensions in oil may be formed by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or even a mineral oil, for example liquid paraffin. Suspensions in oil may contain thickeners, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavor compounds may also be added to make the composition orally administrable. In addition, this type of composition may contain an antioxidant, for example ascorbic acid.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. In these compositions, the active ingredient is in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. The dispersing or wetting agents as well as suspending agents which may be mentioned are those mentioned above. The compositions may also contain other excipients, for example, the abovementioned sweeteners, flavorings 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 or peanut oil, or even a mineral oil. A suitable emulsifying agent is, for example

1) natural gum, for example from acacia or tragacanth,

2) optionally occurring phosphatidyl such as soybean and lecithin; 3) esters or partial esters derived from fatty acids and hexitol anhydrides such as 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 emollients, preservatives, flavorings and coloring agents.

The pharmaceutical compositions may also take the form of sterile injectable solutions or suspensions or solutions in oil. Suspensions may be obtained by known methods, as well as 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 parenteral administration by a suitable diluent or solvent, 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 may be employed. These are, in particular, synthetic mono- or diglycerides and also 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 and 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 may be sterilized, for example, by filtration through a bacteria-retaining filter, by the 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 injectable medium immediately prior to use.

The combination of the invention may also be administered rectally in the form of suppositories. These formulations for rectal administration may be prepared by mixing the active ingredient with a suitable, non-irritating vehicle which is solid at ambient 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 sublingual administration can also be prepared using standard excipients in a known manner.

For topical administration, the combination of the invention may be formulated into liquid or semi-solid compositions such as ointments, oil-in-water or water-in-oil emulsions, creams, jellies or pastes including toothpaste, or solutions or suspensions such as drops and so on.

In addition, the pharmaceutical compositions of the present invention may also contain other active ingredients as are commonly used in the treatment of the above pathological conditions. These may be, for example, vitamins D2 and Dj and their hydroxylated derivatives, for example, ε-hydroxy-vitamin D2, β-hydroxy-vitamin D2, β-25-dihydroxyvitamin D2, β-25-dihydroxyvitamin D2, human, pig or salmon calcitonin. mitramycin such as acetylsalicylic acid, indomethacin, prolosyn and timegadine.

The dosage of the active ingredients in the compositions of the invention may be varied so as to always achieve a suitable dosage form. The dose employed will depend upon the desired therapeutic effect, the route of administration, and the total duration of treatment. Typically, the doses of bisphosphophate are in the range of 0.001 to 10 mg / kg by weight, preferably 0.01 to 1.0 mg / kg. The doses of the compound to promote growth hormone secretion are usually in the range of 0.0001 to 25 mg / kg per day.

The combination of the invention may be administered by an intermittent route. For the treatment or prophylaxis of bone resorption diseases, a typical oral bisphosphophate dose is 0.001-10 mg / kg and the growth hormone releasing agent dose is 0.0001-25 mg / kg, after administration of said dose. if necessary, it is possible to administer a maintenance dose of one or both components of approximately half the original dose once or twice a week, once or twice a month, once every two or three months, once every half year, once a year or once every two years.

Preferred compounds suitable for use in the combination of the invention may be prepared as described in the following examples. A full description of a process for the production of growth hormone secretagogue compounds 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; 144 230 and 513 974 and published international applications WO 94/07486, WO 94/08583 and WO 94/13696, and also in Science, 260, 1640-1643, June 11, 1993.

The following examples are intended to illustrate the practice of 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 ° C. At this temperature, it is added with vigorous stirring

1.5 moles of phosphorus trichloride. The mixture is stirred at 100 ° C for about 3 hours, during which time a solid phase forms and the mixture is allowed to cool. The solid was 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 decolourised with charcoal. The material was filtered and the product was precipitated with excess hot methanol. The crude material thus obtained was refluxed in 20% hydrochloric acid for 8 hours. The hydrochloric acid was distilled off and the residue was recrystallized from water. 4-Amino-1-hydroxybutane-1,1-bisphosphonic acid is obtained as a white crystalline powder with the following structure and properties:

(CH ₂ ) ₃ NH ₂ h ₂ o ₃ p - c - PO ₃ H ₂

OH

Elemental analysis

C% H% N% % 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] -1--ΙΗ benzazepin3 (R) -yl] butanamide

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

A solution of 3-azido-2,3,4,5-tetrahydro-1H-benzazepin-2-one (9.22 g, 45.6 mmol) (prepared according to Vatthey et al., J. Med. Chem., 28, 1511-31). 1516, 1985) in 30 ml of methanol is hydrogenated at 50 psi in the presence of 1.0 g of 5% platinum on activated carbon for a total of 4.5 hours. The filtrate was concentrated and then allowed to stand at room temperature for 16 hours to form crystals. The product was filtered off and dried under vacuum to give the title compound (4.18 g, 23.7 mmol) in 52% yield. Dilute the mother liquor to 100 ml with methanol, add 2 g of activated carbon, filter through a pad of celite and concentrate the filtrate in vacuo to a volume of approximately 15 ml. A second crop of product was obtained, yielding 2.02 g (11.5 mmol) of the title compound in 25% yield. After further treatment of the mother liquor, a third crop of 0.88 g (5.0 mmol) of product is obtained in a yield of 11%. A total of 7.08 g (40.2 mmol) of the title compound 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 calc. 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-tetrahydro-ΙΗ-1-benzazepin-2-one from Step A and 2.02 g, 13.5 mmol of L-tartaric acid are added. is suspended in 40 ml of ethanol. The mixture is heated gently, complete dissolution is achieved by dropwise addition of 5 ml of distilled water. The solution was cooled to room temperature and then allowed to stand overnight. The solid formed in this way was filtered off, washed with ethanol: diethyl ether 1: 1 and dried in vacuo to give 1.75 g of crude L-tartrate. The mother liquor is evaporated to dryness in vacuo, redissolved in 40 ml of water and adjusted to pH 10-11 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 original 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 in 24% yield with an optical rotation [α] P = -212 '(c). = 1, water). The purified L-tartrate is dissolved in 20 ml of water and the pH is adjusted to 10-11 by 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] P = -446, (c = 1, chloroform).

The remaining 1.29 g, 7.33 mmol of partially enriched 3 (R) amine is treated with 1.10 g, 7.33 mmol of D-tartaric acid as described above and the resulting salt is recrystallized twice from aqueous ethanol to give

1.20 g of purified D-tartrate with optical rotation [α] P = -214,, (c = 1, water). The purified D-tartrate is dissolved in 20 ml of water and the free base is isolated as above to give 629 mg, 3.57 mmol of 3 (R) -amine with an optical rotation of [α] p = +455 in 26% yield. (C = 1, CH 2 OH).

