IE83327B1 - Substituted 3-aminoquinuclidines - Google Patents

Description

SUBSTI’I'UTED 3-AMINOQUINUCLIDINES This invention relates to novel and useful quinuclidine derivatives of interest to those in the field of medical chemistry. More particularly, it is concerned with a novel series of substituted 3~aminoquinuclidines, including their pharmaceutically acceptable salts, which are of special value in view of their ability to antagonize substance P.

These compounds are useful in treating gastrointestinal disorders, central nervous system disorders, inflammatory diseases, asthma, pain and migraine. The invention also includes a new method of therapy within its scope.

E. J. Warawa, in United States Patent 3,550,510, discloses certain 3-amino benzhydryl-quinuclidines as being useful as diuretic agents, with the corresponding unsubstituted 3-benzylamino compounds acting as intermediates for same. Additionally, E. J. Warawa et al. in the Journal of Medicinal Chemistry, Vol.18, p.587 (1975) extends this work to other members of the series wherein the 3-amino moiety is ethylamino, ,6- phenylethylamino, ,3-isopropylarnino, or 2-furiurylamino.

Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specially, substance P is a pharmaceutically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in United States Patent 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, Vol. 25, p.1009 (1982)), as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, and in gastrointestinal disorders and diseases of the GI tract, like ulcerative colitis and Crohn‘s diseases, etc. (see D.

Fiegoli in ‘Trends in Cluster Headache“ edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pages 85-95). in the recent past, some attempts have been made to provide peptide-like substances that are antagonists tor substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above. The peptide- *t‘ 83327 like nature of such substances renders them too labile from a metabolic point of view to serve as practical therapeutic agents in the treatment of disease‘. The non-peptidic antagonists of the present invention, on the other hand, do not possess this drawback, being far more stable from a metabolic point of view than the peptic-like prior art agents.

Other non~peptide substance P receptor antagonists are referred to in pending patent applications assigned in common with the present application. Ouinuclidine derivatives and related compounds that exhibit activity as substance P receptor antagonists are referred to in PCT Patent Application PCT/US 89/05338, filed November , 1989 and United States Patent Application Serial No. 557,442, filed July 23, 1990.

Other quinuclidine derivatives and related compounds that exhibit activity as substance P receptor antagonists are referred to in the PCT patent applications entitled '3-Amino- 2-Aryl Ouinuclidines' and 'Ouinuclidine Derivatives’ and filed, respectfully, on April 25, 1991 and May 15, 1991. Piperidine derivatives and related heterocyclic nitrogen containing compounds that are useful as substance P antagonists are referred to in United States Patent Application Serial. No. 619,361, filed November 28, 1990 and United States Patent Application Serial No. 590,423, filed September 28, 1990.

Azanorbomane derivatives that exhibit activity as substance P receptor antagonists are referred to in United States Patent Application Serial No 07/719,884, filed June 21, 1991.

Fluoroalkoxy derivatives of nitrogen containing heterocycles that exhibit activity as substance P receptor antagonists are referred to in United States Patent Application Serial No. 07/717,943, filed June 20, 1991. All of the above patent applications are assigned in common with the present application.

WO 90/05729 discloses a series of cis~3-llcyclicl-methylamino]-2~l_(ot- substitutedlarylmethyliquinuclidines, 3-llcycliclmethyliminol[(oi-substituted)- aryimethyllquinuclidenes and cisllcyclicl-methyleneamino][(oi—substituted)- arylmethyll—quinuclidines having substance P antagonist activity.

The present invention relates to compounds having the formula wherein W is X(CH2)n; X is optionally substituted (C,-C6)alkoxy, CONR_‘R2, CO2R‘, CHR‘OR2, CHR‘NR’R3, COR‘, CONR‘OR_’ or optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n is an integer from zero to six; Ar‘, Ar’ and Ar3 are each, independently, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and R‘, R’ and R3 are independently selected from hydrogen, optionally substituted (C,-C5)alkyl, optionally substituted (C,—C6)alkoxy, optionally substituted (C3- Cacydoakw, aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thlenyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and optionally substituted (C,—C5)heterocyclic groups, wherein said heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl and thiamorpholino; and wherein the substituents on the foregoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halo, nitro, amino, (C1- C,,)alkyl, (C,-C,)alkoxy, trifluoromethyl and trifluoromethoxy; and wherein the substituents on the foregoing substituted heterocyclic groups are attached to an oxygen or nitrogen atom on the ring and are independently selected from oxygen and (C,-C,,)alkyl; and wherein the substituents on said substituted Ar‘ groups are independently selected from (C,-C5)alky| optionally substituted with from one to three halo groups, (C,-C6)alkoxy optionally substituted with from one to three halo groups, (C,- (C2-C6)alkenyl, (C,-C6)alky|thio, (C,-C,,)alky|sulfonyl, (C,- C6)a|kylsulfonylamino, and di—(C,-C6)alkylamino wherein one or both of the alkyl groups may be optionally substituted with a (C,—C5)alky|su|fonyl, or (C,-C6)alkylsu|finyl group; and wherein the substituents on said substituted Ar’ and Ar3 groups are independently selected from (C,-C,,)alkyl, (C,-C,,)alkoxy, (C,-C4)alkylthio, (C,~ C,,)alkylsulfinyl, di-(C,-C4)alkylamino, trifluoromethyl and trifluoromethoxy; C6)alky|sulfinyl, and wherein the substituents on said substituted (C,-C5) heterocyclic groups are independently selected from oxygen and (C,-C_,)alkyl.

The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which form non—toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate [i.e., 1,1 ’-methylene-bis-(2-hydroxynaphthoate]salts.

The term ‘alkyl’ is used herein to mean straight or branched hydrocarbon chain radicals including, but not limited to, methyl, ethyl, n—propyl, isopropyl, n-butyl, isobutyl, t—butyl, and the like.

The term 'alkenyl' is used herein to mean straight or branched hydrocarbon chain radicals having one double bond including, but not limited to, ethenyl, 1- and 2- propenyl, 2-methylpropenyl, 1- and 2-butenyl and the like.

The term 'alkoxy' is used herein to mean -OR (R is alkyl) including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like.

The term “alkylthio' is used herein to mean -SR (R is alkyl) including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t- butylthio and the like.

The term 'cyc|oalkyl' is used herein to mean cyclic hydrocarbon radicals including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term “halo” is used herein to mean chloro, fluoro, bromo or iodo.

Preferred compounds of the present invention are those wherein Y is —COOH, Ar’ and Ar’ are diphenylmethyl and Ar‘ is a disubstituted phenyl group.

