CA2205586A1 - Certain substituted 1-aryl-3-piperazin-1'-yl propanones - Google Patents
Certain substituted 1-aryl-3-piperazin-1'-yl propanonesInfo
- Publication number
- CA2205586A1 CA2205586A1 CA 2205586 CA2205586A CA2205586A1 CA 2205586 A1 CA2205586 A1 CA 2205586A1 CA 2205586 CA2205586 CA 2205586 CA 2205586 A CA2205586 A CA 2205586A CA 2205586 A1 CA2205586 A1 CA 2205586A1
- Authority
- CA
- Canada
- Prior art keywords
- piperazinyl
- hydrogen
- benzyl
- loweralkyl
- propanone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Abstract
Disclosed are compounds of formula (I), wherein X is a carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl; Z is nitrogen or CH; Ar1 and Ar2 independently represent aryl groups; and Y is hydrogen; or Y and R1 or R2 together represent CH2; CH2CH2; CH20; CH2S forming a five or six membered ring and such ring may be optionally substituted with loweralkyl or phenyl; or the pharmaceutically acceptable salts thereof, useful in the treatment of neoplastic diseases, and bacterial or fungal infections, and in preventing or decreasing the production of abnormally phosphorylated paired helical filament (PHF) epitopes associated with Alzheimer's Disease and, therefor, useful for treating Alzheimer's Disease.
Description
2 PCr/US95/14987 CERTAIN SUBSTITUTED l-ARYL-3-PIPERAZIN-l'-YL PROPANONES
BAC~GROUND OF THE INVENTION
l. Field of the Invention This invention relates to substituted l-aryl-3-piperazin- l'-yl prop~nones and 1-arvl-3-piperidin-1'-yl propanones. These coll,pou.lds are useful in the l,~ t of Al7hr.imL~r's Disease, neopl~stic disease, and ba~t~ or fungal i~ cli 2. Description of the R~l~t~ Art 0 Al7hrimer's Disease is a progressive neurodegenerative disorder affecting 7% of the population over 65 years of age and characterized clinically by progressive loss of intel1~ctu~l function. This in,pai"l.ent of function is caused by the presence of neuri~ic plaques in the ne~co l~.~ and the loss of ~l~sy~la~Llc m~l~cl~~cholinergic neurons. Neuritic plaques are composed of degcn~ lg axons and nerve terrnin~lc~ often surrounding an amyloid core and I5 usually containing reactive glial elements. Another characteristic pathologic feature of ~l7heimer's Disease is the neurofibrillary tangle, which is an intraneuronal mass which C~ ,o,lds to an accum~ tiQn of abnormally phosphorylated tau protein polymerized into fibrillar structures termed paired helical hl~m~onrs In addition, the neurofibrillary ~angle also contains highly phosphorylated neurofii~mrnt proteins. Even the earliest papers on .A17~ 'S
20 Disease were clear that both "senile" plaques and neurofibrillary tangles had to be present in ablln-i~nr,e to allow a post-mortem diagnosis of the disease. Before any un~iersr:~n~i;ng of the molecular nature of these ~LIuClul~;S was obtained, efforts were being made to understand the relationship ~el~n the ~lulllb~ of these lesions and the progression or severity of the ~lemrrln~
expr ienre~ by the patient. The limit~ion.c of silver staining were such that early workers in this 25 field were unable to appreciate the complexity of these abnormal ~illU~;IulGs (Ball, MJ, Neurobiol.
of Aging, 8: 564-565, I987). Although early at~G,llpls to correlate pathologic lesion counts with clinical S~ (JIlls generally yielded poor results, it was clear that the inri~lenre of lar_e llulll~ls of both type lesions were invariably associated with ~iemen~ia (Perry et al. J. ~eural Transmission, 24: 131-136, 1987; Alafuzoff, I., Acta Neuropath, 74: 209-225, 1987;
SUBSTlTUtE SHEET (RULE 26) CA 0220~86 1997-0~-16 Wll;~ ho"se et al, Prog. Clin. Biol. Res., 317: 131-142, 1989; Tomlincon~ NeuloyaLllol. Appl.
Neurobiol, 15: 491-512, 1989).
More recent work has allowed a clearer clefinition of the nature of the lesions stained by silver salts. "Senile" plaques are actually two distinct types of ~Llu-;LulcS. the cl~ccic~l plaques S described by Al7heimçr being composed of degenerating neuronal elements (neurites) ~ulluundillg a central core of amyloid, while the other so-called "diffuse" or "pli~lliLivc" plaque is usually a deposit of amyloid without a halo of de~ ;,.g neurites (Tagliavini,, et al, Neurosci.
Lett., 93, 191-196, 1988; Dickson, DW, et al, Am. J. Path., 132, 86-101, 1988). These ~Llu~_lul~,s are liffie-llt to ~ictin~llich from each other with silver stains or with the widely used 10 nuor~,scc.,L dye, thioflavin S. Early attempts, using silver staining, at correlations bCL..~,.,ll plaque number and extent of ~1~ .. l ;~ as well as some more recent studies using thioflavin S, were flawed by this inability to define what type of plaque was being counted (Hansen, LA, et al, Neurology, 38, 48-54, 1988; ~t7.m~n, R, et al, Ann. Neurol., 23, 138-144, 1988). This bcco.l..,s very obvious in recent studies, which have corlcictently l~polL~d that amyloid plaques 15 can be found in large nu~ in the brains of the lllaJol;Ly of the very elderly (over 80 years), and are only rarely ~ccoci~ted with clem~nti~ when present without evidence of de~ul .a~il,g n~lritç5 (Davies, L, et al, Neurology, 38, 1688-1693, 1988; Delaere, P, et al, Nc~lusci. Lett., 116, 87-93, 1990; Dickson, DW, et al, Neurobiol. Aging, 13, 179-189, 1991).
The counting of neurofibrillary tangles also fails to give an ~cur~t~ picture of the extent 20 of neurofibrillary degeneration. Again, the presence of large numbers of tangles is invariably associated with a profound dçmtonti~, and some index of disease severity can be gained from tangle counts (Tomlinson, BE, Neul~palllol. Appl. Neurobiol., 15, 491-512, 1989; Delaere, P, et al, Acta Ne~l,u~atll., 77, 645-653, 1989). Electron mi~luscuy~ first revealed that tangles were cc.lll~osed of masses of paired helical fil~m~-,nt~ (PHF) filling the cytoplasm of neurons (Terry, 25 RD, et al, pages 145-155, In CIBA Fol-n~tion Symposium on ~ c;ll~'s Disease and Related Con-1ition~ Ed. by Wolstenholme, GEW, O'Conner, M, J and A Churchill, London, 1970).
These studies also clearly showed that degenerating neurites also co-,lai-,cd PHF, a fact only widely appreciated much later, when the use of antibodies to PHF became common (Wolozin, BL, et al, Sciçnre, 232, 648-650, 1986). Thus, both the plaques and the tangles of Al~ c 's SUBSTITUTE SHE-tT (RULE 26) Disease contain PHF. The use of antibodies to PHF also revealed the widespread presence of these paired helical fil~mentc in neuronal processes (Brun, A, Prog. Clin. Biol. Res., 317, 285-293, 1989~. Thus, the presence of PHF is much more widespread than was first s~lcpecte,l and is today concidered to be an infliratinn of a widespread neuronal disease, of which the neuritic 5 plaque and the neurr~fibrill~ry tangle are only the most obvious signs (McKee, AC, et al, Ann.
Neurol., 30, 156-165, 1991). It has been ectim~ted that as much ~s 90% of the PHF in the cortex of the average ~l,l.e~ . case is present in neuronal ~ ce,sses r~ther than in the plaque or tangle (Wolozin, BL, Ann. Neurol., 22, 521-526, 1987). Much of the early and indeed the present confusion with regard to ~ gnosic and severity of ~17~ f ~ 'S Disease comes from the 10 failure to a~l, ciale the complexity of the pathology in this disease. ~Ithough the oc~ tnce of si~ni~r~nt ~ 0~ of PHF in the brain is always ~cso~ tr~ with severe Citl,.f -,l;~ (Hyman, BT, Current Opinions in Neurology and Neurosurgery, S, 88-93, 1992). These results suggest that good coll~laLions can be obtailled bcL~ I the conce ~ JII of PHF proteins (COIllf.l;ll~f S referred to as ,A~ e;--~"'S Disease ~ccoci~d Proteins or ADAP) in the cerebr31 cortex and the degree of 5 tl~ n~;~ measured prior to the death of the patient (Gh~nb~ i, HA~ et al, JAMA, 263, 2907-2910, 1990).
It is noted that the terminology used to describe the abnormal protein complexescGIll~)osing the fibrillar pathology in Alzheimer's Disease can be confusing. PHF is a morphological Aecign~ti~n, describing abnormal fil~ment.c found in neurofihrill~ry tangles. An '~0 abnormal protein species migr~tinP at 68 kDa, elc~,llopho.cucally, and observed on immlmt blots of tissue from AD brains was termed A68 (Wolozin, B, et al, Science,232, 648-650, 1986). A
protein complex shown to be specific for AD by immnnochemical analyses was design~t~7 ~l~h~im~r~s Disease ~coci~le~l Protein or by the acronym, ADAP (Ghanbari, HA, et al, JAMA, 263, 2907-2910, 1990). It is now known that A68 and ADAP, when viewed by the electron r 2~ microscope, are PHFs. These PHFs have been further shown to contain, primarily, the microtubule-~ccoci~rt~(l protein, tau. Hence, the terms A68, ADAP, PHF and PHF-tau are often used int~l~h~l-ge~hly. Thus, they are meant to be interch~n~l~ herein.
A series of important studies have suggested that the progression of ~l7h~im~r's Disease can be defined pathologically by careful n~ulu~n~lo~ studies of large nU~11~1S of brains from SUBSTITUTE SHEET (RlJLE 26) WO 96/160~2 PCT/US95114987 elderly hl1m~ns, (Braak, H, et al, Neurosci. Lett., 103, 24-28, 1989; Braak, H, et al, Ntulu~alh. and Applied Neurobiol., lS, 13-26, 1989; Braak, H, et al, Acta Nc.llupdlll., 82, 239-259, 1991; Braak, H, et al, European Neurology, 33, 403-408, 1993). The Braak's focus is almost entirely on the dc~, elu~ ,l of neurofihnll~ry pathology, which begins in the ~ ,. h; . .~l S cortex perhaps years before the clinical signs of the disease are app~cnt. The progression of A~ F ;~ 'S Disease is thought to be soll~ l,at unllc~ , in the sense that the disease ~ ,a3eS
by the involvement of more and more neurons in the formation of PHF, in an ~n~tomic sequence which is to some extent pre~iirt~hl~. In the initial stages, only those neurons of the ~ \lo,~
cortex contain PHF, in latçr stages, neurons of the CA1 and CA2 pyramidal layer of the 10 hippocampus contain these StluCLul~,S, and still later, neurons of the ~ccoci~tinn cortex begin to show evidence of PHF forrnation. Clearly, pl~,.lLion of PHF formation even after the process is underway in the hippocampus could limit the disease to this brain region, at which point clinical problems are co, r; r~ to some loss of short terrn Ill~.llul y. Patients first seek help at a stage when PHF pathology is largely limited to the l~i~oc~ll~us (Berg, L, et al, pages 9-25, in 15 Al,l.~ 's Disease, Eds., Terry, RD; K~r7rn~n, R; Bick, Kl. Raven Press, New York, 1994).
To prevent the pr~ ion of ~l7l.. ~ 's Disease at this point would clearly be a major benefit to the patient (Davies, P, pages 327-334, in Al,l.- ;...- 's Disease, Eds., Terry, RD; ~t7m~n, R;
Bick, KL. Raven Press, New York, 1994; Kh~rh~tllri~n ZS, et al, pages 445-454, in ,,'s Disease, Eds., Terry, RD: K~t7m~n, R; Bick, KL. Raven Press, New York, 1994).
Attempts to cl~lr-.,.. ;n~ the mol~ocul~r nature of the PHF were h~~ lc;d at first by an approach which attempted to purify PHF from isolated neurofibrillary tangles. Once h~cc,l~ulaL~d into the llla ;lulllolecular CO~1CA that is the tangle, PHFs become eAI-~.llely difficult to soll-bili7.o for protein analysis. The microtubule-acsoci~t~ protein tau appears to be a major ~nri~eniC c~ n~llt of PHF. The repeat region of microtubule-~c~oci~ 1 protein tau forms part 25 of the core of the paired helical fil~m~nt of ~I,l.. ;...-, 's Disease (Goedert, M, et al, Proc. Nat'l.
Acad. Sci., 8S, 4051-4055, 1988; Wischik, CM, et al, Proc. Nat'l. Acad. Sci., 85, 4506-4510, 1988).
The involvement of prolein phosphorylation in the fr)rm~tion of PHF has been su~esteA
by a variety of studies which have shown that tau in PHF is hy~ hf ~l~hs~ ylated (Kosik, KS, et SUBSTITUTE SHEET (RULE 26) WO 96116052 PCT/US95tl4987 al, Ann. Med., 21, 109-112, 1989; Goedert, M, Trends in Neuroscienres~ 16, 460-465, 1993;
Iqbal, K, et al, Act Neurobiologiae E~ t,.li!c~ 53, 325-335, 1993). There is su~ h,~, evidence that several other ~rolcins, especi~lly neurofil~mrntc and other ll.icluL-~L ule ~soci~trd proteins (MAPs) are also hy~ ho ,~hr~ylat~d in the brains of patients with ~1,1.~ IIIF~- 's Disease .~ S (Lovestone, S, et al, Current Opinions in Neurology and ~ u:,ul~,.,,y, S, 883-888, 1992).
In 1985, a monoclonal antibody ALZ50 was raised (produced by hybridoma cell lineATCC No. HB9205) that recognized a 68 kDa polypeptide (termed A68) in imm--nnb1Ots of the vulnerable brain regions in AD, but not in control brains, (Wolozin, B, et al, Science,232, 648-650, 1986). T.. nohi~loc~ .. ;r~l analysis with this anti'oody in~'ir~.rçd an intense reaction with 10 neurofibrill~ry tangles and. in later cA~ illJ~nls, with the PHF's, as well. The discovery of A68 was the first report of a bioçhrmically ~ ...i.,e~ abnormal protein species ~ccoci~t~fl with the fibrillar pathology in AD.
In o~her iaboratories in 198~5, monoc~onal and polyclonal antibodies recognizing the microtubule-associated protein, tau, were shown to react with neurofibrillary tangles, and 15 subsequently, with PHFs (Grundke-Iqbal, I, et al, Proc. Nat'l,. Acad. Sci., 83, 4913-4917, 1986; Kosik, KS, et al, Proc. Nat'l. Acad. Sci., 83, 4044-4048, 1986). Furthermore, biocl....,;~l analyses of the ~lutGase-resistant "core" of the PHF d~ oll~L,attd the ~lesencG of peptides cont~ining the tau selluence, (Goedert, M, et al, Proc. Nat'l. Acad. Sci., 85, 4051-4055, 1988; Wischik, CM, et al. Proc. Nat'l. Acad. Sci., 85, 4506-4510, 1988). ~cldition~lly~
20 monoclonal antibodies, whose epiLol,eS sp~nnr-l the tau molecule, all were shown to react with neurofibrillary tangles in AD brain (Kosik, KS, et al, Neuron, 1, 817-825, 1988). Much later, it was ~letermin~l that the ALZ50 antibody reacts with the e~ cllle amino terrninus of the tau mrJlecllle (Goedert, M, et al, Neurosciçnr,e Letters, 126, 149-154, 1991).
In 1990, in an attempt to purify A68, a more readily soluble ~ Ou~lion of PHFs was 25 isolated (Greenberg, S and Davies, P, Proc. Nat'l. Acad. Sci., 87, 5827-5831, I990).
Tmml~nnblots of these ~,~uclulcs in~ir~tçd that three closely migrating cleclluyhulclic species, the slowest migrating of which was ca. 68 kDa in size, all reacted with ALZ50 and tau antibodies (Lee, V, et al, Science, 251, 675-678, 1991). This in~ic~tç~l that the A68 complex of proteins SUBSTITUTE Sl IEET (RULE 26) WO 96~16052 PCT/US95/14987 is, to a large extent, coll.yo3ed of the tau protein. This polymerized form of tau was shown over the years to be in a hyy~hn~l~horylated state.
Other monoçlon~l antibodies raised against human PHF l,l~aldlions are the antibodies PHF-1 and TG3. While these antibodies display robust affinity for paired helical fil~m~-5 ~ alalions~ they only have trace l-,aclivily towards normal adult tau. Further studies revealed that the mo~oclon~l antibody PHF-1 has a reduced affinity for PHF which has been treated with alkaline phosphatase or hy~LunLIulic acid, thereby suggesting that this antibodv recognized a ph~spl.o.ylat.,d epitope(s) in paired helical fil~m~n-c These pho~yllolylated ~,piluyCS (recogniæd by PHF-1) reside within the C-tçrTnin~l fragment of the tau protein, at serine 396 and 404 10 (Trojanowski, J.Q., et al, Clin. Neurosci., 1, 184-191, 1993). The epitope(s) l~cûg-li~cd by TG3 has not been mapped yet.
To date, it has not been possible to c ?ncictently induce the fo~nation of ~l71,f ;."f -like e~iluyes either in vivo or in vitro. Hence~ there is a need for an assay for the ric~r , l l;l~ on of tau protein, paired helical fil~mf ntc and ..,fcl-~-;cmc involved with ~17hçimf r's Disease. There is 15 further a need for an assay suitable for S~ ling for drugs which may prevent or decrease Al,l.~ . 's Disease activity.
SUBSTITUTE SHEET (RULE 26) SUMMARY OF THE INVENTION
The co~ -ds of this invention and an al,Lil yscl~otic agent, chlo~ r are active in an assay indicative of the potential of certain drugs to inhibit a h:~llm~rk trait of ~ 's Disease. Further, chlol~ e is shown herein to be capable of treating and/or preventing 5 ~l7hçim~r~s Disease. Const.lu~ iy~ the compounds of this invention are useful for treating and/or ~.c~".Lillg the disease.
The human neurobl~ctom~ MSNla cell line G~ 5CS the plvt~;ns known to be involvedin PHF formation (inclllfling tau, other MAPs and neurofil~mf nt plc,Le;~,s, and thus is a cell line in which ~l7llf ;...l 's Disease e~iLo~e,s can be G~ ,ssGd. (Arias et al, J. Ne.,-~he,ll., 61: 673-10 682, 1993; Vincent et al, J. Nc.~ ., 62: 715-723, 1994).
Immunohistochemi~ ~l st~inin~ of brains from normal and Alzheimer's Disease (AD)patients using the monoclonal antibodies PHF-1 and TG3 inrii~pr~s that these monoclonal antibodies specificallv stain c~ of AD brain, but not normal brain (hgure 1). C`onrlitions were est~klich~od which led to hyperphosphorylation of the proteins known to be involved in 15 PHF formation. Using monoclonal antibodies PHF-1 and TG3 generated to human PHF
aldtions, the effects of a variety of manipulations of the pho5phorylation state of these proteins were tested. These tests c~luilcd that most of the aLncl ,lldl c~ilo~es l~,co~ cd by these monoclonal antibodies in the human ~l7h~imer brain should be gcll~ tcd in the MSNla cells.
The llc~ nr of MSNla cells with okadaic acid and other selecte~ inhibitors of protein 20 phosphatases has been found to generate the epitopes associated with these ~l~h~im~:r brain specifi. monoslona! antibodies, thereby meeti;.g, the re4ui~cil.c.its described above. These e~i~s are either absent or present at a very low level in ~Illllc~Lt~d MSNla cells.
The AD specifi~ity of the PHF-l and TG3 ~ntiho~ s was also demonstrated using anELISA assay. Shown in Figure 2A are bar graphs (percent of AD) of the ELISA
25 immllnoreactivity of brain plc~dlions (AD or normal) to either PHF-1 or TG3. Shown in Figure 2B are bar graphs (percent of MSN+) of the ELISA immnnoreactivity of MSNla cell Jaldlions (minus or plus okadaic acid) to either PHF- 1 or TG3. The MSNla cell ~ ~dlions plus vs minus okadaic acid closely parallel the AD vs normal brain l,lep~ ;o~c This clearly shows the relationship belv~ecn disease pathology (i.e. AD brain) and what is recognized by the SUBSTITUTE SHEET (RULE 26) CA 0220~x6 1997-0~-16 WO 96116052 PcrluS95/14987 antibodies in the MSNla in vilro cell culture assay. The cell culture system according to the LiOIl in which ~.p;~f,S C~ af`~ tiC of PHF can be readily ge~ tf -i and sul: s~ y l~eeo~ i by the specific ~1~1.. ;,.... brain specifie antibodies provides an assay suitable for screening cu~ oullds for their ability to block the ~luJI~ l;ol. of these pi~osL.hfj ylated c~itupcs.
PHF tau protein has lower affinity for microtubules as colllpdlcid to normal tau protein, which is likely the result of the abnf)rm~l pho~ .ulylatiûn (Lindwall et al, J. Biol. Chem., 259:
5301-5305, 1984). As a co..se~l~le..ce, microtubule ~lest~kili7~tion occurs which i~telr~..,s with illll,c,lia.ll neuronal ~lucesses such as rapid axonal Llansl,uli and, subsequently, this process leads to the follllaLiol. of PHF and the neurofibrillary tangles (Bancher, et al, Brain Res., 477, 10 90-99, 1989). Thus, inhibition of the ~ iul,l;on of the abnorrnal phosphorylated PHF f~)iL~)e S
will i~ .r~.e with and/or prevent the fO..l-atioll of PHF. Since PHF formation is a major feature of 1~ f l pathology, the development of co~ ol"~ds that intu.rcl~ with all or part of this process inhibit or prevent the ~lu~ ion of this disease.
The invention provides co-l-yuul-ds of formula I:
O
Ar~ N ~~
Y R24 ~ Z~ X~ Ar2 I
or the l,h~ e~ ;c~lly ~cceptA hle salts thereof wherein X is a c~ L~nyl, sulfonyl, methylene, or methylene ~ ,sl ;l l l~. cl with optionally snh~l ;n ~l-,d phenyl; and Z is nitrogen or C~I; and Arl and Ar2 in~rp~.,Ae.~tly ~ylcis~n~ aryl groups; and R24 is hydrogen; or when Y is other than hydrogen, R24 is hydrogen, loweralkyl, or optionally ~ l;nllrA phenyl; and Y is hydrogen, or Y and a substit~Pnt on the Arl group togethem~l~sellt a CH2.
CH2CH2, CH20, or CH2S group to form a five or six l-~-.-~.~d ring where the ring is optionally slll~ llrA with loweralkyl orphenyl.
SUBSTITUTE SHEET (RULE 26) , These co~ )(,ullds are useful for treating ~l7heimçrs Disease neoplastic disease and bat~teri~1 or fungal infections. Thus these coll,~ou,lds are antilleoplastic. ~nrihacterial. and 5 ~ntifim~l agents.
The coll",~)u"ds of this invention by preventing or decreasing the production ofah.l.~. ",~11y phnspht. ~ldl~d paired helical fil~mt m e~ u~es ~csoçi~rt t1 with the prot1l~ctin~l of the neurofibri11~ry tangles, a cl,a. .r~ ;r pathological feature of ~l,l.- h..~ s Disease. are useful in the Ll~ of this n~ cleg~ .- alive t1i~nrt1er.
The colll~ullds of forrnula I inhibit and/or prevent the formation of abnornallyphosphorylated epi~opes on PHF tau. Through inhibitory il~L~ ~acLions of the phosphorvlation events associated with the forrnation of PHF tau and other proteins involved in PHF ~",~I;Ol"
one can rno~ te the ~çmhly of tnicrotubules, thereby affecting neuronal processes such as rapid axonal transport, thus preventing the forrnation of PHF and the production of the 15 neurofih ill~ry tangles. Thus, the co",~ou,~ds of the present invention are lhc. .~ 11y useful in various neurodeg.--.~ aLive disorders such as ~ ;".t~ s Disease. In ~t1tlition the com~ou"ds of the present invention are useful for the ll~allll nl of certain neoplastic ~ e~es. and can be used as ~nti~rt~ori~l and antifun~l agents.
Thus the invention provides m~oth xls of ~ e.i~ii,g and/or treating ~ s Disease 20 in a patient comprising ~ mini~tering to the patient a co",pou,.d of formula I in an amount effective to inhibit forrnation of ah,-- ",~11y ~ho~l,o,ylated paired helical fil~m~nt epitopes.
SUBSTITUTE SHEET (RULE 26) Wo 96/16052 PCT/US95/14987 BRIEF DESCRIPTION OF THE DRAWrNGS
Figures lA-lD are images produced by light miclùsco~,y showing immnnoh~ e...~
staining of brain tissue from normal ~l~heim~ s Disease patients with monoclon~l ~ntibo~lies PHF-l and TG3.
SFigure 2A is a graphic CO~ O.I of normal (Norm) and Al,l.P:..... 's Disease (AD) brain hu...ngf ~t.o. ;...~ ,acLiv-ity toward PHF-1 and TG3 antibodies ~I,~sscd as a percent of total AD ;~ a~;livity.
Figure 2B is a graphic cu---~ ;con of MSNla cell lysate (minus or plus okadaic acid) immllnoreactivity toward PHF-1 and TG3 antibodies expressed as a percent of total 10 ;~ U~ a~,livi~y in lysates of MSN+ okadaic acid.
Figure 3 is a western blot showing PHF-1 ;....... ~ ,.eactivity in Iysates from control and chloll,lo...~ trea~ed MSN cells treated with okadaic acid.
Figure 4A is a chart showing relative ADAP conc~.~udLions in Brodman Area 10 in 's Disease p~tient~, normal controls and patients treated with chlul~lo---~ (Rx).
Figure 4B is a chart showing relative ADAP col-~e.~dlions in Brodman Area 38 in .Al,l.~;...~ ~ 's Disease pati~ont~l normal controls and patients treated with chl~ 7;~
SUBSTITUTE SHEET (RULE 26) Wo 96/16052 PCT/US95/14987 DETAILED DESCRIPrION OF THE INVENTION
The invention provides colllyuu,lds of formula I or the pharm~eut~ y acceptable salts thereof wherein X ~ carbonyl, sulfonyl, methylene, or methylene ~ulJ~1 with optionally ~ul . 5 phenyl;
Z is ni~u~c.l or CH with the proviso that when Ar1 is phenyl or ~ phenyl Z is ni~UO_.l;
Arl is a group of the forrnula:
R2R~
wherein Rl, R2 and R3 in~epen~l~ntly ~y.~sent hydrogen, fluoro, iodo, phenyl, nitro, trifluoroaL~cyl, thioloweralkoxy, cyclohexyl, amino, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, alkylsulfonylamino, optionally substitllted phenylethynyl, 4~s-~ih~loimi~l~7ole~ optionally suhstitl-te(l phenoxy, optionally ~ d phenyl amino, optionally sul~ 1 phenyl~lfi~1e, provided that Rl, R2 and R3 are not all hydrogen; or two of R1, R2 and R3 taken together can form an ethvlenedioxy, ethyleneoxy, or a lower straight alkylene chain alkyl bridge of 3-5 atoms op~ionally ~lb~ cl by loweralkyl; or Rl, R2 and R3 are the same or dirr~.cl~- and lGyl~s~n~ a group of the fo~
l~N J~; or Ar1 is a group of the forrnula:
SUBSTITUTE SHEET (RULE 26 r\ S~ ~R2s R7~$
R23 R23 ~
R26_N~N~R R25 N)~N~ 50~--R 54--R
R23 /~ R23~ ~R23 R23~_R23 R23--~N3--~R23 ~f~ R28~ R2-~R23 R6~o R~
or ~0 wherein X2 is oxygen or sulfur;
Rs is hydrogen, halo, loweraL~cyl, loweraLIcoxy or thioloweraL~coxy;
R6 is hydrogen, halo, or lowera~cyl;
R7 is hydrogen, lowerakyl, halo, nitro, cyano, optionally substitl1t~ri thienyl, 5 optionally substitllteci phenyl, morpholino, piperidinyl, piperazinyl, optionally SUBSTITUTE SHEET (RULE 26) substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulÇonyl~ h~yl, or optionally sllhstitl~t~o~ phenylca~ lyl~ ,.~illyl, R8 is loweralkyl or phenyl;
Rg and Rlo are independently selecte~l from hydrogen, halo, loweralkoxy, f 5 IIYC1~VAY;
R14 is s~lect~ from hydrogen, loweralkyl, nitro or halo;
Rlg and R20 are intle~e fie..lly select~l from hydrogen, loweralkyl, halo, nitro, oroptionally ~.b~ d phenyl;
R 21 is hydrogen, loweralkyl, nitro, halo, cyano, thienyl, phenyl, or phenylethynyl;
R22 is hydrogen, C~U ;~I1~ hUAY~ optionally ~.lbsl ;l ~.lrd phenyl or loweralkyl;
R23 is hydrogen or loweralkyl;
R24 is hydrogen; or when Y is other than hy~ug~ll R24 is hydrogen, loweralkyl, or optionally ~ d phenyl;
R25 is hydrogen, loweralkyl or thio~lko,lcy;
R26 is loweralkyl, optionally substitutecl phenyl or optionally sllb~
phenylmethylenyl; and R27 is loweralkyl, optionally subsl;~ e~ phenyl or optionally sub~itulcd ph~.lylln~ ylenyl; and R28 is hydrogen, optionally substitute~ phenyl, loweralkyl, or optionally A .t.hieny!; ~nd R2g is hydrogen, nitro, or loweralkyl; and provided that R7, R14 and R2g are not all hydlugell; and providcd that R23 and R28 are not both hydrogen; and Ar2 is a group of the formula:
R
r ~Rl Z
~UBSTITUTE SHEET (~ULE 26) WO 96/16052 PCT/US95tl4987 where Rl 1 and R12 independently lc~ulcsent hydrogen, halo, trifluo~u,l~ yl, amino, nitro, cyano, acetyl, thioloweraLIcoxy, or loweralkyl;
or Rl 1 and R12 together form a methyl~ncdioxy or ethylen~~ yy bridge; or Ar2 is naphthyl, optionally su~stitntP~l thienyl, furyl, 1~2~3-thi~Ai~7olyl~ or a group of the S fn~m-lR
CF~ R4 wherein R4 illd~p.,.ldently lc~ scnts lly~gen, halo, or loweralkyl;
R13 is selected from hydrogen or halo; and Y is hydrogen, or Y and Rl, R2, R3, R1g, R20, R22, R23, or R2g together lc~l~se.lt CH2, C(R24)2cH27 C(R24)2o~ or C(R24)2S forming a five or six membered ring.
f~.l~ coll~.uul,ds of formula I are those where Arl is a group of the formula:
R1~,~
R2~J
wherein Rl, R2 and R3 in~epen~ently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweraL~coxy, cyclohexyl, amino, acetyl, morpholino, cyano, piperidinyl, trifluoroaL~oxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihak>imi~701e, optionally sl1bstitllt~rl phenoxy, optionallysubstit~ted phenylclllfi~le, provided that Rl, R2 and R3 are not all hydrogen; or SUBSTITUTE SHEET (RULE 26) two of Rl, R2 and R3 taken together can form an ethylenedioxy, ethyleneoxy, or a lower straight alkylene chain aLkyl bridge of 3-5 atoms optionally ~u~ t~A by lowe~aLkyl;
Z is N; X is CH2; and Ar2 is sn~l ;lul~ phenyl.
Most pl~,r~ ,d culll~ounds of formula I are those where Arl is nilluphe.lyl. Other ~ul~ d colll~ûunds of formula I are those where Arl is iodo- or fluc~luphellyl. ~ef,.l~d iodo-or nulu~h~llyl colllpûullds are those where the halogen is in the para position with respect to the plu~ ol~e group. More ~ ,ll~ iodo- or fluluphellyl co~ uunds are those where the halogen is in the meta position. Particularly ~ d iodo- or Ilulu~hc.lyl colll~oullds are those where 10 the halogen is in the ortho position.
~ ef~ d c~.lllpou.lds of formula I having a het-,.u~uyl group as the Arl sut-stitllent are those where Arl is N-arylsulf~,nylpyllulyl, more preferably optionally s~ d isoxazolyl, and still more plci~,ably, optionally ~"~ "I A thiazolyl. Most ~IGr~ d colll~oullds of formula I having a hot~,-v~yl group as the Arl substinle~t are those where-Arl is optionally ~ .Jt~
15 thienyl. E~Cr.,ll~d colll~ùullds of formula I where Arl is optionally sllhstit~lto-d thienyl are those where X is CO. Particularly pler.,l,~d col"~oullds of formula I where Arl is optionally s,.l,~l;l.,t~A thienyl are those where X is methylene.
The invention further provides cc,l,lpounds of foîmula II:
Ar1J~ N ~
1 Z~ X~ Ar2 wherein X l~ ,StnL~ Cdll~llyl, sulfonyl, or methylene;
Z is ni~ug~ll or CH with the proviso that when Arl is phenyl or s~ ;lul~l phenyl Z is nitrogen;
25 Arl is a group of the formula:
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 WO 96/16052 PCr/US95/14987 R,~
wherein Rl, R2 and R3 il~d~ n~ y l~,~cse.l~ hydlug~n, fluorine, iodine, phenyl, nitro, I-inuul~alkyl, thioloweraL~coxy, cyclohexyl, amino, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimin'~7ole, optionally substitut~q' phenyl amino, optionally snb~ d phenoxy, optionally substituted pheny1~lllfin7e~ provided that Rl, R2 and R3 are not all nyd-ùg~,.l, or Arl is a group of the formula:
or R1~;
wherein R6 is hydrogen, halo, or loweralkyl;
Rg and Rlo are independently selected from hydrogen, halo, loweralkoxy, hydroxy; and Ar2 is a group of the formula:
~R12 where Rl 1 and R12 independently l~plesent hydrogen, halo, trifluolulllelllyl, amino, nitro, cyano, acetyl, thioloweralkoxy, loweralkyl, or taken together forrn a methyleneaioxy bridge.
SUBSTITUTE SHEET (RULE 26) Wo 96/16052 PCr/US95/14987 The invention also provides co~ uullds of formula m Ar s m wherein Rl 1 and R12 ind~ ie~nly ,c~,~,se.~l hydlugcn, halo, l~ifluun"llcllly-l, nitro, cyano, acetyl, amino, thioloweralkoxy, loweralkyl, or taken together form a methylenedioxy bridge;
Arl is a group of the formula:
R~
R2~J
wherein Rl, R2 and R3 in~epçndlontly lG~ ;S'eU~ hy..l-ugc~, fluorine, iodine, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, acetyl, amino, morpholino, cyano, piperidinyl, loweralkyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino,optionally su~s~ çd phenylethynyl, 4,5- iih~loimir~7t~le, optionallv ~I,h~
~}~_-,o~y, optionally ~ !;llllr(~ phenyi.culfi~e, provided that Rl, R~ and R3 are not all hydrogen; or Rl, R2 and R3 are the same or dirrc~cnL and lc~lcS~ L a group of the forrnula:
~N~
SUBSTITUTE SHcET (~ULE 26) ~=
CA 0220~86 1997-0~-16 The invention further e.~ro, ~ cces cull.~unds of Formula IV:
~~ ~N~Ar2 IV
wL~ Ar2 ~c~lescnl~ phenyl or phenyl mono or riicub~stitlltpc~ with halogen, cyano, nitro, or optionally s~ thienyl groups.
The invention further en~o~ cses culn~u,,ds of Formula V:
R2~N~
~S ~N~x,Ar2 Rl V
wherein X f~ sellla c~ul~llyl, sulfonyl, or methylene; and Rl lcpl~,sellts hydrogen, loweralkyl, halogen, cyano, nitro, optionally substituted thienyl, optionally substinlt~i phenyl, morpholino, piperidinyl, piy~,~a~ yl7 optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenyl~ulr~"lyll.;pr.i.7;..yl, or optionally substih-tetl phenylc~u-AJ"yl~ip~ lyl; and R2 is hydrogen, nitro, loweralkyl or halogen; and R3 is hydrogen, nitro, or loweralkyl; and provided that not all of Rl, R2 and R3 are c;mlllt~ntoollcly hydrogen; ar d Ar2 represents thienyl, phenyl or phenyl mono or riicllbstituted with halogen, cyano, nitro, loweralkyl, or loweraLlcoxy groups; or Ar2 is a group of the fnrrnlli~
~Rs -18- = = =
SUBSTITUTE SHEET (RULE 26) wl~ ,;n R4 and RS are indepenrl~ntly selected from hydrogen, h~lo, or loweralkylgroups.
Re~.~,stl,ld~i~e ~.ef~..~ cc,.l~ou.lds of formula V are those where Arl is a thienyl group s~ t. A as follows:
Cl_~~5sS Brl~ 55s 02N~5SS
~ H3C~ j~, s 02N--~ NC ~ SCH3 The inven~ion further ~ o,..l~c.cbs comyvullds of Forrnula VI:
R~ ~ X' Vl wherein X ~ c:sel.ls carbonyl, sulfonyl, or methylene; and Rl ,~ sel.t~ halogen, loweralkyl, nitro, or cyano; and Ar2 le~r~se-,Ls phenyl or phenyl mono or disubstituted with halogen, cyano, or nitro groups.
The invention further ellco.~ cces cum~ou.1ds of Forrnula VII:
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCI~/US95/1~987 R2 ~N~ ,.
~S ~N~Ar2 R, VII
wherein Rl and R2 are independently selected from hydrogen, halogen, loweraLkyl, nitro, or S optionally ~.u~ lr~ phenyl; and Ar2 ~ scnts phenyl or phenyl mono or riicuhstitute~ with halogen, cyano, nitro, loweraL~cyl or loweralkoxy groups.
Re~ senlative ~lcîtll~,d compoullds of formula VII are those where Rl and R2 arehydrogen The invention further encomp~cses cOlllpC ull~S of ~o~nula VIII:
N~N~
~N~x,Ar2 vm wherein X lc,vl~ ,ents carbonyl, or methylene; and R1 l~,~lcs7cllL~. hydrogen, optionally sllhstinl~qd phenyl, C~I~I11~LhCSAY7 or loweralkyl; and R2 Lyd~ ,n, or loweralkyl; and Ar2 represents phenyl or phenyl su'Qstit-lted with halogen, cyano, nitro, loweralkyl, or loweralkoxy groups.
Re~l~,se.l~ti~e ~lcf~,.l.,d cc.lllp.Jul.ds of formula VIII are those where Rl is phenyl and R2 is methyl.
The invention further encomp~cces compounds of Formula IX:
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCr/US95114987 R1--<~N~
c S ~ N~, Ar2 IX
wherein Rl lcpl~,scnts hydl.,gen, phenyl, or phenyl sub~litul~d with halogen, cyano, or nitro groups; and Ar2 l~,~,csent~ phenyl or phenyl s~lbs-itnt~i with halogen, cyano, nitro, loweralkyl, or loweralkoxy groups.
The invention further encc,~ ac.ces co,lll,ou,lds of Forrnula X:
R1~N~
N--O ~ N~, Ar2 X
wherein Rl lcpn,sents hydrogen, optionally substituted phenyl, c3~ llcLiloxy, or loweralykyl groups; and Ar2 represents phenyl or phenyl sllbstitnte~ with halogen, cyano, nitro. loweralkyl, or loweralkoxy groups.
The invention further er~comracces colllyoullds of Formula XI:
--N~
S2 ~N~X~Ar2 SUBSTITUTE SHEET (RULE 26) CA 0220~86 l997-0~-l6 Wo 96/160S2 PCItUS95/14987 wherein X r~ .,Ls carbonyl, sulfonyl, or methylene; and Ar2 re~,Sel~l~ phenyl or phenyl subs*tll~e~i with halogen, cyano, nitro, lowerallcyl, or loweralkoxy groups.
The inven*on further e~ro".l~c~es co,.,l~ull~c of Forrnula XII:
~N~
)~ O ~,N~, Ar2 R, XII
wherein R~ ,S~illL:~ optionally s~lhsl;L~ phenyl, op*onally ~ub~ d thienyl orloweraLcyl groups; and Ar2 r~ sel,L~ phenyl or phenyl sllb~ A with halogen, cyano, nitro, loweraLI~yl, or loweralkoxy groups.
The invention further ~.nr~,l"l ~cces cc~ ounds of Forrnula XIII:
~N~N~ Ar2 XIII
wherein R~ csel,ts hvdrogen, halo, thioloweraLkoxy, loweralykyl, or loweralkoxy groups;
and SUBSTITUTE SHEET (RULE 26) Ar2 lc~lcse.ll~ phenyl or phenyl subs~ with halogen, cyano, nitro, loweraL~yl, or loweraL~coxy groups.
The invention further e ~oll ll.hc.cf s ~olllyounds of Forrnula XIV:
S
NO ~N~f 3 R1 ~3 R2 XIV
wherein Rl and R2 in~f penrlf nrly lc~l~,sent hydrogen or h~log~n The invention further e'n~ CCeS COlll~)vullllS of Forrnula XV:
R1~` N ~ ~N~, Ar2 XV
15 wherein R1 and R2 infi~ pf...rl~ y lc~c;~cnt hydrogen, nitro or halogen; and Ar2 lc~lcsenl~ phenyl or phenyl ~LIb~Lulcd with halogen, cyano, or nitro groups.
The invention further encomp~scec col~lyoul1ds of Forrnula XVI:
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCI`/US95/14987 R2~=~R3 1--N~ ~Ar2 R1--N`N~ `J
XVI
wherein R 1 is loweralkyl, optionally substituted phenyl, or optionally substituted ~lle.. yll~ ylenyl;and R2 and R3 are hydlu~,~,n or lower alkyl; and X lel,.esen~ carbonyl, sulfonyl, or methylene; and Ar2 l~V~SclllS phenyl or phenyl sub~ lerl wi~h halogen, cyano. nitro, loweraLlcyl, or loweraL~oxy groups.
The invention further e-~o~ cs culll~uullds of Formula XVII:
R ~ N ~
R _N~ R3 ~ N~ X~ Ar2 XVII
wherein R 1 is loweralkyl, optionally substituted phenyl, or optionally substituted phenylmethylenyl; and R2 and R3 are llydlu~ or lower alkyl; and X ~ s~.lLs carbonyl, sulfonyl, or methylene; and Ar2 IG~lcsenl~ phenyl or phenyl substitllt~-l with halogen, cyano, nitro. IoweraL~cyl, or t loweralkoxy groups.
The invention further e..~-....l.~c~es co-l-~ou,-ds of Formula XVIII:
SUBSTITUTE SHEET (RULE 26 WO 96/16052 PCr/US95/14987 (~ ~Z~ , Ar2 xvm wherein Z is CH or nillug_.n, S X is carbonyl, sulfonyl, or methylene;
M is CH2, C(Rl)2CH2, C(RI)2O, or C(RI)2S;
Rl is hy~llu~e,l, loweraL~cyl, optionally ~ d phenyl;
Ar2 is optionally sllb ~ d phenyl, optionally Sl11~ r~ thienyl, or furyl; and ("the A ring") lc~l~se.ll~. an aryl or ncter~,~yl ring having from zero to three he~ero atoms selecteA from the group cQncicting of oxygen, sulfur and nitrogen.
Aryl and heteroaryl groups l~le~.e.,~d by the A ring are aromatic or hetcr~3uulna~ic syste ns rl, ..~rt~ d by 4n+2 7~ electrons.
The invention further e.,( l~lllr~7cses cc,~ uunds of Formula XIX:
R_~ ~ X' XIX
wherein Z is CH or lli~lugC~l; and X is carbonyl, sulfonyl, or methylene; and M is CH2, O, S, or a direct bond; and Rl is hydrogen, loweralkyl, optionally substin~trA phenyl; and SUBSTITUTE SHEET (RULE 2~) _ WO ~6/16052 PCT/US95114987 R2 and R3 are i..~- y,~ nt1y sel~cl~d from hydrogen, halogen, loweralkyl, nitro, cyano, alkylsulfon~mi~lo, arylsulfon~mido, optionally s~ phenyl, or R2 and R3 taken t~,~ e. ~I,ylcsel~L a methylhlc~io~ ring; and Ar2 is optionally sl1b~ ;n ~lr~ phenyl, optionally ~ thienyl, or furyl.
.
The invention further en~rJ~p~cses coll~uullds of Formula XX:
R3 ~ N~z~ X' Ar2 XX
wherein Z is CH or nitrogen; and X is c~ul,onyl, sulfonyl, or methylene; and M is CH2, O, S, or a direct bond; and Rl is hydrogen, loweralkyl, option~11y Sl1b~ 1 phenyl; and R2 and R3 are il,dey."ldently selected from hydrogen, halogen, loweralkyl, nitro, cyano, or optionally s1~bstit-1t~A phenyl; and R4 is hydrogen, loweralkyl, optionally substituted phenyl, or optionally substituted ph~l,yLllcL}l~lenyl; and Ar2 is optionally ~.u~iLuL~d phenyl, optionally substirl-t.od thienyl, or furyl.0 The invention further e.~co, .p~cceS colll~oul,ds of Forrnula XXI:
R 1, ~ N
N ~ M ~ R 1 ~ Z~ X~ Ar2 XXI
SUBSTITUTE SHEET (RULE 26 , wherein Z is CH or ~ ug~ , and X is carbonyl, sulfonyl, or methylene; and M is CH2, O, S, or a direct bond; and S Rl is lly~L~Jg~"~, loweralkyl, optionally s~lkal;lu~-A phenyl; and R2 is hydrogen, halogen, loweralkyl, nitro, or cyano; and R3 is hydrogen, loweralkyl, optionally subsl;l.,l.,d phenyl. or optionally sub~
phenyL~ l,yle,.yl, and Ar2 is optionally ~..h~ phenyl, optionally sub~l ;l it~.l thienyl, or furyl.
The invention further .oncomr~cces coll,~x>ullds of Fonnula XXII:
o R1 R2~ X~
XXII
wherein Z is CH or uillugf;n; and X is carbonyl, sulfonyl, or methylene: and M is CH2, O, S, ûr a direct bond; and Rl is hydrogen, loweralkyl, optionally Su'c~ ;llllf ~ phenyl; and R2 is hydrogen, halogen, loweralkyl, nitro, cyano, optionally substituted phenyl, alkylclllfon~miAo, arylsulfon~miAc)7 or thioloweralkyl; and Ar2 is optionally sub~ ut.,d phenyl, optionally subs~ led thienyl, or furyl.
The invention further encomracses colll~oullds of Fo~nula xxm SUBSTITUTE SHEET (RULE 2B) CA 0220~86 1997-0~-16 WO 96116052 PCr/US95/14987 ~Sx~ N~
XXIII
wherein Z is CH or nitrogen; and S X is ca~ lyl, sulfonyl, or methylene; and M is CH2, O, S, or a direct bond; and Rl is hydrogen, loweraLcyl, optionally ~k~ rl phenyl; and R2 is hvdrogen, halogen, loweralkyl, nitro, cyano, optionally substit1lte~i phenyl, alkylsulfonamido, arylsulfon~mi~o, or thioloweraL~cyl; and Ar2 is optionally sul~ A phenyl, optionally sul~ lr~ thienyl, or furyl.
The invention further e ~ , . .p~cses cc,lllyOullds of Formula XXIV:
R2~ ll R1 R3~ ~Z~ X~ Ar2 XXIV
wherein Z is CH or nitrogen; and X is carbonyl, sulfonyl, or methylene; and M is CH2, O, S, or a chçmic~l bond; and Rl is hydrogen, lowe~L~cyl, optionally sub~LiLuLed phenyl; and Y is O or S; and R2 and R3 are independently selected from hydrogen, halogen, loweraLlcyl, nitro, cyano, or optionally i~b~ lr~ phenyl; and SUBSTITUTE SHEET (RULE 26 WO 96/16052 PCr/US95/14987 Ar2 is optionally suk~ e~ phenyl, optionally sl1hstitut~rl thienyl, or furyl.
The instant invention in~ os optically active cc .lll,oul,ds as well as racemic I~ ,s of such co~ oullds. The invention further in~ es the pk,.. ~r~ ~,I;e~lly acceptable salts of such compounds or racemic ll.i~lu.es. The invention still further includes pharm~eutiral COlllyOC l l l~ c, As used herein, the term "loweralkyl" means straight or branched chain saLuldud hyd~ uL~n radicals having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, ~-butyl and the 10 like.
As used herein, the term "thioloweralkoxy" refers to -SRIs, wherein R1s is loweralkyl.
As used herein, the term "halo or halogen" refers to fluorine, chlorine, bromine, or iodine.
As used herein, the term "aryl" refers to systems ch~dc~ ed by 4n+2 ~ electrons, i.e., 15 aromatic carbocyclic groups having a single ring (e.g., phenyl), mnltirle rings (e.g., IJil~h~nyl) or m~lltirlP conflence~i rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahy~u-laphthyl, naphthyl, anthryl, or phe-n~nth yl), which can optionally be u~ ~ or Sub~ 'lled with e.g., halogen, lower alkyl, lower alkylthio, t.inuulull.~,.l-yl, lower acyloxy, aryl, and hetelua.yl.
