SUBSTITUTED OXIMES DERIVATIVES USEFUL AS NEUROKININ ANTAGONISTS

Abstract: The compounds (a, b, c, d, e, f, g, h, i, j, k or l) are disclosed for use as neurokinin antagonists

Description: SUBSTTTUTED OXIMES DERIVATIVES USEFUL AS NEUROKININ ANTAGONISTS BACKGROUND OF THE INVENTION The present invention relates to a genus of substituted oximes, hydrazones and olefins useful as antagonists of tachykinin receptors, in particular as antagonists of the neuropeptides neurokinin-1 receptor (NK-|) and/or neurokinin-2 receptor (NK2) and/or neurokinin-3 receptor (NK3). Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, and various gastrointestinal disorders such as Crohn's disease. In particular, NK1 receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK2 receptors have been associated with smooth muscle contraction, making NK1 and NK2 receptor antagonists especially useful in the treatment and prevention of asthma. Some NK1 and NK2 receptor antagonists have previously been disclosed: arylalkylamines were disclosed in U.S. Patent 5,350,852, issued September 27, 1994, and spiro-substituted azacycles were disclosed in WO 94/29309, published December 22, 1994. SUMMARY OF THE INVENTION Compounds of the present invention are represented by the formula I or a pharmaceutically acceptable salt thereof, wherein: a is O, 1 , 2 or 3; b and d are independently 0, 1 or 2; R is H, C1-6 alkyl, -OR 6 or C 2 -C6 hydroxyalkyl; A is =N-OR 1 . =N-N(R2)(R3), =C(R 1 )(R 12 ) or =NR 2 5; X is a bond, -C(O)-, -0-, -NR 6 -, -S(0) e -, -N(R 6 )C(0)-, -C(0)N(R 6 )- -OC(0)NR 6 -, -OC(=S)NR 6 -, -N(R 6 )C(=S)0-, -C(=NOR 1 )-, -S(0) 2 N(R 6 )-, -N(R 6 )S(0) 2 -, -N(R6)C(0)0- or -OC(O)-, provided that when d is 0, X is a bond, -C(O)-, -NR 6 -, -C(0)N(R 6 )-, -N(R 6 )C(0)-, -OC(0)NR 6 -, -C(=N0R1)-, -N(R 6 )C(=S)0-, -OC(=S)NR 6 -, -N(R 6 )S(0) 2 - or -N(R 6 )C(0)0-; provided that when A is =C(R 1 1 )(R 12 ) and d is 0, X is not -NR 6 - or -N(R 6 )C(0)-; and provided that when A is =NR 25 , d is 0 and X is -NR 6 - or -N(R 6 )C(0)-; T is H, R 4 -aryl, R -heterocycloalkyl, R 4 -heteroaryl, phthalimidyl, R 4 -cycloalkyl or R 10 -bridged cycloalkyl; Q is R 5 -heteroaryl; R1 is H, Ci- 6 alkyl, -(C(R 6 )(R 7 )) n -G, -G 2 , -(C(R 6 )(R7)) p -M- (C(Rl3)(Rl4)) n .(C(R8)(R9)) u . G , -C(0)N(R 6 )-(C(Rl3)(Rl4) )n .(C(R8)(R9)) u -G or -(C(R 6 )(R 7 )) p -M-(R4-heteroaryl); R 2 and R 3 are independently selected from the group consisting of H, C 1 -6 alkyl, -CN, -(C(R 6 )(R 7 )) n -G, -G 2 , -C(0)-(C(R β )(R9)) n -G and -S(0) e R 13 ; or R 2 and R 3 , together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of -0-, -S- and -N(R 19 )-; R 4 and R 5 are independently 1 -3 substituents independently selected from the group consisting of H, halogeno, -OR 6 , -OC(0)R 6 , -OC(0)N(R 6 )(R 7 ), -N(R 6 )(R 7 ), Cι -6 alkyl, -CF 3 , -C 2 F 5 , -COR 6 , -C0 2 R 6 -CON(R 6 )(R 7 ), -S(0) e R i 3, -CN, -OCF 3 , -NR 6 C0 2 R 16 , -NR 6 COR 7 , -NR 8 CON(R )(R 7 ), Rl5- P henyl, R 5-benzyl, N0 2 , -N(R 6 )S(0) 2 R 13 or -S(0)2N(R 6 )(R 7 ); or adjacent R 4 substituents or adjacent R 5 substituents can form a -O-CH2-O- group; and R 4 can also be R 15 -heteroaryl; R 6 , R 7 , R 8 , R 6a , R 7a , R 8a , R 3 and R 14 are independently selected from the group consisting of H, Ci-6 alkyl, C2-C6 hydroxyalkyl, C * \ -CQ alkoxy-Cι-C6 alkyl, R 5 -phenyl, and R 15 -benzyl; or R 6 and R 7 , together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of -0-, -S- and -N(R19)-; R 9 and R 9a are independently selected from the group consisting of R 6 and -OR 6 R 10 and R 10a are independently selected from the group consisting of H and C-ι-6 alkyl; R 11 and R 12 are independently selected from the group consisting of H, C C 6 alkyl, -C0 2 R 6 , -OR 6 , -C(0)N(R 6 )(R 7 ), d-C 6 hydroxyalkyl, -(CH 2 ) r -OC(0)R 6 , -(CH 2 ) r -OC(0)CH=CH2, -(CH 2 )r-0(CH2)s-C0 2 R 6 , -(CH 2 )r-0-(CH 2 )s-C(0)N(R 6 )(R 7 ) and -(CH 2 ) r N(R 6 )(R 7 ); R 15 is 1 to 3 substituents independently selected from the group consisting of H, C-ι-C-6 alkyl, C-|-C6 alkoxy, C-i-C δ alkylthio, halogeno, -CF 3 , -C 2 F 5 , -COR , -C0 2 R 10 , -C(O)N(R10) 2J -S(O) e R 10a , -CN, -N(R 10 )COR 10 , -N(R1°)CON(R10) 2 and -N0 2 ; R 16 is Ci-6 alkyl, R 15 -phenyl or R 15 -benzyl; R19 is H, Cι-C 6 alkyl, -C(O)N(R10) 2I -C0 2 R 1 °, -(C(R8)(R 9 ))f-C0 2 R 1 ° or -(C(R 8 )(R 9 )) U -C(0)N(R10) 2 ; f, n, p, r and s are independently 1-6; u is 0-6; G is selected from the group consisting of H, R 4 -aryl, R 4 -hetero- cycloalkyl, R 4 -heteroaryl, R -cycloalkyl, -OR 6 , -N(R 6 )(R 7 ), -COR 6 - -C0 2 R 6 , -CON(R 7 )(R 9 ), -S(0) e R 13 - -NR 6 C0 2 R 16 , -NR 6 COR 7 - -NR 8 CON(R 6 )(R 7 ), -N(R 6 )S(0) 2 R 13 , -S(0) 2 N(R 6 )(R 7 ), -OC(0)R 6 , -OC(0)N(R 6 )(R 7 ), -C(=NOR 8 )N(R 6 )(R 7 ), -C(=NR 2 5)N(R 6 )(R 7 ), -N(R 8 )C(=NR 6 )N(R 6 )(R 7 ), -CN, -C(0)N(R 6 )OR 7 , and -C(0)N(R 9 )-(R 4 -heteroaryl), provided that when n is 1 and u is 0, or when R 9 is -OR 6 , G is not -OH or -N(R 6 )(R 7 ); M is selected from the group consisting of a double bond, -0-, -N(R 6 )-, -C(O)-, -C(R 6 )(OR 7 )-, -C(R 8 )(N(R 6 )(R 7 ))-, -C(=NOR 6 )N(R 7 )-, -C(N(R 6 )(R 7 ))=NO-, -C(=NR 2 5)N(R 6 )-, -C(0)N(R 9 )-, -N(R 9 )C(0)-, -C(=S)N(R 9 )-, -N(R9)C(=S)- and -N(R 6 )C(0)N(R 7 )-, provided that when n is 1 , G is not OH or -NH(R 6 ); and when p is 2-6, M can also be -N(R 6 )C(=NR 2 5)N(R 7 )- or -OC(0)N(R 6 )-; G 2 is R 4 -aryl, R 4 -heterocycloalkyl, R 4 -heteroaryl, R 4 -cycloalkyl, -COR 6 , -C0 2 R 16 , -S(0) 