PT98830A - Process for the preparation of tryptophan (Trp) derivatives which are alpha-substituted N-substituted with cycloalkyl and polycycloalkyl and pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to a process for the preparation of a compound of formula <IMAGE> or its pharmaceutically acceptable salt, which comprises condensing <IMAGE> with RNH2.

Description

Description of the invention of the JSMMABBY COMPANY, North American, industrial and commercial, established at 201 Tabor Road, Morris Plains, New York 07950 * United States of America (inventors David Ohristopher Horwell, Martyn Glive Priteliard and Edvard Roberts, residents of the UK), for 'PROCESS FOR FRS-PABATION AND DERIVATIVES FROM TR1PT0FAN0 (Trn) ALPHA-SUBSTITUTES AND COMPLICATIONS WITH CXCLOXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

Disenchantment

Agents acting on the central receptors of cholecystokinin (CCK) can induce satiety (Schick, Yaksh and Go, Regulatory Peptides 14 * 277-291, 1986). They are also thought to act as analgesics (llill, IXuges and Piitaway, Neuropharmacology 26 * 289-300, 1987), and as anticonvulsants (Keratin and Bavison, Brain Research, 406 * 130-135 * 198)

Reduced levels of CCE peptides were found in the brains of schizophrenic patients when compared to controls (Roberte, Ferrier, Lee, Grow, Johnatone, Owens, Bacarese-Hamilton, McGregor, O'Shaughnessey, Polak and Bloom, Brain Research, 288, 99 ** 211, 1983) * It has been proposed that changes in the activity of COK neurons projecting into the Haccumbens nucleus may play an important role in the schizophrenic processes by influencing the dopa-energic function (Totterdel and Smith, Neuroscience 19, 181-192 , 1986). It is consistent with several reports that CCK peptides modulate dopaminergic function in the basal ganglia and particularly in the nucleus, Accumbens, M. et al., Tanzer et al., et al., Biochemistry and Behavior 30, 309-317, 1988). Iversen, Peptides 4, 769-753 (1983). It may thus be expected that agents which modify CCK receptor activity may be of therapeutic value in combinations associated with the disrupted function of dopaminergic function such as schizophrenia and Parkinson's disease,

CCK and gastrin peptides share a common carboxy terminal pentapoptide sequence and the CCK peptides may bind to the gastrin receptor of the stomach mucosa · produce acid secretion in many species including man (Konturek, Gastrointestinal Hormone , Ch. 23, pp. 529, 1980, ed., G.B., Glass, Raven Press, NY), CCK-B receptor antagonists are believed to be antagonists of the gastrin receptor of the and this would also have value for the conditions involving excessive acid secretion.

CCK and gastrin peptides have trafficking effects on the pancreas and various tissues of the gastrointestinal system (Johnson, ibid., Pp. 507-527), actions that are associated with increased synthesis of DNDN and ABN. In addition, gastrin-secreting cells are associated with some gastrointestinal tumors, for example the Zollin-ger-Bllison syndrome (Staclil, ibid., P 729-739), and some rectangular tumors that may also be dependent of gastrin / CCK (Singh et al., Yownsend and Thompson, Cancer Research, 76, 1986 and Smith, JP, Gastroenterology 95, 15, 19, 8). CCK / gastrin receptor antagonists could thus have valuable therapeutic effect as antitumor agents.

CCK peptides are widely distributed in various organs of the body including the gastro-intestinal system, endocrine glands, and nerves of the peripheral nervous system.

rich central. A number of biologically active forms have been identified including a 33 amino acid hormone and various carboxy terminal fragments of this peptide (e.g., CCK26-33 ethotoptide and CCK30-33 tetrapeptide) (GJ Bockray, Med. 3) 253-258, 1982).

The various OCE peptides should be involved in the control of soft muscle contractility, secretion of the exocrine and nondcrrine glands, transmission of sensory nerves, and various functions of the brain. Administration of the native peptides causes a contraction of the bladder vessel, annihilation secretion, excitation of central neurons, inhibition of feeding, anticonvulsive actions, and other effects of behavior, (MCholecystochnology, Structure and Punctuations, 1G, B, J. Glass, Sd, Raven Press, New York, 1980). , pp. 169-221, JB Borley, Life Sciences 27: 355-368, 1980, Cholecystokinin in the Nervous System, J. de Belleroche and GJ Dockray, Ed., Bílis Horwood, Ghichester, 1984, pp. IO-I27),

The high concentrations of CCK peptides in many areas of the brain also indicate important brain functions for these peptides (G, J, Dokray, Br. Med. Bull., 38 (No, 3), 253-258, L9S2) abundant GGK in the brain is CCK26-33 although there are small amounts of GGE30-33 (Rhefeld and Gotterman, J. Neurochem. 32: 1339-1341, 1979). The role in the central nervous system of CCK is not known with safety, but has been implicated in feeding control (Bella-Beira and Baile, Science 206 * 4-71-473, 1979).

Presently available appetite suppressing medications either act peripherally, increase energy expenditure (such as tyrosine), or otherwise (eg, biganosides), or act as a central effect on appetite or satiety.

Acting appetite suppressants centrally potentiate the central catecholamine pathways and tend to be stimulants (eg, amphetamycin), or influence the serotonergic pathways (eg, fenfluramine). therapy agents include the thickening agents which

they act by filling the stomach, thereby inducing a "satiety"

It is known that CCK is present in some cortical interactions which also contain gamma-aminobutyric acid (GABA) (Berneulemeester et al., Heur, Science, 8, 98S-B, -1000, 1988). GABA-modifying agents may have utility as anxiolytic or hypnotic agents (a, C, Harvey, The Pharmacological Basis of Therapeutics (7th ed. 1985, pp 339-371, MacMillan). Thus, agents that modify the action of CCK may have anxiolytic or parallel hypnotic activity. The role of CCK in anxiety is reported in TIJFS 11, 27-23,

The invention relates to novel compounds of formula

and pharmaceutically acceptable salts thereof, wherein R, s, A, E, and G have the following significance. Coprinated applications also assigned 07 / 576,308, 07 / 576,628, 07 / 576,296, 07 / 576,315, 07 / 576,297, filed August 31, 1990 by Horwel, et al, the subject of which is incorporated herein by reference, CCK antagonists are referred to. Such CCK antagonists in the applications were a partial continuation of the above-mentioned claims also owned by the applicant and co-pending. " ... -........................ and . The invention also relates to the preparation of pharmaceutical compositions containing an effective amount of a compound of formula X in combination with a pharmaceutically acceptable carrier in a form of unit dosage effective for suppressing appetite.

The compounds are also useful as anxiolytics, antipsychotics, especially for the treatment of schizophrenic composition, as agents for the treatment of diseases of the extrapyramidal motor system, as agents for the blocking of the strokes and stimulation of the growth of CCS and gastrina | and as agents for the treatment of gastrointestinal motility

The compounds of the invention are also 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

An additional use of the compounds of formula X is that the appropriate radiolabeled isotope of iodine-137 or iodine-127 gives rise to a suitable agent for the treatment of gastrin-dependent tumors such as those found in colon cancers. compounds of formula I radiolabeled with 1-125 may also be used as gestational day agents by locating the gastrin or CCE-B receptors in peripheral and central tissues. The invention further relates to a method for suppressing appetite in mammals comprising administering an amount effective to suppress the appetite of the above described composition to a mammal in need of such treatment. The invention also relates to a composition for reducing the gastric acid secretion Containing an effective amount of a compound of formula I in combination with a 5%

A pharmaceutically acceptable carrier in a dosage unit effective for reducing gastric acid secretion. The invention also relates to a method of reducing gastric acid secretion in mammals which comprises administering an effective amount for reducing the gastric acid secretion of the composition described above 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 an effective dosage unit form for reducing anxiety. The invention also relates to a method for reducing anxiety in mammals comprising administering to mammals an effective amount for reducing the 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 pharmaceutically acceptable carrier in a dosage unit form effective for treating gastrointestinal ulcers. The invention also relates to a method for treating gastrointestinal ulcers in mammals comprising 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 X in combination with pharmaceutically acceptable carrier in a unit dosage form effective for the treatment of psychoses such as schizophrenia. 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 composition described above to the mammalian subject that would require such treatment. to a pharmaceutical composition containing an amount effective to stimulate or block OGK or gastrin receptors for altering the activity of brain neurons, for schizophrenia, to treat extrapyramidal motor system disorders, to block the actions of trophic stimulation and growth of CCK e. of gas and for the treatment of gastrointestinal mobility. The invention also relates to a pharmaceutical composition containing an amount effective to prevent 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 medicaments or alcohol. These medicaments include benzodiazepines, especially diazepam, cocaine, alcohol, caffeine, nicotine and opioids. The withdrawal symptoms are treated by administering an effective amount of withdrawal treatment of a compound according to the present invention. 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 and / or prevention of panic. The invention also relates to a method for the treatment and / or prevention of panic in mammals comprising administering to mammals an amount effective for the treatment and / or prevention of panic of the composition described above to a mammal in need of such treatment . The invention also relates to the use of the compounds of formula I for preparing pharmaceutical and diagnostic compositions for. treatment and diagnosis of the conditions described above.

w3 &gt; SE

The invention further provides novel intermediates useful in the preparation of compound of formula 1 and provides processes for the preparation of the intermediates.

DETAILED DESCRIPTION

The compounds of the present invention are formed by the condensation of two modified amino acids and are therefore not peptides. They are, instead, &quot; peptoids &quot;, synthetic peptide-related compounds that differ from the natural peptides by the substituent group R &quot; not hydrogen.