As used herein, the term "heteroaryl" means ~, 6, or 7 membered aromatic ring systems 20 having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolo. pyrazolo, pyrazinyl, pyridazinyl, oxazolo, furanyl, quinoline, isoquinoline, thiazole, thi~ 7nle, isoxazole, and thienyl, which can optionally be ~ncukstitntPA or ~b~,l;Llll~ with, e.g., halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, cyano, nitro, aryl, and 25 heteroaryl.
As used herein, the term "alkylsulfonylamino" means R16S(0)2NR17 - wherein R16 is loweralkyl, phenyl, or suhstit~ phenyl, and R17 is hydrogen, loweralkyl or -S02R16.
SUBSTITUTE SHEET (RULE 26) -CA 0220~86 1997-0~-16 WO 96/16052 PCr/US95/14987 As used herein, the term "tnfluoroallcoxy!' refers to -R1gCF3, wherein R1g denotes a loweralkoxy group as defined above, atrAehed to the parent molecular moiety through the oxygen atom. Rel"~ sen~ es of such groups include mr thlr~nr oxy, ethyleneoxy and the like.
As used herein, the term "optionally substinlte~ phenyl" refers to a phenyl ring having 5 from zero to three substiturntc independently selected from loweralkyl, halogen, hydroxy, loweralkoxy, am~no, thioloweralkoxy, nitro and cyano.
As used herein, the term "optionally substituted thienyl" refers to a thiophene ring with from zero to three sllbs!;~ r~ inriepen(irntly selected from loweralkyl, halo, phenyl, cyano and nitro.
As used herein, the term "optionally substituted phenoxy" refers to the phenoxy ring ;I- I~A as defined foroptionally s~ ~ phenyl.
As used herein, the term "optionally s,.b:,lin.led phenylsulfide" refers to a thioph~nyl ring ..I.~I;n.t~A as defined from optionally su~ t~ ~ phenyl.
The terrn "~hA..n~ Ally a~ceptAhle salts~' refers to the phz1rm~ceuticAIIy acceptable, 15 leld.i~,~ly non-toxic, inorganic, or organic acid addition salts of the co.ll~uuu,-ds of this invention.
These salts can be pl~?d,Cd in situ during the final icolAtir n and pnnfirAtion of the com~uullds or by sepz~r~t~ly reacting the free base with a suitable organic or inorganic acid. Rc~,~se.,ldlive salts include the hydrochloridr7 hydlub~ ide, sulfate, phosphzltç, nitrate. bicn1fzltç~ acetate, oxalate, valerate, oleate, palmitrate, mr~th~Anesulfonate~ stearate, laurate. borate, ben70At~, lactate, 20 phosphate, tosylate, citrate, mztlrAt~ ru",a.a~e, ~uc~.-inAIr tar~rate. napsylate. lactobionate, and the like. It will be app&cl~L to those skilled in the art that, depending upon the number of available amino groups for salt formation, the salt of this invention can be per N-salts.
The present invention also provides pharmzl~euti~AI cc,lllposiLions which comprise one or more of the culllpoul,ds of fonnnlzle I-XXIV above formlllAt~od together with one or more non-25 toxic phAnmAreutirAlly acceptable carriers. The pharmzl~ ellticAl co~ x~iLions may be specifirz~llyfi~nmlllzAt~ for oral a~minictration in solid or li~uid fiorm, for ~al~.ne~dl injection, or for rectal ~rlmini5tration.
The phArmAreutirZ~l compositions of this invention can be A-lministered to humans and other zlnimAIc orally, rectaly, parenrerally (i.e. intravenously, intramuscularly, or sub-SUBSTITUTE SHEET (RULE 26) WO 96/160!;2 PCT/US95/14987 cutaneously), intracicterll~lly, intravaginally, intraperitoneally, topically (as by powders, Oi.. l.. lc or drops), t,,i,-cA~.. ~lly, bucally, or as an oral or nasal spray.
Pl,~...A~eutil~l coll,~ositions of this invention for parenteral injection comprise pl~ e~ lly acceptable sterile aqueous or nonagueous solutionc~ dispersions, sucpçn~ionc S or emulsions as well as sterile powders for l~,con~ n into sterile injectable solutions or ;o~c just prior to use. F~r~mplec of suit~ble aqueous and nona~ueous carriers, rlilu~ntc, solvents or vehicles include water, eth~nol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and sni~h~ Lul~S thereof, veget~hle oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be m~int~ined, for 10 er~mrle, by the use of coating m~t~ri,~l.c such as lecithin, by the n~int ..~n-e of the required particle size in the case of ~ ;onc~ and by the use of s~ ri1-.,;...,c These CU~ Jo~iLions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. E~ ,ntion of the action of microorg;lni~mc may be ensured by the inclusion of various ~ntiba~tlorial and antifungal agents, for ex~mrle, p~r~hen, 15 chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chlotide~ and the like. Prolonged absorption of the injectable ph~ en~ l form may be brought about by the in~lll$inn of agents which delay absorption such as ~1.. ;.~.. " 111(1115~ t~ and gelatin.
If desired, and for more effective distribution, the colll~unds can be incul~-,laL~d into 20 slow release or targeted delivery systems such as polymer matrices, liposomes, and The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter. or by incorporating sterilizing agents in the form of sterile solid compositions which can he dissolved or dispersed in sterile water or other sterile injectable 25me~ m just prior to use.
Solid dosage forms for oral ~Aminic~ration include capsules, tablets, pills, powders, and "granules. In such solid dosage forms, the active compound is mixed with at least one inert, ph~rm~re-ltic~lly arcept~hle eYcirient or carrier such as sodium citrate or rlic~ -m phosphate and/or a) fillers or e~rt~n~l~rs such as starches, lactose, sucrose, glucose, m~nnitQl, and silicic SUBSTITUTE SHEET (RULE 26 acid, b) binders such as, for example, carboxymethylcellulose, alingnates. gelatin, polyvinyl~yllolidone~ sucrose, and acacia, c) hl.n,~ nl~ such as glycerol, d) disintegrating agents such as agar-agar, c~lri-lm carbonate, potato or tapioca starch, alginic acid, certain Cilir~tes~ and sodium carbonate, e) solution retarding agents such as paraffin. f) absorption 5 accelc,a~ such as 4l~ . . .;., y ~" ", .on ;~.. ., co.ll~ou,lds, g) wetting agents such as, for e~ lc, cetyl alcohol and glycerol IlllJno~ P~ h) absc,~ such as kaolin and benl-J~;Ie clay, and i) Inl..;r,~ such as talc, calcium ste~rat~, m~nP~ st~oA-ate, solid polyethylene glycols, sodium lauryl sulfate, and llli~cLul~.~ thereof. In the case of capsules, tablets and pills, the dosage form may also co...~ b..r~ .;"g agents.
Solid c.,~ u~;l;ons of a similar type may also be employed as fillers in soft and hard-filled gelatin c~ps--lPs using such txci~ s as lactose or milk sugar as well as high molec~ r weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsulPs, pills, and granules can be ~
with co~tingc and shells such as enteric coatings and other coatings well known in the 15 ph~.,,-A~ l;r~l formlll~ting art. They may optionally contain opacifying agents and can also be of a cc,lll~osiLion that they release the active il,~l~diel-L(s) only, or ~l~r~.c.lLially, in a certain part of the in~pstin~l tract, optionally, in a delayed manner. FY~"l,l~ S of emhedriing colllpo~iLions which can be used include polymeric subst~nrec and waxes.
If desired, and for more effective distribution, the co...~oL,nds can be incolluulalcd into 20 slow release or targeted delivery systems such as polymer matrices, liposomes. and microspheres.
The active colll~ullds can also be in micrc~nr~rslli~teri form, if ayl,lUluliate. with one or more of the above-mPntion~l PYripiet~tc Liquid dosage forrns for oral ~riminictration include pharrn~reutic~lly acceptable 25 emlllcinnc, solutions, sncpencionc, syrups and elixirs. In addition to the active co~ o~dds, the liquid dosage forms may contain inert diluents cc,llllllollly used in the art such as, for example, water or other solvents, solubilizing agents and emlllcifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl bPn7nate propylene glycol, 1,3-butylene glycol, dimethyl fol",~ oils (in particular, coSI~ ec~l gr~!un~lnl-t corn, germ, SUBSTITUTE Sl ~'EET (RULE 26) CA 0220~86 1997-0~-16 olive, castor, and sesame oils), glycerol, tetrallydlorullulyl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and ~ ul~,s thereof.
Besides inert rlihl~nt~ the oral co,llpo~ilions can also include adjuvants such as wetting agents, emulsifying and snspen~ing agents, s-.eet~ g, flavoring, and p~,.ru,llil,g agents.
S S.. ~ ;ollc, in ~drlitil~n to the active colllp~llllds, may contain ~ e ~rlhlg agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, ,l~ly~L~lline celllllnse, ~II....in~.... metahydroxide, bentonire, agar-agar, and ~g~nth, and ix lw- s thereof.
Collll,osilions for rectal or vaginal ~lminictration are preferably ~u~pO~ ;F-S which can 10 be ~l~p~ed by mixing the cc,llll)uu,~ds of this invention with suitable non-irritating excirient~ or carriers such as cocoa butter, polyethylene glycol or a ~ul,l)osilo~y wax which are solid at room e~ a~ but liquid at body ~ e and therefore melt in the rectum or vaginal cavity and release the active co,l,~uul,d.
Dosage forms for topical ~rlmini~tration of a compound of this invention include15 powders, sprays, oimmlontc and inh~ nsc. The active co~l~pound is mixed under sterile con~itic n~ with a ph~. ,n~r~ ;c~lly acceptable carrier and any needed preservatives, buffers, or propellants which may be re~uired. Ophth~lmir form-ll~tions, eye ointmrnt~ powdc.~ and sol~tion~ are also conr~ tecl as being within the scope of this invention.
Actual dosage levels of active ingredients in ~he ph~rm~reutical co"l~uo~ilions of this 20 invention may be varied so as to obtain an amount of the ac~ive compound(s) tha~ is effective to achieve the desired therapeutic response for a particular patient, co"lpositions, and mode of a~lmini~tration. The selected dosage level will depend upon the activity of the particular compound, the route of a~lmini~tration, the severity of the condition being treated, and the condition and prior mtoAir~l history of the patient being treated. However, it is within the skill of 25 the art to start doses of the co"l~ound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 0.1 to about 200, more preferably of about 05 to about 150, and most preferably about 1 to about 125 mg of active collJpo.lnd per kilogram of body weight per day are ~rlmini~tered orally to a .. ~.. ~li~n patient suffering from ~ hP.. r.'s Disease, SUBSTITUTE SHEET (RULE 26) CA 0220~86 l997-0~-l6 Wo 96tl60S2 PCr/US95/14987 neoplastic disease, or bacterial or fungal infections. If desired. the effective daily dose may be divided into m1llrirl~ doses for ~u~l,oses of ~flmini~tration, e.g. two to four Sc~dlc doses per day.
All rloc~ e.g., patents and journal articles, cited above or below are hereby 5 il~Cul~ul.. t~l by lcr~ c"cc in their entirety. - =
One skilled in the art will recognize that m~iifir~tion~ may be made in the present invention without deviating from the spirit or scope of the invention. The invention is illnst-~t~
further by the following eY~mpleA which are not to be con:,llued as limiting the invention or scope of the specific IJloc~luu~;s d~osor~ herein.
GENERAL PROCEDURE
As is more fully e~pl~in~d in the following scheme and ~ ...ples, the com~oul.ds of the invention may be ylcp~u~c1 by adding an ~lv~liate seconrl~ry amine (l mole) to a solution of c~ e~ni.tcd hy~llucllloric acid (2-5 moles) in suffisient iso~luyallol to achieve an amine col-~e..l. a~ion of about 0.1 M-0.4 M. To the solution of amine hydrochl~ri~e salt which has been 15 forrned in situ is added p~arollllaldehyde (1-2.2 moles) followed by the desired aryl or hetc.û~L~cetone (1.1-2 moles), and the resulting reaction mixture is then refluxed for about 12-72 hours. The reaction is cooled and the res1llting solid is filtered and recryst~lli7~d from l or lliLul~l~ with ...~ l or ethanol to afford the desired product.
The co..lyuul~ds of the invention may be ~rcl,a.cd according to the reactions set forth in 20 the following reaction scheme.
ArlJlCH2 + ~PrOH ~ Ar~ N ~
HN ~ HCI Y ~ Z~ X~ Ar2 ~Z~x,Ar2 where Arl, X, Y, Z and Ar2 are as defined above for forrnula I.
Using the above-described procedure, the cûllllJu~ ds described in the followingeY~mples were yl~
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 Wo 96/16052 PCr/US95/14987 FY~mrle 1 G
~ ~ ~N v~3 l-~D-Iodoph~ 1)-3-(4'-benzyl-1'~ "a7il~yl)-l-~o~allolledihydrochloride: mpæ4 C (dec.);
lHNMR(300MHz,DMSO-d6) ol2.0(brm,2H),8.0(d,2H),7.65(d,2H),7.6(m,2H), 5 7.45 (m, 3 H), 4.4 (brs, 2 H), 4.0-3.2 (m, 12 H).
FY~rnrl~ 2 ~ uph~nyl)-3-(4'-benzyl-l'-pi~illyl)-1-~ panone dihydrochloride: mp > 240 C; lH
NMR of the free base (300 MHz, CDC13) o 8.0 fm, 2 H), 7.3 (m, 5 H), 7.13 (t, 2 H), 3.5 (s, 2 H), 3.15 (t, 2 H), 2.85 (t, 2 H), 2.55 (brs, 8 H).
FY~mrle 3 1-(3",4"-Dichk~lu~hfnyl)-3-(4'-benzyl-1'-pi~"a~i~lyl)-1-pl~dn(~lle dihydrochloriA~-: The solid was converted to its free base using NH4OH, e.~ a~ ;i with dichlolu~ tl ~l-f and purified via flash ch~,nlal.,graphy (Silica, EtOAc). The resulting oil was converted to its dihydrochl~ride salt by ~AAition of drv ether-HCI to give the desired ~I~Klu~; mp 220 C (dec.); lH NMR of the free 15 base (300 MHz. CDC13) ~ 8.03 (d, 1 H), 7.77 (dd, 1 H), 7.53 (d, 1 H), 7.3 (m, 5 H), 3.5 (s, 2 H), 3.12 (t, 2 H), 2.82 (t, 2 H), 2.5 (brs, 8 H).
Exarnple 4 1 -~D-Chlorophenyl)-3-(4'-benzyl- 1 '-piperazinyl)- 1 -plo~anone dihydrochloride: mp > 230-C; lH
NMR of the free base (300 MHz, CDC13) ~ 7.9 (d, 2 H), 7.43 (d, 2 H), 7.28 (m, 5 H), 3.5 (s, 20 2 H), 3.15 (t, 2 H), 2.83 (t, 2 H), 2.5 (brs, 8 H).
Fx~mrlt~- 5 l-~D-Nitrophenyl)-3-(4'-benzyl-1'-pi~dzillyl)-1-~1ul,dllunc dihydrochloride: A mixture of p-nitroacetophenone (6.09 g, 0.037 mol), I-benzylpiperazine (5.00 g, 0.023 mol), SUBSTITUTE SHEET (RULE 26) - - =
CA 0220~86 1997-0~-16 p~ar~ ehyde (1.11 g, 0.037 mol), and concc~.t.d~A hydrochloric acid (7.00 mL.
0.084 mol) in 100 mL isopropanol were refluxed for 16 h. The reacton was cooled. filtered, and the flter calce was !- ;~ A with m~ nol (4x) to give 4.6 g (51%) of the desired p.~duct:
mp 250-C; IH NMR (300 MHz, DMSO-d6) ~ 11.5 (brm, 2 H), 8.4 (d, 2 H), 8.2 (d, 2 H), 5 7.66-7.36 (m, 5 H), 4.3 (brm, 2 H), 3.8-3.2 (brm, 12 H).
FY~mrle 6 1-(3"-Thienyl)-3-(4'-benzyl-1'-pi~ yl)-1-pl~.p~ edihydT~ch~ Ae mp223 C; lHNMR
(300 MHz, DMSO-d6) o 11.5 (brs, 2 H), 8.56 (s, 1 H), 7.8-7.3 (m, 7 H), 4.3 (brs, 2 H), 3.9-
BAC~GROUND OF THE INVENTION
l. Field of the Invention This invention relates to substituted l-aryl-3-piperazin- l'-yl prop~nones and 1-arvl-3-piperidin-1'-yl propanones. These coll,pou.lds are useful in the l,~ t of Al7hr.imL~r's Disease, neopl~stic disease, and ba~t~ or fungal i~ cli 2. Description of the R~l~t~ Art 0 Al7hrimer's Disease is a progressive neurodegenerative disorder affecting 7% of the population over 65 years of age and characterized clinically by progressive loss of intel1~ctu~l function. This in,pai"l.ent of function is caused by the presence of neuri~ic plaques in the ne~co l~.~ and the loss of ~l~sy~la~Llc m~l~cl~~cholinergic neurons. Neuritic plaques are composed of degcn~ lg axons and nerve terrnin~lc~ often surrounding an amyloid core and I5 usually containing reactive glial elements. Another characteristic pathologic feature of ~l7heimer's Disease is the neurofibrillary tangle, which is an intraneuronal mass which C~ ,o,lds to an accum~ tiQn of abnormally phosphorylated tau protein polymerized into fibrillar structures termed paired helical hl~m~onrs In addition, the neurofibrillary ~angle also contains highly phosphorylated neurofii~mrnt proteins. Even the earliest papers on .A17~ 'S
20 Disease were clear that both "senile" plaques and neurofibrillary tangles had to be present in ablln-i~nr,e to allow a post-mortem diagnosis of the disease. Before any un~iersr:~n~i;ng of the molecular nature of these ~LIuClul~;S was obtained, efforts were being made to understand the relationship ~el~n the ~lulllb~ of these lesions and the progression or severity of the ~lemrrln~
expr ienre~ by the patient. The limit~ion.c of silver staining were such that early workers in this 25 field were unable to appreciate the complexity of these abnormal ~illU~;IulGs (Ball, MJ, Neurobiol.
of Aging, 8: 564-565, I987). Although early at~G,llpls to correlate pathologic lesion counts with clinical S~ (JIlls generally yielded poor results, it was clear that the inri~lenre of lar_e llulll~ls of both type lesions were invariably associated with ~iemen~ia (Perry et al. J. ~eural Transmission, 24: 131-136, 1987; Alafuzoff, I., Acta Neuropath, 74: 209-225, 1987;
SUBSTlTUtE SHEET (RULE 26) CA 0220~86 1997-0~-16 Wll;~ ho"se et al, Prog. Clin. Biol. Res., 317: 131-142, 1989; Tomlincon~ NeuloyaLllol. Appl.
Neurobiol, 15: 491-512, 1989).
More recent work has allowed a clearer clefinition of the nature of the lesions stained by silver salts. "Senile" plaques are actually two distinct types of ~Llu-;LulcS. the cl~ccic~l plaques S described by Al7heimçr being composed of degenerating neuronal elements (neurites) ~ulluundillg a central core of amyloid, while the other so-called "diffuse" or "pli~lliLivc" plaque is usually a deposit of amyloid without a halo of de~ ;,.g neurites (Tagliavini,, et al, Neurosci.
Lett., 93, 191-196, 1988; Dickson, DW, et al, Am. J. Path., 132, 86-101, 1988). These ~Llu~_lul~,s are liffie-llt to ~ictin~llich from each other with silver stains or with the widely used 10 nuor~,scc.,L dye, thioflavin S. Early attempts, using silver staining, at correlations bCL..~,.,ll plaque number and extent of ~1~ .. l ;~ as well as some more recent studies using thioflavin S, were flawed by this inability to define what type of plaque was being counted (Hansen, LA, et al, Neurology, 38, 48-54, 1988; ~t7.m~n, R, et al, Ann. Neurol., 23, 138-144, 1988). This bcco.l..,s very obvious in recent studies, which have corlcictently l~polL~d that amyloid plaques 15 can be found in large nu~ in the brains of the lllaJol;Ly of the very elderly (over 80 years), and are only rarely ~ccoci~ted with clem~nti~ when present without evidence of de~ul .a~il,g n~lritç5 (Davies, L, et al, Neurology, 38, 1688-1693, 1988; Delaere, P, et al, Nc~lusci. Lett., 116, 87-93, 1990; Dickson, DW, et al, Neurobiol. Aging, 13, 179-189, 1991).
The counting of neurofibrillary tangles also fails to give an ~cur~t~ picture of the extent 20 of neurofibrillary degeneration. Again, the presence of large numbers of tangles is invariably associated with a profound dçmtonti~, and some index of disease severity can be gained from tangle counts (Tomlinson, BE, Neul~palllol. Appl. Neurobiol., 15, 491-512, 1989; Delaere, P, et al, Acta Ne~l,u~atll., 77, 645-653, 1989). Electron mi~luscuy~ first revealed that tangles were cc.lll~osed of masses of paired helical fil~m~-,nt~ (PHF) filling the cytoplasm of neurons (Terry, 25 RD, et al, pages 145-155, In CIBA Fol-n~tion Symposium on ~ c;ll~'s Disease and Related Con-1ition~ Ed. by Wolstenholme, GEW, O'Conner, M, J and A Churchill, London, 1970).
These studies also clearly showed that degenerating neurites also co-,lai-,cd PHF, a fact only widely appreciated much later, when the use of antibodies to PHF became common (Wolozin, BL, et al, Sciçnre, 232, 648-650, 1986). Thus, both the plaques and the tangles of Al~ c 's SUBSTITUTE SHE-tT (RULE 26) Disease contain PHF. The use of antibodies to PHF also revealed the widespread presence of these paired helical fil~mentc in neuronal processes (Brun, A, Prog. Clin. Biol. Res., 317, 285-293, 1989~. Thus, the presence of PHF is much more widespread than was first s~lcpecte,l and is today concidered to be an infliratinn of a widespread neuronal disease, of which the neuritic 5 plaque and the neurr~fibrill~ry tangle are only the most obvious signs (McKee, AC, et al, Ann.
Neurol., 30, 156-165, 1991). It has been ectim~ted that as much ~s 90% of the PHF in the cortex of the average ~l,l.e~ . case is present in neuronal ~ ce,sses r~ther than in the plaque or tangle (Wolozin, BL, Ann. Neurol., 22, 521-526, 1987). Much of the early and indeed the present confusion with regard to ~ gnosic and severity of ~17~ f ~ 'S Disease comes from the 10 failure to a~l, ciale the complexity of the pathology in this disease. ~Ithough the oc~ tnce of si~ni~r~nt ~ 0~ of PHF in the brain is always ~cso~ tr~ with severe Citl,.f -,l;~ (Hyman, BT, Current Opinions in Neurology and Neurosurgery, S, 88-93, 1992). These results suggest that good coll~laLions can be obtailled bcL~ I the conce ~ JII of PHF proteins (COIllf.l;ll~f S referred to as ,A~ e;--~"'S Disease ~ccoci~d Proteins or ADAP) in the cerebr31 cortex and the degree of 5 tl~ n~;~ measured prior to the death of the patient (Gh~nb~ i, HA~ et al, JAMA, 263, 2907-2910, 1990).
It is noted that the terminology used to describe the abnormal protein complexescGIll~)osing the fibrillar pathology in Alzheimer's Disease can be confusing. PHF is a morphological Aecign~ti~n, describing abnormal fil~ment.c found in neurofihrill~ry tangles. An '~0 abnormal protein species migr~tinP at 68 kDa, elc~,llopho.cucally, and observed on immlmt blots of tissue from AD brains was termed A68 (Wolozin, B, et al, Science,232, 648-650, 1986). A
protein complex shown to be specific for AD by immnnochemical analyses was design~t~7 ~l~h~im~r~s Disease ~coci~le~l Protein or by the acronym, ADAP (Ghanbari, HA, et al, JAMA, 263, 2907-2910, 1990). It is now known that A68 and ADAP, when viewed by the electron r 2~ microscope, are PHFs. These PHFs have been further shown to contain, primarily, the microtubule-~ccoci~rt~(l protein, tau. Hence, the terms A68, ADAP, PHF and PHF-tau are often used int~l~h~l-ge~hly. Thus, they are meant to be interch~n~l~ herein.
A series of important studies have suggested that the progression of ~l7h~im~r's Disease can be defined pathologically by careful n~ulu~n~lo~ studies of large nU~11~1S of brains from SUBSTITUTE SHEET (RlJLE 26) WO 96/160~2 PCT/US95114987 elderly hl1m~ns, (Braak, H, et al, Neurosci. Lett., 103, 24-28, 1989; Braak, H, et al, Ntulu~alh. and Applied Neurobiol., lS, 13-26, 1989; Braak, H, et al, Acta Nc.llupdlll., 82, 239-259, 1991; Braak, H, et al, European Neurology, 33, 403-408, 1993). The Braak's focus is almost entirely on the dc~, elu~ ,l of neurofihnll~ry pathology, which begins in the ~ ,. h; . .~l S cortex perhaps years before the clinical signs of the disease are app~cnt. The progression of A~ F ;~ 'S Disease is thought to be soll~ l,at unllc~ , in the sense that the disease ~ ,a3eS
by the involvement of more and more neurons in the formation of PHF, in an ~n~tomic sequence which is to some extent pre~iirt~hl~. In the initial stages, only those neurons of the ~ \lo,~
cortex contain PHF, in latçr stages, neurons of the CA1 and CA2 pyramidal layer of the 10 hippocampus contain these StluCLul~,S, and still later, neurons of the ~ccoci~tinn cortex begin to show evidence of PHF forrnation. Clearly, pl~,.lLion of PHF formation even after the process is underway in the hippocampus could limit the disease to this brain region, at which point clinical problems are co, r; r~ to some loss of short terrn Ill~.llul y. Patients first seek help at a stage when PHF pathology is largely limited to the l~i~oc~ll~us (Berg, L, et al, pages 9-25, in 15 Al,l.~ 's Disease, Eds., Terry, RD; K~r7rn~n, R; Bick, Kl. Raven Press, New York, 1994).
To prevent the pr~ ion of ~l7l.. ~ 's Disease at this point would clearly be a major benefit to the patient (Davies, P, pages 327-334, in Al,l.- ;...- 's Disease, Eds., Terry, RD; ~t7m~n, R;
Bick, KL. Raven Press, New York, 1994; Kh~rh~tllri~n ZS, et al, pages 445-454, in ,,'s Disease, Eds., Terry, RD: K~t7m~n, R; Bick, KL. Raven Press, New York, 1994).
Attempts to cl~lr-.,.. ;n~ the mol~ocul~r nature of the PHF were h~~ lc;d at first by an approach which attempted to purify PHF from isolated neurofibrillary tangles. Once h~cc,l~ulaL~d into the llla ;lulllolecular CO~1CA that is the tangle, PHFs become eAI-~.llely difficult to soll-bili7.o for protein analysis. The microtubule-acsoci~t~ protein tau appears to be a major ~nri~eniC c~ n~llt of PHF. The repeat region of microtubule-~c~oci~ 1 protein tau forms part 25 of the core of the paired helical fil~m~nt of ~I,l.. ;...-, 's Disease (Goedert, M, et al, Proc. Nat'l.
Acad. Sci., 8S, 4051-4055, 1988; Wischik, CM, et al, Proc. Nat'l. Acad. Sci., 85, 4506-4510, 1988).
The involvement of prolein phosphorylation in the fr)rm~tion of PHF has been su~esteA
by a variety of studies which have shown that tau in PHF is hy~ hf ~l~hs~ ylated (Kosik, KS, et SUBSTITUTE SHEET (RULE 26) WO 96116052 PCT/US95tl4987 al, Ann. Med., 21, 109-112, 1989; Goedert, M, Trends in Neuroscienres~ 16, 460-465, 1993;
Iqbal, K, et al, Act Neurobiologiae E~ t,.li!c~ 53, 325-335, 1993). There is su~ h,~, evidence that several other ~rolcins, especi~lly neurofil~mrntc and other ll.icluL-~L ule ~soci~trd proteins (MAPs) are also hy~ ho ,~hr~ylat~d in the brains of patients with ~1,1.~ IIIF~- 's Disease .~ S (Lovestone, S, et al, Current Opinions in Neurology and ~ u:,ul~,.,,y, S, 883-888, 1992).
In 1985, a monoclonal antibody ALZ50 was raised (produced by hybridoma cell lineATCC No. HB9205) that recognized a 68 kDa polypeptide (termed A68) in imm--nnb1Ots of the vulnerable brain regions in AD, but not in control brains, (Wolozin, B, et al, Science,232, 648-650, 1986). T.. nohi~loc~ .. ;r~l analysis with this anti'oody in~'ir~.rçd an intense reaction with 10 neurofibrill~ry tangles and. in later cA~ illJ~nls, with the PHF's, as well. The discovery of A68 was the first report of a bioçhrmically ~ ...i.,e~ abnormal protein species ~ccoci~t~fl with the fibrillar pathology in AD.
In o~her iaboratories in 198~5, monoc~onal and polyclonal antibodies recognizing the microtubule-associated protein, tau, were shown to react with neurofibrillary tangles, and 15 subsequently, with PHFs (Grundke-Iqbal, I, et al, Proc. Nat'l,. Acad. Sci., 83, 4913-4917, 1986; Kosik, KS, et al, Proc. Nat'l. Acad. Sci., 83, 4044-4048, 1986). Furthermore, biocl....,;~l analyses of the ~lutGase-resistant "core" of the PHF d~ oll~L,attd the ~lesencG of peptides cont~ining the tau selluence, (Goedert, M, et al, Proc. Nat'l. Acad. Sci., 85, 4051-4055, 1988; Wischik, CM, et al. Proc. Nat'l. Acad. Sci., 85, 4506-4510, 1988). ~cldition~lly~
20 monoclonal antibodies, whose epiLol,eS sp~nnr-l the tau molecule, all were shown to react with neurofibrillary tangles in AD brain (Kosik, KS, et al, Neuron, 1, 817-825, 1988). Much later, it was ~letermin~l that the ALZ50 antibody reacts with the e~ cllle amino terrninus of the tau mrJlecllle (Goedert, M, et al, Neurosciçnr,e Letters, 126, 149-154, 1991).
In 1990, in an attempt to purify A68, a more readily soluble ~ Ou~lion of PHFs was 25 isolated (Greenberg, S and Davies, P, Proc. Nat'l. Acad. Sci., 87, 5827-5831, I990).
Tmml~nnblots of these ~,~uclulcs in~ir~tçd that three closely migrating cleclluyhulclic species, the slowest migrating of which was ca. 68 kDa in size, all reacted with ALZ50 and tau antibodies (Lee, V, et al, Science, 251, 675-678, 1991). This in~ic~tç~l that the A68 complex of proteins SUBSTITUTE Sl IEET (RULE 26) WO 96~16052 PCT/US95/14987 is, to a large extent, coll.yo3ed of the tau protein. This polymerized form of tau was shown over the years to be in a hyy~hn~l~horylated state.
Other monoçlon~l antibodies raised against human PHF l,l~aldlions are the antibodies PHF-1 and TG3. While these antibodies display robust affinity for paired helical fil~m~-5 ~ alalions~ they only have trace l-,aclivily towards normal adult tau. Further studies revealed that the mo~oclon~l antibody PHF-1 has a reduced affinity for PHF which has been treated with alkaline phosphatase or hy~LunLIulic acid, thereby suggesting that this antibodv recognized a ph~spl.o.ylat.,d epitope(s) in paired helical fil~m~n-c These pho~yllolylated ~,piluyCS (recogniæd by PHF-1) reside within the C-tçrTnin~l fragment of the tau protein, at serine 396 and 404 10 (Trojanowski, J.Q., et al, Clin. Neurosci., 1, 184-191, 1993). The epitope(s) l~cûg-li~cd by TG3 has not been mapped yet.
To date, it has not been possible to c ?ncictently induce the fo~nation of ~l71,f ;."f -like e~iluyes either in vivo or in vitro. Hence~ there is a need for an assay for the ric~r , l l;l~ on of tau protein, paired helical fil~mf ntc and ..,fcl-~-;cmc involved with ~17hçimf r's Disease. There is 15 further a need for an assay suitable for S~ ling for drugs which may prevent or decrease Al,l.~ . 's Disease activity.
SUBSTITUTE SHEET (RULE 26) SUMMARY OF THE INVENTION
The co~ -ds of this invention and an al,Lil yscl~otic agent, chlo~ r are active in an assay indicative of the potential of certain drugs to inhibit a h:~llm~rk trait of ~ 's Disease. Further, chlol~ e is shown herein to be capable of treating and/or preventing 5 ~l7hçim~r~s Disease. Const.lu~ iy~ the compounds of this invention are useful for treating and/or ~.c~".Lillg the disease.
The human neurobl~ctom~ MSNla cell line G~ 5CS the plvt~;ns known to be involvedin PHF formation (inclllfling tau, other MAPs and neurofil~mf nt plc,Le;~,s, and thus is a cell line in which ~l7llf ;...l 's Disease e~iLo~e,s can be G~ ,ssGd. (Arias et al, J. Ne.,-~he,ll., 61: 673-10 682, 1993; Vincent et al, J. Nc.~ ., 62: 715-723, 1994).
Immunohistochemi~ ~l st~inin~ of brains from normal and Alzheimer's Disease (AD)patients using the monoclonal antibodies PHF-1 and TG3 inrii~pr~s that these monoclonal antibodies specificallv stain c~ of AD brain, but not normal brain (hgure 1). C`onrlitions were est~klich~od which led to hyperphosphorylation of the proteins known to be involved in 15 PHF formation. Using monoclonal antibodies PHF-1 and TG3 generated to human PHF
aldtions, the effects of a variety of manipulations of the pho5phorylation state of these proteins were tested. These tests c~luilcd that most of the aLncl ,lldl c~ilo~es l~,co~ cd by these monoclonal antibodies in the human ~l7h~imer brain should be gcll~ tcd in the MSNla cells.
The llc~ nr of MSNla cells with okadaic acid and other selecte~ inhibitors of protein 20 phosphatases has been found to generate the epitopes associated with these ~l~h~im~:r brain specifi. monoslona! antibodies, thereby meeti;.g, the re4ui~cil.c.its described above. These e~i~s are either absent or present at a very low level in ~Illllc~Lt~d MSNla cells.
The AD specifi~ity of the PHF-l and TG3 ~ntiho~ s was also demonstrated using anELISA assay. Shown in Figure 2A are bar graphs (percent of AD) of the ELISA
25 immllnoreactivity of brain plc~dlions (AD or normal) to either PHF-1 or TG3. Shown in Figure 2B are bar graphs (percent of MSN+) of the ELISA immnnoreactivity of MSNla cell Jaldlions (minus or plus okadaic acid) to either PHF- 1 or TG3. The MSNla cell ~ ~dlions plus vs minus okadaic acid closely parallel the AD vs normal brain l,lep~ ;o~c This clearly shows the relationship belv~ecn disease pathology (i.e. AD brain) and what is recognized by the SUBSTITUTE SHEET (RULE 26) CA 0220~x6 1997-0~-16 WO 96116052 PcrluS95/14987 antibodies in the MSNla in vilro cell culture assay. The cell culture system according to the LiOIl in which ~.p;~f,S C~ af`~ tiC of PHF can be readily ge~ tf -i and sul: s~ y l~eeo~ i by the specific ~1~1.. ;,.... brain specifie antibodies provides an assay suitable for screening cu~ oullds for their ability to block the ~luJI~ l;ol. of these pi~osL.hfj ylated c~itupcs.
PHF tau protein has lower affinity for microtubules as colllpdlcid to normal tau protein, which is likely the result of the abnf)rm~l pho~ .ulylatiûn (Lindwall et al, J. Biol. Chem., 259:
5301-5305, 1984). As a co..se~l~le..ce, microtubule ~lest~kili7~tion occurs which i~telr~..,s with illll,c,lia.ll neuronal ~lucesses such as rapid axonal Llansl,uli and, subsequently, this process leads to the follllaLiol. of PHF and the neurofibrillary tangles (Bancher, et al, Brain Res., 477, 10 90-99, 1989). Thus, inhibition of the ~ iul,l;on of the abnorrnal phosphorylated PHF f~)iL~)e S
will i~ .r~.e with and/or prevent the fO..l-atioll of PHF. Since PHF formation is a major feature of 1~ f l pathology, the development of co~ ol"~ds that intu.rcl~ with all or part of this process inhibit or prevent the ~lu~ ion of this disease.
The invention provides co-l-yuul-ds of formula I:
O
Ar~ N ~~
Y R24 ~ Z~ X~ Ar2 I
or the l,h~ e~ ;c~lly ~cceptA hle salts thereof wherein X is a c~ L~nyl, sulfonyl, methylene, or methylene ~ ,sl ;l l l~. cl with optionally snh~l ;n ~l-,d phenyl; and Z is nitrogen or C~I; and Arl and Ar2 in~rp~.,Ae.~tly ~ylcis~n~ aryl groups; and R24 is hydrogen; or when Y is other than hydrogen, R24 is hydrogen, loweralkyl, or optionally ~ l;nllrA phenyl; and Y is hydrogen, or Y and a substit~Pnt on the Arl group togethem~l~sellt a CH2.
CH2CH2, CH20, or CH2S group to form a five or six l-~-.-~.~d ring where the ring is optionally slll~ llrA with loweralkyl orphenyl.
SUBSTITUTE SHEET (RULE 26) , These co~ )(,ullds are useful for treating ~l7heimçrs Disease neoplastic disease and bat~teri~1 or fungal infections. Thus these coll,~ou,lds are antilleoplastic. ~nrihacterial. and 5 ~ntifim~l agents.
The coll",~)u"ds of this invention by preventing or decreasing the production ofah.l.~. ",~11y phnspht. ~ldl~d paired helical fil~mt m e~ u~es ~csoçi~rt t1 with the prot1l~ctin~l of the neurofibri11~ry tangles, a cl,a. .r~ ;r pathological feature of ~l,l.- h..~ s Disease. are useful in the Ll~ of this n~ cleg~ .- alive t1i~nrt1er.
The colll~ullds of forrnula I inhibit and/or prevent the formation of abnornallyphosphorylated epi~opes on PHF tau. Through inhibitory il~L~ ~acLions of the phosphorvlation events associated with the forrnation of PHF tau and other proteins involved in PHF ~",~I;Ol"
one can rno~ te the ~çmhly of tnicrotubules, thereby affecting neuronal processes such as rapid axonal transport, thus preventing the forrnation of PHF and the production of the 15 neurofih ill~ry tangles. Thus, the co",~ou,~ds of the present invention are lhc. .~ 11y useful in various neurodeg.--.~ aLive disorders such as ~ ;".t~ s Disease. In ~t1tlition the com~ou"ds of the present invention are useful for the ll~allll nl of certain neoplastic ~ e~es. and can be used as ~nti~rt~ori~l and antifun~l agents.
Thus the invention provides m~oth xls of ~ e.i~ii,g and/or treating ~ s Disease 20 in a patient comprising ~ mini~tering to the patient a co",pou,.d of formula I in an amount effective to inhibit forrnation of ah,-- ",~11y ~ho~l,o,ylated paired helical fil~m~nt epitopes.
SUBSTITUTE SHEET (RULE 26) Wo 96/16052 PCT/US95/14987 BRIEF DESCRIPTION OF THE DRAWrNGS
Figures lA-lD are images produced by light miclùsco~,y showing immnnoh~ e...~
staining of brain tissue from normal ~l~heim~ s Disease patients with monoclon~l ~ntibo~lies PHF-l and TG3.
SFigure 2A is a graphic CO~ O.I of normal (Norm) and Al,l.P:..... 's Disease (AD) brain hu...ngf ~t.o. ;...~ ,acLiv-ity toward PHF-1 and TG3 antibodies ~I,~sscd as a percent of total AD ;~ a~;livity.
Figure 2B is a graphic cu---~ ;con of MSNla cell lysate (minus or plus okadaic acid) immllnoreactivity toward PHF-1 and TG3 antibodies expressed as a percent of total 10 ;~ U~ a~,livi~y in lysates of MSN+ okadaic acid.
Figure 3 is a western blot showing PHF-1 ;....... ~ ,.eactivity in Iysates from control and chloll,lo...~ trea~ed MSN cells treated with okadaic acid.
Figure 4A is a chart showing relative ADAP conc~.~udLions in Brodman Area 10 in 's Disease p~tient~, normal controls and patients treated with chlul~lo---~ (Rx).
Figure 4B is a chart showing relative ADAP col-~e.~dlions in Brodman Area 38 in .Al,l.~;...~ ~ 's Disease pati~ont~l normal controls and patients treated with chl~ 7;~
SUBSTITUTE SHEET (RULE 26) Wo 96/16052 PCT/US95/14987 DETAILED DESCRIPrION OF THE INVENTION
The invention provides colllyuu,lds of formula I or the pharm~eut~ y acceptable salts thereof wherein X ~ carbonyl, sulfonyl, methylene, or methylene ~ulJ~1 with optionally ~ul . 5 phenyl;
Z is ni~u~c.l or CH with the proviso that when Ar1 is phenyl or ~ phenyl Z is ni~UO_.l;
Arl is a group of the forrnula:
R2R~
wherein Rl, R2 and R3 in~epen~l~ntly ~y.~sent hydrogen, fluoro, iodo, phenyl, nitro, trifluoroaL~cyl, thioloweralkoxy, cyclohexyl, amino, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, alkylsulfonylamino, optionally substitllted phenylethynyl, 4~s-~ih~loimi~l~7ole~ optionally suhstitl-te(l phenoxy, optionally ~ d phenyl amino, optionally sul~ 1 phenyl~lfi~1e, provided that Rl, R2 and R3 are not all hydrogen; or two of R1, R2 and R3 taken together can form an ethvlenedioxy, ethyleneoxy, or a lower straight alkylene chain alkyl bridge of 3-5 atoms op~ionally ~lb~ cl by loweralkyl; or Rl, R2 and R3 are the same or dirr~.cl~- and lGyl~s~n~ a group of the fo~
l~N J~; or Ar1 is a group of the forrnula:
SUBSTITUTE SHEET (RULE 26 r\ S~ ~R2s R7~$
R23 R23 ~
R26_N~N~R R25 N)~N~ 50~--R 54--R
R23 /~ R23~ ~R23 R23~_R23 R23--~N3--~R23 ~f~ R28~ R2-~R23 R6~o R~
or ~0 wherein X2 is oxygen or sulfur;
Rs is hydrogen, halo, loweraL~cyl, loweraLIcoxy or thioloweraL~coxy;
R6 is hydrogen, halo, or lowera~cyl;
R7 is hydrogen, lowerakyl, halo, nitro, cyano, optionally substitl1t~ri thienyl, 5 optionally substitllteci phenyl, morpholino, piperidinyl, piperazinyl, optionally SUBSTITUTE SHEET (RULE 26) substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulÇonyl~ h~yl, or optionally sllhstitl~t~o~ phenylca~ lyl~ ,.~illyl, R8 is loweralkyl or phenyl;
Rg and Rlo are independently selecte~l from hydrogen, halo, loweralkoxy, f 5 IIYC1~VAY;
R14 is s~lect~ from hydrogen, loweralkyl, nitro or halo;
Rlg and R20 are intle~e fie..lly select~l from hydrogen, loweralkyl, halo, nitro, oroptionally ~.b~ d phenyl;
R 21 is hydrogen, loweralkyl, nitro, halo, cyano, thienyl, phenyl, or phenylethynyl;
R22 is hydrogen, C~U ;~I1~ hUAY~ optionally ~.lbsl ;l ~.lrd phenyl or loweralkyl;
R23 is hydrogen or loweralkyl;
R24 is hydrogen; or when Y is other than hy~ug~ll R24 is hydrogen, loweralkyl, or optionally ~ d phenyl;
R25 is hydrogen, loweralkyl or thio~lko,lcy;
R26 is loweralkyl, optionally substitutecl phenyl or optionally sllb~
phenylmethylenyl; and R27 is loweralkyl, optionally subsl;~ e~ phenyl or optionally sub~itulcd ph~.lylln~ ylenyl; and R28 is hydrogen, optionally substitute~ phenyl, loweralkyl, or optionally A .t.hieny!; ~nd R2g is hydrogen, nitro, or loweralkyl; and provided that R7, R14 and R2g are not all hydlugell; and providcd that R23 and R28 are not both hydrogen; and Ar2 is a group of the formula:
R
r ~Rl Z
~UBSTITUTE SHEET (~ULE 26) WO 96/16052 PCT/US95tl4987 where Rl 1 and R12 independently lc~ulcsent hydrogen, halo, trifluo~u,l~ yl, amino, nitro, cyano, acetyl, thioloweraLIcoxy, or loweralkyl;
or Rl 1 and R12 together form a methyl~ncdioxy or ethylen~~ yy bridge; or Ar2 is naphthyl, optionally su~stitntP~l thienyl, furyl, 1~2~3-thi~Ai~7olyl~ or a group of the S fn~m-lR
CF~ R4 wherein R4 illd~p.,.ldently lc~ scnts lly~gen, halo, or loweralkyl;
R13 is selected from hydrogen or halo; and Y is hydrogen, or Y and Rl, R2, R3, R1g, R20, R22, R23, or R2g together lc~l~se.lt CH2, C(R24)2cH27 C(R24)2o~ or C(R24)2S forming a five or six membered ring.
f~.l~ coll~.uul,ds of formula I are those where Arl is a group of the formula:
R1~,~
R2~J
wherein Rl, R2 and R3 in~epen~ently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweraL~coxy, cyclohexyl, amino, acetyl, morpholino, cyano, piperidinyl, trifluoroaL~oxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihak>imi~701e, optionally sl1bstitllt~rl phenoxy, optionallysubstit~ted phenylclllfi~le, provided that Rl, R2 and R3 are not all hydrogen; or SUBSTITUTE SHEET (RULE 26) two of Rl, R2 and R3 taken together can form an ethylenedioxy, ethyleneoxy, or a lower straight alkylene chain aLkyl bridge of 3-5 atoms optionally ~u~ t~A by lowe~aLkyl;
Z is N; X is CH2; and Ar2 is sn~l ;lul~ phenyl.
Most pl~,r~ ,d culll~ounds of formula I are those where Arl is nilluphe.lyl. Other ~ul~ d colll~ûunds of formula I are those where Arl is iodo- or fluc~luphellyl. ~ef,.l~d iodo-or nulu~h~llyl colllpûullds are those where the halogen is in the para position with respect to the plu~ ol~e group. More ~ ,ll~ iodo- or fluluphellyl co~ uunds are those where the halogen is in the meta position. Particularly ~ d iodo- or Ilulu~hc.lyl colll~oullds are those where 10 the halogen is in the ortho position.
~ ef~ d c~.lllpou.lds of formula I having a het-,.u~uyl group as the Arl sut-stitllent are those where Arl is N-arylsulf~,nylpyllulyl, more preferably optionally s~ d isoxazolyl, and still more plci~,ably, optionally ~"~ "I A thiazolyl. Most ~IGr~ d colll~oullds of formula I having a hot~,-v~yl group as the Arl substinle~t are those where-Arl is optionally ~ .Jt~
15 thienyl. E~Cr.,ll~d colll~ùullds of formula I where Arl is optionally sllhstit~lto-d thienyl are those where X is CO. Particularly pler.,l,~d col"~oullds of formula I where Arl is optionally s,.l,~l;l.,t~A thienyl are those where X is methylene.
The invention further provides cc,l,lpounds of foîmula II:
Ar1J~ N ~
1 Z~ X~ Ar2 wherein X l~ ,StnL~ Cdll~llyl, sulfonyl, or methylene;
Z is ni~ug~ll or CH with the proviso that when Arl is phenyl or s~ ;lul~l phenyl Z is nitrogen;
25 Arl is a group of the formula:
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 WO 96/16052 PCr/US95/14987 R,~
wherein Rl, R2 and R3 il~d~ n~ y l~,~cse.l~ hydlug~n, fluorine, iodine, phenyl, nitro, I-inuul~alkyl, thioloweraL~coxy, cyclohexyl, amino, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimin'~7ole, optionally substitut~q' phenyl amino, optionally snb~ d phenoxy, optionally substituted pheny1~lllfin7e~ provided that Rl, R2 and R3 are not all nyd-ùg~,.l, or Arl is a group of the formula:
or R1~;
wherein R6 is hydrogen, halo, or loweralkyl;
Rg and Rlo are independently selected from hydrogen, halo, loweralkoxy, hydroxy; and Ar2 is a group of the formula:
~R12 where Rl 1 and R12 independently l~plesent hydrogen, halo, trifluolulllelllyl, amino, nitro, cyano, acetyl, thioloweralkoxy, loweralkyl, or taken together forrn a methyleneaioxy bridge.