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

The mixture was then concentrated in vacuo to a volume of 50 ml and 200 ml of a 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. The mixture was then 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 sodium chloride solution, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The residue was dried under vacuum at room temperature to give a yield of 14.7 g (91.8 mmol) of a viscous oil in 67% yield, which slowly solidified on standing. 1 H-NMR analysis showed that the material was a mixture of the product and 15% isomeric 2,2-dimethylbutanedicarboxylic acid 1-methyl ester. NMR (200 MHz, CDCl 3): for the resulting 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-dimethylbutanedicarboxylic acid 4-methyl ester from Step C containing 15% isomer

1-methyl ester in 150 ml of benzene is added 13 ml, 9.4 g, 93 mmol, 1.01 equivalents of triethylamine and then 21.8 ml,

27.8 g, 101 mmol, 1.1 equivalents of diphenylphosphoryl azide. The mixture was heated under reflux for a total of 45 minutes and then 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 in vacuo to a small volume. The residue was redissolved in ethyl acetate (250 mL), washed with water (1 x), saturated aqueous sodium bicarbonate (2x) and saturated sodium chloride (1x). The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate evaporated in vacuo to a small volume. The crude product was purified by chromatography on silica using medium pressure, eluting with 4: 1 hexane: ethyl acetate to give the title compound (18.27 g, 68.9 mmol) as a pale yellow liquid (75% yield). This gives a small amount of pure methyl 3- [benzyloxycarbonylamino] -2,2-dimethylpropanoate.

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 (d, 7 Hz, 2H, resonance changes to singlet in CD 4 OD), 3.67 (s, 3H), 5.09 (s, 2H), 5.22 (br s, 1H, resonance not observed in CD 4 OD), 7.3 (br s, 5H).

Step E: 3-Benzyloxycarbonylamino-3-methylbutanoic acid

A solution of methyl 3-benzyloxycarbonylamino-3-methylbutanoate (18.27 g, 68.9 mmol) from Step D in 20 mL of methanol was allowed to stand at room temperature and 21 mL, 102 mmol, 1.5 equivalents of a 2 M solution were added dropwise. sodium hydroxide. 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 slowly acidified to pH 2 by dropwise addition of 6M hydrochloric acid solution. Then the mixture is extracted 6 times with ether, the extracts are combined, washed with 1M hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent is evaporated off under vacuum to give 17.26 g (68%). 7 mmol of the title 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 .Delta.3 (s, 5H).

Step F: 3-Benzyloxycarbonylamino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-ΙΗ-1-benzazepin-3 (R) -yl] butanamide

To a solution of 3 (R) -amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (252 mg, 1.43 mmol) from Step B in 4 mL of methylene chloride was added 400 mg at room temperature, 1.60 mmol, 1.1 equivalents of 3-benzyloxycarbonylamino-3-methylbutanoic acid from Step E and then 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 standing at room temperature for 3 hours, the mixture was diluted with 30 mL of ethyl acetate and the resulting solution was washed with 5% aqueous citric acid solution, then twice with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The residue was purified by medium pressure silica chromatography, eluting with ethyl acetate to give 586 mg (1), 100%. 43 mmol of the title compound.

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 to 7, Δ (m, 8H), 7.61 (br s, 1H).

FAB-MS: calcd 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 are added in small portions to 15 ml of N, N-dimethylformamide, maintaining the temperature below 60 ° C. The zinc chloride slurry was then cooled to room temperature and 5.0 g, 48.5 mmol, 1.0 equivalent of benzonitrile was added, followed by 3.2 g, 48.5 mmol, 1.0 equivalent of sodium azide. The heterogeneous mixture is heated to 115 ° C for 18 hours with stirring. The mixture was cooled to room temperature, water (30 ml) was added and the mixture was acidified by addition of concentrated hydrochloric acid (5.1 ml). The mixture was then cooled to 0 ° C and allowed to stand for 1 hour, after which time it was filtered, the filter cake was washed with 15 ml of cold 0.1 M hydrochloric acid solution and then dried under vacuum at 60 ° C Yield: 90% (6.38 g, 43.7 mmol).

Step H: 5-phenyl-2-trityltetrazole

To a suspension of 5-phenyl-tetrazole (5.0 g, 34.2 mmol) in acetone (55 mL) was added triethylamine (5.0 mL, 3.6 g, 35.6 mmol, 1.04 equivalent). After 15 minutes a solution of 10.0 g is added,

35.9 mmol, 1.05 equivalents of triphenylmethyl chloride in 20 ml of tetrahydrofuran and stirred at room temperature for 1 hour. 75 ml of water are then slowly added and the mixture is stirred at room temperature for 1 hour. The product is filtered off, washed with 75 ml of water and dried under vacuum at 60 ° C to give 13.3 g (34.2 mmol) of product in 100% yield.

Step I: N-triphenylmethyl-5- [2- (4'-methylbiphen-4-yl)] tetrazole

A solution of 6.3 g, 46.2 mmol, 0.6 equivalents of zinc chloride in 35 mL of tetrahydrofuran was dried over molecular sieves. 30.0 g, 77.3 mmol, 1.0 equivalent of 5-phenyl-2-trityltetrazole are dissolved in 300 ml of anhydrous tetrahydrofuran and the solution is stirred gently and degassed three times with stirring by alternating pressure reduction and nitrogen purge. . The solution was then cooled to -15 ° C with stirring and 50.5 mL, 80.0 mmol, 1.05 equivalents were added slowly.

Of a 1.6 M solution of n-butyllithium in hexane so that the temperature is kept below -5 C.

1.5 hours at -5 to 15 ° C, then the dried zinc chloride solution prepared above is added and the resulting 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. The mixture was then cooled to 5 ° C and a 1.5 mL, 3.0 M solution of phenylmagnesium chloride in 4.5 mmol, 0.06 equivalents of tetrahydrofuran was added to maintain the temperature below 10 ° C. The solution is then allowed to warm to room temperature and a solution of the aryl zinc compound is added under nitrogen. The reaction mixture was stirred vigorously at room temperature for 8 hours and then quenched by slowly adding a solution of 10 mL, 1.6 mmol, 0.02 equivalents of glacial acetic acid in 60 mL of tetrahydrofuran, keeping the temperature at a lower temperature. than 40 ° C.

After stirring for 30 minutes, 150 ml of an aqueous solution of sodium chloride saturated to 80% 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 higher than 10 by addition of ammonium hydroxide. The organic phase is separated and evaporated in vacuo to a volume of approximately 50 ml, then 250 ml of acetonitrile are added. The mixture was concentrated again in vacuo to a volume of 50 ml and acetonitrile was added to a final volume of 150 ml. The resulting suspension was stirred at 5 ° C for 1 hour, then filtered and washed with 50 ml cold acetonitrile and then 150 ml distilled water. The filter cake was air dried to a free-flowing powder, which was then dried under vacuum at 50 ° C for 12 hours to give the title compound (30.0 g, 62.8 mmol) in 81% yield.

¹ H-NMR (200 MHz, CDCl 3): 2.28 (s, 3H), 6.9-7.05 (m, 10H),

7.2-7.5 (m, 12H), 7.9 (m, 1H).

