FI109689B - Process for the preparation of a therapeutically effective indole derivative - Google Patents

Description

109689

Background of the Invention

Agents that affect central cholecystokinin (CCK) receptors can cause satiety (Schick, Yaksh and Go, Regulatory Peptides 14: 277-291, 1986). They are also expected to act as analgesics (Hill,

Hughes and Pittaway, Neuropharmacology 26: 289-300, 1987) and as anticonvulsants (MacVicar, Kerrin and Davison, Brain Research 406: 130-135, 1987).

Decreased levels of CCK peptides in the brains of schizophrenic patients have been observed compared to controls (Roberts, Ferrier, Lee, Crow, Johnstone, Owens, Bacarese-Hamilton, McGregor, 0'Shaughnessey, Polak and Bloom, Brain Research 288: 199-211, 1983). It has been suggested that changes in the activity of CCK neurons reflected in nucleus accumbens 20 may affect dopaminergic function in schizophrenic processes (Totterdell and Smith, Neuroscience 19: 181-192, 1986). This is consistent with numerous reports that CCK peptides modulate dopaminergic function in the basal ganglion, and in particular nucleus accumben-! (Weiss, Tanzer and Ettenberg, Pharmacology, Biochemistry and Behavior 30: 309-3174, 1988; Schneider, Allpert, ·; and Iversen, Peptides 4: 749-753, 1983). Therefore, it can be expected that agents that modify CCK receptor activity may have therapeutic value in conditions associated with impaired central dopaminergic function, such as schizophrenia and Parkinson's disease. 1 CCK and gastrin peptides share a common carboxyl • pentapeptide sequence, and CCK peptides can bind to the gastrin receptor of the gastric mucosa and cause acid secretion in many species, including humans (Konturek, Gastrointestinal); , Chapter 23, pp. 529-564, 2,109,689 1980, edited by GBJ Glass, Raven Press, NY). CCK-B receptor antagonists could also be expected to be gastric gastrin receptor antagonists, and could also be of value in conditions involving excessive ha-5 production.

CCK and gastrin peptides have trophic effects on the pancreas and various tissues of the digestive tract (Johnson, ibid., Pp. 507-527), effects associated with increased DNA and RNA synthesis. Moreover, gastrin secreting cells are associated with specific tumors of the gastrointestinal tract, such as Zollinger-Ellison syndrome, (Stadil, Ibid, p. 729-739), and some colorectal tumors may also be gastrin / CCK dependent (Singh, Walker, Town 15 send, and Thompson, Cancer Research 46: 1612, 1986; Smith, J..

P., Gastroenterology 95: 1541, 1988). CCK / gastrin receptor antagonists could therefore have therapeutic value as anti-cancer drugs.

CCK peptides are widely distributed to various organs of the body, including the digestive tract, endocrine glands, and peripheral and central nervous nerves. A variety of biologically active forms have been identified, including: the 33 amino acid hormone and various carboxyl-terminal fragments of this peptide (for example, the octapeptide CCK26-33 and the tetrapeptide CCK30-33) (G.J.

: V. Dockray, Br. Med. Bull. 38 (3): 253-258, 1982).

Various CCK peptides are thought to be involved in the regulation of smooth muscle contraction, extracellular and endocrine gland secretion, sensory nerve mediation, and multiple brain function. feeding inhibition), ··· 35 anticonvulsant and other behavioral effects (Cholecystokinin: Isolation, Structure and • · · »3 109689

Functions, G. B. J. Glass, Ed., Raven Press, New York, 1980, pp. 169-221; J. E. Morley, Life Sciences 27: 355-368, 1980; Cholecystokin in the Nervous System, J. de Belleroche and G. J. Dockray, editors, Ellis Horwood, 5 Chichester, England, 1984, pp. 110-127).

High concentrations of CCK peptides in many brain areas also indicate that these peptides have important functions in the brain (G.J. Dockray, Br. Med. Bull. 38 (3): 253-10258, 1982). The most abundant form of cerebral CCK is CCK26-33, although small amounts of CKK30-33 are present (Rehfeld and Gotterman, J. Neurochem. 32: 1339-1341, 1979). The role of central nervous system CCK is uncertain, but it is associated with control of feeding (Della-Fera 15 and Baile, Science 206: 471-473, 1979).

The currently available appetite suppressant drugs act either peripherally, by increasing energy consumption (such as thyroxine) or by some other means (such as biguanides), or by providing a central effect on appetite or satiety.

Centrally acting appetite suppressants; either enhance the central nervous system catecholamine pathways and: are generally stimulants (eg amphetamine) ··· or affect the serotonergic pathways (eg fenfluramine). Other forms of drug therapy include filling-. . ·. agents that act to fill the stomach, thereby creating a "feeling" of satiety.

CCK is known to be present in some cortical media neurons that also contain gamma-aminobutyric acid (GABA) (H. Demeulemeester et al., J. Neuroscience 8: 988-1000, 1988). With agents that modify the GABA effect, ···. 35 may also be useful as anxiolytic or hypnotic agents (S. C. Harvey, The Pharmacological Basis of I t: Therapeutics (7th ed.) 1985, pp. 339-371, MacMillan).

Thus, agents that modulate the CCK activity may exhibit concurrent anxiolytic or hypnotic activities. The role of CCK in anxiety is described in TIPS 11: 271-273, 1990 and is described in great detail in Woodruff, G.N. and Hughes, J., 1991, Ann. Rev. Pharmacol, and Toxicol. 31, 469-501.

WO 92/04045, published March 19, 1992, relates to dipeptoids useful as, for example, anxiolytic agents.

Summary of the Invention

The invention relates to a process for the therapeutically active tri-15 cyclo [3.3.1. 1,3,7] dec-2-yl ester- [1S- [1α (S1) 2β] [2 - [(2-hydroxycyclohexyl) amino] -1- (1H-indol-3-ylmethyl) -1- methyl 2-oxoethyl] carbamate or a pharmaceutically acceptable salt thereof, wherein (R) -2-adamantyloxycarbonyl-α-methyltryptophan is handled with a coupling reagent such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate, followed by -trans-2-aminocyclohexanol, and optionally converting the resulting compound into a pharmaceutically acceptable salt. The compound has the formula I

; 25; ί 8 Π ίΤΤ ° γ "Γ“ ^ '30 Bd 0! ·· *. 35 · ♦ t 5 109689

The compounds are useful as appetite suppressants, anxiolytic agents, antipsychotic agents, in particular for the treatment of schizophrenic behavior, as agents for the treatment of disorders of the extra-pyramidal motor system, as trophic agents for the trophic and growth stimulating effects of CCK and gastrin, and as a nutrient.

The compounds of the invention are also useful as analgesics and potentiate the action of morphine. They can be used in combination with morphine and other opioids to treat severe pain, such as cancer pain, and to reduce the dose of morphine required to treat pain if there are causes that prevent morphine use.

According to the invention, another use of the compounds of is that the suitable radiolabeled isotope gives an agent which is suitable for treating gastrin-20-dependent tumors such as those found in colonic cancers. 125 I-radiolabelled compounds of the invention can also be used as diagnostic agents by localizing gastrin and CCK-B receptors in both peripheral and central tissue.

: 25 * ·· In a method for reducing appetite in mammals, such as: v. a mammal in need of treatment is provided with an effective amount of a compound as described above to suppress appetite.

The pharmaceutical composition for reducing gastric acid secretion contains an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective to reduce gastric acid secretion.

, ···. 35

»I

In a method of reducing gastric acid secretion in a mammal: A mammal in need of such treatment is provided with 6,109,689 an effective amount of a composition described above for reducing gastric acid secretion.

The anxiolytic pharmaceutical composition contains an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in an effective unit dosage form for the alleviation of anxiety.

A method of alleviating anxiety in a mammal comprises administering to a mammal in need of such treatment an effective amount of a composition as described above.

The pharmaceutical composition for treating gastric ulcers comprises an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in an effective unit dosage form for treating gastric ulcers.

A method of treating gastric ulcers in a mammal comprises administering to a mammal in need of such treatment an effective amount of a composition as described above.

A pharmaceutical composition for treating psychosis comprises an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier in an effective unit dosage form for treating psychosis, ie schizophrenia.

In a method of treating mammalian psychosis, a mammal in need of such treatment is provided with a treatment for psychosis; an effective amount of the composition described above.

The compounds prepared according to the invention may be. 35 produces pharmaceutical compositions effective to stimulate or block CCK or gastrin receptors, alter brain neuronal activity, schizophrenia, treat extrapyramidal motor system disorders, inhibit trophic and growth inhibitory effects of CCK and gastrin; as well as pharmaceutical compositions for preventing withdrawal symptoms caused by chronic treatment of drug or alcohol abuse.

In a method of treating withdrawal symptoms caused by withdrawal from chronic therapy or withdrawal from medication or alcohol abuse, the withdrawal symptoms are treated by administering an effective amount of a compound of the invention for the treatment of withdrawal symptoms. Such drugs include e.g. benzodiazepines, especially diazole-15, cocaine, alcohol and nicotine.

The pharmaceutical composition for treating panic comprises an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in an effective unit dosage form for the treatment and / or prophylaxis of panic.

In a method for treating panic mammals and / or eh-; for treating and / or preventing panic disorder, a mammal in need of such treatment is provided with an effective amount of the above-described composition.

. ·. The compounds of formula I may be used in the preparation of pharmaceutical and diagnostic compositions for the treatment and diagnosis of the conditions described above.

* · * · · ...: The absolute oral bioavailability of a compound of formula I and its pharmaceutically acceptable salts is 30% in rats. This bioavailability is * * * substantially higher than other dipeptide-type »* *: CCK-B antagonists.

• · δ 109689

Detailed description

The compounds of the invention are those of formula IA: CH5f

And their pharmaceutically acceptable salts. Also included are all solvates and hydrates of the compounds. These compounds have several chiral centers. In particular, the compounds exist as diastereomers, mixtures of diastereomers, or as mixed or single optical enantiomers. The present invention contemplates all such forms of the compounds. Mixtures of diastereomers are typically obtained as a result of the reactions described more fully below. The individual diastereomers may be separated; V of mixtures of diastereomers by conventional techniques such as column chromatography, HPLC, or repeated ··· recrystallization. The individual enantiomers may be · · isolated by conventional techniques well known in the art, such as desalting with an optically active compound, followed by chromatography, or • recrystallization and subsequent conversion to # non-salt form. Alternatively, they may be synthesized. "da using enantiomerically pure trans- (S, S) -2-aminocyclohexanol and trans- (R, R) -2-aminocyclohexanol prepared as shown in Scheme I (see. al., J. Org. Chem. 50: 4154, 1985; also i.a .; Aube J. et al., Syn. Comm. 22 (20): 3003, 1992).

I> · · I

9 109689 for coupling trans- (S, S) -2-aminocyclohexanol with R-2-Adoc-α-methyl-Trp using a coupling reagent such as DCC, HOBt gave the compound of Example 6.

5 Scheme I

Me3Al / CH2Cl2 / ^ 011 H / iJ + -► +

10 H3C Ph 0 * C

'' J M

'H3C ^ Ph H3C <^ Ph A 1: 1 §

15 OH

Pd / C DCC / HOBt / EtOAc * 1 * Example 6 NH / COO- (H) -2-AdoC-α-Me-Trp 80% 83% 20

The individual substituted α-amino acid starting materials are generally known or, if not known, can be synthesized and, if desired, resolved by techniques known in the art. (Synthesis of racemic [DL] -α-methyltrypto-: 25 phane methyl ester - see Brafia, M.

··· F. et al., J. Heterocyclic Chem., 1980, 17: 829.) *> · · I »a I I«,. One key intermediate in the preparation of compounds of formula I is the compound of formula II.

["CO. II

t · a

ROCONH f '' 'COOH

:: 35 Me ♦ a · »a t * a • a a

t M I

Wherein R is 9-fluorenylmethyl, Bz or any other suitable N-group blocking group. These are useful as intermediates in the preparation of compounds of formula I. Compounds in which R is 1-adamantyl, 2-adamantyl, 4-protoad-5-mantyl, exobornyl, endobornyl, exo-norbornyl, endo-norbornyl, 2-methylcyclohexyl, 2-chlorocyclohexyl or camphoryl are novel and inexpensive.

The technique disclosed in U.S. Patent 4,757,151 is hereby incorporated by reference. It describes a 9-fluorenylmethyl-blocking group.

Compounds of formula II are prepared by reacting a compound of formula III 15

ROH III

wherein R is as defined above, by reaction with phosgene or a phosgene substituent to form the corresponding compound of formula IV 20

R0C0C1 IV

*: and then reacting a compound of formula IV with 25? -methyltryptophan to give the desired compound of formula II above.

> »·»

Alternatively, the compound of formula IV may be reacted with an α-methyltryptophan methyl ester to form a compound of formula V i H.

3 (CO

35.

! · * ·! ROCONH COOMe, \ Me t | · * »I t» brick 11 109689 which can be converted to the compound of formula II by known methods such as hydrolysis with aqueous lithium hydroxide.

The compound of formula I has an absolute bioavailability of 30%. It is therefore unique in the field of CCK-selective dipeptides.

Single doses of 20 mg / kg of compound were administered intravenously by gavage 10 or 20 mg / kg intravenously to fasted male Wistar rats (four modes of administration). For both modes of administration, the drug was administered as a solution of the compound in 0.1 N HCl ethanol: 50% w / v hydroxypropyl-β-cyclodextrin in normal saline (30:70). Blood samples were collected from the carotid vein cannulas prior to dosing and at various times up to 24 hours after dosing. Plasma was collected from blood by centrifugation and stored frozen until analysis. The compound was analyzed on plas-20 samples using a validated liquid chromatography method. The method involves the compound and an internal standard, carbamic acid, (R) - [2 - [(hexahydro-1H-azepin-1-yl) amino] -1- (1H-indol-3-ylmethyl) -1-methyl-2 Liquid extraction of .. oxoethyl], tricyclo [3.3.1.13'7] dec-2-yl ester, liquid chromatographic separation of analytes on a C-18 '···' column and quantitation by fluorescence detection.

»· ♦; The mean (± SD) pharmacokinetic parameters are shown in Table 1. Compound plasma concentrations were decreased; Following intravenous administration, a rapidly multiexponentially harmonic mean terminal elimination half-life of 0.87 (± 0.02) hours was observed. Dir. * ·. Following oral administration, absorption was generally rapid, as evidenced by a mean (± SD) tmax: 35 value of 1.8 (± 1.6) hours. The corresponding mean (± SD) Cmax -... · value was 756 (± 264) ng / ml. The harmonic mean terminal elimination half-life after oral administration of 10,109,689 was 0.99 (± 0.28) hours, which was comparable to the half-life of the intravenously administered dose. The mean (± SD) absolute oral bioavailability, based on the ratio of mean PO (oral 5) to IV (intravenous) AUC (0-∞) was 30 (± 8)%.

Table I. Summary of mean (± SD) pharmacokinetic parameters of Compound 6 in fasted male Wistar rats after a single 20 mg / kg oral (PO) or intravenous (IV) dose

Method of delivery 15 Parameter -

IV PO

N 4 4

Dose 20 20 20 Cmax - 756 (± 264) tmax - 1.8 (± 1.6) t% 0.87 (± 0.02) 0.99 (± 0.28) AUC (0-tldc) 7220 ( ± 1630) 2130 (± 257) AUC (O-oo) 7230 (± 1630) 2160 (± 268) 25% F - 30 (± 8)

Dose = mg / kg

Cmax = Maximum observed plasma drug concentration (ng / ml).

30 tmax = time to Cmax; (Hours).

t% = Terminal half-life, harmonic mean (hours).

<·· AUC (O-tldc) = Plasma concentration versus time curve '· *; 35 area from time zero to last detectable; but to a concentration (ng * hour / ml).

AUC (0-o0) = area under the plasma concentration-time curve from time to time zero to infinite '·' '(ng hour / ml).

40% F = Absolute bioavailability based on the ratio of mean PO and IV-AUC (0-∞).

The absorption of the compound in rats after oral administration of * · ·> 45 was generally rapid. The absolute oral bioavailability was 30%.

• · »13 109689

For the preparation of pharmaceutical compositions from the compounds of this invention, the inert, pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations 5 include: powders, tablets, dispersible granules, capsules, cachets and suppositories.

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

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

For the preparation of suppository preparations, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein, for example by mixing. Then thaw. . the homogeneous mixture is poured into molds of suitable size, allowed to cool and solidify.

The powders and tablets preferably contain from 5% to about 70% of the active ingredient. Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter and the like.

Preferred pharmaceutically acceptable salts are the N-1 · 1 · 35 methylglucamine salt and the sodium salt.

1 · i »14 109689

Pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bi-tartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucapta , Hexyl resorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Malate, Maleate, Mandelate, Mesy-10 Plate, Methyl Bromide, Methyl Nitrate, Methyl Sulfate, , pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, nolumin, , magnesium, potassium, sodium and zinc salts.

The term "preparation" is intended to include the formulation of the active component with the carrier encapsulating material to provide a capsule containing the active component (with or without other carriers). . is surrounded by a bearer who is thus in contact with it. The law includes the cachets.

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

T: 30

Liquid form preparations include e.g. solutions, suspensions and emulsions. Sterile water or water sterile active compounds. ···. propylene glycol solutions may be mentioned as one example of a liquid preparation suitable for parenteral administration. Liquid preparations may also be formulated as a solution in an aqueous solution of polyethylene glycol.

I · »15 109689

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired. Aqueous suspensions for oral administration may be prepared by dispersing the finely divided active component in water with a suspension of a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and others known in the pharmaceutical formulating art.

The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing a certain amount of preparation, for example packaged tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule (capsule), capsule (cachet), or tablet itself, or it can be the appropriate number of any of these packaged forms.

Examples. , Example 1 ; 25 Carbamic acid, N- [2 - [(2-hydroxycyclohexyl) amino] -1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl] -, tri ··· cyclo [3.3.1.13 , 7] dec-2-yl ester, [Ia (R), 2β]

The title compound was synthesized by coupling trans-2-aminocyclic:: 30ohexanol with (R) -2-adamantyloxycarbonyl-2-methyltryptophan using DCC and HOBt.

Elemental Analysis for: C29H39N3O4 * 0.5H2O · ···. Calculated: C, 69.29; H, 8.02; N, 8.35.

'·' Found: C, 69.38; H, 8.46; N, 8.00.

i V 35> »k S · 109689 16

Examples 2 and 3

Carbamic acid, [2 - [(2-hydroxycyclohexyl) amino] -1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl] tricyclo [3.3.1. 13,7] dec-2-yl ester Isomer 15 The TRP center is R; tire center unknown

Carbamic acid, [2 - [(2-hydroxycyclohexyl) amino] -1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl] tricyclo [3.3.1. 13,7] dec-2-yl ester Isomer 2 The TRP center is R; another center unknown

The individual diastereomers of Example 1 were separated by Waters-HPLC (Model 46K) using a 6 μιη silica gel column (Prep Nova Pak®). The mobile phase was ethyl acetate-hex-15 (60:40) and the flow rate was 15 ml / min. The retention time of the first diastereomer (Example 2) (m.p. 130-137 ° C) was 11.92 min. The retention time of the second diastereomer (Example 3) (mp 125-130 ° C) was 13.87 min.

Example 4 (1S, 2S) -trans-2 - [(R) - (α-Methyl-benzyl) -amino] -cyclohexanol (A) and (1R, 2R) -trans-2 - [(R) - (a) -methylbenzyl) -amino-cyclohexanol (B)

To a well-stirred solution of (R) -α-methylbenzylamine (6.06 g, 0.005 mmol) in methylene chloride (60 mL) / Me3Al (27.5 mL, 2.0 M) was added dropwise

A solution in toluene (0.055 mol) at 0-5 ° C. The resulting solution was stirred for an additional 45 min at 0 ° C and then a solution of cyclohexene epoxide in methylene chloride (15 mL) was added dropwise at 0 ° C. The reaction mixture was stirred overnight at room temperature. Aluminaat-, ··. the distillate salt was decomposed at 0 ° C by addition of NaF (8.82 g, * 0.21 mol) followed by 6.0 ml of H 2 O. After stirring at room temperature for 1 hour, the reaction mixture was passed through celite, dried over MgSO 4, and concentrated.

»·» I | *

• I

17 109689

Flash column chromatography (ethyl acetate / hexane / E-t3N 1: 1: 0.1) gave Compound A (4.5 g, 39.2% Rf = 0.5) in the first fraction and Compound B (4.5 g). , 39.2%

Rf = 0.32) in the later fraction.

5

Example 5 (1S, 2S) -trans-2-aminocyclohexanol

A mixture of (1S, 2S) -trans-2 - [(R) - (? -Methyl-benzyl-10I) -amino] -cyclohexanol (2.2 g, 0.01 mol) in 10% Pd / C and ammonium formate (0.38 g, 0.06 mol) in methanol (75 mL) were stirred overnight at room temperature. The reaction mixture was passed through celite and concentrated. The residue was then diluted with ethyl acetate, washed with water, dried and concentrated to give 0.92 g (80%) of the title compound.

Example 6

Tricyclo [3.3.1. 1,3,7] dec-2-yl ester- [1S- [1α (S *) 2β] [2 - [(2-20 hydroxycyclohexyl) amino] -1- (1H-indol-3-ylmethyl) -1- methyl-2-oxoethyl] carbamate

A solution of (R) -2-adamantyloxycarbonyl-α-methyl-litryptophan (0.79 g, 0.002 mol) in ethyl acetate (60 ml) was treated with dicyclohexylcarbodiimide (0.495 g, 0.002 mol) and 1-hydroxybenzotriazole hydrate (0 , 35 g, 0.0022 mol). After stirring for 2 hours at room temperature, the precipitated dicyclohexylurea was removed by filtration. To the clear filtrate was added (IS, 2S) -trans-2-30 aminocyclohexanol (0.23 g, 0.002 mol). The reaction mixture was stirred at room temperature overnight. The ethyl acetate solution was washed with 5% HCl, 5% NaHCO 3 and brine, = ···. la. The organic phase was dried over MgSO 4 and concentrated to give a white foam. The crude product chroma: 35 was chromatographed on silica gel using 50% ethyl acetate / hexane to give 0.72 g of a white solid, which was further purified by Waters-HPLC (model 18 109689 46K) using a 6 μτα silica gel column (Prep Nova Pak). . The mobile phase was ethyl acetate / hexane (1: 1), flow rate 15 ml / min and retention time 9.54 min. 0.4 g (39.5%) of the title compound was obtained, m.p. 137-142 ° C.

5

Elemental Analysis for C29H39N30:

Calculated: C, 70.56; H, 7.96; N, 8.51.

Found: C, 70.76; H, 8.31; N, 7.94.

Claims (2)

19 109689 Claim Process for the therapeutically active tricyclo [3.3.1.1.3.7] dec-2-yl ester [IS- [1α (S *) 2 β] [2 - [(2-hydroxy-5-cyclohexyl) amino] - 1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl] carbamate or a pharmaceutically acceptable salt thereof, characterized in that (R) -2-adamantyloxycarbonyl-α-methyltryptophan is treated with a coupling reagent such as dicyclohexylcarbodi followed by the addition of (1S, 2S) -trans-2-aminocyclohexanol and optionally converting the resulting compound to a pharmaceutically acceptable salt thereof. Tricyclo [3.3.1.1.3.7] dec-2-ylester [IS- [la (S *) 2β] [2 - [(2-hydroxycyclohexyl) amino] - 1- (1H-Indol-3-ylmethyl) -1-methyl-2-20 oxoethyl] carbamate moiety, pharmaceutically acceptable, tetravalent, att (R) -2-adamantyloxycarbonyl-α-methyltryptophan behaving drug, copolymer dicyclohexylcarbodiimide and 1-hydroxybenzotriazolhydrate, varefter man tillate (IS, 2S) -trans-2-aminocyclohexanol! 25 och valfritt omvandlar den erhällna föreningen account sitt ·· *; * f armaceutiskt godtagbara sait. «·« · »* ·