Specific preferred compounds of this invention include the following: (3R,4S,5S,6S)(5-isopropylmethoxybenzylamino)diphenylmethyl azabicyclo[2.2.2]octane—3-carboxylic acid; (3l'-i,4S,5S,6S)(2-methoxymethylthiobenzylamino)diphenylmethyl azabicyclo[2.2.2]octane-3~carboxylic acid; (3R,4S,5S,6S)(2,5-dimethoxybenzylamino)diphenylmethylazabicyclo- [2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)-5—(2-methoxymethylbenzylamino)-6—diphenylmethy| azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,SS.68)(5-ethylmethoxybenzylamino)diphenylmethyl azabicyclo[2.2.2]octane-3—carboxvlic acid; (3R,4S,5S,6S)(2-methoxyln-propylbenzylamino)-6—diphenylmethyl—1- azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(5-sec-butylmethoxybenzylamino)diphenylmethyl azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,GS)(5—aminosulfonylmethylmethoxybenzylamino) diphenylmethylazabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(2-methoxy-5—methylsulfinyibenzylamino)diphenyimethyi azabicyclo[2.2.2]octane-3—carboxyiic acid; (3R,4S,5S,6S)(2-methoxy-Ertrifluoromethoxybenzylamino)diphenylmethyi azabicycio[2.2.2]octanecarboxyiic acid; (3R,4S,5S ,6S)(2-methoxymethylsuifonylbenzylamino)-6—diphenylmethyi-1 - azabicyclo[2.2.2]octane~3-carboxylic acid; (3R,4S,5S,6S)(5—dimethylaminomethoxybenzylamino)diphenylmethyl azabicyclo[2.2.2]oc’(ane-3~carboxylic acid; (3R,4S,5S,6S)—5—(5-isopropylmethoxybenzylamino)diphenylmethyi azabicyclo[2.2.2]octanecarboxyiic acid; (3R,4S.58,6S)(2-methoxy—5—methyIthiobenzylamino)diphenylmethyl azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(2,5-dimethoxybenzylamino)diphenylmethyl-1— azabicyclo[2.2.2]octane-2—carboxyIic acid; (3R,4S,5S,6S)-5—(2~methoxymethylbenzyiamino)diphenylmethyi azabicycio[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(5-ethyl-2—methoxybenzylamino)diphenylmethyi azabicycio[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(2-methoxyln-propyibenzylamino)diphenyimethyI azabicyclo[2.2.2]octane—2-carboxylic acid; (3R,4S,5S,6S)(5-sec-butylmethoxybenzylamino)~6-diphenylmethyl azabicyclo[2.2.2]octane-2—carboxyIic acid; (3R,4S,5S,6S)(5-aminosuifonylmethylmethoxybenzylamino) dipheny!methy|—1-azabicyclo[2.2.2]octanecarboxylic acid; (SR,4S,5S,6S)-5—(2-methoxymethylsuifinylbenzylamino)-6—dipheny|methyl-1 - azabicyclo[2.2.2]octane—2-carboxylic acid; (3R,4S,5S,6S)5(2methoxy-Strifluoromethoxybenzyiamino)—6—diph enylmethyl-1 - azabicycio[2.2.2]octa.necarboxylic acid; (3R,4S,5S,BS)(2-methoxymethyisulfonyibenzylamino)-6—dipheny|methyl-1 - azabicyclo[2.2.2]octane-2—carboxylic acid; and (3R,4S,5S,6S)(5—dimethylaminomethoxybenzyiamino)-6—diphenyimethy| azabicyclo[2.2.2]octanecarboxylic acid.

The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimefs disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimefs disease, AIDS related dementia, diabetic neuropathy and ‘ multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition.

The present invention also relates to a pharmaceutical composition for antagonizing the effects of substance P in a mammal, including a human, comprising a substance P antagonizing amount of a compound of the formula l, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of antagonizing the effects of substance P in a mammal, including a human, comprising administering to said mammal a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.

The compounds of the formula I have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers and all stereoisomers of compounds of the formula I, and mixtures thereof.

Formula l above also includes compounds identical to those depicted but for the fact that one or more hydrogen or carbon atoms are replaced by isotopes thereof.

Such compounds are useful as research and diagnostic tools in metabolism pharmokinetic studies and in binding assays.

The novel compounds of the present invention can be prepared as described in the following reaction schemes and discussions. Unless otherwise indicated, W, Ar‘, Arz, Ar’, X, defined as above.

R‘, R’, R’ and n in the reaction schemes and discussion that follow are f3 CV ~._< 2 / z 3 ZS z 2 4..w.|_.......< o oIoN_< OQ CV r mEwr_om _l0_ o:o_.< .:_z , co_..oc_Eo o>_..o3vo. _< N z co_+o:_um._ ~12 N mEw:ow ~:z~Io._< co__.o w>_+o .o+o .;¢~Io .~¢:z Lmwxoo .mzo.zo.Iuo ouzwz ;+_; c_Eo :_uo.. ___v _ 1 l co_*oo+o.aov ma:o.m _oco_*oc:w m:_mco;o z m.< 1<\/z C L ~L< z n._< _L<)i a mu mrcmcom co_+ow*oLa masogm _oco_+oc:» mc_mco;o The compounds of the formula I may be prepared by a number of synthetic methods. In the above schemes, Ar‘, Ar2 and Ar3 are as previously defined, each of W and W’ represents the substituent—(CH,)nX defined as for formula I above, or an equivalent Of (CH,),,X in the synthetic process. P and Q represent, respectively appropriate nitrogen protecting groups.

Substituted quinuciidineones (i) can be prepared from properly substituted isonicotinates by the method for preparing unsubstituted quinuciidineones reported in Q_rg. Synth. Qgl_l. Vol. V, 989 (1973). For example, 5-methyl-, 5—methoxycarbonyl- and -diethyi-aminocarbonyl-quinuclidinones have already been prepared by this method (J. Chem. Soc. Perkin Trans., 1, 409 (1991)).

Introduction of a benzhydryl group or its congener at the 2 position of a quinuclidine- 3-one (i) can be accomplished using the procedure reported in _.1._Meg g3_l_1gn_.,1_8, 587 (1975). Compound (i) can be converted to the 2-benzyliden compound (ii) by aldol condensation with an aromatic aldehyde (Ar’CHO) catalyzed by a base such as sodium hydroxide in a protic solvent (e.g., ethanol). This reaction is preferably conducted at the reflux temperature of the solvent.