2 N(R 6 )(R 7 ) or -CON(R 6 )(R 7 ); e is 0-2, provided that when e is 1 or 2, R 13 and R 10a are not H; R 25 is H, CrCe alkyl, -CN, R 15 -phenyl or R 16 -benzyl; Z is J , N-( [ N- Fr υ -N N- or morpholinyl; g and j are independently 0-3; h and k are independently 1-4, provided the sum of h and g is 1-7; J is two hydrogen atoms, =0, =S, =NR 9 or =NOR 1 ; L and L 1 are independently selected from the group consisting of H, Cι-C 6 alkyl, C-i-Cε alkenyl, -CH 2 -cycloalkyl, R 15 -benzyl, R 15 - heteroaryl, -C(0)R 6 , -(CH 2 ) m -OR 6 , -(CH 2 ) m -N(R 6 )(R 7 ), -(CH 2 ) m -C(0)-OR 6 and -(CH 2 ) m -C(0)N(R 6 )(R 7 ); m is 0 to 4, provided that when j is 0, m is 1-4; R 26 and R 27 are independently selected from the group consisting of H, C-i-Cβ alkyl, R 4 -aryl and R -heteroaryl; or R 26 is H, Cι-C 6 alkyl, R -aryl or R 4 -heteroaryl, and R 27 is -C(0)R 6 , -C(0)-N(R 6 )(R 7 ), -C(0)(R 4 -aryl), -C(0)(R -heteroaryl), -S0 2 R 13 or -S0 2 -(R 4 -aryl); R 28 is H, -(C(R 6 )(R 9 )) t -G, -(C(R 6 )(R 7 )) V -G 2 or -N0 2 ; t and v are 0, 1 , 2 or 3, provided that when j is 0, t is 1 , 2 or 3; R 29 is H, C1-C-6 alkyl, -C(R 1 0) 2 S(O) e R 6 , R 4 -phenyl or R 4 -heteroaryl; RS0 is H, Cι-C 6 alkyl, R 4 -cycloalkyl, -(C(R 1 0) 2 ) w -(R 4 -phenyl), -(C(R 10 ) 2 ) w -(R 4 -heteroaryl), -C(0)R 6 , -C(0)OR 6 , -C(0)N(R 6 )(R 7 ), w is 0, 1 , 2, or 3; V is =0, =S or =NR 6 ; and q is 0-4. Preferred are compounds of formula I wherein X is -0-, -C(O)-, a bond, -NR 6 -, -S(0) e -, -N(R 6 )C(0)-, -OC(0)NR 6 or -C(=NOR 1 )-. More preferred are compounds of formula I wherein X is -0-, -NR 6 -, -N(R 6 )C(0)- or -OC(0)NR 6 - Additional preferred definitions are: b is 1 or 2 when X is -O- or -N(R 6 )-; b is 0 when X is -N(R 6 )C(0)-; and d is 1 or 2. T is preferably R 4 -aryl, R 4 -heteroaryl, R 4 -cycloalkyl or R 10 -bridged cycloalkyl, with R 4 -aryl, especially R 4 -phenyl, being more preferred. Also preferred are compounds wherein R 6a , R 7a , R 8a and R 9a are independently hydrogen, hydroxyalkyl or alkoxyalkyl, with hydrogen being more preferred. Especially preferred are compounds wherein R 8a and R9a are each hydrogen, d and b are each 1 , X is -0-, -NR 6 -, -N(R 6 )C(0)- or -OC(0)NR 6 , T is R 4 -aryl and R 4 is two substituents selected from C-|-C 6 alkyl, halogeno, -CF3 and C1-C6 alkoxy. Preferred definitions for T being R 4 -heteroaryl include R 4 -quinolinyl and oxadiazolyl. Also preferred are compounds of formula I wherein R is hydrogen. Q is preferably R 5 -heteroaryl wherein R 5 is hydrogen. An especially preferred definition for Q is benzothienyl. Preferred are compounds of formula I wherein A is =N-OR 1 or =N-N(R 2 )(R 3 ). More preferred are compounds wherein A is =N-OR 1 . R 1 is preferably H, alkyl, -(CH 2 ) n -G, -(CH 2 )p-M-(CH 2 )n-G or -C(0)N(R 6 )(R 7 ), wherein M is -O- or -C(0)N(R 9 )- and G is -C0 2 R 6 , -OR 6 , -C(0)N(R 6 )(R 9 ), -C(=NOR 8 )N(R 6 )(R 7 ), -C(0)N(R 9 )(R 4 -heteroaryl) or R 4 - heteroaryl. R 2 and R 3 are independently preferably H, C1-C6 alkyl, -(C(R 6 )(R )) n -G or G 2 . Preferred definitions of Z are with the following groups being more preferred: This invention also relates to the use of a compound of formula I in the treatment of asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, and various gastrointestinal disorders such as Crohn's disease. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I in a pharmaceutically acceptable carrier. The invention also relates to the use of said pharmaceutical composition in the treatment of asthma, cough, bronchospasm, inflammatory diseases such as arthritis, migraine, nociception, and various gastrointestinal disorders such as Crohn's disease. DETAILED DESCRIPTION As used herein, the term "alkyl" means straight or branched alkyl chains. "Lower alkyl" refers to alkyl chains of 1-6 carbon atoms and, similarly, lower alkoxy refers to alkoxy chains of 1-6 carbon atoms. "Cycloalkyl" means cyclic alkyl groups having 3 to 6 carbon atoms. "Bridged cycloalkyl" refers to C7-C10 saturated rings comprised of a cycloalkyl ring or a fused bicycloalkyl ring and an alkylene chain joined at each end to non-adjacent carbon atoms of the ring or rings. Examples of such bridged bicycloalkyl rings are adamantyl, myrtanyl, noradamantyl, norbornyl, bicyclo[2.2.1 ]heptyl, 6,6-dimethylbicyclo[3.1.1 jheptyl, bicyclo[3.2.1]octyl, and bicyclo[2.2.2]octyl. "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl. "Halogeno" refers to fluoro, chloro, bromo or iodo atoms. "Heterocycloalkyl" refers to 4- to 6-membered saturated rings comprising 1 to 3 heteroatoms independently selected from the group consisting of -0-, -S- and -N(R 19 )-, with the remaining ring members being carbon. Examples of heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. R 4 - heterocycloalkyl refers to such groups wherein substitutable ring carbon atoms have an R 4 substituent. "Heteroaryl" refers to 5- to 10-membered single or benzofused aromatic rings comprising 1 to 4 heteroatoms independently selected from the group consisting of -0-, -S- and -N=, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are indolyl, quinolyl, benzothienyl (i.e., thionaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. N-oxides of nitrogen-containing heteroaryl groups are also included. All positional isomers are contemplated, e.g., 1 -pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. R 4 - heteroaryl refers to such groups wherein substitutable ring carbon atoms have an