MXPA98010090A - Non-peptide bombesin receptor antagonists - Google Patents

Non-peptide bombesin receptor antagonists

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Publication number
MXPA98010090A
MXPA98010090A MXPA/A/1998/010090A MX9810090A MXPA98010090A MX PA98010090 A MXPA98010090 A MX PA98010090A MX 9810090 A MX9810090 A MX 9810090A MX PA98010090 A MXPA98010090 A MX PA98010090A
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Mexico
Prior art keywords
phenyl
methyl
ureido
propionamide
diisopropyl
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Application number
MXPA/A/1998/010090A
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Spanish (es)
Inventor
Clive Pritchard Martyn
Christopher Horwell David
Original Assignee
Christopher Horwell David
Clive Pritchard Martyn
Warnerlambert Company
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Application filed by Christopher Horwell David, Clive Pritchard Martyn, Warnerlambert Company filed Critical Christopher Horwell David
Publication of MXPA98010090A publication Critical patent/MXPA98010090A/en

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Abstract

Compounds of Formula (I) or a pharmaceutically acceptable salt thereof wherein Ar is phenyl or pyridyl unsubstituted or substituted. Ar1 can be independently selected from Ar and can also include pyridyl-N-oxide, indolyl, imidazole, and pyridyl;R3 can be independently selected from Ar or is hydrogen, hydroxy, NMe2, N-methyl-pyrrole, imidazole, tetrazole, thiazole (a), (b), (c) or (d), wherein Ar2 is phenyl or pyridyl. The compounds of the instant invention are novel compounds which antagonize the bombesin receptors in mammals and are therefore effective in treating and/or preventing depression, psychoses, seasonal affective disorders, cancer, feeding disorders, gastrointestinal disorders, inflammatory bowel disease, sleep disorders, and memory impairment.

Description

NON-PEPTIDE ANTAGONISTS OF THE BOMBESIN RECEPTOR BACKGROUND OF THE INVENTION Bombesin is a 14 amino acid peptide originally isolated from the skin of the European frog Bombina bombina (Anastasi A., et al., Experientia, 1971; 27: 166). It belongs to a class of peptides which share structural homology in their C-terminal decapeptide region (Dutta A. S., Small Peptides, Chemistry, Biology and Clinical Studies, Chapter 2, pp. 66-82). Currently, two peptides similar to bombesin have been identified (Battey J., et al., TESTS, 1991; 14: 524), the neuromedin B decapeptide (NMB) and a 23 residue amino acid, the peptide that releases gastrin (GRP). . Immunoreactivity similar to bombesin detected in mammalian brains (Braun M., et al., Life, Sci., 1978; 23: 2721) and the gastrointestinal tract (Walsh JH et al., Fed. Proc. Fed. Am. Soc. Exp. Biol., 1979; 38: 2315) together with the most recent studies that measure mRNA levels in the rat brain (Battey J., et al., TESTS, 1991; 14: 524), points to the wide distribution of NMB and GRP in the central and peripheral nervous system of mammals.
It is believed that NMB and GRP are involved in a variety of biological actions by acting on the corresponding bombesin receptors including their action as autocrine growth factors in small cell carcinoma of human lung and other cancers (Taylor JE, et al. , Ann. NY Acad. Sci., 1988; 547: 350; Rozengurt E., Ibid., 277; Cuttitta F., et al., Nature, 1985; 316: 823; Kozacko MF Et al., Proc. Nati. Acad Sci. United States, 1996; 93: 2953), secretion of other neuropeptides and hormones (Ghatei MA Et al., J. Clin Endocrinol Metab., 1982; 54: 980), smooth muscle contraction (Erspamer V ., et al., Pure Appl. Chem., 1973; 35: 463), behavioral effects (Kulkosky PJ et al., Physiol. Behav., 1982; 28: 505; Gmerek DE Et al., Peptides, 1983; 4: 907; Cowan A., Ann., NY Acad. Sci., 1988; 547: 204), thermoregulation (Brown MR.
Et al., Ann. N. Y. Acad. Sci., 1988; 547: 174), effects on satiety (Kiekham T. C. et al., Pharma. Biochem. Behav. , nineteen ninety five; 52: 101 and Ladenheim E. E. Et al., Eur. J. Pharmacol., 1994; 271: R7), circadian rhythm regulation (Afers H., et al., J. Neurosci., 1991; 11: 846), regulation of gastric acid secretion (Walsh J. H., Ann. Rev. Physiol., 1988; 50: 41) and gastrointestinal motility (see Lebacq-Verheyden A., et al., In Manual Experimental Pharmacology, 1990; 95 (Part II) and references therein), effects on locomotor activity and nociception (Pert A., et al., Brain Res., 1980; 193: 209), effects on memory (Flood JF, et al. , Brain Res., 1988; 460: 314) and interaction with neurons containing 5HT (Pinnock RD, et al., Brain Res., 1994; 653: 199 and Pinnock RD, et al., J. Physio., 1991; 440: 55).
Therefore, compounds capable of antagonizing the effects of NMB and / or GRP on bombesin receptors will be useful in the treatment or prevention of a variety of disorders including depression, psychosis, temporary affective disorders, cancer, eating disorders, disorders. gastrointestinal including colitis, Crohn's disease and inflammatory bowel disease, sleep disorders and memory failures.
SUMMARY OF THE INVENTION This invention is for compounds that are antagonists of the bombesin receptor. The compounds have proven to be antagonists of bombesin receptors.
The compounds of the invention are those of Formula I: or a pharmaceutically acceptable salt thereof, wherein: Ar is phenyl or pyridyl unsubstituted or substituted by 1 to 3 substituents selected from alkyl, halogen, alkoxy, nitro, amino, NH2CH2 -, cyano, CF3, - NHCONH2 and CO2R1; R1 is hydrogen or a linear or branched cyclic alkyl of 1 to 7 carbon atoms; R8 is hydrogen or forms a chain with R1 of 3 to 7 carbon atoms; R2 is hydrogen or a straight or branched cyclic alkyl of 1 to 7 carbon atoms with R2 which may contain an oxygen or nitrogen atom; Ar 1 can be independently selected from Ar and also includes pyridyl-N-oxide, indolyl, imidazole and pyridyl; R4, R5, R6 and R7 are each independently selected from hydrogen and methyl; R3 can be independently selected from Ar or is hydrogen, hydroxy, Nme2, N-methyl-pyrrole, imidazole, tetrazole, thiazole, where Ar2 is phenyl or pyridyl.
DETAILED DESCRIPTION The compounds of the invention are those of the Formula I above.
The preferred compounds are those of Formula 1: wherein: Ar is phenyl unsubstituted or substituted with 1 or 2 substituents selected from isopropyl, chloro, nitro and cyano; R4, R5 and R6 are hydrogen; R7 is methyl or hydrogen; R3 is 2-pyridyl or hydroxy; and Ar1 is indolyl, pyridyl, pyridyl-N-oxide and imidazole.
Other preferred compounds are those of Formula I where: Ar is unsubstituted phenyl; R1 is cyclopentyl or tert -butyl; R4 and R5 are hydrogen; R7 is methyl; R6 is hydrogen; R3 is phenyl with two isopropyl substituents, unsubstituted phenyl or ; and Ar is indolil.
Other preferred compounds are those of Formula I wherein: Ar is 2,6-diisopropyl-phenyl, 4-nitro-phenyl and 4-cyano-phenyl; R4, R5 and R6 are hydrogen; R7 is methyl; R2 is hydrogen or cyclohexyl; and R3 is hydroxyl, pyridyl, The most preferred compounds are selected from: N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (lH-indole -3-yl) -2-methyl-propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (lH-indole -3-yl) -N-methyl-propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -1-methyl-ureido] -3- (ÍH-indol-3-yl) -propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -2-methyl-3 - (1-oxy-pyridin-2-yl) - N - (1-pyridin-2-yl-cyclohexylmethyl) - propionamide; 2 - . 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -2-methyl-3-pyridin-2-yl-N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide; 2 - [3 - (2-tert-butyl-phenyl) -ureido] - N -cyclohexylmethyl-3 - (IIH-indole-3 • - il) - 2-methyl-propionamide; 5 N-cyclohexylmethyl-2 - [3 - (2,6-dichloro-phenyl) -ureido] -3- (1H-indole-3 - il) -2-methyl-propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-dimethoxy-phenyl) -ureido] -3- (ÍH-indol-3-yl) -2-methyl-propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-dimethylamino-phenyl) -ureido] -3- (ÍH-10 indol-3-yl) -2-methyl-propionamide; M [1- (cyclohexylmethyl-carbamoyl) -2 - (1H-indol-3-yl) -1-methyl-ethyl] -carbamic acid, 4-nitro-benzyl ester; N-cyclohexylmethyl-2 - [3 - (2, 2-dimethyl-1-phenyl) propyl) -ureido] - 3 - (1H) - indol-3-yl) -2-methyl-propionamide; 15 Acid. { 2 - (ÍH-indol-3-yl) -1-methyl-1 - [(1-pyridin-2-yl-cyclohexylmethyl) -carbamoyl] -ethyl} - carbamic, 3-nitro-benzyl ester; N - (2, 2, - dimethyl-4-phenyl- [1, 3] dioxan-5-yl) -3 - (ÍH-indol-3-yl) -2 - methyl-2 - [3 - (1-phenyl-cyclopentylmethyl) -ureido] -propionamide; (S) - N - (2,6-diisopropyl-phenyl) -2 - [3 - (2, 2, - dimethyl-1-phenyl-propyl) -20-ureido] -3- (IIH-indol-3-yl) ) - propionamide; (R) - N - (2,6-diisopropyl-phenyl) -2- [3 - (2, 2, -dimethyl-1-phenyl-propyl) -ureido] -3- (lH-indol-3-yl) - propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] - N - (2, 2, - dimethyl-4-phenyl- [1,3] dioxan-4-l) -3- (lH-indole -3-yl) -2-methyl-propionamide; N-cyclohexyl-2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (ÍH-indol-3-yl) -2-methyl-propionamide; N - (2-cyclohexyl-ethyl) -2- [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (lH-indol-3-yl) -2-methyl-propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (ÍH-indol-3-yl) -2-methyl-propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (ÍH-indol-3-yl) -2-methyl-N- (3-methyl-butyl) -propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (ÍH-indol-3-yl) -2-methyl-N- (3-phenyl-propyl) -propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl-N- (1, 2, 3, 4-tetrahydro-naphthalene-1) - il) - propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (ÍH-indol-3-yl) -2-methyl-N- (2-phenyl-cyclohexyl) -propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -N-indan-1-yl-3 - (lH-indol-3-yl) -2-methyl-propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] - N - (1-hydroxy-cyclohexylmethyl) -3 - (ÍH-indol-3-yl) -2-methyl-propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (ÍH-indol-3-yl) -2-methyl-N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide; and 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl-N- (6,7,8,9-tetrahydro-5H- benzocyclohepten-5-yl) - propionamide The compounds of the invention include solvates, hydrates, pharmaceutically acceptable salts and polymorphs (different crystalline lattice descriptors) of the compounds of Formula I.
The pharmaceutical compounds of the compounds of the invention are also covered by the present invention.
The method for using the compounds of the present invention are antagonists of the effect of neuromedin B and / or the peptide of gastric release in the bombesin receptors. Other treatments are temporary affective disorders of depression, eating disorders, gastrointestinal disorders, sleep disorders, memory failure, treatment of psychosis and treatment of cancer, for example, treatment of small cell lung cancer.
The compounds of the invention are those for Formula I and pharmaceutically acceptable salts thereof. All stereoisomers of the compounds are included within the scope of the invention.
The prodrugs of the foregoing are also contemplated as would occur to one with skill in the art, see Bundgaar, et al., Acta Pharm. Suec, 1987; 24: 233-246.
The alkyl groups contemplated by the invention include linear, branched or cyclic carbon chains of 1 to 8 carbon atoms, except where otherwise specifically stated. Representative groups are methyl ethyl, propyl, isopropyl, n-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl, 2, 2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
^^ The cycloalkyl groups contemplated by the invention, comprise those which have from 3 to 7 carbon atoms. These can be substituted with 1 to 3 groups selected from halogens, nitro, alkyl and alkoxy.
The alkoxy groups contemplated by the invention comprise linear and branched carbon chains of 1 to 6 carbon atoms unless otherwise stated. 10 The representative groups are methoxy, ethoxy, propoxy, i-propoxy, t-butoxy and hexoxy.
The term "halogen" is intended to include fluoro, chloro, bromo and iodo.
The term "Ar" is intended to include substituted or unsubstituted phenyl. The 15 substituents include one or more substituents such as halogens, nitro, alkyl, alkoxy and others as specified or would occur to someone with skill in the art.
• The term "amine" is free amino, alkylated amines and acylated amines.
The compounds of the present invention are highly selective antagonists of bombesin receptors.
To prepare pharmaceutical compositions of the compounds of this invention, the pharmaceutically acceptable, inert carriers can be solid or liquid. Solid form preparations include powders, tablets, dissolving granules, capsules, caches and suppositories.
A solid carrier can be one or more substances that also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablets of disintegrating agents; It can also be an encapsulation material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active compound is mixed with the carrier having the necessary binding properties in appropriate proportions and compacted in the desired shape and size.
To make suppository preparations, a low-melting wax is first melted as a mixture of fatty acid glycerides and cocoa butter and the active compound is dispersed therein, for example, by stirring. The homogenously melted mixture is poured onto molds of suitable size and allowed to cool and solidify.
The powders and tablets preferably contain from 5% to 70% of the active compound.
Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter and the like.
The compounds of the present invention can have multiple chiral centers in the above Formula I depending on their structures. In particular, the compounds of the present invention can exist as diastereomers, mixtures of diastereomers or as the mixture of individual optical enantiomers. The present invention contemplates all these forms of the compounds. Mixtures of diastereomers are typically obtained as a result of the reactions described more fully below. Individual diastereomers can be separated from mixtures of diastereomers by conventional techniques such as column chromatography or repetitive recrystallizations. The individual enantiomers can be separated by conventional methods well known in the art such as conversions to salts with an optically active compound, followed by separation by chromatography or recrystallization and conversion to the non-salt form.
Where it is suitable to form a salt, the pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisilate, estolate, esylate, fumarate, gluceptate, gluconate, glucoloilarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methyl bromide, methylnitrate, methyl sulfate, mucate, nipsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
Cyclodextrin is an appropriate inclusion in a pharmaceutical preparation.
The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier that supplies a capsule in which the active compound (with or without other carriers) is surrounded by a carrier which is in turn associated with said active compound. Similarly, cachets are included.
Tablets, powders, cachets and capsules can be used as a solid dosage form suitable for oral administration. The liquid form preparations include solutions, suspensions and emulsions.
Solutions with sterile water or water-propylene glycol of the active compounds can be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid preparations can also be formulated in 15 solutions in aqueous solution of the polyethylene glycol.
Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable colorants, flavoring agents, stabilizers and thickening agents as desired. Aqueous suspensions for oral use can be made by dissolving the finely divided active compound in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and other suspending agents known in the pharmaceutical formulating art.
Preferably, the pharmaceutical preparations are in individual dosage form. In such form, the preparation is divided into individual doses containing appropriate amounts of the active compound. The individual dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packed tablets, capsules and powders in vials or ampules, the individual dosage form can also be a capsule, cachet or tablet itself , or it may be the appropriate number of any of these packaged forms.
The compounds of the invention have been evaluated in receptor binding experiments which measure the affinity to the new compounds in a human-homed NMB-preferred receptor (BB.) Experiment and in a human-cloned GRP-preferred receptor experiment (BB2). ).
Protocol for the Linkage Experiments CHO-K1 cells stably expressing NMB and GRP receptors cloned from humans, are routinely cultured in Ham's F12 culture medium supplemented with 10% fetal calf serum and 2 mM glutamine For binding experiment, cells are harvested by trypsinization and stored frozen at -70 ° C in a Ham F12 culture medium containing 5% DMSO until required. On the day of use, the cells are rapidly thawed, diluted in an abundant culture medium and centrifuged for 5 minutes at 2000 g. Cells are resuspended in 50 mM Tris-HCl experiment buffer (pH 7.4 at 21 ° C, containing 0.02% BSA, 40 μg mL bacitracin, 2 μg / mL chemostatin, 4 μg / mL leupeptin and 2 μM of phosphoramidon), counted and polytomed (placed at 5 and 10 seconds) before centrifuging for 10 minutes at 28,000 g. The final pill is resuspended in an experiment regulator at a final cell concentration of 1.5 x 105 / mL. For binding experiments, 200 μL of aliquots of membranes are incubated with [125I] [Tyr4] bombesin (<0.1 nM) in the presence and absence of test compounds (final volume of the 250 experiment ^ μL) for 60 and 90 minutes for the NMB and GRP receptors, respectively. He Non-specific binding is defined by 1 μM of bombesin. The experiments are determined by rapid filtration under vacuum on GF / C Whatman filters previously soaked in PEI at 0. 2% for more than 2 hours, and washed with 50 mM Tris-HCl (pH 6.9 at 21 ° C, 6 x 1 mL). The radioactivity link is determined using a gamma counter. See Table 1.
The compounds of the invention have been tested in functional experiments in? vitro using receptors that prefer NMB cloned from human, expressed in CHO cells.
Protocols for functional experiments: 15 1. Measurement of intracellular calcium levels Culture of Chinese hamster ovarian cells. The Chinese hamster ovarian cells are routinely grown in a Ham F12 nutrient mixture supplemented with 10% FBS and 2 mM glutamine and maintained at 37 ° C under 5% C02. The cells move every 3 or 4 days. Each time they move, the cells are seeded at a density of 3 to 6 million per bottle of 175 cm2. For imaging experiments, the cells are plated on sliding glass covers at a density of 5 to 10,000 / cm2 and are usually used within 2 to 3 days after they are placed on the plates. 25 ~. .