The compounds of the present invention are represented by the formula &gt;

or a pharmaceutically acceptable salt thereof wherein is a cycloalkyl or polycycloalkyl hydrocarbon having three to twelve carbon atoms and zero to four substituents each independently selected from the group consisting of a straight or branched alkyl radical having one to six carbon atoms; carbon, halogen, CN, OR, SR *, CO₂R, CF », and - (O¾) OH wherein R * is hydrogen, linear alkyl, Branched with one to six carbon atoms, R 1 and R 2 are each independently hydrogen or alkyl of one to about six carbon atoms and n is an integer from zero to six, A is - (CH 2) n CO-, - SO 2 (CH2) n -O-C (O) -, -SCO-, -O- (CH2) nC0-, or -HC = CHC0- wherein n is an integer from zero to six, is straight or branched alkyl of one to about six carbon atoms, - (C 1 -C 6) -alkyl, - (CH 2) - (CH2) q -O-Ar-C (O) -CO- or -O- (OCHO) ΜΙΡΙΤ where n is 1, H-5 and R5 are as defined above and Ar is carboxy or heterocyclic or carbamoyl, or substituted or unsubstituted mono- or polycyclic aromatic heterocyclic or aromatic heterocyclic or mono-substituted or unsubstituted poly (C1-

X • (OH) 2 -, - (OH) a S-, -O = - (CH2) m - (CH2) m - ) Wherein m is an integer from 1 - 5;

F is a bond -CB (h) GO- wherein B is - (OH) m OH, - (OH3) e SO2 H3 t -CH2- (CH2) -> (CHR) -COO2 * - (CH3) (CER) -Z wherein m and q are each independently 0 or 1 and wherein F is a genetically modified amino acid amino acid excluding Tyr Phe Trp, His His and B is R 2 and R 3 are each independently selected from hydrogen, R 2 and -BB wherein n is an integer of zero to three and a bond of 1 to 10 carbon atoms,

(CH 2) n -, -CH (CH 2) n -, -CH 2 CH 2), - (CH 2) n - (CH2) n -, -SO2 - (CH2) 2, -OHh2 - (CH2) -S02 KH- (CH2) n -, mio-cac-,

Ti * P Λ, *, A *. CONH-γ-G-, 17β

nr

C? -C? -Alkyl,

- AND IS

CGNH-C-C-. in which R 1 and R 2 are independently selected from hydroxymel and m is 1 to 5, and together form a ring of 1 to 5 and n is as defined above, D is -COOR3 *, -CH3 R9, -C] SSOR *, -CH2 SR2, = 10 to

-H or an acid substitution such as, for example, tetrazole, or

a10 and OH, NH2, OH1, or Cl2; -? -po3h2 k9 4 oxadiasole

H11 is CN, CO2 H, or C1-3

H

PhSOp-IIICQ-J, GF-CONHCO-J, CF SO SO₂NHCO-, H₂SO₂-J; ,

»11»

is i .1

in which s is an integer from 0 to 2, R 1 and R 2, R 1 and are as defined above, and G is as defined above, and G can not be hydrogen when F is a bond

Preferred compounds of the present invention are those where the cyclicalkyl is a radical

substituted or unsubstituted and wherein the polycycloalkyl is selected from

1 was that Y, X, Y, and Z are each independently hydrogen, and 12

alkyl, straight or branched alkyl of one to six carbon atoms, CFâ,ƒ, KlAi6, - (GIIp) OOp R *, or GM, F, O, Br, OR *, SE *, wherein R5 is hydrogen or linear or branched with one to six carbon atoms and R6 and R8 are as defined above and a is an integer from 1 to 3.

Other preferred compounds of the present invention are those wherein R1 is 2-aminoamyl or 1- (S) -2-endobornyl 5-A-NHCQ-, -OCO-, -SO2 -, -S (ao) n,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒR2 is -CH3, -CH2 H2 O, F is a deamino form of alanine, substituted β-alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, isoleucine, leucine, β-lysine, methionine, serine, threonine, valine, © Ohn CME --COOH, NH2, -NHCOCH2 CH2 NH2, -NHCOCH2 OCH3, -NHCOCH2 OCH3, -NHCOCH2 OCH3, -NHCOCH2 OCH3, -NHCOCH2 OCH3, -NHCOCH2 OCH3, - 0H "

Η-N

-CH 2 -C (O)

O

NH-N

The most preferred compounds of the present invention are those in which R 2, 4-adamantyl or 1- (S) -2-endobomyl, A is -NHCO-, -OCO-, -SO 2 -, -S { or -CH₂-; R2 is -CH3, -CH2 or -CH3 CH; E is CGNH; and F is CH (e) G0- wherein R is -GBgCOgH, -CE2CH2SCH3, and 13 *

-CH 2 CH (CH 3) GS 3, - (cn 2) 30, p and G 2, -CH 2 CH 3, -CH 2 CH 2 CH 2, ,

 € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ- CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH configurations B and L are possible. centers and are included within the scope of the invention *

Preferred is when R is -0H / 17,

The most preferred compounds of the present invention are: (R) -3- (1H-indol-3-yl) -2-methyl-1-oxo-2 (tricyclo [3.3.1] 2-yloxy) carbonyl] amino] propyl] glycine, (1R) -4- [3- (3-indol-3-yl) -2- oxo (tricyclo [3.3.1.1.1, 6-S-yloxy) carbonyl] amino] propyl] thieno] butanoic acid, (R) -Î ± - [3- (1H-indol-3-yl ) -2-methyl-1-oxa-2 - [(tricyclo [3.3.1.1, 6,7] decahydro-2-oxoxy) carbonyl]

(R) -3- [3- (1-Indol-3-yl) -2-methyl-1-oxo-2 H - [tricyclo [2.2.1] phenyl) -methyl-aminobenzyloxy) -benzyl] -amino} -propylamino} -propanoic acid,

Methyl N - [(tricyclo [3.3.1.1 4, 7dec-2-yloxy) carbonyl] -D-tryptophyl] -alanine,

2-methyl-N - [(tricyclo [3.3.1.13,7] decan-2-yloxy) carbonyl] -D-tryptophylglycine, N-methyl-N - (tricyclo [3.3.1.13 * 27-dec-2-yloxy) carbont] -B-tryptophyl7-β-alanine * * 14

2-methyl-2-methoxybenzyl (2-methoxyphenyl) -1-methyl-2-methyl-2-oxabicyclo [2.2.1] tricyclo [3.3.1.13,7] decan-2-yl, N, N-dimethylamino] -1- (1H-indol-3 2-oxoethyl] -7-oxoethyl] -7- (trifluoromethyl) -1,2,3,4-tetrahydro-

Dimethyl-2-yloxy) carbonyl) -R-tryptophyl] -L-methionine, N-methyl-N-methyl- 13.5 &gt; c-2-yloxy) carbonyldi-D-tryptophanyl] -L-methionine,

Metil-1 / m - / &quot; 3-yl) methyl] -N-methyl-N- [tricyclo2.3.1.1,17,13,13a-2-yloxy) carbonyl] -B-tryptophan-L-methionyl] -alanine, N- [ -methyl-N - [(tricyclo [3.3.1] heptane-2-carboxylic acid) (S) -methyl-N - [(3-tricyclo [3.3.1] oct-3-yl] -2-yloxy) -benzyl] -2-oxo-1,2,3,4-tetrahydroisoquinoline.

Tricyclo [3.3.1.13] hexane-2-yloxy) carbonyloxy] -7- (trifluoromethyl) -L-e-aminobutanoic acid and (methylsulfonyl) -L-methyl-N-methyl-N-methyl-N- [3- (3-methyl- g &lt; -amino-butanoic acid

The compounds of the present invention include those compounds of formula I wherein the indole moiety is a 2- or 3-indolyl

Compounds of the invention include solvates • &lt; and pharmaceutically acceptable salts and salts of the compounds of formula 1.

The compounds of the present invention may have many chiral centers including those designated in the foregoing formula I by one depending on their structures. In addition, there may exist centers of asymmetry in the substituents 11, 11, 3, 4 and 5. In particular, the compounds of the present invention may,

The present invention encompasses all such forms of the compounds. The present invention encompasses all such forms of the compounds. Mixtures of diastereomers are typically obtained in the reaction results described more fully and hereinafter. The individual diastereomers can be separated from the diastereomeric mixtures by conventional techniques such as column chromatography or repeated recrystallizations, the individual enantiomers can be separated by a conventional beige process known as for example conversion to the salt containing an optically active compound, followed by separation by chromatography or recrystallization and conversion to the non-salt form.

The compounds of the present invention can be obtained by coupling the individual substituted Î ± -amino acids by well-known procedures. (See, for example, the conventional synthetic processes discussed in the volatile article, Peptides, Analysis, Synthesis, Biology, The starting materials of the individual substituted α-amino acids are generally known or if they are not known, can be synthesized, and if desired resolved by procedures known to those skilled in the art (Synthesis. of racemic% 7-1-Kiethyl tryptophan methyl ester-see Brahman, M., et al., J. Chem. Chem., 17, 2929, 1980

A key intermediate in the preparation of the compounds of formula X and a compound of formula

In which R 1 is selected from S 1, 9-fluoromethyl, B 2 and the other 16 suitable N-groups which are useful as intermediates in the preparation of the compounds of formula X. Compounds in which U and 1-adamantyl, 2-adamantyl, proto-adamant, exo-boronyl, endo-bornyl, exo-norborayl, endo-norbornyl, 2-methylcyclone xyl, S-chlorocyclohexyl, or camphoryl. are new and are &quot; U.S. Patents &quot;, U.S. Patent 757 3-51 incorporated herein by reference. It discloses the 9-fluorenylmethyl,

Compounds having the general formula ΊΧ are prepared by reacting a compound of the formula: ## STR3 ## in which 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 XV with (-methyltryptophan to give the compound of formula XX above. Alternatively, a compound of formula XV can be reacted with the methyl ester of (-methyl-tryptophan to give 4-4-

H

which can then be converted to a compound of the formula XI by methods known per se, for example hydrolysis with aqueous lithium hydroxide solution. Scheme I below illustrates procedures for the preparation of useful intermediates in the preparation of the compounds of formula

(2) and is prepared from the alcoholic form of a radical selected from 1-adamantyl, 2-adamantyl-propionamethyl, 9-fluorenylamino, exohexyl, endo-benzoyl, , exo-norborryl, endo-norbornyl, Î ± -methylcyclohexyl, 2-chlorocilia, and the like. The alcohol is dissolved in a solvent such as methylene chloride. And is converted to the corresponding chloroformate by reaction with the bis (trichloromethyl) carbonate and pyridine at about 0 ° C. The product is obtained by condensation with a symbol such as t-methyl-D-iriptophan A The reaction is carried out in a solvent such as THF to give, for example, methyl N - [(2-adamantyloxy) carbonyl] methyl-3-methyl-3-trifluoromethane (2) is treated with the title compound as described in the following Examples: (a) the title compound (2) is treated with the title compound as described in the following Examples:

Alternatively, a chloroformate can be converted into (2) by reception with an alkaline solution of Î ± -ethyl-

SCHEME I

XYYYY)

at 18 m

'P i-

(i) COOH, diphosgene or triphosgene, pyridine (ii) OC-methyl tryptophan, methyl ester (for example) (II)

Scheme IX shows synthetic phases for the preparation of the compounds of the present invention. The key intermediate is 2-Î ± -oct-methyltryptophan. When this compound 4 is treated with N'-dicyclohexylcarbodirimide in the presence of pentafluorophenol in ethyl acetate solution. obtained the active pentafluorophenyl ester of 2-Moc- (β-Bethyltryptophan. This compound was then treated with the appropriate amine to give the compounds of Examples 1, 3, 5, 7, 8 and 9. The esters were converted in the corresponding carboxylic acids by hydrolysis using &gt; or by hydrogenation with Pd / C as adeated, yielding compounds of Ex. 21ht and 6h at 19s

Isobutyl & I

Icitcisol 20

EXAMPLE 10 The compounds of Examples 10, 11 and 12 were synthesized. The key intermediate, 2-epoxy-2-methoxyhexylcarbodiimide was treated with N-dicyclohexylcarbodiimide in ethyl acetate The active H 2 O ester was obtained which was readily reacted with the methionine methyl ester to give the compound of Example 10. This compound was then converted to the compound of Example 11 by the hydrolysis of Ister using LiOH in The aqueous solution of HOBT of this carboxylic acid was prepared as above and then reacted with the methyl ester of β-aminopyridine to provide the compound of Example 12. =

(I.e.

(i) 3GG, HOBT, Methionine, ETOAc (ii) BCG, HOBT, β-alanine, ETOAc

(iii) LiO11, H2 O, THF and 22

Biological ACTXvmass The biological activity of the compounds of the present invention was evaluated using the initial screening assay which rapidly and accurately mediates the binding of the test compound to known COE receptor sites. Specific CCK reactants have been found to exist in the central nervous system (see Hays et al., Keuropeuticles 1155-62, 1980 Cos5, Satuer et al., Science 208, 1155-1156, 1980).

In this screening assay, brain cortexes taken from male GSXP mice weighing about 30% 40 g were dissected in ice, sin, and homogenized in 10 volumes of a buffer of Tris-CHI 50 (pH 7.4 between 0 and 4 ° C.) The resulting suspension was centrifuged, and the pellet was discarded , and the pellet was washed by resuspension in Tris-HCl buffer followed by recentrifugation. The final pellet was resuspended in 20 volumes of 10 μl Hepes buffer (pH 7.2 at 23 ° C) containing 130 mM STaCl , 4.7æM of 2101.5æg of MgO 2, 1æg of R) 1A, 5æg / ml of bovine serum albumin, and bacitracin (0.25mg / ml).

In saturation studies, brain cortical membranes were incubated at 23 ° C for 129 minutes in a final volume of 590 μl of incubation buffer. Hepes (pH 7 * 2) together with tritiated pentagastrin 0.2-20 hV (Amersham International, England).

In the displacement experiments, the membranes were incubated with a single (2 nK) concentration of Xyzante, with increasing concentrates (10-11 to 10-11 M) of competitive assay compound Bm each case, nonspecific binding was defined as which persisted in the presence of the unlabeled GOE-8 peptide (10-11)

After incubation, membrane bound radio activity was separated from free in solution by rapid filtration through Tvhatman GF / B filters and washed three times with 4 ml of ice-cooled Trie-HCl buffer, the filters of the samples incubated with pentagastrin tritiated were placed in vials «23 =

polyethylene glycol with 10 ml of scintillation broth, and the racemic activity was estimated by liquid scintillation spectrometry (yield of 52% æf). Specific binding to the O 10 receptor sites; was defined as total bound tritiated pentagastrin minus the amount of tritiated pentagastrins bound in the presence of 10% octapeptide, 33%

The saturation curves for the specific binding of specific tritiated pentagasirin to the mouse cortical membranes were analyzed by the Scatohard (Isn, et al., Acad, Sei. 51, 66, 67S *, 9, 9, and Hill (1994), to provide estimates for a number, the ratio of equilibrium (li)

SL 2 * displacement assays * inhibition curves were analyzed by logit-Iog curves or by ite curve. of a computer program of the ALLPXT correlation to provide estimates of the values of IgG and Kg (coefficient 50%). (IGF values were defined as the concentration of the test compound required to produce 50) inhibition of specific binding) φ 3 and the dissociation constant of mas: The constant inhibition of the test compound was then calculated according to the Equation (1).

lG to 1 + Γΰ / ¾ in which (L) is the concentration of the racemication and e the equilibrium dissociation constant.

The K. values for various representative compounds of the present invention are shown in Table X *

The compounds of the present invention are useful as appetite suppressants in the assays described below.

In the Pleasant Dietary Feeding assay * 2h · &lt; &gt; ?

Adult male rats of the Hooded Lister species weighing between 200 and 500 g were stored individually and trained to trade in a pleasant diet. The diet consists of condensed milk, sweetened food, mouse powdered food, and water for rats which when mixed together-hardened to a firm consistency. Each mouse was served with 20 to 30 g of the pleasant diet for 30 minutes per day during the lighting phase of the lus-dark cycle during a 5-day training period. Absorption of 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 discharged waste from the diet. Rats have free access to food pellets and water except for the 30-minute test period *

After the training period, dose-rosostate curves GQII8 ® are constructed for various representative compounds of the present invention (n '8 to 10 mice per dosage level)

The values of (95% confidence limit) were obtained for the enortop effects of these compounds and are shown in Table I, in the therapeutic use as appetite suppressing agent, the compounds of the present invention are administered to the patient at levels of dosage of about 200 to about 2800 mg per day. The following Table J shows the binding data for the compounds of the invention. 23

jl Example Number

Affinity binding CCK B (m-i) __ utii.iι · ι · Μ · Μ, Ι · ίJl. ; * '* »&Lt; * | ^ ι. · Ρ | · &quot; Ι &quot; IWHJWW »1 82 * 1 2 N.T * 3 30 * 4 4 I 510 5 K, T * 6 A3S0 7 299 8 292 9 225 10 41 11. 24 12 30 »«!

Male Hooded Lister rats (175-250 g) are individually stored and submitted to batching at night (free access to water). They are anesthetized with uridine (1.3 g / l IP) and the trachea is cannulated to aid spontaneous respiration, the stomach is perfused using a modification of the original method of Qhoah and Schild in &quot; Otintinuous recording of acid secretion in the rat, as described by Par sounds in My Quantitative Studies of Drug-Induced Gastric Acid Secretion (1969, University of London Thesis, 1969) The stomach cavity is drawn to a flow rate of 3 ral / well with a solution of glucose w / v through both the cannulae of the esophagus and the body. The fluid is driven by a roller pump (Gilson liinipuls 2) through heating coils to raise its temperature to 37 ± 1 ° C. The perfusion fluid is collected by the bottom collection funnel passed through the pH measuring electrode connected to a pH meter Jenv ; ai (PHM6) · "A monitor output of p H to a paper recorder of Bikadenki for registration was pH line of gastric perfusion * pentagastria and arraasenacla as slice * 26 =

frozen and diluted to the required coactions with sterile 0.9% w / v solution of M &amp; C1. The new compounds are then dissolved in sterile solution of 0.95% w / v water on the day of the experiment. The medicaments are administered intravenously through a fluted jugular vein as a powder in a dose volume of 1 ml / kg washed with 0.15 ml 0.9% w / v Flufa. The basal value is allowed to stabilize before administration of compounds have started * Typically spend 30 minutes between surgery and the first compound administration.

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

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

All animals are fasted for 2 hours before and throughout the experiment, the drug or vehicle is administered 10 minutes prior to an oral dose to 1 ml of a suspension of h5 ng / aspirin salt in carboxyethyl cellulose at 0.5 / ¾ "

Animals are sacrificed j hours prior to administration of aspirin ô 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 specific dosages used, however, may be varied depending on the patient, for the activity of the compound used. The determination of optimal dosages belongs to the specialist *

The compounds of the present invention are also useful as anxiolytic agonists as described below and are described below. The anxiolytic activity is evaluated by the st. Dark / dark rat assay assay (B. J. Jones, et al.

Britannica, et al., Proc. The device is an open top carton having a length of 27 cm, 27 cm wide, and 27 cm high, divided into a small area (2/5), a large area (3/5) by one partition which extends 20 cm above the walls, has an opening of 7 * 5 x 7 * 5 with a partition at ground level, the small compartment and painted in black and the larger compartment 4 painted white, The floor of each compartment is marked with a 9 cm square, the compartment is white • illuminated with a tungsten lamp 109 lf 17 cm above the housing • The black partition with a similar red lamp of 17 similarly placed, gt; laboratory and illuminated with red light. All tests were carried out between 13 hours of hours, 0 minutes and 18 hours of hours, 0 minutes. The test was carried out by placing it in the center of the white area and giving the fea scanning the new environment for 5 minutes, its behavior is recorded on television magnetic tape and behavior analysis is done subsequently from the record. Five parameters are measured for the delay in the dark compartment, the time spent in each area, the number of transitions between compartments, the number of cross lines in each compartment, and the number of setbacks in each compartment. time spent in the clear area is a sensitive measure of, i.e., directly related to, the aneelic effects of various conventional anxiolytic drugs. Medicaments are dissolved in water or saline and administered either subcutaneously, either intraperitoneally or by mouth (PO) through a stomach needle.

The compounds of the present invention are useful as antipsychotic agents. The compounds are tested for p-

determine their ability to trap the effects of amphetamines in the rat in the manner described below. Male Sprague Dawley (CD) Bradford rats are used. Rats are stored in groups of five at a temperature of 21Â ° C in a cycle of 12 hours of light dark of illumination between 7 hours 00 minutes and 20 hours 00 minutes. Rats are fed diet-safe 05.1-2 (bafe-sure) and water is allowed at will. Rats are anesthetized with calcium hydroxide (*! · 0 · mg / kg SC) and placed in a stereotaxic catheter Chronically introduced cannulae (constructed of 0.65 mm diameter stainless steel tubings held bilaterally in Parspex brackets) are implanted using conventional stereotactic techniques to complete 3 × 5 mm above the. center of the nucleus of &lt; azole (Ant · 9, Vert * 0.0 Lat 1 6) or 5 × 0 mm above the central nucleus of the amygdala (Ant, 5.8, Vet. -1 , 8, Lat, * k, 5) (Atlas de De Groct, 1959) * Guides are maintained & seen during a recovery period of lk days using stainless steel "diameters of 0.3 mm, which extend 0.5" in addition to the guide tips "

Gs x * acts are Biannually restricted and stylets removed. Intra-renal injection cannulae with a diameter of 0.3 g are inserted and the medicaments are admitted in a volume of 0.5 microliter for 5 seconds (a further period of 55 seconds is left for deposition) from Hamilton syringes connected through polyethylene tubes to the injection units. The animals are used at the most. only occasion.

Behavior experiments are conducted between 7 hours and 30 minutes and 21 hours and 3 minutes in a rest room maintained at a temperature of 22Â ° C. The rats are taken from the house at rest and left an hour for The paracentesis activity is evaluated individually in parspex cages scrutinized (25 cm x 15 cm high) (grouped in groups of 30) each equipped with a photocell unit at the end of the experiment. along the axis at 3.5 cm from the wall; m 29 »

it has been found that this position minimized inappropriate activity counts due to, for example, tail and head movements when the animal is stationary1 The light beam interrupts are recorded every 3 minutes. At this time animals are also observed to verify the presence of any non-specific alteration in locomotor activity, by e-xeraph, sweating, prostation, stereotyped movements, which could interfere with recording locomotor activity1 The capacities of the compounds of the invention to inhibit the hyperactivity caused by the injection of amphetamine into the nucleus of mouse falciparum at the locomotor activity followed by the bilateral injection of amphetamine (20 000 g) into the nucleus of 1, peak hyperactivity (40 to 60 counts per 5 minutes) occur 20 to 40 minutes after the injection. Intraperitoneal injection of rats with the compound (20 mg / kg or 30 mg / kg) or (1 g / kg) reduces the activity caused by the intra-amphetamine injection (1). This test is predictive of antipsychotic activity (Gostall, Domeney to Taylor &amp; Yers, Brit. J. Pharmacol., 1988, 2, 881-889).

The compounds of the present invention may prevent and treat the withdrawal response produced when and when the chronic treatment is discontinued or the excessive use of alcohol is stopped. Such compounds are therefore useful as therapeutic agents in the treatment of chronic or excess alcohol as discussed and described below. The compounds of the present invention are shown in the "rat box" assay of rats, for example. Five animals were administered nicotine, 1 g / lEg, i.p.b.d. for 14 days. After a withdrawal period of 24 hours, and administered a compound in a dose of 1 to 100 mg / kg, i.p., b.d. The increase in time spent in the clear area and a significant loss of the effect of the compound as an agent to treat the effects of nicotine withdrawal. 1 3Q-

The effect of the long-term treatment and withdrawal of nicotine using a compound of the invention 4 shown below, and administered nicotine to five rats at doses of 0.1 mg / ml. for 1 day. withdrawal 4 takes place over the period of 2 hours, the compound is administered at 10 erg / kg i.p. The increase in time spent in the clear section reveals the effect of the compound. The effect of long-term treatment and withdrawal of diazepam using the compound of the invention is demonstrated below. administered to five rats at doses of 10 mg / well i.p. b.d. for 7 days. Withdrawal 4 carried out within 24 hours; compound 4 administered at 1.0 mg / kg i.p. The increase in time spent in the clear section reveals the amount of the compound. The effect of a compound of the invention in the long-term treatment and withdrawal of diazepam 4 is shown below. Diazepam was administered to five mice at a dose of 10 mg / lg, i.p. &quot; b.d. for 7 days. After a 24-hour withdrawal period the compound is given at 10 mg / kg b.p., the time spent in the clear section after the compound has been administered reveals the effect of the compound. The effect of a compound of the invention in the long-term treatment and withdrawal of alcohol is shown below. Alcohol is administered in the drinking water of five rats at 5% w / v for 14 days. After a withdrawal period of 24 hours the compound is typically administered in the range of 1 to 100 mg / kg i.p. The time spent in the clear section after the compound is administered reveals the effect of the compound. The effect of a compound of the invention on the long-term treatment and withdrawal of alcohol 4 is shown below. Is alcohol administered in drinking water from five rats to ST? w / v for 14 days. After a withdrawal period of 24 hours, compound 4 is typically administered in the range of 1 to 100 mg / kg i.p. b.d *. The time spent in the clear section after the compound is admixed shows the effect of the compound. The efficiency in the long-term treatment at 31

Withdrawal of cocaine from the compound of the invention is demonstrated as follows: cocaine is administered to five mice at a dose rate of 100 mg / kg for one day, the effect of the compound 4 shown by the cie increase. time in the clear section. The effect in the long-term treatment and withdrawal of cocaine from a compound of the invention is given in the following sections. Cocaine is administered to five mice typically in the dose of 1 to 100 mg / kg, After a withdrawal period of 2 hours, the compound is typically administered at 100 mg / kg ip, b * d. The effect of the compound is illustrated by the increased time in the clear section *

The anxiolytic effects of a compound of the invention are disclosed by the Social Injection Assay when dosed. rats in pairs. The anxiolytic epoxide of the compounds is indicated by the feed of the time spent in the social intersection when compared to the control C value (dostall, B *, University © f Bredford).

The anxioitic effects of a compound of the invention are disclosed by the High Mato Grosso X-Kaze Assay at a dose range of 0.01 to 100 mg / kg sc, the anxiolytic effect I indicated by the time spent at the end section of the arm as compared by control C 1 &gt; of the expected compound in the invention will decrease the flexor response of a mouse will be brain stimulated in the spinal cord similar to morphine. The effect on the administration of this compound with morphine greatly potentiates the effect lasting 3 hours,

For the preparation of pharmaceutical compositions using the compounds of this invention, inert, acceptable carrier vehicles may be solid or liquid, compositions in solid form 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, pro-subilizers, lubricants, suspending and binding agents, or tablet disintegrating agents, may also be a encapsulating material.

The active substance is mixed in the carrier having the necessary binder properties in suitable proportions and contacted to form the active ingredient. The tablets are mixed with the finely divided active component. In order to prepare compositions in the form of suppositories, the melting point of a lower melting point such as a mixture of glycerides of fatty acids and butter is preferably achieved. cocoa powder and the active ingredient 4 is dispersed therein by, for example, stirring. The melt-flow melt mixture is then poured into suitable size molds, allowed to cool and cure.

Preferred carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, peotin, pextrin, starch, tragacanth, methylcellulose, carboxylic acid and the like. sodium cellulose, a low melting wax, cocoa butter, and the like.

Preferred pharmaceutically acceptable counterions are shown below.

Acetate, beasenosulfonate, bensoate, bicarbonate, bitartrate, bromide, calcium acetate, carbonate, chloride, citrate, tetrahydrochloride, odetate, ederyxate, ostolate, esylate, fate, glucaptate, gluconate, glutamate, glycolylarsanilate, hexylsorcinate, hydroxylamine, hydrochloride, hydrochloride, hydroxynaphthoate, hydroxynaphthoate, isothiate, Xactophate, Xactobionate, malate, maleate, mandelate mesylate, methyl bromide, methylnitrate, methylsulfate, uucate napsylate The compounds of the present invention may be prepared by the following methods: nitrate, pamoate, (embonate), pantothenate, phosphate / diphosphate, polygalactonate, salicylate, stearate, succeanate, succinate, sulfate, tartarate, tetraolethate, triethiodide, benzathine, chloroprocaine, choline, etllenodiaiaine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

A preferred pharmaceutically acceptable salt is H-methyl glucanamine salt or the sodium salt. The term &quot; composition &quot; is intended to include the formulation of the active component with an encapsulating material such as vehicle providing a capsule wherein the active component other vehicles) S wrapped by a vehicle which is thus in association with it * The wafers are similarly included *

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

Liquid-form compositions include solutions, suspensions, and emulsions. The water-soluble or water-propylene glycol solutions of the active compounds may be mentioned as examples 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 are prepared by dissolving the active component in water and adding colorants, flavoring agents, stabilizers, thickening agents, as appropriate, in the desired manner. Aqueous stispensions for oral use may be obtained by dispersing the finely divided active component in water with a viscous material such as natural and synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known in the art. pharmaceutical technique.

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

ladas

The following exons are illustrative of the present invention. They are not intended to limit its scope.

(1H-indol-3-yl) -2-methyl-2-oxo-2-methyl-

The title compound was prepared in the same manner as in Example 3 (a) to a solution of the title compound as a white powder (3 g). (1.39 g, 7.60 mmol) and cooled to 0Â ° C. A solution of the title compound was then added dropwise in tetrahydrofuran (10 ml) and dimethylformamide (10 ml). The reaction mixture was then filtered. The acid methyl ester hydrochloride was converted to butyl alcohol (3.00 g, 9.00 mmol) to the filtrate followed by dropwise addition of a solution of triethylamine (-0.91%).

(19 ml). This mixture was allowed to stir at room temperature for 2 hrs., Washed with citric acid. (2 x 50 ml) and water (2 x 50 ml) was cooled to 0 ° C. The organic phase was dried over MgSO4 and the solvent was evaporated. The residue was chromatographed on silica gel reverse phase chromatography on silica gel using Na2 SO4. (3.26 g, 87%); mp 65-70% (CH 2 Cl 2): m / e 27.2 (M +), Leu 1 ) 5 XV (film) 3500-3200, 2908, 2855, 171S, 1703, and 16.55 CHT1'-M (CSCl3) 1.4S-1.55 &lt; 2H, m), I.58 (3H, s), 1 , 65-1.85 (log, s), 1.90 (4H, m), 2.21 (4H, m). J = 7Hz), 3.20 (3H, s), 3.28 (1H, d, J = 7.5Hz), 3.20 (1H, d, J = 8f), b.72 (1, -2, s). Anal. (1H, s), 6.50-6.60 (1H, br m), 6.37 (12, d, J2Bs), 7.07 (1H, , 7.37 (1H, d, J = 7.7Hz), 7.57 (1H, t, J = 7Hz)

3,3,1,1,12,12aβ-yloxy) carboxyamino] pyrrolo [1Î ±, 2aÎ ±, 1β, 1β, "Ί '-τγγμιμΜιι ΙΙΊΙΙ __« 516 * - < The invention relates to a process for the preparation of a compound of the formula: ## STR2 ## in which R 2 is as defined in formula (I). (M + H +)

C02h 36 6

A solution of the methyl ester (Example 1) (2.6 g, 5.2 mmol) in 1,4-dioxane (500 ml) was treated dropwise with a solution of LiOH (10 ml of a 0 solution , 0512, 5.20 mmol) for 2 hours with vigorous stirring. This mixture was stirred at ambient temperature for 2 hours and was added sequentially with HCl (5.2 mL), the solvent was removed in vacuo and the residue chromatographed using 0.5% AcOH, 5% HCl in CH3 CN to give 80 mg of the starting ester together with 1.32 g of the product, 55% yield, 7% conversion factor  € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ Xlf (film) 3600-3200,

2909, 2856, 1702 © 1651 caT1? (3H, s), 1.62-2.00 (m, 51), 2.10-2.25 (2H, m), 3.20 -3-to (2H, m), 3.2 (1H, d, J = 14.5H), 3.30 (1H, d, J = 4.5Hz), 4.84 (1H, m), 5.47 (1H, s) ), 6.58-6.65 (1H, brm), 7.03 (1H, d, 2H), 7.09 (1H, t, 7Hz), 7.17 (1H, t, J = 7Hz). D, J 8 Hz), 7.57 (1H, d, J 8 Hz), 8.59 (1H, s). Anal. s, a, h, o O 2 .0.2HgO |

(3-chloro-3,3,1,1-tetrahydro-2-oxo-3-trifluoromethylphenyl) and (-) -

(3.0 g, 7.6 mol) in JStOAe (40 ml) was treated with pentafluorophenol (1.39 g, 7.6 mmol) in EtOAc (10 μL) which was added dropwise and stirred for 12 hours at 40 ° C and filtered. The glycine benayl ester hydrochloride (1.8 g, 9.0 mmol) was added followed by dropwise addition. the drop of triethylamine (0.9 g, 9.0 mmol) in EtOAc (iodine). This mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then washed with citric acid IA (2 x 30 mL), a solution of NH4 OH (3.times.50 mL), water (2 x 50 mL), dried over organic phase The residue was chromatographed on reverse phase of the silica gel from the customary silica gel column. as the source to 'originate &quot; The crude product (2.83 g, 68%) was added dropwise to 0.9 g of the starting ester, m.p. 76-82Â ° C (Î ±)) Î »max 20Bv360 (a-1, i.e., 5 x 10 -1 T (film) 3500-3200, 2908, 2055, 1745, 1702, and 1665 cm -1

(CDCl 3): 1.45-1.6 (4H), 1.69-2.00 (133, a) δ, 1.11 (3H, s) 4.10 (2H, s), 6.79 (1H, s), 7. Cl (m, d, J 2 Hz), 3.11 (s, 7.03 (1H, t, J 7Ηξ), 7.15 (1H, t, J = 7.7 Hz), 7.39-7.7 (6H, m), 7.57 (1H, d, J = (11B, s) (1S) (FAE) 544.4 (11), 414.3 (11), 348.2 (36), 135.2 (?) Anal. ; * 3B s

(3-methoxyphenyl) -4-oxo-2-oxo-3- (1H-indol-3-yl) (S) (1), (2) and (2) and (2) and (2) and (4). · · Ι tá-.n.rtirnηη ·············································································································································· (i.e., the π-η, π-ΧΚ-ΧΚ-ΧΚ-ΧΚ-ΧΚ-ΧΚ-ΧΚ- ^ ΙΜΜΚ · ίΜΙίΜΐ ^ ΒΜΒ · ΙΙΙιΙ 1 &gt; (2-pyridyl) ethyl]

Co9h

A solution of the besasyl ester (Example 3) (2.5 g, 4.6 mmol) in absolute BtE (10 mL) was treated with 10% FCl / O (250 mg, 10% w / w) and placed under vacuum The reaction mixture was filtered through an auxiliary filter and the filtrate was concentrated in vacuo. The reaction mixture was filtered through an auxiliary filter and the filtrate was concentrated in vacuo. The residue was then chromatographed on silica gel using 9.5 g of the title compound as a white solid (0.9 g, 90%) as a white solid. 112-117 ° (βI) β3 + 400 (Î ± X, γ101) Î »ZV (film) 3500-3200, 2910, 2856, 1702, 1660, and 735 cnT1β1 (CB013) (1H, s), 1.51 (1H, s), 1.53 (3H, m), 1.70-2.00 (12H, m), 3.00-4.00 (1H, br), 3.28 (1H, (1H), 3.45 (1H, d, J 14 * 3He), 3.94 (2H, d, J 5Hz, 4.85 (1H, s), 5.35-5.50 (1H, ?, brt), 7.04 (1H, d, J2Sa), 7.05-7.18 (2H, m), 7.32 (1H, d, J8S2s), 7.56 (1H, d, J8Hz) (i) (i)

2 '* Adoc' fWSrp-β-AIa QMe

A solution of 2-adamantylaminobutyl-E-tryptophan (8.0 g, 20 mmol) in BtOAc (100: 1) was treated with pentafluorophenol (3.68 g, 20.0 nmol ) Was then added at 0 DEG C. Dichlorohexyl carbodiimide B *

21.0 mmol) and the mixture was allowed to stir for 18 hours at 0 ° C. After this time e. The mixture was filtered and washed with methylene chloride (2.78 g, 2%) and the mixture stirred for an additional 18 hours at room temperature, filtered, and the filtrate washed with 1M HGX (3 x 30 water (-2 x 30 ml), a saturated NaHCO 3 solution (3 x 30 ml water (2.times.30 ml). The organic phase was dried over Na2 SO4 (7.8 g, 81%) and the product crystallized from ether to give an ester (7.8 g, 81%) as a white solid (film) 3700-3200, 308 ° C 287 777 3 1695 1659,

EXAMPLE 6 Amino-N-octyl-methyl-3 '- [(tricyclo [3.3.1] ) oarbonyl] -D-tryptophyl (2-amino-1- (p-Alkoxy)

The ester of example 5 (5 x 20 g,

(454 mg, 10.8 mmol) in water (100 ml) was added dropwise and the residue was evaporated to dryness. (10.8 ml) was added and the mixture was distilled off in vacuo and the residue chromatographed on reverse phase on silica gel using 70% of ICeOH in dichloromethane. Water. as eluent to afford the product (323 g, 51%) combined with the starting ester (1.0 g, 0.98%) as a pale yellow oil (98%). (phylBi) 3351, 2911, 2855, 1660, and 1658 cm @ -1) (CPCI3).

1.30-2.00 (17H, m), 2.39 (2H, br s), 3.26 (1H, d, J 15H s), 0.40-3.50 (3H, (1H, s), 5.42 (1H, brs), 6.7 (1H, s), 6.93 (1H, d, 2H), 7.05- (1H, 1 H-NMR (CDCl 3) δ 8.37 (b, s), 7.33 (1H, m), 7.57 (1H, d, 46 ° C (217 (100)) Anal. C 26 H 33 F 3 O 5 • 0 • 25H 2 O, S, K. KSPPLO 7

(1E -indol-3-yl) - (S) -ethylbutyl-1-oxo-5 - [[ · - - - -. ... (R) -cyclohexylcarbodiimidazole-4-carboxylic acid (1-methylphenyl)

As described in Example 5, the use of the glycine asbestos ester, yield of S9> 204.2 ° (KeOS) 17 (iim) 3500- 3200, 2907, 2355, 1718, 1658 cm -1 BHK (01) C13) a 1.52 (3H, s), 1.50-1.60 (SI1.

(1H, d, J 14.5), 3.43 - (1H, d, J m), 1.33 (1H, 2.40-2.55 (2H, m), 3.29 (1H, s), 3.46 (2H, q,

4.83 (1H, s), S.OC (2θ, e), 3.19 (br s), 0.65-6.75 (br, fer), 6.96 (1H, d, J 21Is ), 7.09 (1H, dt, J 7), 7.17 (1H, br.s), 7.27-7.29 (m, 1H), 7.58 , Î ±, Î ±, Î ±, Î ±, Î ±, β, Î ±, Î', β, β, β, β, β, β, Î ±, Î ± -cyclohexanecarboxylic acid, 3-yl) ethyl] -1H-indole-3-carboxylic acid, tricyclo [3.3.1.1] -S-yl] - ((S, S *) J =

The title compound was prepared according to the procedure described in Example 1 for the title compound as a white solid (0.6 g). XV (fllae) 3509-329C, 290 ', 285%, 1703-1620 br γ 1? (CFC13) <T0.85-0.9 (6b, s), 1.25-1.32 (2 H, s), 1. 50 (9: 9 s), 1.51-1, (3H, m), 1.65-2.00 (m, 3H), 3.10 (1H, br), 3.36 (1H, 39 (1-3), 3.55 (1H, d, J = 14.5 Hz), 3.72 (1 H, dd, J 11.5 and 3H), 4.00-4.10 (1H, m) (1H, s), 6.12 (1 H, d, J BHa), 7.00 (1 H, d * J 2 Ea), 7.09 (1 H, t , 7.57 (1 H, d, J = 6 Hz), 8.48 (1H, d, J 7.5 Hz), 7.17 (bs, dt, J 7.5 and 1H), 7.36 ) = 42 =

(1-hydroxyethyl) -2-methylbutyl] amino] -1- (1-methyl-3-methylphenyl) -1-methyl-2-oxoethyl ester, tricyclic ester C3t3, i, i3, Z7 <tec-2-ion Z> is * / * im * (ss) &gt;

Exact procedure as in Example 3 except the use of the ( ±) isoleucinol, yield 76%, mp 79-82 ° C IR (film) 3500-3200, 2923, 2856 * 1697 * and 165? (1H, m), 1.00-1.20 (2H, m), 1.35-1.54 (5H, m), 1.52 (3H, s), 1.50-1.58 (sil, m), 1.65-2.00 (12H, m), 3.36 (1H, d, J = 14.5Hz), Î', 5.5-5.3 (2H, m) ), 1.20 (m, s), 5.17 (1H, s), 6.29 (1H, d, J, 8.5Hz). 7.01 (1H, br, J211), 7.03 (1H, t, J7H), 7.76 (1H, br.s), 7.36 (1H, ,  € ƒâ € ƒâ € ƒ1 H-s (1H, s); Anal.

BSBEELO 10

(7dec-S-yloxy) -carbamic acid tert-butyl ester was prepared as a white solid.

W

SAclocM 1-1 © Tr pOII

00η0 £ Ίο Λ. J

(Heterocyclohexanecarboxylic acid).

S-CH3,

PHASE 1

To a stirred solution of 1-hydroxybenzo-triazole Bionohydrate (0.52 g, 1.51 mmol) and the acid (0.500 g) in dichloromethane , 1.26 Kiao (1) in EtOAc (5 ml) at room temperature. After one hour, s-methionine chloride (0.377 S, 1.89 mmol) was added. followed by triethylamine (0.263 ml, 1.89 mmol) and the mixture was stirred for 10 hours. The filtrate was filtered and the BiOAc washed with a 5% aqueous citric acid solution (2 x 25 ml), a saturated solution of CH2 Cl2 (2 x 25 ml), citric acid (25 ml), and brine (25 ml) was dried over MgSO 4, filtered, and the solvent removed in vacuo. The residue was purified by chromatography on silica using 33% EtOAc Of hexane, then 50% of 3% EtOAc / 50% of n-hexane as eluents, yielding the product (0.7489 g, 72%) as a white solid, m.p. f. 65-72 ° C,? 1 * 7211)? (Î'): νmax (film) 3351, 1763, 1702, and 1665 cm @ -1. (2H, m), 3.30 (1H, d, J 14.7Hz), 3.49 (1H, d, J 14.8Hz), 3.69 (3H, s) , 4.38-4.65 (1H, m), 4.82 (in s), 5.24 (1H, bs), 6.94 (1H, d, J 7.2H), 7.06-7.20 (3H, m), 7.36 (1H, d, J 8.0Hz), 7.59 (1H, br, J 7.9Hz), 8.19 (1H, s), 11-methyl-E - [(tricyclo [ dideoxy-2-yloxy) -carbamoyl] -D-trideoxy] -butyllithione

C02 CH3, 2, 3, 4;

S-CH,

0.1 E I / OH

THF 2Ado cbH-j eXrpMi R

FASB 2

To the solution was added dropwise 44

To a solution of ethyl ether (0.8 g, 0.73 mmol) in CH2 Cl2 (4 ml) at 0 ° C was added a biOB aqueous solution (8.6 ml # 09S6 mmol) and 25 minutes. The cooled solution was stirred for 2 hours and for 18 hours at ambient temperature, the solvent was removed in vacuo and the residue diluted with water (1 ml) in tetrahydrofuran (25 ml). The pH value was taken to 2 with a 0.1% NaCl solution and dried (Na2 SO4). The combined At6Ae contents were washed with brine (25 ml), dried over AgSG4, filtered, and the solvents removed (b) (b) (b) (b) 5â € ²â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ95-102ø05 / 0) | IR (film) 335; 1713, δ -1106 cm-1, Î ± - (ewci), 1.52-1. 60 (5K, 0), 1.71-2.17 (17H, b), 2.35 (3H, t, J 7.2, 6.3), 3.32 (1H, d, 1H) (1A, 1A). (3H, b), 7.33 (1H, d, J = 7.7Hz), 7.03 (1H, s) ), 7.57 (1H, d, J = 7.7Hz), 3.40 (1H, s)

Aetli (tricyclo [3.6.1] carbonyl] -b-tryptophenoxy] -thio] -O-alanine

2-one, iii) stirred solution of 1-hydroxybenzotriazole. The title compound was prepared as a white solid (1.0 g, 0.6 mmol) and the acid (2.5 g, 0.9 mmol) in sodium (25 ml) was added N, N -dicyclohexylcarbodiimide. Elide (0.048 g, 0.13 mmol) and the mixture was stirred for 1 hour at room temperature. This was followed by the addition of the methyl ester hydrochloride Î ± -alanine (0.559 g, 0.71 mmol)

and triethylamine (δ, 099 ml, 0.11 mmol) and the mixture was stirred at room temperature for 48 hours. The N, N '-dicyclohexylurea was filtered and washed with EtOAc. (2 x 25 ml), a saturated sodium hydroxide solution (2 x 25 ml) and citric acid (25 ml), brine (25 ml) was added dropwise.

The St-OAc was dried over MgSO4, filtered, and the solvent was removed by evaporation. The residue was purified by silica chromatography using 50% aq. Hexane / 59% IStOuc, 33a N-hexane / 6% StOAq as eluant, yielding the product as a white solid (0.15g, (s), mp 79-86 ° .alpha.D @ 20 / cCys2-yl .alpha. (O), 2θ, CHCl3). 1T (filsie) 3325, 1737, 1604, and 1857 W1 * ABA (σΐ · 01ο) 1 * .49 (3Π, s), 1.34-2.44 (19E, m), 2.26-2.41 2K, ®), 2.33-2.53 (23, ra), 3.42-3.56 (43, m), 3.6? (3H, s), 4.40-4.59 (m, 4), 4.81, 4.87 (311.2s), 5.08, 5.27 (1E, 2s), 1.99 (1H, d, J 2.33 The),. 7.08-7.38 (5H, m), 7.59 (1H, d, J = 7.9H), 8.28 (1H, 2s), 1.32 (3H, s) , 1,1â € ²-D-tripto [3Î ±, 2Î ±, 3β, 3Î ±] -carbamyl] -D-tripto [Î ±] -cystinyl-β-alanine

2-methyl-1 - [(1R, 2S) -cyclohexyl] S7dOC-2-

(1-hydroxy-2-oxoethyl) -1H-imidazol-1-yl]

Lj- £ ϊ © ΐΙΙΟΙΙΞ.ΐιβ

(0.286 g, 1.39 mmol) was added a stirred solution of 1-ylideneacetic acid: triazole monohydrate (Ob? 32 g, 1 mmol) in dichloromethane? , 51 mBiol), and the like. Krtn. g. 1.26 mmol) in methanol (50 ml) at reflux temperature. After 1 ° C methionine hydrochloride (0.377 g, 1.8 g) was added followed by triethylamine (0.263 g, 1.89 mmol) and the mixture was stirred for 2 hours at room temperature. 1 H-NMR (CDCl3) was filtered and the residue was treated with an aqueous solution of citric acid (5 g). (2 x 25 mL), a saturated solution of HaECO3 (2 x 25 mL) citric acid & (25 ml), and brine (25 ml), the solution was dried over MgSO4, and the residue removed in vacuo. The residue was purified by silica overprint using 330 g of EtOAc / hexane, hexane, hexane / hexane / hexane / hexane, yielding the product (0.89 g) as white solid, m.p. • f. 65-72 ° C / . (c = 0.34, CHO13) g xv (film) 3351, 1-143, 1702, G 1665 ca. 2211, m), 2.34-2.40 (2θ, m) f, 3 &gt; Ji 0 (In, d, J 1¾% 7a) | (1H, s), 3.69 (3H, s), 4.49 (1H, d, J = 8.4 Hz) (1 H, bs), 6.94 (1H, d, J 7 *), 7.2 (2H, m) (1H, d, J 7.4 Hz), 7.59 (1H, d, J 7.4 Hz) 47

To a stirred solution of the ethyl ester (0.4-23 g, 0.78 mmol) in THF-1 P (40 mL) at 0 ° C was added dropwise 0.8 K LiOH (8.6 mL, 0.86 mmol) for 23 minutes. The cooled solution was stirred for 2 hours and for 18 hours at ambient temperature. The solvent was removed in vacuo and the residue diluted with water (10 mL) and extracted with 9 (25 ml). The aqueous solution was washed with 1 N NaOH solution and extracted with EtOAc (2: 25s). The combined extracts of EtOAc were washed with brine (25Âμl), dried over Na2 SO4, filtered, and evaporated to dryness. the solvents were removed in vacuo to give the title compound as a white solid (0.351 g, 83%) as a white solid (mp: 238 DEG-238 DEG C.). The title compound was prepared according to the procedure described in Example 1, which was obtained from the title compound as a white solid (1680 cm-1). 7 * 2H); 3'.3.2 (1H, d, J = 14.6Hz), 3.45 (bd, J 14.4Hz), 4.59-4.66 (1H, m), 4.84 (1H, s), 5.36 (1H, bs ), 7.02 (1H, d, J 2.3Hz), 7.08-7.19 (3H, m), 7.33 (1H, d, J 7.7Hz), 7.57 (1H, d, J 7.7Hz), 8.4 ) Anal. - (C1-4) alkyl, C, E, E ', S.

To a stirred solution of 1- (3,5-bis-trifluoromethylphenylsulfanyl) sulfonic acid (0.932 g, 0.5 mmol) (0.225 g, 0.4-3 keto I) was added NaHCO 3 (25 mL) (0.098 g, 0.03 mole) and the mixture was stirred for 1 hour at room temperature. This was followed by the stearate solution of the β-esterase (0.09 g, 0.71 mmol) and triethylamine (0.99 mL, 0.71 mmol) and the mixture was stirred at room temperature for 48 hours * Hexahydicyclohexylurea was filtered and the StOAc washed with a 5% aqueous citric acid solution

(2 κ 25 ml), a saturated solution of KaHCO 3 (2 κ 25 &quot; ml), 5% citric acid (25 ml), and brine (25 η 4). The reaction mixture was dried over MgSOâ, ", filtered, and the solvent removed in vacuo. The residue was purified by silica chromatography using 50% n-hexane / 2% EtOAc. n-hexane / 67% â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ StOAE as eluant, yielding the product as white solid ^ 49

3, * 2 ~ 3.5δ (? !!!, ο), 3.δ7 (312, s), k.kc-k.59 (1, m), 4.81, (2.29 g, 2.31, δ), 7.0 & 7.38 (3H, s), 7.59 (bs, d, J = J = 7.9 (1H, d, J = 9Hz); The ri 4- &quot; *. Anal. 5-one stirring solution of rutile ether (0.1133 g) in dichloromethane (97 ml) at 0Â ° C was cooled to 0Â ° C. A solution of CHâ,,Clâ, 2.1 ml, 0.21%) overnight. After cooling to 2 hours, the mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was diluted with water (50 ml) . The solution was extracted with a plug of the SCI solution and extracted with EtOAc (2 x 25 ml).

The combined extracts were dried over sodium sulfate, and the solvents were removed in vacuo to give the white solid ionic product (0.05 g, 7%), mp 218-64Â ° C. 1 H-NMR (CDCl3): Î'(CDCl3) Î'(5H, m), 1.71-2.03 (1H, m) , (2R, 5S) -7- (1-S-yloxy) -hexahydro-4-trifluoromethyl- Eisieiaa

= 50 =

(Tricyclic / 3,3,19,13,13,13,13,13,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12, -l-cysteine hydrochloride

To a stirred solution of 1-hydroxy-benzoyl-1,2-dioxide (0.49 g, 0.8 mmol) in dichloromethane (1.15 g, 3.15 mmol) and (1 R)

2.52 mmol) in EtOAc (100 ml) at room temperature. After 1 h, s-racemic-s-cysteine (0.55 g, 3.times.12 mmol) was added followed by dropwise addition of (0.4-4.35 g, 3.24 mmol) in 50 ml of DMF (25 ml). The mixture was stirred at room temperature for 3 hrs, filtered, and the solution was extracted with aqueous sodium hydrogen carbonate solution and the solution of sodium bicarbonate solution. .DC.,. . a solution of citric acid (50 rd), saline (10: 1). EtOAc / 1c was dried over MgBuS (filtered), and the solvent was evaporated in vacuo and the residue purified by flash chromatography on silica gel (50%) as a white solid (50% yielding the product (955 S * 727) as a solid solvent (c 0.23, δ-ClO), ν (rows) 335 e * 1743 * 1700, 3 1567 cm-1 (ORD 013) 1.50-2.02 (17H, m), 2.05 (3H, s), 2.82-2.93 (2H, m), 3 (3H, s), 4.72-4.73 (11H, m), 4.84 (11H, s), 3.43 (1H, d, J = (Br s, m), 7.37 (1H, d, J 8.0Hz), 5.12 (1H, bs), 7.07-7.21 (m, (0.88 g, 1.67 mmol) in DMF (990 mL) at 0Â ° C was added dropwise 1.55 mL of 0.11 L aqueous LiOH solution (18.4 mL, The cooled solution was stirred for 1 hour and the solvent was removed in vacuo, the residue diluted with water (20 ml) and extracted (2 x 25 ml). the reaction was acidified with 110% BOI solution, 1 H (20 mmol, 2 mmol) and extracted with dichloromethane (v. 50 mL) at 0 ° C was dried over,

filtered, and the solvents were removed in vacuo, yielding the product (0.666 g, 71%) as a white solid, mp 218 DEG-170 DEG C., CHC1). (film) 3344, 173-3 * and 1666 cm -1 15 121 (CDCl3): Î »51 ~ -2.04 &quot; (2H, d, J = 4.7Hz), 3.48 (1H, d, J = 14.7122), 4.66-4.72 (1H, m), 4.86 (1H, s), 5.32-6.10 (2H, b), 7.02-7.19 (bs, ra), 7.32 (1H, br.s, 7H), 7.57 (1H, d, J 3.7) s), 8.48 (1H, s), ΛώΙΙ ((C₂ 2H₂ 0N₂O.), CΗ HH₂O, 3-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -b-tryptophyl] -β- (methylsulfinyl) -Î ± - and β-aminobutanoic acid

0

52 = i.1 X 0

Ethyl estradiol (90 g, 5 g) was added in vacuo to a stirred solution of sodium chloride (0.9 g, The cooled soln was stirred at 0 ° C for 1 hour and then under reflux for 2 hours. The solvent was removed by evaporation of the extracted residue as a white solid (0.25 g) and washed with saturated NaHCO 3 (50%), . The aqueous solution evaporated was partitioned between EtOAc (25%), solvent removal was the product yield (0.421 g, 43%) and recrystallization from hexane. -) how tsa yellow syrup? (2β, s), 1.91-2.0 (c, m), 2.20-2.32 (1H, s), 2.29 (3% e): Î'8.77 = 8.95 (2H, m), 3.58-3.6 (1H, br), 3.75 (m, s). (C 6 H 13 W 3 SO 4 .5H 2 O) f .0. Het K # S, F / jSE 2, gr <K-ethyl-IT-3 * (tricyclo [3.3.1.1 (2-chloro-2-methylphenyl) -D-tryptophyl] -N '- (t-butylsulfonyl) -L-tetrazole

N, N '-dicyclohexylcarbodiimine hydrochloride was added to

(0.454 g, 2.2 mmol) was added dropwise to a stirred solution of 1-hydroxy-3-trifluoromethylsulphonamide (0.368 g, 2.4 mmol) and the acid (0.793 g,

(75 mL) at room temperature. After 3 hours, the reaction mixture was cooled to room temperature, and the reaction mixture was stirred at room temperature for 4 days. The organic extracts were dried over magnesium sulfate and evaporated to dryness. the solution was filtered and the solution washed with water, the aqueous solution of citric acid was added to a solution of suturoic acid A 30 (2 ml), citric acid The reaction mixture was cooled to 0 ° C (23 r) t) and brine (100 mL). The solution was evaporated to dryness. The residue was purified by silica gel chromatography on silica, eluting with EtOAc / hexane / EtOAc / hexane / EtOAc and EtOAc The title compound was prepared as an eluent to provide the product (c% 2k-1g9 22,) as a white solid, mp 217 DEG-5 DEG C. (dec.) 3333-5743, 1763, 2667, (s, 1H), 1.64-1.06 (brs), 2.33-2.41 (1H, m), 2.64-2.46 (1H, m) 46-2.63 (5E, m), 3.30-3.44 (2H, s), 3.69 (3H, s), 4.52-4.62 (1H, (1H, m), 5.37-5.42 (1H, m), 6.92-7.93 (1H, m), 7.7-7.6 (2H, m), 7.36 (1H, 7.5 ° (11½ sa) f S. 31-9.37 (H a, a) 3 / mal. A stirred solution of the tert-butyl ester (0.59 g, 10%) and 7% (60 ml) at 0 ° C was added dropwise over 1 hour The solution was cooled to 0 ° C and the residue was diluted with water (15 mL). The residue was diluted with water (15 mL). l) and extracted with water (1 x 25 ml) .The aqueous solution gained a 3 g of a solution of 7.01 g and was extracted with EtOAc (2 x 50 ml). The solution of α-tfAc was dried The residue was purified by chromatography on a silica phase using 7-5% EtOAc / water as eluant, resulting in the product (9.33%) as a white solid, mp 129 DEG-141 DEG. XV (film) 33233-2703, g 1670 was &quot; 1 &quot; (a), 2.74-2.18 &lt; 14tf, si), 2.53 (3H, s), 2.60-2.74 (1H, 3.45 (1H, d, J = 4.0Hz), 4.34 (1H, bs), 4.72 (1A, s), 6.86 (1H, bs), 3.25 (1H, 6.95-7.00 (1H, m), 7.05-7.10 (2H, m), 7.7 / 6

= 54 B

(Ii: 9 cl, 7.91%); 7.5% (d, J 7.8%), 7.58 (m t t), 10.02 [10.0 (e), 12.84 (1H, b). (M + H +), and the title compound was obtained as a white solid (0.25 g, 0.02 mole) in dichloromethane (20 ml). (2-hydroxyethyl) amino] -1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid [2- (1-pyridyl) anaaaaaaaaaaaaa

(0.8-5 g, 4.69 mmol) was added portionwise to the stirred solution of thiosyl chloride (0.681 g, 95%) as a white solid. (25 ml) at 0 ° C, cooled solution was stirred for 2 hours and then warmed to reflux for 3 hours, cooled, the solvent was removed and the residue was purified by crystallization (0.673 g, 60%) as a white solid, mp 15 DEG-166 DEG C., while stirring at -78 DEG C. for 2 hours. (3S, s), 8.87-3.46 (2H, m), 3.82 (2H, d, J = 6.6Hz). 6 (3H, .beta.), 4.19 (1H, t, J 6.4Hz), C.90 (3H, s) (Câ, † Hâ,ƒCHâ,,Oâ, "S), Gâ, ..., Glâ,,,

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, The title compound was prepared according to the procedure described in Example 1, but the title compound was prepared according to the procedure described in Example 1, (9.42 g, 0.078 mole) and the acid (9.38 g, 2.22 mmole) in EtOAc (90 ml) at 0 ° C was added dropwise. After stirring for 1 hour at room temperature, the title compound was obtained as a white solid, mp 218-221øC. 1 H NMR (DMSO-d 6):? (0.371 ml) in EtOAc (xylene). After stirring at room temperature for 19 hours the mixture was filtered and the solvent was removed in vacuo. The residue was purified by silica gel chromatography using EtOAc as eluent yielding the product (0.877 g, 9%) as a white solid, recrystallized from EtOAc, mp 46.5 ° -131 ° C. (DMSO-d6): νmax: 0.23, CG SH) g): TJ (filno) 3358, Uh2, 1703, 1669, 1300, and 1131 Π1-3 (C SSX)) 1.31 = 9.10 (s, 1H); , 2.36 (s, 3H), 2.36 (s, 3H), 2.36 (s, , J 14.7Hz), 3.66 (31, s), 4.54-4.  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ51 (11 -; m), 4.58 (1H, 7.36 (1H, d, J = 6Hz), 7.55 (1H, d, 7.8H), 3.36 (1H, s) Anal. S0.25 (20), 0, Π, 75, '. (0.929 g, 1.68 mmol) of Step 2 in 100 ml) at 0 ° C was added dropwise over 30 minutes in an aqueous solution of LiSII To the cooled solution was stirred for 2 hours and the solvent was removed in vacuo, the residue was diluted with water (20 ml) and extracted with Et2 O (0.18 ml, 1.78 ml, 78%). 2 x 25 ml). The aqueous solution was acidified with a solution of FOI 0.11 (18æl, 1 mmol) and extracted with BtOAc (2 s 50 salt), extra combined β-acetic acids were dried over filtered filtered NaCl , and the solvents removed in vacuo to give the product (0.9 g, 76%) as a white solid, mp 133 DEG-148 DEG C.

(c = 0.s1, .C.-JOl) g7 (m? d) 33 &gt; 917369 and 1671 cr &quot; 9te (tetete6) 1.3 ': • (39, e), 1.40-1.54 (m-e), 1.73-2.66 (m, 1H), 2.9 (3H, s), 3.22 (1H, d, , 3.33 (1H, bs), 3.31 (1H, m), 4.34 (1H, m), 4.73 (bs, s), 6.94-7.9-6 (41- (1H, d, J = 3.0Hz), 7.3 (1H, d, J = 7.5Hz), 13.92 (1.9, s) 1-13.09 (lE, te) 5

(3β-4α, 4α, 4β, 7α) ç,, i - 5 O

w.1 1 57

Claims (1)

S S! ϊ Τ ϊ Η Processo Processo if if if if if if if if if if if if if if if if if if if if if if. or a pharmaceutically acceptable salt thereof, in which: a cycloalkyl or cycloalkyl alkyl having from three to twelve carbon atoms and with zero to four substituents each independently selected from the group consisting of an alkyl radical having one to six carbon atoms, halogen, CN, CO 2 R 3, CO 2 R 3, CF 2, CO 2, or - <OH 2) a D 1 3 wherein R 1 is hydrogen, straight or branched alkyl having 1 to 6 carbon atoms, R 2 and R 3 are each independently hydrogen or alkyl of one to six carbon atoms, is an integer from zero to six, two or four (C1-6) alkyl, - (CH2) , Wherein n is an integer from zero to six, and &quot; and &quot; and hydrogen, &lt; RTI ID = 0.0 &gt; alkyl radical of the straight chain or branched chain with a salt of carbon atoms, - (C 1 -C 8) -alkyl, - (CH 2) n Ar, - (CH 2) OR 2, - (CH 2) (0): wherein n, R 2, R 3 and R 4 are as defined above and Ar is a radical heterocyclic or heterocyclic or unsubstituted or substituted mono- or polycyclic hydrocarbons, 58 to J. 2 '' - (C (p) m S -, -Câ 0 ¡N-1â € ², --SOâ, "NRâ,ƒ), - SOâ,, - CH₂) n -COOH, - (OIIp) CôH-f wherein m is an integer from 1 to 3, "O-·. &lt; A. SF-M 15-O or * and F 9 is a bond. In which - (CH2) r '(CHR') - ', wherein and as defined below, wherein pqq' and q are independently 0, 1 or 2 and wherein F is Biologically significant acid, excluding Tyr, Plie, Trp, Xixs, 3 hr. and II are independently used independently from each other. Λ Α Α * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *. (CH2) n - (CH2) n - (CH2) n - (CH2) n - (CH2) n - (CH2) n - ) &amp; * &gt; (CH2) n-NHS02 - (CH2) n -, -CO (OH ") -, and w2 ^ n" * n 59 »* -only. C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, -CO-H-is-is-. , IR I IV R 7 & wherein R1 and R2 are independently selected from hydrogen, and U or together form a (CH2) 3 ring as an integer from 1 to 5 ne and as defined above, -OH, H or an acidic substitution such as for example, p-totrazole, n-butyl, n-propyl, or oxadiazol- or an integer from 0 to 2, R2 is as defined above and G2 can not be hydrogen when R1 is a bond, The title compound was obtained as a white solid by condensation (1: 6) 2o A process according to claim X, wherein only a cycloalkyl or polycycloalkyl of about one ring carbon atoms is obtained. The process according to claim 1, wherein a compound wherein the cycloalkyl or polycycloalkyl is independently methyl, F, G1 or Br4. The process of claim 1 is characterized in that a compound in which the polycycloalkyl selected from the group consisting of in which u, X, Y to Z are each independently hydrogen, a straight or branched chain alkyl radical having six carbon atoms, CF 2, -C (O) , Wherein R * e. R 2 and R 3 are as defined in claim 1 and an integer from 1 to 3, is as defined in claim 1, wherein R 1 and R 2 are as defined in claim 1. (= O) -, - O 2 -, -8 (= - O), - O - or -CH 2 CO- * '' '' '' '' '' '' '' '' '' '' '' compound wherein &amp; 2-acrylamethyl, i- (S) -S-endobornyl, Δ is -MUCO-, -OCO-, -S09- * S (=: G), C1-6 alkyl, , or -CH? CH? CH? CH? form of the alanine, substituted aliphaine, arginine, acaragine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine synthionine, serine, threonine, or valine, and CrOH, HBL, -MOOOO1C ΪI, -GCGGIIgCUgCOgH-, -CI-XgSCHgCOgH, -CHgSCHgCHgCOgH * f h2- <1, - OCH3, - OCH3, A process according to claim 1 characterized in that a compound in which R1 is 2-adamantyl or 1- (Î ±) -2-andbornyl, Î ± -O- -SO 2 -, -SO 2 -, -SO 2 -, - (SO 2) - or -CyioG0 &quot; '&quot; <â, † -CHâ,, -CHâ,,Oâ,,CHâ,,â,, or -Oâ,,â,ƒ-Ciâ,, â,, - Câ, â,,O-, and F (CHâ,,) (CHO) OCHâ,,, â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ- (CHO) OCHâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒC (H0) -CH 2 CH 2 COOH, -OCH 2 COGH, -OCH 2 COOH, (I.e. The process of Claim 1 is characterized in that the following 5-amino-3 - [(1 H -purin-1-yl) indole-3-yl) -S-methyl-1-oxo-2 - [(tricyclo [3.3.1.1.3] oct-2-yloxy) carbonyl] aminopropane (1 H -indol-3-yl) -2-hydroxy-1-oxo-2-methyl- (trimethylcyclopropylmethyl) -1,3,3,7,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12,12 -3-yl) -2-methyl-1-oxo-2 - [(tricyclo [3.2.1] methyl-1-furyl-2-methyl-1-furan-2-carboxylic acid (3-methyl- 3-yl) -1,2,3,4-hex-2-yl) carbonyl] phenyl] propionate: phenylmethyl propanoate, methyl methacrylate 3-yl) -1H-indol-2-yl) carbonyl] -S-tryptophenyl] - alanine, Penylmethyl K - [2- methyl-N- [tricyclo [3.3.1.13,77.02 (2H, t, J = 7.6 Hz); (tricyclo [3.2.0] hexane-17-dideoxy-2-yloxy) carbonyl] -7-methoxy-7-oxazepin- (Methylamino) -2-methoxymethyl-amino] -1- (1H-indol-3-yl-ethyl) -1-methyl-2-methoxy] (R) - (R) - (hydroxyethyl) -methylbutyl] -2-hydroxy-2-hydroxy- 1 H -indol-3-yl] ethyl) -1-ethyl-2-oxoethyl] carbamic acid 3,3 ' (t-butyldimethylsilyloxy) -pyrrolidine-3-carboxylic acid (N, N -dimethyl- L-ibandionine-6-carboxylic acid (3-chloro-3-chlorophenyl) -1,2,3,4-tetrahydro- The title compound was prepared from the title compound as a white crystalline oil.1H NMR (300 MHz, CDCl3): Î ± -triethoxysuccinimidazole-2-yl) -B-tryptophan-β-alanine. A process according to claim 1, which is characterized in that the compound of formula (I) tricyclo [3.3.1] heptadeca-2-yl) The compound according to claim 1 in which the compound S-methyl-N-α-α- methyl-N '- [(tricyclo [3.3.1] undecyl) amide; , which is in the form of a compound of formula (I). The process of the invention as claimed in claim 1 is prepared by yielding the compound N- (Î ± -methyl- N - [(tricyclo [3.3.1.1.2] dec-2-yloxy ) -Carboxy-3-B-tryptophanyl (methylsulfinyl) -L-α-amino-butoxy- The compound according to claim 1, characterized in that the compound of the formula I-1-N-t-butyldimethyl-1-N- (tricyclo [3.3.1.1 9,7] decyloxy) - A method for the preparation of a pharmaceutical composition for suppressing appetite, a method for the preparation of an efficacious pharmaceutical composition for suppressing appetite A compound as claimed in claim 1, in combination with a pharmaceutically acceptable carrier diluent, The present invention relates to a method for reducing the secretion of mammalian cider gastric acid which is characterized in that the active ingredient is a compound of the formula I or a pharmaceutically acceptable carrier. - A process for the preparation of an effective pharmaceutical composition for reducing the anxiety of a mammalian mammal by incorporating as the active ingredient a compound as prepared according to claim 1 to association with a carrier pharmaceutically acceptable. A process for the preparation of a pharmaceutical composition effective for treating gastrointestinal ulcers in a mammal characterized in that the compound as prepared in accordance with claim 1 is incorporated as an active ingredient with a pharmaceutically acceptable carrier. preparing a pharmaceutical composition effective for treating the psychotic behavior of an ovariectomized mammal for incorporating as the active ingredient a compound as prepared according to claim 1 in association with a pharmaceutically acceptable carrier. An effective pharmaceutical composition for treating panic disorder in a mammal is characterized in that the compound of the formula I in combination with a pharmaceutically acceptable carrier is a compound of the formula the! - &lt; s =. A pharmaceutical composition for blocking the reaction caused by the drug or alcohol combination in a mammal is characterized by incorporating as the active ingredient a compound when prepared according to claim 1 and the present invention as a pharmaceutically acceptable carrier, 2G & - A process for the preparation of an effective pharmaceutical composition for potentiating the effects of morphine and other opioids in the treatment of pain characterized in that the active ingredient is a corticoid when prepared according to claim J. It is an association with a carrier The applicant claims the priorities of the United States applications filed on August 31, 1990, July 12, 1991, under the accession numbers of 5769OZhrt * 70 &lt; Kr &lt; 0 &lt; RTI ID = 0.0 &gt; O. &lt; / RTI &gt; s 67