SUBSTITUTE SHEET (RULE 26) Wo 96/16052 PCr/US95/14987 The invention also provides co~ uullds of formula m Ar s m wherein Rl 1 and R12 ind~ ie~nly ,c~,~,se.~l hydlugcn, halo, l~ifluun"llcllly-l, nitro, cyano, acetyl, amino, thioloweralkoxy, loweralkyl, or taken together form a methylenedioxy bridge;
Arl is a group of the formula:
R~
R2~J
wherein Rl, R2 and R3 in~epçndlontly lG~ ;S'eU~ hy..l-ugc~, fluorine, iodine, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, acetyl, amino, morpholino, cyano, piperidinyl, loweralkyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino,optionally su~s~ çd phenylethynyl, 4,5- iih~loimir~7t~le, optionallv ~I,h~
~}~_-,o~y, optionally ~ !;llllr(~ phenyi.culfi~e, provided that Rl, R~ and R3 are not all hydrogen; or Rl, R2 and R3 are the same or dirrc~cnL and lc~lcS~ L a group of the forrnula:
~N~
SUBSTITUTE SHcET (~ULE 26) ~=
CA 0220~86 1997-0~-16 The invention further e.~ro, ~ cces cull.~unds of Formula IV:
~~ ~N~Ar2 IV
wL~ Ar2 ~c~lescnl~ phenyl or phenyl mono or riicub~stitlltpc~ with halogen, cyano, nitro, or optionally s~ thienyl groups.
The invention further en~o~ cses culn~u,,ds of Formula V:
R2~N~
~S ~N~x,Ar2 Rl V
wherein X f~ sellla c~ul~llyl, sulfonyl, or methylene; and Rl lcpl~,sellts hydrogen, loweralkyl, halogen, cyano, nitro, optionally substituted thienyl, optionally substinlt~i phenyl, morpholino, piperidinyl, piy~,~a~ yl7 optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenyl~ulr~"lyll.;pr.i.7;..yl, or optionally substih-tetl phenylc~u-AJ"yl~ip~ lyl; and R2 is hydrogen, nitro, loweralkyl or halogen; and R3 is hydrogen, nitro, or loweralkyl; and provided that not all of Rl, R2 and R3 are c;mlllt~ntoollcly hydrogen; ar d Ar2 represents thienyl, phenyl or phenyl mono or riicllbstituted with halogen, cyano, nitro, loweralkyl, or loweraLlcoxy groups; or Ar2 is a group of the fnrrnlli~
~Rs -18- = = =
SUBSTITUTE SHEET (RULE 26) wl~ ,;n R4 and RS are indepenrl~ntly selected from hydrogen, h~lo, or loweralkylgroups.
Re~.~,stl,ld~i~e ~.ef~..~ cc,.l~ou.lds of formula V are those where Arl is a thienyl group s~ t. A as follows:
Cl_~~5sS Brl~ 55s 02N~5SS
~ H3C~ j~, s 02N--~ NC ~ SCH3 The inven~ion further ~ o,..l~c.cbs comyvullds of Forrnula VI:
R~ ~ X' Vl wherein X ~ c:sel.ls carbonyl, sulfonyl, or methylene; and Rl ,~ sel.t~ halogen, loweralkyl, nitro, or cyano; and Ar2 le~r~se-,Ls phenyl or phenyl mono or disubstituted with halogen, cyano, or nitro groups.
The invention further ellco.~ cces cum~ou.1ds of Forrnula VII:
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCI~/US95/1~987 R2 ~N~ ,.
~S ~N~Ar2 R, VII
wherein Rl and R2 are independently selected from hydrogen, halogen, loweraLkyl, nitro, or S optionally ~.u~ lr~ phenyl; and Ar2 ~ scnts phenyl or phenyl mono or riicuhstitute~ with halogen, cyano, nitro, loweraL~cyl or loweralkoxy groups.
Re~ senlative ~lcîtll~,d compoullds of formula VII are those where Rl and R2 arehydrogen The invention further encomp~cses cOlllpC ull~S of ~o~nula VIII:
N~N~
~N~x,Ar2 vm wherein X lc,vl~ ,ents carbonyl, or methylene; and R1 l~,~lcs7cllL~. hydrogen, optionally sllhstinl~qd phenyl, C~I~I11~LhCSAY7 or loweralkyl; and R2 Lyd~ ,n, or loweralkyl; and Ar2 represents phenyl or phenyl su'Qstit-lted with halogen, cyano, nitro, loweralkyl, or loweralkoxy groups.
Re~l~,se.l~ti~e ~lcf~,.l.,d cc.lllp.Jul.ds of formula VIII are those where Rl is phenyl and R2 is methyl.
The invention further encomp~cces compounds of Formula IX:
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCr/US95114987 R1--<~N~
c S ~ N~, Ar2 IX
wherein Rl lcpl~,scnts hydl.,gen, phenyl, or phenyl sub~litul~d with halogen, cyano, or nitro groups; and Ar2 l~,~,csent~ phenyl or phenyl s~lbs-itnt~i with halogen, cyano, nitro, loweralkyl, or loweralkoxy groups.
The invention further encc,~ ac.ces co,lll,ou,lds of Forrnula X:
R1~N~
N--O ~ N~, Ar2 X
wherein Rl lcpn,sents hydrogen, optionally substituted phenyl, c3~ llcLiloxy, or loweralykyl groups; and Ar2 represents phenyl or phenyl sllbstitnte~ with halogen, cyano, nitro. loweralkyl, or loweralkoxy groups.
The invention further er~comracces colllyoullds of Formula XI:
--N~
S2 ~N~X~Ar2 SUBSTITUTE SHEET (RULE 26) CA 0220~86 l997-0~-l6 Wo 96/160S2 PCItUS95/14987 wherein X r~ .,Ls carbonyl, sulfonyl, or methylene; and Ar2 re~,Sel~l~ phenyl or phenyl subs*tll~e~i with halogen, cyano, nitro, lowerallcyl, or loweralkoxy groups.
The inven*on further e~ro".l~c~es co,.,l~ull~c of Forrnula XII:
~N~
)~ O ~,N~, Ar2 R, XII
wherein R~ ,S~illL:~ optionally s~lhsl;L~ phenyl, op*onally ~ub~ d thienyl orloweraLcyl groups; and Ar2 r~ sel,L~ phenyl or phenyl sllb~ A with halogen, cyano, nitro, loweraLI~yl, or loweralkoxy groups.
The invention further ~.nr~,l"l ~cces cc~ ounds of Forrnula XIII:
~N~N~ Ar2 XIII
wherein R~ csel,ts hvdrogen, halo, thioloweraLkoxy, loweralykyl, or loweralkoxy groups;
and SUBSTITUTE SHEET (RULE 26) Ar2 lc~lcse.ll~ phenyl or phenyl subs~ with halogen, cyano, nitro, loweraL~yl, or loweraL~coxy groups.
The invention further e ~oll ll.hc.cf s ~olllyounds of Forrnula XIV:
S
NO ~N~f 3 R1 ~3 R2 XIV
wherein Rl and R2 in~f penrlf nrly lc~l~,sent hydrogen or h~log~n The invention further e'n~ CCeS COlll~)vullllS of Forrnula XV:
R1~` N ~ ~N~, Ar2 XV
15 wherein R1 and R2 infi~ pf...rl~ y lc~c;~cnt hydrogen, nitro or halogen; and Ar2 lc~lcsenl~ phenyl or phenyl ~LIb~Lulcd with halogen, cyano, or nitro groups.
The invention further encomp~scec col~lyoul1ds of Forrnula XVI:
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCI`/US95/14987 R2~=~R3 1--N~ ~Ar2 R1--N`N~ `J
XVI
wherein R 1 is loweralkyl, optionally substituted phenyl, or optionally substituted ~lle.. yll~ ylenyl;and R2 and R3 are hydlu~,~,n or lower alkyl; and X lel,.esen~ carbonyl, sulfonyl, or methylene; and Ar2 l~V~SclllS phenyl or phenyl sub~ lerl wi~h halogen, cyano. nitro, loweraLlcyl, or loweraL~oxy groups.
The invention further e-~o~ cs culll~uullds of Formula XVII:
R ~ N ~
R _N~ R3 ~ N~ X~ Ar2 XVII
wherein R 1 is loweralkyl, optionally substituted phenyl, or optionally substituted phenylmethylenyl; and R2 and R3 are llydlu~ or lower alkyl; and X ~ s~.lLs carbonyl, sulfonyl, or methylene; and Ar2 IG~lcsenl~ phenyl or phenyl substitllt~-l with halogen, cyano, nitro. IoweraL~cyl, or t loweralkoxy groups.
The invention further e..~-....l.~c~es co-l-~ou,-ds of Formula XVIII:
SUBSTITUTE SHEET (RULE 26 WO 96/16052 PCr/US95/14987 (~ ~Z~ , Ar2 xvm wherein Z is CH or nillug_.n, S X is carbonyl, sulfonyl, or methylene;
M is CH2, C(Rl)2CH2, C(RI)2O, or C(RI)2S;
Rl is hy~llu~e,l, loweraL~cyl, optionally ~ d phenyl;
Ar2 is optionally sllb ~ d phenyl, optionally Sl11~ r~ thienyl, or furyl; and ("the A ring") lc~l~se.ll~. an aryl or ncter~,~yl ring having from zero to three he~ero atoms selecteA from the group cQncicting of oxygen, sulfur and nitrogen.
Aryl and heteroaryl groups l~le~.e.,~d by the A ring are aromatic or hetcr~3uulna~ic syste ns rl, ..~rt~ d by 4n+2 7~ electrons.
The invention further e.,( l~lllr~7cses cc,~ uunds of Formula XIX:
R_~ ~ X' XIX
wherein Z is CH or lli~lugC~l; and X is carbonyl, sulfonyl, or methylene; and M is CH2, O, S, or a direct bond; and Rl is hydrogen, loweralkyl, optionally substin~trA phenyl; and SUBSTITUTE SHEET (RULE 2~) _ WO ~6/16052 PCT/US95114987 R2 and R3 are i..~- y,~ nt1y sel~cl~d from hydrogen, halogen, loweralkyl, nitro, cyano, alkylsulfon~mi~lo, arylsulfon~mido, optionally s~ phenyl, or R2 and R3 taken t~,~ e. ~I,ylcsel~L a methylhlc~io~ ring; and Ar2 is optionally sl1b~ ;n ~lr~ phenyl, optionally ~ thienyl, or furyl.
.
The invention further en~rJ~p~cses coll~uullds of Formula XX:
R3 ~ N~z~ X' Ar2 XX
wherein Z is CH or nitrogen; and X is c~ul,onyl, sulfonyl, or methylene; and M is CH2, O, S, or a direct bond; and Rl is hydrogen, loweralkyl, option~11y Sl1b~ 1 phenyl; and R2 and R3 are il,dey."ldently selected from hydrogen, halogen, loweralkyl, nitro, cyano, or optionally s1~bstit-1t~A phenyl; and R4 is hydrogen, loweralkyl, optionally substituted phenyl, or optionally substituted ph~l,yLllcL}l~lenyl; and Ar2 is optionally ~.u~iLuL~d phenyl, optionally substirl-t.od thienyl, or furyl.0 The invention further e.~co, .p~cceS colll~oul,ds of Forrnula XXI:
R 1, ~ N
N ~ M ~ R 1 ~ Z~ X~ Ar2 XXI
SUBSTITUTE SHEET (RULE 26 , wherein Z is CH or ~ ug~ , and X is carbonyl, sulfonyl, or methylene; and M is CH2, O, S, or a direct bond; and S Rl is lly~L~Jg~"~, loweralkyl, optionally s~lkal;lu~-A phenyl; and R2 is hydrogen, halogen, loweralkyl, nitro, or cyano; and R3 is hydrogen, loweralkyl, optionally subsl;l.,l.,d phenyl. or optionally sub~
phenyL~ l,yle,.yl, and Ar2 is optionally ~..h~ phenyl, optionally sub~l ;l it~.l thienyl, or furyl.
The invention further .oncomr~cces coll,~x>ullds of Fonnula XXII:
o R1 R2~ X~
XXII
wherein Z is CH or uillugf;n; and X is carbonyl, sulfonyl, or methylene: and M is CH2, O, S, ûr a direct bond; and Rl is hydrogen, loweralkyl, optionally Su'c~ ;llllf ~ phenyl; and R2 is hydrogen, halogen, loweralkyl, nitro, cyano, optionally substituted phenyl, alkylclllfon~miAo, arylsulfon~miAc)7 or thioloweralkyl; and Ar2 is optionally sub~ ut.,d phenyl, optionally subs~ led thienyl, or furyl.
The invention further encomracses colll~oullds of Fo~nula xxm SUBSTITUTE SHEET (RULE 2B) CA 0220~86 1997-0~-16 WO 96116052 PCr/US95/14987 ~Sx~ N~
XXIII
wherein Z is CH or nitrogen; and S X is ca~ lyl, sulfonyl, or methylene; and M is CH2, O, S, or a direct bond; and Rl is hydrogen, loweraLcyl, optionally ~k~ rl phenyl; and R2 is hvdrogen, halogen, loweralkyl, nitro, cyano, optionally substit1lte~i phenyl, alkylsulfonamido, arylsulfon~mi~o, or thioloweraL~cyl; and Ar2 is optionally sul~ A phenyl, optionally sul~ lr~ thienyl, or furyl.
The invention further e ~ , . .p~cses cc,lllyOullds of Formula XXIV:
R2~ ll R1 R3~ ~Z~ X~ Ar2 XXIV
wherein Z is CH or nitrogen; and X is carbonyl, sulfonyl, or methylene; and M is CH2, O, S, or a chçmic~l bond; and Rl is hydrogen, lowe~L~cyl, optionally sub~LiLuLed phenyl; and Y is O or S; and R2 and R3 are independently selected from hydrogen, halogen, loweraLlcyl, nitro, cyano, or optionally i~b~ lr~ phenyl; and SUBSTITUTE SHEET (RULE 26 WO 96/16052 PCr/US95/14987 Ar2 is optionally suk~ e~ phenyl, optionally sl1hstitut~rl thienyl, or furyl.
The instant invention in~ os optically active cc .lll,oul,ds as well as racemic I~ ,s of such co~ oullds. The invention further in~ es the pk,.. ~r~ ~,I;e~lly acceptable salts of such compounds or racemic ll.i~lu.es. The invention still further includes pharm~eutiral COlllyOC l l l~ c, As used herein, the term "loweralkyl" means straight or branched chain saLuldud hyd~ uL~n radicals having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, ~-butyl and the 10 like.
As used herein, the term "thioloweralkoxy" refers to -SRIs, wherein R1s is loweralkyl.
As used herein, the term "halo or halogen" refers to fluorine, chlorine, bromine, or iodine.
As used herein, the term "aryl" refers to systems ch~dc~ ed by 4n+2 ~ electrons, i.e., 15 aromatic carbocyclic groups having a single ring (e.g., phenyl), mnltirle rings (e.g., IJil~h~nyl) or m~lltirlP conflence~i rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahy~u-laphthyl, naphthyl, anthryl, or phe-n~nth yl), which can optionally be u~ ~ or Sub~ 'lled with e.g., halogen, lower alkyl, lower alkylthio, t.inuulull.~,.l-yl, lower acyloxy, aryl, and hetelua.yl.
As used herein, the term "heteroaryl" means ~, 6, or 7 membered aromatic ring systems 20 having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolo. pyrazolo, pyrazinyl, pyridazinyl, oxazolo, furanyl, quinoline, isoquinoline, thiazole, thi~ 7nle, isoxazole, and thienyl, which can optionally be ~ncukstitntPA or ~b~,l;Llll~ with, e.g., halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, cyano, nitro, aryl, and 25 heteroaryl.
As used herein, the term "alkylsulfonylamino" means R16S(0)2NR17 - wherein R16 is loweralkyl, phenyl, or suhstit~ phenyl, and R17 is hydrogen, loweralkyl or -S02R16.
SUBSTITUTE SHEET (RULE 26) -CA 0220~86 1997-0~-16 WO 96/16052 PCr/US95/14987 As used herein, the term "tnfluoroallcoxy!' refers to -R1gCF3, wherein R1g denotes a loweralkoxy group as defined above, atrAehed to the parent molecular moiety through the oxygen atom. Rel"~ sen~ es of such groups include mr thlr~nr oxy, ethyleneoxy and the like.
As used herein, the term "optionally substinlte~ phenyl" refers to a phenyl ring having 5 from zero to three substiturntc independently selected from loweralkyl, halogen, hydroxy, loweralkoxy, am~no, thioloweralkoxy, nitro and cyano.
As used herein, the term "optionally substituted thienyl" refers to a thiophene ring with from zero to three sllbs!;~ r~ inriepen(irntly selected from loweralkyl, halo, phenyl, cyano and nitro.
As used herein, the term "optionally substituted phenoxy" refers to the phenoxy ring ;I- I~A as defined foroptionally s~ ~ phenyl.
As used herein, the term "optionally s,.b:,lin.led phenylsulfide" refers to a thioph~nyl ring ..I.~I;n.t~A as defined from optionally su~ t~ ~ phenyl.
The terrn "~hA..n~ Ally a~ceptAhle salts~' refers to the phz1rm~ceuticAIIy acceptable, 15 leld.i~,~ly non-toxic, inorganic, or organic acid addition salts of the co.ll~uuu,-ds of this invention.
These salts can be pl~?d,Cd in situ during the final icolAtir n and pnnfirAtion of the com~uullds or by sepz~r~t~ly reacting the free base with a suitable organic or inorganic acid. Rc~,~se.,ldlive salts include the hydrochloridr7 hydlub~ ide, sulfate, phosphzltç, nitrate. bicn1fzltç~ acetate, oxalate, valerate, oleate, palmitrate, mr~th~Anesulfonate~ stearate, laurate. borate, ben70At~, lactate, 20 phosphate, tosylate, citrate, mztlrAt~ ru",a.a~e, ~uc~.-inAIr tar~rate. napsylate. lactobionate, and the like. It will be app&cl~L to those skilled in the art that, depending upon the number of available amino groups for salt formation, the salt of this invention can be per N-salts.
The present invention also provides pharmzl~euti~AI cc,lllposiLions which comprise one or more of the culllpoul,ds of fonnnlzle I-XXIV above formlllAt~od together with one or more non-25 toxic phAnmAreutirAlly acceptable carriers. The pharmzl~ ellticAl co~ x~iLions may be specifirz~llyfi~nmlllzAt~ for oral a~minictration in solid or li~uid fiorm, for ~al~.ne~dl injection, or for rectal ~rlmini5tration.
The phArmAreutirZ~l compositions of this invention can be A-lministered to humans and other zlnimAIc orally, rectaly, parenrerally (i.e. intravenously, intramuscularly, or sub-SUBSTITUTE SHEET (RULE 26) WO 96/160!;2 PCT/US95/14987 cutaneously), intracicterll~lly, intravaginally, intraperitoneally, topically (as by powders, Oi.. l.. lc or drops), t,,i,-cA~.. ~lly, bucally, or as an oral or nasal spray.
Pl,~...A~eutil~l coll,~ositions of this invention for parenteral injection comprise pl~ e~ lly acceptable sterile aqueous or nonagueous solutionc~ dispersions, sucpçn~ionc S or emulsions as well as sterile powders for l~,con~ n into sterile injectable solutions or ;o~c just prior to use. F~r~mplec of suit~ble aqueous and nona~ueous carriers, rlilu~ntc, solvents or vehicles include water, eth~nol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and sni~h~ Lul~S thereof, veget~hle oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be m~int~ined, for 10 er~mrle, by the use of coating m~t~ri,~l.c such as lecithin, by the n~int ..~n-e of the required particle size in the case of ~ ;onc~ and by the use of s~ ri1-.,;...,c These CU~ Jo~iLions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. E~ ,ntion of the action of microorg;lni~mc may be ensured by the inclusion of various ~ntiba~tlorial and antifungal agents, for ex~mrle, p~r~hen, 15 chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chlotide~ and the like. Prolonged absorption of the injectable ph~ en~ l form may be brought about by the in~lll$inn of agents which delay absorption such as ~1.. ;.~.. " 111(1115~ t~ and gelatin.
If desired, and for more effective distribution, the colll~unds can be incul~-,laL~d into 20 slow release or targeted delivery systems such as polymer matrices, liposomes, and The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter. or by incorporating sterilizing agents in the form of sterile solid compositions which can he dissolved or dispersed in sterile water or other sterile injectable 25me~ m just prior to use.
Solid dosage forms for oral ~Aminic~ration include capsules, tablets, pills, powders, and "granules. In such solid dosage forms, the active compound is mixed with at least one inert, ph~rm~re-ltic~lly arcept~hle eYcirient or carrier such as sodium citrate or rlic~ -m phosphate and/or a) fillers or e~rt~n~l~rs such as starches, lactose, sucrose, glucose, m~nnitQl, and silicic SUBSTITUTE SHEET (RULE 26 acid, b) binders such as, for example, carboxymethylcellulose, alingnates. gelatin, polyvinyl~yllolidone~ sucrose, and acacia, c) hl.n,~ nl~ such as glycerol, d) disintegrating agents such as agar-agar, c~lri-lm carbonate, potato or tapioca starch, alginic acid, certain Cilir~tes~ and sodium carbonate, e) solution retarding agents such as paraffin. f) absorption 5 accelc,a~ such as 4l~ . . .;., y ~" ", .on ;~.. ., co.ll~ou,lds, g) wetting agents such as, for e~ lc, cetyl alcohol and glycerol IlllJno~ P~ h) absc,~ such as kaolin and benl-J~;Ie clay, and i) Inl..;r,~ such as talc, calcium ste~rat~, m~nP~ st~oA-ate, solid polyethylene glycols, sodium lauryl sulfate, and llli~cLul~.~ thereof. In the case of capsules, tablets and pills, the dosage form may also co...~ b..r~ .;"g agents.
Solid c.,~ u~;l;ons of a similar type may also be employed as fillers in soft and hard-filled gelatin c~ps--lPs using such txci~ s as lactose or milk sugar as well as high molec~ r weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsulPs, pills, and granules can be ~
with co~tingc and shells such as enteric coatings and other coatings well known in the 15 ph~.,,-A~ l;r~l formlll~ting art. They may optionally contain opacifying agents and can also be of a cc,lll~osiLion that they release the active il,~l~diel-L(s) only, or ~l~r~.c.lLially, in a certain part of the in~pstin~l tract, optionally, in a delayed manner. FY~"l,l~ S of emhedriing colllpo~iLions which can be used include polymeric subst~nrec and waxes.
If desired, and for more effective distribution, the co...~oL,nds can be incolluulalcd into 20 slow release or targeted delivery systems such as polymer matrices, liposomes. and microspheres.
The active colll~ullds can also be in micrc~nr~rslli~teri form, if ayl,lUluliate. with one or more of the above-mPntion~l PYripiet~tc Liquid dosage forrns for oral ~riminictration include pharrn~reutic~lly acceptable 25 emlllcinnc, solutions, sncpencionc, syrups and elixirs. In addition to the active co~ o~dds, the liquid dosage forms may contain inert diluents cc,llllllollly used in the art such as, for example, water or other solvents, solubilizing agents and emlllcifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl bPn7nate propylene glycol, 1,3-butylene glycol, dimethyl fol",~ oils (in particular, coSI~ ec~l gr~!un~lnl-t corn, germ, SUBSTITUTE Sl ~'EET (RULE 26) CA 0220~86 1997-0~-16 olive, castor, and sesame oils), glycerol, tetrallydlorullulyl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and ~ ul~,s thereof.
Besides inert rlihl~nt~ the oral co,llpo~ilions can also include adjuvants such as wetting agents, emulsifying and snspen~ing agents, s-.eet~ g, flavoring, and p~,.ru,llil,g agents.
S S.. ~ ;ollc, in ~drlitil~n to the active colllp~llllds, may contain ~ e ~rlhlg agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, ,l~ly~L~lline celllllnse, ~II....in~.... metahydroxide, bentonire, agar-agar, and ~g~nth, and ix lw- s thereof.
Collll,osilions for rectal or vaginal ~lminictration are preferably ~u~pO~ ;F-S which can 10 be ~l~p~ed by mixing the cc,llll)uu,~ds of this invention with suitable non-irritating excirient~ or carriers such as cocoa butter, polyethylene glycol or a ~ul,l)osilo~y wax which are solid at room e~ a~ but liquid at body ~ e and therefore melt in the rectum or vaginal cavity and release the active co,l,~uul,d.
Dosage forms for topical ~rlmini~tration of a compound of this invention include15 powders, sprays, oimmlontc and inh~ nsc. The active co~l~pound is mixed under sterile con~itic n~ with a ph~. ,n~r~ ;c~lly acceptable carrier and any needed preservatives, buffers, or propellants which may be re~uired. Ophth~lmir form-ll~tions, eye ointmrnt~ powdc.~ and sol~tion~ are also conr~ tecl as being within the scope of this invention.
Actual dosage levels of active ingredients in ~he ph~rm~reutical co"l~uo~ilions of this 20 invention may be varied so as to obtain an amount of the ac~ive compound(s) tha~ is effective to achieve the desired therapeutic response for a particular patient, co"lpositions, and mode of a~lmini~tration. The selected dosage level will depend upon the activity of the particular compound, the route of a~lmini~tration, the severity of the condition being treated, and the condition and prior mtoAir~l history of the patient being treated. However, it is within the skill of 25 the art to start doses of the co"l~ound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 0.1 to about 200, more preferably of about 05 to about 150, and most preferably about 1 to about 125 mg of active collJpo.lnd per kilogram of body weight per day are ~rlmini~tered orally to a .. ~.. ~li~n patient suffering from ~ hP.. r.'s Disease, SUBSTITUTE SHEET (RULE 26) CA 0220~86 l997-0~-l6 Wo 96tl60S2 PCr/US95/14987 neoplastic disease, or bacterial or fungal infections. If desired. the effective daily dose may be divided into m1llrirl~ doses for ~u~l,oses of ~flmini~tration, e.g. two to four Sc~dlc doses per day.
All rloc~ e.g., patents and journal articles, cited above or below are hereby 5 il~Cul~ul.. t~l by lcr~ c"cc in their entirety. - =
One skilled in the art will recognize that m~iifir~tion~ may be made in the present invention without deviating from the spirit or scope of the invention. The invention is illnst-~t~
further by the following eY~mpleA which are not to be con:,llued as limiting the invention or scope of the specific IJloc~luu~;s d~osor~ herein.
GENERAL PROCEDURE
As is more fully e~pl~in~d in the following scheme and ~ ...ples, the com~oul.ds of the invention may be ylcp~u~c1 by adding an ~lv~liate seconrl~ry amine (l mole) to a solution of c~ e~ni.tcd hy~llucllloric acid (2-5 moles) in suffisient iso~luyallol to achieve an amine col-~e..l. a~ion of about 0.1 M-0.4 M. To the solution of amine hydrochl~ri~e salt which has been 15 forrned in situ is added p~arollllaldehyde (1-2.2 moles) followed by the desired aryl or hetc.û~L~cetone (1.1-2 moles), and the resulting reaction mixture is then refluxed for about 12-72 hours. The reaction is cooled and the res1llting solid is filtered and recryst~lli7~d from l or lliLul~l~ with ...~ l or ethanol to afford the desired product.
The co..lyuul~ds of the invention may be ~rcl,a.cd according to the reactions set forth in 20 the following reaction scheme.
ArlJlCH2 + ~PrOH ~ Ar~ N ~
HN ~ HCI Y ~ Z~ X~ Ar2 ~Z~x,Ar2 where Arl, X, Y, Z and Ar2 are as defined above for forrnula I.
Using the above-described procedure, the cûllllJu~ ds described in the followingeY~mples were yl~
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 Wo 96/16052 PCr/US95/14987 FY~mrle 1 G
~ ~ ~N v~3 l-~D-Iodoph~ 1)-3-(4'-benzyl-1'~ "a7il~yl)-l-~o~allolledihydrochloride: mpæ4 C (dec.);
lHNMR(300MHz,DMSO-d6) ol2.0(brm,2H),8.0(d,2H),7.65(d,2H),7.6(m,2H), 5 7.45 (m, 3 H), 4.4 (brs, 2 H), 4.0-3.2 (m, 12 H).
FY~rnrl~ 2 ~ uph~nyl)-3-(4'-benzyl-l'-pi~illyl)-1-~ panone dihydrochloride: mp > 240 C; lH
NMR of the free base (300 MHz, CDC13) o 8.0 fm, 2 H), 7.3 (m, 5 H), 7.13 (t, 2 H), 3.5 (s, 2 H), 3.15 (t, 2 H), 2.85 (t, 2 H), 2.55 (brs, 8 H).
FY~mrle 3 1-(3",4"-Dichk~lu~hfnyl)-3-(4'-benzyl-1'-pi~"a~i~lyl)-1-pl~dn(~lle dihydrochloriA~-: The solid was converted to its free base using NH4OH, e.~ a~ ;i with dichlolu~ tl ~l-f and purified via flash ch~,nlal.,graphy (Silica, EtOAc). The resulting oil was converted to its dihydrochl~ride salt by ~AAition of drv ether-HCI to give the desired ~I~Klu~; mp 220 C (dec.); lH NMR of the free 15 base (300 MHz. CDC13) ~ 8.03 (d, 1 H), 7.77 (dd, 1 H), 7.53 (d, 1 H), 7.3 (m, 5 H), 3.5 (s, 2 H), 3.12 (t, 2 H), 2.82 (t, 2 H), 2.5 (brs, 8 H).
Exarnple 4 1 -~D-Chlorophenyl)-3-(4'-benzyl- 1 '-piperazinyl)- 1 -plo~anone dihydrochloride: mp > 230-C; lH
NMR of the free base (300 MHz, CDC13) ~ 7.9 (d, 2 H), 7.43 (d, 2 H), 7.28 (m, 5 H), 3.5 (s, 20 2 H), 3.15 (t, 2 H), 2.83 (t, 2 H), 2.5 (brs, 8 H).
Fx~mrlt~- 5 l-~D-Nitrophenyl)-3-(4'-benzyl-1'-pi~dzillyl)-1-~1ul,dllunc dihydrochloride: A mixture of p-nitroacetophenone (6.09 g, 0.037 mol), I-benzylpiperazine (5.00 g, 0.023 mol), SUBSTITUTE SHEET (RULE 26) - - =
CA 0220~86 1997-0~-16 p~ar~ ehyde (1.11 g, 0.037 mol), and concc~.t.d~A hydrochloric acid (7.00 mL.
0.084 mol) in 100 mL isopropanol were refluxed for 16 h. The reacton was cooled. filtered, and the flter calce was !- ;~ A with m~ nol (4x) to give 4.6 g (51%) of the desired p.~duct:
mp 250-C; IH NMR (300 MHz, DMSO-d6) ~ 11.5 (brm, 2 H), 8.4 (d, 2 H), 8.2 (d, 2 H), 5 7.66-7.36 (m, 5 H), 4.3 (brm, 2 H), 3.8-3.2 (brm, 12 H).
FY~mrle 6 1-(3"-Thienyl)-3-(4'-benzyl-1'-pi~ yl)-1-pl~.p~ edihydT~ch~ Ae mp223 C; lHNMR
(300 MHz, DMSO-d6) o 11.5 (brs, 2 H), 8.56 (s, 1 H), 7.8-7.3 (m, 7 H), 4.3 (brs, 2 H), 3.9-
3.0 (brm, 12 H).
F.y~mrlto 7 1-(2"-Thienyl)-3-(4'-benzyl-1'-pi~.,~inyl)-1-~1ul)ano"cdihydrochln~iA~o: mp240-241 C; lH
NMR (300 MHz, D2O) ~ 7.82 (m, 2 H), 7.4 (brs, 5 H), 7.1 (m, 1 H), 4.3 (s, 2 H), 3.5 (brs, 12 H).
FY~mri~ 8 ~3~ H~c~
1-[3"-~-Chlol~,~hc"yl)snlfon~miAophenyl]-3-t4'-benzyl- 1 '-piperazinyl)- l-p~ one dihydrochln~ mp 151-153 C; lH NMR (300 MHz, D20) ~ 7.7-7.14 (m, 13 H), 4.2 (s, 2 H), 3.55-3.2 (brs, 12 H).
FY~mrle 9 o F3C ~ N~3 -3~
SUBSTITUTE SHEET (RULE 26) 1-[3",5"-Bis-(~inllol"~ yl)phenyl~-3-(4'-benzyl- 1'-~ yl)- l-~lul)al~ûne ~lihy~ nn~ The solid was basified with NH40H, e~ ed with dichlo~ e and purificd via flash clll.~ u~rhy (Silica, EtOAc). The free amine was converted to its dihydl~ nTide salt by the ~ ition of dry ether-HCI: mp 255 C; IH NMR of the free base (300 ~, S MHz, CDC13) o 8.38 (s, 2 H), 8.07 (s, 1 H), 7.29 (m, 5 H), 3.5 (s, 2 H), 3.23 (t, 2 H), 2.87 (t, 2 H), 2.5 (brm, 8 H).
F.Y~nrle 10 O
Il ~~~ ~N~
l-(Bc,,zurL,1-2''-yl)-3-(4'-benzyl-l'-~ i,,yl)-l-plu~ànone dihydro~hlnritle mp 255-257 C;
10 IH NMR (300 MHz, D2O) o 7.7 (m, 2 H), 7.55-7.18 (m, 8 H), 4.3 (s, 2 H), 3.5 (brs, 12 H).
FY~mrl-o. 1 1 1-(m-Nilluph~.,yl)-3-(4'-benzyl-1'-~ .a~ yl)-1-p.~allone di}~y~ llloride: mp 222 C(dec.);
lH NMR (300 MHz, DMSO-d6) ~ 12.40-11.70 (brs, 2 H), 8.70 (s, 1 H), 8.50 (d, 1 H), 8.35 (d, 1 H), 7.90 (dd, 1 H), 7.85-7.35 (m, 5 H), 4.35 (brs, 2 H), 4.00-2.10 ~m, 12 H).
FY~rnrlto 12 l-~D-M~ yl~h~,,lyl)-3-(4'-benzyl-1'-~i~cla~illyl)-1-propanonedihydrochlon~s mp 196-198-C;
lH NMR (300 MHz, CDC13) of the free base: o 7.85 (d, 2 H), 7.40-7.10 (m, 7 H), 3.5 (s, 2 H), 3.15 (t, 2 H), 2.82 (t, 2 H), 2.65-2.40 (m, 8 H), 3.50 (s, 3 H).
FY~mrle 13 20 l-(o-Flu~ vhcllyl)-3-(4~-benzy~ -pipclazillyl)-l-propanonedihydroehlt~nrle mp 185-190C;
lH NMR (300 MHz, DMSO-d6) ~ 12.00-11.20 (brs, 2 H), 7.90-7.30 (m, 9 H), 4.35 (s, 2 H),
F.y~mrlto 7 1-(2"-Thienyl)-3-(4'-benzyl-1'-pi~.,~inyl)-1-~1ul)ano"cdihydrochln~iA~o: mp240-241 C; lH
NMR (300 MHz, D2O) ~ 7.82 (m, 2 H), 7.4 (brs, 5 H), 7.1 (m, 1 H), 4.3 (s, 2 H), 3.5 (brs, 12 H).
FY~mri~ 8 ~3~ H~c~
1-[3"-~-Chlol~,~hc"yl)snlfon~miAophenyl]-3-t4'-benzyl- 1 '-piperazinyl)- l-p~ one dihydrochln~ mp 151-153 C; lH NMR (300 MHz, D20) ~ 7.7-7.14 (m, 13 H), 4.2 (s, 2 H), 3.55-3.2 (brs, 12 H).
FY~mrle 9 o F3C ~ N~3 -3~
SUBSTITUTE SHEET (RULE 26) 1-[3",5"-Bis-(~inllol"~ yl)phenyl~-3-(4'-benzyl- 1'-~ yl)- l-~lul)al~ûne ~lihy~ nn~ The solid was basified with NH40H, e~ ed with dichlo~ e and purificd via flash clll.~ u~rhy (Silica, EtOAc). The free amine was converted to its dihydl~ nTide salt by the ~ ition of dry ether-HCI: mp 255 C; IH NMR of the free base (300 ~, S MHz, CDC13) o 8.38 (s, 2 H), 8.07 (s, 1 H), 7.29 (m, 5 H), 3.5 (s, 2 H), 3.23 (t, 2 H), 2.87 (t, 2 H), 2.5 (brm, 8 H).
F.Y~nrle 10 O
Il ~~~ ~N~
l-(Bc,,zurL,1-2''-yl)-3-(4'-benzyl-l'-~ i,,yl)-l-plu~ànone dihydro~hlnritle mp 255-257 C;
10 IH NMR (300 MHz, D2O) o 7.7 (m, 2 H), 7.55-7.18 (m, 8 H), 4.3 (s, 2 H), 3.5 (brs, 12 H).
FY~mrl-o. 1 1 1-(m-Nilluph~.,yl)-3-(4'-benzyl-1'-~ .a~ yl)-1-p.~allone di}~y~ llloride: mp 222 C(dec.);
lH NMR (300 MHz, DMSO-d6) ~ 12.40-11.70 (brs, 2 H), 8.70 (s, 1 H), 8.50 (d, 1 H), 8.35 (d, 1 H), 7.90 (dd, 1 H), 7.85-7.35 (m, 5 H), 4.35 (brs, 2 H), 4.00-2.10 ~m, 12 H).
FY~rnrlto 12 l-~D-M~ yl~h~,,lyl)-3-(4'-benzyl-1'-~i~cla~illyl)-1-propanonedihydrochlon~s mp 196-198-C;
lH NMR (300 MHz, CDC13) of the free base: o 7.85 (d, 2 H), 7.40-7.10 (m, 7 H), 3.5 (s, 2 H), 3.15 (t, 2 H), 2.82 (t, 2 H), 2.65-2.40 (m, 8 H), 3.50 (s, 3 H).
FY~mrle 13 20 l-(o-Flu~ vhcllyl)-3-(4~-benzy~ -pipclazillyl)-l-propanonedihydroehlt~nrle mp 185-190C;
lH NMR (300 MHz, DMSO-d6) ~ 12.00-11.20 (brs, 2 H), 7.90-7.30 (m, 9 H), 4.35 (s, 2 H),
4.10-3.00 (m, 12 H).
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCTtUS95/lq987 FY~mpl~ 14 l-~-McLl,ylLlliophenyl)-3-(4'-benzyl-1'-pi~ lyl)-1-plupahollc dihydrochlonrl~: mp 216-220 C; lH NMR (300 MHz, DMSO-d6) o 12.10-11.70 (brs, 2 H), 7.95 (d, 2 H), 7.75-7.35 (m, 7 H), 4.35 (s, 2 H), 3.85-3.20 (m, 12 H), 2.75 (s, 3 H).
FY~mrle 15 l-(m-chlul"l,he~lyl)-3-(4~-benzy~ ip~ yl)-l-plo~nolle dihydroehlond~ mp 196-l99 C;
1H NMR (300 MHz, DMSO-d6) o 12.30-11.55 (brs, 2 H), 8.15-7.30 (m, g H), 4.35 (brs, 2 H), 4.00-3.00 (m, 12 H).
Example 16 10 1-~-BIullluph~.nyl)-3-(4'-benzyl-l'-pi~ ~i,,yl)-1-propanone dihydrochlnnrie mp 205-C
(dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.00- 11.20 (brs, 2 H), 7.90 (d, 2 H), 7.80 (d, 2 H), 7.70-7.35 (m, 5 H), 4.35 (brs, 2 H), 4.00-3.10 (m, 12 H).
FY~mrl~ 17 l-(m-Ni~ophenyl)-3-~4'-GD-nuc,lu~",yl)- 1 '-piperazinyl]- i-plu~ c dihydrochloride: mp 15 210 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.50-11.60 (brs, 2 H), 8.70 (s, 1 H), 8.5 (d, 1 H), 8.40 (d, 1 H), 7.90 (dd, 1 H), 7.80-7.60 (m, 2 H), 7.30 (m, 2 H), 4.35 (s, 2 H), 4.00-3.00 (m, 12 H).
Example 18 l-~D-Tlinu~ o~Ly~ yl)-3-(4~-benzy~ yl)-l-propanonedihydrochlnntl~: mp 20 l95 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.00-11.70 (brs, 2 H), 8.12 (dd, 2 H), 7.80-7.30 (m, 7 H), 4.40 (brs, 2 H), 3.85-3.10 (m, 12 H).
Example 19 SUBSTITUTE SHEET (~ULE 26 WO 96/16052 PC~/US95/14987 ~O r ~N~ J~
1 -(2",3"-Dihydro- I ",4"-benzodioxan-6"-yl)-3-(4'-benzyl- 1 '-pi~ azinyl)- I -propanone dil~ydl~l.loride: mp 215-C (dec.); 1H NMR (300 MHz, DMSO-d6) ~ 11.85-11.60 (brs, 2 H), 7.65-7.30 (m, 7 H), 7.00 (d, 1 H), 4.70-4.20 (m, 4 H), 4.00-3.30 (m, 14 H).
Fy~mrle 20 o ~ N~ ~
1-(1",2",3",4"-Tetrahydronaphth-6"-yl)-3-(4'-benzyl-1'-pi~ u~ olle dil-~ocl-lnn~ mp 200 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.35-11.70 (brs, 2 H), 7.80-7.15 (m, 8 H), 4.35 (brs, 2 H), 4.10-3.10 (m, 12 H), 2.90-2.65 (brs, 4 H), 1.70-1.90 10 (brs, 4 H).
Example 21 1 -(4"-Fluoronaphth- I "-yl)-3-(4'-benzyl- 1 '-I~ip~.dzinyl)- I -propanone dihydrochloride: mp 220 C (dec.); 1H NMR (300 MHz, DMSO-d6) ~ 12.50-11.80 (brs, 2 H), 8.75 (d,l H), 8.40-8.10 (m, 2 H), 7.90-7.30 (m, 8 H), 4.45 (brs, 2 H), 4.10-3.10 (m, 12 H).
Example 22 o N~ J~3 SUBSTITUTE SHEEt (RULE 26) WO 96/16052 PCTtUS95/14987 1-p-Biphenyl-3-(4'-benzyl-1'-~il,~,.,.,;.~yl)-l-pl"yanone dihydro~hlori~ mp 225-C (dec.); lH
NMR (300 MHz, DMSO-d6) ~ 12.55-11.50 (brs,2 H), 8.10 (d, 2 H), 7.90 (d, 2 H), 7.80-7.30 (m, 10 H), 4.35 (brs, 2 H), 4.00-3.10 (m, 12 H).
FY~mri~ 23 S 1-(m-TIinuulul.lGlhyll,h~",yl)-3-(4'-benzyl-l '-pi~.~lyl)- l-~l~anone dihydrochloride: mp 215 C (dec.); 1H NMR (300 MHz, DMSO-d6) ~ 12.20-11.00 (brs, 2 H), 8.55-8.00 (m, 2 H), 8.10 (d, 1 H), 7.85 (dd, 1 H), 7.70-7.40 (m, 5 H), 7.60-4.00 (brs, 2 H), 4.00-3.00 (m, 12).
FY~mrl~ 24 1l N ~----N~
10 1-(1"-Methyl-l"-H-pyrazol-4"-yl)-3-(4'-benzyl-1'-~i~"~,lyl)-1-~ one dihydrochlt~nrle mp 221 C (dec.); lH NMR (300 MHz, DMSO-d6) o 12.45-11.60 (brs, 2 H), 8.45 (s, 1 H), 7.95 (s, 1 H), 7.75-7.30 (m, 5 H), 4.35 (brs, 2 H), 3.90 (s, 3 H), 3.80-3.10 (m, 12 H).
FY~mrl~ 25 I-(p-Fluoro-m-b;omophenyl)-3-(4'-benzyl-1'-pi~ zi,lyl)-1-~1.,pano"e dihydrochlonn'~: mp 15 220 C (dec.); 1H NMR (300 MHz, DMSO-d6) o 12.40-11.40 (brs, 2 H), 8.32 (d. 1 H), 8.05 (m, 1 H), 7.80-7.30 (m, 6 H), 4.35 (brs, 2 H), 4.15-3.10 (m, 12 H).
FY~mrle 26 o CH3SO2NH ~ ~N
SUBSTITUTE SHEET (RULE 26) 1 -[p-(h~ nf ~ fon~m~ )phenyl]-3-(4~-benzyl- l '-pi~ ~il.yl)- 1-plù~ onc dihydrochloride:
mp 202-205 C; lH NMR (300 MHz, DMSO-d6) o 12.30-11.20 (brs, 2 H), 8.60 (d, 2 H), 7.75 (d, 2 H), 7.65-7.35 (m, 5 H), 4.33 (brs, 2 H), 4.06-310 (m, 12 H), 3.55 (s, 6 H).
FY~mrl.o 27
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCTtUS95/lq987 FY~mpl~ 14 l-~-McLl,ylLlliophenyl)-3-(4'-benzyl-1'-pi~ lyl)-1-plupahollc dihydrochlonrl~: mp 216-220 C; lH NMR (300 MHz, DMSO-d6) o 12.10-11.70 (brs, 2 H), 7.95 (d, 2 H), 7.75-7.35 (m, 7 H), 4.35 (s, 2 H), 3.85-3.20 (m, 12 H), 2.75 (s, 3 H).
FY~mrle 15 l-(m-chlul"l,he~lyl)-3-(4~-benzy~ ip~ yl)-l-plo~nolle dihydroehlond~ mp 196-l99 C;
1H NMR (300 MHz, DMSO-d6) o 12.30-11.55 (brs, 2 H), 8.15-7.30 (m, g H), 4.35 (brs, 2 H), 4.00-3.00 (m, 12 H).
Example 16 10 1-~-BIullluph~.nyl)-3-(4'-benzyl-l'-pi~ ~i,,yl)-1-propanone dihydrochlnnrie mp 205-C
(dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.00- 11.20 (brs, 2 H), 7.90 (d, 2 H), 7.80 (d, 2 H), 7.70-7.35 (m, 5 H), 4.35 (brs, 2 H), 4.00-3.10 (m, 12 H).
FY~mrl~ 17 l-(m-Ni~ophenyl)-3-~4'-GD-nuc,lu~",yl)- 1 '-piperazinyl]- i-plu~ c dihydrochloride: mp 15 210 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.50-11.60 (brs, 2 H), 8.70 (s, 1 H), 8.5 (d, 1 H), 8.40 (d, 1 H), 7.90 (dd, 1 H), 7.80-7.60 (m, 2 H), 7.30 (m, 2 H), 4.35 (s, 2 H), 4.00-3.00 (m, 12 H).
Example 18 l-~D-Tlinu~ o~Ly~ yl)-3-(4~-benzy~ yl)-l-propanonedihydrochlnntl~: mp 20 l95 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.00-11.70 (brs, 2 H), 8.12 (dd, 2 H), 7.80-7.30 (m, 7 H), 4.40 (brs, 2 H), 3.85-3.10 (m, 12 H).
Example 19 SUBSTITUTE SHEET (~ULE 26 WO 96/16052 PC~/US95/14987 ~O r ~N~ J~
1 -(2",3"-Dihydro- I ",4"-benzodioxan-6"-yl)-3-(4'-benzyl- 1 '-pi~ azinyl)- I -propanone dil~ydl~l.loride: mp 215-C (dec.); 1H NMR (300 MHz, DMSO-d6) ~ 11.85-11.60 (brs, 2 H), 7.65-7.30 (m, 7 H), 7.00 (d, 1 H), 4.70-4.20 (m, 4 H), 4.00-3.30 (m, 14 H).
Fy~mrle 20 o ~ N~ ~
1-(1",2",3",4"-Tetrahydronaphth-6"-yl)-3-(4'-benzyl-1'-pi~ u~ olle dil-~ocl-lnn~ mp 200 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.35-11.70 (brs, 2 H), 7.80-7.15 (m, 8 H), 4.35 (brs, 2 H), 4.10-3.10 (m, 12 H), 2.90-2.65 (brs, 4 H), 1.70-1.90 10 (brs, 4 H).
Example 21 1 -(4"-Fluoronaphth- I "-yl)-3-(4'-benzyl- 1 '-I~ip~.dzinyl)- I -propanone dihydrochloride: mp 220 C (dec.); 1H NMR (300 MHz, DMSO-d6) ~ 12.50-11.80 (brs, 2 H), 8.75 (d,l H), 8.40-8.10 (m, 2 H), 7.90-7.30 (m, 8 H), 4.45 (brs, 2 H), 4.10-3.10 (m, 12 H).
Example 22 o N~ J~3 SUBSTITUTE SHEEt (RULE 26) WO 96/16052 PCTtUS95/14987 1-p-Biphenyl-3-(4'-benzyl-1'-~il,~,.,.,;.~yl)-l-pl"yanone dihydro~hlori~ mp 225-C (dec.); lH
NMR (300 MHz, DMSO-d6) ~ 12.55-11.50 (brs,2 H), 8.10 (d, 2 H), 7.90 (d, 2 H), 7.80-7.30 (m, 10 H), 4.35 (brs, 2 H), 4.00-3.10 (m, 12 H).
FY~mri~ 23 S 1-(m-TIinuulul.lGlhyll,h~",yl)-3-(4'-benzyl-l '-pi~.~lyl)- l-~l~anone dihydrochloride: mp 215 C (dec.); 1H NMR (300 MHz, DMSO-d6) ~ 12.20-11.00 (brs, 2 H), 8.55-8.00 (m, 2 H), 8.10 (d, 1 H), 7.85 (dd, 1 H), 7.70-7.40 (m, 5 H), 7.60-4.00 (brs, 2 H), 4.00-3.00 (m, 12).
