NZ318493A

NZ318493A - Piperazino derivatives as neurokinin antagonists

Info

Publication number: NZ318493A
Application number: NZ318493A
Authority: NZ
Inventors: Ho-Jane Shue; Neng-Yang Shih; David J Blythin; Xiao Chen; John J Piwinski; Kevin D Mccormick
Original assignee: Schering Corp
Priority date: 1995-08-31
Filing date: 1996-08-29
Publication date: 1999-10-28
Also published as: KR19990044138A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 318493 New Zealand No 318493 International No. PCT/IB96/01018 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates 31 081995,01 051996,14 06 19Q96, Complete Specification Filed 29 08 1996 Classification (6) C07D401/12, C07D405/14, C07D409/14, C07D401/14, C07D453/02, C07D487/04, A61K31/445 Publication date 28 October 1999 Journal No 1445 NO DRAWINGS NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention Piperazino derivatives as neurokinin antagonists Name, address and nationality of applicant(s) as in international application form SCHERING CORPORATION, a New Jersey corporation of 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States of America WO 97/08166 PCT/IB96/01018 PIPERAZINO DERIVATIVES AS NEUROKININ ANTAGONISTS 5 BACKGROUND OF THE INVENTION The present invention relates to a genus of compounds useful as antagonists of neurokinin receptors In particular, these can be neurokinin-1 receptor (NKi) antagonists Some can also be neurokinin-1 receptor (NKi )antagonists and neurokinin-2 receptor (NK2) antagonists, that 10 is, NKi / NK2 dual receptor antagonists Some can also be neurokinin-2 receptor (NK2) antagonists Some can also be neurokinin-3 receptor (NK3) antagonists Neurokinin receptors are found in the nervous system and the circulatory system and penpheral tissues of mammals, and therefore are 15 involved in a vanety of biological processes Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of vanous mammalian disease states, for example pulmonary disorders like asthma, cough, bronchospasm, chronic obstructive pulmonary diseases, and airway hyperreactivity, skin disorders and itch, for example, 20 atopic dermatitis, and cutaneous wheal and flare, neurogenic Inflammation inflammatory diseases such as arthntis, migraine, nociception, CNS diseases such as anxiety, Parkinson's disease, movement disorders and psychosis, convulsive disorders, renal disorders, unnary incontinence, ocular inflammation, inflammatory pain, and eating disorders such as food 25 intake Inhibition, allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, depression, and vanous gastrointestinal disorders such as Crohn's disease. In particular, NKi receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK2 receptors have 30 been associated with smooth muscle contraction, making NKi and NK2 receptor antagonists especially useful in the treatment and prevention of asthma Moreover, NK3 receptor antagonists are especially useful in the treatment and prevention of asthma, inflammatory diseases and 35 conditions, such as ocular inflammation, allergic rhinitis, cutaneous wheal 1 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 and flare, psoriasis, atopic dermatitis, CNS diseases such as anxiety and Parkinson's disease Summary of the Invention The invention relates to compounds of the formula x 10 each X is independently, O, (H,H), NRd, or S, n is 0 to 2, u is 0 to 2; I is 0 to 2, m is 1, and y is 1 to 3, or m is 2, and y is 0, and with the further proviso that no more than one Rc is other than H in the 15 moiety, each Rc is independently H, C1-C6 a'kyl. "*CH2WR4 where ni is 1 to 6, Rd is independently selected from the group consisting of H, C1-C6 alky], CN, ORa, phenyl, substituted phenyl, benzyl, substituted benzyl, or allyl, 20 2 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 ./ R4 is -ORa, SRa, O Ha II I Rb —C—N-Rb 1 ■ORa Ra O I II -N— C-Rb 1 -CN, o Ra Rb O II I 11/ O-C—N-Rb or — N-C-ORa O II -O—C—Ra Rc' is H, C1-C6 alkyl or (CH2)nORa, with the proviso that no more than one is other than H, each Ra and R5 is independently selected from the group consisting of H, C1-C6 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, Rb o 1 11 10 allyl; with the proviso that when R4 is ~"N"c"0Ra t ,s not or wnen Raand Rb are attached to the same nitrogen, then Ra and Rb together with the nitrogen to which they are attached, form a 4 to 7 member ring; wherein each Ri and R2 is independently H, Ci-Ce alkyl, CF3, 15 C2F5.CI.Br, I, F. NO2.ORa.CN, NRaRb. o ii -C-Ra 0 II -O—C-Ra ORa Rb O RaO O ORa II I I II I II II II I —O —C-N—Rb —N-C-ORa — N-C-Rb — C-ORa —C—N-Rb V s Ra, s (-sRa, and s NHRa , and where Ra is not H S °w° in "s~Ra , -S-Ra , or -N-c-o* Mimosa V2-05-00 07/21/1998 12 15 57 page W 08166 PCT/1B96/01018 or when R 1 and R2 are on adjacent carbons on a nng, they can form rrf o wherein n'is 1 or 2, 0 II and each R3 is independently H, Ci-Cg alkyl, CF3, C2F5, , o 0 Ra 11 _Ji 1 5 "° c~Ra, C N"Rb CI, Br. I.F.ORg, OCF3, or phenyl, Ari is heteroaryl or substituted heteroaryl, ) ' n R* J 10 or Qis NorCH, Ar2 is heteroaryl or substituted heteroaryl, 15 4 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 Z IS R. -X!> l\A, H mj a 0-1, m2 = 1-2, n3 is 0-4, 10 Rg is -ORa with the proviso that Ra is not H, aryl, substituted aiyl, heteroaryl, substituted heteroaryl, -NRaRb, -0-(CRa,Rb)n7 aryl, -O-(CRa.Rb)n7-substituted aryl, -0-(CRa,Rb)n7-heteroaryl, -0-(CRa,Rb)n7-substrtuted heteroaryl ,-NRa-(CRa,Ro)n7-heteroaryl, -NRa-(CRa,Rb)n7-substituted heteroaryl, -0-(CR#,Rt,)n7-heterocycloalkyl, -0-(CRa,Rb)n7-15 substituted heterocycloalkyi, -NRa-(CRa,Rb)n7 aryl, -NRa-(CRa,Rb)n7- 5 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 substituted aryl, •NHa-(CRBlRt))n7-heterocycloalkyll -NRa-(CRa,Rt))nr substituted heterocycloalkyi, m is 0 to 4, each R0 and Ri «s independently selected from the group consisting of H, 5 Ci-Os alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, allyl, or Re and Rf taken together with the carbon to which they are attached can also form a carbonyl group with the proviso that no more than one carbonyl ns is 1 tc 2, 10 each R5 is independently selected from the group consisting of H, OH, c-Ra ( Q-pCg alkyl, (CH2)ni-R4 wherein ni is 1 to 6 with the proviso that when ni is 1, R4 is not OH or NRaRbl also w'th the proviso that when ns is 2, Rs is C1-C6 a'kyl, and two R5 can be attached to the nitrogen to form a quaternary salt. moiety, o ii 15 R6 is H, C1-C8 alkyl, C3-C6 cycloalkyl, 6 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 wherein X3 is (H,H), O, NR^, or S, or Re is heteroaryl, substituted heteroaryl, heterocycloalkyi, substituted 5 heterocycloalkyi, when n3 is 0-4, when Ra.Rf taken together with the carbon atom to which they are attached form a carbonyl group and n3 is 1, R6 can also be -ORa wherein Ra is not H, or Rg is -NRa.Rb, -0-(CRa,Rb)n7-heteroaryl, -0-(CRa,Rb)n7-substituted heteroaryl, -0-(CRa,Rb)n7-heterocycloalkyl, -0 (CRa,Rb)n7-substituted 10 heterocycloalkyi, -0-(CRa,Rb)n7-aryl, -0-(CRa,Rb)nrSubstituted aryl, -NRa-(CRa,Rb)n7-heteroar/l, -NRa-(CRa,Rb)n7 substituted heteroaryl, -NRa-(CRa,Rb)n7-aryl, -NRa-(CRa,Rb)n7 substituted aryl, -NRa-(CRa,Rb)nr heterocycloalkyl, -NRa"(CRa,Rb)n7-substituted heterocycloalkyi, wherein Ra and Rb are each independently selected from the group consisting of H 15 and C1-C6 alkyl, or any enantiomer thereof, or a pharmaceutical^ acceptable salt thereof All of the variables in the above formulas such as Z, Ri, R2, and Ra, have the same meaning throughout the specification unless otherwise 20 specified 7 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 Preferred compounds of the invention are compounds of formula I, wherein each X is O or (H,H) and at least one X is 0 5 Also preferred are compounds of formula I wherein both X's are O Also preferred are compounds of formula I wherein I is 0, m is 1, and y is 1-3 10 Also preferred are compounds of formula I wherein n is 1 and u is 0 Also preferred are compounds of formula I wherein Ari is /' 15 x>" — "r3 " n4 R 3 8 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/01018 wherein Q is N orCH, each Xi is independently O, S or NRa, each X2 is independently CH or N, and n4 is 0 or 1 5 Also preferred are compounds of formula I wherein Ar2 is or r3. 10 Also preferred are compounds of formula I wherein Z is ! ^ A 1 I H S Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 Also prefe.red are compounds of formula I wherein Z is n3 r6 5 Also preferred are compounds of formula I wherein Z is I a O Rn H wherein Rg is -ORa,-NRaRb, and -0-(CRa,Rb)n7-heteroaryl, with the proviso that when Rg is 0-(CRa,Rb)n7-heteroaryl, Ra and Rb are 10 each independently selected from the group consisting of H and Ci-Cb alkyl. 07 is 0 to 4 Also preferred are compounds of formula I wherein both X's are O, I is 0, m 15 is 1, y is 1 -3, n is 1, u is 0, Ari Is 10 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 wherein n4 is 0 or 1. Z is defined in Formula I, when Re.Rf are H, Oi-C6 alkyl, allyl, n3 is 0-4 and Re is T; ■/ J ■r2 ■cycloalkyl § ? X,"\ H ■Ra Ri Ra V< I R2 k X3 v >—C1-C6 alkyl or Re and Rf taken together with the carbon to which they are attached form a carbonyl group, n3 is 1 and R6 is -0-(CRa,Rb)n7-L, wherein L is ■l-o- .4-0^.4-°^)>'R R3X— ——0-cycloalkyl, <P"""0-<Y'— • Xi 12 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 \ I ri-9~LR t r3 ■|—N-Ra ^3 , ~X—N-IxM^ "» H ' * H *1 ^ H 2 ^—N-cycloalkyl, — k\ J rR1 \ Ra ■Rz •cycloalkyl t -PK| 5 x,-\ V i «-&Q "k K N \ r2 k CrC6 alkyl Also preferred are compounds of formula II 13 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08J 66 PCT/1B96/010I8 Ni^\ A~\ X Tte N N V \ / *1 Al2 where»nRcisH.ni! isOorl.y is 1-3, Ari and Ar2 are both 2 5 R6is 14 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/0101R r3 t irX I " J 5—CvC6 alkyl I "* (% or Re and Rf taken together with the carbon to which they are attached form a carbonyl group, na is 1 and R6 is -0-(CRa,Rb)n7-L, wherein L is -O-Ra J o4>. | o>0- J 1 » A2 >■ •O- cycloalkyl, $ "O—<s r3 B J^P, *1 1—N.Ra I „ R3V=\ £p. J r,>Q ^—^-cycloalkyl, ^ N— 15 Mimosa V2-05-00 07/21/1998 12 15 57 page V< Ra (i ■CrC6 alkyl Also preferred are compounds of the invention of the formula II o rc ■ ■ ■ » y-j 16 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 wherein Ari and Ar2 are both Ri r4 r~Rz r3 Also preferred are compounds of the invention of the formula m 10 wherein An and Ar2 are both Ri ci-., ^\ 15 Exemplary compounds of the invention are compounds of the formulas 17 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/lI19fi/01018 fi c^^_vn2-0 tc^-" Q ° CI CI pH3 s> CHg "U A 0-0 ,=<CH3 CI CI PHa ►fee. A/T\ /-An'v^-n"N^0 I 0 «i CI CI r~~\ , CI CI 1 T ° a 'ci R 083 Cl CI 18 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 rVO'i CI CI HNrO. HN ci a 19 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 H Q. O ■ OvON0-N^ f~\ r^Y^^"NwN"\ n(cha)2 a a ci a CI ci °t U^O ch3 ci a ci ci CI CI CI CI Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/01018 21 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 22 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96MOW Mimosa V2-05-00 07/21/1998 12 15 57 page wo 97/08166 PCT/IB96/01018 or any enantiomer thereof, or a pharmaceutical^ acceptable salt thereof 5 The invention also relates to a pharmaceutical composition compnsing a therapeutically effective amount of a compound of formula I in combination with a pharmaceutical^ acceptable earner In a further aspect the present invention provides use of a compound of the invention in the preparation of a medicament for inducing neurokinin antagonism in a mammal in need thereof In a still further aspect, the present invention provides use of a compound of the invention in the preparation of a medicament for treating chronic airway diseases such as asthma and allergies, inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis, migraine, central nervous system disorders such as depression, psychosis, dementia, and Alzheimer's disease, Down's syndrome, neuropathy, multiple sclerosis, ophthalmic disorders, conjunctivitis, auto immune disorders, graft rejection, systemic lupus erythematosus, Gl disorders such as Crohn's disease and ulcerative colitis, disorders of bladder function, circulatory disorders such as angina; Raynaud's disease, coughing and pain Described but not claimed is a method for inducing neurokinin antagonism which compnses admimstenng a neurokinin antagonistic effective amount of a compound of formula I to a mammal in need thereof Also described but not claimed is a method for treating chronic airway diseases such as asthma and allergies, inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositos, osteoarthntis, and rheumatoid arthntis, migraine, central nervous system disorders such as depression, psychosis, dementia, and Alzheimer's disease, Down's syndrome, neuropathy, multiple sclerosis, ophthalmic disorders, INTELLECTUAL PROPERTY OFFICE OF NZ 24 1 4 SEP 1999 DC^riwi-i^ conjunctivitis, auto immune disorders, graft rejection, systemic lupus erythematosus, Gl disorders such as Crohn's disease and ulcerative colitis, disorders of bladder function; circulatory disorders such as angina, Raynaud's disease, coughing and pain In particular, the invention also relates to a method of treating asthma which compnses administering to a mammal in need of such treatment an anti-asthma effective amount of a compound of formula I for such purpose Detailed Descnption of the Invention As used herein the term alkyl means a straight or branched, saturated hydrocarbon chain having from 1 to 6 carbon atoms The number of carbon atoms may be designated For example, "C1-C6 alkyl" represents a straight or branched, saturated hydrocarbon having from 1 to 6 carbon atoms The term C3-C5 cycloalkyl means a cycloalkyl having from 