Introduction of another aryl group (Ar3) can be accomplished via a Grignard reaction in an aprotic solvent such as tetrahydrofuran (T HF), ether or toluene. The addition of catalytical amount of copper(l) halide such as cuprous bromide or iodide improves the yield of the 1,4-addition product. This reaction is usually conducted at low temperatures such as from -78 to 0°C. in some cases, the procedure reported by (letrahedron, Q, 349 (1989)) hexamethylphosphoramide (HMPA) and cuprous bromide dimethylsulfide complex Kuwajima employing trimethylsilylchloride, (CuBr-DMS) is preferred to improve the selectivity. The resulting compound (iii), if desired, can be converted to the corresponding carboxylic acid by acid catalyzed hydrolysis. The carboxylic acid can be converted, if desired, to corresponding amide by methods well known to those skilled in the art.

Compound (iii) can be converted to the claimed compounds (vi) by two independent routes. The first route involves direct introduction of an arylmethyiamino group (Ar‘CH2NH-) at the 3 position of the quinuclidine ring. This transformation is accomplished by, first, formation of an imine with (iii) and a corresponding benzylamine.

This reaction is usually catalyzed by an acid (e.g., camphor sulfonic acid (CSA)), and conducted in hot toluene under dehydrolytic conditions. Then, the imine is reduced to _.]_3_ afford compound (vi). This reduction can be carried out by catalytic hydrogenation, or with several hydride reagents such as aluminum—based reagents, boranes, borohydrides or trialkylsilanes. In most cases, the reaction with trialkylboranes (e.g., 9—borabicyclo[3.3.1]nonane (9-BBN)) or sodium triacetoxyborohydride (NaBH(OAc)3) in THF at room temperature for a half hour to a few days gives satisfactory results.

The second route involves stepwise syntheses viathe 3—amino of compound (v), which is then alkylated to afford (vi). Compound (iv) is an imino-type derivative such as an oxime, hydrazone or lmine- It can be formed by reaction of (iii) with the corresponding Q-NH, (e.g., a hydroxylamine, N,N-dimethylhydrazone, ammonia or benzylamine). The obtained product (iv) can be reduced using any one of a variety of reducing reagents. Appropriate reducing agents include lithium aluminum hydride (LAH), borane reagents, catalytic hydrogenation or a combination of the foregoing. In the case of imines derived from ammonia, formic acid can be used as a reductant. The formed 3—amino derivative (v) is then arylmethylated with a proper benzaldehyde (Ar‘CHO) under ordinary conditions for reductive amination, e.g., sodium cyanoborohydride in methanol (J. Am. Chem. Soc., gs, 2897 (1971)). Several other reducing agents such as sodium borohydride (NaBH4), sodium triacetoxyborohydride (NaBH(OAc)3) or trialkylsilanes can be also used to perform this transformation.

The functional group W in compound (vi) can be changed to another functionality W’. Some of the claimed compounds (ix) can be obtained in this manner.

For example, a compound (vi) wherein W is an amide can be converted into the corresponding amine derivative by reacting it with an appropriate reducing reagent such as LAH. It can also be converted into the corresponding carboxylic acid by hydrolysis.

The carboxylic acid so obtained can be converted into a corresponding ester by a standard procedures that are known to those skilled in the art.

Compounds (vi) wherein W is an ester or a carboxylic acid can be converted to the corresponding hydroxymethyl by treating with a suitable reducing agent such as LAH.

The above described conversions from one functional group W to another W’ are standard procedures that will be obvious to those skilled in the art. if the benzylamine interferes with such transformation, appropriate protection of NH group of the benzylamine of (vi) is necessary. For such protection, Cbz or Boc group is suitable (c.f. T. W. Greene, Protective Groups in Organic Synthesis, J. Wiley _:L4_ & Sons (1981)). After finishing transformation of the functional group, the protecting group is removed by a suitable standard procedure to provide the claimed compound (ix).

Inasmuch as the quinuclidine compounds of this invention all possess at least one asymmetric center, they are capable of occurring in various stereoisomerio forms or configurations. Hence, the compounds can exist in separated (+)- and (-)<>ptically active forms, as well as in racemic or (:)-mixtures thereof, and in the case of those compounds with two asymmetric centers, they can additionally exist as diastereomers with respective optical isomers thereof. The present invention is meant to include all such forms within its scope. For instance, the diastereomers can be separated by methods well known to those skilled in the art, e.g., by fractional crystallization and the like, while the optically-active isomers can be obtained by simply resolving the chemistry that are known for these purposes. insofar as the majority of 3~arylmethylamino—2-benzhydryl quinuclidine compounds of this invention are basic compounds, they are all capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the quinuclidine base compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert to the free base compound by treatment with an alkaline reagent and thereafter, subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the quinuclidine base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.

The acid which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned quinuclidine base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisuliate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate, gluconate, saccharate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1.1‘- methylene-bis- (2-hydroxy—3—naphthoate))salts. -15..

Some quinuclidine compounds of the invention which have also acidic groups are capable of forming base salts with various pharmacologically acceptable cations.

Examples of such salts include.the alkali metal or alkaline earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non- toxic base salts with the herein described acidic quinuclidine derivatives. These particular non-toxic base salts include those derived form such pharmacologically acceptable cations as sodium,potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the aforementioned acidic quinuclidine compounds with an aqueous solution containing the desired pharmacologically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure.

Alternatively, they may also be prepared by mixing lower alkanoic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum production of yields of the desired final product.

The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to, collectively, as ‘the active compounds of this invention‘) exhibit significant substance P receptor-binding activity and therefore, are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of said substance P activity. Such conditions include gastrointestinal disorders such as ulcer and colitis and other like diseases of the gastrointestinal tract, central nervous system disorders such as anxiety and psychosis, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases, respiratory diseases such as asthma, as well as pain in any of the aforesaid conditions, including migraine. Hence, these compounds are readily adapted to therapeutic use as substance P antagonists for the control and/or treatment of any of the aforesaid clinical conditions in mammals, including humans.

The active compounds of this invention can be administered via either the oral, parenteral or topical routes. in general, these compounds are most desirably administered in doses ranging from about 2.8 mg. up to 1500 mg per day, although _]_6_ variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of form about 0.07 mg to about 21 mg per kg of body weight per day is most desirably employed. Nevertheless, variations may still occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical fonnulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects provided that such higher dose levels are flrst divided into several small doses for administration throughout the day.

The active compounds of this invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any one of the three routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the active compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents orfillers, sterile aqueous media and various non—toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. in general, the therapeutically- effective compounds of this invention are present in such dosage forms at concentration levels ranging about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.

Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight _:L7_ polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH ) 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra- muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

The activity of the compounds of the present invention may be determined by their ability to inhibit the binding of substance P at its receptor sites in bovine caudate tissue or IM-9 cells employing radioactive ligands. The substance P antagonist activity of the herein described quinuclidine compounds is evaluated by using the standard assay procedure described by M. A. Cascleri et al., as reported in the Journal of Biological Chemistry, Vol.258, p.5158 (1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues or IM-9 cells, thereby affording characteristic lC5° values for each compound tested. In this test, some preferred compounds indicated lC5,, values, in the range of O.l—60 nM, with respect to inhibition of binding at its receptor.

The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples.

Proton nuclear magnetic resonance spectra (NMR) were measured at 270 MHz unless othen/vise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsllane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. _l8_ In the reaction schemes and procedures that appear in the examples, Me represents methyl, Et represents ethyl, Ph represents phenyl, TFA represents trifluoroacetic acid, and t-Boc represents t-butoxycarbonyl.

EXAMPLE 1 (3Ft*,4R",5S*,6S*)—NLN-Diethvl~5—(2,5—dimethoxvbenzylamino)-5 1-azabicyc|o[2.2.2]octanecarboxamide (1 Z) A. cis-Methvl(Diethylcarbamoyll(methoxvcarbonylmethyl)—piperidine- 4-carboglate (12) cis-Methyl(Diethylcarbamoyl)(methoxycarbonyl methy|)piperidine~4- carboxylate, 12 was prepared according to the procedure reported in Tetrahedron Letters, 1989, 30, P.5795-5798 and J. Chem. Soc., PERKIN TRANS. 1., 1991, P.409-420.

B. (3R*,4R*)—N,N—Diethvloxo-1—azabicyclo[2.2.2loctanecarboxamide U_3) A solution of Q (159 g, 0.503 mole) in toluene (700 ml) was added dropwise over a period 2.5 hours to a solution of potassium t-butoxide (169 g, 1.51 mole) in toluene (1.9 L) at 110°C under a nitrogen condition. The mixture was heated at reflux for 1 hour and cooled down to room temperature. Water (400 ml) was added then the layers were heated at reflux for 2 hours. After the organic layer was separated, the aqueous layer was neutralized and extracted with EtOAc for 15 hours with continuous extraction apparatus. The combined extracts were dn'ed over MgSO,, and concentrated down. Recrystallization from EtOH gave 3 (34.6 g, 31%) as a colorless crystal. The stereochemistry was determined by X-Ray analysis, “C and NMR.

IR (KBr): 2975, 2915, 2875, 1726, 1629, 1483, 1482, 1454, 1434, 1410, 1382, 1368, 1296, 1253,1141,1081, 1052 cm".

‘H NMR (CDCI3): 3.6 (d, J=8Hz, 1H), 3.5-3.1(m, 8H), 3.0-2.9 (m, 2H), 2.5 (dd, J=6, 3Hz, 1H) 2.2 (dd, J=8.3Hz, 2H), 1.2 (t, J=7Hz, 3H), 1.1 (t, J=8Hz, 3H). ‘3C NMR (CDCI3): 215.4, 173.2, 62.5, 51.5, 45.9, 42.3, 42.0, 41.3, 40.5, 25.9, .0, 12.9.

C. (3R*,4R*)—N,N—Diethyloxobenzvlidene azabicvclo[2.2.2loctane- 3-carboxamide (14) A mixture of 13 (34.6 g, 154 mmole), benzaldehyde (17.4 g, 164 mmole) and NaOH (6.5 g, 164 mmole) in EtOH (400 ml) was refluxed for 3 hours. After cooling the reaction mixture to room temperature, the resulting yellow crystal was collected by _l9_ filtration and washed with cold Et0H and dried in vacuo to give 14 (38.4 g, 128 mmole).

The filtrate was concentrated under reduced pressure to give a second crop (3.3 g, 11 mmole) (total 41.7 g, 139 mmole, 90%).

IR (KBr): 2960, 2930, 2875, 1706, 1640, 1453, 1445, 1427, 1315, 1260, 1136, 1094, 694 cm".

‘H NMR (CDCI3): 8.0 (dd, J=8.6Hz, 2H), 7.3 (m, 3H), 7.1 (s, 1H), 3.4-3.0 (m, 6H), 2.7 (dd, J=5.0, 3.0Hz, 2H), 1.2 (t, J=7Hz, 3H), 1.1 (t, J=8Hz, 3H).

“C NMR (CDCI3): 202.5, 172.9, 143.8, 134.1, 132.0, 129.3, 128.2, 125.2, 52.3, 47.7, 46.4, 43.5, 42.0, 41.9, 40.5, 25.9, 15.1, 13.1.

D. (3R*,4R*.6R*)-N,N-Diethyloxodiphenvlmethvlazabicvclo[2.2.2]- octanecarboxamide (3R*,4Fl* ,6S*)—N,N-Diethvloxodiphenvimethvl-1 - azabicyclo(2.2.21octanecarboxamide (15) & (16) A 1L four necked flask, equipped with a mechanical stirrer and a thermometer was flame dried and iurnished with a nitrogen atmosphere. CuBr/CH_._SCH3 (3.1 g, 15 mmole) was placed in this flask, dry THF (400 ml) was added and cooled to -50°C.

‘H NMR (CDCl3) 15 isomer: 7.43 (d, J=7Hz, 2H), 7.3-7.1 (m, 8H), 4.7 (d, J=7Hz, 1H), 4.4 (d, J=7Hz, 1H), 3.4-3.1 (m, 7H), 2.5-2.4 (m, 3H), 1.9-1.8 (m, 2H), 1.2 (t, J=3Hz, 3H), 1.1 (t, J=7.3Hz, SH). isomer: 7.4-7.2 (m, 10H), 4.8 (d, J=11Hz, 1H), 3.96 (d, J=11Hz, 1H), 3.6-3.5 (m, 1H), 3.4-2.8 (m, 8H), 2.5-2.4 (m, 1H), 1.9-1.8 (m, 2H), 1.2-1.1 (m, 6H). _20.._ A mixture of (6 g, 29 mmol), trimethylsilyl chloride (20 ml) and ethylene glycol (50 ml) was heated at 100°C for 3 hours. After by-products were removed by distillation (93°C/atmosphere pressure), the mixture was poured into cold aqueous sodium bicarbonate (NaHCO3) (250 ml) and extracted with methylene chloride (CH,C|2) (100 ml) three times. The combined extracts were dried over sodium sulfate (Na,SO4)-and concentrated. The clude was purified by recrystallization from ethyl acetate (EtOAc)/hexane to give 21 (1 :2 mixture at &position; 23 mmol, 88%).