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

A solution of N-triphenylmethyl-5- [2- (4'-methylbiphen-4-yl)] tetrazole (3.15 g, 6.6 mmol) from Step I in 25 mL of methylene chloride was treated with 1.29 g, 7.25 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 was refluxed for 2-16 hours, then cooled and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was removed, dried over sodium sulfate, filtered and evaporated to a small volume by distillation at atmospheric pressure. Methyl tert-butyl ether is then added and distillation is continued until all methylene chloride is removed and the total volume is reduced to approximately 12 ml, then 12 ml of hexanes are added. The mixture is allowed to stand at room temperature for 2 hours, then the product is filtered off, 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), 6.9-8.0 (m, 23H, spectrum showed the presence of 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-1-ΙΗ benzazepin3 (R) -yl] butanamide

To a solution of the intermediate of step 437 mg, 1.07 mmol

F in 2 mL of anhydrous dimethylformamide was added at room temperature under nitrogen with 55 mg, 60% sodium hydride dispersion in oil, i.e. 33 mg, 1.38 mmol, 1.3 equivalents of sodium hydride. After 15 minutes, a solution of 715 mg, 1.28 mmol, 1.2 equivalents of N-triphenylmethyl-5- [2- (4'-bromomethylbiphen-4-yl)] tetrazole from Step J in 1.5 mL of anhydrous dimethylformamide was added. and the mixture was stirred for 90 minutes.

The reaction mixture is poured into 100 ml of ethyl acetate and the resulting mixture is washed twice with water and then with a 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 medium pressure silica chromatography, eluting with 1: 1 ethyl acetate: hexane to give 902 mg (1.02 mmol) of product.

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 , IH),

6.65 (d, 8 Hz, 1H), 6.9 to 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] lH-benzazepin-3 (R) -yl] butánamidtrifluóracetát

A solution of the intermediate of Step H (902 mg, 1.02 mmol) in methanol (5 mL) was hydrogenated at room temperature and 50 psi over 160 mg of 20% palladium hydroxide on charcoal for a total of 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 min, Yield: 89%, 568 mg (0.91 mmol) of the title compound.

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, 15Hz, 1H), 7.00 (d, 8Hz, 2H), 7.15-7.35 (m, 6H), 7.45-7.70 (m, 4H).

FAB-MS calculated for C ^ HH ^N-yCC 509 found 510 (M + H, 100%).

Example 3

3-d (2 (R) -hydroxy-propyl) amino] -3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1 - [[2 '- (lH-tetrazol-5-yl) - [1,1'-biphenyl] -4-yl] methyl] lH-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-tetrazol-5-yl)] ) - [1,1'-biphenyl] -4-yl] methyl] -1--ΙΗ benzazepin3 (R) -yl] butánamidtrifluóracetát

The resulting product is prepared from 3-amino-3-methyl-N [2,3,4,5-tetrahydro-2-oxo-1 - [[2 '- (1H-tetrazol-5-yl)] [1,1'] -bi-phenyl] -4-yl] -methyl] -1H-1-benzazepin-3 (R) -yl] -butanamide trifluoroacetate from example laz (R) -2-benzyloxypropanol (prepared from ethyl D-lactate according to Hanessian) and Kloss, Tetrahedron Lett., 26, 1261-1264 (1985) according to the method of Example 86, Step A of U.S. Pat. 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, IH) 3.17 (m, 1H), 3.80 (m, 1H), 4.40 (m, 1H), 4.44 (d, 11 Hz,

1Η), 4.64 (d, 11Hz, 1H), 4.90 (d, 15Hz, 1H), 5.02 (d, 15Hz, 1H), 6.99 (d, 8Hz, 2H) 7.1 - 7.7 (m, 15H).

FAB-MS calcd for C 18 H 18 N 2 O 2: 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] butanes trifluoroacetate

The resulting product is prepared from the intermediate prepared in Step A by the method of U.S. Pat. 5,206,235, Example 86, Step B.

^X H-NMR (200 MHz, CD ₃ 0D): 1.22 (d, 6Hz, 3H), 1.37 (s, 3H), 1.39 (s, 3H), 2.10 (m, 1 H 2.31 (m, 1H), 2.45-2.70 (m,

4H), 2.81 (dd, 10Hz, 12Hz, 1H), 3.08 (dd, 4Hz, 12Hz,

1H), 3.92 (m, 1H), 4.36 (dd, 7Hz, 11Hz, 1H), 4.93 (d, 15Hz, 1H), 5.17 (d, 15Hz, 1H) 7.04 (d, 8 Hz, 2H), 7.19 (d, 8 Hz, 2H), 7.20-35 (m, 4H), 7.54 (m, 2H), 7.65 ( m, 2H). FAB-MS calc. For C32H37N7O3: 567 found: 568 (M + H, 45%).

Example 4 (Procedure 1)

N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-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 according to H. Ong et al., J. Med. Chem., 23 (981-986, 1983) in 20 mL of anhydrous dichloromethane at 0 ° C is added 0.90 mL,

6.4 mmol triethylamine and 0.49 mL, 6.35 mmol methanesulfonyl chloride and stirred for 30 min. The reaction mixture was poured into 15 ml of saturated aqueous sodium bicarbonate solution and the resulting mixture was extracted with 2 x 10 ml of dichloromethane. The organic extracts were combined, washed with 20 mL saturated sodium chloride solution, dried over anhydrous potassium carbonate, filtered and the solvent was evaporated under reduced pressure to give 1.44 g of the methanesulfonamide derivative as a pale yellow oil which was used for the next reaction. without further purification.

To a solution of the above crude product in 20 mL of anhydrous 1,2-dichloroethane at 0 ° C was added 1.0 mL,

9.30 mmol of 1-chloroethyl chloroformate, then the mixture is stirred for another 30 minutes at room temperature and finally refluxed for one hour. The reaction mixture is then concentrated to approximately 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 resulting precipitate was filtered off and washed with a small amount of cold methanol. 1.0 g of piperidine hydrochloride is obtained as a white solid. The filtrate was evaporated to a small 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 expected product is obtained. A total of 1.49 g of product is obtained in a yield of 0%.

⁷ 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-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2 - [(1, l-dimethylethoxy) carbonyl] amino-2-methylpropanamide

To 0.35 g, 1.15 mmol of 2 (R) -2 - [(1,1-dimethylethoxy) -carbonyl] -amino-3- [2- (phenylmethyloxy) ethyl] -1-propanoic acid in 1,2-Dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine] hydrochloride, 0.38 g, 1.07 mmol, 0.18 ml, 1.63 mmol of N-methylmorpholine and 0.159 mmol are added to 13 ml of dichloromethane. g, 1.18 mmol

Of 1-hydroxybenzotriazole, HOBT and the mixture was stirred for 15 minutes. 0.31 g (1.62 mol) of EDC was added and the mixture was stirred for 1 hour. 60 µl of N-methylmorpholine are then added and the mixture is stirred for 45 minutes. The mixture was then poured into 5 ml of water and the organic layer was separated and then washed with 5 ml of a 0.5 M aqueous hydrochloric acid solution and 5 ml of a 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 0.627 g, 1.07 mmol of the product obtained above in 5 ml of dichloromethane was added 1.0 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 75 minutes. Trifluoroacetic acid (1.00 ml) was added and the mixture stirred for 10 minutes. The reaction mixture was then 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 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 title amine as a pale yellow foam which was used without further purification.

