MXPA00001167A - 2-acylaminopropanamines as tachykinin receptor antagonists - Google Patents

Abstract

This invention provides a series of substituted propanamines useful as tachykinin receptor antagonists. This invention also provides methods employing these substituted propanamines as well as pharmaceutical formulations comprising these compounds.

Description

2-ACILAMINOPROPANAMINAS AS ANTAGONISTS OF THE TAQUICININES RECEPTOR BACKGROUND OF THE INVENTION Tachykinins are a family of peptides that share a common carboxy-terminal amidated sequence. Substance P was the first peptide of this family to be isolated, although its purification and determination of its primary sequence did not occur until the early 1970s. Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now called neurokinin A (also known as substance K, neuro edin L, and neurokinin a), and neurokinin B (also known as neuromedin K and neurokinin β). See J.E. Maggio, Peptides, 6 (Supplement 3): 237-243 (1985) for a review of these findings. Tachykinins are widely distributed in the central and peripheral nervous systems, are released from the nerves, and exert a variety of biological actions, which, in most cases, depend on the activation REF .: 32521 of the specific receptors expressed on the membrane of the target cells. Tachykinins are also produced by a number of non-neuronal tissues. The mammalian tachykinins, substance P, neurokinin A and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2 and NK-3, respectively. These receptors are present in a variety of organs. It is believed that substance P, among other things, is involved in the neurotransmission of pain sensations, including pain associated with migraine headaches and arthritis. It has also been found that these peptides are implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. It has also been reported that tachykinins are implicated in playing a role in numerous other diseases, as discussed below. Tachykinins play a major role in the mediation of sensation and transmission of pain or nociception, especially migraine headaches. See for example S.L. Shepheard et al., British Journal of Pharmacology, 108: 11-20 (1993); YE. Moussaoui, et al., European Journal of Pharmacology, 238: 421-424 (1993); and W.S. Lee et al., British Journal of Pharmacology, 112-920-924 (1994). In view of the large number of clinical diseases associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The first tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility due to their metabolic instability. Recent publications have described the novel classes of non-peptidyl tachykinin receptor antagonists that generally have greater oral bioavailability and greater metabolic stability than the first classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in U.S. Patent No. 5,491,140, issued February 13, 1996; U.S. Patent No. 5,328,927, issued July 12, 1994; U.S. Patent No. 5,360,820, issued November 1, 1994; U.S. Patent No. 5,344,830, issued September 6, 1994, U.S. Patent No. 5,344,830, issued September 6, 1994, U.S. Patent No. 5,331,089, issued July 19, 1994; European Patent Publication 591,040 Al, published January 20, 1994; the publication of the Patent Cooperation Treaty O94 / 04494, published on March 3, 1994; publication of the Patent Cooperation Treaty WO93 / 011609, published on January 21, 1993; Canadian Patent Application 215116, published January 23, 1996; European Patent Publication 693,489, published January 24, 1996; and Canadian Patent Application 2151116, published December 11, 1995. U.S. Patent No. 5,530,009, issued June 25, 1996, discloses a 1,2-diacyl inopropane for use under conditions in the treatment of conditions associated with an excess of tachykinins. This patent also teaches the processes for the preparation of this compound. In essence, this invention provides a class of potent non-peptidyl tachykinin receptor antagonists similar to those of U.S. Patent No. 5,530,009. By virtue of their non-peptidyl nature, the compounds of the present invention do not suffer from the drawbacks, in terms of metabolic instability, of the known antagonists of the tachykinin receptor, based on peptides.

BRIEF DESCRIPTION OF THE INVENTION This invention provides novel compounds of Formula I wherein R1 and R2 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, hydroxyl, or alkoxy of 1 to 6 carbon atoms; R5, R6 and R7 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, or hydroxyl; R3 is hydrogen, alkanoyl of 2 to 7 carbon atoms, glycyl, or dimethylglycyl; n is l a d; D is -S (0) m-, -NH-, or -O-, M is O, 1 or 2; and R8 is a carbocyclic or heterocyclic, monocyclic or bicyclic group, optionally substituted with one or more portions selected from the group consisting of oxo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyl, halo and tri fluoromethyl; or a pharmaceutically acceptable salt or solvate thereof.

In yet another embodiment this invention provides methods for treating a condition associated with an excess of tachykinins, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate. of the same. This invention also provides pharmaceutical formulations comprising, as an active ingredient, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

DETAILED DESCRIPTION AND PREFERRED MODALITIES The terms and abbreviations used in the present examples have their normal meanings, unless designated otherwise. For example '° C' refers to degrees Celsius; 'N' refers to normal or normality; "mol" refers to mol or moles; 'mmol' refers to millimole or millimoles; * g 'refers to gram or grams; 'kg' refers to kilogram or kilograms; * L 'refers to liter or liters; 'mi' refers to milliliter or milliliters; 'M' refers to molar or molarity; 'MS' refers to mass spectroscopy, and 'NMR' refers to nuclear magnetic resonance spectroscopy. "C 1-6 alkoxy" represents a straight or branched chain alkyl having one to six carbon atoms attached to an oxygen atom Typical C 1 -C 6 alkoxy groups include methoxy, ethoxy, propoxy , isopropoxy, butoxy, t-butoxy, pentoxy and the like The term 'alkoxy of 1 to 6 carbon atoms' includes within its definition the terms 'alkoxy of 1 to 4 carbon atoms' and 'alkoxy of 1 to 3 atoms' of carbon ". As used herein, the term "alkyl of 1 to 12 carbon atoms" refers to the saturated, monovalent, linear or branched aliphatic chains of 1 to 12 carbon atoms, and includes, but is not limited to, methyl ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl and hexyl The term 'alkyl of 1 to 12 carbon atoms' includes within its definition the terms 'alkyl of 1 to 6 carbon atoms' and 'alkyl of 1 to 4 carbon atoms. 'C2-C7-alkanoyloxy' represents a linear or branched alkyl chain having one to six carbon atoms attached to a carbonyl moiety linked through an oxygen atom.The typical alkanoyloxy groups of 2 to 7 atoms of carbon include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, t-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylpentanoyloxy and the like .. 'C3-C8-cycloalkyl "represents a saturated hydrocarbon ring structure containing from 3 to 8 atoms of carbon. Typical cycloalkyl groups of 3 to 8 carbon atoms include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. "Halo" represents chloro, fluoro, bromo or iodo. "C 1 -C 6 alkylthio" represents a linear or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom. Typical alkyl groups of 1 to 6 carbon atoms include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like. 'C 1 -C 12 alkylenyl' refers to a saturated, divalent, linear or branched aliphatic chain of 1 to 12 carbon atoms and includes, but is not limited to, methylenyl, ethynyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl , t-butylenyl, pentynyl, isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenyl, decylenyl The term 'alkylenyl of 1 to 6 carbon atoms' is encompassed within the term 'alkylenyl of 1 to 12 carbon atoms'. 1 to 10 carbon atoms "represents a group of the formula -NH (alkyl of 1 to 10 carbon atoms) wherein a chain having one to ten carbon atoms is linked to an amino group. Typical alkylamino groups of 1 to 4 carbon atoms include methylamino, ethylamino, propylamino, isopropylane, butylamino, sec-butylamino and the like. 'alkylamino of 1 a. 6 carbon atoms "represents a linear or branched alkylamino chain having one to six carbon atoms bonded to an amino group Typical alkyl groups of 1 to 6 carbon atoms include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like. 'C 1 -C 6 alkylamino' encompasses within this term a 'C 1 -C 4 alkylamino' "C 2 -C 6 -alkanoyl" represents a linear alkyl chain or branched chain having one to five carbon atoms bonded to a carbonyl moiety. Typical alkanoyl groups of 2 to 6 carbon atoms include ethanoyl (acetyl), propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl, hexanoyl, 3-met ilpentanoyl and the like. "C 2 -C 7 alkoxycarbonyl" represents a straight or branched alkoxy chain having one to six carbon atoms bonded to a carbonyl moiety The alkoxycarbonyl groups of 2 to 7 carbon atoms include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and the like The term "carbamoyl" as used herein refers to a portion having the following structures.