‘H NMR (CDC|,): 4.64 (d, J=12.1Hz, Ph2C_HCH of one isomer), 4.33, 4.28 (d+d, J=12Hz, a pair of Ph2CH_CH and Ph2CHCl_~l_ of another isomer).

MS(D|-El): M/z=434 (M+).

B. (3R*.4S*)-N,N-Diethvldiphenvlmethvl-5,5-ethvlenedioxv azabicvclo[2.2.2loctanecarboxamide (22) A suspension of g (9.8 g, 22 mmol) in sodium methoxide (28% in MeOH; 400 g) was heated at reflux temperature for 9 hours. The resulting solution was poured on ice (300 ml) and extracted with CHZCIZ (150 ml) three times. The combined extracts were dried over sodium sulfate (Na2SO,,) and concentrated. The cnrle was purified by recrystallization from ethanol (EtOH) to give Q (1:4 mixture at 6-position ; 8.4 g, 19 mmol, 87%).

‘H NMR (CDCP): 4.40(d, J»=12.1Hz, Ph2C_ljCH of one isomer), 4.34, 3.93 (d +d, J=12.5Hz, a pair of Ph2CfiCH and Ph2CHCfl_ of another isomer).

MS(Dl-El): M/z=434 (M+).

C. (3R*.48‘)-N,N-Diethid-Scllphenvlmethy|oxoazabicyclo[2.2.2]octane- 3-carboxamlde (23) A solution of 22 (6.5 g, 15 mmol) in SN-HCl aq (100 ml) was heated at reflux for hours. The resulting solution of sodium hydroxide (NaOH) (24 g) in water (100 ml) and extracted with CHZCIZ (100 ml) four times. The combined extracts were dried over Na,SO, and concentrated. The clude was purified by recrystallization from EtOH to give 2_3 (1 :1 mixture at 6—position; 10 mmol, 68%).

‘H NMR (CDCl,): 4.71, 3.95 (d+d, J=5.7Hz, a pair of Ph2CCH and Ph2CHC_H of one isomer), 4.47, 4.03 (d+d, J=8.4Hz, a pair of Ph2CflCH and Ph2CHCl_-l_ of another isomer).

D. (3R*,4S*,5S*,6S*)—N,N-Diethyl(2,5dimethoxvbenzvlamino)6-diphenvl- methylazabicyclo[2.2.2]octanecarboxamide (24) A mixture of 2_3_ (3.9 g, 10 mmol), 2,5-dlmethoxybenzyl amine (1.9 g, 11 mmol) (fig. _C_l; toluene (40 ml) was heated at reflux with removal of water for 8 hours and then the solvent was removed. The residue was dissolved in small amount of THF (c.a. 5 ml) __22_ and this solution was added to a solution of sodium triacetoxyborohydride (5.3 g, 25 mmol) in acetic acid (100 ml) at room temperature. The mixture was stirred at room temperature for 4 hours and the solvent was removed. Water (25 ml) was added and the mixture was neutralized with NaHCO3 and extracted with EtOAc three times. The clude was purified by recrystallization from EtOAc to give 24 (2.4 g, 4.4 mmol, 44%).

M.p.: 153.1-154.1°C.

IR (KBr): 1634, 1501, 1466, 1447, 1432, 1266, 1227 cm".

‘H NMR (CDCI3): 7.03-7.37 (m, 10H), 6.68 (dd, J=8.8, 2.5Hz, 1H), 6.62 (d, J=8.8Hz, 1H), 6.38 (d, J=2.5Hz, 1H), 4.51 (d, J=12.1 Hz, 1H), 3.73 (s, 3H), 3.49 (s, 3H), 3.05-3.77 (m, 9H), 2.92 (dd, J=8.1, 4.4Hz, 1H), 2.54-2.89 (m, 3H), 2.11 (br, 1H), 1.70-1.79 (m, 2H), 1.15 (t, J=7.3Hz, 3H), 1.11 (t, J=7Hz, 3H).

EXAMPLE 3 (3R*,4S*,5S*,6S*)-N,N-Dimethyl(2,5-dimethoxybenzylamino)diphenvi- methvlazabicvcloI2.2.2]octane—3-carboxamide (49) A. (3R*,4S*)-6—Diphenvlmethvl-5—oxo-1—azabicvclo[2.2.2]octane3-calboxvlic acid hydrochloride (46) ‘H NMR (DMSO<:l6): Ph2CHCLl).

B. (3R*,4S*) octanecarboxamide (47) .70, 4.81 (d+d, J=11Hz; a pair of Ph2C_l;lCH and N,N-Dimethyldiphenvlmethvloxoazabicyclo[2.2.2L (hexane:EtOAc=1 :4) to give 41 as a single isomer at 3-position (1.4 g, 3.9 mmol, 60%) _23_ ‘H NMR (CDCI3): 4.49, 4.02 (d+d, J=8Hz; a pair of Ph2CHCH and Ph2CHCtl_ of one isomer), 4.66, 3.96 (d +d, J=8Hz; a pair of Ph2CflCH and Ph2CHCH of another isomer).

A mixture of 47 (3.9 g, 10 mmol), 2,5-dimethoxybenzyl amine (1.9 g, 11 mmol) camphor sulfonic acid (120 mg) in toluene (40 ml) was heated at reflux with removal of water for 8 hours and then the solvent was removed. The residue was dissolved in small amount of THF (5 ml) and this solution was added to a solution of sodium triacetoxyborohydride (5.3 g, 25 mmol) in acetic acid (100 ml) at room temperature.

The mixture was stirred at room temperature for 4 hours and the solvent was removed.

Water (25 ml) was added and th_e mixture was neutralized with sodium bicarbonate (NaHCO3) and extracted with ethyl acetate (EtOAc) three times. The combined extracts were dried over sodium sulfate (Na2SO,,) and concentrated. The crude was purified by recrystallization from EtOAc to give 49 (2.4 g, 4.4 mmol, 44%) C. (3R*,4S*,5S*,6S*)-N,N-Dimethyl(2,5-dimethoxybenzy|amino) diphenylmethv|—1-azabicvclo[2.2.21octanecarboxamide (49) M.p.: 142.0142.9°C.

IR (KBr): 1637, 1499 cm“.