3 to 6 carbon atoms, that is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 24a INTELLECTUAL PROPERTY OFFICE OF NZ 1 4 SEP 1999 RFPPn/cn WO 97/08166 PCT/1B96/01018 The term alkenyl means means a straight or branched, saturated alkenyl having from 2 to 6 carbon atoms The number of carbon atoms may be designated For example, "C2-C6 alkenyl" represents a straight or branched alkenyl having from 1 to 6 carbon atoms 5 The term alkynyl means a straight or branched alkynyl having from 2 to 6 carbon atoms The number of carbon atoms may be designated For example, "C2-C6 alkynyl" represents a straight or branched chain alkynyl having from 2 to 6 carbon atoms As used herein, a heavy dark line (—*) denotes a chemical 10 bond coming above the plane of the page A dashed line (••■•m ) denotes a chemical bond coming below the plane of the page As used herein, 3 , for example, means that R1, R2. and R3 can be in either of the rings of the above naphthyl 15 moiety Asymmetric centers exist in compounds of formula I of the invention Accordingly, compounds of formula I include stereoisomers All such isomeric forms and mixtures thereof are within the scope of the present invention Unless otherwise indicated, the methods of 20 preparation disclosed herein may result in product distributions which include all possible structural isomers, although It is understood that physiological response may vary according to stereochemical structure The isomers may be separated by conventional means such as fractional crystallization, preparative plate or column chromatography on silica, 25 alumina, or reversed phase supports or HPLC (high performance liquid chromatography) Enantiomers may be separated, where appropnate, by denvatization or salt formation with an optically pure reagent, followed by separation by one of the aforementioned methods Alternatively, enantiomers may be 30 separated by chromatography on a chiral support The compounds of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e g the hemihydrate In general, the solvated forms, with pharmaceutical^ acceptable solvents such as 25 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 rCT/IB96/01018 water, ethanol, and the like are equivalent to the unsolvated forms for the purposes of the invention Those compounds of formula I which contain a basic group such as -CH2NH2, form pharmaceutical^ acceptable salts The preferred 5 pharmaceutical^ acceptable salts are nontoxic acid addition salts formed by adding to a suitable compound of the invention about a stoichiometnc amount of a mineral acid, such as HCI, HBr, H2SO4 orH3P04 or of an organic acid such as acetic, propionic, valenc, oleic, palmitic, steanc, launc, benzoic, lactic, para-toluenesulfonic, methanesulfonic, citnc, maleic, 10 fumanc, succinic and the like, respectively 15 the following general methods As used herein RT means room temperature Unless otherwise indicated, vanables in the structural formulas below are as defined above Starting matenals and reagents used in the methods and examples below, are known or may be prepared according to known methods 20 As used herein the term "substituted phenyl" means wherein R1, R2, and R3 are as described herein, "substituted" means substituted by R1, R2, and/or R3 as descnbed herein. "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl, 25 indanyl, anthracenyl or fluorenyl "Halogeno" refers to fluoro, chloro, bromo or lodo atoms "Heterocycloalkyi" refers to 4- to 6-membered nngs compnsing 1 to 3 heteroatoms independently selected from the group consisting of -0-, -S- and -N(R6)-, with the remaining nng members being carbon. Examples 30 of heterocycloalkyi nngs are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morphollnyl, thiomorpholinyl and piperazinyl General Methods .of.Preparation The compounds of this invention may be prepared by one of 26 Mimosa V2-05-00 07/21/1998 12 15 57 page \jgp WO 97/08166 PCT/IB96/01018 "Heteroaryl" refers to 5- to 10-membered single or benzofused aromatic rings comprising 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S- and -N= Examples of single-ring heteroaryl groups are pyndyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl.thienyl, 5 imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pynmidinyl, pyridazinyl and tnazolyl Examples of benzofused heteroar/l groups are quinolinyl, thianaphthenyl and benzofurazanyl N-oxides of nitrogen-containing heteroaryl groups are also included All positional isomers are contemplated, e g , 1-pyridyl, 2-pyndyl, 3-pyndyl and 4-pyndyl 10 Where R2 and R3 substituents form a ring and additional heteroatoms are present, the nngs do not include adjacent oxygen and/or sulfur atoms or three adjacent heteroatoms Typical nngs so formed are morpholinyl, piperazinyl and piperidinyl As used herein, the term "BOC" means t-butoxycarbonyl 15 As used herein, the term "Ph" means phenyl As used herein, the term "RT" means room temperature As used herein, the term "parallel synthesis" means the preparation of individual chemical compounds as one of a batch of, for instance, 20, 30, or even 100 identical reactions on usually a single 20 substrate but using a different reagent in each vessel Such reagents are always of the same general class- in this case, either carboxylic acids or organic amines in any set of parallel reactions The conditions used for each reaction are identical to those described in the examples, except that a simplified work-up is employed, generally a simple wash either with acid or 25 base if appropnate, then water The presence of the product is detected by thin layer chromatography (TLC) using known products as representative standards Further charactenzation by combination HPLC/MS is generally performed No further punfication is performed on these materials before they are submitted to biological assays 30 As used herein, each Rc and Rc' is independently selected from the group consisting of H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, unsubstituted or substituted phenyl, and unsubstituted or substituted benzyl, The starting matenals in the methods below are either known 35 or can be prepared in accordance with known methods In particular, the following compounds are either known or can be prepared in accordance 27 Mimosa V2-05-00 07/21/1998 12 15 57 page WD 97/08166 PCT/IB96/0J018 with known methods the diamine A, the compounds of formulas A, VI, vm, X, XI, XTV, XVm, XK, XXa, A', XXV, and Z-H, as well as esters of formula XI, and compounds of formula 11+1 a'k^'. Method 1 If the group Ar2 is an aromatic group with no I or Br substituents, then the following method may be used to prepare the useful intermediates (IV) 10 Ph Ph \ / C><cl /\ XI Ph Ph n N rn rn c,x-—- civ v0^gBr(CI,l) N Ar2 U (»■) Transition metal catalyzed coupling of 2-chloropyrazine with an aromatic Grignard reagent in a dry, ether solvent, such as THF, 15 yields the aryl-substituted pyrazine of formula II'. The catalyst shown, [1,2-bis-(dipheny!phosphino)ethane]nickel11 chloride, is a preferred reagent for this transformation Where Ar2 has no halo substituents, reduction of a compound of formula II' by catalytic hydrogenation, using, for instance, palladium acetate, preferably in acetic acid solvent, results in preferential 20 reduction of the pyrazine ring, leaving the aromatic ring unreduced, that is, it results in a compound of formula II Similarly, 10% Pd on charcoal (Pd-C) can be used in an alcohol solvent, preferably methanol, with or without the addition of a small quantity (1 to 5 equivalents) of acetic acid Reaction times of about 1 to 24 hours generally suffice for this reaction, which is 25 preferentially run at room temperature or slightly above (up to about 50°C) and using from 1 to about 6 atmospheres pressure of hydrogen 28 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08:66 PCT/1B96/II1018 H ,N N, from a compound of formula II', even if the group Ar2 contains halogen atoms, by reduction using a strong hydnde ion donor, preferably lithium 5 aluminum hydride (LAH) or dnsobutyl aluminum hydnde (DIBAL-H) in an ether solvent, such as ether, THF or dimethoxyethane (DME) possible using low temperature conditions Thus, reacting a compound of formula II with a substituted aryl-alkyl halide of formula III where I is 0 to 2, 10 results in the formation of the 4-substituted denvative of formula IV Suitable conditions include use of a halogenated solvent, such as CH2CI2, at low temperature Suitable temperatures are from -78°C initially, allowing the reaction mixture to warm gradually to RT If the reaction is not completed after several hours The reaction is catalyzed by the addition of an 15 equivalent amount of an organic base, such as tnethylamine and diisopropylethylamine (Hunig's base) Method 2 If the group Ar2 contains one or more halogen atoms on an aromatic nng and the other groups are as in Method 1, then an alternate 20 route to a compound of formula IV is preferred In addition, this method can be used to prepare compounds in which I is from 0 to 2 Mono-protection of the diamine of formula (A), preferably with BOC anhydnde, or other agents Selective alkylation of a compound of formula II is H i u 29 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 known to Introduce the t-butyloxycartonyl protecting group, in an alcohol solvent, such as methanol, preferably at about -10°C, produces a compound of formula V ^.NH2 (BOC)JO RC 'NHBOC ft- n (V) 5 These compounds are used to perform a reductive amination reaction with the aldehyde of formula VI to produce an amine of formula VII (In structures (A), (V), (VII), and (IX) herein, Rc can be bound to any position between the two nitrogens In cyclic structures like (IVA) below, Rc can be bound to any available cyclic position that is occupied by carbon, 10 and that is between the two nitrogens) Suitable conditions for this type of reaction include the use of an alcohol solvent, preferably methanol, or 2,2,2-trifluoroethanol, made slightly acidic with a weak organic acid, such as acetic acid, and a reducing agent known to favor reductive amination reactions, preferably 15 sodium cyanoborohydnde, NaBHaCN C' + OHC (Crt^Arj NHBOC m 'NHBOC n (VII) Reaction of a compound of formula VII with an a-haioketone of formula VIII, in which Ar2 preferably represents a halogenated aromatic nng, but may be any of the claimed aromatic nngs, in the presence of an 20 organic base, such as di-isopropylethylamine, also known as Hdmg's Base, in an ether solvent, such as THF, results in the formation of the intermediates of formula IX 30 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 rCT/IU!>6/01011. Be' (CH) i—An CI; Bn Rc- ft- CH' I NH NHBOC (VII) (VIII) W-A rz wu Removal of the BOC protecting group using a suitable acidic catalyst, such as trifluoroacetic acid, followed by an intramolecular reductive amination, under conditions such as those descnbed above for the preparation of a compound of formula VII, leads to the formation of compounds of formula IVA r (pH2 N Be' (CH)i—Ar, AT, (|H2 (k NH-BOC (IX) »'u (IVA) Method 3 An alternate route to compounds of the invention 10 in which lis 0 to 2 is as follows Standard coupling of an N-protected amino acid of formula X, wherein Ar2 is as descnbed above, with an amino acid x. ester denvative COOR' ^R. 1S preferably, the ethy! ester of formula XI, Et in the formulas herein means ethyl), produces a 31 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/01018 dipeptide of formula XII A suitable protecting group is BOC, although many others may also be used Other esters of the amino acid may also be used Standard coupling techniques may be applied, an example being the use of N-hydroxybenztnazole (HOBT) and a water-soluble carbodnmide, such as 1-(3-dimethylaminopropyl)-3-0thylcarbodiimide (DEC), in a non-hydroxylic solvent such as CH2CI2, DMF or a mixture of the two foregoing solvents The reaction is run, preferably, at or below RT, and takes from 1 to 40 hours for completion, depending upon the substrates Ar2 Ji HN C02H . ^ 1 „ 1 + r-T—^ HN"^V .C02Et BOO H2N C02Et ^ ^ (X) (XI) 10 Removal of the protecting group under standard conditions, followed by treatment of the product with a base results in cyclization to the diketopiperazine of formula XIII Suitable conditions for removal of the exemplified BOC group are well known in the art and include catalysis by trifluoroacetic acid (TFA) A suitable base for cyclization is the 15 alkali metal salt of an alcohol in the alcohol itself used as solvent For example, a solution of sodium ethoxide in ethanol may be used The temperature is preferably around RT but may be slightly above or below, in the range 0°C to about 40°C The reaction is generally complete within a few hours Suitable reaction times are from 1 to 24 hours Ar2 (XIII) 20 * 'u Reduction of the diketopiperazine of formula XIII to a compound of formula II may be accomplished preferentially with a strong hydnde reducing agent, such as LAH or a solution of sodium bis(2-methoxy-ethoxy)aluminum hydnde in toluene (also known as Red-AI®), or the 25 BH3.S(CH3)2 complex Suitable solvents for this reaction are DME and 32 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/01018 other higher boiling ethers since the reaction is run at elevated temperatures, from about 50°C to about 110°C, preferably at about 90°C Alternatively, a compound of formula of II may be prepared by the scheme shown below (J Med Chem,2. 