R 4 substituent. Where R 2 and R 3 or R 6 and R 7 substituents on a nitrogen atom form a ring and additional heteroatoms are present, the rings do not include adjacent oxygen and/or sulfur atoms or three adjacent heteroatoms. Typical rings so formed are morpholinyl, piperazinyl and piperidinyl. In the structures in the definition of Z, the substituents L and L 1 may be present on any substitutable carbon atom, including in the second structure the carbon to which the -N(R 26 )(R 27 ) group is attached. In the above definitions, wherein variables R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 and R 30 , for example, are said to be independently selected from a group of substituents, we mean that R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 and R 30 are independently selected, but also that where an R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 or R30 variable occurs more than once in a molecule, those occurrences are independently selected (e.g., if R is -OR 6 - wherein R 6 is hydrogen, X can be -N(R 6 )- wherein R 6 is ethyl). Similarly, R 4 and R 5 can be independently selected from a group of substituents, and where more than one R 4 and R 5 are present, the substitutents are independently selected; those skilled in the art will recognize that the size and nature of the substituent(s) will affect the number of substituents which can be present. Compounds of formula I can have at least one asymmetrical carbon atom and all isomers, including diastereomers, enantiomers and rotational isomers, as well as E and Z isomers of the oxime, hydrazone and olefin groups, are contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I. Those skilled in the art will appreciate that for some compounds of formula I, one isomer will show greater pharmacological activity than other isomers. Compounds of the invention have at least one amino group which can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention. Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. Compounds of formula I can be prepared using methods well known to those skilled in the art. Following are typical procedures for preparing various compounds; the skilled artisan will recognize that other procedures may be applicable, and that the procedures may be suitably modified to prepare other compounds within the scope of formula I. Procedure A: Compounds of formula I as defined above can be prepared as shown in the following reaction scheme: Step 1 : 1 (A: R 21 = alkoxy ^ Mt 3 B: R 21 = Cl Q 2B C: R 21 = -N(CH 3 )OCH 3 ) In step 1 , a compound of formula 2A wherein Q is as defined above, is reacted with a base such as lithium disopropylamide (LDA) or KH in an inert organic solvent such at THF or DME to generate a dianion. An acid chloride, ester or amide of formula _ , IB, or IC is added to give a ketone of formula 3. Preferable reaction temperatures ranges from -78°C to 30°C. Alternatively, compounds of formula 3 can be generated by the reaction of a compound of formula 1, preferably IC, with a metallated species of formula QCH2Mt where Mt is a metal, such as MgHal, wherein "Hal" is halogen, or lithium. The metallated species QCH2Mt can be generated by conventional procedures, such as treatment compounds of formula QCH2Hal with Mg or by treating QCH3 with an organolithium base. In step 2, for compounds of formula I wherein R is not hydrogen, the ketone 3 is reacted with a suitable base, such as LDA or KH in an inert organic solvent such as THF. For compounds wherein R is alkyl or hydroxyalkyl, a compound R-R 17" , wherein R 17" is leaving group such as Br, I or triflate is added. For compounds wherein R is OH, an appropriate oxidizing agent such as dimethyldioxirane or Davis reagent is added. Preferable reaction temperatures range from -78° to 50°C. Step 3: In step 3, ketone 4 is reacted with a base such as LDA in a solvent such as THF, then an olefin of formula 5 is added, wherein R 17 " is as defined above, to give the adduct 6. Preferable reaction temperatures range from -78°C to 60°C. Step 4: In step 4, ketone 6 is reacted with HA', wherein A' is NH-OR 1 , NH- N(R 2 )(R 3 ) or NHR 25 , in an organic solvent such as pyridine at a temperature from 25°C to 150°C to give a compound of formula 7. Step 5: In step 5, a compound of formula 7 is oxidized by ozonolysis to give an aldehyde of formula 8. Suitable organic solvents include EtOAc, ethanol or the like. Preferable reaction temperatures are from -78 to 0°C. In step 6, an aldehyde of formula 8 is reacted with a compound of formula Z-H, wherein Z is as defined above. Step 6 is preferably carried out with a suitably substituted amine (as its acid salt e.g. HCI or maleate or as its free base) and a hydride source such as NaBHsCN or sodium triacetoxyborohydride in a protic solvent (e.g. CH 3 OH, CH3CH2OH, or CF 3 CH 2 OH) with 3A sieves to obtain the compound of formula I. Any suitable temperature can be used with preferable temperatures between 0°C and 25°C. Alternatively, a compound of formula I can be prepared from 6 by the following reaction scheme: ° 3 . Compound 6 is oxidized to a compound of formula 9 under conditions similar to those described for step 5 above. The aldehyde of formula 9 is reacted with a compound of formula Z-H in a manner similar to that described in Step 6, and the resultant ketone is then reacted with a compound of the formula HA' as described above in Step 4 to obtain the compound of formula I. Procedure B: Compounds of formula