The term "C2 to C7 alkylcarbamoyl" as used herein refers to a straight or branched chain of 1 to 6 carbon atoms combined with a carbamoyl group, as such is defined above.This portion has the following structure.

(Alkyl of 1 to 6 carbon atoms) The term "haloformate" as used herein refers to an ester of a haloformic acid, this compound having the formula wherein X is halo, and Rd is' alkenyl of 1 to 6 carbon atoms. Preferred halo formates are bromoformates and chloroformates. Especially preferred are chloroformates. Those haloformates wherein Rd is alkyl of 3 to 6 carbon atoms are especially preferred. More preferred is isobutyl chloroformate. The compounds prepared in the processes of the present invention have an asymmetric center. As a consequence of this chiral example, the compounds produced in the present invention can appear as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. The terms 'R' and 'S' are used herein as commonly used in organic chemistry to denote the specific configuration of a chiral center. The term 'R' (rec t us) refers to that configuration of a chiral center with a counter-clockwise relation of group priorities (the highest to the second lowest) when viewed along the link towards the lowest priority group The term 'S' (if neither ster) refers to that configuration of a chiral center with a counter-clockwise relation of group priorities (the highest to the second lowest) ) when viewed along the link to the lowest priority group. The priority of groups is based on their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in NOMENCLATURE OF ORGANIC COMPOUNDS: PRINCIPLES AND PRACTICE, (J.H. Fletcher et al., Eds., 1974) on pages 103-120. In addition to the (R) - (S) system, the D-L system is also used in this document to denote the absolute configuration, especially with reference to amino acids. In this system, a Fischer projection formula is oriented so that carbon number 1 of the main chain is in the upper part. The prefix 'D' is used to represent the absolute configuration of the isomer in which the functional group (determinant) is on the right side of the carbon atom in the chiral center and 'L', that of the isomer in which this is on the left. The term "amino protecting group" is used in the specification to refer to amino group substituents commonly employed to block or protect the amino functional group while reacting other functional groups on the compound Examples of such protecting groups of amino include formyl, trifly (herein abbreviated as 'Tr'), phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4, methoxybenzyloxycarbonyl, 4- fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl (abbreviated herein as 'BoC'), 1,1-diphenylet-1 -iloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2- (p-toluyl) -prop-2-yloxycarbonyl, cyclopen tanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexaniloxycarbonyl, 1-methylcyclohexanoyloxycarbonyl, 2-methylcyclohexaniloxycarbonyl, 2- (4-toluylsul fonyl) -ethoxycarbonyl, 2- (ethylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphino) -ethoxycarbonyl, fluorenylmethoxycarbonyl ('FMOC'), - (trimethylsilyl) ethoxycarbonyl, allyloxycarbonyl, 1- (trimethylsilylmethyl) prop-1-enyloxycarbonyl, 5-benzyloxylylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4- (decyloxy) benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; benzoylmethylsulfonyl group, 2-nitrophenylsul phenyl, diphenylphosphine oxide and similar amino protecting groups. The species of the amino protecting group employed is usually not critical as long as the derivatized amino group is stable to the subsequent reaction conditions on other intermediate molecule positions and can be selectively removed at the appropriate point without disturbing the remainder of the molecule , including any other amino protecting groups. Preferred amino protecting groups are trifyl, t-butoxycarbonyl (t-BOC), allyloxycarbonyl and benzyloxycarbonyl. Additional examples of groups preferred by the above terms are described by E. Haslam, 'Protective Groups in Organic Chemistry', (JG McQueen, ed., 1973), in Chapter 2, and T. Greene and PGM Wuts. , PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991), in Chapter 7.

The term "carboxyl protecting group" as used in the specification refers to substituents of the carboxyl group commonly employed to block or protect the carboxyl functional group, while reacting with other functional groups on the compound. Carboxyl protectants include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-tri ethylbenzyl, pentamethylbenzyl, , 4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2, 2 ', 4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, triflyl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4, 4 ', 4"- trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, 2- (di- (n-butyl) ethylsilyl) ethyl, p-toluenesulfonylethyl , 4-Nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl) prop-1-en-3-yl and similar portions. Preferred carboxyl groups are allyl, benzyl and t-butyl. Additional examples of these groups are found in E. Haslam, supra, in Chapter 5, and T.W. Greene et al., Supra, in Chapter 5. The term 'hydroxyl protecting groups' as used herein refers to the hydroxyl group substituents commonly employed to block or protect the hydroxyl functional group, while other groups react functional groups on the compound Examples of such hydroxyl protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, methylthiomethyl, 2,2-dichloro-1,1-difluoroethyl, tetrahydropyranyl, phenacyl, cyclopropylmethyl, allyl, alkyl from 1 to 6 carbon atoms, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, t-butyldimethylsilyl, levulinate, pivaloate, benzoate, dimethylsulphonate, dimethylphosphinyl, isobutyrate, adamantoate and tetrahydropyranyl, additional examples of these groups can be found in TW Greene and PGM Wüts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (199.1) in Chapter 3. The term 'salt group "as used herein refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction. The term "leaving group" as used herein encompasses, but is not limited to, the activating groups The term "activating or activating group" as used herein refers to an outgoing group which, when taken with the carbonyl group (-C = 0) to which it is bound, it is more likely to take part in an acylation reaction which could be the case if the group were not present, as in the free acid. Such activating groups are well known to those of skill in the art and can be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluensul fonyloxy, azido, or -O-CO- (alkyl of 4 to 7 carbon atoms ). As noted above, this invention includes the pharmaceutically acceptable salts of the compounds defined by Formula I. A compound of the invention may possess a sufficiently acidic group, a sufficiently basic group or both functional groups, and consequently react with any one of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein, refers to the salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include aqueous salts prepared by the reaction of the compounds of the present invention with a pharmaceutically acceptable organic or mineral acid or an organic or inorganic base.Such salts are known as acid addition or base addition salts.The acids commonly employed to form the salts by addition of acid are Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bro-ofhenylsulfonic acid, caic acid, succinic acid, citric acid, benzoic acid, acid acetic and similar. Examples of such pharmaceutically acceptable salts are the salts of sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monoacid phosphate, diacid phosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride. , dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butin, -1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methansulphonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric, hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid. The salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.