FY~mrl~ 24 1l N ~----N~
10 1-(1"-Methyl-l"-H-pyrazol-4"-yl)-3-(4'-benzyl-1'-~i~"~,lyl)-1-~ one dihydrochlt~nrle mp 221 C (dec.); lH NMR (300 MHz, DMSO-d6) o 12.45-11.60 (brs, 2 H), 8.45 (s, 1 H), 7.95 (s, 1 H), 7.75-7.30 (m, 5 H), 4.35 (brs, 2 H), 3.90 (s, 3 H), 3.80-3.10 (m, 12 H).
FY~mrl~ 25 I-(p-Fluoro-m-b;omophenyl)-3-(4'-benzyl-1'-pi~ zi,lyl)-1-~1.,pano"e dihydrochlonn'~: mp 15 220 C (dec.); 1H NMR (300 MHz, DMSO-d6) o 12.40-11.40 (brs, 2 H), 8.32 (d. 1 H), 8.05 (m, 1 H), 7.80-7.30 (m, 6 H), 4.35 (brs, 2 H), 4.15-3.10 (m, 12 H).
FY~mrle 26 o CH3SO2NH ~ ~N
SUBSTITUTE SHEET (RULE 26) 1 -[p-(h~ nf ~ fon~m~ )phenyl]-3-(4~-benzyl- l '-pi~ ~il.yl)- 1-plù~ onc dihydrochloride:
mp 202-205 C; lH NMR (300 MHz, DMSO-d6) o 12.30-11.20 (brs, 2 H), 8.60 (d, 2 H), 7.75 (d, 2 H), 7.65-7.35 (m, 5 H), 4.33 (brs, 2 H), 4.06-310 (m, 12 H), 3.55 (s, 6 H).
FY~mrl.o 27
5 1-~D-Cycloh~Ayl~h~.lyl)-3-(4'-benzyl-1'-pi~.~u~yl)-l-plu~ o~edihydr~l~lnnde: mp231-C
(dec.); lH NMR (300 MHz, DMSO-d6) o 12.40-12.10 (brs 1 H), 12.1-11.70 (brs 1 H), 7.90 (d, 2 H), 7.80-7.20 (m, 7 H), 4.70-4.20 (brs, 2 H), 4.20-3.10 (m 12 H), 2.70-2.40 (m, 2 H), 2.00-1.15 (m, 9 H).
FY~mple 28 o ~ ~N~
1-(Fluoren-2"-yl)-3-(4'-benzyl-1'-p;~ ,;..yl)-1-propanonedihydro~hlnrir1e: mp225C(dec.);
lH NMR (300 MHz, DMSO-d6) ~ 12.40-11.30 (brs, 2 H), 8.40-7.95 (m, 4 H), 7.75-7.30 (m, 8 H), 4.60-4.20 (brs, 2 H), 4.05 (s, 2 H), 3.95-3.05 (m, 12 H).
FY~mr1~ 29 15 1-~D-Iodophenyl)-3-[4'-(o-fluolubo,l~yl)-1'-P;l~ yl~-1-plul)anoncdihydrochloride: mp215-217 C; lH NMR (300 MHz, DMSO-d6) ~ 11.6 (br, 2 H), 8.0 (d, 2 H), 7.7 (m, 3 H), 7.5 (m, 1 H), 7.3 (m, 2 H), 4.3 (brs, 2 H), 3.8-3.0 (brm, 12 H).
Example 30 1 -(o-Fluorophenyl)-3-[4'-(o-fluorobenzyl)- 1 '-~i~c. d~hlyl]- 1 -~lupanol~c dihydrochloricle The 20 solid formed was converted to its free base using NH40H, ~ d with dichlululllr~ n~ and purified via flash chromato~l~hy (Silica, EtOAc). The resulting colll~ùul-d was converted to its dihydrochlnride salt by the addition of dry ether-HCI to give the desired product: mp 213-216-C;
SUBSTITUTE SHEET (RULE 2G) Wo 96/16052 PCT/US95/14987 lH NMR of the free base (300 MHz, CDC13) ~ 7.83 (t, I H), 7.5 (m, 1 H), 7.4-6.95 ~m, 6 H), 3.6(s,2H),3.2(m,2H),2.8(t,2H),2.5(brs,8H).
FY~mrie 31 l-(m-NiLlù~hc.,yl)-3-[4'-(o-lluulùb~""yl)~ .r ~ yl]-l-~ dlloncdihydrochloride: lH
5 NMR of the free base (300 MHz, CDC13) o 8.78 (s, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 7.7 (t, lH),7.37(t, lH),7.24(m, lH),7.15-6.95(m,2H),3.6(s,2H),3.22(t,2H),2.88(t,2 H), 2.56 (brs, 8 H).
FY~rnrlP 32 l-~D-Nil,u~hellyl)-3-r4'-(o-flllolu~,~yl)-1'-~ "~h~yl]-1-~ )anone dihydrochlnrid~ The 10 solid formed was converted to its free base using NH40H, cAIla.;l~d with dichlcl~ hAl~e and p~ified via flash cl~ull,a~ography (Silica, 9:1 EtOAc~eOH). The resulting colll~uu"d was C~ Lt;d back to its ~ yd~u~ hlotirl~ salt by the A~drlition of dry ether-HCl and recrystAlli7~d from nol (2x) to give the desired ~ludu~ H NMR of the free base (300 MHz, CDC13) o 8.3 (d,2H),8.1(d,2H),7.9-6.95(m,4H),3.6(s,2H),3.2(t,2H),2.85(t,2H),2.5(brs,8 15 H).
FYAmrl~ 33 l-~D-NiL~o}~ht~yl)-3-r4~-(2"~5"-difluulu~l~y~ à~illyl]-~ ol~e dihydrochloride:
The solid was basified with NH40H, c,.uacLcd with dichlc,lu..~ Ih~ purified via flash cll~u~ y (Silica. EtOAc), and converted to the dihydrochlc-n~e salt by the addition of dry 20 ether-HCI. This was recryst~lli7~oA in meth~nol (2x) to give the desired product: mp 212-215-C;
lH NMR of the free base (300 MHz, CDC13) o 8.3 (d, 2 H), 8.1 (d, 2 H), 7.2-6.8 (m, 3 H), 3.55 (s, 2 H), 3.2 (t, 2 H), 2.85 (t, 2 H), 2.55 (brs~ 8 H).
Example 34 SUBSTITUTE SHEET (RULE 26) WO g6116052 PCTIUS9~/14987 3~ / ~--N~
l-~D-NiL~ yl)-3-(4'-~ ,.u~ yl)-1-~ 0l~e d~hy~u~ Ot~ The solid was basified with NH40H, ~xl.n~ ;I with dichlu~ I h ~ and purified via flash ch-~ ug.,.lll.y (Silica, EtOAc). The l~,..ulling co~ ,ou,ld was converted to the dihydroehlntid~ salt by the 5 ~riition of dry etner-HCl and recryst~lli7~ in ~ nol to give the desired ~ lu~;l. mp 211 217 C; lH NMR of the free base (300 MHz, CDC13) o 8.3 (d, 2 H), 8.1 (d, 2 H), 6.9-6.65 (m, 3H),5.95(s,2H),3.4(s,2H),3.21 (t,2H),2.83(t,2H),2.5(brm.8H).
FY~mp3e 35 o N2~ ~N~
~3 10 1-(p-Nitrophenyl)-3-~4'-(1"-p-chlorophenyl-1"-phenylmethyl)-1'-pi~ yl]-1-propanone dihydrochloride: The reaction was cO.I~f .~ ted in vacuo, basified with NH40H, ~ d with dichlorometh~n~ and purified via flash chlv . .~ graphy (Silica, EtOAc). The resulting co~ ,ou~ld was converted to its dihydrochloride salt by the arl~isinn of dry ether-HCl to give the desired product: mp 148-153 C; IH NMR of the free base (300 MHz. CDC13) ~ 8.3 (d, 2 H), 15 8.1 (d, 2 H), 7.45-7.1 (m, 9 H), 4.2 (s, 1 H), 3.2 (t, 2 H), 2.85 (t, 2 H), 2.7-2.3 (brm, 8 H).
Example 36 l-(p-l~oth~n~slllfon~mi~iophenyl)-3-(2l~7s~-difluo~benzyl-l~ yl)-l-~ulu~ one dihydrochlnri~le: mp 230-232 C; lH NMR (300 MHz, D20) â 7.88 (d, 2 H), 7.3-7.05 (m, 5 H), 4.28 (s, 2 H), 3.8-3.3 (brm, 12 H), 3.06 (s, 3 H).
SUBSTITUTE SHEET (RULE 26 =
CA 0220~86 1997-0~-16 Exarnple 37 1 -(3''-Thienyl)-3-[4'-(m-fluc,.uboll ,yl)- 1 '-pip. . ~,; . ,yl]- 1 -propanone dihydrochlnnr~ The solid was basified with NH40H, e~.LIaCh;l with dichlc lu, . ~ nç and purified via flash clll~ ".pl,y (Silica, EtOAc). The free amine was converted to its dihydro~lnntle salt by the 5 addition of dry ether-HCl to give the desired ~10 IU~;L~ lH NMR of the free base (300 MHz, CDC13) ~ 8.06 (d, 1 H), 7.53 (d, 1 H), 7.29 (m, 2 H), 7.08 (m, 2 H), 6.93 (m, 1 H), 3.5 (s, 2 H),3.12(t,2H),2.85(t,2H),2.54(brm,8H).
FY~mpl~ 38 1 -(3 "-Thienyl)-3-[4'-(2"',5"'-difluol ù~"z.yl)- 1 '-pip~,. ~inyl] - 1 -1,l upa~one dihydrochloride: 1 H
10 NMR of the free base (300 MHz, CDC13) o 8.05 (d, 1 H), 7.54 (d, 1 H), 7.32 (m, 1 H), 7.12 (m, 1 H), 6.94 (m, 2 H), 3.57 (s, 2 H), 3.1 (t, 2 H), 2.83 (t, 2 H), 2.56 (brs, 8 H).
FY~rnrl~ 39 l-~D-NiLlu~llC~yl)-3-([4'-(o-llinuululll~ lyl)benzoyl3-l~ yl)-l-~ p~ nt The solid was basified with NH40H, ~ 1t-lrrl with dichlc/l.J~ ,ç and purified via flash 15 clllulllatugraphy (Silica, EtOAc) to give the desired plodu.;l. mp 179-181 C; lH NMR (300 MHz CDC13) ~ 8.32 (d, 2 H), 8.1 (d, 2 H), 7.72 (d, 1 H), 7.56 (m, 2 H), 7.33 (d, 1 H), 3.82 (m, 2 H), 3.2 (m, 4 H), 2.88 (t, 2 H), 2.6 (m, 2 H), 2.62, (m, 2 H).
FY~rnpl~ 40 o NO2~ N~N~
O F
20 l-~-Ni~ophenyl)-3-[4'-(2'',6''-diflllolu~ll2oyl)-ll-pil~e~ yl]-l-l,lupallol~e hydrochlnri~
mp 225-227 C; lH NMR (300 MHz, D2O/CD3OD) ~ 8.21 (d, 2 H), 8.03 (d, 2 H), 7.42 (m, 1 H), 6.98 (t, 2 H), 3.78-3.15 (brm, 12 H).
SUBSTITUTE ~HEET (RULE 26 -CA 0220~86 1997-0~-16 WO 96tl6052 PCTIUS95/14987 FY~mpl~ 41 1 -(o-Fluu.~h~nyl)-3-r4'-(2'',6''-difluorobell~.,yl) 1 '-~ip~ yl]- I -p,opanon~ hydrochlnn-le:
mp 185-187 C; IH NMR (300 MHz, CDC13) ~ 13.55-13.73 (brs, 1 H), 7.87-7.65 (m, 1 H), 7.65-7.35 (m, 2 H), 7.35-6.90 (m, 4 H), 2.92 (d, I H), 4.15 (t, 1 H), 3.90-3.40 (m, 8 H), 5 3.05-2.80 (m, 2 H).
Example 42 1-~7-NiLluph~ yl)-3-[4l-(m-flllo~ yl)-1'-~ a~ yl]- 1-~l.p~lolledihy~ll~hlûride: mp 210-C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.10-11.30 (brs, 2 H), 8.40 (d, 2 H), 8.25 (d, 2 H), 7.60-7.20 (m, 4 H), 4.45-3.00 (m, 14 H).
Fs~mr1-~ 43 1-(o-Flllolu~he,lyl)-3-[4'-(o-llinuolullleLl.ylbenzoyl)-1'-~ yl]-1-~ nol~e hydrochloride:
mp 175-176 C; lH NMR (300 MHz, CDC13) ~ 13.55-13.45 (brs, 1 H), 7.98-7.50 (m, 5 H), 7.45-7.10 (m, 3 H), 4.92 (d, 1 H), 4.12 (t, 1 H), 3.95-3.35 (m, 8 H), 3.10-2.70 (m, 2 H).
FY~mrk~ 44 15 1-(o-Fluolul)h~"~yl)-3-[4'-~D-fluorobenzyl)-1'-~ 7;nyl]- l-propanone dihydl~ 1nn~l~o: mp 209 C (dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.00-11.40 (brs, 2 H), 7.95-7.20 (m, 8 H), 4.30 (s, 2 H), 3.85-3.20 (m, 12 H).
Example 45 1-GD-Ni~Jphe.lyl)-3-r4'-~D-fluorobenzyl)-ll-~ illyl]-1-~1u~ Onf dihydrochlc-n~is: mp 20 200 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.50-11.60 (brs, 2 H), 8.50 (d, 2 H), 8.25 (d, 2 H), 7.85-7.20 (m, 4 H), 4.39 (s, 2 H), 4.00-3.00 (m, 12 H).
Example 46 1-GD-Fluc~ h~nyl)-3-[4'-(p-fluorobenzyl)-1'-pi~ zinyl]-1-propanone dihydrochlori(le mp 224 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.40-11.70 (brs, 2 H), 8.05-7.20 (m, 8 H), 25 4.35 (brs, 2 H), 3.95-3.10 (m, 12 H).
SUBSTITUTE SHEET IRI ILE 2~) -CA 0220~86 l997-0~-l6 WO 96/16052 PCr/US95/14987 FY~mrl~ 47 1-(m-Fluolu~hc.,yl)-3-[4'-~-fluu,u~llL~ yl]-1-~v~dihydrochloride: mp 215 C (dec.); 1H NMR (300 MHz, DMSO-d6) o 12.05-11.75 (brs, 2 H), 7.95-7.15 (m, 8 H), 4.35 (brs, 2 H), 3.9S-3.15 (m, 12 H).
Example 48 1-~-Iodc~hc.~yl)-3-[4'-~D-fluolu~,,~y-l)-l'-pil,~,~i,,yl]-l-~ru~ Jl,cdihydrochlt-rirl~: mp 215 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.25-11.70 (brs, 2 H), 7.95 (d, 2 H), 7.80-7.50 (m, 4 H), 7.40-7.20 (m, 2 H), 4.30 (s, 2 H), 3.90-3.10 (m, 12 H).
Example 49 (a) 4-Fluo~u~nLuyl~ zine: p-Fluolub.~n~ùylcllloride (6.00g) in 30mL
CH3CN was added in one portion to a stirred so1u~inn of pi~,e.~ine (16.25 g) dissolved in lNHCl (285 mL). The reaction was stirred at room t~mrçr.~h~re for 3.5 hrs. then an ~ itinn~l 50 mL of lN HCl was added. The sollltion was c,~L~ ed with 2 x 100 mL EtOAc. Thea~ucous acidic layer was made basic with lN KOH then e~.LI~L~d with 2 x 150 rnL CH2C12.
15 The organic layer was 5~ ",~ , dried (Na2S04), filtered and e~pUldt~, affording a yellow oil which soii-iifi~d upon st~nriing (5.60 g; 71 % yield). M+ 208. lH NMR (300 MHz, CDC13) o 7.50-7.35 (m, 2 H), 7.18-7.00 (m, 2 H), 3.90-3.30 (brd, 4 H), 3.00-2.70 (brs, 4 H), 1.85 (s, 1 H).
(b~ 3-Flu~lubcn~oyl~i~.~ne: Utilizing the ~,l~lulc of FY~mple 49a but repl~ing 20 p-fluorobenzoylchlc ri~ with m-fluolu~n,~ylchloride (3.00 g) afforded the desired product (3.20 g; 82% yield). M+ 208. lH NMR (300 MHz, CDC13) ~ 8.50-7.32 (m, 1 H), 7.25-7.05 (m, 3 H), 3.75 (brs, 2 H), 3.40 (brs, 2 H), 3.05-2.65 (m, 4 H), 1.90 (s, 1 H).
(c) 2-Fluoro~n~uyl~ 7inç: Using the l"ucedu.~ of Example 49a and o-fluorobenzoylchloride (2.00 g) gave the desired product (2 40 g; 90% yield). M+ 208. lH
25 NMR (300 MHz, CDC13) ~ 7.50-7.00 (m, 4 H), 2.90-3.70 (m, 2 H), 3.45 (brs, 2 H), 3.10-2.65 (m, 4 H), 1.85 (s, 1 H).
~6-SU3STITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 WO 96tl6052 PCI/US95/14987 (d) 2,5-Dinu~u~,lzoyl~ à~ e Using the plOCcdulC of Example 49a with 2,5-difluoro~nz~ylchloride (5.00 g) gave the desired product (3.00 g; 51% yield). M+ 226.
lH NMR (300 MHz, CDC13) ~ 7.20-7.00 (m, 3 H), 3.86-3.70 (m, 2 H), 3.40-3.25 (m, 2 H), 3.05-2.75 (m, 4 H), 1.97 (s, 1 H).
(e) 4-Tlinuulul~ ylbenzoyl~ a~ e: Usingthe ~/rlX`~lUlc ofExample49awith p-llinuurol~lell~ylbenzoyl~hlorirls (5.00 g) gave the desired product (1.85 g; 30% yield).
M+ 258. IH NMR (300 MHz, CDC13) o 7.67 (d, 2 H), 7.50 (d, 2 H), 3.75 (brs, 2 H), 3.35 (brs, 2 H), 3.05-2.75 (m, 2 H), 1.85 (s, 1 H).
(f~ 2,3-Dinuulu~.-~uylp;l~ ;--f - Using the l,.uc,~ulc of FY~mrlt~ 49a with 2.3-difluorobenzovlchlori(1e (5.00 g) gave the desired product (3.00 g; 47% yield). M+ 226.
lH NMR (300 MHz, CDC13) ~ 7.35-7.05 (m, 3 H), 3.75 (brs, 2 H), 3.30 (brs, 2 H), 3.06-2.75 (m, 4 H), 1.75 (s, 1 H).
(g) 2-Trifluolulllclllylbenzoyl~;lh,.~l, ;"e Using the ~locedulc of Example 49a with o-~ifluululllc~ lbenzoylchloride (5.00 g) gave the desired product (3.4 g; 55% yield).
M+ 258. lH NMR (300 MHz, CDC13) ~ 795-7.45 (m, 3 H), 7.40-7.25 (m, 1 H), 3.90-3.70 (m, 2 H), 3.25-3.05 (m, 2 H), 3.00-2.85 (m, 2 H), 2.85-2.65 (m, 2 H), 1.70 (s, 1 H).
(h) 4-Nillu~.l,uylpi~-,.~ine: Using the l"uc~lulc of Fy~mrle 49a with p-nitrobenzoylchloride (7.00 g) gave the desired product (4.50 g; 50% yield). M+ 235. lH
NMR (300 MHz, CDC13) ~ 8.27 (d, 2 H), 7.07 (d, 2 H), 3.90-3.60 (brs, 2 H), 3.45-3.25 (brs, 2 H), 3.10-2.70 (m, 4 H), 1.75 (s, 1 H).
(i) 2,~DifluOlu~ll~oyl~i~x,a7;-.c: Using the plvcedulc of Fy~mrle 49a with 2,6-difluorobenzovlchlcn-1e (5.00 g) gave the desired product (3.25 g; 51% yield). M+ 226.
lH NMR (300 MHz, CDC13) ~ 7.45-7.25 (m, 1 H), 7.05-6.85 (m, 2 H), 3.70-3.40 (brs, 2 H), 3.40-3.25 (brs, 2 H), 3.05-2.75 (m, 4 H), 1.70 (s, 1 H).
(1) 4-Iodobenzoyl~,ipe,d~u,c: Using the procedure of Fy~mrle 49a with 4-iodobenzoylchloride (4.24 g) gave the desired product (0.70g; 14% yield). M+-316. 1H
SUE~STlTUTc S~Y~ET (RUL~ 26) CA 0220~86 1997-0~-16 Wo 96/16052 P~USg5114987 NMR (300 MHz, CDC13) o 7.85-7.15 (d,2 H),7.20-7:05 (d,2 H),3.85-3.05 (brs,2 H), 3.55-3.25 (brs, 2 H), 3.10-2.65 (m,4 H),1.75 (s, 1 H).
(k) ~ .An~, ,..Il.hf~..~...;~in a~ernph.onnnlo A CH2C12 (130 mL) solution co,~
4-,....;~.o~e~ f ..on~ (5.00 g) and triethylamine (5.6 mL) was cooled to 0 C and placed under S niL.~g~ll. Then, ..l Ill~npslllfonyichlnririe (3.1 mL) in CH2C12 (5 mL) was added ~ wise over 10 min. Upon co...l-k ~ ad~iition the reaction was sti~rcd at 0 C for an ~ririinnn~l 10 min.
then allowed to warm to room ~ ,,,.l...c with stirring c~ .;Q~ for 2 hrs. Then lN KOH
was added and the layers s~ A The basic layer was made acidic, then c~LIa~ ;i with CH2C12 (2 x 75 mL). The organic extracts were comhinçci, dried (Na2S04), filtered and 10 c~ia~ulaled affording a pale yellow solid (4.10 g; 52% yield). M+ 213. lH NMR (300 MHz, CDC13) o 7.97 (d, 2 H), 7.27 (d, 2 H), 3.10 (s, 3 H),2.07 (s,3 H).
(1) 3 ~ ". ~ .hollA...;~io a~ .- .o.~e- Using the ~luc~ule of FY~mrl~ 49k but starting with 3-~mino~cet~h~ .-one (5.00 g) gave the desired product (6.00 g; 76% yield).
M+ 213. lH NMR (300 MHz, CDC13) o 7.92-7.45 (m, 5 H),3.52 (s, 3 H),2.65 (s,3 H).
(m) 2-Fluorobtl"ylpi~,~,.~i,.e; The product from Fy~mrl~ 49c (3.10 g) was dissolved in dry T~F (75 mL) then a lM B2H6THF solution (45 mL) was added dropwise over ca. 15 min. under N2. Upon cOl. .~ rlition~ the sol-lhnn was refluxed under N2 for 3 hrs. The reaction was cooled to 0 C in an ice bath and then lN HCl (ca. 70 mL) was carefully added d,~pwise. Upon comrlete ~iditiQn, the reaction was allowed to warm to room20 le~ ... c followed by extraction with EtOAc (2 x 100 mL). The organic layer was discarded and the acidic layer made basic with KOH. This was C.~ dcl~ with CH2C12 (2 x 150 mL).
The organic extracts were cnmhineA, dried (Na2S04), filtered and e~a~uldL~ giving an oil that began to solidify upon st~n~1ing This was dissolved in IN HCl (75 mL) then refluxed 1.5 hrs.
The reaction was cooled to 0C then made basic with KOH followed by CH2C12 e~ ion 25 (2 x 100 mL). The organic extracts were co...l~ fA, dried (Na2S04), filtered and e~d~c~ldled ~fforn'ing a pale yellow oil (1.2 g; 41% yield). M+ 194. lH NMR of the dihydrochlori~le salt (300 MHz, CDC13) o 10.00-9.30 (brs, 2 H), 7.15-6.85 (m, 4 H), 3.62 (s, 2 H), 3.35-3.15 (m, 2 H), 2.90-2.70 (m, 2 H).
SUBSTITUTE SHEET ~RULE 26) ~ ==
CA 0220~86 1997-0~-16 WO 96tl6052 PCT/US95/14987 (n) 2,3-Dinuolù~l~yl~i~G~zine: Using the product from Example 49f (1.14 g) and the ~lucGdu~c of Fy~mrle 49m gave the desired product (0.45 g; 43% yield). M+ 212. lH
NMR (300 MHz, CDC13) ~ 7.20-6.97 (m, 2 H), 3.60 (s, 2 H), 2.90 (t, 4 H), 2.55-2.35 (brs, 4 H), 1.67 (s, 1 H).
(o) 4-Ni~ù~yl~ e: Using the product from FY~mrl~ 49h (0.50 g) and the procedure of Fy~mr!e 49m gave the desired product (0.28 g; 59% yield). M+ 221. 1H NMR
(300 MHz, CDC13) o 8.27 (d, 2 H), 7.15 (d, 2 H), 3.75 (s, 2 H), 3.30-3.15 (m, 4 H), 2.85-2.70 (m, 4 H).
(p) 2,5-Dinuclubell~yl~ cl~le: Using the co.nl)ounA of FY~mrle 49d (2.90 g) and the ~lue~lwci of FY~mrle 49m gave the desired product (2.3û g; 83% yield). M+ 212. lH
NMR (300 MHz, CDC13) o 7.36-7.22 (m, 1 H), 7.10-6.90 (m, 3 H), 3.55 (s, 2 H), 3.30-3.10 9m, 4 H), 2.85-2.65 (m, 4 H).
(q) 4-FlllOlu~l~.yl~i~a~ille; Using the co~llpuund of Exarnple 49a (5.25 g) and the ~ruc~luuG of Fy~mrle 49m gave the desired product (4.35 g; 75% yield). M+ 194. lH NMR
(300 MHz, CDC13) ~ 8.95-8.70 (brs, 1 H), 7.40-7.25 (m, 2 H), 7.25-7.05 (m, 2 H), 3.50 (s, 2 H), 3.15-2.95 (brs, 2 H), 2.65-2.35 (m, 2 H).
(r) I-Be.~ lfonylpiperazine: Be~ .lfonyl chloriA~. (2.00 g, 0.011 mol) in 25 mL CH3CN was added in one portion to a stirred solution of ~i~Gl~ine (4.90 g, 0.057 mol) dissolved in lN HCl (100 mL). The reaction was stirred at room IC.ll~.dtu~ for 30 minntes The solution was e~ L~ with EtOAc and the a4u20us acid layc-r was made basic with lN KOH and then extracted with 2 x 10 mL CH2CI2. The organic layer was s~ated, dried (MgS04), filtered, and e~u~ted affording 1.40 g (50%) of a pale yellow solid: mp 109-111 C; IH NMR (300 MHz, CDC13) o 7.75 (m, 2 H), 7.65-7.40 (m, 3 H), 2.96 (m, 8 H).
,~
(s) 1-(2'-Chloro-6'-methylpyrido-4'-yl)l,ip~.dzille: 2-Chloro-6-methylpyridine-4-c~l~nyl chloriA~o~ (5.00 g, 0.026 mol) in 50 mL CH3CN was added in one portion to a stirred solution of pil)~.azille (11.31 g, 0.13 mol) dissolved in lN HCl (180 mL). The reaction was stirred at room le~ .alu~ for 3 hours, then an ~AAitinn~l 50 mL of lN HCl was added. The SUBSTITUTE SHEET ~RULE 26) CA 0220c,c,86 1997-0ct-16 Wo 96tl6052 PCT/US95/14987 solm nn was tAI~tlcl,~i with EtOAc (2 x 150 mL), the a~ueous acid layer was made basic with IN KOH and then e,.ll..cled with 2 x 10 mL CH2C12 (2 x 200 mL). The organic layer was se~ AtcA, dried (MgS04), filtered and cQnçe..~ eA, affording 3.30 g (53%) of a light yellow solid: mp 164-165C; IH NMR (300 MHz, CDC13) ~ 7.12 (s, 1 H), 7.06 (s, 1 H), 3.74 (m, 2 5 H),3.33(m,2H~,2.95(m,2H),2.83(m,2H),2.57(s,3H), 1.72(s, lH).
(t) p-Toll~- IP ~u1rullr~ e Using the ~luee~lul~ of FY~mple 49r withp-~tu~l~le l~slllfonyl chloride gave the desired ~ ~lu~;l. mp 98-101C; IH NMR (300 MHz, CDCl3) o 7.64 (d, 2 H), 7.34 (d, 2 H), 2.95 (m, 8 H), 2.44 (s, 3 H), 1.60 (brs, 1 H).
(u) p-B~u~l~ù~ ..t~lllrul Iyl~ t~;1le- Usingthe~,ucedu~ofExarnple49rwithp-0 L tlUII10~U~ 1fonyl chloride gave the desired plu~lu~l; mp 117-121C; IH NMR (300 MHz, CDC13) ~ 7.66 (dd, 4 H), ~.97 (m, 8 H), 2.44 (s, 3 H), 1.60 (brs, 1 H).
FYS~m~ S 50 and 51 o ~N ~ ~N~
o H3C~ ¦ ~N , 1,4-Bis-t3'-(4"-benzyl-1"-~il)el~i"yl)-propanoyl] benz, "c (50) and 1-(p-Acetylphenyl)-3-(4'-benzyl-l'-~ .,,,;,,yl)-1-~,,u~,~,one dihydr~chloride (51): Using the general method gave bodl 20 collll~ullrl~ afterpnrifir~ti( n via flash Chl~JIIIQ~ hY (Silica, EtOAc). Each was converted to SUBSTITUTE SHEET (RULE 26) its dihydrochlo~ salts by the addition of dry ether-HCl. Higher Rfl = .43 (8:2 EtOAc/MeOH) gave 8 mg (50): mp ~ 250-C; lH NMR of the free base (300 MHz, CDCl3) ~ 8.0 (s, 4 H), 7.3 (m, 5 H), 3.5 (s, 2 H), 3.2 (t, 2 H), 2.85 (t, 2 H), 2.65 (s, 3 H), 2.5 (brm, 8 H). Lower Rf2 =
.14 (8:2 EtOAc/MeOH) gave 0.21 g (51): mp > 245 C; lH NMR of the free base (300 MHz, 5 CDC13) o 8.0 (s, 4 H), 7.3 (m, 10 H), 3.5 (s, 4 H), 3.2 (t, 4 H), 2.85 (t, 4 H), 2.5 (brm, 16 H).
FY~mrl~c 52 and 53 O O
CH3J~ ~ N~N~3 O O
10 ~ N~ ~50~--N~N
1-(8"-Acetylph~nnY~thiin-2"-yl)-3-(4'-benzyl-1'-pi~ a~ yl)-1-pl(,pa.~olle dihydrochloride (52) and 2,8-Bis-[3'(4"-benzyl-1"-~ui~.d~,~yl)propanoyl] ph~.,o~ h;;~ (53): According to Examples 50 and 51, 1,4-diacetyl~..~e"c was replaced with 2,8-diace.vlyhcnox~thiin (0.25 g, 15 0.88,nrnol). After pnrifif~tir)n by flash chlul . .~tography (Silica. EtOAc) the two L ludu- l~. were icol~t~A Rfl = .47 (8:2 EtOAc/MeOH) was converted to its collc~ onding salt by the ~ln'itinn of dry ether-HCl to give 95 mg (52): mp > 250'C; 1H NMR of the free base (300 MHz, CDCl3) ~ 7.8-7.5 (m, 4 H), 7.3 (m, 5 H), 7.15-6.95 (m, 2 H), 3.5 (s, 2 H), 3.1 (m, 2 H), 2.8 (m, 2 H), 2.65-2.3 (brm, 11 H). Rf2 = .24 (8:2 EtOAc/MeOH) was converted to its 20 co~l~ollding hydrochlo~i~e salt to give 35 mg (53): mp ~ 250 C; lH NMR of the free base (300 MHz, CDCl3) â 7.8-7.5 (m, 4 H), 7.3 (m, 10 H), 7.15 (d, 1 H), 7.05 (d, 1 H), 3.55 (s, 4 H), 3.1 (m, 4 H), 2.85 (m, 4 H), 2.5 (brm, 16 H).
F~mrl~ 54 SUBSTITUTE SHEET (RULE 26) Wo 96/16052 PCT/US95tl4987 02N~ ~N~
O F
l-~o-Ni~ h~ rl)-3-(4'-o-fl, o.o~n~oyl-l'-pi~.e.azi-lyl)-l-propanone dihydrochlonri~ The solid was basified with NH40H, e ~ l . j.rt~ A with dichlo~ L~ ç and purified via flash cLI..."~lo~".l.l-y (Silica, EtOAc). The free amine was converted to its hydrochl(~ salt by the 5 addition of dry ether-HCI; filtered and dried: mp 217-218-C; 1H NMR of the free base (300 MHz, CDC13) o 8.32 (d, 2 H), 8.11 (d, 2 H), 7.4 (m, 2 H), 7.27-6.99 (m, 2 H), 3.8 (m, 2 H), 3.48-3.1 (m, 4 H), 2.89 (t, 2 H), 2.7-2.3S (m, 4 H).
FY~mpl~ S5 1-(~7-NiLIuphe~lyl)-3-[4'-(3'',4''-difluolu~,lzyl)-l'-pip~ inyl]-l-plop~ulone dihydrochloride:
10 mp 210-212 C; lH NMR (300 MHz, D20? ~ 8.22 (d, 2 H), 8.04 (d, 2 H), 7.37-7.09 (m, 3 H), 4.35 (s, 2 H), 3.7-3.35 (brm, 12 H).
FY~mrie 56 o ~~ ~N J~3 1 -(S"-Phenyl-2"-thienyl)-3-(4'-benzyl- 1 '-~ ~llyl)- 1 -p-upallone dihydrochloride: mp 224-15 247 C; IH NMR (300 MHz, D20) ~ 7.76 (m, 1 H), 7.67 (m, 2 H), 7.37 (m, 9 H), 4.33 (s, 2 H), 3.5 (brm, 12 H).
Example 57 1-(~"-Bromo-2"-thienyl)-3-(4'-benzyl-1'-,,,;l.e.~.7;.~yl)-1-propanone dihydroçhlon~ The solid was basified with NH40H, G~ ,L~d with dichlc lur . ~ ~ h~ le and purified via flash 20 cll~.,.",.~ rhy (Silica, EtOAc). The free amine was converted to its hydrochl~n~l~ salt by the SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 a~dition of dry ether-HCl; filtered and dried: mp 242-244-C; IH NMR (300 MHz, D20) ~ 7.58 (d, 1 H), 7.37 (brs, 5 H), 7.15 (d, 1 H), 4.32 (s, 2 H), 3.5 (brm, 12 H).
Example 58 ~~ N~
S l-(Biphenylen-2"-yl)-3-(4'-benzyl-1'-pi~ ,inyl)-1-p~,~none: mp 133-134-C; lH NMR (300 MHz, CDC13) ~ 7.46 (d, 1 H), 7.29 (m, 5 H), 7.17 (s, 1 H), 6.9-6.65 (brm, 5 H), 3.52 (s, 2 H),3.04(t,2H),2.81 (t,2H),2.52(brs,8H).
FY~mpl~ 59 1 -(5 "-Chloro-2"-thienyl)-3-(4'-benzyl- 1 '-I)i~, d~ in~l)- 1 -prop~none dihydrochlnri~ mp 248-10 249-C; lH NMR (300 MHz, D2O) ~ 7.63 (d, 1 H), 7.36 (brs, 5 H), 7.0 (d, 1 H), 4.28 (s, 2 H), 3.44 (brm, 12 H).
FY~mpl~ 60 1-(m-Cyanophenyl)-3-(4'-benzyl-1'-~ yl)-1-~ulu~,,..,one dihydrochloride: The solid was basified with NH40H. t;~ acL~,d with dichlulu..~ and purified via flash chlulllalû~;lapl~y 15 (Silica, EtOAc). The free amine was converted to its hydr~chlr-rirl~ salt by the ~n~n~inon ûf dry ether-HCl; filtered and dried: mp 247-248 C; lH NMR (300 MHz, CDCl3) o 8.28-8.1 (m, 2 H), 7.84 (d, 1 H), 7.61 (t, 1 H), 7.3 (brm, 5 H), 3.S1 (s, 2 H), 3.17 (t, 2 H), 2.84 (t, 2 H), 2.5 (brm, 8 H).
~Y~mrl~ 61 20 1 -(6"-Fluoro-2"-methylphenyl)-3-(4'-benzyl- 1 '-pi~,~;l~inyl)- 1 -propanone dihydrochloride: mp 210-C (dec.); lH NMR (300 MHz, DMSO-d6) o 12.15-11.40 (brs, 2 H), 8.05-7.95 (m, 1 H), 7.70-7.40 (m, 5 H), 7.30-7.20 (m, 2 H), 4.55-4.20 (brs, 2 H), 3.90-3.20 (m, 12 H).
Example 62 SUBSTITUTE SHEET (RULE 26) =
N~ ~ r O F
l-(S'''-Bromo-2'''-thienyl)-3-[4'-(2'',6''-dinuo,ubenzoyl)-l' ~ ,.;nyl]-l-~lu~allolle hy~Lo~ l~ln.,i~1e mp 225-226-C; lH NMR (300 MHz, DMSO-d6/D20) o 7.9 (d, 1 H), 7.63 (m, 1 H), 7.49 (d, 1 H), 7.28 (t, 2 H), 4.65 (brs, 2 H), 3.95-3.03 (m, 1~ H).
FY~mrl~ 63 l-~D-Nillu~hc~lyl)-3-r4'-(2'',3''-difluo~u~l~2url)-ll-~ dzillyl]~ lu~ olle dihydrochloril1e The solid was basified with NH~LOH, extracted with dichlo,u,. ,I.~ne and purified via flash C1~ t~ lllY (Silica, EtOAc). The free amine was converted to its hydr~chlnrirl~ salt by the ~rlrlitinn of dry ether-HCI; filtered and dried: mp 213-214 C; IH NMR (300 MHz, DMSO-d6) 10 10.7 (brs, 1 H), 8.39 (d, 2 H), 8.23 (d, 2 H), 7.58 (m, 1 H), 7.34 (m, 2 H), 3.85-3.0 (m, 12 H).
FY~mrle 64 l-(o-Chlo,ul,henyl)-3-(4'-benzyl-1'-pil,e~dzinyl)-1-p~panone dihydrochloride: The solid was basified with NH40H. rx~ d with dichlo~ ne and purified via flash cl~lul~laLography l5 (Silica, EtOAc). The free arnine was converted to its dihydror~hlnrirl~o salt by the addition of dry ether-HCI; filtered and dried: mp ~ 250-C; lH NMR (300 MHz, D20) ~ 7.8-7.18 (m, 9 H), 4.55 (s, 2 H), 3.64 (brs, 12 H).
Exarnple 65 I-(o-Nitrophenyl)-3-(4'-benzyl-1'-pip~"~nyl)-1-propanone dihydrochloride: The solid was 20 basified with NH40H, extracted with dichlolu.~ ne and purified via flash cl.l~"latugraphy (Silica, EtOAc). The free amine was converted to its dihydrochlon~l~ salt by the addition of dry ether-HCI; filtered and dried: mp 226-228-C; lH NMR (300 MHz, D20) ~ 8.25 (d, 1 H),7.89 (t, 1 H), 7.79 (t, 1 H), 7.56 (m, 6 H), 4.4 (s, 2 H), 3.7-3.28 (brm, 12 H).
SUBSTITUTE SHEET (RULE 26) FY~mrle 66 1-(o-Dlu~ .he.~yl)-3-(4'-benzyl-1'-pi~ yl)-1-~ one dihydrochlo7~ mp > 250 C; lH
NMR (300 MHz, DMSO-d6, H20) o 7.73 (d, 2 H), 7.64-7.3 (m, 7 H), 4.25 (brm, 2 H), 3.52 (brs, 12 H).
FY~mrl~ 67 o ~ ~N~
Me 1-(5"-Methyl-2"-furanyl)-3-(4'-benzyl-1'-pipe.~illyl)-1-propanone hydrochlori~ie mp 213-C
(dec.); lH NMR (300 MHz, DMSO-d6) o 12.40-11.60 (brs, 2 H), 7.75-7.55 (brs, 2 H), 7.55-7.35 (brs, 4 H), 6.4 (d, 1 H), 4.55-4.20 (brs, 2 H), 3.80-3.20 (m, 12 H), 2.35 (s, 3 H), 3.90-10 3.30(m,20H).
FY~mpie 68 o N ~--N~N `~1 ~ O
l-(p-N-MoIph~ n~1~h~ yl)-3-r4~-p-iodobenzoy~ illyl]-~ lol~e ~ chlf..~
mp 240 C; lH NMR (300 MHz, CDC13) o 7.91 (d, 2 H), 7.80 (d, 2 H), 7.17 (d, 2 H), 6.85 15 (d, 2 H).
- E,Yample 69 ~S~ N~N
SUBSTITUTE SHEET (RULE 26) WO 96/16052 Pcr/uS95/14987 l-p-p~ y~ yl-3-(4~-benzy~ yl)-3-~ dnon~ dihydro~hlor~ mp 210 C
(dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.30-11.10 (brs, 2 H), 7 90 (d, 2 H), 7.70-7.40 (m, 10 H), 7.30 (d, 2 H), 4.60-3.90 (brs, 2 H), 3.90-3.10 (m, 12 H).
FY~mrl~ 70 O
~ ~N~
O
1-(2"-Thienyl)-3-[4'-(o-fluo,~J'oel,2oyl)-l'-pi~ yl~ u~anonelly~lluehloride: mpl83-184 C: IH NMR (300 MHz, CDC13) o 10.30-10.07 (brs, 1 H), 7.90 (d, 1 H), 7.76 (d, 1 H), 7.55-7.35 (m, 2 H), 7.30-7.05 (m, 3 H), 4.97-4.80 (brd, 1 H), 4.15-3.95 (m, 1 H), 3.90-3.40 (m, 8 H), 3.05-2.8 (m, 2 H).
FY~mrl~ 71 1-[4~-(p-IIyLu~y-m~ upll~nyl)~-3-(4~-'oenzyl-1'-~i~e ~,~ u~anone dihydrochloride:
mp 209-212 C; lH NMR (300 MHz, D20) o 8.75 (s, 1 H), 8.24 (d, 1 H), 7.65-7.50 (brs, 5 H), 7.31 (d, 1 H), 4.51 (s, 2 H), 3.86-3.60 (m, 12 H).
FY~mrl~ 72 15 1-~D-N-Morpholinophenyl)-3-(4'-benzyl-1 '-pire~7inyl)- 1 -~lu~al~olle dihydrochloride: mp 205 C (dec.); lH NMR (300 MHz, D20) o 7.80 (d, 2 H), 7.45-7.30 (brs, 5 H), 6.95 (d, 2 H), 4.32 (s, 2 H), 3.80-3.66 (m, 4 H), 3.60-3.40 (m, 12 H), 3.30-3.20 (m, 4 H).
~Y~mrl~ 73 l-~-Cyanophenyl)-3-(4'-benzyl-1'-~ipt~ l)-1-propanonedihydrochlcri-ie: mpl90C
20 (dec.); lH NMR (300 MHz, DMSO-d6) o 8.29-7.90 (m, 4 H), 7.70-7.15 (m, 5 H), 4.45-4.05 (brs, 2 H), 4.00-3.00 (m, 12 H).
FY~mr1t 74 SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 Wo 96/16052 PCr/US95/14987 MeSO2~ ~~N~ ~
l-(m-lvl~ ..P~..lfon~m; lophpnyl)-3-(4~-benzy~ -pi~ ;..yl)-l-plu~ e dihydrochl~nr~
mp 180-182-C; lH NMR (300 MHz, D2O) o 7.95-7.85 (m, 2 H), 7.65-7.,50 (m, 7 H), 4.49 (s, 2 H), 3.85-3.60 (brs, 12 H), 3.14 (s, 3 H).
Example 75 l-(m-Fl~lolù~henyl)-3-(4'-benzyl-l'-~ yl)-l-plul)anonedih~ lucllloride: mp251-253-C;
1H NMR (300 MHz, DMSO-d6) o 12.2 (brm, 2 H), 7.9-7.3 (m, 9 H), 4.4 (s, 2 H), 4.0-3.18 (m, 12 H).
Example 76 ~ N~3 1-(2-Thiazolyl)-3-(4'-benzyl-1'-~ yl)-l-plù~ olledihydrochlon~e: Thesolidwasbasified with NH40H, e~ r~ with dichlulu...~Ll~ne and purified via flash clllulllaLo~ y (Silica, EtOAc): IH NMR (300 MHz, CDC13) o 8.0 (d, 1 H), 7.66 (d, 1 H), 7.28 (m, 5 H), 3.5(s,2H),3.37(t,2H),2.88(t,2H),2.5(brm,8H).
1~ FY~n~rl~ 77 1-Lp-(Trifluljlulll~,lhyl)-phenyl]-3-(4'-benzyl-1'-pi~.~hlyl)-1-~lu~ one: Thesolidwas basified with lN KOH, extracted with dichlc"u,l.~ane, dried and filtered: mp 59-60 C; lH
NMR (300 MHz, CDC13) ~ 8.06 (d, 2 H), 7.74 (d, 2 H), 7.3 (m, 5 H), 3.52 (s, 2 H), 3.2 (t, 2 H), 2.87 (t, 2 H), 2.53 (brm, 8 H).
Example 78 SUBSTITUTE SHEET (RULE 26) -CA 0220~x6 1997-0~-16 Wo 96/16052 PCT/US95/14987 1 -(5"-Bromo-2"-thienyl)-3-r4'-( 1 "'-p-chlorophenyl- 1 "'-phenylmethyl)- 1 '-pi~ inyl3- 1-~lu~ olle dihydrochlon~ie mp 141-144 C; lH NMR (300 MHz, CDC13) ~ 7.44 (d, 1 H), 7.39-7.12 (m, 7 H), 7.07 (d, 1 H), 4.19 (s, 1 H), 3.10 (t, 2 H), 2.8 (t, 2 H), 2.6S-2.25 (brm, 8 H)-S F-~mrl~ 79 i~Ji N~
1-(4" MLLIIOAY-1 "-n~ph-h~l~nyl)-3-(4'-benzyl-l'-pipcl~il~yl)-1~ ol-edihydro~hlon~e mp 230 C (dec.); lH NMR (300 MHz, D20/DMSO-d6) ~ 8.88 (d, I H), 8.27 (t, 2 H), 7.73-7.35 (m, 7 H), 7.1 (d, 1 H), 4.52-4.02 (m, 5 H), 3.65 (brm, 12 H).
- FY~mrlP 80 1-(5"-Nitro-3"-thienyl)-3-(4'-benzyl-1'-~ zinyl)-1-propanone dihydroch1orit1e mp 220'C
(dec.); lH NMR (300 MHz, D20/DMSO-d6) ~ 88. (d, 1 H), 8.47 (d, 1 H), 7.66-7.42 (m, 5 H), 4.3 (s, 2 H), 3.85-3.2 (m, 12 H).
Example 81 15 1-o-Iodophenyl-3-(4'-benzyl-1'-pip~ yl)-1-propanone dihydrochlonr1e: mp 240-242 C; lH
NMR of the free base (300 MHz, CDC13) ~ 7.9 (d, 1 H), 7.5 (m, 8 H), 3.5 (s, 2 H), 3.08 (t, 2 H), 2.78 (t, 2 H), 2.49 (brs, 8 H).
Example 82 Ç ~N~
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCT/US9~i;/14987 1 -(S"-Chloro-3 "-methylbenzo[b] -2"-thienyl)-3-(4'-benzyl- 1 '-pi~, ~inyl)- 1 -~luyanolle dihydroehl~n~- mp 247 C (dec.); lH NMR of the free base(300 MHz, CDCl3) o 7.84 (d, I
H), 7.76 (d, 1 H), 7.45 (dd, 1 H), 73 (m, 5 H), 3.53 (s, 2 H), 3.15 (t, 2 H), 2.9 (t, 2 H), 2.71 (s,3H),2.55(brm,8H).
FY~mrl~ 83 l-(S"-r2"'-thienyl]-2"-thienyl)-3-(4'-benzyl-1'-~ h~yl)-1-1,lol)dnone dillydr~llloride: mp 249-252 C; lH NMR (300 MHz, D20/DMSO-d6) o 7.96 (d, 1 H), 7.67 (d, 1 H), 7.63-7.34 (m, 7 H), 7.15 (t, 1 H), 4.25 (brs, 2 H), 3.4 (brm, 12 H).
Example 84 10 1-(S"-Bromo-2"-thienyl)-3-(4'-o-fluorobcl"yl-1'-~ipeld~inyl)-1-propanonedihydrochlonr;~o: mp 224-226 C; IH NMR of the free base (300 MHz, CDC13) ~ 7.45 (d, 1 H), 7.36 (m, 1 H),7.23 (m, 1 H), 7.15-6.92 (m, 3 H), 3.6 (s, 2 H), 3.03 (t, 2 H), 2.82 (t, 2 H), 2.54 (brs, 8 H).
FY~mrle 85 l-(S''-Cyano-2''-thienyl)-3-(4'-benzyl-1'-pi~ yl)-l-~lu~anone dihydrochlonrl~ mp 256-15 258 C; lH NMR of the free base (300 MHz, CDC13) ~ 7.63 (dd, 2 H), 7.27 (m, 5 H), 3.5 (s, 2 H),3.1(t,2H~,2.84(t,2H),2.5(brm,8H).