I wherein X is -O- or a bond and d is 1 or 2 can be prepared by the following reaction scheme, starting with ketone 4 from Procedure A. Alternatively, compounds of formula 4 can be prepared from compounds of formula ID, wherein X is -0-, R 6a and R 7a are each H, and d is 1 , which, in turn, are prepared according to the either of two following reaction schemes: Scheme a: wherein A compound of formula 10, wherein R 21 is alkoxy or -N(CH3)OCH3 and R 17 ' is as defined above, is reacted with an alcohol of the formula HO-(C(R 8a )(R 9a ))b-T in the presence of a suitable base such as Cs 2 C0 3 or KHMDS Scheme b: wherein a compound of formula 10a. wherein R 21 is alkoxy, is reacted with a compound of formula R 0 -R 17 wherein R 7 is a leaving group such as Cl or Br and R 20 is either of the formula wherein R 4 , R 8a , R 9a and b are as defined above or R 20 is trialkyl or diarylalkylsilyl, in the presence of a suitable base such as CS2CO3, Hunigs's base or KHMDS In step 1 , compounds of formula 4 treated with an appropriate base, such as NaHDMS, are reacted with alkylating agents of the formula R33C(0)CH 2 R 17 or R 33 C(0)CH=CH 2 wherein R 33 is alkoxy or -N(CH 3 )OCH 3 and R 7 is as defined above. In step 2, compounds of formula J . can be converted to the corresponding oxime of formula 12 in a manner similar to that described in Procedure A, Step 4. ln step 3, a compound of formula 12 (or H, i.e., wherein A' is O) are converted to the corresponding aldehyde 13 (or lactol from the keto-ester 1 1 ) by treatment with a suitable reducing agent such a DIBAL, in an suitable inert organic solvent such as THF, at a temperature from about -100 to -20°C. Step 4: In step 4, compound 13 is reacted with an amine ZH in a manner similar to that described in Procedure A, Step 6, to obtain the compound of formula I. Alternatively, as shown in the following reaction scheme, compounds of the formula 14, wherein R is H, A' is =0, X is -O- and R 33 is alkoxy can be converted to the corresponding lactol of formula 1_5 by treatment with a suitable reducing agent such a DIBAL, in an suitable inert organic solvent such as THF, at a temperature from about -100 to -20°C: The lactol is then reacted with an amine ZH as described in Procedure A, Step 4, to give the amino alcohol 6. When R 20 is diarylalkylsilyl, compound 4 (derived from IE) taken through the same steps (stepsl to 4), is converted to compound 16, which is desilylated by treatment with fluoride ion, preferably TBAF, to give oxime alcohol 17. Step5: Oxime alcohol 17 can be alkylated, acylated, or reacted with isocyanates to obtain ether or carbamate compounds of formula 1 . Alkylations are effected using a base, such as NaH, K2CO3 or CS2CO3, in a solvent such as DMF, THF or CH2CI2, with an alkylating agent such as an alkyl or benzyl halide or sulfonate. Acylations are effected using an appropriate carboxylic acid in the presence of a dehydrating agent, for example DEC in the presence of HOBT. Procedure C: Compounds of formula I wherein A is an oxime derivative and X is an amide or urea are prepared by oxidation of an oxime alcohol and reaction of the resultant aldehyde with an amine, followed by alkylation, acylation, sulfonation or reaction with an isocyanate as shown below: Step 1 : R 1 C^ N step 1 , oxime alcoho z Q » 18 In l 1-7* isw oxidized with o-iodoxybenzoic acid at room temperature in a solvent such as DMSO or DMF in the presence of an acid such as t fluoroacetic acid. In step 2, compound 18 is reacted with an amine R 6 NH, wherein R 6 is as defined above, in an alcohol such as CH3OH, CH3CH2OH, more preferably CF3CH2OH, in the presence of a dehydrating agent such as molecular sieves and a reducing agent such as NaCNBH3 to obtain 19. Step 3: In step 3, amine 19 can be alkylated, acylated, sulfonylated or reacted with isocyanates to obtain compounds of formula 1. Alkylations are effected using a base, such as TEA, K2CO3 or CS2CO3, in a solvent such as DMF, THF or CH2CI2, with an alkylating agent such as an alkyl or benzyl halide or sulfonate. Acylations are effected using an appropriate carboxylic acid in the presence of a dehydrating agent, for example DEC in the presence of HOBT. Sulfonylation is effected by treating with appropriate sulfonyl chlorides in the presence of a base such as diisopropylethyl amine or Et3N in a solvent such as CH2CI2 or THF. In the procedurs above, the corresponding olefins (compounds wherein A is =C(R 11 )(R 12 )) can be prepared from the respective keto compounds by using standard Wittig chemistry known to those skilled in the art. Reactive groups not involved in the above processes can be protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction. The following Table 1 shows some typical protecting groups: Table 1 Compounds of formula I have been found to be antagonists of NKi and/or NK2 and/or NK3 receptors, and are therefore useful in treating conditions caused or aggravated by the activity of said receptors. The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. Compounds of this invention can be administered in conventional oral dosage forms such as capsules, tablets, powders, cachets, suspensions or solutions, or in injectable dosage forms such as solutions, suspensions, or powders for reconstitution The pharmaceutical compositions can be prepared with conventional excipients and additives, using well known pharmaceutical formulation techniques. Pharmaceutically acceptable excipients and additives