The base addition salts include those derived from the inorganic bases, such as the alkali metal or alkaline earth metal ammonium hydroxides, carbonates, bicarbonates, and the like. Such bases, useful in the preparation of the salts of this invention, include in this manner sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred. It should be recognized that the particular counter ion that forms a part of any salt of this invention is not usually of a critical nature, as long as the salt as a whole is pharmacologically acceptable as long as the counter ion does not contribute to undesired qualities the salt, as a whole. This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formula I. Many compounds of Formula I can be combined with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as hydrate, methanolate, ethanolate and corresponding acetonitrilate. This invention also encompasses pharmaceutically acceptable prodrugs of the compounds of Formula I. A prodrug is a drug that has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more processes. enzymatic or other processes in vi to the progenitor bioactive form. This prodrug must have a different pharmacokinetic profile than the parent, making possible the easier absorption through the mucosal epithelium, better salt formation and solubility, or improved systemic stability (an increase in plasma half-life, for example). Typically, such chemical modifications include: 1) ester or amide derivatives which can be cleaved by esterases or lipases; 2) peptides that can be recognized by specific or non-specific proteases; or 3) derivatives that accumulate in a site of action through membrane selection of a prodrug form or a modified prodrug form; or any combination of 1 to 3 above. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in H. Bundgaard, DESIGN OF PRODRUGS, (1985). The compounds of Formula I are generally prepared by the reaction of a compound of Formula II II with an appropriately substituted carboxylic acid, anhydride, or carboxylic acid halide in the presence of typical peptide coupling reagents such as N, N'-carbonyldiimidazole (CDI), N, N'-dicyclohexylcarbodiimide (DCC), and 1- (3-hydrochloride -dimethylaminopropyl) -3-ethylcarbodiimide (EDC). A form supported by EDC polymer has been described (Tetrahedron Letters, 34 (48): 7685 (1993)) and is very useful for the preparation of the compounds of the present invention. The isolation of products from reactions where a reagent bound to polymer has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure. The product from these reactions can be purified chromatographically or recrystallized from a suitable solvent if desired. Another preferred method for preparing the compounds of Formula I wherein D is -0- is by the reaction of a compound of Formula III neither where X is a leaving group, preferably a halo portion, more preferably a bromine group, with an appropriately substituted phenol or naphthol, or the like. The most preferred method to date, for the synthesis of the intermediates of Formulas II and III is described in Scheme I below. Many of the steps of this synthesis are described in the Patent Cooperation Treaty Publication WO95 / 14017, published May 26, 1995; Publication of European Patent Application 693,489, published on January 24, 1996; and U.S. Patent No. 5,530,009, issued June 25, 1996, the contents of which are incorporated by reference herein.Scheme I OH. MM Formula A wherein "Tr" refers to a trityl group and "NMM" refers to N-methylmorpholine.

Scheme I (continued) In another method for the preparation of intermediary intermediates of Formulas II and III, Steps a) and b) can be combined as shown in U.S. Patent Application No. 60 / 021,849, filed July 16, 1996. In this method a compound of the formula is prepared by the reaction of a compound of the formula with bis (trimethylsilyl) amine in acetonitrile, followed by the addition of trityl chloride, N-methylmorpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine, in the presence of acetonitrile, and then adding 2- methoxybenzylamine. The factor possibly found critical for the combination of the steps was the desilylation of the compound of Formula A, in Step (a), before the formation of the ester via the addition of 2-chloro-4,6-dimethoxy-1. , 3, 5-triazine (CDMT). In Step (a), the desilylation has been achieved by the addition of excess water before isolation, which also dissolved any salts 4 present. When Formula A is desililated in the combined chemistry, stoichiometry becomes increasingly important. Consideration should be given to the presence of excess HMDS used in the initial silylation of D-tryptophan. By simply adding a stoichiometric amount of methyl alcohol (or water) relative to D-tryptophan, subsequent esterification will not be allowed to progress. Methyl alcohol must also be added to shut off all remaining HMDS, without reacting. However, any excess methyl alcohol will consume the CDMT and prevent complete esterification. Once the desilylation of the compound of Formula A and the decomposition of the excess HMDS is complete, the chemistry of Step (b) proceeds as expected, and the desired high quality intermediate is produced in good yield. In the above process, the intermediate amides are reduced to amines using procedures well known in the art. These reductions can be made using lithium aluminum hydride as well as through the use of many different aluminum-based hydrides. An especially preferred reagent employed in this reduction is RED-AL®, which is the trade name of a 3.4 M solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene. Alternatively, the amides can be reduced by catalytic hydrogenation, although high temperatures and high pressures are usually required for this. Sodium borohydride in combination with other reagents can be used to reduce the amide. Borane complexes, such as a borane-dimethyl sulfide complex, are especially useful in this reduction reaction. Acylation of the secondary amine can be performed using any of a large number of techniques regularly employed by those of experience in organic chemistry. Such a reaction scheme is a substitution using an anhydride such as acetic anhydride. Another reaction scheme frequently employed to acylate a secondary amine employs a carboxylic acid preferably with an activating agent. One type of amino-de-alkoxylation reaction uses esters as a means of acylating the amine. Activated esters that are attenuated to provide increased activity are very efficient acylating agents. A preferred activated ester of this type is the p-nitrophenyl ester such as p-nitrophenyl acetate. The primary amines can also be acylated using amides to carry out what is essentially an exchange reaction. This reaction is usually carried out with the salt of the amine. Boron trifluoride, usually in the form of a complex of diethyl ether-boron trifluoride, is frequently added to this reaction to form the complex with the leaving ammonia. An additional step is one of the substitution of the secondary amine. For most of the compounds of Formula I this substitution is one of the alkylation, acylation or sulfonation. This substitution is usually carried out using well-recognized means. Typically, alkylations can be achieved using alkyl halides and the like, as well as well-known reductive alkylation methods, using aldehydes or ketones. Many of the acylation reaction protocols discussed above also efficiently acylate the secondary amide. The alkyl- and aryl-sulfonyl chlorides can be used to sulfonate the secondary amine. In many cases one of the last steps in the synthesis of the compounds of Formulas II and III is the elimination of an amino or carboxyl protecting group. Such procedures, which vary, depending on the protective group employed as well as the relative lability of the other portions on the compound, are described in detail in many standard reference works such as T.W. Greene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991). The following Examples and Preparations further illustrate the compounds of the present invention and methods for their synthesis. The Examples are not intended to limit the scope of the invention in any aspect, and should not be considered as such. All experiments were run under a positive pressure of nitrogen or anhydrous argon. All solvents and reagents were obtained from commercial sources and used as received, unless otherwise indicated. The anhydrous tetrahydrofuran was obtained by distillation from sodium or sodium-benzophenone-cetyl before use. The proton nuclear magnetic resonance spectra (1H NMR) were obtained on a GE WH-300 300.15 MHz spectrometer, a 500 MHz Bruker AM-500 spectrometer, or a 200 MHz Bruker AC-200P spectrometer. otherwise designated the term 'NMR' as used herein refers to nuclear magnetic resonance of protons.) Mass spectroscopy by bombardment of free atoms (FAB) was performed on a VG ZAB-2SE instrument. Field desorption mass spectroscopy (FDMS) was performed using either an instrument - VG 70SE or a Varian MAT 731. Optical rotations were measured with a Perkin-Elmer 241 polarimeter. The chromatographic separation on a Waters Prep 500 LC was generally carried out using a linear gradient of the solvents indicated in the text, unless otherwise specified Optical rotations were generally verified periodically for termination using chroma thin-film tography (TLC). Thin layer chromatography was performed using E. Merck Kieselgel 60 F254 plates, 5 cm x 10 cm, 0.25 mm thick. The spots were detected using a combination of UV detection and chemical detection (the plates immersed in a solution of serum ammonium molybdate [75 g of ammonium molybdate and 4 g of cerium (IV) sulphate in 500 ml of aqueous sulfuric acid to 10%] and then heated on a hot plate, centrifugal thin plate chromatography was performed on a Harrison Model 7924A Chromatotron using GF rotors for Analtech silica gel.Cathion exchange chromatography was performed with an exchange resin of Dowex® 50X8-100 ions The anion exchange chromatography was carried out with an anion exchange resin Bio-Rad AG® 1-X8 (the acetate form converted to the hydroxide form) The flash chromatography was performed as described by Still, et al, Journal of Organic Chemistry, 43: 2923 (1978) Optical rotations are reported on the sodium D line (354 nm). Mentals for carbon, hydrogen and nitrogen were determined in a Control Equipment Corporation 440 Elemental Analyzer, or were performed by the Analytical Center of the Complutense University (Faculty of Pharmacy, Madrid, Spain). The melting points were determined in open glass capillaries on a capillary apparatus for Thomas Hoover melting points or an apparatus for Büchi melting points, and they are not corrected. The following methods provide the illustrative protocols for the preparation of the compounds of Formula I as described in the above Schemes. Throughout the Methods and Examples, later the terms 'NMR', 'IR', and 'UV' indicate that proton nuclear magnetic resonance, infrared and ultraviolet spectroscopy, respectively, were consistent with the product desired of the title.

