PT98842B - PROCESS FOR THE PREPARATION OF N-SUBSTITUTED NON-SUBSTITUTED PHENYLALANYL AND PHYETHYLAMINE DERIVATIVES WITH CYCLOALKYL AND POLYCYCLOALQUIL, ALPHA-SUBSTITUTED WITH ARYL AND HETEROARYL AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM - Google Patents

Description

They are also thought to act as analgesics (Hill, Euges and Pittaway, Eeuropharmacology 26: 289-300, 1987), and as anticonvulsants (Macvicar, Kerrin and Davison, Brain Research, 406: 130-135i 1987).

Reduced levels of OCK peptides were found in the brains of schizophrenic patients when compared to controls (Roberts, Ferrier, Lee, Crow, Johnstone, Owens, Bacarese-Lamilton, McGregor, O'Shaughnessey, Polafc, and Bloom, Brain Research 288: 199 -211, 1983). It has been proposed that changes in the activity of CGK neurons projecting to the " accumbens " may play an important role in schizophrenic processes by influencing dopaminergic function (Eotterdell and Smitb, Seuroscience 19, 181-192, 1986) This is consistent with several reports that CCK peptides modulate dopaminergic function in basal ganglia and particularly in the nucleus " accumbens " (Weiss, Tanzer, and Ettenberg, Pharmacologie, Biochemistry and Behavior 30: 309-317, 1988, Schneider, Àllpert, and Iversen, Peptides 4: 74-9-753, 1983). Agents that modify the activity of GOK receptors may be of therapeutic value under conditions associated with the disrupted function of dopaminergic function such as schizophrenia and Parkinson's disease.

The CGK and gastrin peptides share a common carboxy terminal pentapeptide sequence and the GGK peptides can bind to the gastrin receptor of the stomach mucosa and produce acid secretion in many species including man (Konturelc, Gastrointestinal Hormones, OH 23, pp 529-564, 1980, ed. GBJ Glass, Raven Press, NY). GGK-B receptor antagonists are believed to be gastrin receptor antagonists of the stomach and this also has value for conditions involving excessive acid secretion. - 2 -

KSXSwasffisss

Rasaste

The CCK and gastrin peptides have efes. and in various tissues of the gastrointestinal system (Jahnson, ibid., pp. 507-52), actions which are associated with increased synthesis of DNA and RNA. In addition, cells secreting gastrin are associated with some gastrointestinal tumors such as Zollinger-Ellison's Syndrome (Stadil, ibid., Pp. 729-739), and some colorectal tumors which may also be dependent of gastrin / CGK (Singh, Walker, Townsend, and Thompson, Canoer Research 46: 1612, 1986; Smith, JP, Gastroenterology 95: 1541, 1988). Antagonists of CCK / gastrin reservatives could thus have a valuable therapeutic effect as antitumor agents.

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

The various CCK peptides should be involved in the control of the eontractility of soft muscles, excretory and endocrine gland secretion, transmission of sensory nerves, and various brain functions. Administration of the native peptides causes bladder vessel contraction, amylase secretion, central neuron excitation, feed inhibition, anticonvulsive actions, and other behavioral effects. Cholecystokinin: Isolation, Structure and Punctures, G. B. J. Glass, Ed., Raven Press,

New York, 1980, pp 169-221; J.E. Morley, Life Sciences 27: 335-368, 1980; Cholecystokinin in the Nervous System. J. de Belleroche and G.J. Dockray, Ed., Ellis Horwood, Chichester, England, 1984, pp. 110-12). - 3 -

Elevated concentrations of COK peptides in large areas of the brain also indicate important cere-hai * functions for these peptides (GJ Dokray, Br. Med. Bull., 38 (Ho. 3) ϊ 253-258, 1982). abundance of the brain is GCK26-33 although there are small amounts of CCK30-33 (Hhefeld and Gotterman, J. Neurochem., 32: 1339-1341, 1979). Paper in the central nervous system of 00K is not known with safety , but has been implicated in feed control (Della-3? era and Baile, Science 206: 471-473, 1979).

Presently available appetite suppressants act either peripherally, increasing energy expenditure (such as tyrosine), or otherwise (such as biguanides), or they act to have a central effect on appetite or satiety.

Central acting appetite suppressants potentiate central catecholamine pathways and tend to be stimulants (eg amphetamine), or influence serotonergic pathways (eg, fenfluramine). Other forms of drug therapy include thickening agents which act by filling the stomach, thereby inducing a feeling of satiety.

COK is known to be present in some cortical interneurons which also contain gamma-aminobutyric acid (GABA) (H. Demeulemeester et al, J. Heuroscience 8, 988-1000, 1988). Agents that modify the action of GABA may have utility as anxiolytic or hypnotic agents (S. 0. Harvey, The Pharmaceutical Basis of Therapeutics (bd ed. 1985, pp. 339-371, Macmillan). 00K action may have parallel anxiolytic or hypnotic activities. The role of 00K in anxiety I referred to in TIPS 11: 271-275, 1990). - 4 -

SUMMARY OF THE INVENTION The present invention relates to novel compounds

(X) < RTI ID = 0.0 > (5) < RTI ID = 0.0 > (GHH4) g (Y)

Ar - (CHR 13) -Ar 1 and to the pharmaceutically acceptable salts thereof wherein R 1, R 2. R 3, R 5, R 5, R 6, R 12, R 13, R 20, A X X T> E, Ar 1, Ar 2, n, m, p, q, r, s, t, u and v have the following significance.

In copending applications also assigned 07 / 576,308, 07 / 576,296, 07 / 576,315, 07 / 576,024, and 07 / 576,297 filed August 31, 1990 by Horwel, et al., The contents of which are incorporated herein by reference. 00K. GOK antagonists are also referred to in the partial continuation applications of the above claims also owned by the applicant and co-pending 07 / 726,656, 07 / 726,654, 07 / 726,653, 07 / 726,652, 07 / 726,651, filed the same date by Horwel et al., the contents of which are hereby incorporated by reference. Similarly, the present invention relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in a dosage unit form effective for suppressing appetite.

The compounds are also useful as antipsychotics, especially for the treatment of schizophrenic behavior, as agents for the treatment,

of diseases of the motor-extractramidal system, as agents for blocking the trophic actions and stimulating the growth of OGK and gastrin, and as agents for the treatment of gastrointestinal motility.

The compounds of the invention are useful as analgesics and potentiate the effect of morphine. They may be used as adjuncts to morphine and other opioids in the treatment of severe pain such as cancer pain and reduce the dose of morphine in the treatment of pain when morphine is contraindicated.

A further use of the compounds of formula I as for example the iodinated compound is that the appropriate radiolabeled iodo-131 or iodo-127 compound gives rise to a suitable agent for the treatment of gastrin-dependent tumors such as those found in the colon cancers. Compounds of formula I radiolabeled with 1-125 may also be used as diagnostic agents by localization of gastrin and CCK-B receptors in peripheral and central tissues. The invention further relates to a method for suppressing appetite in mammals comprising administering an appetite suppressing amount described above to a mammal in need of such treatment. The invention also relates to a composition for reducing gastric acid secretion containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in dosage unit form effective to reduce the secretion of gastric acid. The invention also relates to a method for reducing gastric acid secretion in mammals which comprises -

an effective amount for reducing the gastric acid secretion of the composition described above is administered to a mammal in need of such treatment. The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in a unit dosage form effective for reducing anxiety. The invention also provides a method of reducing anxiety in mammals which comprises administering to mammals an amount effective for reducing anxiety of the above-described composition to a mammal in need of such treatment. The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in dosage unit form effective for the treatment of gastrointestinal ulcers. The invention also relates to a method for the treatment of gastrointestinal ulcers in mammals which comprises administering to mammals an amount effective for the treatment of gastrointestinal ulcers of the above described composition to a mammal in need of such treatment. The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in dosage unit form effective for the treatment of psychoses such as schizophrenia. - 7 -

The invention also relates to a method for the treatment of psychoses in mammals which comprises administering to mammals an amount effective for the treatment of psychoses of the above-described composition to a mammal in need of such treatment. The invention also relates to a pharmaceutical composition containing an amount effective to stimulate or block OCK or gastrin receptors for altering the activity of brain neurons, for schizophrenia, for the treatment of extrapyramidal motor system disorders, for blocking the actions of trophic stimulation and growth of OCK and gastrin and for the treatment of gastrointestinal mobility. The invention also relates to a pharmaceutical composition containing an amount effective for the prevention of the withdrawal response produced by the chronic treatment or abuse of drugs or alcohol. The invention also relates to a method of treating the withdrawal response produced by the chronic treatment or abuse of drugs or alcohol. These drugs include benzodiazepines, especially diazepam, cocaine, alcohol, caffeine, and nicotine. The withdrawal symptoms are treated by administering an effective amount of withdrawal of a compound of the invention. The invention also relates to a pharmaceutical composition containing an effective amount of a compound having the formula I in combination with a pharmaceutically acceptable carrier in a unit dosage form effective for the treatment and / or prevention of panic. The invention also relates to a method for the treatment and / or prevention of panic in mammals which comprises administering to a mammal,

comprises administering to mammals an amount effective for the treatment and / or prevention of panic of the above described composition to a mammal in need of such treatment. The invention also relates to the use of the compounds of formula I to prepare pharmaceutical and diagnostic compositions for the treatment and diagnosis of the conditions described above. The invention further provides novel intermediates useful in the preparation of the compound of formula I and also provides processes for the preparation of the intermediates.

DETAILED DESCRIPTION

The compounds of the present invention are represented by the formula t-, (CH2) m C- (CH2) - (X) (j- (OCH3) r- (CHE4) a) t- (OH20E12) οε5η6) π

Ar is a cyclo or polycycloalkyl hydrocarbyl or a mono- or polyheterocyclic radical in which the heteroatom (s) may be N, O, and R is a pharmaceutically acceptable salt thereof; or S, having 3 to 12 carbon atoms and 0 to 4 substituents each independently selected from straight or branched chain alkyl of 1 to 6 carbon atoms, halogen, NG, OR *, SR *, CC * , NR 6, or -

(OH) 2 R 3 wherein R 2, R 3 and R 6 are each independently hydrogen or alkyl of 1 to about 6 carbon atoms, m, n, p, q, r, s, t, u and p are each independently with the proviso that q, r, and s are not all 1 when m, p, t, u, and v are all 0 with the exception when X is not CORR 9 or AE is - (CH 2) n - Wherein n is as defined above, A is a bond, O, S, RR *, - (CH 2) 2 -OH, -SO 2 -Z , -so-z, -sz, -NHCO-Z, O

Wherein Z is a bond, oxygen, sulfur, or -Râ, â, <â, â, â, â, <â, â, â, wherein R * is as defined above, E is a bond, - (GHR3) r -, (GHR5) r - (GHR4) s -, -CORH-, -RHGO-, -OCO-, -

(E5) -, -OH2-, -gh2s-, -C = C-)

s

II -g-nr3, -SO2 R3 -, -NR3 SO2 -, -NHGONH-

- 11 -

wherein R 2 and R 2 are each independently as defined above, and R 2 and R 3 are each independently hydrogen, a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, -HG (CH 2) n Ar 2, - (CH 2) n OR 2, - (CH 2) n OH, - (CH 2) n OH, - (OH) ) nOAr, - (OH) GO 2, - (OHp) n NR 5 R 6 wherein R 9, R 5 and R '' are as defined above. are as defined above and Ar n, and Ar are as defined below X and ϊ are each independently -GONH-, -CONR 9, -NHG 0-, -OCO-, -000-, -OH, R 5) GH20-, -gh2s-, -ogh2-, -sgh2-, -0 * 0-, s II -G-NR5, s II -JttL-O-, -S02RR5-, -rr5so2-, -NHG0RH-, -CH (O R *) CH 2 -, -gogh 2 -, -

-GH2G0-} -NR5OH-,

Wherein Q is O, S, or NR 2 '

Br and R are each independently the same as R 1 or - (CH 2) n -BD wherein n * is an integer from 0 to 3, B is a bond -O CO (CH 2) b-, -O (CH 2) n -, -NHC0 (CH2) n -, -OH (CIH2) n -, -

(CH2) n -, -CO (OH2) n -, -SO (OHP) -, -S (OH2) n -, -SO2 (CH2) n -, moo-σ - 0

-O-, t 'E? Wherein R 7 or R 8 are independently selected from hydrogen and R 2, or together form a ring (C 1 L min-1) wherein m is an integer of 1 to 5 and n is as defined above, D is -COORR *, -CH2 OR *, -ORHR20 R *, -OH2, -SR *, -COHRAR5, -ON, -R5 R6, -OH , -H, and acid substitutions such as tetrazole-14-

HO

r1V4n4% 'n2; (I.e.

R10 and OH, NH2, CH3, or Cl2: oxadiazole

HS. <5 r N-N N-N, = 3 'V-T' &quot; Ai ™ γΝ Η ^ 'Η *' I 11

Rn6 CN, co2h, or cf3

N H

H N-N ο ^ Αξ o ir

PhS02NHCO- *, CF3 CONHCO-, CF3SO2NHCO-,

HO

N

CH3, n-ns (o) b-4

N '- (S) - N - (S)

n-n S (0) b-4 K N Ν ', nr5rh-s <0)> HO io io & & & <0, b ~ Y ^. - N -

in which b is an integer from 0 to 2, Ex, R 1 and R 2 are as defined above, is H, or a linear or branched alkyl radical having one to six carbon atoms - (CH 2) n CO 2 R 2, ), wherein n, R 2, R 5 and are as defined above or taken from R 1 and Ar is taken from Ar as defined below, R 12 and R 11, are each independently hydrogen or taken together form a double bond, or are (OH) -BD as defined above, and

Ar and Ar are each independently an unsubstituted or substituted carbo- or heterocyclic aromatic or carbo- or heteroaromatic mono-oupolic cyclic radical, and the preferred Ar1 value is substituted phenyl, fused aryl, heterocycle, fused heterocycle, or perhydroaryl Preferred Ar 1 value is 2 or nyl, 2 or 3-furanyl, 2, 3 or 4-pyridinyl or an unsubstituted or substituted benzyl ring

in which E1 and P are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl, nitro, hydroxy, KS2, OCP4, NHOOOHgOHgOH, or

substituted or unsubstituted, and wherein the poly (cycloalkyl) is selected from

in which I, X, Y, and Z are each independently hydrogen, linear or branched alkyl having one to six carbon atoms, CF 2, NR 5 R 6, - (CH 2) a CO 2 R 3, or CN, F, Cl, Br, , Wherein R * is hydrogen or straight or branched alkyl of one to six carbon atoms and R 2 and R 3 are as defined above and n is an integer from 1 to 3.

Mono- or polyheterocyclic radicals in which the heteroatom may be W, O, and / or mono-and polycyclic hydrocarbons include those compounds wherein

- 18 -

Other preferred compounds of the present invention are those wherein R 1 is 2-adamantyl or 1- (S) -2-endoborn; -NHCO-, -CO-, -SO-, -S (= O) - or -OH-O-; R 2 is -OH, -OH, -OH, -OH, or -CH 2 OH = OH, R 5 is - (OH) n -B-D or H; and R4 is - (OH) n, -B-D or H.

The most preferred compounds of the present invention are those wherein: R 1 is 2-adamantyl or 1- (S) -2-endobornyl,

A is -O-O-, R2 is -GH3; R5 is H, -0H20H, -CH20C00H20H2002H, -GHgOOOCHCH2CH2, -GHgGQgH-, -GHgSCHgOOgH-, -CHgSGHgGHgGOgH-, -GH2 THOOGHgGHgGOgH, or -OHgRHCOGHaCHCOCH3. and R4 is H, -HFGOOTgOHgGOgH (configuration / 07) or -NHGQCH = 10HG0HH (configuration.

The D and L configurations are possible at the chiral centers and are within the scope of the invention: 1.2.

Preferred I when R2 I of configuration -0Η, / Ρ7:

Preferred I when R5 is -OH, -OHgOOOH, -OHgNHOOOHgOHgCOgH having the β-β-configuration β-Trp-carbon atom and the configuration at the carbon atom Phe-Î ±; eur-lex.europa.eu eur-lex.europa.eu

Preferred is when R4 is of the configuration -ITHGOCHgGHgGO gH / 57 or RHGOGH-GHGQ configuration with the configuration / 357 on the carbon atom Trp-q '.

The most preferred compounds of the present invention are: Acid, N - (1-Oxoethyl) -2-phenylethyl] amino] -1- (1H-indol-3-ylmethyl) ethyl] carbamate, tricyclo [3.3.0] 2-yl, [S - (R *,

2- (7-Hydroxymethyl) -2-phenylethyl] amino] -1- (1H-indol-3-ylmethyl) ethylcarbamic acid, tricyclo [3.1.1] dec-2-yl ester 3-yl) ethyl] carbamate [3.3.1 (1 H, d, J = 7.7 Hz) (1H-indol-3-ylmethyl) -1-methylethyl] -carbamic acid, tricyclo [3.3.1.1] hexane -2-yl (hydroxy center I ester of RS, another center is R),

2- (7-Hydroxymethyl) -2-phenylethyl] amino] -1- (1H-indol-3-ylmethyl) -1-methylethyl] -carbamic acid, tricyclo [3.3.1] 2-yl, R- (R *), 4-methylbenzenesulfonate (1: 1) (salt),

Benzenopropanol, β- [7- (1H-indol-3-yl) -2- [7-cyclic-β. (S) -7- (R), S-27-, 4-methylbenzenesulfonate (1: 1) (salt), N, N -dimethylaminocarbonyl- 1- (Methylsilyl) -2-phenylethyl] amino] -1- (1H-indol-3-ylmethyl) -1-methyl] ethyl] carbamic acid, tricielo [ 5- (R *, S *) -, 5,13-dioxo-2,8-diazatetradec-10-enoic acid, 3- (1H-indol-3- (1H-indol-3-ylmethyl) -3-methyl -4,9,12-trioco-7-phenyl-tricyclo [3.3.1.1.5] oxazepin-2-yl ester, S- (R *, S * 13-Bioxo-2,8-diazatetradecanoic acid, 3- (1H-indol-3-ylmethyl) -3-methyl-4,9 g 12-trioxo-7-phenyl-, tricyclo [3.1.1] (1 H -indol-3-yl-ethyl) -1-methyl-2-methyl-1H-indol- (R) -, 5- (benzoylamino) -1- (1H-tetrazol-3-yl) ethyl] carbamic acid, tricyclo [3.3.0] indol-3-ylmethyl) -1-methylethyl] -carbamic acid, tricyclo [3.3.1.1.1,7] decan-2-yl (R) -, Acid, N - [(1H-indol-3-ylmethyl) methyl-2 - [(1-oxo-3-phenylpropyl) amino] ethyl] -carbamic acid tert-butyl ester (R) -, [1- (1H-indol-3-ylmethyl) -1-methyl-2- (2-phenylacetyl) 3-oxo-propyl] amino] -1-hydroxyethyl] -7-oxo-propyl] -7- (2-hydroxyethyl) (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl] -carbamoyloxymethyl-N, N -dimethyl- (3-oxoethyl) -2-phenylethyl] amino] -3-oxopropyl] amino] -1-ethyl-2-oxoethyl] carbamic acid, tricyclo [3.3.1.1.2,7] de 2-yl, R-D-phenylalaninamide, Î ± -methyl- N, N -diphexy-3,11,11,12dec-2-yloxy) carbonyl] -D-tryptophyl-β-alanyl-,

1-yl) -7-dec-2-yloxy) carbonyl] -D-tryptophyl-β-alanyl-, L-phenylalaninamide, o-C-methyl- methyl-N- [tricyclo3.3.1.1.alpha-7-deoxy-2-yloxy) carbonyl] -L-tryptophyl-β-alanyl-, D-phenylalaninamide, 12-oxo-2,5,9-triazatridecanoic acid, 3- (1H-indol-3-ylmethyl) -1,2,3,4-tetrahydronaphthalen- -3-methyl-4,8,11-trioxo-10- (phenylmethyl) -, tri- (R *, R *), 7-, 7-

L-Renylalanine, β-Z-Z-methyl-1,2,3-tricyclo [3.2.1] oxadiazol-2-yloxy) carbonyl] -D-tryptophyl] -androstane- propanoic acid, 2- [2 - [[(3 - [[(3-yl) -2-methyl-1-oxo-2- 1.13 (S) -cis-2-yloxy) carbonyl] amino] propyl] amino] -1-oxopropyl] amino] -3-phenyl-phenyl ester, ZS- (R *), D-Phenylalanine, N- [ 7-dec-2-yloxy) carbonyl] -D-tryptophyl] -p- -alanyl] -,

Methylcyclohexanecarboxylate, N-methyl-N- [tricyclo [5.3.1] hept-2-yloxy) carbonyl] -D-tryptophyl] -alanyl] -L -7-dec-2-yloxy) carbonyl] -L-tryptophyl] -? - alanyl] -, benzenopropanol, &lt; / RTI &gt; [3- (3-chlorophenyl) -2-methyl-1-oxo-2- amino] propyl] amino] -1-oxopropyl] amino] -7 - [(R *, S *

Glycine, N-2-methyl-N-tricyclo [3.3.1.1.03,7] decyl-2-yloxy) carbonyl] -D-tryptophyl], phenylmethyl ester, [5- (1H-indole -3-ylmethyl) -2,5-dioxo-1- (2-phenylethyl) -3-pyrrolidinyl], tricyclo [2.3.1.1.2,7] deic-2-yl ester, imidazol-4-ylmethyl) -1-methyl-2-oxo-2 - [(2-phenylethyl) emino] ethyl] carbamic acid, 1,1-dimethylethyl ester, (+) - 3-yl) -1-methyl-1 - [(2-phenylethyl) amino] carbonyl] propyl] carbamic acid tert-butyl ester, tricyclo [3.3.1.13,7] deic-2-yl, - 22 -

(1 H -indol-3-yl) -1-methylpropylcarbamic acid, tricyclo [3.3.0] -15,13- (3-methylphenyl) , Another center is RS), 12-oxa-2,5 (4-triazatetradec-10-ene-2-enoic acid) ethyl-5-methyl-4β, trioxo-7-phenyl-, tri-cyclohexane ester, 3,3,11,17β-2-110 / center 3 'EP is R / S mixture, another center is L-phenylalaninamide, -, 1-dimethylethoxy) carbonyl] &lt; 3j-methyl7-L-tryptophan &quot; L-methionyl-L-C-aspartyl-,

Glycerine, N- [2-methyl-N- [tricyclo [3.3.1.1.1,7] decan-2-yloxy) carbonyl] -D-tryptophyl] -L-phenylalanyl-, (hydroxymethyl S-center, other RS centers), 3-chloro-3-hydroxy-2-hydroxyethyl-2-phenylethyl] amino] carbonyl] -2- (1H-indol- 2,4-Heptadienoic acid, 6- (7H-indol-3-yl) -2-methyl-1-oxo-2- (R, S *) - (E, E)] -, and

Glycine, H- [2-methyl-N- (tricyclo [3.1.1], 3-and-2-yloxy) carbonyl] -D-tryptophyl], phenylmethyl ester. Table I, below, illustrates the representative compounds of the invention. The numbers in the left column of Table I correspond to the numbers of the above compounds. All compounds shown in Table I have their chiral configurations shown.

In addition to the compounds shown in Table I, the compounds of the present invention include the compounds of formula I wherein the indole moiety is a 2-indolyl.

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

24

TABLE I

25

TABLE I

26

TABLE I

TABLE I

TABLE I

29

TABLE I

30

TABLE I

pq &lt; Si Μ - = 5 0

Other examples of compounds of the present invention include: 2- [7-hydroxy-1- (hydroxymethyl) -2-phenylethyl] amino] -1- (1H-imidazol-1-yl) 3-ylmethyl) -1-methyl-2-oxoethyl, N- [5-hydroxy-1- (hydroxymethyl) -2-phenylethyl] - (methyl) - (2-oxo-2-tricyclo) 3.3 (2-hydroxy-2-hydroxyethyl) -1H-indole-3-propanamide, N- [2-hydroxy-1- (hydroxymethyl) -2-phenylethyl] 2-ylethoxy) -O-methyl-1H-indole-3-propanamide, Triciclo [3.3.1.1] octane-2-carboxylic acid, (hydroxymethyl) -2-phenylethyl] amino] -1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl ester, [2 - [[ (2 H -indol-3-ylmethyl) -2-phenylethyl] amino] -1- (1 H -indol-3-ylmethyl) (1 H -indol-3-ylmethyl) -1-methyl-2-oxoethyl ester, 5-hydroxy-1- (hydroxymethyl) -2-phenylethylamino- methyl-2-oxoethoxy] sulfonyl] carboxamido ester, tricyclo [5.3.1.1.beta. 7dec-2- yl] -N- [5-hydroxy-1- (hydroxymethyl) -2-phenylethyl] -methyl] -75-oxo-2- (tricyclo [3.3.1.1,7,8- ylamino) -ethyl] amino] -1H-indole-3-propanamide, N- [2-hydroxy-1- (hydroxymethyl) -2-phenylethyl] 2-ylamino) acetyl] amino] -1H-indole-3-propanamide, N- [5-hydroxy-1- (hydroxymethyl) -2-phenylethyl] - N -methyl- [2- [2-oxo-2-tricyclo] 1-yl) -7-deec-2-ylethyl) amino] -1H-indole-3-propanamido,

(2-hydroxyethyl) -2-phenylethyl] -2-hydroxy-2-tricyclo [3.3.1] heptadeca-2-ylethyl) amino] (N-methyl-1H-indole-3-propanamide, N- [2-hydroxy-1- (hydroxymethyl) -2-ferylethyl] -cyclohexanecarboxylate, 2-ylamino) oxycarbonylamino] sulfonyl] amino] -1H-indole-3-propanamide, N- [5-hydroxy-1- (hydroxymethyl) -2-phenylethyl] -Ct-methyl- 3-propanamide, (R) -cyclohexanecarboxylate, 3-propanamide, (R) -cyclohexanecarboxylic acid, 3-propanamide, 7-sulphonyl] carbamate, tricyclo [5.5.1.13,7] dex-2-yl ester,

(1E -indol-3-ylmethyl) -1-methyl-2-oxoethyl] amino] carbonyl] sulfonic acid, tricile ester [5.3 g] N-2-hydroxy-1- (hydroxymethyl) -2-phenylethyl] -7- (2-methyl- [1,2,3] N-2-hydroxy-1- (2-hydroxymethyl) -2-phenylethyl] -2- (1H-indol-3-ylmethyl) -1H-indole- (hydroxymethyl) -2-phenylethyl] -2- (2-methyl-2-hydroxyethyl) -propanoic acid, 3-ylmethyl) -2-methyl-N, -tricyclo [5.3.1] heptane-2-hydroxypropyranamide, N- [2-hydroxy-1- (hydroxymethyl) -2- (Cyclo [5.beta., 3.beta., 13.beta.-2-ylamino) methyl] amino] -OC. methyl-1H-indole-3-propanamide,

7-amino-7-amino-7- [2 - [(1-hydroxyethyl) -2-phenylethyl] OC (3-hydroxyethyl) -1H-indole-3-propanamide, N- [3-Hydroxy-1- (hydroxymethyl) -2-phenylethyl] 7-enec-2-ylamino) methyl] amino] -1H-indole-3-propanamide,

2- (7H-indol-3-ylmethyl) -1-methyl-2-oxoethyl] phosphoramidic acid, phenyl tricyclo [3.3.0] 1? 1? 7?

(1 H -indol-3-ylmethyl) -1-methyl-2-oxoethyl] -N'-tricyclohexyl] -2- 2-ylphosphoramidioic acid, 2-hydroxy-1- (2-hydroxyphenyl) -3- hydroxymethyl) -2-phenylethyl] amino] -1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethylphenyl ester, (1H-indol-3-ylmethyl) -1-methyl-2-oxoethylphenyl tricyclo [3.1.1] heptadec-2-yl.

The compounds of the present invention may have many chiral centers including those designated in formula X by the + symbol, depending on their structures. For example x 4111¾ when R formed with R and R taken with R J form double bonds to these carbon atoms they are no longer chiral.

In addition, centers of asymmetry may exist in the other substituents. In particular the compounds of the present invention may exist as diastereomers, mixture of diastereomers or as mixed or individual optical enantiomers. The present invention encompasses all such forms of the compounds. Mixtures of diastereomers are typically obtained in reaction results described more fully below. The days-

Single thermomers can be separated from the diastereomeric mixtures by conventional techniques such as repeated column chromatography or recrystallization. The individual enantiomers may be separated by a well known conventional procedure such as for example conversion to the salt with an optically active compound, followed by separation by chromatography or recrystallization and conversion to the non-salt form.

The compounds of the present invention may be obtained by coupling substituted individual OC-amino acids by well known procedures. (See, for example, the conventional synthetic methods discussed in the Multi-Vol. 3, Vol. 9, p. 2, p. 4. Peptides, Analysis, Synthesis, Biology, &quot; by Gross and Meienhofer, Academic Press, New York.) Substituted individual GC-amino acid starting materials are generally known or if not known, can be synthesized, and if desired resolved by processes known to those skilled in the art. (Synthesis of racemic-methyl tryptophan methyl ester-see Brana, M.F., col.J. Heterocyclic Qhem., 1980, 17 * 829)

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

- 36 -

II

in which R is selected from R 1, 9-fluoromethyl, B 2 and other suitable N-blocking groups. The compounds in which R is 1-adamantyl, 2-adamantyl, 4-proanadamantyl, exo-borayl, endo-bornyl, exo-norbornyl, endo 2-methylcyclohexyl, 2-chlorocyclohexyl, are novel and are preferred. The disclosure of U.S. Patent 4,757,151 is hereby incorporated by reference. It describes the 9-fluorenylmethyl blocking group.

The compounds of general formula II are prepared by reacting

Wherein R 2 is as defined above with phosgene or a phosgene substituent to give a corresponding compound of formula

And then reacting a compound of formula IV with N-methyltryptophan to give the desired compound of formula II above.

Alternatively, a compound of formula IV can be reacted with the methyl ester of CC-methyl tryptophan to give

- 37-

which can then be converted to a compound of formula II by known processes such as hydrolysis with aqueous lithium hydroxide solution.

The following Schemes I illustrate procedures for the preparation of intermediates useful in the preparation of the final products of formula I. Scheme I below illustrates preparation steps of compounds of the present invention. Treatment of 2-adamantyloxycarbonyltryptophan 1 with N-methylmorpholine followed by isobutyl chloroformate afforded the mixed anionate intermediate, which was then mixed with N, O-dimethylhydroacylamine hydrochloride to provide the hydroxamate 2 which produced the aldehyde by reduction with LiAlH 3. Reductive amination of E with S-phenylalaninol and NaONBH4 afforded the amino methylene 4 (Example 1). The compound of Example 2 (compound 5) was prepared in exactly the same way. The above mixed anhydrous intermediate was treated with MeSiN4 to prepare the acid azide which was then reacted with the p-nitrobenzyl alcohol in the presence of DABOO to provide bis-urethane 6. Hydrogenation with the Pearlman for monouretane, and treatment of the amine with the ΗΒΪ és ester of 2- (acetoxymethyl) -3-phenylpropionic acid yielded compound 2. Example 3 after saponification of the ester with LeOH in aqueous 5DH. In Example 4, compound 10 was prepared in a reverse phase from 1. Here the mixed anhydride of 1 was treated with diazomethane to provide diazoketone 8. Reaction with HCl for chloroketone produced by reaction with diethylbenzyl malonate sodium produced a diester which. after saponification, decarboxylated to the acid 10,

vii

(I.e.