To 0.486 g, 1.01 mmol of the amine obtained above and 10 ml of dichloromethane were added 0.26 g, 1.28 mmol of 2 - [(1,1-dimethylethoxy) carbonyl] amino-2-methylpropanoic acid, 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. 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 a 0.5 M aqueous hydrochloric acid solution, 5 mL of a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated to give 0.751 g of crude product as a yellow foam. A solution of this crude product in dichloromethane is chromatographed on 25 g of silica gel, eluting with hexanes / acetone / dichloromethane (70: 25: 5) and then with 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): the 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, 2 / 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, IH),

1.45 (s, 4H), 1.42 (s, 2H), 1.39 (s, 9H).

Step C: N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2 -amino-2-methylpropanamide hydrochloride

To 0.637 g, 0.101 mmol of the intermediate from Step 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 were 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 the product as a white solid.

1 H-NMR (400 MHz, CD 3 OD): the compound exists as a 3: 2 mixture of rotamers: 7.40-7.28 (m, 4H), 7.25-7.17 (m,

2Η), 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 (b, 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-l-methanesulfonylspiro [3H-indole-3,4'-piperidine] -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-propanoic acid 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

To a stirred solution of 6.7 g (15.9 mmol) of the crude intermediate obtained in Step A, 1.8 g (0.1 equivalents) of tetrakis (triphenylphosphine) palladium and 1.25 g (0.3 equivalents) of triphenylphosphine was added 35 mL, Of a 0.5 M solution of potassium 2-ethylhexanoate in ethyl acetate. The reaction mixture is stirred under nitrogen at room temperature for 1 hour, then diluted with 100 ml of ether and poured into a mixture of water and 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 were combined, washed with saturated brine, dried over sodium sulfate, filtered and evaporated to give the title product 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 1.6 (m, 1H); 1.4 (d, 6H); 1.3 (s, 9H).

Step C: N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2 - [(1,1-dimethylethoxy) carbonyl] amino-2-methylpropanamide

To a solution of 1-methanesulfonylspiro [indoline-3,4'-piperidine] hydrochloride, 1.0 g, 3.44 mmol, 1.44 g, 3.78 mmol of 2 (R) - [[2- (1,1-dimethylethoxy) -carbonyl acid] [amino] -2,2-dimethyl-loxoethyl] 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-hydroxybenztriazole, HOBT in 50 ml of dichloromethane are added 1.03 g,

5.20 mmol of EDC and stirred at room temperature for 16 hours. The reaction mixture was then 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 oil was flash chromatographed on 50 g of silica gel to give 2.148 g (90%) of the desired product as a colorless foam.

1 H-NMR (400 MHz, CDCl 3): the compound exists as a mixture of rotamers in a ratio of 3: 2: 7.40-7.10 (m, 6H), 7.06 (d, 1 / 3H), 7, O 2 (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, 2 / 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 D: N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2 amino-2-methylpropanamide hydrochloride

To a solution of 2.148 g, 3.41 mmol of the intermediate of step

C in 10 ml of dichloromethane is added 5 ml of trifluoroacetic acid and the mixture is stirred for 1 hour. The reaction mixture was concentrated and basified by addition of 100 ml of 5% aqueous sodium carbonate solution, then extracted with 3 x 50 ml of dichloromethane. The organic extracts were combined, washed with 50 mL saturated sodium chloride, 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 resulting precipitate was 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 in a yield of 93%.

1 H-NMR (400 MHz, CD 3 OD): the 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 [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2- methylpropanamide

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

The resulting product can be prepared from 2 (R) -2 - [(1,1-dimethylethoxy) carbonyl] amino-4-phenyl-1-butanoic acid and

1,2-dihydro-1-methylsulfonylspiro [3H-indole-3,4'-piperidine] hydrochloride using the coupling method 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, O (m, 2H), 1.7 (m, 4H), 1.5 (s, 6H), 1.4 (s, 9H).

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

The product can be prepared from the intermediate of step

And by deprotection as described in step 18 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), 2.0 (m, 4H), 1.6 (s, 6H).

Example 7

Combination therapy using N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] 3-phenylpropyl] -2- amino-2-methylpropanamide and pamidronate. Experiments in older female rats lasting 9 weeks

The purpose of these experiments was to evaluate the effect of N- [1 (R) [(1,2-dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl ] -2-amino-2-methylpropanamide alone and in combination with pamidronate, 3-aminol-hydroxypropylidene-1,1-bisphosphonic acid for bone tissue of older rat females. The experiments lasted 9 weeks. The propanamide derivative was administered once daily 7 days a week. Pamidronate was administered once a week, the first day of the week, the propanamide derivative was administered by the esophagus tube. The control group was administered only distilled water, in which the respective derivative was also dissolved as in the vehicle, the propanamide derivative was administered in a volume of 5 ml / kg, pamidronate in a volume of 1 ml / kg. Female Sprague-Dawley Cr1: CD 4 (SD) BR rats were used for the experiments, the approximate age of the females at the start of the experiment was greater than 18 months and the average weight at the start of the experiment was 300-400 g.

There were no substances present in the feed and water that were known to interfere with the experiment. No such substances were found in the cage material, the rats were housed individually in wire and stainless steel cages. The litter was also free from interfering substances.

Dosing code for number of animals dose male female control 1 01 control 2 distilled water 07

N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indole-3,4 'piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide ( 50 mg / kg / day) pamidronate (120 gg / kg / weekly)

N- [1 (R) - [(1,2-Dihydro-1-methanesulfonyl-spiro [3H-indole-3,4'-piperidin] -1'-yl) -carbonyl] -3-phenyl-propyl] -2-amino-2-methyl-propanamide + pamidronate (50 mg / kg / day +

120 gg / kg / once a week)

7

8

11

10

Hormone analysis

Day 1: administration of the active substances. Blood was collected at approximately 1.5 ml from the sinus orbitalis of rats of all groups fed with normal feed for GH (growth hormone), blood collection was performed 15 minutes after distilled water administration in both control and active groups. substances individually or in combination.

Weeks 2 ^X and 9: Blood was collected approximately

1.5 ml in the same way for all groups except growth hormone control group 1, blood was collected 15 minutes after the administration of distilled water in control group 2 and the groups treated with the propanamide derivative as such or in combination. In addition, a large blood sample was taken from the hollow vein after killing the 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-methanesulfonylspiroph 3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2-methylpropanamide

N- [1 (R) - [(1,2-Dihydro-1-methanesulfonyl-spiro [3H-indole-3,4'-piperidin] -1'-yl) -carbonyl] -3-phenyl-propyl] -2-amino-2-methyl-propanamide + pamidronate ng / ml 10 ng / ml ng / ml ng / ml ng / ml

Bone tissue labeling

All rats were given bone labelers, oxytetracycline and calcein, namely oxytetracycline 9 days and calcein 2 days prior to sacrifice.

Oxytetracycline was injected subcutaneously in two doses over a period of 5 hours, each dose given 25 mg per kg body weight, calcein given intraperitoneally in a single dose of 15 mg / kg.