include non-toxic and chemically compatibile fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like. The daily dose of a compound of formula I for treating asthma, cough, bronchspasm, inflammatory diseases, migraine, nociception and gastrointestinal disorders is about 0.1 mg to about 20 mg/kg of body weight per day, preferably about 0.5 to about 15 mg/kg. For an average body weight of 70 kg, the dosage range is therefore from about 1 to about 1500 mg of drug per day, preferably about 50 to about 200 mg, more preferably about 50 to about 500 mg/kg per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient. Following are examples of preparing starting materials and compounds of formula I. As used herein, Me is methyl, Bu is butyl, Br is bromo, Ac is acetyl, Et is ethyl and Ph is phenyl. Preparation 1 Treat methyl glycolate (1.4 g , 0.015 mole) in 50 ml anhydrous THF at 0°C with sodium hydride (0.65 g, 0.0165 mole). Stir the mixture for 0.5 h and add 3,5-bis trifluoromethyl benzyl bromide (5 g, 0.0165 mole). Allow the mixture to warm to room temp and stir for an additional 10h. Quench the reaction with CH3OH (5 mL). Wash with water (3 x100 mL) and brine (2 x 100 mL), separate the organics, dry over MgSθ4, filter, and concentrate under vacuum to obtain a crude oil. Purify by silica gel chromatography (10%EtOAc/Hexane) to obtain pure product (4.2 g). Preparation 2 2 Treat methyl glycolate (14 g , 0.15 mole) in 200 ml CH 2 CI2 with Et3N (23 mL, 0.165 mole), dimethylaminopyridine (3 g, 0.03 mole), and t-butyldiphenyl silylchloride (46 g, 0.165 mole). Stir the mixture for 24h and then dilute with 200 mL CH 2 CI 2 . Wash with water (3 xlOOmL) and brine (2 x 100 mL), separate the organics, dry over MgSθ 4 , filter, and concentrate under vacuum to obtain a crude oil. Purify by silica gel chromatography (hexane as the elutant) to obtain pure product (46g). Preparation 3 Treat a solution of 2-thiopheneaceticacid (1.6 g, 11.2 mmole) in anhydrous THF (100 mL, -78°C) with lithiumhexadimethylsilazide (24.5 mmole, 1 M THF soln.). Warm the solution to 0°C over a period of 2 h, then cool to -78°C and add ethyl [[3,5-bis(trifluoromethyl)phenyl]-methoxy]- acetate (3.55 g, 11.2 mmole) dropwise as a THF solution (10 mL). Stir the resulting mixture for 4 h and allow the temperature to warm to 0°C. Quench the reaction with 1 ml HOAc and stir for 4h. Dilute the reaction with EtOAc (100mL), wash the organics with water (2X 50mL) and brine (1X 50 mL), dry (Na2Sθ4) and concentrate to obtain 3.4 g of crude product. Purify by silica gel chromatography (3:7 Et2θ:hexane ) to give the title compound, 2.8 g (7.3 mmole, 65.4 %) as a colorless foam. MS: (CI+/CH4) (M+H+) 383. Preparation 4 Treat a solution of 4-picoline (1.42g, 15 mmole) in anhydrous THF (50 mL, -10°C) with phenyllithium (15 mmole, 8.3 mL cyclohexane:Et2θ) and stir for 1 h at 0°C. Cool the solution to -78°C and add the product of Example 47, Step 1 (5.27g, 15 mmole) dropwise as a THF solution (10 mL). Stir the resulting mixture for 4 h (-78°C to 0°C) and quench with saturated aqueous NH4CI (10 mL). Extract with EtOAc (100mL), wash with water (2X50mL), brine (50 mL), dry (Na2S04), and concentrate. Purify by silica gel column chromatography (8:2 EtOAc:hexane) to obtain the title compound. (2.5 g, 44%). MS: (CI+/CH4) (M+H+) 378. Using a similar procedure with the appropriate heteroaryl acid or heteroaryl methyl compound and corresponding methyl ester, the following compounds were prepared, wherein Q and T are as defined in the table: Preparation 5 Step 1 : The ketone of Preparation 4H is taken through steps 1 to 4 of Example 1. Step 2: Treat the product of Step 1 (6.3 g , 0.009 mole) in 50 ml anhydrous THF with tetrabutyl ammonium fluoride (0.01 mole). Stir the mixture at room temperature for 24 h and then dilute with 100 mL EtOAc. Wash with water (2 x50mL) and brine (2 x 50 mL), separate the organics and dry over MgSθ4, filter, and concentrate under vacuum to obtain a crude oil. Purify by silica gel chromatography (1.5% ammonia saturated CH 3 OH / 3:1 hexane:EtOAc) to obtain the title compound (4.1 g). MS: (FAB +M+H+) = 439.2. Preparation 6 Substituted piperidines - Method A StepJ: Dissolve 4-aminomethyl-piperidine (30.00 g, 0.263 mol) in CH3OH (500 mL), cool to -30°C under N 2 , add di-t-butyl dicarbonate (38.23 g, 0.175 mol) in CH3OH (100 mL) dropwise, warm slowly to 23°C and stir for 16 h. Concentrate, add CH2CI2 (700 mL), wash with saturated aqueous NaCI (2x200 mL), dry organic solution (MgS04), filter and concentrate to give 36.80 g of a 86:14 mixture of the title compound and 1 ,1 -dimethyl- ethyl 4-[(1 ,1 -dimethylethyloxycarbonyl)methyl]-1 -piperidinecarboxylate. Dissolve the product (19.64 g, 0.0916 mol, 22.84 g of the mixture) of Step 1 in dry CH2CI2 (350 mL) and cool to 0°C under N2. Add pyridine (10.87 g, 11.1 mL, 0.137 mol) then chlorovaleryl chloride (15.63 g, 13.0 mL, 0.101 mol), warm slowly to 23°C and stir for 16 h. Add saturated aqueous NH4CI (300 mL), separate layers and extract with CH2CI2 (2x250 mL). Dry combined organic extracts (MgSθ4), filter and concentrate. Purify by chromatography (1000 mL of flash silica gel; eluant: 1 :1 EtOAc:hexane, then EtOAc). Combine appropriate fractions and concentrate to give 25.36 g (0.0762 mol, 84%) as a colorless oil. MS (CI/CH 4 ): m/e 333 (M+1) Step 2B: ^ B Treat the product of Step 1 in a procedure similar to that described for Step. 2A, using chlorobutryl chloride. MS (FAB): m/e 319 (M+1) Step 