Preparation 1 Preparation of (R) -3- (1H-indol-3-yl) -N- (2-methoxybenzyl) -2- (N-triphenyl-ethylamino) propanamide.

In a 190 liter (50 gallon) glass lined reactor, L-tryptophan (4.50 kg, 22.0 mol) was added to acetonitrile (30 L, 6.7 vol) at 20 ° C. This reactor was vented to a scrubber that contained water, designed to purify. ammonia, generated during the silylation reaction and the HCl generated during the tritylation and esterification reactions. The bis (trimethylsilyl) amine (HMDS, 5.81 L, 27.5 mol, 1.25 eq.) Was transferred by gravity to the suspension of L-tryptophan from a plastic jug. The jug was rinsed with 0.5 L of acetonitrile. The suspension was heated to 55 ° C and stirred until completion of the reaction. The end point of the reaction was defined as the point at which the suspension had completely entered solution. The reaction was light yellow to completion and took approximately 2 hours. Trityl chloride (6.45 kg, 23. 1 mol, 1.05 eq.) In acetonitrile (30 L, 6.7 vol) and transferred into the reactor at 47 ° C, using a vacuum trap at 325 mmHg. The N-methylmorpholine (5.38 L, 48.9 mol, 2.20 eq.) Was also transferred to the reactor at this time. The reaction suspension was heated and maintained at 55 ° C until completion of the reaction, determined by high performance liquid chromatography analysis. The reaction time was about 2.5 hours. The reactor was isolated from the scrubber, and cooled to 35-40 ° C. Methyl alcohol (2.29 L, 56.5 mol, 2.55 eq) was charged to the reactor and the mixture was cooled to 25 ° C. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 4.14 kg, 23.61 mol, 1.07 eq) was added to the reactor with acetonitrile (28 L, 6.2 vol) at 25 ° C. The reactor was vented back to the scrubber. The reaction suspension was stirred at room temperature until completion. The final reaction point is determined by high performance liquid chromatography analysis. The reaction time is approximately 2 hours. The reactor was isolated from the scrubber after the reaction. 2-Methoxybenzylamine (3.11 L, 23.8 mol, 1.08 eq) was charged to the reactor from a plastic jug, by gravity. The suspension is thickened with the addition of 2-methoxybenzylamine. The reaction suspension was heated to 35 ° C and stirred until completion of the reaction, determined by high performance liquid chromatography analysis. The reaction time was 2.5 hours. Water (45 kg, 10 vol) was previously weighed into a separate 190 liter (50 gallon) tank lined with glass. The water was transferred by pressure into the suspension of the reaction mixture in about 45 minutes. The resulting yellow suspension was cooled to 0-5 ° C in two hours and stirred overnight.

The title intermediate was isolated by centrifugal isolation in a vertical basket using the three-micron polyethylene multiple filament isolation bag. During centrifugation, the loading speed was generally between 900 to 1050 rpm, the washing speed was 900 to 1500 rpm, and the centrifugation speed was between 1500 and 2300 rpm. The title intermediate was then dried by rotary drying under vacuum. Yield: 86.4% with purity of 99.6% isomer.

Preparation 2 Carbonyl reduction Preparation of (R) -3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) amino] -2- (N-trifexethylamino) propane.

RED-AL® [a 3.4 M solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene] (535 ml, 1819 mol), dissolved in 400 ml of anhydrous tetrahydrofuran was added slowly using an addition funnel, to a refluxing solution of the acylation product (R) -3- (lH-indol-3-yl) -N (2-methoxybenzyl) -2- (N-triphenylmethylamino) propanamide (228.6 g, 0.404 mol) produced above, in 1 L of anhydrous tetrahydrofuran under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched after at least 20 hours by the slow addition of saturated Rochelle's saline solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered and concentrated to an oil on a rotary evaporator. No further purification was performed and the product was used directly in the next step.

Preparation 3 Acylation of Secondary Amine Preparation of (R) -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) -acetylamino] -2- (N-triphenylmethylamino) propane To a solution in 'stirring of (R) -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) amino] -2- (N-triphenylmethylamino) propane (0.404 mol) in 1.2 Liters of anhydrous tetrahydrofuran under a nitrogen atmosphere at 0 ° C was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol).