191 (1966)) As used herein L is any readily available ester residue such as Ci -C7 alkyl, more preferably methyl or ethyl Ar2"^t^COO-L halogenabon Arj-^ry' X X = CI, Br, I COO-L H w u Ar? (II) 10 A compound of formula II may be converted to a compound of formula IV by the processes descnbed in Method 1 above or Method 6 below Method 4 The intermediates of formula IV or IVA, formed via any of the previous methods, may be further processed as follows A 15 compound of formula IVA will be used in the Schemes Reaction of a compound of formula IVA with an activated halo-acid, generally the acid halidc of formula XIV, in which Hal represents CI, Br, or I, yields the acylated denvative of formula XV that is, m is 1 for formula I An organic base is used to take up the hydrogen halide formed in the reaction, suitable 20 bases being triethylamine (TEA) and Hunig's Base Suitable reaction media 33 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 include halogenated solvents, such as methylene chloride and chloroform The reaction is preferably run at low temperature, at least initially Suitable temperatures are in the region of -50°C down to -80°C Later in the reaction it may be desirable to allow the mixture to warm up to about RT to ensure 5 completion of the reaction amine of formula Z-H results in formation of the products of formula XVI, which are compounds of the invention in which X is O and m is 1 10 Compounds of formula XVI have been modified to show the fact that these products could have been prepared from compounds of formula IVA as well as from IV Suitable solvents for this reaction are halogenated hydrocarbons, such as methylene chloride, and an organic base is present to absorb the H-Hal formed Appropnate bases include HOnig's Base The 15 reaction is performed at or around RT, a suitable temperature being generally in the range of from 0°C to 40°C Reaction is complete within 1 to 48 hours CH2(CH)i-Ar, £ (XIV) (XV) (CH)y —Hal (IVA) Rc Reaction of the halogenated amides of formula XV with an 34 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08106 PCT/IB96/01018 CH2(CH)i-An I 'o rc | & + Z-H ch2(ch)i-ap, (xvi) ■Ar2 0^(0^ -z Rc Method 5 Compounds of formula XVI where y * 0 may be converted to other compounds of the invention of formula XVII by reduction under 5 controlled conditions Suitable reducing agents to effect this transformation include the borane-dimethyl sulfide complex, as well as other less selective reagents, such as LAH, (assuming that no other group reactive to LAH is present), 10 Red-AI®, and diborane in ether Effective temperatures for the borane-dimethylsulfide complex to reduce compounds of formula XVI, range from RT to the reflux temperature of the solution of the reagent in THF (about 80°C) Method 6 Intermediates of the formula XVIII may be 15 selectively acylated by coupling with an acid of the formula XIX Standard coupling techniques may be applied, an example being tne use of HOBT, a water-soluble carbodiimide, such as DEC, and an organic base, such as tnethylamine, in a non-hydroxylic solvent, such as CH2CI2, at a temperature ■Jcr CH2(CH)|-An (XVI) Rc Rc 35 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 of about -20°C initially complete the reaction The mixture may be allowed to warm to RT to The product of reaction is the amide of formula XX O vRc1 (CH)i —An H02c -«5H)I ,Rc -(CH)i—Ari (XIX) (XVIII) Compounds of the formula XX, may be further acylated using an acid halide of formula XIV The reaction is run, preferably at about -7B°C, over a penod of 1 to 12 hours, in a halogenated solvent, such as methylene chlonde or similar solvent An organic tertiary amine is used to absorb the H-Hal produced in the reaction Suitable amines include tnethylamine and Hunig's Base As used herein Hal means CI, Br, or I ,Re- Hal ( QH)yO O-Hal (XIV) Rc (XX) The compounds of formula XXI , that is, m is 1 in formula I, y = 1-3,I= 0-2 may be used for further reaction without isolation Additional organic base, for instance, Hunig's Base, is added to the mixture followed by Z-H, at or around -7B°C The reaction is completed by allowing the 36 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 mixture to warm to RT overnight yielding the compounds of formula XXII after work-up and purification by standard methods Z-H (XXI) The compounds of formula XXII, in which y = 1-3 may be converted to other products of formula XXIII by reduction under controlled conditions An (XXII) (XXIII) Suitable reducing agents to effect this transformation include the borane-methyl sulfide complex, as well as other less selective reagents, 10 such as LAH, Red-At®, and diborane in ether or other unreactive solvents, such as THF Using the borane-methyl sulfide complex in THF, at the reflux temperature of the solution, which is about 80°C, the reaction is complete in about 2 hours to 48 hours depending on the precise substrate Some of the substrates Z-H for the alkylation reaction were 15 synthesized from diamino compound (A) by initial conversion to the t-BOC protected denvative(B) followed by removal of the benzyl group by hydrogenolysis over a suitable catalyst such as Pd(OH)2 to yield the t-BOC 37 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 protected denvative (C) Subsequent elaboration of (C) can be accomplished by either alkylation or reductive alkylation depending on the availability of reagents for these reactions 5 Reaction of the intermediate (C) with an aldehyde or ketone (D) under the conditions of reductive amination, such as in methanol and in the presence of NaBHaCN with sufficient AcOH (acetic acid) present to allow the reaction to proceed at a suitable rate, produces the amine (E) from which the t-BOC group may be removed with 4N-HCI in dioxane followed by 10 basification, for instance, with an aqueous solution of NaOH, to produce the compound of formula (F) The same product, (Ea), ma/ be prepared from (C) by alkylation with the halide denvative (G) in which "Hal" is CI, Br, or I Other activated leaving groups are also possible for this reagent, such as 15 mesylates or tosylates The reagent is preferably pnmary but the reaction can also often be made to work acceptably for secondary derivatives The product of the alkylation, (Ea), may be treated as described above to produce the re agent (Fa) which represents one of the preferred forms of Z which can be used to convert a compound of formula 20 XXI to a compound of formula XXII The intermediate (C) (below) may also be modified by acylation, for instance with an acid halide of formula (H), to produce the intermediate (I), in which na * 0 Removal of the BOC protecting group, as described previously, leads to the amine (J) which represents one of the 25 preferred forms of Z This may be used to convert a compound of formula (XXI) to a compound of the invention, as descnbed above 3B Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/01D18 Method 6a A useful intermediate for certain vanations in the group Z is the compound (K) This may be prepared from (XXI) and the protected amine (L) The starting matenal for this process is the N-BOC protected amine (M) which may be converted to (L) by standard techniques involving formation of the oxime using hydroxylamine hydrochloride in pyndine 39 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/081 fi6 FCT/1B96/01018' followed by reduction with hydrogen over Raney nickel in ethanol solution Removal of the protecting group from (K), under conditions described previously, results in the amine (N) (N) 5 - -Use of this intermediate under conditions of acylation, under controlled conditions, results in reaction at the nng nitrogen atom to yield products such as (O) Either the acid halide , e g chlonde (P), may be used, or a coupling reaction with a carboxylic acid may be used under conditions essentially similar to those descnbed earlier using a water-10 soluble carbodimide reagent, for instance Sometimes the starting matenal (N) is provided as a salt, such as the HCI salt In this case, it is necessary to add an organic tertiary base, such as Hunig's base to produce the free amine 40 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01UIH n3-1 Alkylation of (N) may be accomplished with a suitable halogen-containing reagent, for instance, to produce (Q) Reagents such as (G) may be used for this conversion In some cases, one of the -C(Re)(R0- groups may be a carbonyl group with the exception that the carbon in the carbonyl can not 10 be directly attached to the nitrogen atom since these products are amides which are described above Under certain circumstances, specifically where at least one of the groups Re and Rf on the carbon atom to be directly attached to the nng 41 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 nitrogen Is H, then a reductive alkylation reaction may be performed, as descnbed previously, to produce the compound of the invention (R) The 5 Method 7 The acylated derivatives of formula XX from Method 6 may be reduced to the saturated alkyl chain derivatives of formula IVA (XX) (IVA) 10 The process to conduct this conversion is the same as descnbed in Method 6 for conversion of a compound of formula XXII to a compound of formula XXIII The reagent of preference is the borane-methyl sulfide complex A compound of formula IVA can be converted to a target 15 compound of formula XVI as descnbed previously 42 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 An alternate route to compounds of structure (XXII) also starts with compound (XVm) Initial reaction with an amine protecting group reagent, preferably BOC anhydnde, produces the N-t-butyloxycarbonyl derivative of 5 the formula XXVIII 10 OH Rc 1 .N N-H N N' 0-|- V / Ar?JL/f (xxvm) \ / u pcvm) *"*'2 h-vi As before, reaction occurs preferentially at the nitrogen atom further away from the Ar2 group Reaction of this intermediate with a reagent of structure (XIV) as descnbed above, leads to the halo-denvative (XXIX) Reaction of (XXIX) with Z-H, again as descnbed above, produces the intermediate (XXX) which may be de-protected to produce (XXXI) Suitable reagents include trifluoroacetic acid and HCI *?e\ _ Rc (XXVIII) +(XIV) fK? , (XXIX) +(Z-H) (XXX) 43 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 (XXX) +CF3CO2H U (XXXI) af2 Reaction of (XXXI) with a carboxylic acid (XIX) under such coupling conditions as described above, leads to the products of formula (XXII) Method 7a Synthesis of the compounds of the invention wherein the pendant aromaticgroup Ar2, orthe pendant aromatic group Ar2 and its sidechain, are located in the alternate ring position to the compounds of formula XXII (1 e compounds of formula C below), may be prepared using compounds of formula XXVIII from method 7 as starting materials Coupling of 10 compounds of formula XXVIII with any of the acids (CH)|C02H under standard coupling conditions, for instance using HOBT, Et3N and DEC in CH2CI2, produces the intermediate (A) Removal of the t-BOC or other protecting group under standard conditions releases the free amine (B) Acyiation of (B) and further reaction with Z-H proceeds as described in 15 Method 6 for the conversion of (XX) via (XXI) to (XXII) to produce compound (C) of the invention 44 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 10 15 (xxviii) (B) US. (C) Method 8. A method for introducing a group, Rc, into the sidechain of a compound of the invention begins with a previously prepared compound of formula (XX) This may be coupled with a suitably protected amino-acid denvative of formula (XXXII) in which the t-BOC group is used as a representative protecting group Use of a relatively reactive coupling agent, such as BOP-CI of formula (XXXIII), is preferred and the reaction is run under standard coupling conditions well known to one skilled in the art Suitable conditions include the use of CH2CI2 and/or DMF as solvent, with tnethylamine or Hunig's Base, and a temperature between 0°C initially and RT. Usual work-up conditions yield the protected intermediate of formula (XXXIV) In the case of (XXXIV), in which the N-protecting group is t-BOC, the usual conditions for removal of such a group may be used to free the amine function Various concentrations of CF3CO2H in CH2CI2 will usually suffice In some substrates a fairly dilute solution (eg 2N) will be 45 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 rCT/in96/01018 sufficient whereas in other cases a more concentrated solution, up to neat TFA, may be necessary In addition, other N-protecting groups may be employed and removed by methods well known In the art An example is use of the N-Cbz which may be removed under either acidic or hydrogenolytic conditions The result of deprotectlon is the amine intermediate of the formula (XXXV) 46 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 0 /R°' VWr*i & Ar2 (XX) XXXII, XXXIII o Rc V (!« ft Ar2 NH-BOC Rc (XXXIV) Rc HO2C' NH-BOC 0 O 0 XXXII> h o-^ « ci XXXIII Conversion of intermediate of the formula (XXXV) to compounds of the invention is then carried out by a reductive alkylation process 47 Mimosa V2-05-00 07/21/1998 12 15 57 page WO Q7/0R166 I'CT/IIM/01018 The group Z is introduced Into the molecule using an aldehyde or ketone in which the aforementioned group Is present at the carbon atom that is to be joined to the amino group of the formula (XXXV), An example of such an Intermediate is a compound of the formula (XXXVI). xxxvi After the reaction this group becomes the Z group of the compounds of the invention, that is, the "Y-NH" group shown in compounds 10 of the formula (XXXVII) Just below Rc 15 «s equivalent to the "Z" group shown in the Summary of the Invention Conditions for this reductive amination procedure are known in the art and are exemplified by the use of NaBH3CN in MeOH with the addition of several equivalents of acetic acid Generally, the reaction is performed at RT and is left to react overnight 20 48 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 Product is isolated by standard means, such as decomposition of excess reagent with H2O and extraction of the product Into an organic solvent such as CH2CI2 or a mixture of Et20 and CH2CI2 5 Using procedures similar to those descnbed in the above or using procedures Known to those skilled in the art, one can produce all of the compounds of formula I of the invention. For example, one can obtain compounds of the Invention of formula I wherein the Rc moiety is on vanous carbons of the piperazine nng 10 The in vitro and in vivo activity of the compounds of formula I can be determined by the following procedures 15 In vitro procedure to Identify NKi activity Test compounds are evaluated for their ability to inhibit the activity of the NKi agonist Substance P on the isolated guinea pig vas 20 deferens Freshly cut vas deferens are removed from male Hartley guinea pigs (230-350g) and suspended in 25 ml tissue baths containing Kreb's Henselert solution warmed to 37°C and constantly aerated with 95% O2 and 5% CO2 Tissues are adjusted to 0 5 g and allowed to equilibrate for a period of 30 minutes The vas deferens are exposed to an electncal field 25 stimulation (Grass S48 Stimulator) every 60 seconds at an intensity that will cause the tissue to contract 80% of its maximum capacity All responses are recorded isometncally by means of a Grass force displacement transducer (FT03) and Harvard electronic recorder Substance P inhibits the electncal field stimulated-induced contractions of the guinea pig vas 30 deferens In unpaired studies, all tissues (control or drug treated) are exposed to cumulative concentrations of Substance P(1X10_1° M-7X10 7 M) Single log-concentrations of the test compounds are given to separate tissues and allowed to equilibrate for 30 minutes before a Substance P concentration-response curve is generated At least 5 separate tissues are 35 used for each control and individual drug-concentration for every drug assay 49 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08165 PCT/in96/01018 Inhibition of the Substance P is demonstrated by a rightward shift of its concentration-response curve. These shifts are used to determine the pA2 value, which is defined as the negative log of the molar 5 concentration of the inhibitor which would require that twice as much agonist be used to elicit a chosen response This value is used to determine relative antagonist potency 10 Isolated Hamster Trachea NK2 Assay General methodology and charactenzation of hamster trachea 15 responses to neurokinin agonists as providing an NK2 monoreceptor assay is found In C A Maggi, et al, Eur J Pharmacol 166 (1989) 435 and J L Ellis, et al, J Pharm Exp Ther 267 (1993) 95 Continuous isometric tension monitonng is achieved with 20 Grass FT-03 force displacement transducers connected to Buxco Electronics preamplifiers built Into a Graphtec Unearcorder Model WR 3310 Male Charles River LAK LVG (SYR) hamsters, 100-200 g fed weight, are stunned by a sharp blow to the head, loss of corneal reflex is 25 assured, the hamsters are sacrificed by thoractomy and cutting the heart Cervical trachea segments are removed to room temperature Krebs buffer, pH 7 4, aerated with 95% 02 - 5% C02 gas and cleaned of adhenng tissue The segments are cut into two 3-4 mm long nng segments Tracheal nngs are suspended from transducers and anchored in 15 0 ml water jacketed 30 organ baths by means of stainless steel hooks and 6-0 silk Baths are filled with Krebs buffer, pH 7.4, maintained at 37°C and continuously aerated with 95% O2 - 5% CO2 gas Tracheal nngs are placed under 1 0 g initial tension and allowed a 90 mm equilibration penod with four 1 jiM NKA challenge, wash and recovery cycles at 20 min intervals 30 min vehicle pretreatment 35 is followed by cumulative additions of nsing doses of NKA (3 nM -1 nM final concentration, 5 mm intervals between additions) The final NKA response 50 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/M018 is followed by a 15 min wash and recovery period SO min pretreatment with a test compound or its vehicle is followed by cumulative additions of nsing doses of NKA (3 nM -10 jiM final concentration if necessary, 5 minutes intervals between additions) The final NKA response is followed by a 1 mM 5 carbachol challenge to obtain a maximal tension response in each tissue Tissue responses to NKA are recorded as positive pen displacements over baseline and converted to grams tension by companson to standard weights Responses are normalized as a % of the maximal 10 tissue tension EDso's are calculated for NKA from the control and treated NKA dose responses and compared Test compounds resulting in an agonist dose ratio > 2 at a screening concentration of 1 nM (i e pA2£ = 6 0) are considered actives Further dose response data is obtained for actives so that an apparent pA2 estimate can be calculated pA2 is calculated either 15 by estimation of K| as described by Furchgott (where pA2 = - Log Kj, R F Furchgott, Pharm Rev 7 [1995] 183) or by Shild Plot Analysis (O Arunlakshana & H O Shild, Br J Pharmacol 14[1959] 48) if the data is sufficient 20 Effect of NK^Antaaonlsts on Substance P-lnduced Alrwav Microvascular Leakage in Guinea Pias Studies are performed on male Hartley guinea pigs ranging in 25 weight from 400-650 g The animals are given food and water ad libitum The animals are anesthetized by intrapentoneal injection of diaiurethane (containing 0 1 g/mi diailylbarbitunc acid, 0 4 g/mi ethyiurea and 0 4 g/ml urethane) The trachea Is cannulated just below the larynx and the animals are ventilated (Vt = 4 ml, f = 45 breaths/min) with a Harvard rodent 30 respirator The jugular vein is cannulated for the injection of drugs The Evans blue dye technique (Danko, G et al, Pharmacol. Commun.. 1,203-209, 1992) is used to measure airway microvascular leakage (AML) Evans blue (30 mg/kg) is injected intravenously, followed 1 min later by iv injection of substance P (10 ng/kg) Five min later, the 35 thorax is opended and a blunt-ended 13-guage needle passed into the aorta An incision is made in the nght atrium and blood is expelled by 51 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 flushing 100 ml of saline through the aortic catheter The lungs and trachea are removed en-bloc and the trachea and bronchi are then blotted dry with filter paper and weighed Evans blue is extracted by incubation of the tissue at 37°C for 18 hr in 2 ml of formamide in stoppered tubes The absorbance 5 of the formamide extracts of dye is measured at 620 nm The amount of dye is calculated by interpolation from a standard curve of Evans blue in the range 0 5-10 j-ig/rnl in formamide The dye concentration is expressed as ng dye per mg tissue wet weight Test compounds were suspended in cyclodextran vehicle and given i v 5 min before substance P 10 Measurement of NK2 Activity »n Vivo Male Hartley guinea pigs (400-500 gm) with ad lib access to food and water are anesthetized with an intraperitoneal injection of 0 9 ml/kg 15 dialurethane (containing 01 g/m diailylbarbitunc acid, 0 4 g/ml ethylurea and 0 4 g/ml urethane) After induction of a surgical plane of anesthesia, tracheal, esophageal and jugular venous cannulae are implanted to facilitate mechanical respiration, measurement of esophageal pressure and administration of drugs, respectively. 20 The guinea pigs are placed inside a whole body plethysmograph and the catheters connected to outlet ports in the plethysmograph wall Airflow is measured using a differential pressure transducer (Validyne, Northridge CA, model MP45-1, range ± 2 cmH20) which measures the pressure across a wire mesh screen that covers a 1 25 inch hole in the wall of the plethysmograph The airflow signal is electrically integrated to a signal proportional to volume Transpulmonary pressure is measured as the pressure difference between the trachea and the esophagus using a differential pressure transducer (Validyrie, Northndge, CA, model MP45-1, range ± 20 cm H2O) The volume, airflow and 30 transpulmonary pressure signals are monitored by means of a pulmonary analysis computer (Buxco Electronics, Sharon, CT, model 6) and used for the denvation of pulmonary resistance (R|_) and dynamic lung compliance (Coyo)- PrQnchQgonstrlction pue \q nka 35 increasing iv doses of NKA are administered at half log (0 01 -3 ng/kg) intervals allowing recovery to baseline pulmonary mechanics 52 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IH96/01018 between each dose Peak bronchoconstriction occurs within 30 seconds after each dose of agonist The dose response is stopped when Coyn is reduced 80-90% from baseline One dose-response to NKA is performed in each animal Test compounds are suspended in cyclodaxtran vehicle and 5 given i v 5 min before the initiation of the NKA dose response For each animal, dose response curves to NKA are constructed by plotting the percent increase in Rl or decrease in Coyn against log dose of agonist The doses of NKA that increased Rl by 100% (RL100) or decreased CDyn by 40% (Coyn40) from baseline values are 10 obtained by log-linear interpolation of the dose response curves Neurokinin Receptor Binding Assavfsl Chinese Hamster ovary (CHO) cells transfected with the coding regions for the human neurokinin 1 (NK-t) of the human neurokinin 2 (NK2) receptors are grown in Dulbecco's minimal essential medium 15 supplemented with 10% fetal calf serum, 0 1 mM non-essential amino acids, 2 mM glutamine, 100units/ml of penicillin and streptomycin, and 0 8 mg of G418/ml at 37°C in a humidified atmosphere containing 5% CO2 Cells are detached from T-175 flasks with a sterile solution containing 5mM EDTA in phosphate buffered saline Cells are harvested by 20 centnfugation and washed in RPMI media at 40°C for 5 minutes The pellet is resuspended inTns-HCI (pH7 4) containing 1 uM phosphoramidon and 4 ug/ml of chymostatin at a ceil density of 30 x 106 cells/ml The suspension is then homogenized in a Bnnkman Polytron (setting 5) for 30-45 seconds The homogenate is centnfuged at 800 x g for 5 min at 4°C to collect 25 unbroken cells and nuclei The supernatant is centnfuged in a Sorvall RC5C at 19,000 rpm (44,00 x g) for 30 min at 4°C The pellet is resuspended, an aliquot is removed for a protein determination (BCA) and washed again The resulting pellet is stored at -80°C To assay receptor binding, 50 ^l of [3H]-Substance P (9-Sar, 30 11-Met [02]) (specific activity 41 Ci/mmol) (Duporrt-NEN) (0 8 nM for the NK-1 assay) or pHJ-Neurokinin A (specific activity 114 Ci/ mmole) (Zenca) (1 0 nM for the NK-2 assay) is added to tubes containing buffer (50 mM Tris-HCI (pH 7 4) with 1 mM MnCI2 and 0 2% Bovine Serum Albumin) and either DMSO or test compound Binding is initiated by the addition of 100^1 of 35 membrane (10-20 jig) containing the human NK-1 or NK-2 receptor in a final volume of 200 nl After 40 minutes at room temperature, the reaction is 53 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 stopped by rapid filtration onto Whatman GF/C filters which have been presoaked In 0.3% polyethylenimme Filters are washed 2 times with 3 ml of 50 mM Tns-HCI (pH7 4) Filters are added to 6 mis of Ready-Safe liquid scintillation cocktail and quantified by liquid scintillation spectrometry in a 5 LKB 1219 RackBeta counter Non-specific binding is determined by the addition of either 1 jiM of CP-99994 (NKi) or 1fiM SR-4896B (NK2) (both synthesized by the chemistry department of Schenng-Plough Research Institute) IC50 values are determined from competition binding curves and Ki values are determined according to Cheng and Prusoff using the 10 expenmentally determined value of 0 8 nM for the NKi receptor and 2 4 nM for the NK2 receptor For all of the compounds of the invention, the NKi binding Is in a range of about 0-100 % inhibition at 1 p.M concentration For all of the 15 compounds of the invention, the NK2 binding is in a range of about 0-100 % inhibition at 1 jiM concentration It should be understood that while the NK binding for certain compounds of the invention is as low as 0% at 1 concentration, that at higher concentrations these compounds aie expected to have NK binding inhibition activity 20 The K, of a compound is that concentration at which the compound caused 50% inhibition of either NKi or NK2 For those compounds of the invention having higher than 50% inhibition of NKi , K, 's for NKi were determined The K, *s for NKi for such compounds fell within a range of 25 about 0 1 nM to about 1 nM For those compounds of the invention having higher than 50% inhibition of NK2 ,K|'s for NK2 were determined The K, 's for NK2 for such compounds fell within a range of about 01 nM to about 1 fiM Compounds of formula I exhibit NKi and NK2 antagonist activity to 30 varying degrees, 1 e , certain compounds have strong NKi antagonist activity, but weaker NK2 antagonist activity Others are strong NK2 antagonists, but weaker NKi antagonists Certain compounds have both strong NKt and NK2 antagonist activities Some compounds can also be NK3 antagonists 35 Many compounds of formula I have an asymmetnc center and therefore exist as a pair of enantiomers In such cases, one enantiomercan 54 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 have different biological activity than the other For example, one enantiomer can have strong NKi activity and weak NK2 activity while the other enantiomer has weak NKi activity and strong NK2 activity Certain compounds of formula I have been found to be antagonists of 5 both NKi and NK2 receptors, and are therefore useful in treating conditions caused or aggravated by the activity of NKi and NK2 receptors The present invention also relates to a pharmaceutical composition compnsing a compound of formula I and a pharmaceutical^ acceptable earner. Compounds of this invention can be administered in conventional 10 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 formulation techniques Pharmaceutical^ acceptable 15 excipients and additives