Example 86 ~ ~N~
Br o 1 -(5"-Bromo-2"-thienyl)-3-[4'-(3"'-chlorobenzo~b]-2"'-thienoyl)- 1 '-~ yl]- 1-propanone 20 dihydrochloride: mp 188-189 C; lH NMR of the free base (300 MHz, CDC13) ~ 7.84 (m,2 H),7.48(m,3H),7.12(d, lH),3.83(brm,2H),3.5(brm,2H),3.04(t,2H),2.88(t,2H), 2.58 (brs, 4 H).
SUBSTITUTE SHEET (RULE 26~
WO 96/16052 PCI~/US95/14987 FY~rl~ 87 1-(6"-M~ y-2"-n~phth~l~nyl)-3-(4'-benzyl~ ip~,~dzillyl)-l-ll,updllo,-edihydrochloride: mp 243-246 C; lH NMR (300 MHz, D20/DMSO-d6) o 8.62 (s, 1 H), 8.12-7.86 (m, 3 H), 7.65-7.34 (m, 6 H), 7.27 (m, 1 H), 7.42-7.32 (m, 17 H).
Fr~mpl~ 88 l-(p-Methylthiophenyl)-3-(4'-(2'',6''-difl,lolubGI,,.yl)-l'-~ ,dzinyl)-l-p,upallone dihydroçhlnTi~ mp 187-188 C; lH NMR (300 MHz, CDCl3/MeOD) o 7.90 (d, 2 H),7.65-7.50 (m, 1 H), 7.30 (d, 2 H), 7.23-7.10 (m, 2 H), 4.00-3.40 (m, 14 H~, 255 (s, 3 H).
Fr~mrl~ 89 o ~~~ ~N"~
1 -(2"-Thienyl)-3-r4'-(1 "'-p-chlorophenyl- 1 "'-phenylmethyl)- 1 '-~ ~nyl]- 1-~,upanu--c dihydrochloride: mp 189-201 C; IH NMR (300 MHz, DMSO-d6) â 8.05 9d, 1 H), 8.00 (d, 1 H), 7.55-7.20 (m, 10 H),4.60 (brs, 1 H), 3.80-3.20 (m, 12 H).
~r~mpl~ 90 15 1-~D-N-Piperidinophenyl)-3-(4'-benzyl-1'-pi~ yl)-1-plu~anoné dihydrochloride: mp 135-C
(dec.); lH NMR (300 MHz, CDC13tDMSO-d6) o 8.00 (d, 2 H), 7.90-7.40 (m, 7 H), 4.35 (s, 2 H), 4.15-5.00 (m, 2 H), 4.00-3.80 (m, 2 H), 3.80-3.40 (m, 12 H), 2.15-1.95 (m, 4 H), 1.80-I.65(m,2H).
Example 91 SUBSTITIJTE SHEET (RULE 26) Wo 96tl6052 PCT/US95/14987 N~
l-(N-Phenylsulfonylpyrro1-2-yl)-3-(4'-benzyl-1'-P;l ~ yl)-1-p,u,.)anul-cdihydrochlonde: mp 215-C (dec.); lH NMR (300 MHz, DMSO-d6) â 8.0807.85 (m, 2 H), 7.75-7.35 (m, 10 H),
(dec.); lH NMR (300 MHz, DMSO-d6) o 12.40-12.10 (brs 1 H), 12.1-11.70 (brs 1 H), 7.90 (d, 2 H), 7.80-7.20 (m, 7 H), 4.70-4.20 (brs, 2 H), 4.20-3.10 (m 12 H), 2.70-2.40 (m, 2 H), 2.00-1.15 (m, 9 H).
FY~mple 28 o ~ ~N~
1-(Fluoren-2"-yl)-3-(4'-benzyl-1'-p;~ ,;..yl)-1-propanonedihydro~hlnrir1e: mp225C(dec.);
lH NMR (300 MHz, DMSO-d6) ~ 12.40-11.30 (brs, 2 H), 8.40-7.95 (m, 4 H), 7.75-7.30 (m, 8 H), 4.60-4.20 (brs, 2 H), 4.05 (s, 2 H), 3.95-3.05 (m, 12 H).
FY~mr1~ 29 15 1-~D-Iodophenyl)-3-[4'-(o-fluolubo,l~yl)-1'-P;l~ yl~-1-plul)anoncdihydrochloride: mp215-217 C; lH NMR (300 MHz, DMSO-d6) ~ 11.6 (br, 2 H), 8.0 (d, 2 H), 7.7 (m, 3 H), 7.5 (m, 1 H), 7.3 (m, 2 H), 4.3 (brs, 2 H), 3.8-3.0 (brm, 12 H).
Example 30 1 -(o-Fluorophenyl)-3-[4'-(o-fluorobenzyl)- 1 '-~i~c. d~hlyl]- 1 -~lupanol~c dihydrochloricle The 20 solid formed was converted to its free base using NH40H, ~ d with dichlululllr~ n~ and purified via flash chromato~l~hy (Silica, EtOAc). The resulting colll~ùul-d was converted to its dihydrochlnride salt by the addition of dry ether-HCI to give the desired product: mp 213-216-C;
SUBSTITUTE SHEET (RULE 2G) Wo 96/16052 PCT/US95/14987 lH NMR of the free base (300 MHz, CDC13) ~ 7.83 (t, I H), 7.5 (m, 1 H), 7.4-6.95 ~m, 6 H), 3.6(s,2H),3.2(m,2H),2.8(t,2H),2.5(brs,8H).
FY~mrie 31 l-(m-NiLlù~hc.,yl)-3-[4'-(o-lluulùb~""yl)~ .r ~ yl]-l-~ dlloncdihydrochloride: lH
5 NMR of the free base (300 MHz, CDC13) o 8.78 (s, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 7.7 (t, lH),7.37(t, lH),7.24(m, lH),7.15-6.95(m,2H),3.6(s,2H),3.22(t,2H),2.88(t,2 H), 2.56 (brs, 8 H).
FY~rnrlP 32 l-~D-Nil,u~hellyl)-3-r4'-(o-flllolu~,~yl)-1'-~ "~h~yl]-1-~ )anone dihydrochlnrid~ The 10 solid formed was converted to its free base using NH40H, cAIla.;l~d with dichlcl~ hAl~e and p~ified via flash cl~ull,a~ography (Silica, 9:1 EtOAc~eOH). The resulting colll~uu"d was C~ Lt;d back to its ~ yd~u~ hlotirl~ salt by the A~drlition of dry ether-HCl and recrystAlli7~d from nol (2x) to give the desired ~ludu~ H NMR of the free base (300 MHz, CDC13) o 8.3 (d,2H),8.1(d,2H),7.9-6.95(m,4H),3.6(s,2H),3.2(t,2H),2.85(t,2H),2.5(brs,8 15 H).
FYAmrl~ 33 l-~D-NiL~o}~ht~yl)-3-r4~-(2"~5"-difluulu~l~y~ à~illyl]-~ ol~e dihydrochloride:
The solid was basified with NH40H, c,.uacLcd with dichlc,lu..~ Ih~ purified via flash cll~u~ y (Silica. EtOAc), and converted to the dihydrochlc-n~e salt by the addition of dry 20 ether-HCI. This was recryst~lli7~oA in meth~nol (2x) to give the desired product: mp 212-215-C;
lH NMR of the free base (300 MHz, CDC13) o 8.3 (d, 2 H), 8.1 (d, 2 H), 7.2-6.8 (m, 3 H), 3.55 (s, 2 H), 3.2 (t, 2 H), 2.85 (t, 2 H), 2.55 (brs~ 8 H).
Example 34 SUBSTITUTE SHEET (RULE 26) WO g6116052 PCTIUS9~/14987 3~ / ~--N~
l-~D-NiL~ yl)-3-(4'-~ ,.u~ yl)-1-~ 0l~e d~hy~u~ Ot~ The solid was basified with NH40H, ~xl.n~ ;I with dichlu~ I h ~ and purified via flash ch-~ ug.,.lll.y (Silica, EtOAc). The l~,..ulling co~ ,ou,ld was converted to the dihydroehlntid~ salt by the 5 ~riition of dry etner-HCl and recryst~lli7~ in ~ nol to give the desired ~ lu~;l. mp 211 217 C; lH NMR of the free base (300 MHz, CDC13) o 8.3 (d, 2 H), 8.1 (d, 2 H), 6.9-6.65 (m, 3H),5.95(s,2H),3.4(s,2H),3.21 (t,2H),2.83(t,2H),2.5(brm.8H).
FY~mp3e 35 o N2~ ~N~
~3 10 1-(p-Nitrophenyl)-3-~4'-(1"-p-chlorophenyl-1"-phenylmethyl)-1'-pi~ yl]-1-propanone dihydrochloride: The reaction was cO.I~f .~ ted in vacuo, basified with NH40H, ~ d with dichlorometh~n~ and purified via flash chlv . .~ graphy (Silica, EtOAc). The resulting co~ ,ou~ld was converted to its dihydrochloride salt by the arl~isinn of dry ether-HCl to give the desired product: mp 148-153 C; IH NMR of the free base (300 MHz. CDC13) ~ 8.3 (d, 2 H), 15 8.1 (d, 2 H), 7.45-7.1 (m, 9 H), 4.2 (s, 1 H), 3.2 (t, 2 H), 2.85 (t, 2 H), 2.7-2.3 (brm, 8 H).
Example 36 l-(p-l~oth~n~slllfon~mi~iophenyl)-3-(2l~7s~-difluo~benzyl-l~ yl)-l-~ulu~ one dihydrochlnri~le: mp 230-232 C; lH NMR (300 MHz, D20) â 7.88 (d, 2 H), 7.3-7.05 (m, 5 H), 4.28 (s, 2 H), 3.8-3.3 (brm, 12 H), 3.06 (s, 3 H).
SUBSTITUTE SHEET (RULE 26 =
CA 0220~86 1997-0~-16 Exarnple 37 1 -(3''-Thienyl)-3-[4'-(m-fluc,.uboll ,yl)- 1 '-pip. . ~,; . ,yl]- 1 -propanone dihydrochlnnr~ The solid was basified with NH40H, e~.LIaCh;l with dichlc lu, . ~ nç and purified via flash clll~ ".pl,y (Silica, EtOAc). The free amine was converted to its dihydro~lnntle salt by the 5 addition of dry ether-HCl to give the desired ~10 IU~;L~ lH NMR of the free base (300 MHz, CDC13) ~ 8.06 (d, 1 H), 7.53 (d, 1 H), 7.29 (m, 2 H), 7.08 (m, 2 H), 6.93 (m, 1 H), 3.5 (s, 2 H),3.12(t,2H),2.85(t,2H),2.54(brm,8H).
FY~mpl~ 38 1 -(3 "-Thienyl)-3-[4'-(2"',5"'-difluol ù~"z.yl)- 1 '-pip~,. ~inyl] - 1 -1,l upa~one dihydrochloride: 1 H
10 NMR of the free base (300 MHz, CDC13) o 8.05 (d, 1 H), 7.54 (d, 1 H), 7.32 (m, 1 H), 7.12 (m, 1 H), 6.94 (m, 2 H), 3.57 (s, 2 H), 3.1 (t, 2 H), 2.83 (t, 2 H), 2.56 (brs, 8 H).
FY~rnrl~ 39 l-~D-NiLlu~llC~yl)-3-([4'-(o-llinuululll~ lyl)benzoyl3-l~ yl)-l-~ p~ nt The solid was basified with NH40H, ~ 1t-lrrl with dichlc/l.J~ ,ç and purified via flash 15 clllulllatugraphy (Silica, EtOAc) to give the desired plodu.;l. mp 179-181 C; lH NMR (300 MHz CDC13) ~ 8.32 (d, 2 H), 8.1 (d, 2 H), 7.72 (d, 1 H), 7.56 (m, 2 H), 7.33 (d, 1 H), 3.82 (m, 2 H), 3.2 (m, 4 H), 2.88 (t, 2 H), 2.6 (m, 2 H), 2.62, (m, 2 H).
FY~rnpl~ 40 o NO2~ N~N~
O F
20 l-~-Ni~ophenyl)-3-[4'-(2'',6''-diflllolu~ll2oyl)-ll-pil~e~ yl]-l-l,lupallol~e hydrochlnri~
mp 225-227 C; lH NMR (300 MHz, D2O/CD3OD) ~ 8.21 (d, 2 H), 8.03 (d, 2 H), 7.42 (m, 1 H), 6.98 (t, 2 H), 3.78-3.15 (brm, 12 H).
SUBSTITUTE ~HEET (RULE 26 -CA 0220~86 1997-0~-16 WO 96tl6052 PCTIUS95/14987 FY~mpl~ 41 1 -(o-Fluu.~h~nyl)-3-r4'-(2'',6''-difluorobell~.,yl) 1 '-~ip~ yl]- I -p,opanon~ hydrochlnn-le:
mp 185-187 C; IH NMR (300 MHz, CDC13) ~ 13.55-13.73 (brs, 1 H), 7.87-7.65 (m, 1 H), 7.65-7.35 (m, 2 H), 7.35-6.90 (m, 4 H), 2.92 (d, I H), 4.15 (t, 1 H), 3.90-3.40 (m, 8 H), 5 3.05-2.80 (m, 2 H).
Example 42 1-~7-NiLluph~ yl)-3-[4l-(m-flllo~ yl)-1'-~ a~ yl]- 1-~l.p~lolledihy~ll~hlûride: mp 210-C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.10-11.30 (brs, 2 H), 8.40 (d, 2 H), 8.25 (d, 2 H), 7.60-7.20 (m, 4 H), 4.45-3.00 (m, 14 H).
Fs~mr1-~ 43 1-(o-Flllolu~he,lyl)-3-[4'-(o-llinuolullleLl.ylbenzoyl)-1'-~ yl]-1-~ nol~e hydrochloride:
mp 175-176 C; lH NMR (300 MHz, CDC13) ~ 13.55-13.45 (brs, 1 H), 7.98-7.50 (m, 5 H), 7.45-7.10 (m, 3 H), 4.92 (d, 1 H), 4.12 (t, 1 H), 3.95-3.35 (m, 8 H), 3.10-2.70 (m, 2 H).
FY~mrk~ 44 15 1-(o-Fluolul)h~"~yl)-3-[4'-~D-fluorobenzyl)-1'-~ 7;nyl]- l-propanone dihydl~ 1nn~l~o: mp 209 C (dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.00-11.40 (brs, 2 H), 7.95-7.20 (m, 8 H), 4.30 (s, 2 H), 3.85-3.20 (m, 12 H).
Example 45 1-GD-Ni~Jphe.lyl)-3-r4'-~D-fluorobenzyl)-ll-~ illyl]-1-~1u~ Onf dihydrochlc-n~is: mp 20 200 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.50-11.60 (brs, 2 H), 8.50 (d, 2 H), 8.25 (d, 2 H), 7.85-7.20 (m, 4 H), 4.39 (s, 2 H), 4.00-3.00 (m, 12 H).
Example 46 1-GD-Fluc~ h~nyl)-3-[4'-(p-fluorobenzyl)-1'-pi~ zinyl]-1-propanone dihydrochlori(le mp 224 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.40-11.70 (brs, 2 H), 8.05-7.20 (m, 8 H), 25 4.35 (brs, 2 H), 3.95-3.10 (m, 12 H).
SUBSTITUTE SHEET IRI ILE 2~) -CA 0220~86 l997-0~-l6 WO 96/16052 PCr/US95/14987 FY~mrl~ 47 1-(m-Fluolu~hc.,yl)-3-[4'-~-fluu,u~llL~ yl]-1-~v~dihydrochloride: mp 215 C (dec.); 1H NMR (300 MHz, DMSO-d6) o 12.05-11.75 (brs, 2 H), 7.95-7.15 (m, 8 H), 4.35 (brs, 2 H), 3.9S-3.15 (m, 12 H).
Example 48 1-~-Iodc~hc.~yl)-3-[4'-~D-fluolu~,,~y-l)-l'-pil,~,~i,,yl]-l-~ru~ Jl,cdihydrochlt-rirl~: mp 215 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.25-11.70 (brs, 2 H), 7.95 (d, 2 H), 7.80-7.50 (m, 4 H), 7.40-7.20 (m, 2 H), 4.30 (s, 2 H), 3.90-3.10 (m, 12 H).
Example 49 (a) 4-Fluo~u~nLuyl~ zine: p-Fluolub.~n~ùylcllloride (6.00g) in 30mL
CH3CN was added in one portion to a stirred so1u~inn of pi~,e.~ine (16.25 g) dissolved in lNHCl (285 mL). The reaction was stirred at room t~mrçr.~h~re for 3.5 hrs. then an ~ itinn~l 50 mL of lN HCl was added. The sollltion was c,~L~ ed with 2 x 100 mL EtOAc. Thea~ucous acidic layer was made basic with lN KOH then e~.LI~L~d with 2 x 150 rnL CH2C12.
15 The organic layer was 5~ ",~ , dried (Na2S04), filtered and e~pUldt~, affording a yellow oil which soii-iifi~d upon st~nriing (5.60 g; 71 % yield). M+ 208. lH NMR (300 MHz, CDC13) o 7.50-7.35 (m, 2 H), 7.18-7.00 (m, 2 H), 3.90-3.30 (brd, 4 H), 3.00-2.70 (brs, 4 H), 1.85 (s, 1 H).
(b~ 3-Flu~lubcn~oyl~i~.~ne: Utilizing the ~,l~lulc of FY~mple 49a but repl~ing 20 p-fluorobenzoylchlc ri~ with m-fluolu~n,~ylchloride (3.00 g) afforded the desired product (3.20 g; 82% yield). M+ 208. lH NMR (300 MHz, CDC13) ~ 8.50-7.32 (m, 1 H), 7.25-7.05 (m, 3 H), 3.75 (brs, 2 H), 3.40 (brs, 2 H), 3.05-2.65 (m, 4 H), 1.90 (s, 1 H).
(c) 2-Fluoro~n~uyl~ 7inç: Using the l"ucedu.~ of Example 49a and o-fluorobenzoylchloride (2.00 g) gave the desired product (2 40 g; 90% yield). M+ 208. lH
25 NMR (300 MHz, CDC13) ~ 7.50-7.00 (m, 4 H), 2.90-3.70 (m, 2 H), 3.45 (brs, 2 H), 3.10-2.65 (m, 4 H), 1.85 (s, 1 H).
~6-SU3STITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 WO 96tl6052 PCI/US95/14987 (d) 2,5-Dinu~u~,lzoyl~ à~ e Using the plOCcdulC of Example 49a with 2,5-difluoro~nz~ylchloride (5.00 g) gave the desired product (3.00 g; 51% yield). M+ 226.
lH NMR (300 MHz, CDC13) ~ 7.20-7.00 (m, 3 H), 3.86-3.70 (m, 2 H), 3.40-3.25 (m, 2 H), 3.05-2.75 (m, 4 H), 1.97 (s, 1 H).
(e) 4-Tlinuulul~ ylbenzoyl~ a~ e: Usingthe ~/rlX`~lUlc ofExample49awith p-llinuurol~lell~ylbenzoyl~hlorirls (5.00 g) gave the desired product (1.85 g; 30% yield).
M+ 258. IH NMR (300 MHz, CDC13) o 7.67 (d, 2 H), 7.50 (d, 2 H), 3.75 (brs, 2 H), 3.35 (brs, 2 H), 3.05-2.75 (m, 2 H), 1.85 (s, 1 H).
(f~ 2,3-Dinuulu~.-~uylp;l~ ;--f - Using the l,.uc,~ulc of FY~mrlt~ 49a with 2.3-difluorobenzovlchlori(1e (5.00 g) gave the desired product (3.00 g; 47% yield). M+ 226.
lH NMR (300 MHz, CDC13) ~ 7.35-7.05 (m, 3 H), 3.75 (brs, 2 H), 3.30 (brs, 2 H), 3.06-2.75 (m, 4 H), 1.75 (s, 1 H).
(g) 2-Trifluolulllclllylbenzoyl~;lh,.~l, ;"e Using the ~locedulc of Example 49a with o-~ifluululllc~ lbenzoylchloride (5.00 g) gave the desired product (3.4 g; 55% yield).
M+ 258. lH NMR (300 MHz, CDC13) ~ 795-7.45 (m, 3 H), 7.40-7.25 (m, 1 H), 3.90-3.70 (m, 2 H), 3.25-3.05 (m, 2 H), 3.00-2.85 (m, 2 H), 2.85-2.65 (m, 2 H), 1.70 (s, 1 H).
(h) 4-Nillu~.l,uylpi~-,.~ine: Using the l"uc~lulc of Fy~mrle 49a with p-nitrobenzoylchloride (7.00 g) gave the desired product (4.50 g; 50% yield). M+ 235. lH
NMR (300 MHz, CDC13) ~ 8.27 (d, 2 H), 7.07 (d, 2 H), 3.90-3.60 (brs, 2 H), 3.45-3.25 (brs, 2 H), 3.10-2.70 (m, 4 H), 1.75 (s, 1 H).
(i) 2,~DifluOlu~ll~oyl~i~x,a7;-.c: Using the plvcedulc of Fy~mrle 49a with 2,6-difluorobenzovlchlcn-1e (5.00 g) gave the desired product (3.25 g; 51% yield). M+ 226.
lH NMR (300 MHz, CDC13) ~ 7.45-7.25 (m, 1 H), 7.05-6.85 (m, 2 H), 3.70-3.40 (brs, 2 H), 3.40-3.25 (brs, 2 H), 3.05-2.75 (m, 4 H), 1.70 (s, 1 H).
(1) 4-Iodobenzoyl~,ipe,d~u,c: Using the procedure of Fy~mrle 49a with 4-iodobenzoylchloride (4.24 g) gave the desired product (0.70g; 14% yield). M+-316. 1H
SUE~STlTUTc S~Y~ET (RUL~ 26) CA 0220~86 1997-0~-16 Wo 96/16052 P~USg5114987 NMR (300 MHz, CDC13) o 7.85-7.15 (d,2 H),7.20-7:05 (d,2 H),3.85-3.05 (brs,2 H), 3.55-3.25 (brs, 2 H), 3.10-2.65 (m,4 H),1.75 (s, 1 H).
(k) ~ .An~, ,..Il.hf~..~...;~in a~ernph.onnnlo A CH2C12 (130 mL) solution co,~
4-,....;~.o~e~ f ..on~ (5.00 g) and triethylamine (5.6 mL) was cooled to 0 C and placed under S niL.~g~ll. Then, ..l Ill~npslllfonyichlnririe (3.1 mL) in CH2C12 (5 mL) was added ~ wise over 10 min. Upon co...l-k ~ ad~iition the reaction was sti~rcd at 0 C for an ~ririinnn~l 10 min.
then allowed to warm to room ~ ,,,.l...c with stirring c~ .;Q~ for 2 hrs. Then lN KOH
was added and the layers s~ A The basic layer was made acidic, then c~LIa~ ;i with CH2C12 (2 x 75 mL). The organic extracts were comhinçci, dried (Na2S04), filtered and 10 c~ia~ulaled affording a pale yellow solid (4.10 g; 52% yield). M+ 213. lH NMR (300 MHz, CDC13) o 7.97 (d, 2 H), 7.27 (d, 2 H), 3.10 (s, 3 H),2.07 (s,3 H).
(1) 3 ~ ". ~ .hollA...;~io a~ .- .o.~e- Using the ~luc~ule of FY~mrl~ 49k but starting with 3-~mino~cet~h~ .-one (5.00 g) gave the desired product (6.00 g; 76% yield).
M+ 213. lH NMR (300 MHz, CDC13) o 7.92-7.45 (m, 5 H),3.52 (s, 3 H),2.65 (s,3 H).
(m) 2-Fluorobtl"ylpi~,~,.~i,.e; The product from Fy~mrl~ 49c (3.10 g) was dissolved in dry T~F (75 mL) then a lM B2H6THF solution (45 mL) was added dropwise over ca. 15 min. under N2. Upon cOl. .~ rlition~ the sol-lhnn was refluxed under N2 for 3 hrs. The reaction was cooled to 0 C in an ice bath and then lN HCl (ca. 70 mL) was carefully added d,~pwise. Upon comrlete ~iditiQn, the reaction was allowed to warm to room20 le~ ... c followed by extraction with EtOAc (2 x 100 mL). The organic layer was discarded and the acidic layer made basic with KOH. This was C.~ dcl~ with CH2C12 (2 x 150 mL).
The organic extracts were cnmhineA, dried (Na2S04), filtered and e~a~uldL~ giving an oil that began to solidify upon st~n~1ing This was dissolved in IN HCl (75 mL) then refluxed 1.5 hrs.
The reaction was cooled to 0C then made basic with KOH followed by CH2C12 e~ ion 25 (2 x 100 mL). The organic extracts were co...l~ fA, dried (Na2S04), filtered and e~d~c~ldled ~fforn'ing a pale yellow oil (1.2 g; 41% yield). M+ 194. lH NMR of the dihydrochlori~le salt (300 MHz, CDC13) o 10.00-9.30 (brs, 2 H), 7.15-6.85 (m, 4 H), 3.62 (s, 2 H), 3.35-3.15 (m, 2 H), 2.90-2.70 (m, 2 H).
SUBSTITUTE SHEET ~RULE 26) ~ ==
CA 0220~86 1997-0~-16 WO 96tl6052 PCT/US95/14987 (n) 2,3-Dinuolù~l~yl~i~G~zine: Using the product from Example 49f (1.14 g) and the ~lucGdu~c of Fy~mrle 49m gave the desired product (0.45 g; 43% yield). M+ 212. lH
NMR (300 MHz, CDC13) ~ 7.20-6.97 (m, 2 H), 3.60 (s, 2 H), 2.90 (t, 4 H), 2.55-2.35 (brs, 4 H), 1.67 (s, 1 H).
(o) 4-Ni~ù~yl~ e: Using the product from FY~mrl~ 49h (0.50 g) and the procedure of Fy~mr!e 49m gave the desired product (0.28 g; 59% yield). M+ 221. 1H NMR
(300 MHz, CDC13) o 8.27 (d, 2 H), 7.15 (d, 2 H), 3.75 (s, 2 H), 3.30-3.15 (m, 4 H), 2.85-2.70 (m, 4 H).
(p) 2,5-Dinuclubell~yl~ cl~le: Using the co.nl)ounA of FY~mrle 49d (2.90 g) and the ~lue~lwci of FY~mrle 49m gave the desired product (2.3û g; 83% yield). M+ 212. lH
NMR (300 MHz, CDC13) o 7.36-7.22 (m, 1 H), 7.10-6.90 (m, 3 H), 3.55 (s, 2 H), 3.30-3.10 9m, 4 H), 2.85-2.65 (m, 4 H).
(q) 4-FlllOlu~l~.yl~i~a~ille; Using the co~llpuund of Exarnple 49a (5.25 g) and the ~ruc~luuG of Fy~mrle 49m gave the desired product (4.35 g; 75% yield). M+ 194. lH NMR
(300 MHz, CDC13) ~ 8.95-8.70 (brs, 1 H), 7.40-7.25 (m, 2 H), 7.25-7.05 (m, 2 H), 3.50 (s, 2 H), 3.15-2.95 (brs, 2 H), 2.65-2.35 (m, 2 H).
(r) I-Be.~ lfonylpiperazine: Be~ .lfonyl chloriA~. (2.00 g, 0.011 mol) in 25 mL CH3CN was added in one portion to a stirred solution of ~i~Gl~ine (4.90 g, 0.057 mol) dissolved in lN HCl (100 mL). The reaction was stirred at room IC.ll~.dtu~ for 30 minntes The solution was e~ L~ with EtOAc and the a4u20us acid layc-r was made basic with lN KOH and then extracted with 2 x 10 mL CH2CI2. The organic layer was s~ated, dried (MgS04), filtered, and e~u~ted affording 1.40 g (50%) of a pale yellow solid: mp 109-111 C; IH NMR (300 MHz, CDC13) o 7.75 (m, 2 H), 7.65-7.40 (m, 3 H), 2.96 (m, 8 H).
,~
(s) 1-(2'-Chloro-6'-methylpyrido-4'-yl)l,ip~.dzille: 2-Chloro-6-methylpyridine-4-c~l~nyl chloriA~o~ (5.00 g, 0.026 mol) in 50 mL CH3CN was added in one portion to a stirred solution of pil)~.azille (11.31 g, 0.13 mol) dissolved in lN HCl (180 mL). The reaction was stirred at room le~ .alu~ for 3 hours, then an ~AAitinn~l 50 mL of lN HCl was added. The SUBSTITUTE SHEET ~RULE 26) CA 0220c,c,86 1997-0ct-16 Wo 96tl6052 PCT/US95/14987 solm nn was tAI~tlcl,~i with EtOAc (2 x 150 mL), the a~ueous acid layer was made basic with IN KOH and then e,.ll..cled with 2 x 10 mL CH2C12 (2 x 200 mL). The organic layer was se~ AtcA, dried (MgS04), filtered and cQnçe..~ eA, affording 3.30 g (53%) of a light yellow solid: mp 164-165C; IH NMR (300 MHz, CDC13) ~ 7.12 (s, 1 H), 7.06 (s, 1 H), 3.74 (m, 2 5 H),3.33(m,2H~,2.95(m,2H),2.83(m,2H),2.57(s,3H), 1.72(s, lH).
(t) p-Toll~- IP ~u1rullr~ e Using the ~luee~lul~ of FY~mple 49r withp-~tu~l~le l~slllfonyl chloride gave the desired ~ ~lu~;l. mp 98-101C; IH NMR (300 MHz, CDCl3) o 7.64 (d, 2 H), 7.34 (d, 2 H), 2.95 (m, 8 H), 2.44 (s, 3 H), 1.60 (brs, 1 H).
(u) p-B~u~l~ù~ ..t~lllrul Iyl~ t~;1le- Usingthe~,ucedu~ofExarnple49rwithp-0 L tlUII10~U~ 1fonyl chloride gave the desired plu~lu~l; mp 117-121C; IH NMR (300 MHz, CDC13) ~ 7.66 (dd, 4 H), ~.97 (m, 8 H), 2.44 (s, 3 H), 1.60 (brs, 1 H).
FYS~m~ S 50 and 51 o ~N ~ ~N~
o H3C~ ¦ ~N , 1,4-Bis-t3'-(4"-benzyl-1"-~il)el~i"yl)-propanoyl] benz, "c (50) and 1-(p-Acetylphenyl)-3-(4'-benzyl-l'-~ .,,,;,,yl)-1-~,,u~,~,one dihydr~chloride (51): Using the general method gave bodl 20 collll~ullrl~ afterpnrifir~ti( n via flash Chl~JIIIQ~ hY (Silica, EtOAc). Each was converted to SUBSTITUTE SHEET (RULE 26) its dihydrochlo~ salts by the addition of dry ether-HCl. Higher Rfl = .43 (8:2 EtOAc/MeOH) gave 8 mg (50): mp ~ 250-C; lH NMR of the free base (300 MHz, CDCl3) ~ 8.0 (s, 4 H), 7.3 (m, 5 H), 3.5 (s, 2 H), 3.2 (t, 2 H), 2.85 (t, 2 H), 2.65 (s, 3 H), 2.5 (brm, 8 H). Lower Rf2 =
.14 (8:2 EtOAc/MeOH) gave 0.21 g (51): mp > 245 C; lH NMR of the free base (300 MHz, 5 CDC13) o 8.0 (s, 4 H), 7.3 (m, 10 H), 3.5 (s, 4 H), 3.2 (t, 4 H), 2.85 (t, 4 H), 2.5 (brm, 16 H).
FY~mrl~c 52 and 53 O O
CH3J~ ~ N~N~3 O O
10 ~ N~ ~50~--N~N
1-(8"-Acetylph~nnY~thiin-2"-yl)-3-(4'-benzyl-1'-pi~ a~ yl)-1-pl(,pa.~olle dihydrochloride (52) and 2,8-Bis-[3'(4"-benzyl-1"-~ui~.d~,~yl)propanoyl] ph~.,o~ h;;~ (53): According to Examples 50 and 51, 1,4-diacetyl~..~e"c was replaced with 2,8-diace.vlyhcnox~thiin (0.25 g, 15 0.88,nrnol). After pnrifif~tir)n by flash chlul . .~tography (Silica. EtOAc) the two L ludu- l~. were icol~t~A Rfl = .47 (8:2 EtOAc/MeOH) was converted to its collc~ onding salt by the ~ln'itinn of dry ether-HCl to give 95 mg (52): mp > 250'C; 1H NMR of the free base (300 MHz, CDCl3) ~ 7.8-7.5 (m, 4 H), 7.3 (m, 5 H), 7.15-6.95 (m, 2 H), 3.5 (s, 2 H), 3.1 (m, 2 H), 2.8 (m, 2 H), 2.65-2.3 (brm, 11 H). Rf2 = .24 (8:2 EtOAc/MeOH) was converted to its 20 co~l~ollding hydrochlo~i~e salt to give 35 mg (53): mp ~ 250 C; lH NMR of the free base (300 MHz, CDCl3) â 7.8-7.5 (m, 4 H), 7.3 (m, 10 H), 7.15 (d, 1 H), 7.05 (d, 1 H), 3.55 (s, 4 H), 3.1 (m, 4 H), 2.85 (m, 4 H), 2.5 (brm, 16 H).
F~mrl~ 54 SUBSTITUTE SHEET (RULE 26) Wo 96/16052 PCT/US95tl4987 02N~ ~N~
O F
l-~o-Ni~ h~ rl)-3-(4'-o-fl, o.o~n~oyl-l'-pi~.e.azi-lyl)-l-propanone dihydrochlonri~ The solid was basified with NH40H, e ~ l . j.rt~ A with dichlo~ L~ ç and purified via flash cLI..."~lo~".l.l-y (Silica, EtOAc). The free amine was converted to its hydrochl(~ salt by the 5 addition of dry ether-HCI; filtered and dried: mp 217-218-C; 1H NMR of the free base (300 MHz, CDC13) o 8.32 (d, 2 H), 8.11 (d, 2 H), 7.4 (m, 2 H), 7.27-6.99 (m, 2 H), 3.8 (m, 2 H), 3.48-3.1 (m, 4 H), 2.89 (t, 2 H), 2.7-2.3S (m, 4 H).
FY~mpl~ S5 1-(~7-NiLIuphe~lyl)-3-[4'-(3'',4''-difluolu~,lzyl)-l'-pip~ inyl]-l-plop~ulone dihydrochloride:
10 mp 210-212 C; lH NMR (300 MHz, D20? ~ 8.22 (d, 2 H), 8.04 (d, 2 H), 7.37-7.09 (m, 3 H), 4.35 (s, 2 H), 3.7-3.35 (brm, 12 H).
FY~mrie 56 o ~~ ~N J~3 1 -(S"-Phenyl-2"-thienyl)-3-(4'-benzyl- 1 '-~ ~llyl)- 1 -p-upallone dihydrochloride: mp 224-15 247 C; IH NMR (300 MHz, D20) ~ 7.76 (m, 1 H), 7.67 (m, 2 H), 7.37 (m, 9 H), 4.33 (s, 2 H), 3.5 (brm, 12 H).
Example 57 1-(~"-Bromo-2"-thienyl)-3-(4'-benzyl-1'-,,,;l.e.~.7;.~yl)-1-propanone dihydroçhlon~ The solid was basified with NH40H, G~ ,L~d with dichlc lur . ~ ~ h~ le and purified via flash 20 cll~.,.",.~ rhy (Silica, EtOAc). The free amine was converted to its hydrochl~n~l~ salt by the SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 a~dition of dry ether-HCl; filtered and dried: mp 242-244-C; IH NMR (300 MHz, D20) ~ 7.58 (d, 1 H), 7.37 (brs, 5 H), 7.15 (d, 1 H), 4.32 (s, 2 H), 3.5 (brm, 12 H).
Example 58 ~~ N~
S l-(Biphenylen-2"-yl)-3-(4'-benzyl-1'-pi~ ,inyl)-1-p~,~none: mp 133-134-C; lH NMR (300 MHz, CDC13) ~ 7.46 (d, 1 H), 7.29 (m, 5 H), 7.17 (s, 1 H), 6.9-6.65 (brm, 5 H), 3.52 (s, 2 H),3.04(t,2H),2.81 (t,2H),2.52(brs,8H).
FY~mpl~ 59 1 -(5 "-Chloro-2"-thienyl)-3-(4'-benzyl- 1 '-I)i~, d~ in~l)- 1 -prop~none dihydrochlnri~ mp 248-10 249-C; lH NMR (300 MHz, D2O) ~ 7.63 (d, 1 H), 7.36 (brs, 5 H), 7.0 (d, 1 H), 4.28 (s, 2 H), 3.44 (brm, 12 H).
FY~mpl~ 60 1-(m-Cyanophenyl)-3-(4'-benzyl-1'-~ yl)-1-~ulu~,,..,one dihydrochloride: The solid was basified with NH40H. t;~ acL~,d with dichlulu..~ and purified via flash chlulllalû~;lapl~y 15 (Silica, EtOAc). The free amine was converted to its hydr~chlr-rirl~ salt by the ~n~n~inon ûf dry ether-HCl; filtered and dried: mp 247-248 C; lH NMR (300 MHz, CDCl3) o 8.28-8.1 (m, 2 H), 7.84 (d, 1 H), 7.61 (t, 1 H), 7.3 (brm, 5 H), 3.S1 (s, 2 H), 3.17 (t, 2 H), 2.84 (t, 2 H), 2.5 (brm, 8 H).
~Y~mrl~ 61 20 1 -(6"-Fluoro-2"-methylphenyl)-3-(4'-benzyl- 1 '-pi~,~;l~inyl)- 1 -propanone dihydrochloride: mp 210-C (dec.); lH NMR (300 MHz, DMSO-d6) o 12.15-11.40 (brs, 2 H), 8.05-7.95 (m, 1 H), 7.70-7.40 (m, 5 H), 7.30-7.20 (m, 2 H), 4.55-4.20 (brs, 2 H), 3.90-3.20 (m, 12 H).
Example 62 SUBSTITUTE SHEET (RULE 26) =
N~ ~ r O F
l-(S'''-Bromo-2'''-thienyl)-3-[4'-(2'',6''-dinuo,ubenzoyl)-l' ~ ,.;nyl]-l-~lu~allolle hy~Lo~ l~ln.,i~1e mp 225-226-C; lH NMR (300 MHz, DMSO-d6/D20) o 7.9 (d, 1 H), 7.63 (m, 1 H), 7.49 (d, 1 H), 7.28 (t, 2 H), 4.65 (brs, 2 H), 3.95-3.03 (m, 1~ H).
FY~mrl~ 63 l-~D-Nillu~hc~lyl)-3-r4'-(2'',3''-difluo~u~l~2url)-ll-~ dzillyl]~ lu~ olle dihydrochloril1e The solid was basified with NH~LOH, extracted with dichlo,u,. ,I.~ne and purified via flash C1~ t~ lllY (Silica, EtOAc). The free amine was converted to its hydr~chlnrirl~ salt by the ~rlrlitinn of dry ether-HCI; filtered and dried: mp 213-214 C; IH NMR (300 MHz, DMSO-d6) 10 10.7 (brs, 1 H), 8.39 (d, 2 H), 8.23 (d, 2 H), 7.58 (m, 1 H), 7.34 (m, 2 H), 3.85-3.0 (m, 12 H).
FY~mrle 64 l-(o-Chlo,ul,henyl)-3-(4'-benzyl-1'-pil,e~dzinyl)-1-p~panone dihydrochloride: The solid was basified with NH40H. rx~ d with dichlo~ ne and purified via flash cl~lul~laLography l5 (Silica, EtOAc). The free arnine was converted to its dihydror~hlnrirl~o salt by the addition of dry ether-HCI; filtered and dried: mp ~ 250-C; lH NMR (300 MHz, D20) ~ 7.8-7.18 (m, 9 H), 4.55 (s, 2 H), 3.64 (brs, 12 H).
Exarnple 65 I-(o-Nitrophenyl)-3-(4'-benzyl-1'-pip~"~nyl)-1-propanone dihydrochloride: The solid was 20 basified with NH40H, extracted with dichlolu.~ ne and purified via flash cl.l~"latugraphy (Silica, EtOAc). The free amine was converted to its dihydrochlon~l~ salt by the addition of dry ether-HCI; filtered and dried: mp 226-228-C; lH NMR (300 MHz, D20) ~ 8.25 (d, 1 H),7.89 (t, 1 H), 7.79 (t, 1 H), 7.56 (m, 6 H), 4.4 (s, 2 H), 3.7-3.28 (brm, 12 H).
SUBSTITUTE SHEET (RULE 26) FY~mrle 66 1-(o-Dlu~ .he.~yl)-3-(4'-benzyl-1'-pi~ yl)-1-~ one dihydrochlo7~ mp > 250 C; lH
NMR (300 MHz, DMSO-d6, H20) o 7.73 (d, 2 H), 7.64-7.3 (m, 7 H), 4.25 (brm, 2 H), 3.52 (brs, 12 H).
FY~mrl~ 67 o ~ ~N~
Me 1-(5"-Methyl-2"-furanyl)-3-(4'-benzyl-1'-pipe.~illyl)-1-propanone hydrochlori~ie mp 213-C
(dec.); lH NMR (300 MHz, DMSO-d6) o 12.40-11.60 (brs, 2 H), 7.75-7.55 (brs, 2 H), 7.55-7.35 (brs, 4 H), 6.4 (d, 1 H), 4.55-4.20 (brs, 2 H), 3.80-3.20 (m, 12 H), 2.35 (s, 3 H), 3.90-10 3.30(m,20H).
FY~mpie 68 o N ~--N~N `~1 ~ O
l-(p-N-MoIph~ n~1~h~ yl)-3-r4~-p-iodobenzoy~ illyl]-~ lol~e ~ chlf..~
mp 240 C; lH NMR (300 MHz, CDC13) o 7.91 (d, 2 H), 7.80 (d, 2 H), 7.17 (d, 2 H), 6.85 15 (d, 2 H).
- E,Yample 69 ~S~ N~N
SUBSTITUTE SHEET (RULE 26) WO 96/16052 Pcr/uS95/14987 l-p-p~ y~ yl-3-(4~-benzy~ yl)-3-~ dnon~ dihydro~hlor~ mp 210 C
(dec.); lH NMR (300 MHz, DMSO-d6) ~ 12.30-11.10 (brs, 2 H), 7 90 (d, 2 H), 7.70-7.40 (m, 10 H), 7.30 (d, 2 H), 4.60-3.90 (brs, 2 H), 3.90-3.10 (m, 12 H).
FY~mrl~ 70 O
~ ~N~
O
1-(2"-Thienyl)-3-[4'-(o-fluo,~J'oel,2oyl)-l'-pi~ yl~ u~anonelly~lluehloride: mpl83-184 C: IH NMR (300 MHz, CDC13) o 10.30-10.07 (brs, 1 H), 7.90 (d, 1 H), 7.76 (d, 1 H), 7.55-7.35 (m, 2 H), 7.30-7.05 (m, 3 H), 4.97-4.80 (brd, 1 H), 4.15-3.95 (m, 1 H), 3.90-3.40 (m, 8 H), 3.05-2.8 (m, 2 H).
FY~mrl~ 71 1-[4~-(p-IIyLu~y-m~ upll~nyl)~-3-(4~-'oenzyl-1'-~i~e ~,~ u~anone dihydrochloride:
mp 209-212 C; lH NMR (300 MHz, D20) o 8.75 (s, 1 H), 8.24 (d, 1 H), 7.65-7.50 (brs, 5 H), 7.31 (d, 1 H), 4.51 (s, 2 H), 3.86-3.60 (m, 12 H).
FY~mrl~ 72 15 1-~D-N-Morpholinophenyl)-3-(4'-benzyl-1 '-pire~7inyl)- 1 -~lu~al~olle dihydrochloride: mp 205 C (dec.); lH NMR (300 MHz, D20) o 7.80 (d, 2 H), 7.45-7.30 (brs, 5 H), 6.95 (d, 2 H), 4.32 (s, 2 H), 3.80-3.66 (m, 4 H), 3.60-3.40 (m, 12 H), 3.30-3.20 (m, 4 H).
~Y~mrl~ 73 l-~-Cyanophenyl)-3-(4'-benzyl-1'-~ipt~ l)-1-propanonedihydrochlcri-ie: mpl90C
20 (dec.); lH NMR (300 MHz, DMSO-d6) o 8.29-7.90 (m, 4 H), 7.70-7.15 (m, 5 H), 4.45-4.05 (brs, 2 H), 4.00-3.00 (m, 12 H).
FY~mr1t 74 SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 Wo 96/16052 PCr/US95/14987 MeSO2~ ~~N~ ~
l-(m-lvl~ ..P~..lfon~m; lophpnyl)-3-(4~-benzy~ -pi~ ;..yl)-l-plu~ e dihydrochl~nr~
mp 180-182-C; lH NMR (300 MHz, D2O) o 7.95-7.85 (m, 2 H), 7.65-7.,50 (m, 7 H), 4.49 (s, 2 H), 3.85-3.60 (brs, 12 H), 3.14 (s, 3 H).
Example 75 l-(m-Fl~lolù~henyl)-3-(4'-benzyl-l'-~ yl)-l-plul)anonedih~ lucllloride: mp251-253-C;
1H NMR (300 MHz, DMSO-d6) o 12.2 (brm, 2 H), 7.9-7.3 (m, 9 H), 4.4 (s, 2 H), 4.0-3.18 (m, 12 H).
Example 76 ~ N~3 1-(2-Thiazolyl)-3-(4'-benzyl-1'-~ yl)-l-plù~ olledihydrochlon~e: Thesolidwasbasified with NH40H, e~ r~ with dichlulu...~Ll~ne and purified via flash clllulllaLo~ y (Silica, EtOAc): IH NMR (300 MHz, CDC13) o 8.0 (d, 1 H), 7.66 (d, 1 H), 7.28 (m, 5 H), 3.5(s,2H),3.37(t,2H),2.88(t,2H),2.5(brm,8H).
1~ FY~n~rl~ 77 1-Lp-(Trifluljlulll~,lhyl)-phenyl]-3-(4'-benzyl-1'-pi~.~hlyl)-1-~lu~ one: Thesolidwas basified with lN KOH, extracted with dichlc"u,l.~ane, dried and filtered: mp 59-60 C; lH
NMR (300 MHz, CDC13) ~ 8.06 (d, 2 H), 7.74 (d, 2 H), 7.3 (m, 5 H), 3.52 (s, 2 H), 3.2 (t, 2 H), 2.87 (t, 2 H), 2.53 (brm, 8 H).
Example 78 SUBSTITUTE SHEET (RULE 26) -CA 0220~x6 1997-0~-16 Wo 96/16052 PCT/US95/14987 1 -(5"-Bromo-2"-thienyl)-3-r4'-( 1 "'-p-chlorophenyl- 1 "'-phenylmethyl)- 1 '-pi~ inyl3- 1-~lu~ olle dihydrochlon~ie mp 141-144 C; lH NMR (300 MHz, CDC13) ~ 7.44 (d, 1 H), 7.39-7.12 (m, 7 H), 7.07 (d, 1 H), 4.19 (s, 1 H), 3.10 (t, 2 H), 2.8 (t, 2 H), 2.6S-2.25 (brm, 8 H)-S F-~mrl~ 79 i~Ji N~
1-(4" MLLIIOAY-1 "-n~ph-h~l~nyl)-3-(4'-benzyl-l'-pipcl~il~yl)-1~ ol-edihydro~hlon~e mp 230 C (dec.); lH NMR (300 MHz, D20/DMSO-d6) ~ 8.88 (d, I H), 8.27 (t, 2 H), 7.73-7.35 (m, 7 H), 7.1 (d, 1 H), 4.52-4.02 (m, 5 H), 3.65 (brm, 12 H).
- FY~mrlP 80 1-(5"-Nitro-3"-thienyl)-3-(4'-benzyl-1'-~ zinyl)-1-propanone dihydroch1orit1e mp 220'C
(dec.); lH NMR (300 MHz, D20/DMSO-d6) ~ 88. (d, 1 H), 8.47 (d, 1 H), 7.66-7.42 (m, 5 H), 4.3 (s, 2 H), 3.85-3.2 (m, 12 H).
Example 81 15 1-o-Iodophenyl-3-(4'-benzyl-1'-pip~ yl)-1-propanone dihydrochlonr1e: mp 240-242 C; lH
NMR of the free base (300 MHz, CDC13) ~ 7.9 (d, 1 H), 7.5 (m, 8 H), 3.5 (s, 2 H), 3.08 (t, 2 H), 2.78 (t, 2 H), 2.49 (brs, 8 H).
Example 82 Ç ~N~
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCT/US9~i;/14987 1 -(S"-Chloro-3 "-methylbenzo[b] -2"-thienyl)-3-(4'-benzyl- 1 '-pi~, ~inyl)- 1 -~luyanolle dihydroehl~n~- mp 247 C (dec.); lH NMR of the free base(300 MHz, CDCl3) o 7.84 (d, I
H), 7.76 (d, 1 H), 7.45 (dd, 1 H), 73 (m, 5 H), 3.53 (s, 2 H), 3.15 (t, 2 H), 2.9 (t, 2 H), 2.71 (s,3H),2.55(brm,8H).