After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with two portions of water and with two portions of brine, dried over anhydrous sodium sulfate, filtered and concentrated to a solid, in a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and diluted with a 1: 1 mixture of ethyl acetate and hexanes. The product was then crystallized from a mixture of ethyl acetate / hexanes. The resulting product of (R) -3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] -2- (N-triphenylmethylamino) propane was crystallized and isolated in three crops yielding 208.97 grams (87% yield) of analytically pure material. Analysis for C oH39N302: Theory: C, 80.91; H, 6.62; N, 7.08. Found: C, 81.00; H, 6.69; N, 6.94.

Preparation 4 Deprovement Preparation of (R) -2-amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane dihydrochloride A stirring solution of (R) -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] -2- (N-triphenylmethylamino) propane in two volumes of methylene chloride is cooled to -40 ° C to -50 ° C. Anhydrous hydrogen chloride gas was then added at a rate such that the temperature of the reaction mixture did not exceed 0 ° C. The reaction mixture was stirred for 30 minutes at one hour at 0-10 ° C. To this reaction mixture were added two volumes of methyl t-butyl ether and the resulting mixture was allowed to stir for 30 minutes at one hour at 0-10 ° C. The resulting crystalline solid was removed by filtration and then washed with methyl t-butyl ether. The reaction product was dried under vacuum at 50 ° C (Yield> 98%) Analysis for C2? H25N302 * 2HCl: Theory: C, 59.44; H, 6.41; N, 9.90. Found: C, 60.40; H, 6.60; N, 9.99.

Preparation 5 Preparation of (R) -2 - [(2-broo) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane.

To a stirred solution of (R) -2-amino-3- (1H-indol-3-yl) -l- [N- (2-methoxybenzyl) acetylamino] propane (7.51 g, 21 369 mmol) in 100 ml of Anhydrous tetrahydrofuran under a nitrogen atmosphere at 0 ° C was added diisopropylethylamine (4.1 ml, 23.537 mmol) and bromoacetyl bromide (2.05 ml, 23.530 mmol). After 2 hours, ethyl acetate was added and the reaction mixture was washed with water twice, with 1.0N hydrochloric acid (2X), saturated sodium bicarbonate solution (2X) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a colored foam burned in a rotary evaporator. In this manner, 2- [(2-bromo) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane was obtained in a quantitative yield. No further purification was necessary.

Preparation 6 Preparation of an isocyanate resin bound to polystyrene.

To a stirred suspension of 50 grams (61 mmol) of the aminomethylated polystyrene resin (1.22 mmol / g) in 800 ml of toluene was added 193 ml (366 mmol) of 1.9 M phosgene in toluene. After stirring the reaction mixture for 10 minutes, 67 ml (482 mmol) of triethylamine was added and the reaction mixture was stirred for 18 hours at room temperature. The mixture was filtered and the recovered solid was washed with 10 portions of dichloromethane. A light pink resin mixed with a white solid was obtained. This solid mixture was resuspended in 700 ml of dichloromethane, stirred for 10 minutes and then filtered and washed thoroughly with dichloromethane. The resulting solid was again suspended, stirred and washed with dichloromethane to provide the desired resin. IR (KBr): 2252 cm "1 (characteristic peak for -N = C = 0).

General Procedure I To a suspension of three equivalents of 1-piperidine bound to polymer, in 1 ml of chloroform, the dihydrochloride of (R) -2-amino-3 (lH-indol-3-yl) -1- [N- ( 2-methoxybenzyl) acetylamino] propane (10 mg, 0.024 mmol, 1 eq). To this mixture was added the appropriate carboxylic acid (0.036 mmol, 1.5 eq) and the polymer-linked 1- (3-dimethylaminopropyl) -3-propylcarbodiimide hydrochloride (108 mg, 0.108 mmol, 4.5 eq).

The resulting mixture was stirred at room temperature for approximately 2 to 3 days. The unreacted (R) -2-amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane dihydrochloride was removed by the addition of an excess of isocyanate resin bound to polystyrene, and stirred by oscillation for four hours. The reaction mixtures were filtered and the filtrates were concentrated.

General Procedure II Potassium tert-butoxide (19.38 mg, 0.158 mmol, 3 eqj and an appropriate phenol or substituted naphthol (0.158 mmol, 3 eq) in 0.7 ml of anhydrous tetrahydrofuran were mixed in a reaction flask. -2- [(2-Bromo) acetyl] amino-3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane (25 mg, 0.053 mmol, 1 eq) and the The resulting mixture was heated for two hours at 80 ° C. The solvents were removed in vacuo and the residue was redissolved in methylene chloride and washed once with water, the organic fraction was dried over sodium sulfate. empty.

Example 1 Preparation of 2- [[3- [benzothiazol-2-ylthio] propanoi] amino] -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane NMR was consistent with the proposed structure of the title.

Example 2 Preparation of 2- [(quinolin-6-yloxy) acetamido] -3- (lH-indol-3-yl -1- [N- (2-methoxybenzyl) acetylamino] propane NMR was consistent with the proposed structure of the title. The following compounds were prepared essentially as described above. The structures were all confirmed by one or more physicochemical methods. All structures were confirmed by mass spectrometry.

Example 3 Preparation of 2- [(pyrid-2-yloxy) acetamido] -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane.

Example 4 Preparation of 2- [(pyrid-3'-yloxy) acetamido] -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane.

Example 5 Preparation of 2 [(5-methyloxazol-3-yloxy) acetamido] -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane.

Example 6 Preparation of 2 - [(indol-5-yloxy) acetamido] -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane.

Example 7 Preparation of 2- [(naphth-2-yloxy) acetamido] -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propan EXAMPLE 8 Preparation of 2- [(quinolin-5-yloxy) acetamido] -3- (lH-indol-3-yl) -1 [N- (2-ethoxybenzyl) acetylamino] propane.

Example 9 Preparation of 2- [(cuman-2-on-5-yl) acetamido] -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane.

Example 10 Preparation of 2- [(benzothiazol-6-yloxy) acetamido] -3- (1H-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] propane.

Example 11 Preparation of 2- [(quinolin-5-yloxy) acetamido] -3- (lH-indol-3-yl) -1- [N- (2-chlorobenzyl) acetylamino] propane Example 12 Preparation of 2- [(quinolin-5-yloxy) acetamido] -3- (1H-indol-3-yl) -1- [N- (3,5-bis (trifluoromethyl) benzyl) acetylamino] propane.

The compounds of the present invention possess tachykinin receptor activity. The biological efficacy of a compound that is believed to be effective as a taguicinin receptor antagonist can be confirmed by the use of an initial screening assay which rapidly and accurately measures the binding of the tested compound to the NK receptor sites -1 and NK-2 known. Useful assays for evaluating tachykinin receptor antagonists are well known in the art. See for example J. Jukic et al, Life Sciences, 49: 1463-1469 (1991; N. Kucharczyk et al., Journal of Medicinal Chemistry, 36: 1654-1661 (1993); N. Rouissi et al., Biochemical and Biophysical Research Communications, 176: 894-901 (1991).