Effect on osteoblast surface treatment method of osteoblast surface treatment in% ± SEM control 2

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

N- [1 (R) - [(1,2-Dihydro-1-methanesulfonyl-spiro [3H-indole-3,4'-piperidin] -1'-yl) -carbonyl] -3-phenyl-propyl] -2-amino-2-methyl-propanamide + pamidronate

3.51 (0.63)

3.91 (0.73) 0.80 (0.26)

3.05 (0.36)

As can be seen from the results, growth hormone secretion enhancers can be used to restore the formation of bone tissue that has been suppressed by pamidronate to the control level. In addition, no difference in the surface of the osteoblasts (bone resorption) could be observed due to treatment with growth hormone secretagogues. The results observed are obvious 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 illustrated in particular cases in various specific embodiments. However, it is quite obvious that a number of changes and modifications could be proposed

I

70 and modifications of said processes without departing from the spirit and scope of the invention. For example, it would be possible to administer dosages other than said dosages, for example as a result of another response 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 employed or also on the type of pharmaceutical composition chosen or the mode of administration. All such modifications and expected changes are within the scope of the invention.

Claims (24)

1) nh ₂ 1) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ) ethyl] 2-amino-2-methylpropanamide. 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 NHON, -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, -0C (O) N (R ^2a ) (R ^2a ), -0C (O) N (R ^2a ) (CH ₂ ) _q -aryl, -SO ₂ (CH ₂ ) _q CONH- (CH ₂ ) _w NHC (O) R ^11L , where w is an integer from 2 to 6 and R is a biotin, aryl or aryl radical substituted with 1 or 2 OR, 1 or 2 atoms 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 halo, azido or nitro; 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 individual diastereomers. 1) NH ₂ , 1) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl ] 2-amino-2-methylpropanamide. 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 NHON, -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, -0C (O) N (R ^2a ) (R ^2a ), -0C (O) N (R ^2a ) (CH ₂ ) _q -aryl, -SO ₂ (CH ₂ ) CO-NH- (CH ₂ ) _w NHC (O) R ^{1: L} wherein w is an integer from 2 to 6 and R is a biotin, aryl or aryl residue O substituted by 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 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 may be absent to form a 5 or 6-membered heterocyclic aromatic ring as well as pharmaceutically acceptable salts thereof, and individual diastereomers. 1) nh ₂ A combination preparation for the treatment or prevention of osteoporosis, characterized in that it comprises a bisphosphonate and a growth hormone secretagogue. 2 -C (O) N (R ^2a ) (R ^2a ) groups, 1 to 2 groups -C (O) N (R ^2a ) (CH ₂ ) _q -aryl, 1 to 5 halogen atoms, 1 to 5 2 alkyl groups having 1 to 4 carbon atoms and R and the aryl moiety is optionally further substituted with 1 to 4 carbon atoms; 2) pyridyl, 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. 2) pyridyl, 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. 2) pyridyl, Combination preparation according to claim 1, characterized in that it comprises a biphosphonate of the general formula X 0 R ² O HO-P-C-P-OH (X) OH R ¹ OH where R1 is selected from the group (a) alkyl of 1 to 5 carbon atoms optionally substituted by one of the following groups 3 alkyl groups having 1 to 4 carbon atoms or substituents from 1,2,4-triazolyl, 1H-tetrazol5-yl, -C (O) NHSO ₂ R ^2a , -S (O) m R ^2a , -C (O) NHSO 2 (CH ₂ ) _q -aryl, -SO ₂ NHON, -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, -0C (O) N (R ^2a ) (R ^2a ), -0C (O) N (R ^2a ) (CH ₂ ) _q -aryl, -SO ₂ (CH ₂ ) CONH- (CH ₂ ) _w NHC (O) r H where w is an integer from 2 to 6 and R is a biotin residue, aryl or aryl O substituted by 1 or 2 OR, 1 or 2 halogen atoms, azido or nitro, represents an integer of 0, 1 or 2, represents an integer of 1 or 2, optionally represents 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 individual diastereomers. -0R 3 groups ^ ^and, -0 _{(CH2) q} aryl, 1 to 2 groups, -C (O) OR ^2a , 1 to 2 -C (O) O (CH ₂ ) _q -aryl, 1 to 2 groups; 3) pyrrolidyl, 3) N- [1 (R) - [(1,2-dihydro-1-benzenesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ) ethyl] 2-amino-2-methylpropanamide. 3) pyrrolidyl, 3) N- [1 (R) - [(1,2-dihydro-1-benzenesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ) ethyl] 2-amino-2-methylpropanamide. 3. The combination preparation of claim 1 wherein the bisphosphonate is selected from the group consisting of alendric, etidronic, clodronic, pamidronic, tiludronic, risedronic, 6-amino-1-hydroxyhexylidene biphosphonic acid, 1-hydroxy-3- (methylpentylamino). propylidene bisphosphonic acid or pharmaceutically acceptable salts of these acids. 3) pyrrolidyl, 4) NR ³ R ⁴ (b) NR ⁵ , (c) SR ** or d) chlorine atom, ^R2 is H, OH or Cl, R ³ is H or C 1 -C 4 alkyl, R ⁴ is C 1 -C 4 alkyl, r ⁵ is C 1 -C 10 alkyl, and r 6 is aryl as well as pharmaceutically acceptable salts thereof. 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. 4) NR ³ R ⁴ (b) NR ⁵ , (c) SR ⁵ or d) chlorine atom, R is hydrogen, hydroxy or chlorine, R is hydrogen or alkyl of 1 to 4 carbon atoms, R ⁴ is C 1 -C 4 alkyl, R ⁵ is C 1 -C 10 alkyl and R ⁵ is a pharmaceutically acceptable salt, as well as a salt of these compounds. 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. Combination preparation according to claim 3, characterized in that it contains alendronic acid or a pharmaceutically acceptable salt thereof as the bisphosphonate. 4) NR ³ R ⁴ (b) NR ⁵ , (c) SR ** or d) chlorine atom, R is hydrogen, hydroxy or chlorine, q R is hydrogen or alkyl of 1 to 4 carbon atoms, R ⁴ is C 1 -C 4 alkyl, R ³ is C 1 -C 10 alkyl and r 6 is aryl as well as the pharmaceutically acceptable salts of these compounds. Cycloalkyl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) having a cycloalkyl moiety of 3 to 7 carbon atoms, wherein K is 0, S (O) _m , N ( R ² ) C (0), C (0) N (R ² ), 0C (0), C (0) 0, or -CR = CR-, or -OC-, wherein the aryl groups have The meanings given below and the R group and the alkyl groups may be further substituted by 1 to 9 halogen atoms or S (O) _m R ^2a , 1 to 3 OR ^2a or C (O) OR ^2a groups and the aryl groups are optionally further substituted by a phenyl group , phenoxy, halophenyl, 1 to 3 alkyl of 1 to 6 carbon atoms, 1 to 3 halogens, 1 or 2 substituents from the group -0R ^R, methylenedioxy, -S ^ R ^"6, -CF _{3, 3} -0CF , nitro, -N ^{(R2) (R2),} -N ^(R2) C (0) ^R2, -C (O) OR ^2, -C (0) N (R ²⁾ (R ^2), -SO 2 N (R ²⁾ (R ^2), -N ^(R2) S (0) 2 aryl, and -N (R ² ) S0 ₂ R ² R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 carbon atoms, and when there are two alkyl groups of 1 to 6 carbon atoms per atom 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. 