Example 3 5 4 Example 15 Example 2

P! W

Example 4

KEY i) isobutyl chloroformate, N-methyl morpholine, OH3OHH (CH3) .HCl; ii) LiAlH3

iii) S-phenylalaninol, NaCNBH3; iv) isobutyl chloroformate, N-methylm

Me = SiO2, then 40 ° C then para-NO DABCO; 2,4-diazabicyclo [2.2.2] octane (DAB1 v) Fd (OH) 2 H2, then KS-H02OCOH (OH4 Fh) CI2 OAc; then LiOH, IHF; vi) isobutyl chloroformate, N-methylmorpholine, CH 2 N 2; vii) HCl-dioxane; viii) Nal, NaOMe, then sodium diethylbenzyl malonate, then NaOH, then HCl, then heating.

Scheme 2

In Example 5, compound 12 was prepared by reduction of the amide in 11 using LiBH e and NaSiCl. In Example 6, compound 14 was prepared in a similar manner from 1%. Compound 14 was treated with acetyl chloride to provide the compound of Example 7 in the presence of a base. The major product was compound 15a, which was hydrolyzed to compound 16 of Example 8 by treatment with lithium hydroxide. Thiazoline (Example 9) was prepared by heating with Lawesson's reagent. 2-AdOCOHN '1

Me 'CONH- 2a

SCHEME 2

Ph

2-AdOCOHN '

2-AdOCOHN '

Ph

H

13. EXAMPLE 6 ii

3

2-AdOCOHN

Ph

H

nExample 16

Example 7 Example 8 R c = Ac, R 1 = H, R 2 = Ac, R 2 = Ac

Ac = H 41

KEY i) LiBH4, Me2 SiCl3 (ii) OH4 OOCl (Example 7), or later LiQH (Example 8); CH3 COCl, Et3 H iii) Lawesson's reagent. Scheme 3 shows the synthesis of Example 3 of esters and iso-esters. The condensation of monomethyl fumarate with R-phenylglycinol via the HOBT ester thereof afforded 18. Further condensation of this compound with R- or S-2-Adocec-MeTrpOH in the presence of Î ±, Î'-carbonyldiimidazole afforded the compounds of Example 10 (compound 19) and 11 (compound 20), respectively. In an exactly analogous manner the compound of Example 12 (compound 22) was prepared using monomethyl succinate. - 42 -

The compounds of formula (I) are as defined in formula (I). Js. K'Ph

1 R li

Example 11 = Configuration-R Example 11 &quot; Co-figuration, S02Me i, &quot; H02CT-

NHCO2 CH2 Cl2 PIP 21 iii

CQ

RTI ID = 0.0 &gt; 1 &lt; / RTI &gt;

He Νν- / λ ph Example 12

KEY i) Η0ΒΪ; ii) E-phenylalaninol; iii) E- or S-2-Adoc-cc Melro-OH (Compound 25)

Scheme 4 Reduction of 23a to the primary alcohol 24 with LiAlH2 followed by treatment with phenyl acetic acid and Î ±, Î''-carbonyldiimidazole gave isostere ester 23 &gt; Example 13 · Oxidation of 24 to the aldehyde 25 afforded a very versatile intermediate. This aldehyde 26 was treated with Wittig reagent to give 2 (Example 14) and compound 2 was further modified to 50%, by the hydrolysis of the ester and subsequent condensation with aniline. Treatment of the aldehyde 26 with the 3-phenylpropyl magnesium bromide Grignant reagent afforded the secondary alcohol 28 (Example 15)

SCHEME 4

Example 25

2-AdOCOHN

Ph 2 ' Example 15 Example 15 (a) (i) LiAlH3; ii) PliGH4 OO4 H; caryldiimidazole; iii) tetrapropylammonium perruthenate; -iv) PhOH-H 2 + P 2 Br-; v) PhOH2GH2GH2MsBr. - 44 -

Scheme 5 shows the synthetic routes of some homologous o-methyltryptophan examples, and their reverse amine isosteresters. The mixed 2β-anhydride prepared using isobutyl chloroformate and N-methylmorpholine was treated with diazomethane to give the diazoketone 1. this as a solution in benzyl alcohol was treated with ben. and Etâ,,O to give the homologous benzyl ester. Hydrogenation afforded the acid which was condensed. The title compound was prepared in the usual manner via pentafluorophenyl ester with S-phenylalaninol to give 4 (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 6 with Me2SiCl / LiBH3 in CH2 Cl2. This amine was then reacted with acyl phenyl chloride to give the compounds of Examples 19 to 22 inclusive. - 45 -

- 46 -

isobutyl chloroformate, mm, THE; ii) CH 2 H 2, EtOAc; KEY Reagents: i) iii) Ag + -OCOCH, EtHS, PHcH20H; iv) H2 / Pd / C; v) PEP, DCO, H2M (CH2 O) O H2 P1, EtOAc; vi) PEP, DCC, EtOAc; vii) HE5 (g), THE; viii) TMS-Cl, THE; ix) Ph (CH 2) n COOCl, pyridine, EtOAc. Scheme 6 illustrates the synthesis of α-methyltryptophol-α-alanine derivatives. The 2-adamantyl oxycarbonyl CC-methyltryptophan 25 (isomer R) or 58 (S-isomer) is condensed with p-alanine ester in the usual manner. This ester can then be hydrolyzed using standard procedures (for example aqueous LiOH, etc.) to give the carboxylic acid 41 or 42. Any of these two isomers may be condensed with an appropriate amine to give the compounds of Examples 25 and 24 (using S-phenylalaninol), Examples 25 and 28 inclusive (using R and S-phenylalanine-mide and Examples 29 to 51 inclusive (using phenylalanine ester).) The compounds of Examples 29 to 51 and compound 52 may then hydrolyzed using known procedures to give the compounds of Examples 52 to 35 inelu-siv-

ROCOHNHN.

Me

~ C02H

aa s? .3b R

.CONH

OH

SCHEME 6

ROCOHNH N, -CONH -

Zi R 1Q S 1 ii

Ph

ROCOHN

1 H-NMR (DMSO-d 6)

. Δ ExN ° • Δ ExN ° liR R 25 11 R R 29 41 R Ξ 26 ia r S 30 41 S S 27 51 S S 31 ia s R 28 iZ s R - vi H N, ROCOHN '

I conh ^ / conh co2h • Δ ExN '11 R R 32 ϋ R S 33 ϋ S S 34 ϋ S 35 35 48

GHAYA Reagents: i) PEP, DOO, cr-Alanine methyl ester, EtOAc; ii) LiOH, aq dioxane; iii) DOO, (S) - (-) - 2-amino-3-phenyl-1-propanol EtOAc; iv) PPP, DOO, (R) -phenylalaninamide, EtOAc; v) PFP, DOO, (S) -phenylalanine Benzyl ether, EtOAc or PPP, DOO, (R) -phenylalanine methyl ester, EtOAc; vi) Hg, Pd / G, EtOH. Scheme 7 describes the synthetic steps for the preparation of the CC-methyl tryptophyl glycine derivatives. As an illustration, 2-Adoc-α-methyltryptophan 23b can be easily condoned with the benzyl islet of glycine through the pentafluorophenyl ester 23b. Hydrogenation of this ester using 10% palladium on carbon in a solution of ethanol affords the carboxylic acid 58 with a high yield. Treatment of this acid with β- [N, N-dicyclohexylcarbodiimide and pentafluorophenol affords the active ester which is reacted with phenylalaninol in an easy manner to give the product of compound 59,

ESOU η

Example 11

(I.e.

Μ OHAVE Reagents: i) PPP, DOO, glycine hydrochloride, benzyl ester, Et3U, EtOAc; ii) H2 Pd / O, EtOH *, iii) PEP, DOO, s-phenylalaninol, EtOAc. - 50 -

Scheme 8 describes the synthetic steps for the Î ± -methyltryptophile and Î ± -aminobutyric acid derivatives. As an illustration, the carboxylic acid 23b can be condensed with the methyl ester of the β-aminobutyric acid to give 60, the hydrolysis of this compound with LiOH yields the product 62, Example 39 is produced when it is condensed with phenylalaninol through a pentafluorophenyl ester.

51 ΤΓΌ r ^ TTF7 '> 8

Me, 2AdOCHF

/ H, = CONH

.OH

If £ S £ T

Example 39

XXI

Me 2 -OCHN &quot; CONH R xi

(1) Reagents: i) ΡΞΡ, DOO, gamma-aminobutyric acid hydrochloride methyl ester

Et N, EtOAc; Ii) LiOH, aq 1,4-dioxane; iii) PPP, DOO, s-phenylalaninol., EtOAc. - 52 -

Scheme 9 shows the synthesis of substituted β-tri-p -phenylphenethylphenethylamides and their intra molecular cyclizations for compound 68, Example 40. The isopenitril 63 (prepared by the method described in Synthesis 465, 1990) in ethanol at -5 ° 0 with ethanolic HCl to give the amine 64. This compound was couplated in 2-adamantyl chloroformate to give the urethane 65. Hydrogenation of 65 with 10% palladium on charcoal at 310 KPa yielded mono Which was condensed in the usual manner to 2-phenethylamine to give 67. The product was formed by treatment of LiOH which subtracted the NH proton from the amide and cyclized to the ester group, releasing methoxide.

55 -

COOCH2Ph COOCH NC '&quot;

Κ2

CONHCH2CH2Ph

Example 40 Reagents: i) EtOH.HCl, 67%; ii) 2-adamantyl-00001, Et3 N, EtOAc, 58% iii) Pd / H2, EtOH, 88%; iv) H₂OHHOHOH · Ph, PFP, DOO, DMAP, EtOAc, 73% ν) LiOH (0.01M), 0Â ° .05 HF / S20, 79%. for the preparation. Scheme 10 refers to the synthetic phases of tryptophan derivatives f &gt; substituted. Isopropylamine was added to acetaldehyde and treated with HDI to give reaction which was reacted with indole in glacial acetic acid for 5 days to afford 70.0 g of isopropylamino ethylidene. then reacted with 71 in the presence of NaMeOH in hot toluene, yielding 72. Saponification and decarboxylation yielded 74 as a mixture of separable diastereomers. The amide 74 is dissolved in 4-sulfuric acid under reflux, then cooled to room temperature, and treated with 0.4 N barium hydroxide until the pH value is obtained at 8, yielding a free amine 75 which was reacted with 2-adamantyl chloroformate 76, producing the urethane 77. This compound was then condensed with phenylalaninol in a usual manner to give the product 78, Example 89.

56

GERMAN PROCESS FOR THE REACTION SCHEMES

Scheme 13a

The cyanoacetic esters or substituted derivatives 1 are alkylated with gramine and with a base such as, for example, NaOH in toluene to provide compounds 2 in analogy to known procedures. Compounds 2 are catalytically hydrolyzed with a nickel alloy of Raney refers to the amino esters 3 which are reacted with chloro-fluoroformamates for the esters of the carbamate 4. The esters 4 are hydrolyzed to the acids which are converted into the activated esters, for example with pentafluorophenol and dicyclohexylcarbodiimide for the pentafluorophenyl esters. The activated esters are reacted with an amine suitable for an amide of formula 6. Further conversions on the amide moiety of the molecules are made in analogy with known processes

Compounds of the general formula 13a: wherein R 1 is hydrogen; (CHR5) c-CHR4 -Ar 1a

OH 2

Εχ * 1-adamantyl, 2-adamantyl, (1S) -2-endo-bornyl

c = 0 or 1b? * η, -oh2oh, -σΗ2ο-σο- (σΗ2) 2σθ2Η &amp; * H, -NH-G02-t-Bu,

-CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2- Synthetic 15a:

- 58 -

SYNTHETIC SCHEME 15a gramine analogous to J. Org. Chem. 1953, 18, 1440, 1447

LiOH R1 R2

R2

,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒR1 -O-CO-NH-CH2-C-CO-NH- (CHR3) c-CHR4 -C6 H5 CH2

- 59 -

Scheme 15b:

Compounds of general formula Ia, wherein R1, R2 and R3 are H, are also prepared according to Synthetic Scheme 15b. Cyanoacetic esters 2 are reacted with amines suitable for cyano-8-acetamides, which are condensed with indole-3-carboxaldehyde and catalytic amounts of piperidine to provide the compound analogously according to the known procedures, is then catalytically hydrogenated with a Raney nickel alloy for substituted 3β-fnβ-aminopropionamides. Reaction with chloro or fluoroformates gave the carbamic acid derivatives 11.

60-indole-3-NC-CH 2 -CO 2 Et 7

h2 carboxamide aldehyde analogous to J. Org. Chem. 1331, 2, 1165

NC-C-CO-NH- (CH2) c-CH2 -Cg H5 CH

Ni by Raney

CHN-CH 2 -CH-CO-NH- (CH 2) c -CH 2 -C 6 H 5 ch 2

line

R1

-O-CO-NH-CH2-CH-CO-CH2-NH- (CH2) c-CH2-CeHi

11 61

Scheme 15o;

The compounds of general formula Ia,

are also prepared according to Synthetic Scheme 15c.

Damage acetamides 8 are alkylated with gramine and gramine and with a base, for example NaOH in toluene, to provide compounds 12 and 13 which are catalytically hydrogenated with an Eaney nickel alloy for the mono- or bis: substituted-(3-indolymethyl) -aminopropionamides 10 and 16. Reaction with chloro- or fluoroformates gave the carbamic acid derivatives 11 and 17.

sswkx »» ** SYNTHETIC SCHEME 15c

NC-CH2-CO-NH- (CH2) c-CH2-C6H5 & grams. NC -CH-CO-NH- (CH 2) c-CH 2 -C 6 H 5 CH 2 +

12.

h2Ni of Raney H2N-CH-CO-NH- (CH2) c-CH2-CgH5

R 20 = O-CO-Cl

O-CO-NH-CH 2 -CH-CO-NH- (CH 2) c -CH 2 -C 6 H 5 I

11 R 20 -O-CO-Cl

CH2 -O-CO-NH-CH2-C-CO-NH- CH2) c - θ | 2 - C6H5 nu

Scheme 16:

Compounds of general formula Ib,

Wherein E, E, Έτ, E and c are as defined above are also prepared according to Synthetic Scheme 16. The amino esters are reacted with carboxylic acid chlorides to give the amides 18. The Is-ester of compounds 18 are hydrolyzed with lithium hydroxide to the carboxylic acids 19, which are converted to the activated asters, for example with pentafluorophenol and dicyclohexylcarbodiimide for the pentafluorophenyl esters.

The activated esters are reacted with a suitable amine of formula 20. Other converters in Br and E are then made analogously to known processes.

SYNTHETIC SCHEME 16 R2 R2 η2ν-ch2

I-CO-NH-CH2-C-CO2

12 ch2

/ N H

R2

LiOH. i

R1-CO-NH-CH2-C-CO2

I ch2

H R 2 R 1 -CO-NH-CH 2 -C-CO-NH- (CHR 3) c-CHR 4 -Ar 2 CH

H 21-65 -

Scheme 17

Compounds of the general formula Ic,

Xc 0H o I 2 CH 2

are prepared according to Synthetic Scheme 17A and converted to 1- (3'-indole) -butan-3-one with potassium cyanide and ammonium carbonate in a synthesis of

Bucherer to give the hydantoin 21, which is hydrolyzed with an aqueous solution of sodium hydroxide to the amino acid 22, which is then esterified with methanol and hydrogen chloride to afford 2 '. Compound 23 is reacted with chloro- or fluoro-furanates to give the carbamic acid esters 24. The ester groups of compounds 24 are hydrolyzed with lithium hydroxide to provide the 2 'carboxylic acids. The 2 'acids are converted to the activated esters, for example, with pentafluorophenol and dicyclohexylcarbodiimide for the pentafluorophenyl esters.

The activated esters are reacted with the appropriate amine to give an amine of formula 26. Next, And other conversions in Ir and E analogously to known processes. - 66 -

67

Compounds of the general formula Id, R 1a -O-H-CCH 2 -CO-CO- (CHR 5) c -HR 4 - 6H 5

wherein R1, R2,

R 4 and R 5 are as defined above and R

They are prepared according to Synthetic Scheme 18, diethyl methylmalonate 2 'with gramine and with a base, for example NaOH in toluene, are obtained to give compounds 28 by known procedures. The diester 28 is hydrolyzed with potassium hydroxide to the 2? Mono-acid. The ester group 20 is selectively reduced with methyl borane sulfite complex to give the compound 10 which is esterified with methanol and sulfuric acid to the methyl ester 31. The hydroxy compound is reacted with p-toluenesulfonyl chloride and pyridine to give the tosylate 32. Nucleophilic substitution with potassium cyanide yielded the β-cyanoester, which is catalytically hydrogenated with a Raney nickel alloy for the amino ester 544. The 4-amino ester is reacted with chloro or fluoroformates to give the carbamic acid esters. The ester groups of compounds 5 are methylated with lithium hydroxide to give the carboxylic acids 36 which are converted into activated esters, for example with pentafluorophenol and dicyclohexylcarbodiimide for the pentafluorophenol esters. The activated esters are reacted with a suitable amine to give an amine of formula 37. Conversions are then made to sP and R 2 analogously to the known procedures. - 68 -

Et02C

CH-C02Et -> Et02C-C-CO2Et analog to J. Org. Chem 1 191.3, l, 1440, 1447 '21 11 11

Et02C

I TsCl ho-ch2 nc-ch2

H

Me I KCN 0 -CH 2 -C-CO 2 Me-CH 2

H R1 -O-

Me

I CO-NH- (CH 2) 2 -C-CO 2 Me

Me

R1 -O-CO-NH- <CH2) 2-C-CH2 CH2

H ch2

H R2

R1-0-CO

I NH- (CH2) 2-C-CO-NH- (CHR31 c-CHR4 -C &lt;

H 69

SYNTHETIC SCHEME 19 H

5

H

Reagents;

1) Methylmorpholine, iBuOCOCl; 2) GHJT · 3) Â · COCHâ,ƒ, HOGâ, ..., PU, AgOGHâ, ... Piâ, Hâ, ... d / G; 5) DPP, DOGi, Phenylglycine methyl ester; 6) GluOH-70 - Slimline Scheme 20

Reagents: 1) DGCi, DMF; 2) Eenylglycine, Dl-1,

SYNTHETIC SCHEME 21

Me v * 3-ind / 2-Ad-OCON COOH H 17

Me-3-ind Ph

2-AdOCON CONH H

1) LBH4 / 2) pTsOH Me3SiCl THF

Me4 λ-3-ind-X-Ph

2-AdOCON CH 2 NH H Thiosylate 11 (30% based on rec SM)

Et02C

Et3 N COCl

Me. λ-3-ind V '

2-AdOCON CH 2 N

Ph

Me-3-ind-X

2-AdOCON CH 2 N Η I

Ph COCH-: ISâ

CO19b (81%) LiOH COOEt

Me. Λ-3-ind X rtt

2-AdOCON CH 2 N

COOH

H L

CO 19d (81%) 72 - [3-indan-

2-AdOCON R COOH H 5.

SYNTHETIC SCHEME 23 (See Examples 97-102)

- 74

SYNTHETIC SCHEME 25 (cont) nh2 Κ2

O

O

- 75 -

BB®see írossaasaa

SYNTHETIC SCHEME 23 (cont) NH, j s Π o -CH,

COOH

NH 4 H 2 O

DCC

Q

Ι) HCl (g) 2) K 2 CO 3 3 CH 2 Cl 2

NH

1-yl)

the ia

NCO o

a, b-

- 77 -

The biological activity of the compounds of the present invention was evaluated using an initial screening assay that rapidly and accurately mediates the binding of the test compound to known CCK receptor sites. Specific COK receptors have been found to exist 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 assay, cerebral cortices taken from male CFI1P rats weighing about 30 to 40 g were weighed, weighed, and homogenized in 10 volumes of a 50 mM Tris -OH1 buffer (pH 7.4 from 0 to 4 ° 0). The resulting suspension was centrifuged, and the supernatant was stripped, and the pellet was washed by resuspension in Tris-HO1 buffer followed by recentrifugation. The final pellet was resuspended in 20 volumes of 10 nM Hepes buffer (pH 7.2 at 23Â ° C) containing 130 mM NaCl, 4.7 nM KOI, 5 nM Mg012, 1 nM EDI A, 5 mg / ml bovine serum albumin, and bacitracin (0.25 mg / ml).

In saturation studies, cortical brain membranes were incubated at 23øC for 120 minutes in a final volume of 500æl Hepes incubation buffer (pH 7v-) together with 0.2-20 nM tritiated pentagastrin (Amersham Irland, England ) ·

In the displacement experiments, the membranes were incubated with a single concentration (2 nM) of binder, along with increasing concentrations (10 to 10-14 M) of the competitive test compound. In each case, non-specific binding was defined as that which persisted in the presence of the unlabelled octapeptide W & 26-33 M).

After incubation, the membrane bound radioactivity was separated from the free in solution by rapid filtration through Whatman OF / B filters and washed by three-

times to 4 ml of ice cold Sris-HOl buffer. Filters of the samples incubated with tritiated pentagastrin were placed in polyethylene vials with 4 ml of scintillation broth, and the radioactivity was estimated by liquid scintillation spectrometry (47% to 52% yield). Specific binding to the OOK receptor sites was defined as the total bound tritiated pentagastrin minus the amount of tritiated pentagastrin bound in the presence of &quot; of octapeptide,

The saturation curves for specific binding of specific tritiated pentagastrin to rat cortical membranes were analyzed by the Scatcbard (Ann. New York Acad Sci. -VIII, 1910), to provide estimates for a maximum number of connection points (B #) and the constant

1B0A of equilibrium dissociation (Κ &amp;).

In the shift assays, inhibition curves were analyzed by logit-log curves or by a computer program of iterative adjustment of AIiLFII curves to provide estimates of ΐσΠΛ and nH values (apparent Hill coefficient). (10 μg values were defined as the concentration of the test compound required to give 50% inhibition of the specific binding). The inhibition constant (K +) of the test compound was then calculated according to the Obeng-Prusoff equation:

IC K.. 50 * and the

in which L 7 is the radiomation concentration and K - '- c is the equilibrium dissociation constant. - 79 -

Values a and for various representative compounds of the present invention are shown in Table III. The utilities of the compounds of the present invention as appetite suppressants are estimated based on the assays described below.

In the Agreeable Dietary Feeding test, adult male Hooded Lister rats weighing between 200 and 400 g are individually stored and trained to eat a pleasant diet. This diet consists of sweetened Nestll condensed milk, rat food powder, and water for rats, which when mixed together harden to a firm consistency. Each mouse is served with 20-30 g of pleasant diet for 30 minutes per day during the illumination phase of the dark-light cycle over a 5-day training period. The absorption of the pleasant diet is measured by weighing the food container before and after the 30 minute access period (0.1 g precision limit). Care is taken to collect and correct any wasted diet. Rats have free access to food pellets and to the base except for the 30 minute test period.

After the training period, they are built! dose response curves for 00K8 and for various repro- ductive compounds of the present invention (n = 8 to 10 mice per dosage level). MPE values (confidence limit of + 95%) were obtained for the anoretic effects of these compounds and are shown in Table III.

In therapeutic use as appetite suppression agents, the compounds of the present invention are administered to the patient at dosage levels of about 200 to about 2800 mg per day. . Table III shows the binding data | for some compounds. - 80 -

TABLE III

Binding data in Cerebral Cortexes taken from Macbo CELP Rats

Binding to Example Receptors CCK Number Central Ki (nM) 1 11500 5 Isomer 1 1230 3 Isomer 2 780 5 220 6 200 7 37 * 8 318

14 NT 9 808 11 260 10 39 2 1120

4 NT 19 353 20 493 21 &gt; 100 22 704 35 540 34 560 32 103 26 92 24 1100 31 1200 27 910 28 1400 29 240 30 &gt; 104 25 550 33 22 23 800

37 NT-

50 lbs 36 39 17 ΝΦ = Not rehearsed

Male Hooded Lister rats (175-250 g) are individually stored and fasted overnight (free access to water). They are anesthetized with urethane (1.5 g / kg IP) and the tracheas are cannulated to aid spontaneous breathing. The stomach is perfused continuously using a modification of the original method of Ghosh and Schild in HContinuous recording of secretion in the rat &quot;,

Br, J. Pharmac. 13: 54-61 as described by Parsons in &quot; Quantitative studies of drug-induced gastric acid secretion &quot;. (Pt. D, University of London, 1969). The stomach cavity is perfused at a flow rate of 3 ml / min with a 5.4% w / v glucose solution through both the esophageal and body cannulae. The fluid is driven by a roller pump (Gilson, Minipuls 2) through heating coils to raise its temperature to 37 ± 1 ° C. The perfusion fluid is collected by the bottom collection funnel and passed through the pH measuring electrode connected to a Jenwai pH meter (ΡΞΜ6). An output of the pH monitor is attached to a Rikadenki paper recorder for the online recording of the pH of gastric perfusion. Pentagastrin is stored as frozen aliquot and diluted to the required concentrations as required. solution sterilized at 0.9% pA cLe NaCl. The new compounds are dissolved in sterile 0.9% Na Na solution on the day of the experiment. The medicaments are administered intravenously through a jugular cannulated jugular vein in a dose volume of 1 ml / kg washed with 0.15 ml 0.9% w / v NaG1. The basal pH value was allowed to stabilize before administration of the compounds had begun. Typically pass. 30 minutes between surgery and the first administration of compound -

The compounds of the present invention are also useful as anti-ulcer agents as described below. to.

Aspirin-induced gastric damage is assessed in groups of 10 mice each.

All animals are fasted for 24 hours before and throughout the experiment. The medicament or vehicle is administered 10 minutes before an oral dose of 1 ml of a 45 mg / ml suspension of aspirin in 0.5% carboxymethyl cellulose &quot; CMC &quot;.

Animals are sacrificed 5 hours prior to administration of aspirin and the stomachs are removed and opened for examination. Gastric damage is classified according to the following scale:

Grade 1 Small haemorrhage 2 Large haemorrhage 3 Small ulcer 4 Large ulcer 5 Perforated ulcer

The dosages specified herein may, however, vary depending on the patient, severity of the condition being treated and the activity of the compound used. The determination of the optimum dosages belongs to the person skilled in the art.

The compounds of the present invention are also useful as anxiolytic agents as hereinafter described and discussed. Anxiolytic activity is assessed by the light / dark scanning assay in the rat (B.J. Tones, et al., Brit. J, Pharmaol., 93: 985-993, 1988). - 85 -

The device I is an open top carton, having a length of 45 cm in width and 27 cm in height, divided into a small area (2/5) and a large area (3/5) by a partition extending 20 cm above the walls. There is a 7,5 x 7,5 cm opening in the partition at ground level. The small compartment is painted black and the larger compartment I painted white. The floor of each compartment and marked with squares of 9 cm. The white compartment I illuminated with a 100 W tungsten lamp 17 cm above the housing and the black compartment by a similar red 60 f lamp placed similarly. The laboratory is illuminated with red light.

All assays were performed between 13 hundreds of hours, 0 minutes and 18 hours, 0 minutes. The mouse is rehearsed. placing it in the center of the white area and letting it explore the new environment for 5 minutes. Their behavior is recorded on television magnetic tape and behavior analysis is done later on from the record. Five parameters are measured: the delay in entering the dark compartment, the time spent in each area, the number of transitions between compartments, the number of crossed lines in each compartment, and the number of setbacks in each compartment.

In this study an increase in the time spent in the clear area is a sensitive measure, that is directly related to the anxiolytic effects of various conventional anxiolytic drugs. Medicaments are dissolved in water or saline and administered either subcutaneously, interperitoneally or by the mouth (F0) through a stomach needle.

The compounds of the present invention are useful as antipsychotic agents. Compounds are tested for their ability to reduce the effects of amphetamine intra-accumbens on the rat in the manner described below. - 84 -

Male Sprague Dawley (CD) Bradford male rats are used. The rats are stored in groups of five at a temperature of 21 ± 2 ° C in a 12 hour cycle of light-dark illumination between 7:00 p.m. and 20:00 p.m. Rats are fed the CBM diet (Labsure) and water infusion is allowed at will.

Rats are anesthetized with chloral hydrate (400 mg / kg SC) and placed in a stereotactic Eopf structure. Chronically introduced guide cannulas (constructed of 0.65 am stainless steel tubing held bilaterally in Parspex brackets) are implanted using standard stereotactic techniques to terminate 3,5 nun above the center of the nucleus of &quot; accumbens * 1 (Ant. 9.4, Vert 0.0, Lat 1.6) or 5.0 mm above the central nucleus of the amygdala (Ant. 5 * 8, Vet. -1.8, Lat. + 4.5) (Atlas de De Groot, 1959) · The guides are kept in view during a 14-day recovery period using 0.3 mm diameter stainless steel stilettos, which extends 0.5 mm to the ends of the guide.

Rats are manually restricted and stylets removed. Intracerebral injection cannulae, having a diameter of 0.3 mm, are given and the medicaments are administered in a volume of 0.5 microliters for 5 seconds (a further period of 55 seconds is left for deposition) from Hamilton syringes attached through polyethylene pipes for the injection units. Animals are used on a single occasion. Behavior experiments are conducted between 7 hours and 30 minutes and 21 hours and 30 minutes in a rest room maintained at a temperature of 22 ± 2 ° C. The rats are taken from the nursing home and left an hour to adjust to the new environment. The locomotor activity is evaluated individually in scrutinized Parspex cages

(25 x 15 x 15 cm height) (grouped in groups of 30) each equipped with a photocell unit along the 3.5 cm axis of the wall; this position has been found to minimize inappropriate activity counts due to, for example, tail and head movements when the animal is stationary. Interruptions of the light beam are recorded every 5 minutes. At this time animals are also observed to check for the presence of any non-specific alteration in locomotor activity, e.g. sweating, prostation, stereotyped movements, which could interfere with the recording of locomotor activity. The capabilities of the compounds of the invention to inhibit the hyperactivity caused by the injection of amphetamine in the &quot; acetumbens &quot; of the mouse. Increased locomotor activity followed by bilateral enfetamine (20 yag) ingrowth into &quot; acetumbens &quot;nucleus; peak hyperactivity (50 to 60 counts per 5 minutes &quot; 1) occur 20 to 40 minutes after the injection. This assay is predictive of antipsychotic activity (Costall, Domeney & Taylor & Tyers, Brit. J. Phar-mac., 92: 881-894).

The compounds of the present invention may prevent and treat the withdrawal response produced when chronic treatment with a drug is stopped or when excessive use of alcohol is stopped. These compounds are therefore useful as therapeutic agents in the treatment of chronic or excess alcohol drugs as discussed and described below. The effect of the compounds of the present invention is illustrated, for example, in the low lite / of mice in which nicotine is administered to five animals in a range of 0.1 to 100 mg / kg i.p. b.d. for 14 days. After a withdrawal period of 24 hours, a compound at 1.0 mg / kg, i.p. The increase in time spent in the clear area is a sensitive measure of the effect of the compound as an agent for treating the effects of nicotine withdrawal.