‘H NMR (CDCI3): 7.03-7.37 (m, 10H), 6.68 (dd, J=8.8,2.5Hz, 1H), 6.64 (d, J=8.8Hz, 1H), 6.39 (d, J=2.5Hz, 1H), 4.51 (d, J=12.1Hz, 1H), 3.73 (s, 3H), 3.49 (s, 3H), 3.05-3.82 (m, 9H), 2.96 (s, 6H), 2.62-2.95 (m, 4H), 2.17 (br, 1H), 1.62-1.77 (m, 2H).

EXAMPLE 4 (3R*,4S*,5S*,6S*)(2,5-Dimethoxybenzylarnino)diphenvlmethyl—1-azabicvclo- [2.2.2]octanecarboxamide (50) A. (3R*,4S*) octanecarboxamide (46) N,N-Dimethvl—6—diphenvlmethvl-5—oxo-1 -azabicvclo[2.2.21- A suspension of 46 (1.1 g, 3.3 mmol) in THF (10 ml) was treated with triethylamine (0.66 g, 6.6 mmol) at room temperature. To this suspension was added ethyl chloroformate (0.36 g, 3.3 mmol) at 0°C. After 30 minutes, NH3 aq (0.67 g, 6.7 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, poured into H20 and extracted with EtOAc three times. The combined extracts were dried over Na,SO4 and concentrated to give Q (12 g, 3.0 mmol, 90%; 4:1 mixture of isomers at 3-position). This was used without further purification. _24__ ‘H NMR (CDCI3): 4.43, 3.98 (d+d, J=9Hz; a pair of Ph2CflCH and Ph2CHCl_1_ of one isomer), 4.51, 4.28 (d+d, J=8Hz; a pair of Ph2CflCH and Ph2CHCfl of another isomer).

B. (3FI*,4S*,5S*.68‘)(2,5-Dimethoxvbenzylaminc)diphenvlmethvl azabicvclo[2.2.21octanecarboxamide (50) A mixture of 4;} (1.2 g, 3 mmol), 2,5-dimethoxybenzyl amine (0.6 g, 3.3 mmol) camphor sulfonic acid (45 mg) in toluene (15 ml) was heated at reflux with removal of water for 3 hours and then the solvent was removed. The residue was dissolved in small amount of THF (3 ml) and this solution was added to a solution of sodium triacetoxyborohydride (1.7 g, 8 mmol) in acetic acid (40 ml) at room temperature. The mixture was stirred at room temperature for 3 hours and the solvent was removed.

Water was added and the mixture was neutralized with NaHCO3 and extracted with EtOAc three times. The combined extracts were dried over Na,SO4 and concentrated.

Recrystallization from MeOH/acetone to give by-product. The mother liquor was concentrated and the residue wasipurified by recrystallization from MeOH/EtOAc to give 59 (0.27 g, 0.56 mmol, 19%) M.p.: 127-129°C.

IR (KBr): 3350, 1686, 1493 cm“.

‘H NMR (CDCI3): 7.05-7.32 (m, 10H), 6.69 (dd, J=8.8,2.5Hz, 1H), 6.64 (d, J=8.8Hz, 1H), 6.36 (d, J=2.5Hz, 1H), 4.47 (d, J=12.1Hz, 1H), 3.74 (s, 3H), 3.53 (s, 3H), 3.48-3.75 (m, 3H), 2.95-3.26 (m, 6H), 2.11 (br, 1H), 2.59-2.62 (m, 1H), 2.37-2.50 (m, 2H), 1.76-1.89(m, 1H).

EXAMPLE 5 (3R*,4S*,5S*,6S*)(2,5-Dimethoxvbenzvlamino)6 [2.2.2]octanecarboxylic acid hydrochloride (51) A solution of compound 50 (100 mg, 0.2 mmol) in conc. HCl (2 ml) was heated at reflux for 15 hours. After cooling down to room temperature, the mixture was basified with NH3 aq and extracted with CHZCIZ twice. The combined extracts were dried and concentrated. 10% HCl—MeOH was added and evaporated. The resulting precipitate was recrystallized from MeOH-ether to give 51 (30 mg, 0.054 mmol, 27%).

M.p.: 230°C (dec).

IR (KBr): 2945, 1726, 1502, 1451 cm“. __25_ ‘H NMR (free base, CDCI3): 6.95~7.32 (m, 10H), 6.65 (dd, J=8.8,2.5Hz, 1H), 6.61 (d, J=8.8Hz, 1H), 6.49 (d, J=2.5Hz, 1H), 4.41 (d, J=12.1Hz, 1H), 3.68 (s, 3H), 3.53 (s, 3H), 2.70-3.70 (m, 7H), 2.31-2.60 (m, 3H), 1.67-1.85 (m, 1H), 1.33-1.49 (m, 1H).

EXAMPLE 6 (3R*,4S*,5S*,6S*)(5-lsopropylmethoxvbenzvlamino)diphenvlmethvl- 1- azabicvclo[2.2.2loctanecarboxvlic acid dihvdrochloride The title compound was prepared using a procedure similar to that described in Example 2.

M.p.: 15o1s5°c.

IR (KBr, free amine): 3400, 1730, 1510 cm".

‘H NMR (CDCI3, free amine): 7.36—7.00 (m, 11H), 6.63 (d, J=8.8Hz, 1H), 6.57 (d, J=1.8Hz, 1H), 4.47 (d, J=12.4Hz, 1H), 4.00 (br s, 1H), 3.51 (s, 3H), 3.70—3.45 (m, 2H), 3.40-2.40 (m, 8H), 2.00-1.55 (m, 2H), 1.19 (d, J=6.9Hz, 3H), 1.18 (d, J=6.9Hz, 3H).

EXAMPLE 7 (3R,4S,5S,6S)(5-lsopropvl—2-methoxvbenzv|amino)—6-diphenvlmethvl azabicvclo[2.2.2loctane-3—carboxamide dihvdrochloride Optical resolution of (3R*,4R*)-N,N-Diethyloxoazabicyclo[2.2.2]octane carboxamide. (3R*,4R*)-N,N-Diethyloxoazabicyclo[2.2.2]octane—3—carboxamide (180 g, 0.804 mol) and (-)-dibenzoyl-L~tartaric acid (L—DBT) monohydrate (211 g, 0.561 mol) were added to ethanol (3.65 L), and the resultant mixture was heated at reflux until a clear solution was obtained. The solution was rapidly cooled down to c.a. 40°C in a water-bath, and allowed to stand overnight to form crystals, which were collected by filtration. The obtained crystals (100.5 g, 21.5%) were found to be the L-DBT salt of (+)-(3R,4R)-N,N-diethyloxoazabicyclo[2.2.2]-octanecarboxamide with 97% optical purity. An additional amount of the (-)-L-DBT monohydrate (90.6 g, 0.241 mol) was added to the mother liquor, which was concentrated to c.a. 3.5 L by evaporation.