Studies of [Ca2 + | in cells alone. The cells are incubated in plaque with 2 μM of Fura-2-AM between 45 and 120 minutes at 25 ° to 29 ° C. This procedure charges the cells with the ink that is hydrolysed to the free acid form within the cells intact The sliding cover alone is mounted on a camera on top of an inverted fluorescence microscope and is flooded with a Brebs-Hepes experiment regulator (composition in mM: NaCl 118, KCl 4.7, MgSO4 1.2, CaCk 1.2, Hepes 10, glucose 11, pH 7.2 at 37 ° C). { 332.}. .
The measurement of [Ca2 +]? in individual cells is made from the proportion of fluorescence (340/380 excitation, emission> 510 nM for Fura-2) using a specially designed filter wheel assembly, CCD camera or photomultiplier tubes, and specially designed software programs (MAGICAL OR focal, Applied Imaging, Sunderland, United Kingdom), whose emission of samples after excitation at different wavelengths at regular intervals. The [Ca2 +] _ could be calculate from a calibration curve using the equation [Ca2 +] = Kd * ß ((R - Rmin) / (Rmax - R)) where Rmax, Rmin and R are, respectively, the maximum proportion, the proportion? minimum and the proportion measured at? lower /? higher. Rmax (14.5), Rmin (0.75) and ß (8.51) are determined from free standing solutions of 2 mM and zero [Ca2 +] 0 (+1 mM EGTA) in a Hepes buffer as previously described. { 458,457} . This values do not vary significantly from day to day. The information is displayed in emission ratio values after excitation a? lower and? higher (ie, 340/380 nM) due to the uncertainty in cytosolic calculations of [Ca2 +] of a calibration curve determined in free-standing solutions. The relative concentration of the interior Fura-2 cells during the course of an experiment is monitored by measuring the emission after excitation at the isobestic point of ink (360 nM). 2. Measurement of extracellular acidification (CYTOSENSOR) It has been demonstrated that the Cytocenter Microfisiómetro (Molecular Devices Corp., California, United States) measures the activity of isolated cells in terms of their range of hydrogen ion production. This range of acidification is detected as a change in the potential crossing of a light sensor directed to silicon, during periods of medium cessation (McConnell, et al., 1992).
The CHO-NMB cells seeded in cups of polycarbonate micropore capsules are placed in sensor chambers at 37 ° C inside the microphysiometer and are maintained by a flow of Ham's F12 nutrient medium without regulator (growth medium without NaHC? 3, pH 7.3-7.4) at about 120 μL / min. The flow stops for 22 seconds at the end of each repeated cycle of 2 minutes, and the acidification range (μ volts / sec) is measured for 15 seconds in that period.
The agonists are introduced sequentially every 28 to 30 minutes into the flood medium, 20 seconds before the periods in which the flow is removed, and it is removed after two proportional measures by means of the automatic circuit breaker of the valve.
The effects of several antagonists after flooding continues 30 minutes before, and during the application of the agonists. All the agents were applied at the working pH of the medium.
TABLE 1. Link Affinities of the NMB and Human GRP Receptors.
* IA is defined as those compounds that bind to those that are less than 10 in micromolar affinity to the receptor.
TABLE 2. In Vitro Functional Activity of the Compounds in the Receptor that Prefer NMB (BB, 1) The General Synthetic Schemes for the compounds of the invention are presented below.
DESCRIPTION OF SYNTHETIC SCHEMATICS Scheme I describes the synthesis of C-terminal derivatives. Examples 1 to 6. Intermediate I is prepared by the addition of 2,6-diisopropyl phenyl isocyanate aa-methyl Trp in DMF at 100 ° C. The linkage of Intermediate I to a selection of amines using HBTU and DIPEA in DMF forms the Examples 1 to 6.
Scheme II indicates the synthesis of Example 7. The addition of 2,6-diisopropyl phenyl isocyanate to (RS) -tryptophan in DMF at 100 ° C provides Intermediate IV. This is then linked to N-methyl cyclohexyl methylamine using HBTU and DIPEA in DMF to give Example 7.
In Scheme III the intermediate acid V is prepared after the addition of p-nitrophenyl isocyanate to (S) -α-methyl tryptophan in DMF at 60 ° C. The subsequent binding of intermediate acid V to cyclohexyl methyl amine and cyclohexan-1 - ol methyl amine using HBTU and DIPEA in DMF produces Examples 8 and 9, respectively.
Scheme IV highlights the preparation of Example 10. The initial addition of 2,6-diisopropyl phenyl isocyanate to (RS) -N-methyl tryptophan in DMF at 50 ° C forms intermediate acid VI which is subsequently linked to cyclohexyl methyl amine to give Example 10.
In Scheme V, the intermediate acid VTI is prepared after the addition of Boc20 to (S) -α-methyl tryptophan in dioxane / water in the presence of NaHCO 3. The linkage of this intermediate to either cyclohexyl methyl amine or 1- (2-pyridyl) -1-aminomethyl cyclohexane (Intermediate II) in the presence of HBTU, DIPEA or DCC, PFP, produces the required intermediate VIII. Deprotection of the Boc group using TFA in CH2C12 followed by the binding of the revealed amine to a selection of isocyanates in THF provides Examples 11 to 17.
Scheme VI describes the preparation of Example 18. Intermediate X is generated by adding Boc20 in dioxane / water in the presence of NaHCO 3, to (S) -α-methyl tryptophan. The binding of the free carboxylic acid in Intermediate X to 2,6-diisopropyl phenyl amine using HBTU and DIPEA in DMF yields intermediate XI. Subsequent removal of the Boc protecting group using TFA in CH2Cl2 followed by reaction of the revealed amine with (RS) -α-1-butyl benzyl isocyanate in THF, forms Example 18.
In Scheme VII, intermediate acid XIII is prepared by the addition of 2,6-diisopropyl phenyl isocyanate to the amino acid (RS) -α-methyl amino required in DMF at 60 ° C. This intermediate is then bound to 1 - (2) pyridyl) -1-aminomethyl cyclohexane (Intermediate II) using HBTU and DIPEA in DMF to produce Examples 19 to 21. The catalytic hydrogenation of Example 19 forms Example 22.
Scheme VHI indicates the preparation of Example 23. Reaction (RS) -N-trityl-histidine is reacted with 2,6-diisopropyl-phenyl isocyanate in DMF at 60 ° C to provide Intermediate XIV. This acid is then linked to 1- (2-pyridyl) -1-aminomethylcyclohexane (Intermediate II) using HBTU and DIPEA in DMF to give Intermediate XV which is subsequently reacted with formic acid in CH2C12 to give Example 23.
The synthesis of Example 24 is noted in Scheme IX. By reacting p -nitrophenyl chloroformate with (RS) -methyl tryptophan methyl ester, it provides Intermediate XVI reagent which is then added to 2,6-diisopropylphenyl-N-methyl amine in toluene to produce Intermediate XVII. Hydrolysis of the methyl ester using LiOH in MeOH / water gives intermediate XVIII which is then joined with cyclohexyl methyl amine using HBTU and DEPEA in DMF to give Example 24.
In Scheme X, Intermediary XIX is prepared by adding the (S) -phenyl serinol acetonide to (RS) -N-Boc-a-methyl tryptophan using DCC and HOBt in CH2Cl2. Subsequent removal of the N-Boc protecting group using gas HCl in Et20 gives the Intermediary XX which is reacted with 2,6-diisopropyl phenyl isocyanate in EtOAc to give Example 25 after column chromatography.
Intermediate II is prepared after the initial alkylation of pyridine-2-acetonitrile with 1,5-dibromopentane followed by reduction of the nitrile with Raney-nickel.
Intermediate III is prepared by the initial displacement of the alcohol in 2-phenyl cyclohexan-1-ol with azide by the use of DEAD, PPh3, and (PhO) 2PON3 in THF followed by catalytic reduction of the azide to give the amine Intermediate III.
SCHEME 1 1-6 Reagents and conditions: i) 2,6-diisopropyl phenyl isocyanate, triethylamine, DMF, 100 ° C. Ii) HBTU, R, DIPEA, DMF, 20 ° C.
Table for Scheme 1 Example number R RS NHPh I Synthesis of Examples 1 to 6 Step 1 To a stirred solution of a-methyl-tryptophan (1.0 g, 4.6 mmol) in DMF (50 mL) was added 2,6-diisopropyl phenyl isocyanate (1.0 g, 5 mmol) followed of triethylamine (1.4 g, 14 mmol) and the mixture is heated at 100 ° C. for 1 hour. The reaction mixture is allowed to cool to room temperature and placed in EtOAc, washed with IN HCl, saline and dried (MgSO). The solvents are removed in vacuo and the residue triturated with ether to yield Intermediate 1 as a white solid (1.38 g, 71%). 1H NMR (DMSO): d 1.15 (12H, br, 4 x CH3 (Pr)), 1.46 (3H, s, aCHj), 3.26 (3H, br, 2 x CH (Pr), CHH Nature), 3.41 (ÍH, d, 14.1 Hz, (CHH Nature), 6.32 (ÍH, br s, urea NH), 6.96-7.39 (7H, br m, 3 x CH (Ph), Nature H - 2, H - 5, H - 6, H - 7), 7.56 (2H, br, type H - 4, benzyl urea NH), 10.96 (OH, br, NH type), 12.59 (OH, br, OH acid), IR (film): 3357 , 2959, 1704, 1657, 1620, 1526, and 1456 cm1; MS m / e (Cl) 422 (M ++ H) (4%) 204 (100%); Analysis: C25H31N3? 3 • 0.25 H20, C, H, N, melting point: 194 ° -195 ° C EXAMPLE 1 2 - . 2 - . 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl-N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide A a stirred solution of the acid (I) (674 mg, 1.6 mmol) in DMF (80 mL) is added 2 - (1H-benzotriazol-1-yl) -1,3,3-tetramethyl uranium hexafluorophosphate (HBTU) (607 mg, 1.6 mmol) followed by diisopropyl ethyl amine (620 mg, 4.8 mmol) and the mixture is stirred at room temperature for 5 minutes. Amine II (304 mg, 1.6 mmol) is added to the solution which is stirred for an additional 2 hours. The reaction mixture is taken up in EtOAc and washed with NaHCO3 (aqueous), saline, dried (MgSO) and concentrated in vacuo. The residue is purified in reversible silica phase which is eluted with a gradient of 50% to 100% MeOH / H20 to give Example 1 as a white solid (696 mg, 73%). 1H NMR (CDC13): d 0.75 and 0.88 (6H, 2 x br d, (CH ^ CH). 1.03 (6H br d, (CH 9CH), 1.22-1.64 (8H, m, cyclohexyl), 1.64 (3H, s, aCH3), 2.09-2.13 (2H, m, cyclohexyl), 2.97-3.04 (3H, m, (CH3) 2 CH x 2, CHH Type), 3.22) H, D, O II 14.65 Hz, CHH Nature), 3.38-3.39 (2H, m, CNHCHA 4.94 (ÍH, br s, O II PhNHCNH (, 5.44 (ÍH, br s, PhMH), 6.34 (ÍH, br s, NH amide), 6.93-7.00 (2H, m, 2ArH), 7.03-7.11 (4H, m, 4 ArH), 7.22 ( HH, d, 8.06 Hz, ArH), 7.26-7.31 (2H, m, 2ArH), 7.36 (HH, d, 8.06 Hz, ArH), 7.633 and 7.63 (HH, dt, 7.60 Hz, ArH), 7.73 (HH) , br s, NH character), 8.54 (ÍH, d, 3.17 Hz, ArH), IR (film): 3291.0, 2955.0, 2870.0, 1652.0, 1532.0, 1457.0, and 742.0 cm "1; MS m / e (APCI) : 594.7 (M -H) Analysis: C, H, N, melting point of 116 ° -117 ° C, HPLC RT = 12.88, reversible phase C18, 40% to 100% MeCN: TFA H20: TFA.
EXAMPLE 2 2 - . 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl-N- (1. 2. 3, 4-tetrahydro-naphthalene-1) - il) - propionamide Example 2 is prepared as in Scheme 1 using 1, 2, 3, 4-tetrahydro-1-naphthyl amine (s).
Example 2 is isolated in a 24% yield. 1 H NMR (CDCl 3): d 0.43-0.52 (3 H, br d, CH 3 CH), 0.90-0.94 (3 H, br d, CH 3 CH), 0. 98 and 1.07 (6H, 2 x d, 6.59 and 6.11 Hz, (CH3) 2CH), 1.70 (3H, s, aCH3), 1.78-1.84 (3H.
CHCHHCH2 tetralin), 1.87-2.04 (HH, m, CH2CHH tetralin), 2.69-2.91 (3H,, (CH3) 2CH), PhCH2), 2.89. (HH, d, 14.65 Hz, CHH type), 3.06-3.15 ( ÍH, m, (CH3) 2CH), 3.47 (ÍH, d, 14. 40 Hz, CHH Nature), 4.75 (HH, br s, OOO PhNHC NH), 5.01-5.06 (HH, m, CNH CH), 5.30 (HH, br s, PhNHC NH), 6.28 (H, s, NH amide), 6.63 (HH, br d, 7.57 Hz, ArH), 6.71 (HH, t, 7.32 Hz, ArH), 7.04 (2H, t, 6.84 Hz, ArH), 6.91 (H H, t, 7.82 Hz, ArH), 6.98 (ΔH, t, 7.32 Hz, ArH), 7.04 (2H, t, 6.84 Hz, ArH), 7.09-7.16 (2H, m, 2ArH), 7.22-7.37 (3H, m, 3 ArH) , 7.39 (ÍH, d, 8.3 Hz, ArH), 7.77 (ÍH, br s, NH type); IR (film): 3291.0, 2962.0, 1674.0, 1651.6, 1506.0, 1456.0, and 737.0 cm "1; MS m / e (APCI) 551.5 (M + H +); Analysis: C35H42N402, C, H, N:" D = -45.33 (MeOH, c-0.075 g, 100 mL "1); fi xing point of 210 ° -212 ° C; HPLC R. T. = 17.90, C18 reversible phase, 40% to 100% MeCN: TFA / H20: TFA.
EXAMPLE 3 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -N-indan-1-yl-3 - (1H-indol-3-yl) -2-methyl-propionamide Example 3 is prepared as in Scheme 1 using S - (+) - 1-aminoindone. Example 3 is isolated in a 45% yield. 1 H NMR (CDCl 3): d 0.55 (3 H, br s, CH 3 CH), 0.94 (3 H, br d, 5.62 Hz, CH-CH), 0.99 (3 H, br d, 6.35 Hz, CH 3 CH), 1.07 (3 H, br , d, 6.10 Hz, CH-CH), 1.70 (3H, s, OO II II aCH3, 1.71-1.86 (ÍH, m, CNHCHCHH), 2.53-2.61 (ÍH,, CNHCHCHH), 2.78-2.97 (4H, m, CHH Nature, PhCH2, (CH3) 2CH), 3.01-3.20 (ÍH, Br m, (CH ^ CH), 3.47 (ÍH, d, 14.40 OO II II Hz, CHH Índole), 4.77 (ÍH, br s, NHCNH), 5.36 (ÍH, q, 7.57 Hz, CNHCH), 5.58 (ÍH, s, NHCNH), 6.30 (ÍH, br s, NH amide), II or 6.60 (ÍH, br d, 6.59 Hz, ArH), 6.65 (ÍH, br d, 8.06 Hz, ArH), 6.94-7.06 (3H, m, 3 ArH), 7.11-7.20 (4H, m, 4ArH) , 7.26-7.34 (2H, m, 2ArH), 7.38 (ΔH, d, 7.32 Hz, ArH), 7.82 (ΔH, br s, NH type); IR (film): 3354.0, 1668.0, 1506.0 and 1060.0 cm "1; MS / me (APCI) 537.7 (M + H +); Analysis C34H40N4O2, C, H, N; aD = -30.29 ° (MeOH, c = 0.175 g , 100 mL "1; melting point 228 ° -230 ° C; HPLC RT = 16.96, C18 reversible phase, 40% to 100% MeCN: TFA / H20: TFA.
EXAMPLE 4 N - (2-Cyclohexyl-ethyl) -2- [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl-propionamide Example 4 is prepared as for Scheme 1 using cyclohexyl ethyl amine.
Example 4 is isolated in a 54% yield. 1 H NMR (DMSO-de): d 0.50-1.73 (28H, br, aCH3 + cyclohexyl + 2 x (CH-T CH + CH2 cyclohexyl), 2.92-3.30 (5H, br, CH2N + 2 x (CH3) 2CH + CHH Nature), O 3. 50 (ÍH, br d, CHH Índole), 6.42 (ÍH, br s, PhNHCNH), 6.83-7.38 (7H, br m, 3 ArH + 4 O II Character HL 7.52 (ÍH, d, 8.0 z, Nature H), 7.71 2H, br, PhNHC + amide NH), 10.90 (ÍH, br, NH type); IR (film): 3289.0, 2924.0, 1668.0, 1652.0, 1520.0, 1456.0, and 740.0 cm "1; MS m / e (Cl) 531.8 (M + + H); Analysis C33H46N O2 • 0.2 H20, C, H, N; melting point of 113o- 1 16 ° C.
EXAMPLE 5 2 - . 2 - . 2-F3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl N -phenyl-propionamide Example 5 is prepared as in Scheme 1 using phenylamine.
Example 5 is isolated in a 69% yield. 1H NMR (DMSO-de): d 1.11 (12H, br, 2 x (CH3) 2CH), 1.47 (3H, br s, aCH3), 3.29 (2H, br, 2 x (CH3) 2CH), 3.45 (2H, br, CH2), 6.43 (H, br, O) II PhNHCNH), 6.90-7.39 (10H, br m, 6 ArH + 4 H-type), 7.50-.71 (4H, br, O II. 2 ArH + type H + PhNHCNH), 9.70 (ΔH, br s, NH-amide), 10.98 (ΔH, br, NH-type); IR (film: 3278.0, 2927.0, 1599.0, 1519.0, 1499.0; MS m / e (Cl) 497.6 (M1"+ H); Analysis: C3? H36N402 • 0.5 H20, C, H, N, melting point: 12 Io - 124 ° C.