include nontoxic and chemically compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavonngs, thickeners, colonng agents, emulsifiers and the like The daily dose of a compound of formula I for treating asthma, cough, bronchospasm, inflammatory disease, migraine, nociception and 20 gastrointestinal disorders is about 01 mg to about 20 mg/kg of body weight per day, preferably about 0 5 to about 15 mg/kg, more preferably 0 5 to about 5 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 100 mg , given in a single dose or 2-4 divided doses The exact 25 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 The invention disclosed herein is examplified by the following examples, which should not be construed to limit the scope of the 30 disclosure Alternative mechanistic pathways and analogous structures within the scope of the invention will be apparent to those skilled in the art 35 55 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/01018 10 EXAMPLE 1 Preparation of 2-(3,4-dichlorophenyl)piperazine A. Synthesis of racemic compound 2-(3,4-Dichlorophenyl)piperazme was synthesized according to the method published in J Med Chem 3,191,1966 A General method for the synthesis of 2-aryl-piperazme derivatives ^q_0( ,) nbs vi| ||. l0CH3 HaN NHz ^ or BH3. S(CHa)2 , EtjO KzC03/ EtOH when R1- Rz = ^Fa Ri - CI, H or other substituents I e 0CH3i CFa, Br, I, F, etc R2 - CI, H or other substituents i e OCH3i CFs, Br, I, F, etc B Resolution of 2-(3,4-dichlorophenyi)piperazine Stepl 15 A solution of 2-{3,4-dichlorophenyl)piperazine (36 05 g, 0 156 mol) In methanol (200 mL) was treated with a solution containing two equivalents of N-acetyl-L-leucine (54 02 g, 0 312 mol) and heated until all of the matenal was dissolved EtOAc (2 2 L) was added to this solution and allowed to stand at ambient temperature overnight The solvent phase was decanted 20 from the precipitated salt and concentrated in vacuo This procedure was repeated using 37 88 g of 2-(3,4-dichlorophenyl)piperazine (0 164 mol) and 56 68 g of N-acetyl-L-leucine (0 327 mol) Step 2 56 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 The concentrated salts from both solvent phases in step 1 were combined and heated in methanol (550 mL) until all of the matenal dissolved EtOAc (2 75 L) was added to this solution and allowed to stand at ambient temperature overnight The solvent phase was decanted from 5 the precipitated salt and concentrated in vacuo to give -95 g of piperazine salt (72% ee of enantiomer A) Step 3 The salt from the solvent phase in step 2 was dissolved in a solution of H2O (800 mL) and aq ammonia (400 mL) and extracted with CH2CI2 (4 x 10 400 mL) The combined organic layers were dried with MgS04 and concentrated to give 37 g of the piperazine free base The free base was recrystallized three times from hexane (890, 600 and 450 mL)to give 16 g of piperazine (>99 9% ee of enantiomer A) 247°C [a] »-45 ()0(MeOH) Step 4 The precipitated salts from step 1 were combined and heated in 20 methanol (220 mL) until all of the matenal dissolved EtOAc (2 2 L) was added to this solution and allowed to stand at ambient temperature overnight The solvent phase was decanted from the precipitated salt and diied in vacuo to give -43 g of piperazine salt (93% ee of enantiomer B) Step 5 25 A 12 3 g portion of salt (75% ee of enantiomer B) prepared by an analogous procedure to that in step 4 was dissolved in 0 5 M NaOH (400 mL) and extracted wrth CH2CI2 (4 x 155 mL) The combined organic layers were dned with MgS04 and concentrated to give 3 72 g of the piperazine free base. The free base was recrystallized twice from hexane (90 and 70 30 mL) to give 21 g of piperazine (98% ee of enantiomer B) C Analytical procedure for measuring piperazine enantiomenc punty 57 Mimosa V2-05-00 07/21/1998 12 15 57 page # WO 97/08166 PCT/IB96/01018 The enantiomeric purity of the piperazine was measured by 10 15 20 25 chiral HPLC analysis of the di-tert-butoxycarbonyl piperazine derivative The di-tert-butoxycarbonyl denvative was prepared by adding a small piperazine sample (free base or salt)(~ .2 mg) to di-tert-butyl dicarbonate (~ 1 mg) and methanol (0 5 mL) and heating at 80°C for 1 h If the piperazine sample is a salt, triethylamine (20 gL) is also added The denvative was analyzed by HPLC using a ChiralPak AD column eluting with 95 5 hexane-isopropyl alcohol EXAMPLE 2 Preparation of (+,-)-[3,5-dimethylbenzoyl]-3-(3,4-dichiorophenyl)piperazine To a cooled solution of CH2CI2 (600 mL) containing 2-(3,4-dichlorophenyl)piperazine (6 934 g, 30 mmol), 3,5-dimethylbenzoic acid (4.55 g, 30 mmol), and N-hydroxybenzotriazole monohydrate (4 05 g, 30 mmol) at -20 °C were added Et3N (4 2 mL, 30 mmol) and N,N-dimethylammopropylethylcarbodimide (DEC) (5 86 g, 30 mmol) under nitrogen The reaction was kept at -20 °C for an hour and gradually warmed to RT overnight After stirring 22 hours, the reaction was complete and CH2CI2 (200 mL) was added The organic solution was washed with brine (150 mL, 3x), dried over MgS04, filtered and concentrated under "dcuum to give 8 2 g of crude product The product was crystallized from CH2Cl2/Hexane to give a light yellow solid (6 3 g, 17 34 mmol, 57 8%), m p 139-141 °C, FAB MS [M+1]+ 35d 363 1. 58 Mimosa V2-05-00 07/21/1998 12 15 57 page WW tQpr WO 97/08166 PCT/IB96/01018 10 15 EXAMPLE 3 Preparation of (+,-)-bromoacetyl-2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)piperazine To a cooled solution of (+,-)-[3l5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazine (11.5 g, 31 65 mmol) in CH2CI2 (200 mL) at 0 °C was added Hunig's base (4 5 g, 35 mmol) and bromoacetyl bromide (6 4 g, 31.65 mmol) The solution was stirred at 0 °Q overnight under N2 After completion the reaction was diluted with CH2CI2 (400 mL) and washed with bnne (300 mL, 2x). dned over MgS04, filtered and concentrated The crude matenal was punfied by flash grade silica gel chromatography, eluting with 2% [NH40H/Me0H (1 9)] / 98% CH2CI2 to give the title compound as a light yellow solid (7 1 g, 47 3%), m p 77-79 °C, FAB MS [M+1]+ 35q 79Br 482 9, 484 9 (+H3,5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazine (Enantiomer B) The title compound was prepared by an analogous method to that desecnbed in Example 2 using (-)2-(3,4-dichlorophenyl)piperazine in place of (+,-)- EXAMPLE 4 Preparation of 59 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/01018 10 2-(3,4-dichlorophenyl)piperazine, m p 97-100 °C; FAB MS [M+1]+ 35CI363 1, 22£°C [oQ 0 ■ +87 2°(MeOH) EXAMPLE 5 Preparation of (-)-bromoacetyl-2-(3,4-dlchlorophenyl)-4-(3,5-dimethylbenzoyl)piperazine (Enantiomer B) o XyBf Br ^ CH, CH, °y6- The title compound was prepared by an analogous method to that desecnbed in Example 3 using (+H3,5-dimethylbenzoyl]-3-(3,4-dichloro-phenyl)piperazine (Enantiomer B) (Example 4) in place of (+,-)-[3,5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazine, m p 68-71 °C, FAB MS , ,2190c „c __ «=-45 6°(MeOH) 15 [M+1]+35C| 79er 482 9, 484 8, D EXAMPLE 6 Preparation of (+,-)-2-(3,4-dichlorophenyl)-4-(3,5-dimethyIbenzoyl)-1-[[{1-[1-oxo-2-phenyl)ethyl]-20 4-piperidinyl]amino]acetyl]piperazine Step 1 To a solution of 4-amino-1-benzylpiperidine (9 5 g, 50mmol) in methanol (150 mL) at -10°C was added a solution of di-t-butyldicarbonate (10 9 g, 50 mmol) in methanol (60 mL) The mixture was 25 gradually warmed to room temperature overnight After the reaction was complete, solvent was removed to give a white solid 2, FAB MS [M+1]+35CI 291 3 60 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 l'CT/IB96/01018 NH2 , BOC 1-B0C MWM.n NH"< B0C A anhydride^ ^1*. fS Sr Me OH NPh MeOH N I k H Ph 1 2 3 Step 2 To a soultion of compound 2 (11.6 g, 40 mmol) in methanol (140 mL) was added Pd(OH)2(20% on carbon) (2 4 g) and hydrogenolyzed at 47 psi After the reaction was complete, the catalyst was filtered off The filtrate was evaporated to give compound 3 (8 g, 40 mmol) as a white solid 0 NH-t-BOC JT^CI NH-t BOC ^ NH2 _. rS 0 rS Ha Mo,an. rS 'HCI V y*-< >cw oix» ~hdo Q 6 CI CI O' 4 5 VH £5 CI CI Step 3 Compound 3 (0 69 g, 3 mmol) was mixed with phenylacetyl 10 chloride (0 46 g,3 mmol) and Hunig's base (0 43 g, 3 3 mol) in CH2CI2 (10 mL) at -5 °C and the solution was gradually warmed to RT overnight After completion the reaction was diluted with CH2CI2 (50 mL) and washed with bnne (30 mL, 3x) The CH2CI2 layer was dned over MgS04. filtered, and concentrated to give compound 4)as a white solid (0 81 g) 15 Step 4 This crude matenal was dissolved in dry CH2CI2 (3 mL) and treated with 4N HCI-dioxane (6 mL) After stirnng at RT for 2 h, solvents were evaporated to give 4-amino-1-(1-oxo-2-phenylethyt)pipendme 5 (0 8 g) as a white solid HCI salt FAB MS [M+1 ]+ 219 Step 5 To a solution of compound 5 (0 31 g, 1 2 mmol) in CH2CI2 20 (10 mL) was added Hunig's base (0 62 g, 4 8 mmol) followed by the addition of compound 6 (O 3 g, 0 6 mmol) (prepared in Example 3) The mixture was stirred 61 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 rCT/lB96/01018 at RT for 5 days under N2 After completion the reaction was diluted with CH2CI2 (50 mL) and washed with bnne (30 mL x2), dried over MgS04, filtered and concentrated to give a brown gummy crude matenal (0 56 g). This crude material was punfied by silica gel chromatography on flash grade silica (60 g), 5 elutlng with 5% [NH4OH / MoOH (1 9)] / 95% CH2CI2 to give the title compound as a white solid (0 28 g, 0 45 mmol) In 75% of yield FAB MS [M+1]+ 3&CI 621 1, m p 87-89 °C EXAMPLE 7 10 Preparation of (+,-)-1,1-dimethylethyl-4-[[2-[2-(3l4-dichlorophenyl)-1-(3,5-dimethylbenzoyl)-1-piperazinyl]-2-oxoethyl]amino]-1 -piperidinecarboxylate O NHz A 1 NH20H-HCI/pyridlna X N 2 Raney-Ni/EtOH/H2 N oJ*o+ oVf- 1 2 NHz r\jj O r-, 2 ^ Z hboc-NQ-n^*| >1 + £ Hunig's base / ChteCfe /=\ 0 o-f- O50Q^CI 4 Cl Cl Br ii 2 3 To a solution of N-t-butoxycarbonyl-4-pipendone 1 (15 g, 75 3 15 mmol) in pyndine (50 mL) was added hydroxylamine • HCI (5 23 g, 75 3 mmol) The mixture was heated in an oil bath at 65 °C for one hour After cooling, pyndine was removed under reduced pressure and the residue was dned under high vacuum overnight to give a solid To this solid was added water (100 mL) and the mixture was sonicated The preapitate was filtered and washed with 20 water then dned under high vacuum to give the oxime denvative of compound 1 (10 5 g, 65%) FAB MS [M+1]+ 215 3 The oxime compound (10 g, 46 67 mmol) was dissolved in absolute EtOH (100 mL) followed by the addition of Raney Ni (29 g, washed with absolute EtOH) The mixture was hydrogenated in a Parr shaker at 50 psi overnight After reaction was complete, the Raney Ni was 25 filtered off (caution nsk of fire) and the filtrate was concentrated to give 62 Mimosa V2-05-00 07/21/1998 12 15 57 page 9 WO 97/08166 PCT/II196/010IN compound 2 (9.2 g, 46 mmol,98% yield) as an oil which solidified under high vacuum drying FAB MS [M+1]+ 201.3. To a solution of bromoacetyl denvative 3 (3 0g,6 2 mmol) (prepared In Example 3) in CH2CI2 (62 mL) at -10 °C were added Hunig's base 5 (1.2 mL, 6 82 mmol) and compound 2 (2 48 g, 12 39 mmol) The solution was gradually warmed to RT overnight After reaction was complete, CH2CI2 (300 mL) was added and washed with brine (100 mL, 3x), dned over MgS04 and filtered The filtrate was evaporated to dryness to give a light yellow solid which was punfied by flash chromatography on flash grade silica gel (200 g), elutmg 10 with 5% [NH40H/Me0H (1.9)] /CH2CI2 to give 71% yield of the title compound 4 as a white solid (2 66 g, 4 4 mmol), m p 78-81 °C; FAB MS [M+1]+35Cl 603 1, Calcd for C31H40N4O4CI2, C, 61 69, H, 6 68, N,9 28, Cl,11 74 Found. C, 61 33, H, 6 94, N, 9 17, Cl, 11.27 15 EXAMPLE 8 Preparation of (-)-1,1-dimethylethyl 4-[[2-[2-(3,4-dichlorophenyl)-1-(3,5-dimethylbenzoyl)-1-piperazinyl]-2-oxoethyl]amino]-1-piperidinecarboxylate (Enantiomer B) 20 By employing methods analogous to those described in Example 7 using chiral bromoacetyl compound (prepared in Example 5), the title compound was obtained as a white solid, m p 72-75 °C, FAB MS [M+1]+35CI 603 2, 22°C [al =-32 8°(MeOH) D 25 l:\AMPLE 9 Preparation of (+,-)-2-(3,4-dichlorophenyl)-4-[3,5-dimethylbenzoyl]-1-[(4-pipendinylamino)acetyl]piperazine,dihydrochloride 30 t-BOC-N^-^w2-N^Nii»^^ 4NHCI HN0~ dioxane • 2 HCI Cl Cl Cl Cl 63 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 I,cr/I»%/U1()1H To a solution of (vH.1*dimethylethyl-4-[[2-[2-(3,4-dichlorophenyl)-1 «(3,5-dimethylbenzoyl)-1 -piperaziny l]-2-oxoethyl]ammo]-l -piperidinecarboxylate (Example 7) (2.5 g, 4.14 mmol) in CH2CI2 (20 rnL) at 0 °C was added 4N HCI-dioxane (10.35 mL, 41.4 mmol) The mixture was stirred at 0 °C for 1 h and it was gradually warmed to RT over 3 h. After reaction was complete, excess HCI and solvent were evaporated to give a pale yellow solid which was used without further purification FAB MS [M+1]+ 35ci 5031 10 EXAMPLE 10 15 Preparation of (-)-2-(3,4-dichlorophenyl)-4-[3,5-dimethylbenzoyl]-1-[(4-piperidinyl-amino)acetyl]piperazine, dihydrochloride (Enantiomer B) By employing method analogous to that descnbed in Example 9 using chiral material obtained from Example 8, the title compound was obtained ,22.1°C 20 as a pale yellow solid, FAB MS [M+1 ]+ 35CI503 2, M, -38°(MeOH) >2 HCI EXAMPLE 11 __ u n. O ✓ aromatic or substituted aromatic methyl nalid^ hsterocycfic CHjX. X • Cl. Br chiral target Cl Cl 2 25 A series of Y denvatives of (-)-2-(3,4-dichlorophenyl)-4-[3,5- dimethylbenzoyl]-1-[(4-pipendinylamino)acetyl]piperazine, dihydrochloride (Enantiomer B) was prepared by parallel synthesis To a suspension of compound 1 obtained from Example 10 (1 05 g, 1.822 mmol) in CH2CI2 (40 mL) was added HOnig's base (1 0 mL 5 74 mmol) 30 The mixture was dissolved by sonication This solution was divided into 20 parts 64 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 07/08166 rCT/HM/OIOIR and transferred into 20 vials Each vlal contained 2-(3,4-dichlorophenyl)-4-[3,5-dimethylbenzoyl]-1-[(4-piperidinylamino)acetyi]plperazine, dlhydrochloride (Enantiomer B) (0.091 mmol), HUnlg's base (0 287 mmol) and CH2CI2 (2 mL). To each vial was added separately 0.1 mmol of aromatic or substituted aromatic 5 methyl chloride or bromide or heterocyclic halide reagent After reaction was complete it was diluted with CH2CI2 (5 mL), washed with brine (2 mL 3x), dried (MgS04), filtered and evaporated to dryness. Representative compounds 2 made by the above routes are shown below 65 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/()I018 K. chiral target Cl Cl fab ms fab ms [m+1)+35ci y [m+1]+ 35 cl 638 2 ^tX2OH 65,2 rxa 6502 '^o 67'2 so2ch3 6772 *Xr' 673 9 N0 644 2 NH ^C00H 637 2 Cl Cl 6362 ^at0aoch3 594 2 594 2 612 2 633 2 ^0-cn 61b1 601' 662 0 651 1 6331 663 Cl 66 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 l'CT/ID9fi/01018 M chiral target cr ci FAB MS FAB MS [M+1}*35CI Y [M+1]+35CI VTKOH A 651 1 680 1 OH I /N N-o 693 1 €671 ? N.0» G41 1 585 1 ^NCN0H 688 1 6791 6 EXAMPLE 12 Preparation of 5 (+,-)-1-benzoyl-4-fl2-[2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-piperazinyl]-2-oxoethy)]amino]pipenains h r» O / ^ HQnig's base n __ H O -O ✓ + pk HOBT/CHzCb >0-N^N J-* W l&J EtaN/DEC* Q) M _ i] .R O^OH -v H o S HN^ • 2 HCI cr *ct ci" ci To a solution of compound obtained from Example 9 (0 23 g, 0 4 10 mmol) in CH2CI2 (5 mL) was added HOnig's base (013 g, 1 0 mmol) This was followed by the addition of benzoic acid (49 mg, 0 4 mmol), HOBT (54 mg, 0 4 mmol), Et3N (40 mg, 0 4 mmol) and DEC (77 mg, O 4 mmol) at 0 °C The 67 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT7IB96/01018 solution was gradually warmed to RT and stirred overnight After reaction was complete, the solution was diluted with CH2CI2 (50 mL) and washed with saturated NaHC03 solution (30 mL, 2x) and brine (20 mL, 3x) The organic layer was dried over MgS04, filtered and concentrated to give crude material as an oil. 5 The product was punfied by chromatography on flash grade silica gel (50 g), e'uting with 5% [NH4OH/Me0H (1.9)]/ CH2CI2 to give the title compound as a white solid (0.1 B g). m p 94-96 ®C, FAB MS (M+1]+ S^CI 607.3 EXAMPLE 13 10 Preparation of (+,-)-2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[1-(2-oxo-2-phenylethyl)-4-pipendinyl]amino)acetyl]pipera2ine * XBr ~ •SHO rf M o ^ M ci ci 1 2 ci ci 15 To a solution of compound 1 obtained from Example 9 (0 23 g, 0 4 mmol) in CH2CI2 (5 mL) were added Hunig's base (O 21 g, 1 6 mmol) and phenylacyl bromide (80 mg, 0 4 mmol) at RT The mixture was stirred at RT overnight under N2 After reaction was complete, it was worked up and punfied according to the methods descnbed in Example 7 to give the title compound 2 as 20 a solid, m.p. 69-71 °C, FAB MS [M+1]+ 35 ci 621 3 EXAMPLE 14 Preparation of (+,-)-2-(3,4-dichloropheny!)-4-(3,5-dimethylbenzoyl)-1 -[[[1-(3-phenylpropyl)-4-25 pipendinyl]amino]acetyl]piperazine u _ 0 j O 1 HQnig's base u _ o > + ^ cf3ch2qh, I 1 O 2 R * 2 hci cr ci 1 ci ci To a solution of compound 1 obtained from Example 9 (0 4 g, 0 7 mmol) in CF3CH2OH (5 mL) was added Hunig's base (0 21 g, 1.6 mmol) at 0 °C 30 After stirring at O °C for 10 min, hydrocinnamaldehyde (94 mg, 0 7 mmol) was 68 Mimosa V2-05-00 07/21/1998 1215 57 page WO 97/08166 PCT/IB96/01018 added The reaction was stirred at 0 °C for additional 2 5 h, and NaBH3CN (100 mg, 1 6 mrnol) was added The mixture was stirred at 0 °C and gradually warmed to RT overnight After reaction was complete, it was worked up and purified as described in Example 7 to give the title compound as a white solid, 5 m p 52-54 °C, FAB MS [M+1]* ^Cl 621 3 EXAMPLE 15 Preparation of (-)-N-[4-[[4-[[2-[2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-piperazinyl]-2-10 oxoethyl]amino]-1-piperidmyl]methyl]-2-thiazoyl)acetamide (Enantiomer B) _( Hunig's base Hj| /=\ ^ •2 HCI Q CH2CI2 ovNV © cT%l I Cl ci chiral target chiral 1 2 By an analogous method to that described in Example 13, using the chiral intermediate 1 made in Example 10 and 2-acetamido-4-(chloromethyl)-thiazole, in the present of HUnig's base in CH2CI2, the title compound 2 was 15 obtained as a white solid after purification by flash grade silica gel chromatography, m p 104-107 °C, HRMS Calcd for[M+H+] (2x35)CI , 241°C (al «-40 1° (MeOH) C32H39N6SO3CI2 657 2181, Found 657.2172, D 20 25 EXAMPLE 16 Preparation of (+,-)-2-(3,4-dichlorophenyl)-4-[3,5-dimethylbenzoyl]-1-[[[3-methyl-1-(phenyimethyl)-4-pipendinyl]amino]acetyl]piperazine (diastereorners A and B) 69 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 jfyr -n0" J$ °f - ,.<1 "" Cl 1 1 2 1 P-(N(CH3)2)3 . HCl/MoOH I NaHC03 OXv,oV" OTP-o r.w SX OH, a*. h!N^Y V C|AJ NaBHgCN («^S CHa Cl Ti(OiPf)4 Cl'^y Cl 3 Step 1 To a solution of BOC glycine (0 979 g, 5 59 mmol) and Et3N (0 B5 mL, 61 mmol) in CH2CI2 (10 mL) was added BOP (benzotnazol-1-yloxy-5 tns(dimethylamino)phosphonium hexafluorophosphate) reagent (2 46 g, 5 57 mmol) After stirnng for 15 mm, (+,-)-(3,5-dimethylbenzoyl)-3-(3,4-dichlorophenyl)piperazine (1 83 g, 5 03 mmol) (prepared in Example 2) was added After 5 h, the reaction mixture was added to 0 2 N HCI (100 mL) and extracted with CH2CI2 (3 x 60 mL) The combined organic layers were washed 10 with bnne, dned with MgSO* and concentrated The crude material was punfied by flash chromatography on silica gel eluting with 501 to 30 1 CHaCfe-MeOH to give 2 15 g of compound 2 (shown above) as a white foam (4 1 mmol, 82%) Step 2 Compound 2 (1 32 g, 2.5 mmol) was treated with MeOH saturated 15 HCI (15 mL) for 2 5 h and concentrated The resulting powder was dissolved in CH2CI2, washed with sat NaHC03, dried with MgS04 and concentrated to give compound 3 as the free base Step 3 To a -78°C solution of LDA (10 79 mmol) in THF (30 mL) was 20 added 1-benzyl-4-pipendone (2 OmL, 10 8 mmol) The reaction mixture was warmed to 0°C for 20 min and then cooled back to -78°C Methyl iodide (0 67 mL, 10 8 mmol) was added to the enolate solution which was stirred at 0°C for 70 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 2 h then warmed to RT overnight The reaction mixture was quenched with sat NH4CI and concentrated The residue was suspended in H2O and extracted with CH2CI2 The combined organic layers were dried with MgSCU, filtered and concentrated The product was punfied by flash chromatography on silica gel 5 eluting with 1 1 hexane-EtOAc to give the 1 -benzyl-3-methyl-4-pipendone 4 as a yellow oil (0 65 g, 30%) Step 4 A mixture of the ketone 4 from step 3 (70 mg, 0 13 mmol) and the compound 3 (34 mg, 017 mmol) was stirred in titanium isopropoxlde (45 mg, 10 0 16 mmol) for 1 5 h To the mixture were added ethanol (1 0 mL) and NaCNBH3 (5 4 mg, 8 6 mmol) and the mixture was stirred overnight The reaction mixture was filtered and washed with EtOAc The filtrate was washed with H2O and bnne, dned with MgS04 and concentrated The residue was chromatographed on silica gel eluting with 5% NH3 sat MeOH in CH2CI2 to give both 15 diastereomers pure Diastereomer A (15 mg) HRMS (FAB, M+H+) m/e calc'dfor[C34H4iN4Cl202]+ 607 2607, found 607 2603 Diastereomer B (17 mg) HRMS (FAB, M+H+) m/e calc'd for [C34H41N4CI2021+ 607 2607, found 607 2597 20 EXAMPLE 17 Preparation of 2-(3,4-dichlorophenyl)-4-[3,5-dimethylbenzoyl]-1-[[[1-(phenylmethyl)-3-piperidinyl]amino]acetyl]piperazme, diastereomers 25 O Cl By a procedure analogous to the method described in Example 16 step 4, using 3-benzyl piperidine in place of 1-benzyl-3-methyl-4-piperidone, the title compound was prepared as a solid foam. 71 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 HRMS (FAB, M+H+). m/e calc'd for [033^9^0202]+ 593 2450, found 593 2458 EXAMPLE 18 5 Preparation of 2-(3l4-dichiarophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[B-(phenylmethyl)-8-azabicyclo[3 2 1]oct-3-yl]amino]acetyl]plperazine "• <XM ^ Cl L from Example 16, compound 3 By an analogous method to that descnbed in Example 16, the 10 product from Example 16, compound 3 (185 mg, 0 44 mmol) was combined with 8-benzyl-8-azabicyclo[3 2 1]octan-3-one (97 mg, 0 45 mmol) and Ti(0/ Pr)4 (105 mL, 0 50 mmol) and left stirnng for 1 h To the thick reaction mixture was added NaBHaCN (59 5 mg, 0 95 mmol) and the mixture was stirred overnight To the reaction mixture was added H2O (1 15 mL) and it was filtered Ths filtrate was washed with EtOH, concentrated and purified by silica gel chromatography, eluting with 30 1 0 1 to 151 0 1 CH2Cl2-MeOH-NH3 aq to give the title product as a white foam HRMS (FAB, M+H+); m/e calc'd [C35H4iCI2N402]+ 619 2607, found 619 2594 20 EXAMPLE 19 Preparation of 2-(3,4-dichlorophenyl)-4-(3,5-dimethyibenzoyl)-1-[[[8-methyl-8- azabicyclo[3.2 1]oct-3-yl]amino]acetyl]piperazine (enantiomer B) o 72 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 rCT/IB96/010I8 10 15 20 25 This compound was prepared by a procedure analogous to Example 16 except for the use of (+)-[3,5-dimethylbenzoyI]-3-(3,4-dichlorophenyl)-piperazine (Enantiomer B) in stepl and tropinone in place of 1-benzyl-3-methyl-4-pip9ridone. HRMS (FAB, M+H+), m/e calc'd [C29H37CI2N4021+ 543 2294, found 543 2282 EXAMPLE 20 Preparation of 2-(3,4-dich!orophenyl)-4-[3,5-dimethylbenzoyl]-1-[[[1,3-bis(phenylmethyl)-4- pipendinynaminojacetynpiperazme, diastereomers 1rom enantiomer B Step 1 A solution of 1-benzyl-3-carbomethoxy-4-pipendone (1 0 g, 4 0 mmol) in THF (10 mL) was treated with 0 5 M potassium bis(tnmethylsilyl)amide in toluene (9 6 mL, 4 8 mmol) for 15 mm, followed by the addition of benzyl bromide (1 2 g, 4 8 mmol) After 2 h, the reaction mixture was quenched with sat NH4CI and extracted with ether The combined organic layers were washed with bnne, dned with MgSC>4 and concentrated The product was purified by silica gel chromatography eluting with 41 hexane-EtOAc to give 3-carbomethoxy-1,3-dibenzyl-4-pipendone (0.61 g) as a light yellow oil Step 2 A solution of 3-carbomethoxy-1,3-dibenzyl-4-pipendone (0 61 g, 1 78 mmol), MeOH (10 mL) and 5 M HCI aq (25 mL, 125 mmol) was refluxed overnight The reaction mixture was concentrated and chromatographed (silica gel, eluting with 4 1 hexane-EtOAc) to give 1,3-dibenzyl-4-piperidone (0 31 g) Step 3 A solution of 1,3-dibenzyl-4-pipendone (0 033 g, 0 12 mmol) and [[2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-amino]acetyl]-pipenazine (Enantiomer B) (0 05g, 0 12 mmol) [prepared according to the methods 73 Mimosa V2-05-00 07/21/1998 12 15 57 page WO «J7/08166 PCT/IB96/01018 described in Example 16, except using (+H3,5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)plperazme (Enantiomer B) (Example 4) in step 1] in CH2CI2 (1 0 mL) was treated with NaBH(OAc)3 (0 035 g, 0 16 mmol) and acetic acid (0 07 mL, 0 12 mmol) The mixture was stirred overnight After completion, 5 the reaction mixture was quenched with 1N NaOH and extracted with CH2CI2 The combined organic extracts were washed with bnne, dned with MgS04, concentrated and punfied by silica gel chromatography, eluting with 5% NH3 sat. MeOH/ChteCk to give 32 mg of the titled product as a white solid. HRMS (FAB, M+H+), m/e calc'd [C4oH45Cl2N402]+. 683 2920, found 10 683 2932 EXAMPLE 21 Preparation of 15 2-(3,4-dichlorophenyl)-4-[3,5-dimethylbenzoyl]-1-[[[3-methyl-1- (phenylmethyl)-4-pipendinyl]amino]acetyl]pipera2ine (diastereomers A from enantiomer B) This compound was prepared by a procedure analogous to Example 16 20 except for the using of (+)-[3,5-dimethylbenzoyl]-3-(3,4-dichiorophenyl)-piperazine (Enantiomer B) in Example 16, step 1 HRMS (FAB, M+H+), m/e calc'd [C34H4iCI2N402]+. 607 2607, found 607 2594 EXAMPLE 22 25 Preparation of 2-(3,4-dichlorophenyl)-4-[3,5-dimethylbenzoyll-1-[[[1-(phenylmethy!)-3-(2-propenyl)-4-piperidinyl]amino]acetyl]piperazine (diastereomers from enantiomer B) Ci 30 This compouna was prepared by a procedure analogous to Example 20 except for the substitution of aliyl bromide in place of benzyl bromide in step 74 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 I'CT/IB96/01018 1. HRMS (FAB, M+H+), m/e calc'd [C36H43Cl2N402]-'- 633 27, found 633 2763 EXAMPLE 23 5 Preparation of trichloroethyl-4-[[2-(3,4-dichlorophenyl)-4-(3,5-dimethylb9nzoyl)-1-pipera2inyl]-2-oxoethyJ]amino]-2-phenyl-1-pipendinecarboxylate (diastereomers from enantiomer B) methoxypyridlne (3 5 g, 32 5 mmol) (prepared according to Synthesis 1989, 645, at -15°C was added 2,2,2-trichloroethyl chloroformate (4.5 mL, 32 7 mmol) After 30 min at -15°C, 2M PhMgCI in THF (19 5 mL, 39 mmol) was added and the mixture was stirred at -15°C for 30 mm followed by 30 min 15 at RT The reaction mixture was quenched with 10% aq HCI (100 mL), added to brine (200 mL) and partitioned The aqueous layer was extracted with Et20 (50 mL) The combined organic layers were dried with MgSC>4 and concentrated to give 11 4 g of compound 3 shown above as a light tan solid 20 Step 2 To a cooled solution of compound 3 from step 1 (8.65 g, 34 8 mmol) in THF (100 mL) at -23°C was added 27.8mL of 1M L-selectnde (27 8 mmol) The mixture was stirred at -23°C for 2 h After warming to RT, the 75 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/01018 reaction mixture was added to sat NaHCC>3 and partitioned The aqueous layer was extracted with Et20 (2 x 50 mL) The combined organic layers were washed with bnne (50 mL), dned with MgS04 and concentrated The product was punfied by silica gel chromatography eluting with 6 1 to 3 1 5 hexane-EtOAc to give 2 47 g of compound 4 and 2.75 g of recovered starting material. Step 3 To a solution containing the compound 4 from step 2 (284 mg, 0.81 mmol) in 1,2-dichloroethane (3 ml) and compound 5 (324 mg, 0.81 mmol) [made in Example 16, step 3 except using (+)-[3,5-dimethylbenzoyl]-10 3-(3,4-dlchlorophenyl)piperazine (Enantiomer B) in step 1] was added NaBH(OAc)3 (179 mg, 0 84 mmol) and acetic acid (50 mL, 0 87 mmol) After stirnng overnight, the reaction mixture was added to 1N NaOH (40 mL) and was extracted with Et20 (3 x 15 mL) The combined organic layers were washed with brine (15 mL), concentrated, and purified by silica gel 15 chromatography eluting with 25 1 0 1 CH2Cl2-MeOH-NH3 aq to give 423 mg of the title compound as a white foam HRMS (FAB, M+H+), m/e calc'd [C35H38CI4N4041+- 753 1336, found 753 1338 EXAMPLE 24 20 Preparation of 2-(3,4-dichlorophenyl)-4-(3,5-<Jimethylbenzoyl)-1-[3-[5-(phenylmethyl)-(1 S,4S)-2,5-diazabicyclo[2 2 1]heptane-2-yl]-1-oxopropyl]piperazine (diastereomer A from enantiomer B) Cl Cl 25 To a cooled solution of CH2CI2 (10 mL) containing dnsopropylethylamine (0.275 mL, 2 0 mmol) and [3,5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazine (Enantiomer B) (Example 4) (305 mg, 0 84 mmol) was added chloropropionyl chloride (0 075 mL, 0 8 mmol) The reaction mixture was allowed to warm to room temperature After 20 30 minutes, (lS,4S)-2-benzyl-2,5-diazabicyclo(2 2 1)heptane 2HBr (297 mg, 0 85 mmol) and dnsopropylethylamine (0 275 mL, 2 0 mmol) were added 76 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 and the mixture was left over night, after which the reaction mixture was concentrated The product was purified by flash chromatography on flash grade silica gel, eluting with 30:1 0 1 CH2Cl2/MeOH/NH3 to give a foamy solid (140 mg, 0 23 mmol, 29%), High Res MS [M+1]+ calcd for C34H39CI2N4O2 605.2450, Found, 605 2465 10 15 20 ..... -r ^ EXAMPLE 25 Preparation of Y-N-C-O —> Y- pyridine Cl Cl ExamplelO chiral and chiral target Cl Cl A y - aromatic or substituted aromatic or cycloalkyl group cJM chiral target Cl Cl B y ■= aromatic or substituted aromatic or cycloalkyl group A series of urea analogs of (-)-2-(3,4-dichlorophenyl)-4-[3,5-dimethylbenzoyl)-1-[(4-piperidinyl amino)acetyl]piperazine,dihydrochlonde (Enantiomer B) (Example 10) as shown above was prepared by parallel synthesis The product from Example 10 (0 75 g, 1 3 mmol) was dissolved in dry pyndine (13 mL) 1 ml of the above solution was translered into a vial (2 dram size) To each vial was added 0 1 mmol of an aromatic or substituted aromatic isocyanate reagent After completion the reaction was diluted with CH2CI2 (5 mL) and washed with water (3x5 mL), dned over Na2S04, filtered and evaporated to dryness Most of reactive reagents gave (2'1) adduct B as the major product Several less reactive reagents gave the product A Crude products were identified by FAB MS. 77 Mimosa V2-05-00 07/21/1998 12 15 57 page >VO 97/08166 PCT/1B96/01018 chiral target Cl' NCI A y - aromatic or substituted aromatic group or cycloalkyl oJM 0 and y — ^ \ chiral target Cl Cl B y - aromatic or substituted aromatic group or cycloalkyl Product FAB MS [M+1h 35 Cl _ . _ FAB MS Product [W+1]+3SCI "So 741 1 633 3 At O tx°c; 694 4 692 2 Jv^CHa V CH3 B 797 lxr 769 3 =tx OCFa B 909 !tJT CN A 647 3 664 3 B 797 4 OCHa B A B 841 4 672 3 801 *o B 753 5 78 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 I'CT/IIWfi/OlOIS EXAMPLE 26 5 10 15 79 Mimosa V2-05-00 07/21/1998 12 15 57 page , Y CQQH _>> Y-S-tfy ^ • 2 HCI /Hs HOnig's base M HOBT/ DEC/CH2CI2 chiral target Cl Cl Cl Cl from Example 10 V - aroma,ic or substituted cniral aromatic or heterocyclo group A series of amido analogs of (-)-2-(3,4-dtchlorophenyl)-4-[3,5-dimethylbenzoyl-1-[(4-piperidlnyl-amino)acetyl]piperazine, dihydrochlorlde (Enantiomer B) (Example 10) shown above were prepared by parallel synthesis The chiral product from Example 10 (1 15 g, 2 mmol) was dissolved In a mixture of dry CH2CI2 (20 mL) and Hunig's base (0 9 g, 7 mmol) followed by the addition of HOBT (0 3 g, 2 2 mmol) After stirring at RT for one hour, 1 mL of this solution was transfered Into a brown vial (4 dram size) To each vial was added the appropriate aromatic or heterocyclic acid (0 1 mmol) DEC (0 38 g, 2 mmol) was dissolved in CH2CI2 (5 mL) and EtsN (0.2 mL) and 0 4 mL(0 2 mmol) of this DEC solution was added into each vial The reaction was stirred at RT overnight After completion each reaction mixture was diluted with CH2CI2 (4 mL) and washed with water (2x4 mL), dried over Na2S04, filtered and evaporated to dryness Crude product was identified by FAB MS WO 97/08166 rCT/11196/01018 chiral target V/ Cl Cl y - aromatic or substituted aromatic or hetercycio group fab ms v fab ms (M+ll+^CI [M+ll**501 IsQ 607 5 iy* j S J 624 4 5^*1 Kp 663' tco 6095 -|Cnh 5976 |rD srO «" h 5 0 ^"CO "" "NX' 6777 . s ochj qi Cl 'A} 6.35 I^N 597 7 607 8 612 7 Ko 6602 % o 597 6 608 8 S O *11 674 7 614 8 698 7 682 7 6078 80 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/0R166 PCI/III96/U1018 EXAMPLE 27 Preparation ot (-)-phenyl 4-[[2-[2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-piperazinyl-2' 5 oxoethyl]amino]*1 -piperidinecarboxylate, hemihydrate (Enantiomer B) p-O • 2 HCI (Tj HOnlg's base ^gi |arge^ X CH2Cb/-78 0C n^rl Cl Cl 2 01 w 1 chiral To a cold solution of compound 1 Irom Example 10 (0.2 g, 0 347 mmol) in CH2CI2 (8 mL) at -78 °C was added HUnig's base (0 193 mL, 1 11 mmol) and 10 phenylchloroformate (0 046 mL, 0 364 mmol) After stirnng at -78 °C for 24 h, the reaction was diluted with CH2CI2 (200 mL), washed with bnne (80 mL, 3x), dned (MgSCM), filtered and evaporated to dryness The crude material was punfied by flash chromatography, using flash grade silica gel (50 g), eluting with 5% [(1.9) (MH4OH / MeOH)] 195% CH2CI2 to give a 50% yield of the title compound 2 as a 15 white solid (0 108 g,0 173 mmol), m p 71-75 °C, FAB MS (M+1J+ 35CI 623.0, Calcd for C33H36N4O4CI2 • 0 5 H2O, C, 62 66,H. 5 90. N, 8 86, Cl 11 38 [eg - -42 0° (MeOH) Found C, 62 52, H, 5 95, N, 8 87, Cl, 11 01, D EXAMPLE 28 20 Preparation of 2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1 -[([ 1 -[ (1H-pyrro l-2-y I) methy f]-4 -plperidinyI]amino]acetyl]piperazine, hemihydrate (Enantiomer B) 81 Mimosa V2-05-00 07/21/1998 12 15 57 page WO pcr/uwoiois 0 • 2 hci NaBHjCN CF3CH2OH J—- laBHjCN {J O :f-,ch?oh chiral target Cl Cl 2 1 chiral To a solution of compound 1 from Example 10 (0 2 g, 0.347 mmol) in CF3CH2OH (3 47 mL) was added HOnig's base (0 12 rnL, 0 694 mmol) and 5 pyrrole-2-carboxaldehyde (40 mg, 0 42 mmol) at RT under nitrogen After stirnng at RT for 1 h, NaBH3CN (67 mg, 0 694 mmol) was added and the mixture was stirred overnight After the reaction was complete, solvent was evaporated and the residue was mixed with 5% NaHCC>3 solution (50 mL) and bnne (100 mL) then it was extracted with CH2CI2 (80 mL,3x) The organic layers were 10 combined, dried (MgS04). filtered and evaporated to dryness The crude material was purified by flash chromatography on flash grade silica gel (50 g), eluting with 7.5% [(1 9)(NH40H / MeOH)] / 92 5% CH2CI2 to give the title compound 2 in 43% of yield as a white solid, m p 73-76 °C, HRMS , Calcd for [M+H+]35c, C31H38N5O2CI2 .582 2403 Found 582 2403 Preparation of 2-(3,4 dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[1-[(1 H-pyrrol-2-yl)carbonyl]-4-20 pipendinyl]amino]acetyl]piperazine, hemnhydrate (Enantiomer B) chiral By an analogous method to that descnbed in Example 26, using the chiral compound 1 from Example 10 (100 mg, 0 173 mmol) and pyrrole-2-carboxyiic 15 EXAMPLE 29 fn?h 2 82 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 acid {20 mg, 0.178 mmol), the title compound 2 was obtained as a white solid after flash grade silica gel chromatography, m p 95-100 °C, HRMS, Calcd. for [M+H+]35 Cl, C31H36N5O3CI2 596.2159 Found. 596.2204. 10 EXAMPLE 30 Preparation of (-)-2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[1-[(1H-imidazol-2-yl)methyl]-4-pipendinyl]amino]acetyl]pipera2ine, dihydrate (Enantiomer B) ■ 2 HCI rf ^ W W CF3CH2OH ch ,, , C,"CI awow" chiral ,argel c, 'ci 15 chiral 1 2 By an analogous method to that described in Example 28, using the chiral compound 1 1rom Example 10, (200 mg, 0 347 mmol) and 2-imidazole-carboxaldehyde (34 mg, O 347 mmol), the title compound 2 was obtained as a 20 white solid after flash grade silica gel chromatography, m p 73-76 °C, HRMS , Calcd for [M+H+] ^Cl, C30H37N6O2CI2 583 2355 Found 503 2369, . ,237t =-46 5°(MeOH) Example 31 25 Preparation of 2-(3,4-dichloropheny l)-4-(3,5-dimethylbenzoyl)-1 -[1 -oxo-3-[[1 -(phenylmethyl)-4-piperidinyl]amino]propyl]piperazine (Enantiomer B) 83 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 l'CT/IB96/01018 10 15 20 from Example 4 Step 1 To a cold solution of [3,5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazme (Enantiomer B)1 (3 0 g, 8 26 mmol) (Example 4) in CH2CI2 (82 6 mL) at -78 °C was added Hunig's base (1 582 mL, 9 08 mmol) and bromopropionyl chloride (0 874 mL, 8 67 mmol) After stirnng at -78 °C for 5 h, the reaction mixture was diluted with CH2CI2 (300 mL), washed with brine (150 mL, 2x), dried with MgSC>4, filtered and concentrated to dryness to give the crude bromopropionyl intermediate 2 (3 2 0). Step 2 To a solution of compound 2 (300 mg, 0 6 mrnol) in CH2CI2 (6 mL) were added 4-amlno-1-benzyl piperidine (0 245 mL, 1.2 mmol) and Hunig's base (0 1 mL, 0.6 mmjl) at 0 °C The reaction was gradually warmed to RT and stirred for 3 days After completion the reaction mixture was diluted with CH2CI2 (200 mL) and washed with brine (50 mL, 2x), dned over MgS04, filtered and concentrated to dryness to give a light yellow solid The crude matenal was punfied by flash chromatography on flash grade silica gel (80 g). eluting with 6 5% [(1 9) (NH4OH / MeOH)] / 93 5% CH2CI2 to give the title compound as a white solid (O 18 g, 0 3 mmol, 50%), m p 51-54 °C; HRMS, Calcd for [M+H+] 35 ci, C34H41N4O2CI2 607.2607 Found 607 2600 25 84 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 I'CT/IB96/01018 EXAMPLE 32 Preparation of 2-(3,4-dichlorophenyl)-4-(3,5-dlmethylbenzoyl)-1-[1-oxo-3-N-methyl-[[1 • 5 (ph8nylmethyl)-4-plperidinyl]amino]propyl]piperazine (Enantiomer B) 4-Methylamino-1-benzyl piperidine 3 was prepared analogous 10 to the reductive amination method descnbed in Example 28 using 4-amlno-1-benzyl pipendine and methylamino hydrochloride as starting materials The title compound 4 was prepared as a white soid, analogous to the methods descnbed in Example 31, except using 4-methylamino-1-benzyl pipendine 3 in place of 4-amino-1 -benzyl piperidine in 15 step 2 mp. 47-49 °C, FAB MS [M+1]+35ci 621 2, Calcd for C35H42N4O2CI2 • 0.5 H2O C.66 66.H, 6 87, N, 8 88.CI, 11 24 Found C, 67.02, H, 7 07, N, 8 81, Cl. 10 75 EXAMPLE 33 20 Preparation of (-)-1,2-dimethylethyl 5-[3-[2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1 -plperazinyl]-3-oxopropyl]-(1 S,4S)-2,5-diazab!cyclo[2 2 1]heptane-2-carboxylate (diastereomer A from enantiomer B) 85 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 CHa CH3 °Y^"CH3 °yO"CH3 Y^^CH3 ci'R^Br ^Ns. 3-4^0^°° fNsi r i .cl s#*- fXX H^b-. fTX tic <A 01 cHzci2 <A n H "Cl chiral Example 4 2 Br • +3- 10 The title compound 4 was prepared as a white solid analogous to the methods descnbed in Example 31 except using (1s,4s)-N-t-BOC-2,5-diazobicyclo[2 21]-heptane in place of 4-amino-1-benzyl pipendine in step , 22 0°C W _ - -51 1°(MeOH) 2. m p 78-82 OC, FAB MS [M+1J+35 Cl 6151, D Example 34 Preparation of (-)-1-[3-(1 S,4S)-(2,5-diazabicyclo[2.2 1]heptan-2-yl)-1 -oxopropyl]-2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl) piperazine dihydrochlonde (diastereomer A from enantiomer B) 15 86 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/JB96/01018 10 CHa CHa 4N HCI / dioxane CHa CW' ^Sjl CH2Cl2 43 >=o To a solution of compound 1 obtained from Example 33 (0 74g, 1 2 mmol) in CH2CI2 (6 mL) at RT was added 4N HCI (3mL, 12 mmol). After stirnng at RT for 4 h, excess acid and solvents were evaporated to give a light yellow solid 2, m,p 60-64 °C, FAB MS [M+1]+ ,. 