3: Prep. 6A: Wash NaH (3.84 g, 0.160 mol, 6.40 g of 60 wt%) with hexane (25 mL), suspend in dry THF (150 mL) and cool to 0°C under N2. Add the product (25.35 g, 0.0762 mol) of Step. 2A in dry THF (150 mL) dropwise. Stir at 23°C for 30 mins, reflux for 6 h, and stir at 23°C for 16 h. Cool to 0°C and add water (150 mL) and 1 N HCI (150 mL). Concentrate and extract with EtOAc (3x200 mL). Wash combined organic extracts with saturated aqueous NaCI, dry (MgS04), filter and concentrate. Purify by chromatography (600 mL of flash silica gel; eluant: 5% CH3OH-CH2CI2). Combine appropriate fractions and concentrate to give 21.62 g (0.0729 mol, 96%) of the title compound as a yellow oil. MS (FAB): m/e 297 (M+1) Prep. 6B: Treat the product of Step 2B in a procedure similar to that described for Prep. 6A. MS (FAB): m/e 283 (M+1). Prep. 6C: Combine the product (1.50 g, 5.06 mmol) of Prep. 6A and Lawesson reagent (1.13 g, 2.78 mmol) in dry THF (20 mL) under N2. Stir at 23°C for 20 h. Concentrate and purify by chromatography (200 mL of flash silica gel; eluant: 1 :3 EtOAc:hexane, 1 :2 EtOAc:hexane, then 1 :1 EtOAc:hexane). Combine appropriate fractions and concentrate to give 1.30 g (4.16 mmol, 82%) as a green oil. MS (FAB): m/e 313 (M+1). Prep. 6D: Dissolve the product (2.50 g, 8.43 mmol) of Prep. 6A in dry THF (30 mL), add borane-DMS (16.9 mL of 2.0 M in THF, 33.74 mmol) and reflux for 20 h. Cool to 0°C and add CH 3 OH (20 mL). Concentrate, add EtOH (50 mL) and K 2 C0 3 (4.66 g, 33.74 mmol). Reflux for 4 h and cool to 23°C. Add water (100 mL), concentrate and extract with CH2CI2 (4x50 mL). Dry combined organic extracts (MgSθ4), filter and concentrate. Purify by chromatography (200 mL of flash silica gel; eluant: 7% CH3OH-CH2CI2). Combine appropriate fractions and concentrate to give 1.72 g (6.09 mmol, 72%) of the title compound as a colorless oil. MS (FAB): m/e 283 (M+1). Prep. 6E: Dissolve the product (1.50 g, 5.06 mmol) of Prep. 6A in dry THF (20 mL) and cool to -78°C under N 2 . Add [(CH 3 ) 3 Si]2NLi (5.5 mL of 1.0 M in THF, 5.5 mmol) and stir at -78°C for 1 h. Add bromomethylcyclopropane (0.820 g, 0.59 mL, 6.07 mmol), warm slowly to 23°C and stir for 16 h. Add saturated aqueous NH4CI (40 mL), extract with EtOAc (3x30 mL), wash combined organic extracts with saturated aqueous NaCI, dry (MgS04), filter and concentrate. Purify by chromatography (175 mL of flash silica gel; eluant: 2% CH3OH-CH2CI2 then 4% CH 3 OH-CH 2 CI 2 ). Combine appropriate fractions and concentrate to give 0.93 g (2.65 mmol, 53%) of the title compound as a colorless oil. MS (FAB): m/e 351 (M+1) Prep. 6F: Treat the product of Prep. 6A in a procedure similar to that described for Prep. 6G, using allyl bromide. MS (CI/CH4): m/e 337 (M+1). Step 3: Separately dissolve the products of Prep. 6A to 6H in CH2CI2, add trifluoroacetic acid and stir at 23°C for 4 h. Concentrate, add 1 N NaOH, extract with CH2CI2, dry the combined organic extracts (MgS04), ridines: Preparation 7 Substituted piperidines - Method B Step 1 : Prep. 7A: Combine 1-benzyl-4-piperidone (2.00 g, 10.6 mmol) and 3- pyrrolinol (0.92 g, 10.6 mmol) in titanium isopropoxide (3.75 g, 3.9 mL, 13.2 mmol) and dry CH CI 2 (4 mL). Stir at 23°C under N 2 for 5 h. Add EtOH (30 mL) and NaCNBH 3 (0.66 g, 10.6 mmol) and stir for 16 h. Add water (50 mL) and CH2CI2 (50 mL), filter through celite, separate filtrate layers and extract with CH2CI2 (2x50 mL). Wash combined organic extracts with saturated aqueous NaHCθ3, dry (MgS04), filter and concentrate. Purify by chromatography (150 mL of flash silica gel; eluant: 10% CH3OH with NH3-CH2CI2, 15% CH3OH with NH3-CH2CI2, then 20% CH3OH with NH 3 -CH2CI 2 .) Combine appropriate fractions and concentrate to give 1.88 g (7.22 mmol, 68%) as a colorless oil. MS (CI/CH4): m/e 261 (M+1). Using the procedure of Prep. 7A and the appropriate amine, prepare Preps. 7B and 7C: Prep. 7B: MS (FAB): m/e 302 (M+1) Prep. 7C: MS (CI/CH4): m/e 271 (M+1). Step 2: Separately treat each of Preps. 7A, 7B and 7C with Pd/C catalyst in CH3OH and formic acid at 23°C under N2 for 16 h. Filter each mixture through celite, washing with CH3OH, concentrate the filtrates, add 1.0 N NaOH and extract with 1 :4 EtOH:CH2Cl 2 , dry, filter and concentrate to Preparation 8 Substituted Piperidines - Method C Step 1 : Using 1 ,1 -dimethyethyl 4-formyl-piperidinecarboxylate and the appropriate amine in a reductive amination procedure similar to that described in Example 42, Step 9, Preparations 8A, 8B and 8C are prepared: Prep. 8A: OH MS(CI/isobutane): m/e313 (M+1) Prep. 8B: MS(CI/CH 4 ):m/e313 (M+1) Prep. 8C t-BuO N — ' S OH MS(FAB):m/e299 (M+1 ) Step 2: Using the procedure described in Preparation 6, Step 3, prepare the followin com ounds: Preparation 9 Dissolve the product of Preparation 5 (0.146 g, 0.33 mmole) and o-iodoxybenzoic acid (0.186g) in 10mL anhydrous DMSO and add dropwise trifluoroacetic acid as a 1 mL THF solution. Stir the mixture for 4 h. Neutralize the reaction with aqueous solution of Na 2 Cθ3 (5mL). Dilute the reaction with 30 mL EtOAc. Separate the organics and wash with 2X 10 mL water and 2X10 mL brine. Dry over MgSθ4 and concentrate under vacuum. Treat the crude aldehyde product in 10 mL anhydrous toluene with methyl amine (0.66 mmole). Stir for 2 h and then remove the solvent under vacuum. Redissolve in 10 mL trifluoroethanol and treat with sodium cyanoborohydride (0.041 g, 0.66 mmole). Stir the resulting mixture for 10 h and then quench the reaction