NO312298B1 - Analogous Process for Preparation of Therapeutically Active Indole Derivatives - Google Patents

Description

BACKGROUND OF THE INVENTION

Agents acting on central cholecystokinin (CCK) receptors can induce satiety (Schick, Yaksh & Go, Regulatory Peptides 14:277-291, 1986). They are also expected to act as analgesics (Hill, Hughes & Pittaway, Neuropharmacoloqy 26:289-300, 1987) and as anticonvulsants (MacVicar, Kerrin & Davison, Brain Research 406:130-135, 1987).

In the brains of schizophrenic patients, reduced levels of CCK peptides have been found compared to controls (Roberts, Ferrier, Lee, Crow, Johnstone, Owens, Bacarese-Hamilton, McGregor, O'Shaughnessey, Polak & Bloom, Brain Research 288:199- 211, 1983). It has been suggested that changes in the activity of CCK neurons projecting to the nucleus accumbens may play a role in schizophrenic processes by affecting dopaminergic function (Totterdell & Smith, Neuroscience 19:181-192, 1986). This is in agreement with a number of reports that CCK peptides modulate dopaminergic function in the basal ganglia and particularly in the nucleus accumbens (Weiss, Tanzer & Ettenberg, Pharmacology, Biochemistry and Behavior 30:309-317, 1988; Schneider, Allpert & Iversen, Peptides 4:749-753, 1983). It can therefore be expected that agents that change CCK receptor activity may have therapeutic value in conditions associated with disturbed function of central dopaminergic function, such as schizophrenia and Parkinson's disease.

CCK and gastrin peptides have a common carboxy-terminal pentapeptide sequence and CCK peptides can bind to gastrin receptors in the gastric mucosa and cause acid secretion in many animal species, including humans (Konturek, Gastrointestinal Hormones, Ch. 23, pp. 529-564, 1980, ed. G. B. J. Glass, Raven Press, NY). Antagonists of CCK-B receptors would also be expected to be antagonists of gastrin receptors in the stomach, and this would also be of value in conditions where excessive acid secretion occurs.

CCK and gastrin peptides have trophic effects on the pancreas and various tissues in the gastrointestinal tract

(Johnson, ibid., pp 507-527), effects which are associated with increased DNA and RNA synthesis. Gastrin-secreting cells are also associated with certain gastrointestinal tumors such as Zollinger-Ellison syndrome (Stadil, ibid., pp 729-739), and certain colorectal tumors can also be gastrin/CCK dependent (Singh, Walker, Townsend & Thompson, Cancer Research 46:1612, 1986; Smith, J.P., Gastroenterology 95:1541, 1988). Antagonists of the CCK/gastrin receptors could therefore have therapeutic value as antitumour agents.

The CCK peptides are widely distributed in various organs of the body, including the gastrointestinal tract, endocrine glands and the nerves of the peripheral and central nervous system. Different biologically active forms have been identified, including a 33-amino acid hormone and various carboxyl-terminal fragments of this peptide (eg the octapeptide CCK26-33 and the tetrapeptide CCK30-33). (G. J. Dockray, Br. Med. Bull. 38 (3): 253-258, 1982).

The various CCK peptides are believed to be involved in the control of smooth muscle contractility, secretion from exocrine and endocrine glands, transmission in sensory nerves and numerous brain functions. Administration of the native peptides causes gallbladder contraction, amylase secretion, excitation of central neurons, refusal to eat, anticonvulsant effects and other behavioral effects (Cholocvstokinin: Isolation, Structure and Functions, G.B.J. Glass, Ed., Raven Press, New York, 1980, pp. 169-221; J.E. Morley, Life Sciences 27:355-368, 1980; Cholecystokinin in the Nervous System, J. de Belleroche & G.J. Dockray, Ed. Ellis Horwood, Chichester, England, 1984, pp. 110-127).

The high concentrations of CCK peptides in many brain areas also suggest that the peptides have important brain functions (G.J. Dockray, Br. Med. Bull. 38 (3):253-258, 1982). The most abundant form of brain CCK found is CCK26-33, but small amounts of CCK30-33 are also present (Rehfeld & Gotterman, J. Neurochem. 32:1339-1341, 1979). What role CCK plays in the central nervous system is not known with certainty, but has been implicated in the regulation of nutrient uptake (Della-Fera & Baile, Science 206:471-473, 1979).

Available, centrally acting appetite suppressants strengthen central catecholamine pathways and appear to act as stimulants (eg amphetamines), or influence serotonergic pathways (eg fenfluramine). Other forms of drug therapy include bulking agents that work by filling up the stomach and thereby inducing a "feeling" of satiety.

CCK is known to occur in some cortical interneurons that also contain gamma-aminobutyric acid (GABA) (H. Demeulemeester et al., J. Neuroscience 8:988-1000, 1988). Agents that alter the action of GABA may be useful as anxiolytics or hypnotics (S.C. Harvey, The Pharmacological Basis of Therapeutics (7th. ed.) 1985, pp 339-371, MacMillan). Agents that change the CCK effect can thus have parallel anxiolytic or hypnotic effects. What role CCK plays in anxiety is discussed in TIPS 11:271-273, 1990.

SUMMARY OF THE INVENTION

The invention relates to the preparation of new compounds of formula

or a pharmaceutically acceptable salt thereof,

where:

R<1> is adamentyl or bornyl,

R<2> is hydrogen or C1-C4 alkyl,

R<3> is hydrogen, (CH2)nOH, (CH2)n0Ac or (CH2)n0C0 (CH2)nCOOH, R<4> is hydrogen, OH or phenyl,

R<12> is hydrogen or forms a double bond together with R13, R<13> is hydrogen or forms a double bond together with R<12>,

R<20> is hydrogen, (CH2)nOH, CONH2, CCVCVCValkyl, CO2Bz or

COOH,

Ar<1> is phenyl, COj-C^-Cj-alkyl, bicyclo [2 . 2 .1] heptane or optionally with (CH2)nOH, COOH, CN, C^Q-alkyl or CONH-Q-C-alkyl substituted C3-C7-cycloalkyl,

X and Y are independently selected from NH, NHCO, CONH, C00 or CSNH, p, r, s, t, u and v are independently selected from 0 or 1, and n is 1-4.

In our co-pending applications 07/576.3 08, 07/576,296, 07/576,315, 07/576,024 and 07/576,297 of August 31, 1990 (Horwell et al.), CCK antagonists are described.

A pharmaceutical preparation may contain an effective amount of a compound according to formula I, in combination with a pharmaceutically acceptable carrier, in unit dosage form which provides effective appetite suppression.

The compounds are also useful as anxiolytics, anti-psychotics, especially for the treatment of schizophrenic behaviour, as agents for the treatment of disorders in the extrapyramidal motor system, as agents for blocking the trophic and growth-stimulating effects of CCK and gastrin and as agents for the treatment of gastrointestinal motility.

Compounds produced according to the invention are also useful as analgesics, and they enhance the effect of morphine. They can be used as a supplement to morphine and other opioids in the treatment of severe pain, such as cancer pain, and reduce the necessary morphine dosage in pain treatment when morphine is contraindicated.

A further application for compounds produced according to the invention follows from the fact that a suitable radioactive isotope provides a suitable agent for the treatment of gastrin-dependent tumours, such as e.g. those found in colon cancer. I-125-radioactively labeled compounds according to the invention can also be used as diagnostic agents for the localization of gastrin and CCK-B receptors in peripheral and central tissue.

The compounds can also be used to reduce the appetite of mammals, by administering a sufficient amount of the compound described above, to a mammal in need of such treatment.

A pharmaceutical preparation for reducing gastric acid secretion may contain an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier, in unit dose form, effective for reducing gastric acid secretion.

A pharmaceutical preparation containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier, in unit dosage form, is effective for reducing anxiety.

A pharmaceutical preparation containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier. in unit dose orm, is effective for the treatment of gastrointestinal ulcerations.

A pharmaceutical preparation containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier, in unit dosage form, is effective for the treatment of psychoses, i.e. schizophrenia.

Pharmaceutical preparations that effectively stimulate or block CCK or gastrin receptors, alter the activity of neurons in the brain, are effective in schizophrenia, in the treatment of disorders of the extrapyramidal motor system, block the trophic and growth-stimulating effects of CCK and gastrin, and treatment of gastrointestinal motility.

A pharmaceutical preparation containing a compound of formula I is effective in preventing withdrawal in the chronic treatment of drug or alcohol abuse.

Such drugs include benzodiazepines, especially diazepam, cocaine, alcohol and nicotine. Withdrawal symptoms are treated by administering a compound prepared according to the invention in an amount which effectively treats withdrawal symptoms.

A pharmaceutical composition containing an effective amount of a compound of formula I, in combination with a pharmaceutically acceptable carrier, in unit dosage form, is effective for the treatment and/or prevention of panic.

Compounds of formula I can be used for the preparation of pharmaceutical and diagnostic compositions for the treatment and diagnosis of the conditions described above.

The process according to the invention for the preparation of compounds of formula I is characterized by the fact that

a) linking the corresponding individual α-amino acids, which may be unprotected or protected, to form the desired

compound of formula I,

or that when preparing compounds with the general formula Ia

where R<1> is 1-adamantyl, 2-adamantyl or (IS)-2-endo-bornyl,

R 1 is H or methyl

C is 0 or 1,

R<3> is H, CH2OH or CH2O-CO-(CH2)2C02H'

R<4> is H and Ar is taken from Ar<1> as defined above, or a pharmaceutically acceptable salt thereof,

b) transforms the compound with the formula

where R<1> and R<2> have the meanings given above, to an activated ester, e.g. with penta-fluorophenyl and dicyclohexylcarbodiimide, and then reacting the activated ester with an appropriate amine to form a compound of formula Ia, or

c) reacts a compound with the formula

where c is 0 or 1,

with a compound of the formula R<1->0-CO-Cl, where R<1> has the meaning given above, to obtain a compound of the formula Ia, where R<2>, R<3> and R<4 > is hydrogen, or

d) reacts a compound with the formula

R<2> is H with a compound of formula Rl-o-CO-Cl to obtain a compound of formula Ia, where R<3> and R<4> are hydrogen, and if desired, converting a compound of formula Ia to a pharmaceutically acceptable salt thereof in a conventional manner.

Preferably, Ar<1> is phenyl.

Preferred compounds prepared according to the present invention are those where

R<1> is 1-adamantyl, 2-adamantyl or bornyl, especially 1-(S)-2-endobornyl.

Most preferred compounds prepared according to the present invention are: carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)ethyl]-, tricyclo [3, 3 , 1, 13'7] dec-2-yl ester, [S-(R<*>,S<*>)]-,

carbamic acid, [2- [[1-(hydroxymethyl)-2 - phenylethyl] amino] - 1-(1H-indol-3-ylmethyl) ethyl] , tricyclo [3 , 3 ,1, 13'7] dec-2- yl ester, [S-(R<*>,R<*>)]-,

tricyclo [3.3.1.13'7] dec-2-yl [1- [ [ [1-hydroxymethyl)-2-phenylethyl]carbonyl]amino]- 2 -1H-indol-3-yl)ethyl]carbamate,

carbamic acid, [2- [(2-hydroxy-2-phenylethyl)-amino]-1-(1H-indol-3-ylmethyl)-1-methylethyl] - , tricyclo [3,3,1, l3'7] dec -2-yl ester (hydroxy center is RS the other center is R),

carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]amino] - 1-(1H-indol-3-ylmethyl) -1-methylethyl] - , tricyclo [3 , 3 , 1, l3'7] dec-2-yl ester, [R-(R<*>,S<*>)]-, 4-methylbenzenesulfonate (1:1) (salt),

benzenepropanol, ph-[[2-(1H-indol-3-yl)-2-[[tricyclo-[3 . 3 .1.13,7] dec-2-yloxy) carbonyl] amino] propyl] amino] - , acetate (ester), [R-(R<*>,S<*>)]-, 4-methylbenzenesulfonate (1: 1) (salt),

carbamic acid, [[2-[acetyl[1-(hydroxymethyl)-2-phenylethyl]-amino]-1-(1H-indol-3-ylmethyl)-1-methyl]-ethyl]-, tricyclo-[3 . 3 .1.13'7] dec-2-yl ester, [R- (R* , S*) ] - ,

carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(1-oxo-4-phenylbutyl) amino] ethyl] - , tricyclo [3.3.1.13'7] dec-2-yl -ester,

(R) -,

carbamic acid, [2-(benzoylamino)-1-(1H-indol-3-ylmethyl) 1-methylethyl]-, tricyclo [3 , 3 , 1, 13-7] dec-2-yl ester, (R)- ,

carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2- [ (1-oxo-3-phenylpropyl) amino] ethyl] - , tricyclo [3.3.1.13,7] dec-2- yl ester,

(R)-,

carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(2-phenylacetyl) amino] ethyl] -, tricyclo [3,3,1,13,7]dec-2-yl -ester,

(R)-,

carbamic acid, [2-[[3-[[1-(hydroxymethyl)-2-phenylethyl]-amino] -3-oxopropyl] amino] -1-(1H-indol-3-ylmethyl)-1-methyl-2- oxoethyl]-, [R, (R<*>,S<*>)]-,

carbamic acid, [1-(1H-indol-3-ylmethyl)-2-[[3- [ [1-(hydroxymethyl)-2-phenylethyl] amino] -3-oxopropyl] amino] -1-methyl-2-oxoethyl ] -, (tricyclo [3,3,1,13,7]dec-2-yl ester,

[S-(R<*>,R<*>)]-,

D-phenylalanine amide, α-methyl-N- [ (tricyclo [3.3.1.13,7] dec-2-yloxy)carbonyl]-D-tryptophyll-S-alanyl-, L-phenylalanine amide, α-methyl-N- [ ( tricyclo [3.3.1.13,7] dec-2-yloxy)carbonyl]-D-tryptophyll-S-alanyl-, L-phenylalanine amide, α-methyl-N- [ (tricyclo [3.3.1 .13,7] dec-2 -yloxy)carbonyl]-L-tryptophyll-B-alanyl-, D-phenylalaninamide, α-methyl-N- [ (tricyclo [3.3.1.13,7] dec-2-yloxy)carbonyl]-L-tryptophyll-S- alanyl-, L-phenylalanine, N- [N- [α-methyl-N- [ (tricyclo [3.3.1.13,7] dec-2-yloxy)carbonyl]-D-tryptophyll]-S-alanyl] -, phenylmethyl ester ,

propanoic acid, 2-[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[ [ (tricyclo [3.3.1.13,7] dec-2-yloxy) carbonyl ]amino]propyl]-amino]-1-oxopropyl]amino]-3-phenyl-, phenylmethyl ester,

[S-(R<*>,R<*>)]-,

D-phenylalanine, N- [N- [α-methyl-N- [ (tricyclo [3.3.1.13'7] dec-2-yloxy)carbonyl]-D-tryptophyll]-S-alanyl] -, L-phenylalanine, N- [N- [α-methyl-N- [ (tricyclo [3.3.1.13-7] dec-2-yloxy)carbonyl]-D-tryptophyll]-S-alanyl]-, L-phenylalanine, N- [N - [α-methyl-N- [ (tricyclo [3 .3 .1.13-7] dec-2-yloxy)carbonyl]-L-tryptophyll]-S-alanyl]-,

benzenepropanoic acid, α-[[3-[[3-[ (1H-indol-3-yl)-2-methyl-1-oxo-2- [ [ (tricyclo [3.3.1.13,7] dec-2-yloxy) carbonyl] amino] - propyl] amino]-1-oxopropyl] amino]-, [S-(R<*>,S<*>)]-,

glycine, N- [2-methyl-N- [ (tricyclo [3.3.1.13'7] dec-2-yloxy) - carbonyl]-D-tryptophyll]-, phenylmethyl ester,

carbamic acid, [3-(1H-indol-3-ylmethyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidinyl]-, tricyclo[3.3.l.l3'7]dec-2 -yl ester, (±)-,

carbamic acid, [1-(1H-imidazol-4-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]-, 1,1-dimethylethyl ester, (±)-,

carbamic acid, [3-(1H-indol-3-yl)-1-methyl-1-[[(2-phenylethyl) amino] carbonyl] propyl] - , tricyclo [3 . 3 .1.13,7] dec-2-yl ester, ( + )-,

carbamic acid, [1- [ [ [1-hydroxymethyl)-2-phenylethyl]amino]-carbonyl]-3-(1H-indol-3-yl)-1-methylpropyl]-, tricyclo-[3 . 3 .1.13,7] dec-2-yl ester (hydroxymethyl center is S, the other center is RS), L-phenylalanine amide, N-[[(1,1-dimethylethoxy)carbonyl]-α-methyl]- L-tryptophyll]-L-methionyl-L-α-aspartyl-,

glycine, N-[2-methyl-N-[(tricyclo[3.3.1.13'7]dec-2-yloxy)-carbonyl]-D-tryptophyll]-L-phenylalanyl-,

carbamic acid, [1- [ [ [1-(hydroxymethyl)-2-phenylethyl]amino]-carbonyl] -2-(1H-indol-3-yl) propyl] -, tricyclo [3 . 3 .1.13'7] dec-2-yl ester (hydroxymethyl center is S, other centers RS),

2,4-heptadienoic acid, 6-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [ [ (tricyclo [3.3.1.13,7] dec-2-yloxy) carbonyl ]amino]propyl]-amino]-7-phenyl-, [R,R<*>,S<*->(E,E)]]-, and

glycine, N-[2-methyl-N-[(tricyclo[3.3.1.13'7]dec-2-yloxy)-carbonyl]-D-tryptophyll]-, phenylmethyl ester.

Table I, below, illustrates representative compounds prepared according to the invention. The stereochemical configuration of all compounds listed in Table I is shown.

In addition to the compounds shown in Table I, the compounds prepared according to the present invention include compounds of formula I where the indole part is 2-indolyl.

The compounds prepared according to the invention include solvates and hydrates and pharmaceutically acceptable salts of the compounds of formula I.

Other examples of compounds according to the invention include: tricyclo [3.3.1.13,7] dec-2-ylcarbamic acid, 2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H- 3-ylmethyl)-1-methyl-2-oxoethyl ester,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-α-methyl-α-(2-oxo-2-tricyclo[3.3.1.13'7]dec-2-ylethoxy)-1H- indole-3-propanamide,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-a-(2-hydroxy-2-tricyclo[3.3.1.13'7]dec-2-ylethoxy)-a-methyl-1H- indole-3-propanamide,

[ (tricyclo [3 . 3 .1.13'7] dec-2 -ylamino) carbonyl] - sulf amine - acid, 2-[[2-(hydroxy-1-(hydroxymethyl)-2-phenylethyl] amino] -1 -(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl ester,

[ (tricyclo [3.3.1.13,7] dec-2-ylamino) sulfonyl] -carbamic acid, 2- [[2-(hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino] -1-(1H-indole- 3-ylmethyl)-1-methyl-2-oxoethyl ester,

[[2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino] -1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethoxy]sulfonyl]carbamic acid, tricyclo [3.3 .1.13,7] dec-2-yl ester,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-methyl- [ [2-oxo-2-(tricyclo [3.3.1.13,7] dec-2-ylamino) ethyl] amino] -1H- indole-3-propanamide,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-α-methyl-α-[ [ (tricyclo [3.3.1.13'7] dec-2-ylamino) acetyl] amino] -1H- indole-3-propanamide,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-a-methyl-a-[(2-oxo-2-tricyclo[3.3.1.13'7]dec-2-ylethyl) amino]-1H-indole-3-propanamide,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-α-[(2-hydroxy-2-tricyclo[3.3.1.13'7]dec-2-ylethyl)amino]-α-methyl-1H -indole-3-propanamide,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-α-methyl-α-[ [ [ [ (tricyclo [3.3.1.13,7] dec-2 - ylamino) carbonyl] amino] - sulfonyl] amino]-1H-indole-3-propanamide,

N- [2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-α-methyl-α-[ [ [ [ (tricyclo [3.3.1.13,7] dec-2-ylamino] sulfonyl] amino] - carbonyl] amino]-1H-indole-3-propanamide,

[ [ [2- [ [2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]amino]sulfonyl]- carbamic acid, tricyclo [3.3.1.13,7] dec-2-yl ester,

[ [ [2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl] amino] carbonyl] - sulfamic acid, tricyclo [3.3.1.13,7] dec-2-yl ester,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-α-methyl-α-[[ (tricyclo[3.3.1.13,7]dec-2-ylamino)-sulfonyl]amino]-1H-indole -3-propanamide,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-2-(1H-indol-3-ylmethyl)-2-methyl-N'-(tricyclo [3.3.1.I3'7] dec- 2-ylmethyl)propanediamide,

N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-2-(1H-indol-3-ylmethyl)-2-methyl]-N'-tricyclo[3.3.1.13'7]dec-2- ylpropanediamide,

N- [2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]- a-[[imino-(tricyclo [3 . 3 .1.13,7] dec-2-ylamino) methyl] amino] -a-methyl- 1H-indole-3-propanamide,

a- [ [ (cyanoimino) (tricyclo [3.3.1.13,7] dec-2-ylamino)-methyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]- a-methyl- 1H-indole-3-propanamide,

N- [2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-of-methyl-of-[ [ (nitroimino) (tricyclo [3.3.1.13,7] dec-2-ylamino) methyl] amino] - 1H -indole-3-propanamide,

The compounds prepared according to the present invention may have several chiral centers, depending on their structures. In addition, there may be centers of asymmetry on the other substituents. In particular, the compounds produced according to the present invention can occur as diastereomers, mixtures of diastereomers and as mixed or individual optical enantiomers. The present invention includes the production of all such forms of the compounds. The mixtures of diastereomers are obtained as a result of reactions more fully described below. Individual diastereomers can be isolated from mixtures of the diastereomers through conventional techniques, such as column chromatography or repeated recrystallizations. Individual enantiomers can be separated by well-known conventional methods, such as conversion to a salt with an optically active compound and subsequent separation by chromatography or recrystallization and conversion back to the non-salt form.

The compounds of formula I can be formed by linking individual substituted α-amino acids according to well-known methods. (See, for example, the synthesis method standards discussed in the multi-volume work "The Peptides, Analysis, Synthesis, Biology", by Gross & Meienhofer, Academic Press, New York). The individual substituted α-amino acids which make up the starting materials are generally known, but can otherwise be synthesized and possibly cleaved according to well-known methods. (Synthesis of racemic [DL]-α-methyl-tryptophan methyl ester - see Braha, M.F. et al., J. Heterocyclic Chem.. 1980, 17:829).

A key product in the preparation of compounds of formula I is a compound of formula

where R is selected from R<1>, 9-fluorenylmethyl, Bz and other suitable N-blocking groups. These are suitable as intermediates in the preparation of compounds of formula I. The compounds where R is 1-adamantyl, 2-adamantyl, exobornyl or endo-bornyl are new compounds which are also preferred.

The description in US patent 4,757,151 to which reference is made here describes 9-fluorenylmethyl blocking groups.

Compounds of formula II are prepared by reacting

where R is as defined above, with phosgene or a phosgene substitute, to form a corresponding compound of formula and then reacting a compound of formula IV with α-methyltryptophan to form the desired compound of formula II. Alternatively, a compound of formula IV may be reacted with an α-methyltryptophan methyl ester, to form

which can be converted into a compound of formula II according to known techniques, such as hydrolysis with aqueous lithium hydroxide.

The reaction schemes below illustrate procedures. for the production of intermediate products suitable for the production of final products with formula I.

The reaction charts I below illustrate preparative steps

in the process leading to compounds according to the invention. Treatment of 2-adamantyloxycarbonyltryptophan 1 with N-methylmorpholine and then with isobutylchloroformate gave an intermediate, mixed anhydride which on mixing with N,0-dimethylhydroacylamino hydrochloride gave the hydroxamate 2 which led to the aldehyde 3_ on reduction with LiAlH4. Reductive amination of 3. with S-phenylalaninol and NaCNBH3 gave aminomethylene 4 (Example

1). Example 2 (compound 5) was prepared in an exactly analogous manner. The intermediate mixed anhydride described above was treated with Me3SiN3 to produce the acid azide which was then reacted with p-nitrobenzyl alcohol in the presence of DABCO

to give the bisureethane 6. Hydrogenation to the monourethane using Pearlman's catalyst, and treatment of the amine with the HOBT ester of 2-(acetoxymethyl)-3-phenylpropionic acid gave compound 7, Example 3, after hydrolysis of the ester with LiOH in aqueous THF. Example 4, compound 10, was prepared in three steps from 1. The mixed anhydride of 1 was treated below with diazomethane to give the diazoketone 8. Reaction with HCl to the chloroketone and subsequent reaction with sodium diethylbenzyl gave a diester which, after hydrolysis, was decarboxylated to the acid 10, Example 4.

Explanation: 1) isobutyl chloroformate, N-methylmorpholine, CH30NH(CH3).HC1; ii) LiAlH 4 ; iii) S-phenylalaninol, NaCNBH 3 ; iv) isobutyl chloroformate, N-methylmorpholine, Me3SiN3 then 40°C then p_ara-NO2-C5H4CH20H/ DABCO; 2,4-diazabicyclo[2.2.2]octane (DABCO); v) Pd(OH)2 H2, then RS-H02CCCH(CH2Ph)CH2OAc; then LiOH, THF; vi) isobutyl chloroformate, N-methylmorpholine, CH2N2; vii) HCl-dioxane; viii) NAI, NaOMe, then sodium diethyl benzyl malonate, then NaOH, HCl and heating.

Reaction scheme 2

Example 5, compound 12, was prepared by reduction of the amide in 11 using LiBH4 and Me3SiCl. Similarly, Example 6, compound 14, was prepared from 13. 14 was treated with acetyl chloride to give Example 7, in the presence of base. The major product was compound 15a, which was hydrolyzed to Example 8, compound 16, after treatment with lithium hydroxide. The thiazoline .17, Example 9, was prepared by heating 13. with Lawesson's reagent.

Explanation

i) LiBH 4 / Me 3 SiCl; ii) CH3COCl (Example 7); or CH3COCl, Et3N then LiOH (Example 8);

iii) Lawesson's reagent.

Reaction core 3 shows the synthesis of examples of ester isosteres. Monomethyl fumarate was condensed with R-phenylglycinol via its HOBT ester to give 18.. Further condensation of this with R- or S-2-Adoc-α-MeTrpOH in the presence of N,N'-carbonyldiimidazole respectively gave Example 10 (compound 19) and 11 (compound 20). In exactly analogous fashion, except for the use of monomethyl succinate, Example 12 (compound 22) was prepared.

Explanation

i) HOBT, DCCI; ii) R-phenylalaninol; iii) R- or S-2-Adoc-a-MeTrp-OH (compound 23)

Reaction scheme 4

Reduction of 23a to the primary alcohol 24 with LiAlH4 and subsequent treatment with phenylacetic acid and N,N'-carbonyldiimidazole gave the ester isostere 25, Example 13. Oxidation of 24 to the aldehyde 26 led to a very useful intermediate. This aldehyde 26. was treated with Wittig reagents to give 27 (Example 14) and 29. Compound 2_9 was further converted to 30., Example 16, by hydrolysis of the ester and subsequent condensation with aniline. Treatment of the aldehyde .26. with the Grignard reagent 3 - phenylpropylmagnesium bromide led to the secondary alcohol 28 (Example 15).

Explanation

i) LiAlH 4 ; ii) PhCH 2 CO 2 H; carbonyldiimidazole;

iii) tetrapropylammonium perruthenate;

iv) PhCH2CH2P<+>Ph3Br", NaH; v) PhCH2CH2CH2MgBr.

Reaction charts 5 show the synthesis process for some examples of homologated α-methyltryptophans and their opposite amide isosteres. The mixed anhydride of 23b prepared using isobutyl chloroformate and N-methylmorpholine was treated with diazomethane to give the diazoketone 3_1 and, as in a solution in benzyl alcohol, was treated with silver benzoate and Et3N to give the homologated benzyl ester 3_2. Hydrogenation led to the acid 3J3 which was condensed in the usual way via the pentafluorophenyl ester with S-phenylalaninol to give 34 (Example 18).

The amide of 23b, 35 was prepared by bubbling ammonia gas through a solution of the pentafluorophenyl ester. This amide was reduced to the amine 3_6 with Me3SiCl/LiBH4 in THF. This amine was then reacted with phenyl acyl chlorides to give Examples 19-22.

Explanation

Reagents: i) isobutyl chloroformate, NMM, THF;

ii) CH 2 N 2 , EtOAc;

iii) Ag<+>~OCOPh, Et3N, PhCH2OH;

iv) H2/Pd/C;

v) PFP, DCC, H2NCH(CH2OH)CH2Ph, EtOAc;

vi) PFP, DCC, EtOAc;

vii) NH3(g), THF;

viii) TMS-Cl, LiBH 4 , THF;

ix) Ph(CH2)nCOCl, pyridine, EtOAc

Reaction scheme 6 illustrates the synthesis of α-methyltryptophyl-S-alanine derivative. 2-adamantyl-oxycarbonyl-α-methyltryptophan 23b (R-isomer) or 38. (S-isomer) is condensed with S-alanine esters in the usual way. This ester can then be hydrolyzed using standard methods (eg aqueous LiOH, etc.) to give the carboxylic acid 4_1 or 42. Both of these two isomers can be condensed with an appropriate amine to give Examples 23 and 24 (using S-phenylalaninol), Example 25-28 (using R- and S-phenylalanine amide) and Example 29-31 (using phenylalanine ester). Example 29-31 and connection

52 can then be hydrolysed according to known methods to give the products in Examples 32-35.

Explanation Reagents:

i) PFP, DCC, J3-alanine Me ester, EtOAc;

ii) LiOH, aqueous dioxane; iii) DCC, (S)-(-)-2-amino-3-phenyl-1-propanol EtOAc; iv) PFP, DCC, (R)-phenylalanine amide, EtOAc; v) PFP, DCC, (S)-phenylalanine benzyl ester, EtOAc or PFP, DCC, (R)-phenylalanine methyl ester, EtOAc; vi) H 2 , Pd/C, EtOH.

Reaction scheme 7 describes the synthesis steps up to derivatives of α-methyltryptophyllglycine. As an illustration, 2-Adoc-α-methyltryptophan 23b can be readily condensed with glycine benzyl ester via the pentafluorophenyl ester of 23b. Hydrogenation of this ester using 10% palladium on charcoal in ethanol solution leads to the carboxylic acid 58 in high yield. Treatment of this acid with N,N'-dicyclohexylcarbodiimide and pentafluorophenol gives the active ester which readily reacts with phenylalanol to give the product compound 59, Example 37.

Explanation Reagents:

i) PFP, DCC, glycine benzyl ester hydrochloride, Et 3 N, EtOAc; ii) H 2 Pd/C, EtOH; iii) PFP, DCC, s-phenylalaninol, EtOAc.

Reaction scheme 8 describes the synthesis steps leading to derivatives of α-methyltryptophyll-γ-aminobutyric acids. As an illustration, the carboxylic acid 23b can be condensed with -γ-amino-butyric acid methyl ester to give 6_0 which on hydrolysis with LiOH leads to acid 61. The product 62, Example 39, occurs when 61 is condensed with phenylalaninol via an active pentafluorophenyl ester.

Explanation Reagents:

i) PFP, DCC, gamma-aminobutyric acid methyl ester hydrochloride, Et 3 N, EtOAc;

ii) LiOH, aqueous 1,4-dioxane;

iii) PFP, DCC, s-phenylalaninol, EtOAc.

Reaction scheme 9 outlines the synthesis of α-substituted tryptophanylphenethylamides and their intramolecular cyclizations to compound 68, Example 40. The isonitrile 63.

(prepared according to the procedure described in Svnthesis 465, 1990) in ethanol at -5°C, was treated with ethanolic HCl to give the amine 64.. This underwent coupling with 2-adamantyl chloroformate to the urethane 65.. Hydrogenation of 65 using 10 % palladium on charcoal under a pressure of 3.2 kg/cm<2>, led to the monoacid monoester 6_6 which was condensed in the usual way to 2-f enethylamine to form .67. The product was formed by treatment of 6_7 with LiOH which abstracts the amide NH proton and is cyclized over to the ester group with liberation of methoxide.

Explanation Reagents:

i) EtOH.HCl, 67%; ii) 2-adamantyl-COCl, Et3N, EtOAc, 58%; iii) Pd/H2/EtOH, 88%; iv) H 2 NCH 2 CH 2 Ph, PFP, DCC, DMAP, EtOAc, 73%; v) LiOH(0.01M), 0°C, THF/H2O, 79%.

Reaction scheme 10 outlines the synthesis steps towards S-substituted tryptophan derivatives. Isopropylamine when added to acetaldehyde and treated with KOH gives 69 which reacts with indole in glacial acetic acid over 5 days to give 70. The isopropylaminoethylidene .70 then reacts with 7_1 in the presence of NaOMe in hot toluene to give 72.. Hydrolysis and decarboxylation leads to 74. as a mixture of separable diastereoisomers.

The amide 74 is dissolved in 4N sulfuric acid under reflux, then cooled to room temperature and treated with 0.4N barium hydroxide until a pH of 8 is reached, leading to the free amine 75 which reacts with 2-adamantyl chloroformate 76 to give the urethane 22 - This is then condensed with phenylalaninol in the normal way to give the product 28, Example 89.

GENERAL PROCESS FOR REACTION FORMS

Reaction core 15a:

Cyanoacetic acid esters or substituted derivatives 1 are alkylated with gramine and a base, e.g. NaOH, in toluene, to compounds 2 analogously to known methods. The compounds 2 are catalytically hydrogenated with Raney nickel to the amino ester 3_, which is reacted with chlorine or fluorine mates to the carbamic acid esters 4. The esters 4 are hydrolyzed to the acids 5_ which are converted into activated esters, e.g. with pentafluorophenol and dicyclohexylcarbodiimide, to the pentafluorophenyl esters. The activated esters are reacted with a suitable amine to an amide of formula 6. Further conversions of the amide part of the molecule are carried out analogously to known methods.