FY~mrl~ 83 l-(S"-r2"'-thienyl]-2"-thienyl)-3-(4'-benzyl-1'-~ h~yl)-1-1,lol)dnone dillydr~llloride: mp 249-252 C; lH NMR (300 MHz, D20/DMSO-d6) o 7.96 (d, 1 H), 7.67 (d, 1 H), 7.63-7.34 (m, 7 H), 7.15 (t, 1 H), 4.25 (brs, 2 H), 3.4 (brm, 12 H).
Example 84 10 1-(S"-Bromo-2"-thienyl)-3-(4'-o-fluorobcl"yl-1'-~ipeld~inyl)-1-propanonedihydrochlonr;~o: mp 224-226 C; IH NMR of the free base (300 MHz, CDC13) ~ 7.45 (d, 1 H), 7.36 (m, 1 H),7.23 (m, 1 H), 7.15-6.92 (m, 3 H), 3.6 (s, 2 H), 3.03 (t, 2 H), 2.82 (t, 2 H), 2.54 (brs, 8 H).
FY~mrle 85 l-(S''-Cyano-2''-thienyl)-3-(4'-benzyl-1'-pi~ yl)-l-~lu~anone dihydrochlonrl~ mp 256-15 258 C; lH NMR of the free base (300 MHz, CDC13) ~ 7.63 (dd, 2 H), 7.27 (m, 5 H), 3.5 (s, 2 H),3.1(t,2H~,2.84(t,2H),2.5(brm,8H).
Example 86 ~ ~N~
Br o 1 -(5"-Bromo-2"-thienyl)-3-[4'-(3"'-chlorobenzo~b]-2"'-thienoyl)- 1 '-~ yl]- 1-propanone 20 dihydrochloride: mp 188-189 C; lH NMR of the free base (300 MHz, CDC13) ~ 7.84 (m,2 H),7.48(m,3H),7.12(d, lH),3.83(brm,2H),3.5(brm,2H),3.04(t,2H),2.88(t,2H), 2.58 (brs, 4 H).
SUBSTITUTE SHEET (RULE 26~
WO 96/16052 PCI~/US95/14987 FY~rl~ 87 1-(6"-M~ y-2"-n~phth~l~nyl)-3-(4'-benzyl~ ip~,~dzillyl)-l-ll,updllo,-edihydrochloride: mp 243-246 C; lH NMR (300 MHz, D20/DMSO-d6) o 8.62 (s, 1 H), 8.12-7.86 (m, 3 H), 7.65-7.34 (m, 6 H), 7.27 (m, 1 H), 7.42-7.32 (m, 17 H).
Fr~mpl~ 88 l-(p-Methylthiophenyl)-3-(4'-(2'',6''-difl,lolubGI,,.yl)-l'-~ ,dzinyl)-l-p,upallone dihydroçhlnTi~ mp 187-188 C; lH NMR (300 MHz, CDCl3/MeOD) o 7.90 (d, 2 H),7.65-7.50 (m, 1 H), 7.30 (d, 2 H), 7.23-7.10 (m, 2 H), 4.00-3.40 (m, 14 H~, 255 (s, 3 H).
Fr~mrl~ 89 o ~~~ ~N"~
1 -(2"-Thienyl)-3-r4'-(1 "'-p-chlorophenyl- 1 "'-phenylmethyl)- 1 '-~ ~nyl]- 1-~,upanu--c dihydrochloride: mp 189-201 C; IH NMR (300 MHz, DMSO-d6) â 8.05 9d, 1 H), 8.00 (d, 1 H), 7.55-7.20 (m, 10 H),4.60 (brs, 1 H), 3.80-3.20 (m, 12 H).
~r~mpl~ 90 15 1-~D-N-Piperidinophenyl)-3-(4'-benzyl-1'-pi~ yl)-1-plu~anoné dihydrochloride: mp 135-C
(dec.); lH NMR (300 MHz, CDC13tDMSO-d6) o 8.00 (d, 2 H), 7.90-7.40 (m, 7 H), 4.35 (s, 2 H), 4.15-5.00 (m, 2 H), 4.00-3.80 (m, 2 H), 3.80-3.40 (m, 12 H), 2.15-1.95 (m, 4 H), 1.80-I.65(m,2H).
Example 91 SUBSTITIJTE SHEET (RULE 26) Wo 96tl6052 PCT/US95/14987 N~
l-(N-Phenylsulfonylpyrro1-2-yl)-3-(4'-benzyl-1'-P;l ~ yl)-1-p,u,.)anul-cdihydrochlonde: mp 215-C (dec.); lH NMR (300 MHz, DMSO-d6) â 8.0807.85 (m, 2 H), 7.75-7.35 (m, 10 H),
6.60-6.50 (m, 1 H), 4.30 (brs, 2 H), 3.80-3.00 (m, 12 H).
Fy~mrle 92 1-[3',5'-Bis(llinuul~lLoxy)phenyl]-3-(4'-benzyl- 1 '-P;l~ yl)- I -propanone dihydrochlnnde mp 170-172 C; lH NMR (300 MHz, DMSO-d6) ~ 7.70-7.20 (m, 8 H), 4.70-4.95 (m, 4 H),
Fy~mrle 92 1-[3',5'-Bis(llinuul~lLoxy)phenyl]-3-(4'-benzyl- 1 '-P;l~ yl)- I -propanone dihydrochlnnde mp 170-172 C; lH NMR (300 MHz, DMSO-d6) ~ 7.70-7.20 (m, 8 H), 4.70-4.95 (m, 4 H),
7.25 (brs, 2 H), 3.80-3.20 (m, 12 H).
FY~mpl.o 93 10 1-(2''-Bromo-5''-l~iLlù~he,lyl)-3-(4'-benzyl-1'-piy~ lyl)-1-propanone dihydrochlon~ mp 230 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 8.60 (s, 1 H), 8.25 (d, 1 H), 8.05 (d, 1 H), 7.65-7.40 (m, 5 H), 4.30 (brs, 2 H), 3.80-3.20 (m, 12 H).
Example 94 3-(4'-Benzyl-l'-p;l.e..~ -yl)-thioch~ -4-one dihydrochloride: mp >250 C (dec.); lH
15 NMR (300 MHz, D2O) o 7.90 (d, 1 H), 7.37 (m, 6 H), 7.25 (m, 1 H), 7.14 (m, 1 H), 4.32 (s, 2 H), 3.70-3.33 (m, 10 H), 3.24 (m, 2 H), 3.17 (m, 1 H).
Example 95 1-(5"-Chloro-4"-nitro-2"-thienyl)-3-(4'-benzyl- 1 '-pi~l~lyl)- 1-~1upallullc dihydrochloride: To a mixture of isoplv~ ol (25 mL) and concellt,~Led hydrochloric acid (1.45 mL,0.017 mol) was 20 added l-~,l~ylpi~ e (1.00 g, 5.68 mmol) to form the hydrochloride salt in situ.
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCI~/USgS/14987 P~ d~hyde (0.34 g, 11.36 mmol) was then added followed by 5-acetyl-2-chloro-3-niL~ ic~hene (1.28 g, 6.25 mmol). The resulting mixture was refluxed for 72 h. A white solid ~ formed, was filtered and the filter cake was ~ ,. ..lf d with ~ llr)l to give 0.99 g (44%) of the desired product: mp 220-223-C; lH NMR (300 MHz, D20/DMSO-d6) o 5 8.57 (s, l H), 7.65-7.45 (m, 5 H), 4.37 (s, 2 H), 7.65-7.45 (m, 5 H), 4.37 (s, 2 H), 3.65-3.30 (m, 12 H).
FY~PIO 96 I-(2"-Thienyl)-3-(4'-benzyl-1 '-piperidinyl)-1-propanone hydrochloride: mp 189-l90 C; 1H
NMR (300 MHz, CDC13) o 12.55-12.35 (brs, 1 H), 7.95 (d, 1 H), 7.73 (d, 1 H), 7.35-7.05 10 (m, 6 H), 3.73 (t, 2 H), 3.60-3.35 (m, 4 H), 2.75-2.55 (m, 4 H), 2.35-1.95 (m, 2 H), 1.90-1.65 (m, 3 H).
FY~m~l~ 97 1 -(5~-Bromo-2~-thienyl)-3-(4~-p-fluorobenzoyl- 1 '-piperidinyl)- I -propanone hydrochloride: mp 201-203 C; IH NMR (300 MHz, DMSO-d6) o 10.55-10.33 (brs, 1 H), 8.30-8.20 (m, 2 H), 15 8.07 (d, 1 H), 7.70-7.50 (m, 3 H), 3.90-3.15 (m, 6 H), 2.25-1.95 (m, 5 H).
Example 98 NO2~ F
1 -t2 "-Mtro-4 "-thienyl)-3-(4'-p-fluul ~Ibcnzc yl- 1 '-piperidinyl)- 1 -propanone hydrochloride: mp 205-206 C; lH NMR (300 MHz, DMSO-d6) ~ 10.55-10.35 (brs, 1 H), 8.80 (s, 1 H), 8.08 (s, 20 lH),8.10(dd,2H),7.37(dd,2H),3.75-3.50(m,5H),3.50-3.35(m,2H),3.20-3.00(m,2 H), 2.10-1.80 (m, 4 H). '`
Example 99 SUBSTITUTE SHEET (RULE 26 , CA 0220~86 1997-0~-16 WO 96/16052 PCr/US95/14987 -1-(5"-Bromo-2"-thienyl)-3-(4'-benzyl-1'-pil,~,.i lillyl)-1-propanone hydrochlori(le. mp 205-208 C; lH NMR (300 MHz, CDC13) o 7.44 (d, 1 H), 7.35-6.9~ (m, 6 H), 3.2 (t, 2 H), 2.88 (m, 2 H), 2.77 (t, 2 H), 2.53 (m, 2 H), 1.96 (m, 2 H), 1.74-1.43 (m, 3 H), 1.3 (m, 2 H).
FY~n~rl~ 100 1 -(5"-Bromo-2"-thienyl)-3-(4'-~2"'-chloro-6"'-methylpyrido-4"'-yl]- 1 '-piperazinyl)- 1 -~lul)anone dihydrochlnri-le A mixture of 2-acetyl-~-blulllotl~iophene (0.50 g, 2.44 mmol), the cG.ll...oul~d from ex~mp!e 49s (0.45 g, 1.88 m!I~.o!), p~ fc~ dehyde (73.0 mg, 2.44 m.m..o!), and co,-rcf.~ .,d hydrochloric acid (0.19 mL, 2.26 mmol) in 20 mL iso~ a-~ol were refluxed 10 72 h. The reactiûn was cooled and filtered. The mother liquor was ~ol-ce ,I . ~.t. rl, basified (NaHCO3) and c~ rt. ~ with CH2CI2. The c~,al)ulalGd residue was purified via flash cL~,lllaLu~la~l.y (Sili~ ~-FtOAc). The resulting oil was dissolved in ether and forrned into its coll~,;,yul~ding hydro~hlo~i~e salt by the ~rl~litio~ of dry ether/HCI to give 25 mg (2.7%) of the desired pl~lu-;L. mp 214-215C; lH NMR of the free base (300 MHz, CDC13) ~ 7.46 (d, 1 H), 15 7.18-6.99 (m, 3 H), 3.75 (brm, 2 H), 3.35 (brm, 2 H), 3.04 (t, 2 H), 2.87 (t. 2 H), 2.70-2.32 (m, 7 H).
Example 101 1-(5"-Bromo-2"-thienyl)-3-(4'-b~,.-7~.~r~..lfonyl-l'-l)ipe,a~illyl)-1-~,upanolle dihydrochloride: A
mixture of 2-acetyl-5-b.~"l,oLl,iophene (0.33 g, 1.60 mmol), the co,ll~u"d of ex~mple 49r 20 (0.30 g, 1.33 mmol), paraformaldehyde (48.0 mg, 1.60 mmol), and concentrated hydrochloric acid (0.17 mL, 1.99 mmol) in 15 mL isopropanol were refluxed for 16 h. The reaction was cooled, filtered and the filter cake was recryst~lli7~d from meth~nol to give 40 mg (7.4%) of the desired product: mp 129-130C; IH NMR free base (300 MHz, CDC13/NaOD) SUBSTITUTE SHEET (RULE 26 =
WO 96/16052 PCr/US95114987 7.74 (m, 2 H), 7.65-7.45 (m, 3 H), 7.40 (m, 1 H), 7.07 (m, 1 H), 2.98 (m, 6 H), 2.8 (m, 2 H), 2.57 (m, 4 H).
FY~mI~l.o 102 Nillu~h~"~yl)-3-(4'-ben7. .~e;".ifonyl-l' p;l.~,.a,;.,yl)-l-prop~no~e dihydrochloride: mp 193-5 195C; IH NMR free base (300 MHz, CDC13) ~ 8.30 (d, 2H), 8.10 (d, 2H), 7.75 (m, 2H), 7.57 (m, 3H), 3.18 (t, 2H), 3.03 (m, 4H), 2.86 (t, 2H), 2.60 (m, 4H).
FY~mrl~ 103 1-~D-Nitrophenyl)-3-[4'-(4"-methyl- 1 ",2",3"-thi~ 7-5"-oyl)]- 1 '-piperazinyl)- I -propanone dihydrochlonde mp 207-209C; IH NMR (300 MHz, D20) o 8.38 (d, 2H), 8.21 (d, 2H~,10 4.40-3.25 (m, 12H~, 2.72 (s,3H).
FY~mrl~ 104 1-(4''-Morpholino-3''-nillupllenyl)-3-(4'-benzyl-l'-pip,,,~inyl)-1-propanone trihydroch1- n-ie:
IH NMR (300 MHz, DMSO-d6) ~ 12.25-11.55 (brs, 2H), 9.65-9.45 (brs, lH), 8.75 (s, lH),
FY~mpl.o 93 10 1-(2''-Bromo-5''-l~iLlù~he,lyl)-3-(4'-benzyl-1'-piy~ lyl)-1-propanone dihydrochlon~ mp 230 C (dec.); lH NMR (300 MHz, DMSO-d6) ~ 8.60 (s, 1 H), 8.25 (d, 1 H), 8.05 (d, 1 H), 7.65-7.40 (m, 5 H), 4.30 (brs, 2 H), 3.80-3.20 (m, 12 H).
Example 94 3-(4'-Benzyl-l'-p;l.e..~ -yl)-thioch~ -4-one dihydrochloride: mp >250 C (dec.); lH
15 NMR (300 MHz, D2O) o 7.90 (d, 1 H), 7.37 (m, 6 H), 7.25 (m, 1 H), 7.14 (m, 1 H), 4.32 (s, 2 H), 3.70-3.33 (m, 10 H), 3.24 (m, 2 H), 3.17 (m, 1 H).
Example 95 1-(5"-Chloro-4"-nitro-2"-thienyl)-3-(4'-benzyl- 1 '-pi~l~lyl)- 1-~1upallullc dihydrochloride: To a mixture of isoplv~ ol (25 mL) and concellt,~Led hydrochloric acid (1.45 mL,0.017 mol) was 20 added l-~,l~ylpi~ e (1.00 g, 5.68 mmol) to form the hydrochloride salt in situ.
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCI~/USgS/14987 P~ d~hyde (0.34 g, 11.36 mmol) was then added followed by 5-acetyl-2-chloro-3-niL~ ic~hene (1.28 g, 6.25 mmol). The resulting mixture was refluxed for 72 h. A white solid ~ formed, was filtered and the filter cake was ~ ,. ..lf d with ~ llr)l to give 0.99 g (44%) of the desired product: mp 220-223-C; lH NMR (300 MHz, D20/DMSO-d6) o 5 8.57 (s, l H), 7.65-7.45 (m, 5 H), 4.37 (s, 2 H), 7.65-7.45 (m, 5 H), 4.37 (s, 2 H), 3.65-3.30 (m, 12 H).
FY~PIO 96 I-(2"-Thienyl)-3-(4'-benzyl-1 '-piperidinyl)-1-propanone hydrochloride: mp 189-l90 C; 1H
NMR (300 MHz, CDC13) o 12.55-12.35 (brs, 1 H), 7.95 (d, 1 H), 7.73 (d, 1 H), 7.35-7.05 10 (m, 6 H), 3.73 (t, 2 H), 3.60-3.35 (m, 4 H), 2.75-2.55 (m, 4 H), 2.35-1.95 (m, 2 H), 1.90-1.65 (m, 3 H).
FY~m~l~ 97 1 -(5~-Bromo-2~-thienyl)-3-(4~-p-fluorobenzoyl- 1 '-piperidinyl)- I -propanone hydrochloride: mp 201-203 C; IH NMR (300 MHz, DMSO-d6) o 10.55-10.33 (brs, 1 H), 8.30-8.20 (m, 2 H), 15 8.07 (d, 1 H), 7.70-7.50 (m, 3 H), 3.90-3.15 (m, 6 H), 2.25-1.95 (m, 5 H).
Example 98 NO2~ F
1 -t2 "-Mtro-4 "-thienyl)-3-(4'-p-fluul ~Ibcnzc yl- 1 '-piperidinyl)- 1 -propanone hydrochloride: mp 205-206 C; lH NMR (300 MHz, DMSO-d6) ~ 10.55-10.35 (brs, 1 H), 8.80 (s, 1 H), 8.08 (s, 20 lH),8.10(dd,2H),7.37(dd,2H),3.75-3.50(m,5H),3.50-3.35(m,2H),3.20-3.00(m,2 H), 2.10-1.80 (m, 4 H). '`
Example 99 SUBSTITUTE SHEET (RULE 26 , CA 0220~86 1997-0~-16 WO 96/16052 PCr/US95/14987 -1-(5"-Bromo-2"-thienyl)-3-(4'-benzyl-1'-pil,~,.i lillyl)-1-propanone hydrochlori(le. mp 205-208 C; lH NMR (300 MHz, CDC13) o 7.44 (d, 1 H), 7.35-6.9~ (m, 6 H), 3.2 (t, 2 H), 2.88 (m, 2 H), 2.77 (t, 2 H), 2.53 (m, 2 H), 1.96 (m, 2 H), 1.74-1.43 (m, 3 H), 1.3 (m, 2 H).
FY~n~rl~ 100 1 -(5"-Bromo-2"-thienyl)-3-(4'-~2"'-chloro-6"'-methylpyrido-4"'-yl]- 1 '-piperazinyl)- 1 -~lul)anone dihydrochlnri-le A mixture of 2-acetyl-~-blulllotl~iophene (0.50 g, 2.44 mmol), the cG.ll...oul~d from ex~mp!e 49s (0.45 g, 1.88 m!I~.o!), p~ fc~ dehyde (73.0 mg, 2.44 m.m..o!), and co,-rcf.~ .,d hydrochloric acid (0.19 mL, 2.26 mmol) in 20 mL iso~ a-~ol were refluxed 10 72 h. The reactiûn was cooled and filtered. The mother liquor was ~ol-ce ,I . ~.t. rl, basified (NaHCO3) and c~ rt. ~ with CH2CI2. The c~,al)ulalGd residue was purified via flash cL~,lllaLu~la~l.y (Sili~ ~-FtOAc). The resulting oil was dissolved in ether and forrned into its coll~,;,yul~ding hydro~hlo~i~e salt by the ~rl~litio~ of dry ether/HCI to give 25 mg (2.7%) of the desired pl~lu-;L. mp 214-215C; lH NMR of the free base (300 MHz, CDC13) ~ 7.46 (d, 1 H), 15 7.18-6.99 (m, 3 H), 3.75 (brm, 2 H), 3.35 (brm, 2 H), 3.04 (t, 2 H), 2.87 (t. 2 H), 2.70-2.32 (m, 7 H).
Example 101 1-(5"-Bromo-2"-thienyl)-3-(4'-b~,.-7~.~r~..lfonyl-l'-l)ipe,a~illyl)-1-~,upanolle dihydrochloride: A
mixture of 2-acetyl-5-b.~"l,oLl,iophene (0.33 g, 1.60 mmol), the co,ll~u"d of ex~mple 49r 20 (0.30 g, 1.33 mmol), paraformaldehyde (48.0 mg, 1.60 mmol), and concentrated hydrochloric acid (0.17 mL, 1.99 mmol) in 15 mL isopropanol were refluxed for 16 h. The reaction was cooled, filtered and the filter cake was recryst~lli7~d from meth~nol to give 40 mg (7.4%) of the desired product: mp 129-130C; IH NMR free base (300 MHz, CDC13/NaOD) SUBSTITUTE SHEET (RULE 26 =
WO 96/16052 PCr/US95114987 7.74 (m, 2 H), 7.65-7.45 (m, 3 H), 7.40 (m, 1 H), 7.07 (m, 1 H), 2.98 (m, 6 H), 2.8 (m, 2 H), 2.57 (m, 4 H).
FY~mI~l.o 102 Nillu~h~"~yl)-3-(4'-ben7. .~e;".ifonyl-l' p;l.~,.a,;.,yl)-l-prop~no~e dihydrochloride: mp 193-5 195C; IH NMR free base (300 MHz, CDC13) ~ 8.30 (d, 2H), 8.10 (d, 2H), 7.75 (m, 2H), 7.57 (m, 3H), 3.18 (t, 2H), 3.03 (m, 4H), 2.86 (t, 2H), 2.60 (m, 4H).
FY~mrl~ 103 1-~D-Nitrophenyl)-3-[4'-(4"-methyl- 1 ",2",3"-thi~ 7-5"-oyl)]- 1 '-piperazinyl)- I -propanone dihydrochlonde mp 207-209C; IH NMR (300 MHz, D20) o 8.38 (d, 2H), 8.21 (d, 2H~,10 4.40-3.25 (m, 12H~, 2.72 (s,3H).
FY~mrl~ 104 1-(4''-Morpholino-3''-nillupllenyl)-3-(4'-benzyl-l'-pip,,,~inyl)-1-propanone trihydroch1- n-ie:
IH NMR (300 MHz, DMSO-d6) ~ 12.25-11.55 (brs, 2H), 9.65-9.45 (brs, lH), 8.75 (s, lH),
8.75 (d, lH), 7.75-7.30 (m, 6H), 4.60-4.20 (brs, 2H3, 4.00-3.00(m, 20H).
FY~mrle 105 1-(3"-Nitro-4"-N-piperidinophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone trihydrochloride:
IH NMR (300 MHz, DMSO-d6) ~ 11.95-11.70 (brs, 3H), 8.35 (s, lH), 8.04 (d, IH), 7.75-7.55 (brs, 2H), 7.55-7.40 (brs, 3H), 7.35 (d, lH), 4.60-3.00 (m, 18H), 1.80-1.30 (brs, 6H).
Example 106 20 1-(5"-Methyl-2"-thienyl)-3-(4'-benzyl-1'-pip~illyl)-1-propanone dihydrochloride: mp 220C
(dec.); IH NMR (300 MHz, CDCl3/NaOD) ~ 7.53 (m, I H), 7.40-7.08 (m, 5 H), 6.78 (m, 1 H), 3.50 (s, 2 H), 3.04 (t, 2 H), 2.83 (l, 2 H), 2 67-2.30 (m, 11 H).
FY~mrl~ 107 SUBSTlTlJTE SHEET (RULE 2~r,~
CA 0220~86 1997-0~-16 Wo 96/16052 PCT/US95/14987 1-[4"-p-(5"',l"'-Dichloroimi~7O1-l"'-yl)phenyl]-3-(4'-benzyl-l'-piperazinyl)-1-propanone dihydrochloride: mp 200-202C; IH NMR (300 MHz, DMSO-d6) ~ 12.25-11.30 (brs, 2 H), 8.30-8.10 (m, 3 H), 7.77 (d, 2 H), 7.70-7.30 (m, 5 H), 4.35 (brs, 2 H), 3.90-3.20 (m, 12 H).
FY~n~ e 108 5 1-r5~-(phenylethynyl)-2~-thienyl]-3-(4-benzy~ -pi~e~ lyl)-l-plup~one dihydr~!chlnrirl~:
mp 205C (dec.); IH NMR (300 MHz, DMSO-d6) o 12.30-11.20 (brs, 2 H), 8.00 (d, 1 H), 7.80-7.30 (m, 11 H), 4.30 (brs, 2 H), 3.90-3.00 (m, 12 H).
Exarnple 109 1-(3"-Nillu~hc"yl)-3-(4'-~ lonyl-1'-~i~cla.i~yl)-1-1,l~onedil~y~llucl~loride: mp215C
lO (dec.); IH NMR (300 MHz, DMSO-d6) o 12.35-11.20 (brs, 2 H), 8.70 (s, 1 H), 8.52 (d, 1 H), 8.40 (d, 1 H), 7.70 (dd, 1 H), 7.25 (s, 1 H), 7.15-6.90 (m, 2 H), 6.05 (s, 1 H), 4.25 (brs, 2 H), 3.90-3.10 (m, 12 H).
FY~rnri~llO
1 -(5"-Methyl-3"-phenylisoxazol-4"-yl)-3-(4'-benzyl- 1 '-~ip~l~inyl)- 1 -l~lupallone 15 dihydrochloride: mp 220C (dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.35-11.40 (brs, 2 H), 7.70-7.30 (m, 10 H), 4.35 (brs, 2 H), 3.70-3.10 (m, 12 H), 2.80 (s, 3 H).
FY~n rl-o. 1 1 1 1-(2"-Phenylthiazol-4"-yl)-3-(4'-benzyl-1'-pi~,la2ih~yl)-1 propanonedihydrochlonrlç: mp 220C (dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.20-11.50 (brs, 2 H), 8.65 (s, 1 H), 8.10-20 7.90 (brs, 2.H), 7.75-7.30 (m, 8 H), 4.30 (brs, 2 H), 3.80-3.20 (m, 12 H).
Fy~mrl~ 112 1 -(3"-Phenylisoxazol-4"-yl)-3-(4'-benzyl- 1 '-piperazinyl)- 1-propanone dihydrochloride: mp 212C (dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.25-11.40 (brs, 2 H), 8.10-7.90 (m, 3.H), 7.70-7.30 (m, 8 H), 4.35 (brs, 2 H), 3.80-3.10 (m, 12 H).
Example 113 SUBSTITUTE SHEET (RULE 26) WO g6/16052 PCr/US95114987 1 -(4"-t2"',4"'-di~ ùphenylamino]phenyl)-3-(4'-benzyl- 1 '-piperazinyl)- 1 -propanone dihydroehl~rid.o.: mp 248-250C; IH NMR (300 MHz, CDC13/NaOD) o 9.20 (m, 1 H), 8.26 (m, 1 H), 8.08 (m, 2 H), 7.50-7.10 (m, 8 Hj, 3.53 (s, 2 H), 3.21 (m, 2 H), 2.87 (m, 2 H), 2.55 (brrn, 8 H).
Exarnple 114 1 -(2",4"-dilll~;Ll,ylLl,iazol-5"-yl)-3-(4'-benzyl- I '-piperazinyl)- 1 -~ulupanol1e di~lyd~ uchloride:
mp: 228-C (dec); IH NMR (300 MHz, D20) ~ 7.55 (brs, 5 H~, 4.50 (s, 2 H), 3.87-3.42 (m, 12 H), 2.75 (s, 3 H), 2.67 (s, 3 H).
FYarnple 115 10 1-(m-NiL,u~,hc,lyl3-3-(4'-benzyl-l'-piperidinyl)-l-prûpanonehydrochloride: mpl89-191C;IH
NMR (300 MHz, CDC13) ~ 12.60-12.40 (brs, 1 H), 8.35 (d, 2 H), 8.18 (d, 2 H), 7.35-7.05 (m, 5 H), 3.95 (t, 2 H), 3.65-3.3S (m, 4 H), 2.80-2.55 (m, 4 H), 2.~0-1.65 (m, 5 H).
Exarnple 116 The following cullllJuull~L. may be ,u~ cd by the general method:
(a) 1-(6"-Blul,locoull,~ill-3"-yl)-3-(4'-benzyl-l'-pirer~7inyl)-l-propanone dihy~lluchlnrit~ .
O
Br ~ N~ ~3 (b) 1-(6"-Bromocoumdlill-3"-yl)-3-(4'-benzoyl-1'-pip~ yl)-1-propanone dihydrochln7 i~
(c) 1 -(I ",1 "-Dimethyl-6"-tert-butylindan-4"-yl)-3-(4'-benzyl- 1 '-piperazinyl)- 1 -propanone dihydrochlorirl~
(d) 1 -(1 ",1 "-Dimethyl-6"-tert-butylindan-4"-yl)-3-(4'-benzoyl- 1 '-piperazinyl)- 1-~,u~ano,le dihydrochlr~ri-i~
SUBSTITUTE SHEET (RUEE 26) WO g6/16052 PCI`/US95tl4987 (e) l-(cou~ -3~r-yl)-3-(4~-benzy~ yl)- l-ylùl)anolle dihydro~hlt Ti~
(f) l-(Cou~ -3"-yl)-3-(4'-benzoyl-1'-~ip.~ yl)-1-,~1u~allûlle dihydrochlnnrle (g) 1 -(5"-Cyano-4"-methyl-2"-(methylthio)thien-3"-yl)-3-(4'-benzyl- 1'--pl~:)pd~lollc clil~ydluc1~1nril1.o (h) 1 -(5"-Cyano-4"-methyl-2"-(methylthio)thien-3"-yl)-3-(4'-benzoyl- 1'-pip. .~illyl)- l-~l~anone dihydr~hlnnde (i) 1 -~-(2",4"-Dichlorophenoxy)-phenyl)-3-(4'-benzyl- 1 '-pi~ zinyl)- 1-pl~ ullC dihydroc hlnri~
(i) 1-~-(2",4"-Dichlorophenoxy)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-10 plupanone dihydr~hlonde (k) 1 -(5"'-(2",4"-Difluorophenoxy)-fur-2"'-yl)-3-(4'-benzyl- 1 '-piperazinyl)- 1-propanone dihydroehlr)ri~
~ ~ N~
(1) 1-(5"'- (2",4"-Difluorophenoxy) -fur-2"'-yl)-3-(4'-benzoyl- 1 '-piperazinyl)- 1-propanone dihydrochlnnrle (m) 1 -(2",3"-Dihydrobenzo[b]fur-5"-yl)-3-(4'-benzyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride SUBSTITUTE SHEET (RULE 2~) NJ~3 (n) 1 -(2",3"-Dihydrobenzorb~fur-5"-yl)-3-(4'-benzoyl- 1 '-pip~ lyl)- I -propanone dihydrochloride 5(o) 1 -(3",5"-Dillletilylbenzorb]thien-2"-yl)-3-(4'-benzyl- 1'-~ d~inyl)- 1-plo~anolle dihydroçhloritl~
(p) I -(3",5"-Dimethylbenzorb]thien-2"-yl)-3-(4'-benzoyl- 1 '-piper~7invl)- 1-propanone dihydroçhlonrle Me O
Me ~~N~N~
10(q) 1-(2",4"-Dimethylthien-5"-yl)-3-(4'-benzyl-1'-pi~ a~inyl)-1-~.op~,olle dihydrochloride Me o Me N~N~ ~
(r) 1 -(2",4"-Dimethylthien-5"-yl)-3-(4'-benzoyl- 1 '-piperazinyl)- 1 -propanonedihydrochloride 15(s) 1-GD-[Phenylthio~phenyl)-3-(4'-benzyl-1'-~ilJel~hlyl)-l-propanone dihydrochloride SUBSTlTUrE SHEET (RULE 26) WO 96/16052 PCrlUS95/14987 (t) l-(p-~Pl,~nyl~,io~iphenyl)-3-(4'-benzoyl-1'-pip~ yl)-1-plvpanone dihydrorhlnntit.
(u) 1 -(3"-Metho,~ye~ bonyl-5"-methylisoxazol-4"-yl)-3-(4'-benzyl- 1 '-piperazinyl)-u~lol~e dihydrochlnrid~
(v) 1-(3"-Metho,~yc~L.onyl-5"-methylisoxazol-4"-yl)-3-(4'-benzoyl-1'-pi~e. ~ yl)- l-~lu~ one dihydrof hlnncle (w) 1-(5''-(2'''-C~l~ulll~llloxythien-3~-yl)-furan-2~-yl)-3-(4~-b ~i~e.d~illyl)-l-~lop~-t,.~ dihydrothlnnrit~.
(x) 1 -(5"-(2"'-C~ bonl~,~hoxythien-3"'-yl)-furan-2"-yl)-3-(4'-benzoyl- 1'-10 pi~.~inyl)-l-~lu~anone dihydroçhinn~
(y) l-(p-(4"-Methox~heno~y)-phenyl)-3-(4'-benzyl- 1 '-pi~,.~inyl)- l-~ro~ olle dihy~lluchloride (z) l -(p-(4"-Methoxyphenoxy)-phenyl)-3-(4'-benzoyl- 1 '-pi~,.azinyl)- 1 -1,-upanolle dihydrochloride 1~ (aa) 1-(p-(4"-Nh~ul)hEnoxy)-phenyl)-3-(4'-benzyl-1'-1,ip~,.~illyl)-1-p~upanone dihydrochloride (bb) l-(p-(4''-Ni~uphelloxy)-phenyl)-3-(4'-benzoyl-l'-~ ,.a~illyl)-l-propanone dihydrochloride (cc) 1 -(m-Nitro-p-(phenylthio!-phenyl)-3-(4'-benzyl- 1 '-~i~.~inyl)- l-propanone 20 dihydror hlr)riti ~Oz~ N~
(dd) 1-(m-Nitro-p-(phenylthio)-phenyl)-3-(4'-benzoyl-1'-~ lyl)-1-~u~upallonc dihydroçhk)rifi.-.
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 (ee) l-(m-Mtro-p-(1"-piperidinyl)-phenyl)-3-(4'-benzoyl-1'-pi~ inyl)-1-plup&no~e dihydrochlnT-A~
(ff) I-(m-Nitro-p-(4"-morpholino)-phenyl)-3-(4'-benzoyl~ Jipc.~illyl)- 1-p~u~ .,.e dihydro~hlnri-lP.
(gg) 1-(p-Nitrophenyl)-3-(4'-(5"-(1"'-methyl-3"'-trifluo.olllcLllylpyrazol-5"'-yl)-thien-2"yl)- 1 '-p;l.~f ,~ yl)- l-l,-u~ano..e dihyd~ocll1nri~le NO~ ~N~CF3 (hh) 1-(5"Bromo-2"-thienyl)-3-(4'-p-bromobc.,,~ne~lllfonyl-1'-pip~ illyl)-1-~u~no~e hydrochlnride lû (ii) l-(S"Bromo-2"-thienyl)-3-(4'-p-toluenesulfonyl-1'-pi~,e.~illyl)-1-plupanolle hydroçhlnriflp (ii) 1 -~D-Nillupl~e~lyl)-3-(4 -p-l~l u~ot~n ~f l~r i,ulfonyl- 1 '-pil,ei~zi--yl)- 1 -~-ùpanonc hydrochlnnde (ii) 1 -(5"-Chloro-4"-nitro-2"- thienyl)-3-(4'-bf n 7enes~ 1 If onyl- I '-piperazinyl)- 1-15 ~ru~,anollc hydrochlnri~
(kk) 1-(2"-Chloro-3"-nitrothien-5"-yl)-3-(4'-o-trifluolo~llcLhylbenzoyl-l'-P;l~ yl)-l-p.op~one dihydrochlnntie (Il) 1 -~n-Nitrophenyl)-3-(4'-{4"-methyl- 1 ",2",3"-thiadiaz-5"-oyl]- 1 '-piperazinyl)-u~allolle dihydrochloride.
(mm) 1 -(5"-Chloro-4"-nitro-2"-thienyl)-3-~4'-(4"'-methyl- 1 "',2"',3"'-thia~
5"'-ûyl)- 1'-pi~e.d~ yl]-1-propanone dihydrochloride.
S~B~ J I t s~E~ (RlJ~E 26) WO 96/16052 PC'r/US95/14987 (nn) I -r5"-Cyano-4"-methyl-2"-(methylthio)-3"-thienyl~-3-(4'-benzyl- 1'-P;l~ a~ yl)-1-y~ o,le dihydroçhlnri~ie (oo) 1-(2",4"-Dimethyl-5"-thiazolyl)-3-(4'-benzyl-1'-~ ,c.azillyl)-1-propanone dihydroçhlori~
S (pp) 1-(5"-Nitro-3"-thienyl)-3-(4'-o-fluoro~.~zoyl-1'-yil,e.~zinyl)-1-propanone dihy~L~uçl .olr~ride (qq) 1-(5"-Bromo-2"-thienyl)-3-(4'-o-fluolubenzc.yl-1'-~ip~ inyl)-l-plupanone dihydrochnlori-le F~m,rle 117 Effect of Chlc,-~lu.. ~ .~;.. e on Paired Helical Filament Levels in Human Brain Tissue The in vitro analyses desçrihed herein to investigate the activity of the co~ oullds of this invention can also be used to ~letP-rmine the nature of abnorrnally phosphorylated paired helical fil~m~nt epitopes involved in ~l7hpimer~s Disease, the regulatory mech~nicm~ involved with 15 ~17hrimrr~s Disease and mo l~;r;rAI;Ol-c of the protein tau and other polypeptides ~c$ociAtç~ with PHFs and involved in ~1,1.~.;...~.. 's Disease.
Certain phenorhi~7in.-s, for e~ . .plc chlu~ ;nr. can mArk~Aly inhibit the expression of PHF epitopes (as determined by loss of immllnoreactivity with ~l7hrim-or~s Disease specific antibodies) upon ~ llllfnt of MSNla cells with okadaic acid (cf. Figure 33. These co,.l~lou~lds 20 are effective at micromolar conce-lL-ations, with increased ~OL..;~ y being evident when cells are treated prior to the ad-iition of okadaic acid. The effective concelltlations appear to be in the range at which these drugs are present in the brain following chronic treatment of psychiatric patients (Svendsen, CN, Psychoph~rm~rolngy, 90, 316-321, 1986). These results indicate that patients who were chronically treated with phenothi~7ines would be ~lotecled from the 25 development of PHF, and thus would have a low probability of development of Alzheimer's Disease.
SUBSTITUTE SHEET (RULE 26 CA 0220~86 l997-0~-l6 WO 96/16052 PCrlUS95/14987 Frontal and cortical brain tissue ~I,ec-;...~,n~ obtained at autopsy from patients chronically treated with chlo~lu~ 7;nr- were ana}yzed using the ALZ-EIA method previously described (Gh~nh~ri, HA, et al, JAMA, 263, 2907, 1990). The results are shown in Figures 4A and 4B
frontal (Broadman area 10) and ltj11lPI)~ (Broadman area 38) regions, res~cc~ively. The brain S tissue (post-mortem) from a~ d.. .~ y the sarne number of (age .. .~ -d) normal controls and Al7h/ .... 's Disease patients were also analyzed and are ~ ,sented in these figures as nc~ativc and positive controls (for normal and AD, rcsp.,~ively). As the data inrli~ ~tç, the samples from chlol~lu~ treated patients (Rx) had low PHF epitope levels similar to normal controls, wh~l~as the PHF epitope levels in the AD group were clearly much higher. EU1~ 1IU1C~ these 10 results were conci-ctent with histopathological diagnosis of the brain ~ec;.. -c. St~tictir~lly~ in the general population, about 20-30% of the individuals in the Rx age group would have developed AD and hence much higher PHF in the brain regions inriir~t~d (~t7m~n, R., Kawas.
C. H., pages 105-122, in ,~l,l.. ;.... r's Disease, Eds., Terry, RD; K~t7m~n, R; Bick, KL. Raven Press, New York, 1994). This evidence shows that chronic Ll~O~ ent of patients with 15 chlol~,.,...~,;..e pl~ PHF formation and AD.
In a subsequent study, 51 additional patients were idtqntifiçd and the analysis was Icl,ealcd as above using the TG3 antibody in an ELISA format. The results, ~u~ ali~ in Table 1, clearly reproduce and confirm the first l~,~u~l,e~ e study. TmmllnohictQpathological studies ca~Tied out on several brain regions from these patients were concict~nt with these ELISA
~0 results. Taken together, these two studies provide evidence of the therapeutic benefit of chlo~ u...~,;ne in AD and validate the use of the MSNla model for the identification of p~;r~lly usefulcompoundsforthe~lca~ ltofAD.
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 N MEAN AGE + SEM SIGNAL$ + SEM
Frontal Temporal Normal (12) 79.50 i 3.33 0.12 i 0.12 0.00 i 0.00 AD (28) 82.54 i 1.94 16.54 i 2.59 17.55 i 2.82 Rx (51) 76.88i 1.55 0.12iO.11 0.16iO.ll * Signal is c~lr~ t~A by ~ the means of r~llrlir~t~ al~solbdllce readings (direct ELISA using TG3 antibody) for 8 dilutions of all lysates ~ ~ by one to two serial lillltion.$
s Efforts to dissect the characteristic lesions of Alzheimer's Disease, namely the neurofihnll~ry tangles and the neuritic plaques have inrlirterl that aberrant protein y~ yllu~ on is a h~llm~rk of the ~;ylOS~ l abnorrn~lities in AD. Phosphorylated sites on the PHFs found in 10 neurofibrill~ry tangles and abnormal neurites are detected by AD-specific antibodies, such as TG3 and PHF-1, in the brains of AD pati~ntc and not in normal or other neuro~eg,~ e disease controls (cf. Figure 1, 2A). In the MSNla cell culture model (cf. Figure 2B, 3), these ly phosphorylated PHF sites are also rlet~cted by these ~ntihodies Th~.~r...~, the Ih~a~ lic activitv of the co~ c of the invention was ~csecsed by the 15 ability of these agents to affect the ~-u.lu~,Lion of abr-orm~lly phosphorvlated c~ u~ues p~Li~ to the production of PHFs of AD, utili7ing a human neuroblastoma cell line (MSNla) in the presence of the protein phosphatase inhibitor, okadaic acid (OKA). As described above, chlo~ olllazine, a clinically used antipyschotic, prevents production of the aberrantly phosphorylated PHF c~ ûl)es and, hence, the production of PHFs, thereby preventing AD. As 20 shown in Figures 2B and 3, and in Table 2, chlc,ll,lu.,,~7ine is effective in inhibiting the production of these aberrant phosphorylated epitopes in the MSNla cell culture model as det~ h~cd by the prevention of the imm~lnoreactivity ~ccoci~no~l with PHF antibodies such as TG3 which was utilized in the l~o~ ;Live clinical analysis.
SUBSTITUTE SHEcT ~RULE 26) CA 0220~86 1997-0~-16 Wo 96tl60S2 PCI/US95/14987 To detelllline the effect of chlorprom?7ine on the paired helical filament epitopes ~c~ 1 with AD, MSNla cells e,.~le~ing paired helical fil~ment c~,itopcs were i~ lt A with 100 mM chlc~ ,",~,;..e (CPZ) or a 0.2% DMSO vehicle control for 2 hours at 37 C. The cells were isolated by centrifi-g~tirJn, boiled for 10 ...;..~ ,5 and 25 mg protein from the resulting heat S stable s~ t~ were loaded per lane on an SDS-PAGE gel. The gel was clccLI~ph.lGlically transferred to nitrc!ce~ lose m.omhr~nP and then immllnost~int~cl with PHF-l. As shown in Figure 3, CPZ greatly dccl~ascd the pnxillrtion of paired helical fil~m-o.nt ~ opes by the MSNla cells. In comr~ct, the control shows that without the ari iition of CPZ, there was prc.~-iurtion of paired helical fil~mrnt ~ilupes by the MSNla cells. The use of the MSNla cell culture model 10 for scl~ g of novel cO~ ,ou,-ds for Lllc~ Lic activity in AD is, Ll,~ ,îulc, quite w,- .t;~nel1 This assay can thus be used to determine whether a drug is capable of pl~ r,tillg or intervening in AD by ~ .n~ g the production of abnorrnally phosphorvlated paired helical fil~m~ont ~iLc,~es :~c.coci~t~ with AD. To ~i~,~ ...;ne wl~cihcr a drug is capable of ~ ,cLing or intervening in AD activity, the MSNla cells con~ g tau and ~csoci~t~ci ~lOkillS are treated 15 with OKA capable of greatly in~,~asi,lg ;, ....~ ea.;LiviLy of the MSNla cells with AD specific mt~n~l~ n~i antibodies. Then, either prior to or concGIl,iLt;ulLly with OKA Ll~ 1, a coll,~oulld of the present invention is added to the culture. If the c.,lll~ul-d ~ ,n~ the induction of the AD e~ .pes in the MSNla cells treated with OKA, then it is said to have anti-AD activity. If the AD-specific antibodies are highly reactive with the neurobl~ctom~ cells following OKA L~ealllle.,L
20 in the presence of compound, then the coll,~ound is said to be in~offectn~l against AD.
The MSNla human neurobl~ctom~ line was subclonrd from a population of MSN cells obtained from the labold~ of Dr. Peter Davies (Albert Finctein College of Medicine, New York, NY). Cells were grown and m~inr~inerl in flasks in RPMI 1640 Il-el~ l, suppl~m~nted with lS% fetal calf serum, 100 U/ml penicillin, 100 U/ml S~ L.,-,ly~;in, 0.5 ug/ml fungizone 25 under7.5% CO2 at37 C.
Stock solutions of drugs were p.ep~d by dissolving the anhydrous powders to final conre..l.,.l;ons of either 10 or 20 mM in 50% ac~ueous or 100% dill~lhyl sulfoxide (DMSO), l~pccli~ely. Working solutions of drugs were ~ d by dilution of the stock solutions with Kreb's Ringer in Hepes buffer (KRH) (128 mM NaC12 5 mM KCl, 2.5 mM CaCl2 1.2 mM
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 MgS04, 1 mM Na2HPO4, 10 mM dextrose, 20 mM Hepes, pH 7.4). OKA is ",~h.~h~d as a 1 mM stock so~ nn in DMSO prior to dilution to 4 ~uM in KRH.
MSN cells grown in 225 cm2 flasks are removed from the inrubator, their .~fd;.~
der~ ed and ~ )laced with 50 ml pre-wa.lll~i KRH. The cells are harvested by 5~ping prior to 5 s~1;,n~...1i.1;1~n at 1000 rpm for 5 min. The s.~ la~nts are discarded and the cell pellets are 1, the cells counted and diluted to a density of 2 x 104 cells/50 ml. The cells are then plated in a 96 well plate at 50 ~Vwell and 25 ~1 of 4 ~LM OKA and 25 ~ul of drug are then added to the a~lOI,lialt; wells; the entire 96 well plate is then int~lb~ted for 2 hrs at 37 C. Depf ,~1;ng on the dilution of drug added, this yields individual wells co~ h~;ng 1 ~M OKA, 0-64 ~lM drug and 10 2 x 104 cells in 0.26% DMSO in KRH. The il~;uh~t;oll is t~ d by the ~ 1i*o~ of 20 111 of 6X extraction buffer and immedi~7ts freezing at -80 C for at least one hr. The 6X extraction buffer contains: 25 mM Tris-HCI, pH 7.6. 150 mM NaCI, 5 mM EDTA, 24 tnM ~-glycerol l hosl.hal~, 10 ~g/ml APMSF (4-~min~inophe"ylll~ethane-sulfonyl flouride), and 2.5 ~g/ml each of le.l~e~li", a~l.,Li"i." and p~ The plates are thawed in a 37 C water bath and 20 ~11 of 15 cell lysate is added to a replica well in an ELISA plate that already cont~in.c 80 ~,11 of coating buffer (15 mM Na2CO3 and 35 mM NaHCO3, pH 9.6). The plates are allowed to coat overnight at 4 C. The plates are washed four times with deionized water and then blocked for 30 min at 37 C with 200 ~Vwell pre-warmed 1% bovine serum ,7lbumin in 10 mM Tris-HCl, pH
7.4, 150 mM NaCI, 3 mM NaN3 (BSA-TBS). After the blocking solution is removed, 100 20 ~Vwell of an ~.~liate dilution of pre-warmed primary antibody (eg., TG3 or PHF-1) in BSA-TBS is added and incubated at 37 C for 30 min. Tnrub~tion is tt~ tf:(l' by washing four times in deionized water at which time 100 ~11 of an a~pl~.iate dilution of pre-warmed secondary antibody (conjugated to alkaline pho,l,hatase) in BSA-TBS is added to each well in the ELISA
plate. Tnrnh~tion is ~lÇwmed for 30 min at 37 C followed by washing 4 times with deionized 25 water. 100 ~l/ml of prewarmed chromogenic substrate (1 mg/ml p-nitrophenyl phosphate in 10% t1isth~nt)lamine7 3 mM NaN3, 0.5 mM MgC12, pH 9.8) is added and the plate incubated for 30 min at 37 C. Absul bance at 405 nm is then determined by reading the plate on a BioRad UV
Microplate Reader.
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCr/US95/14987 Results oblailled from the MSNla cell culture model studies utilizing the TG3 antibody are shown in Table 2.