with 2 ml water. Dilute the reaction with EtOAc (50mL) and wash the organics with water (2X 25mL) and brine (1X 25 mL). Dry (Na2S04) and concentrate to obtain crude product. Purify by silica gel preparatory plate chromatography (20% ammonia saturated CH 3 OH / 3:1 hexane:EtOAc) to give the title compound, 0.09 g. MS: (El M+H+) = 452.1. Example 1 Step 1 : Dissolve the product of Preparation 3 (2.6 g, 0.0068 mole) in 30 mL anhydrous THF, cool to -78°C and add dropwise sodium hexadimethyl silazide (0.0075 mole ) as 1 M THF solution. Stir the mixture for 0.5 h at -78°C . Treat the resulting yellow solution with N,N-methyl methoxy iodoacetamide (0.0068 mole) as a 5 mL THF solution. Warm the reaction to 0°C over 4h and then quench with an aqueous solution of NH4CI (5 mL). Dilute the reaction with 100 mL EtOAc. Separate the organics and wash with 2X 50 mL water and 2X50 mL brine. Dry over MgSθ4 and concentrate under vacuum. Purify the crude by flash silica gel chromatography eluting with 10% EtOAc/hexane to obtain 1.6 g of pure product. MS:EI M+ = 422. Step 2: Stir a mixture of the product of stepl (0.5 g, 0.00105 mole), methoxyl amine hydrochloride (0.52 g, 0.0045 mole) and NaOAc (0.42g) in 15 mL EtOH:water (5:1 ) for 20 h. Remove the solvent under vacuum, redissolve the crude in 50 mL EtOAc and wash with 2 X 50 mL water. Dry the organics and remove the solvent under vacuum. Purify the crude by silica gel flash chromatography, eluting with 20% EtOAc/hexane to obtain two isomeric oximes. Yield of isomer A : 0.33 g; yield of isomer B :0.05 g. MS:isomer A FAB (M+H)+ 513.2; MS:isomer B FAB (M+H)+ 513.2. Step 3: Dissolve the major isomer from step 2 (0.65 g , 0.00127 moles) in 20 mL anhydrous THF and cool to -78°C. Add dropwise diisobutylaluminium hydride (0.0045 mole) as 1 M hexane solution. Monitor the reaction by drawing samples at intervals for presence of starting material (about 1h). Quench the reaction at -78°C by adding a saturated solution of Na2Sθ4. Warm the reaction with vigorous stirring (2 h) and remove the precipitated aluminum salts by filtration. Wash the collected solids with 2 X 50 mL Et2θ. Combine the filtrates and concentrate under vacuum. Step 4: Redissolve the crude aldehyde of step 3 in trifluoroethanol (10 mL) and add phenyl hydroxy piperidine (0.15g, 0.0008 mole) and powdered 3A molecular sieves (1g). After stirring for 0.5 h, add sodium cyanoborohydride (0.002 mole) and continue stirring for 20h. Dilute the reaction with Et2θ (100mL), filter off the molecular sieves and remove the solvent under vacuum. Purify by flash silica gel chromatography eluting with 1% ammonia saturated CH3θH/3:1 hexane:EtOAc. Yield: 0.04 g isomer A. MS: (FAB + M+H+) =615. Example 2 Starting with the appropriate ketone from Preparation 4 and using the corresponding product of Step 3 of Example 1 and the appropriate amines from above (Preparations 6-8) in the procedure of Example 1 , the following compounds are prepared: Example 3 Prepare the allyl oxime ether of the product of Example 2K, using a procedure similar to that used in Example 1 , employing O- allylhydroxyl-amine HCI as the alkoxyl amine. MS : FAB (M+H+) : 690.9. Example 4 Using the procedures described below, compounds of the following structural formula were prepared, wherein the definitions of R 1 are shown in the following table: Example 4A: Treat a solution of the product of Example 3 (367 mg, 0.53 mmol) in 80% aqueous EtOH with Pd(PPh3)4 (60 mg, 0.053 mmol, 0.05 eq) and triethylammoniumformate (3 mL of 1 M solution in THF, 5 eq) and stir at reflux for 4 h. Cool, concentrate and purify by silica gel chromatography (2.5 x 16.5 cm; CH2CL2/Hex 8:2 w/ 6% NH3/MeOH) to give 150 mg of the product as a film. Example 4B: Treat a solution of Example 4A (93 mg, 0.143 mmol) in dry DMF (10 mL) at 0 °C with 60% NaH in mineral oil (7 mg), stir for 40 min and treat with bromo acetonitrile 0.034g. Stir for 30 min, pour into EtOAc (250 mL) / half saturated NaHC0 3 (200 mL) and extract. Wash the organic layer with water (2x100 mL), then brine (10 mL) and dry over Na 2 S0 4 . Purify the crude mixture by silica gel chromatography (4 x 15 cm; hex/EtOAc 1 :1 w/ 2% NEt 3 ) to give 30 mg of the pure product as an oil. Example 4C: Treat a suspension of H 2 NOH»HCI ( 0.14 mmol, 5 eq) in ethanol with KOH in MeOH (680 μL, 0.68 mmol, 5 eq), sonicate for 5 min and then add to a solution of Example 4B (24 mg, 0.035 mmol) in ethanol (5 mL). Heat for 2.5 h at 60 °C, filter, concentrate in vacuo and purify by silica gel chromatography (2.5 x 14 cm; CH 2 CI 2 /MeOH (NH 3 ) 95:5) to give 9 mg of the product . Example 4D: Treat the product of Example 4A (23mg), in a similar fashion to Example 4B, using 2-bromo-1-(f butyldimethylsiloxy)ethane (10mg) as the alkyl halide, followed by desilylation (3 h, 23°C) with 1 M TBAF in THF. Example 4E: Treat the product of Example 4A in a similar fashion to Example 4B using CH3I as the alkyl halide to obtain the desired product. Example 5 Treat a solution of Preparation 5 (0.1 g, 0.23 mmole) in anhydrous THF (5 mL) with 3,5 dicholorophenyl isocyanate (0.065 g, 0.35 mmole). Stir the resulting mixture for 1h and then quench the reaction with 2 ml water. Dilute the reaction with EtOAc (50 mL) and wash the organics with water (2X 25 mL), brine (1X 25 mL). Dry (Na 2 S04) and concentrate to obtain crude product. Purify by silica gel preparatory plate chromatography (5% ammonia saturated CH3OH / 3:1 hexane:EtOAc) to give the title compound, 