Compounds of general formula 15a

where R<1> = 1-adamantyl, 2-adamantyl,

(1S)-2-endobornyl

R2 = H or

c = 0 or 1 is produced according to Synthesis Scheme 15a:

Synthesis scheme 15b:

Compounds of general formula Ia, where R<2>, R3 and R<4> are H, are also prepared according to Synthesis Core 15b. Cyanoacetic acid esters 7 are reacted with suitable amines to the cyanoacetamides 8, which are condensed with indole-3-carboxaldehyde and catalytic amounts of piperidine to compounds 9 analogously to known methods and then catalytically hydrogenated with Raney nickel to 3-indolylmethyl-substituted S-aminopropionamides 10. Reaction with chloro or fluoroformates lead to the carbamic acid ester derivatives 11.

Synthesis scheme 15c:

Compounds of general formula Ia, where R2 = H or

and R3 and R4 are H

is also produced according to Synthesis scheme 15c.

Cyanoacetamides 8 are alkylated with gramine and a base, e.g. NaOH, in toluene, to compounds 12 and 12 which are hydrogenated catalytically with Raney nickel to mono- or bis-(3-indolylmethyl)-substituted B-aminopropionamides 10 and 16. Reaction' with chloro or fluoroformates leads to the carbamic acid ester derivatives 11 and 17.

Synthesis scheme 16:

Compounds of general formula Ib,

where R<1>, R<2>, R<3>, R4 and c are as defined above, are produced according to Synthesis Core 16.

Amino esters 3_ are reacted with carboxylic acid chlorides to give the amides 18. The ester groups in the compounds 18 are hydrolysed with lithium hydroxide to the carboxylic acids 19, which are converted into activated esters, e.g. with pentafluorophenol and dicyclohexylcarbodiimide, to the pentafluorophenyl esters. The activated esters are reacted with a suitable amine to an amide of formula 20. Further conversions at R<3> and R4 are carried out analogously to known methods.

SYNTHESIS FORM 17

Compounds of general formula Ic,

produced according to Synthesis Scheme 17.

l-(3'-indolyl)-butan-3-one is converted with potassium cyanide and ammonium carbonate after a Bucherer synthesis to the hydantoin 21, which is hydrolyzed with aqueous sodium hydroxide to the amino acid 22, which is then esterified with methanol and hydrogen chloride to 23. Compound 23 is reacted with chlorine - or fluoroformates to the carbamic acid esters 2A- The ester groups in the compounds 24 are hydrolysed with lithium hydroxide to the carboxylic acids 25. The acids .25 are converted into activated esters, e.g. with pentafluorophenol and dicyclohexylcarbodiimide, to the pentafluorophenyl esters. The activated esters are reacted with a suitable amine to an amide of formula 26. Further conversions at R<3> or R<4> are carried out analogously to known methods.

SYNTHESIS FORM 18

Compounds of general formula Id,

where R1, R3, R4 and c are as defined above and R2 = Me, is produced according to Synthesis Core 18.

Diethyl methyl malonate 27_ is alkylated with gramine and a base, e.g. NaOH, in toluene to compound 28, according to known methods. The diester 28 is hydrolyzed with potassium hydroxide to the monoacid 29. The ester group in 29 is selectively reduced with a borane methyl sulfide complex to compound 30, which is esterified with methanol and sulfuric acid to the methyl ester 31. The hydroxy compound 31 is reacted with p-toluenesulfonyl chloride and pyridine to the tosylate 32. Nucleophilic substitution with potassium cyanide gives the cyanoester 33, which is catalytically hydrogenated with Raney nickel to the aminoester 34. The aminoester 34 is reacted with chlorine or fluorine mates to the carbamic acid esters 3-5. The ester groups in compound 3-5 are hydrolyzed with lithium hydroxide to the carboxylic acids 36 which are converted into activated esters, e.g. with pentafluorophenol and dicyclohexylcarbodiimide, to the pentafluorophenyl esters. The activated esters are reacted with a suitable amine to an amide of formula 37. Further conversions at R<3> and R<4> are carried out analogously to known methods.

The biological activity of the compounds produced according to the present invention was assessed using a screening test which quickly and accurately measures the test compound's binding to known CCK receptor sites. It has been shown that specific CCK receptors occur in the central nervous system. (See Hays et al., Neuropeptides 1:53-62, 1980; and Satuer et al., Science, 208:1155-1156, 1980).

In this screening test, cerebral cortex sections from male CFLP mice weighing 30-40 g were dissected on ice, after which they were weighed and homogenized in 10 volumes of 50 mM Tris-HCl buffer (pH 7.4 at 0 -4°C). The resulting suspension was centrifuged, the supernatant discarded and the centrifuge button washed by resuspension in Tris-HCl buffer and subsequent centrifugation again. The final centrifuge tube was resuspended in 20 volumes of 10 nM Hepes buffer (pH 7.2 at 23°C) containing 130 mM NaCl, 4.7 nM KCl, 5 nM MgCl2, 1 nM EDTA, 5 mg/ml bovine albumin and bacitracin (0.25 mg/ml).

For saturation studies, cerebral cortical membranes were incubated at 23°C for 120 minutes in a final volume of 500 μl Hepes incubation buffer (pH 7.2) together with 0.2-20 nM tritiated pentagastrin (Amersham International, England).

In the displacement experiments, membranes were incubated with a single concentration (2 nM) of ligand, along with increasing concentrations (10"<11> to 10"<14>M) of competing test compound. In each case, the non-specific binding was defined as the persistent binding in the presence of unlabeled octapeptide CCK26.33 (10<6>M).

After the incubation, the membrane-bound radioactivity was separated from the free activity in the solution by rapid filtration through Whatman GF/B filters and washed 3 times with 4 ml of ice-cold Tri-HCl buffer. Filters from samples incubated with tritiated pentagastrin were placed in polyethylene glass with 4 ml of scintillation liquid, and the radioactivity determined by liquid scintillation spectrometry (efficiency 47-52%).

The specific binding to CCK receptor sites was defined as the total bound tritiated pentagastrin minus the amount of tritiated pentagastrin bound in the presence of the IO"<6> octapeptide, CCK26_33.

Saturation curves for specific tritiated pentagastrin binding to mouse cortical membranes were analyzed according to Scatchard ( Ann. New York Acad. Sei. 51:660-672, 1949) and Hill (CL

Physiol. 40:IV-VIII, 1910) to provide estimates of the maximum number of binding sites (Bmax) and the dissociation constant (Ka) at equilibrium.

In displacement experiments, the inhibition curves were analyzed either by logit-log diagrams or by the iterative curve-fitting computer program ALLFIT (DeLean, Munson & Redbard, 1978) to provide estimates of IC50 and nH (apparent Hill coefficient) values. (IC50 values were defined as the concentration of test compound required to produce 50% inhibition of the specific binding).

The inhibition constant (KJ) of the test compound was then calculated according to the Cheng-Prusoff equation:

where [L] is the concentration of the radioactively labeled compound and Ka is the dissociation constant at equilibrium.

The Ki values for several representative compounds according to the present invention are given in Table III.

The applicability of the compounds produced according to the present invention as an appetite suppressant is examined according to the method described below.

In the so-called "Palatable Diet Feeding assay", adult male Hooded Lister rats weighing 200-400 g are placed in individual cages and trained to eat a palatable diet. The diet consists of Nestlé's sweetened condensed milk, powdered rat feed and water, which hardens to a firm consistency when mixed together. Each rat is allocated 20-30 g of the palatable diet for 30 minutes per day during the illumination phase of a light/dark cycle over a habituation period of 5 days. Intake of palatable diet is measured by weighing the container before and after the 30 minute access period (accuracy limits 0.1 g). It is ensured that spillage is collected and corrected for. The rats are given free access to pelleted feed and water, except during the 30-minute test period.

After the training period, a dose-response curve is constructed for CCK8 and several representative compounds produced according to the present invention (n=8-10 rats per dose level). MPE50 values (±95% confidence limits) are obtained for the anorectic effects of these compounds and these are shown in Table

III.

When used therapeutically as appetite suppressants, the compounds produced according to the present invention are administered to the patient in dosages of from 200 to approx. 2800 mg per day.

Table III shows binding data:

Male Hooded Lister rats (175-250 g) are housed in individual cages and fasted overnight (free access to water). They are anesthetized with urethane (1.5 g/kg i.p.) and the trachea cannulated to facilitate spontaneous respiration. The stomach is continuously perfused using a modification of the original method of Ghosh & Schild in "Continuous recording of acid secretion in the rat", Brit. J. Pharmac. 13:54-61,

1956 as described by Parsons in "Quantitative studies of drug-induced gastric acid secretion". (Ph. D. Thesis, University of London, 1969) . The gastric cavity is perfused at a rate of 3 ml/min. with 5.4% w/v glucose solution both

through the esophageal and corpus cannula. The liquid is propelled by a peristaltic pump (Gilson, Minipuls 2), through heating coils to bring the temperature to 3 7 + 1°C. The perfusion fluid

is collected through the collection funnel in the fundus and sent to a pH electrode connected to a Jenway pH meter (PHM6). The output signal from the pH meter is transferred to a Rikadenki printer for direct recording of the pH in the gastric perfusate.

Pentagastrin is stored as a deep-frozen aliquot and diluted to desired concentrations with sterile 0.9% w/v NaCl. New compounds are dissolved in sterile 0.9% w/v. NaCl on the day of the experiment. The drugs are administered i.v. as a bolus through a cannula in the jugular vein in a volume of 1 ml/kg which is washed in with 0.15 ml of 0.9% w/v. NaCl. The basal pH must be stabilized before the administration of compounds is initiated. Generally, 30 minutes elapse between the surgical procedure and the first administration of compound.

The compounds produced according to the present invention are also suitable as antiulcer agents as discussed below.

Aspirin-induced damage to the stomach is determined in groups of 10 rats.

All animals are fasted for 24 hours before and during the experiment. Drug or vehicle is given 10 minutes before an oral dose of 1 ml of a 45 mg/ml suspension of aspirin in 0.5% carboxymethylcellulose (CMC).

The animals are killed 5 hours after the aspirin administration and the stomachs are removed and opened for examination. The stomach injuries are assessed as follows:

However, the specific dosages can be varied according to the patient, the severity of the condition in question and the activity of the compound used. Optimum doses can be determined by the expert.

The compounds prepared according to the present invention are also useful as anxiolytic agents as described and discussed below. Anxiolytic activity is determined in mice following a light/dark exploration test (B.J. Jones, et al., Brit. J. Pharmac. 93:985-993, 1988).

The apparatus used is an open-top box, 45 cm long, 27 cm wide and 27 cm high, divided into a small (2/5) area and a larger (3/5) area with a dividing wall that protrudes 20 cm above the walls. In the partition, there is a 7.5 x 7.5 cm opening at floor level. The small room is painted black and the large room white. The floor in each room is marked out in 9 cm squares. The white room is lit by a lOOWatt light bulb 17 cm above the box and the black room by a correspondingly placed 60 Watt red light bulb. The laboratory is illuminated with red light.

All examinations are carried out between 1pm and 6pm. Each mouse is tested by being placed in the center of the white area and given the opportunity to explore the new environment for 5 minutes. The behavior is recorded on video and the behavioral analysis is carried out later from the recording. 5 parameters are measured: the waiting time before entering the dark room, the time spent in each area, the number of transitions between rooms, the number of lines crossed in each room and the number of inclines in each room.

In this investigation, an increase in the time spent in the illuminated area is a sensitive measure, which is directly related to the anxiolytic effects of several standard anxiolytic drugs. The drugs were dissolved in water or saline and administered subcutaneously, intraperitoneally or per os (p.o.) through a stomach tube.

The compounds prepared according to the invention are useful as antipsychotic agents and can be examined for their ability to reduce the effects of intra-accumbens amphetamine in rats as described below.

Male Sprague Dawley (CD) rats of the Bradford strain are used. The rats are housed in groups of 5 at a temperature of 21±2°C under a 12-hour light/dark cycle with lights on between 07.00 and 20.00. The rats are given CRM feed (Labsure) and water ad libitum.

The rats are anesthetized with chloral hydrate (400 mg/kg s.c.) and placed in a Kopf stereotactic frame. Permanently indwelling guide cannulas (made of stainless steel tubing 0.65 mm diameter held bilaterally in Parspex holders) are implanted using standard stereotactic technique so that they end 3.5 mm above the center of the nucleus accumbens (Ant. 9.4, Vert. 0 .0, Lat. 1.6) or 5.0 mm above the central nucleus of the amygdala (Ant. 5.8, Vert. -1.8, Lat. ±4.5) (Atlas: De Groot, 1959). .The guide cannulas are kept open during a 14-day recovery period using stainless steel stylets, 0.3 mm diameter, which project 0.5 mm past the guide tip.

The rats are restrained manually and the stylets are removed. Intra-cerebral injection cannulas, 0.3 mm diameter, are inserted and drugs are delivered in a volume of 0.5 fil over 5 seconds (an additional 55 seconds are expected for deposition) from Hamilton syringes connected via polyethylene tubing to the injection units. The animals are only used once.

The behavioral experiments are carried out between 07.30 and 21.30 in a quiet room kept at 22±2°C. The rats are taken from the animal stable and allowed to adapt to the new environment for 1 hour. Locomotor activity is determined in individual Perspex cages (25 x 15 x 15 cm (height)) (arranged in groups of 30) each equipped with a photocell unit along the longitudinal axis, 3.5 cm from the side. This positioning has been shown to reduce erroneous activity counts as a result of, for example, grooming movements and head movements when the animal is standing still. Disturbance of the light beam is registered every 5 minutes. At this point, the animals are also assessed for non-specific changes in the locomotor activity, e.g. sedation, prostration, stereotyped movements that can affect the recording of locomotor activity.

The property of the compounds produced according to the invention that they inhibit the hyperactivity caused by injection of amphetamine into the nucleus accumbens in rats is measured.

An increase in locomotor activity after the bilateral injection of amphetamine (20 /xg) into the nucleus accumbens; hyperactivity peak (50 to 60 counts per 5 minutes) occurs 20 to 40 minutes after injection. This examination is considered predictive of antipsychotic activity (Costall, Domeney & Naylor & Tyers, Brit. J. Pharmac. 92:881-894).

The compounds produced in accordance with the present invention prevent and treat withdrawal symptoms that occur upon cessation of drug treatment or alcohol abuse. These compounds are therefore useful as therapeutic agents in the treatment of chronic drug or alcohol abuse as discussed and described below.

The effect of the compounds produced according to the present invention is illustrated, for example, in the "light/dark box" where 5 mice are given nicotine, within the range of 0.1 to 100 mg/kg i.p. b.d. for 14 days. After a 24-hour withdrawal period, 1.0 mg/kg i.p. b.d. of compound (20). The prolonged residence time in the illuminated area is a sensitive measure of the effectiveness of compound (20) as a means of treating withdrawal effects from nicotine.

For the preparation of pharmaceutical preparations of the compounds prepared according to the invention, inert pharmaceutically acceptable carriers can be solid or liquid. Solid preparation forms include powders, tablets, dispersible granules, capsules, lozenges and suppositories.

A solid carrier can be one or more substances that can also serve as diluents, flavor enhancers, solubilizers, smoothing agents, suspending agents, binders or tablet disintegrants, and can also be an encapsulating material.

In powders, the carrier is a finely divided solid which is mixed with the finely divided active substance. In tablets, the active substance is mixed with a carrier that has the necessary binding properties in appropriate proportions and compressed to the desired shape and size.

For the production of suppositories, a low-melting wax, such as a mixture of fatty acid glycerides and cocoa butter, is first melted, after which the active ingredient is dispersed in this, for example by stirring. The molten homogeneous mixture is then poured into molds of appropriate size, where it is allowed to cool and solidify.

Powders and tablets preferably contain 5% to approx. 70% active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter and the like.

Preferred pharmaceutically acceptable salts are the N-methyl-glucamine salt and the sodium salt.

Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, "camsylate", carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucoptate, gluconate, glutamate, glycolyl arsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate , salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, triiodide, benzathine, chlor-procaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

The term "preparation" shall include formulations of the active substance with encapsulation material as a carrier which provides a capsule where the active substance (with or without other carriers) is surrounded by a carrier with which it is thus connected. Lozenges are also included.

Tablets, powders, lozenges and capsules can be used as fixed dosage forms for oral administration.

Liquid preparation forms include solutions, suspensions and emulsions. Sterile water or water/propylene glycol solutions of the active substances can be mentioned as examples of liquid preparations suitable for parenteral administration. Liquid preparations can also be formulated as a solution in aqueous polyethylene glycol.

Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colourings, flavor enhancers, stabilizers and thickeners. Aqueous suspensions for oral use can be prepared by dispersing the finely divided active ingredient in water together with a viscous material, such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and other suspending agents known in the field of pharmaceutical formulation.

Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the preparation is divided into unit doses that contain appropriate amounts of the active ingredient. The unit dosage form can be a preparation package, where the package contains discrete amounts of the preparation, for example tablets, capsules and powders, packed in glass or ampoules. The unit dosage form may also be a capsule, lozenge or tablet itself, or it may be a suitable number of one of these packaged forms.

EXAMPLES

EXAMPLE 1

Tricyclo\ 3 . 3. 1. 13- 71 dec- 2- vl ( R ) - fl - ( 1H- indol- 3- vlmetvl ) - 2-( methoxymethylamino)- 2- oxoethyl] carbamate ( 2 )

To a solution of acid (1) (859 mg, 2.25 mmol) in dichloromethane (8 ml) was added N-methylmorpholine (495 µl, 4.50 mmol). The mixture was cooled to -15°C (CO 2 /benzyl alcohol) and isobutyl chloroformate (292 µL, 2.25 mmol) was added. The mixture was stirred at -15°C for 15 minutes and then N,O-dimethylhydroxylamine hydrochloride (219 mg,

2.25 mmol). The reaction mixture was stirred at -15°C for 1 hour, then warmed to room temperature and stirred for an additional 15 hours. The mixture was filtered and the filtrate washed successively with sodium bicarbonate, water, 10% citric acid and brine, dried (MgSO 4 ) and evaporated to dryness. The crude material was purified by column chromatography to give hydroxamate (2) (694 mg, 73%) as a white foam; m.p. 72-80°C. Found: C, 67.4; H, 7.35; N, 9.8%.

C 24 H 31 N 3 O 4 requires: C, 67.7; H, 7.3; N, 9.9%

[α] 20 = -9.411° (C = 0.3, CHCl 3 ); (S-ISOMER)

[α] 20 = +8.911° (C = 0.3, CHCl 3 ); <v>max (<f>ilm); 1.695 (CO-urethane) , 1.657 (CO amide) 741 cm"<1> (disubstituted Ph); H (CHCl3) , 6 1.30-2.01 (14H, m, adamantyl), 2.99-3 .24 (5H, m, indole CH2 + NCH3) , 3.58 (3H, s, OCH3) , 4.7 (1H, s, adamantyl 2-H) , 5.00 (1H, br d, CH (NHR )CON") , 5.36 (1H, br d, urethane NH) , 6.92-7.17 (3H, m, indole 2,5,6-H), 7.27 (1H, d, J 8Hz , indole 7-H), 7.53 (1H, d, J 8Hz, indole 4-H), 7.99 (1H, s, indole NH).

Tricvklo r3 . 3. 1. l3' 7l. dec- 2- we ( R ) - ri- formvl- 2- ( 1H- indol- 3- yl) - ethyl- carbamate ( 3)

Lithium aluminum hydride (45 mg, 1.2 mmol) was added portionwise over 30 minutes to a solution of the hydroxamate (2) (197 mg, 0.460 mmol) in THF (3 ml) at 0°C. The mixture was stirred for a further 30 minutes, after which ether (30 ml) and then an ice-cold solution of 10% citric acid (40 ml) were added. The mixture was stirred vigorously for 30 minutes, after which the layers were separated and the aqueous layer extracted with ether

(5 x 10 ml). The ether extracts were combined and washed successively with saturated sodium bicarbonate (25 mL), water (25 mL), 10% citric acid (25 mL) and brine (25 mL), dried (Na 2 SO 4 ) and concentrated in vacuo to aldehyde (3) (140 mg , 83%) as a white foam;

vmax (film) 1725 sh (aldehyde C=0) and 1693 cm"<1> (urethane C=0) ; H (300 MHz; CDC13) , v 1.47-2.13 (14H, m, adamantyl ), 3.26 (2H, d of d, J 15 and 7Hz, indCH2) , 4.58 (1H, br d, CH(NHR)CHO), 4.84 (1H, s, adamantyl 2-H), 6.98-7.26 (3H, m), 7.35 (1H, d, J 8Hz, indole 7-H), 7.60 (1H, br d, J 8Hz, indole 4-H), 8, 24 (1H, br s, indole NH), 9.64 (1H, s, CHO).

Tricyclo [ 3 . 3. 1. 13, 71 dec- 2- vi fS-( R) 1 - [ 2- f Tl- ( hydroxymethyl) - 2-phenylethyl] aminol - 1-( 1H- indol- 3- vlmethyl)- ethylcarbamate ( 4) , Example 1

Sodium cyanoborohydride (37 mg, 0.59 mmol) was added portionwise over the course of 15 minutes to a solution of aldehyde (3) (136 mg, 0.370 mmol) and (S)-2-amino-3-phenyl-propanol (61 mg , 0.40 mmol) in methanol-acetic acid (99:1) (5 ml). The mixture was stirred for 2 hours at room temperature and then cooled (ice bath). Saturated sodium bicarbonate (30 mL) was added with stirring followed by ethyl acetate (45 mL). The organic layer was separated, washed with brine (5 mL), dried (Na 2 SO 4 ) and evaporated to dryness. The crude product was purified by column chromatography (SiO 2 :dichloromethane-methanol (95:5) as eluent) to give aminoalcohol (4) (60 mg, 32%) as a beige foam; mp 59-61°C.

Found: C, 73.7; H, 7.8; N, 8.3% C31H39N3O3. 0.2H2O requires: C, 73.7; H, 7.9; N, 8.3%

vmax (film) 3325 (OH), 1690 (CO urethane), 1496 (N-H), 1266 (OH), 1048 (C-0), 740 and 701 cm"<1> (monosubstituted Ph); H (CDCI3) 5 1.31-2.04 (16H, m, adamantyl + NH + OH), 2.44-3.01 (7H, m, indCH2, -CH2NH-, CH2Ph, NH-CH (CH2OH) CH2Ph) , 3.21 (1H, dd, J 11 and 6Hz, CH of CH2OH) , 3.47 (1H, dd, J 11 and 4Hz, CH of CH2OH) , 3.97 (1H, m, -CH2CH ( NHC02R) CH2NH-), 4.66 (1H, br d, urethane NH), 4.73 (1H, s, adamantyl 2-H), 6.87 (1H, d, J 2Hz, indole 2-H), 6.96-7.24 (7H, m, indole 5,6-H + Ph), 7.29 (1H, d,

J 8Hz, indole 7-H) , 7.55 (1H, d, J 7Hz, indole 4-H) , 7.97 (1H, br s, indole NH),

EXAMPLE 2

Tricyclo f3. 3. 1. 13, 71 dec- 2-vl fS-( S) 1 - 2- f fl-( hydroxymethyl) - 2-phenvletvllaminol- 1-( 1H- indol-3- ylmethyl) ethyl] carbamate ( 5), Example 2

Compound 5 (253 mg, 23%) was synthesized using the same procedure as described above for compound (4). White foam, m.p. 62-63°C.

Found: C, 73.3; H, 7.8; N, 8.3% C31H39N3O3.0.4H2O requires: C, 73.2; H, 7.9; N, 8.3%

vmax (film) 3331 (OH) , 1692 (CO urethane) , 1513 (N-H) , 1360 (O-H) , 1048 (C-O) , 739 and 701 cm"<1> (monosubstituted Ph) ; H (CDC13) , a 1.47-2.10 (16H, m, adamantyl + NH + OH) , 2.54-3.04 (7H, m, CH2 indole, CH2NH, CH2Ph + CH2CH (CH20H) CH2Ph) , 3.30 (1H, dd, J 11 and 6Hz, CH of CH2OH) , 3.59 (1H, dd, J 11 and 4Hz, CH of CH2OH) , 4.06 (1H, m, -CH2CH(NHC02R)CH2NH-) , 4.81 (2H, br s, adamantyl 2-H + urethane NH), 6.86 (1H, br s, indole 2-H), 7.06-7.32 (7H, m, indole 5,6- H + Ph), 7.35 (1H, d, J 8Hz, indole 7-H), 7.59 (1H, d, J 8Hz, indole 4-H), 8.03 (1H, br s, indole

NH).

EXAMPLE 3

Tricyclo r3. 3. 1. 13' 7! dec- 2- yl \ 2 - ( 1H- indol- 3- vi) - 1- f f T ( 4- nitrophenyl) methoxylcarbonyl] amino] ethyl] carbamate ( 6)

To a solution of acid (1) (3.62 g, 9.74 mmol) in anhydrous THF (36 ml) at -10°C was added N-methylmorpholine (1.15 ml, 10.4 mmol) and n-isobutyl chloroformate (1.35 ml,

10.4 mmol). This mixture was stirred for 20 minutes at -10°C and then filtered. Trimethylsilyl azide [Aldrich] (1.89 mL, 14.2 mmol) was added to the filtrate and the resulting solution stirred at -10°C for 1 hour. The solvent was then removed in vacuo at 25°C and the residue partitioned between ethyl acetate (100 ml) and saturated sodium bicarbonate (100 ml). The layers were separated and the organic phase washed with brine, dried (MgSO 4 ) and concentrated in vacuo at 25°C.

The residue was taken up in toluene (100 ml) and treated at 40°C until rearrangement to the isocyanate was complete.

(IR <i>>max N3 2139 , vmax NCO 2249 cm"1 ). p-nitrobenzyl alcohol (2.20 g, 14.3 mmol) and DABCO (14 9 mg, 1.33 mmol) were added and the mixture allowed to sit at 40°C for 15 h The solvent was removed in vacuo and the crude product purified by column chromatography [SiO 2 :ether-hexane (4:1) as eluent] to give (6) (2.12 g, 42%) as a yellow solid which was recrystallized from ether/hexane, mp 148-149°C.

<X>H NMR (300 MHz), δ 1.309-2.03 (m, 14H, adamantyl), 3.07 (br s, 12H, CH2 ind + H2O/HOD), 4.64 (s, 1H, adamantyl 2-H), 5.14 (s, 2H, CH2Ph) , 5.37 (m, 1H, CH(NHC02)-NHC02) , 6.90-7.29 (m, 4H, indole H-2, H -5, H-6 and NH), 7.34 (d, J 8Hz, 2H, H-subst. Ph), 7.46-7.62 (m, 3H, ind H-4, ind H-7, NH), 8.16 (d, J 8Hz, 2H, 4-subst. Ph), 10.61 (s, 1H, ind NH);

IR (film)• 2908 + 2855 (adamantyl), 1703 (br, CO urethane), 1520 (N02) , 1347 (N02) .

Analysis, calculated for C29H32N406

C, 65.40; H, 6.06; N, 10.52

Found: C, 65.25; H, 6.03; N, 10.50

Tricyclo T3. 3. 1. 13' 7] dec- 2-yl [ 1 - [ \ \ 1 - hydroxymethyl) - 2- phenyl-ethylcarbonyl amino] - 2-( 1H- indol- 3- vl)- ethylcarbamate Compound (7), Example 3

The urethane (6) (190 mg, 0.357 mmol) in ethyl acetate (36 mL) was hydrogenated over palladium hydroxide on charcoal (Pearlman's catalyst) at 3.2 kg/cm<2> and 30°C for 1 hour. The mixture was filtered through Celite to remove the catalyst into a flask containing the HOBT ester of 2-(acetoxymethyl)-3-phenyl-propionic acid [the latter was formed by reaction of 2-(acetoxymethyl)-3-phenylpropionic acid (81 mg, 0 .36 mmol) in ethyl acetate (5 mL) with l-hydroxybenzotriazbl (57.5 mg, 0.426 mmol) and DCCl (85.9 mg, 0.416 mmol) at 0°C for 30 min]. The resulting mixture was stirred at room temperature for 18 hours. The solution was concentrated in vacuo, cooled (ice bath), filtered and evaporated to dryness. The residue was taken up in THF:MeOH:H 2 O (3:2:1) (6 mL), added lithium hydroxide monohydrate

(28 mg; 0.67 mmol) and the mixture stirred at room temperature for 18 hours. The reaction mixture was poured into 2N HCl (50 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phase was washed with saturated NaCl, dried (MgSO 4 ), filtered and evaporated to dryness. The crude product was purified by column chromatography [SiO 2 :dichloromethane-methanol (95:5) as eluent] to give an approx. 50:50 mixture of diastereomeric alcohols (7) (16 mg total, 8%) as yellow oils. Isomer I: TLC Rf = 0.24 (CH 2 Cl 2 -MeOH (95:5));

<X>H NMR (300 MHz) : δ 1.43-2.04 (br m, 17H, adamantyl + H 2 O) , 2.42 (m, 1H, NHCO, CH), 2.67-3.22 ( br m, 5H, CH2 ind + CH2Ph + OH) , 3.67 (m, 2H, CH2OH) , 4.78 (s, 1H, adamantyl H=2), 5.40 (br s, 1H) , 5, 58 (br s, 1H) , 6.26 (br s, 1H, amide NH) , 6.82 (s,

1H, ind H-2), 7.02-7.37 (m, 9H, Ph + ind H-5, ind H-6, ind H-7, + CHC13), 7.44 (d, J 8Hz, ind H-4), 8.16 (s, 1H, ind NH); IR (film)": 3540-3140 (br, OH), 2910 + 2855 (adamantyl), 1695 (urethane CO), 1660 (amide CO);

Isomer II: TLC Rf = 0.19 [CH 2 Cl 2 -MeOH (95:5);

<X>H NMR (300 MHz): δ 1.47-2.08 (m, 17H, adamantyl + H 2 O), 2.42 (m, 1H, NHCO.CH), 2.61-2.97 (m , 3H, -CH2 + OH) , 3.19 (d, J 7Hz, CH2) , 4.68 (br s, 2H, CH2OH) , 4.75 (s, 1H, adamantyl H-2), 5.18 (br s, 1H) , 5.49 (br s, 1H) , 6.30 (br s, 1H, amide NH) , 6.96

(s, 1H, ind H-2), 7.02-7.30 (m, 9H, Ph + ind H-5, ind H-6 + CHCl3) , 7.37 (d, J 8Hz, 1H, ind H-7), 7.57 (d, J 8Hz, 1H, ind H-4), 8.12 (s, 1H, ind NH);

IR (film) : 3520-3160 (br, OH), 2907 + 2855 (adamantyl), 1696 (urethane CO), 1660 (amide CO).

EXAMPLE 4

2- adamantyloxycarbonyltryptophandiazoketone ( 8 )

Production of diazomethane. CAREFUL!

DIAZOMETHANE IS VERY TOXIC AND EXPLOSIVE (NO GLASS-SLIP COMPOUND) . HANDLE WITH CAUTION IN EXTRACT. N-METHYNLITROSOUREA IS VERY TOXIC AND CARCINOGENIC. TREATED IN EXTRACTS WHEN USING A FULL FACE MASK AND GLOVES.

A solution of 40% potassium hydroxide (4.5 mL, 32 mmol) was added dropwise to a suspension of N-methylnitrosourea

(1.5 g, 15 mmol) in ether (25 mL), cooled in an ice/salt bath. After the solid was dissolved (more base is added if necessary), the ether solution of diazomethane was dried over solid potassium hydroxide. This drying process was repeated two more times and the diazomethane was used immediately.

To a solution of 2-adamantyloxycarbonyltryptophan (1)

(1.77 g, 4.61 mmol) in THF (25 mL) was added at 0°C with N-methylmorpholine (557 µl, 5.07 mmol) and isobutyl chloroformate (658 µl, 5.07 mmol ). The mixture was stirred for 20 minutes at 0°C and then filtered. The filtrate was added to a solution of diazomethane (10 mL) in ether (prepared from N-methylnitrosourea (1.0 g, 10 mmol)). The resulting solution was stirred for 15 min at 0°C and then for 15 h at room temperature. The solvent was removed in vacuo and the residue taken up in ethyl acetate (100 mL). This solution was washed with water (12 x 10 mL), 5% citric acid (2 x 10 mL), 1 N NaHCO 3

(10 ml) and saline (10 ml) . It was dried (MgSO 4 ) and the solvent was removed in vacuo. The crude product was purified by column chromatography in [SiO 2 : hexane-ethyl acetate (5:4) as eluent] to give diazoketone (8) (1.35 g, 72%) as a yellow foam, m.p. 72-75°C

vmax CDC13 (film) 2109 (N2) ; 1697 (CO) and 740 cm"<1> (disubstituted Ph); H (d6-acetone), δ 1.39-2.02 (14H, m, adamantyl), 3.13 (1H, dd, J 15 and 8Hz, CH of CH2 indole), 3.29 (1H, dd, J 15 and 5Hz, CH of CH2indole) , 4.51 (1H, m, CH2CH(NHR)CO) , 4.69 (1H, s, adamantyl 2-H), 5.90 (1H, br s, CHN2), 6.41 (1H, s, NH CO), 7.01 (1H, t, J 7Hz, indole 5 or 6-H), 7, 09 (1H, t, J 7Hz, indole 7-H), 7.61 (1H, d, J 9Hz, indole 4-H), 10.05 (1H, br s, indole NH).