EXAMPLE 6 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl-N- (2-phenyl-cyclohexyl) -propionamide. Example 6 is prepared as in Scheme 1 using Intermediary III. Production of (78 mg, 53%). 1H NMR (CDC13): 0.85-2.04 (20H, m, 4 x CU2), 1.36 (3H, s, a, CU3), 2.79 (ÍH, d, CHH), 2.92-3.10 (3H, m, CHH, 2 x CU (CU3) 2), 4.46-4.51 (2H, m, NHCH, PhCU). 5.63 (ÍH, s, CONH), 6.14 (ÍH, s, NHCO), 6.91-7.28 (13H, m, aromatic), 7.70 (ÍH, s, NH), 7. 92 (ÍH, bs, CONH); IR (film): 3286, 3061, 2928, 2867, 1674, 1662, 1496, 906 and 734; MS m / e " 580, 405, 377; HPLC 97.6%, R.T.:16.55, 60% to 100% acetonitrile in water 22 (_TFA); [a] - + 67.5 ° (c = 0.57, acetone). D SCHEME 2 Reagents and conditions: i) 2,6-diisopropyl phenyl isocyanate, triethylamine, DMF, 100 ° C. Ii) HBTU, DIPEA, DMF, 20 ° C, N-methyl cyclohexyl methyl amine.
Synthesis of Example 7 Step 1 To a stirred solution of tryptophan (203 mg, 1.0 mmol) and triethylamine (9 mL, 65 mmol) in dioxane (50 mL) is added diisopropyl phenyl isocyanate (203 mg, 1.0 mmol) and the mixture is mixed. reflux for 3 hours. The reaction mixture is allowed to cool to room temperature and put in EtOAc and washed with INN of HCl (aqueous), saline, and dried (MgSO4). The solvents are removed in vacuo and the residue triturated with ether to yield Intermediate IV as a white solid (191 mg, 47%).
IR (film): 2962.0, 1614.0 and 1456.Q cm'1; MS m / e (Cl) 408 (M + H).
EXAMPLE 7 N-hexylmethyl-2 - [3-2-6-diisopropyl-phenyl) -ureido] -3-OH-indol-yl) -N-methyl-propionamide. The Example is isolated in a 75% yield.
To a stirred solution of IV acid (122 mg, 0.3 mmol), HBTU (114 mg, 0.3 mmol) and diisopropyl ethyl amine (116 mg, 0.9 mmol) in DMF (50 mL) which has been stirred for 5 minutes was add N-methylcyclohexyl methyl amine (76.2 mg, 0.6 mmol). The mixture is stirred for 2 hours and then placed in EtOAc (150 mL) and washed with NaHCO 3 (aqueous), IN HCl (aqueous), saline, dried (MgSO 4) and concentrated in vacuo. The residue is purified in the normal silica phase by eluting it with a heptane gradient of 6: 4 heptane: EtOAc to yield 7 (116.3 mg, 75%). 1H NMR (CDC13): d 0.51-1.07 (6H, m, cyclohexyl), 1.14 and 1.16 (12H, 2 xd, 6.83 Hz, [(CH3) 2 x 2), 1.23-1.60 (5H, m, cyclohexyl), 2.53-2.89 (2H, m, [(CH3) 2CH x 2), 2.57 and 2.67 O II (3H, 2 x s, CN-CH3), 3.01-3.26 (4H, m, CHH, Nature, and N (Me) CH2), 5.06-5.20 O O II II (ÍH, m, NHCNHCH), 5.22-5.27 (ÍH, m, aH), 5.72 (ÍH, m, NHCNH), 6.98-7.02 (ÍH, m, ArH), 7.08-7.19 (4H, m, 4 ArH), 7.26-7.34 (2H, m, 2 ArH), 7.69 (ÍH, d, 8.06 Hz, ArH), 7. 95 (ÍH, brs, NH type): IR (film): 3291.0, 2925.0, 1615.0 1538.0 1213.0 and 740.0 cm "1; MS m / e (Cl) 518 (M + H); Analysis C32H45N402, C, H, N; melting point: 179o- 18 Io C; HPLC R. T. = 18. 09, C18 reversible phase, MeCN from 10% to 80%: TFA / H20: TFA.
SCHEME 3 v Reagents and conditions: i) p-nitrophenyl isocyanate, pyridine, DMF, 60 ° C. ii) HBTU, R, DIPEA, DMF, 20 ° C. iii) 2N HCl, MeOH, at reflux.
Table for Scheme 3 Example number R HN XXIV Table for Scheme 3 (continued) Example number R T he E n ects 8 and 9 and 26 to 30 Step 1 To a mixture of (S) - aMe tryptophan (2.51 g, 11.5 mmol) in DMF (100 mL) is added p-nitro phenyl isocyanate (1.89 g, 1.5 mmoles) followed by pyridine (1 mL) and the mixture of The reaction is heated at 60 ° C for 30 minutes. The solvent is removed in vacuo and the residue is taken to INN of NaHCO 3 (aqueous) and extracted with ether. The aqueous layer is acidified with 5 N HCl (aqueous) to pH 1 and re-extracted with EtOAc, dried (MgSO 4) and concentrated in vacuo to give V as a yellow solid (4.07 g, 96.1%). 1H NMR (DMSO): d 1.55 (3H, s, aCH 3.31 (ΔH, d, obscured by water peak, CHH ○), 3.48 ΔH, d, 14.40 Hz, CHH type), 6.57 O II (ÍH, s, NHCNH), 6.82 (ÍH, t, 7.81 Hz, type H5), 6.99 (ÍH, t, 7.32 Hz, Type H6), 7.04 (ÍH, s, 2.2 Hz, Type H2), 7.30 ( ÍH, d, 8.3 Hz, Hz Character H7), 7.49 (ÍH, d, 8.06 Hz, Nature H4), 7.62 (2H, d, 9.04 Hz, 2 xp - NO ^ h ArH), 8.16 (2H, d, 9.03 Hz, 2 x P - N02 ArH), OR 9.45 (HH, s, NHCNH), 10.89 (HH, s, NH type).
EXAMPLE 8 N-cyclohexylmethyl-3 - (ÍH-indol-3-yl) -2-methyl-2 - [3 - (4-nitro-phenyl) ureido] -propionamide. Example 8 is isolated in a production of 54.4%.
To a solution of acid V (150 mg, 0.4 mmol), HBTU (155 mg, 0.4 mmol) and diisopropyl ethyl amine (158 mg, 1.2 mmol) in DMF (100 mL) which has been stirred for 5 minutes, add cyclohexyl methyl amine (250 mg, 2.17 mmol), and stir the reaction mixture for 2 hours. The mixture is taken up in EtOAc and washed with 1 N HCl (aqueous), 1 N NaHCO 3 (aqueous), saline, dried (MgSO 4) and concentrated in vacuo. The residue is purified on silica which is eluted with heptane: EtOAc in a ratio of 1: 1 to EtOAc to give a yellow solid which is washed with EtOAc to yield pure compound 8 (104 mg, 54.4%).
? NMR (DMSO): d 0.78-0.86 (2H, m, cyclohexyl), 1.06-1.20 (3H, m, cyclohexyl), 1.40-1.49 (H, m, cyclohexyl), 1.57 (3H, s, aCH3), 1.56- 1.63 (5H, m, cyclohexyl), OO 2.82-2.89 (HH, m, CNHCHH), 2.95-3.01 (HH, m, CNHCHH), 3.34 (HH, d, 14.89 Hz, CHH O II nature), 3.58 (ÍH, d, 14.65 Hz, CFJH Índole), 6.66 (ÍH, s, PhNHCNH), 6.81 (ÍH, t, 7.57 Hz, Character H6), 7.27 (ΔI, d, 8.06 Hz, type H7), 7.48 (ΔI, d, 8.06 Hz, type H4), 7.62 O (2H, d, 9.3 Hz, 2 - p - N02Ph ArH), 7.99 (ÍH, t, 5.62 Hz, CNH), 8.15 (2H, d, 9.03 Hz, 2 x O II pN02Ph ArH), 9.60 (HH, s, NHCNH), 10.81 (HH, s, NH type); IR (film): 3345.0, 2924.0, 2852.0, 1695.0, 1644.0, 1557.0, 1505.0, 1456.0, 1329.0, 1302. 0, 1231.0, 11 12.0, and 741.0 cm_1; MS m / e (APCI) 478.6 (M + H); Analysis C26H3? N504 • 0.35 H20, C, H, N; melting point 129 ° - 131 ° and then 208 ° - 225 ° C; HPLC R. T. = 13. 52 C18 reversible phase, 40% to 100% MeCN: TFA / H20: TFA.
EXAMPLE 9 N - (1-hydroxy-cyclohexylmethyl) -3- (ÍH-indol-3-yl) -2-methyl-2 - [3 (4-nitro-phenyl) -ureido] -propionamide.
Example 9 is prepared as in Scheme 3 using 1-amino methyl-1-cyclohexanol.
Example 9 is isolated in a yield of 59%. 1 H NMR (DMSO): d 1.13-1.57 (8H, m, cyclohexyl), 1.42 (3H, s, aCH3), 2.07 - O II 2.12 (2H, m, cyclohexyl), 2.98 (IH, dd, 13.19 and 5.13 Hz, CNHCHH, 3.27 (IH, dd, 12.94 and O II 6.84 Hz, CNHCHH), 3.41 and 3.37 (2H, 2 xd, 14.90 Hz, CHH Nature), 6.54 (ÍH, s, NHCNH), 6.81 (ÍH, t, 7.57 Hz, type H5), 6.93 (ÍH, s , H2 character), 6.98 (ΔH, t, 7.57 Hz, II oo ll H6 character), 7.10 (ΔI, t, 7.33 Hz, ArH), 7.15 - 7.21 (3H, m, 2ArH + NHCNH, 7.27 - 7.30 (3H, m, 3 ArH), 7.44 (ÍH, d, 8.06 Hz, type H7), 7.66 (2H, d, 9.28 Hz, 2 x pN02Ph ArH), OR II 8.18 (2H, d, 9.28 Hz, 2pN02Ph ArH), 9.52 (ÍH, s, CNH), 10.81 (ÍH, s, NH nature).
IR (film): 3323.0, 1698.3, 1645.0, 1615.2, 1558.5, and 1505.0 cm "1; MS m / e (APCI) 554.5 (M + H +); Analysis C26H31N505; melting point 182 ° - 184 ° C; HPLC RT = 10.53, C18 reversible phase, 40% to 100% MeCN: TFA / H20: TFA.
SCHEME 4 SAW Reagents and conditions: i) 2,6-diisopropyl phenyl isocyanate, triethylamine, DMF, 50 ° C. Ii) HBTU, cyclohexyl methylamine, DIPEA, DMF Synthesis of Example 10 Step 1 To a suspension of N-methyl (RS) tryptophan (500 mg, 2.3 mmol) in DMF (30 mL), 2,6-isopropyl phenyl isocyanate (0 54 mL, 2.53 mmol) was added, and triethylamine (697 mg, 6.9 mmol) and the reaction mixture is heated to 50 ° C and stirred for 30 minutes. The mixture is allowed to cool to room temperature before being placed in EtOAc and washed with 1 N HCl, saline, dried (MgSO 4), and concentrated in vacuo to give VI (966 mg, 100%).
H NMR (CDCb): d 1.15 (6H_ d, 6.84 Hz, (CH3) 2CH), 1.25 (6H, d, 6.84 Hz, (_ H3) 2CH), 2.94 (3H, s, N-me), 2.88- 3.05 (2H, 2 xm, [(CH3) 2CH] 2), 3.45-3.47 (2H, m, O II CHH Índole), 4.97 (ÍH, t, 8.06 Hz, aH) 5.81 (ÍH, s, NHC), 7.10-7.20 (5H, m, 5 ArH), 7.22 (ÍH, t, 7.1 Hz, ArH), 7.26- 7.30 (HH, m, ArH), 7.38 (HH, d, 8.06 Hz, ArH), 7.66 (HH, s, J = 7.82 Hz, ArH), 8.17 (HH, s, type NH), IR (film): 3320.8, 2963.0, 2291.5, 1716.0, 1652.0, 1507.0, 1466.8, and 743.0 cm "1; MS m / e (ES) 420.7 (M-H +) 421.7 (M4).
EXAMPLE 10 N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -1-methyl-ureido] -3- (1H-indol-3-yl) -propionamide Example 10 is isolated in a yield of 32.6% .
To a solution of the acid VI (211 mg, 0.5 mmol) in DMF (50 mL) is added HBTU (189.6 mg, 0.5 mmol), diisopropyl ethyl amine (194 mg, 1.5 mmol), and the mixture is stirred for 10 minutes. Cyclohexyl methyl amine (80 mg, 0.7 mmol) is then added to the reaction mixture and stirred for an additional 5 hours. The mixture is taken up in EtOAc and washed with IN of HCl (aqueous), NaHCO 3 (aqueous), saline, dried (MgSO 4) and concentrated in vacuo. The residue is purified in the normal silica phase which is eluted with a heptane gradient so that a heptane: EtOAc mixture in a ratio of 6: 4 produces a solid which is washed with ether to yield pure compound (84.2 mg , 32.6%). 1H NMR (CDC13): d 0.82-0.91 (2H, m, cyclohexyl), 1.10-1.20 (8H, m, cyclohexyl), 1.14 (12H, d, 6.84 Hz, [(CH3) 2CH] x 2), 1.38 - 1.43 (ÍH, tn, O II CNHCH2CH), 1.58-1.70 (2H, m, [(CH3) 2CH] x 2), 3.03 (3H, s, N-CHb), 3.08 O II (2H, t, 6.35 Hz, CNHCHA 3.30 (ÍH, dd, 9.77 and 15.87 Hz, CHH Nature), 3.36 (ÍH, dd, 6.10 and 15.87 Hz, CHH type) 5.29 - 5.33 (ÍH, m, dH), 5.65 (HH, s, PhNHC), 6.50 (HH, bt, II or amide NH), 7.08 (HH, d, 2.2 Hz, Type H2), 7.10 - 7.20 (3H, m, 3ArH), 7.20 (HH, t , 7.10 Hz, Arh), 7.22 - 7.26 (HH, m, ArH), 7.37 (HH, d, 8.3 Hz, ArH), 7.67 (HH, d, 7.57 Hz, 1 ArH), 7.97 (HH, s, Nature NH); IR (film: 3323.0, 1668.2, 1645.0 and 1506.0 crn "1; MS me (APCI) 515.9 Qrf), 517.7 (M + ET); Analysis 52H44N4O2, C, H, N; melting point: 183 ° - 185.5 ° C; HPLC RT = 18.41, C18 reversible phase, 40% to 100% MeCN: TFA / H2O: TFA.
SCHEME 5 Reagents and conditions: i) B002, NaHCO3, dioxane. ii) LiOH, THF, MeOH. iii) HBTU, R, D1PEA, DMF or DCC, PFP, R, EtOAc. iv) TFA, DCM. v) R'NCO, THF Table for Scheme 5 Example number R R 'Table for Scheme 5 Example number R R' (R, S - stereo Synthesis of Examples 12 to 16 Step 1: as for Examples 11 to 17. Step 2: To a solution of the acid VII (2.067 g, 6.5 mmol), HBTU (2.47 g, 6.5 mmol) and diisopropyl ethyl amine (2.52 g, 19.5 mmol) in DMF (130 mL) which has been stirred for 5 minutes, amine II is added. (1.24 g, 6.5 mmoles) and continue stirring for 2 additional hours. The reaction mixture is taken up in EtOAc and washed with NaHCO 3 (aqueous), 1 N HCl (aqueous), dried (MgSO 4) and concentrated in vacuo. The residue is purified in a reversible phase of silica gel eluting with 77% MeOH / H20 to obtain pure compound VIII (R = II) (2.17 g, 68%). 1H NMR (CDC13): d 1.27-1.63 (8H, m, cyclohexyl), 1.40 (9H, s, (CH3) 3C), 1.52 (3H, s, aCH3), 2.0-2.23 (2H, m, cyclohexyl), 3.31 (ÍH, d, 14.65 Hz, CHH Nature), 3.29 OO II II 3.50 (3H, m, CHH Nature and CNHCH2), 5.05 - 5.15 (ÍH, br s, CNH), 6.93 (1H, s, Nature O II H2), 7.0 - 7.12 (2H, m, 2ArH), 7.16 (ÍH, t, 8.06 Hz, ArH), 7.10 - 7.22 (ÍH, m, NHC), 7.31 (2H, t, 7.81 Hz, 2ArH), 7.52 (ÍH, d, 7.57 Hz, AtH), 7.36 (ÍH, t, 7.81 Hz, ArH), 7.99 (ΔH, br s, NH type), 8.50 (ΔH, d, 3.66 Hz, pyridyl H); IR (film): 3333.0, 2928.0, 1652.0, 1471.0, and 1163.0 cm "1; MS m / e (APCI) 491.6 (M + H +); Analysis: C2 H38N403, C, H, N; melting point: 78.5 ° - 79.5 ° C; HPLC RT = 8.47 and 8.73, C18 reversible phase, 40% to 100% MeCN: TFA H20: TFA.