0.105 g. MS: (FAB +M+H+) = 626.3. Using a similar procedure, prepare compounds of the following formula, wherein the variables are as defined in the table: Example 6 Treat a solution of Preparation 9 (0.1 g, 0.23 mmole) in anhydrous THF (5 mL) with 3,5-bis trifluoromethylphenyl isocyanate (0.065g, 0.35 mmole). Stir the resulting mixture for 1h and then quench the reaction with 2 ml water. Dilute the reaction with EtOAc (50mL) and wash the organics with water (2X 25mL) and brine (1X 25 mL). Dry (Na2Sθ4) and concentrate to obtain crude product. Purify by silica gel preparatory plate chromatography (5% ammonia saturated CH3OH / 3:1 hexane:EtOAc) to give the title compound 0.105 g . MS: (FAB +M+H+) = 706. Example 7 To a CH2CI2 (2 mL) solution containing the product of Preparation 9 (0.05 g, 0.11 mmole), 3,5 dichlorobenzoic acid (0.023g, 0.13mmole), and hydroxybenzotriazole (0.0171 g, 0.13 mmole), add 1-(3- dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.025 g, 0.13 mmole). Stir the mixture for 4 h and then dilute with 25 mL CH2CI2. Wash the organics with water (2X 25mL) and brine (1X 25 mL). Dry (Na2S04) and concentrate to obtain crude product. Purify by silica gel preparatory plate chromatography (10% ammonia saturated CH3OH / 3:1 hexane:EtOAc) to give the title compound 0.09 g . MS: (El M+H+) = 624.2 Using a similar procedure, prepare compounds of the following formula, wherein the variables are as defined in the table: Example 8 Treat a CH 2 CI 2 solution (5 mL) of amine 12 (0.069 g, 0.152 mmole)and diisopropyl ethyl amine (0.04mL) with 3,5-bis trifluoromethyl- phenylsulfonyl chloride (0.057 g, 0.18 mmole). Stir the mixture for 1 h and then dilute with 25 mL CH2CI2. Wash the organics with water (2X 25mL) and brine (1X 25 mL). Dry (Na2Sθ4) and concentrate to obtain crude product. Purify by silica gel preparatory plate chromatography (10% ammonia saturated CH3OH / 3:1 hexane:EtlOAc) to give the title compound, 0.03 g. (FAB +M+H+) = 728.7. Using a similar procedure, prepare compounds of the following formula, wherein the variables are as defined in the table: The following formulations exemplify some of the dosage forms of this invention. In each, the term "active compound" refers to a compound of formula I. EXAMPLE A T Taabblleettss No. Inαredie jnntt mα/tablet mα/tablet 1 Active Compound 100 500 2 Lactose USP 122 1 13 3 Corn Starch, Food Gra ddee,, aass aa 1100%% 30 40 paste in Purified Water 4 Corn Starch, Food Gra ,ddee 45 40 5 Magnesium Stearate 3 7 Total 300 700 Method of Manufacture Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weight on a suitable tablet machine. EXAMPLE B Capsules No. Ingredient mα/tablet mg/tablet 1 Active Compound 100 500 2 Lactose USP 106 123 3 Corn Starch, Food Grade 40 70 4 Magnesium Stearate NF 4 7 Total 250 700 Method of Manufacture Mix Item Nos. 1 , 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine. EXAMPLE C Sterile Powder for Injection Ingredient mg/vial mg/vial Active sterile powder 100 500 For reconstitution add sterile water for injection or bacteriostatic water for injection. The in vitro and in vivo activity of the compounds of formula I can be determined by various procedures known in the art, such as a test for their ability to inhibit the activity of the NKi agonist Substance P, an isolated hamster trachea NK2 assay, a test of the effect of NKi antagonists on Substance P-induced airway microvascular leakage, measurement of NK2 activity in vivo in guinea pigs, measurement of bronchoconstriction due to NKA, and neurokinin receptor binding assay(s). Typical procedures are published in W096/34864. NK3 activity is determined by following a procedure similar to that described in the literature, e.g., Molecular Pharmacol., 48 (1995), p. 711-716. % Inhibition is the difference between the percent of maximum specific binding (MSB) and 100%. The percent of MSB is defined by the following equation, wherein "dpm" is disintegrations per minute: (dpm of unknown) - (dpm of nonspecific binding) % MSB = X 100 (dpm of total binding) - (dpm of nonspecific binding) It will be recognized that compounds of formula I exhibit NKi , NK2 and/or NK3 antagonist activity to varying degrees, e.g., certain compounds have strong NKi antagonist activity, but weaker NK2 and NK3 antagonist activity, while others are strong NK2 antagonists, but weaker NKi and NK3 antagonists. While compounds with approximate equipotency are preferred, it is also within the scope of this invention to use compounds of with unequal NK1/NK2/NK3 antagonist activity when clinically appropriate. Using the test procedures described above, the following data (Ki) were obtained for preferred and/or representative compounds of formula I: Compounds of the present invention exhibit a range of activity: percent inhibition at a dosage of 1μM ranges from about 0 to about 100% inhibition of NKi and/or about 0 to about 100% inhibition of NK2. Preferred are compounds having a Ki <100nM for the NKi receptor. Also preferred are compounds having a Ki <100nM for the NK2 receptor. Another group of preferred compounds are those having a Ki ≤100nM for each of the NK-iand NK2 receptors.

Claims: What is claimed A compound represented by the formula:

Inventors: SHANKAR BANDARPALLE B, SHANKAR, BANDARPALLE, B.
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1997
Main classification: C07D401
IPC codes: A61K31, A61P1, A61P11, A61P19, A61P25, A61P29, A61P43, C07D333, C07D401, C07D405, C07D409, C07D413