S IC50forinhihitionofTG3 h,,..,...,ulcacLi~ yin OKA treated MSNla cells FY~mrl~ ~ IC50 (~M) yl. .~ 70.0 6.0 11 4.2 13 11.0 14 5.8 16 5.2 19 15.6 21 6.6 26 14.7 29 8.7 32 6.2 36 25.0 39 10.0 42 5.7 44 7.5 6.3 57 6.8 63 7.3 67 20.0 69 I5.0 76 10.5 5.7 91 9.5 2.8 ` 78 34.0 SUBSTITUTE SHEET (RULE 26 CA 0220~86 1997-0~-16 As seen in Table 2, the co.l,l,o~ ds of the present invention are potent inhihitors of the ;nl- of the ~I~..,...~Iy pho~ ./ylated c~iLo~es as d~,t~,cl~d in tne MSNla cell culture model system nti1i7ing the anti'oody TG3. As shown, the col.l~unds of the present invention are more potent than chlu~ 7ine~ a co.ll~o~ d shown to inhibit the pl~luc~ion of the AD ~ou~
5 e~ilopcs and to prevent AD. The cc,~ .ouilds of the present invention are thus useful in the ~,d~ of AD.
FY~mrl~ 118 1~h..~ ll of ~ rv~ Activity The collll~o.~l,ds of the invention according to formula I are effective in dest ~'t ili~ing 10 ~ ,lù~ .ul.oc, thus are useful in treating certain neoplastic lic~cçs Indirect imm~ln~ s~ nce llliClosco~,y using the mnnoclon~l antibodies to tubulin is used herein to ~l~.h'.. .n;.~e the activity of the co.ll~uu,lds of this invention in ~,ollluLh,g depol~ lir.n of the llli~,lolucjule cytos~ ton in cultured cells. The following assay was employed.
Cultured human CG neurobl~ctom~ cells were seeded 1:3 from conflu~nt cultures onto 15 sterile llx22 mtn coverslips in 6 well tissue culture plates 16 hr prior to L.e~t~ nt The fol~owing day, the tissue culture ..~ef~ " is removed and the cells are exposed to various cni-~el.~ ;nnc of co-llpuu,lds of this invention in Krebs Ringer Hepes (KRH) buffer cou~ a final concentration of 0.5% DMSO as carrier. Tncubations were pc,rulllled at 37 C in a hnmi-lifie~l 5% C02 ~tmnsphPre for 2 hr. After incubation, the cells were fixed in 3% TEM
20 grade fnrm~ ohyde in PBS for 45 min at room ~elllp~;ld~
To visualize the effects of the compounds of the invention on the microtubule cytoCL~I~tnn, the cells were processed for tubulin i.. ,.. l~oflnorescence Briefly, the cells were permeabili7~ in 0.5% Triton-X 100 in PBS for 5 min. The cells were washed 2x with PBS and aldehydes reduced using 0.5 mglml NaBH4 in PBS for 5 min. Subsequently, the cells were 25 blocked for 10 min in 1.5% BSA and 1.5 % nonfat dry milk in PBS (blocking solution, BS) for 10 min. The cells were then incllha~ecl for 30 min at 37 C with the mnnnelon~l antibody Tu27B
which recognizes b-tubulin (dilution 1:20 in BS). Subseu~u~,~ltly, the cells were washed 2x in PBS and once in BS. The cells were then incub~te~ for 30 rnin at 37 C with sheep an~ luuse IgG cûnjug~l~d to FITC. After in~ubation, the cells were washed 2x in PBS and once in BS and Sl~STITUTE SHEET (RULE 26) inCllb~t~A for 30 min at 37 C with rabbit antisheep IgG conjugated to ~llC. The cells were rinsed in PBS, cuu~ a~illcd with Hoechst 33285 in PBS (1 ~g/ml). and rinsed in PBS. The co~ ,s were . . ,.,u..l~ in g: 1 glycerol:PBS cr)~ g 1 mg/ml p-phenylel~e~ " ,; "e and sealed with nail polish.
S The cells were viewed using a Jen~ium~r epifluo~esc.,.. ec mi~_lu~co~e c~lui~ed with the proper filters for Flllol~,scc;ll Tcothiocyanate (FlTC) eycit~tinn and c . "i~ Lack of effect of a cu~ vulld is evidenced by the ~ sc~nce of an intact microtubule network in ir~ hase cells, or a mitotic spindle in dividing cells. Antineoplastic col.~ .ric of the invention at effective doses result in the di~a~ e of llli~;lu~ r c in both inte~ ase and mitotic cells.
The results of s.;l.,.,.li"g of cclll~uullds of the invention are shown in Table 3. Shown for co...l~.vtive ~ul~oSes iS vinbl~cttne ("Velban", Lilly Research La~lalolics), a clinir~lly useful amill~lastic agent which ~lulll~t~ microtubule rl~st~hili7~tir~n, hence llli~;lu~ubllle iic~ccr.mhly.
Al~ f.clulubllleActivity C JQ. ~ 1 "~l1 r F~mrle # ~M)
FY~mrle 105 1-(3"-Nitro-4"-N-piperidinophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone trihydrochloride:
IH NMR (300 MHz, DMSO-d6) ~ 11.95-11.70 (brs, 3H), 8.35 (s, lH), 8.04 (d, IH), 7.75-7.55 (brs, 2H), 7.55-7.40 (brs, 3H), 7.35 (d, lH), 4.60-3.00 (m, 18H), 1.80-1.30 (brs, 6H).
Example 106 20 1-(5"-Methyl-2"-thienyl)-3-(4'-benzyl-1'-pip~illyl)-1-propanone dihydrochloride: mp 220C
(dec.); IH NMR (300 MHz, CDCl3/NaOD) ~ 7.53 (m, I H), 7.40-7.08 (m, 5 H), 6.78 (m, 1 H), 3.50 (s, 2 H), 3.04 (t, 2 H), 2.83 (l, 2 H), 2 67-2.30 (m, 11 H).
FY~mrl~ 107 SUBSTlTlJTE SHEET (RULE 2~r,~
CA 0220~86 1997-0~-16 Wo 96/16052 PCT/US95/14987 1-[4"-p-(5"',l"'-Dichloroimi~7O1-l"'-yl)phenyl]-3-(4'-benzyl-l'-piperazinyl)-1-propanone dihydrochloride: mp 200-202C; IH NMR (300 MHz, DMSO-d6) ~ 12.25-11.30 (brs, 2 H), 8.30-8.10 (m, 3 H), 7.77 (d, 2 H), 7.70-7.30 (m, 5 H), 4.35 (brs, 2 H), 3.90-3.20 (m, 12 H).
FY~n~ e 108 5 1-r5~-(phenylethynyl)-2~-thienyl]-3-(4-benzy~ -pi~e~ lyl)-l-plup~one dihydr~!chlnrirl~:
mp 205C (dec.); IH NMR (300 MHz, DMSO-d6) o 12.30-11.20 (brs, 2 H), 8.00 (d, 1 H), 7.80-7.30 (m, 11 H), 4.30 (brs, 2 H), 3.90-3.00 (m, 12 H).
Exarnple 109 1-(3"-Nillu~hc"yl)-3-(4'-~ lonyl-1'-~i~cla.i~yl)-1-1,l~onedil~y~llucl~loride: mp215C
lO (dec.); IH NMR (300 MHz, DMSO-d6) o 12.35-11.20 (brs, 2 H), 8.70 (s, 1 H), 8.52 (d, 1 H), 8.40 (d, 1 H), 7.70 (dd, 1 H), 7.25 (s, 1 H), 7.15-6.90 (m, 2 H), 6.05 (s, 1 H), 4.25 (brs, 2 H), 3.90-3.10 (m, 12 H).
FY~rnri~llO
1 -(5"-Methyl-3"-phenylisoxazol-4"-yl)-3-(4'-benzyl- 1 '-~ip~l~inyl)- 1 -l~lupallone 15 dihydrochloride: mp 220C (dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.35-11.40 (brs, 2 H), 7.70-7.30 (m, 10 H), 4.35 (brs, 2 H), 3.70-3.10 (m, 12 H), 2.80 (s, 3 H).
FY~n rl-o. 1 1 1 1-(2"-Phenylthiazol-4"-yl)-3-(4'-benzyl-1'-pi~,la2ih~yl)-1 propanonedihydrochlonrlç: mp 220C (dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.20-11.50 (brs, 2 H), 8.65 (s, 1 H), 8.10-20 7.90 (brs, 2.H), 7.75-7.30 (m, 8 H), 4.30 (brs, 2 H), 3.80-3.20 (m, 12 H).
Fy~mrl~ 112 1 -(3"-Phenylisoxazol-4"-yl)-3-(4'-benzyl- 1 '-piperazinyl)- 1-propanone dihydrochloride: mp 212C (dec.); IH NMR (300 MHz, DMSO-d6) ~ 12.25-11.40 (brs, 2 H), 8.10-7.90 (m, 3.H), 7.70-7.30 (m, 8 H), 4.35 (brs, 2 H), 3.80-3.10 (m, 12 H).
Example 113 SUBSTITUTE SHEET (RULE 26) WO g6/16052 PCr/US95114987 1 -(4"-t2"',4"'-di~ ùphenylamino]phenyl)-3-(4'-benzyl- 1 '-piperazinyl)- 1 -propanone dihydroehl~rid.o.: mp 248-250C; IH NMR (300 MHz, CDC13/NaOD) o 9.20 (m, 1 H), 8.26 (m, 1 H), 8.08 (m, 2 H), 7.50-7.10 (m, 8 Hj, 3.53 (s, 2 H), 3.21 (m, 2 H), 2.87 (m, 2 H), 2.55 (brrn, 8 H).
Exarnple 114 1 -(2",4"-dilll~;Ll,ylLl,iazol-5"-yl)-3-(4'-benzyl- I '-piperazinyl)- 1 -~ulupanol1e di~lyd~ uchloride:
mp: 228-C (dec); IH NMR (300 MHz, D20) ~ 7.55 (brs, 5 H~, 4.50 (s, 2 H), 3.87-3.42 (m, 12 H), 2.75 (s, 3 H), 2.67 (s, 3 H).
FYarnple 115 10 1-(m-NiL,u~,hc,lyl3-3-(4'-benzyl-l'-piperidinyl)-l-prûpanonehydrochloride: mpl89-191C;IH
NMR (300 MHz, CDC13) ~ 12.60-12.40 (brs, 1 H), 8.35 (d, 2 H), 8.18 (d, 2 H), 7.35-7.05 (m, 5 H), 3.95 (t, 2 H), 3.65-3.3S (m, 4 H), 2.80-2.55 (m, 4 H), 2.~0-1.65 (m, 5 H).
Exarnple 116 The following cullllJuull~L. may be ,u~ cd by the general method:
(a) 1-(6"-Blul,locoull,~ill-3"-yl)-3-(4'-benzyl-l'-pirer~7inyl)-l-propanone dihy~lluchlnrit~ .
O
Br ~ N~ ~3 (b) 1-(6"-Bromocoumdlill-3"-yl)-3-(4'-benzoyl-1'-pip~ yl)-1-propanone dihydrochln7 i~
(c) 1 -(I ",1 "-Dimethyl-6"-tert-butylindan-4"-yl)-3-(4'-benzyl- 1 '-piperazinyl)- 1 -propanone dihydrochlorirl~
(d) 1 -(1 ",1 "-Dimethyl-6"-tert-butylindan-4"-yl)-3-(4'-benzoyl- 1 '-piperazinyl)- 1-~,u~ano,le dihydrochlr~ri-i~
SUBSTITUTE SHEET (RUEE 26) WO g6/16052 PCI`/US95tl4987 (e) l-(cou~ -3~r-yl)-3-(4~-benzy~ yl)- l-ylùl)anolle dihydro~hlt Ti~
(f) l-(Cou~ -3"-yl)-3-(4'-benzoyl-1'-~ip.~ yl)-1-,~1u~allûlle dihydrochlnnrle (g) 1 -(5"-Cyano-4"-methyl-2"-(methylthio)thien-3"-yl)-3-(4'-benzyl- 1'--pl~:)pd~lollc clil~ydluc1~1nril1.o (h) 1 -(5"-Cyano-4"-methyl-2"-(methylthio)thien-3"-yl)-3-(4'-benzoyl- 1'-pip. .~illyl)- l-~l~anone dihydr~hlnnde (i) 1 -~-(2",4"-Dichlorophenoxy)-phenyl)-3-(4'-benzyl- 1 '-pi~ zinyl)- 1-pl~ ullC dihydroc hlnri~
(i) 1-~-(2",4"-Dichlorophenoxy)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-10 plupanone dihydr~hlonde (k) 1 -(5"'-(2",4"-Difluorophenoxy)-fur-2"'-yl)-3-(4'-benzyl- 1 '-piperazinyl)- 1-propanone dihydroehlr)ri~
~ ~ N~
(1) 1-(5"'- (2",4"-Difluorophenoxy) -fur-2"'-yl)-3-(4'-benzoyl- 1 '-piperazinyl)- 1-propanone dihydrochlnnrle (m) 1 -(2",3"-Dihydrobenzo[b]fur-5"-yl)-3-(4'-benzyl- 1 '-piperazinyl)- 1 -propanone dihydrochloride SUBSTITUTE SHEET (RULE 2~) NJ~3 (n) 1 -(2",3"-Dihydrobenzorb~fur-5"-yl)-3-(4'-benzoyl- 1 '-pip~ lyl)- I -propanone dihydrochloride 5(o) 1 -(3",5"-Dillletilylbenzorb]thien-2"-yl)-3-(4'-benzyl- 1'-~ d~inyl)- 1-plo~anolle dihydroçhloritl~
(p) I -(3",5"-Dimethylbenzorb]thien-2"-yl)-3-(4'-benzoyl- 1 '-piper~7invl)- 1-propanone dihydroçhlonrle Me O
Me ~~N~N~
10(q) 1-(2",4"-Dimethylthien-5"-yl)-3-(4'-benzyl-1'-pi~ a~inyl)-1-~.op~,olle dihydrochloride Me o Me N~N~ ~
(r) 1 -(2",4"-Dimethylthien-5"-yl)-3-(4'-benzoyl- 1 '-piperazinyl)- 1 -propanonedihydrochloride 15(s) 1-GD-[Phenylthio~phenyl)-3-(4'-benzyl-1'-~ilJel~hlyl)-l-propanone dihydrochloride SUBSTlTUrE SHEET (RULE 26) WO 96/16052 PCrlUS95/14987 (t) l-(p-~Pl,~nyl~,io~iphenyl)-3-(4'-benzoyl-1'-pip~ yl)-1-plvpanone dihydrorhlnntit.
(u) 1 -(3"-Metho,~ye~ bonyl-5"-methylisoxazol-4"-yl)-3-(4'-benzyl- 1 '-piperazinyl)-u~lol~e dihydrochlnrid~
(v) 1-(3"-Metho,~yc~L.onyl-5"-methylisoxazol-4"-yl)-3-(4'-benzoyl-1'-pi~e. ~ yl)- l-~lu~ one dihydrof hlnncle (w) 1-(5''-(2'''-C~l~ulll~llloxythien-3~-yl)-furan-2~-yl)-3-(4~-b ~i~e.d~illyl)-l-~lop~-t,.~ dihydrothlnnrit~.
(x) 1 -(5"-(2"'-C~ bonl~,~hoxythien-3"'-yl)-furan-2"-yl)-3-(4'-benzoyl- 1'-10 pi~.~inyl)-l-~lu~anone dihydroçhinn~
(y) l-(p-(4"-Methox~heno~y)-phenyl)-3-(4'-benzyl- 1 '-pi~,.~inyl)- l-~ro~ olle dihy~lluchloride (z) l -(p-(4"-Methoxyphenoxy)-phenyl)-3-(4'-benzoyl- 1 '-pi~,.azinyl)- 1 -1,-upanolle dihydrochloride 1~ (aa) 1-(p-(4"-Nh~ul)hEnoxy)-phenyl)-3-(4'-benzyl-1'-1,ip~,.~illyl)-1-p~upanone dihydrochloride (bb) l-(p-(4''-Ni~uphelloxy)-phenyl)-3-(4'-benzoyl-l'-~ ,.a~illyl)-l-propanone dihydrochloride (cc) 1 -(m-Nitro-p-(phenylthio!-phenyl)-3-(4'-benzyl- 1 '-~i~.~inyl)- l-propanone 20 dihydror hlr)riti ~Oz~ N~
(dd) 1-(m-Nitro-p-(phenylthio)-phenyl)-3-(4'-benzoyl-1'-~ lyl)-1-~u~upallonc dihydroçhk)rifi.-.
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 (ee) l-(m-Mtro-p-(1"-piperidinyl)-phenyl)-3-(4'-benzoyl-1'-pi~ inyl)-1-plup&no~e dihydrochlnT-A~
(ff) I-(m-Nitro-p-(4"-morpholino)-phenyl)-3-(4'-benzoyl~ Jipc.~illyl)- 1-p~u~ .,.e dihydro~hlnri-lP.
(gg) 1-(p-Nitrophenyl)-3-(4'-(5"-(1"'-methyl-3"'-trifluo.olllcLllylpyrazol-5"'-yl)-thien-2"yl)- 1 '-p;l.~f ,~ yl)- l-l,-u~ano..e dihyd~ocll1nri~le NO~ ~N~CF3 (hh) 1-(5"Bromo-2"-thienyl)-3-(4'-p-bromobc.,,~ne~lllfonyl-1'-pip~ illyl)-1-~u~no~e hydrochlnride lû (ii) l-(S"Bromo-2"-thienyl)-3-(4'-p-toluenesulfonyl-1'-pi~,e.~illyl)-1-plupanolle hydroçhlnriflp (ii) 1 -~D-Nillupl~e~lyl)-3-(4 -p-l~l u~ot~n ~f l~r i,ulfonyl- 1 '-pil,ei~zi--yl)- 1 -~-ùpanonc hydrochlnnde (ii) 1 -(5"-Chloro-4"-nitro-2"- thienyl)-3-(4'-bf n 7enes~ 1 If onyl- I '-piperazinyl)- 1-15 ~ru~,anollc hydrochlnri~
(kk) 1-(2"-Chloro-3"-nitrothien-5"-yl)-3-(4'-o-trifluolo~llcLhylbenzoyl-l'-P;l~ yl)-l-p.op~one dihydrochlnntie (Il) 1 -~n-Nitrophenyl)-3-(4'-{4"-methyl- 1 ",2",3"-thiadiaz-5"-oyl]- 1 '-piperazinyl)-u~allolle dihydrochloride.
(mm) 1 -(5"-Chloro-4"-nitro-2"-thienyl)-3-~4'-(4"'-methyl- 1 "',2"',3"'-thia~
5"'-ûyl)- 1'-pi~e.d~ yl]-1-propanone dihydrochloride.
S~B~ J I t s~E~ (RlJ~E 26) WO 96/16052 PC'r/US95/14987 (nn) I -r5"-Cyano-4"-methyl-2"-(methylthio)-3"-thienyl~-3-(4'-benzyl- 1'-P;l~ a~ yl)-1-y~ o,le dihydroçhlnri~ie (oo) 1-(2",4"-Dimethyl-5"-thiazolyl)-3-(4'-benzyl-1'-~ ,c.azillyl)-1-propanone dihydroçhlori~
S (pp) 1-(5"-Nitro-3"-thienyl)-3-(4'-o-fluoro~.~zoyl-1'-yil,e.~zinyl)-1-propanone dihy~L~uçl .olr~ride (qq) 1-(5"-Bromo-2"-thienyl)-3-(4'-o-fluolubenzc.yl-1'-~ip~ inyl)-l-plupanone dihydrochnlori-le F~m,rle 117 Effect of Chlc,-~lu.. ~ .~;.. e on Paired Helical Filament Levels in Human Brain Tissue The in vitro analyses desçrihed herein to investigate the activity of the co~ oullds of this invention can also be used to ~letP-rmine the nature of abnorrnally phosphorylated paired helical fil~m~nt epitopes involved in ~l7hpimer~s Disease, the regulatory mech~nicm~ involved with 15 ~17hrimrr~s Disease and mo l~;r;rAI;Ol-c of the protein tau and other polypeptides ~c$ociAtç~ with PHFs and involved in ~1,1.~.;...~.. 's Disease.
Certain phenorhi~7in.-s, for e~ . .plc chlu~ ;nr. can mArk~Aly inhibit the expression of PHF epitopes (as determined by loss of immllnoreactivity with ~l7hrim-or~s Disease specific antibodies) upon ~ llllfnt of MSNla cells with okadaic acid (cf. Figure 33. These co,.l~lou~lds 20 are effective at micromolar conce-lL-ations, with increased ~OL..;~ y being evident when cells are treated prior to the ad-iition of okadaic acid. The effective concelltlations appear to be in the range at which these drugs are present in the brain following chronic treatment of psychiatric patients (Svendsen, CN, Psychoph~rm~rolngy, 90, 316-321, 1986). These results indicate that patients who were chronically treated with phenothi~7ines would be ~lotecled from the 25 development of PHF, and thus would have a low probability of development of Alzheimer's Disease.
SUBSTITUTE SHEET (RULE 26 CA 0220~86 l997-0~-l6 WO 96/16052 PCrlUS95/14987 Frontal and cortical brain tissue ~I,ec-;...~,n~ obtained at autopsy from patients chronically treated with chlo~lu~ 7;nr- were ana}yzed using the ALZ-EIA method previously described (Gh~nh~ri, HA, et al, JAMA, 263, 2907, 1990). The results are shown in Figures 4A and 4B
frontal (Broadman area 10) and ltj11lPI)~ (Broadman area 38) regions, res~cc~ively. The brain S tissue (post-mortem) from a~ d.. .~ y the sarne number of (age .. .~ -d) normal controls and Al7h/ .... 's Disease patients were also analyzed and are ~ ,sented in these figures as nc~ativc and positive controls (for normal and AD, rcsp.,~ively). As the data inrli~ ~tç, the samples from chlol~lu~ treated patients (Rx) had low PHF epitope levels similar to normal controls, wh~l~as the PHF epitope levels in the AD group were clearly much higher. EU1~ 1IU1C~ these 10 results were conci-ctent with histopathological diagnosis of the brain ~ec;.. -c. St~tictir~lly~ in the general population, about 20-30% of the individuals in the Rx age group would have developed AD and hence much higher PHF in the brain regions inriir~t~d (~t7m~n, R., Kawas.
C. H., pages 105-122, in ,~l,l.. ;.... r's Disease, Eds., Terry, RD; K~t7m~n, R; Bick, KL. Raven Press, New York, 1994). This evidence shows that chronic Ll~O~ ent of patients with 15 chlol~,.,...~,;..e pl~ PHF formation and AD.
In a subsequent study, 51 additional patients were idtqntifiçd and the analysis was Icl,ealcd as above using the TG3 antibody in an ELISA format. The results, ~u~ ali~ in Table 1, clearly reproduce and confirm the first l~,~u~l,e~ e study. TmmllnohictQpathological studies ca~Tied out on several brain regions from these patients were concict~nt with these ELISA
~0 results. Taken together, these two studies provide evidence of the therapeutic benefit of chlo~ u...~,;ne in AD and validate the use of the MSNla model for the identification of p~;r~lly usefulcompoundsforthe~lca~ ltofAD.
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 N MEAN AGE + SEM SIGNAL$ + SEM
Frontal Temporal Normal (12) 79.50 i 3.33 0.12 i 0.12 0.00 i 0.00 AD (28) 82.54 i 1.94 16.54 i 2.59 17.55 i 2.82 Rx (51) 76.88i 1.55 0.12iO.11 0.16iO.ll * Signal is c~lr~ t~A by ~ the means of r~llrlir~t~ al~solbdllce readings (direct ELISA using TG3 antibody) for 8 dilutions of all lysates ~ ~ by one to two serial lillltion.$
s Efforts to dissect the characteristic lesions of Alzheimer's Disease, namely the neurofihnll~ry tangles and the neuritic plaques have inrlirterl that aberrant protein y~ yllu~ on is a h~llm~rk of the ~;ylOS~ l abnorrn~lities in AD. Phosphorylated sites on the PHFs found in 10 neurofibrill~ry tangles and abnormal neurites are detected by AD-specific antibodies, such as TG3 and PHF-1, in the brains of AD pati~ntc and not in normal or other neuro~eg,~ e disease controls (cf. Figure 1, 2A). In the MSNla cell culture model (cf. Figure 2B, 3), these ly phosphorylated PHF sites are also rlet~cted by these ~ntihodies Th~.~r...~, the Ih~a~ lic activitv of the co~ c of the invention was ~csecsed by the 15 ability of these agents to affect the ~-u.lu~,Lion of abr-orm~lly phosphorvlated c~ u~ues p~Li~ to the production of PHFs of AD, utili7ing a human neuroblastoma cell line (MSNla) in the presence of the protein phosphatase inhibitor, okadaic acid (OKA). As described above, chlo~ olllazine, a clinically used antipyschotic, prevents production of the aberrantly phosphorylated PHF c~ ûl)es and, hence, the production of PHFs, thereby preventing AD. As 20 shown in Figures 2B and 3, and in Table 2, chlc,ll,lu.,,~7ine is effective in inhibiting the production of these aberrant phosphorylated epitopes in the MSNla cell culture model as det~ h~cd by the prevention of the imm~lnoreactivity ~ccoci~no~l with PHF antibodies such as TG3 which was utilized in the l~o~ ;Live clinical analysis.
SUBSTITUTE SHEcT ~RULE 26) CA 0220~86 1997-0~-16 Wo 96tl60S2 PCI/US95/14987 To detelllline the effect of chlorprom?7ine on the paired helical filament epitopes ~c~ 1 with AD, MSNla cells e,.~le~ing paired helical fil~ment c~,itopcs were i~ lt A with 100 mM chlc~ ,",~,;..e (CPZ) or a 0.2% DMSO vehicle control for 2 hours at 37 C. The cells were isolated by centrifi-g~tirJn, boiled for 10 ...;..~ ,5 and 25 mg protein from the resulting heat S stable s~ t~ were loaded per lane on an SDS-PAGE gel. The gel was clccLI~ph.lGlically transferred to nitrc!ce~ lose m.omhr~nP and then immllnost~int~cl with PHF-l. As shown in Figure 3, CPZ greatly dccl~ascd the pnxillrtion of paired helical fil~m-o.nt ~ opes by the MSNla cells. In comr~ct, the control shows that without the ari iition of CPZ, there was prc.~-iurtion of paired helical fil~mrnt ~ilupes by the MSNla cells. The use of the MSNla cell culture model 10 for scl~ g of novel cO~ ,ou,-ds for Lllc~ Lic activity in AD is, Ll,~ ,îulc, quite w,- .t;~nel1 This assay can thus be used to determine whether a drug is capable of pl~ r,tillg or intervening in AD by ~ .n~ g the production of abnorrnally phosphorvlated paired helical fil~m~ont ~iLc,~es :~c.coci~t~ with AD. To ~i~,~ ...;ne wl~cihcr a drug is capable of ~ ,cLing or intervening in AD activity, the MSNla cells con~ g tau and ~csoci~t~ci ~lOkillS are treated 15 with OKA capable of greatly in~,~asi,lg ;, ....~ ea.;LiviLy of the MSNla cells with AD specific mt~n~l~ n~i antibodies. Then, either prior to or concGIl,iLt;ulLly with OKA Ll~ 1, a coll,~oulld of the present invention is added to the culture. If the c.,lll~ul-d ~ ,n~ the induction of the AD e~ .pes in the MSNla cells treated with OKA, then it is said to have anti-AD activity. If the AD-specific antibodies are highly reactive with the neurobl~ctom~ cells following OKA L~ealllle.,L
20 in the presence of compound, then the coll,~ound is said to be in~offectn~l against AD.
The MSNla human neurobl~ctom~ line was subclonrd from a population of MSN cells obtained from the labold~ of Dr. Peter Davies (Albert Finctein College of Medicine, New York, NY). Cells were grown and m~inr~inerl in flasks in RPMI 1640 Il-el~ l, suppl~m~nted with lS% fetal calf serum, 100 U/ml penicillin, 100 U/ml S~ L.,-,ly~;in, 0.5 ug/ml fungizone 25 under7.5% CO2 at37 C.
Stock solutions of drugs were p.ep~d by dissolving the anhydrous powders to final conre..l.,.l;ons of either 10 or 20 mM in 50% ac~ueous or 100% dill~lhyl sulfoxide (DMSO), l~pccli~ely. Working solutions of drugs were ~ d by dilution of the stock solutions with Kreb's Ringer in Hepes buffer (KRH) (128 mM NaC12 5 mM KCl, 2.5 mM CaCl2 1.2 mM
SUBSTITUTE SHEET (RULE 26) CA 0220~86 1997-0~-16 MgS04, 1 mM Na2HPO4, 10 mM dextrose, 20 mM Hepes, pH 7.4). OKA is ",~h.~h~d as a 1 mM stock so~ nn in DMSO prior to dilution to 4 ~uM in KRH.
MSN cells grown in 225 cm2 flasks are removed from the inrubator, their .~fd;.~
der~ ed and ~ )laced with 50 ml pre-wa.lll~i KRH. The cells are harvested by 5~ping prior to 5 s~1;,n~...1i.1;1~n at 1000 rpm for 5 min. The s.~ la~nts are discarded and the cell pellets are 1, the cells counted and diluted to a density of 2 x 104 cells/50 ml. The cells are then plated in a 96 well plate at 50 ~Vwell and 25 ~1 of 4 ~LM OKA and 25 ~ul of drug are then added to the a~lOI,lialt; wells; the entire 96 well plate is then int~lb~ted for 2 hrs at 37 C. Depf ,~1;ng on the dilution of drug added, this yields individual wells co~ h~;ng 1 ~M OKA, 0-64 ~lM drug and 10 2 x 104 cells in 0.26% DMSO in KRH. The il~;uh~t;oll is t~ d by the ~ 1i*o~ of 20 111 of 6X extraction buffer and immedi~7ts freezing at -80 C for at least one hr. The 6X extraction buffer contains: 25 mM Tris-HCI, pH 7.6. 150 mM NaCI, 5 mM EDTA, 24 tnM ~-glycerol l hosl.hal~, 10 ~g/ml APMSF (4-~min~inophe"ylll~ethane-sulfonyl flouride), and 2.5 ~g/ml each of le.l~e~li", a~l.,Li"i." and p~ The plates are thawed in a 37 C water bath and 20 ~11 of 15 cell lysate is added to a replica well in an ELISA plate that already cont~in.c 80 ~,11 of coating buffer (15 mM Na2CO3 and 35 mM NaHCO3, pH 9.6). The plates are allowed to coat overnight at 4 C. The plates are washed four times with deionized water and then blocked for 30 min at 37 C with 200 ~Vwell pre-warmed 1% bovine serum ,7lbumin in 10 mM Tris-HCl, pH
7.4, 150 mM NaCI, 3 mM NaN3 (BSA-TBS). After the blocking solution is removed, 100 20 ~Vwell of an ~.~liate dilution of pre-warmed primary antibody (eg., TG3 or PHF-1) in BSA-TBS is added and incubated at 37 C for 30 min. Tnrub~tion is tt~ tf:(l' by washing four times in deionized water at which time 100 ~11 of an a~pl~.iate dilution of pre-warmed secondary antibody (conjugated to alkaline pho,l,hatase) in BSA-TBS is added to each well in the ELISA
plate. Tnrnh~tion is ~lÇwmed for 30 min at 37 C followed by washing 4 times with deionized 25 water. 100 ~l/ml of prewarmed chromogenic substrate (1 mg/ml p-nitrophenyl phosphate in 10% t1isth~nt)lamine7 3 mM NaN3, 0.5 mM MgC12, pH 9.8) is added and the plate incubated for 30 min at 37 C. Absul bance at 405 nm is then determined by reading the plate on a BioRad UV
Microplate Reader.
SUBSTITUTE SHEET (RULE 26) WO 96/16052 PCr/US95/14987 Results oblailled from the MSNla cell culture model studies utilizing the TG3 antibody are shown in Table 2.
S IC50forinhihitionofTG3 h,,..,...,ulcacLi~ yin OKA treated MSNla cells FY~mrl~ ~ IC50 (~M) yl. .~ 70.0 6.0 11 4.2 13 11.0 14 5.8 16 5.2 19 15.6 21 6.6 26 14.7 29 8.7 32 6.2 36 25.0 39 10.0 42 5.7 44 7.5 6.3 57 6.8 63 7.3 67 20.0 69 I5.0 76 10.5 5.7 91 9.5 2.8 ` 78 34.0 SUBSTITUTE SHEET (RULE 26 CA 0220~86 1997-0~-16 As seen in Table 2, the co.l,l,o~ ds of the present invention are potent inhihitors of the ;nl- of the ~I~..,...~Iy pho~ ./ylated c~iLo~es as d~,t~,cl~d in tne MSNla cell culture model system nti1i7ing the anti'oody TG3. As shown, the col.l~unds of the present invention are more potent than chlu~ 7ine~ a co.ll~o~ d shown to inhibit the pl~luc~ion of the AD ~ou~
5 e~ilopcs and to prevent AD. The cc,~ .ouilds of the present invention are thus useful in the ~,d~ of AD.
FY~mrl~ 118 1~h..~ ll of ~ rv~ Activity The collll~o.~l,ds of the invention according to formula I are effective in dest ~'t ili~ing 10 ~ ,lù~ .ul.oc, thus are useful in treating certain neoplastic lic~cçs Indirect imm~ln~ s~ nce llliClosco~,y using the mnnoclon~l antibodies to tubulin is used herein to ~l~.h'.. .n;.~e the activity of the co.ll~uu,lds of this invention in ~,ollluLh,g depol~ lir.n of the llli~,lolucjule cytos~ ton in cultured cells. The following assay was employed.
Cultured human CG neurobl~ctom~ cells were seeded 1:3 from conflu~nt cultures onto 15 sterile llx22 mtn coverslips in 6 well tissue culture plates 16 hr prior to L.e~t~ nt The fol~owing day, the tissue culture ..~ef~ " is removed and the cells are exposed to various cni-~el.~ ;nnc of co-llpuu,lds of this invention in Krebs Ringer Hepes (KRH) buffer cou~ a final concentration of 0.5% DMSO as carrier. Tncubations were pc,rulllled at 37 C in a hnmi-lifie~l 5% C02 ~tmnsphPre for 2 hr. After incubation, the cells were fixed in 3% TEM
20 grade fnrm~ ohyde in PBS for 45 min at room ~elllp~;ld~
To visualize the effects of the compounds of the invention on the microtubule cytoCL~I~tnn, the cells were processed for tubulin i.. ,.. l~oflnorescence Briefly, the cells were permeabili7~ in 0.5% Triton-X 100 in PBS for 5 min. The cells were washed 2x with PBS and aldehydes reduced using 0.5 mglml NaBH4 in PBS for 5 min. Subsequently, the cells were 25 blocked for 10 min in 1.5% BSA and 1.5 % nonfat dry milk in PBS (blocking solution, BS) for 10 min. The cells were then incllha~ecl for 30 min at 37 C with the mnnnelon~l antibody Tu27B
which recognizes b-tubulin (dilution 1:20 in BS). Subseu~u~,~ltly, the cells were washed 2x in PBS and once in BS. The cells were then incub~te~ for 30 rnin at 37 C with sheep an~ luuse IgG cûnjug~l~d to FITC. After in~ubation, the cells were washed 2x in PBS and once in BS and Sl~STITUTE SHEET (RULE 26) inCllb~t~A for 30 min at 37 C with rabbit antisheep IgG conjugated to ~llC. The cells were rinsed in PBS, cuu~ a~illcd with Hoechst 33285 in PBS (1 ~g/ml). and rinsed in PBS. The co~ ,s were . . ,.,u..l~ in g: 1 glycerol:PBS cr)~ g 1 mg/ml p-phenylel~e~ " ,; "e and sealed with nail polish.
S The cells were viewed using a Jen~ium~r epifluo~esc.,.. ec mi~_lu~co~e c~lui~ed with the proper filters for Flllol~,scc;ll Tcothiocyanate (FlTC) eycit~tinn and c . "i~ Lack of effect of a cu~ vulld is evidenced by the ~ sc~nce of an intact microtubule network in ir~ hase cells, or a mitotic spindle in dividing cells. Antineoplastic col.~ .ric of the invention at effective doses result in the di~a~ e of llli~;lu~ r c in both inte~ ase and mitotic cells.
The results of s.;l.,.,.li"g of cclll~uullds of the invention are shown in Table 3. Shown for co...l~.vtive ~ul~oSes iS vinbl~cttne ("Velban", Lilly Research La~lalolics), a clinir~lly useful amill~lastic agent which ~lulll~t~ microtubule rl~st~hili7~tir~n, hence llli~;lu~ubllle iic~ccr.mhly.
Al~ f.clulubllleActivity C JQ. ~ 1 "~l1 r F~mrle # ~M)
9 20 SUBSTITUTE Sl-IEET (RULE 26) vinhl~ctin~. 0 05 - * a CQ~e .~ 1;orl where ,l.icluLui,,lle ~st~hili7~tion occurs As shown in Table 3, the compounds of the present invention ~ ol~; microtubule iest~i1i7~tion and thus are useful in the ~ L~ nl of neoplastic lic~c~s 5FY~rnrl~o 119 ,~ntih~rt~ri~l Activity Assay The co~ .oullds of the present invention are also effective antibacterial and antifungal agents.
The activity of the colllyounds is de~ n;ne~ using the following assay. The colllyound
The activity of the colllyounds is de~ n;ne~ using the following assay. The colllyound
10 is dissolved in DMSO at a concentration of 6 mg/ml and then diluted with water to a final corlcentr~tion of 3 mglml in 50% DMSO (% DMSO was shown not to be inhihitnry to the test org~nicmc). An aliquot (0.08 ml) of each drug solution was transferred to filter paper discs (12.7 mm diameter, Scmeicherand Schuell) for use in the agar diffusion assay. The CQnt~ 1 ;nn of each drug on the filter paper disc was 240 ug/disc. The test ol~liSll~
15 the following: Gram-positive aerobes (Staphylococcus aureus SRI 1323, Streptococcus pneu~noniae SRI 1167); Gram-negative ærobe (Proteus vulgaris SR~ 180); and the yeast Candida albicans S~ 523. An agar disc diffusion assay was used to evaluate the ~ntimicrobial activity of the test compounds. Briefly, cultures were prepared from 16-20 hr agar slant cultures by in~nl~ting in phyc~ ogir~l saline to a turbidity equivalent to a #0.5 McF~land turbidity ~ d~d 20 for the bacteria and a #3 McFarland st~n~rd for C. albicans. The surface of Mueller-Hinton agar (lSxlOO mrn plates, mm) were evenly inoculated with each stand~di~d culture using a cotton swab. Filter paper discs cont~ining the drug concentration listed above were then placed on the inocul~ted agar plates along with a disc co..~ g the solvent used to dissolve each drug. The plates were incubat~osi at 37 C for about 24 hr and the fli~meters of the zones of inhibition 25 lllea~ul~d with a vernier caliper. Positive control drugs consisted of ~ ycin for use with the bacterial strains and 5-fluor~yL~sille for use with C. albicans. The positive control drugs were assayed as described above for the cu.l~you~lds of the present invention using the same SUBSTITUTE SHEET (RULE 2~) CA 0220~86 1997-0~-16 concen-ration. Results of screeing a lc~ ,e,.Lative sample of the co~ ounds of the present invention are shown in Table 4.
-8~
SUBSTITUTE SHEET (RULE 2c) CA 0220~86 1997-0~-16 WO 96/16052 PCrrUS95/14987 Table 4 AIlLuluulubial and filngi~l activity Di~ll~.,. of the zone of inhibirit-n (mm) ExamDle # P. vulRaris S. pneu~noniae S. aureus C. albicans 17.3 29.9 22.817.6 =-21 o1 40.7 33.826.6 16.0 36.3 27.526.0 43 15.9 25.3 17.722.5 76 20.5 35.5 19.320.9 78 14.5 19.7 16.215.2 13.8 +2 17.214.5 86 13.9 19.3 16.217.3 sLIc~ nlJycill 37.6 39.8 28.4ND3 5-fluorocvtosine ND ND ND 33.5 no IllF~ Ahle zone of inhihi*on a~.~und the disc.
2 zone of inhihition too large to 111~7U~C.
3 not ~1f ~ .rrl As is shown in Table 4, the colll~ounds of the present invention inhibit growth and proliferation of Gram positive and Grarn-negative or~nicmc to a degree similar to that ~e~ c(lal~d by the known thr~ c"~ ly useful agent sL~ L~ Iy-;ill. These co~ ou-lds also inhibit growth and proliferation of C. albicans to a degree similar to that dem~nctrated by the therapeutically useful 5-fluorocytosine. Therefore, the compounds are therapeutically useful antibacterial andlor ~ntifilng~1 agents.
The foregoing is merely illustrative of the invention and is not intencled to limit the 15 invention to the ~liccloserl co,llpoullds. From the Ço.~going, it will be appreciated that although specific embo l;...~...t~ of the invention have been described herein for pu-~uOses of illustration, vatious i..~;r;-.~lir)nC may be made without deviating from the spirit or scope of the invention.
~ , .
SUBSTITUTE SHEET (RULE 26)
15 the following: Gram-positive aerobes (Staphylococcus aureus SRI 1323, Streptococcus pneu~noniae SRI 1167); Gram-negative ærobe (Proteus vulgaris SR~ 180); and the yeast Candida albicans S~ 523. An agar disc diffusion assay was used to evaluate the ~ntimicrobial activity of the test compounds. Briefly, cultures were prepared from 16-20 hr agar slant cultures by in~nl~ting in phyc~ ogir~l saline to a turbidity equivalent to a #0.5 McF~land turbidity ~ d~d 20 for the bacteria and a #3 McFarland st~n~rd for C. albicans. The surface of Mueller-Hinton agar (lSxlOO mrn plates, mm) were evenly inoculated with each stand~di~d culture using a cotton swab. Filter paper discs cont~ining the drug concentration listed above were then placed on the inocul~ted agar plates along with a disc co..~ g the solvent used to dissolve each drug. The plates were incubat~osi at 37 C for about 24 hr and the fli~meters of the zones of inhibition 25 lllea~ul~d with a vernier caliper. Positive control drugs consisted of ~ ycin for use with the bacterial strains and 5-fluor~yL~sille for use with C. albicans. The positive control drugs were assayed as described above for the cu.l~you~lds of the present invention using the same SUBSTITUTE SHEET (RULE 2~) CA 0220~86 1997-0~-16 concen-ration. Results of screeing a lc~ ,e,.Lative sample of the co~ ounds of the present invention are shown in Table 4.
-8~
SUBSTITUTE SHEET (RULE 2c) CA 0220~86 1997-0~-16 WO 96/16052 PCrrUS95/14987 Table 4 AIlLuluulubial and filngi~l activity Di~ll~.,. of the zone of inhibirit-n (mm) ExamDle # P. vulRaris S. pneu~noniae S. aureus C. albicans 17.3 29.9 22.817.6 =-21 o1 40.7 33.826.6 16.0 36.3 27.526.0 43 15.9 25.3 17.722.5 76 20.5 35.5 19.320.9 78 14.5 19.7 16.215.2 13.8 +2 17.214.5 86 13.9 19.3 16.217.3 sLIc~ nlJycill 37.6 39.8 28.4ND3 5-fluorocvtosine ND ND ND 33.5 no IllF~ Ahle zone of inhihi*on a~.~und the disc.
2 zone of inhihition too large to 111~7U~C.
3 not ~1f ~ .rrl As is shown in Table 4, the colll~ounds of the present invention inhibit growth and proliferation of Gram positive and Grarn-negative or~nicmc to a degree similar to that ~e~ c(lal~d by the known thr~ c"~ ly useful agent sL~ L~ Iy-;ill. These co~ ou-lds also inhibit growth and proliferation of C. albicans to a degree similar to that dem~nctrated by the therapeutically useful 5-fluorocytosine. Therefore, the compounds are therapeutically useful antibacterial andlor ~ntifilng~1 agents.
The foregoing is merely illustrative of the invention and is not intencled to limit the 15 invention to the ~liccloserl co,llpoullds. From the Ço.~going, it will be appreciated that although specific embo l;...~...t~ of the invention have been described herein for pu-~uOses of illustration, vatious i..~;r;-.~lir)nC may be made without deviating from the spirit or scope of the invention.
~ , .
SUBSTITUTE SHEET (RULE 26)
Claims (54)
1. A compound of the formula:
or the pharmaceutically acceptable salts thereof wherein X represents carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl;
Z is nitrogen or CH with the proviso that when Ar1 is phenyl or substituted phenyl Z is nitrogen;
Ar1 is a group of the formula:
wherein R1, R2 and R3 independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl. amino, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy, optionally substituted phenylsulfide, provided that R1, R2 and R3 are not all hydrogen; or two of R1, R2 and R3 taken together can form an ethylenedioxy, ethyleneoxy. or a lower straight alkylene chain alkyl bridge of 3-5 atoms optionally substituted by loweralkyl; or R1, R2 and R3 are the same or different and represent a group of the formula:
; or Ar1 is a group of the formula:
or wherein X2 is oxygen or sulfur;
R5 is hydrogen, halo, loweralkyl, loweralkoxy or thioloweralkoxy;
R6 is hydrogen, halo or loweralkyl;
R7 is hydrogen, lowerakyl, halo, nitro, cyano, optionally substituted thienyl, optionally substituted phenyl morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl;
R8 is loweralkyl or phenyl;
R9 and R10 are independently selected from hydrogen, halo, loweralkoxy, hydroxy;
R14 is selected from hydrogen, loweralkyl, nitro or halo;
R19 and R20 are independently selected from hydrogen, loweralkyl, halo, nitro, or optianally substituted phenyl;
R21 is hydrogen, loweralkyl, nitro, halo, cyano phenyl, thienyl or phenylethynyl;
R22 is hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;
R23 is hydrogen or loweralkyl, R24 is hydragen; or when Y is othler than hydrogen R24 is hydrogen, loweralkyl, or optionally substituted phenyl;
R25 is hydrogen, loweralkyl or thioalkoxy;
R26 is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyl; and R27, is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyl; and R28 is hydrogen, optionally substituted phenyl, loweralkyl, or optionally substituted thienyl; and R29 is hydrogen, nitro, or loweralkyl; and provided that R7, R14 and R29 are not all hydrogen; and provided that R23 and R28 are not both hydrogen; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo. trifluoromethyl, nitro, cyano, acetyl, loweralkoxy thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge, or Ar2 is naphthyl, optionally substituted thienyl, furyl, 1,2,3-thiadiazolyl. or a group of the formula:
wherein each R4 independently represents hydrogen, halo, or loweralkyl;
R13 is hydrogen or halo; and Y is hydrogen, or Y and R1. R2, R3, R19, R20, R22, R23, or R29 together represent CH2, C(R24)2CH2, C(R24)2 0, or C(R24)2S forming a five or six membered ring.
or the pharmaceutically acceptable salts thereof wherein X represents carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl;
Z is nitrogen or CH with the proviso that when Ar1 is phenyl or substituted phenyl Z is nitrogen;
Ar1 is a group of the formula:
wherein R1, R2 and R3 independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl. amino, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy, optionally substituted phenylsulfide, provided that R1, R2 and R3 are not all hydrogen; or two of R1, R2 and R3 taken together can form an ethylenedioxy, ethyleneoxy. or a lower straight alkylene chain alkyl bridge of 3-5 atoms optionally substituted by loweralkyl; or R1, R2 and R3 are the same or different and represent a group of the formula:
; or Ar1 is a group of the formula:
or wherein X2 is oxygen or sulfur;
R5 is hydrogen, halo, loweralkyl, loweralkoxy or thioloweralkoxy;
R6 is hydrogen, halo or loweralkyl;
R7 is hydrogen, lowerakyl, halo, nitro, cyano, optionally substituted thienyl, optionally substituted phenyl morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl;
R8 is loweralkyl or phenyl;
R9 and R10 are independently selected from hydrogen, halo, loweralkoxy, hydroxy;
R14 is selected from hydrogen, loweralkyl, nitro or halo;
R19 and R20 are independently selected from hydrogen, loweralkyl, halo, nitro, or optianally substituted phenyl;
R21 is hydrogen, loweralkyl, nitro, halo, cyano phenyl, thienyl or phenylethynyl;
R22 is hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;
R23 is hydrogen or loweralkyl, R24 is hydragen; or when Y is othler than hydrogen R24 is hydrogen, loweralkyl, or optionally substituted phenyl;
R25 is hydrogen, loweralkyl or thioalkoxy;
R26 is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyl; and R27, is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyl; and R28 is hydrogen, optionally substituted phenyl, loweralkyl, or optionally substituted thienyl; and R29 is hydrogen, nitro, or loweralkyl; and provided that R7, R14 and R29 are not all hydrogen; and provided that R23 and R28 are not both hydrogen; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo. trifluoromethyl, nitro, cyano, acetyl, loweralkoxy thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge, or Ar2 is naphthyl, optionally substituted thienyl, furyl, 1,2,3-thiadiazolyl. or a group of the formula:
wherein each R4 independently represents hydrogen, halo, or loweralkyl;
R13 is hydrogen or halo; and Y is hydrogen, or Y and R1. R2, R3, R19, R20, R22, R23, or R29 together represent CH2, C(R24)2CH2, C(R24)2 0, or C(R24)2S forming a five or six membered ring.