Step 3 The compound VUI (R = p) (473 mg, 0.96 mmol) is dissolved in formic acid (30 mL) and stirred for 5 hours. The mixture is basified with a sodium hydroxide solution diluted to pH 14 and extracted with EtOAc, dried (MgSO 4) and concentrated in vacuo to give compound IX (R = II) (300 mg, 80%). 1H NMR (CDC13): d 1.27-1.63 (8H, m, cyclohexyl), 1.32 (3H, s, aCH3), 2.0-2.2 (2H, 2 xm, cyclohexyl), 2.79 (H, d, 14.65 Hz, Character CHH ), 3.35 (ÍH, d, 14.65 Hz, Nature CHH), 3.36 (ÍH, dd, 6.35 Hz, 13.18 Hz, CNHCHH), 3.42 (ÍH, dd, 6.10 and 13.18 Hz, CHHNHC), 7.00 (ÍH, d, 2.44 Hz, H2 type), 7.03 - 7.19 (4H, m, 4ArH), 7.35 (ÍH, d, 8.06 Hz, ArH), 7.52 (ÍH, td, 1.95 and 7.57 Hz, ArH), 7.59 (HH, d, 7.82 Hz, ArH), 7.60-7.68 (HH, br t, CNH), 8.02 (HH, br, NH nature), 8.51 - 8.58 (HH, m, pyridyl H); MS m / e (ES) 391.7 (M + HP ").
EXAMPLE 12 3 - . 3 - (ÍH-indol-3-yl) -2-methyl-2 - (3 - [1 - (4-nitro-phenyl) -etill -ureido.} - N - (1-pyridin-2-yl- hexymethylmethyl cycle) -propionamide To a solution of amine IX (R = II) (100 mg, 0.26 mmol) in THF (100 mL) is added 4-nitrol-a-methyl benzyl isocyanate (180 mg, 0.94 mmol), The solution is stirred for 4 hours at room temperature, the reaction mixture is taken up in EtOAc and washed (H20), dried (MgSO 4) and concentrated in vacuo, the residue is taken up in EtOAc and crystallized. to produce compound 12 (58.6 mg, 39%). 1 H NMR (DMSO): d 1.08-1.48 (8H, m, cyclohexyl), 1.24 (3H, s, aCH), 1.33 (3H, d, 7.08 Hz, PN02PhCHCH3), 2.03-2.28 (2H, m, cyclohexyl) , 3.07 (ÍH, dd, 5.62 and 12.94 OO II II Hz, CNHCHH), 3.21 - 3.15 (2H, m, CHH Nature and CNHCHH), 3.34 - 3.29 (H, d, obscured by water peak CHH Nature), 4.90 (H, m, CHCH3), 5.93 (H) , s, OO II II CHNHCNH), 6.77 (ÍH, d, 7.32 Hz, ArH), 6.86-6.90 (2H, m, lArH and CNH), 7.01 (ÍH, t, 7.32 Hz, ArH), 7.13 - 7.16 (1.H, m, ArH), 7.27 - 7.30 (2H, m, 2ArH), 7.36 - 7.40 (2H, m, O CNH and ArH), 7.55 (2H, d, 8.79 Hz, 2 xp - N02Ph ArH), 7.64 (ΔH, td, 1.95 and 7.81 Hz, ArH), 8.16 (2H, d, 8.54 Hz, 2 xp - N02Ph ArH), 8.50 (ΔH, d, 2.93 Hz, pyridyl H), 10.85 (ΔH, s, NH type); IR (film): 3340.0, 2923.6, 1642.0, 1520.0, 1345.6 and 1107.0 cm "1; MS m / e (APCI) 583.6 (M + H +); Analysis C33H38N604, C, H, N, melting point: 202-203 ° C; HPLC RT = 9.38 and 9.77, C18 reversible phase, 40% to 100% MeCN: TFA / HO: TFA.
EXAMPLE 13 2 - . 2-f 3 - (4-cyano-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl-N- (T-pyridin-2-yl-cyclohexylmethyl) -propionamide. Example 13 is prepared as in Scheme 5 using Intermediate II and 4 cyano phenyl isocyanate. Example 13 is isolated in a 37% yield. 1 H NMR (DMSO): d 1.13-1.55 (8H, m, cyclohexyl), 1.41 (3H, s, dCH3), 2.16 - O II 2.23 (2H, m, cyclohexyl), 3.09 (ΔH, dd, 5.37 and 12.94 Hz, CNHCHH), 3.28 - 3.39 (3H, m O O II II obscured by water peak, CNHCHH and Nature CHH). 6.44 (ÍH, s, NHCNH), 6.81 (ÍH, t, 7.32 Hz, type H5), 6.92 (ÍH, d, 2.20 Hz, type H2), 6.98 (ÍH, t, 7.08 Hz, type H6), 7.07 - 7.10 (ÍH, m, ArH), 7.28 (2H, t, 8.06 Hz, 2ArH), 7.41 (ÍH, d, 8.06 Hz, type H7), OR II 7.44 - 7.52 (3H, m, 2ArH and CNH), 7.56 (2H, d, 8.79 Hz, 2 x pN02Ph ArH), 7.68 (2H, d, O II 8.79 Hz, 2 x pN02Ph ArH), 8.47 - 8.49 (HH, m, pyridyl H), 9.22 HH, s, CNH), 10 81 (1H, s, IR (film): 3352.0, 2934.2, 1652.0, and 1113.0 was 1; MS m / e (APCI): 535.5 (M + H +); Analysis C32H34N602, C, H, N; melting point: 234.5 ° -237 ° C; HPLC RT = 6.75; , 18 7.02, C1S reversible phase, 40% to 100% MeCN: TFA / H20: TFA; EXAMPLE 14 3 - . 3-HH-indol-3-yl) -2-methyl-2 -? 3 - (4-nitro-phenyl) -ureido] - N - (1-pyrimidin-2-yl-cyclohexylmethyl) -propionamide. Example 14 is isolated in a 63.3% yield. Example 14 is prepared as in Scheme 5 using Intermediate II and 4-nitrophenyl isocyanate. 1 H NMR (DMSO): d 1.11 - 1.55 (8 H, m, cyclohexyl), 1.44 (3 H, s, a CH 3), 2.18 - O II 2.25 (2 H, m, cyclohexyl), 3.09 (H, d, 5.37 and 13.18 Hz , CNHCHH), 3.29 - 3.38 (3H, m, OO II II CHH Nature and CNHCHH), 6.54 (ÍH, s, NHCNH), 6.81 (1H, t, 8.06 Hz, Nature H5), 6.93 (ÍH, s, nature H2), 6.93 (ÍH, s, Nature H2), 6.98 (HH, t, 7.08 Hz, type H6), 7.07 -7.10 (HH, m, ArH), 7.28 (2H, t, 9.03 Hz, 2ArH), 7.42 (HH, d, 7.81 Hz, Type H7), 7.49 - 7.60 (2H, m, amide NH and 1 ArH), 7.62 (2H, d, 9.28 Hz, 2 xp - N02Ph ArH), 8.16 (2H, d, 9.28 O Hz, 2 xp - N02Ph ArH), 8.48 - 8.50 (H H, m, pyridyl H), 9.49 (HH, s, Ph NHCNH), 10.81 (1H, s, NH type); IR (film): 3363.0, 2934.2, 1644.2, 1454.1, 1433.0 and 1046.0 cm "1; MS m / e (APCI): 555.5 (M + H +); Analysis C3iH34N604, C, H, N, melting point 215 ° - 219 ° C; HPLC RT = 8.79, C18 reversible phase, 40% to 100% MeCN: TFA H30: TFA.
EXAMPLE 15 3 - . 3 - (ÍH-indol-3-yl) -2-methyl-N- (1-pyridin-2-yl-cyclohexylmethyl) -2 - [3- (4-trifluoromethyl-phenyl) -ureido] -propionamide.
Example 15 isolates in a 20% yield.
• Example 15 is prepared as in Scheme 5 using Intermediate II and 4-trifluoromethyl phenyl isocyanate. 1 H NMR (DMSO): d 1.12 - 1.55 (8H, m, cyclohexyl), 1.40 (3H, s, aCH3), 2.18 - 10 2.26 (2H, m, cyclohexyl), 3.08 (ΔH, dd, 5.37 and 12.94 Hz, CNHCHH), 3.27 - 3.36 (3H, II ooo 15 II II obscured by water peak, CHH Nature and CNHCHH), 6.38 (H, s, NHCNH), 6.81 (H, t, 7.81 (H, t, 7.81 Hz, Character H5), 6.93 (ΔI, d, 2.2 Hz, type H2), 6.98 (ΔI, t, 7.57 Hz, Type H6), 7.07 - 7.10 (ΔI, m, ArH), 7.29 (2H, t, 9.03 Hz, 2ArH), 7.42 (ΔH, d, 8.06 Hz, O 20 II type H7), 7.46 - 7.51 (2H, m, ArH and NHC), 7.59 (4H, s, 4 x ArH), 8.48 - 8.49 (≤H, m , O II 25 pyridyl H), 9.13 (1H, s, NHC), 10.83 (1H, br s, NH character); IR (film): 3360.0, 2934.2, 1651.9, 1559.3, 1440.3, 1334.6 and 1070.0 cm 1; MS m / e (APCI): 578.5 (M + H +); Analysis C32H34N502F3, C, H, N; HPLC R. T. = 10.99, C18 30 reversible phase, 40% at 100% MeCN: TFA / H20: TFA.
EXAMPLE 16 4 - (3 -. {2 - ÍH - indol - 3 - yl) - 1 - methyl - 1 - \ (l - pyridin - 2 - yl - cyclohexylmethyl) - carbamoyl] - ethyl acid} ureido) -benzoic acid ester Example 16 is prepared as in Scheme 5 using Intermediate II and ethyl-4-isocyanatobenzoate. Example 16 is isolated in a 55% yield. 1H NMR (CDC13): d 1.26-1.61 (8H, m, cyclohexyl), 1.39 (3H, t, 7.08 Hz, CH * CH20), 1.70 (3H, s, aCH3), 2.03-2.1 (2H, m, cyclohexyl), 3.18 (1H, dd, 4.15 and 13.18, O CNHCHH), 3.30 (ÍH, d, 14.65 Hz, CHH Índole), 3.51 (ÍH, dd, 5.86 and 12.94 Hz, O II CNHCHH), 3.53 (ÍH, d, 14.65 Hz, CHH type), 4.35 (ÍH, ql, 7.08 Hz, CH3CH20), 5.83 O O || II (HH, s, NHCNH), 6.85 (HH, d, 2.44 Hz, ArH), 6.98 (HH, t, 7.81 Hz, AxH and NHC, 7.11 (HH, O II t, 7.08 Hz, ArH), 7.24 - 7.33 (4H, m, 4ArH), 7.41 - 7.45 (2H, m, ArH and NHC), 7.59 (ΔH, td, 7.57 and 1.95 Hz, ArH), 7.90 (2H , d, 8.79 Hz, 2ArH), 7.95 (1H, br s, NH type), 8.44 -8.45 (lH, m, pyridyl H); IR (film): 3342.0, 2931.0, 1645.0, 1538.0, 1279.0, 1174.0 and 1107.0 cm "1; MS m / e (APCI) 582.5 (M + H1"); Analysis: C34H39N5? 4, C, H, N; melting point: 117 ° - 120 ° C; HPLC R. T. = 9.58, C18 reversible phase, 40% to 100% MeCN: TFA / H20: TFA.
Synthesis of Examples 11 and 17 Step 1 To a stirred solution of (S) -α-methyl tryptophan methyl ester (5.0 g, 22 mmol) in dioxane (50 mL) water (50 mL) is added NaHCO3 (3.0 g, 36 mmol) followed by di - t - butyl bicarbonate (5.0 g, 23 mmol). Stir continuously for 18 hours at room temperature. The mixture is acidified (HCl, 200 mL, aqueous 2 N, carefully at the beginning) and the products are extracted (EtOAc, 300 mL). The organic phase is dried (MgSO 4) and evaporated to dryness in vacuo (60 ° C). The brown residual oil is purified by flash column chromatography (silica gel, eluent to 40% EtOAc / 60% heptane). 7.0 g (99%) of the protected ester is recovered as a pale yellow oil, which is not completely characterized. To a stirred solution of this ester (7.0 g, 21 mmol) in MeOH (60 mL) is added a solution of LiOH.H20 (1.5 g, 35 mmol) in water (20 mL). Stir continuously for 18 hours at room temperature. The mixture is acidified (HCl, 200 mL, 2 N aqueous) and the products are extracted (EtOAc, 2 x 150 mL). The combined organic extracts are dried (MgSO 4) and evaporated to dryness in vacuo (60 ° C). 6.8 g (99%) is recovered (VE) as a pale yellow oil. This is not completely characterized.
IR (film): 1702 and 1694 cm "1.
Step 2 To a stirred solution of (VII) (0.5 g, 1.6 mmol) in EtOAc (30 mL) is added N. N - dicyclohexyl carbodiimide (0.5 g, 2.4 mmoles) and pentafluorophenol (0.4 g, 2.2 mmoles). Stir continuously for 30 minutes at room temperature and then remove the white precipitate by filtration. Amino methyl cyclohexane (0.4 mL, 0.3 g, 3.0 mmol) is added to the filtrate while stirring. Stirring is continued for 30 minutes at room temperature and then the reaction mixture is washed with HCl (50 mL, 2 N aqueous), dried (MgSO 4) and evaporated to dryness in vacuo (60 ° C). The residue is purified by flash column chromatography (silica gel, eluent 80% EtOAc / heptane) followed by reversible phase by column chromatography (74% MeOH / 26% H20). This gives (Vffl) (R = CH2 cyclohexyl) as a white foam (0.54 g, 83%). 1 H NMR (DMSO-de): d 0.83 (2H, br, cyclohexyl), 1.08-1.72 (21H, m, a-CH 3 + (CH 3) 3 + cyclohexyl), 2.78-3.02 (2H, br, CH 2 -N) , 3.18 (ÍH, br, CHH nature), 3.31 OR II (obscured, CHH Índole), 6.40 (1H, brs, OCNH), 6.92 (ÍH, t, 7.6 Hz, type H), 6.96 (ÍH, s, type H), 7.03 (ÍH, t, 7.6 Hz, type H), 7.31 (ÍH, d, 8.0 Hz, type H), 7.48 (ÍH, d, 7.6 Hz, type H), 7.61 ( ÍH, br, amide NH), 10.85 (HH, br, NH character); IR (film): 3322, 2922, 1698, 1652, 1519, 1490 and 1455 cm _1; MD m / e (Cl) 414 (M * + H); melting point: 82 ° - 85 ° C; Analysis C24H35N303 • 0.1 H20, C, H, N; ß _20 = -29 ° (c = 0.5, MeOH). D Step 3 To a solution of (VIII) (0.14 g, 0.34 mmol) in CH2Cl2 (30 mL) is added trifluoroacetic acid (0.1 mL, 1.3 mmol) and the solution is heated at reflux for 30 minutes, then allowed to cool to room temperature. ambient. The mixture is placed in EtOAc (100 mL) and washed (Na 2 CO 3, 2 N aqueous, 100 mL), dried (MgSO 4), and evaporated to dryness in vacuo (60 ° C). Recover (IX) as a yellow oil (109 mg, 103%). This is completely characterized.
EXAMPLE 11 N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (IH-indol-3-yl) -2-methyl-propionamide.
Example 11 is isolated in a 74% yield.
To a stirred solution of compound (IX) (109 mg, 0.34 mmol) and THF (40 mL) is added 2.6-diisopropyl phenyl isocyanate (0.15 g, 0.7 mmol) and the reaction is heated at reflux for 30 minutes, then Let it cool to room temperature. The volatiles are removed in vacuo (60 ° C) and the residue is purified by flash column chromatography (silica gel, eluent 50% EtOAc / 50% heptane) followed by reversible phase column chromatography (63 &acetonitrile / 37 % Water). Example 11 is recovered as a white solid (132 mg, 74%); melting point: 229 ° - 231 ° C. 1 H NMR (DMSO-de): d 0.50-1.70 (26H, br m, a CH 3 + 2 x (CH *) 2CH + cyclohexyl), 2.88 (2H, br, CH 2 N), 3.10-3.60 (4H, br, 2 x (CH3) 2CH + CHH Nature), 6.45 O II (ÍH, br, PhNHCNH), 6.94 (ÍH, br, CH character), 7.00 - 7.80 (9H, br m, 4 x type CH + O II PhNHCNH + amide NH + 3 x aromatic CH), 10.90 (ΔH, br s, NH character); IR (film): 3287, 2925, 1668 and 1519 cm "1; MS m / e 517 (M + + H); Analysis C32H44N402, C, H, N, melting time: 229 ° - 231 ° C; 2 • 0 = 2 ° (c = 0.25, MeOH) D EXAMPLE 17 N-cyclohexylmethyl-2 - [3 - (2,6-dimethoxy-phenyl) -ureido] -3- (ÍH-indol--yl) -2-methyl-propionamide Example 17 is prepared as in Scheme 5 using cyclohexyl methyl amine and 2, -dimethoxy phenyl isocyanate.
Example 17 is isolated as a white amorphous solid (70 mg). 1H NMR (CDC13): d 0.90 (2H, m), 1.20 (3H, m), 1.30 (2H, m), 1.40 (1H, m), 1.65 (3H, s), 1.70 (2H, m), 2.90. (HH, m), 3.05 and 3.45 (2H, Abq, J = 15 Hz), 3.20 (HH, m), 3.58 (6H, s), 5.20 (HH, s), 5.70 (HH, s), 6.45 ( 2H, m), 6.82 (IH, s), 6.90 (IH, br s), 7.00 (IH, br s), 7.15 (2H, m), 7.30 (IH, d, J = 6 Hz), 7.45 (1H , d, J = 6 Hz), 8.10 (ÍH, br s); IR (CDC13, film): 3306, 3050, 2924, 1668, 1652, 1594 and 1258 cm'1; Analysis calculated for C28H36N404: C, 68.27; H, 7.37; N, 11.37. It was found: C, 68.21; H, 7.55; N, 11.01.
SCHEME 6 Reagents and conditions: i) Boc2, 10% Na2C03, dioxane. ii) HBTU, 2,6-diisopropyl phenyl amine, DIPEA, DMF. iii) TFA, DCM iv) a-t-butyl benzyl isocyanate, THF.
Synthesis of Example 18 Step 1 To a solution of (S) -tryptophan (5.1 g, 25 mmol) in 10% Na 2 CO 3 (aqueous) (61 mL) and dioxane (150 mL) is added tertiary butyl bicarbonate (5.67 g, 26 mmol), and the mixture is stirred for 18 hours. The solvent is removed in vacuo and the residue is placed in water and EtOAc. The mixture is acidified to pH 2-3 and extracted with EtOAc, dried (MgS? 4) and concentrated in vacuo to produce X as a white foam II. 6 g, 100%). 1 H NMR (CDCl 3): d 1.43 (9H, s, C HCH ^), 3.32 (2 H, m, CH 2 Character), 4.66 (1 H, m, a CH), 5.06 (H, m, NH), 7.02 (H, s) , ArH), 7.10 (HH, t, ArH), 7.20 (HH, t, ArH), 7.35 (HH, d, 8 Hz, ArH), 7.60 (HH, d, 7.6 Hz, ArH), 8.14 (HH, br s, NH nature).
Step 2 To a mixture of the acid X (3.04 g, 10 mmol), HBTU (3.79 g, 10 mmol), and diisopropyl ethyl amine (3.77 g, 30 mmol) in DMF (100 mL) which has been stirred for 20 minutes Diisopropyl aniline is added and the mixture is stirred for an additional 18 hours. The solvent is removed in vacuo and the residue is taken up in EtOAc and washed with a solution of saturated ammonium chloride, saline, dried (MgSO 4) and concentrated in vacuo. The residue is purified over normal silica phase with 2.5% MeOH in DCM to produce XI (1.39 g, 30%). 1H NMR (CDC13): d 0.98-1.06 (12H, m, [(CH3) 2CH] 2), 1.46 (9H, s, C (CH3) 3), 2.7 (2FI, m, [CH (CH3) 2] 2), 3.34 (2H, dd, 3.6 and 8 Hz, CH2 Character), 4.70 (ÍH, m, aH), 5.20 (ÍH, OO II II m, aH), 5.20 (1H, br s, CNH), 7.09 - 7.27 (7H, m, 6ArH + CNH), 7.39 (HH, d, 8.0 Hz, ArH), 7.75 (HH, d, 8.0 Hz , ArH), 8.10 (Í H, s, NH type); IR (movie): 3289.0, 2966.0, 1694.9, 1668.0, 1505.0, 1366.0, 1250.0, 1167.0, 910.0 and 739. 0 cm "1; MS m / e (FAB) 464 (M + H +); Analysis C28H37N303, C, N, H, melting point: 98o - 100 ° C.
Step 3 Compound XI (1.0 g, 2.2 mmol) is dissolved in formic acid (30 mL) and stirred for 5 hours. The mixture is basified with a sodium hydroxide solution diluted to pH 14 and extracted with EtOAc, dried (MgSO 4) and concentrated in vacuo to give compound XII (745 mg, 95%) as a crude yield which it is used without further purification in the next step.
EXAMPLE 18 N - (2,6-diisopropyl-phenyl) -2- [3 - (2-dimethyl-1-phenyl-propyl) -ureido] -3- (1H-indol-3-yl) -propionamide To one solution of amine XII (51.0 g, 0.14 mmol) in THF (50 mL) is added to -1-butyl benzyl isocyanate (27 mg, 0.14 mmol) and the mixture is stirred at room temperature for 15 hours. The solvent is removed under reduced pressure and the residue is purified by column chromatography using EtOAc / heptane at a ratio of 1: 1 as eluent to yield compound 18 as a white solid (> 7 mg,> 10%). 1H NMR (CDC13): d 0.81 and 0.85 (9H, 2 xs, t-butu), 0.93 (6H, d, 7.20 Hz, (CHs ^ CH), 1.025 (6H, d, 6.8 Hz, (CHb) 2CH) , 2.58 - 2.68 (2H, m, [(CH3) 2CH] 2, 3.2 - 3.7 O II (2H, m, CH2 type), 4.40 - 4.50 (H, m, aH), 4.8 - 5.5 (3H, m, CNH x 2 and PhCHC (CH3) 3, O II 6.7 - 6.8 (ÍH, m, CNH), 7.0 - 7.26 (11H, m, 11 ArH), 7.4 and 7.44 (ÍH, 2 xd, ArH), 7.65 -7.75 (ÍH, m, lArH), 7.85 and 7.05 (ÍH, 2 x br s, NH type); IR (film): 3387.7, 3296.8, 1653.8, 1663.8, 1663.3 and 1552.8 cm "1; Analysis: C35H44N402, C, H, N; melting point: 160 ° - 161 ° C.
SCHEME 7 19 -. 19-21 (iii: Reagents and conditions: i) 2,6-diisopropyl phenyl isocyanate, DMF, 60 ° C. Ii) Intermediate II, HBTU, DIPEA, DMF. iii) Pd / C, H2; EtOH.
Table for Scheme 7 Example number Ar Synthesis of Example 19 Step 1 To a suspension of the racemic amino acid (500 mg) in THF (10 mL) is added NEt3 (244 mg) followed by isocyanate (250 mg). The reaction mixture is refluxed for 4 days, evaporated to dryness and the residue is partitioned between EtOAc and 0.1 M HCl to produce the crude acid XIII (Ar = 2-pyridine-N-oxide) as a yellow gum (405 mg). The compound is put without purification in the next step.
EXAMPLE 19 2 - . 2 - . 2 - . 2 - . 2 - [3 - ("2,6-diisopropyl-phenyl) -ureido] -2-methyl-3 - (1-oxy-pyridin-2-yl) - N - (1-pyridin-2-yl-cyclohexylmethyl) - propionamide To a solution of acid XIII (Ar = 2-pyridine-N-oxide) (200 mg), HBTU (198 mg) and Intermediate II (100 mg) in DMF (3 mL) is added DIPEA (135 mg) The reaction mixture is stirred at room temperature for 2 days, evaporated to dryness and the residue is partitioned between EtOAc (H20 to produce the crude product as a yellow gum.This is purified by column chromatography to produce Example 19 as a white amorphous solid (195 mg). 1H NMR (CDC13): d 0.95 (2H, br s), 1.05 (2H, br s), 1.20 - 1.60 (8H, m), 1.70 (3H, br s), 2.20 (2H, m), 3.10 - 3.50 (4H, m), 5.50 (ÍH, s), 7.00 - 7.20 (5H, m), 7.40 (3H, m), 7.60 (2H, m), 7.80 (1H, br s), 8.60 (ÍH, s); 1R (CDC13, film): 3253, 3050, 2931, 1667, 1661, 1531-y 1441 cm "1; Analysis for C34H45N503" 0.5 CH2C12: Calculated: C, 67.47; H, 7.55; N, 11.40. 67.89; H, 7.58; N, 11.63.
Synthesis of Example 20 Step 1 As in step 1 in the synthesis of Example 19, the production of XIII (Ar = 2 trifluoromethyl phenyl) is 280 mg. It is used without further purification in the next step.
EXAMPLE 20 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -2-methyl-N- (1-pyridin-2-yl-cyclohexylmethyl) -3- (2-trifluoromethyl-phenyl) -propionamide. As in Step 2 in the synthesis of Example 19, the production of Example 20 is 100 mg. (as an amorphous solid). 1H NMR (CDC13): d 0.90 (2H, br s), 1.10 (12H, br s), 1.30 - 1.60 (8H, m), 1.55 (3H, s), 2.00 (2H, m), 3.10 (ÍH, br s), 3.30 - 3.50 (3H, m), 5.10 (HH, s), 5.50 (1H, s), 7.10 - 7.30 (9H, m), 7.50 (HH, d, J = 8 Hz), 7.65 ( ÍH, t, J = 7 Hz), 8.50 (ÍH, d, J = 2 Hz); IR (CDC13, film): 3334, 3050, 2932, 1668, 1651, 1538, and 131 1 cm "1; Analysis for C36H45F3N4? 2: Calculated: C, 69.43, H, 7.28; N, 8.99. Found: C, 69.43: H, 7.38; N, 8.70.
Synthesis of Example 21 Step 1 As in step 1 of the synthesis of Example 19, the production of XIII (Ar = 2 nitrophenyl) is 450 mg. Be used without further purification in the next step.
EXAMPLE 21 2-Methyl-3 - (2-nitro-phenyl) -2 - ["3 - (4-nitro-phenyl) -α] -N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide. Step 2 of Example 19, the production of Example 21 is 80 mg (as a white amorphous solid). 1 H NMR (CDCl 3): d 0.90 (2 H, br s), 1.10 (12 H, br s), 1.30 - 1.50 (8 H, m), 1.60 (3 H, s), 2.10 (2 H, m), 3.10 (1 H, m), 3.30 - 3.60 (3H, m), 5.50 (2H, br s), 7.10 (4H, m), 7.30 (3H, m), 7.35 (2H, d, J = 8 Hz), 7.65 (2H, m), 8.60 (ÍH, d, J = 2 Hz); IR (CDC13, film): 3335, 3050, 2931, 1667, 1651, 1527 and 1351 cm "1; Analysis for C55H45N5O4 ° 0.2 heptane: Calculated: C, 70.53; H, 7.84; N, 11.30. Found: C, 70.92; H, 7.91; N, 11.06.
EXAMPLE 22 • 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -2-methyl-3-pyridin-2-yl-N- (1-pyridin-2-yl-N- (l-pyridin-2- il-cyclohexylmethyl) -propionamide To a solution of N-oxide 19 (153 mg, 0.27 mmol) in ethanol (50 mL) is added palladium on carbon at 10% and the reaction mixture is stirred on an apparatus of Parr hydrogenation under 55 psi of hydrogen at 35 ° C. for 20 hours. • reaction is filtered through celite and the filtrate is concentrated in vacuo. The residue is purified on silica phase which is eluted with a gradient of heptane in a 1: 1 ratio of Heptane: EtOAc to yield compound 22 (24.9 mg, 16.7%). 1H NMR (CDC13): d 0.99 - 1.05 (6H, m, (CH3) 2CH), 1.05 - 1.20 (6H, m, (CHV CH) 1.31 - 1.69 (8H, m, cyclohexyl), 1.56 (3H, s , aCH3), 2.12-2.21 (2H, m, cyclohexyl), 2.72-2.75 (H, m, (CH3) CH), 3.10-3.20 (3H, m, pyridyl CH2, (CH3) 2CH), O O II. II 3.40 (ÍH, dd, 13.43 y 5.86 Hz, CNHCHH), 3.53 (ÍH, dd, 13.43, 6.35 Hz, CNHCHH), 5.46 5 O O II II I (ÍH, s, PhNHCNH). 6.92 (ÍH, br t, 5.13 Hz, CNH-amide), 7.08 - 7.12 3H, m, 3 ArH), O II 7.22 - 7.26 (2H, br s, PhNHCNH, ArH), 7.27 - 7.48 (4H, m, 4ArH), 7.62 - 7.66 (2H, m, 2ArH), 8.60 - 8.62 (ÍH, m, ArH); IR (film): 3278.0, 1919.0, 1668.0, 1590.0, 1520.0, 1471.0, and 1208.0 cm "1; MS m / e (APCI) 556.0 (M + H "); Analysis C34H45N502 • 0.25 H20, C, H, N, melting point:> 185 - 186 ° C; HPLC RT = 6.16, C18 reversible phase, 40% a 100% MeCN: TFA / H20: TFA SCHEME 8 Reagents and conditions: i) 2,6-diisopropyl phenyl isocyanate, DMF, 60 ° C. Ii) Intermediate II, HBTU, DIPEA, DMF. iii) Formic acid, DCM Synthesis of Example 23 Step 1 To the mixture of N-trityl histidine (0.99 g, 2.5 mmol) in THF (70 mL) and DMF (20 mL) is added pyridine (396 mg, 5 mmol) followed by diisopropyl phenyl isocyanate (1.02 g, 5%). mmoles) and the mixture is refluxed for 1.5 hours. The reaction mixture is allowed to cool to room temperature before being placed in EtOAc and washed with 1 N HCl (aqueous), dried (MgSO 4) and concentrated in vacuo. The residue is used crude for the next step (2.20 g, 100%) XIV.
Step 2 To a solution of the acid XIV (500 mg, 0.81 mmol) in DMF (50 mL) is added HBTU (309 mg, 0.81 mmol) and diisopropyl ethyl amine (316 mg, 2.43 mmol) and the mixture is stirred for 5 hours. minutes Amine II (155 mg, 0.81 mmol) is then added to the reaction mixture which is stirred for an additional 2 hours. The mixture is placed in EtOAc and washed with NaHCO3 (aqueous), saline, dried (MgSO4) and concentrated in vacuo. The residue is purified on a normal silica phase which is eluted with a gradient of heptane: EtOAc in a ratio of 1: 1 to EtOAc and then further purified on a reversible phase of silica eluting with MeOH to produce the pure XV compound ( 120 mg, 7.8%). 1H NMR (CDC13): d 0.90-1.64 (20H, 4 xm, [(CH3) 2CH] 2 and cyclohexyl-8H), 2.05-2.18 (2H, m, cyclohexyl), 2.60-2.70 (1H, m, (CH3 ) 2CH), 2.96 (ÍH, dd, 14.65 and 4.39 Hz, OR II Character CHH), 3.35 (ÍH, dd, 5.86 and 13.19 Hz, CNHCHH), 3.45 (ÍH, dd, 6.35 and 13.43 Hz, or II CNHCHH), 3.03 - 3.25 (2H, m, CHH Nature and (CH3) 2CH), 4.47 (H, m, 5.58 - 5.65 (H, O O II II m, CNH), 6.5 (HH, s, PhNHCNH), 6.85 - 7.04 (HH, m, 1 ArH), 7.03 (8H, t, 1.46 Hz, 8ArH), 7.11 (2H, d, 7.82 Hz, 2ArH ), 7.20-7.38 (14H, m, 14ArH), 7.57 (ΔH, td, 1.71 and 7.81 Hz, ArH), 8.53 (ΔH, d, 3.17 Hz, pyridyl H).
EXAMPLE 23 2 - . 2-T3 - (2,6-diisopropyl-phenyl) -ureido] -3- (TH-imidazol-4-iO-N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide) A mixture of XV (120 mg, 0.15 mmole) in formic acid (5 mL) and DCM (50 mL) is stirred at room temperature for 24 hours.The solvents are removed in vacuo and the residue is placed in water (50 mL) and washed with water. EtOAc The aqueous layer is concentrated in vacuo at less than 40 ° C. and the residue is taken up in DCM and ether and concentrated by vacuo to obtain compound 23 as a solid (57.8 mg, 65.4%). 1 H NMR (DMSO): d 1.05-1.60 (8H, m, cyclohexyl), 1.06 (12H, d, 6.84 Hz, O [(CH3) 2CH] 2), 2.10-2.13 (2H, m, cyclohexyl), 2.67- 2.72 (ÍH, m, CNHCHH), 2.80 - 2.98 OR II (ÍH, m, CH (CH3) 2), 3.0 - 3.16 (1H, m, CH (CH3) 2), 3.18 - 3.21 (ÍH, m, CNHCHH), 3.31 - 3.41 (2H obscured by water peak, CHH imidazole, 4.384.42 (OH, m, aH), 6.43 (OH, br OO II II s, CNH), 6.77 (ÍH, br s, CNH), 7.08 (2H, d, 7.32 Hz, 2 ArH), 7.18 - 7.21 (2H, m, 2ArH), OR 7.34 (ÍH, d, 8.06 Hz , lArH), 7.52 - 7.69 (2H, mx 2, CNH, lArH), 7.71 (ÍH, t, 7.81 Hz, lArH), 8.56 (ÍH, d, 4.15 Hz, ArH), 12.00 (lh, br s, Nature NH); IR (film): 3291.0, 2929.0, 1733.0, 1645.0, 1589.0, 1539.0, 1741.0, 1632.0 and 1238.0 cm "1; ME m / e (E1 +) 530 (Nf *) 531 (M + lí); Analysis for C31H42N6O2 • 0.7 HCOOH; fiysis point: 114 ° - 116 ° C; HPLC R. T. = 17.045 and 17.36, C18 reversible phase 10% to 80% MeCN: TFA H20: TFA.
SCHEME 9 Reagents and conditions: P - nitrophenyl chloroformate, NEt3, THF ii) 2,6 - diisopropyl phenyl N methyl amine, NEt3, toluene,? iii) LiOH, H20, MeOH,? iv) HBTU, cyclohexyl methyl amine, DIPEA, DMF.
Synthesis of Example 24 Step 1 To a cold (0 ° C) solution of a-Me (RS) tryptophan methyl ester (2 g, 8.6 mmol) in dry THF (100 mL) is added dropwise p-nitro phenyl chloroformate (1.74) g, 8.6 mmol) followed by triethylamine (1.2 mL, 8.6 mmol) per drop. The reaction mixture is warmed to room temperature and stirred for 2 hours. The solution is placed in EtOAc and washed with 1 N HU (aqueous), saline, dried (MgSO4) and concentrated in vacuo. The residue is purified on normal phase silica with a heptane gradient at a 7: 3 ratio of heptane / EtOAc as eluent to give compound XVI (1.85 g, 54%) which is used without further purification in the next step .
Step 2 To a solution of carbamate XVI (318 mg, 0.8 mmol) in toluene (60 mL) was added N-methyl diisopropyl aniline (XX) (153 mg, 0.8 mmol) followed by triethyl amine (1 mL) and the mixture was mixed. reflux for 9 hours. The mixture is taken up in EtOAc and washed with INN of HCl (aqueous), saline, NaHCO 3 (aqueous), dried (MgSO 4) and concentrated in vacuo. The residue is purified by normal phase chromatography eluting it with a gradient of heptane at a 6: 4 ratio of heptane / EtOAc to yield pure compound XVII (213 mg, 59.2%). 1H NMR (CDC13): d 0.77, 0.86, 1.10, 1.14 (12H, 4 xd, 6.84, 6.59, 7.08, 6.84 Hz, respectively, [(CH3) 2CH] 2), 1.68 (3H, s, dCH3), 2.86 (ÍH, q ", 6.84 Hz, (CH3) 2CH), 2.98 (ÍH, qn, 6.84 Hz, (CH3) 2CH), 3.03 (ÍH, d, 14.40 Hz, CHH type), 3.08 (3H, s. - CHA O II 3.13 (ÍH, d, 14.40 Hz, CHH type), 3.63 (3H, s, CO2CH3), 4.68 (H, s, N (CH3) CNH), 6.23 (H, d, 2.44 Hz, lArH) , 6.99 (ÍH, t, 7.08 Hz, lArH), 7.09 - 7.16 (3H, m, 3 ArH), 7.25 - 7.27 (ÍH, m, ArH), 7.31 - 7.36 (2H, m, 2ArH), 7.77 (ÍH , s, NH type); IR (film): 3280.0, 2963.0, 1737.0, 1650.0, 1508.0, 1459.0, 1343.0, 1256.0, 1105.0, 910.0 and 739.0 cm "1.
Step 3 To a solution of ester XVII (151.6 mg, 0.34 mmol) in THF (20 mL) is added lithium hydroxide (529 mg, 12.6 mmol) as a solution in water (30 mL) followed by methanol (10 mL) and the reaction mixture is refluxed. The mixture is concentrated in vacuo to remove only the organic solvents and the remaining aqueous mixture is extracted with ether. The aqueous layer is acidified to pH 1 with JPIC (aq uso) and re-extracted with EtOAc, dried (MgSO 4) and concentrated in vacuo to yield pure acid XVD3 (105 mg, 71%). 1H NMR (CDC13): d 0.69 (3H, d, 6.84 Hz, CH3CH), 0.82 (3H, d, 6.84 Hz, CH3CH), 1.13 (3H, d, 6.84 Hz, CH-CH), 1.65 (3H, s , dCH3), 2.72 (ΔI, q ", 7.08 Hz, (CH3) 2CH), 2.79 (ΔI, qn, 6.59 Hz, (CH3) 2CH), 2.99 (ΔI, d, 14.89 Hz, Character CHH), 3.32 ( ÍH, d, 14.89 Hz, O II CHH type, 3.10 (3H, s, N - CH *), 4.72 (HH, s, NMeCNH), 6.46 (HH, d, 2.69 Hz, Type H2), 6.93 (HH, t, 7.08 Hz, Type H5), 6.99 (ÍH, t, 4.15 Hz, type H6), 7.08 - 7.33 (5H, m, 5ArH), 7.79 (ÍH, brs, NH type); IR (film) - 3383.0, 1634.0, 1505.0 and 1053.0 cm "1; MS m / e (APC1) 436.7 (M + H. +).
EXAMPLE 24 N-Cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -3-methyl-ureido] -3- (1H-indol-3-yl) -2-methyl-propionamide. 15 To a solution of acid XVIII (104 mg, 0.24 mmol), HBTU (91 mg, 0.24 mmol) and diisopropyl ethyl amine (93 mg, 0.72 mmol) which has been stirred for 10 minutes, cyclohexyl methyl amine ( 54 mg, 0.48 mmol) and the mixture is stirred for 1 hour. The reaction mixture is taken up in EtOAc and washed with 1 N HCl (aqueous), NaHCO 3 (aqueous), saline, dried (MgSO 4) and concentrated in vacuo. He The residue is purified by normal phase chromatography eluting it with a gradient of heptane at a 1: 1 ratio of heptane / EtOAc to give pure compound 24 (56 mg, 45%), melting point: 214 ° -216 ° C . 1H MR (CDC13: d 0.68, 0.95, 1.11, 1.15 (12H, 4 xd, 7.08 Hz, [(CHVbCHj ?. 0.82-0.93 (2H, m, cyclohexyl), 1.30-1.36 (2HS m, cyclohexyl), 1.56- 1.66 (6H, m, cyclohexyl), 1. 66 (3H, s, aCH3), 2.76 - 2.83 (ÍH, m, (CH3) 2CH), 2.78 (ÍH, d, 14.40 Hz, CHH Nature), OR II 2.90 (OH, qn, 6.84 Hz, (CH3) 2CH), 3.05 (2H, t, 6.10 Hz, CNHCH.), 3.08 (3H, s, N-CH3), OR II 3.37 (ÍH, d, 14.65 Hz, CHH Nature), 4.67 (ÍH, s, N (CH3) CNH), 6.19 (ÍH, d, 2.4 Hz, ArH), OR II 6.83 (ÍH, br t, CNHCH2), 6.95 (ÍH, t, 7.81 Hz, ArH), 7.08 (2H, t, 7.57 Hz, 2ArH), 7.16 (ÍH, d, 7.57 Hz, ArH), 7.23 (ÍH , d, 8.3 Hz, ArH), 7.31-7.36 (2H, m, 2ArH), 7.73 (OH, br s, NH type); IR (film): 3307.0, 2925.0, 1625.0, 1505.0, 1339.0, and 739.0 cm "1; MS m / e (APCI) 531. 7 (M + H +); Analysis for C33H46N402, C, H, N; melting point: 214 ° - 216 ° C; HPLC R. T. = 19.77, C1S reversible phase, 40% to 100% MeCN: TFA / H20: TFA.
SCHEME 10 xx Reagents and conditions: i) DCC, HOBt, amine, DCM ii) HCl gas, Et20 iii) 2,6-diisopropyl phenyl isocyanate, EtOAc,? iv) Separated diasteroisomers by chromatography.
Synthesis of Example 25 Step 1 A solution of BOC (RS) - (a-methyl) tryptophan (3.00 g, 9.4 mmol), (4S, 5S) - (+) - 5-amino-2, 2-dimethyl-4- phenyl-1,3-dioxane (1.95 g, 9.4 mmol), 1-hydroxybenzotriazole hydrate (1.07 g, 94 mmol) in dichloromethane (100 mL), cooled to 0 ° C.
C. and stir for 5 minutes at which time dicyclohexylcarbodiimide is added (1.94 g, 9.4 mmol) and the reaction mixture is stirred for 10 days at room temperature. The reaction mixture is concentrated to dryness, put into ethyl acetate, washed with 10% aqueous potassium carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to a yellow oil. .
The oil is filtered through silica gel using ethyl acetate as eluent. The product (Intermediary XIX) is obtained as a white foam, 4.70 g.
FAB mass spectrum (M + H) * = 508.6.
Analysis for C29H37N3? 5 (507.63).
Step 2 Anhydrous hydrogen chloride gas is bubbled into gas in a solution of BOC-amide-acetonitrile (1.00 g, 2.0 mmol) (Intermediate XIX) for approximately 3 minutes. The reaction mixture is allowed to stand at room temperature for 3 hours and no initial material remains per tic. The reaction mixture is concentrated in vacuo in a light brown solid. The solid is divided between 0.1 N of sodium hydroxide and ethyl acetate, the ethyl acetate is dried over magnesium sulfate, filtered and concentrated to a white foam. The white foam is filtered through silica gel using ethyl acetate as eluent. The product (Intermediary XX) is obtained as a white solid, 0.33 g.
Mass spectrum The M + = 407.
Original molecular weight = 407.5 Analysis calculated for C24H29N303 • 0.33 H20, C, H, N.
A product of the reaction is aminodiol 0.25 g. A larger run that uses 3.4 g of BOC-amide-acetonide, produces 2.18 g of amino acetonide and 0.58 g of aminodiol.
EXAMPLE 25 2 - . 2-T3 - (2,6-diisopropyl-phenyl) -ureido] - N - (2, 2-dimethyl-4-phenyl-f 1. 31 dioxan-5-yl) - 3 - (1H - indole - 3 - il) -2-methyl-propionamide A solution of amino acetonide (0.40 g, 0.98 mmol) (Intermediate XX) and 2,6-diisopropyl phenyl isocyanate (0.23 g, 1.13 mmol) in ethyl acetate (30 mL) is briefly heated to achieve the solution. The reaction mixture is allowed to stand for 2 days at room temperature and then concentrated to a viscous oil. The oil is chromatographed on silica gel using ethyl acetate as eluent to yield 0.288 g of the less polar product (Example 25).
Mass spectrum FAB (M + H4) 4 = 611.2. Analysis for C37H46N4? 4 • 0.33 C4H802, C, H, N. Original molecular weight = 610.78. 0.237 g of the most polar product are also obtained. Mass spectrum FAB (M + H +) + = 61 1.2.
EXAMPLE 26 (S) Example 26 is prepared as in Scheme 3 using Intermediary XXI. Example 26 is isolated in a 24.5% yield. 1 H NMR (DMSO): d 1.12-1.15 (8H, mm, cyclohexyl), 1.47 (3H, s, dCH3), 1.96-2.03 (2H, m, cyclohexyl), 2.56 (3H, s, N-C-CHA 3.06 (ÍH, dd, J = 5.37 and 13.19 OO II II Hz, CNHCHH), 3.27 (IH, dd, J = 6.59 and 13.18 Hz, CNHCHH), 3.40 (2H, 2 x d, J = 15.62 and O II 15.14 Hz, respectively, CHH Nature), 6.56 (ÍH, s, NHCNHaC), 6.81 (1H, t, J = 7.81 Hz, Character H - 5), 6.95 (ÍH, d, J = 2.20 Hz, type H - 2), 6.98 - 7.00 (2H, m, Character H - 6 and CH - 5), 7.28 (ÍH, d, J = 8.06 Hz, ArH), 7.43 (1 H, d, J = 7.81 Hz, ArH), 7.46 (1H, Bt, JO = 5.37 Hz, CNHCH2), 7.63 (2H, d, J = 9.28 Hz, p - N02 ArH x 2), 8.16 (2H, d, J = 9.27 O II Hz, p - N02 ArH x 2), 9.50 (ΔH, s, NHCNH), 10.83 (ΔH, s, NH type); IR (film): 3342.0, 2933.4, 1704.3, 1645.0, 1555.9, 1505.0, 1456.4, 1329.0, 1 112.0 cm "1; MS m / e (ES) 573.05 (M4), 575.08 (M + H); Analysis: C3oH34N6? 4S: C, H, N; melting point: 205 ° -209 ° C; HPLC RT = . 85, C, 1l8d reversible phase, 40% to 100% MeCN: TFA / H20: TFA.
EXAMPLE 27 (S) Example 27 is prepared as in Scheme 3 using Intermediary XXII. Example 27 is isolated in a 26.2% yield. 1 H NMR (DMSO): d 1.03-1.53 (8H, m, cyclohexyl), 1.44 (3H, s, aCH *), 2.10 - O II 2.20 (2H, m, cyclohexyl), 3.065 (HH, dd, J = 5.13 and 12.94 Hz, CNHCHH), 3.28 (HH, dd, O II obscured by water peak, CNHCHH), 3.38 (2H, 2 xd, J = 15.14 Hz, CHH Nature), OR 3.68 (3H, s, OCH3), 6.55 (1_H, s, NHCHaC), 6.81 (H, t , J = 7.08 Hz Character H - 5), 6.94 (HH, d, J = 1.71 Hz character H2), 6.98 (HH, t, J = 7.08 Hz, type H6), 7.04 (HH, dd, J = 2.93 and 8.79 Hz, type H7), 7.19 (HH, d, J = 8.79 Hz, pyridyl H3), 7.23 (HH, d, J = 8.3 Hz, pyridyl O II H4), 7.41 - 7.45 (2H, m, CNHCH2 and ArH), 7.62 (2H, d, J = 98.28 Hz, p - N02 ArH x 2), 8.16 (2H, d, J = 9.52 Hz, p -N02 ArH x 2), 8.17 - 8.19 (ÍH, m, ArH), 9.49 (ÍH, s, O II NHCNH), 10.82 (ÍH, s, NH nature); IR (film): 3355.0, 2925.0, 1652.1, 1558.0, 1504.7, 1453.6, 1328.2 and 1052.5 cm "; MS m / e (APCI) 584.1 (M), (M + H4") = 585.1; Analysis: C32H36N6O5 • 0.3 H20: C, H, N; melting point 213 ° -215 ° C; HPLC R. T. = 9.81 and 10.40, C18 reversible phase, 40% to 100% MeCN: TFA / H20: TFA.
EXAMPLE 28 Example 28 is prepared as in Scheme 3 using Intermediary XXIII. He Example 28 is isolated in a 48% yield. 1 H NMR (DMSO): d 1.10-1.23 (3H, m, cyclohexyl), 1.37-1.60 (5H, m, cyclohexyl), 1.40 (3H, s, aCH3), 1.98-2.08 (2H, m, cyclohexyl), 2.06 (6H, s, N Mea). 2.98 OR II (ÍH, dd, J = 5.62 and 13.43 Hz, CNHCHH), 3.22 (2H, s, ArCH-> NMe7). 3.27 (ÍH, dd, J = 7.08 O and 14.16 Hz, CNHCHH), 3.35 (HH, d, J = 14.65 Hz), CHH type), 3.40 (HH, d, J = 14.65 O II Hz, CHH type), 6.49 (ÍH, s, NHCNHaC), 6.81 (ÍH, t, J = 7.81 Hz, type H5), 6.93 (ÍH, d, J = 2.2 Hz, type H - 2), 6.98 ( ÍH, t, J = 7.08 Hz, type H6), 7.05 (2H, d, J = 8.06 Hz, OR II 2 x ArH), 7.16 (HH, bt, J = 6.35 Hz, CNHCH2), 7.23 (2H, d, J = 8.30 Hz, 2 x ArH), 7.27 (HH, d, J = 8.06 Hz, type H7) , 7.43 (ÍH, d, J = 7.81 Hz, type H4), 7.64 (2H, d, J = 9.28 O II Hz, p - N02 ArH x 2), 8.18 (ΔH, d, J = 9.28 Hz, 2 x p - N02 ArH), 9.45 (ΔH, s, NHCNH), 10.82 (lH, s, NH type); IR (film): 3339.0, 2930.8, 1705.3, 1651.2, 1599.0, 1329.0, 1112.0 (cm "1); MS m / e (APCI) 611.2 (M + H4); Analysis: C35H42N604: C, H, N; fusion: 200 ° -202 ° C; HPLC RT = 23.35, C18 reversible phase, 10% to 80% MeCN: TFA / f? 20: TFA.
EXAMPLE 29 Example 29 is prepared as in Scheme 3 using Intermediary XXIV. He Example 29 is isolated in a 70% yield. 1 H NMR (DMSO): d 1.10-1.22 (2H, m, piperidino CH's), 1.24-1.42 (4H, m, piperidino CH's), 1.39 (1.5H, s, aMe). 1.43 (1.5H, s, aMe). 2.02 - 2.16 (2H, m, piperidino CH's), 2.21 - 2.30 (2H, m, piperidino CH's), 3.22 - 3.60 (5H, m, CH, and CONHCH2CHN), 6.53 (0.5H, s, CONH), 6.57 (0.5H, s, CONH ), 6.77 - 6.84 (ÍH, m, nature H5), 6.95 - 7.04 (2H, m, Nature H6 and H2), 7.12 - 7.32 (6H, nature • H7 and 5 x ArH's), 7.45 (IH, d, J = 8.1 Hz, I-type H4), 7.48-7.63 (IH, m, CONHCH.), 7.62 (2H, d, J = 9.0 Hz ArHN02 chain), 8.14 - 8.17 (2H, m, ArHN02 chain), 9.49 (0.5 H, s, CONH), 9.50 (0.5H, s, CONH), 10.84 (0.5H, s, NH type) and 10.87 (0.5H, s, NH type); IR (film): 3336.0, 2934.0, 1710.0, 1657.0, 1506.0, 1329.0, 1229.0, 1112.0 and 851.0 cm "1; MS m / e (ES +) 64.2 (20%), 205.2 (37%), 431 1 (12% ), 569.2 (M + H, 100% +), melting point: 133 ° -137 ° C, HPLC RT = 10.57 and 10.77, C18 reversible phase, 40% at 100% MeCN: TFA / H20: TFA.
EXAMPLE 30 Example 30 is prepared as in Scheme 3 using Intermediary XXV. Example 30 is isolated in an 83% yield. 1 H NMR (DMSO): d 1.05-1.20 (3H, m, cyclohexyl CH), 1.30 - 1.42 (5H, m, cyclohexyl CH), 1.47 (3H, s, dCH), 1.70 - 1.90 (2H, m, cyclohexyl CH ), 3.00 -3.10 (HH, m, CHHNHCO), 3.20 - 3.28 (HH, m, CHHNHCO), 3.37 (HH, d, 14.4 Hz, CHH type), 3.45 (HH, d, 14.4 Hz, CHH Nature), 6.51 (HH, s, PhNHCONH or CH imidazole), 6.58 (1H, s, PhN, PhNHCONH or CH imidazole), 6.77 - 6.81 (HH, m, C5 -H nature), 6.93 - 7.04 (8H, m, 6 x ArH, C6 - H nature, C2 - H nature), 7.19 (H, s, imidazole CH), 7.27 (H, d, 7.9 Hz, C7 - H, nature), 7.32 - 7.39 (9H, m, ArH), 7.42 (1H, d, 8.1 Hz C4 - H type), 7.56 (2H, d, 9.0 Hz, PhN02CH), 7.86 (ÍH, t, 5.4 Hz, NH amide), 8.07 (2H, d, 9.0 Hz, PhN02CH), 9.48 (ÍH, s, PhNHCO), 10.82 (ÍH, s, NH type); IR (film): 3335, 3060, 2932, 2855, 1704, 1645, 1599, 1557, 1505, 1446, 1330, 1303, 1230, 1176, 1113, 1039, 101 1, 852 and 745 cm "1; MS m / e (APCI): 786.3 (M + H); melting point: 148 ° - 154 ° C; HPLC R. T. = 16.79, C18 reversible phase, 40% to 100% MeCN: TFA / H20: TFA for 20 minutes.
EXAMPLE 31 To a stirred solution of Example 30 (0.23 g, 0.29 mmol) in MeOH (50 mL) is added 2N HCl (2 mL). The reaction mixture is refluxed for 2 hours. The solution is neutralized using IN of NaOH and evaporated in vacuo. The residue is purified in a reversible phase of silica eluting it with a gradient of MeOH / H20 0% to 100%. The product is eluted with 60% MeOH / H 2 O to give Example 31 as a solid yellow (0.073 g, 44%). 1H NMR (DMSO + DCL / D20): d 1.05-1.25 (3H, m, cyclohexyl CH), 1.35-1.55 (5H, m, cyclohexyl CH), 1.36 (3H, s, dCH3), 1.90-2.00 (2H, m, cyclohexyl CH), 3.10 (HH, d, 13.2 Hz, CHH - type or CHH - cyclohexyl), 3.23 (HH, d, 13.4 Hz, CHH type or CHH - cyclohexyl), 3.28 (2H, s, CH2 - Nature or CH2 - cyclohexyl), 6.78 - 6.80 (H, m, C5 - H), 6.93 - 6.97 (H, m, C6 - H), 7 01 (H, s, ArH), 7.24 - 7.26 (2H , m, C7 - H, Ar - H), 7.40 (ÍH, d, J = 8.1 Hz, C4 - H), 7.59 - 7.61 (2H, m, PhN02 CH), 8.1 1 - 8.14 (2H, m, PhN02 CH), 9.05 (1H, d, 1O Hz, CH imidazole); IR (film): 3356, 2935, 2859, 1699, 1652, 1597, 1557, 1505, 1458, 1331, 1303, 1232, 1208, 1195, 1177, 11 12, 851 and 746 cm "1; MS m / e (High Resolution ES), Measured: (M + H) 4 544.2677, Expected: (M + H) 4 544.2672, Deviation (ppm) + 0.9, Melting point: 150 ° - 152 ° C, HPLC RT = 17.9 minutes C18 reversible phase, 10% to 80% MeCN: TFA / H20: TFA for 20 minutes.
EXAMPLE 32 Example 32 is prepared as in Scheme 5 using Intermediary XXII; melting point: 1 10 ° - 115 ° C. 1 H NMR (DMSO): d 1.05-1.25 (6H, m), 1.40 (3H, s), 1.40-1.50 (4H, m), 2.15 (2H, m), 3.05 and 3.25 (2H, Abq, J = 15 Hz), 3.70 (3H, s), 6.40 (HH, s), 6.80 (HH, t, J = 6Hz), 6.95 (HH, s), 7.00 (HH, t, J = 6 Hz), 7.20 (HH) , d, J = 7 Hz), 7.30 (ÍH, d, J = 7 Hz), 7.40 (2H, m), 7 57 (2H, d, J = 8 Hz), 7.70 (2H, d, J = 8 Hz), 8.20 (HH, s), 9.20 (1H, s), 10.80 (HH, s); MS 565.1 1 (M + H).
PREPARATION OF THE INTERMEDIARY II Reagents and conditions: i) Sodium hydride, 1, 5 - dibromopentane, DMSO, Et20, 15 ° C. ii) Raney nickel, ETOH - NH3, H2, 50 psi, 40 ° C.
PREPARATION OF THE INTERMEDIARIES Synthesis of the Intermediary II Step 1 To a stirred suspension of sodium hydride (60% dissolved in oil) (4 g, 0.1 mmol) in DMSO (70 mL) under nitrogen at 15 ° C, a solution of 2-pyridyl acetonitrile (6 g, 51 mmol) and 1,5-dibromopentane (6.81 mL, 51 mmol) in ether (40 mL) and DMSO (10 mL) for 1 hour. The mixture is allowed to warm to room temperature and stirred for an additional 24 hours under nitrogen. The reaction mixture is carefully quenched by adding isopropanol (10 mL), followed by water (100 mL) 10 minutes later. The reaction solution is taken up in EtOAc and washed with water. The aqueous layer is back extracted with EtOAc and the two organic layers are combined, dried (MgSO 4) and concentrated in vacuo. The residue is purified on silica gel with a gradient of heptane at a 9: 1 ratio of heptane / EtOAc to give 1-cyano-1- (2-pyridyl) cyclohexane (6.77 g, 72%). 1H NMR (CDC13): d 1.77-2.17 (10H, 2 x m, cyclohexyl), 7.20-2.27 (1H, m, pyridyl) H), 7.60-7.62 (1H, m, pyridyl H), 7.70-7.73 (1H, m, pyridyl H), 8.4- 8.42 (1H, m, pyridyl H) - Intermediary II Wash Raney nickel (8 g) with water to obtain a pH of 7 and then wash with ethanol to remove water (making sure that the catalyst is always wet). The Raney nickel is placed in ethanolic ammonia (100 mL) and 1-cyano-1- (2-pyridyl) cyclohexane (6.7 g, 0.036 mmol) is added to the mixture which is then stirred in a Parr 50 hydrogenation apparatus. psi of hydrogen at 40 ° C. for 22 hours. The reaction mixture is filtered through celite and concentrated in vacuo to give the pure Intermediate II as a clear oil (6.89 g, 100%). 1 H NMR: d 1.20-1.65 (10H, m, cyclohexyl), 2.20-2.36 (2H, m, NHA CT 2.70-2.90 (2H, br s, NH--) 7.00 - 7.20 (HH, m, ArH), 7.3 - 7.4 (ÍH, m, ArH), 7.6 - 7.73 (ÍH, m, ArH), 8.6 - 8.7 (ÍH, m, ArH), 7.6 - 7.73 (ÍH, m, ArH), 8.6 - 8.7 (ÍH, m, ArH).
PREPARATION OF THE INTERMEDIARY III 1 '(i i) I I I Reagents and conditions: i) DEAD, PPh3, (PhO) 2PON3, THF ii) Lindiar, EtOH Synthesis of Intermediary III Step 1 A solution of diphenylphosphonyl azide (473 mg, 1.72 mmol) in THF (10 mL) is added dropwise over 20 minutes to a stirred solution of IR, 2S, trans-2-phenyl-1 - cyclohexanol (303 mg, 1.72 mmol), triphenylphosphene (451 mg 1.72 mmol) and diethyl ozodicarboxylate (300 mg, 1.72 mmol) in dry THF (10 mL) at room temperature. The resulting mixture is stirred for 3 days and then the solvent is removed in vacuo. The product is purified by chromatography (silica, 10-20% ethyl acetate in heptane) to leave a clear oil A (217 mg, 63%).
? NMR (CDC13): 1.34 - 2.4 (8H, m, 4 x CH2), 2.76 - 2.80 (ΔH, m, CH), 3.94 (1H, d, CH - N3, J = 2.8 Hz), 7.22 - 7.34 (5H , m, Ph); IR (film): 3028, 2984, 2860, 2103, 1602, 1486, 1447 and 1267; [a] .18 + 81.4 ° D (c = 1.05, acetone) Step 2 Compound A (1.89 mg, 0.84 mmol) is hydrogenated in absolute ethanol (50 mL) at 30 ° C and 45 psi on Lindiar catalyst (25 mg). The catalyst is filtered and the solvent is removed to produce an oil (130 mg, 79%). 1 H NMR (CDC13): 1.01 (2H, bs, NH 2), 1.35 - 2.06 (8H, m, 4 x CH 2) 2.77 - 2.83 (ÍH, m, CH), 2.24 - 2.26 (ÍH, m, CHCH2), 7.20 - 7.34 (5H, m, Ph), IR (film): 3360, 3060, 3025, 2927, 2855, 1601, 1582, 1495 and 1447; [a] 21 + 72.9 ° (c = 1.04, methanol). 15 D PREPARATION OF THE INTERMEDIARY XXI XXI Reagents and conditions: i) (a) EtOAc, NaHCO3 (aqueous); (b) 95% ethanol, water, potassium cyanide, reflux. ii) Sodium hydride, 1,5-dibromopentane, DMSO, Et20, room temperature, Ar. iii) Raney nickel, EtOH-NH3, H2, 50 psi, 35 ° C.
Synthesis of Intermediary XXI Step 1 4-Chloromethyl-2-methyl thiazole hydrochloride (lg, 5.4 mmol) is placed in an aqueous solution of saturated sodium bicarbonate and extracted with EtOAc, dried (MgSO) and concentrated in vacuo. The residue is dissolved in 95% ethanol (50 mL) and potassium cyanide (353 mg, 5.4 mmol) followed by water (5 mL) is added to the reaction mixture. The mixture is refluxed for 18 hours and cooled to room temperature. The reaction mixture is taken up in EtOAc and washed with water, dried (MgSO 4) and concentrated in vacuo. The residue is purified on silica gel with a gradient of heptane at a 1: 1 ratio of heptane / EtOAc to give 4-cyanomethyl-2-methyl thiazole (180 mg, 24%). 1 H NMR (CDCl 3): d 2.71 (3 H, s, CHA 3.85 (2 H, s, CH-CN), 7.13 (H, s, Ar H); IR (film): 2923.0, 2863.7, 2255.6, 1525.0, 1412.0, 1261.0, 1101.0, 1020.0 and 799.0 cm "1; MS m / e (ES) 139.06 (M + H4").
Step 2 As for Intermediary p, Step 1. - "1 - Cyano - 1 - (2 - methyl thiazol - 4 - yl) cyclohexane isolated in a production at 100% 1H NMR (CDC13): d 1.70-2.00 (8H, mm, cyclohexyl), 2.12-2.20 (2H, m, cyclohexyl), 2.70 (3H, s, CH3), 7.12 (lh, s, ArH); IR (film): 2929.0, 2858.7, 1453.1 and 1227.0 cm "1; MS m / e (APCI) 207.12 (M + H4") (100%).
Step 3 As for Intermediary II, Step 2. Intermediate XXI, 1-aminomethyl-1 - (2-methyl thiazol-4-yl) cyclohexane is isolated in a 98% yield. 1H NMR (CDC13): d 1.68-2.00 (8H, mm, cyclohexyl), 2.03-2.20 (4H, mm, 2 x cyclohexyl H, NH2), 2.69 (2H, s, CHJSTH: *), 2.70 (3H, s , CHA 7.12 (ÍH, s, ArH); IR (film): 2927.0, 2857.0, 2237.0, 1667.0, 1515.0, 1453.0, 1376.0, 1185.0, 1169.0, 1141.0, 957.0 and 745.0 cm "1; MS m / e (APCI) 211.15 (M + H4), 207.13 (100%).
PREPARATION OF THE INTERMEDIARY XXII (iii) XXII Reagents and conditions: (i) Sodium hydride, methyl iodide, DMF, 0o C. - room temperature under argon (ii) M - chloro - peroxybenzoic acid, sodium sulfate, DCM, room temperature ( iii) Acetic anhydride, reflux. (iv) Sodium hydroxide, methanol, reflux, (v) Thionyl chloride, DCM, reflux, (vi) Potassium cyanide, 95% ethanol, water, reflux (vii) Sodium hydride, 1,5-dibromopentane, DMSO , Et20, room temperature, Ar. (viii) Raney nickel, EtOH-NH3, H2, 57 psi, 35 ° C.
Synthesis of Intermediary XXII Step 1 To a stirred solution of sodium hydride (60% dissolved in oil) (1.8 g, 45 mmol) in DMF (60 mL) at 0 ° C. under argon, add to a solution of 2 - hydroxy-5-methyl-pyridine (4.91 g, 45 mmol) in DMF (60 mL). Effervescence is observed and the reaction mixture is allowed to warm to 18 ° C. Methyl iodide (2.8 mL, 45 mmol) is added to the reaction mixture which is allowed to warm to room temperature and stirred for 1 hour. hour. The reaction mixture is quenched by adding isopropanol (20 mL) followed by water (20 mL) 30 minutes later, under argon. The reaction mixture is taken up in EtOAc and washed with NaHCO 3 (aqueous), dried (MgSO 4) and concentrated in vacuo to give 2-methyl-methoxy-pyridine as a pure volatile liquid (2.93 g, 53%). 1H NMR (CDC13): d 2.49 (3H, s, CH3-C), 3.83 (3H, s, OCH3, 7.05 - 7.13 (2H, mm, pyridyl H4 and 5), 8.19 (ΔH, d, J = 2.8 Hz , pyridyl H2), IR (film): 2924.0, 2854.0, 1575.0, 1497.0, 1464.0, 1378.0, 1270.0, 1243.0, 1211.0, and 1034.0 cm "1.
Step 2 To a solution of 2-methyl-5-methoxy-pyridine (2.93 g, 24 mmol) in DCM (100 mL) is added sodium sulfate (5 g, 35 mmol), followed by m-chloro-peroxy acid. benzoic acid (10 g, 58 mmol) and the mixture is stirred at room temperature for 48 hours. The reaction mixture is filtered and the white solid is washed with DCM. The filtrate is concentrated and purified by normal phase chromatography which is eluted with a gradient of EtOAc / heptane in a ratio of 1: 1 to EtOAc to give 2-methyl-5-methoxy-pyridine-N-oxide (2.41 g, 72%). %). 1 H NMR (DMSO): d 2.27 (3 H, s, C-CHs), 3.79 (3 H, s, OCH 3), 6.96 (H, d, J = 2.4 and 8.8 Hz, pyridyl H 5), 7.36 (H, d, J = 8.8 Hz, pyridyl H4), 8.08 (ΔH, d, J = 2.4 Hz, pyridyl H2); IR (film): 3386.0, 1616.0, 1566.0, 1452.0, 1375.0, 1304.0, 1197.0, 1172.0, 1131.0, 1030.0, 996.0 and 960.0 cm "1; MS m / e (ES) 140 (M + H4").
Step 3 A mixture of 2-methyl-5-methoxy-pyridyl-N-oxide (1082 g, 7.8 mmol) and acetic anhydride (abundant, 5 mL) is heated gently to reflux for 10 minutes. The reaction mixture is allowed to cool to room temperature before being placed in EtOAc, washed (NaHCO3 (aqueous)), dried (MgSO4) and concentrated in vacuo to give 2-acetoxymethyl-5-methoxy. crude pyridine, which is taken through the next step without further purification. OO 1H MR (CDCl 3): d 2.13 (3H, s, QCCHA 3.87 (3H, s, CHsO), 5.16 (2H, s, CH2OC), 7.20 (ÍH, dd, J = 3.2 and 8.8 Hz, pyridyl H), 7.30 (HH, d, J = 8.4 Hz, pyridyl H), 8.30 (HH, d, J = 3.2 Hz, pyridyl H), IR (film): 2943.0, 1740.0, 1576.0, 1499.0, 1377.0, 1293.0, 1227.0 and 1029.0 cm "1; MS m / e (ES) 182.16 (100%) (M + H4).
Step 4 To a stirred solution of 2-acetoxy-methyl-5-methoxy-pyridine (1.41 g, 7.8 mmol) in methanol (30 mL) is added potassium hydroxide in excess (1.6 g) and the mixture is refluxed for 2 hours. hours. The solvent is removed in vacuo and the residue is purified by column chromatography which is eluted with a gradient of heptane to ethyl. The extremely volatile 2-hydroxy-methyl-5-methoxy-pyridine compound is obtained as a solution in ethyl acetate (0.68 g, 63% yield). 1 H NMR (CDCl 3): d 3.87 (3 H, s, OCHA 4.70 (2 H, s, CH 2 OH), 7.18 - 7.24 (2 H, m, pyridyl H 4 and 5), 8.25 (OH, d, J = 2.8 Hz, pyridyl H2 ); IR (film): 3346.0, 1575.0, 1499.0, 1271.0, 1210.0, and 1028.0 cm'1; ME m / e (ES) 140.18 (M + H).
Step 5 To a solution of 2-hydroxy-methyl-5-methoxy-pyridine (0.68 g, 4.9 mmol) in dry DCM, abundant thionyl chloride is added dropwise (2.0 mL) and the mixture is refluxed for 2 hours. hours. The solvent is removed in vacuo and the residue is taken up in EtOAc and washed with NaHCO 3 (aqueous), dried (MgSO 4) and concentrated in vacuo. The extremely volatile 2-chloromethyl-5-methoxy-pyridine compound is obtained as a solution in ethyl acetate to yield (984.0 mg, 83.5%) of production. 1H MR (CDC13): d 3.87 (3H, s, OCH3), 4.65 (2H, s, CH? Cl) 7.21 (H, dd, J = 2.8 and 8.4 Hz, pyridyl H4), 7.39 (H, d, J = 8.4 Hz, pyridyl H5), 8.27 (ΔH, d, J = 2.8 Hz, pyridyl H2); IR (film): 3337.1, 2930.0, 2854.7, 1731.3, 1639.5, 1537.9, 1423.2, 1301.9 and 1158.0 cm "MS m / e (ES) 158.15 (M + H4) (100%).
Step 6 As for Intermediary XXI, Step 1. 2 - Cyanomethyl-5-methoxy-pyridine is isolated in a 73% pure yield. 1HNMR (CDC13): d 3.87 (3H, s, OCH3), 3.88 (2H, s, CH2CN), 7.22 (ΔI, dd, J = 3.2 and 8.8 Hz, pyridine H4), 7.34 (ΔI, dd, J = 0.4 and 8.4 Hz, pyridyl H5), 8.27 (OH, d, J = 2.8 Hz, pyridyl H2); IR (film): 2922.8, 1575.5, 1496.0 and 1271.5 cm 1; MS m / e (APCI) 149.18 (M + H) (100%).
Step 7 As for Intermediate II, Step I The compound 1-cyano-1- (4-methoxy-pyrido-2-yl) cyclohexane is isolated in a 60% yield. NMR (CDC13): d 1.76-2.12 (10H, mm, cyclohexyl), 3.87 (3H, s, OCH3), 7.21 (ΔI, dd, J = 2.8 and 8.8 Hz, pyridyl H4), 7.51 (ΔI, dd, J = 0.8 and 9.6 Hz, pyridyl H5), 8.29 (ΔH, d, 3.2 Hz, pyridyl H2); IR (film): 2935.0 2863.7, 1575.0, 1478.0, 1299.0, 1269.0, 1244.0, and 1017.0 can "1; MS m / e (ES) 217.16 (M + H4).