22.0 °c M »= -34 4°(MeOH) 35CI5151, D Example 35 Preparation of (-)-N-[4-[[5-[3-[2-(3,4-dichlorophenyl-4-(3,5-dimethylbenzoyl]-1-piperazinyl]-15 3-oxopropyl]-(1S,4S)-2,5-diazabicyclo[2 2 1]heptan-2-yl]methyl-2-thiazolyl]]acetamide (diastereomer A from enantiomer B) 87 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1II96/01018 CHa CHa By an analogous method to that descnbed in Example 13, using the chiral intermediate 1 made in Example 34 and 2-acetamido-4-5 chloromethyl thiazols, in the present of Hunig's base in CH2CI2, the title compound 2 was obtained as a white solid 2 after punfication by flash grade silica gel chromatography, m p 105-110°C, FAB MS [M+1]+ 35 ci 669 0, [a]2;7* = -23 4° (MeOH) 10 EXAMPLE 36 Preparation of (-)-N-[4-[[5-[3-[2-(3,4-dichlorophenyl-4-(3,5-dimethylbenzoyl]-1-piperazinyl]-15 3-oxopropyl]-(1S,4S)-2,5-diazabicyclo[2 21]heptan-2-yl]methyl]phenyl] acetamide (diastereomer A from enantiomer B) 88 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 FCT/IB96/OJ018 CH3 CHa By an analogous method to that descnbed in Example 13, using the chiral intermediate made in Example 34 and 4-acetamidobenzyl 5 chlonde, in the present of Hunig's base in CH2CI2, the title compound 2 was obtained as a white solid after purification by flash grade silica gel chromatography, m p 101-106 °C, FAB MS[M+1]+35CI 6621, 23-3°C [eg D ■ -27 3 (MeOH) 10 EXAMPLE 37 Preparation of 2-(3,4-dichlorophenyl-4-(3I5-dimethylbenzoyl]-1-[3-[5-(1H-pyrroll-2-yl)methyl]-(1S,4S)-2,5-diazabicyclo[2 21]heptan-2-yl]-1-oxopropyl] 15 piperazine (diastereomer A from enantiomer B) 89 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 rCT/11196/01018 1 NaBH3CN CF3CH2OH Oh By an analogous method to that descnbed in Example 28, using the chiral intermediate of Example 34, the title compound 2 was obtained as a white solid after punfication by flash grade silica gel chromatography, m p 81-83 °C, FAB MS [M+1]+ 35Cl 594 1 EXAMPLE 38 Preparation of (■»-,-)-2- (3,4-dlchlorophenyl)-4-[(4-fluoro-1 -naphthalenyl)carbonyl]-1 -[[[1 -(phenylmethyl)-4-pipendinyl]amino]acetyl]piperazme 90 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 1'CT/1B96/01018 H t BOC t-BOC A A N fcl Ar^ MaOH /-7B °C N Af2 2 4 Amino 1-benzyl N'Sat2 n ninarlHino J 11 piperidine 100% w Ph 3 61 5 % Cl OMe .OMe Ar2 - f ^"0"CI -^-^-OMe etc Ar1 04 CN1 N Ar2 5 General Method To a cooled solution of (+,-)-2-(3,4-dlchlorophenyl)piperazine (1, Ar2 = 3,4-dichlorophenyl) (20g, 86 53 mmol) in MeOH (900 mL) at -78 5 °C was added dropwise a solution of t-BOC anhydride (19 47g, 86 53 mmol) in MeOH (263 mL) over 3h penod under N2 The solution was gradually warmed up to RT overnight After reaction was complete, the solvent was evaporated and the residue was dried under high vacuum overnight to give 2 (28 g) as a white solid (Ar2 = 3,4-dichlorophenyl) FAB 10 Mass [M+1 ]+ 35ci 331.2 To a cooled solution of compound 2 (23 8g, 71 85 mmol) in CH2CI2 (500 mL) at -78 °C was added a solution of bromoacetylbromide (6 88 mL, 79 04 mmol) in CH2CI2 (10 mL) through a dropping funnel under 15 N2 0vera 10 min period After stirnng at-78 °C for 3 h, TLC showed that the reaction was complete To this cooled solution were added Hunig's base (13 76 mL,79 mmol) and 4-amino-1-benzylpipendine (29 30 mL, 143 7 mmol) It was kept at -78 °C for one hour then gradually warmed up to RT overnight After completion CH2CI2 (200 mL) was added and 20 washed with brine (200 mL, 3x), dned over MgS04, filtered and concentrated to give a light brown residue of compound 3 (46g) (Ar2 = 3,4- 1 4 N HCI in dioxane 2 NaOH to pH 10 O N Ph 95 % coupling with k "» aromatic acid or heterocyclic acid HOBT DEC-CH2Cb 91 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/m9fi/01018 dichlorophenyl) Compound 3 was purified by flash chromatography on 400g of flash grade silica gel, eluting with 3 5 % NH3-MeOH/CH2Cl2 to give 24 8 g (44,2 mmol, 61 5 %) of pure compound 3 (Ar2 = 3,4-dichlorophenyl) FAB MS [M+1J+ 35CI 561 3 5 To a solution of compound 3 (Ar2= 3,4-dichlorophenyl) (16g, 28 49 mmol) in CH2CI2 (142 5 mL) at 0 °C was added 4N HCI-dioxane solution (71 24 mL, 284 9 mmol) through a dropping funnel The reaction was gradually warmed up to RT and stirred for 4h After completion the solvents were evaporated to give a light yellow solid which was dissolved in 10 H2O (400 mL) and brought to pH 10 with 1 N NaOH The product was extracted from basic aqueous solution with CH2Cl2(200mL, 4x), dned over MgS04, filtered and concentrated to give compound 4 (Ar2 = 3,4-dichlorophenyl) as a light yellow solid (12 5g, 27 09 mmol, 95%) FAB MS [M+1]+35 Cl 461 1 Compound 4 was the key intermediate which was used 15 to couple with various aromatic acid lor the synthesis of many compounds To a solution of compound 4 (Ar2 = 3,4-dichlorophenyl) (200 mg, 0 433 mmol) in CH2CI2 (5 mL) were sequentially added 4-fluoro-1-naphtholc acid (84 B mg, 0 433 mmol), HOBT (58 5 mg, 0 434 mmol), Et3N (0 634 mL, 0 455 mmol) and DEC (85 mg, 0 434 mmol) at RT The reaction 20 was stirred at RT under N 2 overnight After completion the reaction was diluted with EtOAc (150 mL) and washed with brine (50 mL, 3x), dried over MgS04, filtered and concentrated to give a crude product 5 (Ar2 = 3,4-dichlorophenyl, AH « 4-fluoro-1-naphthyl) which was punfied by flash chromatography ( 50 g Hash grade silica gel), eluting with 4% sat'd NH3-25 MeOH in CK2CI2 to give pure compound 5 Fab Mass [M+1]+ 35ci 633 2, m p 78-81 °C EXAMPLE 39 The following compounds were prepared according to the 30 procedures descnbed in Example 38 The key intermediate compound 4 (Ar2« 3,4-dichlorophenyl) was coupled with the appropnate aromatic acid to obtain the target compounds Those compounds without melting points were prepared via parallel synthesis 92 Mimosa V2-05-00 07/21/1998 12 15 57 page </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 97/08166 PCT/1B96/0101H FAB and/or Cl MS[M+1]+ 35CI MP °C <xa_ Cl Cl 634 / 636 (M+1)+ for (4xa5Ci)/(3xa5CI+1x37CI) Cl Cl 655 1 70-73 o-c 0" u N(CH3)2 Cl Cl Calcd lor Cart-UiNsOzCk • 3 HCI • 3 HzO 65B C, 54 06, H, 6 13, N, B 52 Found C, 54 28, H, 6 23, N,B 77 made pure from chiral enantiomer B intermediate 4 analogous lo Example 38 Calcd ,or C»H31 NSOzCU • 2 HCI • 2 H2O OvrO" 614 C, 48 41, H, 5 01, N, 9 41 Cl Found C,4616, H, 5 41. N. 9 30 a ci made purelrom chiral enantiomer B intermediate 4 analogous to Example 38 5 10 93 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/1B96/01018 WHAT IS CLAIMED IS A compound of the formula: each X is independently, O, (H,H), NRd, or S, n Is 0 to 2, u is 0 to 2,1 is 0 to 2, m is 1, and y is 1 to 3, or m Is 2, and y is 0, and with the further proviso that no more than one Rc Is other than H in the 10 moiety, each Rc is independently H, Ci-Cb alkyl, where m Is 1 to 6, Rd is independently selected from the group consisting of H, Ci -C6 alkyl, CN,ORa, phenyl, substituted phenyl, benzyl, substituted benzyl, or allyl, 15 94 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/JH96/01018 •n; R4 is -ORa. SRa ~f=w f'^L 0 Ra \ II I Rb —C—N-Rb I '0Rn ,-CN, o 11 -O—C-Ra O Ra Rb O II l l II -O-C— N-Rb nf -N-C-ORa * or Rc' is H, C1-C6 a'kyl or (CH2)nORa, with the proviso that no more than one R^ is otherthan H, each Ra and Rb is independently selected from the group consisting of H, Ci -Cb a,kyl. phenyl, substituted phenyl, benzyl, substituted benzyl, Rb 0 1 11 10 allyl, with the proviso that when R4 is N~c~0Ra, Ra isnot H, orwhen Ra and Rb are attached to the same nitrogen, then Ra and Rb tog ether with the nitrogen to which they are attached, form a 4 to 7 member nng, wherein each R1 and R2 is independently H, C1-C6 alkyl, CF3, 15 o ii o II C2F5. Cl, Br, I, F, N02> ORa, CN, NRaRb, —C-Ra , c-* , O Ra Rb O Ra 0 O ORa II I I II I II II II I —0-—C-N—Rb -N-C-ORa —N-C-Rb — C-ORa —C—N-Rb i V ' ' s Ra f S R, > .SRgi and —S —NHRa ^ ^ Rg |g ^ H O O 0 Rb O II ^ // I II ■ ~S—Rq -S—Ra _r —N-C-ORa in 1 1 or 95 Mimosa V2-05-00 07/21/1998 12 15 57 page wo 97/08166 i'ct/ibqfi/olols or when Ri and R2 aro on adjacent carbons on a nng, they can form rf 0 wherein n'is 1 or 2; and each R3 is independently H, Ci-Ce alkyl, CFa, C2F5, c""Ba , 0 ^ 5 "O c^Ra ( C N~Rb CI.BrJ, F,ORa, OCF3, or phenyl, An is heteroaryl or substituted heteroaryl, Ri 10 or QisNorCH, af2 is heteroaryl or substituted heteroaryl; J ■Ra 15 ,Ri V\ Rj •R, ■R2 •r3 or 96 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/ORlfif. PCT/nm/oiois Zls •X!> .A, mi = 0-1; tt»2 = 1-2, n3 is 0-4, 10 Rg is -ORa with the proviso that Ra is not H, aryl, aubstituted aryl, heteroaryl, substituted heteroaryl, -NRaRb, -0-(CRa,R|))n?-aryl, -O-(CRa,Rt,)n7-substiluted aryl, -0-(GRa,Rb)n7-heteroaryl, »0-(CRa.Rb)n7-substttuted heteroaryl ,-NRa-(CR„Rb)n7-heteroaryl, -NRa-(CR„Rb)n7 substituted hetoroaryl, -0-(CR»,Rb)n7-hete.rocyclo3.lkyll -0-(CRa,Rt))n7-15 substituted heterocycloalkyi, -NRa-(CR»,Rb)ri7-aryl, -NRa-tCRa.ReW- 97 Mimosa V2-05-00 07/21/1998 12 15 57 page $ WO 97/0816(1 Pn7IJI%/i)l018 10 substituted aryl, .NRa-(CRa,Rb)n7-helorocycloalkyl, -NRa-(CRa,Rb)nr substituted heterocycloalkyi; ny Is 0 to 4; each Re and R( Is Independently selected from the group consisting of H, CrCe alkyl, phenyl, substituted phenyl, bonzyl, substituted benzyl, allyl, or Re and Ri taken together with the carbon to which they are attached can also form a carbonyl group with the proviso that no more than one carbonyl ns is 1 to 2, each Rs is independently selected from the group consisting of H, OH, o II c""Ra , CvCe alkyl, (CH2)m Ra, wherein n^ is 1 to 6 with tho proviso that when m Is 1, R4 is not OH or NRaRb. also with the proviso that when n5 is 2, R5 Is CvCe alkyl and two R5 can be attached to the nitrogen to form a quaternary salt Rg Is H, C1-C6 alkyl, Ca-Ce cycloalkyl, moiety, >a 98 Mimosa V2-05-00 07/21/1998 12 15 57 page e I'Cl/IUWltlOlB wherein Xa is (H,H), O, NR<j, or S, or Re is heteroaryl, substituted heteroaryl, hctorocycloalkyl, substituted heterocycloalkyi when na is 0-4, 5 when Re.Rf taken together with the carbon atom to which they are attached form a carbonyl group and na Is 1, Re can also bo -ORa wherein Ra is not H, or Rs Is -NRa,Rb, -0(CRa,Rb)nrheleroaryl, -0-(CRa,Rb)n7-substituted heteroaryl, -0-(CRa,Rb)n7 heterocycloalkyi, -Q-(CR0,Rb)n7-3ubstituted heterocycloalkyi, -O (CRa,Rb)nr8f/l, -0-(CRa,Rb)n7-substituted aryl, 10 -NRa-(CRa,RD)n7-heteroaryl, -NR^-(CRa,Rb)n7 substituted heteroaryl, -NRa-(CRa,Rb)n7-aryl, -NRa-(CRa,Rb)n7 substituted aryl, -NRa-(CRaiRb)n7-heterocycloalkyi, -NRa (CRa,Rb)nr5ubstituted heterocycloalkyi, wherein Ra and Rb are each independently selected Irom the group consisting of H andCrC6 alkyl, 15 or any enantiomer thereof, or a pharmaceutioally acceptable salt thereof 2 A compound according to claim 1, wherein m Is 1, both X"s are 0,1 is 0, n is 1, u is 0, and y is 1 to 3, 20 and An is 99 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/IB96/01018 R| -6c* q^R2 Rj <?> wherein Q is N orCH, 5 each Xi is independently O, S or NRa, each X2 is independently CH or N; and n4 is 0 or 1, or and wherein Ar2 is 10 K) t Rl v Q. -My ? X,-\ ^ -V n*\ I R2 k «3 or 100 Mimosa V2-05-00 07/21/1998 12 15 57 page W0 97/081GG PCT/IB96/01018 3. A compound acxording to claim 2 wherein 2 Is L2 I \ Rs n3 4. A compound according to claim 2 wherein 2 is 1), 5 A compound according to claim 2 wherein Z is 10 Ra 0 ~\ N H 101 Mimosa V2-05-00 07/21/1998 12 15 57 page rn*—* ^ ^ ® vi I' ' I u '< - ) 6 A compound according to claim 1 wherein Re and Rf are independently selected from the group consisting of H, C1-C6 alkyl and allyl, ri3 is 0-4, n7 is 0 to 4, and R6 is CrC6 alkyl | or \—cycloalkyl , • ? ? or wherein Re and Rf, taken together with the carbon to which they are attached, form a carbonyl group, n3 is 1 and R6 is -ORa, wherein Ra is not H, or -0-(CRa,Rb)n7-L, wherein L is c RtQ-^ _ , Ri R3V= >—(J. y 3 £ r-^r^-R^ t. r_O-<V S 3 > f'X If H3 S R xi • HxK or WO 97/08166 PCT/IB96/01018 - V or wherein Re and Rf, taken together with the carbon to which they are attached, form a carbonyl group, n3 is 1 and R6 is -NRaRb or -NH-(CRa,Rb)n7-L, wherein L is RrQ!LR —(j, ,H3 X, Ri •\V^R, X or Rqv or wherein Re and Rf, taken together with the carbon to which they are attached, form a carbonyl group, n3 is 1 and R6 is c, S R3 ri. * r3 M ) O-j-Cg alkyl N \ r2 or ?— ,°/n. cycloalkyl 10 7 A compound according to claim 1 of formula II 103 INTELLECTUAL PROPERTY OFFICE OF NZ 1 h sep 1999 received WO 97/08166 PCT/1B96/01018 •N Ar i At2 wherein Rc is H; mi is 0 or 1, y Is 1-3, Ari and Ar2 are both yR| -C4- r3 J 'R> 8. A compound according to claim 4 of the formula o Rc r\-\ X. N N ^ y ' 10 wherein Ari and Ar2 are both 104 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 ITT/1B96/01018 9 A compound according to claim 1 of the formula 10 wherein Ari and Ar2 are both /Rl —L. rj r2 r3 Rc /"K \ N N Xr \ / Ar, m 10 A compound according to claim 1 selected from the group consisting of 15 105 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCT/11196/01018 Cl Cl pHa » CH3 "*\A A O -°/=<CH3 Cl Cl ,CH3 Cl Cl o /^N-^Vn^0°H3 0-^n A*"*^ 0 Cl a ch3 ch3 OV^B's^pa<^ h,C.nA^^nSL^ O^n^7« yx. Q ch3 ci ci ci' ci or any enantiomer thereof, or a pharmaceutical^ acceptable salt thereof 11 A compound selected from the group consisting of 106 Mimosa V2-05-00 07/21/1998 12 15 57 page 107 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/(18166 rnyiiwfi/oiois ci ci ci ci Ao"-: H O /—t. 0 N„>-N N-\, CH3 Cl Cl NsN CHa ca a 108 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/0H166 rcT/iniG/oioiH 109 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 rci/i»%/oioi8 0"0-n-%>kr ..rf" o n CH3 , o^d-B^k>^ .R Cl Cl o _ o —^CHa CH3 ci Cl Cl Cl O __PH3 r ch3 CHa O .CHa OvXy"^""^ O 0 P"k h~mx> 0 -3, Cl CI Cl Cl r" ff H, Cl Cl o-vQ" 110 Mimosa V2-05-00 07/21/1998 12 15 57 page SVO 97/(181(16 lTT/imfi/OIOIK 111 Mimosa V2-05-00 07/21/1998 12 15 57 page WO 97/08166 PCr/IB%/01018 or any enantiomer thereof, or a pharmaceutical^ acceptable salt thereof 12 A composition comprising a neurokinin antagonistic effective amount of a compound according to claim 1 and a pharmaceutical^ acceptable earner material 13 Use of a compound according to claim 1 in the preparation of a medicament for inducing neurokinin antagonism in a mammal in need thereof 14 Use of a compound according to claim 1 in the preparation of a medicament for treating chronic airway diseases such as asthma and allergies, inflammatory diseases such as inflammatory bowel disease, psoriasis, fibroses, osteoarthritis, and rheumatoid arthritis, migraine, central nervous system disorders such as depression, psychosis, dementia, and Alzheimer's disease, Down's syndrome, neuropathy, multiple sclerosis, ophthalmic disorders, conjunctivitis, auto immune disorders, graft rejection, systemic lupus erythematosus, GI disorders such as Crohn's disease and ulcerative colitis, disorders of bladder function, circulatory disorders such as angina, Raynaud's disease, coughing and pain 15 A compound of the formula I as defined in claim 1 or any enantiomer or pharmaceutical^ acceptable sal' thereof substantially as herein described with reference to any example thereof 16 A compound as claimed in claim 11 or any enantiomer or pharmaceutical^ acceptable salt thereof substantially as herein described with reference to any example thereof INTELLECTUAL PROPERTY OFFICE OF NZ 1 4 sep 1999 _ received 17 A composition as claimed in claim 12 substantially as herein described with reference to any example thereof 18 use as claimed in claim 13 for inducing neurokinin antagonism substantially as herein described with reference to any example thereof 19 use as claimed in claim 14 for treating chronic airway disease substantially as herein described with reference to any example thereof \ END OF CLAIMS 113 ["iwtUtCTUAL PROPERTY OFFICE! OF NZ J 1 4 sep 1399 i RECEIVED J </div>