For the preparation of pharmaceutical compositions using the compounds of this invention, the pharmaceutically acceptable inert carriers may be solid or liquid. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories.

A solid carrier may be one or more substances which also act as diluents, flavoring agents, solvents, lubricants, suspending agents, binders, or tablet disintegrating agents; may also be an encapsulating material.

After the vehicle is a finely divided solid which is in admixture with the finely divided active component. The tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted to the desired shape and size.

In order to prepare compositions in the form of suppositories, the melting of a low melting wax such as a mixture of fatty acid glycerides and cocoa butter is first carried out and the active ingredient is dispersed therein by, for example, stirring. The homogeneous melt is then poured into convenient sized molds and allowed to cool and cure.

The powders and tablets preferably contain 5 to about 70% of the active component. 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 similar products.

A pharmaceutically preferred salt is the sodium H-methyl glucamine salt.

Preferred pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, cansylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycolylarsanilate hydrochloride, hydrochloride, hydroiodide, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate , polygalacturanate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc · The term &quot; composition &quot; is intended to include the formulation of the active component with an encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association therewith. Hostias are similarly included.

Tablets, powders, wafers, and capsules may be used as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. They can be mentioned -.88 -

the sterilized water or water-propylene glycol solutions of the active compounds as an example of liquid compositions suitable for parenteral administration. The liquid compositions may also be formulated in an aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration may be prepared by dissolving the active component in water and adding colorants, flavoring agents, stabilizers, and thickening agents, as appropriate, as desired. Aqueous suspensions for oral use may be obtained by dispersion of the finely divided active component together with a viscous material such as synthetic and natural gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known in the art pharmaceutical.

The pharmaceutical compositions are preferably in a dosage unit. In this manner, the drop is divided into unit doses by obtaining amounts of the active component. The unit dosage form may be a packaged composition, the package containing discrete amounts of the composition, for example, tablets, capsules, and feet packed in vials or ampoules. The unit dosage form may also be a capsule, wafer, or the tablet itself, or may be a suitable number of any of these packaged forms.

BXEEPLOS

Example 1 (R) - N - (1H-indol-5-ylmethyl) -2- (methoxymethylamino) -2-oxoethyl] -carbamic acid tert-butyl ester 5.5.1.1 To a solution of acid (1) (859 mg, 2.25 mmol) in dichloromethane (8 ml) was added H-methyl-

morpholine (495 mg, 1.45 mmol). The mixture was cooled to -15Â ° C (benzyl alcohol) and isobutyl chloroformate (292æL, 2.25 mmol) was added. The mixture was stirred at -15 ° C for 15 minutes followed by the addition of E, O-dimethylhydroxylamine hydrochloride (219 mg, 2.25 mmol). The reaction mixture was stirred at -15 ° C for 1 hour, then warmed to ambient temperature and stirred for a further period of 15 hours. The mixture was filtered and the filtrate washed successively with sodium hydrogen carbonate, water, 10% citric acid and brine, dried (MgSO 4) and evaporated to dryness. The crude material was purified by flash chromatography to give the hydroxamate (2) (694 mg, 73%) as a white foam; mp 72-80 ° C. (Det., G, 67.4; H, 7.35; N, 9.8%). S-ISOMER0) / C * / 20 ** + 8.9 (0-0.3, CHG13)); ^ max (film); 1 695 (00 urethane), 1 657 (00 amide) 741 cm 2 - (disubstituted Ph) 5 H (GHG 1), & 1.30-2.01 (14H, m, adamantyl), 2.99-3.24 (5H, m, indole GH2 + KGH3), 3. 58 (3H,

(1H, br d, urethane ΒΓΗ), 6.92-7.17 (3H, m), 5.6 (1H, br d, (1H, d, J 8 Hz, indole 7-H), 7,53 (1H, d, J 8 Hz, indole 4-H), 7.99 (1H, , s, indole HH). (R) - [1-formyl-2- (1H-indol-5-yl) ethylcarbamate tricyclo [5.5.1.1 3,7]

Lithium aluminum hydride (45 mg, 1.2 mmol) was added in portions over a period of 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 period of 30 minutes, then ether (30 ml) was added followed by an ice-cooled solution of 10% citric acid (40 ml). The mixture was stirred vigorously for 30 minutes, then the phases were separated to the aqueous phase extracted with ether (5 x 10 ml). The ether extracts were combined and successively washed with saturated sodium hydrogen carbonate (25 ml), water (25 ml), 10% citric acid and Bassa. .ysi. (25 ml) and brine (21 ml), dried (Na2 SO4) and concentrated in vacuo to give the aldehyde (5) (140 mg, 83%) as a white foam; ΛΓ (film) 1725 sh (aldehyde 0 0 0) and 1696 cm -1 (urethane 0-0) HH (300 MHz DOOl ^),), ΠΠ77-2.1.1 14 (14-H, m, adamantyl ), 3.26 (2H, d of d, J 15 and 7 Hz, indGH 2), 4.58 (1H, br d, OH (H H R OCH), 4.84- (1H, s, adamantyl- (1H, br d, 8Hz, indole 4-H), 8.24 (1H, d, J = 8Hz) br s, indole RH), 9.64 (1H, s, CHO). (2-phenylethyl) amino] -7- (1H-indol-3-ylmethyl) ethyl] carbamate, tricyclo [3.3.1.1.2,7] dec-2 (4), Example 1

(37 mg, 0.59 mmol) was added portionwise over a period of 15 minutes and a solution of aldehyde (3) (136 mg, 0.370 mmol) and (5) -2-amino-3 -phenyl propanol (61 mg, 0.40 mmol in methanol-acetic acid (99 ml) (5 ml) The mixture was stirred for 2 hours at ambient temperature then cooled (ice-bath) Saturated sodium hydrogen carbonate The organic phase was separated, washed with brine (5 ml), dried (Na2 SO4) and evaporated to dryness. The crude product was purified by chromatography on silica gel (50 ml). Column chromatography (SiO2: dichloromethanemethanol (95: 5) as eluant7 to give the aminoalcohol (4) (60 mg, 32%) as a beige foam; mp: 59-61 ° C (Det: C, 73.7; H, 7.8, N, 8.3%, 3.01H 3 H 3 O 2 O 2 requires C, 73.7; H, 7.9; 8.3%), Vmax (film) 3125 (OH), 1,690 (urethane) , 1 266 (OH), 1048 (O-O), 740 and 701 cm-1 (monosubstituted Pb); , 4.44 (1H, dd, J = 11.2Hz), 4.44 (1H, m, (1H, dd, J 11 and 4 Hz, of OH OH), 3.97 (1H, m, -CH2 CH2 OH), 4.66 (1H, br d (1H, m, indole, 5,6-H + Pb), 4.73 (1H, s, adamantyl 2-H), 6.87 (1H, d, , 7.29 (1H, d, 8Hz, indole 7-H), 7.55 (1H, d, 7Hz, indole 4-H), 7.97 (1H, brs, indole 1). - 91 -

Example 2: 5- (S) -7-2- [(hydroxymethyl) -2-phenylethyl] amino] -1- (1H-indol-3-ylmethyl) ethyl] carbamate and tricyclo [5.1.1.2.1,7dec-2 (5), Example 2 Compound 5 (253 mg, 23%) was synthesized using the same procedure as described above for compound (4). White foam, mp: 62-63Â ° C (Det: C, 73.3; H, 7.8; M, 8.3%) requires C, 73.2; H, 7.9; H, 8.3%). 3 331 (OH), 1669 (urethane), 1113 (H-H), 1360 (O-H), 1048 (O-O), 739 and 701 cm -1. H (O D +), § 1.47-2.10 (16H, m, aAhantil + MH + OH), 2.54-3.04 (TH, m, OH, OH, OH, OH), Pb + OH2 <5H (OEy) H) OH (1H, m), 3.30 (1H, AA, J 11 and 6 Hz, OH of OH OH), 3-59 (1H, AA, J, 11 and 4 Hz, OH of OH) (1H, br-s), 6.86 (1H, brs, inAole 2-H), 7.06-7.32 (7H, m, inAole 5 1H), 7.35 (1H, br s), 7.59 (1H, d, J = 8Hz, indole 4-H), 8.03 (1H, br s, ).

To a solution of (1-hydroxyethyl) -6- ) (3.62 g, 9.74 mmol) in anhydrous THF (36 mL) at -10 ° was added H-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.

Azide A and trimethylsilyl (S) -Alcohol (1.89 ml, 14.2 mmol) was added to the filtrate and the resulting solution was 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 hydrogen carbonate (100 ml). The phases were separated and the organic phase was 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 40Â ° C until the preparation of the isocyanate was complete (IV: 0 N, 2139.0øC). P-Nitrobenzyl alcohol (2.20 g, 14.3 mmol) and DABC0 (149 mg, 1.33 mmol) were added and the mixture was left at 40 ° C for 15 minutes. The solvent was removed in vacuo and the crude product purified by column chromatography (4: 1) as eluent / to give (6) (2.12 g, 42%) as a yellow solid which was recrystallized from ether / hexane, mp: 138-149 ° C. (S, 1H, adamantyl-2-H), 5.14 (s, 1H), 3.85 (brs, , 2H), 5.37 (m, 1H, OH (ISCEDCfOg) -JSEBXX> 2), 0.90-7.29 (m, 4H, indole H-2, b-5, H-6, and MH), 7.34 (m, 3H, ind H-4, ind H-7, H H), 8.16 (d, J 8 Hz, 2H, J = 8 Hz) Pb), 10.61 (s, 1H, ind MH); IR (film): 2908 + 2855 (adamantyl), 1703 (br. 00 urethane), 1520 (sro2), 13.77 (ho2)

Anal. C29 H32 N4 O6 requires C, 65.40; H, 6.06; N, 10.52.

Det. 0.65.25; H, 6.03; 10.50. (1H) -indol-3-yl) ethyl] carbamate, tricyclo [3.3.1.1]), 7dec-2-yl Compound (7), Example 30 Urethane (6) (190 mg, 0.357 mmol) in ethyl acetate (36 ml) was hydrogenated in palladium on carbon hydroxide (Pearlman's catalyst) at 310Â ° C and 30Â ° for 1 hour. The mixture was filtered through celite to remove the catalyst in a flask containing the ester of 2- (acetoxymethyl) -3-phenylpropionic acid HBOT. The latter was produced by the reaction of 2- (acetoxymethyl) -3-phenylpropionic acid ( 81 mg, 0.36 mmol) in ethyl acetate (5 mL) was treated with 1-benzyloxybenzotriazole (57.5 mg, 0.426 mmol) and DOCI (85.9 mg,

0.416 mmol) at 0 ° C for 30 minutes. 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 EHF: MeOH: H 2 O (3: 2: 1) (6 mL) was added lithium hydroxide monohydrate (28 mg, 0.67 mmol), and the mixture was 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 crude product was purified by column chromatography (SiO 2): dichloromethane / methanol (95: 5) as eluent / to give a white solid. (300 mg): δ 1.43-2.04 (m, 2H), 2.00 (s, 3H), 1.40 (s, 3H) (m, 17H, adamantyl + H 2 O), 2.42 (m, 1H, HH00, OH), 2.67-3.22 (br m, 5H, CH2 + OH); 1H NMR (CDCl3): 4.78 (s, 1H, adamantyl H = 2), 5.40 (brs, 1H), 5.58 (brs, 1H), 6.26 (brs, 1H, amide MH), 6.82 (s, 1H, ind H-2 ), 7 · 02-7 · 37 (m, 9H, Ph + ind H-5, ind H-6, ind H-7, + CHCl 3), 7.44 (d, J 8 Hz, ind H-4), 860 (br, OH), 2910 + 2855 (adamantyl), 1695 (urethane 00), 1660 (amide 00) Isomer II: TLC Rf = 0.19 (s, 1H, ind MH) NMR (300 MHz): δ 1.47-2.08 (m, 17H, adamantyl + H 2 O), 2.42 (m, 1H, MH + O), 2.61-2.97 (m, , 3H, OH (Brs, 2H, OH), 4.75 (s, 1H, adamantyl H-2), 5.18 (brs, 1H), 5.49 (brs, 1H), 6.30 (brs, 1H, amide MH), 6.96 (s, 1H, ind H-2), 7.02-7.30 (m, 9H, Ph + ind H-5, ind H-6 + OHCl), 7.37 (d, J 8 Hz, 1H, ind H-7), 7.57 (c, J = 8 Hz, 1H, ind H-4), 8.12 (s, 1H, ind MH); IR (film): 3520-3160 (br, OH), 2907 + 2855 (adamantyl), 1696 (urethane CO), 1660 (amide 00).

Example 4 2-Adamantiloxycarbonyltriptophandiazocetone (8) • Preparation of diagomethane. DIAZOMETANO IS VERY TOXIC Ξ EXPLOSIVE (USE RUGGED GLASS CONNECTIONS). HANDLE WITH CARE IN A HOTE. The n - METHYLNITROSUEEIA is HIGHLY TOXIC AND CARCINOGENIC. HANDLE A HOTE USING A FULL MASK AND GLOVES.

A 40% potassium hydroxide solution (4.5 mL, 32 mmol) was added dropwise to a suspension of N-methylnitrosurea (1.5 g, 15 mmol) in ether (25 mL), cooled ice-salt bath. After all the solid has dissolved an additional base is added if necessary), the ethereal diazomethane solution is dried over solid potassium hydroxide. This drying process was repeated twice more and the diazomethane used immediately. To a solution of 2-adamantyloxycarbonyl-tryptophan (1) (1.77 B &gt; 4.61 mmol) in THF (25 ml) at 0 ° C was added N-methylmorpholine (557 μl, 5.07 mmol) and isobutyl chloroformate (658 μl, 5.00 mmol). The mixture was stirred for 20 minutes at 0 ° C and then filtered. To the filtrate was added a solution of diazomethane (10 mmol) in ether (produced from N-methylnitrosurea (1.0 g, 10 mmol)). To the resulting solution was stirred for 15 minutes at 0 ° C, then for 15 hours 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 (2 x 10 ml), 5% citric acid (2 x 10 ml), NaOH 1 IN (10 ml), and brine (10 ml). Dried (MgSO 4) and the solvent removed in vacuo. The product was purified by silica gel column chromatography (5: 4) as eluent to afford the diazoketone (8) (1.356, 72%) as a yellow foam, mp: 72-75 ° 0. Î »max (CDCl3) λ 109 (N2); (CO) and 740 cm-1 (disubstituted Ph); (1H, dd, J 15 and 8 Hz, OH of GH 2 indole), 3.29 (1H, dd, J 15 and 5 Hz, 1H) , CH of 0H2indole), 4.51 (1H, m, CH2 CH (NHR) Î'), 4.69 (1H, s, adamantyl-2-H); 5.90 (1H, brs, CHN2); 6.41 (1H, s, NH CO); 7.10 (1H, t, J 7 Hz, indole 5 or 6-H), 7.09 (1H, t, J = 7)

Hz, indole 7-H), 7.64 (1H, d, J 9 Hz, indole 4-H), 10.05 (1H, brs, indole NH). - 95 -

2-Adamantiloxycarbonyltriptophanyl 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 diazoeetone (8) (1.35 g, 3.52 mmol) in THF (100 mL) at 0 ° C. The reaction was followed by infrared to detect the disappearance of the Hg peak (2309 cm-1) in the starting material. When all of the diazoeetone was removed (about 60 minutes) the reaction mixture was neutralized with saturated sodium hydrogen carbonate (20 ml). The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (100 ml) and sodium hydrogen carbonate (1090 ml). The phases were made up with brine (50 ml), dried (MgSO 4), and the solvent removed in vacuo. The crude product was recrystallized from ethyl acetate-hexane to provide the chloroketone (9) (1.29 g, 94%), m.p. 138-140 ° C. (DMSO-d6): δ 6.66 (1H, d, J = 6.6%), 17.92% (CO-chloroketone), 1668 (CO-urethane), and 736 cm-1 (disubstituted Ph); (CDCl3): Î'1.4-5.2.06 (14-H, m, adamantyl), 3.27 (2H, m, CHâ,,ind), 3.96 (1H, d, J 16 Hz, CH of CH 2 Cl), 4 -11 (1H, d, J 16 Hz, OH of CH 2 Cl 2), 4.83 (2H, m, OCH2 OH and adamantyl 2-H), 5.35 (1H, d, J = 7 Hz, NH), 7.00 (1H, d, J 2 Hz, 2-H indole), 7.14 (1H, t, 6 Hz, indole 5 or 6-H), 7.22 (1H, t, J 6 Hz, indole 5 or 6-H ), 7.37 (1H, d J 8Hz, indole 4-H), 8.20 (1H, s, indole MH), 7.37 (1H, d, J 8Hz, indole 7- 3 - [(1 H -indol-3-yl) -2-oxo-5-methylcyclopropyl] -3- [1 - [(2-yloxy) carbonyl] butyl] benzenepropanoic acid, 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. This mixture was stirred at room temperature for 15 minutes,

(800 mg, 0.30 mmol) of an anionic solution produced by the reaction of sodium hydride (60% oil dispersion) (88 mg, 2.2 mmol) in anhydrous DME (3 ml) with diethylbenzyl D-malonate (950 μmol, 40 mmol) at room temperature. 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 crude material was purified by column chromatography (SiO2) and hexane-ethyl acetate (2: 1) as eluant7 to give the keto-diester (100 mg, 59%). M.p .: 49-54 ° C. (Det: C 70.8, 5.7, 2, H, 4.4%, requires 0.707, H, 7.05; N, 4.5%). ^ max (0E2012 film) 1728 cnT1 (00); (1H, dd, J 19 Hz), 3.18 (1H, dd, J 15 and 6 Hz, OH H 2ind), 3.24 (1H, dd, J 15 Hz), 3.18 (1H, , 4.18 (4H, m, 2 x CH 2), 4.62 (1H, m, C H 2 CH (G 0) NH), 4.79 (1H, s, adamantyl 2 (1H, d, J 2 Hz, 2-H indole), 6.40 (1H, d, J = 8 Hz, , 7.07-7.25 (5H, m, indole 5, 6-H, Ph 3,4,5-H), 7.34 (1H, d-J 8 Hz, ind 7- H), 7.62 (1H, d, J 8). Hz, indole 4-H), 8.07 (1E, s., Indole HE).

A solution of the keto-diester (1.19 g, 1.89 mmol) in ethanol (5 mL), and 6 N NaOH (946 Âμl, 5.67 mmol) at room temperature for 1 hour was stirred. The solvent was removed in vacuo and the residue diluted with H2O (10 mL).

This aqueous solution was acidified to pH 2 with concentrated HCl, then extracted with ethyl acetate (3 x 50 ml). The organic extract was washed with brine, 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 (SiO2: toluene-acetic acid (9: 1) as eluant to give the keto acid (10 (783 mg, 78%) as a yellow foam, mp -80 ° C ¹H-NMR (300 mHz): δ 1.38-2.22 (m, 16H, adamantyl + H2O), 2.55-3.25 (m, m, 1H, H HCOOH), 4.57 (s, 1H,

adamantyl 2-H), 6.95-7.77 (m, 10H, Ph + ind 2-H, ind 5-H, ind 6H, ind 7-H + EH), 7.49 (d, J 8 Hz, 1H, ind 4-H), 10.58 (s, 1H, ind KH). IR (film): 3460-3200 (br, OH), 2920 + 2856 (adamantino) 1707 (br, ketone ester 00? Acid, urethane CO). Anal. 1 H-NMR (CDCl 3):? N, 5.30%. Found: C, 73.18; H, 6.98; M, 5.05%.

EXAMPLE 5 Trifluoromethyl-5-hydroxy-2-phenylethyl) amino] -3- (1H-indole-3-yl) -2-methylprop-2-yl] carbamate )

This compound was prepared in a similar manner to that used to prepare compound (14) (example 6) except compound (11) was used. 0.42 g (43%) are recovered; m.p. 78-80 ° C; I? (br) 2910, 1694 (C = O urethane) cm -1; (1H, d, J = 8Hz, indole H-4), 7.4-7.1 (8H, m, Ph + indole H-5, (1H, m, indole H-2), 5.0-4.6 (3H, m, adamantyl H-2 + urethane EH + 'OH), 3.5-2.6 (6H, m, 3 x CH2), 2.1-1.5 (15H, m, adamantyl + OH) 1.4 (3H, s, OH)) / δ + + 18 ° (HOH3, 22 ° C, c = 0.2); FABLIS (m + / e) 502 (m * + H); anal ° 31H39N303 * 0.5 H2 ° »re luer σ 72.91% &gt; H 7.90%, H 8.23%; det: 0 72.56%, 7.84%, Έ 7-95%.

Example 6 [3R- (R)] [S] (cis) -7- [1- (2-Hydroxymethyl) -2-phenylethyl] amino] -5- (1H-indol- (14) To a solution of lithium borohydride (4 ml, 2M solution, 8 mmol) in tetrahydrofuran under nitrogen was added a solution of chlorotrimethylsilane (1.75 g &gt; 16.0 mmol) in tetrahydrofuran (5 mL). A white precipitate of lithium chloride was observed. After 2 minutes a gentle addition (over a period of 3 to 4 minutes)

solution of Compound (13) (1 g, 2 mmol) in tetrahydrofuran (15 ml) and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was cautiously treated with methanol (5 ml) and the volatiles were removed in vacuo (40øC). The residue was purified by flash chromatography on the normal silica gel phase using hexane / ethyl acetate as eluent ( an elution gradient technique, comprising from 80% hexane: 20% ethyl acetate to 100% ethyl acetate) was used. 0.60 g of the starting material and 0.26 g (27%) of the desired product (14) were recovered as a white foam; IR (br) 2900, 1694 (C = O urethane) in &quot;1; (1H, br s, indole EH), 7.6 (1H, d, J 8 Hz, indole H-4), 7.4-7.1 (8H, m, Ph + indole H-5, H-6 (1H, s, adamantane H-2), 3-6-3.3 (2H, s, urethane CH), 6.9 (1H, d, J2Hz, m), 3.0-2.6 (5H, m, 2x0H2 + 1xOH), 2.1-1.5 (15H, m, adamantane + OH) , 1.25 (3H, s, CH2).

A solution of (14) (0.2 g, 0.4 mmol) and 4-toluenesulfonic acid monohydrate (0.074 S, 0.40 mmol) in acetone (10 mL) and subsequent removal of the solvent in vacuo to give a white solid; m.p. 110-113 ° C IR (crude)

Found: C, 67.23; H, 7.26; H, 5.84; S, 4.36. - 99 -

Example 7

[(R *, S *)] 7-A-772- (1H-indole-3-ylmethyl) -2- [imidazolidinyl] To a solution of (14) (0.05 g, 0.10 mmol in dichloromethane (10 mL) at ambient temperature was added acetyl chloride (0.10 mL, 1.4 mmol) and the reactants were stirred for 1 hour, the volatiles were removed in vacuo (40øC) and the residue purified by flash chromatography using 80% hexane: 20% ethyl acetate as the eluant 0.024 g (44% ) of (88) as an amorphous white solid.1YY (crude) 2910, 1739 (C = O ester, 1700 (O = urethane) cm-1 NMR (CDCl3): Î'8.2 (1H, s, indole NH ), 7.6 (1H, d, J 8 Hz, indole H-4), 7.04-7.0 (8H, m, Ph + indole H-5, H-6, H-7), 6.9 (1H, d, (1H, s, urethane NH), 4.8 (1H, s, adamantane H-2), 5.9 (2H, d, J 4 Hz, 2H), 5.1 (2K , m), 3.0-2.5 (4H, m, CHâ,ƒHâ,ƒHâ,,NH2N), 2.1-1.4 (17β, m, CHâ,, GOâ,, + adamantane), 1.3 (3H, s, OH).

A mono-4-toluenesulfonate salt was prepared by dissolving (15) (0.02 g, 0.04 mmol) and 4-toluenesulfonic acid monohydrate (0.007 0.04 mol) in acetone (5 ml) and subsequent Removal of the solvent in vacuo to give a white solid mp 98-101 ° C. + -. + 32 ° (GH +), 24 ° C, O = 0.5); PAB MS (m + / e) 558.5 (m + + H); Anal. Calc'd for C 20 H 18 ClN 3 O 6 requires 65.84%, H 7.14%, 3.SST 5.62%, S 4.29%. Det: G 65.48%, Η 7 .Οβ%, Μ 5 · 53 3 4.31%.

Example 8

[5 - ((R), S, 7] -hexyl] -2- (1H-indol-3-ylmethyl) -2-norycyclo5.3.1.1 7dec-2-yloxycarbonyl] amino] propyl] amino] benzenepropanol (15a) To a solution of (14) (0.05 g, 0.10 mmol) in dichloromethane (10 ml) at room temperature was added triethylamine (1 ml, 7 mmol) followed by acetyl chloride 1 ml, 1.4 mmol) and the reactants were stirred for 1 hour. The volatiles were removed in vacuo and the residue purified by flash chromatography using hexane: ethyl acetate as eluent. 0.045 g, (74%) of (88a) was recovered as an amorphous solid; 17 (br) 2920, 1740 (C = O ester), 1709 (C * C urethane), 1632 (C = O) in &quot; 1. And / or j. tricyclo [5.1.1] dec / 2-yl (16) [R] - (R) - (-) - To a solution of (15a) (0.03 g, 0.05 mmol) in tetrahydrofuran (5 mL) was added methyl A solution of lithium hydroxide (0.1 g, 2.4 mmol) in water (5 ml) was added and the reactants were stirred for 15 minutes. The reaction mixture was then acidified with hydrochloric acid (2 g) and The extracts were dried (magnesium sulfate) and evaporated in vacuo (40Â ° C).

The residue was purified by flash chromatography using hexane: ethyl acetate as eluent. 0.024 g (86%) of 89) was recovered as a white solid; m.p .: 109Â °-H2 O /% 7d + 51Â ° (22Â ° C, 0H013, c = 0.5); 17 (br) 2900, 1694 (C = O urethane), 1621 (C = 0) cm -1; EESN (CDCl3): 8.1 (1H, s, indole KH); (1H, d, J = 8 Hz, indole H-4), 7.4-7.0 (8H, m, Ph + indole H-5, H-6, H-7), 6.9 (1H, s, indole H-2 ),

(1H, br, urethane NH), 4.8 (1H, br, adamantane K-2), 4.4 (1H, s, OH), 3.9 (1H, d, J 12 Hz, (1H, m, OH), 3.4 (1H, d, J 14 Hz, one of CH2 indole), 3.3 (1H, d, J 13 Hz, one of (1H, d, J 14 Hz, one of GH 2 -indole), 2.0 (3H, s, CH 2 CO), 1.9 (1.4H, d, J 8 Hz, (14H, m, adamantane), 1.1 (3H, s, OH), Anal: Calculated for C 20 H 20 N 2 O 3: 7.73% H 7.30%, FAB MS (m / e) 558 (m + H)

(R) -4- [2-hydroxy-1-phenylethyl) amino] -4-oxo-2-butenoate (18) To a solution of monomethyl fumarate Ae (3.0 g, 23 mmol) in ethyl acetate (40 g) was added 1-hydroxybenzotriazole hydrate (3.0 g, 22 mmol) followed by N, N -dicyclohexylcarbodiimide (4.5 g, aa mmol) and the reaction mixture was stirred at room temperature for 1 hour. The solid was collected by filtration and discarded. To the filtrate was added (R) -C? -Phenylglycinol (3.0 g, 22 mmol) and stirring was continued for 20 minutes. The volatiles were removed in vacuo (40 ° C) and the residue purified by flash chromatography on silica gel using hexane: ethyl acetate (1: 1) as the eluent. 2.5 g (46%) of (18) were recovered as a white solid, m.p .: 75-77 ° C; 17 (crude) 3250 (OH), 1729 (C = O ester), 1666 (C = O amide), 1640 (C = C) cm-1; (1H, d, J 15 Hz, trans alkene), 6.8 (1H, d, J 15 Hz, trans alkene), 6.6 (1H, (1H, m, OH), 3.9 (2H, t, J 3 Hz, OH), 3.8 (3H, s, GHj), 2.3 (1H, t, J 5 Hz, OH ):  € ƒâ € ƒâ € ƒ0.53% (MH +): C = 0.6% (MH +); Trihydroxymethyl-3,9-dioxo-7-phenyl-5,13-dioxa-2,8-diazotetradec-10-enoate / 5.3. To a solution of Î ±, Î'-carbonyldiimidazole (0.15 g, 0.90 mmol) in dichloromethane (40 ml) was added the compound (23b) (0.25 g , 0.63 mmol). After 20 minutes of stirring at room temperature the compound (18) (0.2 g, 0.8 mmol) was added and the reaction mixture was heated under reflux for 10 hours. After cooling to room temperature the volatiles were removed in vacuo (40 ° C) and the residue was purified by flash chromatography (hexane / eluent 1 of ethyl acetate). 0.28 g (71%) of (19) -10β-

as a white solid, m.p .: 96-99 ° C. IR (br) 2910, 1730 (O = O), 1695 (O = urethane), 1670 (C = O amide + C = O) in NMR (CDCl3): 8.3 (1H, br, indole, (1H, d, J 8 Hz, indole H-5), 7.03-6.9 (10H, m, indole H-6, H- 7, H-2 + phenyl + amide MH + one of alkene OH), 5.3 (1H, br, one of CH2 -Q), 5.1 (1H, s, urethane MH), 5.0 (1H, br, (1H, brs, adamantane H-2), 4.1 (1H, dd, J 11 Hz, 4 Hz, one of CH 2 O), 3.8 (3H, s, CH 2), 3. 5 (1H, d (1H, d, J = 14 Hz, one of OH-indole), 2.1-1.5 (18H, m, adamantane + OH): (M + H +) 6281 (M + + H): Anal. = 68.88%, H, 6.58%, M, 6.69% H, 6.83% N, 6.57%.