Step 8 As for Intermediary II, Step 2 Intermediary XXH, 1-amino-methyl-1- 1 - (4-methoxy-pyrido-2-yl) cyclohexane is isolated in an 82% yield. 1 H NMR (DMSO): d 1.13-1.58 (8H, mm, cyclohexyl), 2.14-2.22 (2H, m, cyclohexyl), 2.56 (2H, s, NH? CHA 3.80 (3H, s, OCH3), 7.30 (2H , m, pyridyl H4 and H5), 8.26 (H, m, pyridyl H2), IR (film): 2925.0, 2858.6, 1569.4 and 1477.8 cm "1; ME m / e (APCI) 221.14 (M + H4).
PREPARATION OF THE INTERMEDIARY XXIII XXIII Reagents and conditions: (i) N-bromo-succinimide, benzoyl peroxide, carbon tetrachloride, room temperature under argon. (ii) Dimethyl amine, DCM, room temperature, (iii) Raney - nickel, EtOH • NH3, 50 psi, 30 ° C.
Synthesis of Intermediary XXIII Step 1 To a solution of 1- (4-methyl-phenyl) -1-cyclohexyl-carbonitrile (2g, 0.01 m) in CC14 (20 mL) under argon at room temperature is added N-bromine Succinimide (1.96 g, 0.011 m) followed by benzoyl peroxide (30% water) (2.3 mg, 1.6 mmol) in CC14 (10 mL), and the reaction mixture is refluxed for 5 hours. The mixture is cooled to room temperature, filtered, washed with DCM and concentrated in vacuo. The residue is purified by normal phase chromatography eluting with a gradient of 10% heptane EtOAc: heptane to give the bromide (2.57 g, 92%). 1 H NMR (CDCl 3): d 1.71-1.86 (8H, mm, cyclohexyl), 2.14 (2H, d, J = 11.96 Hz, cyclohexyl), 4.49 (2H, s, CH2-Br), 7.41 (2H, d, J = 8.54 Hz, 2ArH), 7.47 (2H, d J = 8.06 Hz, 2ArH); IR (film): 2936.0, 2860.0, 2232.0, 1940.0, 1789.0, 1765.0, 1610.0, 1515.0, 1451.0, 1415.0, 1355.0 and 1231.0 cm "1" Step 2 To a stirred solution of 1- (4-bromomethyl-phenyl) -1-cyclohexylcarbonitrile (0.89 g, 3.2 mmol) in DCM (30 mL) under argon at room temperature is added dimethylamine (2 M in HCl). THF) (6.42 mL), 12.8 mmol) and the reaction mixture is stirred for 20 hours at room temperature. IN NaOH (aqueous) (15 mL) is added to the reaction mixture and the solution is stirred for 10 minutes. The reaction mixture is placed in water and extracted with DCM, dried and concentrated in vacuo. The residue is purified on silica (normal phase) eluting it with a gradient of heptane to ethyl acetate to give the dimethylamine in a yield of 76% (593 mg). 1H NMR (CDC13): d 1.72-1.88 (8H, m, cyclohexyl), 2.15 (2H, d, J = 11.71, cyclohexyl), 2.24 (6H, s, N (CH3) 2), 3.4 (2H, s, CH2NMe2), 7.32 (2H, d, J = 8.3 Hz, 2ArH); IR (film): 3375.0, 2932.9, 2859.7, 1645.8, 1455.6 and 1042.0 cm "1; ME m / e (APCI) 243.2 (M + H 4).
Step 3 As for Intermediary 11, Step 2 Intermediary XXIII, 1-aminomethyl-1 - [4 - (N, N-dimethylaminomethyl) -phenyl] cyclohexane is isolated in a quantitative production. 1H NMR (CDC13): d 1.22-1.63 (8H, mm, cyclohexyl), 2.07-2.17 (2H, m, cyclohexyl), 2.25 (6H, s, N (CH3) 2), 2.68 (2H, s, CH2NH2) , 3.41 (2H, s, ArCE NMej), 7.27 (4H, 2 xd, J = 6.8 Hz, 4 x ArH); IR (film): 2931.0, 2856.0, 2814.0, 2766.0, 1513.0, and 1455.0 cm "1; MS m / e (ES) 247 (M + H +).
PREPARATION OF THE INTERMEDIARY XXIV XXIV Reagents and conditions: (i) Lithium aluminum hydride / aluminum chloride, Et 0 THF 0o C.
Synthesis of Intermediary XXIV Step 1 To an ice-cold solution of Et20 (30 mL) under nitrogen is added aluminum chloride (0.5 g, 3.74 mmol) while stirring, for 2 minutes. This solution is added to an ice solution of lithium aluminum hydride, IM in Et20 (3.74 mL), 3.74 mmol) in anhydrous THF (50 mL) stirring under nitrogen. The reduction solution is allowed to warm to room temperature before gradually adding alpha- (1-piperidino) phenylacetonitrile (0.75 g, 3.74 mmoles) dissolved in THF (20 mL). The reaction mixture is stirred for 3 hours before cooling and a mixture of H.O / THF in a ratio of 1: 1. He adds 50% of the aqueous potassium hydroxide (20 mL) producing two layers. The organic layer is separated, dried (K2CO3) and concentrated in vacuo. The residue is purified on silica by eluting it with a gradient of DCM at 25% of MeOH / DCM to give the pure compound XXIV as a white oil (0.47 g, 62%). 1H NMR (CDC13): d 1.28-1.40 (2H, m, piperidino CH's), 1.48-1.63 (4H, m, piperidino CH's), 2.17-2.51 (6H, m, NH2 and 4 piperidino CH's), 2.99 - 3.04 ( ÍH, m, CHCHHNH2), 3.19 - 3.24 (HH, m, CHCHHNH2), 3.45 - 3.48 (HH, m, CHCH2NH), 7.20 - 7.37 (5H,, ArH); IR (film): 2932.0, 2853.0, 2804.0, 1492.0, 1452.0, 1158.0, 1104.0, and 765. 0 cm "1; MS m / e (ES +) 205.2 (M + H4, 100%).
PREPARATION OF THE INTERMEDIARY XXV XXV Reagents and conditions: (i) Triphenylmethyl chloride, triethylamine, DMF, room temperature (ii) Sodium hydride, 1,5-dibromopentane, DMSO, room temperature. (iii) Lithium aluminum hydride / aluminum chloride, Et20, THF, 0 ° C.
Synthesis of intermediate XXV Step 1 To a stirred solution of 4-cyano-methyl imidazole (2.24 g, 20.9 mmol) in DMF (50 mL) is added trifexmethyl chloride (6.42 g, 23.0 mmol) and triethylamine (2.12 g, 20.9 mmol) ), The reaction mixture is stirred at room temperature overnight. The DMF is evaporated in vacuo and the residue is placed in ethyl acetate (100 mL). The resulting white solid is filtered and separated. The filtrate is evaporated in vacuo and purified on silica with a gradient of heptane at a 2: 5 ratio of heptane / EtOAc to give the desired product (6.52 g, 89%). 1H MR (CDC13): d 3.69 (2H, s, CHaN), 6.84 (ΔH, d, 1.0 Hz, imidazole CH), 7.10 -7.15 (6H, m, 6 ArH), 7.32-7.37 (9H, m, 9 ArH), 7.41 (1H, d, 1.5 Hz, imidazole CH); IR (film): 3059, 1597, 1493, 1445, 1412, 1240, 1187, 1156, 1120, 1087, 1037, 991, 907, 871 and 751 cm "1; Analysis: C24H19N3: C, H, N; fusion: 139 ° - 142 ° C.
Step 2 As for Intermediary II, Step 1. The desired compound is isolated in a 63% yield. - - _ - - 1 H NMR (CDC13): d 1.20 - 1.35 (ΔH, m, cyclohexyl CH), 1.65 - 1.90 (7H, m, cyclohexyl CH), 2.13 - 2.18 (2H, m, cyclohexyl CH), 6.82 ( ÍH, d, 1.5 Hz, imidazole CH), 7. 09-7.50 (6H, m, ArH), 7.39 (1H, d, 1.0 Hz, imidazole CH); IR (film): 3060, 2934, 2859, 2233, 1492, 1446, 1161, 1134, 1036, 974, 907, 832, and 747 cm "1; MS (ES4) 418.5 (M4 + H); Analysis: C29H27N3: C, H, N; melting point: 184 ° - 186 ° C.
Step 3 As for Intermediary XXV, it is isolated in a production of 73%. 1H NMR (CDC13): 1.10 - 1.70 (2H, br s, NEb), 1.26 - 1.52 (8H, m, cyclohexyl CH), 1.95 - 1.99 (2H, m, cyclohexyl CH), 2.67 (2H, s, CIfcNH2) , 6.54 (ΔH, d, 1.6 Hz, imidazole CH), 7.12 - 7.17 (6H, m, ArH), 7.31-7.35 (9H, m, ArH) 7.41 (1H, d, 1.6 Hz, imidazole CH); IR (film): 3374, 3059, 2927, 2852, 1598, 1493, 1445, 1324, 1231, 1184, 1118, 1087, 1036, 906, 870, 825 and 747 cm "1.

Claims (20)

    CLAIMS 1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: Ar is phenyl or pyridyl unsubstituted or substituted by 1 to 3 substituents selected from alkyl, halogen, alkoxy, nitro, amino, NH2CH2 -, cyano, CF3, - NHCONH2 and C02R1; R1 is hydrogen or a linear or branched cyclic alkyl of 1 to 7 carbon atoms; R8 is hydrogen or forms a chain with R1 of 3 to 7 carbon atoms; R2 is hydrogen or a straight or branched cyclic alkyl of 1 to 7 carbon atoms with R2 which may contain an oxygen or nitrogen atom; Ar 1 can be independently selected from Ar and also includes pyridyl-N-oxide, indolyl, imidazole and pyridyl; R4, R5, R6 and R7 are each independently selected from hydrogen and methyl; R3 can be independently selected from Ar or is hydrogen, hydroxy,
  1. NMe2, N - methyl where Ar2 is phenyl or pyridyl.
  2. 2. A compound according to Claim 1 wherein: Ar is phenyl unsubstituted or substituted with 1 or 2 substituents selected from isopropyl, chloro, nitro and cyano; R2 forms a chain of 5 to 7 carbon atoms with R9; R4, R5 and R6 are hydrogen; R7 is methyl or hydrogen; R3 is 2-pyridyl or hydroxy; and Ar1 is indolyl, pyridyl, pyridyl-N-oxide and imidazole.
  3. 3. A compound according to Claim 1 wherein: Ar is unsubstituted phenyl; R1 is cyclopentyl or tert -butyl; R4 and R5 are hydrogen; R7 is methyl; R6 is hydrogen; R3 is phenyl with two isopropyl substituents, unsubstituted phenyl or ; and Ar1 is indolil.
  4. 4. A compound according to Claim 1 wherein: Ar is 2,6-diisopropyl-phenyl, 4-nitro-phenyl and 4-cyano-phenyl; R4, R5 and R6 are hydrogen; R7 is methyl; R is hydrogen or forms a chain of 6 carbon atoms with R9; R3 is hydroxyl, 2-pyridyl, And Ar is indolyl, pyridyl-N-oxide, pyridyl.
  5. 5. A compound according to Claim 1 selected from: 20 N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (lH-indole -3-yl) -2-methyl-propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (lH-indole -3-yl) -N-methyl-propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -1-methyl-ureido] -3-25 (lH-indol-3-yl) -propionamide;
  6. 6. A compound according to Claim 4 and selected from: 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -2-methyl-3- (1-oxy-pyridin-2-yl) -N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide; '5 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -2-methyl-3-pyridin-2-yl-N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide;
  7. 7. A compound according to claim 1 and selected from: N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol 0-3 -yl) -2-methyl - propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (ÍH-indol-3-yl) -N-methyl-propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -3-methyl-ureido] -3- (ÍH-indol-3-yl) -2-methyl-propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-diisopropyl-phenyl) -1-methyl-ureido] -3- (ÍH-indol-3-yl) -2-methyl-propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -2-methyl-3 - (1-oxy-pyridin-2-yl) - N - (1-pyridin-2-yl-cyclohexylmethyl) - propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -2-methyl-3-pyridin-2-yl-N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide; 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -2-methyl-N- (1-pyridin-2-yl-cyclohexylmethyl) -3- (2-trifluoromethyl-phenyl) -propionamide 2-methyl - 3 - (2-Nitro-phenyl) -2 - [3 - (4-nitro-phenyl) -ureido] - N - (1-pyridin-2-yl-cyclohexylmethyl) -propionamide; 2 - . 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-imidazol-4-yl) - N - (1-pyridin-2-yl-cyclohexylmethyl) -3- (2-trifluoromethyl) - phenyl) - propionamide; N-cyclohexylmethyl-2 - [3 - (2,6-dimethoxy-phenyl) ureido] -3- (ÍH-indol-3-yl) -2-methyl-propionamide; 3 - (ÍH-indol-3-yl) -2-methyl-2 -. { 3 - [1 - (4-Nitro-phenyl) -ethyl] -ureido} - N - (1-pyridin-2-yl-cyclohexylmethyl) -propionamide; 3 - (ÍH-indol-3-yl) -2-methyl-2 - [3 - (4-nitro-phenyl) -ureido] -N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide; 4 - (3 -. {2 - (ÍH-Indol-3-yl) -1-methyl-1 - [(1-pyridin-2-yl-cyclohexylmethyl) -carbamoyl] -ethyl} -ureido acid) - benzoic ethyl ester; 3 - (ÍH-indol-3-yl) -2-methyl-N- (1-pyridin-2-yl-cyclohexylmethyl) -2 - [3- (4-trifluoromethylphenyl) -ureido] -propionamide; 2 - [3 - (4-cyano-phenyl) -ureido] -3- (ÍH-indol-3-yl) -2-methyl-N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide; N -cyclohexylmethyl-3 - (1H-indol-3-yl) -2-methyl-2 - [3 - (4-nitro-phenyl) -ureido] -propionamide; and N - (1-hydroxy-cyclohexylmethyl) -3 - (ÍH-indol-3-yl) -2-methyl-2 - [3 - (4-nitro-phenyl) -ureido] -propionamide.
  8. 8. A compound according to Claim 1 and called: (S) - N - (2,6-diisopropyl-phenyl) -2- [3 - (2, 2, -dimethyl-1-phenyl-propyl) -ureido] - 3 - (ÍH-indol-3-yl) -propionamide;
  9. 9. A compound according to Claim 1 and is selected from: 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -N- (2, 2, -dimethyl-4-phenyl- [1, 3] dioxan-5-yl) -3 - (lH-indol-3-yl) -2-methyl-propionamide; N - (2-cyclohexyl-ethyl) -2- [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (lH-indol-3-yl) -2-methyl-propionamide; "5 2 - [3 - (2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl-propionamide; 2 - [3 - (2,6-diisopropyl- phenyl) -ureido] -3- (ÍH-indol-3-yl) -2-methyl-N- (1, 2, 3, 4-tetrahydro-nañalen-1-yl) -propionamide; 2 - [3 - ( 2,6-diisopropyl-phenyl) -ureido] -3- (1H-indol-3-yl) -2-methyl-10 N- (2-phenyl-cyclohexyl) -propionamide; 2 - [3 - (2, 6-diisopropyl-phenyl) -ureido] -N-indan-l-yl-3 - (lH-indol-3-yl) -2-methyl-propionamide, and 2 - [3 - (2,6-diisopropyl-phenyl) ) - ureido] -3- (1H-indol-3-yl) -2-methyl-N- (1-pyridin-2-yl-cyclohexylmethyl) -propionamide
  10. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 in combination with an acceptable carrier.
  11. 11. A method of antagonizing the effects of neuromedin B and / or peptide releasing gastrin at bombesin receptors comprising administering a compound according to Claim 1 to a patient.
  12. 12. A method for treating depression in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.
  13. 13. A method for treating temporary affective disorders in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.
  14. 14. A method for treating feeding disorders in a patient in need of said treatment comprising administering a therapeutically effective amount of a compound according to Claim 1. •
  15. 15. A method for treating gastrointestinal disorders in a patient in need of said treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.
  16. 16. A method for treating sleep disorders in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.
  17. 17. A method for treating memory failure in a patient in need. of said treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.
  18. 18. A method for treating cancer in a patient in need of said treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.
  19. 19. A method for treating small cell lung carcinoma in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.
  20. 20. A method for treating psychosis in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1. EXTRACT OF THE INVENTION Compounds of Formula (I) or a pharmaceutically acceptable salt thereof wherein Ar is phenyl or pyridyl unsubstituted or substituted. Ar1 can be chosen independently from Ar or can also include pyridyl-N-oxide, indolyl, imidazole and pyridyl; R can be chosen independently of Ar or is hydrogen, hydroxy, NMe2 N-methyl-pyrrole, imidazole, tetrazole, thiazole (a), (b), (c) or (d), wherein Ar2 is phenyl or pyridyl. The compounds of the present invention are novel compounds that antagonize bombesin receptors in mammals and are therefore effective in the treatment and / or prevention of depression, psychosis, temporary affective disorders, cancer, eating disorders, gastrointestinal disorders, disease inflammation of the bowel, sleep disorders and memory impairments.
MXPA/A/1998/010090A 1996-08-22 1998-11-30 Non-peptide bombesin receptor antagonists MXPA98010090A (en)

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Application Number Priority Date Filing Date Title
US60/024,323 1996-08-22

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MXPA98010090A true MXPA98010090A (en) 1999-04-27

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