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. Combination preparation according to claim 1, characterized in that it contains an amide derivative of the general formula I or II as growth hormone secretagogue. R ² R ⁶ • R R ^ N-C-C-A-N. you ABOUT RR ² R ⁶ R ¹ -C-N-C-A II o 'R ⁵ c = oc = o (Ό 3a (Π) where R ¹ represents alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl of about 1 to 6 carbon atoms in the alkyl moiety, alkyl-C-alkyl of 1 to 5 atoms carbon 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) 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) ) 0 or 6 carbon atoms may optionally be joined to form a ring containing 3 to 8 carbon atoms and optionally an oxygen, sulfur or NR ^Z atom, R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, R ^a and R b are independently selected from hydrogen, halo well, alkyl of 1 to 6 carbon atoms, -OR, -CN, -OCF _3, methylenedioxy, nitro, -S (O) _m R, _-CF3 or -C (O) OR ² , provided that when R 1a ^and R 1b are in the ortho position, they may be joined to form an aliphatic or aromatic ring of 5 to 8 carbon atoms, optionally containing 1 or 2 heteroatoms from oxygen, sulfur or nitrogen, and are independently selected from hydrogen, alkyl, optionally substituted, in which the substituents are selected from 1 to 5 halogen atoms, 1 to 3 substituents from hydroxy, C 1 -C 10 alkanoyloxy or alkoxy (C 1 -C 6) -phenyl, phenoxy, 2-furyl, (C 1 -C 6) alkoxycarbonyl, -S (O) _m- C 1 -C 6 -alkyl, or r 4 and r 5 together may form - ( CH ₂ ) _r L ^a (CH 2) s -, wherein L ^a represents a -C (R ² ) 2 - group. -O-, -S (O) _m - or -N (R ² ) -, wherein r a is independently an integer of 1 to 3 and R is as defined above, r 6 is a hydrogen atom or an alkyl of 1 to 6 carbon atoms, A represents a group R ⁷ - (CH ₂ ) -O- (CH ₂ ) _y - R ^7a or -Z- (CH ₂ ) _X -C- (CH ₂ ) _y - R ^7a wherein x and y independently represent integers from 0 to 3, Z represents an N-R group or an oxygen atom, R ⁷ and R ^7a are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, -OR, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms, wherein the substituents are selected from imidazolyl, phenyl, 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 94 ka, -N (R ² ) (R ² ), -C (O) N (R ² ) (R ²⁾ ) or R ⁷ and R ^7a may be independently linked to one or both R 6 and R 6 to form alkyl bridges between the terminal nitrogen atom and the alkyl moiety of R 1 or R 2, which may contain 1 to 5 atoms alkyl, B, D, E and F are independently selected from -C (R ®) (R ¹¹ ) -, -O-, -C = O-, -S (O) _m - or -NR 6 -, 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 4 ®) - or -C = 0- only if one of the other symbols B, D, E and F simultaneously represents -0-, “® (θ) πι“ or -NR ^ - or B a D or D and E may together form the group -N = CR ¹⁰ - or -CR ¹⁰ = N- or B and D or D and E may together form the group -CR = CR - provided that one of the remaining symbols B and E or F simultaneously represents -O-, -S (O) _m - or -NR 4 -, R (R) and R (R) * independently represent a hydrogen atom, -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 ) - (1H- tetrazol-5-yl), wherein the aryl moiety is optionally substituted with 1 to 3 halogen atoms, 1 or 2 alkyl groups of 1 to 8 carbon atoms, 1 to 3 -OR groups or 1 or 2 -C (O) OR ² groups, represents -R ² , - (CH 2) qaryl, -C (O) R ² , -C (O) (CH 2) _q aryl, -SO ₂ R ² , -SO ₂ (CH ₂ ) _q -aryl, -C (0) N (R ²⁾ (R ^2), -C (O) N (R ² ) (CH 2) q -aryl, -C (O) OR ² , -1H-tetrazol-5-yl, -SO 3 H, -SO ₂ NHON, -SO ₂ N (R ² ) aryl or -SO ² N (R ² ) (R ² ), wherein the group (CH 2) is optionally substituted with 1 to ² carbon atoms 6) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) 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. Combination preparation according to claim 1, characterized in that it contains a compound of the general formula V (V) wherein R ¹ is selected from the group • CH ₂ CH ₂ -, as growth hormone secretagogue. QcH ₂ CH ₂ -, CH ₂ CH ₂ CH ₂ -, CH ₂ OCH ₂ -, Y J) ^CH 2 .ch ₂ - _, ^F jf Q-CH ₂ OCH, ch ₂ ch ₂ -, N CH ₂ CH ₂ CH ₂ -, ^- F F- / CH ₂ CH ₂ -, f- / CH ₂ CH ₂ CH ₂ -; R ^a is H or F, D is selected from -O-, -S-, -S (O) _m -, N (R ² ), NS0 ₂ (R ² ), NSO 2 (CH 2) t -aryl, NC (O) R ² ), NSO ₂ (CH ₂ ) _q OH, NS0 ₂ (CH ₂ ) _q COOR, NS0 ₂ (CH ₂ ) _q C (0 ) -N (R ² ) (R ² ), N-SO 2 (CH 2) C (O) -N (R ² ) (CH 2) _w OH. N-NH N-SO ₂ (CH ₂ ) _q —J N = N 'aryl means phenyl or pyridyl, wherein the phenyl is optionally substituted with 1 to 2 halogen atoms, n 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 their individual diastereomers. 7) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] 2-amino 2-metylpropánamidmesylát, 7) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] 2-amino 2-metylpropánamidmesylát, 7. The combination preparation of claim 1 wherein the growth hormone secretagogue comprises: 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. Combination preparation according to claim 1, characterized in that it contains alendronic acid or pamidronic acid or a pharmaceutically acceptable salt thereof as the bisphosphonate and contains as growth hormone secretion enhancer N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino2 methylpropanamide. N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2- methylpropanamide, or a pharmaceutically acceptable salt thereof. 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-fluoro-spiro [3H] indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] - 2-amino-2-methylpropanamide. Combination preparation according to claim 1, characterized in that it contains alendronic acid or a pharmaceutically acceptable salt thereof as the bisphosphonate and contains as growth hormone secretion enhancer. N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino2 methylpropanamide or a pharmaceutically acceptable salt thereof. 9) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5-fluorospiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl ] -2-amino-2-methylpropanamide. 