Example 11 3 - [(1-indol-5-yl) methyl] -3-methyl-4,9-dioxo-7-phenyldioxane-2,8-diazetetradec-10-enoate (20)

Prepared by a route similar to that used to prepare compound (19) 0.30 g (76%) of compound (20) was recovered as a white solid, m.p .: 104-105Â ° C; IR (crude) 2920, 1728 (O = 0 ester), 1720 (O = O) urethane), 1700 (C = O), 16.0 (O = O amide) cuT1; (1H, d, J 8 Hz, indole H-5), 7.4 (1H, br, indole ME), 7.15 (1H, (7H, m, indole H-2 + amide HH + alkene), 5.3 (2H, br, urethane), 7.1-6.7 (4H, m, (1H, m, OH), 4.1 (1H, dd, J 11 Hz, 4 Hz, one of OH-O-OH), 4.8 (1H, br.adamantane H- ), 3.8 (3H, s, ester, OH), 3.4 (1H, d, J 14 Hz, one of HO 2 -indole), 3.2 (1H, d, J 14 Hz, one of HO 2 -indole), 2.1 -1.5 (17H, m, adamantane + OH): FAB MS (m + / e) 628 (m ++ H):

Anal; 7 hours, 68.88%; H, 6.58%; N, 6.69%;

Det; 0, 68.86%; H, 6.57%; M, 6.77 # · -103 -

12

Example (R) 4 - [(2-hydroxy-1-phenylethyl) amino] -4-oxobutenoate

Prepared by a route similar to that used to prepare compound (18) (see Example 10). 3 (6.6 g, 65%) of (21) were recovered; m.p .: 59-61 ° C; IR (crude) 3250 (OH), 1737 (C = O ester), 1651 (C = O amide) cm -1; NMR (Î'D015) Î'7.2-7.4 (5H, m, Ph), 6.4 (1H, br d, Î'), 5.11 (1H, m, OH), 3.7 (3H, s, OH), 2.8-2.5 (6H, m, 3 x O), 1.7 (1H, br, OH);  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ7 D-33 ° anal requires: 0 62.14% H 6.82% M 5.57%;

Det: 0 62.21% H 7 * 13% M 5 · 73%. Triiodo-3,3-dihydro-3 H -indol-3-yl) methyl] -3-methyl-4,9-dioxo-7-phenyl-5.13-dioxo-2.8-diazetetradecanoate 22) To a solution of 1,3-dicyclohexylcarbodiimide (0.38 g, 1.5 mmol) and 4-dimethylaminopyridine (0.05 g, 0.40 mmol) in dichloromethane (40 ml) was added the compound (23 ) (0.50 g, 1.3 mmol). After stirring for 20 minutes at room temperature the compound (21) (0.30 g, 12 mmol) was added and the reaction mixture was heated under reflux for 2 hours. The volatiles were removed in vacuo (40Â ° C) and the residue purified by flash chromatography (hexane / ethyl acetate eluent). 0.41 g (52%) was recovered as a white solid, mp: 69-71Â ° C IR (crude 2920, 1739 (C = O ester),

(1H, d, J = 8Hz, indole H-4), 7.4-6.9 (1H, d, J = 8Hz) (1H, brs, urethane MH), 4.8 (2H, m), 5.2 (1H, brs, (1H, m, one of CH2 OH), 3.7 (3H, s, OH ester), 3.4 (2H, M, CH2-indole), 2.7 -2.5 (4H, m, 2xOH), 2.1-1.5 (m, 7H, m, adamantane + OH): ZCl ^ = -180 (CHCl,, 22.0 = 1.0). FAB MS (m + / e), 630.0 (m * + H); Anal: Calc'd for C 20 H 15 N 3 O 4 • • 5H 2 O requires C, 67.69; H, 6.94; M, 6.58; det: 0, 67.36; H, 6.99; M, 6.51. Some small peaks at 4-, 4-, 4, 2, 3 in the RMBT spectrum may indicate the presence of a small amount of another isomer,

Example 13 (R) - [[2-hydroxy-1- (1H-indol-3-ylmethyl) -1-methylethyl] acetamamate (24) To a solution of compound (23) (E = Me) (1 (1.0 g, 2.4 mmol) in anhydrous THF (20 mL) at 0 ° C under a nitrogen atmosphere was added a solution of lithium aluminum hydride in ethyl acetate (20 ml) was added cautiously and the resulting solution was washed with acid (H 2 O 2, 2 x 100 ml), dried over sodium sulfate, and evaporated to dryness. (24%) as a white solid, mp: 72 DEG-46 DEG C. (crude 2918, 1693 (C = O-urethane) (1H, d, J 8 Hz, 1H), 7.35 (1H, d, J = 8 Hz, 1H) indole H-5), 7.2-7.0 (3E, m, indole H-6, H-7, H-2), 4.85 (1H, br s, urethane RH), 4.8 (1H, br, , 4.0 (1H, d, J = 14 Hz, one of C--indole), 3.0 (1H, d, J 14 Hz , 1 H -indole), 2.1-1.5 (14H, m, adamantane), 1.2 (3H, s, CH3); Α D + 42 ° (GHG 13, 22 ° C = 1); FAB MS (m / e) 383 (m + + H); Anal: C23 H30 N2 O3 · 0.55 requires C, -0.56%; H, 7-98%; H, 7.15%

Found: C, 7.35%; H, 7.83%; E, 6.94%. (R) -benzene acetate of 5 (R) -indol-5-yl) -2-methyl-2- (0.40 g, 2.5 mmol) in dichloromethane (20 ml) was added to a solution of N, N'-carbonyldiimidazole (0.40 g, 2.5 mmol) phenylacetic acid (0.30 g, 2.2 mmol). After stirring for 10 minutes at room temperature, the alcohol (24) -105%

(0.5 g, 0.8 mmol) and stirring was continued for 40 hours Volatiles were removed in vacuo and the residue was purified by flash chromatography (hexane / 5% ethyl acetate element). 0.30 g (77%) of (25) was recovered as a white foam, m.p .: 57-60 ° C; 17 (crude) 2917, 1722 (C = O ester), 1700 (C = O urethane) cm -1; NMR (ODCl 3) δ 8.05 (1H, br, indole NH), 75 (1H, d, J 8 Hz, indole E-4), 7.4-7.2 (6H, m, indole E-5 + phenyl), 7.16 (1H, (1H, t, J 7 Hz, indole H-7), 6.9 (1H, d, J 2 Hz, indole H-2), 4.8 (1H, (1H, br, urethane NE), 4.3 (1H, d, J 11 Hz, one of CH 2 -O), 4.2 (1E, d, J 11, CH 2 O) 3.0 (1H, d, J 14 Hz, one of OH-indole), 2.1 (1.4H, s, CH 2 -Ph, 3.2 (1H, d, J 14 Hz, one of OEG- m, adamantane), 1.2 (3H, s, CH3); + 13 ° (CHCl3)

Anal: Calc'd: C, 54.42; H, 7.32%; 0 = 0.5); FAB MS 501 (m + H). 0.77-37%; H, 7.25%; N, 5.60%; N, 5.52%. (26) To a solution of the compound (24) (0) in the presence of a solution of the compound of formula (I) , N-methylmorpholine-N-oxide (0.1 g, 0.9 mmol) was added in dry dichloromethane (40 ml) at ambient temperature in argon (4 g, 5 g), and tetra-n-propylammonium perruthenate (0.01 g, 0.03 mmol). After stirring for 30 minutes the volatiles were removed in vacuo (40Â ° C). The residue was taken up in ethyl acetate and purified by flash chromatography (eluent of Hexane / ethyl acetate 5%). 0.2 g (67%) of (24) was recovered as a white solid, m.p .: 178-179 ° C; 17 (br) 2900, 1752 (C = O aldehyde), 1692 (C = O urethane) in &quot;1; (1H, br s, indole NH), 7.6-6.9 (5H, m, indole), 5.22 (1H, br, urethane NH ), 4.8 (1H, s, adamantane H-2), 3.3 (2H, br, OH-indole), 2.1-1.3 (173%), adamantane + OH4); The? -22D (CH 3 O, 22 ° C, O = 1); FAB MS (m + / e) 381 (m + + H). Anal:. C25 H20 N2 O requires 0.72.61%; H, 7.42%; N, 7.83%; Det; ; 0, 72.31%; H, 7.46%; N, 7.31%. -106 -

Example 14 5- (Z) -7- [1 H-indol-3-ylmethyl) -1-methylethyl-5-phenyl-2-pentyl] -carbamic acid tert- 11ο (27)

A mixture of tri-phenylphosphine (0.35 g, 1.3 mmol) and 1-bromo-3-phenylpropane (0.27 B &gt; mmol) was heated at 110 ° C at which point the molten reactants solidified. Cooling to ambient temperature and trituration with hexane gave a white solid (0.4 g, 65%). This compound was added to a suspension of sodium hydride (50 mg of 50% in oil dispersion, 1 mmol) in toluene (40 mL) and the reaction mixture was refluxed for 20 minutes. An aldehyde (0.2 g, 0.5 mmol) was added and heating was continued for 1 hour. The volatiles were removed in vacuo and the residue purified by flash chromatography. (eluent of bexane / 10% ethyl acetate). 0.20 g (79%) of (27) were obtained as a white solid, m.p .: 49-52Â ° C; IR (br) 294-0, 1696 (C = O urethane), 1683 (C = O) cm-1; (1H, d, indole EB), 7.6 (1H, d, 8.8 Hz, indole H-4), 7.3-7.0 (8H, m, indole H-5, H-6, H-7 + phenyl), 6.9 (1H, s, indole H-2), δ 6.91H, d, J 12bz, OH by the cC-center 5.4. (1H, dt, J 5, 12 Hz, CH-CH 2), 4-8 (2H, m, urethane NH + adamantane H-2), 3.33 (1H, d, J 14 Hz), one of (1H, m, adamantane), 1.4 (3H, m, 2xOH), 3.1 (1H, d, s, OH).

(28) To a stirred mixture of metal (1) to give the title compound as a white crystalline solid.1H NMR (DMSO-d6): δ of magnesium (0.5 g, 21 mmol) and anhydrous ether (20 mL) at 0 ° C under a nitrogen atmosphere was added 1-bromo-3-phenylpropane (0.20 mL, 0.26 g, mmol) and a crystal of iodine. After 20 minutes the reaction mixture became colorless, and thus the solution was-

removed by syringe and added to a solution of compound (26) (0.30 g, 0.8 mmol) in anhydrous ether at 0 ° C under a nitrogen atmosphere. After 20 minutes the reaction mixture was allowed to warm to room temperature and was neutralized with dilute hydrochloric acid (2%, 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 eluent); 0.31 g (79%) of compound (28) was recovered as an oil which revealed to be a 1: 1 mixture of possible diastereomers. Subsequent chromatography afforded a single diastereoisomer: IR (crude) 2908, 1690 (C = O urethane): NMR (CDCl3) δ 8.1 (1H, br, indole ΜΗ), 7.6 (1H, d, J 8 Hz, (1H, br, adamantane H-2), 4.7 (1H, br-s), 7.4-6.9 (9H, n, indole H-5, (1H, m, OH-OH), 3.5 (1H, d, J 14 Hz, one of OH-indole), 3.1 (1H, d, J 14 Hz, one of OH- indole), 2.7 (2H, m, CH3 -Bb), 2.1-1.3 (19H, m, adamantane + 2xOH2 + OH), 1.1 (3H, s, OH).

Example 16 R - (R *, 3 *) 7- [4,5- dihydro-4- (phenylmethyl) -2-thiazolyl] -2- (1H-indol-3-yl) -1-methylethyl] carbamate (17) To a solution of (13) (0.1 g, 0.2 mmol) in toluene (10 ml) was added the Lawesson reagent (0) , 10 g, 0.25 mmol) and the reaction mixture was heated under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and was purified by flash chromatography (dichloromethane / ether eluent). 0.07 g (70%) of the product was obtained; IR (br) 2910, 1697 (O = urethane), 1620 (C = H) cm-1: HMM (CDCl3) 8.1 (1H, br, indole MH), 7.7 (1H, d, J 8 Hz, indole H-4), 7.4-5.9 (9H, m, indole H-5, H-6, H-7, H-2 + phenyl), 5.8 (1H, br, urethane MH), 4.9 (1H, br, adamantane H-2), 4.6 (1H, m, CH), 3.7 (1H, m, one of CH2 --S), 2.9 (1H, m, one of CH3 --S), 2.8 (1H, br , one of "± sjO-

2 H), 2.2 (1H, br, one of OH 2 -Ph), 2.1-1.4 (14α, m, adamantane), 1.3 (3H, s, CH₂); MB MS (m / z): 529 (m + Π), 49%), 398 (M + - (indole-CH 2), 44%), 130 (indole-0¾), 100%);

Rf (30% ethyl acetate / hexane), 0.85

EXAMPLE 17 Phenylmethyl (β) -β-methyl-β-triethylol-3β, 5Î ±, 11β-dec-B-yloxy) carbonyl] amino] -1H-indole-5-butanoate

A solution of N-methylmorpholine (253 mg, 2.50 mmol) and 2-Adoc-XMe-T-5 (r) -OH (23) (990 mg, 2.50 mmol) of anhydrous TBF ml) at 0 ° C and was treated with a solution of i-butyl chloroformate (360 mg, 2.5 mmol) in anhydrous THF (10 mL) dropwise over 10 minutes. This solution was stirred at 10 ° C for the next 20 minutes and then filtered. A solution of diazomethane (6 mmol) in StgO was added to the filtrate and left at 0 ° C for 4 hours, then allowed to warm gently to room temperature for 12 hours. The excess diazomethane was neutralized with acetic acid and the solvent removed in vacuo. The residue was chromatographed using 25% EtOAc in n-hexane to afford diazoketone (300 mg, 29%); IR (film) 300-200-3200, 2913, 2854, 2106, 1693, and 1353 cm -1; (CDCl3): 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, Brs), 5.20 (1H, d, J 2Hz), 7.08 (1H, t, J 7Hz), 7.16 (1E, t, 7Hz) , 7.33 (3H, d, J 8Hz), 7.55 (1H, d, J 8Hz), 8.50 (1H, s).

Level 2

A solution of the diazo ketone (Scheme 5, Ns. 31) (1.04 g, 2.50 mmol) in benzyl alcohol (10 mL) was treated with a solution of silver benzoate (4 mL, 17 mmol) in triethylamine (5 ** 1) in portions, and allowed to stir during?

1 hour. EtOAc (30 mL) was then added and this solution was treated with activated charcoal and filtered through a filter and 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, 33%); IR (film) 3500-3200, 2907, 2855, 1720 and 1698 cm @ -1; (2H, m), 1.65-1.85 (8H, m), 1.90-2.05 (4H, m), 2.67 (1H, d, J = 14.5 Hz) , 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 , 6.95 (1H, d, J 2Hz), 7.06 (1H, dt, J 7.5 and 1Hz), 7.15 (1H, dt, J = 7 Hz, 7.35 (6H, m), 7.57 (1H, d, J 8Hz), 8.28 (1H, s).

Example 18

3-tricyclo [3.1.1] undec-2-yl] - (R *, S *)] [5- [7- (hydroxy-methyl) -2-phenylethyl] amino] -1- ol-3-ylmethyl] -1-methyl-5-oxo-propyl] carbamic acid

Phase 1

A solution of benzyl ester (Example 17, Scheme 5 He. 32) (440 mg, 0.88 mmol) in absolute EtOH (100 mL) was treated with Pd / C (50 mg, ca. 10% w / w) and was placed under a hydrogen atmosphere at 345 ° C and 30 ° C with stirring for 16 hours. The reaction mixture was. filtered through a filter and the filtrate evaporated and taken to dryness in vacuo.

The residue was chromatographed on silica reverse phase chromatography using 25% H 2 O in MeOH as eluent to provide the acid (180 mg, 50%), m.p .: 91-99 ° C (MeOH / H2 O); 20.0 ° (C = 1, MeOH); IR (film) 5500-3500, 2912, 2856, 1704 cm -1; NMR (CDCl3): 1.41 (3H, s), 1.53 (1E, s), 1.57 (1H, s), 1.70-1.85 (93, m), 1-95-2.10 (4H, m), 2.69 (1H (1H, d, J = 14.5Hz), 3.32 (1H, d, J = 14.5Hz), 4.86 (1H, s), 5.10- (1H, d, J = 8Hz), 7.30 (1H, br s), 7.04 (1H, d, J = 2Hz), 7.07-7.20 (2H, m) (1H, s).

Level 2

A solution of carboxylic acid (Phase 1, Scheme 5, S, 33) (160 mg, 0.3 mmol) and pentafluorophenol (72 mg, 0.39 mmol) in EtOAc (20 mL) was cooled to 0 ° C and was treated with a solution of N, N-dicyclohexylcarbodiimide (80 mg, 0.39 mmol) in EtOAc (5 mL) and allowed to stir at 0 ° C for 18 hours. After this time, S-phenylalaninol (121 mg, 0.8 mmol) was added and the mixture was allowed to stand at room temperature for 24 hours. 0 sun

was then removed in vacuo and the residue chromatographed using 30% EtOAc in n-hexane as eluant to afford the product as a white solid (140 mg, 66%); IR (film) 3500-3200, 2909, 2855, 1694, 1651, and 1570 cm -1; M), 1.55 (1H, s), 1.70-2.05 (12H, m), 2.46 (1H, d, J 13.5Hz), 2.75 (1H, 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, (1H, dd, 11 and 3.5 Hz), 4.10-4.20 (1H, m), 4.81 (1H, s), 5.14 (1H, s), 6.26 (1H, d, J 8 Hz), 6.99 (1H, d, J 2 Hz), 7.08 (1H, t, J 7 Hz), 7.10-7.30 (6H, m), 7-33 (1H, d, 8 Hz), 7.58 (1H, d, J 8 Hz), 8.32 (1H, s).

Example 19

(1 H -indol-5-ylmethyl) -1-methyl-2- (1-oxo-4-phenylbutyl) aminoethyl] carbamic acid, tricyclo [3.1.1] 1-yl) -2-yl,

This compound was prepared in the same manner as described in Example 21. 37d, m.p .: 70-75 ° C (foam); Ζ Χ -9.2 (= = 1, MeOH); IR (film) 3400-J100, 2908, 2853, 694, 1645, and 1526 cm -1; M), 2.20 (2H, t, J = 7 Hz), 2.64 (2H, t, J = 7 Hz), 2.98 (1 H, d, (1H, dd, J 14, 6Hz), 3.70 (1H, dd, J 14 and 6Hz), 4.81 (1H, s), 4.94 (1H, (1H, d, J 2 Hz), 7.05-7.30 (1H, m), 7.35 (1H, d, J 8 Hz), 7.57 (1H, 1H, d, 8Hz), 8.17 (1H, s); Anal. N, O, Η, K.

Example 20 2- (benzoylamino) -1- (1H-indole-3-ylmethyl) -1-methylethyl-carbamic acid, tricyclo [ 3,1,1,12,12dec-2-yl, (R) -

_ 112 _

This compound was prepared in the same manner as described in Example 21. Rf. 37a, mp: 220.0-220.1 ° C (MeOH); + 24 ° C (C = 0.25, MeOH); IR (film) 3500-3200-2907, 2855, 1695, 1646, and 1533 cm @ -1 NMR (DMSO): 1.30 (3H, s), 1.50-1.60 (2E, m), 1.70-2.10 (12H, (1H, dd, J 14 and 6Hz), 3.76 (1H, dd, JMe 6Hz), 3.07 (1H, d, J 14.5Hz) (1H, d), 7.05-7.20 (2H, m), 7.35-7.50 (4H, m), 7.50 (1H, d), 7.04 (1H, s) (1H, br), 8.39 (1H, s), FAB MS m / e 486.3 (34), 355.3 (63), 290.3 (2H, d, J 7Hz), 7.60-7.90 29), 177.2 (37), 154.1 (100);

Anal. 0, Η, I.

Example 21

(1 H -indol-3-ylmethyl) -1-methyl-2-oxo-5-phenylpropyl) aminoethylcarbamate, tricyclo [3.3.1] ylp, (H) -

Phase 1

Acid / 2-amino-1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl) -carbamic acid. (R) -AdOO-Me (R) -AdOO-Me (R) -OH) (See Scheme 5, Hs, 2-Adoc-6-Me-R (1H, s)

The suspension was allowed to stir for 6 hours, and then at 4 ° C in the subsequent 12 hours. This mixture was then filtered and the filtrate evaporated to dryness in vacuo. The residue was dissolved in THE (100 ml) and ammonia gas was bubbled at 0 ° C for 1 hour. The solvent was removed in vacuo and the residue chromatographed on reverse phase silica using 30% Et3p in MeOH as eluent to afford the amide (35, Scheme 5) (9.2 g, 97%) as white crystals, mp: 136-149 ° C (MeOH); + 42.1 (0 * 1), EeQH); IY (film) 3351, 2906, 2855, 1675, and 1588 cm -1; (1H, m), 1.58 (3H, s), 1.70-2.05 (12H, m), 3.33 (1H, d, J = 14.5Hz), 3.51 (1H, d, J = 14.5 Hz), 4.86 (1H, s), 5.24 (1H, s), 5.40-5.55 (1H, br), 6.20-6.35 (1H, br), 7.04 (1H, d, 7.08-7.21 (2H, m), 7.36 (1H, d, J 8 Hz), 7.63 (1H, d, J 8 Hz), 8.24 (1H, s); MS (FAB) m / e 396 (100);

Anal. G23 H29 N3 O35 • H • 1 •

Step 2 (Scheme 5, Scheme 36)

Chloride

-1-trimethylsilyl (4.34 g, 40 mmol) was added to a solution of LiBH4 (11 mL of a 2M solution, 22 mmol) in TEF under a nitrogen atmosphere. It was added dropwise over 20 min. A solution of 2-Adoc-α-Me-R-TrpHH2 (Scheme 5, â¼35) obtained from the previous step (3.95 g, 10.0 mmol) in anhydrous THF (20 ml) The reaction mixture was stirred for 10 minutes at room temperature, then at gentle reflux for 3 hours. This solution was then cooled to 0 ° C and MeOH (16.5 mL) was added cautiously. All solvents were then removed in vacuo and the residue was chromatographed on silica reverse phase using 30% Et 2 in MeOH as eluant to give 1.25 g (32%) of the starting amide and 1.29 g (34%) of the starting amide. %) of the amine product, mp: 138-144 ° C (MeOH); + νmax + 51.6 ° (0-1, MeOH); IR (film) 2912, 2854 and 1690 cm (CDCl3): 1.32 (3H, s), 1.40-1.55 (2H, m), 1.65-2.05 (12E, m), 3.04 (1H, d, 3.20-3-30 (2H, m), 3.40-3.50 (1H, m), 4.78 (1H, s), 5.10-5-30 (1H, br s), 7-6-7.20 (3H, m), 7.34 (1H, d, J 8 Hz), 7.52 (1H, d, J 8 Hz), 8.56 (1H, s), 8.67 (2E, br s); FABMS m / e 382.3 (100):

Step 3 (See Scheme 5, ^ 2 * 37 <0

A solution of 3-phenylpropionic acid (75 mg, 0.5 mmol) in EtOAc (5 mL) was treated with pentafluorophenol (92 mg, 0.5 mmol) and cooled to 0 ° C. A solution of H-H * -cyclohexylcarbodiimide (103 mg, 0.5 mmol) in EtOAc (2 mL) was added and the mixture was left for 12 hours at 4 ° C. This mixture was then filtered and solid amine (from Step 2, Scheme 540 * 36) (198 mg, 0.5 mmol) was added, and left at room temperature for 24 hours. To the reaction mixture was washed with 1 M citric acid solution (2 x 10 ml), NaHCO 3 (2 x 10 ml of a 1M solution), and H2 O (2 x 10 ml) and the organic phase dried with IgSO4. The solvent was then removed in vacuo and the residue chromatographed on silica gel using 2% MeOH in CH 2 Cl 2 as eluant to give the product (250 mg, 90%) as white crystals,

• mp: 171-175 ° C-115

-1 (MeOH); [α] D = -12.3 ° (c = 0.56, MeOH); IR (KBr)

(3H, s), 1.50-2.10 (14H, m), 2.50 (2H, t, J = 7 Hz), 2.90 (2H, (1H, dd, J 14, 6Hz), 3.65 (1H, dd, J 14 and 6Hz), 4.81 (1H, s), 4.88 (1H, s), 6.40-6.60 (1H, br), 6.96 (1H, 1H, d, J 3Hz), 7.05-7.30 (1H, m), 7.55 (1H, d, 8Hz), 9.53 (1H, d, 8Hz), 8.15 (1H, s); EAB MS m / e 514.4 (8), 383-3 (32), 205.2 (32), 170.2 (47), 135-2 (100); Anal. N.

Example 22 N- (1S-Indol-5-ylmethyl) -1-methyl-2- [2- (2-phenylacetyl) amino] ethylcarbamic acid, trityloxalic acid [3 ', 3β, 11β, 7β-2-yl , (R)

0

This compound was prepared in the same manner as described in Example 21 (see Scheme 5, R2.37b), m.p. 176.5-180 ° C (MeOH); â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒÎ ±: IR (film) 3400-3100, 2911, 2854, 1694, 1656, and 1520 cm -1. BME (CDCl3): 1.16 (3H, s), 1.50-2.10 (14H, m), 2.90 (1H, d, J14Hz), 3.16 (1H, d, (1H, dd, J 14, 6Hz), 4.93 (1H, s), 4.80 (1H, s), 6.30-6.40 (1H, brs), 6.94 (1E, d, J2 Hz), 9.0? (1H, t, 8Hz), 7.16 (1H, t, 8Hz), 9.25-7.40 (6H, m), 7.48 (1H, d, 8Hz), 8.11 (1H, s); MB IM m / e 500.5 (100), 369.3 (87); Anal. σ5ΐΗ59Η503; 0, Η, I.

EXAMPLE 25 [2 - [[(1-Indol-3-ylmethyl) -1-methyl-2-oxoethylcarbamic acid, 2-oxoethyl] -2-phenylethylamino] -3- tricyclo [3.3.1.1] dec-4-yl, 5- (R *, S *) 7-

The acid prepared in Example 30, Step 2 (1.17 g, 2.80 mmol) and pentafluorophenol (461 mg, 2.3 mmol) as a solution in EtOAc (50 mL) was treated with dicyclohexyl carboximide (542 mg , 2.60 mmol) and was added dropwise. left at 0 ° C for 18 hours. This product was filtered and the filtrate was treated with s-phenylalaninol (454 mg, 3.00 mmol) and the reaction mixture was allowed to stir for 18 hours at room temperature. This mixture was then concentrated in vacuo and the residue was flash chromatographed on silica using 75% MeOH in H2 O as eluent to give the product as a white, non-crystalline solid (1.17%, 8%); 94-98Â ° C) + 14.7Â ° (c * 1), UteOE) 17 (film) 3306, 2904, 2854, 1693, and 1651 cm @ 1; (2H, m), 2.62 (1H, dd, J 14 and 8Hz), 2.83 (1H, m), 1.60-2.00 (2H, (1H, m), 4.70-4.80 (20, m), 6.70 (1H, br s), 6.90 (1H, 7.35 (9H, m), 7.44 (1H, d, J 8 Hz), 7.70 (1H, d, J 8 Hz), 7-75 (1H, br s), 10.85 (1H, s); FAB Eli m / e 601 (m + 1), 100); anal. 0, H, H.

Example 24 N- (1E -indol-3-ylmethyl) -2- [7 '- (1-hydroxymethyl) -2-phenylethyl] amino] -3-oxopropyl] amino] -1-methyl-2-oxoethylcarbamate, tricyclic ester (R *, H *) 7-methyl-

This compound was prepared in the same manner as described in Example 23 (see Scheme 6, H2 44) m.p .: 95-97 ° C (MeOH / E2 O); /¾.¾20-33. .30 (c = 1), MeOH); IR (film) 3314, 2910, 2856, 1696, and 1651 cm -1; NMR (CDCl3) 2.79 (2H, d, J7Hz), 3.25 (1H, d, J = 14.5Hz), 1.45-2.05 (12H, m), 2.20-2.30 (2H, ), 3-35 (1H, d, J = 14.5Hz), 3.30-3.35 (3H, m), 3.65-3.70 (1H, m), 4.10-4220 (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, J2Hz), 7.06-7.29 (1H, m), 7.34 (1H, d , 8.8 Hz), 7.57 (1H, d, 8 Hz), 8.49 (1H, s); FABMS m / e 601 (100); Anal. ¹H-NMR (CDCl-):? 0, Η, M. FAB MS m / e 614 (m + 1) and 217 (100); Anal. Hâ, ... Hâ,,Oâ, ... Hâ,,O; 0, H, H1.

Example 25 (C) -Methyl- N - [tolyl] cyclopentyl] , 77-dec-2-yloxy) -cartonyl-B-tryptophyl-β-alanyl-D-phenylalanamide

Ph

This compound was prepared using a similar method to Example 26. The acid from Example 30,

Ease 2 (117 mg, 0.25 nmol) and pentafluorophenol (46 mg, 0.25 mmol) as a solution in EtOAc (10 ml) were treated with dicyclohexylcarbodiimide (52 mg, 25 mmol) and allowed to stir at room temperature for 2 hours before being filtered. S (CDCl3) δ 1.49

Then S-phenylalaninamide (50 mg, 0.3 mmol) was added and the mixture was allowed to stir at ambient temperature for 72 hours. The reaction mixture was then washed with 1M HCl (10 mL), H2O (10 mL), 1M NaOH (10 mL), and H2 O (10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was flash chromatographed on silica gel using 75% MeOH in H2 O as eluant to give the product as a white crystalline solid (130 mg , 85%); m.p .: 113-118 ° C; [Î ±] D + 27-5ø (0-0.5, MeOH); IR (film) 3311, 3055, 2908, 1100, and 1659 cm @ -1; (2H, t, J 6 Hz), 3.01 (1H, dd, J 7.5 and 14 Hz), 3.98 (1H, (1H, d, J 14.5Hz), 3.42 (1H, d, J 14.5Hz), 3.35-3.50 (2H, m), 4.59 (1H, dd, J = (1H, s), 5.47 (1H, s), 6.20 (1H, s), 6.50 (1H, d, J 7 Hz) , 6.76 (1H, t, J6Hz), 6.96 (1H, d, J2Hz), 7.05-7.35 (Th, m), 7.34 (1H, d, J8Hz), 7.57 (1H, d, J 8 Hz), 8.36 (1H, s).

Example 26 OC-Methyl-H -tricyclo [3.3.1.1 (7-dec-2-yloxy) carbonyl] -D-tryptophyl-alanyl-L-phenylalaninamide

m.p. 112-118 ° C (MeOH / Al2 O); / ¾¾2 ° +16 * 3 ° (o * 1, MeOH); IR (film) 3309, 290-7, 2855, 1690, 1652 cm-1; (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), 3.25-3.53 (2H, m), 4.58 (1H, dd, J 15 and 7.5Hz), 4.84 (1H, br s), 6.54 (1H, br s), 6.75 (1H, m), 6.99 (1E, d, 2 Hz), 7.05-7.30 (1H, m), 7.34 (1H, d, 8Hz), 7.58 (1H, d, 8Hz), 8.41 (1H, s); EI ELI m / e 614.3 (100);

Anal. 055H45H5050.75H20; Ο, Η, I.

Example 27 6β-Methyl-N -tricylic [3.3.1.1Î ±, 7-dec-1-yloxy) carbonyl] -L-triotrophyl-alanyl-E-phenylalaninamide

120 mp: 114-119 ° σ (MeOH / H2O); Î'-15.2 ° (c = 0.55, νH) IR (film) 5325, 2909, 2835, 1700-1640 cm -1; 1 H-NMR (CDCl 3): 1.50 (2H, s), 1.54 (3H, s), 1165-2.00 (12H, m), 2.10-2.20 (2H, br s), 2.95 (1H, dd, J 14 and 8 (1H, d, J = 14Hz), 5.52 (1H, d, J 14Hz), 3.20-3.50 (1H, m), 3.40 (1H, s), 5.85 (1H, s), 5.85 (1H, m), 4.55 (0.5H, .08 Hz), 4.60 (0.5H d, 1H), 6.41 (1H, s), 6.65-6.85 (1H, m), 6.82 (1H, t, J6Hz), 6.97 (1H, d,

Hz), 7.05 - Î'(TH, m), 7.35 (1H, d, 8 Hz), 7.57 (1H, d, 8 Hz), 8.55 (1H, s); PAB 3M m / e 614.3 (50.), 236.1 (100); Anal. 055H45N505-r0-r5H20; 0, Η, N.