Receptor Link Test NK-1 The radio-receptor binding assays were performed using a derivative of a previously published protocol. D. G. Payan et al., Journal of I munology, 133: 3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 106 cells / tube in RPMI 1604 supplemented with 10% fetal calf serum) was incubated with substance P labeled with 20 pM 125 I, in the presence of increasing competitor concentrations, by 45 minutes at 4 ° C. The IM9 cell line is a well-characterized cell line which is readily available to the public. See for example Annals of the new York Academy of Science, 190: 221-234 (1972); Nature (Lodon), 251: 443-444 (1974); Proceedings of the National Acade and of Sciences (USA), 71: 84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 μg / ml gentamicin sulfate and 10% fetal calf serum. The reaction was terminated by filtration through a fiberglass filter harvest system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. The specific binding of the marked substance P was determined in the presence of the unlabeled ligand 20 nM. Many of the compounds employed in the methods of the present invention are also effective antagonists of the NK-2 receptor.

Receptor Link Test NK-2 CHO-hNK-2R cells, a cell line derived from CHO transformed with the human NK-2 receptor, which expresses approximately 400,000 such receptors per cell, were developed in 75 cm2 flasks or in spinner bottles in minimal essential medium (modification alpha) with 10% fetal bovine serum. The gene sequence of the human NK-2 receptor is given in N.P. Gerard et al., Journal of Biological Chemistry, 265: 20455-20462 (1990). For the preparation of membranes, 30 confluent cultures in rotating bottle were dissociated by washing each spinner bottle with 10 ml of Dulbecco's phosphate buffered saline (PBS) without calcium and magnesium, followed by the addition of 10 ml of dissociation solution enzyme-free cell phone (based on PBS, from Specialty Media, Inc.). After an additional 15 minutes, the dissociated cells were combined and centrifuged at 1,000 RPM for 10 minutes in a clinical centrifuge. Membranes were prepared by homogenizing the cell buttons in 300 ml of 50 mM Tris buffer, pH 7.4, with a Tekmar® homogenizer for 10 to 15 seconds, followed by centrifugation at 12,000 RPM (20,000 xg) for 30 minutes using a rotor Beckman JA-14®. The buttons or concentrates were washed once using the above procedure, and the final buttons were resuspended in 100-120 ml of 50 mM Tris buffer, pH 7.4, and 4 ml aliquots were stored frozen at -70 ° C. the protein concentration of this preparation was 2 mg / ml.

For the receptor binding assay, a 4 ml aliquot of the membrane preparation CH0-hNK-2R was suspended in 40 ml of assay buffer containing 50 M Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 μg / ml of qui-tar. A volume of 200 μl of the homogenate (40 μg of protein) was used per sample. The radioactive ligand was [125I] iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci / mol. The ligand was prepared in assay buffer at 20 nCi per 100 μl; the final concentration in the assay was 20 pM. The non-specific binding was determined using 1 μM eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve. All samples and standards were added to the incubation in 10 μl of dimethyl sulfoxide (DMSO) for selection (single dose) or in 5 μl of DMSO for IC50 determinations. the order of the additions for the incubation was • 190 or 195 μl of assay buffer, 200 μl of homogenate, 10 or 5 μl of sample in DMSO, 100 μl of radioactive ligand. Samples were incubated 1 hour at room temperature and then filtered on a cell harvester through filters that had been pre-soaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 mm polystyrene tubes and counted in a gamma counter. Animal and human clinical models demonstrating the effectiveness of the methods of the present invention are well known to a person skilled in the art. For example, the following experiment clearly demonstrates the inhibitory effect of the compounds of the present invention in an animal model predictive of anti-migraine therapies.

Neurogenic Plasma Extravasation in the Dural layer, Induced Electrical Stimulation Sprague-Dawley rats (225-325 g) or guinea pigs from Charles River Laboratories (225-325 g) are anesthetized with sodium pentobarbital (65 mg / kg or 45 mg / kg, respectively, intraperitoneally) and placed in a tereotaxic frame ( David Kopf Instruments) with the incision bar adjusted to -3.5 mm for rats or -4.0 mm for guinea pigs. After an incision in the intermediate sagittal scalp, two pairs of bilateral holes were drilled through the skull (6 mm posteriorly, 2.0 and 4.0 mm laterally for the rats, 4 mm posteriorly, 3.2 and 5.2 mm laterally for guinea pigs - all the coordinates are with reference to the bregma). Pairs of stainless steel stimulation electrodes, isolated except at the tips, are lowered through the holes in both hemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) from the dura. The femoral vein is exposed and a dose of the test compound is injected intravenously (1 ml / kg). Approximately seven minutes later, a dose of 50 mg / kg Evans Blue is also injected intravenously. Evans Blue was formed in complex with the proteins in the blood and functioned as a marker for the extravasation of proteins. Exactly ten minutes after the injection of the test compound, the left trigeminal ganglion is stimulated for three minutes at a current of 1.0 mA (5 Hz, 4 msec duration) with a potentiostat / galvanostat. Fifteen minutes after the stimulation, the animals are sacrificed and bled with 20 ml of saline. The upper part of the skull is removed to facilitate the collection of the dural membranes. The membrane samples are removed from both hemispheres, rinsed with water, and spread flat on microscope slides. Once dry, the tissues are covered with a coverslip with 70% glycerol / water solution. A fluorescence microscope equipped with a grid monochromator and a spectrophotometer is used to quantify the amount of Evans Blue dye in each tissue sample. An excitation wavelength of about 535 nm is used and the emission intensity at 600 nm is determined. The microscope is equipped with a motorized stage and is interconnected with a personal computer. This facilitated the computer controlled movement of the stage with fluorescence measurements at 25 points (500 μm steps) on each dural sample.

The mean deviation and standard deviation of the measurements are determined by computer. Oral extravasation induced by electrical stimulation of the trigeminal ganglion is an ipsilateral effect (for example, this occurs only on the side of the dura in which the trigeminal ganglion is stimulated). This allowed the other half of the dura, unstimulated, to be used as a control. The proportion of the amount of extravasation in the dura from the stimulated side compared to the unstimulated side is also calculated. Saline controls produced a ratio of approximately 2.0 in rats and 1.8 in guinea pigs. In contrast, a compound that effectively prevented extravasation in the dura from the stimulated side could have a ratio of approximately 1.0. A dose-response curve is generated and the dose that inhibited extravasation by 50% (IDso) is estimated. The compounds prepared by the processes of the present invention are useful as tachykinin receptor binding compounds. As such, they can be used as antagonists or agonists of the various tachykinins. These compounds are, therefore, useful in the treatment or prevention of conditions associated with an excess or deficiency of tachykinin. The term 'physiological disorder associated with an excess or deficiency of tachykinins' encompasses those disorders associated with inappropriate stimulation of tachykinin receptors, notwithstanding the effective amount of tachykinin present at the site.These physiological disorders may include disorders of the nervous system. such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, dementia associated with AIDS, and Down syndrome, deinvitation diseases such as multiple sclerosis and amyotic lateral sclerosis and other neuthological disorders such as peripheral neuthy, such as diabetic neuthy induced by chemotherapy, and post-herpetic and other neuralgia, acute and chronic respiratory obstructive diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, driver's cough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis, disorders of the musculoskeletal system, such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; addiction disorders such as alcoholism; somatic disorders related to stress or tension; Reflex sympathetic dysty such as shoulder / hand syndrome, dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune augmentation or suppression such as systemic lupus erythematosus; gastrointestinal disorders or diseases associated with neuronal control of the viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; disorders of bladder function, such as hyperreflex detrusor of the bladder and incontinence; atherosclerosis; fibrosis and collagen diseases such as scleroderma and eosinophilic fascioliasis, irritating symptoms of benign prostatic hyperty; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; emesis; and pain and nociception, for example, that attributable to or associated with any of the above conditions, especially the transmission of pain in migraine. For example, the compounds of Formula I can be suitably used in the treatment of disorders of the central nervous system such as anxiety, psychosis, and schizophrenia; neurodegenerative disorders such as Alzheimer's disease and Down syndrome; respiratory diseases such as bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immune disorders such as rejection of transplanted tissues; gastrointestinal disorders and diseases such as disorders associated with neuronal control of the viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the above conditions or the transmission of pain in migraine. The results of several experiments show that many of the compounds of Formula I are selective antagonists of the tachykinin receptor. These compounds are preferably linked to a tachykinin receptor subtype compared to other such receptors. Such compounds are especially preferred. For example, NK-1 antagonists are more especially preferred in the treatment of pain, especially chronic pain, such as neuthic pain, postoperative pain, and migraines, pain associated with arthritis, pain associated with cancer, chronic pain of low back, headaches in groups, herpetic neuralgia, phantom limbic pain, central pain, dental pain, pain from sunburn, neuthic pain, opioid-resistant pain, visceral pain, surgical pain, pain from bone damage, pain during Labor and delivery, pain resulting from burns, post-partum pain, pain from angina, and pain related to the genitourinary tract including cystitis. In addition to pain, NK-1 antagonists are especially preferred in the treatment and prevention of urinary incontinence; irritating symptoms of benign prostatic hypertrophy; disorders of the motility of the gastrointestinal tract, such as irritable bowel syndrome; obstructive disease of the acute and chronic respiratory tract, such as bronchospasm, bronchopneumonia, asthma and adult respiratory distress syndrome; atherosclerosis; inflammatory conditions, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, allergies, rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis, iosis induced by irritation; rejection of tissue transplantation; plasma extravasation resulting from chemotherapy with cytokine and the like; trauma of the spine; apoplexy; cerebral apoplexy (ischemia); Alzheimer disease; Parkinson disease; multiple sclerosis; Amyotrophic Lateral Sclerosis; schizophrenia; anxiety; and depression.

NK-2 antagonists are especially preferred in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, gastrointestinal tract otility disorders, such as irritable bowel syndrome, and pain. In addition to the binding assays described above, many of the compounds prepared by the processes of the present invention have also been tested in model systems for conditions associated with an excess of tachykinins. Of these compounds tested, many have proven effective against these conditions. While it is possible to administer a compound employed in the methods of this invention directly without any formulation, the compounds are usually administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient. These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See for example REMINGTON 'S PHARMACEUTICAL SCIENCES, (16th edition, 1980). In making the compositions employed in the present invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within a carrier, which may be in the form of a capsule, sack, paper or other container . When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, troches, sacks, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing example up to 10% by weight of the active compound, soft and hard gelatine capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In the preparation of a formulation, it may be necessary to grind the active compound to provide the appropriate particle size before combining with the other ingredients. If the active compound is substantially insoluble, it is ordinarily ground to a particle size smaller than 200 mesh. If the active compound is substantially soluble in water, the particle size is usually adjusted by milling to provide a substantially uniform distribution in the formulation, for example approximately 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose , water, syrup and methylcellulose. The formulations may further include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl- and propyl-hydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient, by employing procedures known in the art. The compositions are preferably formulated in a unit dosage form, each dose containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg of the active ingredient. The term 'unit dose form' refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of the active material, calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active compounds are generally effective in a wide range of doses. For example, the doses per day normally fall within the range of about 0.01 to about 30 mg / kg of body weight. In the treatment of adult humans, the range of from about 0.1 to about 15 mg / kg / day, in single or divided doses, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the route of administration chosen, the effective compound or compounds administered, the age , the weight and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dose ranges are not intended to limit the scope of the invention in any way. In some cases, dose levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses may be employed without causing any harmful side effects, provided that such larger doses they are first divided into several smaller doses for administration throughout the day.

Preparation of Formulation 1 Hard gelatin capsules containing the following ingredients are prepared: Ingredient Quantity (mg / capsule! Active Ingredient 30.0 Starch 305.0 Magnesium Stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in amounts of 340 mg.

Preparation of Formulation 2 A tablet formula is prepared using the following ingredients: Ingredient Quantity (mg / tablet) Active ingredient 25.0 Microcrystalline cellulose 200.0 Silicon dioxide 10.0 colloidal Stearic acid 5.0 The components are mixed and compressed to form tablets, each weighing 240 mg.

Preparation of Formulation 3 A formulation for dry powder inhaler is prepared containing the following components: Ingredient Weight% Active Ingredient 5 Lactose 95 The active mixture is mixed with the lactose and the mixture is added to a device for inhalation of dry powder.

Preparation of Formulation 4 Tablets each containing 30 mg of active ingredient are prepared as follows: Ingredient Quantity (mg / tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as a 10 'solution in water) Carboxymethylcellulose 4.5 mg sodium Magnesium stearate 0.5 mg Talcum 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a No. 20 American mesh screen and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a North American mesh No. 16 screen. The granules thus produced are dried at 50-60 ° C and passed through a sieve. US No. 16 mesh. Sodium carboxymethylcellulose, magnesium stearate and talcum, previously passed through a No. 30 mesh North American sieve, are then added to the granules which, after mixing, are compressed into a tablet-forming machine for producing tablets each weighing 120 mg.

Formulation preparation 5 Capsules are prepared each containing 40 mg of medication, as follows: Ingredient Quantity (mg / capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a No. 20 American mesh screen, and filled into hard gelatin capsules in amounts of 150 mg.

Preparation of Formulation 6 The following are prepared as suppositories, each containing 25 mg of active ingredient: Ingredient Quantity Active ingredient 25 mg Fatty acid glycerides 2,000 mg saturated to The active ingredient is passed through a North American No. 60 mesh screen and suspended in the saturated fatty acid glycerides previously melted using the minimum necessary heat. The mixture is then emptied into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Preparation of Formulation 7 Suspensions are prepared as follows, each containing 50 mg of medication per 5.0 ml dose: Ingredient Quantity Active Ingredient 50.0 mg Xanthan gum 4.0 mg Carboxymethylcellulose 50.0 mg sodium (11%) microcrystalline cellulose (89%) Sucrose 1.75 g Sodium benzoate 10.0 mg Taste and color q.v. Purified water up to 5.0 ml The drug, sucrose and xanthan gum are mixed, passed through a No. 10 mesh American screen, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethylcellulose in water. Sodium benzoate, flavor and color are diluted with some water and added with agitation. Sufficient water is then added to produce the required volume.

Formulation Preparation 8 Capsules are prepared as follows, each containing 15 mg of medicament .: Ingredient Quantity (mg / capsule) Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, the cellulose, the starch, and the. Magnesium stearate are mixed, passed through a No. 20 American mesh screen, and filled into hard gelatin capsules in amounts of 425 mg.

Formulation Preparation 9 An intravenous formulation can be prepared as follows: Ingredient Quantity Active Ingredient 250.0 mg Isotonic saline 1000 ml Formulation Preparation 10 A topical formulation can be prepared as follows: Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin Up to 100 g The white soft paraffin is heated until it melts. The liquid paraffin and the emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and the stirring is continued until it is dispersed. The mixture is then cooled until solidified.

Preparation of Formulation 11 Sublingual or buccal tablets, each containing 10 mg of active ingredient, can be prepared as follows: Ingredient Quantity Per tablet Active Ingredient 10.0 mg Glycerol 210.5 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl Alcohol 26.5 mg Polyvinylpyrrolidone 15.5 mg Total 410.0 mg Glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are mixed together by continuous stirring and maintaining the temperature at approximately 90 ° C. When the polymers have come into solution, the solution is cooled to approximately 50-55 ° C and the drug is mixed slowly. The homogenous mixture is emptied into molds or shaped forms of an inert material to produce a diffusion matrix containing the drug, which has a thickness of about 2 to 4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size. Another preferred formulation used in the methods of the present invention employs the transdermal delivery devices ('patches') Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts The construction and use of transdermal patches for the administration of pharmaceutical agents is well known in the art. See for example U.S. Patent No. 5,023,252, issued June 11, 1991, incorporated herein by reference, such patches may be constructed for continuous, pulsatile or on demand distribution of pharmaceutical agents, it will often be desirable or necessary to introduce The pharmaceutical composition to the brain, either directly or indirectly, direct techniques usually involve the placement of a drug distribution catheter within the host's ventricular system to bypass the blood-brain barrier. the transport of biological factors to the r Anatomical specific anatomies of the body is described in U.S. Patent No. 5,011,472, issued April 30, 1991, which is incorporated by reference herein. Indirect techniques, which are generally preferred, usually involve the formulation of the compositions to provide the latency of the drug by the conversion of the hydrophilic drugs to drugs or lipid-soluble prodrugs. Latency is generally achieved by blocking the hydroxyl, carbonyl, sulfate and primary amine groups present on the drug, to make the drug more soluble in lipid and suitable for transportation through the blood-brain barrier. Alternatively, the distribution of hydrophilic drugs can be increased by the intraarterial infusion of hypertonic solutions which can transiently open the blood-brain barrier. The type of formulation used for the administration of the compounds used in the methods of the present invention can be dictated It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (3)

1. Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula characterized in that R1 and R2 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, hydroxyl or alkoxy of 1 to 6 carbon atoms; R5, R 'are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl or hydroxyl; R3 is hydrogen, alkanoyl of 2 to 7 carbon atoms, glycyl or di ethylglycyl; n is 1 to 6; D is -S (0) m-, -NH-, or -O-, m is O, 1 6 2; and R8 is a carbocyclic or heterocyclic, monocyclic or bicyclic group, optionally substituted with one or more portions selected from the group consisting of oxo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyl, halo, and trifluoromethyl ilo; or a pharmaceutically acceptable salt or solvate thereof.
2. 2. The use of a compound of the formula I wherein: R1 and R2 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, hydroxyl or alkoxy of 1 to 6 carbon atoms; R5, R6 and R7 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl or hydroxyl; R3 is hydrogen, alkanoyl of 2 to 7 carbon atoms, glycyl or di ethylglycyl; n is l to 6; D is -S (0) m-, -NH-, or -0-, m is O, 1 6 2; and R8 and R9 are independently hydrogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, (alkoxy of 1 to 6 carbon atoms) - (alkylenyl) from 1 to 6 carbon atoms), alkoxycarbonyl of 2 to 7 carbon atoms, (alkoxycarbonyl of 2 to 7 carbon atoms) - ((alkylenyl of 1 to 6 carbon atoms), trifluoromethoxy, trichloromethoxy, alkylthio of 1 to 6 atoms of carbon, alkylamino of 1 to 6 carbon atoms, di (C 1 -C 6 alkyl) amino, formyl, cyano, halo, trifluoromethyl R 10 R 1: LN (C 1 -C 6 alkylenyl) -, pyrrolyl, triazolyl , imidazolyl, tetrazolyl, thiazolyl, thiazolinyl, thiadiazolyl, thiadiazolinyl, piperidinyl, pyrrolidinyl, morpholinyl, morpholinyl, morpholinocarbonyl, hexamethyleneiminyl, methylsulfonyl, methylsulfinyl, phenoxy, benzyloxy, carboxyl, carbamoyl, (C 2 -C 7 -alkylcarbonyl) - (C 1-6 -alkylenyl) -, R10 and R11 are independently hydrogen, or alkenyl of 1 to 6 carbon atoms, said alkyl groups of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms are optionally substituted with one, two or three portions selected from the group it consists of hydroxyl, halo, cyano, amino, nitro, carboxyl, carbamoyl and thiol; or R8 and R9 can be combined, together with the benzo ring to which they are attached, to form a naphthyl, dihydronaphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, 2-coumaranonyl, benzothiazolyl, benzimidazolyl, indolyl, benzothienyl, benzofuryl, 2, 3- group dihydrobenzofuryl, indolinyl, or 2-dihydrobenzothienyl, which may be attached to D at any position of the bicyclic group; or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a condition associated with an excess of tachykinins.
3. 3. A pharmaceutical formulation, comprising a compound of the formula characterized in that R1 and R2 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, hydroxyl or alkoxy of 1 to 6 carbon atoms; R5, R6 and R7 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl or hydroxyl; R3 is hydrogen, alkanoyl of 2 to 7 carbon atoms, glycyl or dimethylglycyl; n is 1 to 6; D is -S (0) m-, -NH-, or -O-, is O, 1O 2; and R8 is a carbocyclic or heterocyclic, monocyclic or bicyclic group, optionally substituted with one or more portions selected from the group consisting of oxo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyl, halo, and trifluoromethyl; or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.