9 9 -CR - CR -, or -OC-, wherein the aryl groups are as defined below and the R ¹⁴ group and the alkyl groups may be further substituted by 1 to 9 halogen atoms or S (O) mR ^2a , 1 to 3 OR ^2a or C (O) OR ^2a and the aryl groups are optionally further substituted by phenyl, phenoxy, halophenyl, 1 to 3 alkyl groups of 1 to 6 carbon atoms, 1 to 3 halogen atoms, 1 or 2 substituents from -OR, methylenedioxy , -S (O) mR, -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 ^(R2) S (O) 2 aryl, and -N (R ²⁾ SO ₂ R ^2, ABOUT R is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, and if there are two alkyl groups of 1 to 6 carbon atoms in one atom, they can optionally be joined to form a ring containing 3 to 6 carbon atoms 8 carbon atoms and optionally an oxygen, sulfur or NR ^2a atom, R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, R ^a and R b are independently selected from hydrogen, halo well, alkyl of 1 to 6 carbon atoms, -OR, -CN, -OCF _3, methylenedioxy, nitro, -S (O) _m R, _-CF3 or -C (O) oR ^2, wherein, if R ^a and R b, and _s are in the ortho position, can be joined to form an aliphatic or aromatic ring having 5 to 8 carbon atoms, optionally containing 1 or 2 heteroatoms oxygen, sulfur or nitrogen, R ⁴ and r ⁵ are independently selected from hydrogen, alkyl, optionally substituted, wherein the substituents are selected from 1 to 5 halogen atoms, 1 to 3 substituents from hydroxy, C 1 -C 10 alkanoyloxy or C 1 -C 6 alkoxy carbon atoms, phenyl, phenoxy, 2-furyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety, -S (O) alkyl of 1 to 6 carbon atoms, or R ⁴ and r ⁵ together may form - (CH 2) _r L ^and (CH ₂ ) -, wherein L ^a is -C (R ² ) ₂ -, -O-. S (O) _m - ^or -N ^(R2) -, wherein • _the race ZZVZV 9 independently represent an integer of 1 to 3 and R ² * is as defined above, R ⁵ represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, A represents a group R ⁷ - (CH ₂ ) -C - (CH ₂ ) _y - r ⁷ or or R ⁷ - Z - (CH ₂ ) _X -C - (CH ₂ ) _y - R ^7a wherein x and y independently represent integers from 0 to 3, ABOUT Z is ^NR or O, R ² and R ^7a are independently selected from hydrogen, alkyl O with 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, o 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 may be independently linked to one or both R ⁴ and R ⁵ to form alkylene bridges between the terminal nitrogen atom and the alkyl portion of R ⁷ or R ^7a , which may contain 1 to 5 atoms alkyl, B, D, E and F are independently selected from -C (R 8) (R 6) -, -O-, -C = O-, -S (O) _m - or -NR 6 -, 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 4 ®) - or -C = O- only if one of the other 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 forming a group -N = Cr1®- or -Cr1® = N- or B and D or D and E may together form a group -CR® = Cr10-, provided that one of the remaining symbols B and E or F simultaneously represents - O-, -S (O) _m - or -NR ⁹ -, R ® and R 10 independently represent a hydrogen atom, -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 of 1 to 8 carbon atoms, 1 to 3 -OR groups, or 1 or 2 -C (O) groups 0R ² , R ⁹ is -R ² , - (CH ₂ ) _q -aryl, -C (O) R ² , -C (O) (CH ₂ ) _q -aryl, -SO ₂ R ² , -SO ₂ (CH ₂ ) _q -aryl, -C (O) N (R ² ) (R ² ), -C (O) N (R ² ) (CH 2) q -aryl, -C (O) OR ² , -1H-tetrazol-5-yl, - SO ^ H, -S02NHON, -S0 ₂ N ^(R2) aryl, or -SO 2 N (R ²⁾ (R ^2), wherein (CH 2) _q is optionally substituted by 1 to 2 alkyl groups of 1 to 4 carbon atoms and R, and the aryl moiety is optionally further substituted with 1 to 3 radicals -0R ^ ^a, -0 _{(CH2) q} aryl, 1 to 2 -C (0) 0R ^2, 1 to 2 groups, -C (O) O (CH ₂ ) _q -aryl, 1 to 2 -C (O) N (R ^2a ) (R ^2a ), 1 to 2 -C (O) N (R ^2a ) (CH ₂ ) groups ) _q -aryl, 1 to 5 halogen atoms, 1 to 3 alkyl groups having 1 to 4 carbon atoms or substituents from the group 10) N- [1 (S) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethylthio) ethyl] -2- amino-2-methylpropanamide. A pharmaceutical composition for the treatment or prevention of osteoporosis, characterized in that it comprises a bisphosphonate and a growth hormone secretagogue together with an inert carrier as active ingredients. 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 . Pharmaceutical composition according to claim 10, characterized in that it contains a compound of formula X as the bisphosphonate 0 R ² O HO-P-C-P-OH OH ^R10H (X) wherein R ⁷ is selected from the group consisting of (a) alkyl of 1 to 5 carbon atoms optionally substituted by one of the following groups 11) N- [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 . Pharmaceutical composition according to claim 10, characterized in that the bisphosphonate is selected from the group of alendric, etidronic, clodronic, pamidronic, tiludronic, risedronic, 6-amino-1-hydroxyhexylidene biphosphonic acid, 1-hydroxy-3- (methylpentylamino) propylidene biphosphonic acid or from pharmaceutically acceptable salts of these acids. 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 . Pharmaceutical composition according to claim 12, characterized in that it contains alendronic acid or a pharmaceutically acceptable salt thereof as the bisphosphonate. 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 [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro-1H-indole) -3-yl) ethyl] -2-amino-2-methylpropanamide. 14. A pharmaceutical composition according to claim 10, wherein the growth hormone secretagogue comprises an amide derivative of the formula I or II wherein: R1 denotes alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl of about 1 to 6 carbon atoms in the alkyl moiety, alkyl-C-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) C 3 -C 7 cycloalkyl, wherein K is O, S (O) _m , N (R ² ) C (O), C (O) N (R ² ), OC (O), C (O) 0 or -CR-CR-, or -OC-, wherein the aryl groups are as defined below and the R 6 group and the alkyl groups may be further substituted by 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 by phenyl, phenoxy, halophenyl, 1 to 3 alkyl groups of 1 to 6 carbon atoms, 1 to 3 halogen atoms, 1 or 2 substituents from -OR, methylenedioxy, -S (O) _m R, -CF ₃ , -OCF ₃ , nitro, -N (R ² ) (R ² ), -N (R ² ) C (O) R ² , C (0) 0R ^2, -C (0) N (R ²⁾ (R ^2), -SO 2 N (R ²⁾ (R ^2), -N ^(R2) S (0) 2 aryl, and -N (R ² ) S0 ₂ R ² R ² is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, and in the event of one atom contains two alkyl groups having 1 to 6 carbon atoms, may be joined to form a ring containing 3 up to 8 carbon atoms and optionally oxygen, sulfur or NR ^2a ; R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, R ^3a and R ^3b are independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, -OR, cyano, -OCF ₃ , methylenedioxy, nitro, -S (O) _m R, -CF _3, or -C (0) OR ² , wherein when R ^3a and R ^3b are in the ortho position, they may be joined to form an aliphatic or aromatic ring of 5 to 8 carbon atoms, optionally containing 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen, R ⁴ and R ⁵ are independently selected from hydrogen, alkyl, optionally substituted, wherein the substituents are selected from 1 to 5 halogen atoms, 1 to 3 substituents from hydroxy, C 1 -C 10 alkanoyloxy or C 1 -C 10 alkoxy 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 ⁴ and R ³ together may form - (CH 2) _r L ^a (CH 2) s -, wherein L ^a is -C (R ² ) 2 -, -O-, -S (O) _m - or -N (R ² ) -, wherein _r ^and _r are independently an integer of 1 to 3 and R is as defined above, R ³ is H or alkyl of 1 to 6 carbon atoms, A represents a group - (CH ₂ ) -c - (CH ₂ ) _y - R ^7a or -Z- (CH ₂ ) _x -C- (CH ₂ ) _y -, 7a wherein x and y independently represent integers from 0 to 3, ABOUT Z represents an N-R group or an oxygen atom, R? and R? ^and are independently selected from hydrogen, alkyl O with 1 to 6 carbon atoms, -OR, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from the group of imidazolyl, phenyl, 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 can R? and R? ^0, independently linked to one or both of the groups for R ^4, and R ^ to form alkylene bridges between the terminal nitrogen and the alkyl portion of R? or R ^a, and these bridges may have 1 to 5 carbon atoms, B, D, E and F are independently selected from -C (R ®) (R ^X ®) -, -O-, -C = O-, -S (O) m - or -NR 6 -, 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 ^X ®) - or -C = O- only if one of the other symbols B, D, E and F simultaneously represents -O-, -S (O) m- or -NR 6 - or B a D or D and E may together form -N = CR ^X ®- or -CR ^X ® = N- or B and D or D and E may together form -CR -CR - provided that one of the other B and E or F simultaneously represent -O-, -S (O) _m - or -NR 6 -, R ® and R ^X ® independently represent a hydrogen atom, -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 having 1 to 8 carbon atoms, 1 to 3 -OR groups, or 1 or 2 -C (O) OR groups ² , R is a group R ^2, - _{(CH2) q} -aryl, -C (0) ^R2, -C (O) (CH ₂ ) _q -aryl, -SO ₂ R ² , -SO ₂ (CH ₂ ) _q -aryl, -C (O) N (R ² ) (R ² ), -C (O) N (R ² ) (CH ₂ ) _q -aryl, -C (O) OR ² , -1H-tetrazol-5-yl, -SO ₃ H, -SO ₂ NHON, -SO ₂ N (R ² ) aryl or -SO ₂ N (R ² ) (R ² ), wherein the group (CH 2) _q is optionally substituted with 1 C 1-4 alkyl groups having 1 to 4 carbon atoms and R and the aryl moiety optionally further substituted by 1 to 3 groups -OR ^3a , -O (CH ₂ ) _q -aryl, 1 to 2 -C (O) OR ^2a , 1 up to 2 groups -C (O) O (CH ₂ ) _q -aryl, 1-2 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 to 3 alkyl groups having 1 to 4 carbon atoms or substituents from the group 14) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro-1H-indole) -3-yl) ethyl] -2-amino-2-methylpropanamide. 15) N- [1 (R) - [(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro) -lHindol-3-yl) ethyl] -2-amino-2-methylpropanamide. 15. A pharmaceutical composition according to claim 10, wherein the growth hormone secretion enhancer is a compound of formula (V) ## STR5 ## wherein R is selected from the group of ch ₂ ch ₂ ch ₂ CH ₂ OCH ₂ -, F - / y - CH ₂ CH ₂ CH ₂ -; R ^2a represents a hydrogen or fluorine atom, D is selected from -O-, -S-, -S (O) _m -, N (R ² ), NSO ₂ (R ² ) NSO ₂ (CH ₂ ) _t -aryl, NC (O) R ² ), NS02 (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 (O) -N (R ² ) (CH ₂ ) _w OH. N-SO ₂ (CH ₂ ) q - ( ^z 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, w is an integer of 2, 3, 4, 5 or 6, as well as their pharmaceutically acceptable salts and their individual diastereomers. 15) N- [1 (R) - [(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro) -lHindol-3-yl) ethyl] -2-amino-2-methylpropanamide. 16) N- [1 (R) - [(1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- ( 1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide. 16. A pharmaceutical composition according to claim 10, wherein the growth hormone secretagogue comprises: 16) N- [1 (R) - [(1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- ( 1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide. Pharmaceutical composition according to claim 10, characterized in that it contains alendronic acid or pamidronic acid or one of the pharmaceutically acceptable salts thereof as the bisphosphonate and contains as growth hormone secretion enhancer N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-3,4 'piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino2 methylpropanamide. N- [1 (R) - [(1,2-Dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2-amino-2- methylpropanamide, or a pharmaceutically acceptable salt thereof. 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 of these compounds. 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. Pharmaceutical composition according to claim 10, characterized in that it contains as a bisphosphonate alendronic acid or a pharmaceutically acceptable salt thereof and as growth hormone secretion enhancer it comprises: N- [1 (R) - [(1,2-Dihydro-l-methanesulfonylspiro [3H-indole-3,4'-piperidine] -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 a medicament for the treatment of osteoporosis. Use according to claim 19, characterized in that a biphosphonate of the formula X is administered as a component of the combined preparation to the patients. OR ² O HO-P-C-P-OH (X) OH R ¹ OH where R1 is selected from the group (a) alkyl of 1 to 5 carbon atoms optionally substituted by one of the following groups Use according to claim 19, characterized in that alendric acid, etidronic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1-hydroxyhexylidene-biphosphonic acid, 1-hydroxy-3- ( methylpentylamino) propylidene bisphosphonic acid or a pharmaceutically acceptable salt thereof. Use according to claim 19, characterized in that alendronic acid or a pharmaceutically acceptable salt thereof is administered to the patients as a component of the combination preparation. Use according to claim 19, characterized in that a growth hormone secretagogue of the formula I or II is administered to the patient as a component of the combination preparation. R @ ² R @ 1 R @ 1 -O-N-C — A — N R ² R ⁶ R ¹ -N-NC-A-N _with R- (II) where R 1 represents alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl of about 1 to 6 carbon atoms in the alkyl moiety, alkyl-C-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) 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. R N where R · * · is selected from group (V) CH ₂ CH ₂ -, θ-ΟΗ ₂ ΟΚ ₂ ΟΗ ₂ , θ-ΟΗ ₂ ΟΟΗ ₂ -. p · y-CH2CH2CH2; M R @ ³⁸ means a hydrogen or fluorine atom, D is selected from -0-, -S-, -S (0) _m -, -N (R ²⁾ NS02 (R ²⁾ n SO2 _{(CH2) t} aryl, NC (O) R ^2), n SO2 (CH2) q OH, NS02 (CH2) qC00R, NS02 (CH 2) q C (0) -N (R ²⁾ (R ²⁾ n SO2 _{(CH2) q} C (O) -N ^(R2) ( CH ₂ ) _w OH.