Example 28 N-Methyl-N -tricylic [4,3,1-d] -dec-2-yloxy) carbonyl] -L · -tryptoph-alanyl-L-phenylalaninamide

PH

113-118 ° C (MeOH / H2 O); 20-30 ° (c = 0.5, MeOH); IR (film) 3313, 2909, 2856, 1694-1652 br. cm-1; NMR (CDCl3): 1.45 (3H, s), 1.50 (2H, s), 1.65-2.00 (1211, m), 2.14 (2H, s), 2.90 (1H, dd, J 14 and 8Hz), 3.06 (1H, d, J = 5.5 Hz), 3.2-3.4 (4H, m), 4.56 (0.5H, d, J 7.5 Hz), 4.60 (0.5H, d, J 7.5 Hz), 4.80 (1H, s ), 5.54 (1H, s), 6.14 (1H, s), 6.7 (1H, s), 6.87 (1H, s), 7.00-7.30 (10H, m), 7-51 (1H, d, Hz), 8.87 (1H, s); PAB US 636.4 (100), 614.4 (61); . Anal. 35H43N505,0,5H2 O! ® &gt; H &gt; K-

Example 29 12-Oxa-2,5,9,9-triazatridecanoic acid, 3- (1H-indol-3-ylmethyl) -3-methyl-4,8,11-trioxo-1- (phenylmethyl) (R *, R *), 7- (Yer Scheme 6, no.49)

Pil

Oog-Me

In a manner similar to that of Example 30, the following compound was prepared, m.p. 86-90Â ° C (Foam); [Α] 20D +17.4 ° (c = 0.5, MeOH); 17 (film) 1738, 1698, and 1656 cm -1; (2H, br s), 1.65-2.05 (12H, m), 2.10-2.35 (2H, m), 2.99 (1H, dd, J 14 and 8 (1H, m), 3.31 (2H, s), 3.55-3.65 (1H, m), 3.68 (3H, s), 3.11 (1H, dd, J 14 and 5Hz) ), 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), 7.05-3.35 (SH, m), 7.59 (1H, d, J 8Hz), 8.45 (1H, s), MS FAB m / e 629.2 (100) Anal C36 H44 N4 O6 .0.25H2 O, δ, H.

Example 30

L-Phenylalanine, N - [[7-methyl-1 H -tricylic / 5,3,1,1-dec-2-yloxy) carbonyl] -β-tryptophyl] -β-alanyl] -phenylmethyl ester

Step-1 (Yer Scheme 6, HS 39)

A solution of 2-Adamantiyloxycarbonyl-α-methyl-R-tryptophan (0.8 g, 20 mmol) in EtOAc (100 mL) was treated with pentafluorophenol (3.68 g, 20.0 mmol) and cooled at 0 DEG C. Dicyclohexylcarbodiimide (4.33 g, 21.0 mmol) was then added and the mixture allowed to stir for 18 hours at 0 DEG C. After this time the mixture was filtered and the ester (2.47 g, 240 mmol) and the mixture was allowed to stir for an additional 18 hours at room temperature, filtered, and the filtrate was washed with 1 M HCl (3 x 30 mL), H2 O (2 x 30 mL) ), saturated RaHCO 3 solution (3 x 30 mL), H2 O (2 x 30 mL) .The organic phase was dried over MgSO4 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 Scheme 6, No. 41) [alpha] Alanine, 3apos; -methyl- [N -tricyclo [5.5.1.1, 7dec-2-yloxy) carbonyl] -D-tryptophyl ester 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 allowed to stir 18 hours. 1M HCl (10.8 ml) was added and the mixture was distilled to dryness in vacuo and the residue was chromatographed on reverse phase silica gel using 70% IvleE in ELP; as eluant to give the product (3.23 g, 51%) along with the starting ether (1 g); m.p. 9S-103 ° C (MeOH / H2O); / ¾¾2 ° + 29 ° (Cal, MeOH); IR (film) 3351, 2911, 2855, 1706, and 1658 cm -1; NMR (CDCl3) δ 1.50-2.00 (1?, M), 2.39 (2H, br s) 3.26 (1E, d, J 15 Hz), 3.40-3.50 (3H, m), 4.80 (1H, d, J 6 Hz), 6.99 (1H, d, J 2 Hz), 7.05-7.20 (2E, m), 7.33 (1H, d, J 8 Hz), 7-57 (1H, d, J 8 Hz), 8.37 (1H, s); FAB MS m / e 468 (m + 1) and 217 (100);

Anal. G26H33N3 ° 5 * ° * 25Η2 ° »Ο, Ε, I.

Phase 3

A solution of the Phase 2 acid (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 allowed to stand for 18 hours.

This solution was then filtered and benzyl isomer of the S-phenylalanine (506 mg, 1.20 mmol) was added and allowed to stir for 18 hours at room temperature.

This solution was then washed with 1M HCl (2 x 20 mL), H2 O (20 mL), saturated NaOH solution (2 x 20 mL), and H2 O (20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo and the residue was chromatographed on silica gel using 75% to 85% MeOH as eluents to give the product (500 mg, 71%). Mp: 75-82 ° C (MeOH / H2 O); + 28.1 ° (c = 0.45, MeOH); IR (film) 3324, 2908, 2855, 1737, 1698, and 1657 cm -1; (1H, m), 1.70-2.00 (12H, m), 2.10-2.30 (2H, m), 3.06 (1H, dd, J 14 and 7 (2H, m), 5.08 (1H, d, J = 9Hz), 3.14 (1H, dd, J 14 and 6Hz), 3.29 (1H, d, (1H, br s), 6.20-6.30 (1E, br m), 6.81 (1H, br m), 6.95 (1H, d, J 2 Hz), 5.15 (1H, d, Hz), 7.00-7.35 (13H, m), 7.57 (1H, d, 8Hz), 8.20 (1H, s);

Anal. H

Example 31

In a manner similar to that of Example 30, the following compound was prepared, m.p .: 77-82Â ° C (foam) Z &lt; 2 d 19.20 (c = 0.5, MeOH); IR (film) 3305, 2906-2857, 1735, 1696, and 1658 cm -1; (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, br), 3.31 (1H, s), 3.55-3.65 (1H, m), 4.75-4.85 (2H, m), 5 (1H, d, J 12 Hz), 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 Τθ5 · 2 (1 1) and 32. 2 (100); ; Anal. H, N. 124 (M +

Example 52 [(R) -cyclohexyl] tricyclo [3.3.1] , 77-dec-2-yloxy) -carbonyl-D-tryptophyl-β-alanyl-β-fePiananine

Ph

(2H, br s), 2.95-3.05 (1H, m), 2.45-2.05 (2H, br s), 2.95-3.05 (1H, m)

This compound was prepared in a similar manner to that described in Example 33, m.p. 119-129 ° C (MeOH / EE2 O); Z17 D20 + 5.8 ° (c = 0.5, ivleOH); IR (m-e) 615.2 (1H, m), 7.00-7.40 (9H, m), 7.57 (1H, d, J8Hz) (58), 216.9 (100); Anal. σ55Η42Ε406.0.5Η20; 0, Η, M.

Example 33 H- [H] [[1-methyl-N- [trihydroxy] , 7-deo-2-yloxy) carbonyl] -R-tryptophyl-β-alanyl-5-phenylalanine

A solution of the benzyl ester (450 mg, 0.64 mmol) in absolute EtOH (100 mL) was treated with 10% Pd / O (45 mg, 10% w / w) and was placed under an atmosphere of hydrogen at 345 KPa for 2 hours with stirring. The mixture was then filtered through a filter and concentrated in vacuo and the residue chromatographed on reverse phase silica gel

This compound was prepared in a similar manner to that described in Example 33, m.p .: 115-120 ° C (MeOH / H2 O); (E = 0.5, KeOH) IR (film) 3391, 2906, 2854, 1700, and 1646 (s) cnT1; NMR (ODCl3 + CD3 OD) 1.51 (3H, s), 1.54 (1H, s), 1.57 (1H, s), 1.70-2.05 (123, m), 2.15-2.30 (2H, 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 8 EZ): EAB MS m / e 615 (100) Anal.

Example 35 3 - [(3-Chlorophenyl) -2-methyl-1-oxo-2-methylcyclopropyl] Yloxy) carbonyl] amino] propyl] -N-7-oxopropyl] amino] -Denpanopropanoic acid, 5- (R *, S *) 7-

m.p .: 116-124 ° C (ΜθΟΗ / SgO); [Î ±] 20-35Â ° (c = 0.5, MeOH); IR (film) 3500-3200, 2912, 2856, 1700, and 1654 cm-1; NMR (DMSO-d6): 1.42 (3H, s), 1.4? (1H, m), 3.90-3.50 (5H, m), 3.50-4.50 (1H, m), 3.50-4.50 (1H, m) (1H, s), 6.50-6.80 (1E, br s), 6.85-7.30 (11H, m), 7.52 (1 H, s) (d, J = 8Hz), 8.58 (1H, s), 5ABAB MS m / e 615.2 (100%).

EXAMPLE 56 Ethyl N- [triethyl] -3,3 ', 1,1apos; -dideoxy-2-yloxy) carbonyl-D-tryptophylglycine, phenylmethyl ester

A solution of 2-Adoc-dT-Me-R-2rpOH (scheme 7, Ma. 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. Then, a solution of H, H * -hexylohexylcarbodiimide (1.56 g, 7.6 mmol in EtOAc (10 mL) was added dropwise and stirred for 12 hours at 4 ° C and filtered. (1.8 g, 9.0 mmol) followed by dropwise addition of triethylamine (0.9 g, 9.0 mmol) in EtOAc (10 mL) .This solution was allowed to stir for 18 h at the temperature The reaction mixture was then washed with 1 M citric acid solution (2 x 50 ml), 1 M NaOH solution (2 x 50 ml) and H 2 O (2 x 50 ml) .The organic phase was dried over Na 2 SO 4 and evaporated to dryness in vacuo The residue was chromatographed on silica reverse phase using 25% Hg in MeOH as eluant to give the product as a white foam (2.83 g, 68%) along with 0.9 g of starting active ester, mp : 76-82Â ° (foam): Î »20 + 35Â ° (c = 1, MeOH): IR (film) 3500-3200, 2908, 2855, 1745, 1702, and 1665 chT1 NMR (GD013) 1.45-1.60 (4H, m), 1.69-2.00 (13H , 3.30 (1H, d, J 14.5 Ha), 3-50 (1H, d, J 14.5Hz), 3.95-4.10 (2H, m), 4.84 (1H, s), 5-13 (2H , 5.11 (1H, s), 6.79 (1H, s), 7.01 (1H, d, J2Hz), 7.8 (1H, t. J 7 Hz), 7.15 (1H, t, J 7 Hz), 7.30-7.40 (6H, m),? (1H, d, J 8 Hz),. 8.26 (1H, s); EAB MS 544.4 (11), 414.3 (11), 348.2 (36), 135.2; (100); Anal,; C, H, tt. -128 -

1 - [[5 - [(1H-indol-3-yl) -2-methyl-1-oxo-2 (R) -cyclohexyl] Z ^ ..... ....... ^ ..... .......... /3.3 »1 *; 7? 3ec-2-yloxy) carbonyl] amino] -7β-olyl-glycine (K) -

Adpg- (OC-Me) PO? Rp-Gly

A solution of the benzyl ester (Example 36, Scheme 2, Î ± 2, 57) (2.5 g, 4-6 mmol) in absolute EtOH (100 mL) was treated with 10% Pd / C (250 mg , 10% w / w) and was placed under a hydrogen atmosphere at 34-5 KPa and 20 ° C for 5 hours with stirring. The reaction mixture was filtered through an acute filter and the filtrate was concentrated in vacuo. The residue was then chromatographed on silica gel using 0.5% AcOH, 5% MeOH in CH 2 Cl 2 as eluant to give the product (1.87-3 g, 90%) as a white solid; mp 112-117 ° C (MeOH / H2 O); [Α] 20 D + 40 ° (c = 1, MeOH); IR (film) 3500-3200, 2910, 2856, 1702, 1660, and 735 cm-1; (1H, s), 1.58 (3H, s), 1.70-2.00 (12H, m), 3.00-4.00 (1H, br), 3.28 (1H, , 3.45 (1H, d, J = 14.5Hz), 3.94 (2H, d, J 5Hz), 4.85 (1H, s), 5.35-5.5 (1H, brs) ), 6.85 (1H, br t), 7-04 (1H, d, J2 Hz), 7.05-7.18 (2H, m), 7.32 (1H, d, 8 Hz), 7.56 (3H, d, 8 Hz), 8.39 (1H, s); Anal. 025 ° C 31 ° C 55 H * M *

Level 2

A solution of the acid (scheme 7, 59.5, 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). This 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 hours, evaporated and dried in vacuo and the residue was chromatographed using 30% n-hexane in EtOAc as eluant to give the product (202 mg, 66%); IR (film) 3500-3200, 2911, 2855, 1695, and 1658 cm-1; (2H, m), 1.70-2.10 (14H, m), 2.78 (1H, dd, J 13.5 and 8Hz), 2.93 (1H, dd, (1H, d, J = 14.5 Hz), 3.53 (2E, d, J 5.5 Hz), 3.57 (1H, d, J = 17 Hz) ), 3.71 (1H, d, J = 17Hz), 4.05-4.41 (1H, m), 4.88 (1H, s), 6.98 (1H, dt, J 7.5 and 1Hz); 7.00-7.25 (1H, m), 7.32 (1H, d, J 8 Hz), 7.50 (1H, d, J 8 Hz). - I30 -

.example 39

(1 H -indol-3-ylmethyl) -1-methyl-2-oxoethyl] -7- [1- (2-methoxyphenyl) (R *, S *), 7-methyl-3-oxo-1,2,3,4-tetrahydro-

O

Ph

2-methyl-1-oxo-2- (trifluoromethyl) -1H-imidazol-3-yl) aryl-17-amino-propyl] amino-7-butanoic acid,

O

- 131 -

A solution of the methyl isomer (Example 38, Scheme 8, Ns, 60) (2.6 g, 3.2 mmol) in 1,4-dioxane (500 ml) was treated dropwise with a solution of LiOH (104 mL of a 0.05% solution, 5.20 mmol) for 24 hours with vigorous stirring. This mixture was stirred at room temperature for 24 hours and neutralized with 1M HCl (5.2 mL). The solvent was removed in vacuo and the residue chromatographed using 0.5% of AcQH, 5% of Ι, ΙθΟΚ in CH2 Cl2 to give 80 mg of the starting ester together with 1.32 g of the product, 55% yield, % conversion, mp: 92-96 ° C (GHâ,ƒâ, ...): υ7.7 + 29.3 ° (c =, MeOH); 17 (film) 3600-3200, 2909, 2855, 1302, and 1651 cm-1; (2H, m), 1.61 (3H, s), 1.62-2.00 (14H, m), 2.10-2.25 (23, m), 3.20-3.40 (2H, m), 3.24 (2H, (1H, d, J = 14.5 Hz), 3.45 (1H, d, J = 14.5 Hz), 4.84 (1H, s), 5.47 (1H, (1H, t, J = 7 Hz), 7.17 (1H, t, J 7 Hz), 7.35 (1H, d, J = 8 Hz).

Hz), 7.57 (1H, d, 8 Hz), 8.59 (1H, s);

Anal. .0.2 ^ 20; G, Η, I. 2 ise

A solution of the acid (Phase 1, Scheme 8, 222.61) (240 mg, 0.5 mmol), and pentafluoro-phenol (92 mg, 0.8 mmol) in EtOAc (20 mL) at 0 ° C and treated with a solution of N, N -dicyclohexylcarbamimide (108 mg, 0.55 mmol) in EtOAc (5 mL). This solution was left for 12 hours at 0 ° C, filtered and the filtrate treated with S-phenylalaninol. This reaction mixture was allowed to stir at room temperature for 24 hours, the solvent removed in vacuo and the residue chromatographed using 10% NaOH in CH 2 Cl 2 as eluent to give the product as a white solid (153 mg, 50%) as a white solid. ; 17 (film) 3500-3200, 207, 2850, 1692, and 1642 cm-1; (3H, s), 1.50-1.70 (4H, m), 1.75-1.95 (1H, m), 2.00-2.15 (6H, m), 2.7 (1H, dd, (3H, m), 3.45-3.50 (3H, m), 4.07-4.17 (1H, m), 4.81 (1H, HDD), 2.91 (1H, dd, J = 14 and 6Hz), 2.95-5.35 6.93-7-09 (1H, m), 7.10-: -7.30 (5H, m), 7.31 (1H, d, 8 Hz), 7-53 (1H, d, J 8 Hz). - 132 -

Example 40 Tricyclic (4 -) - 5- (1H-indol-3-ylmethyl) -2,3-dioxo-1- (2-phenylethyl) -3-pyrrolidinylcarbamate / 3Î ±, 11β, 17Î ± -dec-2-yl (68)

Step 1: Preparation of methyl (64) - [(N, N-dimethylaminocarbonyl) -1H-indole-3-

1-Methyl (Î ±) -β-cyano-11-dimethylethoxy) carbonyl-1H-indole-3-butanoate (63) (0.241 g, 0.50 mmol) was dissolved in ethanol (5 mL). The solution was cooled to -5 ° C in an ice-acetone bath and ethanolic H2 O was added dropwise. The solution was allowed to stir for 24 hours, and the solvent was removed by evaporation in vacuo, and the oil was dissolved in ethyl acetate (50 ml) and washed with ethyl acetate. The organic phase was dried (NaHSO4), filtered, and evaporated to dryness. The product was isolated by flash chromatography (ethyl acetate: hexane, 1: 1) to give (0.120 g, 67%) as a yellow oil, V max (cm -1, fine film) 3350 (KH), 3425 (EH br), 1741 (00 ester), E (300M Es, CDCl3) , 2.12 (2S, brs, KEg) δ 3.17 (1H, d, J 18 Hz, OH), 3.28 (1H, d, J 18 Hz, CH 2 OCH 2), 3.37 (1H, d, (1H, d, J 15 Hz, indole-OH), 4.43 (3H, s, OOH) (1H, m, 5-H + 6-H +? -H +? Tm)); 7.47 (1H, , s, 4-E), 8.42 (1H, s, m).

Step 2. (+) - N '- (phenylmethoxy) carbonyl] -β- [

Amino-2-yloxy) carbonyl] -amino] -1H-indole-5-butanoate (65) Methyl (+) - P- [4- (phenylmethoxy) carbonyl] -1H-indol- ) (120 mg, 0.33 mmol) was dissolved. (10 ml) under argon. Triethylamine (55æl, 0.40 mmol) was infected. The solution was cooled to 0 ° C in an ice bath and 2-adamantyl chloride (7 mg, 0.36 mmol) dissolved in THF (5 mL) was injected. The solution was stirred for 12 hours at room temperature before triethylamine chloride was collected by filtration. After dichloromethane (50 ml) was added and the solution was washed with water (2 x 25 ml). The organic phase was dried (Na2 SO4), filtered, and evaporated to dryness. The product was isolated by flash chromatography (iter: hexane, 1: 1) to provide the title compound (105%).

mg, 58%), m.p .: 61.5-62.5 ° C. (Om, 1, thin film) J412 I (HE), 1738 (00), II (300MHz, ODO13), 1.49-2.09 (14H, m, adamestyyl-H); (1H, d, J = 15Hz, 2H), 3.38 (s, 3H, OCH3), 3.72 (1H, d, (1H, d, J = 9 Hz), 5.11 (1H, d, J = 9 Hz, 1H) (1H, d, J 12 Hz, PhGH 2), 6.88 (1H, s, M), 6.79 (1H, (1H, d, J = 8 Hz, 5-H), 7.17-7.45 (6H, m, 7-H, H) , 8.30 (1H, s, 1H), m / z (PAB) 545 (M + 1), 501, 130. Det: G, 70.6%, H, 6.8%; 6 (re) -70.6%, H-5 * 1%) (7dec-2-yloxy) (66)

Step 3: Methyl methyl ester -carboxy-7-methylcyclobutanecarboxyl-7-methyl-1H-indole-3-butanoate

Methyl (R) -phenylmethoxy) carbonyl-β - [(tricyclo [3.3.1.1 7,7] deca-2-yloxy) carbonyl] amino] -1H-indole-3-butanoate ) in a 250 ml glass vial. Palladium on charcoal (10%, ca 20 mg) and ethanol (75 ml) were added. The vessel was closed in a Parr Hydrogenation Apparatus and charged with Hg gas (310 psig). Stirring was started after pressurizing and continued for 12 hours. After 12 hours the palladium on charcoal (10%) was filtered and the filtrate evaporated to dryness. The product was isolated by flash chromatography (methanol: water, 2: 1) to give a white powder (77 mg, 88%), mp: 108-9. ); 1753 (00). S Η (300M Ha, GD 01 *), 1.47-2.09 (14H, m, adamantyl-H); 3.14 (1E, d, J = 16 Hz, CH2 OH);

 € ƒâ € ƒâ € ƒâ S ¥ 3.26 (1H, d, J = 16 Hz, Câ, 3.64 (3H, s, OOE3); 3-76 (1H, c, J 13 Kz, indole-OH 2); 3.84 (1H, d, J 15 Hz, indole-C H 3); 4.33 (1H, brs, GE); 5.75 (1H, brs, OH); 5 * 98 (1E, s, HE); 6.98-7.04 (2H, m, 2-H + 6-H); 7-10 (1H, t, J = 7 Hz, 5-H); 7.28 (1H, d, J 8 Hz, 7-H); 7.64 (1H, d, J 8 Hz, 4-H); 8.34 (1H, s, SE). C (73.5MHz, CDCl3) Î'2.32-3.31 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. Det: 6.65 × 7%; H, 6.78; H, 6.0%. ^ 25 ^ 30 ^ 2 ^ 6 reQuer ^ 66.1%; H, 6.65%; H, 6.2%.

Step 4. (+) - p - [(R) - (Ethylethyl) amino] carbonyl] - [(trihydrocyclo [3.3.1] &gt; (C-2-yloxy) carbonyl] -aninyl] -1H-indole-3-butane (67)

Methyl 3 - [[(2-yloxy) carbonyl] amino] -1 H -pyrazole-3-carboxylate (66) (200 g, 0.44 mmol) followed by dicyclohexylcarbodiimide (100 mg, 0.48 mmol). The solution was allowed to stir for 2 hours before phenylethylamine (60 mg, 0.50 mmol) was infected. The mixture was allowed to stir overnight. The solution was evaporated to dryness, ethyl acetate was added, and the dicyclohexylurea was separated by filtration. 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. (cm-1, thin film), 3333 (HE), 1730 (GO), 1659 (GO starch), Η (300MHz, δDGX), 1.5 1.51-2.04 (14H, m, adamantyl-H); 2.61 (2H, m, CH3); 2.94 (1H, d, J 16 Hz, COCO2); 3.21 (1E, d, J 16 Hz, GH2 CO2 HCl); 3.37 (1H, d, J Hz, CH2 Ph); 3.41 (1H, d, J 7 Ez, G H h h); 3.46 (1E, d, J 15 Ez, indole-GH 2); 3. 57 (1H, d, J 15 Hz, indole-GEp); 3.62 (3H, s, OCH3); 4.78 (1H, brs, CH); 5.88 (1H, brs, HH urethane); 6.58 (1H, brs, 1H); 6.92 (1E, d, J 2 Hz, 2-H); 7.03-7.26 (1 H, m, 5-H + 6-E + HOTtft);

7.33 (δ, d, J 8 Hz, 7-3); ? 56 (III, d, J 8 Hz, 4-K). m / z (MB). 1538 (M + 1), 362, 331, 231, 135, 130, 105,

Dets: 0.69; H, 6.8; I, 7.2 requires O, 69.4; h, 7.1; E, 7 * 4). gaae 5, (♦ ·) -β-β-β1-3-1β-β11) -2,3-β1 â † '1 -β- (2-β, 11β, 13β) -β, 17β-Pyrrolidinyl] of tricyclo [3.3.1.1 (7dec-2-yl)

The above ester (57) (110 mg, 0.20 mmol) was dissolved in 20 ml of TKF and cooled to 0Â ° C. Lithium hydroxide (21 ml, 0.01 M) was added dropwise to the solution over a period of 3 hours. The solution was allowed to stir for an additional hour and then allowed to warm to room temperature. Hydrochloric acid (2.1 mL, 0.1 M) was added and the solution was extracted with ethyl acetate (3x20 mL). The organic phases were combined, dried (Na2 SO4), filtered, and evaporated to dryness to give (105 g, 98%) of crude product. The product was isolated by flash chromatography (methanol: water, 4: 1) as a white powder (84 mg, 78.5%). 'vrmaac (cm-1, thin film), 3347 (HS), 2912 (Ξ) 5 1781 (00), 1070 (00). H (300MHz, CDCl3) δ 1.55-1.97 (14H, m, adamantyl-H); 2.38 (2H, m, HEGKg); 3.00 (1H, d, 18 Hz, CH 2 CH 2); 3.05 (1H, d, J 15 Hz, indole-GH2); 3.47 (2H, t, J 8 Hz, CH 2 Ph); 4.80 (1H, s, OH); , 5.49 (1H, s, HH), 7.04-7.35 (8H, m, 5-H + 6-H + 73. + H-57-56 (1E, d, J 8 Hz, 4-H), 8.58 ( 1H, s, m), 0.9 (75.5MHz, DMSO), 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, 125.4 , 127.4, 128.7, 136.0, 138.0, 154.9, 174.1, 176.1. M / z (0.1.) 528 (M + 1) 527, 526, 374, 331, 130. Det: 0.72.6%; H, 6.8%, S, 7.9%, δ 32H35H3030N2H2O3 (re), 72.5%, H, 6.7%, H, 7-9%).

Example 41 (R2 to Me, see Scheme 15a)

A suspension of powdered 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 at 100 ° C and gramine (30.1 g g, 172 mmol) in portions. After 30 minutes the temperature was raised to 130Â ° C (oil bath) and the mixture was refluxed well for 16 hours. Then 100 ml of water and 200 ml of ethyl acetate were added, the mixture was neutralized with acetic acid, the organic phase was separated, washed with water (100 ml), dried (sodium sulfate) and evaporated. The residue was purified by silica gel chromatography using toluene / ethyl acetate (1: 1, v / v, Rf 0.4). Compound 2a was isolated as a light brown viscous oil (34.5%, 86%). MS (? Ee): m / z 256 (M +, 8%), 130 (100%).

Example 42 (E2-Me, see Scheme 15a)

Compound 2a (5 g, 19.5 mmol) in 250 ml of dioxane, saturated with ammonia (100 bar, 80øC) was hydrogenated with Raney nickel alloy (0.95 g) in an autoclave for 1 hour . After filtration and evaporation the residue was purified by silica gel chromatography using dichloromethane / methanol (95: 5, v / v, Rf 0.1). Compound 3a was isolated as a colorless viscous oil (4.76 g, 94%). (L) (70: 7): m / z 260 (M +, 17), 130 (100), 117 (48).

Example 45

To a stirred solution of 2-adamantyl chloroformate (4.45 g, 20.7 mmol) in anhydrous 2HP (50 ml) in dry CH2Cl2

A solution of compound J1 (4.76 g, 18.3 mmol) in anhydrous TEF (100 mL) was added followed by a solution of triethylamine (3.7 g, 36.6 mmol) in IEF (50 ml) was added dropwise. After 15 minutes the reaction mixture was filtered, the solvent removed and the residue column chromatographed on silica gel using CH2 Cl2 (98: 2) as eluant. producing compound 4a. as a colorless amorphous solid (7.8 g, 97%). MS (70eV): m / z 438 (M +, 20), 130 (100).

To a solution of compound 4a (3.9 S, 8.9 mmol) in dioxane / H2 O 2 (1: 1) (60 mL) an excess of LiOH (0.325 g, 13.5 mmol) was added and 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 (50 ml), neutralized with acetic acid, extracted with CH2 Cl2 and the organic layer was separated and dried (sodium sulfate ). After filtration and evaporation the residue was chromatographed using 95: 5 (v / v, Hf 0.3) GE2 Cl2 / MeOH as eluant to afford the acid 5a as a colorless amorphous solid (2.5 g, 69%). MS (70: 7): m / z 410 (M +, 4), 130 (100). (E = 2-adamantyl, ΈΓ Me, Έ? -GH20H, o = 1, R = E, see Scheme 15a)

7β- (2-Aminoethyl) -2-phenylethyl] amino] -2- (1E -indol-3-ylmethyl) -2-methyl-3-oxopropyl] -carbamic acid, tricyclo [3.3.1.1] To a solution of compound 5a (1 g, 2.44 mmol) in anhydrous ethyl acetate (40 mL) was added pentafluorophenol (0.45 g, 2 , 44 mmol) and stirred for 10 min. The reaction mixture was cooled to 0 ° C,

A solution of dicyclohexylcarbodiimide (0.505 g, 2.44 mmol) in ethyl acetate (10 ml) was added dropwise. This solution was added for one hour at 0 ° C and then at room temperature for four hours. then cooled to 4 ° C. The mixture was filtered and the precipitate washed with cooled ethyl acetate (10 mL) and a solution of (3) - (-) - phenylalaninol (0.405 g The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL), and extracted with ethyl acetate (25 mL). The residue was chromatographed on silica gel using CH 2 Cl 2 / MeOH (98%) as eluent to provide compound 6a as a colorless amorphous solid (0.780 g, 59%, mixture of two diastereomers ), mp S5-95 ° C ♦ 01-Eli (70eV, M3) m / z 544 (MH +, 100), m92 (6%).

The compounds of Examples 46-57 were prepared in a similar manner; (O 2 = configuration of the radical of the substituted 2-phenylethylamide residue, the center R2 is always ES).