The resulting mixture was heated at reflux to give a clear solution, which was allowed to stand at room temperature. After 2 days, formed crystals were collected by filtration.

The crystals (117 g, 25%) were found to be the L—DBT salt of (-)-(38,4S)-N,N-diethyl oxo-1—azabicyclo[2.2.2]-octanecarboxamide with 92% optical purity. The same resolution process was repeated starting with 220 g of (3R*,4R*)-N,N-diethyl—5-oxo—1- azabicyclo[2.2.2]-octanecarboxamide. From this run, 180 grams of the L—DBT salt _26_ of the (+) enantiomer (31%) with 95% optical purity and 91 grams of the L-DBT salt of the (-) enantiomer (16%) with 97% optical purity were obtained. The L-DBT salt of one (-) enantiomer from the above two runs were combined, and suspended in 1.5 liters (l) of ethanol. The resulting suspension was heated at reflux for 3 hours, and allowed to stand overnight at room temperature. The obtained crystals were converted to the free amine by base treatment (aqueous bicarbonate) followed by extraction with methylene chloride to afford (-)-(3S,4S)-N,N (73 g, 18%) having greater than 99% optical purity. Similarly, 83 g of (+)-(3R,4R)-N,N- diethyloxo-1 -azabicyclo[2.2.2]-octanecarboxamide (21 %)was obtained with greater than 99% optical purity. The above mentioned optical purities were determined using a chiral HPLC. The absolute configuration was determined by X—ray crystallography of the dibenzoyl-L-tartaric acid salt of the (-) enantiomer. (3R,4R)-N,N-Diethyloxoazabicyclo[2.2.2]octanecarboxamide (69) dibenzoyl-L—tarataric acid salt M.p.: 120-135°C (dec, no clear mp).

Analysis calc‘d.: C, 60.27%; H, 6.48%; N, 4.39%. Found: C, 60.10%; H, 6.43%; N, 4.45%. (+)-(3Ft,4R)-N,N—Diethyloxo-1—azabicyclo[2.2.2]octanecarboxamide (69) M.p.: 108.6-112.1°C (ethyl acetate).

Analysis calc‘d.: C, 64.26%; H, 8.99%; N, 12.49%; Found: C, 63.96%; H, 9.24%; N, 12.38%. [a]D=+59.0° (c=1.00, ethanol). (38,4S)-N,N-Diethyl-5—oxoazabicyclo[2.2.2]octanecarboxamide dibenzoyl—L—tarataric acid salt M.p.: 158.7-159.3°C (dec.). (70) Analysis calc‘d.: C, 61.85%; H,5.88%; N,4.81%. Found: C, 61.54%; H, 5.91%; N, 4.81%. (-)—(3S,4S)—N,N—Diethyl—5-oxoazabicyclo[2.2.2]octanecarboxamide (70) M.p.: 108.6 - 111.5°C (ethyl acetate).

Analysis calc‘d.: C, 6426%; H, 8.99%; N, 12.49%. Found C, 63.90%; H, 9.24%; N, 12.33%. [a]D’5 = -58.8° (c=1.00, ethanol). _27_ The title compound was prepared from E in a manner similar to those described in Examples 1, 2, 3 and 4.

M.p.: 215-219°C.

IR (KBr): 3320, 3200, 1685, 1505, cm".

‘H NMR (270 MHz, CDC|,, ppm): 7.35 - 7.00 (m, 11H), 6.67 (d, J=8.4Hz, 1H), 6.57 (d, J=2.8Hz, 1H), 5.57 - 5.36 (m, 2H),‘4.48 ( d, J=11.7Hz, 1H), 3.70 - 3.62 (m, 2H), 3.55 (s, 3H), 3.26 - 2.90 (m, 5H), 2.80 - 2.26 (m, 2H), 2.51 - 2.40 (m, 2H), 1.92 - 1.80 (m, 1H), 1.70 - 1.66 (m, 1H), 1.21 (d, J=7.0Hz, 3H), 1.18 (d, J=7.0Hz, 3H). [a],,’‘'’ = +15.5° (c=1.00, DMSO) EXAMPLE 8’ (3R,4S,5S,6S,)—5—(5—lsopropylmethoxvbenzvlamino)fidiphenvlmethylaza- bicvclo[2.2.2]octanecarboxylic acid dihydrochloride The title compound is an optical isomer of the title compound of Example 6, and was prepared from the title compound of Example 7 in a manner similar to that described in Example 5.

M.p.: > 230°C.

IR: (KBr): 3400, 3200, 1735, 1500 cm".

‘H NMR (270 MHz, CDCI3, ppm, free base): 7.40 - 6.98 (m-, 11H), 6.63 (d, J=8.8Hz, 1H), 6.57 (s, 1H), 4.45 (d, J=12.4Hz, 1H), 3.50 (s, 3H), 3.97 - 3.80 (m, 1H), 3.64 (d, J=12.4Hz, 1H), 3.50 - 3.00 (m, 6H), 2.90 - 2.50 (m, 4H), 1.97 - 1.82 (m, 1H), 1.70 - 1.52 (m, 1H), 1.19 (d, J=7.0Hz, 3H), 1.17 (d, J=7.0Hz, 3H). [a],,"°' = +9.9o° (c=1.00, EtOH).

Claims (12)