2- adamantyloxycarbonyltryptophanyl- chloromethyl- ketone ( 9)

Hydrochloric acid (11.1 mL of a 0.30 M solution in dioxane) was added dropwise with stirring to a solution of diazoketone (8) (1.35 g, 3.32 mmol) in THF (100 mL) at 0 °C. The reaction was followed by infrared spectrometry for the disappearance of the N2 peak (2109 cm"<1>) in the starting material. After all the diazoketone had disappeared (about 60 minutes), the reaction was quenched with saturated sodium bicarbonate (20 ml). The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate (1090 mL). The layers were separated and the aqueous layer further extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate fractions were washed with brine (50 mL ), dried (MgSO 4 ) and the solvent removed in vacuo The crude product was recrystallized from ethyl acetate-hexane to give chloroketone (9)

(1.29 g, 94%), m.p. 138-140°C

Found: C, 66.6; H, 6.7; Cl, 8.3; N, 6.9% C 23 H 27 C 1 N 2 O 3 requires C, 66.6; H, 6.6; Cl, 8.5; N, 6.75% vmax (CDCl3 film) 1740 (CO a chloroketone), 1698 (CO urethane) and 736 cm"<1> (disubstituted Ph);

H (CDC13) 6 1.45-2.06 (14H, m, adamantyl), 3.27 (2H, m, CH2ind) , 3.96 (1H, d, J 16Hz, CH of CH2Cl) , 4.11 (1H, d, J 16Hz, CH av CH2C1), 4.83 (2H, m, CH2CHCO and adamantyl 2-H), 5.35 (1H, d, J 7Hz, NH), 7.00 (1H, d , J 2Hz, indole 2-H), 7.14 (1H, t, 6Hz, indole 5 or 6-H), 7.22 (1H, t, J 6Hz, indole 5 or 6-H), 7.37 (1H, d, J 8Hz, indole 7-H), 7.61 (1H, d, J 8Hz, indole 4-H), 8.20 (1H, s, indole NH).

a - \ 4 - ( 1H- indol-3- vi) - 2- oxo-3- f \ ( tricyclo f3 . 3 . 1. 13' 71 - dec- 2-yloxy) carbonylamino] butvl] benzene- propanoic acid, compound ( 10), Example 4

Sodium iodide (Aldrich) (51 mg, 0.34 mmol) was added to a solution of chloroketone (126) (112 mg, 0.27 mmol) in anhydrous DME (5 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes, after which an aliquot (800 µl,

0.30 mmol) of an "anion solution" [prepared by reacting sodium hydride (60% dispersion in oil) (88 mg, 2.2 mmol) in anhydrous DME (5 mL) with diethyl benzyl malonate (950 fil, 4.0 mmol) at room temperature] was added. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo, the residue taken up in dichloromethane (50 mL), washed with brine, dried (MgSO 4 ) and evaporated under reduced pressure. The raw material was purified by column chromatography

[SiO 2 :hexane-ethyl acetate (2:1) as eluent] to give a keto diester (100 mg, 59%); m.p. 49-54°C.

Found: C, 70.8; H, 7.2; N, 4.4%

C37H44N2O7 requires C, 70.7; H, 7.05; N, 4.5%

<y>max (CH2C12 film) 1728 cm"<1> (CO) ;

H (CDC13) 6 1.42-2.08 (14H, m, adamantyl), 2.98 (1H, d, J 19Hz), 3.18 (1H, dd, J 15 and 6Hz, CH2ind), 3, 24 (1H, dd, J 15 and 6Hz, CH2ind) , 3.34 (2H, s, CH2) , 4.18 (4H, m, 2 x CH2) , 4.62 (1H, m, CH2CH(CO) NH) , 4.79 (1H, s, adamantyl 2-H), 5.30 (1H, d, J 8Hz, NH), 6.84 (2H, d, J 7Hz, Ph 2,6-H), 6.92 (1H, d, J 2Hz, indole 2-H), 7.07-7.25 (5H, m, indole 5, 6-H, Ph 3,4,5-H), 7.34 ( 1H, d, J 8Hz, ind 7-H), 7.62 (1H, d, J 8Hz, indole 4-H), 8.07 (1H, s, indole NH).

A solution of the ketodiester (1.19 g, 1.89 mmol) in ethanol (5 mL) and 6N NaOH (94 6 µl, 5.67 mmol) was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue diluted with H 2 O (10 mL). The aqueous solution was acidified to pH 2 with concentrated HCl and then extracted with ethyl acetate (3 x 50 mL). The organic extract was washed with saturated sodium chloride solution, dried (MgSO 4 ) and concentrated in vacuo. The residue was taken up in dioxane (30 ml) and refluxed for 18 hours. The solvent was removed in vacuo and the crude material purified by column chromatography [SiO 2 ; toluene-acetic acid (9:1) as eluent] to give keto acid (10) (783 mg, 78%) as a yellow foam, m.p.

66-80°C

<X>H NMR (300 MHz): δ 1.38-2.22 (m, 16H, adamantyl + H2O) , 2.55-3.25 (vbr m, 12H, CH2ind, CH2Ph CO, CH2CH + H2O/ HoD) , 4.26 (m, 1H, NHCHCO), 4.57 (s, 1H, adamantyl 2-H), 6.95-7.37 (m, 10H, Ph + ind 2-H, ind 5- H, ind 6H, ind 7-H + NH), 7.49 (d, J 8Hz, 1H, ind 4-H), 10.58 (s, 1H, ind NH).

IR (film) : 3460-3200 (br OH), 2920 + 2856 (adamantyl) 1707

(br, ester ketone CO, acid CO, urethane CO).

Analysis, found: C, 73.18; H, 6.98; N, 5.05%

C32H36N2O5 requires C, 72.70; H, 6.86; N, 5.30%

EXAMPLE 5

Tricyclo [ 3. 3. 1. I3' 7! dec- 2- yl fl- T ( 2- hydroxy- 2- phenylethyl) aminol - 3-( 1H- indol- 3- yl)- 2- methylpropyl- 2- yl] carbamate ( 12)

This compound was prepared in a similar manner to compound (14) (Example 6) except that compound (11) was used. 0.42 g (43%) was obtained; m.p. 78-80°C;

IR (undiluted) 2910, 1694 (C=0 urethane) cm"<1>;

NMR (CDCl 3 ), 6 8.1 (1H, br s, indole NH) , 7.6 (1H, d, J 8Hz, indole H-4), 7.4-7.1 (8H, m, Ph + indole H-5, H-6, H-7), 7.0

(1H, m, indole H-2), 5.0-4.6 (3H, m, adamantane H-2 + urethane NH + CHOH), 3.5-2.6 (6H, m, 3 x CH2) , 2.1-1.5 (15H, m, adamantane + OH) , 1.4 (3H, s, CH3) ;

[α]D +18° (CHCl 3 , 22°C, C = 0.2);

FABMS (m<+>/e) 502 (m<+>+H) ;

/Analysis, found: C, 72.56%; H, 7.84%; N, 7.95% C31H39N303.0", 5H20, requires: C, 72.91%; H, 7.90%; N, 8.23%

EXAMPLE 6

Tricyclof 3 . 3. 1. 13- 71 dec- 2- vl \ R - ( R*, S*) 1 - 1- \ fl- ( hydroxymethyl) - 2- phenvletyl aminol - 3- ( lH- indole- 3- vl) - 2- metvlprop- 2- ylcarbamate

( 14)

To a solution of lithium borohydride (4 ml, 2M solution, 8 mmol) in dry tetrahydrofuran was added under a nitrogen atmosphere a solution of chlorotrimethylsilane (1.75 g, 16.0 mmol) in dry tetrahydrofuran (5 ml). A white precipitate of lithium chloride was observed. After 2 min, a solution of compound (13), (1 g, 2 mmol) in tetrahydrofuran (15 mL) was slowly added (over 3 to 4 min), and the reaction mixture was stirred for 20 h at room temperature. The reaction mixture was carefully treated with methanol (5 mL) and volatile compounds removed in vacuo (40°C). The residue was purified by flash chromatography on normal phase silica gel using hexane/ethyl acetate as eluent (a gradient elution technique was used ranging from 80% hexane:20% ethyl acetate to 100% ethyl acetate). 0.60 g of starting material and 0.26 g (27%) of the desired product (14) were obtained as a white foam;

IR (undiluted) 2900, 1694 (C=0 urethane) cm"<1>;

NMR (CDCl 3 ) 6 8.1 (1H, br s, indole NH), 7.6 (1H, d, J 8Hz, indole H-4), 7.4-7.1 (8H, m, Ph + indole H-5, H-6, H-7), 6.9 (1H, d, J 2Hz, indole H-2), 4.9 (1H, s, urethane NH), 4.8 (1H, s, adamantane H-2), 3.6-3.3 (2H, m, CH2-0H), 3.1 (2H, m, CH2-indole) , 3.0-2.6 (5H, m, 2 x CH2 + 1 x CH) , 2.1-1.5 (15H, m, adamantane + OH) , 1.25 (3H, s, CH3) .

A mono-4-toluenesulfonate salt was prepared by dissolving (14) (0.2 g, 0.4 mmol) and 4-toluenesulfonic acid monohydrate (0.074 g, 0.40 mmol) in acetone (10 mL) and then remove the solvent in vacuo to give a white solid;

m.p. 110-113°C.

IR (undiluted) 2915, 1790 (C=0 urethane) cm"<1>;

[a] D + 20° (CHCl3, 23°C, c = l)

X FAB MS (mVe) 516 (m<+> + H);

Analysis,

C32<H>41N303 . C7H8S03. 0.5<H>2O

Calculated: C, 67.22; H, 7.23; N, 6.03; S, 4.60

Found: C, 67.23; H, 7.26; N, 5.84; S, 4.36.

EXAMPLE 7

[ R- ( R*. S*) 1- S- l12 -( lH- indole- 3- vlmetvl)- 2-

r [ tricyclo [ 3 . 3. 1. 13, 71 dec- 2 - yloxy) carbonyl] aminol <p>ro<p>yl - aminol- benzenepropanol- acetate ( 15)

To a solution of (14) (0.05 g, 0.10 mmol) in dichloromethane (10 ml) was added at room temperature acetyl chloride (0.10 ml, 1.4 mmol) and the reactants were stirred for 1 hour, after which volatile compounds were removed in vacuo (40°C) and the residue purified by flash chromatography using 80% hexane:20% ethyl acetate as eluent. 0.024 g (44%) of (88) was obtained as an amorphous white solid.

IR (undiluted) 2910, 1739 (C=0 ester), 1700 (C=0 urethane) cm"<1>; NMR (CDCl3) <5 8.2 (1H, s, indole NH), 7.6 (1H , d, J 8Hz, indole

H-4), 7.4-7.0 (8H, m, Ph + indole H-5, H-6, H-7), 6.9 (1H, d, J 2Hz, indole H-2), 5.1 (1H, s, urethane NH), 4.8 (1H, s, adamantane H-2), 3.9 (2H, d, J 4Hz, CH2OCO), 3.1 (2H, m, CH2- indole), 3.0-2.5 (4H, m, CH2Ph + CH2N) , 2.1-1.4 (17H, m, CH3CO + adamantane), 1.3 (3H, s, CH3) .

A mono-4-toluenesulfonate salt was prepared by dissolving (15) (0.02 g, 0.04 mmol) and 4-toluenesulfonic acid monohydrate (0.007 g, 0.04 mmol) in acetone (5 mL) and then remove the solvent in vacuo to give a white solid, m.p. 98-101°C;

[α] D +32° (CHCl 3 , 24°C, c = 0.5);

FAB MS (m<+>/e) 558.5 (m<+> + H);

Analysis,

<C>34<H>43N304 . C7H8S03. H 2 O requires C, 65.84%; H, 7.14%; N, 5.62%; S, 4.29% found: C, 65.48%; H, 7.08%; N, 5.53%; S, 4.31%

EXAMPLE 8

TR-( R*, S* H- 6- Facetvl\ 2 -( 1H- indol- 3- vlmetvl)- 2- rtricyclo-[ 3 . 3 . 1. 13, 71 dec- 2- yloxycarbonyl aminol - propyl] amino] benzenepropanol acetate ( 15a)

To a solution of (14) (0.05 g, 0.10 mmol) in dichloromethane (10 ml) was added at room temperature triethylamine (1 ml, 7 mmol) and then acetyl chloride (0.1 ml, 1.4 mmol ), after which the reactants were stirred for 1 hour. The volatile compounds were removed in vacuo and the residue purified by flash chromatography using hexane:ethyl acetate as eluent. 0.043 g, (74%) of (88a) was obtained as an amorphous solid;

IR (undiluted) 2920, 1740 (C=0 ester), 1709 (C=0 urethane), 1632 (C=0 amide) cm"<1>.

Tricyclof 3 . 3. 1. 1. 3' 71 dec- 2- yl f R- ( R* , S*) ] - facetvl ri - ( hydroxymethyl) - 2- phenylethyl] aminol - 2-( 1H- indol- 3- ylmethyl)- prop - 2-yl carbamate ( 16)

To a solution of (15a) (0.03 g, 0.05 mmol) in tetrahydrofuran (5 mL) was added a solution of lithium hydroxide (0.1 g, 2.4 mmol) in water (5 mL) and the reactants stirred for 15 minutes. The reaction mixture was then acidified with hydrochloric acid (2N aq.) and the products extracted with ethyl acetate: (50 ml). The extract was dried (magnesium sulfate) and evaporated in vacuo (40°C). The residue was purified by flash chromatography using hexane:ethyl acetate as eluent. 0.024 g (86%) of (89) was obtained as a white solid, m.p. 109-112°C

[α]D +31° (22°C, CHCl 3 , c=0.5);

IR (neat) 2900, 1694 (C=0 urethane), 1621 (C=0 amide) cm"<1>; NMR (CDCl3) δ 8.1 (1H, s, indole NH), 7.5 (1H, d, J 8Hz, indole H-4), 7.4-7.0 (8H, m, Ph + indole H-5, H-6, H-7), 6.9 (1H, s, indole H- 2), 5.3 (1H, br, urethane NH), 4.8 (1H, br, adamantane H-2), 4.4 (1H, s, OH), 3.9 (1H, d, J 12Hz , one of CH2OH) , 3.8-3.7 (2H, m, one of CH2OH + one of CH2N) , 3.5 (1H, m, CH) , 3.4 (1H, d, J 14Hz, one of CH2 indole), 3.3 (1H, d, J 13Hz, one of CH2N) , 3.1 (2H, d, J 8Hz, CH2Ph) , 2.8 (1H, d, J 14Hz, one of CH2- indole) , 2.0 (3H, s, CH3CO) , 1.9-1.4 (14H, m, adamantane), 1.1 (3H, s, CH3) ;

Analysis,

C34H43N304 . 0.5 H 2 O, requires C, 72.06%; H, 7.82%; N, 7.41% found C, 72.20%; H, 7.73%; N, 7.30% FAB MS (m/e) 558 (m<+> + H)

EXAMPLE 9

Tricyclo f 3 . 3. 1. I3' 7! dec- 2- vi ( R ) - Tl - ( 1H - indole - 3 - vylmethyl) - 2-methyl - 2-[( 2- phenylethyl) aminol- 2 - 1ioxoethyl carbamate

To a solution of (29) (0.1 g, 0.2 mmol) in toluene

(10 mL) was added Lawesson's reagent (0.10 g, 0.25 mmol) and the reaction mixture refluxed for 1 h. The reaction mixture was allowed to cool to room temperature and was purified by flash chromatography (dichloromethane/ether as eluent). 0.065 g (63%) of (30) was obtained as a white foam, m.p. 81-85°C;

IR (Undiluted) 2916, 1703 (C=0 methane), 1520 (C=S) cm"<1>;

NMR (CDCl3) 6 8.1 (1H, br, indole NH), 7.8 (1H, br, this amide NH), 7.6 (1H, d, J 8Hz, indole H-4), 7.5 -6.9 (9H, m, indole H-5, H-6, H-7, H-2, + phenyl), 5.3 (1H, br, urethane NH), 4.7 (1H, br s , adamantane H-2), 3.8 (2H, m, CH2N) , 3.6 (1H, d, J 14Hz, one of CH2-indole), 3.4 (1H, d, J 14Hz, one of CH2 -indole), 2.6 (2H, m, CH2Ph), 2.0-1.6 (14H, m, adamantane), 1.5 (3H, s, CH3);

R£ (30% ethyl acetate/hexane) 0.3.

EXAMPLE 10

Metvi ( R )- 4- f( 2- hydroxy- l- phenylethyl) aminol- 4- oxo- 2- butenoate

( 18)

To a solution of monomethyl fumarate (3.0 g, 23 mmol) in ethyl acetate (40 mL) was added 1-hydroxybenzotriazole hydrate (3.0 g, 22 mmol) and then N,N'-dicyclohexylcarbodiimide (4.5 g , 22 mmol), after which the reaction mixture was stirred at room temperature for 1 hour. The solid was filtered off and discarded. To the filtrate was added (R)-α-phenylglycinol (3.0 g, 22 mmol) and stirring continued for 20 minutes. The volatile compounds were removed in vacuo (40°C) and the residue purified by flash chromatography on normal phase silica gel using hexane:ethyl acetate (1:1) as eluent. 2.5 g (46%) of (18) was obtained as a white solid, m.p. 75-77°C;

IR (undiluted) 3250 (OH), 1729 (C=0 ester), 1666 (C=0 amide), 1640 (C=C) cm"<1>;

NMR (CDCl 3 ) 6 7.3-7.4 (5H, m, Ph), 7.0 (1H, d, J 15Hz, trans-alkene), 6.8 (1H, d, J 15Hz, trans-alkene ), 6.6 (1H, br d, NH), 5.2 (1H, m, CH) , 3.9 (2H, t, J 3Hz, CH2) , 3.8 (3H, s, CH3) , 2.3 (1H, t, J 5Hz, OH);

[α] D -53° (CHCl 3 , 24°C, c = 1);

Analysis,

C13H15N04, requires: C, 62.64%; H, 6.07%; N, 5.62%

found: C, 62.72%; H, 5.92%; N, 5.48%

Tricyclo r3. 3. 1. 13-71 dec-2-yl 3-r (1H-indol-3-vl) metvll - 3- metvl-4. 9- dioxo- 7- phenyl- 5, 13- dioxa- 2, 8- diazatetradec- 10- enoate ( 19)

To a solution of N,N'-carbonyldiimidazole (0.15 g, 0.90 mmol) in dichloromethane (40 ml) was added (23b)

(0.25 g, 0.63 mmol). After 20 minutes of stirring at room temperature, (18) (0.2 g, 0.8 mmol) was added, after which the reaction mixture was boiled under reflux for 10 hours. After cooling to room temperature, volatile

bonds removed in vacuo (40°C) and the residue purified by flash chromatography (hexane/ethyl acetate as eluent). 0.28 g (71%) of (19) was obtained as a white solid, m.p. 96-99°C.

IR (undiluted) 2910, 1730 (C=0 ester), 1695 (C=0 urethane), 1670 (C=0 amide + C=C) cm"<1>;

NMR (CDCl 3 ), 6 8.3 (1H, br, indole, NH) , 7.5 (1H, d, J 8Hz, indole H-4), 7.4 (1H, d, J 8Hz, indole H- 5), 7.3-6.9 (10H, m, indole H-6, H-7, H-2 + phenyl + amide NH + one of alkene CH), 5.3 (1H, br, one of CH2 -0), 5.1 (1H, s, urethane NH), 5.0 (1H, br, CH), 4.8 (1H, br s, adamantane H-2), 4.1 (1H, dd, J 11Hz, 4Hz, one of CH2-0) , 3.8 (3H, s, CH3) , 3.5 (1H, d, J 14Hz, one of CH2 - indole) , 3.3 (1H, d, J 14Hz, one of CH2-indole) , 2.1-1.4 (18H, m, adamantane + CH3) ;

[Qf]D +25° (CHCl 3 , 24°C, c = 0.2);

F/AB MS (m<+>7e) 6281 (m<*> + H)

Analysis,

C36H41N307, requires C, 68.88%; H, 6.58%; N, 6.69%;

found: C, 68.56%; H, 6.83%; N, 6.57%

EXAMPLE 11

Tricyclo r3. 3. 1. I3' 7! dec- 2- vi 3- f ( 1H- indol- 3 - vi) methyl 1 - 3- metvl-4 , 9- dioxo- 7- phenyldioxa- 2, 8- diazatetradec- 10- enoate ( 20)

Prepared according to a similar method to that used for compound (19). 0.30 g (76%) of (20) was obtained as a white solid, m.p. 104-105°C;

IR (undiluted) 2920, 1728 (C=0 ester), 1720 (C=0 urethane), 1700 (C=C), 1670 (C=0 amide) cm"<1>;

NMR (CDCl 3 ); 5 8.3 (1H, br, indole NH) , 7.5 (1H, d, J 8Hz, indole H-4), 7.4 (1H, d, J 8Hz, indole H-5), 7.3 -7.1 (7H, m, indole H-6, H-7 + phenyl), 7.1-6.7 (4H, m, indole H-2 + amide NH + alkenes), 5.3 (2H, br, urethane NH + one of CH2-0), 4.8 (1H, br, adamantane H-2), 4.7 (1H, m, CH), 4.1 (1H, dd, J 11Hz, 4Hz, one of CH2-0) , 3.8 (3H, s, ester, CH3) , 3.4 (1H, d, J 14Hz, one of CH2 - indole) , 3.2 (1H, d, J 14Hz, one of CH2-indole) , 2.1-1.5 (17H, m, adamantane + CH3) ;

[or]D -36° (CHCl3, 22°C, c = 1)

FAB MS' (m<*>/e) 628 (m<+> + H)

Analysis,

C3SH41N307 requires: C, 68.88%; H, 6.58%; N, 6.69%

found: C, 68.86%; H, 6.57%; N, 6.77%

EXAMPLE 12

Methyl ( R )- 4-\( 2- hydroxy-l- phenylethyl) amino]- 4- oxobutanoate

( 21)

Prepared according to a similar procedure to that used for compound (18) (see Example 10). It was obtained g (65%) of (21), m.p. 59-61°C;

IR (undiluted) 3250 (OH), 1737 (C=0 ester), 1651 (C=0

amide) cm"<1>;

NMR (CDCl 3 ) 6 7.2-7.4 (5H, m, Ph), 6.4 (1H, br d, NH), 5.1 (1H, m, CH) , 3.7 (3H, s , CH3 ), 2.8-2.5 (6H, m, 3 x CH2 ), 1.7 (1H, br, OH); "

[ct]D -53° (CHCl 3 , 22°C, c = 1);

Analysis,

C13H17N04, requires: C, 62.14%; H, 6.82%; N, 5.57%;

found: C, 62.21%; H, .7.13%; N, 5.73%.

Tricyclo f 3 . 3. 1. 13-7! dec- 2 - vl- 3- \ ( lH- indole- 3- vl) metvll - 3- metvl-4, 9- dioxo- 7- phenvl- 5, 13- dioxo- 2, 8- diazatetradecanoate ( 22)

To a solution of 1,3-dicyclohexylcarbodiimide (0.3 g, 1.5 mmol) and 4-dimethylaminopyridine (0.05 g, 0.40 mmol) in dichloromethane (40 mL) was added (23) (0 .50 g, 1.3 mmol). After stirring for 20 minutes at room temperature, (21)

(0.30 g, 12 mmol) added and the mixture boiled under reflux for 2 hours. Volatile compounds were removed in vacuo (40°C) and the residue purified by flash chromatography (hexane/ethyl acetate as eluent). 0.41 g (52%) was obtained as a white solid, m.p. 69-71°C. IR (undiluted) 2920, 1739 (C=0 ester), 1700 (C=0 urethane), 1660 (C=0 amide): NMR 6 (CDCl3) 8.3 (1H, br, indole-NH), 7, 5 (1H, d, J 8Hz, indole-H-4), 7.4-6.9 (10H, m, indole-H-5, H-6, H-7, H-2 + amide-NH + phenyl), 5.3 (1H, m, CH), 5.2 (1H, brs, urethane-NH), 4.8 (2H, br, adamantane H-2 + one of CH2O), 4.1 (1H , m, one of CH2O) , 3.7 (3H,

s, ester CH3) , 3.4 (2H, m, CH2-indole), 2.7-2.5 (4H, m, 2xCH2) , 2.1-1.5 (17H, m, adamantane + CH3) : [α]D -18° (CHCl 3 , 22°C, C=1) . FAB MS (m+/e), 630.0 (m<+> + H); Analysis: C36H43N307 . 0.5H2O requires C, 67.69; H, 6.94; N, 6.58

found C, 67.36; H, 6.99; N, 6.51 Note: some small peaks at 6 4.4-4.2 in the NMR spectrum may indicate the presence of small amounts of another isomer.

EXAMPLE 13

Tricvchlor3. 3. 1. 13' 71dec- 2- vl ( R) - r2- hydroxy- 1-( 1H- indol-3-yl) methylvl- 1- methylethyl] carbamate ( 24 )

To a solution of (23) (R=Me) (1.0 g, 2.4 mmol) in dry THF (20 mL) was added at 0°C under a nitrogen atmosphere a solution of lithium aluminum hydride in ether (3 mL of a IM solution, 3 mmol) and the reaction mixture stirred for 20 minutes. Ethyl acetate (20 mL) was carefully added and the resulting solution washed with acid (2N HCl, 2x100 mL), dried over magnesium sulfate and evaporated to dryness.

0.85 g (91%) of (24) was obtained as a white solid, m.p. 72-74°C. IR (undiluted) 2918, 1693 (C=0 urethane) cm"<1>;

NMR (CDCl3) 6 8.1 (1H, br, indole-NH), 7.6 (1H, d, J 8Hz, indole-H-4), 7.35 (1H, d, J, 8Hz, indole- H-5), 7.2-7.0 (3H, m, indole H-6, H-7, H-2), 4.85 (1H, br s, urethane-NH), 4.8 (1H , br, adamantane H-2), 4.0 (1H, br, OH), 3.8 (2H, m, CH2-0), 3.25 (1H, d, J 14Hz, one of CH2 - indole) , 3.0 (1H, d, J 14Hz, one of CH2-indole) , 2.1-1.5 (14H, m, adamantane), 1.2 (3H, s, CH3) ;

[α]D +42° (CHCl 3 , 22°C, C=1). FAB MS (m<+>/e), 383 (m<+> + H); Analysis: C23H30N2O3 . 0.5H2O requires C, 70.56; H, 7.98; N, 7.15

found C, 70.35; H, 7.83; N, 6.94

3- (lH- indole- 3- vl) - 2- metvl- 2- r rtricvklo\ 3 . 3. 1. 13- 71 dec-2-yloxy) carbonyl] amino] propyl ( R )- benzene acetate ( 25 )

To a solution of N,N'-carbonyldiimidazole (0.40 g,

2.5 mmol) in dichloromethane (20 ml) was added phenylacetic acid (0.30 g, 2.2 mmol). After stirring for 10 minutes at room

temperature, alcohol (24) (0.3 g, 0.8 mmol) was added and stirring continued for 40 hours. Volatile compounds were removed in vacuo and the residue purified by flash chromatography (hexane/5% ethyl acetate as eluent). 0.30 g (77%) of (25) was obtained as a white foam, m.p. 57-60°C. IR (undiluted) 2917, 1722 (C=0 ester), 1700 (C=0 urethane) cm"<1>;

NMR (CDCl 3 ) δ 8.05 (1H, br, indole-NH), 7.5 (1H, d, J 8Hz, indole H-4), 7.4-7.2 (6H, m, indole H- 5 + phenyl), 7.16 (1H, t, J 7Hz, indole H-6), 7.07 (1H, t, J 7Hz, indole H-7), 6.9 (1H, d, J 2Hz, indole H-2), 4.8 (1H, br, adamantane H-2), 4.6 (1H, br, urethane NH), 4.3 (1H, d, J 11Hz, one of CH2O) , 4, 2 (1H, d, J 11Hz, one of CH2O) 3.7 (2H, s, CH2-Ph) , 3.2 (1H, d, J 14Hz, one of CH2-indole) , 3.0 (1H, d, J 14Hz, one of CH2-indole) , 2.1-1.4 (14H, m, adamantane), 1.2 (3H, s, CH3) ;

[Qf]D +13° (CHCl 3 , 22°C, C=0.5). FAB MS, 501 (m<+> + H);

Analysis:

C 31 H 36 N 2 O 4 requires C, 1 74.37; H, 7.25; N, 5.60 found: C, 74.20; H, 7.32; N, 5.52 Tricvklo r3 . 3. 1. I3' 7] dec- 2- vi ( R ) - ri- formvyl- 2- ( 1H- indol- 3- ylmethyl]- 1- methylethylcarbamate ( 26) To a solution of (24) (0.03 g, 0.08 mmol) in dichloromethane (40 ml) was added at room temperature under argon N-methylmorpholine-N-oxide (0.1 g, 0.9 mmol), molecular sieve (4Å activated powder, 0.5 g) and tetra -n-propylammonium perruthenate (0.01 g, 0.03 mmol). After stirring for 30 min, volatile compounds were removed in vacuo (40°C). The residue was taken up in ethyl acetate and purified by flash chromatography (hexane/5% ethyl acetate as eluent).0.2 g (67%) of (24) was obtained as a white solid, mp 178-179°C; IR (undiluted) 2900, 1732 (C=0 aldehyde), 1692 (C =0 urethane) cm"<1>; NMR (CDCl3) 6 9.6 (1H, s, CHO) , 8.1 (1H, br s, indole NH) , 7.6-6.9 (5H, m , indole), 5.2 (1H, br, urethane NH), 4.8 (1H, s, adamantane H-2), 3.3 (2H, br, CH2-indole) , 2.1-1.3 (17H, m, adamantane + CH3) ; [ ot ] D +22° (CHCl 3 , 22°C, C=1). FAB MS (m+/e), 381 (m<+> + H); Analysis: C 23 H 28 N 2 O 3 requires C, 72.61; H, 7.42; N, 7.36

found C, 72.31; H, 7.46; N, 7.31

EXAMPLE 14

Tricyclo\ 3 . 3. 13- 71 dec- 2- vl [ R-( Z) ] - ri-( 1H- indol- 3- vl) methyl) - 1-methyl- 5- phenyl- 2- pentenyl carbamate ( 27)

A mixture of triphenylphosphine (0.35 g, 1.3 mmol) and 1-bromo-3-phenylpropane (0.27 g, 1.3 mmol) was heated to 110°C, whereupon the molten reactants solidified. After cooling to room temperature and trituration with hexane, a white solid was obtained (0.4 g, 65%). This was added to a suspension of sodium hydride (50 mg of a 50% dispersion in oil, 1 mmol) in toluene (40 mL) and the reaction mixture refluxed for 20 minutes. The aldehyde (0.2 g, 0.5 mmol) was added and heating continued for 1 hour. Volatile compounds were removed in vacuo and the residue purified by flash chromatography (hexane/10% ethyl acetate as eluent).

0.20 g (79%) of (27) was obtained as a white solid, m.p. 49-52°C; IR (undiluted) 2904, 1696 (C=0 urethane), 1683 (C=C) cm"<1>;

NMR (CDCl 3 ) δ 8.3 (1H, s, indole NH), 7.6 (1H, d, J 8Hz, indole H-4), 7.3-7.0 (8H, m, indole H-5 , H-6, H-7 + phenyl), 6.9 (1H,

s, indole H-2), 5.6 (1H, d, J 12Hz, CH at a-center), 5.4 (1H, dt, J 5, 12Hz, CH-CH2) , 4.8 (2H, m, urethane NH + adamantane H-2), 3.3 (1H, d, J 14Hz, one of CH2-indole) , 3.1 (1H, d, J 14Hz, one of CH2-indole) , 2.6 -2.4 (4H, m, 2xCH2) , 2.1-1.4 (14H, m, adamantane) , 1.4 (3H, s, CH3)

EXAMPLE 15

Tricyclo [ 3. 3. 1. 13' 71 dec- 2- vl T2- hydroxy- 1 - ( 1H- indol- 3- vlmethvl) - 1- methyl- 5- phenylpentyl] carbamate ( 28)

To a stirred mixture of magnesium metal (0.5 g,

21 mmol) and dry ether (20 ml) were added at 0°C under nitrogen atmosphere 1-bromo-3-phenylpropane (0.20 ml, 0.26 g,

1.3 mmol) and a crystal of iodine. After 20 minutes, the reaction mixture became colorless, and the solution was then withdrawn with a syringe and, under a nitrogen atmosphere at 0°C, added to a

solution of (26) (0.30 g, 0.8 mmol) in dry ether. After 20 minutes, the reaction mixture was allowed to warm to room temperature, after which the reaction was terminated in dilute hydrochloric acid (2N, 50 ml). The products were extracted with ethyl acetate (50 mL), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (hexane:ethyl acetate as eluent) to give 0.31 g (79%) of (28) as an oil which appears to be a 1:1 mixture of the possible diastereomers. Further chromatography gave a single diastereoisomer: IR (undiluted) 2908, 1690 (C=0 urethane);

NMR (CDCl 3 ) δ 8.1 (1H, br, indole NH), 7.6 (1H, d, J 8Hz, indole H-4), 7.4-6.9 (9H, m, indole H-5 , H-6, H-7, H-2 + phenyl), 4.8 (1H, br, adamantane H-2), 4.7 (1H, br, s, urethane NH), 3.6 (1H, m, CH-OH), 3.5 (1H, d, J 14Hz, one of CH2-indole) , 3.1 (1H, d, J 14Hz, one of CH2 - indole) , 2.7 (2H, m , CH2-Ph) , 2.1-1.3 (19H, m, adamantane"+ 2xCH2 + OH) , 1.1 (3H, s, CH3) .

EXAMPLE 16

Tricyclo\ 3 . 3. 1. 13-7! dec- 2- ylR- ( R*, S*) 1 - ri- U , 5- dihydro- 4 ( femvl-methyl- 2- thiazolyl- 2-( 1H- indol- 3- yl)- 1- methylethylcarbamate ( 17 )

To a solution of (13) (0.1 g, 0.2 mmol) in toluene

(10 mL) was added Lawesson's reagent (0.10 g, 0.25 mmol) and the reaction mixture was refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature and was purified by flash chromatography (dichloromethane/ether as eluent). 0.07 g (70%) of the product was obtained; IR (undiluted) 2910, 1697 (C=0 urethane), 1620 (C=N) cm<1>;

NMR (CDCl3) a 8.1 (1H, br, indole NH), 7.7 (1H, d, J 8Hz, indole H-4), 7.4-6.9 (9H, m, indole H-5 , H-6, H-7, H-2 + phenyl), 5.8 (1H, br, urethane NH) , 4.9 (1H, br, adamantane H-2), 4.6 (1H, m, CH) , 3.7 (lH, m, one of CH2-S) , 2.9 (1H, m, one of CH2-S) , 2.8 (1H, br, one of CH2-Ph) , 2, 2 (1H, br, one of CH2-Ph) , 2.1-1.4 (14H, m, adamantane), 1.3 (3H, s, CH3) ;

FAB MS (m<V>e) , 529 (m<*> + H) , 47%), 398 (m+-(indole-CH2) , 44%), 130 (indole-CH2), 100%): Rf (30% ethyl acetate/hexane), 0.85.

EXAMPLE 17

Phenvlmetvl ( R) - S- metvl- S- r r ( tricyclo f 3 . 3 . 1. 13' 71 dek- 2vloxv) - carbonyl aminol- 1H- indole- 3- butanoate

Step 1

A solution of N-methylmorpholine (253 mg, 2.50 mmol) and 2-Adoc-aMe-R-TrpOH (23b) (990 mg, 2.50 mmol) in anhydrous THF

(20 mL) was cooled to 0 °C and treated dropwise with a solution of i -butyl chloroformate (360 mg, 2.5 mmol) in anhydrous THF (10 mL) over 10 min. It was stirred at 0°C for a further 20 minutes and filtered. A solution of diazomethane (6 mmol) in Et 2 O was added to the filtrate which was then left at 0°C for 4 hours, after which it was allowed to warm slowly to room temperature over 12 hours. Excess diazomethane was decomposed with acetic acid and the solvents removed in vacuo. The residue was chromatographed using 25% EtOAc in n-hexane to give the diazo ketone (300 mg, 29%)

IR (film) 3400-3200, 2913, 2854, 2106, 1693 and 1353 cm'<1>;

NMR (CDCl 3 ) δ 1.49 (3H, s), 1.50-1.60 (2H, m), 1.70-2.05 (12H, m), 3.30-3.40 (2H, br s), 4.86 (1H, br s), 5.20-5.40 (1H, br s) , 5.56 (1H, s) , 6.95 (1H, d, J 2Hz), 7 .08 (1H, t, J 7Hz), 7.16 (1H, t, J 7Hz), 7.33 (1H, d, J 8Hz), 7.55 (1H, d, J 8Hz), 8.50 (1H, p).

Step 2

A solution of the diazoketone (Reaction scheme 5, no. 31)

(1.04 g, 2.50 mmol) in benzyl alcohol (10 mL) was treated portionwise with a solution of silver benzoate (4 mL, 17 mmol) in triethylamine (5 mL) and allowed to stand under stirring for 1 hour. EtOAc (30 mL) was then added and this solution was treated with activated charcoal and filtered through a filter, after which the solvent was removed in vacuo and the residue chromatographed using 30% EtOAc in n-hexane as eluent to give the benzyl ester (44 .0 mg, 35%);

IR (film) 3500-3200, 2907, 2855, 1720 and 1698 cm"<1>;

NMR (CDCl 3 ) δ 1.37 (3H, s), 1.50-1.55 (2H, m), 1.65-1.85 (8H, m), 1.90-2.05 (4H, m), 2.67 (1H, d, J 14.5Hz), 2.97 (1H, d, J 14.5Hz), 3.22 (1H, d, J 14Hz), 3.29 (1H, d , J 14Hz), 4.68 (1H, s), 4/82 (1H, s), 5.09 (2H, s), 6.95 (1H, d, J 2Hz), 7.06 (1H, dt, J 7.5 and 1Hz), 7.15 (1H, dt, J 7.5 and 1Hz), 7.25-7.35 (6H, m), 7.57 (1H, d, J 8Hz) , 8.28 (1H, p).

EXAMPLE 18

Tricyclo [ 3. 3. 1. lj^,] dec- 2- yl f R- ( R* , S*) ] [ 3- [ [ 1- ( hydroxymethyl) - 2- phenylethyl] amino]- 1-( 1H - indol-3-ylmethyl-1-methyl-3-oxopropyl] carbamic acid

Step 1

A solution of benzyl ester (Example 17, Reaction scheme 5, no. 32) (440 mg, 0.88 mmol) in absolute EtOH (100 mL) was treated with Pd/C (50 mg, ca. 10 wt%) and placed under a hydrogen pressure of 3.5 kg/cm<2> and 30°C with stirring for 16 hours. The reaction mixture was filtered through filter aid and the filtrate evaporated to dryness in vacuo. The residue was chromatographed over reverse phase silica using 25% H 2 O in MeOH as eluent to give the acid (180 mg, 50%), m.p. 91-99°C (MeOH/H 2 O);

[α]D +20.0° (c=1, MeOH);

IR (film) 3500-3300, 2912, 2856, 1704 cm<-1>;

NMR (CDCl 3 ) δ 1.41 (3H, s), 1.53 (1H, s), 1.57 (1H, s), 1.70-1.85 (9H, m), 1.95-2 .10 (4H, m), 2.69 (1H, d, J 14.5Hz), 3.05 (1H, d, J 14.5Hz), 3.21 (1H, d, J 14.5Hz), 3.32 (1H, d, J 14.5H), 4.86 (1H, s), 5.10-5.30 (1H, br, s), 7.04 (1H, d, J 2Hz), 7.07-7.20 (2H, m), 7.35 (1H, d, J 8Hz), 7.60 (1H, d, J 8Hz), 8.16 (1H, s).

Step 2

A solution of the carboxylic acid (Step 1, Reaction core 5, no. 33) (160 mg, 0.39 mmol) and pentafluorophenol (72 mg,

0.39 mmol) in EtOAc (20 mL) was cooled to 0 °C and treated with a solution of N,N'-dicyclohexylcarbodiimide (80 mg, 0.39 mmol) in EtOAc (5 mL) and stirred at 0°C for 18 hours. The mixture was then filtered and S-phenylalaninol (121 mg, 0.8 mmol) was added and left at room temperature for 24 hours. The solvent was then removed in vacuo and the residue chromatographed using 30% EtOAc in n-hexane as eluent to give the product as a white solid (140 mg, 66%);

IR (film) 3500-3200, 2909, 2855, 1694, 1651 and 1570 cm"<1>;

NMR (CDCl 3 ) δ 1.27 (3H, s) , 1.51 (1H, s) , 1.55 (1H, s) , 1.70-2.05 (12H, m), 2.46 (1H , d, J 13.5Hz), 2.75-2.81 (2H, m), 2.87 (1H, d, J"13.5Hz), 2.90-3.05 (1H, br), 3.08 (1H, d, J 14Hz), 3.28 (1H, d, J 14Hz), 3.50 (1H, dd, J 11 and 5Hz), 3.61 (1H, dd, J 11 and 3 ,5Hz), 4.10-4.20 (1H, m), 4.81 (1H, s), 5.14 (1H, s), 6.26 (1H, d, J 8Hz), 6.99 (1H, d, J 2Hz), 7.08 (1H, t, J 7Hz), 7.10-7.30 (6H, m), 7.33 (1H, d, J 8Hz), 7.58 ( 1H, d, J 8Hz), 8.32 (1H, s).

EXAMPLE 19

Carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(1-oxo-4-phenylbutyl)amino]ethyl]-, tricyclo[3. 3. 1. lj^ ldec- 2- yl- ester

(R)-

This was prepared in the same way as described in Example 21, Reaction scheme 5, no. 37d, m.p. 70-75°C (foam); [α]D -9.2° (c=1, MeOH);

IR (film) 3400-3100, 2908, 2853, 694, 1645 and 1526 cm<-1>;

NMR (CDCl 3 ) δ 1.24 (3H, s), 1.50-2.10 (16H, m), 2.20 (2H, t, J 7Hz), 2.64 (2H, t, J 7Hz) , 2.98 (1H, d, J 14.5Hz), 3.25 (1H, d, J 14.5Hz), 3.55 (1H, dd, J 14 and 6Hz) , 3.70 (1H, dd , J 14 and 6Hz), 4.81 (1H, s), 4.94 (1H, s), 6.50-6.60 (1H, br s), 7.00 (1H, d, J 2Hz) , 7.05-7.30 (7H, m), 7.35 (1H, d, J 8Hz), 7.57 (1H, d, J 8Hz), 8.17 (1H, s);

Analysis, C33H41<N>303; C, H, N.

EXAMPLE 20

Carbamic acid, [ 2-( benzoylamino)- 1-( 1H- indol- 3- ylmethyl)- 1- methylethyl-, tricyclo[ 3. 3. 1. 13, 7]- dec- 2- yl- ester ( R)-

This was prepared in the same way as described in Example 21, Reaction scheme 5, no. 37a, m.p. 220.0-220.1°C (MeOH);

[α]D +24° (c=0.25, MeOH);

IR (film) 3500-3200-2907, 2855, 1695, 1646 and 1533 cm"<1>;

NMR (CDCl 3 ) 6 1.30 (3H, s), 1.50-1.60 (2H, m), 1.70-2.10 (12H, m), 3.07 (1H, d, J 14 ,5Hz), 3.31 (1H, d, J 14.5Hz), 3.76 (1H, dd, J 14 and 6Hz), 3.89 (1H, dd, J 14 and 6Hz), 4.84 ( 1H, s), 5.03 (1H, s), 7.01 (1H, d, 2Hz), 7.05-7.20 (2H, m), 7.35-7.50 (4H, m) , 7.60 (1H, d, J 8Hz), 7.77 (2H, d, J 7Hz), 7.60-7.90 (1H, br), 8.39 (1H, s);

FAB MS m/e 486.3 (34), 355.3 (63), 290.3 (29), 177.2 (37), 154.1 (100);

Analysis, C30<H>35<N>303; C, H, N.

EXAMPLE 21

Carbamic acid, [ 1-( lH- indol- 3- ylmethyl)- l- methyl- 2- f( l- oxo- 3-phenylpropyl) amino] ethyl]-, tricyclo[ 3. 3. 1. ljlZ l- dec- 2-yl ester

Step 1

Carbamic acid, [ 2- amino- 1-( 1H- indol- 3- ylmethyl)- 1- methyl- 2- oxoethyl)-, tricyclo[ 3. 3. 1. ljl^] - flec- 2- yl- ester

( R)- AdOC- g- Me) DTrp- NH, (See reaction core 5, no. 35 2-Adoc-a-Me-R-Trp-NH2)

2-Adoc-α-Me-R-Trp-OH (23b) (9.5 g, 24 mmol) as a solution in EtOAc (150 mL), was treated with pentafluorophenol (4.4 g, 24 mmol) and cooled to 0°C. A solution of N,N'-dicyclohexylcarbodiimide (5.15 g, 25 mmol) in EtOAc (20 mL) was added dropwise and the resulting mixture was allowed to stir for 6 h and was then allowed to stand for 12 h at 4°C. It became

then filtered and the filtrate evaporated to dryness in vacuo. The residue was redissolved in THF (100 mL), whereupon ammonia gas was bubbled through at 0°C for 1 hour. The solvent

was removed in vacuo and the residue chromatographed over reverse phase silica using 30% H 2 O in MeOH as eluent to give the amide (35, Reaction core 5) (9.2 g, 97%) as white crystals, m.p. 136-149°C (MeOH);

[α] D +42.1° (c=1, MeOH) ;

IR (film) 3351, 2906, 2855, 1675 and 1588 cm"<1>

NMR (CDCl 3 ) δ 1.50-1.60 (2H, m), 1.58 (3H, s), 1.70-2.05 (12H, m), 3.33 (1H, d, J 14 .5Hz), 3.51 (1H, d, J 14.5Hz), 4.86 (1H, s), 5.24 (1H, s), 5.40-5.55 (1H, br), 6 .20-6.35 (1H, br), 7.04 (1H, d, J 2Hz), 7.08-7.21 (2H, m), 7.36 (1H, d, J 8Hz), 7 .63 (1H, d, J 8Hz) , 8.24 (1H, s);

MS (FAB) m/e 396 (100);

Analysis, C23H29N3O3; C, H, N.

Step 2 (See Reaction core 5, no. 36)

Trimethylsilyl chloride (4.34 g, 40 mmol) was added dropwise to a solution of LiBH 4 (11 mL of a 2 M solution, 22 mmol) in THF under a nitrogen atmosphere. A solution of 2-AdocOMe-R-TrpNH2 (Reaction core 5, no. 35) from the previous step (3.95 g, 10.0 mmol) in anhydrous THF (20 mL) was added dropwise over 20 min and the reaction mixture stirred for 10 minutes at room temperature, after which it was gently boiled under reflux for 3 hours. The mixture was cooled to 0°C and carefully added MeOH (16.5 mL). The solvents - were then removed in vacuo and the residue chromatographed over reverse phase silica using 30% H 2 O in MeOH as eluent to give 1.25 g (32%) of the starting amide and 1.29 g (34%) of the product amine, m.p. 138-144°C (MeOH);

[α] D +51.6° (c = 1, MeOH);

IR (film) 2912, 2854 and 1690 cm"<1>

NMR (CDCl 3 ) δ 1.32 (3H, s) , 1.40-1.55 (2H, m) , 1.65-2.05 (12H, m), 3.04 (1H, d, J 14Hz ), 3.20-3.30 (2H, m), 3.40-3.50 (1H,

m) , 4.78 (1H, s) , 5.10-5.30 (1H, br s) , 7.00-7.20 (3H, m) ,

7.34 (1H, d, J 8Hz), 7.52 (1H, d, J 8Hz), 8.56 (1H, s), 8.67 (2H, br s);

FAB MS m/e 382.3 (100).

Step 3 (See Reaction core 5, no. 37c)

A solution of 3-phenylpropionic acid (75 ng, 0.5 mmol) in EtOAc (5 mL) was treated with pentafluorophenol (92 mg,

0.5 mmol) and cooled to 0°C. A solution of N,N'-dicyclohexylcarbodiimide (103 mg, 0.5 mmol) in EtOAc (2 mL) was added and the mixture allowed to stand for 12 h at 4°C. This mixture was then filtered and the solid amine (from Step 2, Reaction core 5, no. 36) (198 mg, 0.5 mmol) added, after which the mixture was allowed to stand at room temperature for 24 hours. The reaction mixture was washed with 1M citric acid solution

(2 x 10 ml), NaHCO 3 (2 x 10 ml of an IM solution) and H 2 O (2

x 10 ml) and the organic phase dried over MgSO 4 . The solvent was removed in vacuo and the residue chromatographed over silica gel using 2% MeOH in CH 2 Cl 2 as eluent to give the product (230 mg, 90%) as white crystals, m.p. 171-175°C (MeOH);

[α]D -12.3° (c=0.56, MeOH);

IR (KBr) 3400-3100, 2906, 2854, 1694, 1649 and 1528 cm"<1>;

NMR (CDCl 3 ) δ 1.13 (3H, s), 1.50-2.10 (14H, m), 2.50 (2H, t, J 7Hz) , 2.90 (1H, d, J 14 and 6Hz), 3.65 (1H, dd, J 14 and 6 Hz), 4.81 (1H, s) , 4.88 (1H, s) , 6.40-6.60 (1H, br), 6 .96 (1H, d, J 3Hz), 7.05-7.30 (7H, m), 7.35 (1H, d, J 8Hz), 7.53 (1H, d, J 8Hz) , 8, 15 (1H, p) ;

FAB MS m/e 514.4 (8), 383.3 (32), 205.2 (32), 170.2 (47), 135.2 (100);

Analysis, C32H39N3O3; C, H, N.

Example 22

Carbamic acid, [ 1-( 1H- indol- 3- ylmethyl)- 1- methyl- 2-[( 2- phenyl-acetyl) amino] ethyl]-, tricyclo[ 3. 3. 1. ll^]- dec- 2 - yl- ester ( R)-

This was prepared in the same way as described in Example 21 (see Reaction core 5, no. 37b), m.p. 176.5-180°C (MeOH);

[α]D -1.6° (c=0.56, MeOH);

IR (film) 3400-3100, 2911, 2854, 1694, 1656 and 1520 cm<-1>;

NMR (CDCl 3 ) δ 1.16 (3H, s), 1.50-2.10 (14H, m), 2.90 (1H, d, J 14Hz), 3.16 (1H, d, J 14Hz) , 3.50 (1H, dd, J 14 and 6Hz), 3.57 (2H, s), 3.65 (1H, dd, J 14 and 6Hz), 4.73 (1H, s), 4.80 (1H, s), 6.30-6.40 (1H, br s), 6.94 (1H, d, J 2Hz), 7.07 (1H, t, J_ 8Hz), 7.16 (1H, t, J 8Hz), 7.25-7.40 (6H, m), 7.48 (1H, d, J 8Hz), 8.11 (1H, s);

FAB MS m/e 500.5 (100), 369.3 (87);

Analysis, C31<H>37N303; C, H, N.

EXAMPLE 23

Carbamic acid, [ 2-[[ 3-[[ l-( hydroxymethyl)- 2- phenylethyl] amino]- 3-oxopropyl] amino]- 1-( 1H- indol- 3- ylmethyl)- 1- methyl- 2- oxoethyl ]- , tricyclo[ 3 . 3. 1. lfjI jdec- 2- yl- ester, [ R-( R* , S*) ]-

The acid prepared in Example 30, Step 2 (1.17 g,

2.80 mmol) and pentafluorophenol (461 mg, 2.5 mmol) as a solution in EtOAc (50 mL) were treated with dicyclohexylcarbodiimide (542 mg, 2.60 mmol) and left at 0°C for 18 h. The mixture was filtered and the filtrate treated with s-phenylalaninol (454 mg, 3.00 mmol), whereupon the reaction mixture was

IN

left under stirring for 18 hours at room temperature. It was then concentrated in vacuo and the residue chromatographed over reverse phase silica using 75% MeOH in H 2 O as eluent to give the product as a white, non-crystalline solid (1.17 g, 78%); m.p. 94-98°C;

[α]D +14.7° (c=1, MeOH);

IR (film) 3306, 2904, 2854, 1693 and 1651 cm"<1>;

NMR (DMS0-d6) 6 1.29 (3H, s), 1.60-2.00 (14H, m), 2.05-2.25 (2H, m), 2.62 (1H, dd, J 14 and 8Hz), 2.83 (1H, dd, J 14 and 6Hz), 3.10-3.40 (5H, m) , 3.85-3.95 (1H, m) , 4.70- 4.80 (2H, m) , 6.70 (1H, br s), 6.90-7.35 (9H, m), 7.44 (1H, d, J 8Hz), 7.70 (1H, d, J 8Hz), 7.75 (1H, br s), 10.85 (1H, s);

FAB MS m/e 601 (m+1), (100);

Analysis, C35H44N4<0>5 . 0.25 H 2 O; C, H, N

EXAMPLE 24

Carbamic acid, [ 1-( 1H- indol- 3- ylmethyl)- 2-[[ 3-[ 1- hydroxymethyl))- 2- phenylethyl] amino]- 3- oxopropyl] amino]- 1- methyl- 2-oxoethyl- , tricyclo[ 3 . 3. 1. liL l] dec- 2- yl- ester, TS-( R*, R*)]-

This was prepared in the same way as described in Example 23 (see Reaction core 6, no. 44), m.p. 95-97°C (MeOH/H 2 O);

[α]D<20> -31.3° (c=1, MeOH) ;

IR (film) 3314, 2910, 2856, 1696 and 1651 cm"<1>;

NMR (CDCl 3 ) δ 1.53 (5H, s), 1.70-2.05 (12H, m), 2.10-2.30 (2H, m), 2.79 (2H, d, J 7Hz ), 3.25 (1H, d, J 14.5Hz), 3.35 (1H, d, J 14.5Hz), 3.30-3.55 (3H, m) , 3.65-3.70 (1H, m), 4.10-4.20 (1H, m), 4.79 (1H, s), 5.26 (1H, s), 6.20-6.35 (1H, br s) , 6.69 (1H, t, J Hz), 6.97 (1H, d, J 2Hz), 7.06-7.29 (7H, m) , 7.34 (1H, d, J 8Hz), 7.57 (1H, d, J 8Hz), 8.49 (1H, s);

FAB MS m/e 601 (100);

Analysis, C35H44N405 . 0.25H2O; C, H, N

FAB MS m/e 614 (m+1) and 217 (100);

Analysis, C35H43<N>505 . 0.5H2O; C, H, N.

EXAMPLE 25

D- f enylalanamide, a- methyl- N- [ ( tricyclo f 3 . 3 . 1 . ljll l dec- 2- yloxy) - carbonyl ] - D- tryptoph yl- J3- alanyl-

The compound was prepared using a procedure similar to that of Example 26. The acid from Example 30, Step 2 (117 mg, 0.25 mmol) and pentafluorophenol (46 mg, 0.25 mmol) as a solution in EtOAc (10 mL) was treated with dicyclohexylcarbodiimide (52 mg, 25 mmol) and allowed to stir at room temperature for 2 h before filtration. S-phenylalanine amide (50 mg, 0.3 mmol) was then added, after which the mixture was allowed to stir at room temperature for 72 hours. The reaction mixture was then washed with 1M HCl (10 mL), H 2 O (10 mL), 1M NaOH (10 mL) and H 2 O (10 mL). The organic phase was dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed over reverse phase silica gel using 75% MeOH in H 2 O as eluent to give the product as a white non-crystalline solid (130 mg, 85%); m.p. 113-118°C;

[α]D<20> +27.5° (c=0.5, MeOH);

IR (film) 3311, 3055, 2908, 1700 and 1659 cm<-1>;

NMR (CDCl 3 ) 6 1.49 (2H, s), 1.52 (3H, s), 1.60-2.05 (12H, m), 2.19 (2H, t, J 6Hz), 3, 01 (1H, dd, J 7.5 and 14Hz), 3.08 (1H, dd, J 7.5 and 14Hz), 3.27 (1H, d, J 14.5Hz), 3.42 (1H, d, J 14.5Hz), 3.35-3.50 (2H, m), 4.59 (1H, dd, J 15 and 7Hz), 4.80 (1H, s), 5.29 (1H, s,), 5.47 (1H, s), 6.20 (1H, s), 6.50 (1H, d, J 7Hz), 6.76 (1H, t, J 6Hz), 6.96 ( 1H, d, J 2Hz), 7.05-7.35 (7H, m), 7.34 (1H, d, J 8Hz), 7.57 (1H, d, J 8Hz), 8.36 (1H , s)

EXAMPLE 26

L- f enylalanine amide, a- methyl- N-[ (tricyclo [ 3 . 3. 1. ljL l] dec- 2-yloxy) carbonyl]- D- tryptophyll- B- alanyl-

m.p. 112-118°C (MeOH/H 2 O);

[α]D<20> +16.3° (c=1, MeOH) ;

IR (film) 3309, 2907, 2855, 1690, 1652 cm<-1>;

NMR (CDCl 3 ) δ 1.50-2.05 (17H, m), 2.10-2.20 (2H, m), 2.98 (1H, dd, J 14 and 8Hz), 3.09 (1H , dd, J 14 and 7Hz), 3.24 (1H, d, J 14.5Hz), 3.35 (1H, d, J 14.5Hz), 3.25-3.55 (2H, m), 4.58 (1H, dd, J 15 and 7.5Hz), 4.78 (1H, s), 5.28 (1H, s), 5.48 (1H, s), 6.27 (1H, br s), 6.54 (1H, br s), 6.75 (1H, m), 6.99 (1H, d, J 2Hz), 7.05-7.30 (7H, m), 7.34 (1H, d, J 8Hz), 7.58 (1H, d, J 8Hz), 8.41 (1H, s);

FAB MS m/e 614.3 (100);

Analysis, C35<H>43<N>505 . 0.7 5H2O; C, H, N.

EXAMPLE 27

L- phenylalanine amide, α- methyl- N-[( tricyclo[ 3. 3. 1. lllI] dec- 2-yloxy) carbonyl ] - L- tryptoph yl- 13- alanyl-

m.p. 114-119°C (MeOH/H 2 O);

[α]D<20> -15.2° (c=0.5, MeOH);

IR (film) 3323, 2909, 2855, 1700-1640 cm"<1>;

NMR (CDCl 3 ) δ 1.50 (2H, s), 1.54 (3H, s), 1.65-2.00 (12H, m), 2.10-2.20 (2H, br s), 2.95 (1H, dd, J 14 and 8Hz), 3.10 (1H, dd, J 14 and 6Hz), 3.23 (1H, d, J 14Hz), 3.32 (1H, d, J 14Hz ), 3.20-3.30 (1H, m), 3.40-3.50 (1H, m), 4.55 (0.5H, 0, J 8Hz), 4.60 (0.5H, d, J 8Hz), 4.78 (1H, s), 5.35 (1H, s), 5.68 (1H, s), 6.41 (1H, s), 6.65-6.85 ( 1H, m), 6.82 (1H, t, J 6Hz), 6.97 (1H, d, J 2Hz), 7.05-7.30 (7H, m), 7.33 (1H, d, J 8Hz), 7.57 (1H, d, J 8Hz), 8.55 (1H, s);

FAB MS m/e 614.3 (50.7), 236.1 (100);

Analysis, C35H43N505 . 0.5H2O; C, H, N.

EXAMPLE 28

D- phenylalanine amide, a- methyl- N-[(tricyclo[ 3. 3. 1. ljl I] dec- 2-yloxy) carbonyl ] - L- tryptoph yl- J3- alanyl-

m.p. 113-118°C (MeOH/H 2 O);

[α]D<20> -30° (c=0.5, MeOH);

IR (film) 3313, 2909, 2856, 1694-1652 br. cm"<1>;

NMR (CDCl 3 ) δ 1.45 (3H, s), 1.50 (2H, s), 1.65-2.00 (12H, m), 2.14 (2H, s), 2.90 (1H , dd, J 14 and 8Hz), 3.06 (1H, d, J 14 and 5.5Hz), 3.2-3.4 (4H, m), 4.56 (0.5H, d, J 7 .5Hz), 4.60 (0.5H, d, J 7.5Hz), 4.80 (1H, s), 5.54 (1H, s), 6.14 (1H, s), 6.70 (1H, s), 6.87 (1H, s), 7.00-7.30 (10H, m), 7.51 (1H, d, J 8Hz), 8.87 (1H, s);

FAB MS 636.4 (100), 614.4 (61);

Analysis, C35H43N505 . 0.5H2O; C, H, N.

EXAMPLE 29

12- oxa- 2, 5, 9- triazatridecanoic acid, 3-( 1H- indol- 3- ylmethyl)- 3-methyl- 4, 8, ll- trioxo- 10- ( f enylmethyl) - , tricyclo [ 3. 3. 1. lfjjjdec-2- yl-esterf [ R-( R*, R*) 3~ (see Reaction scheme 6, no. 49)

1 NM

In a similar manner as in Example 30, the following was prepared, m.p. 86-90°C (foam);

[α]D<20> +17.4° (c=0.5, MeOH);

IR (film) 1738, 1698 and 1656 cm"<1>

NMR (CDCl 3 ) δ 1.55 (3H, s), 1.50-1.60 (2H, br s), 1.65-2.05 (12H, m), 2.10-2.35 (2H , m) , 2.99 (1H, dd, J 14 and 8Hz), 3.11_

(1H, dd, J 14 and 5Hz), 3.20-3.30 (1H, m) , 3.31 (2H, s), 3.55-3.65 (1H, m), 3.68 ( 3H, s), 4.73 (1H, dd, J 13 and 8Hz), 4.80 (1H, s), 5.33 (1H, s), 6.40-6.60 (1H, br s) , 6.90 (1H, br s), 6.98 (1H, d, J 2Hz), 7.05-7.35 (8H, m), 7.59 (1H, d, J 8Hz), 8, 45 (1H, p);

MS FAB m/e 629.2 (100);

Analysis, C36<H>44<N>406 . 0.25H2O; C, H, N.

EXAMPLE 30

L- phenylalanine, N- TN- fa- methyl- N- \ ( tricyclo 3 . 3 . 1. 13' 71 dec- 2-yloxy) carbonyl] - d- tryptophyll - S- alanvl] - phenvlmethyl- ester

Step 1 (See Reaction core 6, no. 39)

A solution of 2-adamantyloxycarbonyl-α-methyl-R-tryptophan (8.0 g, 20 mmol) in EtOAc (100 mL) was treated with pentafluorophenol (3.68 g, 20.0 mmol) and cooled to 0 °C . Dicyclohexylcarbodiimide (4.33 g, 21.0 mmol) was then added and the mixture allowed to stir for 18 hours at 0°C. It was then filtered and S-alanine methyl ester (2.47 g, 240 mmol) was added and allowed to stir for an additional 18 hours at room temperature, after which it was filtered and the filtrate washed with 1M HCl (3 x 30 mL), H 2 O (2 x 30 mL), saturated NaHCO 3 solution (3 x 30 mL), H 2 O (2 x 30 mL). The organic phase was dried over MgSO 4 and concentrated in vacuo and the product crystallized from ether to give the ester (7.8 g, 81%);

IR (film) 3700-3200, 3000-2800, 2723, 1695 and 1659 cm"<1>

Step 2 (See Reaction core 6, no. 41)

S- alanine, N- fa- metvl- N- f ( tricvklo [ 3 . 3 . 1 . 13- 7! dec- 2- vloxv) - carbonyl]- D- tryptophyll]

The ester from Step 1 (5.20 g, 10.8 mmol) as a solution in 1,4 dioxane (300 mL) was treated dropwise with a solution of LiOH.H 2 O (454 mg, 10.8 mmol) in H 2 O (100 ml) at room temperature and left under stirring for 18 hours. 1M HCl (10.8 mL) was added and the mixture distilled to dryness in vacuo, after which the residue was chromatographed over reverse phase silica gel using 70% MeOH in H 2 O as eluent to give the product (3.23 g, 51%) together with starting ester (1 g), m.p. 98-103°C (MeOH/H 2 O);

[a] D 2 O +29° (c=1, MeOH) ;

IR (film) 3351, 2911, 2855, 1706 and 1658 cm"<1>;

NMR (CDCl 3 ) 6 1.50-2.00 (17H, m) , 2.39 (2H, br s) , 3.26 (1H, d, J 15Hz), 3.40-3.50 (3H, m), 4.80 (1H, s), 5.42 (1H, br s), 6.75 (1H, t, J 6Hz), 6.99 (1H, d, J 2Hz), 7.05- 7.20 (2H, m), 7.33 (1H, d, J 8Hz) , 7.57 (1H, d, J 8Hz), 8.37 (1H, s);

FAB MS-m/e 468 (m+1) and 217 (100);

Analysis, C26H33<N>305 . 0.25H2O; C, H, N.

Step 3

A solution of the acid from Step 2 (467 mg, 1.00 mmol) and pentafluorophenol (184 mg, 1.00 mmol) in EtOAc (50 mL) was treated with dicyclohexylcarbodiimide (206 mg, 1.00 mmol) at 0 °C and reserved for 18 hours. It was then filtered and S-phenylalanine benzyl ester (306 mg, 1.20 mmol) was added and left under stirring for 18 hours at room temperature. It was then washed with 1M HCl (2 x 20 mL), H 2 O (20 mL), saturated NaHCO 3 solution (2 x 20 mL) and H 2 O (20 mL). The organic phase was dried over MgSO 4 and concentrated in vacuo and the residue chromatographed over reverse phase silica gel using 75% to 85% MeOH in H 2 O as eluent to give the product (500 mg, 71%), m.p. 75-82°C (MeOH/H 2 O);

[α]D2<O> +28 , 1° (c = 0.45, MeOH);

IR (film) 3324, 2908, 2855, 1737, 1698 and 1657 cm"<1>;

NMR (CDCl 3 ) δ 1.50 (3H, s), 1.50-1.55 (2H, m), 1.70-2.00 (12H, m), 2.10-2.30 (2H, m) , 3.06 (1H, dd, J 14 and 7Hz), 3.14 (1H, dd, J 14 and 6Hz) , 3.29 (1H, d, J 15Hz) , 3.25-3.60 (3H, m) , 4.75-4.85 (2H, m), 5.08 (1H, d, J 12Hz), 5.15 (1H, d, J 12Hz), 5.29 (1H, br s) , 6.20-6.30 (1H, br m) , 6.81 (1H, br m) , 6.95 (1H, d, J 2Hz) , 7.00-7.35 (13H, m ) , 7.57 (1H, d, J 8Hz), 8.20 (1H, s);

Analysis, C42H48N406 ; C, H, N.

EXAMPLE 31

In a similar manner to Example 30, the following was prepared, m.p. 77-82°C (foam);

[α]D<20> -19.2° (c=0.5, MeOH);

IR (film) 3305, 2906-2857, 1735, 1696 and 1658 cm<-1>;

NMR (CDCl 3 ) δ 1.51 (3H, s), 1.50-1.60 (2H, m), 1.70-2.10 (12H, m), 2.10-2.30 (2H, m), 3.01 (1H, dd, J 14 and 8Hz), 3.12 (1H, dd, J 14 and 5Hz), 3.20-3.30 (1H, m), 3.31 (1H, s), 3.55-3.65 (1H, m), 4.75-4.85 (2H, m), 5.07 (1H, d, J 12Hz), 5.15 (1H, d, J 12Hz), 5.28 (1H, br s), 6.30-6.50 (1H, br s), 6.80-6.90 (1H, br), 6.97 (1H, d, J 2Hz ), 7.05-7.35;

MS FAB m/e 705.2 (71) and 327.2 (100);

Analysis, C42H48<N>406; C, H, N.

EXAMPLE 32

D-phenylalanine, N-[ N-[ a- methyl- N-[ (tricyclo[ 3. 3. 1. lyl l 1 dec- 2-yloxy) carbonyl]- D- tryptophyll]- G- alanyl]-

The compound was prepared in a similar manner as described in Example 33, m.p. 119-129°C (MeOH/H 2 O);

[α]D<20> +5.8° (c=0.5, MeOH);

IR (film) 2907, 2855, 1700, 1651 cm<-1>;

NMR (CDCl3 + CD3OD) δ 1.53 (5H, s), 1.70-2.05 (12H, m), 2.10-2.30 (2H, br s), 2.95-3.05 (1H, m), 3.15-3.60 (5H, m), 4.65 (1H, s), 7.00-7.40 (9H, m), 7.57 (1H, d, J 8Hz);

FAB MS m/e 615.2 (58), 216.9 (100);

Analysis, C35H42N406 . 0.5H2O; C, H, N.

EXAMPLE 3 3

S- phenvlalanine, N- FN- fa- methyl- N- \ (tricyclo f3 . 3 . 1. 13' 71 dec- 2-yloxy) carbonyl] - R- tryptophyll - 15- alanyl

A solution of the benzyl ester (450 mg, 0.64 mmol) in absolute EtOH (100 mL) was treated with 10% Pd/C (45 mg, 10 wt%) and placed under a hydrogen atmosphere at 3.5 kg/cm<2> for 2 hours with stirring. The mixture was then filtered through filter aid and concentrated in vacuo, after which the residue was chromatographed over reverse phase silica gel using 70% MeOH in H 2 O as eluent to give the product as a white, non-crystalline solid (300 mg, 76%); m.p. 114-119°C;

[α]D<20> +37.8° (c=1, MeOH);

IR (film) 3331, 2911, 2856, 1700 and 1656 cm'<1>

NMR (CDCl 3 ) δ 1.41 (3H, s), 1.45-1.55 (2H, m), 1.70-2.00 (12H, m), 2.10-2.20 (2H, m) , 3.01 (1H, dd, J 14 and 8Hz), 3.15-3.50 (5H, m), 4.00-5.00 (1H, v.br), 4.66 (1H , dd, J 13 and 7Hz), 4.82 (1H, s), 5.46 (1H, br s), 6.50-6.70 (1H, br s), 6.87 (2H, br s ) , 7.00-7.30 (8H, m) , 7.52 (1H, d, J 8Hz), 8.44 (1H, s) ; Analysis, C35H42N406 ; C, H, N.

EXAMPLE 34

L- phenylalanine, N- [ N- [ a- methyl- N- [ ( tricyclo[ 3. 3. 1. 1. H] dec- 2-yloxy) carbonyl]- L- tryptophyll]- B- alanyl]-

The compound was prepared in a similar manner as described in Example 33, m.p. 115-120oC (MeOH/H 2 O);

[α]D<20> -7.2° (c=0.5, MeOH);

IR (film) 3391, 2906, 2854, 1700 and 1646 (s).crrf<1>;

NMR (CDC13 + CD3OD) δ 1.51 (3H, s), 1.54 (1H, s), 1.57 (1H, s), 1.70-2.05 (12H, m), 2.15 -2.30 (2H, m), 2.99 (1H, dd, J 14 and 8Hz), 3.15-3.55 (5H, m), 4.66 (1H, dd, J 8 and 5Hz) , 4.79 (1H, s), 7.00-7.40 (9H, m), 7.56 (1H, d, J 8Hz);

FAB MS w/e 615 (100)

Analysis, C35<H>42<N>406; C, H, N.

EXAMPLE 35

Benzenepropanoic acid, a-[[ 3-[[ 3-[( 1H- indol- 3- yl)- 2- methyl- 1- oxo- 2-[ [ ( tricyclor3 . 3. 1. lll I] dec- 2- yloxy ) carbonyl] amino] propyl]-amino]- 1- oxopropyl] amino-, [ S-( R*, S*)]-

m.p. 116-124°C (MeOH/H 2 O);

[α]D<20> -35° (c=0.5, MeOH) ;

IR (film) 3500-3200, 2912, 2856, 1700 and 1654 cm<-1>;

NMR (CDCl 3 ) δ 1.42 (3H, s), 1.47 (1, s), 1.51 (1H, s), 1.65-2.20 (14H, m), 2.90-3 .00 (1H, m) , 3.10-3.50 (5H, m) , 3.50-4.50 (br, COjH and H2O), 4.61 (1H, s), 4.82 (1H , s), 5.45 (1H, s), 6.50-6.80 (1H, br s), 6.85-7.30 (11H, m), 7.52 (1H, d, J 8Hz ) L 8.58 (1H, s);

FAB MS m/e 615.2 (100);

Analysis, C35<H>42<N>406 . 0.4H 2 O; C, H, N.

EXAMPLE 36

Glycine, N-[ 2- methyl- N-[(tricyclo[ 3. 3. 1. 13' 7] dec- 2- yloxy)-carbonyl]- D- tryptophyll]-, phenylmethyl- ester

A solution of 2-Adoc-α-Me-R-TrpOH (Reaction Scheme 7, entry 23b) (3.0 g, 7.6 mmol) in EtOAc (40 mL) was treated with pentafluorophenol (1.39 g, 7 .6 mmol) and cooled to 0°C. A solution of N,N'-dicyclohexylcarbodiimide (1.56 g, 7.6 mmol) in EtOAc (10 mL) was then added dropwise and the mixture stirred for 12 h at 4°C and filtered. Glycine benzyl ester hydrochloride (1.8 g, 9.0 mmol) was added followed by the dropwise addition of triethylamine (0.9 g, 9.0 mmol) in EtOAc (10 mL). It was stirred for 18 hours at room temperature. The reaction mixture was then washed with IM citric acid solution (2 x 50 mL), IM NaHCO 3 solution (2 x 50 mL) and H 2 O

(2 x 50 ml). The organic phase was dried over MgSO 4 and evaporated to dryness in vacuo. The residue was chromatographed over reverse phase silica using 25% H 2 O in MeOH as eluent to give the product as a white foam (2.83 g, 68%) together with 0.9 g of the starting active ester, m.p. 76-82°C (foam);

[α]D<20> +36° (c=1, MeOH);

IR (film) 3500-3200, 2908, 2855, 1745, 1702 and 1665 cm<-1>;

NMR (CDCl 3 ) δ 1.45-1.60 (4H, m), 1.69-2.00 (13H, m), 3.30 (1H, d, J 14.5Hz), 3.50 (1H , d, J 14.5Hz), 3.95-4.10 (2H, m), 4.84 (1H, s), 5.13 (2H, s), 5.21 (1H, s), 6 .79 (1H, s), 7.01 (1H, d, J 2Hz), 7.08 (1H, t, J 7Hz), 7.15 (1H, t, J 7Hz), 7.30-7, 40 (6H, m), 7.57 (1H, d, J 8Hz), 8.26 (1H, s);

FAB MS 544.4 (11), 414.3 (11), 348.2 (36), 135.2 (100); Analysis, C32H37N3O5; C, H, N.

EXAMPLE 37

Carbamic acid, [ 2-[[ 2-[[ l-( hydroxymethyl)- 2- phenylethyl] amino]- 2-oxoethyl] amino]- 1-( 1H- indol- 3- ylmethyl)- 1- methyl- 2- oxoethyl ]-, tricyclo[ 3 . 3. 1. ljlI] dec- 2-yl- ester,

[ R-( R*, S*)]- Adoc-( g- Me) DTrp- Gly- NH(( S)- 1-( hydroxymethyl)- 2-phenylethyl)

Step 1

Glycine, N-[ 3-( 1H- indol-3- yl)- 2- methyl- 1- oxo- 2-[[(tricyclo[ 3 . 3 . 1 . ljlI] dec- 2- yloxy) carbonyl] amino] propyl]-, (R)-Adoc-(g-Me)DTrp-Gly

A solution of the benzyl ester (Example 36, Reaction Scheme 7, entry 57) (2.5 g, 4.6 mmol) in absolute EtOH (100 mL) was treated with 10% Pd/C (250 mg, 10 wt%) and placed under a hydrogen atmosphere at 3.5 kg/cm<2> and 20°C for 5 hours with stirring. The reaction mixture was filtered through filter aid and the filtrate concentrated in vacuo. The residue was then chromatographed over silica gel using 0.5% AcOH, 5% MeOH in CH 2 Cl 2 as eluent to give the product (1.87-3 g, 90%) as a white solid; m.p. 112-117°C (MeOH/H 2 O);

la] D 2 O +40° (c = 1, MeOH);

IR (film) 3500-3200, 2910, 2856, 1702, 1660 and 735 cm"<1>;

NMR (CDCl 3 ) δ 1.26 (1H, s) , 1.51 (1H, s) , 1.58 (3H, s), 1.70-2.00 (12H, m), 3.00-4 .00 (1H, br), 3.28 (1H, d, J 14.5Hz), 3.45 (1H, d, J 14.5Hz), 3.94 (2H, d, J 5Hz) , 4, 85 (1H, s) , 5.35-5.50 (1H, br s) , 6.85 (1H, br t) , 7.04 (1H, d, J 2Hz) , 7.05-7.18 (2H, m), 7.32 (1H, d, J 8Hz), 7.56 (1H, d, J 8Hz), 8.39 (1H, s);

Analysis, C25H31N3O5; C, H, N.

Step 2

A solution of the acid (Reaction Core 7, No. 59, Step 1) (226 mg, 0.5 mmol) and pentafluorophenol (92 mg, 0.5 mmol) in EtOAc (20 mL) was cooled to 0 °C and treated with a solution of N,N'-dicyclohexylcarbodiimide (108 mg, 0.525 mmol) in EtOAc (5 mL). The solution was left for 12 hours at 0°C, filtered and the filtrate treated with S-phenylalaninol (91 mg, 0.6 mmol). This reaction mixture was stirred at room temperature for 18 h, evaporated to dryness in vacuo and the residue chromatographed using 30% n-hexane in EtOAc as eluent to give the product (202 mg, 66%);

IR (film) 3500-3200, 2911, 2855, 1695 and 1658 cm"<1>;

NMR (CD3OD) a 1.44 (3H, s), 1.52-1.62 (2H, m), 1.70-2.10 (14H, m), 2.78 (1H, dd, J 13 .5 and 8Hz), 2.93 (1H, dd, J 13.5 and 6Hz), 3.24 (1H, d, J 14.5Hz), 3.41 (1H, d, J 14.5Hz), 3.53 (2H, d, J 5.5Hz), 3.57 (1H, d, J 17Hz), 3.71 (1H, d, J 17Hz), 4.05-4.15 (1H, m) , 4.88 (1H, s), 6.98 (1H, dt, J 7.5 and 1Hz), 7.00-7.25 (7H, m), 7.32 (1H, d, J 8Hz) , 7.50 (1H, d, J 8Hz).

EXAMPLE 39

Carbamic acid, [ 2-[[ 4-[[ l-( hydroxymethyl)- 2- phenylethyl] amino]- 4-oxobutyl] amino]-!-( 1H- indol- 3- ylmethyl)- 1- methyl- 2- oxoethyl ]-, tricyclo[ 3. 3. 1. ljlI] dec- 2- yl- ester, [ R-( R*, S*)]-

Step 1.

Butanoic acid, 4-[[ 3-( 1H- indol-3- yl)- 2- methyl- 1- oxo- 2-[ [ ( tricyclo[ 3 . 3 . 1 . ljj^ dec- 2- yloxy) carbonyl] amino ]-propyl] amino]-, ( R )-

A solution of the methyl ester (Example 38, Reaction Scheme 8, No. 60) (2.6 g, 5.2 mmol) in 1,4-dioxane (500 mL) was treated dropwise with a solution of LiOH (104 mL of a 0 .05M solution, 5.20 mmol) during 24 hours under vigorous stirring. This mixture was stirred at room temperature for 24 h, after which the reaction was quenched with 1M HCl (5.2 mL). The solvent was removed in vacuo and the residue chromatographed using 0.5% AcOH, 5% MeOH in CH 2 Cl 2 to give 80 mg of starting ester along with 1.32 g of product, 55% yield, 77% conversion, m.p. 92-96°C (CH 2 Cl 2 ) : [α]D 2<0> +29.3° (c=, MeOH) ;

IR (film) 3600-3200, 2909, 2856, 1702 and 1651 cm"<1>;

NMR (CDCl 3 ) δ 1.50-1.55 (2H, m), 1.61 (3H, s), 1.62-2.00 (14H, m), 2.10-2.25 (2H, m) , 3.20-3.40 (2H, m) , 3.24 (1H, d, J 14.5Hz), 3.45 (1H, d, J 14.5Hz), 4.84 (1H, s), 5.47 (1H, s), 6.58-6.65 (1H, br m), 7.03 (1H, d, J 2Hz), 7.09 (1H, t, J 7Hz), 7.17 (1H, t, J 7Hz) , 7.35 (1H, d, J 8Hz), 7.57 (1H, d, J 8Hz) , 8.59 (1H, s) ;

Analysis, C 27 H 35 N 3 O 5 . 0.2H2O; C, H, N.

Step 2

A solution of the acid (Step 1, Reaction core 8,

no. 61) (240 mg, 0.5 mmol) and pentafluorophenol (92 mg,

0.8 mmol) in EtOAc (20 mL) was cooled to 0 °C and treated with a solution of N,N'-dicyclohexylcarbodiimide (108 mg,

0.55 mmol) in EtOAc (5 mL). This mixture was left at 0°C for 12 hours, filtered and the filtrate treated with S-phenylalaninol. The reaction mixture was allowed to stir at room temperature for 24 h, after which the solvent was removed in vacuo and the residue chromatographed using 10% MeOH in CH 2 Cl 2 as eluent to give the product as a white solid (153 mg, 50%);

IR (film) 3500-3200, 207, 2850, 1692 and 1642 cm"<1>;

NMR (CD3OD) δ 1.43 (3H, s) , 1.50-1.70 (4H, m) , 1.75-1.95 (8H, m) , 2.00-2.15 (6H m ), 2.7s (1H, dd, J 14 and 8Hz), 2.91 (1H, dd, J 14 and 6Hz), 2.95-3.35 (3H, m), 3.45-3.50 (3H, m), 4.07-4.17 (1H, m) , 4.81 (1H, + HOD), 6.93-7.09 (3H, m) , 7.10-7.30 ( 5H, m) , 7.31 (1H, d, J 8Hz) , 7.53 (1H, d, J 8Hz) .

EXAMPLE 4 0

Tricvchlor3. 3. 1. 13- 71dec- 2- vl( + ) - f3- ( 1H- indole - 3- vlmetvl) - 2. 5-dioxo- 1-( 2- phenylethyl)- 3- pyrrolidinyl carbamate ( 68)

Step 1. Methyl-(+)- S- amino- 6-[( phenylmethoxy)- carbonyl]- 1H-indole- 3- butanoate ( 64)

1-Methyl-( + )-S-cyano-1-[1,1-dimethylethoxy)-carbonyl]-1H-indole-3-butanoate (63) (0.241 g, 0.50 mmol) was dissolved in ethanol (5 ml). The solution was cooled to 0°C in an acetone/ice bath and ethanolic HCl was added dropwise. H 2 O (0.1 mL) was added and the mixture warmed to room temperature. The solution was stirred for 24 hours and the solvent was evaporated in vacuo. The oil was dissolved in ethyl acetate (50 mL) and washed with 10% Na 2 CO 3 solution (50 mL). The organic layer was dried (MgSO 4 ), filtered and evaporated to dryness. The product was isolated by flash chromatography (ethyl acetate:hexane, 1:1) to give the desired product (0.120 g, 67%) as a yellow oil,

i>max (cm"<1>, thin film) 3350 (NH) , 3425 (NH br) , 1741 (CO ester) ,

H (300 MHz, (CDC13) 6 2.12 (2H, br s, NH2) , 3.17 (1H, d, J 18Hz, CH2CO2CH3) , 3.28 (1H, d, J 18Hz, CH2CO2CH3); 3 .37 (1H, d, J 15Hz, indole-CH2) ; 3.43 (3H, s, 0CH3) ; 3.53 (1H, d, J 15Hz, indole-CH2) ; 4.82 (1H, d, J 12Hz, CH2Ph) ; 4.92 (1H, d, J 12Hz, CH2Ph) ; 6.73 (1H, d, J 2Hz, 2-H); 6.95-7.21 (8H, m, 5- H + 6-H + 7-H + Harom) 7.47 (1H, s, 4-H); 8.42 (1H, s, NH).

Step 2. Methyl-( + ) [ ( ph enylmethoxy) - carbonyl] - iS- [ ( tricyclo-[ 3. 3. 1. 13, 7] dec- 2- yloxy) carbonyl] - amino- 1H- indol- 3 - butanoate

(65)

Methyl-(+)-S-amino-6-[(phenylmethoxy)-carbonyl]-1H-indole-3-butanoate (64) (120 mg, 0.33 mmol) was dissolved in dry THF

(10 mL) under argon, after which triethylamine (55 µl, 0.40 mmol) was injected. The solution was cooled to 0°C in an ice bath and 2-adamantyl chloride (77 mg, 0.36 mmol) dissolved in THF (5 mL) was added. The solution was stirred for 12 hours at room temperature before the triethylamine hydrochloride was filtered off. Dichloromethane

(50 mL) was added and the solution washed with water (2 x 25 mL). The organic layer was dried (MgSO 4 ), filtered and evaporated to dryness. The product was isolated by flash chromatography in (ether:hexane, 1:1) to give the title compound (105 mg, 58%), mp 61.5-62.5°C.

"max (cm"<1>, thin film) 3412 (NH) ; 1738 (CO) ,

H (300 MHz, (CDC13) , 1.49-2.09 (14H, m, adamantyl-H) ; 3.12 (1H, d, J 15Hz, CHH2CO2CH3) ; 3.30 (1H, d, J 15Hz , CH2CO2CH3) ; 3.38 (s, 3H, OCH3) ; 3.72 (1H, d, J 15Hz, indole - CH2) ; 3.80 (1H, d, J 15Hz, indole-CH2) ; 4.83 (1H, br s, CH) ; 4.98 (1H, d, J 112Hz, PhCH2) ; 5.11 (1H, d, J 12Hz, PhCH2) ; 6.88 (1H, s, NH) ; 6, 79 (1H, s, 2-H); 7.03 (1H, t, J 7Hz, 6-H); 7.14 (1H, t, J 7Hz, 5-H); 7.17-7.34 (6H, m, 7-H, HaroJ ; 7.48 (1H, d, J 8Hz, 4-H); 8.30 (1H, s, NH), m/z (FAB) 545 (M+1) ; 501; 130.

C32H36N2O6 requires C, 70.6; H, 6.7; N, 5.1

found C, 70.6; H, 6.8; N, 5.0

Step 3. Methyl-( + ) - 15- carboxyl- 1S- \ [ ( tricyclo- f 3 . 3 . 1. I3' 7! dec- 2-yloxy) carbonyl]- aminol- 1H- indole- 3- butanoate ( 66)

In a 250 ml glass container, methyl-(±)

[ (phenylmethoxy)-carbonyl] [ [ (tricyclo [3 . 3 .1.1.3'7]-dec-2-yloxy)carbonyl]amino]-1H-indole-3-butanoate (65) (105 mg,

0.19 mmol) added palladium on charcoal (10%, approx. 20 mg) and ethanol (75 ml). The container was sealed in a Parr hydrogenation apparatus and placed under H 2 gas (3.2 kg/cm<2>). Shaking was started after the pressure was applied, and continued for 12 hours. After completion of the reaction, palladium on charcoal (10%) was filtered off and the filtrate was evaporated to dryness. The product was isolated by flash chromatography (methanol:water, 2:1) to give a white powder (77 mg, 88%), m.p. 108-9°C.

vmaK (cm"<1>, thin film) 3413 (NH) ; 1733 (CO) .

6 H (300 MHz, CDCl 3 ), 1.47-2.07 (14 H, m, adamantyl-H); 3.14 (1H, d, J 16 Hz, CH 2 CO 2 CH 3 ); 3.26 (1H, d, J 16 Hz, CH 2 CO 2 CH 3 ); 3.64 (3H, s, 0CH3); 3.76 (1H, d, J 15Hz, indole-CH2); 3.84 (1H, d, J 15 Hz, indole-CH 2 ); 4.83 (1H, br s, CH); 5.75 (1H, br s, OH) ; 5.96 (1H, s, NH); 6.98-7.04 (2H, m, 2-H + 6-H); 7.10 (1H, t, J

7Hz, 5-H); 7.28 (1H, d, J 8Hz, 7-H); 7.61 (1H, d, J 8Hz, 4-H); 8, 34 (1H, S, NH). 5 c (75.5 MHz, CDC13) 27.0, 27.2, 31.3, 31.7, 32.1, 36.4, 37.4, 39.7, 51.8, 62.4, 78.0, 108.9, 111.1, 118.7, 119.4, 121.7, 124.1, 128.2, 135.7, 154.8, 171.3, 176.2. m/z (FAB) 455 (M+1); 411, 217, 135, 130.

C25H30N2O6 requires C, 66.1; H, 6.65; N, 6.2 found C, 65.7; H, 6.7; N, 6.0

Step 4. Methyl - ( + ) - 6- f \ ( 2- phenylethyl) amino] carbonyl- IS- [ \ ( tricyclo- T3 . 3 . 1. 13' 7! dec- 2- vloxv) carbonyl! - aminol - 1H-indole-3-butanoate ( 67)

Methyl-(±)-&-[[(tricyclo[3.3.1.1.3'7]-dec-2-yloxy)-carbonyl]amino]-1H-indole-3-butanoate (66) (200 mg, 0.44 mmol) was dissolved and dicyclohexylcarbodiamide (100 mg,

0.4 8 mmol). The solution was stirred for 2 h before phenylethylamine (60 mg, 0.50 mmol) was injected. The mixture was allowed to stand under stirring overnight. The solution was evaporated to dryness and ethyl acetate was added, after which dicyclohexylurea was filtered off. The filtrate was evaporated to dryness and the product isolated by flash chromatography (hexane:ethyl acetate, 3:1) to give a white solid (180 mg, 73%), m.p. 78.0-79.5°C.

vmax (cm'<1>, thin film) 3333 (NH) ; 1730 (CO) , 1659 (CO amide) .

H (300 MHz, CDCl 3 ), δ 1.51-2.04 (14 H, m, adamantyl-H); 2.61 (2H, m, CH2NH); 2.94 (1H, d, J 16 Hz, CH 2 CO 2 CH 3 ); 3.21 (1H, d, J 16 Hz, CH 2 CO 2 CH 3 ); 3.37 (1H, d, J 7Hz, CH2Ph); 3.41 (1H, d, J 7Hz, CH2Ph) ; 3.46 (1H, d, J 15 Hz, indole-CH 2 ); 3.57 (1H, d, J 15 Hz, indole - CH 2 ); 3.62 (3H, s, OCH3); 4.78 (1H, br s, CH); 5.88 (1H, br s, NH urethane); 6.58 (1H, br s, NH amide); 6.92 (1H, d, J 2Hz, 2-H); 7.03-7.26 (7H, m, 5-H + 6-H + Harom); <7>.33 (1H, d, J 8Hz, 7-H); 7.56 (1H, d, J 8Hz, 4-H). m/z (FAB) 558 (M+1); 362, 331, 231, 135, 130, 105.

C33H39N305 . 0.75H2O requires C, 69.4; H, 7.1; N, 7.4 found C, 69.0; H, 6.8; N, 7.2

Step 5. Tricyklo T3 . 3. 1. 13-7! dec-2-vl-( + )-T3 - (1H-indol-3-ylmethyl)-2. 5- dioxo-l-(2-phenylethyl)-3- pyrrolidinyl carbamate

(68)

The ester (67) (110 mg, 0.20 mmol) obtained above was dissolved in 20 mL of THF and cooled to 0°C. Lithium hydroxide

(21 mL, 0.01M) was added dropwise to the solution over 3 hours. The solution was kept under stirring for a further 1 hour and then allowed to warm to room temperature. Hydrochloric acid (2.1 ml, 0.1 M) was added, after which the solution was extracted with ethyl acetate (3 x 20 ml). The organic layers were combined, dried with MgSO 4 , filtered and evaporated to dryness to give (105 g, 98%) crude product. The product was isolated by flash chromatography (methanol:water, 4:1) as a white powder (84 mg, 78.5%).

i/max (cm"<1>, thin film) 3347 (NH) ; 2912 (CH) ; 1781 (CO) , 1701

(CO) .

H (300 MHz, CDCl 3 ), δ 1.55-1.97 (14 H, m, adamantyl-H); 2.38 (2H, m, NHCH 2 ); 3.00 (1H, d, J 18Hz, CH2CON); 3.05 (1H, d, J 15 Hz, indole - CH 2 ); 3.47 (2H, t, J 8Hz, CH2Ph); 4.80 (1H, S, CH ) ; 5.49 (1H, s, NH); 7.04-7.35 (8H, m, 5-H + 6-H + 7-H + HaroJ ; 7.56 (1H, d, J 8Hz, 4-H); 8.68 (1H, s, NH) ;

C (75.5 MHz, CDCI3), 26.9, 27.1, 31.7, 32.0, 36.3, 37.3, 39.8, 40.2, 59.95, 76.4, 107.3, 111.4, 118.6, 120.2, 122.7, 123.7, 126.4', 127.4, 128.7, 136.0, 138.0, 154.9, 174 ,1, 176,1. m/z (Cl.) 528 (M+1); 527, 526, 374, 331, 130.

C32H35N304 . 0.25H2O requires C, 72.5%; H, 6.7%; N, 7.9% found C, 72.6%; H, 6.7%; N, 7.9%

EXAMPLE 41

(R2 = Me, see Reaction nucleus 15a)

A suspension of crushed sodium hydroxide (2 g, 50 mmol)

and ethyl 2-cyanopropionate (20 g, 157 mmol) in 150 ml of toluene was heated under a nitrogen atmosphere to 100°C and gramine (30.1 g, 172 mmol) was added portionwise. After 30 minutes, the temperature was raised to 130°C (oil bath) and the mixture was carefully refluxed for 16 hours. Then 100 ml of water and 200 ml of ethyl acetate were added, the mixture neutral

acidified with acetic acid, the organic layer separated, washed with water (100 ml), dried (sodium sulfate) and evaporated. The residue was purified by chromatography over silica gel using toluene/ethyl acetate (1:1, parts by volume, Rf 0.4). 2a was isolated as a light brown viscous oil (34.5 g, 86%).

MS (70eV): m/z 256 (M<+>, 8%), 130 (100%).

EXAMPLE 4 2

(R2 = Me, see Reaction scheme 15a)

Compound 2a (5 g, 19.5 mmol) in 250 mL dioxane, saturated with ammonia, was hydrogenated (100 bar, 80 °C) with Raney nickel (0.95 g) in an autoclave for 1 h. After filtration and evaporation, the residue was purified by chromatography over silica gel using dichloromethane/methanol (95:5, parts by volume,

Rf 0.1). 3a was isolated as a colorless viscous oil (4.76 g, 94%).

MS (70eV): m/z 260 (M\ 17), 130 (100), 117 (48).

EXAMPLE 4 3

(R1 = 2-adamantyl. R2 = Me, see Reaction scheme 15a)

To a stirred solution of 2-adamantyl chloroformate

(4.45 g, 20.7 mmol) in dry THF (50 mL) under N2 atmosphere was added a solution of 3a (4.76 g, 18.3 mmol) in dry THF (100 mL) and then dropwise a solution of triethylamine (3.7 g, 36.6 mmol) in dry THF (50 mL). After 15 min, the reaction mixture was filtered, the solvent removed and the residue column chromatographed over silica gel using CH 2 Cl 2 /MeOH (98:2) as eluent to give 4a as a colorless amorphous solid (7.8 g, 97%).

MS (70 eV): m/z 438 (M\ 20), 130 (100).

EXAMPLE 44

(R1 = 2-adamantyl. R<2> = Me, see Reaction scheme 15a)

To a solution of 4a (3.9 g, 8.9 mmol) in dioxane/H 2 O 2:1 (60 mL) was added an excess of LiOH (0.325 g, 13.5 mmol), after which the mixture was stirred at room temperature for 72 hours. After removal of the solvent in vacuo, the residue was suspended in water (50 ml), neutralized with acetic acid, extracted with CH 2 Cl 2 and the organic layer separated and dried (sodium sulfate). After filtration and evaporation, the residue was chromatographed using CH2Cl2/MeOH 95:5 (v/v, Rf 0.3) as eluent to give the acid 5a as a colorless amorphous solid (2.5 g, 69%).

MS (70eV): m/z 410 (M<+>, 4), 130 (100).

EXAMPLE 45

( R1 = 2- adamantyl. R2 = Me. R<3>= - CH-. 0H. c = 1. R4 = H,

see Reaction scheme 15a)

Carbamic acid. [ 3- \ [ 1-( hydroxymethyl)- 2- phenylethyl] amino]- 2-( 1H-indol-3- ylmethyl)- 2- methyl- 3- oxopropyl]-, tricyclo-[ 3 . 3. l. l3' 7! dec- 2- vi- ester \ S - ( R*. RS) 1 -

To a solution of 5a (1 g, 2.44 mmol) in dry ethyl acetate (40 mL) was added pentafluorophenol (0.45 g,

2.44 mmol), after which the mixture was stirred for 10 minutes. The reaction mixture was cooled to 0°C and a solution of dicyclohexylcarbodiimide (0.505 g, 2.44 mmol) in ethyl acetate

(10 ml) added dropwise. This solution was stirred for one hour at 0°C and then at room temperature for four hours before being left overnight at 4°C. The mixture was filtered, the precipitate washed with cold ethyl acetate (10 mL), and a solution of (S)-(-)-phenylalaninol (0.405 g, 2.68 mmol) in ethyl acetate (25 mL) added dropwise to the combined filtrates . The mixture was allowed to stand under stirring for 4 days at room temperature. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (100 ml), dried (sodium sulfate) and evaporated. The residue was chromatographed on silica gel using CH 2 Cl 2 /MeOH 98:2 as eluent to give 6a as a colorless amorphous solid (0.780 g, 59%, mixture of two diastereomers), m.p. 85-95°C. CI-MS (70 eV, NH 3 ): m/z 544 (MH<+>, 100), 392 (76).

Examples 46-57 were prepared in an analogous manner:

(C<*> = configuration at the chiral C atom on the substituted 2-phenylethylamide residue, the R<2-> center is always RS) .

EXAMPLE 46

( R1 = ( IS)- 2- bornvl, R2 = Me, R<3>=R<4>= H, c = 1) Carbamic acid, \ 2 -( 1H- indol- 3- ylmethyl)- 2- methyl- 3- oxo- 3- r ( 2-phenylethyl) amino] propyl-, 1, 7, 7- trimethylbicyclo-[ 2. 2. 1]- hept- 2-vl- ester ( Bicyclosvstem is 1S- endo, chiedene center is RS )

m.p. 60-70°C, MS (70eV): m/z 515 (M<+>, 5), 130 (100)

EXAMPLE 4 7

(R1 = 1- adamantyl, R<2> = Me, R<3> = R<4> = H, c = 1)

Carbamic acid, [ 2-( 1H- indol- 3- vlmethyl)- 2- methyl- 3- oxo- 3-[ ( 2-phenylethyl) amino] propyl- , tricyclo- [ 3. 3. 1. 13, 7] dec - l- vl- ester m.p. 75-85°C, MS (70eV): m/z 513 (M\ 100), 305 (91)

EXAMPLE 4 8

( R1 = 2- adamantyl. R<2> = Me, R<3> = R<4> = H, c = 1)

Carbamic acid, [ 2-( 1H- indol- 3- ylmethyl)- 2- methyl- 3- oxo- 3-[( 2-phenylethyl) amino] propyl] - , tricyclo- [ 3. 3. 1. 13, 7 ] dec- 2-yl- ester ( <+> ) <->

m.p. 75-85°C, MS (70eV): m/z 513 (M<+>, 25), 305 (88), 134 (100)

EXAMPLE 4 9

( R1 = ( IS)- 2- bornvl, R<2>= Me, R3 = CH, OH, R<4>= H, c = 1. C<*> =S) Carbamic acid, [ 3- f fl- ( hydroxymethyl)- 2- phenylethyl] amino] - 2-( 1H-indol- 3- ylmethyl)- 2- methyl- 3- oxopropyl- 1, 7, 7- trimethyl bicclo- [ 2. 2. li hept- 2- yl - ester (Bicyclosystem is IS-endo, hydroxymethyl center is S, other center is RS)

m.p. 75-85°C, MS (70eV): m/z 545 (M<+>, 7), 130 (22), 95 (77), 44

(100)

EXAMPLE 5 0

( R1 = 2- adamantyl. R<2>= Me, R<3> = H, R<4> = NHCOCH^ CHo CO-, Bz, c = 1,

C<*> = R)

14-oxa-2,6,9-triazapentadecanoic acid, 4-(1H-indol-3-ylmethyl-4-methyl-5,10,13-trioxo-8,15-diphenyl-,tricyclo[3.3.1 . 13' 7] - dec-2- vl- ester, rR-( R*. R*) l-

m.p. 80-90°C, Cl-MS (CH4): m/z 611 (21), 459 (21), 135 (100)

EXAMPLE 51

( R1 = 2 - adamantyl, R<2>= Me, R3 = H, R<4>= NHCOCH = CHCO. Me,

c = 1. C<*> = R)

14- oxa- 2, 6, 9- triazapentadec- ll- ensvre, T4-( 1H- indol- 3- ylmethyl- 4- methyl- 5 , 10 , 13- trioxo- 8- phenyl- , tricyclo [ 3 . 3 . 1. 13' 7] - dec- 2- vl- ester, fR- [ R*. R*-( E) 1 -

m.p. 105-120°C, CI-MS (CH4) : m/z 641 (MH<+>, 1) , 151 (18) , 135

(100)

EXAMPLE 52

( R1 = 2- adamantyl. R<2> = Me, R3 = H. R<4>= NHCO,- t- Bu,

c = 1. C<*> = R)

11-oxa-2, 6, 9- triazatridecanoic acid, 4-(1H-indol-3-ylmethyl)-4, 12, 12- trimethvl-1, 5, 10- trioxo-8- f envl-, tricyclo\ 3 . 3. 1. 13- 71 - dec- 2- vl- ester. TR-( R*. R*) 1 -

m.p. 100-110°C, Cl-MS (CH4) : m/z 629 (MH<+>, 8), 135 (100)

EXAMPLE 53

( R1 = 2-adamantyl. R<2> = Me, R<3>= H,

R<4>= NHCOCH, CH-, CO-, H, c = 1, C<*> = R)

Butanoic acid, 4-\\ 2 - f[ 2-( lH- indol-3- ylmethyl)- 2- methyl- l- oxo- 3-r ftricyclo [ 3 . 3. 1. 13, 71 - dec-2- yloxy) carbonyl] amino] - propyl! - aminol- l- phenylethyl] amino]- 4- oxo-, [ R-( R*, R*) ] -

m.p. 110-125°C, Cl-MS (CH4): m/z 628 (M~, 21), 164 (100)

EXAMPLE 54

( R1 = 2- adamantyl, R<2>= Me, R3 = H, R<4>= NHCOCH = CHCCsH,

c = 1. C<*> = R)

2- butenoic acid, [ 4-[ 2-[[ 2-( 1H- indol- 3- ylmethyl)- 2- methyl- l- oxo- 3-[ f ( tricyclo [ 3. 3. 1. 13, 7] - dec- 2 - yloxy) carbonyl] aminol - propyl] - amino]- l- phenylethyl]- 4- oxo- (Trp- center RS; other center R; double bond E)

m.p. 210-220°C, CI-MS (CH4): m/z 626 (M~, 7), 474 (100), 164

(88)

EXAMPLE 55

(R1 = 2-adamantyl, R2 = Me, R4 = H, c = 0)

Carbamic acid, [ 2-( 1H- indol- 3- ylmethyl)- 2- methyl- 3- oxo- 3-

[ (phenylmethyl) aminol propyl] - , tricyclo [ 3. 3. 1. 13, 71 - dec- 2- vl-ester, (+)-

m.p. 80-90°C, MS (70eV) : m/z 499 (M<+>, 25) , 291 (47) , 130 (100)

EXAMPLE 56

( R1 = ( IS)- 2- bornvl, R2 = Me, R<3>= CH, OCOCH,CH,CO, H, R<4>= H,

c = 1. C<*> = S)

Butanedioic acid, mono- 2- [ [ 2-( 1H- indol- 3- ylmethyl)- 2- methyl- l- oxo- 3-f[( 1, 7, 7- trimethylbicyclo[ 2. 2. 1] hept- 2 - yloxy) carbonyl]- amino] - propyl] aminol- 3- phenylpropyl ester (Bicyclo- system is 1S- endo, phenylmethyl- center is S, other center is RS)

m.p. 115-130°C, Cl-MS (CH4) : m/z 646 (MH<+>, 34), 528 (78), 101

(100)

EXAMPLE 57

( R1 = 2- adamantyl, R2 = Me, R3 = CH-, OCOCH,CH?CO, H, R4 = H,

c = 1. C<*> = S)

Butanedioic acid, [ 2-[ [ 2-( 1H- indol- 3- ylmethyl)- 2- methyl- 1- oxo- 3-[ [ ( tricyclo [ 3. 3. 1. 13, 7] dec- 2- yloxy) carbonyl] amino] propyl] - aminol- 3- phenylpropyl ester (Trp center RS; other center S) m.p. 85-95°C, Cl-MS (C4H10) : m/z 643 (M", 16), 642 (19), 235

(100)

The conversion of compound 5a (R<1> = 2-adamantyl, R<2> = Me) into compounds 6f, 6g, 6h, 6i, 6k and the conversion of compounds 6a and 6e into compounds 6m and 6n is carried out analogously to those already described procedures. Compounds with the general formula Ia, where R<2>, R3 and R<4> are H, have also been prepared according to synthesis core 15b:

EXAMPLE 58

( c = 1. see Reaction scheme 15b)

A solution of N-(S-phenylethyl)cyanoacetamide (8a,

18.8 g, 0.1 mol), indole-3-carboxaldehyde (14.5 g, 0.1 mol) and piperidine (5 drops in ethanol (100 mL) were refluxed

run cooling for 16 hours. After cooling to room temperature, the precipitate was filtered off, washed with ethanol (2 x 20 mL) and dried to give 9a as yellow crystals (29 g, 92%).

MS (70 eV): m/z 315 (M 14), 195 (100).

EXAMPLE 59

(c = 1, see Reaction scheme 15b)

Compound 9a (3.15 g, 10 mmol) in 50 mL dioxane, saturated with ammonia, was hydrogenated (100 bar, 80 °C) with Raney nickel (0.5 g) in an autoclave for 17 h. After filtration and evaporation, the residue was chromatographed on silica gel using CH 2 Cl 2 /MeOH 9:1 (v/v) as eluent. 10a was obtained as colorless crystals from ethyl acetate (1.16 g, 36%).

MS (70eV): m/z 321 (M<*>f 46), 170 (93); 130 (100).

EXAMPLE 60

(R1 = 2- adamantyl. c = 1. see Reaction scheme 15b)

Carbamic acid, [ 2-( 1H- indol- 3- vlmethyl)- 3- oxo- 3- l ( 2- phenylethyl) - aminol propvll - , tricyclo\ 3 . 3. 1. 13, 71 - dec- 2- vl- ester, ( + )-The conversion of 10a to 11a was carried out according to the conversion of 3a to 4a. After chromatographic separation using CH2Cl2/MeOH 98:2 as eluent, lia was isolated as a colorless amorphous solid (87%), m.p. 115-140°C, MS (70eV): m/z 499 (M<+>, 3), 291 (100).

EXAMPLES 61 AND 62

( c = 1, see Reaction scheme 15c)

A suspension of crushed sodium hydroxide (0.5 g,

12.5 mmol) and N-(JS-phenylethyl)cyanoacetamide (8a, 8 g,

42.5 mmol) in 50 ml of toluene was heated under a nitrogen atmosphere to 100°C and gramine (7.4 g,

42.5 mmol). After 30 minutes, the temperature was raised to 130°C (oil bath) and the mixture was gently boiled under reflux for 2 hours. Then 50 ml of water and 200 ml of ethyl acetate were added, the mixture neutralized with acetic acid, the organic layer separated, washed with water (100 ml), dried (sodium sulfate) and evaporated. The residue was separated by

chromatography on silica gel using CH2Cl2/EtOAc 9:1 (v/v) as eluent. 1st fraction: compound 13a as colorless crystals (4.5 g, 47%). MS (70 eV): m/z 446 (M<+>, 4), 130 (100). 2nd fraction: compound 12a, colorless crystals from ethanol (3.05 g, 23%). MS (70 eV): m/z 317 (M<+>, 18), 130 (100).

EXAMPLE 63

( R1 = 2- adamantyl, c = 1)

Carbamins<y>re, [ 2, 2- bis( 1H- indol-3- ylmethyl)- 3- oxo- 3-\( 2- phenylethyl) aminol propyl- , tricyclo f 3 . 3. 1. 13, 71 - dec-2- yl- ester

The conversion of 13a (c = 1) to 17a (R<1> = 2-adamantyl, c = 1) was carried out analogously to the conversion of 2a to 4a. After purification by chromatography on silica gel using CH2Cl2/MeOH 98:2, 17a was isolated as a colorless amorphous solid (yield 50% from 13a), m.p. 105-110°C, Cl-MS (NH 3 ): m/z 629 (MH<+>, 100%).

EXAMPLE 64

(R1 = 1-adamantyl. R<2> = Me, see Reaction scheme 16)

To a stirred solution of 3a (3 g, 11.5 mmol) in anhydrous THF (100 mL) was added at room temperature adamantane-1-carbonyl chloride (2.28 g, 11.5 mmol) and then a solution of triethylamine dropwise (3.2 mL, 23 mmol) in THF (20 mL). According to thin layer chromatography, the reaction was complete after 30 minutes. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified by chromatography over silica gel using CH 2 Cl 2 /MeOH 98:2 as eluent. 18a was isolated as a colorless amorphous solid (3.25 g, 67%).

MS (70 eV): m/z 422 (M<+>, 35), 293 (34), 130 (100).

EXAMPLE 65

(R1 = 1-adamantyl. R<2> - Me, see Reaction Scheme 16)

To a solution of 18a (3.25 g, 7.7 mmol) in 1,4-dioxane/H 2 O (2:1, 90 mL) was added an excess of LiOH (0.37 g, 15.4 mmol) , after which the solution was stirred at room temperature for 48 hours. After removal of the solvent in vacuo, the residue was dissolved in water (150 mL), acidified with citric acid (10% in water) and extracted with dichloromethane (2

x 100 ml). The organic layer was dried (Na 2 SO 4 ) and evaporated. 19a was isolated as a colorless, amorphous solid (3 g, ca. 100%). TLC (silica gel): Rf 0.2 (CH 2 Cl 2 /MeOH 95:5).

EXAMPLE 66

( R1 = 1- adamantyl. R<2> = Me, R<3>= - CH, OH. c = 1 R<4> = H.

see Reaction scheme 16)

lH- indol- 3- propanamine, N- Tl- ( hydroxymethyl) - 2- phenylethyl - ot - methyl- a- \ \ ( tricyclo [ 3 . 3 . 1. 13, 71 dec- 2 - ylcarbonyl) amino] methyl] -

(indole center is RS, other center is S)

The conversion of 19a to 20a was carried out analogously to the conversion of 5a to 6a. After purification by chromatography on silica gel using CH2Cl2/MeOH 98:2, 20a was isolated as a colorless amorphous solid (52%), m.p. 85-95°C.

MS (70 eV): m/z 527 (M<+>, 30), 335 (100).

Analogously, it was obtained:

EXAMPLE 67

( R1 = 1- adamantyl. R<2>= Me, R<3>= H. c = 1. R<4> = H)

1H-indole-3-propanamide, α-methyl-N-(2-phenylethyl)-α-\f( tricyclo[3.3.1.13-7]dec-2-ylcarbonyl)amino]methyl], ( + ) -

A colorless amorphous solid, m.p. 80-90°C.

MS (70eV): m/z 497 (M<+>, 9), 305 (43), 184 (56), 135 (64), 130

(100).

EXAMPLE 68

(See Reaction scheme 17)

In an autoclave, 1-(3'-indolyl)-butan-3-one (12.32 g, 65.9 mmol), potassium cyanide (4.7 g, 72.3 mmol), ammonium carbonate (6.9 g, 71.8 mmol) and ammonium hydroxide (25%, 13 mL) in water (25 mL) and methanol (75 mL) heated to 60°C for 16 h with stirring. The solution was diluted with water (100 ml), the methanol evaporated and the remaining mixture acidified (2N HCl). The precipitated hydantoin 21 was filtered off, washed with water and dried. Yield: 15.2 g (90%) colorless crystals.

MS (70eV): m/z 257 (M<+>, 22), 144 (96), 130 (100).

EXAMPLE 6 9

(See Reaction scheme 17)

In an autoclave, 21 (10 g, 38.9 mmol) in 5% sodium hydroxide (125 mL) was heated to 150 °C for 16 h. After cooling to room temperature, the solution was neutralized with hydrochloric acid (37%) and, if necessary, immediately filtered to remove traces of hydantoin 21. The solution was stirred at room temperature for 2 hours and the precipitated amino acid 22 was filtered off, washed with water (20 ml) and dried. 22 was isolated as pale-beige crystals (8.52 g, 94%)

MS (70 eV): m/z 232 (M<+>, 26), 144 (100), 130 (92).

EXAMPLE 70

(See Reaction scheme 17)

A solution of 22 (5 g, 21.5 mmol) in dry methanol

(3 75 mL) was heated to 40°C and saturated with hydrogen chloride (1 hour). After stirring at 40-45°C for 5 hours and at room temperature for a further 15 hours, the solvent was evaporated. Water (100 mL) was added, the mixture neutralized with aqueous sodium carbonate and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with dilute sodium bicarbonate solution (50 mL) and then with water (50 mL) and dried (Na 2 SO 4 ). After removal of the solvent, the residue was chromatographed on silica gel using CH 2 Cl 2 /MeOH 98:2 (v/v) as eluent. 23 was isolated as beige crystals (4.0 g, 75%).

MS (70 eV): m/z 246 (M\ 25), 144 (71), 130 (100).

EXAMPLE 71

(R1 = 2-adamantyl. see Reaction scheme 17)

The reaction of amino ester 23 with 2-adamantyl chloroformate was carried out according to the conversion of 3a to 4a. 24a was isolated in 86% yield as a colorless amorphous powder.

MS (70eV): m/z 424 (M<+>, 42), 281 (41), 144 (100), 135 (78).

EXAMPLE 72

(R1 = 2-adamantyl, see Reaction scheme 17)

The hydrolysis of 24a with lithium hydroxide was carried out according to the hydrolysis of 4a to 5a. 25a was isolated without chromatography in quantitative yield as a pale beige amorphous powder, sufficiently pure for use in the next step (see Example 73). MS (70eV): m/z 410 (M<+>, 5), 130 (100).

EXAMPLE 73

(R1 = 2-adamantyl. R<3> = R<4> = H, c = 1. see Reaction scheme 17)

Carbamic acid, f3-(1H-indole-3-vi)-1-methyl-1-r\2-(phenylethyl)-aminol carbonyl propyll-,tricyclo\3. 3. 1. I3, 7] - dec- 2- vl- ester,

The conversion of 25a with 2-phenylethylamine to 26a was carried out according to the conversion of 5a to 6a. After chromatographic separation on silica gel using CH2Cl2/MeOH 98:2 (v/v), 26a (Rf 0.2) was isolated in 69% yield as a colorless amorphous powder, m.p. 75-85°C.

MS (70 eV): m/z 513 (M<+>, 1), 370 (67), 130 (100).

In an analogous way, it was produced:

(C<*> = configuration at the chiral C atom in the substituted 2-phenylethylamide residue, other center is always RS)

EXAMPLE 74

(R1 = 2-adamantyl, R3 = CH, 0H, R4 = H. c = 1. C<*> = S)

Carbamic acid, Tl-\\ Tl-( hydroxymethyl)- 2- phenylethyl]- amino]-carbonyl]- 3-( 1H- indol- 3- yl)- 1- methylpropyll-,

tricyclo f3 . 3. 1. 13, 7] dec-2-yl ester (hydroxymethyl center is S, other center is RS)

m.p. 80-90°C. Cl-MS (C 4 H 10 ) : m/z 544 (MH\ 2 ), 392 (100)

EXAMPLE 75

( R1 = ( IS)- 2- bornvl, R<3> = R4 = H, c = 1

Carbamic acid, [3-(1H-indol-3-yl)-1-methyl-1-[[(2-phenylethyl)-aminolcarbonyl]propyl]-,1,7,7-trimethyl-bicyclo[2. 2. 1 ] hept-2-vl-ester, [ IR -[ la . 2 &(S) , 4al1 -

m.p. 70-80°C. CI-MS (CH 4 ): m/z 516 (MH<+>, 2), 362 (100)

EXAMPLE 76

( R1 = 2- adamantyl. R<3>= H, R4 = NHCOCH = CHCO, Me,

c = 1, C<*> = R)

13-oxa-2,5,8-triazatetradec-10-enoic acid, 3-[2-(1H-indol-3-yl)-ethyl]-3-methyl-4,5,12-trioxo-7-phenyl - , tricyclo f 3 . 3. 1. I3' 7] - dek- 2- vl- ester (TRP center is R/S- mixture, other center is R, double-bonded E)

m.p. 117-123°C, Cl-MS (C4H10) : m/z 640 (M", 19), 487 (100)

EXAMPLE 77

( R1 = 2- adamantyl. R3 = H, R4 = NHCOCH,CH-,CO, Bz,

c = 1. C* = R)

13-oxa-2.5,8-triazatetradecanoic acid, 3-[2-(1H-indol-3-yl)ethyl! - 3- methyl- 4 , 9 , 12 - trioxo- 7 , 14-di f phenyl - . tricyclo [ 3 . 3. 1. 13, 7] - dec-2-yl- ester ( TRP center is R/S- mixture, other center is R, m.p. 85-95°C, CI-MS (C4H10) : m/z 627 (20 ), 475 (100), 251 (44)

EXAMPLE 78

( R1 = ( IS) - 2- bornvl, R<3> = CH, OH, R4 = H, c = 1. C<*> = S) Carbamic acid, [ 2 -[[[ 1-( hydroxymethyl)- 2 - phenylethyl] amino] - carbon vll - 3-( 1H- indol- 3- yl)- 1- methylpropyl] -, 1, 7, 7- trimethylbicyclo[ 2. 2. 1] hept- 2- yl ester ( Bicyclo system is lS- endo, hydroxymethyl center is S, other center is RS)

m.p. 75-85°C, CI-MS (CH 4 ): m/z 546 (MH<+>, 82), 153 (100)

EXAMPLE 79

( R1 = 2- adamantyl, R<3>= H, R<4>= NHCOCH,CH,CO, H, c = 1. C<*> = R)

Butanoic acid, 4-\[ 2-[[ 4-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3. 3. 1. 13, 71 - dec- 2- yloxy) carbonyl] aminol butyl aminol - 1-phenylethylamino]- 4- oxo- ( indole center is RS, other center is El

m.p. 115-125°C, Cl-MS (C4H10) : m/z 629 (MH<+>, 1), 191 (28),

135 (100)

EXAMPLE 80

( R1 = 2- adamantyl, R<3> = H, R<4>= - NHCOCH=CHCO-, H. c = 1. C<*> = R) 2- butenesvre, 4-[ 2-[[ 2 -[ 2-( 1H- indol-3- yl) ethyl - 2- methyl- 1- oxo-3- [ [ ( tricyclo [ 3. 3. 1. 13, 71 - dec- 2- yloxy) carbonyl] amino] propyl] - aminol- l- phenylethyl]- 4- oxo- (indole center is RS, other center is R, double bond E)

m.p. 190-200°C, Cl-MS (NH3) : m/z 626 (M", 24), 201 (60),

151 (100)

The conversion of 26d to 26h and the conversion of 26e to 26g was carried out analogously to methods already described.

EXAMPLE 81

(See Reaction scheme 18)

The procedure is as described for 2a (conf. J. Org. Chem. 18:1440-1447, 1953. Alkylation of diethyl methyl malonate with gramine led to compound 28 after chromatographic separation on silica gel using CH2Cl2/MeOH 98:2 (volume parts ) as eluent, in the form of a light red-brown syrup (yield 90%) MS (70eV): m/z 303 (M<+>, 11), 130 (100).

EXAMPLE 82

(See Reaction scheme 18)

To a solution of the diester 28 (31 g, 0.102 mol) in dry ethanol (80 ml) a solution of potassium hydroxide (6.5 g, 0.116 mol) was added dropwise (1 hour) at room temperature, after which the solution was stirred for a further 16 hours. The reaction mixture was filtered and the filtrate evaporated. The residue was suspended in water (700 ml), neutralized with hydrochloric acid and extracted with ether (3 x 250 ml). The ether solution was dried (Na 2 SO 4 ) and evaporated and the residue purified by chromatography on silica gel using CH 2 Cl 2 /MeOH 95:5 (v/v) as eluent. The monoacid 29 (Rf 0.1) was isolated as a light reddish-brown syrup (18 g, 64%).

MS (70 eV): m/z 275 (M<+>, 9), 130 (100).

EXAMPLE 83

(See Reaction scheme 18)

To a solution of compound 29 (37 g, 0.134 mol) in dry tetrahydrofuran (500 mL) was added dropwise under nitrogen at 0°C a 2M solution of borane methyl sulfide complex in tetrahydrofuran (100 mL, 0.2 mol) (45 min .) and the mixture stirred for 3 hours at 0°C. Then water (100 ml) was added dropwise, the mixture diluted with more water (400 ml) and ethyl acetate (800 ml). The organic layer was separated, washed with water (3 x 150 mL), dried (Na 2 SO 4 ) and evaporated. The residue was suspended in CH 2 Cl 2 (100 mL), the precipitate 29 filtered off and washed with CH 2 Cl 2 (30 mL). 29 was isolated as colorless, sometimes slightly red, crystals (26.74 g, 85%), sufficiently pure for use in the next step.

TLC (silica gel): Rf 0.15 (toluene/tetrahydrofuran 1:1).

EXAMPLE 84

(See Reaction scheme 18)

To a solution of 30 (26.6 g, 0.114 mol) in dry methanol (1.5 L), 4 mL of sulfuric acid (95-97%) was added and the solution stirred at room temperature for 2 days. The solution was neutralized with sodium bicarbonate solution, partially evaporated to remove the methanol, diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The organic layer was washed with water (250 mL), dried (Na 2 SO 4 ) and evaporated. The residue was chromatographed on silica gel using toluene/ethyl acetate 3:1 (parts by volume) as eluent. 31 was isolated as a colorless, viscous syrup (25.7 g, 91%).

MS (70 eV): m/z 247 (M<+>, 8), 130 (100).

EXAMPLE 85

(See Reaction scheme 18)

To a solution of 31 (5.0 g, 20.2 mmol) and pyridine (3.2 g, 40.4 mmol) in dry dichloromethane (100 ml) was added at 0°C p-toluenesulfonyl chloride (5.0 g, 26.3 mmol) in small portions. The solution was allowed to stand for 4 days in a refrigerator at 0-5°C. The solution was washed with sodium bicarbonate solution (2 x 50 mL), dried (Na 2 SO 4 ) and evaporated. The residue was chromatographed on silica gel using toluene/ethyl acetate 95:5 (parts by volume) as eluent. Compound 32 (Rf 0.3) was isolated as a viscous oil which was recrystallized from diisopropyl ether to give colorless crystals (6.94 g, 85%).

MS (70 eV): m/z 401 (M<+>, 8), 130 (100).

EXAMPLE 86

(See Reaction scheme 18)

Compound 32 (3.5 g, 8.13 mmol) and potassium cyanide

(0.850 g, 13.1 mmol) in dry dimethylformamide (60 mL) was stirred at 110 °C for 16 h. The solution was evaporated in vacuo and the residue dissolved in ethyl acetate (200 ml) and water (200 ml). The organic layer was separated, dried (Na 2 SO 4 ) and evaporated. The residue was purified by chromatography on silica gel using toluene/ethyl acetate 9:1 (parts by volume) as eluent. Compound 33 was isolated (Rf 0.4 in toluene/ethyl acetate 4:1) as a colorless syrup (1 g, 45%).

MS (70 eV): m/z 256 (M<+>, 8), 130 (100).

EXAMPLE 87

( R1 = 2- adamantyl. R<3>= R4 = H. c = 1.

see Reaction scheme 18)

Carbamic acid, T3-(1H-indol-3-ylmethyl)-3-methyl]-4-oxo-4-[(2-phenylethyl)-amino]butyl]-, tricyclo f3. 3. 1. 13, 71 dec-2-yl ester,

The conversion of compound 33 to compounds 37 is carried out analogously to the conversion of compounds 2 to compounds 6 (see synthesis core 15a). 37a was isolated after chromatographic separation on silica gel, using CH2Cl2/MeOH 98:2 (v/v) as eluent, as a colorless amorphous solid in 52% yield, m.p. 70-80°C.

MS (70 eV): m/z 527 (M<+>, 2), 130 (100).

EXAMPLE 88

( R1 = 2- adamantyl. R<3> = - CH, 0H, R<4> = H, c = 1.

see Reaction scheme 18)

Carbamic acid, T4-[[ 1-( hydroxymethyl)- 2- phenylethyl]- aminol - 3-( 1H- indol- 3- ylmethyl)- 3- methyl- 4- oxobutyl]-,

tricyclo 3 . 3. 1. 13- 7] dek- 2- vi- ester

Analogous to the synthesis of 37a, compound 37b has been isolated after chromatographic separation on silica gel, using CH2Cl2/MeOH 98:2 (v/v) as eluent, as a colorless amorphous solid in 52% yield, m.p. 70-80°C.

MS (70 eV): m/z 527 (M<+>, 2), 130 (100). 37b is a mixture of two diastereomers (S-configuration at the chiral center arising from (S)-(-)-phenylalaninol).

EXAMPLE 8 9

Ethylidene-isopropylamine (69)

Isopropylamine (85 ml, 1.0 mol) was gradually added over 1 hour to acetaldehyde (56 ml, 1.0 mol) cooled in an ice bath. After the addition was complete, the mixture was stirred for an additional 20 minutes. Potassium hydroxide shavings were added until the solution separated into two layers. The organic phase was separated and stored over crushed potassium hydroxide at 0°C. The dried material was distilled under vacuum at room temperature to give the title compound (1) (51.4 g, 60%) b.p. 25-30°C/10 mm; 6H (300 MHz, CDCl 3 ), 1.09 (6H, d, J 6.3Hz, 2CH 3 ), 1.88 (3H, d, J 4.8Hz, CH 3 CH ).

3-( isopropyl- aminoethylidene)- indole ( 70)

A solution of indole (25.0 g, 0.213 mol) in glacial acetic acid

(150 mL) was cooled in an ice bath and ethylidene-isopropylamine (69) (17.3 g, 0.203 mol) in toluene (50 mL) was added dropwise with stirring over 1 hour. The resulting mixture was

kept at 0°C for 5 days. After this time, the mixture was completely transferred to an ice/ether mixture. The ether layer was separated and extracted with 1N potassium hydrogen sulfate (2 x 100 ml). The combined aqueous phases were washed with ether (2 x 50 mL), then basified with 1N sodium hydroxide (keeping the temperature below 25°C). The alkaline solution was extracted with ether (4 x 250 mL). The organic phase was dried (MgSO 4 ) and evaporated to dryness to give the title compound (2) (24.6 g, 60%), m.p. 107-112°C (lit., <1 >108-114°C);

"max (film) 3479 cm"<1> (indole NH)

6 H (300 MHz, CDC13) , 1.01 (3H, d, J 6Hz, CH3) , 1.09 (3H, d, J 6Hz, CH3) , 1.52 (3H, d, J 6, 6Hz, CH3) , 2.88 (1H, sept J 6Hz, CH(CH3), 4.27 (1H, q, J 6.6Hz, indCH(CH3), 7.08-7.25 (4H, m) , 7 .35 (1H, s, J 8Hz, NH), 7.71 (1H, d, J 8Hz, indole 4-H), 8.21 (1H, br s, indole NH).

Dibenzvlacetamidomalonate ( 71)

Diethylacetamidomalonate (9.1 g, 42 mmol) [Aldrich] in benzyl alcohol (26 mL, 0.25 mmol) was heated on an oil bath to 200°C. A slow stream of nitrogen was bubbled through the solution during which the ethanol distilled off. After 4 hours, the reaction mixture was cooled to room temperature and the excess of benzyl alcohol removed in vacuo, during which the oil bath temperature was slowly raised to 185-190°C, at which point the distillation proceeded very slowly. The solution was cooled to room temperature and the resulting precipitate recrystallized from isopropanol to give the title compound (71) (12.2 g, 85%); m.p. 111-112°C (lit., <1> 110-113°C);

vmx (film) 1752, 1734 (ester C=0), 1651 (amide C=0), 740 and 694 cm"<1> (monosubstituted Ph);

6 H (300 MHz, CDCl3) , 2.05 (3H, s, CH3CO) , 5.17 (2H, s, CH2Ph) , 5.18 (2H, s, CH2Ph) , 5.29 (1H, d, J 7 Hz, CHCO 2 CH 2 Ph) 2 ), 6.53

(1H, br d, J 6Hz, NH), 7.27 (10H, m, 2Ph),

5 c (75.5 MHz, CDC13), 22.5, 56.5, 68, 128.5, 134.5, 166, 170.

Dibenzvl-(3- indolylethylidene) acetamidomalonate ( 72 )

The amine (70) (5.41 g, 26.7 mmol), diester (71) (9.12 g, 26.7 mmol) and sodium methoxide (38 mg, 0.70 mmol) were heated in toluene (30 ml) to 85-95°C (bath temperature) while a slow stream of nitrogen was bubbled through the solution. The reaction mixture was kept at this temperature for 5 hours, after which it was cooled to -40°C (freezer). The crude product was filtered off and recrystallized from isopropanol to give the title compound (72) (8.22 g, 64%), m.p. 162-163°C (P^OH)

(lit., <1> 161-163°C);

vmax 1737 (ester C=0) , 1672 (amide C=0) , 743 and 697 cm"<1> (mono-, substituted Ph); 5 H (300 MHz, CDCl 3 ) , 1.57 (3H, d, J 7Hz CH3) , 1.97 (3H, s, CH3CO) , 4.32 (1H, q, J 7Hz, CH CH3) ) , 4.72 (1H, d, J 12Hz, one of CH2Ph) 4.89 (1H, d, J 12Hz, one of CH2OH) , 5.08 (1H, d, J 12Hz, one of CH2Ph), 5.20 (1H, d, J 12Hz, one of CH2Ph), 6.56 (1H , s, NH), 6.86 (1H, d, J 2Hz, indole 2-H), 7.02-7.33 (13H, m, indole + 2Ph), 7.54 (1H, J 8Hz, indole 4-H), 8.15 (1H, br s, indole NH), 5 C (75.5 MHz, CDCl 3 ), 18, 23, 37, 68, 70, 111.5, 115, 119.5, 122 , 122.5, 127, 128, 134.5, 136, 167, 168, 169.5.

(3-indolylethylidene)acetamidomalonic acid (73)

The diester (72) (930 mg, 1.92 mmol), palladium hydroxide on charcoal (Pearlman's catalyst (1250 mg) and 95% ethanol (110 mL) was placed in a Parr hydrogenation vessel and placed under a hydrogen pressure of 3.2 kg/cm <2> at 25°C for 3 h (until hydrogen uptake ceased).The reaction mixture was filtered through Celite to remove the catalyst, then evaporated to dryness to give the title compound (73) (576 mg, 99%) which was used without further cleansing.

6 H (300 MHz, D20) , 1.55 (3H, d, J 7Hz CH3), 1.99 (3H, s, CH3CO) , 4.09 (1H, br d, J 7Hz, CH, (CH3) , 7.12-7.24 (3H, m) , 7.49 (1H, d, J 8Hz, indole 7-H), 7.71 (1H, d, J 8Hz, indole 4-H)

2-acetamido-3-(3-indolyl)butanoic acid (74)

The malonic acid (73) (5.48 g, 18.0 mmol) was refluxed in pyridine/water (1:1) (20 mL) until none of the diacid remained (SiO 2 : EtOH-EtOAc (1:1) + 1% AcOH; Rf 0.26). The reaction mixture was cooled, diluted with water (50 mL) and acidified with 10% sulfuric acid (50 mL). The resulting solution was allowed to stand at 0°C overnight to crystallize. The brown solid was filtered off and dried to give 2-acetamido-3-(3-indolyl)butanoic acid isomer A (74A) (1.30 g, 28%);

6 H (300 MHz, d6-DMSO) , 1.32 (3H, J 9Hz CH3) , 1.84 (3H, s, CH3CO) , 3.46-3.55 (1H, m indCH (CH3) -) , 4.58-4.67 (1H, m, CH(COOH)NHAc), 6.93-7.19 (3H, m), 7.34 (1H, d, J 8Hz, amide NH) , 7, 54 (1H, J 8Hz, indole 7-H), 8.04 (1H, d, J 9Hz, indole-4H), 10.81 (1H br s, indole NH), ca. 12.4 (vbrs, CO 2 H). The filtrate was extracted with ethyl acetate (4 x 100 mL). The ethyl acetate extracts were combined and washed with water (2 x 50 mL) and then extracted with 10% sodium bicarbonate

(2 x 100 ml) . The sodium bicarbonate extract was acidified with 4N sulfuric acid and then extracted with ethyl acetate (2 x 75 mL). The ethyl acetate solution was washed with water (2 x 25 mL), then evaporated to dryness to give a beige foam, 2-acetamido-3-(3-indolyl)butanoic acid isomer B (74B) (2.17 g, 46%) ; 5 H (300 MHz, d6-DMSO) , 1.32 (3H, d, J 7Hz CH3) , 1.84 (3H, s, CH3CO) , 3.50 (1H, m indCH (CH3) - ) , 4 .66 (1H, m, CH (COOH) NHAc), 6.93-7.19 (3H, m), 7.34 (1H, d, J 8Hz, amide NH), 7.63 (1H, d, J 8Hz, indole 7-H), 7.84 (1H, d, J 9Hz, indole 4-H), 10.83 (1H, s, indole NH), ca. 12.5 (vbrs, CO 2 H).

Deacetylation of the acids ( 74A) and ( 74B)

The acids (74A) and (74B) were deacetylated separately according to the same procedure. Nitrogen was bubbled through a mixture of the acid (74B) (3.96 g, 15.2 mmol) in 4N sulfuric acid (25 mL) for 30 minutes, after which the mixture was refluxed until all the solid had dissolved. The solution was cooled to room temperature and neutralized to pH 8 with 0.4N barium hydroxide. The barium salts were precipitated with solid carbon dioxide, the mixture heated to the boiling point and filtered while hot. The solvent was removed in vacuo and the crude product purified by reverse phase column chromatography [methanol-water (1:6) as eluent] to give 2-amino-3-(3-indolyl)butanoic acid (75) (2.34 g , 71%) in a ratio of 1:3 (75A:75B), m.p. 198-212°C.

(lit., <1> 218-225°C (decomp));

isomer A 6 H (300 MHz, D2O) , 1.33 (3H, d, J 7Hz CH3) , 3.66-3.75 (2H, m, indCH(CH3)- + CH(CO2H)NH2) , 7 .20-7.34 (2H, m), 7.57 (1H, d, J 8Hz, indole 7-H), 7.87 (1H, d, J 8Hz, indole 4-H); isomer B 3 H (300 MHz, D2O) , 1.37 (3H, d, J 7Hz CH3) , 3.30-3.42 (2H, m, indCH(CH2)- + CH(CO2H)NH2) , 7 .09-7.24 (3H, m) , 7.48 (1H, d, J 8Hz, indole 7-H), 7.73 (1H, d, J 8Hz, indole 4-H) .

2- adamantyl chloroformate

A solution of 2-adamantanol (10.1 g, 66.5 mmol) in dichloromethane (200 mL) was cooled in an ice bath. Bis(trichloromethyl)carbonate(triphosgene) (7.55 g, 25.4 mmol) and then pyridine (6.2 g, 77 mmol) were added dropwise at a rate which caused the temperature to remain below 20°C . After an additional 10 minutes, the mixture was warmed to room temperature and stirred for an additional 2.5 hours. The dichloromethane was removed in vacuo without heating and the residue slurried with ethyl acetate (50 mL). The pyridinium hydrochloride was filtered off and the filtrate evaporated to dryness, without heating, to give 2-adamantyl chloroformate (76) (13.7 g, 96%); δ H (300 MHz, CDCl 3 ), 1.48-2.32 (14H, m, adamantyl), 5.01 (1H, t, J 3Hz, adamantyl 2-H); (lit., 2 6 H (CC14) 1.3-2.4 (14H, m) , 4.95 (1H, s) .

2-( 2- adamantyloxycarbonyl) amino- 3-( 3- indolyl) butanoic acid ( 77)

One percent amino acid (75) (449 g, 2.29 mmol) in 1N sodium hydroxide (2.29 mL) was added to sodium bicarbonate (211 mg, 2.5 mmol). This mixture was cooled to 0°C (ice bath). Dioxane (2.29 ml) was added and then dropwise, with stirring, a solution of the chloroformate (76)

(742 mg, 34.46 mmol) in dioxane (2.29 mL). After that amino acid

had completely disappeared (TLC SiO2: 4% methanol in dichloromethane), the dioxane was removed in vacuo and the residue partitioned between 10% citric acid and ethyl acetate. The aqueous phase was further extracted with ethyl acetate. The organic extracts were combined and dried (MgSO 4 ) and evaporated to dryness. The crude acid was purified by column chromatography on normal silica [hexane:ethyl acetate 3:20 + 0.5% acetic acid as eluent] to give 2-( 2- adamantyloxycarbonyl) amino- 3-( 3- indolyl) butanoic acid ( 77 )

(570 mg, 63%);

6 H (300 MHz, d6-DMS0) , 1.34 (3H, d, J 8Hz CH3) , 1.68-2.00 (14H, m, adamantyl), 3.40-3.53 (1H, m , indCH(CH3)), 4.36 (1H, br t, CH(CO2H)), 4.59 (1H, s, adamantyl 2-H), 6.73 (1H, d, J 9Hz, urethane NH) , 6.96 (1H, t, J 7Hz, indole 5-H), 7.06 (1H, t, J 7Hz, indole 6-H), 7.17 (1H, br s, indole 2-H), 7.33 (1H, d, J 8Hz, indole 7-H), 7.60 (1H, d, J 8Hz, indole 4-H), 10.83 (1H, s, indole NH), ca. 12.6 (vbrs, CO 2 H). 2- Adamantyloxycarbonyl- D. L- S- methyl- D, L- tryptophan- L- phenylalaninol ( 78) The carboxylic acid (77) (288 mg, 0.726 mmol), N, N'-dicyclohexylcarbodiimide (DCCI) (173 mg, 0.838 mmol) and 1-hydroxybenzotriazole (HOBT) (121 mg, 0.895 mmol) in ethyl acetate (5 mL) was stirred for 1 h at 0°C. Dimethylaminopyridine (DMAP) (23 mg, 0.19 mmol) and phenylalaninol (163 mg, 1.08 mmol) were added, after which the mixture was stirred for an additional 2 h at 0 °C and then for 48 h at room temperature. The mixture was filtered and the filtrate washed with 5% citric acid (2 x 10 ml), saturated sodium bicarbonate (10 ml), again with 5% citric acid (10 ml) and brine (10 ml), dried (MgSO 4 ) and evaporated to dryness. The crude product was purified by column chromatography on normal silica [ethyl acetate:hexane (1:1) as eluent] to give 2-adamantyloxycarbonyl-D,L-JS-methyl-D,L-tryptophan-L-phenvlalaninol (78) (45 mg, 12%); 99-101°C (Found C, 71.7%; H, 7.65%; N, 7.4%. C32H39N304 . 0.5H2O requires C, 71.35; H, 7.5%; N, 7 .8%. vmax (film) 3360 (OH) , 1695 (urethane C=0) , 1658 (amide C=0) , 746 and 702 cm"<1> (monosubstituted Ph) ; 5 H (300 MHz, CDCl3) , 1.42 (3H, d, J 7Hz, CH3) , 1.45-2.10 (14H, m, adamantyl), 2.20 (1H, br s, OH), 2.43-2.69 (2H, m, CH2Ph), 2.84 (1H, br s, indCH(CH3-), 3.39 (2H, br m, CH2OH), 3.86 (1H, br s, CH(CH2Ph) CH2OH) , 4.49 ( 1H, m, CH(NMR) (CONH-) , 4.79 (1H, s, adamantyl 2-H), 5.49 (1H, br s, urethane NH), 6.87 (1H, br s, amide NH), 6.95-7.38 (9H, m, indole + Ph), 7.69 (1H, d, J 7Hz, indole 4-H), 8.26 (1H, s, indole NH) ; m /z (FAB) 530 (M<+> + 1), 257, 232, 217, 181, 144, 126 (100%), 109 .

EXAMPLE 90

N- FD- 3- ( 1H- indol- 3- vlmetvl)- 3- metvl- N- \ ( tricyclo\ 3 . 3 . 1. I3' 7] - dec- 2- yloxy) carbonyl 1 - S- alanyl] - L- 2- phenylqlycine, AdOC-(( D)- 3-( 1H- indol- 3- vylmetvl) bAla-( L)- 2- phenvl) Glv

Step 1. Synthesis of 2AdocaMeRTrp CHN2 (diazoketone).

A solution of N-methylmorpholine (253 mg, 2.50 mmol) and 2-AdocaMe-R-TrpOH (990 mg, 2.50 mmol) in anhydrous THF (20 mL) was treated dropwise at 0°C with a soln. of isobutyl chloroformate (340 mg, 2.50 mmol) in anhydrous THF (10 mL) and stirred for 10 min. The reaction mixture was then filtered and a solution of diazomethane (6 mmol) in ether added to the filtrate. This was then allowed to warm to room temperature where it was kept for 12 hours. Excess diazomethane was decomposed with AcOH (1 mL) and the mixture evaporated to dryness in vacuo. The residue was then separated by silica gel chromatography using n-hexane:EtOAc (4:1 then 3:1) as eluent to give the diazoketone (Reaction Core 19, No. 2) as yellow crystals. Temp. 182.2-182.7°C (MeOH); [α]D2<0> = +64° (c = 0.5, MeOH);

IR (film) 3400-3200, 2913, 2854, 2106, 1693 and 1352 cm"<1>;

NMR (CDCl 3 ) 6 1.49 (3H, s) , 1.50-1.60 (2H, m) , 1.70-2.05 (12H, m) , 3.30-3.40 (2H, br s) , 4.86 (1H, s) , 5.20-5.40 (1H, br s) , 5.56 (1H, s), 6.95 (1H, d, J 2Hz), 7, 08 (1H, t, J 7Hz), 7.16 (1H, t, J 7Hz), 7.33 (1H, d, J 8Hz), 7.55 (1H, d, J 8Hz),

8.50 (1H, s);

MS 71e (FAB) 421.3 (11), 393.2 (54), 351.2 (9), 307.2 (22) and 259.1 (100);

Analysis of C24H28N403 :

Calcd: C, 68.55; H, 6.71; N, 13.32%

Found: C, 68.51; H, 6.73; N, 13.26%

Phenvlmetvl ( R) - S- metvl- S- r r ( tricyclo [ 3 . 3 . 1 . I3' 7! dec- 2vl- oxv) - carbonyl! aminol - 1H- indole- 3- butanoic acid

Step 2. Synthesis of the above compound (Reaction scheme 19, no. 3)

A solution of the diazoketone (as prepared in Step 1)

(4.20 g, 10.0 mmol) in benzyl alcohol (30 ml) was treated with a solution of silver benzoate (6 ml of a solution containing 1 g of silver benzoate in 10 ml of Et3N) at room temperature. The solution was stirred for 4 hours, treated with activated carbon and filtered through gypsum. The benzyl alcohol was removed in vacuo and the residue separated by silica gel chromatography using CH 2 Cl 2 as eluent to give the benzyl ester (Reaction Scheme I, No. 2 as a glass (3.3 g, 66%); mp 47-52°C;

[α]D2<0> = +17.6° (c = 1, MeOH);

IR (film) 3500-3200, 2908, 2855, 1750-1680 cm"<1>;

NMR (CDCl 3 ) δ 1.39 (3H, s), 1.51 (1H, s), 1.54 (1H, s), 1.70-2.05 (12H, m), 2.68 (1H , o, J 14.3Hz), 2.97 (1H, d, J 14.3Hz), 5.10 (3H, s) , 6.99 (1H, d, J 2.3Hz), 7.08 ( 1H, t, J 7Hz), 7.16 (1H, b, J 7Hz), 7.30-7.35 (6H, m), 7.58 (1H, d, J 7.8Hz), 8.05 (1H, p,);

MS M/e (FAB) 501.3 (28), 370.3 (24), 326.3 (29), 306.2 (32) and 135.2 (100);

Analysis of C31H36N204<:>

Calculated: C, 74.37; H, 7.25; N, 5.60

Found: C, 74.44; H, 7.20; N, 5.75

(R) - S- metvl- S- \ \ ( tricyclof 3 . 3 . 1. 13- 7! dec- 2vl- oxv) - carbonvll - aminol- 1H- indole- 3- butanoic acid, AdOC-( g- Me ) DTrp

Step 3. Synthesis of the above compound (Reaction scheme 19, no. 4)

A solution of the benzyl ester (as prepared in

Step 2) (1.0 g, 2 mmol) in absolute ethanol (100 mL) was treated with 10% palladium on charcoal (100 mg, 10 wt%) and the resulting suspension was subjected to 3.5 kg/cm<2> hydrogen for 4 hours with stirring at 30°C. The reaction mixture was then filtered through gypsum and the solvent removed in vacuo. The residue was column chromatographed over reverse phase silica using MeOH:H 2 O (3:1) as eluent and the solid product recrystallized from chloroform to give the acid as a white solid (700 mg, 85%), m.p. 198-201°C (CHCl 3 );

[α]D<20> = +20° (c = 1, MeOH);

IR (film) 3500-3300, 2912, 2856, 1704 and 734 cm"<1>;

NMR (CDCl 3 ) δ 1.41 (3H, s), 1.53 (1H, s), 1.57 (1H, s), 1.70-1.85 (9H, m), 1.95-2 .10 (4H, m), 2.69 (1H, d, J 14.3Hz), 3.05 (1H, d, J 14.3Hz), 3.21 (1H, d, J 14.3Hz), 3.32 (1H, d, J 14.4Hz), 4.86 (1H, s), 5.10-5.30 (1H, br s), 7.04 (1H, d, J 2.2Hz) , 7.07-7.20 (2H, m), 7.35 (1H, d, J 8Hz), 7.60 (1H, d, J 7, 7Hz) , 8.16 (1H, s,) ;

MS M/e (FAB) 411.5 (9) and 217.2 (100);

Analysis of C24H30N4O4:

Calculated: 70.22; H, 7.37; N, 6.82

Found: 70.03; H, 7.38; N, 6.78

Methyl- N- fD- 3-( 1H- indol- 3- ylmethyl)- 3- methyl- N-[( tricyclo-[ 3. 3. 1. 13, 71 - dec- 2- vloxy) carbonyl] - S- alanyl] - L- 2- phenylglycine Step 4. Synthesis of the above compound (Reaction scheme 19 no. 5)

A stirred solution of the acid (as prepared in step 3)

(500 mg, 1.20 mmol) and pentafluorophenol (224 mg, 1.20 mmol) in EtOAc (50 mL) were treated at 0°C with N,N'-dicyclohexylcarbodiimide (263 mg, 1.30 mmol). This mixture was stirred for 18 hours at 0°C and filtered, after which S-phenylglycine methyl ester (303 mg, 1.50 mmol) was added to the filtrate. The reaction mixture was allowed to stand at room temperature for 48 hours and was then washed with 1M citric acid solution (2 x 20 mL), saturated NaHCO 3 solution (2 x 20 mL) and H 2 O (2 x 20 mL). The dried (MgSO 4 ) organic phase was evaporated to dryness in vacuo and the residue separated by reverse phase silica gel chromatography using MeOH:H 2 O (3:1) as eluent to give

the ester (Reaction scheme 1, no. 5) as a non-crystalline solid (600 mg, 90%). Temp. 72-82°C;

[α]D<22> = +55 , 3° (c = 1, MeOH);

IR (film) 3500-3200, 2916, 2856, 1743, 1694, 1657 and 1504 cm<-1>; NMR (CDCl 3 ) δ 1.35 (3H, s), 1.40-1.55 (2H, m), 1.70-2.05 (12H, m), 2.54 (1H, d, J 13 ,3Hz), 3.04-3.15 (2H, m), 3.31 (1H, d, J 14.2Hz), 3.71 (3H, s), 4.71 (1H, s), 5 .09 (1H, s), 5.48 (1H, d, J 2Hz), 7.08 (1H, d, J 7Hz), 7.17 (1H, d, J 7Hz), 7.30-7, 40 (6H, m), 7.59 (1H, d, J 7.6Hz), 8.14 (1H, s);

MS M/e (FAB) 558.3 (12), 383 (11), 198.1 (34), 170.1 (27) and 135.1 (100);

Analysis of C33<H>39<N>305:

Calculated: C, 71.07; H, 7.05; N, 7.53%

Found: C, 71.31; H, 7.30; N, 7.28%

Glycine, N-[ D- 3-( 1H- indol- 3- ylmethyl)- 3- methyl- N-[( tricyclo-[ 3. 3. 1. lyl]- dec- 2- yloxy) carbonyl]- B - alanyl]- L- 2- phenyl- AdOC-(( D)- 3-( 1H- indol- 3- ylmethyl) bAla-( L)- 2- phenyl) Gly

Step 5. Synthesis of Example 90, Reaction Scheme 19, No. 6

A stirred solution of the ester (as prepared in step 4) (399 mg, 0.70 mmol) in THF (20 mL) was treated with a solution of ClOH (30 mg, mmol) in H 2 O (5 mL) at room temperature. After 2 hours, the mixture was acidified against pH paper by the addition of 1M HCl solution. The solvent was then removed under vacuum and the residue separated by reverse phase silica gel chromatography using MeOH:H 2 O (3:1) as eluent to give the product (Example 90) as a non-crystalline solid (200 mg, 53%) . Temp. 120-125°C;

[α]D<2>° =* +49.2° (c = 0.5, MeOH);

IR (film) 3450-3250, 2916, 2856, 1750-1600, 1510 and 1256 cm"<1>; NMR (CDCl 3 ) δ 1.34 (3H, s), 1.50-1.55 (2H, m ), 1.60-2.00 (12H, m) , 2.58 (1H, d, J 12.7Hz), 3.00-3.25 (3H, m) , 2.50-4.00 ( 1H, br), 4.60-4.75 (1H, br s) , 4.90-5.20 (1H, br s) , 5.54 (1H, d, J 6.5Hz), 7.00 -7.60 (10H, m), 7.58 (1H, d, J 7.9Hz), 8.14 (1H, s, ) ;

Analysis of C32H37N305. 03 . H20:

Calculated: C, 70.00; H, 6.90; N, 7.65

Found: C, 69.97; H, 6.85; N, 7.64

EXAMPLE 91

[ R- ( R* , S) 1 - of- f [ 3- ( 1H- indole- 3- vi)- 2- methyl- l- oxo- 2- f r ( tricvclo-[ 3. 3. 1. 13, 71 - dec- 2- yloxy) carbonyl] aminol propyl] aminol benzene-acetic acid, [ R- ( R* , S*) 1- AdOC- a- Me) DTrp- L- phenylglycine

(See Reaction form 20)

Step 1. Synthesis of oxazolone-(R)-(4-(1H-indol-3-ylmethyl)-4-methyl-2-(tricyclo [3.3.1.13'7]-dec-2-yloxy)-5 (4H ) -oxazolone)

(No. 2, Reaction form 20)

A solution of AdOCaMe-R-TrpOH (1.0 g, 2.5 mmol) and N,N'-dicyclohexylcarbodiimide (0.52 g, 2.5 mmol) in anhydrous DMF (5 mL) was stirred for 1 h at room temperature. The mixture was then filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on silica gel using hexane:EtOAc (6:1) as eluent to give the oxazoline (2, Scheme 20) as white crystalline needles (850 mg, 90%). Temp. 150.5-150.9°C (hexane);

[α] D 2 O = +9.0° (c = 1, MeOH);

IR (film) 2910, 2857, 1823, 1681 and 1399 cm"<1>;

NMR (CDCl 3 ) δ 1.10-1.20 (1H, m), 1.30 (15H, m), 2.04 (1H, s), 3.20 (1H, d, J 14.5Hz), 3.25 (1H, J 14.5Hz), 4.72 (1H, t, J 3.5Hz), 6.99 (1H, d, J 2.4Hz), 7.07 (1H, dt, J 7 ,1Hz), 7.14 (1H, dt, J 7.5 and 1Hz), 7.29 (1H, d, J 7.3Hz), 7.64 (1H, d, J 7.6Hz), 8, 02 (1H, s);

MS M/e (CI) 379.2 (52), 178.3 (47), 163.3 (61), 135.2 (74) and 130.2 (100);

Analysis of C23H26N203<:>

Calculated: C, 72.99; H, 6.92; N, 7.40

Found: C, 72.88; H, 6.96; N, 7.37

Step 2

A suspension of S-phenylglycine (42 mg, 0.28 mmol), NaHCO 3 (23 mg, 0.28 mmol) and the oxazolone (Reaction scheme 20, no. 2)

(100 mg, 0.26 mmol) in DMF:H 2 O (1:1) (10 mL) was stirred at room temperature for 18 h. The solvent was then removed in vacuo and the residue suspended between EtOAc (20 mL) and 1M citric acid solution (20 mL). The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic phases washed with H 2 O (3 x 10 mL) and dried over MgSO 4 , after which the solvent was removed in vacuo. The residue was then subjected to silica gel chromatography using 3% MeOH in CH 2 Cl 2 and then 5% MeOH, 0.5% H 2 OH in CH 2 Cl 2 to give the product (Example 91) as a non-crystalline solid (106 mg, 77%). Temp. 138-143°C;

[α]D<24> = +82° (c = 1, MeOH);

IR (film) 3500-3200, 2913, 2855, 1696, 1666 and 1499 cm"<1>;

NMR (CDCl 3 ) δ 1.40-1.50 (2H, m), 1.56 (3H, s), 1.60-1.95 (12H, m), 3.26 (1H, d, J 14 ,6Hz), 3.40 (1H, d, J 14.6Hz), 4.73 (1H, s), 5.68 (1H, d, J 6.8Hz), 5.40-5.80 (1H , br), 6.90 (1H, s), 7.00-7.15 (2H, m), 7.20-7.30 (6H, s), 7.35 (1H, d, J 6, 8Hz), 7.53 (1H, d, J 7.5Hz), 8.41 (1H, s);

MS M/e (FAB) 530.5 (13), 217.2 (38);

Analysis of C31H35N305. 2H20:

Calcd: C, 69.83; H, 6.69; N, 7.88

Found: C, 69.85; H, 6.66; N, 7.74

EXAMPLE 92

Tricyclo r3. 3. 1. 13-7! - dec- 2-yl (r) - \ 2 - ( 2-phenylethyl) - aminol - 1- ( 1H-indol- 3- vl)- 1- methylethylcarbamate (See Reaction Scheme 21)

To a solution of lithium borohydride (4 mL, 2M solution, 8 mmol) in dry THF was added under a nitrogen atmosphere a solution of chlorotrimethylsilane (1.75 g, 16.0 mmol) in dry THF (5 mL). A white precipitate (of lithium chloride) was formed

observed. After 2 minutes, a solution of (18) (1 g,

2 mmol) in THF (15 ml) slowly added (over 3-4 minutes) and the reaction mixture stirred for 20 hours at room temperature. The reaction mixture was carefully treated with MeOH (5 mL) and volatiles removed in vacuo at 40°C. The residue was purified by silica gel chromatography using hexane:ethyl acetate (80:20) as eluent to give (19) (0.14 g, 14%) as a colorless oil, yielding (18)

(0.52 g; yield of (19) based on recovered starting material, 30%). The amine (19) (0.14 g, 0.28 mmol) was dissolved in MeOH (5 mL) and treated with 4-toluenesulfonic acid hydrate

(0.054 g, 0.28 mmol). The solution was evaporated to a white solid.

[α]D = +22° (c = 0.25, MeOH);

IR (film) 2928 and 1708 (c=urethane).

NMR (DMSO-d6) 6 1.2 (3/x, s, CH3) , 1.4-2.1 (14H, m, adamantyl), 2.3 (3H, s, CH3Ph) , 2.9- 3.7 (8H, m, 4 x CH2), 4.7 (1H, br s, adamantyl H-2), 6.9-7.6 (15H, m, aromatics), 8.3 (1H, br , one of NH2*) , 8.5 (1H, br, one of NH2*) , 11.0 (1H, s, indole NH) ;

MS M/e (FAB) 486 (M<+> + H) (100), 136 (52);

Analysis of C31H39N302. C7H8S03. 0.75H2O:

Calculated: C, 67.98; H, 7.28; N, 6.26

Found: C, 67.96; H, 7.31; N, 6.00 Smp. 90-93°C

Etvl [ R- ( R*. S*) 1- 4 r f- 2- phenylethyl1 - f3-( 1H- indol- 3- vi)- 2- metvl- 2-[ f ( tricyclo [ 3. 3. 1. I3, 7] dec-2-yloxy) carbonyl] aminol propyl-aminol-4-oxo-butanoate (19b, Reaction scheme 21).

Prepared in a similar manner to compound (19a). Obtained a white solid 0.102 g (81%);

[a]D<21> = +26° (c = 0.5, CHCl 3 );

IR (film) 2905, 2853, 1732, 1711, 1634 cm'<1>;

NMR (CDCl 3 ) 6 1.2 (6H, m) , 1.3-2.1 (14H, m) , 2.6 (4H, br s) , 2.9 (2H, m) , 3.0 ( 1H, d, J 14Hz), 3.3-3.8 (4H, m) , 4.0-4.2 (3H, m) , 4.8 (1H, br s) , 5.3 (1H, br), 6.9-7.6 (10H, m), 8.1 (1H, br s);

MS M/e (FAB) 614 (36) (M<+> + H), 483 (100), 419 (24);

Analysis of C37H47N305:

Calculated: C, 72.40; H, 7.72; N, 6.85%

Found: C, 72.11; H, 7.87; N, 6.16% M.p. 67-70°C

Tricyclo\ 3 . 3. 1. 13' 7] dec- 2- vl \ R - ( R*, S*) 1 - \ 2 - racetvl 12 - phenyleth<y>llaminol - 1-( 1H- indol- 3- vlmethyl)- 1 - methyl ethyl carbamate

(19a in Reaction Scheme 21)

To a solution of (19) (0.1 g, 0.2 mmol) in dichloromethane (20 mL) at 0°C was added acetyl chloride (0.3 mL, 4 mmol), followed by triethylamine (4 drops). Stirring was continued at 0°C for 20 minutes, whereupon the reaction mixture was dissolved in ethyl acetate (50 mL), washed (HCl aq, H 2 O, NaHCO 3 aq), dried (MgSO 4 ) and evaporated to dryness. The residue was purified by column chromatography using hexane-ethyl acetate as eluent to give an off-white solid (0.092 g, 85%).

[α]D<21> = +24° (c = 0.25, CHCl 3 );

IR (film) 2909, 2855, 1709, 1610 cm"<1>;

NMR (CDCl 3 ) 6 1.3 (3H, s) , 1.4-2.1 (17H, m), 2.8 (2H, m) , 3.1 (1H, d, J 14Hz) , 3, 3-3.7 (4H, m), 4.0 (1H, d, J 14Hz), 4.8 (1H, s), 5.5 (1H, br s), 6.9-7.7 ( 10H, m), 8.1 (1H, br s);

MS M/e (FAB) 528 (45) (M<+> + H), 397 (100), 333 (27).

4- f \ 3 - ( 1H- indol-3- vl) - 2- metvl- 2- f \ ( tricyclo 13 . 3 . 1. 13| 71 dec- 2 - yloxy) carbonyl] amino] propyl] -( 2 - phenylethyl) aminol-4-oxo-butanoic acid ( 19d, Reaction scheme 21).

To a stirred solution of (19b) (0.04 g, 0.06 mmol) in THF (5 mL) was added methanol (5 mL), water (5 mL) and lithium hydroxide monohydrate (0.1 g, 2 .4 mmol). The reaction mixture was stirred for 40 min at room temperature and then acidified (2N HCl aq, 50 mL) and the products extracted into ethyl acetate (50 mL). The organic phase was dried with magnesium sulfate and evaporated in vacuo (40°C). The oily residue was purified by column chromatography using dichloromethane/methanol (9:1) as eluent. 0.031 g (81%) of a white solid was obtained;

IR (film) 340 (br), 2912, 2852, 1714, 1700, 1635 cm"<1>;

NMR (MeOH-d4) 6 1.1-2.2 (17H, m, CH3 + adamantane), 2.6-3.2 (6H, m, 3 x CH2) , 3.4-4.1 (6H , m, 3 x CH2 ), 4.8 (1H, br, adamantane H-2), 7.0-7.6 (10H, m, aromatics);

[α]D = +4° (MeOH, c = 0.2, 22°C);

FAB MS 586 (51) (M<+> + H), 455 (100), 391 (24).

Analysis of C35H43N305. 0.2 5H2O:

Calculated: C, 71.22; H, 7.43; N, 7,12

Found: C, 71.24; H, 7.46; N, 6.87% m.p. 99-96°C

EXAMPLE 93

Tricycle 13. 3. 1. I3- 7] dec- 2- vl fR- ( R* , S*) 1 - \ 2 - \ fl- ( hydroxymethyl) - 2- phenylethyl] aminol- 1-( lH- indol- 3- ylmethyl)- 2- oxoethyl carbamate

The carboxylic acid 56 (380 mg, 1.0 mmol) and N,N'-dicyclohexylcarbodiimide (230 mg, 1.1 mmol) and pentafluorophenol (200 mg, 1.1 mmol) were suspended in EtOAc (25 mL) and stirred in 2 hours, then treated with (S)-2-amino-3-phenyl-1-propanol (150 mg, 1.0 mmol) and stirred at 40°C for 18 hours. The mixture was filtered and the filtrate washed with saturated aqueous citric acid and then with saturated aqueous NaHCO 3 followed by H 2 O. The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo and purified by reverse phase silica gel chromatography (LiChroprep<®> RP-18) using MeOH:H 2 O (4:1) as eluent to give the product 6 (0 .36 g, 71%)

[α]D<20> = 20 , 4° (c = 0.25, CH 2 Cl 2 );

NMR (CDCl 3 ) δ 1.8 (14H, m), 2.60 (2H, d), 3.30 (4H, m), 4.05 (1H, m), 4.42 (1H, q, J ), 4.78 (1H, m), 5.45 (1H, br s), 6.15 (1H, br s) , 7.30 (8H, m) , 7.37 (1H, d, J) , 7.67 (1H, d) , 8.25 (1H, br s).

Hydroxyamide (6) (See Reaction scheme 22) (517 mg,

1.00 mmol), imidazole (146 mg, 2.15 mmol) and tert-butyldimethylsilyl chloride (354 mg, 2.35 mmol) in DMF (6 mL) was stirred at room temperature for 18 h. The reaction was quenched with H 2 O

(40 ml). The emulsion was extracted with ether (80 mL). The ether was washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude material was purified by column chromatography in [SiO 2 :hexane-ethyl acetate (2:1) as eluent] to give the silyl-protected amide (474 mg, 75%) as a white foam.

<X>H NMR '(CDCl3) 6 8.12 (1H, s, indNH) , 7.76 (1H, d, J 7 Hz, indH-4), 7.40 (1H, d, J, 8Hz, ind H-7), 7.34-7.06 (8H, m, Ph+ind H-2, H-5, H-6), 6.98 (1H, s), 5.91 (6H, br s, NH?), 5.44 (0.4H, br s, NH?), 4.90 (1H, s, adamantyl H-2), 4.53 (1H, m, NHCH(CH2ind)CO) , 4.14 (1H, m, NHCH(CH2OSi)CH2Ph) , 3.39 (2H, m, CH2ind) , 3.22 (2H, br, m, CH2Ph) , 2.12-1.54 (14H, br , m, adamantyl), 0.88 (2, 9H, fcBu) , 0.02 (6H, s, 2 x CH 3 );

IR (film) vmax 2927 + 2856 (adamantyl) , 1703 (CO urethane) ,

1663 cm"<1>(CO amide) .

Silyl-protected amide (418 mg, 0.664 mmol) and Lawesson's reagent [Aldrich] (268 mg, 0.663 mmol) were refluxed in toluene (10 mL) for 30 min. The solution was cooled to room temperature and poured onto a column of silica gel. The column was eluted with CH 2 Cl 2 to remove the toluene and a high Rf (0.74) by-product from Lawesson's reagent. Elution was then continued with a hexane-ethyl acetate gradient (0-30%) to give the thiazole (9) (73 mg, 21%) as a white foam. Temp. 56-63°C.

<X>H NMR (CDCl3) δ 8.16 (1H, s, ind NH), 7.63 (1H, d, J 8Hz, ind H-4), 7.38-6.96 (9H, m, ind H-7, H-6, H-5, H-2 + Ph) 5.44 (1H, br d, J 7Hz, urethane NH) , 4.88 (1H, br s, ind CH2CH) , 4, 82 (1H, s, adamantyl H-2), 4.62 (1H, m, NCHCH2Ph) , 3.44-2.83 (5H, m, ind CH2 + PhCH2 + CH of CH2S) , 2.68 (1H , dd, J 9 , 14Hz, CH of CH2S), 2.09-1.43 (14H, m, adamantyl);

IR (film) vmax 2909 + 2854 (adamantyl) , 1698 (CO urethane) ,

1621 cm"<1> (C=N) .

Analysis of C31H35N3S02:

Calculated: C, 72.48; H, 6.87; N, 8.18; S, 6.24%

Found: C, 72.32; H, 7.09; N, 7.75; S, 6.09%

EXAMPLE 94

( 1- fenvlcvklopentvl) metvi fIS-[ IR*( R*) . 2R* 11 and flS-

riR*( S*) . 2R* 11 - r2- rr2- hydroxy- 1-( hydroxymethyl)- 2- phenylethylamino]- 1-( 1H- indol- 3- ylmethyl)- 1- methyl- 2- oxoethylcarbamate

(1-phenylcyclopentyl) methyl carbonochloridate

Step A. To a stirred solution of l-phenylcyclopentyl methanol (0.53 g, 3.0 mmol) in methylene chloride (15 mL) was added bis(trichloromethyl)carbonate (0.33 g, 1.1 mmol) followed by of pyridine (0.24 g, 3.3 mmol) in methylene chloride at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated and diluted with ethyl acetate (25 mL). The pyridinium hydrochloride precipitate was filtered off and the filtrate was concentrated to give a semi-solid (0.65 g, 90%).

<*>H NMR (200 MHz, CDCl3) δ 7.50-7.10 (5H, m) , 4.30 (2H, s) , 2.10-1.90 (4H, m), 1.90 -1.75 (4H, mj .

α- methyl- N-[[( 1- phenylcyclopentyl) methyl] carbonyl] - DL- tryptophan methyl ester

Step B. To a stirred solution of 1-phenyl-1-cyclopentyl methyl chloroformate (0.65 g, 2.75 mmol) in dry THF (10 mL) was added a solution of α-methyl-DL-tryptophan methyl ester (0.60 g, 2.5 mmol) followed by triethylamine (0.5 g, 5.0 mmol) 1 dry THF. The reaction mixture was stirred for 30 min and then filtered, concentrated and chromatographed to give an oil (0.9 g, 90%)

<X>H NMR (200 MHz, CDCl3) 6 8.0 (1H, br s) , 7.50 (1H, d, J 7 Hz), 7.40-7.0 (8H, m), 6, 6 (1H, br s), 5.35 (1H, br s), 4.15 (2H, s), 3.65 (3H, s), 3.6-3.0 (2H, m), 2 .10-1.85 (4H, m), 1.85-1.60 (4H, m), 1.55 (3H, s).

a- methyl- N- [ r ( 1 - p phenylcyclopentyl) methyl] carbonyl] - DL- tryptophan Step C. To a stirred solution of intermediate B (0.87 g, 2 mmol) in aqueous 1,4-dioxane ( 1:2) (6 mL) was added LiOH (0.13 g, 3 mmol) and the mixture stirred at room temperature overnight. The reaction mixture was concentrated, diluted with

water (50 mL), acidified with dilute HCl, extracted with ethyl acetate and chromatographed to give a white foam (0.8 g, 95%).

<X>H NMR (200 MHz, CDCl 3 ) 8.05 (1H, br s) , 7.55 (1H, d, J 7Hz) , 7.45-7.00 (9H, m), 5.25 ( 1H, br s), 4.20-3.90 (2H, s), 3.35-3.05 (2H, m), 2.00-1.85 (4H, m), 1.85-1 .65 (4H, m), 1.50 (3H, br s) .

( 1 - f enylcyclopentyl) metvl [ IS- TIR* ( R*.) , 2R* 1 1 oa \ 1S - riR*( S*), 2R* 11 - \ 2 - fr2- hvdroksv- l-( hydroxymethyl)- 2-phenylethylaminol-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethylcarbamate Step D. A solution of intermediate C (0.42 g, 1.0 mmol) in ethyl acetate (10 mL) ) was treated with dicyclohexylcarbodiimide (0.23 g, 1.1 mmol) and 1-hydroxybenzotriazole hydrate (0.17 g, 1.1 mmol). After stirring for one hour at room temperature, it was filtered. To the filtrate was added 2-amino-1-phenyl-1,3-propanediol (0.18 g, 1.05 mmol) in a 1:1 mixture of methylene chloride and ethyl acetate and stirred overnight. The reaction mixture was filtered, concentrated and chromatographed to give (0.25 g, 44%) of the title compound as a white foam.

Temp. 78-83°C.

EXAMPLE 95

( 4- nitrof enyl) methyl F4S- T4a, 5a ( R*) 1 1 and f4S- f4a, 5a ( S*) 1 1 - \ 2 -

[ ( 2, 2- dimethyl- 4- phenyl- 1, 3- dioxane- 5- vi ) aminol - 1-( 1H- indol- 3-ylmethyl)- 1- methyl- 2- oxoethylcarbamate

a- methyl- N-[f( 4- nitrophenyl) methoxyl carbonyl - DL- tryptophan methyl ester

Step A. The procedure was as described in Step B, Example 94, except that p-nitrobenzyl chloroformate was used. The title compound was obtained as a semi-solid (2.5 g, 49%).

<*>H NMR (250 MHz, CDCl3) b 8.20 (2H, d, J 8.5Hz), 8.10 (1H, br s), 7.60-6.80 (7H, m), 5 .64 (1H, br s), 5.2-5.0 (2H, m), 3.71 (3H, s), 3.55 (1H, d, J 14Hz), 3.35 (1H, d , J 14Hz), 1.72 (3H, s) .

α-methyl-N-[\(4-nitrophenyl)methoxylcarbonyl]-DL-tryptophan Step B. The procedure was as described in Step C, Example 94, except that the product from Step A was used. The title compound was obtained as a foam (1.8 g, 75%).

<J>H NMR (250 MHz, CDCl 3 ) δ 8.15-7.95 (3H, m) , 7.60-6.9 (7H, m) , 5.53 (1H, br s), 5, 20 (2H, s), 3.60-3.20 (2H, m), 1.73 (3H, br s) .

( 4-nitrophenyl) methyl US- Ua, 5a ( R*) 1 1 oa US- Ua. 5a ( S*) 1 1 - f2-[ ( 2, 2- dimethyl- 4- phenyl- 1. 3- dioxan- 5- yl) amino]- 1-( 1H- indol- 3-ylmethyl)- 1- methyl - 2- oxoethyl] carbamate

Step C. The procedure was as described in Step D, Example 94, except that the product from Step B and 5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane were used instead of the product from Step C and 2-amino-1-phenyl-1,3-propanediol. The title compound was obtained as a foam (2.3 g, 85%). Temp. 92-102°C.

EXAMPLE 96

US-Ua. 5a ( R* ) 1 ] and f 4S- f 4a. 5a ( S*) 1 1 - N - ( 2 , 2- dimethyl- 4 - phenyl - 1, 3- dioxan- 5- yl)- a- methyl- a-[[[[( l- phenyl-cyclopentyl) methyl]-amino]carbonyl]-1H-indole-3-propanamide

f4S- Ua. 5a ( R* ) 1 1 and US- Ua, 5a ( S* ) 1 1 - a- amino- N - ( 2 , 2- dimethyl-4-phenyl- 1 , 3- dioxan-5- yl)- a- methyl-1H-indole-3-propanamide Step A. A solution of the title compound from Example 95 (1.65 g, 2.8 mmol) in absolute ethanol was treated with a catalytic amount of 10% palladium on charcoal and stirred overnight under a hydrogen overpressure. The reaction mixture was then filtered over Celite and washed with ethanol. The filtrate was concentrated and passed through a small plug of silica gel to give a white foam (1.1 g, 100%). Temp. 182-185°C.

US-Ua, 5a ( R*) 11 and US-Ua. 5a (S*) 11- N-(2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-a-methyl-g-f[[\(1-phenylcyclopentyl)methyl]-amino ] carbonyl-1H-indole-3-propanamide

Step B. To a stirred solution of the product from Step A (0.49 g, 1.2 mmol) in dry THF (15 mL), was added 1-

phenyl-cyclopentylmethyl isocyanate (0.26 g, 1.3 mmol) in dry THF (5 mL) at room temperature. The reaction mixture was concentrated, chromatographed and crystallized to give the title compound (0.21 g, 30%), m.p. 125-28°C.

EXAMPLE 97

fart- TUE*( R*) . 2R* 11 and phys- TIR*( S*) , 2R* 1 l - N- r2- hvdroxv- l-( hydroxymethyl) - 2- phenylethyl - 2- ( lH- indol- 3- ylmethyl) - 2- methyl- N1 tricyclo [ 3. 3. 1. 13, 71 dec- 2- ylpropane diamide

N,N,N-trimethyl-1H-indole-3-methanaminium-iodide

Gramine methiodide ( 2 ) (JACS 66 200 (1944))

Gramine (1) (43.5 g, 0.29 mmol) (see Synthesis Core 23 for

Compounds 1-23) were dissolved in absolute ethanol (200 mL) and methyl iodide (17 mL, 0.27 mmol) was added dropwise over 0.5 h. A slight exothermic reaction occurred with the formation of a white precipitate. The reaction mixture was stirred overnight at room temperature and then cooled to 0°C for 2 hours. The white solid was collected by filtration, washed four times with ethanol (50 mL), three times with diethyl ether (50 mL) and dried in vacuo. The product was obtained as a white solid, 70.4 g (83%).

IR (KBr) 3306, 1483, 1346, 810, 760 cm'<1>.

Diethyl (1H-indol-3-ylmethyl)methylpropanedioate (3)

Sodium hydride (4.0 g, 0.1 mmol) was added portionwise over 10 minutes to a mixture of diethyl methyl malonate (17.4 g, 0.1 mmol) in DMF (200 mL) at room temperature. The reaction mixture was stirred for 5 min and gramine methiodide (33.5 g, 0.11 mmol) was added, after which the entire mixture was heated to 50°C for 0.5 h and then stirred overnight at room temperature. Water (200 mL) was carefully added to quench the reaction. The whole mixture was diluted with diethyl ether (500 ml) and water (300 ml). The layers were separated and the organic layer washed with water (3 x 200 ml). The combined aqueous layers were extracted with diethyl ether (1 x 500 mL), the ether layer washed with water, the organic extracts combined, dried (MgSO4, filtered and concentrated. The residue was filtered through silica gel (70-230 mesh) using hexane/ethyl acetate , 1/1, as eluent. Product-containing fractions were combined, concentrated and filtered through silica gel (70-230) using hexane/EtOAc, 8/2, as eluent. The product was obtained as a red viscous oil, 13.1 g (43%).

IR (film) 3397, 2983, 1731, 1376, 1254, 1108 cm"<1>.

Ethyl hydrogen (1H-indol-3-ylmethyl) methylpropanedioate ( 4)

To a solution of diester (4.85 g, 0.016 mmol) in 95% ethanol (50 mL) was added at room temperature 1N aqueous sodium hydroxide solution (16 mL) and sufficient water to make the solution just cloudy. As the reaction progressed, water was added. After 2 hours, the reaction mixture was concentrated on a rotary evaporator to remove ethanol, diluted with water, washed with ethyl acetate, acidified with 10% citric acid solution, brine added and the whole mixture extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO 4 ), filtered and concentrated to a brown oil. The brown oil was chromatographed on silica gel (70-230 mesh) using ethyl acetate as eluent and then rechromatographed on silica gel (70-230 mesh) using hexane/ethyl acetate, l/l, as eluent. The product 4 was obtained as an orange/light brown oil, 2.92 g, 66%

IR (film) 3402, 2982, 1718, 1458, 1098, 742 cm'<1>.

Ethyl ( + ) - g- methyl- g f ( tricyclo [ 3. 3. 1. 13' 71 dec- 2- ylamino) carbonvll - 1H- indole- 3- propanoate ( 5)

A mixture of acid (1.41 g, 0.005 mmol), adamantanamine hydrochloride (0.95 g, 0.005 mmol), 1-hydroxybenzotriazole, H 2 O (0.68 g, 0.005 mmol) and CH 2 Cl 2 (50 mL) was cooled to 0°C and added triethylamine (0.8 mL, 0.0057 mmol) and the mixture stirred for 5 minutes. Then dicyclohexylcarbodiimide (1.04 g, 0.005 mmol) was added in one portion. The reaction mixture was stirred for 3 days at room temperature and concentrated to dryness, whereupon the residue was taken up in ethyl acetate, washed with 10% citric acid, sodium carbonate and sodium chloride solutions. The organic layer was dried (MgSO 4 ), filtered and concentrated to an orange oil. Addition of hexane/ethyl acetate, 1/1, led to the oil turning into solid form. The solid was collected by filtration, 2.05 g (98%).

IR (KBr) 3418, 3327, 2907, 1713, 1630, 1540, 1457, 1113 cm"<1>.

( + ) - a- methyl- a \ ( tricyclo f 3 . 3 . 1. 13, 71 dec- 2- ylamino) carbonyl] - 1H-indole- 3- propanoic acid ( 6)

The ester (1.04 g, 2.5 mmol) was dissolved in ethanol (10 mL) and 1N sodium hydroxide solution (3.5 mL) and just enough water to cloud the solution were added. The reaction mixture was briefly heated to 50°C to achieve dissolution. The reaction mixture was then allowed to stand for 14 days at room temperature. The reaction mixture was concentrated to remove ethanol, diluted with water, and the aqueous solution washed with ethyl acetate. the aqueous layer acidified with 10% citric acid solution, extracted with ethyl acetate, whereupon the ethyl acetate solution was washed with brine, dried (MgSO 4 ), filtered and concentrated to a whitish foam. The foam was filtered through silica gel (70-230 mesh) using ethyl acetate as eluent. The product was obtained as a whitish solid.

(0.87 g, 90%).

IR (KBr) 3411, 2908, 1716, 1617, 1540, 740 cm"<1>.

[ 4S- T4a, 5a ( R*) 1 1 and f4S- r4a. 5a ( S*) 1 1 - N- ( 2. 2 - dimethvl - 4 - phenyl - 1. 3- dioxane- 5- vl) - 2- ( 1H- indole- 3- vlmetvl) - 2- metvl- N1- (tricvklo-T3 . 3 . l. l3' 7! dec- 2- vl) propanediamide ( 7)

Dicyclohexylcarbodiimide (0.30 g, 1.46 mmol) was added to a mixture of (4S,5S)-(+)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane (0, 31 g, 1.44 mmol), acid (0.53 g, 1.39 mmol) and 1-hydroxybenzotriazole (0.22 g, 1.63 mmol) in a mixture, 10/1, CH 2 Cl 2 /DMF, (30 ml) at 0°C. The reaction mixture was allowed to stand for one hour at 0°C and then for 3 days at room temperature. The reaction mixture was concentrated to dryness, the residue taken up in ethyl acetate, after which the ethyl acetate solution was washed with saturated sodium chloride solution, dried (MgSO 4 ), filtered and concentrated to an orange oil. The oil was purified by filtration through silica gel (70-230 mesh) using hexane/ethyl acetate, 7/3, as eluent. The product was obtained as a white solid, 0.247 g (31%).

IR (KBr) 3341, 2910, 1665, 1508, 1201, 742 cm"<1>.

fis- TIR*( R*) , 2R* 11 oa fis- TIR*( S*) , 2R*] I - N-[ 2- hydroxy- l-( hydroxymethyl)- 2- phenylethyl]- 2-( lH- indol- 3- ylmethyl)- 2- methyl- N1 tricyclo [ 3. 3. 1. I3' 7] dec- 2- ylpropane diamide ( 8)

A mixture of the acetonide (0.16 g, 0.28 mmol), methanol

(10 mL) and IN HCl (1 mL) was allowed to stand at room temperature for 4 hours. The reaction mixture was concentrated to dryness without heating. Ethyl acetate was added and the ethyl acetate dried (MgSO 4 ). filtered and concentrated, after which the residue was chromatographed on silica gel (70-230 mesh) using ethyl acetate as eluent. The product was obtained as a white foam. 0.0727 g (49%).

EXAMPLE 98

riS- TUES*( R*) . 2R* 11 and [ IS- flR* ( S*) . 2R* 1 1 - N-[ 2- hydroxy- 1-( hydroxymethyl)- 2- phenylethyl]- 2-( 1H- indol- 3- ylmethyl)- 2- methyl- N' tricyclo [ 3. 3. 1. I3 , 7] dec-l-ylmethyl)propanediamide

Ethyl a- methyl- a [ [ ( tricyclo [ 3. 3. 1. I3' 7] dec- l- ylmethyl) amino] - carbonyl]- 1H- indole- 3- propanoate ( 9)

Compound 9 was prepared from Compound 4 according to the procedure for Compound 5. The product was obtained as an off-white solid, 3.49 g (58%).

IR (KBr) 3402, 3337, 2913, 2904, 1718, 1652, 1116 cm"<1>.

( + ) - a- methyl- a [ [ ( tricyclo [ 3. 3. 1. 13, 7] dec- l- methyl) amino] - carbonyl]- 1H- indole- 3- propanoic acid ( 10)

Compound 10 was prepared from Compound 9 according to the procedure for Compound 6. The product was obtained as a white solid, 1.95 g (71%).

IR (KBr) 3440, 2912, 1713, 1652, 1621, 1189, 746 cm"<1>.

US- Ua, 5a ( R*) 1 1 oa US- Ug, 5g ( S*) 1 1 - N- ( 2. 2- dimethyl- 4- phenyl-1, 3- dioxan- 5- yl)- 2- (1H-indol-3-ylmethyl)-2-methyl-N'-(tricyclo-T3.3.1.13'71dec-1-ylmethyl)propanediamide (11)

Compound 11 was prepared from Compound 10 according to the procedure for Compound 7. The product was obtained as a white foam, 0.83 g (72%).

IR (KBr) 3418, 2904, 1666, 1558, 1106 cm'<1>.

riS- TUE*( R*). 2R* 11 and rIS- fIR*( S*). 2R* 11- N- r2- hydroxymethyl-1-(hydroxymethyl)-2-phenylethyl! - 2-(1H-indol-3-ylmethyl)-2-methyl-N'-tricyclo\3. 3. 1. 13' 7! dec-l-ylmethyl)propanediamide (12)

Compound 12 was prepared from Compound 11 according to the procedure for Compound 8. The product was obtained as a white foam, 0.2633 g (91%).

IR (KBr) 3341, 1652, 1588, 1544, 1477, 699 cm"<1>.

EXAMPLE 99

riS- TUE*( R*). 2R* 11 and riS- TIR*( S*), 2R* 11- a-\ f\\ 2 . 6- bis( 1-methylethyl) phenyl] aminolcarbonyl] aminol - N- r2- hydroxy- 1-( hydroxymethyl)- 2- phenylethyl]- a- methyl- 1H- indole- 3- propanamide

r4S- r4a, 5a( R*) 1 1 and US- Ua, 5a ( S*) 1 1 - 1. 1- dimethylvletvl r2- r ( 2 . 2-dimethyl- 4- phenyl- 1, 3- dioxane- 5 -yl)-amino]- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate (14)

Compound 14 was prepared according to the procedure for Compound 7. The product was obtained as a white foam, 4.70 g (98%).

IR (KBr) 3413, 1707, 1663, 1507, 1501, 1458, 1168, 743 cm"<1>.

US- Ua, 5a ( R*) 1 1 and US- Ua, 5a ( S*) ] 1 - a- amino- N - ( 2 , 2- dimethyl-4-phenyl- 1, 3- dioxan-5-yl )- g- methyl- 1H- indole- 3- propanamide ( 15)

Anhydrous hydrogen chloride gas was bubbled through a solution of t-butyloxycarbonylamine 14 (3.4 g, 6.7 mmol) in dichloromethane (80 mL) for 5 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour and was then poured into saturated aqueous sodium bicarbonate solution. Sodium chloride solution was added and the aqueous solution was extracted twice with ethyl acetate. The organic extracts were combined, dried (MgSO 4 ), filtered and concentrated. The residue was filtered through silica gel (70-230 mesh) using ethyl acetate as eluent to give the product as an off-white solid, 2.18 g (80%).

IR (KBr) 3356, 3244, 1646, 1514, 744 cm"<1>.

[ 4S- Ua, 5o?( R*) 1 1 or US- Ua, 5a ( S*) 1 1 - a - \ \ \ \ 2 , 6- bis ( 1- metvl-ethyl) phenyl 1 amino] carbonyl] amino]- N-(2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl)-α-methyl-1H-indol-3-propanamide (16a)

US- [ 4a. 5a ( R*) 1 1 or US- Ug, 5a ( S*) 1 1 - a - \ \ \ \ 2 , 6- bis ( 1- metvl-ethyl) phenyl] amino] carbonyl] amino] - N-( 2, 2- dimethyl- 4- phenyl- 1, 3-dioxan- 5- yl)- a- methyl- 1H- indol- 3- propanamide ( 16b)

A mixture of amine 15 (0.40 g, 1 mmol) and 2,6-diisopropylphenyl isocyanate (0.23 g, 1.1 mmol) in ethyl acetate (30 mL) was briefly heated to obtain solution. The reaction mixture was then allowed to stand for 2 days at room temperature. The reaction mixture was concentrated to a viscous oil which was chromatographed on silica gel (70-230 mesh) using ethyl acetate as eluent. The less polar diastereomer, 16a, was obtained as a white solid, 0.2876 g. The more polar diastereomer, 16b, was obtained as a white solid, 0.2369 g. Overall yield 87%.

IR (KBr) 3431, 2964, 1675, 1500, 1239, 741 cm"<1>.

fis- [ IR*( R*) , 2R* 11 and flS - [ IR*( S*) 2R* 11- a- \ \ \ [ 2, 6- bis( l-methylethyl) phenyl] amino] carbonyl] amino ]- N- \ 2 - hydroxy- 1-( hydroxymethyl)- 2- phenylethyl] - a- methyl- 1H- indole- 3- propanamide

(17a)

Compound 17a was prepared from Compound 16a according to the procedure for Compound 8. The product was obtained as a white foam, 0.0893 g (48%).

IR (KBr) 3400, 3343, 1733, 1663, 1513, 742 cm"<1>.

EXAMPLE 100

TUE- TUE*( R*) , 2R* 11 or flS- TlR*( S) , 2R* 11- a - \ \ \ \ 2 . 6- bis(1-methylethyl) phenylamino] carbonyl aminol - N- T2- hydroxy- 1-( hydroxymethyl) - 2- phenylethyl] - g- methyl- 1H- indole- 3- propanamide

(17b)

Compound 17b was prepared from Compound 16b according to the procedure for Compound 8. The product was obtained as a white foam, 0.096 g (66%).

IR (KBr) 3420, 3299, 1734, 1716, 1662, 1507, 1058 cm'<1>.

EXAMPLE 101

N- r (1, 1- dimethylethoxy) carbonyl] - L- f enylalanvl- a- methyl- N- tricyclo f3 . 3. 1. I3, 7] dec-2-yl-DL-trvptoph anamide

US-Ua, 5a( R*) 1 1 o.a. -amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate (18)

The amine 15 (0.4 g, 1 mmol) and 2,6-diisopropylphenyl chloroformate (0.51 g, 2 mmol) were taken up in tetrahydrofuran

(50 mL) and added triethylamine (0.34 mL, 2.4 mmol). The reaction mixture was stirred for 5 days at room temperature and then concentrated to dryness. The residue was filtered through silica gel (70-230 mesh) using hexane/ethyl acetate, 1/1, as eluent. The product was obtained as a foam/solid, 0.395 g (66%).

IR (KBr) 3326, 1654, 1636, 1520, 1257, 742 cm'<1>.

N- TN- r ( 1, 1- dimethylethoxy) carbonyl]- L- phenvlalanyl- a- methyl- DL-tryptoph an- methyl ester ( 19)

Compound 19 was prepared from BOC-L-phenylalanine and RS-α-Me-tryptophan methyl ester according to the procedure of Example 7 (4.74 g, (99%).

IR (KBr) 3408, 3353, 1734, 1696, 1617, 1507, 1457, 1165 cm"<1>.

a- methyl- N- L- phenylalaryl- DL, methyl ester,

monohydrochloride ( 20)

Anhydrous hydrogen chloride gas was bubbled through a solution of 19 (1.50 g, 3.1 mmol) in dichloromethane (50 mL) for 2 min at room temperature. The reaction mixture was allowed to stand overnight at room temperature. The solvent was removed in vacuo. Ether was added twice and concentrated. The residue was taken up in methanol and then concentrated. Ether was added and then removed on a rotary evaporator to give the product as a light brown foam, 1.32 g (100%).

IR (KBr) 3403, 3396, 3343, 3231, 1734, 1684, 1677, 1498, 1216, 743 cm"<1>

N- fN- f( 1, 1- dimethylethoxy) carbonyl]- L- phenylalanyl]- g- methyl- DL-trv<p>tofvl ( 21)

Compound 21 was prepared from 19 according to the procedure for Compound 6. The product was obtained as a white foam, 2.34 g (96%).

IR (KBr) 3375, 1716, 1708, 1702, 1498, 1457, 1368, 1164,

743 cm"<1>.

N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-α-methyl-N-trichlorof3. 3. 1. 13' 7! dec- 2- vi- DL- tryptoph anamide ( 22)

Compound 22 was prepared from 21 and 2-adamantamine according to the procedure for Compound 7. The product was obtained as a white solid, 0.585 g (38%).

IR (KBr) 3411, 3333, 1696, 1672, 1653, 1519, 1165 cm"<1>

EXAMPLE 102

N- fN- r ( tricyclo f3 . 3. 1. I3' 7] dec- 2- vloxv) carbonyl] - L-phenylalanyl]- DL- tryptophan, methyl ester ( 23)

Compound 20 (1.25 g, 3.0 mmol) was added to 2-adamantyl chloroformate (0.70 g, 3.3 mmol) in THF (80 mL), followed by triethylamine (0.9 mL, 6.5 mmol) was added and the reaction mixture cooled to 0°C. After 0.5 hours, the reaction mixture was concentrated to dryness and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with 10% aqueous citric acid and saturated sodium chloride solution, dried (MgSO 4 ), filtered and concentrated. The residue was filtered through silica gel (70-230 mesh) using hexane/ethyl acetate as eluent. The product was obtained as a white foam, 1.12 g (67%). IR (KBr) 3342, 2912, 1672, 1663, 1507, 1361, 1254, 1101 cm"<1>

EXAMPLE 103

Tricyclo 3 . 3. 1. I3- 7! dec- 2- vi ( + ) - \ 2 - \ ( 3 . 4- dihydro- 2H- l-benzopyran- 3- vl) aminol - 1- ( 1H- indol- 3- ylmethyl) - l- metvl- 2- oxoethyl] carbamate

A solution of 2-adamantyloxycarbonylamethyl, DL-tryptophan (0.79 g, 0.002 mmol) in ethyl acetate (60 mL) was treated with dicyclohexylcarbodiimide (0.495 g, 0.002 mmol) and 1-hydroxybenzotriazole hydrate (0.3 g, 0.0023 mmol). After stirring for 2 hours at room temperature, the precipitated dicyclohexylurea was removed by filtration. To the clear filtrate was added 3,4-dihydro-2,4-1-benzopyran-3-amine (0.37 g, 0.002 mmol). The reaction mixture was stirred at room temperature overnight. The ethyl acetate solution was washed with 5% citric acid, 5% NaHCO 3 and brine. The organic phase was dried over MgSO 4 and concentrated in vacuo to give a white foam. The product was chromatographed over silica using 50% ethyl acetate, 50% hexane as eluent to give the title compound (0.66 g, 61%). Analysis for C 32 H 37 N 3 O 4 l/2H 2 O MW 536.679;

Calculated: C, 71.61; H, 7.13; N, 7.82;

Found: C, 71.67; H, 6.93; N, 7.75.

EXAMPLE 104

Tricyclo\ 3 . 3. 1. I3* 7] dec- 2- vi ( + ) - ri - ( 1H- indol- 3- vlmetvl) - 1-metvl- 2- oxo- 2- r f( 1, 2, 3, 4- tetrahydro- 1 - naphthalenyl)methyl]aminolcarbamate

Following a procedure analogous to that in Example 103 by using 1,2,3,4-tetrahydro-1-naphthalenylmethenamine (0.32 g, 0.002 mmol) instead of 3,4-dihydro-2,4-1-benzopyran -3-amine, the title compound is obtained (0.76 g, 69%).

Analysis for C34H41N303 l/2H20 MV 548,734:

Calculated: C, 74.42; H, 7.71; N, 7.65;

Found in C, 74.27; H, 7.57; N, 7.36.

EXAMPLE 105

Tricyclo r3. 3. 1. 13- 71 dec- 2- we ( + )-!"!- (1H-indol-3-vlmethyl)-1-methyl-2-oxo-2-[(9H-xanthen-9-ylmethyl) aminoletvl carbamate

A solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.79 g, 0.002 mmol) in methylene chloride (60 mL) was treated with hydroxybenzothiazole hydrate (0.3 g, 0.0022 mmol), 1-( 2-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (0.38 g,

0.002 mmol) and triethylamine (0.202 g, 0.002 mmol). After stirring at room temperature for 2 hours, a solution of 3H-xanthan-9-methenamine (0.495 g, 0.002 mmol) in methylene chloride (10 mL) was added. The reaction mixture was stirred at room temperature overnight. The clear solution was concentrated in vacuo. The resulting oil was taken up in ethyl acetate. The ethyl acetate solution was washed with 1N HCl, saturated NaHCO 3 and brine. The organic phase was dried over MgSO 4 and concentrated in vacuo to a white foam. The product was chromatographed over silica using 50% ethyl acetate:50% hexane as eluent to give the title compound (0.72 g, 59%). Analysis for C37H39N304. H 2 O MV 607.761: Calcd: C, 73.13; H, 6.79; N, 6.91;

Found: C, 73.53; H, 6.80; N, 6.61.

Claims (4)

1. Analogy process for the preparation of a therapeutically active compound of formula I or a pharmaceutically acceptable salt thereof, where: R<1> is adamentyl or bornyl, R2 is hydrogen or C1-C4 alkyl, R3 is hydrogen, (CH2)nOH, (CH2)nOAc or (CH2)n0C0 (CH2)nCOOH, R4 is hydrogen, OH or phenyl, R<12> is hydrogen or forms a double bond together with R<13>, R<13> is hydrogen or forms a double bond together with R<12>, R<20> is hydrogen, (CH2)nOH, CONH2, C02-C!-C4-alkyl, C02Bz or COOH, Ar<1> is phenyl, C02-C1-C4-alkyl, bicyclo [2 . 2 .1] heptane or optionally with (CH2)nOH, COOH, CN, C1-C4-alkyl or C0NH-C1-C4-alkyl substituted C3-C7-cycloalkyl, X and Y are independently selected from NH, NHCO, CONH, C00 or CSNH, p, r, s, t, u and v are independently selected from 0 or 1, and n is 1-4 characterized by a) connecting the corresponding individual α-amino acids, which may be unprotected or protected, for to form the desired compound of formula I, or that when preparing compounds of the general formula Ia where R<1> is 1-adamantyl, 2-adamantyl or (IS)-2-endo-bornyl, R<2> is H or methyl C is 0 or 1, R<3> is H, CH2OH or CH2O-CO-(CH2)2C02H' R<4> is H and Ar is taken from Ar<1> as defined above, or a pharmaceutically acceptable salt thereof, b) converting the compound of the formula where R<1> and R<2> have the meanings given above, to an activated ester, e.g. with pentafluorophenyl and dicyclohexylcarbodiimide, and then reacting the activated ester with an appropriate amine to form a compound of formula Ia, or c) reacting a compound of formula where c is 0 or 1, with a compound of formula R< 1->0-CO-Cl, where R<1> has the . meaning given above, to obtain a compound of formula Ia, where R<2>, R<3> and R<4> are hydrogen, or d) reacts a compound of the formula R<2> is H with a compound of the formula R<1->O-CO-Cl to obtain a compound of formula Ia, where R<3> and R<4> are hydrogen, and if desired, convert a compound of formula Ia into a pharmaceutically acceptable salt thereof in a conventional way. 2. Process according to claim 1, for the production of a compound of formula I where Ar<1> is phenyl characterized by the fact that corresponding starting materials are used. 3. Method according to claim 1, for the preparation of a compound of formula I where R<1> is selected from 1-adamantyl, 2-adamantyl and 2-endo-bornyl, characterized by the fact that corresponding starting materials are used. 4. Process according to claim 1, for the production of a compound selected from: carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl] amino] - 1-(1H-indol-3-ylmethyl) ethyl] - , tricyclo [3 , 3 ,1, 13'7] dec-2-yl ester, [S-(R<*>,S<*>)]-, carbamic acid, [2-[[1-(hydroxymethyl)- 2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)ethyl], tricyclo[3,3,1,13'7]dec-2-yl ester, [S-(R<*>, R<*>)]-, tricyclo [3.3.1.13'7] dec-2-yl [1- [ [ [1-hydroxymethyl)-2-phenylethyl]carbonyl]amino]-2-1H-indole-3 -yl)ethyl]carbamate, carbamic acid, [2-[(2-hydroxy-2-phenylethyl)-amino]-1-(1H-indol-3-ylmethyl)-1-methylethyl] - , tricyclo [3 , 3 , 1, 13,7] dec-2-yl ester (hydroxy center is RS other center is R), carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]amino] - 1-(1H-indol-3-ylmethyl)-1-methylethyl] - , tricyclo [3 , 3 , 1 , 13'7] dec- 2-yl ester, [R-(R<*>,S<*>)]-, 4-methylbenzenesulfonate (1:1) (salt), benzenepropanol, IS- [ [2- (1H-indole-3- yl) -2- [ [tricyclo-[3 . 3 .1.13,7] dec-2 -yloxy) carbonyl] amino] propyl] amino] - , acetate (ester), [R-(R<*>,S<*>)]-, 4-methylbenzenesulfonate (1: 1) (salt), carbamic acid, [[2-[acetyl[1-(hydroxymethyl)-2-phenylethyl]-amino]-1-(1H-indol-3-ylmethyl)-1-methyl]-ethyl] -, tricyclo-[3 . 3 .1.13'7] dec-2-yl ester, [R- (R* , S*) ] - , carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(1-oxo-4-phenylbutyl) amino] ethyl] - , tricyclo [3.3.1.13-7] dec-2-yl -ester, (R)-, Carbamic acid, [2-(benzoylamino)-1-(1H-indol-3-ylmethyl)-1-methylethyl]-, tricyclo[3,3,1,13'7]dec-2-yl ester, (R) -, carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(1-oxo-3-phenylpropyl) amino] ethyl] - , tricyclo [3.3.1.13,7] dec-2-yl -ester, (R) carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(2-phenylacetyl) amino] ethyl] - , tricyclo [3,3,1,13,7] dec-2-yl -ester, (R)-, carbamic acid, [2-[[3-[[1-(hydroxymethyl)-2-phenylethyl]-amino] -3-oxopropyl] amino] -1-(1H-indol-3-ylmethyl)-1-methyl-2- oxoethyl]-, [R, (R<*>,S<*>)]-, carbamic acid, [1-(1H-indol-3-ylmethyl)-2-[[3- [ [1-(hydroxymethyl)-2-phenylethyl]amino]-3-oxopropyl]amino]-1-methyl-2-oxoethyl ] tricyclo [3,3,1,13,7]dec-2-yl ester, [S-(R<*>,R<*>)]-, D-phenylalanine amide, α-methyl-N- [ ( tricyclo [3 .3 .1.13,7] dec-2-yloxy) carbonyl] -D-tryptophyll-S-alanyl-., L-f enylalanine amide, a-methyl-N- [ (tricyclo [3.3 .1.13,7] dec- 2-yloxy)carbonyl] -D-tryptophyll-S-alanyl-, L-phenylalanine amide, α-methyl-N- [ (tricyclo [3 .3 .1.13,7] dec-2-yloxy)carbonyl] -L-tryptophyll- S-alanyl-, D-phenylalanine amide, α-methyl-N- [ (tricyclo [3.3.1.13,7] dec-2-yloxy)carbonyl] -L-tryptophyll7jS-alanyl-, L-phenylalanine, N-[N- [α-methyl-N-[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]-D-tryptophyll]-S-alanyl]-,phenylmethyl ester, propanoic acid, 2-[[3- [ [3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [ [ (tricyclo [3 .3 .1.13,7] dec-2-yloxy) carbonyl] amino] propyl] - amino] -1-oxopropyl] amino] -3-phenyl-, phenyl methyl ester, [S-(R< *>,R<*>)]-, D-phenylalanine, N-[N-[α-methyl-N-[ (tricyclo [3 .3 .1.13-7] dec-2-yloxy)carbonyl]-D- tryptophyll]-S-alanyl] -, L-phenylalanine, N- [N- [α-methyl-N- [ (tricyclo [3 .3 .1.13-7] dec-2-yloxy)carbonyl]-D-tryptophyll] -S-alanyl]-, L-phenylalanine, N-[N-[α-methyl-N-[(tricyclo[3.3.1.13.7]dec-2-yloxy)carbonyl]-L-tryptophyl]- S-alanyl] -, benzenepropanoic acid, α-[[3-[[3-[(1H-indol-3-yl)-2-methyl-1-oxo-2- [ [ (tricyclo [3.3.1.13,7] dec-2-yloxy) carbonyl] amino] - propyl] amino]-1-oxopropyl] amino]-, [S-(R<*>,S<*>)]-, glycine, N- [2-methyl-N- [ (tricyclo [3 .3 .1.13-7] dec-2-yloxy) - carbonyl]-D-tryptophyll]-, phenyl methyl ester, carbamic acid, [3-(1H-indol-3-ylmethyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidinyl]-, tricyclo[3.3.1.13,7]dec-2-yl- ester, (±)-, carbamic acid, [1-(1H-imidazol-4-ylmethyl)-1-methyl-2-oxo-2-[ (2-phenylethyl)amino]ethyl]-, 1,1-dimethylethyl ester, (±)-, carbamic acid, [3-(1H-indol-3-yl)-1-methyl-1-[[(2-phenylethyl) amino] carbonyl] propyl] - , tricyclo [3.3.1.13,7] dec-2-yl- ester, (±) -, carbamic acid, [1-[[[1-hydroxymethyl)-2-phenylethyl]amino]-carbonyl]-3-(1H-indol-3-yl)-1-methylpropyl]-, tricyclo-[3 . 3 .1.13,7] dec-2-yl ester (hydroxymethyl center is S, other center is RS), L-phenylalanine amide, N- [ [ (1,1-dimethylethoxy) carbonyl] - ct -methyl]-L- tryptophyll]-L-methionyl-L-α-aspartyl-, glycine, N- [2-methyl-N- [ (tricyclo [3.3.1.13-7] dec-2-yloxy)-carbonyl]-D-tryptophyll]-L-phenylalanyl-, carbamic acid, [1-[[[1-(hydroxymethyl)-2-phenylethyl]amino]-carbonyl] -2-(1H-indol-3-yl) propyl] - , tricyclo [3 . 3 .1.13'7] dec-2-yl ester (hydroxymethyl center is S, other centers RS), 2,4-heptadienoic acid, 6-[ [3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [ [ (tricyclo [3.3.1.13'7] dec-2-yloxy) carbonyl ] amino] propyl] - amino]-7-phenyl-, [R,R<*>,S<*->(E,E)]]-, glycine, N- [2-methyl-N- [ (tricyclo [3.3.1.13'7] dec-2-yloxy) - carbonyl]-D-tryptophyll]-, phenylmethyl ester, tricyclo [3 . 3 .1.13'7] dec-2-yl-R-(R*,S*)] - [1- [4 , 5-dihydro-4-(phenylmethyl)-2-thiazolyl]-2-(1H-indole -3-yl)-1-methylethyl]-carbamate, characterized by the fact that corresponding starting materials are used.