Example 46 (E1) (1S) -2-bornyl, S3 = He2, = B4 = H, O = 1)

3- [7,2-Phenylethyl) amino] pyrrole-2-carboxylic acid, 17β-trimethylbenzyl [2] -T] -7-heptadecyl ester -2-yl (bicycloheterocyclic system, central chain B3) Mp: 60-70 ° C (70eV): m / z 515 (M +, 5), 130 (100)

Example 47 (R, 1-adamantyl, R2 ', Me, H, c' 1 '

2- (1-Indol-3-ylmethyl) -2-methyl-3-oxo-3- (4-methylpiperazin-1-yl) propyl] carbamic acid, tricyclo [3.1.1] 7dec-1-yl (Â ±) mp: 75-85Â ° C, (70e), m / z 513 (M +, 100), 305 (91-

Example 48 (Î ± 1 = 2-adamantyl, R2 = g), 3Î ±, 2Î ±, 3β, 7β- (1H-Âpipol-3-ylmethyl) -2- (+) - Mp: 75-55 ° C, Eli (70eV): m / z 513 (M +, 25): 305 (M + H) +. 88), 134 (100)

Example 49 (R 1 = (18) -2-bornyl, R 2 = Ile, R 2 = GEgOH, E 4, H, c = 1.0, = 3) Carboxylic acid, [5- [N- (3-oxymethyl) -2 3-yl] -2-methyl-1,2,7,8-trimethylbicyclo [2.2.1] -tol-2- yl (bicyclo system is 15-endo, hydroxymethyl center is S, other center is 55) mp: 75-85øC, MS (? 0eY) 5 m / z 545 (M +, 7), 130 (22), 95 77), 44 (100)

Example 50 (R 1 to 2-adamantyl, R 2, Me, R 2 = H, R 4 = xff), 14-oxa-2,6,9-triazaper-4-carboxylic acid, ester of 4 3-ylmethyl-4-methyl-5,10,15-trioxo-8,15-diphenyl-, tricyclo [5.3.1.1,7,7-tetra] -2,2- (A), 459 (21), 135 (100) Example 51 (R-2-yl) adamantyl, R 2 = Me, R 2 = H, R 4 = EHGQGH-OHEGgMe, c = 1.0, E) 14 - [[2- (2,6-Trifluorophenyl) 3-yl) methyl] -4-ethyl-5,10,15-trioxo-S-phenyl-, tricyclo [3.3.1] hexahydro-2-yl, (R) - (E) 7 - &quot; - 140 -

mp: 105-120 ° C, Cl-MS (ESI): m / z 641 (ES +, 1), 151 (C18)

Example 52 (E 1 = 2-adamantyl, R 2 = Me, a 3, H, R 4 iso -o-t-butoxycarbonyl) 5-ylmethyl) -4,12,12-trimethyl-1,5,10-trioxo-8-phenyl-, tricyclo [4.5.1] -oxazolyl, M.p. 100-110Â ° C, OI-M (CH 4): m / z 629 (M +, 8), 155 (100)

Example 53 (R, 2-adamethyl), R 2 = Me, - R 4 = R 4 = R 4 = O, R 1 =

5-ylmethyl) -2-methyl-1-oxo-3 - [(4-methoxyphenyl) -1H-indol- (R * <R *) 7- mp: 110-125 ° C, 1-MS (CH 3): m / z 628 (M +), , 164 (100)

Example 54 (E) = 2-adamantyl, R 2 = Me, 7 '= 11, R 4 = CHOHOH = CHOQqH, e = 1, 1-oxo-3-chloro-5,5,1,1,11,12dec-2-yloxy) carbonyl] amino] propyl] amino] -1-phenylethyl] -4-oxo -2-butenylic acid (grp center RS, another center R, double bonded E)), 4.43 (100) mp 210-220 ° .01-MS (O): m / z 626 (M +

Example 55 (R 2a-2-adamantyl, R 2 = Me, R 4 'H, c a 0),

2- (1H-Indol-5-ylmethyl) -2-methyl-5-oxo-5-cyclohexylmethyl) amino] pallopyranosuccinic acid tricyclo [3.3.1] 1? V.7dec-2-yl (±) - - 141

mp: 80-90 ° α, m (70eY): m / z 499 (L + +, 25), 291 (47), 130 (100) (1H, indole-5-yl) -benzenesulfonamide, butanedioic acid, mono-2- [7- (1H-indol-5-yl) 2-methyl-1-oxo-3- [7,7-trimethylbicyclo [2.2.1] oct-2-yloxy) carbonyl] amino] piperidinyl] amino] -3-phenylpropyl} endo, phenylmethyl center is 5, another within is E3) mp 115-130,01-Eu (0¾): m / z 646 (MH +, 34), 528 (78), 101 (100)

Example 57 (B 1 = 2-adamantyl, R 2 = He, R 2 = H, C = O)

[2- (7-Indol-3-ylmethyl) -2-methyl-1-oxo-3 - [(3-methyl-1 H -indol-3-yl) amino] -3-phenylpropyl] amino] -3-phenylpropyl] amino] -3-phenylpropyl] amino] -3- [ (100) Conversion of Compound 5a (R1 = 2-p-azazanyl, R = Me) to compounds 6f, 6g, 6h, 6i, 6k, and conversion of compounds 6a and 6e to compounds 6m and 6n in which R 1, B 2 and E are also prepared according to the synthesis scheme 15b:

Example 58 (c = see Chart 15b)

A solution was refluxed for 16 hours. (8a, 18.8 g, 0.1 mol) was added,

indole-3-carboxaldehyde (14.5 g, 0.1 mol) and piperidine (5 drops) in ethanol (100 ml). After cooling to room temperature the precipitate was filtered off, washed with ethanol (2 x 20 mL) and dried to provide compound 9a as yellow crystals (29 g, 92%). MS (rt = 0.7) s m / z 315 (+) 14), 195 (100).

Example 59 (c = 1. see Scheme 15b)

It was hydrogenated (100 bar, 80øC with a Saney nickel alloy (0.5 g of compound 9a (3.15 g, 10 mmol) in 50 ml of dioxane, saturated with ammonia in an autoclave for 17 hours. and evaporation the residue was chromatographed on silica gel using Q1 (v / v) as the eluent. Compound 10a was obtained as colorless crystals from ethyl acetate (1.16 g, 36%). (70eY): m / z 321 (M +, 46), 170 (93); 130 (100).

Example 50 (5α to 2-adamantyl, c = 1, see Scheme 15b)

Acid 5- (1H-indol-3-ylmethyl) -3-oxo-3 - [(2-phenylethyl) amino] propyl] carbamic acid, tricyclo [3.5.1.1 (7-methyl-2- Conversion from 10a to 11a was carried out according to the conversion of 3a to 4a. After chromatographic separation using GH 2 O / MeOH 98: 2 as eluant, compound 11a was isolated as a colorless amorphous solid

(87%), m.p .: 105-140 ° C. MS (70: 7): m / z 499 (M + +) = 291 (100)

Examples 61 and 62 (c-1, see Scheme 15c)

A suspension of powdered sodium hydroxide (0.5 g, 12.5 mmol) and β- (4-phenylethyl) cyanoacetamide (8.8 g, 42.5 mmol) in 50 mL of toluene was heated in an atmosphere of nitrogen at 100 ° C and gramine (7.4 g, 42.5 mmol) was added portionwise. After 50 minutes the temperature was raised to 150Â ° C (oil bath) and the mixture was moderately refluxed for 2 hours. Then 50 ml of water and 200 ml of ethyl acetate were added, the mixture was neutralized with acetic acid, the organic phase was separated, washed with water (100 ml), dried (sodium sulfoxide) and dried evaporated. The residue was separated by silica gel chromatography using EtOAc / EtOAc (v / v) as eluent. 1. Bracing; Compound 15a as colorless crystals (4.5 g, 47%) MS (70%): m / z 446 (M +, 4), 150 (100). 2. Working: Compound 12a, colorless ethanol crystals (5.05 g, 25%). MS (? EeV): m / z 517 (M +, 18), 150 (100).

Example 65 (R 1 '= 2-adamantyl, c = 1) 1- [2-bis (ΙΗ-indol-5-ylmethyl) -3- [5- [2-phenylethyl) The conversion of 1α (c = 1) to 17α (2α, 2α-adamantyl, c 1¹) was completed in a similar manner to that described in Example 1. analogous to the conversion of 2a to 4a. After purification by silica gel chromatography using 98: 2 CH2 Cl2 / MeOH The compound 1a was isolated as a colorless amorphous solid (50% yield of 15a), m.p .: 105-110Â °. 01-MS (ES +): m / z 629 (MH +, 100%).

Example 64 1 (R-1-adamantyl, R-Me, see Scheme 16)

To a stirred stirred solution of 3a (3 g, 11.5 mmol) in anhydrous THF (100 mL) at ambient temperature was added adamantane-1-carbonyl chloride (2.28 g, 11.5 mmol), a solution of triethylamine (3 g, 3 mL, 23 mmol) in 5HF (20 mL) dropwise. The reaction was completed after 30 minutes as verified by thin layer chromatography. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography using CH 2 OH / MeOE 98: 2 as eluent. Compound 18a was isolated as a colorless amorphous solid (3.25 g, 67%) as a colorless amorphous solid (3.25 g, 67%), m.p. 130-100 ° C.

Example 65 To a solution of compound 18a (3.25 g, 7.4 mmol) in 1 H -dioxane / H2 O (2: 1, 90 mL ) an excess of LiOH (0.39 S, 15.4 mmol) was added and 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 phase was dried (sodium sulfate) and evaporated. Compound 19a was isolated as a colorless amorphous solid (3 g, 100%). ELC (silica gel): HE1 0.2 (OH / OHP / MeOH 95: 5).

Example 56

Cl-1-adamantyl ", R2 = Me, v = -qh-OH. C = 1, R4 H, see Scheme 16) 1-Indole-3-propanamine, N- [1- (hydroxymethyl) -2-phenylethyl] X-methyl- -2-ylcarbonyl) amino] methyl] -2-oxo-pyridin-2-yl ester (in the same manner as in Example 1). After purification -

by silica gel chromatography using CH2 Cl2 / LfeOH 98: 2 compound 20a was isolated as a colorless amorphous solid (52%), m.p. 85-95Â ° C. m (TOeV): m / z 527 (M +, 50), 335 (100). t obtained in an analogous way:

Example 67 (1 H-1-adamantyl, B2 = Me, E ', or 1, E4) 1 H-Indole-3-propanamide, &lt; Xaaethyl- (2-phenylethyl) 7-decyl-2-yl-benzoyl) amino] -methyl] -amide. (*) -

Colorless amorphous sol, m.p .: 80-90 ° C. | MS (70eV): m / z 497 (M +, 9), 305 (43), 184 (56), 135 (64), 130 (100).

Example 68 (See Scheme 17) were heated at 60 ° C for 16 hours with stirring and in an autoclave to 1- (3'-indolyl) -butan-3-one (12.32 g, 65.9 mmol), potassium cyanide ( 4.7 g, 72.3 mmol), ammonium carbonate (5.9 g, 71.8 mmol) and ammonium hydroxide (25%, 13 mL) in water (25 mL) and methanol (75 mL). The solution was diluted with water (100 ml), the methanol was evaporated and the residual mixture was acidified (HCl 2H), the precipitated hydantoin 21 was filtered off, washed with water and dried. Yield 15.2 g (90%) of colorless crystals. MS (73eV): m / z 257 (M +, 22), 144 (96), 130 (100).

Example 69 (See Scheme 17) Compound 21 (10 g, 38.9 mmol) in 5% aqueous sodium hydroxide solution (125 mL) was heated at 150 ° C for 16 hours in an autoclave. After cooling to room temperature, the solution was neutralized with

To remove traces of hydantoin 21. The solution was stirred at room temperature for 2 hours and the precipitated amino acid 22 was separated, washed with water (20 ml) ) and dried. Compound 22 was isolated as light beige crystals (8.52 g, 94%). EIl (TDeT): m / z 232 (M +, 26), 144 (100), 130 (92).

Example 70 (7er Scheme 1)

A solution of compound 22 (5 g, 21.5 mmol) in dry methanol (3.5 mL) was heated at 40 ° C and saturated with hydrogen chloride (1 hour). After stirring at 40-45 ° C for 5 hours and at room temperature for an additional 15 hours the solvent was evaporated. Water (100 ml) was added, the mixture was neutralized with aqueous potassium carbonate solution and extracted with ethyl acetate (2 x 100 ml). The organic phase was washed with dilute sodium bicarbonate solution (50 ml) and then with water (50 ml) and dried (Naâ,,SOâ, "). After removal of the solvent the residue was chromatographed on silica gel using 2- / MeOH 98.2 (v / v) as eluent.

Compound 23 was isolated as beige crystals (4.0 g,? 5%). Eli (Î ± 0eV): νmax 246 (M +, 25), 144 (Î »1), 130 (100).

The reaction of aminoaster 23 with 2-adamantyl chloroformate was carried out according to the conversion of 3a to 4a. Compound 24a was isolated in 86% yield as a colorless amorphous powder. MS (70: 7): m / z 424 (M +, 42), 281 (41), 144 (100), 135 (78). 147 -

2-adamantyl, see Scheme 17)

Hydrolysis of 24a with lithium hydroxide was carried out according to the hydrolysis of 4a to 5a. Compound 2Sa was isolated without chromatography as a pale beige amorphous powder in quantitative yield, pure enough to be used in the next step (see Example 73) without further purification. MS (70: 7): m / z 410 (ii +, 5), 130 (100).

Example 75 (E1 is 2-Aminoyl, Î ± -E, Î ±, Î ± 1, see Scheme 17)

(1 H -indol-3-yl) -1-methyl-1 - [(2-phenylethyl) amino] carbonyl] propyl] carbamic acid, tricyclo [3.3.1] dec-2 (+) - Conversion of 25a with 2-phenylethylamine to 26a was effected according to the conversion of 5a to

After chromatographic separation on silica gel using CH 2 Cl 2 / MeOH 98: 2 (v / v) compound 26a (Rf 0.2) was isolated in 69% yield as a colorless amorphous powder, mp 95-85 ° 0. SM (70: 7): m / z 513 (Μ 41 2, 1), 370 (67), 130 (100). Are prepared analogously: (02 = configuration on the chiral carbon atom of the substituted 2-phenylethylamide residue, the other center is always R3) - (1R, 2-adamantyl, R1 = CH2 CH2, c '1, 02-3)

5-Cyclopropyl] -1-methylpropyl] carbamoyloxymethyl] -2-phenylethyl] amino] carbonyl] -3- (1H-indole-2-yl) yl (hydroxymethyl) 3, another (C1-6) alkyl,

Example 75 (S1 = (1 S) -2-bornyl, = Ητ or -Ca,-Cl,,,,,,,,,,, Cl Cl Cl,,,,,,, T T T T T T T T T T T T T T T T T T T T T T T T Ister Aβ1-β-trimethoxybenzolp- and β.2.27β-2-yl, β- [Î ±] -2- (3) ihiSZz pfi 70-80 ° .01-MS (OBL) sm / z 516 (M +), 562 (100).

Example 76 (S) -1,2-adamantyl, R 1 = H, H 4, H 4 O, OCH 3, Me = O, 740.9 ... ester of ethyl 3- [2- (1-indol-3-yl) ethyl] -5-methyl-4,5,12-trioxo-Î ± -phenyl-, trioxy- [5.3.1.13] (SEQ ID NO: 2), SEP is a mixture of the R / 3, another center R, double bond E) mp 11-123 ° α, 01-MS (04H10) sm / z 640 (M-, 19), 487 (100) Example 77 (R-α-2-adamantyl, 5- (1H-indole-3-yl) )] ethyl] -3-methyl-4,9,12-trioxo-7,14-diphenyl-, 15-oxa-2,5,8-triazatetrand Glyoxophosphoric Acid Trihalolo [5.5.1.13,77dec-2-yl center ΐΗΡ and B / S mixture, another center and R) mp: 85-95øC, 01-MS (4-11) * / 2 62 / (20), 475 (100), 251 (44).

Example 78 (R) = (13) -2-boronyl, 3α, 4α, 4α, 4α, 1α, 1α,

7Î ±, 17β, 17β- (hydroxyhydroxymethyl) -2-phenylethyl) amino] carbonyl] -3- (1 H -indol-5-yl) -1-ethylpropyl] 1,7,7-trimethylbicyclo [2.2.1] hept-2-yl ester (I-endo bicydole system, hydroxymethyl center is S, other center); GH3); m / z 546 (MH +, 82), 153 (100).

Example 79 (B1 = 2-Aminomethyl), β- [Î ±] E4 = MHâ,,Oâ, ... Hâ, â, ... Hâ,,Oâ,, - 2-yl) -2-methyl-1-oxo-2 (R) 1-enyl] amino] -4-oxo-butanoic acid (indole center is RS, another center is), mp 115-125 ° C, Cl-MS (σ 4 · 10): m / z 629 (MH +, 1), 191 (28), 155 (100)

Example 80 (R1 to 2-aminothienyl, S '= H, R4 = -NHCOCHCHO2H, c = 1. Acid A 2- [2- (1H-indol-5-yl) ethyl] -2-methyl-1-oxo-3-trifluorolo [3,2-c] [1,4] deca-2-yloxy) carbonyl] amino] propyl] amino] -1-phenylethyl] -? - oxo-2-oxo- indole is RS, another center IR, double bond E) mp 190-200 ° .01-MS (m3): m / z 626 (M +, 24), 201 (60), 151 (100) 26d to 26b. and the conversion of 26e to 26g was carried out in analogy to the procedures already described.

Example 81 (See Scheme 18)

The alkylation of the diethyl methylmalonate with gramine afforded compound 28 after chromatographic separation on silica gel using C 20 H 15 Cl 2 O 2 (KBr, 18: 1440, 1447, 1953) 98/2 (v / v) as eluent as a light red-brown syrup (yield 90%). MS (70eV): m / z 303 (M +, 11), 130 (100).

To a solution of the diester 28 (31 g, 0.102 mol) in dry methanol (80 ml) was added a solution of potassium hydroxide (6.5 g, 0.116 mol) in ethanol (65 ml) was added dropwise at room temperature (1 hour) and stirred for another 16 hours. The reaction mixture is filtered and the filtrate is evaporated. The residue is suspended in water (700 ml), neutralized with hydrochloric acid and extracted with ether (3 x 250 ml). The ether solution was dried, evaporated and the residue purified by silica gel chromatography using 95: 5 (v / v) GHgCl2 / MeOH as eluent. Q. flionoic acid 29 (Rf 0.1) was isolated as light reddish brown syrup (18 g, 64%). MS (TOeV): m / z 275 (M +, 9) 130 (100).

Example 85 To a solution of compound 29 (37 g, 0.134 mol) in anhydrous tetrahydrofuran (500 mL) at 0 ° C under nitrogen was added dropwise a 2 M solution of the bore-sulfide complex in tetrahydrofuran (100 ml, 0.2 mol) (45 min) and stirred for 3 hours at 0 ° C. Then water (100 ml) was added dropwise, the mixture was diluted with more water (400 ml) and ethyl acetate (800 ml). The phase. The organic extract was separated, washed with water (3 x 150 ml), dried

(Na2 SO4) and evaporated. The residue was suspended in CH2 Cl2 (100 ml), the precipitate 29 filtered off and washed with CH2 Cl2 (30 ml). Compound 29 was isolated as colorless, sometimes slightly red (26.74 g, 85%) crystals pure enough to be used in the next step TLO (silica gel): Rf 0.15 (toluene / tetrahydrofuran 1: 1)

To a solution of compound 30 (26.6 g, 0.114 mol) in dry methanol (1.5 L) was added 4 ml of sulfuric acid (95-97%) and the solution was stirred at 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 phase was washed with water (250 ml), (Na2 SO4) and evaporated. The residue was chromatographed on silica gel using 5: 1 (v / v) toluene / ethyl acetate as the eluent. Compound 31 was isolated as a viscous colorless syrup (25.7 g, 91%). MS (70eV): m / z 247 (M +, 8), 130 (100).

To a solution of compound 31 (5.0 g, 20.2 mmol) and pyridine (3.2 g, 40.4 mmol) in anhydrous dichloromethane (100 mL) at 0 ° C was added p-toluenesulfonyl chloride (5.0 g, 26.3 mmol) in small portions. The solution was allowed to stand for 4 days in the refrigerator at 0-5 ° C. The solution was washed with sodium bicarbonate solution (2 x 50 mL), dried (Na2 SO4) and evaporated. The residue was chromatographed on silica gel using toluene / ethyl acetate

95: 5 (v / v) as eluent. Compound 32 (Rf 0.3) was isolated as a viscous oil, and recrystallized from diisopropyl ether to give colorless crystals (6.94 g, 85%). MS (TOeV): m / z 401 (M +, 8), 130 (100).

Compound 32 (3.55 g, 8.13 mmol) and potassium cyanide (0.850 g, 13.1 mmol) in anhydrous dimethylformamide (60 ml) were stirred at 110 ° C for 16 hours . The solution was evaporated in vacuo and the residue was dissolved in ethyl acetate (200 ml) and water (200 ml). The organic phase was separated, dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography using toluene / ethyl acetate (v / v) as eluent. Compound 35 was isolated (Rf 0.4 in toluene / ethyl acetate 4: 1) as a colorless syrup (1 g, 45%). MS (70%): m / z 256 (M +, 8) 130 (100).

Example 87 (R1 to 2-adamantyl, Î ± -R4  · H, c1, see Scheme 18) Î ±, β-Indol-3-ylmethyl) -3-methyl-4-oxo-4- - [(2-phenylethyl) amino] butyl], tricyclo [5.5.1.1] undec-2-yl ester, (+) - Conversion of compound 33 to compounds 37 was done in analogy to the conversion of compounds 2 for compounds 6 (see synthetic scheme 15a). Compound 37a was isolated after chromatographic separation on silica gel using 98: 2 (v / v) CH2 Cl2 / MeOH as eluent as a colorless amorphous solid in 52% yield, mp: 70-80 ° 0. MS (70eV): m / z 527 (M +, 2), 130 (100).

Example 88 • (R 1 = 1-adamnyl, R 2 = O-OH), R 2 = H, c = 1, See Scheme 18 &gt;

aawactf ** 1 '

Acetyl [4- (N-hydroxymethyl) -2-phenylethyl] amino] -3- (1H-indol-5-ylmethyl) -5-methyl-4-oxobutyl] -arboxamide, trihydroxy ester [3.3.1 ,1? , 77dec-2-yl,

Analogously to the synthesis of compound 37a, compound 37b was isolated after chromatographic separation on silica gel using 98: 2 (v / v) CH2Cl2 / MeOH as eluents as a colorless amorphous solid in a yield of 52 %, mp 70-80 ° C. SM (TOeV): m / z 527 (M +, 2), 130 (100). Compound 37b is a mixture of two diastereomers (the S configuration of the guiral center derived from (S) - (-) - phenylalaninol).

Example 89

Ethylidene-isopropylamine (69)

Isopropylamine (85 ml, 1.0 mol) was added gradually over a period of one hour to acetaldehyde (56 ml, 1.0 mol) cooled in an ice bath. After the addition was complete, the mixture was stirred for another 20 minutes. Potassium hydroxide flakes were added until the solution separated into two phases. The organic phase was separated and stored on ground potassium hydroxide at 0 ° C. The dried material was distilled in vacuo at room temperature to give the title compound (1) (51.4 g, 60%), m.p .: 25-30 ° C / 10 mm; 1 H-NMR (300 MHz, CDCl3); 1.09 (6H, d, J 6.3

Hz, 20H 2), 1.88 (3H, d, J 4.8 Hz, OH CH 3). (isopropyl-aminoethylidene) -oleole (70)

A solution of indole (25.0 g, 0.213 mol) in glacial acetic acid (150 ml) cooled in an ice bath was added dropwise and ethylideneisopropylamine (69) (17.3 g, 0.203 mol) mol) in toluene (50 ml) with stirring over a period of one hour. The resulting mixture was kept at 0 ° C for 5 days. After this time the mixture was poured into a mixture of ice-ether. THE

1 '' - * '^' · Γ; Ώ3ββ 'βτ

The ether phase was separated and extracted with 1N potassium hydrogen sulfate (2 x 100 ml). The combined aqueous phase was washed with ether (2 x 50 mL), and then made basic with 10H sodium hydroxide (keeping the temperature below 25 ° C). The alkaline solution was extracted with ether (4 x 250 ml). The organic phase was dried (Na2 SO4) and evaporated to dryness to give the title compound (2) (24.6 g, 60%), mp 107-111øC (bp: 108-114øC) Νmax (film) 3 479 cm -1 (indole 13H); (3H, d, J = 6.6Hz, 1H), 1.09 (3H, d, 6Hz, CH), 1.52 (1.52 (3H, d, 2.88 (1H, septet, 6 Hz, OH), 4.27 (1H, q, J = 6.6 Hz, 1H), 7.08- (4H, m), 7.35 (1H, s, , HE), 7-71 (1H, d, 8 Hz, indole 4-H), 8.21 (1H, brs, indole NH).

Dibenzyl acetamidomalonate (71)

Diethyl acetamidomalonate (9.1 g, 42 mmol) in Aldrich / benzyl alcohol (26 mL, 0.25 mmol) was heated in an oil bath at 200 ° C. A small flow of nitrogen was bubbled through the solution and the ethanol was distilled off. After 4 hours the reaction mixture was cooled to room temperature and the benzyl alcohol in excess was removed as the oil being slowly raised to 185-190øC, at which point the distillation became very slow. The solution was cooled to room temperature and the resulting β-β-cyclic recrystallized from isopropanol to give the title compound (71) (12.2 g, 85%); m.p .: 111-112 ° C (lit., 116-113 ° C); Omax (film) 1752, 1734 (ester O = 0), 1651 (starch 0 = 0), 7.04 and 694 cm ^¹ (mono-substituted pH); (300 MHz, CDCl3), 2.05 (3H, s, OCH3), 5-17 (2H, s, OH), 5.18 (2H, s, OH), 5.29 (1H, d, 7 Hz), 7-27 (10H, m, 2Ph), Jc (75-5 M Hz, 0D013), 22.5, 56.5, 68.5, 128.5, 134.5, 166, 170. (3-indolylethylidene) acetamidomalonate dibenzyl (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) in toluene (30 mL) at 85-95 ° C (bath temperature) maintaining a small flow of nitrogen bubbling in the solution. The reaction mixture was maintained at this temperature for 5 hours, and then cooled to -40 ° C (freezer). The product was filtered and recrystallized from isopropanol to give the title compound (72) (8.22 g, 64%), m.p. 162-163 ° (ρΛη) (lit., 161-163 ° C); 1737 (ester 0 = 0), -L-LX-1672 (amide 0 = 0), 743 and 697 cm-1 (monosubstituted Ph); 1 H-NMR (300 MHz, CDCl3), 1.57 (3H, d, J2 Hz, OH), 1.97 (3H, s, OH2 O), 4.32 (1H, q,  € ƒâ € ƒâ € ƒ4.72 (1H, d, J 12 Hz, one of OHâ, ") (1H, d, J 12 Hz, one of Ohr), 6.56 (1H, s, HH), 6.86 (1H, d, J = 2 Hz, indole 2-H), 7.02-7.33 (13H, m, indole (1H, br s, indole 0 (75 * M Hz, 0D015), 18, 23, 37, 68, 70, 111, 5, 115, 119-5, 122, 122.5 127,128, 134.5, 136, 167, 168, 169-5, (3-iodolylethylidene) acetamidomalonic acid (73)

Diester (72) (930 mg, 1.92 mmol), palladium hydroxide on carbon (Pearlman's catalyst) (125 mg) and 95% ethanol (50 ml) were placed in a Parr hydrogenation flask and subjected to hydroxynation pressure of 310 by 25øC for 3 hours (until the absorption of hydrogen has stopped). The reaction mixture was filtered through Oelite to remove the catalyst, and then evaporated to dryness to give the title compound (73) (576 mg, 99%) which was used without further purification SH (300 MHz; (3H, d, J 7 Hz, CH 2), I.99 (33, s, GH300), 4.09 (1H, brd, 7 Hz, OH, (OH)), 7-12-7.24 (3H , 7- (1H, d, 8 Hz, indole 4-H), 2-acetamido-5- (5-indolyl) butanoic acid (74)

(73) (5.48 g, 18.0 mmol) was refluxed in pyridine / water (1: 1) (20 mL) until the diacid (SiCi i EtOH-EtOAc (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 brown solid was separated by filtration and dried to give 2-acetamido-3- (3 "indolyl) butanoic acid isomer A (? 4A) (1.30 g, 28%); 1 H-NMR (300 MHz, d6 -DMSO), 1.32 (3H, .delta.H, .delta.), 1.84 (3H, s, cp2O2), 3.46-3.55 (1H, m, (1H, d, J = 8 Hz, amide MH), 7.44 (1H, d, J = 8 Hz) 1H), 8.04 (1H, d, J 9 Hz, indole-4H), 10.81 (1H brs, indole EH), ca 12.4 (vrt, GO 2) 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 hydrogen carbonate solution (2 x 100 ml) .The hydrogen extract sodium carbonate 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) and then evaporated to dryness to give (3-indolyl) butanoic acid isomer B (74B) (2.17 g, 46%), SH (300 MHz, d6 -DMSO), 1.32 (3H, d, 7 Hz, OH), 1.84 (3H, s, CH 3 CO), 3.50 (1H, (3H, m), 7.34 (1H, d, J 8 Hz, amide MH), 7.63 (1H, (1H, d, J = 9 Hz, indole 4-H), 10.83 (1H, s, indole MH), ca 12.5 (v brs, 1.00 H).

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

Acids (74A) and (74B) were deacetylated separately by the same procedure. Was it made bubble? nitrogen through a mixture of (74B) acid (3.96 g, 15 g, 2 mmol) in 4N sulfuric acid (25 ml) for 30 minutes, and then the mixture was refluxed until all the solid had dissolved. The solution was cooled to room temperature and neutralized.

The barium salts were precipitated with solid carbon dioxide, and the mixture was warped to the boiling point and filtered while still hot. The solvent was removed in vacuo and the crude product was purified by reverse phase / methanol-water column chromatography (1: 6) as eluent to provide 2-amino-3- (3-indolyl) butanoic acid (75) (2.34 g , 71%), a ratio of 1: 3 (75A: 75B), mp: 198-212 ° C (lit., 218-225 ° C dec), isomer A HH (300MHz, D₂O), 1.33 (2H, m, indOH (CH 2) - + CH (Co 2 H) H H 2), 7.20-7.34 (2H, m), 7.57 (1H, d, 1H), 7.87 (1H, d, 8 Hz, indole 4-H), isomer Β, Î'H (300 MHz, d2 O), I.37 (3H, d, J = 7 Hz) Hz, OH), 3.30-3.42 (2H, m, ind OH), -0.4 (2H), 7.09-7.24 (3H, m), 7.48 (1H, d, , indole 7-H), 7.73 (d, 1H, indole, 4-H).

2-adamantyl gloroformate A solution of 2-adamantyl (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) was added followed by the dropwise addition of pyridine (6.2 mL, 77 mmol) at a rate such that the temperature remained below 20 ° C. After a further 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 was suspended in ethyl acetate (50 ml). The pyridine hydrochloride was filtered off and the filtrate was evaporated to dryness without heating to provide 2-adamantyl chloroformate (76) (13.7 g, 96%); δH (300MHz, CDCl3), 1.48-2.32 (14H, m, adamantyl), 5.01 (1H, t, 3H, adamantyl 2-H); (14H, m), 4.95 (1H, s) 2- (2-Adaiaantiloxycarbonyl) amino-3- (3-indolyl) butarncoic acid (77)

The amino acid (75) (44-9 mg, 2.29 mmol) in 3N sodium hydroxide (2.29 ml) was added to sodium hydrogencarbonate (211 mg, 2.5 mmol). This mixture was cooled to 0øC (ice bath), and dioxane (2.29 ml) was added followed by the dropwise addition with stirring of a solution of chloroformate (67) (742 mg, 34.46 mmol) in dioxane (2.29 ml). When the entire amino acid had been consumed (ELO SiO 3 - 4% methanol in dichloromethane), dioxane was removed in vacuo and the residue was partitioned between 10% citric acid and ethyl acetate. The aqueous phase was further extracted with ethyl acetate. The organic extracts were combined, dried (MgSO4) and evaporated to dryness. The crude acid was purified by column chromatography on standard silica Kexane: ethyl acetate (3.20 + 0.5% acetic acid as eluant to give 2- (2-adamantyloxycarbonyl) amino-3- (5 -indolyl) butanoic acid (77) (570 mg, 63%): 1 H-NMR (300 MHz, d6 -DMSO), 1.34 (3H, d, J 8 Hz, OH), 1.68-2.00 (14H, m, adamantyl),  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ3 H-NMR (d6 -DMSO) urethane 1), 6.96 (1H, t, J 7 Hz, indole 5-H), 7.06 m (1H, t, J 7 Hz, indole 6-H), 7:17 (1H, brs, (1H, d, J 8 Hz, indole 7-H), 7.60 (1H, d, J 8 Hz, indole 4-H), 10.83 (1H, s, indole HH), ca 12.6 (VBs, 002) 2-Aminothioxycarbonyl-D, L-β-methyl-β-tryptophan-L-phenylalaninol (7B)

Carboxylic acid (77) (288 mg, 0.726 mmol), N, N-dicyclohexylcarbodiimide (DOOI) (173 mg, 0.838 mmol) and 1-hydroxybenzo-triazole (HOBT) 121 mg, 0.895 mmol) in ethyl acetate (5 mL) &lt; Dimethylaminopyridine (DMP) (23 mg, 0.19 mmol) and phenylalaninol (163 mg, 1.08 mmol) were added and the mixture was stirred for an additional 2 hours at 0 ° C and then for 48 hours at room temperature environment. The mixture was filtered and 0 -

The filtrate was washed with 5% citric acid (2 x 10 ml), saturated sodium hydrogen carbonate (10 ml), 5% new citric acid (10 ml), and brine (10 ml), dried H 2 SO 4), and evaporated to dryness. The crude product was purified by column chromatography on standard silica: ethyl acetate / hexane (1: 1) as eluent to provide 2-adamantyloxycarbonyl-D, L-3-methyl-D-triptophan-1 -phenylalaninol (78) (45 mg, 12%); mp: 99-101Â ° C (Det: 0.71.7 *, H, 7.65; 31.74; 32.49; 33.4; 46.5; 29.2; 71.35; ). * Max (film) 560 (OH), 1695 (urethane 0 = 0), 1658 (amido 0 = 0), 746 and 702 cm-1 (monosubstituted Ph); (1H, brs, OH), 2.43-2.69 (2H, m), 1.45-2.10 (14H, m, adamantyl), 2.20 (1H, brs, (1H, br, m, OH), 3.86 (1H, brs, OH), 4.49 (1H, brs, ind OHOH) (1H, brs, urethane NE), 6.87 (1H, brs, amide KH), 6-95-7.38 (8H, m, indole + H), 7-69 (1H, d, J 7 Hz, indole 4-H), 8.26 (1H, s, indole MH), m / z (MB) 530 (H + + 1), 257.232, 217 181, 144, 126 (100%), 109.

Example 90 1- [3- (1H-indol-3-ylmethyl) -3-methyl-N-Cyclo [3.3.1.1, 7,7-dec-2-yloxy) carbonyl] -Î ± -alanyl] -L-2-phenylglycine, AdOO - ((3)) - 5- (1H-Inol-5-ylmethyl) -Ala- (Ii) -2-Phenyl) Gl) and ITase 1. Synthesis of 2-Adoc ccUeHTrp 0HN2 ( diazoketone).

A solution of N-methylmorphol. (990 mg, 2.50 mmol) in anhydrous THF (20 mL) at 0 ° C was treated with a solution of iso -butyl chloroformate (340 mg, 2 mmol) in dry THF (253 mg, 2.50 mmol) and 2D0000CMe-E-TrpOII , 50 mmol) in anhydrous (10 mL) and allowed to stir for 20 minutes). The reaction mixture was then filtered and a solution of diazomethane (6 mmol) in ether was added to the filtrate. It was then allowed to warm to room temperature and stand for 12 hours. The excess thiazomethane was cooled 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 eluant to give the zocetone (Scheme 19, H2.2) as yellow crystals, mp: 182.2-182.7 ° C (MeOH); Calc'd: + 64 ° (c = 0.5, MeOH); IY (film) 3400-3200, 2913, 2854, 2006, 1693 and 1352 cm-1; NMR (CDCl3): 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 (1H, d, J 2 Hz), 7.08 (1H, t, J 7 Hz), 7-16 (1H, t, J = 7 Hz) Hz), 7-33 (1H, d, J 8Hz), 7.55 (1H, d, J 8Hz), 8.50 (1H, s); MS: Tl (FAB) 421.3 (11), 393.2 (54), 351.2 (9), 307.2 (22) and 259.1 (100);

Calc'd for C 24 H 28 N 4 O 4 • 35

Oalc: C, 68.55; Η, 6.7I; H, 13.32%

Det: C, 68.51; H, 6.73; K, 13.26% Phenylmethyl (H) -Î ± -methyl-β-methyl-Î ±, Î ± 5.1.1 (2H, d, J = 2-yloxy) -carbonyl] -7H-indole-3-butanoic acid

Step 2. Synthesis of the above compound (Scheme 19, He 3)

A solution of the diazo ketone (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 benzoate in 10 ml Et2 O) at room temperature. This solution was stirred for 4 hours, treated with activated charcoal and filtered through gypsum. The benzyl alcohol was removed in vacuo and the residue was separated by silica gel chromatography using EtOAc as eluant to give the benzyl ester (Scheme I, 2) as a glass (3.3%, 66%); m.p .: 47-52 ° C; + 17-6 ° (o = 1, MeOH); IY (film) 3500-3200, 2908, 2855, 1750-1680 cm-1; EI® (GDG1): Î'1.39 (3H, s), 1.61 (1H, s), - 161

1.51 (1H, s), 1.54 (1H, s), 1.70-2.05 (12E, m), 2.68 (1H, .delta., 14.3Hz), 2.97 (1H, d, ), 6.99 (1H, d, J 2.3 Hz), 7.8 (1H, t, J 7 Hz), 7.6 (1H, b, J 7 Hz), 7.30-7.35 (6H, 1H, d, J = 7.8 Hz), 8.05 (1H, s); EMM / e (FAB) 501.3 (28), 370.3 (24), 326.3 (29), 306.2 (32) and 135.2 (100):

Anal. For Câ, â, ... Hâ, â, Ν:: Oâ, ": C, 74.37; H, 7.25; Det .: 0, 74.44; H, 7.20; H, 5.60% S, 5.75% (Η) -β-methyl-Î ± -cyclohexanecarboxylic acid β- - Me) DTrp

Step 3. Synthesis of the above compound (Scheme 19, Hs 4)

A solution of the benzoyl ester (as prepared in Step 2) (1.0 g, 2 mmol) in absolute ethanol (100 ml) was treated with 10% palladium on carbon. (100 mg, 10% w / w) and the resulting suspension was subjected to a hydrogen atmosphere at 345 ° C for 4 hours with stirring at 30 ° C. This reaction mixture was then filtered through gypsum and the solvent removed in vacuo. The residue was chromatographed on a reverse phase silica column using MeOH: H2 O (3: 1) as the eluent and the solid product was recrystallized from chloroform to give the acid as a white solid (700 mg, 85%) &gt;; mp: 198-201 ° C (CHCl3): .alpha.] [α] D = + 20 ° (c = 1, MeOH); IR (film) 3500-3300, 2912, 2856, 1704 and 734 cm -1; (1H, s), 1.57 (1H, s), 1.70-1.85 (9H, m), 1.95-2.10 (4H, m), 2.69 (1H, 1H, d, J = 14.3Hz), 3.05 (1H, d, J = 14.3

(1H, d, J = 14.4Hz), 4.86 (1H, s), 5.10-5.30 (1H, br s), 4.04 (1H, d, J = 2.2Hz), 7.07-7.7 (2H, m), 7.35 (1H, d, J 8Hz), 7.60 (1H, d, J = 7Hz), 8.16 (1H, s); EMM / e (FAB) 411.5 (9) and 21? .2 (100); - 162 -

s® »slite2s

Calc'd for C 244.50 (MH +) Calc'd: 70.22; H, 7.37; H, Det .: 70.03; H, 7.38; M, 6.82% 6.78%

Step 4. Synthesis of the above compound (Scheme 19, Ho 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) at 0 ° C was treated with H, H-dichlorohexylearbodiimide (263 mg, 1.30 mmol). This mixture was stirred for 18 hours at 0 ° C, filtered and the methyl ester of S-phenyl glycine (303 mg, 1.30 mmol) was added to the filtrate. This reaction mixture was allowed to stand at ambient temperature for 48 hours, washed with a 1M solution of citric acid (2 x 20 ml), saturated NaHCO 3 solution (2 x 20 ml) and H2 0 (2 x 20 ml). The organic phase dried (MgSO4) was evaporated to dryness in vacuo and the residue was separated by reverse phase silica gel chromatography using MeOH / H2 O (3: 1) as eluent to give the ester (Scheme 1 H2.5) as non-crystalline solid (600 mg, 90%). m.p .: 72-82 ° C; = + 55.36 (c = 1, MeOH); 17 (film) 3500-3200, 2916, 2856, 1743, 1694, 1657 and 1504 cm -1; (1H, m), 2.54 (1H, d, J 13.3Hz), 3.04~3.15 (2S, m), 1.40-1.55 (2H, , 3.31 (1H, d, J = 14.2Hz), 3.71 (3H, s), 4.71 (1H, s), 5.09 (1H, s), 5.48 (1H, d, (1H, d, J = 7 Hz), 7-17 (1H, g, 7 Hz), 7.30-7.40 (6H, m), 7.04 1 H-NMR (DMSO-d 6): δ (DMSO-d 6): δ (DMSO-d 6) 100);

Analysis for: 33%

Calc'd: C, 71.07; H, 7.05; M, 7.53% Found: C, 71.31; H, 7-30; H, 7.28%

Glycine, H- [5- (1H-indol-3-ylmethyl) -3-methyl- N -tricyclo- [3.3.1.1] hexane- 2-phenyl-AdOG- ((D) -3-indol-3-ylmethyl) -Ala - ((L) -2-phenyl)

Ss

Synthesis of Example 90, Scheme 19, 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 C 10 H (30 mg, mmol) in E 2 O (5 mL) at room temperature. After 2 hours the mixture was made acidic with a pH paper control by addition of 1 M EGI solution, the solvent was then removed in vacuo and the ether

The residue was separated by reverse phase silica gel chromatography using MeOH: 1340 (3: 1) as eluant to give the product (Example 90) as a non-crystalline solid (200 mg, 53%); Mp 120-125 ° C; + 49.2 ° (c = 0.5, MeOH); IR (film) 3450-3250, 2916, 2856, 1750-1600, 1510 and 1256 cm -1; NMR (CDCl3): 1.34 (3H, s), 1.50-1.55 (2H, m), 1.60-2.20 (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 6.5 Hz), 7.00-7.60 (10H, m) , 7.58 (1H, d, J = 7.9Hz), 8.14 (1H, b);

Analysis for C 32 H 37 N 3 O 5 • • 2 • * 7.65% 7.64%

Galley. 50.00, 70.00; H, 6.90; I,

Found: C, 69.97; H, 6.85; M,

Example 91. (R *, S) 7- [3- [3- (1H-indol-3-yl) -2-methyl-1-oxo-2-

cyclopropyl] amino] benzeneacetic acid, N - (R *, 3 *) 7-Amino-C-Me) DTrp-: L-phenylglycine (See Scheme 20)

Step 1 Synthesis of ox azolone (R) (4- (1H-indol-3-ylmethyl) -4-methyl-2- (tricyclo [3.3.1.1.beta. 7dec-2-yloxy) -5 (4H) oxazolone) (Hs.2, Scheme 20)

A solution of AdOOcMe-R-IrpOH (1.0 g, 2.5 mmol) and N, N'-dicyclohexylcarbodiimide (0.52 g, 2.5 mmol) in anhydrous β1 (5 ml) was stirred at room temperature for 1 hour. ml). This 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%). m.p .: 150.5-150.9 ° C (hexane); = + + 9.0 ° (c = 1, MeOH); IR (film), 2910, 2857, 1823, 1681 and 1399 cm -1; (1H, m), 2.04 (1H, s), 3.20 (1H, d, J = 14.5Hz), 3.25 (1H, J = 14.5Hz), 1.25-1.20 (1H, m) (1H, dt, J = 3.5 Hz), 6.99 (1H, d, J = 2.4 Hz), 7.07 (1H, dt, J 7.1 Hz), 7.14 (1H, d, J = 7 Hz), 7.64 (1H, d, J = 7.6 Hz), 8.02 (1H, s); MS M / e (00) 379.2 (52), 178.3 (47), 163.3 (61), 135.2 (74) and 130.2 (100);

Anal. Calc'd for C 23 H 20 N 2 O 3 '

Calc .: C, 72.99; H, 6.92; I, 7.40%

Det .: 0, 72.88; Δ, 6.96; h, 7.37%

Level 2.

A suspension of S-phenylglycine (42 mg, 0.28 mmol), Hâ,,Oâ, "(23 mg, 0.28 mmol) and oxazalone (Scheme 20, H-2) were stirred at ambient temperature for 18 hours (100 mg , 0.26 mmol) in DMF 1 H 2 O (1: 1) (10 mL). The solvent was then removed in vacuo and the residue was suspended between EtOAc (20 mL) and 1 M citric acid solution (20 mL). - 165 -

The aqueous phase was partitioned and stripped with EtOAc &gt; (2 x 20 ml), and the combined organic phases were washed with water (3 x 10 ml), and the solvent was removed in vacuo. The residue was then chromatographed on silica gel using 3% MeOH in CH 2 Cl 2, then 5% MeOH, 0.5% H 2 O in CH 2 Cl 2, to afford the product (Example 91) as a non-solid. crystalline (106 mg, 77%). m.p .: 138-143 ° C; / ¾24 * + 82 ° (A = 1, MeOH); IR (film) 3500-3200, 2913, 2855, 1696, 1566 and 1499 cm -1; NMR (DMSO-d6): 1.40-1.50 (2H, m), 1.56 (3H, s), 160-1.95 (12H, m), 3.26 (1H, d, J 14.6Hz), 3.40 (1H, d (1H, br s), 6.90 (1H, s), 7.00-7.15 (2H, m), 7.96 (1H, , 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 ES / e (EAB) 530.5 (13), 217.2 (3Q).

Anal. Calc'd for C 20 H 13 N 3 O 4:

Calc .: C, 69.83; H, 6.69; 7-yl

Det., 0.69.85; H, 6.66; N, 7.74%

Example 92 Tricyclo [3.3.1.1] undec-7-ene-2-yl (1 H -indol-3-yl) -1-methylethyl] To a solution of lithium borohydride (4 mL, 2M solution, 8 mmol) in anhydrous IHF in a nitrogen atmosphere was added a solution of chlorotrimethylsilane (1.75 g, 16.0 mmol) in IHP (5 ml), a white (lithium chloride) precipitate formed. After 2 minutes a solution of the compound (18) (1 g, 2 mmol) in Et3 (15 ml) was added slowly (over a period of 3 to 4 minutes) and the reaction mixture was stirred for 20 hours at room temperature. To the reaction mixture was treated thoroughly with MeOH (5 mL) and the volatiles were removed in vacuo at 40 ° C. The residue was purified by silica gel chromatography using hexane: ethyl acetate (80:20) as eluent to give compound (19) (0.14 g, 14%) as a colorless oil, and compound (18) (0.52 g was recovered to give the title compound)

(19) with &quot; based on the recovered starting material 30%). The anine (19) (0.14 g, 0.28 mmol) was dissolved in MeOH (5 mL) and treated with toluenesulfonic acid hydrate (0.054 g, 0.28 mmol). To the solution was evaporated to give a white solid ZCl7 + 22 ° (c at 0.25, MeOH) (film) 2928 and 1908 (ethanol). 2.3 (3H, s, OH-Ph), 2.9-3.9 (8H, m, 4 x OH), 1.4-2.1 (14-H, m, adamantyl) ), 4.9 (1H, br s, adamantyl H-2), 6.9-7.6 (15H, m, aromatics), 8.3 (1H, br, one of CH3), 8.5 (1H, br, one of ΗΗ *), 11.0 (1H, s, indole ΪΤΗ); MS M / e (FAB) 486 (m + + H) (100), 136 (52);

Analysis for .75H2 O:

Gale .: G, 67.98; H, 7.28; I, 6.26

Det .: C, 6 ', 96; H, 7.31; (600 MHz, CDCl3) δ (9H-indol-3-yl) -2-methyl-2-hydroxy- yloxy) ethyl] amino] -4-oxo-butanoate (19b, Scheme 21).

Prepared by a method similar to step (19a). A white solid, 0.102 g (81%), Z = 7.10 + 26 ° (c = 0.5, 0HG13) was recovered; IR (film) 2905, 2853, 1732, 1911, 1634 cm -1; (1H, m), 2.6 (4H, br s), 2.9 (2H, m), 3.0 (1H, d, J 14 Hz), 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 for

Gale .: G, 72.40; H, 7.72; H, 6.85%

Det .: G, 72.11; H, 7-87; H, 6.16%, mp: 67-70Â ° C, 3) 7 - [[(acetyl / 2-phenylethyl) amino] -1- (pyridin-5-ylmethyl) -1-methylethyl] carbamate ? ? -7-dec-2-yl (19a) NMCM1

To a solution of the compound (19) (0.1 g, 0.2 mmol) in dichloromethane (20 mL) at 0 ° C was added acetylchloride (0.3 mL, 4 mmol), followed by triethylamine (4 drops). Stirring was continued at 0Â ° C for 20 minutes, then the reaction mixture was dissolved in ethyl acetate (50 ml), washed (aq HCl, H2 O, THF) and dried (MgSO4) and evaporated to dryness. dryness The residue was purified by column chromatography using hexane-ethyl acetate as eluant to give an off-white solid (0.092 g, 8%). + 24 ° (? 0.25, CHCl3), IR (film) 2909, 2855 1-9, 1610 cm -1; (1H, m), 4.0 (1H, d, 14Hz), 4.8 (1H, s), 5.5 (1H, Pr s), 6.9-7.7 (10H, m), 8.1 (1H, Pr s); MS M / e (FAB), 528 (45) (M + + H), 397 (100), 333 (27). 2-methyl-2- (2-phenylethyl) amino] -4-oxo-butanoic acid [4- (2-methyl-2 H -indole- (19d, Scheme 21). To a stirred solution of the compound (19P) (0.04 g, 0.06 mmol) in IHF (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 minutes at ambient temperature, then acidified (2E HCl aq, 50 ml) and the products extracted with ethyl acetate (50 ml). The organic phase was dried over magnesium sulfate and evaporated in vacuo (40øC). The oily residue was purified by column chromatography using dichloromethane / methanol (9: 1) as eluent. 0.031 g (81%) of a solid Pranco IV (film) 340 (Pr), 2912, 2852, 1714, 1700, 1635 and 1 H NMR (MeOH-dâ, ...) were recovered. (2H, m, OH, + adamantane), 2.6-3.2 (6H, m, 3 x OH), 3.4-4.1 (6H, m, 3 x OH), 4.8 (1H, Pr, adamantane H-2 ), 7.7-7.6 (10H, m, aromatic); + 4 ° (MeOH, Oâ € ¢ 0.2, 22Â ° C); EAB MS 586 (51) m + + H), 455 (100), 391 (24)

Analysis for C 35 H 43 N 3 O 5 -? 0.25 H 2 O; Oalc: 0, 71.22, H, 7-43; 7.12 Det .: 0, 71.24; H, 7.46; H, 6.87%, m.p. 99-96 ° C.

Example 93 Tricyclohexanecarboxylate (1: 1) in dichloromethane: 1 H-NMR (300 MHz, CDCl3):? Dec-2-yl

Carboxylic acid 56 (580 mg, 1.0 mmol) and N, N -dicyclolyxylcarbodiimide (250 mg, 1.1 mmol) and pentafluorophenol (200 mg, 1.1 mmol) were suspended in EtOAc (25 mL) and stirred was stirred for 2 hours and 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 was washed with saturated aqueous citric acid followed by saturated aqueous Na2 SO4 followed by water. The organic phase was dried (MgSO4), filtered, concentrated in vacuo and purified by silica gel chromatography (LiOhroprep® EP-18) using MeGH1H2O) (4: 1) as eluant to give product 6 (0.56 g, 71%);  € ƒâ € ƒâ € ƒ0.48 (c = 0.25, CH2 Cl2), MS (CDCl3) Î'1.8 (14.4, m), 2.60 (2H, d), 5-30 (4H, m), 4.05 (1H, m), 4.42 (1H, q, J), 4.78 (ffl, m), 5.45 (1H, br s), 6.15 (1H, br s), 7.30 (8H, m), 7-37 , J), 7:67 (1H, d), 8.25 (1H, br s).

Hydroxyamide (6) (see Scheme 22) (5117 mg, 1.00 mmol), imidazole (146 mg, 2.15 mmol), and t-butyldimethylsilyl chloride (350 mg, 2.35 mmol) in DMF (6 mL). The reaction mixture was quenched with water (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 (SiO2: hexane-ethyl acetate (2: 1) as eluent to give the silyl protected amide (474 mg, 75%) as a white foam, (1H, s, indEH), 7.76 (1H, d, J Hz, ind H-4), 7.40 (1H, d, J 8 Hz, ind H-7), 7.34-7.06 (8H, m, Ph (1H, br s, δ), 4.90 (1H, brs, 1H), 5.98 (1H, , s, adamantyl H-2), 4.53 (1H,

m), 3.34 (2H, m, G Hgind), 3.22 (2H, br, m, CH3b), 2.12-1.54 (m, 2H); 14H, br, m, adamantyl), 0.88 (2, 9H, MeOH), 0.02 (6H, s, 2 x CH3); IR (m / z)) νmax 2929 + 2856 (adamantyl), 1703 (CO urethane), 1663 cm -1 (amido CO). The protected silyl amide (418 mg, 0.664 mmol) and Lawesson's reagent 7 (268 mg, 0.663 mmol) in toluene (10 mL) were refluxed for 30 minutes. The solution was cooled to room temperature and poured onto a silica gel column. The column was eluted with CH2 Cl2 to remove toluene and a by-product of Lawesson's reagent with a high rf value (0.74). Elution was then continued with a gradient of bexane-ethyl acetate (0-30%) to give the thiazolene (9) (73 mg, 21%) as a white foam. M.p .: 56-63 ° C. 1 H-NMR (CDCl 3) δ 8.16 (1H, s, ind H H), 7-63 (1H, d, J8 Hz, ind H-4), 7.38-6.96 (9H, m, (1H, s, adamantyl H-2), 4.88 (1H, br s, ind 0 H 2 O), 4.82 (1H, s, adamantyl H 2) , 4.62 (1H, HCHCH3), 3.44-2.83 (5H, m, ind CH2 CH2 PhCH2 + CH of GH2 S), 2.68 (1E, dd, J 9, 14 Hz, GHgS GH), 2.09-1.43 (14H , m, adamantyl); IR (film) ν max 2909 + 2854 (adamantyl), 1698 (urethane), 1621 cm -1 (O = H); In me;

For C31 H35 Cl3 N3 O4. O, 72.48; H, 6.87; H, Br,: C, 72.32; H, 7.095 a, 8.18; S, 6.24% 7.75; S, 6.09%.

Example 94 [1S- (1R *), 2R *, 77 and 1S *] - (S *), 2R *] - [2 - [(1-hydroxyethyl) -2-phenylethyl] amino] (1-phenylcyclopentyl) methyl-1 H -indol-3-ylmethyl) -1-methyl-2-oxoethyl] carbamate

Step A. To a stirred solution of 1-phenyl-cyclopentylmethane (0.53 g, 3 g, 0 mmol) in methylene chloride (15 ml) was added bis (trichloromethyl) carbonate (0.33 g, 1.1 mmol) followed by pyridine (0.24 g, 3.33 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 precipitate of pyridinium hydrochloride was filtered and the filtrate was concentrated to give a semiselide (0.65 g, 90%), λΕ mm (200 MHz, CDCl3): Î'7.50-7.10 (5H, m), 4.50 (2H , s), 2.10-1.90 (4H, m), 1.90-1.75 (4H, m). CC-Methyl-N- [7-phenylcyclopentyl) methyl] carbonyl] -Dh-tryptophan methyl ester

Step B. To a stirred solution of 1-phenylcyclopentyl methyl chloroformate (0.65 g, 2.75 mmol) in anhydrous THE (10 ml) was added a solution of the Î ± -methyl-D-tryptophan (0, 60, 2.5 mmol) followed by triethylamine (0.5 g, 5.0 mmol) in anhydrous THF. The reaction mixture was stirred for 50 minutes, then filtered, concentrated and chromatographed to give an oil (0.9 g, 90%). NMR (200 MHz, CDCl3): δ 8.0 (1H, br s), 7.50 (1H, br s), 5.35 (1H, br s), 4.15 (2H, s), 5.65 (3H, s), 3.6-3.0 (2H, m), 2.10-1.85 (4H, m), 1.85-1.60 (4H, m), 1.55 (3H, s). CK-Methyl-N- [1R-phenylcyclopentyl) methyl] carbonyl] -1H-tryptophan

Step 0. 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) cooled to room temperature overnight. The reaction mixture was concentrated and diluted with water (50 ml), acidified with HCl, extracted with ethyl acetate and chromatographed to give a white foam (0.8 g, 95%). (1H, br s), 7.55 (1H, d, J 7 Hz), 7.45-7.00 (9H, m), 5.25 (1H, br s), - 171-

2.00-1.85 (4H, m), 4.20-3.90 (2H, m), 3.35-3.05 (2H, m), 1.85-1.65 (4H, br), 1.50 (3H, br s). (R *), 2R *, 77 and Is * TR * (S *), 2R *, 77- [2- [7S-hydroxy-1-hydroxy-2-oxoethyl) -2-phenylethyl; (1 H -nol-3-ylmethyl) -1-methyl-2-oxoethyl] carbamate (1-phenylcyclopentyl) methyl

Step D. A solution of intermediate 0 (0.42 g, 1.0 mmol) in ethyl acetate (2 mL) was treated with dicyclohexylcarbodiimide (0.23 g, 1.1 mmol) and 1-hydroxybenzotriazole hydrate (0.17 g, 1.1 mmol). After stirring for 1 hour at room temperature, the compound was filtered. To this 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%) the title compound as a white foam. M.p .: 78-83Â ° C.

Example 95 43- [2- [2,2-dimethyl-4-phenyl-1,5-dioxan-5 (R *)] and [ 1-yl) amino] -1-methyl-1- (1H-indol-5-ylmethyl-1-methyl-2-oxoethyl] carbamate methyl

Step A. The procedure followed 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%). (2H, d, J 8.5 Hz), 8.10 (1H, br s), 7.60-6.80 (1H, m), 5-64 (1H, br s), 5.2-5.0 (2H, m), 3.71 (3H, s), 3.55 (1H, d, J14Hz), 3.35 (1H, d, J14Hz), 1.72 (3H, s). Methyl-N- [7- (4-nitrophenyl) methoxy] carbonyl] -DTI-tryptophan

Step B. The procedure followed was described in Step 0, Example 94-, except that the product of Step A was used. The title compound was obtained as a foam. (1.8 g, 75%). (2H, s), 5.60-3.20 (2H, m), 5.53 (1H, br s), 5.20 (2H, s), 5-60-3.20 (2H, m) ), 1.73 (3H, br s). A.S-AOC, 5Î ± (R *), 77 and As-AÎ ±, 5Î ± (S *)] - [2- [2,2-dimethyl-4-f. (4-nitrophenyl) -methyl-2-oxo-2-oxo-2-oxoethyl]

Step 0 The procedure followed was as described in step I), except that the product of Step B and 5-amino-2,2-dimethyl-4-phenyl, 3-dioxane instead of the product of Step 0 and 2-amino-1-phenyl-1,3-propanediol, respectively. The title compound was obtained as a foam (2.3%, 85%). Mp: 92-102 ° C.

Example 96 A3-A CC, 5cC (R *) 77 and AS-A o550C (S *) 77-H- (2,2-dimethyl-4-phenyl-1-3-dioxan-5-yl) -7-amino-6-carbonyl] -1H-indole-3-propanamide

Aa-Aoe, 5c (Hâ,ƒ) 77 and Ascorbâ,, (Câ, -Câ, €)) 77-6-Amino-N- (2,2-dimethyl-4-phenyl-1,5-dioxan-5 -yl) -α-methyl-1H-indole-3-propanamide

Fs. A solution of the title compound of Example 95 (1.65 g, 2.8 mmol) in absolute ethanol was treated with a catalytic amount of 10% palladium on carbon and stirred overnight under positive hydrogen pressure. The reaction mixture was then filtered through celite and washed with ethanol. The filtrate was concentrated and passed through a small bed of silica gel to give a white foam (1.1 g, 100%). Mp: 182-185 ° C. / ¾-A CC, 5 CC (R *) 77 and AS-A CC, 5 QT (S *) 77- 2,2 2,2-dimethyl-4-phenyl-1,5-dioxan-5-yl) oC phenyl] cyclopentyl) methyl] amino] carbonyl] -1H-indole-3-propanamide

Ease B. To a stirred solution of the product of Step A (0.49 g, 1.2 mmol) in anhydrous THF (15 mL) was added 1-phenyl cyclopentylmethylisocyanate (0.26 g, 1.3 mmol) in anhydrous (5 mL) at room temperature. To the reaction mixture was concentrated, chromatographed and crystallized to give the title compound (0.21 g, 30%), M.p .: 125-28 ° C.

EXAMPLE 97 1S- [1R * (R *), 2R *, 77 and 1S- [1R * (S *), 2R *] - N-2-Hydroxy-1- (hydroxymethyl) -2- ethyl] -2- (1H-indol-5-ylmethyl) -2-oxoethyl] -8-tricyclo [5.5.1.1.0,7] de 2-ylpropanediamine. indole-3-methanaminium hydrazide (2) (JAOS 66200 (1944)) was dissolved gramine (1) (45.5 g, 0.29 mmol) (see Synthetic Scheme 23 for compounds 1-23) in absolute ethanol (200 ml) and methyl iodide (17 ml, 0.27 mmol) was added dropwise over a period of 0.5 hours. A moderate isotonic reaction was formed with the formation of a white precipitate. The reaction mixture was stirred overnight at room temperature and then cooled to 0 ° for 2 hours. The white solid was collected by filtration, washed four times with ethanol (50 ml) and 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. (5 g) was added sodium hydride (4.0 g, 0.1 mmol) portionwise over a period of 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 minutes and gramine methiodete (33.5æ, 0.11 mmol) was added and the whole mixture was heated at 50 ° C for 0.5 hours and then stirred during night 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 phases were separated and the organic phase was washed with water (3 x 200 ml). The combined aqueous phases were extracted with diethyl ester (1 x 500 ml), the organic phase was washed with water, the organic extracts were combined, dried (MgSO4), filtered and concentrated. The residue was filtered through silica gel (70 to 230 mesh) using hexane / ethyl acetate 1/1 as eluent. The fractions containing the product were combined, concentrated and filtered through silica gel (70 to 230) using hexane / StOAc 8/2 as the eluent. The product was obtained as a viscous red oil. 13 g (4-3%) IR (film) 3397, 2983, 1731, 1376, 1254, 1108 cm @ -1.

(4) To a solution of the diester (4.85 g, 0.016 mmol) in 95% ethanol (50 ml) at ambient temperature was added an aqueous solution of 1 N hydrochloric acid of sodium hydroxide (16 ml) and enough water for the solution to become cloudy. Water was added as the reaction proceeded. After 2 hours the reaction mixture was concentrated on a rotary evaporator to remove ethanol, diluted with water, washed with ethyl acetate, made acidic with 10% citric acid, brine, and the whole mixture was extracted with ethyl acetate . The ethyl acetate solution was dried (MgSO4), filtered and concentrated to give a brown oil. The brown oil was chromatographed on silica gel (70 to 230 mesh) using ethyl acetate as the eluent and then rechromatographed on silica gel (70 to 230 mesh) using hexane / ethyl acetate 1/1 as the eluent. The product 4 was obtained as a light orange oil. 2.92 g (66%) IY (film) 3402, 2982, 1787, 1458, 1098, 742 cm -1. (+) - Ethyl (5-hydroxyethyl) carbonyl] -1H-indole-5-propanoate (5)

A mixture of the acid (1.41 g, 0.005 mmol) adamantanamine hydrochloride (0.95 g, 0.005 mmol) was added at 0 ° C 1-hydroxybenzotriazole.H2 O (0.68 g, 0.005 mmol), and OH4 Ol (50 ml) and triethylamine (0.8 ml, 0.0177 mmol) was added and the mixture was stirred for 5 minutes. Then dicyclohexylcarbodiimide (1.04 g, 0.005 mmol) was added all at once. The reaction mixture was stirred for 3 days at ambient temperature, concentrated to dryness, the residue was taken up in ethyl acetate, washed with 10% citric acid solution, sodium carbonate and sodium chloride. The organic phase was dried (MgSO4), filtered and concentrated to give an orange oil. Addition of hexane / ethyl acetate 1/1 caused the oil to solidify. The solid was collected by filtration. 2.05 S (9%). IY (KBr) 3418, 3327, 2907, 1713, 1630, 1540, 1457, 1113 cm-1. - &gt; 5 7

Carboxyl-1H-indole-5-propanoic acid (6) The ester (1.04 g) 2.5 mmol) was dissolved in ethanol (10 mL) and a 1N solution of sodium hydroxide (3.5 mL) and water alone sufficient to make the solution cloudy. The reaction mixture was heated to 50 ° C moderately to dissolve. The reaction mixture was allowed to stand for 14 days at room temperature. The reaction mixture was concentrated to remove ethanol, diluted with water, washed with aqueous solution with ethyl acetate, the aqueous phase was made acidic with a 10% solution of citric acid, extracted with ethyl acetate, the solution of ethyl acetate was washed with brine, dried (MgSO 4), filtered and concentrated to give an off-white foam. The foam was filtered through silica gel (70-230 mesh) using ethyl acetate as eluent. The product obtained was an off-white solid. 0.87 S (90%). IY (KBr) 3411, 2908, 1716, 1617, 1540, 740 cm-1. (R *) 77 e / 53/5 g, 5 (S *) 77 H- (2,2-dimethyl-4-phenyl-1,3-oxoo -5-yl) -2- (1H-indol-5-ylmethyl) -2-methyl-ETH1- (trifluoromethyl) -3,5,6,7,12dec-2-yl) propanediamide )

Dicyclohexylcarbodiimide (0.30 g, 1.46 mmol) was added to a mixture of (4S, 53) - (49,5-dimethoxy-2,2-dimethyl-4-phenyl-1,3- 31 g, 1.44 mmol), acid (0.53 g, 1.39 mmol), and 1-hydroxybenzotriazole (0.22 g, 1.63 mmol) in a 10/1 mixture of CH2 Cl2 / ml) at 0 DEG C. The reaction mixture was allowed to stand for 1 hour at 0 ° C and then for 3 days at ambient temperature. The reaction mixture was concentrated to dryness, the residue was taken up in dichloromethane ethyl acetate and the ethyl acetate solution was washed with brine, dried (Na2 SO4), filtered and concentrated, the oil was purified by silica gel filtration (70-230 mesh) using hexane / The product was obtained as a white solid, 0.247 g (31%) IR (KBr) 3341, 2910, 1665, 1508, 1201, 732 cm -1. (R *) and R * = R * (R *), 2S *] - [2 H -hydroxy-1- (hydroxymethyl) -2-phenyl] ethyl] -2- ( indol-5-ylmethyl) -2-methyl-N-tri dichloro-2,3,4a, 7,12dec-2-ylpropanediamide (8)

A mixture of acetonide (0.16 g, 0.28 mmol), methanol (10 mL), and 1N HCl (1 mL) was allowed to stand for 4 hours. The reaction mixture was concentrated to dryness without heating. Ethyl acetate was added, the ethyl acetate was dried (MgSO4), filtered, concentrated and the residue chromatographed on silica gel (70-230 mesh) using ethyl acetate as eluent. The product was obtained as white foam. 0.0727 g (39%).

Example 98 [1S- [1R-2 (R *), 2R *] and 1S- [1R * (S *) - [2 - Hydroxy-1- (hydroxymethyl) -2-phenylethyl] -2- ( indol-3-ylmethyl) -2-methyl-N '- (tricyclo [3.3.1.13,7] decan-1-ylmethyl) propanediamide

ethyl (9-methylethyl) amino] carbonyl] -1H-indole-5-propanoate (9)

Compound 9 was prepared from Compound 4 according to the procedure followed for Compound 5 The product was obtained as an off-white solid. 3.49 S (58%). IR (KBr) 3-402, 3337, 2913, 2904, 1718, 16652, 1116 cm -1. (+) - Compound 10 was prepared from Compound 9 of (+) - Compound 10 (Compound 9). Compound 10 was prepared from Compound 9 according to the procedure followed for Compound 6. The product was obtained as a white solid, 1.95 g (71%) IR (KBr) 3440, 2912, 1713, 1652, 1621, 1189, 946 cm -1. (S *) 77 - ^ - (2,2-dimethyl-4-phenyl-1,5-dihydro- 5-yl) -2- (1H-indol-3-ylmethyl) -2-methyl- N - (tricyclo [5.3.1.13,7] de] -1-ylmethylpropanoiate (11) Compound 11 was prepared from Compound 10 according to the procedure followed for Compound 7 The product was obtained as a white foam, 0.83 g, (72%) IR (KBr) 3418, 2904, 1666, 1558, (R *), 2R *, 77 and 13- [TR * (8 *), 2R *] - [2-hydroxy-1- (3ahydroxymethyl) -2- 3-ylmethyl) -2-methyl-H1- (tricyclo [3.3.1.1] undec-1-ylmethyl) propanediamide (12) Compound 12 was prepared from Compound 11 was prepared according to the procedure followed for Compound 8. The product was obtained as a white foam: 0.2633 g (91%) IR (KBr) 3341, 1652, 1588, 1544, 1477, 899 cm -1 .

EXAMPLE 99 [1S- [1R- (4-Aminoethyl) phenyl] amino] carbonyl] amino] -7H-indol- (2-hydroxyethyl) -2-phenylethyl] -7-methyl-1H-indole-5-propanamide / 4S- [ (2-dimethyl-4-phenyl-1,3-dioxan-5-yl) amino] -1- (1H-indol- -3-ylmethyl) -1-methyl-2-oxoethyl] carbamate (14.4) Compound 14 was prepared according to the procedure of Compound 7, the product was obtained as a white foam. 4.70 g (98%). IR (KBr) 3413, 107-200, 1663, 1507, 1501, 1458, 1168, 745 cm -1. (S *) 77-Ot-amino-N- (2,2-dimethyl-4-phenyl-1,1-dimethylethyl) 3-dioxan-5-yl) -OC-methyl-1H-indole-3-propanamide (15)

Anhydrous hydrogen chloride gas was bubbled through a solution of t-butyloxycarbonyl amine 14 (3.4 g, 6.7 mmol) in dichloromethane (80 mL) over 5 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour and then poured into saturated aqueous sodium bicarbonate solution. A solution of sodium chloride was added and the aqueous solution was extracted twice with ethyl acetate. The 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 at * 1. (4-methoxyphenyl) amino] carbonyl] amino] -N- [2 (R) -cyclohexyl] 2-dimethyl-4-phenyl-1,3-dioxan-5-yl) - N -methyl-1H-indole-3-propanamide (16a)

(Î ±, Î ±, Î ±, β-, β-, β-, Î ± -cyclohexyl] amino] carbonyl] amino] -N- (2,2- 4-feryl] -1,3-dioxan-5-yl) -Î ± -methyl-1H-indole-5-propanamide (16b)

A mixture of amine 15 (0.40 g, 1 mmol) and 2,6-diisopropylphenyl isoeianate (0.23 g, 1.1 mmol) in ethyl acetate (30 mL) was heated sparingly to provide a solution. The reaction mixture was allowed to stand for 2 days at room temperature. The reaction mixture was concentrated to give a viscous oil, which was chromatographed on silica gel (70-230 mesh) using ethyl acetate as the eluent. The less polar diastereomer, 16a, was obtained as a white solid giving 0.2876 g. The more polar diastereomer, 16b was obtained as white solid giving 0.2369 g. Total yield (8%) • IR (KBr) 3431, 2964, 1675, 1500, 1239, 741 cm -1. (3 *), 2R *, 77-6,7,7,6-bis (1-methylethyl) phenyl] amino] carbonyl] amino] -N- Compound 17a was prepared from compound 16a according to the procedure followed for Compound 8 (a) and Compound 17a was dissolved in dichloromethane The product was obtained as a white foam. 0.893 g (48%). IR (KBr) 3400, 3343, 1733, 1663, 1513, 742 cm -1.

Example 100 [1S- [1R * (R *), 2R *, 7S *, 1S *, 1R * (S), 2R *, 7,7C-bis (1-methylethyl) phenyl] amino] carbonyl] amino] (17b) Compound 17b was prepared from 16b according to the procedure followed for Compound 17b 8, the product was obtained as a white foam. 0.096 g (66%). IR (KBr) 3420, 32991, 1734, 1716, 1662, 1507, 1058 cmâ € ²-

EXAMPLE 101 N- [1,1,1-Dimethylethoxy) carbonyl] -1H-phenylalanyl] methyl-N-trityl [3.3.1.14] heptane-di-tryptophanamide AS-A, 3-yl) amino] -1H-indole-3-carboxylic acid tert-butyl ester 3-ylmethyl) -1-methyl-2-oxoethyl] carbamate (18) Amine 15 (0.4 g, 1 mmol) and 2,6-diisopropylphenyl chloroformate (0.51 g, 2 mmol ) were taken in tetrahydrofuran (50 mL) and triethylamine (0.34 mL, 2.4 mmol) was added. The reaction mixture was stirred for 5 hours 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 S (66.8). IR (KBr) 3326, 1654-1636, 1520, 1257, 74-2 cm -1. (19) Compound 19 was obtained from BOG-L-phenylalanine and the methyl ester (19) was obtained as a white solid in dichloromethane of ES-CC-Me tryptophan according to the procedure followed in Example 7.4- g (99%). IR (KBr) 3408, 3353, 1734, 1696, 1617, 1507, 1457, 1165 cm-1.

1-methyl-N-phenylalanyl-DL (1R) -one hydrochloride

Anhydrous gaseous hydrogen chloride was bubbled into a solution of 19 (1.50 g, 3.1 mmol) in dichloromethane (50 ml) for 2 minutes at room temperature. The reaction mixture was allowed to stand overnight at room temperature. The solvent was removed in vacuo. Ether was added 2 times ether and concentrated. The residue was taken up in methanol and then concentrated. Poe added ether and in 181 -

then removed by rotary evaporation to give the product as a dark foam. 1.32 g (100%). IR (KBr) 3403, 5396, 334-3, 3231, 1734, 1684, 1677, 1498, 1216, 43 cm -1. (21) Compound 21 was prepared from Compound 19 according to the procedure followed 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. Î ± - [1 - [(1,1-dimethylethoxy) carbonyl] -L-phenylalanyl] -N-methyl-N, N -dicyclo [3.3.1.13,7] dec-2-yl-DL-tryptophanamide (22) Compound 22 was prepared from Compound 21 and 2-adamantanamine according to the procedure followed for Compound 7 The product was obtained as a white solid. O.585 g (38%). IR (KBr) 3411, 333, 1696, 1672, 1653, 1519, 1165 cm -1.

Example 102 K- [1 - [(Trimethoxy) 5.5] 2-yloxy) 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), and then triethylamine (0.9 ml, 6.5 mmol) and the reaction mixture cooled to 0 ° C. After 0.5 hour the reaction mixture was concentrated to dryness, the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with a 10% aqueous solution of citric acid and saturated sodium chloride solutions, dried (MgSO4), filtered and concentrated. The residue was filtered,

through silica gel (70-230 ml) using hexane / ethyl acetate as eluent. The product was as a white foam. 1.12 g (67%). IR (KBr) 3342, 2912, 1672, 1663, 1507, 1361, 1254, 1101 cm-

Example 103 (+) - [2 - [(3,4-dihydro-2H-1-benzopyran-3-yl) amino] -1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl] carbamate trioxy- [3.3.1.13,77dec-2-yl

A solution of 2-adamantyl oxyarbonyl methyl, DL tryptophan (0.79 g, 0.002 mmol) in ethyl acetate (60 ml) was treated with dicyclolexylcarbodiimide (0.495 g, 0.002 mmol) and 1-hydroxybenzotriazole hydrate (0.3 g , 0.0023 mmol). After stirring for 2 hours at ambient temperature the precipitated dicyclohexyl urea 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% EtOAc and brine. The organic phase was dried over MgSO4 and concentrated in vacuo to afford a white foam. The product was chromatographed on silica using 50% ethyl acetate, 50% hexane as eluant to give the title compound. (0.66 g, 61%).

Analysis for 1/234-MV 536,679;

Calc .: C, 71-61; H, 7-13; 7.82;

Det .: 0, 71.67; H, 6.93; 7-75-

Example 104 (+) - (1H-Indol-3-ylmethyl) -1-methyl-2-oxo-2- [1,2,3,4-tetrahydro-1-napthalenyl) methyl] amino] carbamate, tricyclo [ 5.3.1.1 (1H, 7a) -2-yl-

A procedure analogous to Example 105 was obtained by substituting 1,2,4,4-tetrahydro-1-naphthalenemethanine (0.52 g, 0.002 mmol) for 5,4-dihydro-2,4- benzopyran-3-amine the title compound is obtained. (0.76 g, 68%).

Calc'd: C, 74.42; H, 7.71; 7 * 65; Det .: 0, 74.27; H, 7.75; h, 7.36

Example 105 (+) - [1- (1H-indol-3-ylmethyl) -1-methyl-2-oxo-2- (9H-xanthen-9-ylmethyl) amino] ethyl] carbonate 1-yl, 7-deec-2-yl

A solution of 2-adamantyl oxycarbonyl-C-methyl DL tryptophan (0.79 g, 0.002 mmol) in methylene chloride (60 ml) was treated with hydroxybenzotriazole hydrate (0.3 g, 0.0022 mmol), 1 - (2-dimethylamino propyl) -3-ethylcarbodiimide.HCl (0.38 g, 0.002 mmol) and triethyl amine (0.202 g, 0.002 mmol). After stirring at room temperature for 2 hours a solution of 3 H-xanthan-9-metenazine (0.495 g, 0.002 mmol) in methylene chloride (10 ml) was added. To the reaction mixture was stirred at room temperature overnight. The clean solution was concentrated in vacuo. The resulting oil was taken up in ethyl acetate. The ethyl acetate solution was washed with H2 O, saturated Na2 SO4 and brine. The organic phase was dried over MgSO4 and concentrated in vacuo to give a white foam. The product was chromatographed on silica using 50% ethyl acetate, 50% hexane as eluant to give the title compound. (0.72 g, 59%).

Analysis for H2 O: 607: 761:

Gale: 0.73 * 13; H, 6.79; N, 6.91;

Det., 0.73 * 53; H, 6.80; H, 6.61. -. η ώ ί ί ί ί ί ί ί ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ ώ-----

ΗΕΙ7Π3Ι C AC CES - ia -

A process for the preparation of a compound of formula R2 H1-AB- (CH2) m -OI (OH2) - (Σ) ϊ- (σΕΕ5) Γ- (σΒΕ4) β- (Τ) ΐ- (σΕ20Ε12) ιι · N (OE5E6)

Ar '- (OHR 15) -Ar 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is a cyclo or polycycloalkyl hydrocarbon or a mono- or polyheterocyclic radical in which the heteroatom (s) may be H, O, and / or 8 with 3 to 12 carbon atoms and 0 to 4 substituents each independently selected from straight or branched chain alkyl of 1 to 6 carbon atoms, halogen, SO2, SO2, SR R6, R6, or - (OE2) n OR2 wherein R *, B ' and R 4 are each independently hydrogen or alkyl of 1 to about 6 carbon atoms, m, n, p, q, r, s, t, u and p are each independently an integer from 0 to 6, with the proviso that q, r, and s are not all 1 when m, p, t, u, and v are all 0 with the exception when X is not OO 1 TR 9 or AE is not (OH) Wherein n is as defined above, A is a bond or a bond selected from the group consisting of: (a) - (CH2) n -O- (CH2) n -O- , - 185 -

Claims (1)

-SO 2 -Z, -SO 2 -Z, -SO 2 -Z, -SZ, -MHOO-Z, O - (CH 2) n -O-Z, -SCO-Z, - wherein Z is a bond, oxygen, sulfur, or -ER * - wherein R 1 is as defined above, R 1 is a bond of an amino acid (CHH5) r -, - (OCHR5) r - (OCH4) s -, -OHH-, -EO00-, -OCO-, -COO-, -CH2I (R5) -, -Ch2 O--, -CH 2 -, -CH 2 -, -CH 2 -, -CH 2 -, -CH 2 -, -SO 2 -, - the the 1 I 4 I I I I-o are independently as defined above defined, each independently hydrogen &gt; linear or branched chain of 1 to 6 wherein r is 0 and Έ? and are as R and R are an alkyl radical of carbon atoms -H0 = GH2, -CsOii, - (GH2) nGH = GH2, - (CH2) η0Ξ0Η, - (O¾) 11, - (GH2) nir2, - (GH2) n OR2, - (GH2) nOAr, - (GH2) nG02R *, - (O4) ¾¾6 -18? - And E are as defined above and Ar and Ar are as defined below, 1 and T are each independently -COHH-, -GOSE9, -HHCO-, -OOC- , -CH2 I (E5) -, -O2-, -gh2s-} -ogh2-, -8GH2-, -0 = 0-, s- ..., -O-mP, s-R 1 -O-O, -SO 2 R 5 -, -CH 2 SO 4 -, -Ehgonh-, -oh (oe *) CH 2 -, -OH, - (R) - 188 or -000 (OH) n -, -O (CH2) n -, -SO (OH2) n -, -S (O H2) n -, -SO2 (CH2) n-, Η Η II ΐΗοο-σ-σ-,! I β? Ε8 00ΜΗ-0 = 0-, or I I Ε7Ε8 Η Η I! Wherein 77 or 88 are independently selected from hydrogen and E or together form a ΟΟ Η-Ο anel ring wherein m is an integer from 1 to 5 and η is as defined above, D -OH, -OH, -OH 2, and -OH, -OH 2, -OH 2 R 3, -OH 2 R 3, -OH 2 R 3, -CH 2 R 5 E 6, -CM, -IR 5 R 6, -OH, -H, and substitution of acids such as tetrazole, a, and S are as defined above, R 2 is H or a linear or branched alkyl radical having one to six carbon atoms - ( (OH) 2, wherein n, R 2, R 3 and R 6 are as defined above or taken as defined above R 2 and R 3 are each independently hydrogen or taken together form a double bond, or are (CH 2) 2 -BD as defined above, and Ar is Ar are each independently an unsubstituted or substituted carbo- or heterocyclic aromatic or carbo- or heteroaromatic mono- or polycyclic radical, characterized in that the coupling of the individual substituted α-amino acids defined for the preparation of the compounds of formula I 2. A process for the preparation of an intermediate of formula II in which R is selected from the above-defined R values, 9-fluorenylmethyl, benzyl and other suitable E-blocking groups, wherein ROH III is reacted as defined above with phosgene to give a corresponding compound with the formula - Ηοσοσι and then reacting a compound of formula IV with OC-methyltryptophan to give the desired compound of formula II above. 3. A process as claimed in claim 1 in which Ar is a compound wherein Ar is phenyl; substituted phenyl, fused aryl, heterocycle, fused heterocycle, or perhydroaryl. A process according to claim 1 in which a compound in which Ar1 is 2- or 3-Vienly, 2- or 3-furanyl, 2-, 3-, or 4-pyridinyl, Wherein E and F are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl, nitro, hydroxy, OCP 3, and? I as defined acyl, - A process according to claim 1, characterized in that a compound is obtained wherein the polycycloalkyl is selected from the group consisting of in which W, X, Y, and Z are each independently selected from hydrogen, straight-chain or branched alkyl wherein R, &quot; Br and R are as defined, R, 01, Br, OR , SR 1 with one to six carbon atoms, CF 2, NR 3 R 6, - (OH 2) p is the integer from 1 to 3, and w is an integer from 1 to 3, A process according to claim 1, characterized in that, in particular, the following compounds are obtained: acid, C2 -C6 - (hydroxymethyl) -2-phenyl-ethylamino] -1- (1H-indol-3- (hydroxymethyl) -2- (3-methyl-ethyl) -carbamic acid, tricyclo [3.3.1] phenylethyl] amino] -1- (1H-indol-3-ylmethyl) ethylcarbamic acid, tricyclo [3.3.1.15,7] oct-2-yl, [S - (R *, R *)] 2-phenylethylcarbonyl] amino] -2- (1H-indol-3-ylmethyl) -1H-indol-3-yl] yl) ethyl] carbamic acid, 4 ' 2 - [(2-hydroxy-2-phenylethyl) amino] -1- (1E -indol-3-ylmethyl) -1-methylethyl] carbamic acid, tricyclo [ 3 '', 7 '' ', 7' '', 7 '' 'and 7' '- 2-yl hydroxyl center, the other center IR), Acid 2 - [[1- (hydroxymethyl) -2-phenyl-ethyl] (1 H -indol-3-ylmethyl) -1-methylethyl] carbamic acid, tricyclo [3.3.1.1 7,7] dec-2-yl] 7-, 4-methyl-benzenesulfonate (1: 1) (salt). Benzenopropanol, β- [2- (1H-indol-3-yl) -2- (tricyclo [3.3.1.1.1, 7dec-2-yloxy) carbonyl] amino] propyl] aminocarbonyl] (4-methylbenzenesulfonate (1: 1)), acetic acid (1: 1), acetyl [1- (hydroxymethyl) ) 2-phenylethyl] amino] -1- (1H-indol-3-ylmethyl) -1-methyl-7-carbamic acid, tricyclo1.3.1.1,7,7,8- ) 3- (1H-indol-3-ylmethyl) -3-methyl-4,9,12-trioxo-7-phenyl-5-gt; 13-dioxa-2,8-diazatetradec-10-enoic acid, ester (R *, 3) -7- (3-hydroxy-2,8-diazatetradecanoic acid, 3- (1H-imidazo [1,2-a] -indol-3-ylmethyl) -3-methyl-4,9,12-trioxo-7-phenyl-tricyclo [3.3.1.13,7] -cis-2-yl, (1 H -indol-3-ylmethyl) -1-methyl-2 - [(1-oxo-4-phenylbutyl) amino] ethyl) carbamic acid, (2- (benzoylamino) -1- (1H-indol-3-ylmethyl) -1-methylethyl] carbamic acid, isopropyl ester (R) -, (1 H -indol-3-ylmethyl) -1-methyl-2 - [(1-pyrrolidinyl) oxo-3-phenyl-propyl) amino] ethyl] -carbamic acid, tricyclo [3.3.1.1.1,7] dec-2-yl ester, (R) - (i.e., a) (2-Phenylacetyl) amino] ethyl] carbamic acid, tricyclo [3.2.1] octane-3-carboxylic acid, 2-yl, (R) -, 1, 2, 3-oxo-4-oxopropyl] amino] 3-ylmethyl) -1-methyl-2-oxo-ethyl] -carbamic acid tert-butyl ester, 3-ylmethyl) -2 - [(3-hydroxy-methyl) -2-phenylethyl] methyl] -2-oxopropyl] amino] -7- 3-oxoethyl) carbamic acid, tricyclo [3.3.1.13,7] -oxazol-2-yl ester, Z3- (R *, E *) D-phenylalaninamide, Î ± -methyl- 3-yl) -7-dec-2-yloxy) carbonyl] -D-tryptophyl-p-alanyl-, L-phenylalaninamide, &lt; t -methyl-1 - [(tricyclo [ 2-yloxy) carbonyl] -D-tryptophyl] -alanyl-, L-phenylalaninamide, N-methyl-N '- (tricyclo [3.3.1] 2-yloxy) carbonyl] -L-tryptophyl-3-alanyl-, D-phenylalaninamide, N-methyl-H-tetradicyclo [3.3.1.13] dec-2-yloxy) carbonyl] -L-tryptophyl- &gt; 3- (1H-indol-3-ylmethyl) -3-methyl-4,8,11-trioxo-10 (phenylmethyl) -12-oxa-2,5,9-triazatridecanoic acid, ester (R) -cyclohexanecarboxylic acid, tri-cyclopentylalanine, N- [N- (3-methyl-LZ) (tricyclo [3.3.1.13,77,7] 3- (1H-indol-3-yl) carbonyl] -D-triptophthalic acid, phenylmethyl ester, yl) -2-methyl-1-oxo-2- [3- (3-chlorophenyl) -3- [1,3] -oct-2-yloxy) carbonyl] amino] propyl] amino] -1-oxopropyl] amino] -3- -phenyl-, propanoic acid, phenylmethyl ester, Z "S- (H *, R *)] - 7- (D-phenylalanine, 17 - [[1- [1- (1-hydroxy-2-hydroxyethyl) - - β-tryptophan-β-alanyl], L-phenylalanine, 17β- [N- [Î ± -methyl- [1- (3-chlorophenyl) 2-yl-oxy) -cyclopentyl] -D-trityl-7-yl] -7-, L-phenylalanine, 17- [ [(3-chlorophenyl) amino] -7- (3-chlorophenyl) -1H-indole-3-carboxylic acid [ (1H-indol-3-yl) -2-methyl-1-oxo-2 - [(tricyclo [3.3.0] 1-yl] -7-deoxy-2-yloxy) carbonyl] amino] propyl] amino] -1H-pyrazol-4-yl] benzenepropanoic acid, Zs- (R *, S *) 7-, Glycine, N- [2-methyl-3- [3- (3-chlorophenyl) (2-phenylethyl) -3-pyrrolidinyl) -carbamic acid tert-butyl ester, phenylmethyl ester, 3- (1H-indol-3-ylmethyl) -2,5-dioxo- (1E-imidazol-4-ylmethyl) -1-methyl-2-oxo-2-yl, (+) - (2-phenylethyl) amino] -7-ethyl] carbamic acid, 1,1-dimethylethyl ester, (+) -, Ethyl 3- (1H-indol-3 (2-phenylethyl) amino] carbonyl] propyl] -7-carbamic acid tert-butyl ester, triethyl ester, (+) - [(1H-indol-3-yl) -1-methylpropyl] carbamic acid, methyl ester, tricyclo [3.3.1.1.1,7,7,12,12d-2-yl (hydroxymethyl) -8- (3-chlorophenyl) -3- (2-methoxyphenyl) triethyl-7-phenyl-13-oxa-2,5-P-triazatetradec-10-enoic acid, trityl ester 3.3.1.1, 7,7] decan-2-yl (TRP ce The other center is Râ,, -L-phenylalaninamide, N-Î ± -Î ±, Î ± -dimethyl-ethoxy) -carbonyl] -GM-methyl] -L-tryptophyl] -benzenyl-L- 2-methyl-N- [tricyclo [3.3.1], 7,7-dec-yloxy) carbonyl] -D-tryptophyl] -L-phenylalanyl-, (hydroxymethyl) -2-phenyl-1-azabicyclo [2.2.1] heptane-2-carboxylic acid [1- (1H-indol-3-yl) -piperidin- (hydroxymethyl center S, another RS center), 6-Z-3- (1H-indole-3-carboxylic acid, 2-yl) -2-methyl-1-oxo-2- [2-oxo-2-oxo-2-oxo-2-oxo-2-oxo-2- , 2-methyl-MZ (tricyclo-Z &quot; 3 &quot;), 2-methyl-MZ &lt; / RTI &gt; 7-yl-2-yloxy) carbonyl] -D-tryptophyl] phenylmethyl ester. (R) -1,3,4-Trihydrocyclo [3.3.1.1] hept-2-yl-R- (R *, Z ~ 4) 5-dibutyl-4- (phenylmethyl) -2- 3-yl) -1-methyl-ethylcarbamate A process for the preparation of a pharmaceutical composition effective for suppressing appetite in a mammal characterized in that a compound as prepared according to claim 1 is incorporated in association with a In a preferred embodiment of the present invention the present invention relates to a method for reducing the secretion of gastric acid in a mammal which comprises incorporating a compound as claimed in claim 1 in association with a pharmaceutically acceptable carrier. 198 - 9. A process for the preparation of an effective pharmaceutical composition for reducing anxiety in a mammal characterized in that a compound as claimed in claim 1 is incorporated in association with a pharmaceutically acceptable carrier. 10. A process for the preparation of an effective pharmaceutical composition for treating gastrointestinal ulcers in a mammal characterized in that a compound as prepared according to claim 1 is incorporated in association with a pharmaceutically acceptable carrier. 11. A process for the preparation of a pharmaceutical composition effective for treating psychotic behavior in a mammal characterized in that a compound when prepared according to claim 1 is incorporated in association with a pharmaceutically acceptable carrier. 12. A process for the preparation of a pharmaceutical composition effective to block the reaction caused by the withdrawal of medicament or alcohol from a mammal characterized in that a compound as set forth in claim 1 is incorporated in association with a pharmaceutically acceptable carrier . 13. A process for the preparation of a pharmaceutical composition effective to potentiate the effects of morphine and other opioids in the treatment of pain characterized by incorporating a compound as prepared according to claim 1 in association with a pharmaceutical carrier Acceptable. 14. A process for the preparation of an effective pharmaceutical composition for treating and / or preventing panic in a mammal characterized by incorporating a compound in the presence of a compound of formula according to claim 1 in association with a pharmaceutically acceptable excipient. The applicant claims the priorities of the United States applications filed on 31 August 1990 and 12 July 1991, serial numbers 576,628 and 726,655 respectively. Lisbon, August 30, 1991 200 &quot; PROCESS FOR THE PREPARATION OF FERILALARIRA DERIVATIVES Ξ PE FERETIEAMIRA R-SUBSTITUTES GQúGICLOALQ.UILQ Ξ PQLICI-GLOALgPILO ΑΕΡΑ REPLACED CQI.L ARILQ AND HEUEROARILQ Ξ PE CXXIPOSICCES EARiACETJTICAS QUE 03 CORTEM &quot; The invention relates to a process for the preparation of a compound of the formula: â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (OH) 4 - (OH) (OE2OE12) u- (CH5K6) n - (OBp2 -Ar1) or a pharmaceutically acceptable salt thereof, which comprises coupling of the appropriate substituted &lt; &apos; -amino acids according to the compounds of formula I intended.