CLAIMS:-

1. A compound having the chemical formula H l N\/A r ( I ) W A r 2 N 3 A r wherein W is X(CH2)n7 X is optionally substituted (C,-C5)alkoxy, CONR‘Fl’, COZR‘, CHR‘OR’, CHR‘NR’R3, COR‘, CONR‘OR’ or optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imldazolyl and pyrazolyl; and n is an integer from zero to six; Ar‘ , Ar’ and Ar3 are each, independently, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imldazolyl and pyrazolyl; and R‘, R’ and R3 are independently selected from hydrogen, optionally substituted (C,-C6)alkyl, optionally substituted (C,-C6)alkoxy, optionally substituted (C3- CgcydoaRyL aryl, wherein said aryl is selected from phenyl naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and optionally substituted (C,-C._.,)heterocyclic groups, wherein said heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl and thiamorpholino; and wherein the substituents on each of the foregoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halo, nitro, amino, (C,- C4)alky|, (C,-C,,)alkoxy, trifluoromethyl and trifluoromethoxy; and wherein the substituents on the foregoing substituted heterocyclic groups are attached to an oxygen or nitrogen atom on the ring and are independently selected from oxygen and (C,-C,,)alkyl; and wherein the substituents on said substituted Ar‘ groups are independently selected from (C,-C6)alkyl optionally substituted with from one to three halo groups, _29.. (C,-C6)alkoxy optionally substituted with from one to three halo groups, (C,- C5)alky|suliiny|, (C,-C6)alkenyl, (C,-C6)alky|thio, (C,-C5)alky|sulionyl, (C,~ C6)alkylsulfonylamino, and di-(C,-C6)alkylamino wherein one or both of the alkyl groups may be optionally substituted with a (C,-C6)alkylsulfonyl, or (C,-C6)alkylsulfinyl group; and wherein the substituents on said substituted Ar’ and Ar’ groups are independenty selected from (C,—C_,)alkyl, (C,-C4)alkoxy, (C,-C4)alkylthio, (C,- C,)alkylsulfinyl, di-(C,-C,,)alkylamino, trifluoromethyl and trifluoromethoxy; and wherein the substituents on said substituted (C,-C5) heterocyclic groups are independently selected from oxygen and (C,-C4)alkyl; or a pharmaceutically acceptable salt of such compound.

2. Acompound accordingto claim l, wherein Ari is substituted aryl.

3. A compound according to claim 1 or 2, wherein Arl is mono—, di- or trisubstltuted phenyl.

4. A compound according to claim 3, wherein Arl is a phenyl group that is disubstituted at the 2- and 5- positions.

5. A compound according to claim 1, wherein said compound is selected from : (3R,4S,5S,6S)—N,N—diethyl(5—isopropylmethoxybenzylamino) diphenylmethylazabicyclo[2.2.2]octane-3—carboxamide; (3R,4S,5S,6S)-N,N-diethyl(2,5-dimethoxybenzylamino)diphenylmethyl azabicyclo[2.2.2]octanecarboxamide; (3R,4S,58,6S)(5-isopropyl-2—methoxybenzylamino)diphenylmethyl—1- azabicycio[2.2.2]octanecarboxyllc acid; (3R,4S,5S,6S)(2—methoxymethylthiobenzylamino)diphenylmethyl azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,BS)-5—(2,5—dimethoxybenzylamino)-6—diphenylmethyl—1-azabicyclo- [2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(2-methoxy-5—methylbenzylamino)diphenylmethyl azabicyclo[2.2.2]octane—3—carboxylic acid; _30_. (3R,4S,5S,6S)(5-ethylmethoxybenzylamino)diphenylmethyl azabicyclo[2.2.2]octanecarboxyiic acid; (3R,4S,5S,6S)(2—methoxyln-propylbenzyiamino)diphenylmethyl azabicyc|o[2.2.2]octane—3-carboxylic acid; (3R,4S,5S,6S)(5-sec-butyimethoxybenzylamino)diphenylmethyl azabicycio[222]octane—3—carboxy|ic acid; (3R,4S,5S,6S)(5-aminosulfonylmethylmethoxybenzyiamino) diphenylmethylazabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(2-methoxymethyisuifinylbenzyiamino)dipheny1methyl azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)-5~(2—methoxy—5—trifluoromethoxybenzyiamino)—6—diphenyimethyl—1 - azabicyclo[2.2.2]oc'(ane—3—carboxylic acid; (3R,4S,5S,6S)(2-methoxy-5—methylsuifonylbenzylamino)diphenylmethyi azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)—5-(5-dimethyiaminomethoxybenzyiamino)diphenyimethyl azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(5-isopropylmethoxybenzylamino)diphenyimethyi azabicycio[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(2—methoxy-5—methylthiobenzylamino)—6—diphenylmethyI azabicyc|o[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)(2,5-dimethoxybenzylamino)diphenylmethyb1— azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,68)(2-methoxy—5-methyibenzylamino)—6-diphenylmethyl azabicyclo[2.2.2]octane-2—carboxylic acid; (3R,4S,5S,6S)(5-ethylmethoxybenzylamino)diphenyimethy|—1- azabicyclo[2.2.2]octanecarboxylic acid; (3R,4S,5S,6S)-5—(2-methoxyln-propyibenzylamino)-6—diphenyimethyl azabicycIo[2.2.2]octanecarboxylic acid; (3R,4S,SS,6S)(5—sec-butyimethoxybenzylamino)-6—diphenyime’thyl-1 - azabicyclo[2.2.2]octanecarboxyiic acid; (3R,4S,5S,6S)-5—(5-aminosulfonylmethylmethoxybenzy|amino)—6— diphenylmethyiazabicyclo[2.2.2]octanecarboxylic acid; _31_ (3R,4S,5S,68)(2-melhoxymelhylsulfinylbenzylamlno)dlphenylmethyl2 azablcyclo[2.2.2]octane-2—carboxyllc acld; (3R,4S,5S,6S)-5(2-methoxyfrtrifluoromethoxybenzylamlno)'6-diphenylmethyl azablcyclo[2.2.2]oclanecarboxyllc acld; (3R,4S.58,6S)~5-(2-melhoxymethylsulfonylbenzylamino)~6-diphenylmethyl azablcyclo[2.2.2]octanecarboxylic acid; and (3R,4S,5S,6S)-5o(5-dimethylamlnomethoxybenzylamlno)-Gdiphenylmelhyl azablcyclo[2.2.2]octanecarboxylic acid.

6. A compound of the formula (1) given and defined in claim 1 or a pharmaceutically acceptable salt thereof, which is specifically hereinbefore mentioned, other than a compound as claimed in claim 5.

7. A process for the preparation of a compound of the formula (1) given and defined in claim 1 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with particular reference to the accompanying Examples.

8. A pharmaceutical composition comprising a compound according to any one of claims 1-6 in association with a pharmaceutically acceptable diluent or carrier therefor.

9. A pharmaceutical composition according to claim 8. substantially as hereinbefore described. -32.

10. Use of a compound of the formula (1) given and defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating or preventing a condition selected from inflammatory diseases, anxiety, colitis, depression or dysthymic disorders, psychosis, pain, allergies, chronic obstructive airways disease, hypersensitivity disorders, vasospastic diseases, fibrosing and collagen diseases, reflex sympathetic dystrophy, addiction disorders, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders, disorders related to immune enhancement or suppression and rheumatic diseases in a mammal.

11. Use of a compound of the formula (1) given and defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in antagonising the effects of substance P in a mammal.

12. Use according to claim 10 or 11, substantially as hereinbefore described. ANNE RYAN & CO. AGENTS FOR ’I'HE APPLICANTS