2 A compound of the formula:
or the pharmaceutically acceptable salts thereof wherein X represents carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl;
Ar1 is a group of the formula;
wherein R1, R2 and R3 independently represent hydrogen, phenyl, nitro. trifluoroalkyl, thioloweralkoxy, cyclohexyl, amino, acetyl, morpholino. cyano, piperidinyl, trifluoroalkoxy, arylsulfonylamino. alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy. optionally substituted phenylsulfide, provided that R1, R2 and R3 are not all hydrogen; or two of R1, R2 and R3 taken together can form an ethylenedioxy, ethyleneoxy, or a lower straight alkylene chain alkyl bridge of 3-5 atoms optionally substituted by loweralkyl; or R1, R2 and R3 are the same or different and represent a group of the formula:
; or wherein R24 is hydrogen; or when Y is other than hydrogen R24 is hydrogen, loweralkyl, or optionally substituted phenyl;
Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo. trifluoromethyl.
nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;
or R11 and R1 together form a methylenedioxy or ethylenedioxy bridge; or AR2 is naphthyl, optionally substituted thienyl, furyl, 1,2,3-thiadiazolyl. or a group the formula:
wherein R4 independently represents hydrogen. halo. or loweralkyl;
R13 is selected from hydrogen or halo; and Y is hydrogen, or Y and R1, R2, or R3, together represent CH2; C(R24)2CH2;
C(R24)2 0; or C(R24)2S forming a five or six membered ring.
or the pharmaceutically acceptable salts thereof wherein X represents carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl;
Ar1 is a group of the formula;
wherein R1, R2 and R3 independently represent hydrogen, phenyl, nitro. trifluoroalkyl, thioloweralkoxy, cyclohexyl, amino, acetyl, morpholino. cyano, piperidinyl, trifluoroalkoxy, arylsulfonylamino. alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy. optionally substituted phenylsulfide, provided that R1, R2 and R3 are not all hydrogen; or two of R1, R2 and R3 taken together can form an ethylenedioxy, ethyleneoxy, or a lower straight alkylene chain alkyl bridge of 3-5 atoms optionally substituted by loweralkyl; or R1, R2 and R3 are the same or different and represent a group of the formula:
; or wherein R24 is hydrogen; or when Y is other than hydrogen R24 is hydrogen, loweralkyl, or optionally substituted phenyl;
Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo. trifluoromethyl.
nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;
or R11 and R1 together form a methylenedioxy or ethylenedioxy bridge; or AR2 is naphthyl, optionally substituted thienyl, furyl, 1,2,3-thiadiazolyl. or a group the formula:
wherein R4 independently represents hydrogen. halo. or loweralkyl;
R13 is selected from hydrogen or halo; and Y is hydrogen, or Y and R1, R2, or R3, together represent CH2; C(R24)2CH2;
C(R24)2 0; or C(R24)2S forming a five or six membered ring.
3. A compound of the formula:
or the pharmaceutically acceptable salts thereof wherein X represents carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl;
Z is nitrogen or CH;
Ar1 is a group of the formula:
or wherein X2 is oxygen or sulfur;
R5 is hydrogen, halo, loweralkyl, lowerlkoxy or thioloweralkoxy;
R6 is hydrogen, halo, or loweralkyl;
R7 is hydrogen, lowerakyl, halo, nitro, cyano, optionally substituted thienyl, optionally substituted phenyl morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl. optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl;
R8 is loweralkyl or phenyl;
R9 and R10 are independently selected from hydrogen, halo, loweralkoxy, hydroxy;
R14 is selected from hydrogen, loweralkyl, nitro or halo;
R19 and R20 are independently selected from hydrogen, loweralkyl, halo, nitro.
or optionally substituted phenyl;
R21 is hydrogen, loweralkyl, nitro, halo, cyano, phenyl, thienyl, or phenylethynyl;
R22 is hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;
R23 is hydrogen or loweralkyl, R24 is hydrogen; or when Y is other than hydrogen R24 is hydrogen, loweralkyl, or optionally substituted phenyl;
R25 is hydrogen, loweralkyl or thioalkoxy;
R26 is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyl; and R27 is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyi; and R28 is hydrogen, optionally substituted phenyl, loweralkyl, or optionally substituted thienyl; and R29 is hydrogen, nitro, or loweralkyl; and provided that R7, R14 and R29 cannot simultaneously be hydrogen; and provided that R23 and R28 cannot simultaneously be hydrogen, and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge; or Ar2 is naphthyl, optionally substituted thienyl, furyl 1,2,3-thiadiazolyl, or a group of the formula:
wherein R4 independently represents hydrogen. halo, or loweralkyl;
R13 is selected from hydrogen or halo; and Y is hydrogen, or Y and R19, R20, R22, R23, or R29 together represent CH2;
C(R24)2CH2; C(R24)2 0; or C(R24)2S forming a five or six membered ring.
or the pharmaceutically acceptable salts thereof wherein X represents carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl;
Z is nitrogen or CH;
Ar1 is a group of the formula:
or wherein X2 is oxygen or sulfur;
R5 is hydrogen, halo, loweralkyl, lowerlkoxy or thioloweralkoxy;
R6 is hydrogen, halo, or loweralkyl;
R7 is hydrogen, lowerakyl, halo, nitro, cyano, optionally substituted thienyl, optionally substituted phenyl morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl. optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl;
R8 is loweralkyl or phenyl;
R9 and R10 are independently selected from hydrogen, halo, loweralkoxy, hydroxy;
R14 is selected from hydrogen, loweralkyl, nitro or halo;
R19 and R20 are independently selected from hydrogen, loweralkyl, halo, nitro.
or optionally substituted phenyl;
R21 is hydrogen, loweralkyl, nitro, halo, cyano, phenyl, thienyl, or phenylethynyl;
R22 is hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;
R23 is hydrogen or loweralkyl, R24 is hydrogen; or when Y is other than hydrogen R24 is hydrogen, loweralkyl, or optionally substituted phenyl;
R25 is hydrogen, loweralkyl or thioalkoxy;
R26 is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyl; and R27 is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyi; and R28 is hydrogen, optionally substituted phenyl, loweralkyl, or optionally substituted thienyl; and R29 is hydrogen, nitro, or loweralkyl; and provided that R7, R14 and R29 cannot simultaneously be hydrogen; and provided that R23 and R28 cannot simultaneously be hydrogen, and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge; or Ar2 is naphthyl, optionally substituted thienyl, furyl 1,2,3-thiadiazolyl, or a group of the formula:
wherein R4 independently represents hydrogen. halo, or loweralkyl;
R13 is selected from hydrogen or halo; and Y is hydrogen, or Y and R19, R20, R22, R23, or R29 together represent CH2;
C(R24)2CH2; C(R24)2 0; or C(R24)2S forming a five or six membered ring.
4. A compound of the formula;
wherein X represents carbonyl, sulfonyl, or methylene;
Z is nitrogen or CH with the proviso that when Ar1 is phenyl or substituted phenyl Z is nitrogen;
AR1 is a group of the formula:
wherein R1, R2 and R3 independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, aminoacetyl morpholino, cyano. piperidinyl, trifluoroalkoxy, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenylamino, optionally substituted phenoxy, optionally substituted phenylsulfide; provided that R1, R2 and R3 are not all hydrogen; or Ar1 is a group of the formula:
or wherein R6 is hydrogen, halo, or loweralkyl;
R9 and R10 are independently selected from hydrogen, halo, loweralkoxy, hydroxy; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, amino, nitro, cyano, acetyl, thioloweralkoxy, loweralkyl, or taken together form a methylenedioxy bridge.
wherein X represents carbonyl, sulfonyl, or methylene;
Z is nitrogen or CH with the proviso that when Ar1 is phenyl or substituted phenyl Z is nitrogen;
AR1 is a group of the formula:
wherein R1, R2 and R3 independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, aminoacetyl morpholino, cyano. piperidinyl, trifluoroalkoxy, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenylamino, optionally substituted phenoxy, optionally substituted phenylsulfide; provided that R1, R2 and R3 are not all hydrogen; or Ar1 is a group of the formula:
or wherein R6 is hydrogen, halo, or loweralkyl;
R9 and R10 are independently selected from hydrogen, halo, loweralkoxy, hydroxy; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, amino, nitro, cyano, acetyl, thioloweralkoxy, loweralkyl, or taken together form a methylenedioxy bridge.
5. A compound of the formula:
wherein R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro. cyano, acetyl, amino, thioloweralkoxy, loweralkyl, or taken together form a methylenedioxy bridge;
Ar1 is a group of the formula:
wherein R1. R2 and R3 independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, acetyl, amino, morpholino, cyano, piperidinyl, loweralkyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazo1e, optionally substituted phenoxy optionally substituted phenylsulfide, provided that R1, R2 and R3 are not all hydrogen; or R1, R2 and R3 are the same or different and represent a group of the formula:
wherein R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro. cyano, acetyl, amino, thioloweralkoxy, loweralkyl, or taken together form a methylenedioxy bridge;
Ar1 is a group of the formula:
wherein R1. R2 and R3 independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, acetyl, amino, morpholino, cyano, piperidinyl, loweralkyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazo1e, optionally substituted phenoxy optionally substituted phenylsulfide, provided that R1, R2 and R3 are not all hydrogen; or R1, R2 and R3 are the same or different and represent a group of the formula:
6. A compound of the formula;
wherein R1 and R2 are independently selected from hydrogen, nitro, iodo. or fluoro; provided that R1 and R2 are not both hydrogen; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, nitro; or optionally substituted thienyl groups.
wherein R1 and R2 are independently selected from hydrogen, nitro, iodo. or fluoro; provided that R1 and R2 are not both hydrogen; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, nitro; or optionally substituted thienyl groups.
7. A compound of the formula:
wherein Rl represents hydrogen, loweralkyl, halogen, cyano, nitro, optionally substituted thienyl, optionally substituted phenyl, morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperinyl, or optionally substituted phenylcarbonylpiperazinyl; and R2 is hydrogen, nitro, loweralkyl or halogen; and R3 is hydrogen, nitro, or loweralkyl; and provided that R1, R2 and R3 are not all hydrogen; and Ar2 represents thienyl, phenyl or phenyl mono or disubstituted with halogen. cyano, nitro, loweralkyl, or loweralkoxy groups; or Ar2 is a group of the formula:
wherein R4 and R5 are independently selected from hydrogen, halo, or loweralkyl groups.
wherein Rl represents hydrogen, loweralkyl, halogen, cyano, nitro, optionally substituted thienyl, optionally substituted phenyl, morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperinyl, or optionally substituted phenylcarbonylpiperazinyl; and R2 is hydrogen, nitro, loweralkyl or halogen; and R3 is hydrogen, nitro, or loweralkyl; and provided that R1, R2 and R3 are not all hydrogen; and Ar2 represents thienyl, phenyl or phenyl mono or disubstituted with halogen. cyano, nitro, loweralkyl, or loweralkoxy groups; or Ar2 is a group of the formula:
wherein R4 and R5 are independently selected from hydrogen, halo, or loweralkyl groups.
8. A compound of the formula:
wherein X represents methylene, carbonyl or sulfonyl;
R1 represents halogen, loweralkyl, nitro or cyano; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, or nitro groups.
wherein X represents methylene, carbonyl or sulfonyl;
R1 represents halogen, loweralkyl, nitro or cyano; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, or nitro groups.
9. A compound of the formula:
wherein R1 and R2 are independently selected from hydrogen, halogen, loweralkyl, nitro, or optionally substituted phenyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.
wherein R1 and R2 are independently selected from hydrogen, halogen, loweralkyl, nitro, or optionally substituted phenyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.
10. A compound of the formula:
wherein R1 represents hydrogen, optionally substituted phenyl, carbomethoxy or loweralkyl; and R2 hydrogen, or loweralkyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl.
loweralkoxy or nitro groups.
wherein R1 represents hydrogen, optionally substituted phenyl, carbomethoxy or loweralkyl; and R2 hydrogen, or loweralkyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl.
loweralkoxy or nitro groups.
11. A compound of the formula:
wherein R1 represents hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy, or nitro groups.
wherein R1 represents hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy, or nitro groups.
12. A compound of the formula:
wherein X represents carbonyl or sulfonyl; and Ar1 is a group of the formula:
wherein R1, R2 and R3 independently represent hydrogen, fluorine, iodine, phenyl, nitro,trifluoroalkyl, thioloweralkoxy, cyclohexyl, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy, optionally substituted phenylsulfide, provided that R1, R2 and R3 are not all hydrogen; andAr2 represents, phenyl or phenyl mono or disubstituted with halogen, cyano, or nitro groups; or Ar2 is a group of the formula:
wherein R4 independently represents hydrogen, halo, or loweralkyl;
wherein X represents carbonyl or sulfonyl; and Ar1 is a group of the formula:
wherein R1, R2 and R3 independently represent hydrogen, fluorine, iodine, phenyl, nitro,trifluoroalkyl, thioloweralkoxy, cyclohexyl, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy, optionally substituted phenylsulfide, provided that R1, R2 and R3 are not all hydrogen; andAr2 represents, phenyl or phenyl mono or disubstituted with halogen, cyano, or nitro groups; or Ar2 is a group of the formula:
wherein R4 independently represents hydrogen, halo, or loweralkyl;
13. A compound of the formula:
wherein X represents carbonyl or sulfonyl;
R1 represents hydrogen, loweralkyl, halogen, nitro, or cyano; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano loweralkyl, loweralkoxy or nitro groups.
wherein X represents carbonyl or sulfonyl;
R1 represents hydrogen, loweralkyl, halogen, nitro, or cyano; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano loweralkyl, loweralkoxy or nitro groups.
14. A compound of the formula:
wherein X represents carbonyl or sulfonyl;
R1 represents hydrogen, loweralkyl, halogen, cyano, nitro, optionally substituted thienyl, optionally substituted phenyl, morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl; and R2 is hydrogen, nitro, loweralkyl or halogen; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.
wherein X represents carbonyl or sulfonyl;
R1 represents hydrogen, loweralkyl, halogen, cyano, nitro, optionally substituted thienyl, optionally substituted phenyl, morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl; and R2 is hydrogen, nitro, loweralkyl or halogen; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.
15. A compound of the formula;
wherein X represents carbonyl or sulfonyl; and Ar1 is a group of the formula:
or or wherein R1 and R2 independently represent hydrogen, halogen, nitro, cyano, phenyl, or loweralkyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, or nitro groups; or thienyl or thienyl optionally substituted with halo, loweralkyl, cyano or nitro groups.
wherein X represents carbonyl or sulfonyl; and Ar1 is a group of the formula:
or or wherein R1 and R2 independently represent hydrogen, halogen, nitro, cyano, phenyl, or loweralkyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, or nitro groups; or thienyl or thienyl optionally substituted with halo, loweralkyl, cyano or nitro groups.
16. A compound of the formula;
wherein R1 and R2 independently represent hydrogen, halogen, cyano, loweralkoxy or loweralkyl groups.
wherein R1 and R2 independently represent hydrogen, halogen, cyano, loweralkoxy or loweralkyl groups.
17. A compound of the formula:
wherein R1 and R2 independently represent hydrogen, halogen, or loweralkyl groups.
wherein R1 and R2 independently represent hydrogen, halogen, or loweralkyl groups.
18. A compound of the formula:
wherein R1 and R2 independently represent hydrogen, halogen, or loweralkyl, or taken together form a methylenedioxy bridge.
wherein R1 and R2 independently represent hydrogen, halogen, or loweralkyl, or taken together form a methylenedioxy bridge.
19. A compound of the formula:
wherein Z is CH or nitrogen;
X is carbonyl, sulfonyi, or methylene;
M is CH2, C(RI)2CH2, C(R1)2O, or C(R1)2S;
R1 is hydrogen, loweralkyl, optionally substituted phenyl;
Ar2 is optionally substituted phenyl, optionally substituted thienyl, or furyl; and A re[resemts an aryl or heteroaryl ring having from zero to three hetero atoms selected from the group consisting of oxygen, sulfur or nitrogen.
wherein Z is CH or nitrogen;
X is carbonyl, sulfonyi, or methylene;
M is CH2, C(RI)2CH2, C(R1)2O, or C(R1)2S;
R1 is hydrogen, loweralkyl, optionally substituted phenyl;
Ar2 is optionally substituted phenyl, optionally substituted thienyl, or furyl; and A re[resemts an aryl or heteroaryl ring having from zero to three hetero atoms selected from the group consisting of oxygen, sulfur or nitrogen.
20. A compound selected from the group consisting of:
(a) 1-(p-Iodophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dibydrochloride;
(b) 1-(p-Fluorophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;(c) 1-(o-Fluorophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochlaride;(d) 1-(p-Iodophenyl)3-[4'-(o-fluorobenzyl)1'-piperazinyl]-1-propanone dihydrochloride;
(e) 1-(o-Fluorophenyl)-3-[4'-(o-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(f) 1-(o-Fluorophenyl)-3-[4'-(p-f1uorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(g) 1-(p-Fluorophenyl)-3 [4'-(p-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(h) 1-(m-Fluorophenyl)-3-[4'-(p-fluorobenzyl)-1'-piperazinyl]-l-propanone dihydrochloride, (i) 1-(p-Iodophenyl)-3-[4'-(p-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(j) 1-(6"-Fluoro-2-methylpheny])-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(k) 1-(m-Fluorophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;(l) 1-o-Iodophenyl-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride
(a) 1-(p-Iodophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dibydrochloride;
(b) 1-(p-Fluorophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;(c) 1-(o-Fluorophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochlaride;(d) 1-(p-Iodophenyl)3-[4'-(o-fluorobenzyl)1'-piperazinyl]-1-propanone dihydrochloride;
(e) 1-(o-Fluorophenyl)-3-[4'-(o-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(f) 1-(o-Fluorophenyl)-3-[4'-(p-f1uorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(g) 1-(p-Fluorophenyl)-3 [4'-(p-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(h) 1-(m-Fluorophenyl)-3-[4'-(p-fluorobenzyl)-1'-piperazinyl]-l-propanone dihydrochloride, (i) 1-(p-Iodophenyl)-3-[4'-(p-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(j) 1-(6"-Fluoro-2-methylpheny])-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(k) 1-(m-Fluorophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;(l) 1-o-Iodophenyl-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride
21. A compound selected from the group consisting of:
(a) 1-(2",3"-Dihydro-1",4"-benzodioxan-6"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(1".2",3",4"-Tetrahydronaphth-6"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(2",3"-Dihydro-1",4"-benzodioxan-6"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(1".2",3",4"-Tetrahydronaphth-6"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
22. A compound selected from the group consisting of;
(a) 1-(4"-Fluoronaphth-1"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-p-Biphenyl-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride:
(c) 1-(p-Cyclohexylphenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(Fluoren-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride:
(e) 1-(p-Methanesulfonamidophenyl)-3-(2",5"-difluorobenzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(m-Methanesulfonamidophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(g) 1-(4"-Methoxy-1"-naphthalenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(6'-Methoxy-2"-naphthalenyl)-3-(4'-benzyl-1-piperazinyl)-1-propanone dihydrochloride;
(i) 1-(Biphenylen-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone;
(j) 1-p-Phenylthiophenyl-3-(4'-benzyl-1'-piperazinyl)-3-propanone dihydrochloride.
(a) 1-(4"-Fluoronaphth-1"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-p-Biphenyl-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride:
(c) 1-(p-Cyclohexylphenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(Fluoren-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride:
(e) 1-(p-Methanesulfonamidophenyl)-3-(2",5"-difluorobenzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(m-Methanesulfonamidophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(g) 1-(4"-Methoxy-1"-naphthalenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(6'-Methoxy-2"-naphthalenyl)-3-(4'-benzyl-1-piperazinyl)-1-propanone dihydrochloride;
(i) 1-(Biphenylen-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone;
(j) 1-p-Phenylthiophenyl-3-(4'-benzyl-1'-piperazinyl)-3-propanone dihydrochloride.
23. A compound selected from the group consisting of;
(a) 1-(p-Nitrophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;(b) 1-(m-Nitrophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;(c) 1-(m-Nitrophenyl)-3-[4'-(p-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrocholoride;
(d) 1-(m-Nitrophenyl)-3-[4'-(o-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(e) 1-(p-Nitrophenyl)-3-[4'-(o-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride:
(f) 1-(p-Nitrophenyl)-3-[4'-(2",5"-difluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(g) 1-(p-Nitrophenyl)-3-[4'-(m-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(h) 1-(p-Nitrophenyl)-3-[4'-(p-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(i) 1-(p-Nitrophenyl)-3-[4'-{3",4"-difluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(j) 1-(o-Nitrophenyl)-3-(4'-benzyl-1-piperazinyl)-1-propanone dihydrochloride;
(l) 1-(p-Nitrophenyl)-3-(4'-piperonyl-1-piperazinyl)-1-propanone dihydrochloride;
(k) 1-(2"-Bromo-5"-nitrophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(l) 1-(3"-Nitrophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(p-Nitrophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;(b) 1-(m-Nitrophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;(c) 1-(m-Nitrophenyl)-3-[4'-(p-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrocholoride;
(d) 1-(m-Nitrophenyl)-3-[4'-(o-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(e) 1-(p-Nitrophenyl)-3-[4'-(o-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride:
(f) 1-(p-Nitrophenyl)-3-[4'-(2",5"-difluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(g) 1-(p-Nitrophenyl)-3-[4'-(m-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(h) 1-(p-Nitrophenyl)-3-[4'-(p-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(i) 1-(p-Nitrophenyl)-3-[4'-{3",4"-difluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(j) 1-(o-Nitrophenyl)-3-(4'-benzyl-1-piperazinyl)-1-propanone dihydrochloride;
(l) 1-(p-Nitrophenyl)-3-(4'-piperonyl-1-piperazinyl)-1-propanone dihydrochloride;
(k) 1-(2"-Bromo-5"-nitrophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(l) 1-(3"-Nitrophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
24. A compound selected from the group consisting of:
(a) 1-(p-Methylthiophenyl)-3 -(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(b) 1-[3",5"-Bis-(trifluoromethyl)phenyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(c) 1-(p-Trifluoromethoxyphenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(d) 1-[3"-(p-Chlorophenyl)sulfonamidophenyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(e) 1-(p-Methylthiophenyl)-3-(4'-(2",6"-difluorobenzyl)-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-[3",5"-Bis(trifluoroethoxy)phenyl}-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(p-Methylthiophenyl)-3 -(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(b) 1-[3",5"-Bis-(trifluoromethyl)phenyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(c) 1-(p-Trifluoromethoxyphenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(d) 1-[3"-(p-Chlorophenyl)sulfonamidophenyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(e) 1-(p-Methylthiophenyl)-3-(4'-(2",6"-difluorobenzyl)-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-[3",5"-Bis(trifluoroethoxy)phenyl}-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
25. A compound selected from the group consisting of:
(a) 1-(1"-Methyl-1"H-pyrazol-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(b) 1-(5"-Methyl-2"-furanyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone hydrochloride;
(c) 1-(2-Thiazolyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(N-Phenylsulfonylpyrrol-2-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(p-Nitrophenyl)-3-[4'-(4"-methyl-1",2",3"-thiadiaz-5"-oyl)]- 1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-[4'-(5''',4'''-Dichloroimidazol-1'''-yl)phenyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(g) 1-(5"-Methyl-3"-phenylisoxazol-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(5"-Methyl-3"-phenylisoxazol-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(i) 1-(2"-Phenylthiazol-4"-yl}3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(j) 1-(2",4"-Dimethylthiazol-5"-yl)-3-(4'-benzyl-1-piperazinyl)-1-propanone dihydroch1oride.
(a) 1-(1"-Methyl-1"H-pyrazol-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(b) 1-(5"-Methyl-2"-furanyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone hydrochloride;
(c) 1-(2-Thiazolyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(N-Phenylsulfonylpyrrol-2-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(p-Nitrophenyl)-3-[4'-(4"-methyl-1",2",3"-thiadiaz-5"-oyl)]- 1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-[4'-(5''',4'''-Dichloroimidazol-1'''-yl)phenyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(g) 1-(5"-Methyl-3"-phenylisoxazol-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(5"-Methyl-3"-phenylisoxazol-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(i) 1-(2"-Phenylthiazol-4"-yl}3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(j) 1-(2",4"-Dimethylthiazol-5"-yl)-3-(4'-benzyl-1-piperazinyl)-1-propanone dihydroch1oride.
26. A compound selected from the group consisting of:
(a) 1-(3"-Thienyl)3-[4'-[m-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(b) 1-(3"-Thienyl)3-[4'-(2''',5'''-difluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride.
(a) 1-(3"-Thienyl)3-[4'-[m-fluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(b) 1-(3"-Thienyl)3-[4'-(2''',5'''-difluorobenzyl)-1'-piperazinyl]-1-propanone dihydrochloride.
27. A compound selected from the group consisting of:
(a) 1-(p-Nitrophenyl)-3-(4'-(o-trifluoromethyl)benzoyl-1'-piperazinyl)-1-propanone;
(b) 1-(p-Nitrophenyl)-3-[4'-(2",6"-difluorobenzoyl)-1'-piperazinyl]-1-propanone hydrochloride;
(c) 1-(o-Fluorophenyl)-3-[4'-{2",6"-difluorobenzoyl)1'-piperazinyl]-1-propanone hydrochloride;
(d) 1-(o-Fluorophenyl)-3-[4'-(o-trifluoromethylbenzoyl)-1-piperazinyl]-1-propanone hydrochloride;
(e) 1-(p-Nitrophenyl)-3-(4'-o-fluorobenzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(p-Nitrophenyl)-3-[4'-(2",3"-difluorobenzoyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(g) 1-(2"-Chloro-3"-nitrothien-5"-yl)-3-(4'-o-trifluoromethylbenzoyl-1'-piperazinyl)-1-propanone dihydrochloride, (h) 1-{p-Nitrophenyl)-3-(4'-[4'''-methyl-1",2",3"-thiadiaz-5"-oyl]-1'-piperazinyl)-1-propanone dihydrochloride;
(i) 1-(5"-Chloro-4"-nitro-2"-thienyl)-3-[4'-(4'''-methyl-1'''.2''',3'''-thiadiaz-5'''-oyl)-1'-piperazinyl]-1-propanone dihydrochtoride;
(j) 1-(5"-Nitro-3"-thienyl)-3-(4'-o-fluorobenzoyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(k) 1-(5"-Bromo-2"-thienyl)-3-(4'-o- fluorobenzoyl-1'-piperazinyl)-1-propanone dihydrocholoride.
(a) 1-(p-Nitrophenyl)-3-(4'-(o-trifluoromethyl)benzoyl-1'-piperazinyl)-1-propanone;
(b) 1-(p-Nitrophenyl)-3-[4'-(2",6"-difluorobenzoyl)-1'-piperazinyl]-1-propanone hydrochloride;
(c) 1-(o-Fluorophenyl)-3-[4'-{2",6"-difluorobenzoyl)1'-piperazinyl]-1-propanone hydrochloride;
(d) 1-(o-Fluorophenyl)-3-[4'-(o-trifluoromethylbenzoyl)-1-piperazinyl]-1-propanone hydrochloride;
(e) 1-(p-Nitrophenyl)-3-(4'-o-fluorobenzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(p-Nitrophenyl)-3-[4'-(2",3"-difluorobenzoyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(g) 1-(2"-Chloro-3"-nitrothien-5"-yl)-3-(4'-o-trifluoromethylbenzoyl-1'-piperazinyl)-1-propanone dihydrochloride, (h) 1-{p-Nitrophenyl)-3-(4'-[4'''-methyl-1",2",3"-thiadiaz-5"-oyl]-1'-piperazinyl)-1-propanone dihydrochloride;
(i) 1-(5"-Chloro-4"-nitro-2"-thienyl)-3-[4'-(4'''-methyl-1'''.2''',3'''-thiadiaz-5'''-oyl)-1'-piperazinyl]-1-propanone dihydrochtoride;
(j) 1-(5"-Nitro-3"-thienyl)-3-(4'-o-fluorobenzoyl-1'-piperazinyl)-1-propanone dihydrocholoride;
(k) 1-(5"-Bromo-2"-thienyl)-3-(4'-o- fluorobenzoyl-1'-piperazinyl)-1-propanone dihydrocholoride.
28. A compound selected from the group consisting of;
(a) 1,4-Bis-[3'-(4"-benzyl-1"-piperazinyl)-propanoyl] benzene;
(b) 1-(p-Acetylphenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(8"-Acetylphenoxathiin-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanane dihydrochloride;
(d) 2,8-Bis-[3'-(4"-benzyl-1"-piperazinyl)propanoyl] phenoxathiin.
(a) 1,4-Bis-[3'-(4"-benzyl-1"-piperazinyl)-propanoyl] benzene;
(b) 1-(p-Acetylphenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(8"-Acetylphenoxathiin-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanane dihydrochloride;
(d) 2,8-Bis-[3'-(4"-benzyl-1"-piperazinyl)propanoyl] phenoxathiin.
29. A compound selected from the group consisting of:
(a) 1-(5"-Phenyl-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(5"-Bromo-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(5"-Chloro-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydroehloride;
(d) 1-(5"-Nitro-3"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(5"-[2'''-thienyl]-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(5"-Bromo-2"-thienyl)-3-(4'-o-fluorobenzyl-1'-piperazinyl)-1-propanone dihydrochloride, (g) 1-(5"-Cyano-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(5"-Chloro-4"-nitro-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride:
(i) 1-(5"-Methyl-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(5"-Phenyl-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(5"-Bromo-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(5"-Chloro-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydroehloride;
(d) 1-(5"-Nitro-3"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(5"-[2'''-thienyl]-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(5"-Bromo-2"-thienyl)-3-(4'-o-fluorobenzyl-1'-piperazinyl)-1-propanone dihydrochloride, (g) 1-(5"-Cyano-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(5"-Chloro-4"-nitro-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride:
(i) 1-(5"-Methyl-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
30. A comnpound selected from the group consisting of;
(a) 1-(5'''-Bromo-2'''-thienyl)-3-[4'-(2",6"-difluorobenzoyl)-1'-piperazinyl]-1-propanone hydrochloride;
(b) 1-(2"-Thienyl)-3-[4'-(o-fluorobenzoyl)-1'-piperazinyl]-1-propanone hydrochloride;
(c) 1-(5"-Bromo-2"-thienyl)-3-(4'-[2'''-chloro-6'''-methylpyrido-4'''-yl]-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(5'''-Bromo-2'''-thienyl)-3-[4'-(2",6"-difluorobenzoyl)-1'-piperazinyl]-1-propanone hydrochloride;
(b) 1-(2"-Thienyl)-3-[4'-(o-fluorobenzoyl)-1'-piperazinyl]-1-propanone hydrochloride;
(c) 1-(5"-Bromo-2"-thienyl)-3-(4'-[2'''-chloro-6'''-methylpyrido-4'''-yl]-1'-piperazinyl)-1-propanone dihydrochloride.
31. A compound selected from the group consisting of:
(a) 1-(p-N-Morpholinophenyl)-3-(4'-p-iodobenzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(p-N-Morpholinophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(p-N-Piperidinophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(p-N-Morpholinophenyl)-3-(4'-p-iodobenzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(p-N-Morpholinophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(p-N-Piperidinophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
32. A compound selected from the group consisting of:
(a) 1-(m-Cyanophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) l-(p-Cyanophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(m-Cyanophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) l-(p-Cyanophenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
33. A compound selected from the group consisting of;
(a) 1-(5"-Bromo-2"-thienyl)-3-[4'-(1'''-p-chlorophenyl-1'''-phenylmethyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(b) 1-(2"-Thienyl)-3-[4'-(1'''-p-chlorophenyl-1'''-phenylmethyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(c) 1-(p-Nitrophenyl)-3-[4'-(1"-p-chlorophenyl-1"-phenylmethyl)-1'-piperazinyl]-1-propanone dihydrochloride.
(a) 1-(5"-Bromo-2"-thienyl)-3-[4'-(1'''-p-chlorophenyl-1'''-phenylmethyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(b) 1-(2"-Thienyl)-3-[4'-(1'''-p-chlorophenyl-1'''-phenylmethyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(c) 1-(p-Nitrophenyl)-3-[4'-(1"-p-chlorophenyl-1"-phenylmethyl)-1'-piperazinyl]-1-propanone dihydrochloride.
34. A compound selected from the group consisting of;
(a) 1-(Benzofur-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;(b) 1-(5"-Chloro-3"-methylbenzo[b]-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(5'-Bromo-2"-thienyl)-3-[4'-(3'''-chlorobenzo[b]-2'''-thienoyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(d) 1-[5"-(Phenylethynyl)-2"-thienyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(Benzofur-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;(b) 1-(5"-Chloro-3"-methylbenzo[b]-2"-thienyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(5'-Bromo-2"-thienyl)-3-[4'-(3'''-chlorobenzo[b]-2'''-thienoyl)-1'-piperazinyl]-1-propanone dihydrochloride;
(d) 1-[5"-(Phenylethynyl)-2"-thienyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
35. A compound selected from the group consisting of:
(a) 3-(4'-Benzyl-1'-piperazinomethyl)-thiochroman-4-one dihydrochloride;
(b) 1-(6'-Bromocoumarin-3"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(6"-Bromocoumarin-3"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(Coumarin-3"-yl)-3-(4'-benzyl-1'-pipcerazinyl)-1-propanone dihydrochloride;
(e) 1-(Coumarin-3" yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 3-(4'-Benzyl-1'-piperazinomethyl)-thiochroman-4-one dihydrochloride;
(b) 1-(6'-Bromocoumarin-3"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(6"-Bromocoumarin-3"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(Coumarin-3"-yl)-3-(4'-benzyl-1'-pipcerazinyl)-1-propanone dihydrochloride;
(e) 1-(Coumarin-3" yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
36. A compound selected from the group consisting of:
(a) 1-(5"-Cyano-4"-methyl-2"-(methylthio)thien-3"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(5"-Cyano-4"-methyl-2"-(methylthio)thien-3"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(2",4"-Dichlorophenoxy)-phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(2",4"-Dichlorophenoxy)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(5'''-(2",4"-Difluorophenoxy)-fur-2'''-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(5'''-(2",4"-Difluorophenoxy)-fur-2'''-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(g) 1-(1",1"-Dimethyl-6"-tert-butylindan-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(1",1"-Dimethyl-6"-tert-butylindan-4"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(5"-Cyano-4"-methyl-2"-(methylthio)thien-3"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(5"-Cyano-4"-methyl-2"-(methylthio)thien-3"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(2",4"-Dichlorophenoxy)-phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(2",4"-Dichlorophenoxy)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(5'''-(2",4"-Difluorophenoxy)-fur-2'''-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(5'''-(2",4"-Difluorophenoxy)-fur-2'''-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(g) 1-(1",1"-Dimethyl-6"-tert-butylindan-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(1",1"-Dimethyl-6"-tert-butylindan-4"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
37. A compound selected from the group consisting of:
(a) 1-(2",3"-Dihydrobenzo[b]fur-5"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride:
(b) 1-(2",3"-Dihydrobenzo[b]fur-5"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanonedihydrochloride;
(c) 1-(3",5"-Dimethylbenzo[b]thien-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(3",5"-Dimethylbenzo[b]thien-2"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(2",4"-Dimethylthien.5"-yl)-3-(4'-benzyl-1-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(2",4"-Dimethylthien-5"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(2",3"-Dihydrobenzo[b]fur-5"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride:
(b) 1-(2",3"-Dihydrobenzo[b]fur-5"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanonedihydrochloride;
(c) 1-(3",5"-Dimethylbenzo[b]thien-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(3",5"-Dimethylbenzo[b]thien-2"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(2",4"-Dimethylthien.5"-yl)-3-(4'-benzyl-1-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(2",4"-Dimethylthien-5"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
38. A compound selected from the group consisting of:
(a) 1-(p-Phenylthio]phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(p-Phenylthio]phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(p-Phenylthio]phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(p-Phenylthio]phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
39. A compound selected from the group consisting of:
(a) 1-(3"-Methoxycarbonyl-5"-methylisoxazol-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(3"-Methoxycarbony1-5"-methylisoxazol-4"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(5"-(2'''-Carbomethoxythien-3'''-yl)-furan-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(5"-(2'''-Carbomethoxythien-3'''-yl)-furan-2"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(p-(4"-Methoxyphenoxy)-phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1 -(p-(4"-Methoxyphenoxy)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(3"-Methoxycarbonyl-5"-methylisoxazol-4"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(3"-Methoxycarbony1-5"-methylisoxazol-4"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(5"-(2'''-Carbomethoxythien-3'''-yl)-furan-2"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(5"-(2'''-Carbomethoxythien-3'''-yl)-furan-2"-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(p-(4"-Methoxyphenoxy)-phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1 -(p-(4"-Methoxyphenoxy)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
40. A compound selected from the group consisting of:
(a) 1-(p-(4"-Nitrophenoxy)-phenyl)-3-(4'-benzyl-1'piperazinyl)-1-propanone dihydrochloride;
(b) 1-(p-(4"-Nitrophenoxy)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(m-Nitro-p-(phenylthio)-phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(m-Nitro-p-(phenylthio)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(m-Nitro-p-(1"-piperidinyl)-phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(m-Nitro-p-(1"-piperidinyl)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(g) 1-(m-Nitro-p-(4"-morpholino)-pheny1)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(m-Nitro-p-(4"-morpholino)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(i) 1-(p-Nitrophenyl)-3-(4'-(5"-(1'''-methyl-3'''-trifluormethylpyrazol-5'''-yl)-thien-2"yl)-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(p-(4"-Nitrophenoxy)-phenyl)-3-(4'-benzyl-1'piperazinyl)-1-propanone dihydrochloride;
(b) 1-(p-(4"-Nitrophenoxy)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(m-Nitro-p-(phenylthio)-phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(d) 1-(m-Nitro-p-(phenylthio)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(e) 1-(m-Nitro-p-(1"-piperidinyl)-phenyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(f) 1-(m-Nitro-p-(1"-piperidinyl)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(g) 1-(m-Nitro-p-(4"-morpholino)-pheny1)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(h) 1-(m-Nitro-p-(4"-morpholino)-phenyl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride;
(i) 1-(p-Nitrophenyl)-3-(4'-(5"-(1'''-methyl-3'''-trifluormethylpyrazol-5'''-yl)-thien-2"yl)-1'-piperazinyl)-1-propanone dihydrochloride.
41. A compound selected from the group consisting of:
(a) 1-(2"-Thienyl)-3-(4'-benzyl-1'-piperidinyl)-1-propanone hydrochloride;
(b) 1-(5"-Bromo-2"-thienyl)-3-(4'-p-fluorobenzoyl-1'-piperidinyl)-1-propanone hydrochloride;
(c) 1-(4"-Nitro-2"-thienyl)-3-(4'-p-fluorobenzoyl-1'-piperidinyl)-1-propanone hydrochloride;
(d) 1-(5"-Bromo-2"-thienyl)-3-(4'-benzyl-1'-piperidinyl)-1-propanone hydrochloride;
(e) 1-(m-Nitrophenyl)-3-(4'-benzyl-1'-piperidinyl)-1-propanone hydrochloride.
(a) 1-(2"-Thienyl)-3-(4'-benzyl-1'-piperidinyl)-1-propanone hydrochloride;
(b) 1-(5"-Bromo-2"-thienyl)-3-(4'-p-fluorobenzoyl-1'-piperidinyl)-1-propanone hydrochloride;
(c) 1-(4"-Nitro-2"-thienyl)-3-(4'-p-fluorobenzoyl-1'-piperidinyl)-1-propanone hydrochloride;
(d) 1-(5"-Bromo-2"-thienyl)-3-(4'-benzyl-1'-piperidinyl)-1-propanone hydrochloride;
(e) 1-(m-Nitrophenyl)-3-(4'-benzyl-1'-piperidinyl)-1-propanone hydrochloride.
42. A compound selected from the group consisting of:
(a) 1-(p-Nitrophenyl)-3-(4'-benzenesulfonyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(5"-Bromo-2"-thienyl)-3-(4'-benzenesulfonyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(5"-Bromo-2"-thienyl)-3-(4'-p-bromobenzenesulfonyl-1'-piperazinyl)-1-propanone hydrochloride:
(d) 1-(5"-Bromo-2"-thienyl)-3-(4'-p-toluenesulfonyl-1'-piperazinyl)-1-propanone hydrochloride;
(e) 1-(p-Nitrophenyl)-3-(4'-p-bromobenzenesulfonyl-1'-piperaziny1)-1-propanone hydrochloride;
(f) 1-(p-Nitropheny1)-3-(4'-p-toluenesulfonyl-1'-piperazinyl)-1-propanone hydrochloride;
(g) 1-(5"-Chloro-4"-nitro-2"-thienyl)-3-(4'-benzenesulfonyl-1'-piperazinyl)-1-propanone hydrochloride.
(a) 1-(p-Nitrophenyl)-3-(4'-benzenesulfonyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(5"-Bromo-2"-thienyl)-3-(4'-benzenesulfonyl-1'-piperazinyl)-1-propanone dihydrochloride;
(c) 1-(5"-Bromo-2"-thienyl)-3-(4'-p-bromobenzenesulfonyl-1'-piperazinyl)-1-propanone hydrochloride:
(d) 1-(5"-Bromo-2"-thienyl)-3-(4'-p-toluenesulfonyl-1'-piperazinyl)-1-propanone hydrochloride;
(e) 1-(p-Nitrophenyl)-3-(4'-p-bromobenzenesulfonyl-1'-piperaziny1)-1-propanone hydrochloride;
(f) 1-(p-Nitropheny1)-3-(4'-p-toluenesulfonyl-1'-piperazinyl)-1-propanone hydrochloride;
(g) 1-(5"-Chloro-4"-nitro-2"-thienyl)-3-(4'-benzenesulfonyl-1'-piperazinyl)-1-propanone hydrochloride.
43. A compound selected from the group consisting of:
(a) 1-[5"-Cyano-4"-methyl-2"-(methylthio)-3"-thienyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(2",4"-Dimethyl-5"-thiazolyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanonedihydrochloride.
(a) 1-[5"-Cyano-4"-methyl-2"-(methylthio)-3"-thienyl]-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride;
(b) 1-(2",4"-Dimethyl-5"-thiazolyl)-3-(4'-benzyl-1'-piperazinyl)-1-propanonedihydrochloride.
44. A compound of the formula:
or the pharmaceutically acceptable salts thereof wherein X represents carbonyl, methylene, or methylene substituted with optionally substituted phenyl;
Ar1 is a group of the formula:
or R22 is hydrogen, carbomethoxy. optionally substituted phenyl or loweralkyl;
R23 is hydrogen or loweralkyl; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge; or Ar2 is naphthyl.
or the pharmaceutically acceptable salts thereof wherein X represents carbonyl, methylene, or methylene substituted with optionally substituted phenyl;
Ar1 is a group of the formula:
or R22 is hydrogen, carbomethoxy. optionally substituted phenyl or loweralkyl;
R23 is hydrogen or loweralkyl; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge; or Ar2 is naphthyl.
45. A compound of the formula:
or the pharmaceutically acceptable salts thereof wherein Ar1 is a group of the formula:
R22 is hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;
R12 is hydrogen or loweralkyl; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy. thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge, or Ar2 is naphthyl.
or the pharmaceutically acceptable salts thereof wherein Ar1 is a group of the formula:
R22 is hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;
R12 is hydrogen or loweralkyl; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy. thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge, or Ar2 is naphthyl.
46. A compound of the formula:
or the pharmaceutically acceptable salts thereof wherein Ar1 is a group of the formula:
R22 is hydrogen, carbomethoxyt optionally substituted phenyl or loweralkyl;
R23 is hydrogen or loweralkyl; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge: or Ar2 is naphthyl.
or the pharmaceutically acceptable salts thereof wherein Ar1 is a group of the formula:
R22 is hydrogen, carbomethoxyt optionally substituted phenyl or loweralkyl;
R23 is hydrogen or loweralkyl; and Ar2 is a group of the formula:
where R11 and R12 independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;
or R11 and R12 together form a methylenedioxy or ethylenedioxy bridge: or Ar2 is naphthyl.
47. A compound according to Claim 14, which is 1-(3''-Phenylisoxazo1-5"-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride.
48. A compound according to Claim 44 which is selected from the group consisting of:
(a) 1-(3"-Methoxycarbonyl-5"-methylisoxazol-4''-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride; and (b) 1-(3"-Methoxycarbonyl-5''-methylisoxazol-4''-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
(a) 1-(3"-Methoxycarbonyl-5"-methylisoxazol-4''-yl)-3-(4'-benzyl-1'-piperazinyl)-1-propanone dihydrochloride; and (b) 1-(3"-Methoxycarbonyl-5''-methylisoxazol-4''-yl)-3-(4'-benzoyl-1'-piperazinyl)-1-propanone dihydrochloride.
49. A compound according to Claim 44, which is:
50. A compound according to Claim 44, which is:
51. A compound according to Claim 44, which is:
52. A compound according to Claim 44, which is:
53. A compound according to Claim 44 which is:
wherein R1 represents hydrogen, optionally substituted phenyl, carbomethoxy or loweralkyl;
and R2 hydrogen, or loweralkyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.
wherein R1 represents hydrogen, optionally substituted phenyl, carbomethoxy or loweralkyl;
and R2 hydrogen, or loweralkyl; and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.
54. A compound according to Claim 44 which is:
wherein R1 represents hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;
and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl.
loweralkoxy, or nitro groups.
wherein R1 represents hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;
and Ar2 represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl.
loweralkoxy, or nitro groups.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/341,507 | 1994-11-17 | ||
| US08/341,507 US5693804A (en) | 1994-11-17 | 1994-11-17 | Substituted 1-aryl-3-piperazin-1'-yl propanones |
| PCT/US1995/014987 WO1996016052A2 (en) | 1994-11-17 | 1995-11-16 | Certain substituted 1-aryl-3-piperazin-1'-yl propanones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2205586A1 true CA2205586A1 (en) | 1996-05-30 |
Family
ID=29405861
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2205586 Abandoned CA2205586A1 (en) | 1994-11-17 | 1995-11-16 | Certain substituted 1-aryl-3-piperazin-1'-yl propanones |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2205586A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947928A (en) * | 2018-07-03 | 2018-12-07 | 江苏大学 | Nitrogenous, oxygen, oxygen three replace compound and preparation method and purposes in hexatomic ring |
| CN115894195A (en) * | 2021-09-30 | 2023-04-04 | 迈克斯(如东)化工有限公司 | Method for preparing 1-aryl-3-substituted acetone compound and intermediate |
-
1995
- 1995-11-16 CA CA 2205586 patent/CA2205586A1/en not_active Abandoned
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947928A (en) * | 2018-07-03 | 2018-12-07 | 江苏大学 | Nitrogenous, oxygen, oxygen three replace compound and preparation method and purposes in hexatomic ring |
| CN108947928B (en) * | 2018-07-03 | 2022-05-20 | 江苏大学 | Nitrogen, oxygen and oxygen-containing tri-substituted six-membered ring lactone compound and preparation method and application thereof |
| CN115894195A (en) * | 2021-09-30 | 2023-04-04 | 迈克斯(如东)化工有限公司 | Method for preparing 1-aryl-3-substituted acetone compound and intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6306857B1 (en) | Methods for treating or preventing alzheimer's disease using substituted 1-aryl-3-piperazin-1′-yl propanones | |
| US5693804A (en) | Substituted 1-aryl-3-piperazin-1'-yl propanones | |
| WO1996015792A9 (en) | Methods for treating or preventing alzheimer's disease using substituted 1-aryl-3-piperazin-1'-yl propanones | |
| US7534787B2 (en) | Method of treating diseases and conditions associated with an altered level of amyloid beta peptides and new enolcarboxamide compounds | |
| US6214994B1 (en) | Certain substituted 1-aryl-3-piperazin-1′-yl propanones | |
| US5877193A (en) | Use of N-(4-aryl-thiazol-2-yl)-sulfonamides | |
| JP2008525425A (en) | Methods and compositions for treating amyloid-related diseases | |
| RU2183955C2 (en) | Combination of reuptake inhibitor of 5-ht with selective 5-ht1a antagonist | |
| US6228878B1 (en) | Methods for treating or preventing alzheimer's disease using substituted 2-aryl-3-morpholinopropanones | |
| EP1138678B1 (en) | Process for making N-((4-phenyl) methylphenyl) piperazines | |
| AU707290B2 (en) | Method of using triaryl-ethylene derivatives in the treatment and prevention of osteoporosis | |
| CA2205586A1 (en) | Certain substituted 1-aryl-3-piperazin-1'-yl propanones | |
| AU711703C (en) | Certain substituted 1-aryl-3-piperazin-1'-yl propanones | |
| EP0843675B1 (en) | Aza-anthracyclinone derivatives | |
| CA2205530C (en) | Use of substituted aryl-morpholino-, thiomorpholino-or piperazino-propanones for the treatment of prevention of alzheimer's disease | |
| CA2417262A1 (en) | Cdc25 phosphatase inhibitors | |
| EP0853619B1 (en) | Disubstituted piperidine derivatives | |
| JPH0971562A (en) | Thiocarbamic acid derivative | |
| MXPA99001382A (en) | Derivatives of pirrolidine and piperid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |