CA2230487A1 - Inhibitors of tumor necrosis factor alpha - Google Patents
Inhibitors of tumor necrosis factor alpha Download PDFInfo
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- CA2230487A1 CA2230487A1 CA002230487A CA2230487A CA2230487A1 CA 2230487 A1 CA2230487 A1 CA 2230487A1 CA 002230487 A CA002230487 A CA 002230487A CA 2230487 A CA2230487 A CA 2230487A CA 2230487 A1 CA2230487 A1 CA 2230487A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C07—ORGANIC CHEMISTRY
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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Abstract
Novel nitriles are inhibitors of tumor necrosis factor .alpha. and phosphodiesterase and can be used to combat cachexia, endotoxic shock, retrovirus replication, asthma, and inflammatory conditions. A typical embodiment is 3-Phthalimido-3-(3,4-dimethoxyphenyl)propionitrile.
Description
INHIBITORS OF TUMOR NECROSIS FACTCR ALPHA
Ba~ d of the I~v~ ol~
The present invention relates a method of re~vring levels of TNFa in a ~ 1 and to cu~ vunds and compositions useful therein.
TNFa, or tumor nec.osis factor a, is a cytokine which is released primariIy by ~o~ l.r1e~r phagocytes in l~s~G,~e to various ;.~ o~ tnr.s. When a~l...in;~t~red to animals or 1 nlm~n~ it causes i--n~-.---.~ion~ fever, cal~iov~ lar effects, h~ o, .1.5~ge7 Co~ tio7t and acute phase r~s~ollscs similar to those seen during acute infections and shock states.
FX~s~ive or unregulated TNFa production has been implicated in a l.ullll)el of disease con~1itit)nc These include endoto~Pmi~ and/or toxic shock ~ylld~ulllc {Tracey et al., Nature 330, 662-664 (1987) and Hinshaw et al., Circ. Shock 30, 279-292 (1990)}; c~rl~ {Dezube et al., Lancet, 335(8690), 662 (1990)}; and Adult Re~ildL~ly Distress Syl~lr~lue where TNFa collcc~ dlion in excess of 12,000 pglmillilit~rs have been ~I~?tected in p~ n~ y- asl.hd~s from ARDS patients {Millar et al., Lancet 2(8665), 712-714 (1989)}. Sy~l~.nic infil~icn of recombinant TNFa also resulted in c~ g~s typically seen in AR~S {Ferrai-Baliviera et al., Arch.
Surg. 124(12), 1400-1405 (1989)}.
TNFa appears to be involved in bone resorption ~ e5, in-~ln~ a,~ is where it hasbeen ~ lr~ " ~ FA that when a~;Liv~ d, leukocytes will ~lc luc~ a bone-l~s~ll,illg activity, and data sug~est that TNFa cc,llLLil,ul~s to this activity ~Bertolini et al., Nature 319, 516-518 (1986) and Johnson et al., Endocrinology 124(3), 1424-1427 (1989)}. It has been r1~ t~""i~ that TNFa stim~ t~ bone resorption and inhibits bone form~tion in vitro and in vivo through stim~ tion of osteoclast forrnation and activation colllbhled with inhibition of osteoblast fimrtion Although TNFa may be involved in many bone resorption ~ s, inr~ arthritis, the most coInpellin~
link with disease is the association be~ l production of TNFa by tumor or host tissues and m~ n~nry associatedhyperc~ {Calci. TissueInt. (US) 46(Suppl.), S3-10 (1990)}. InGraft versus Host ~ction~ increased serum TNFa levels have been ~soci~l~d with major complications following acute allogenic bone lnallUW transplants ~Holler et al., Blood, 75(4), 1011-1016 (1990)}.
~ Cerebral malaria is a lethal hypela~;u~ neurological ~ylldlull~c ~csoci~t~-i with high blood levels of TNFa and the most severe complication oc~;ulling in malaria p~ti~ntc Levels of serum TNFa coll~lalc;d directly with the severiy of the disease and the plu~llosis in pà~iellLs with acute malaria attacks {Grau et al., N. Engl. J. Med. 320(24), 1586-1591 (1989)}.
W O 97/08143 PCTrUS96/14077 TNFa also plays a role in the area of chronic plll.,,on~y ;..n ~ y ~ c~s ~hedepQ.~ition of silica particles leads to ~iliro.~ a disease of yluglessi~e l~SpuaLuly failure caused by a fibrotic re~rtinn Antibodies to TNPa completely blocked the silica-in~ re~l lung fibrosis in mice {Pignet et al., Nature, 344:245-247 (1990)}. High levels of TNFa y~u~ n (ill the 5 serum and in isolated ,~a~oyllages) have been delnul~Lialed in animal models of silica and asbestos i..rl.~red fibrosis ~Bisso~ e et al., ~nflammation 13(3), 329-339 (1989)}. Alveûlar macl~hages from pUlll~l)~y sarcoidosis patients have also been found to yun~e-ou~.ly release massive qn~ntities of TNFa as coll-ydl~d with macrophages firom normal donors {R?~nghm~n et al., J. Lab. Clin. Med. 115(1), 36~2 (1990)}.
TNFa is also implicated in the i-~n~ .y response which follows rC~Clru~iOn, called L~elÇu~ion injury, and is a major cause of tissue damage after loss of blood flow {Vedder er al., PNAS 87, 2643-2646 (1990)}. TNFa also alters the ~lo~cl~ies of endothelial cells and has various pro-coagulant activities, such as producing an increase in tissue factor pro-co~ nt activity and ~uyylt;SSiOn of the ~ntit~s~ulant protein C L~aLllway as well as down-regulating the tAyl~,ssion of ll.rul,ll,o.. -d-llin {Sherry et al., J. Cell Biol. 107, 1269-1277 (1988)}. TNFa has pro-infl~ ..ly ac;LiviLies which tog~LI~l with its early procl~ction (during the initial stage of an infli~ ly event) make it a likely .n~ or of tissue injury in several illlyOl~lll disu-~
in-ln~lin~ but not limited to, llly~aldial infarction, stroke and circulatory shock. Of ~.e~;l;c i~yOl~lCC may be TNFa-in-lllred e~l~ ion of adhesion molecules, such as intercellular adhesion molecule (ICAM) or endothelial leukocyte ~lh~sion molecule (ELAM) on endothelial cells {Munro et al., Am. J. Path. 13~(1), 121-132 (1989)}.
Moreover, it is now known that TNFa is a potent activator of retrovirus replication activation of HIV-l. {Duh et al., Proc. Nat. Acad. Sci. 86, 597~5978 (1989); Poll et al.~ Proc. Nat. Acad. Sci. 87, 782-785 (1990); Monto et al., Blood 79, 2670 (1990); Clouse et 2'S al., J. Imm~nol. 142, 431~38 (1989); Poll et al., AIDS Res. Hum. Retrovirus, 191-197 (1992)} .
AIDS results from the illre~Lion of T ly~ ho-;yles with Human Tllllll~ rriri~ y Virus (HIV).
At least three types or strains of HIV have been i~ rird~ i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV ;--Lcl;u~-, T-cell ...eA;~ ;ly iS il~ ailcd and infected individuals .-.~,.ir. ~l severe V~ulLulli:~ic infections and/or unusual neoplasms. HIV entry into the T
30 lymphocyte requires T Iymphocyte activation. Other viruses, such as HIV-1 and HIV-2, infect T lymphocytes after T cell activation and such virus protein e~l.r~,s:,ion and/or replication is mP.~ ted or ...~ ;.;..rd by such T cell activation. Once an activated T lymphocyte is inf~ctetl -PCTrUS96/14077 with HIV, the T lymphocyte must co~ we to be m~int~inpd in an activaled state to permit HIV
gene e~ies~ion and/or HIV rep1i~-~tiQn. Cytokines, slJEcirlr~lly TNFo~, are implicated in acti-vated T-cell ...Fdi~ HIV protein e~ ssion andlor virus replication by playing a role in T Iymphocyte activation. Th~.~ro,e, hlL~lr.,~ ce with cytokine activity such as by 5 pl~v~.lLion or inhibition of cytokine production, notably TNE~a, in a HIV-infPctP~ illdividùal aids in l;...il;l,g the Ill~;lllrl~nre of T Iymphocyte activation caused by HIV infection.
Mo~ y~s, n aclopha~,es, and related cells, such as kupffer and glial cells, have also been implicated in ~n~ e of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activatio~ state of the cells 10 {Rosellbelg et al., The Immunopat~logenesis of HIV Infection, A~lv~ces in Tlll~llology, ~7 (1989)}. Cytokines, such as TNFa, have been shown to activate HIV replication in l.~ono-~t~s and/or macrophages ~Poli et al. Proc. Natl. Acad. Sci., 87, 782-784 (1990)}, lll.,.cr~
prevention or inhibition of cytokine production or activity aids in limitin~ HIV pL~ i,sion as stated above for T cells. A(lditic-n~l studies have j~lpntifipd TNFa as a common factor in the activation of HIV in vitro and has provided a clear mP~h~ni~m of action via a nuclear regulatory protein found in the cytoplasm of cells (Osborn, et al., PNAS 86, 2336-2340). This evidence suggests that a reduction of TNFa synthesis may have an antiviral effect in HIV infections, by re~1ncin~ the L~sc~ ion and thus virus production.
AIDS viral replication of latent HIV in T cell and macrophage lines can be in~ red by TNFa {Folks et al., PNAS 86, 2365-2368 (1989)}. A molecular ",Prl.~ ", for the virus in-lncing activity is suggested by TNFc~s ability to activate a gene regulatory protein (NFlcB) found in the cytoplasm of cells, which plOmO~t;S EIIV replication through binding to a viral regulatory gene seq~l~nre (LTR) {Osborn et al., PNAS 86, 2336-2340 (1989)}. TNFoc in AIDS
~csori~tPrlc~rh~yi~is suggested by elevated serum TNFcc and high levels of spontaneous TNFx production in peripheral blood monocytes from patients {Wright et al. J. Immunol. 141(1),99-104 (1988)}.
TNFcc has been implicated in various roles wi~ other viral infections, such as the ~y~ Fg~ virus (CMV), inflllen7~ virus, adenovirus, and the herpes family of viruses for similar reasons as those noted.
Pl~e.~ g or inhibi~ g the production or action of TNFx (e.g. with ~r~tll.f ~,l with the compounds of this illvcll~ioll) is, Ll,~.crole, predicted to be a potent ~ e~ LldLcgy for many ;.,n5.-.. ~,c~ly~ infectious, immlmnlogical or m~lign~nt r1ice~es These include but are not W O 97/08143 PCT~US96/14077 ~ i.;Lc;d to septic shock, sepsis, Glldvlu~c shock, hemo lyl~lic shock and sepsis sy,lLo~e, post i~r1.~.n;r ~ ruiion injury, malaria, mycobacterial il~Lion, ~ ;e, IJ~O1;~;C, congci~liv~
heart failure, fibrotic disease, cacl.- Y ;A, graft rejection~ cancer, aulù;l.~ disease, o~olLuni~Lic infections in AIDS, .~ oid ~l~h.ilis"l. ~.~ uid spondylitis, o~o~iLis, other a~ ilic 5 cU~ io~ Crohn's disease, ulcerative colids, multiple sclerosis, ~y~t-,,llic lupus e,yLl~ lu~;c, ENL in leprosy, radiation damage, and hyperoxic alveolar injury. Efforts directed to the su~ s~ion of the effects of TNFc~ have ranged from the nfili7~tion of steroids such as dexa-lllcillasol~ and pl~,dnisolone to the use of both polyclonal and monoclonal antibodies {Beutler et al., Science 234, 470-474 (1985); WO 92/11383}.
The nuclear factor lcB (NFKB) is a pleiotropic ~.d~ Lional activator (Lenardo, et al.
Cell 1989, 58, 227-29). NFl~B has been implicated as a Llailscli~Lional a~;~ivalor in a variety of disease and ;.,n~ states and is thought to regulate cytokine levels in~ln(lin~ but not limited to TNFa and also to be an a.;Li~dlul of HIV tlansclil.~ion (Dbaibo, et al. J. Biol. Chem. 1993, 17762-66; Duh et al. Proc. Natl. Acad. Sci. 1989, 86, 5974-78; Ba~ ie et al. Nature 1991, 350, 709-12; Boswas et al. J.. Acquired T.. ,.~"~ Deficiency Sy~ ome 1993, 6, 778-786; Suzulci et al. Biochem. And Biophys. Res. Comm. 1993, 193, 277-83; Suzuki et al. Bior~lPrll- And Biophys. Res Comm. 1992, 189, 1709-15; Suzuki et al. Biochem. Mol. Bio. Int. 1993, 31(4), 693-700; Shak'hov et al. 1990, 171, 3547; and Staal et al. Proc. Natl. Acad. Sci. USA 1990, 87, 9943~7). Thus, inhibition of NFIcB binding can regulate ~ ~cliL,lion of cytokine gene(s) and 20 ~lru~ll this mn~ tioIl and other ",P~ c be useful in the i~ .oll of a mllltihl~ito of disease states. The culll~uullds claimed in this patent can inhibit the action of NFlcB in the mlclPllc and thus are useful in the ~ I of a variety of di~ce,c inr~]~din~ but not lirruted to .l-. ~ foicl a~ is"l.~ id spondylitis, osteoa,LLuilis, other arthritic colldiLions, septic shock, septis, ~n-loto~ic shock, graft versus host rlice~ce, waSLillg, Crohn's disease, ulcerative colitis, mnl~irle 25 scl~o~is, ~y~ lic lupus e.yllu~ cic, ENL in leprosy, HIV, AII:)S, and oppu,Lulli~Lic infections in AIDS.
TNFa and NFKB levels are infll~en~ed by a reci~rocàl feedb~cl~ loop. As noted above, the compounds of the present invention affect the levels of both TNF~ and NFlcB. It is not known at this time, however, how the compounds of the present invention regulate the levels of 30 TNFoc, NFlcB, or both.
Many cellular ~ln-~tio~c can be "--o~ ttod by levels of ~ nosillF 3',5'-cyclic ullul~ho~l~h~(cAMP). Such cellular functions can collLlibule to infl~"...._lo.,y conditions and W O 97/081~3 PCTAUS96/14077 e~ces including a~thm~ ;oll, and other colldi~iolls ~Lowe and Cheng, Drugs of the Future, 17(9), 799-807, 1992). It has been shown that the elevation of cAMP in i~
l~uko~;yLcs inhibits their a;Livalion and the su~sc~luent release of i"n;.,.,~ tOl,~ ...P(~ ,J i.
Illcreased levels of cAMP also leads to the re~ tion of airway smooth muscle.
The ~ cellular ~-.Pr~ --- for the inacLivaLioll of cAMP is the breakdown of cAMP
by a family of isoe.~yl~les lefclled to as cyclic nucleotide ph-)srh~ iPstPr~ces(PDE). There are seven known lll~lll~LS of the family of PDEs. It is leCO~l~i2e;i, for e~i~...ple, that the inhibition of PDE type IV is particularly crfeclive in both the inhibition of ;.. nZ.. ,.~Oly me~i~tQr release and the rel~ tion of airway smooth muscle. Thus, COlll~oul ds that inhibit PDE IV ~I,~ircally, 10 would exhibit the desirable inhibition of ;~.n~".,~ ;on and rela~cation of airway smooth muscle with a ...i..i....~." of u~w~lltd side effects, such as cardio-vascular or anti-platelet effects.
Cullclllly used PDE IV inhibitors lack the sel~;livt; action at arcept~hle lhel~euLic doses.
The com~u~lds of the present invention are useful in the i~ iLion of phncpho.l;~ ,L~ s, particularly PDE III and PDE IV, and in the ~ l"e.,l of disease states mPAi~terl thereby.
15 Detailed Des~.;ylion The present invention is based on the discovery that a c,lass of non-polypeptide imides more fully described herein appear to inhibit the action of TNFc~.
The present h.-,e.-lioll ~e~ s to co.n~u~..ds of the formula:
o R~ ~N ~ H-(CH2)~Y
R~ ~,7 in which:
Y is -C--N or -C(CH2)mCH3;
m is 0-3;
R5 is: (i) o-phenylene, lln~llb~ "lP(1 or sn'c stitllt~d with one or more s~lbstit lent~ each select~d independently from nitro, cyano, trifluolo~ llyl, carbethoxy, ca~ l-o~y, ~bo~lopo~Ly, acetyl, ca.ballloyl, ca~ lloyl ..~ Pd with and aLIcyl of 1 to 3 carbon atoms, acetoxy, ca.bo~Ly, hydlo~y, amino, amino ~ ed witn an allyl of 1 to 3 carbon atoms, allyl PCT~US96/14077 of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; (ii) the divalent residue of pyridine, pyrrolidine, imidizole"~ h~ lf n~, or thiophene, W~ till the divalent bonds are on vicinal ring carbon atoms; (iil~ a divalent cycloaL~cyl of 4 - 10 carbon atoms, u~ub~ u~d or ,SI;I~ (1 with one or more ~ e~ ; each select~d ii~ lly of the other from the group 5 co...~ of nitro, cyano, trifluoromethyl, cal~hoxy, c~lJv~ lloxy, c~bo~lu~u~y, acetyl, calb~ulloyl, acetoxy, carboxy, hydroxy, amino, ~.lb~ A. amino, aL~yl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iv) di-~ stihlt-f~d vinylene, sllk,~ (l with nitro, cyano, trifluoromethyl, carbethoxy, Ca1bV111ClhOXY~ ca~bv~lv~o~y, acetyl, callJ~vyl~
~l,~lloyl snhstihltPA with and aL~yl of 1 to 3 carbon atoms, acetoxy, c~l,o,Ly, hydroxy, amino, 10 amino sul,~ lecl with an alkyl of 1 to 3 carbon atoms, aLkyl of 1 to 4 carbon atoms, aIkoxy of 1 to 4 carbon atoms, or halo; or (v) ethylene, ~h.~lb5l;l~ or ~ub~ /r~ with 1 to 2 ~ b~ t~;
each scl~ct-d indepen~lfntly from nitro, cyano, trifluolulll~,~yl, carbethoxy, cdllJol..~ y, callJv~lu~o~y, acetyl, ca~ uloyl~ carbamoyl sllbstit~lt-f d with and alkyl of 1 to 3 carbon atoms, acetoxy, c~l,o~y, hydlu~Ly, armino, amino, ~ with an aL~cyl of 1 to 3 carbon atoms, alkyl 15 of 1 to 4 carbon atoms, aLkoxy of 1 to 4 carbon atoms, or halo;
R6 is -CO-, -CH2-, -CH2CO-, or -SO2-;
R7 is (i) straight or l..~ f d aLlcyl of 1 to 12 carbon atoms; (i~ cyclic or bicyclic aLlcyl of 4 to 12 carbon atoIns; (iil~ pyridyl; (iv) phenyl subsLiLulcd with one or more sllbstitll~.nt~ each sel~tfA~ f~ fntlyoftheotherfromnitro,cyano,Lli~luClu~ ,Lllyl,c~l,~w~y, c~l,.. ~ y, 20 CO1IJO~1OPO~Y~ acetyl, c~lJdllluyl, acetoxy, carboxy, Ly~u~Ly, amino, straight, blallched, cyclic, or bicyclic aLkyl of 1 to 10 carbon atoms, straight, bl,..~rl-~(l, cyclic, or bicyclic aLkoxy of 1 to 10 carbon atoms, CH2R where R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms, or halo;
(v) benzyl ~bs~ with one to three ~ "l~i each selff~te~ d~,pendclllly from the group cc....~ of nitro, cyano, trifluolo..l~hyl, call~cllloky, c~bu...~ nxy, calllo~lupoxy, acetyl, . 25 c~l,~luyl, acetoxy, carboxy, hy~lloxy, amino, allyl of 1 to 4 carbon atoms, aLkoxy of 1 to 10 carbon atoms, or halo; (vi) l~l)hlllyl; or (vii) benzyloxy;
and, where n has a value of 0, 1, 2, or 3;
A first pl~rcllcd sllbcl~cc p~.~i,ls to compounds in which:
Y is -C-N;
Rs is o-phenylene, ~ubsl;l~ ,cl or ...~.~ub~
R6 is -CO- or -CH2-;
R7 is an aryl; and nis 1.
Typical compolmds of this invention include:
S -CO- 3,4~imrthc)xyphenyl -CO- 3~tho7cy~-methoxyphenyl -CH2CO- 3,4~imPthoxyphenyl -CH2CO- 3-ethoxy~-methoxyphenyl -CO- 3-propoxy4-metho~y~h.,.lyl -CH2CO- 3-propoxy4-me~oxyphenyl -CO- 3-cyclopentoxy-4-methoxyphenyl (cyclopentoxy = cyclic C5HgO-) -CH2CO- 3-cycl~ycllLu~y4-methoxyphen -CO- 3,4~1iule~hylyhenyl -CO- 3-ethoxy4~y~ hellyl -CH2- 3,4-dimetho~yyhe~lyl -CH2- 3-ethoxy4-methoxyphenyl -CH2- 3,4-diul~lylyhellyl Tbe term alkyl as used herein denotes a univalent 5,,l.. ".~ clled or str~i~ht hydrocarbon chain. Unless uLll~. wi~e stated, such chains can contain from 1 to 18 carbon atoms.
Re~,lf,sf~ e of such alkyl groups are methyl, ethyl, propyl, isoyrvyyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoyc,.llyl, u~oycLlLyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, uu~euyl, dodecyl, tridecyl, tetradecyl, pf nt~(ltocyl~ hf-Y~-1.ocyl, heptadecyl, octadecyl, and the like. When ~u~liftto~ by "lower", the alkyl group will contain from 1 to 6 carbon atoms. The same carbon content applies to the parent term "aLkane" and to de~ivative terms such as "aL~coxy".
The term cycloalkyl (or cyclic aLkyl) as used herein denotes a univalent saturated cyclic hydrocarbon chain. Unless oLlleL~ise stated, such chains can contain from 1 to 18 carbon atoms.
R~yl~se~ e of such cycloaLkyl groups are methyl, ethyl, ~;y~lopluy~l, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclo~odff~yl, cycloLIide.;yl, cyclotetradecyl, cyclop~n~ cyl, cyc~hrY~fl.ocyl, cycloheptadecyl, cyclooctadecyl, cyclic l~y~ 5, and the like. When q~ fird by "lower", the cycloaLkyl group will contain from 3 to 6 carbon atoms. The same carbon content applies tO the parent term "cycloalkane" and to d~Li~a~ e terms such as "cyclo~lkoxy".
The colllyuu~ds can be used, under the supervision of qualified ylor~sionals~ to ~nhibit the undesirable effects of TNFa and/or phrt~phf llircl~, ce~. The collly-)uuds can be ~ ;";~ d 3~ orally, rectally, or y~e~lh~dlly~ alone or in col.. bi~ion with other ~ .a~culic agents inr.llltlin~
W O 97/08143 PCT~US96/14077 antibiotics, steroids, etc., to a ...~ 1 in need of L~ o,ll Oral dosage forms include tablets, c~rs111Ps, dragees, and similar shaped, co~ ressed ph~rm~re11tir~1 forms. Isotonic saline solutions co.~ ;n~ 20-100 milligrams/mi11ilitPr can be used for ~alullL~làl ~r1.n;n;~l.aLion which inr~lrlPs illLl~ r, illLlaLIlecal, intravenous and intra-arterial routes of ~ il aLion. Rectal S a~ .aLion can be effecteri through the use of supposiLclics forrn111~te(l from col~ lLiorlal carriers such as cocoa butter.
Dosage l~;"~r ~ must be titrated to the particular inriir~tir)n the age, weight, and genersl physical conrlitir)n of the patient, and the lc~onse desired but generally doses will be from about 1 to about 1000 milligramslday as needed in single or multiple daily ~h..;..;~alion. In general, 10 an initial Ll~n~ f .1 Lc~hnell can be copied from that known to be erre-;l~ve in hl~f .Ç~.i~ with TNFa activity for other TNFoc IllP~ lrcl disease states by the compounds of the present h~ Lioll.
Treated individuals will be regularly rhPc~pA for T cell numbers and T4/T8 ratios and/or easul~s of vh~,nia such as levels of reverse ~à~,cli~Lase or viral ~lolchls, and/or for progression of cytokine~ lrd disease associated problems such as c~rhPYi~ or muscle 15 dcge.l.,.dlion. If no effect is observed following the normal L.~ ..f~ , then the amount of cytokine activity hlLf .Ç~.,ng agent ~ d is illulf ascd, e.g., by fifty percent a week.
The compounds of the present invention can also be used topically in the Lle~l~..f..l or prophylaxis of topical disease states mPflj~tPcl or exacerbated by excessive TNFa production, such as viral infections, for example those caused by the herpes viruses or viral conj~ ;LiviLis, psoriasis, other skin disorders and ~iic~P~cesJ etc.
The compounds can also be used in the vt;~ inaly ll.~l.. l.. l of .. i.. ~1~ other than h-1m~nc in need of ~lcve~.Lion or inhibition of TNFa pro.1.~r! ion TNFoc mPAi~tf ~ P~cf~c for f ~~ a~wuLically or ~lo~hylactically, in animals include disease states such as those notcd above, but in particular viral illr~Lions. Examples include feline immnnn~PfiriPnry virus, equine 25 inff ctiollc ~n~Pmi~ virus, caprine a,Ll~ is virus, visna virus, and maedi virus, as well as other lentiviruses.
~ ertain of these coll~o~ ds possess centers of chirality and can exist as optical isomers.
Both the r~f ~..~lf s of these isomers and the individual isc.ll~ tll.,~sclves, as well as dia~ ,oisol"~ when there are two chiral centers, are within the scope of the present invention.
30 The ~ e-.~lf,, can be used as such or can be sr~ alp~l into their individual isomers ,~.fLrl~ 11y as by cl~,ll-aLography using a chiral abso-l,e~lt. ~ ly, the individual isomers can be ~a~ed in chiral form or se~al~led cl.~ lly from a mixture by r~"lllin~, salts with a chiral W O 97J08143 PCT~US96/14077 acid, such as the indi\~i~lual en~ntil~m~r~ of lO~l~hoi~..lforir. acid, cam~hulic acid, alpha-c~...phrJric acid, methokyaceLic acid, tartaric acid, ~liac~yl~i~ acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, and then freeing one or both of the resolved bases, optionally ~ the process, so as to obtain either or both isomers subst~nri~lly free of the S other, i. e., in a form having an optical purity of > 95 % .
F~ ion or inhibition of ~ l ion of TNF~ by these co~ u~ds can be CU11~G~ 1Y
assayed using methods known in the art. For e~r~mple, TNF~ Inhibition Assays in LPS
stim~ trd PBMC have been ~c~rull-led as follows:
PBMC ;~Q1~t;~n~ PBMC from normal donors were ol~ .ed by Ficoll-Hypaque density cellllir.lgation. Cells were culhlred in RPMI ~u~)k ~-r ~lrd with 10% AB~
serum, 2mM L-~ 100 U/rnL penicillin and 100 ~g/mL ~ olllycill.
PBMC ~ -.c- Drugs were dissolved in DMSO ~Sigma ChloTnir~l), further dilutions were done in supplem~ntPd RPMI. The final DMSO co..rP~ ;on in the ~l~SG.lCc or ~hs~onre of drug in the PBMC sllsI~pn~ n~ was 0.25 wt %. Drugs wereassayed at half-log dilutions starting at 50 ~g/mL. Drugs were added to PBMC (106 cells/mL) in 96 wells plates one hour before the ~1dition of LPS.
Cell ~ PBMC (1O6 cells/mL) in the ~lcs~"~ce or ~hsenre of drug were stim~ t~l by ~ I with 1 ~g/mL of LPS from Salmonella minnesota R595 (List Biological Labs, Campbell, CA). Cells were then i~rub~tP~I at 37~C for 18-20 hours.
S~ f .l~i were then ha~ ~d and assayed ;............ l;;.l~ly for TNFa levels or kept frozen at -70~C (for not more than 4 days) until assayed.
TNFa D~ lion: The col-~r~-l-aLion of TNFa in the SU~f~ WâS
de~ ...;.)rd by human TNFa ELISA kits (ENDOGEN, Boston, MA) accol-l.~ to the m~nnf~r.hlrer's dih~.liulls.
2~ The compounds can be ~ aled using mPthorlc which are known in general for the .dl;nl~ of nitriles. General reaction srh.omrs are illllctr~t~ by the formulas:
lil) R6 ~N--CO2E t ~ ~CO2H ' R~ ,Nl~CO2EI
or R~ HN~L(CEI2)1rX ~ ~ R7 1) Acti~rate 0 7 ~ R7 CDI or U R
R6 2 ) NH3 Rs/\N~CONH2 or 3) R5RNl~CoNEI Dehydrate R 1~C=N
5 where X is CO2H, CONH2, or CN
The following e~ pl- s will serve tO filrther ~pify lhe na~re of ltbis ill~ ion but should not be construed as a limit~tion in the scope thereof? which scope is defined solely by the ~ppPn-l~P~l claims.
W O 97/08143 PCT~US96/14077 Fx~n~ple 1 3-Phth~ 3-(3,4d;~thoxyphe ,~I)pr~ ;~ile.
To an ice bath cooled stirred ~ e-l~;;oll of 3-phth~limiflo-3 (3,4-diethoxyphenyl)propion~mi~1~ (0.96 g, 2.5 mmol) and 4~ yllllorpholine (0.66 mL, 6 mmol) S in DMF (9 mL) under nitrogen, was added thionyl chloride (0.35 mL, 4.8 mmol) dlc,yw~e.
There was a slight exotherm after which the lllL~ lC was stirred at 0 - 5~C for 30 l~ ~c and at room Lel,l~claLulc for 2 hours. The led~iLion was ~ u~d by HPLC (Waters Nova-PaklC-18 column, 3.9xlS0 mm, 4 micron, 1 mL/min, 240 nm, 50/50 CH3CN/H3PO4 0.1%(aq)). Thel~a~liull ll~lule was poured into a llfuL~ of NaHCO3 (8.5 mL) and ice (40 g) and stirred until the ice had lmelted. The ~ lule was filtered and the solid was washed with copious amounts of H20. The wet solid was dissolved in C~CI2 (25 mT ) and the organic layer was se~ P~ and dried over MgSO4 and cf ~ i in vacuo to a sticly semi-solid. The solid was ~ulirled twice by flash column elll~ o~ hy (silica gel, 3% ethyl acetate/methylene chloride) to afford a solid which was dried in vacuo (50~C, < 1 mm) to afford 0.5 g (55%) of ~lO-lU~;I, as a pale yellow solid; 'H NMR (CDCl3) o 7.91-7.65(m, 4EI), 7.12-6.98(m, 2EI), 6.90-6.78(m, lH), 5.61(dd, J
= 6.4, 10.3 Hz, lH), 4.19-3.96(m, 4H), 3.83(dd, J = 10.3, 16.8 Hz, lH), 3.26(dd, J = 6.4, 16.8 Hz, lH), 1.55-1.30(m, 6H); 13C NMR (CDC13) o 167.7, 149.2, 148.9, 134.3, 131.5, 129.1, 123.6, 120.2, 116.9, 113.2, 112.9, 64.7, 64.5, 51.1, 21.1, 14.7; HPLC 98.4 %. Anal. Calcd for C2~H20N~O4. Theo.cLical: C, 69.22; H,5.53; N,7.69. Found: C, 69.06; H, 5.48; N, 7.58.
F.Y~m~ple 2 3 ph~hs~ 3 (3,/1 "l;... ~ y~lh..yl)propionitrile To an ice bath cooled stirred ~ el-~ion of 3-phth~limit1Q-3-(3,4-~im.oth~ y~ lyl)~r~;.~ (1.77 g, 5.00 mmol) and 4-1llt~hllu~ oline (1.3 mL, 12 mmol) in DMF (17 mL) under N2, was added thionyl cloride (0.7 mL, 9.6 mmol) dr~ise via a 25 syringe. There was a slight exotherm and after 30 minutes the cooling bat_ was ~ ved and the reaction llli~LIUl~, was stirred for 2 hours at room hm~lalule~ The reaction llliAIUlC; was poured into a mixture of NaHC03 (17 g) and 75 mL of ice water and stirred until the ice h-ad melted. The slurry was filtered and the solid was washed with copious ~ of H20. The wet solid was dissolved in CH2Ck (50 mL) and the organic layer was s~d,dted, dried over2Na4SO, and co.lc~,l.LldLed in vacuo to afford an orange solid. The solid was purified by flash column clllolllatography (silica gel, 5/95 EtOAc/CH2C12, 50 mm id column) to afford 1.32 g (79%) of S the product as a white solid: IH NMR (CDCl3) ô 7.9-7.6(m, 4H), 7.10 (m, 2H), 6.83 (m, lH), 5.64 (dd, J = 6.5, 10.2 Hz, lH), 3.88 (s, 3H), 3.85 (s, 3H), 3.82 (dd, lH), 3.30 (dd, J = 6.5, 16.8 Hz, 1 H); '3C NMR (CDC13) ô 167.7, 149.5, 149.2, 134.4, 131.5, 129.1, 123.6, 120.1, 116.9, 111.1, 110.7, 56.0, 55.9, 51.1, 21.1. Andl. Calcd for Cl9H,6N204-0.18 ~ O.
The~"~,Li-,al: C, 76.2; H,4.85; N,8.25. Found: C, 67.23; H, 4.79; N, 8.27.
FY~m~ple 3 3-(3'-Nitrophthalimido)-3-(3'-ethoxy-4'-metho~y~ I)propionitrile A stirred ~- .~e. ~ n of 3-niLIulJl .~ lic anhydride (0.24 g, l .13 rnmol) and 3-amino-3-(3 '-ethoxy-4'-methoxyphenyl)propionitrile (0.25 g, l .13 rnmol) in 6 mL of acetic acid was heated to reflux under nitrogen for 12 hours. The acetic acid was removed in vacuo to afford an orange 15 gum which was dissolved in methylene chloride (10 rnL) and was washed with a s~tl~r~tP~1 aqueous solution of sodium bicarbonate (2 x 10 mL). The organic layer was s~ rd and the aqueous layer was extracted with methylene chloride (10 mL). The combined organic extracts were dried over m~nP~ m sulfate, filtered and con- P.ntr~t~d in vacuo to afford a yellow oil. The crude product was purified by flash column cl~ollldlography (silica gel, 5% ethyl 20 acetate/methylene chloride) and the resulting solid was dried in vacuo (60~C, < I rnm) to afford 0.25 g (56%) ofthe product as a yellow solid: mp 155.5-157 ~C; 'H NMR (CDCl3) o 8.20-8.09 (m, 2 H), 8.02-7.86 (m, l H), 7.15-7.02 (m, 2 H), 6.88-6.76 (m, 1 H), 5.64 (dd, J = 6.3, 10.6 Hz, 1 H), 4.09 (q, J = 7 Hz, 2 H), 3.85 (s, 3 H), 3.84 (dd, J = l0.6, 16.7 Hz, l H), 3.26 (dd, J = 6.3, 16.7 Hz, 1 H), 1.46 (t, J = 7 Hz, 3 H); ~3C NMR (CDC13) o 165.3, 162.3, 150.1, 148.7, 144.9, 135.7, 133.5, 129.0, 128.1, l27.4, 123.2, 120.3, 116.6, 112.1, 111.5, 64.6, 55.9, 51.9, 20.9, 14.7;
Anal. calcd for C2oHI7N306. Theoretical: C, 60.76, H, 4.33; N, l0.63. Found: C, 60.59, H, 4.22;
N, 10.65.
W O 97/08143 PCTnJS96/14077 Fx~n~?le 4 3-(3'-Aminop~ o)-3-(3~-ethoxy-4~ etho~lJh; ~I)propionitrile To a solution of 3-(3'-1~,llo~.~"l,~limi(lQ)-3-(3'-ethoxy- 4'-methoxyphenyl)propionitrile (0.2 g, 0.5 mmol) in 30 mL of ethyl acetate was added 0.05 g of 10% p~ m on carbon catalyst. The S ~ Lulc was hydrogenated in a Parr-Shaker ~ aLus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was cOl~'r~ in vacuo to afford a yellow oil. The crude product was purified by flash column cl,~ rhy (silica gel, 3% ethyl acetate/methylene chloride). The rP~nltin~ yellow solid was then dried in vacuo (60~C, < 1 mm) to afford 0.09 g (50%) of the product: mp 171 -172.5 ~C; 'H NMR (CDCl3) 8 7.47-7.35 (m, 1 H);
7.19-7.00 (m, 3 H), 6.90-6.29 (m, 2 H), 5.56 (dd, J = 6.6, 10 Hz, 1 H), 5.24 (s, 2H), 4.09 (q, J = 7 Hz, 2 H), 3.84 (s, 3 H), 3.77 (dd, J = 10, 16.8 Hz, 1 H), 3.27 (dd, ~ = 6.6, 16.8 Hz, 1 H), 1.45 (t, J
= 7 Hz, 3 H), ~3C NMR (CDCl3) o 169.4, 167.9, 149.6, 148.5, 145.5, 135.5, 132.1, 129.4, 121.3, 120.0, 117.1, 113.0, 112.2, 111.4, 110.6,64.5,55.9,50.7,21.1, 14.7;HPLC(WatersNova-Pak C,8 column, 3.9 x 150 mm, 4 micron, 1 mL/min, 240 nm, 40/60, CH3CN/0.1% H3PO4(~q~) 4.5 min, 100%; Anal. calcd. for C20HIgN3O4. Theoretical: C, 65.74, H, 5.24, N, 11.50. Found: C, 65.54; H, 5.23; N, 11.23.
FY~m,ple S
3 ph" -I ~'o 3-(3'-ethoxy-4'-metho~y~ I)propionitrile Oxalyl ~hlori-le (0.49 mL, 5.64 mmol) was added dropwise to an ice bath cooled stirred solution of DMF (0.48 mL, 6.16 mmol) i~ accLo~JiL,ile (10 mL). A white plc~ipiL~c formed imm~ t~:ly and was accn.,.p~ l by gas evolution. The mixture was stirred for 30 mimlt~ at 2-3 ~C and then a solution of 3-phth~limi-1O-3-(3'-ethoxy-4'-metho~y~,hc,l~l)propionarnide ~1.89 g, 5.13 mmol) in DMF (15 mL) was added slowly. After 10 ~ s pyridine was added and the ll~ e was stirred for 30 minllt~s at 2-3 ~C. The reaction mixture was then poured into 60 mL of ice 25 and stirred for 20 ,;~ es. The slurry was filtered and the solid was washed with water, air dried and then dried in vacuo (60 ~C, < 1 mmHg) to afford 1.7 g (95%) of the product as a white solid:
mp 135-137 ~C; 'H NMR (CDCl3) ~ 7.86-7.71 (m, 4 H), 7.08-7.05 (m, 2 H), 6.84-6.81 (m, 1 H), 5.63 (dd, J = 6.5, 10.3 Hz, 1 H), 4.11 (q, J - 7 Hz, 2 H), 3.88-3.77 (m, 1 H), 3.84 (s,3 H), 3.32-W O 97/08143 PCTrUS96/14077 3.23 (m, 1 H)7 1.45 (t, J = 7 Hz, 3 H); 13C NMR (DMSO-d6) o 167.4, 149.0, 147.8, 134.9, 130.8, 129.2, 123.5, 119.4, 118.2, 112.1, 111.7, 63.8, 55.4, 50.0, 20.5, 14.6; Anal. calcd. for C20H,8N2O4. Theoretical: C, 68.56, H, 5.18, N, 8.00. Found: C, 68.46; H, 5.37; N, 8.02.
F.Y~mple 6 S l-(l'-Oxo-isoindoline)-1-(3', 4'-dimetho~yp~ ~I)propic lle To an ice cooled stirred ~ ion of 1-(1 '-oxo-isoin-loline)-1-(3', 4'-im~thn~y~ ellyl)propion~mi-l~ (1.7 g, 5.0 mmol) and 4-n~elhyll~orpholine (1.3 mL, 12 mmol) in DMF (20 mL) under N2, was added thionyl chloride (0.7 mL, 9.6 mmol) dropwise via a syringe. There was a slight exotherm and after 1 hour the cooling bath was removed and the reaction mixture was stirred for 1 hour at room It;nl~e~alule. The reaction l.lixlLIle was poured into 100 mL of ice and stirred until the ice had melted. The slurry was filtered and the solid was washed with copious amounts of water. The solid was purified twice by flash column chrom~fo~T~rhy (silica gel, 1/9 and 24/76, EtOAc/CH2C12). The reclllting solid was dried in vacuo to afford 0.97 g (60%) of the product as an orange tan solid: mp 119-121 ~C; 'H NMR
(CDCl3) ~ 7.94-7.85 (m, 1 H), 7.61-7.30 (m, 3H), 7.05-6.85 (m, 3 H), 5.73 (t, J = 7 Hz, 1 H), 4.46 (d, J = 16.7 Hz, lH), 4.19 (d, J = 16.7 Hz, 1 H), 3.89 (s, 3H), 3.8~ (s, 3H), 3.23(m, 2 H); '3C
NMR(CDCl3) o 168.5, 149.5, 149.4, 141.1, 131.9, 131.8, 128.7, 128.2, 123.9, 122.9, 119.1, 117.4, 111.2, 111.0, 56.0, 55.9, 51.6, 47.3, 21.1; Anal. calcd for ClgHlgN2O3. Theoretical: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.26; H, 5.56; N, 8.47.
FY~m~le 7 l-(l'-Oxo ~ linc)-1-(3'-ethoxy-4'-metho~p!r ~ ic it~ile To an ice cooled stirred ~u~l~ion of 1~ oxo-isoindoline)-1-(3'-ethoxy-4'-metho~y~ yl)propion~mi~llo (1.0 g, 2.8 mmol) and 4-1llc~lyhnGll~lloline (0.75 mL, 6.8 mmol) in DMF (10 mL) under N2, was added thionyl chloride (0.4 mL, 5.5 mmol) d~ vise via a 25 syringe. There was a slight t Aolll~nl and after 1 hour the cooling bath was removed and the reaction llliAlul~ was stirred for 1 hour at room ~ a~ule. The reaction lllixlul~ was poured into 100 mL of ice and stirred until the ice had melted. The slurry was filtered and the solid was washed with copious amounts of water. The solid was purified by flash column chromatography (silica gel, 1.5/8.5, EtOAc/CH2Cl2). The r~snltin~ solid was dried in vacuo to afford 0.57 g (60%) of the product as an ivory solid: mp 125-125.5 ~C; 'H NMR (CDCI3) ô 7.88 (d, J = 7 Hz, 1 S H), 7.60-7.30 (m, 3H), 7.05-6.80 (m, 3 H), 5.71 (t, J = 6.9 Hz, 1 H), 4.45 (d, J = 14 Hz, lH), 4.20-4.00 (m, 3 H), 3.87 (s, 3H), 3.23 (m, 2 H), 1.44 (t, 7 Hz, 3 H); 13C NMR (CDCl3) o 168.5, 149.7, 148.8, 141.2, 131.9, 131.8, 128.6, 128.2, 123.9, 122.9, 119.2, 117.4, 112.4, 111.5,64.6, 55.9, 51.6, 47.3, 21.1, 14.6; Anal. calcd for C20H20N2O3. Theoretical: C, 71.41; H, 5.99; N, 8.33.
Found: C, 71.11; H, 5.91; N, 8.17.
F~an~le 8 Tablets, each cont~inin~ 50 milligrams of active hly,ledie~llL~ can be plG~al~d in the following ~
Con~thll~nt~ (for 1000 tablets) active hlgl.,diellL 50.0 grams lactose 50.7 grams wheat starch 7.5 grams polyethylene glycol 6000 5.0 g;rarns talc 5.0 grams g~f~ stearate 1.8 grams de~ i7e~1 water q.s.
The solid iny,lGd;ellL. are first forced through a sieve of 0.6 mm mesh width. The active hl~ , the lactose, the talc, the m~ stearate and half of the starch then are mixed. The other half of the starch is .~ .d/od in 40 milliliters of water and this suspel~io is added to a boiling solution of the polyethylene glycol in 100 milli1it.ors of water. The 25 resllhin$ paste is added to the pulverulent ..ub~.L~ilces and the llli~LlUle iS gramllatt~d, if ~.PC~ .y with the a~ hion of water. The gramll~t~ is dried ovel~ight at 3~C, forced through a sieve of 1.2 mm mesh width and culll~r~ssed to forrn tablets of approximat~ly 6 mm ,1i .. ~ ~ which are coll~ave on both sides.
W O 97/08143 PCT~US96/14077 F.Y~n~l?le 9 Tablets, each CO..~ .;,.g 100 milligrams of active hlgl~,diGllL, can be ~ al~d in the following ~I1~1eL.
CO~ P..I!~ (for 1000 tablets) S active ingl~dienL100.0 grams lactose 100.0 grams wheat starch 47.0 grams m~.r~ stearate 3.0 grams All the solid hl~lGdiGllL~ are first forced through a sieve of 0.6 mm mesh width. The 10 active hlgledien~, the lactose, the m~ r~ , stearate and half of the starch then are mi~ed.
The other half of the starch is sllc~enrlPd in 40 millilitrrs of water and this ~ e~.~ion is added to 100 millilit~rs of boiling water. The reslllfing paste is added to the pulverulent s~ r~s and the mixlule is gr~mll~t.orl, if ..rce~.y with the addition of water. The granulate is dried overnight at 35~C, forced through a sieve of 1.2 mm mesh width and collll)lGs~ed to form 15 tablets of a~loxilllatGly 6 rnm rli~.... r~l which are CO11C~VG on both sides.
F.Y~ le 10 Tablets for ch~..illg, each co..l;~;.-;..g 75 milligrams of active h~ .lielll, can be ~,d in the following lll~e~.
Co~ osil;or (for 1000 tablets) active ingredient75.0 grarns ,n~ .;lol 230.0 grams lactose 150.0 grams talc 21.0 grams glycine 12.5 grarns stearic acid 10.0 grams ~ ~cch~ 1.5 grams 5% gelatin solutionq.s.
All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The ........ ilol and the lactose are mixed, gr~mll~tPd with the addition of gelatin solution, forced through a sieve of 2 mrn mesh width, dried at 50~C and again forced through a sieve of 1.7 mm mesh width. The active ingredient, the glycine and the s~rl-~. ;.. are carefully mixed, the In~ ;lrJl~ the lactose granulate, the stearic acid and the talc are added and the whole is W O 97/08143 PCT~US96/14077 mixed thoroughly and col~ essed to form tablets of ~plo~Li~ately 10 mm ~ which are concave on both sides and have a breaking groove on the upper side.
F.x~ ple 1 1 ,~
Tablets, each co,~ 10 miltigr~m.c of active ingredient. can be p~ cd in the S following lllam~
Co~position (for 1000 tablets) active ingl~dielll 10.û grams lactose 328.5 grams corn starch 17.5 grams polyethylene glycol 6000 S.0 grams talc 25.0 grams m~.. Pc;.. , stearate 4.0 grams 11~ .1l;nf'r.~li7Prl water q.s.
The solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the lS active i-lgrediclll, lactose, talc, m~.,P~ , stearate and half of the starch are i..l;ln-lely mixed. The other half of the starch is ~ çn~lpcl in 65 millilhPr.~ of water and this s~ Pncio.-is added to a boiling solution of the polyethylene glycol in 260 millilitPrs of water. The resllltin~ paste is added to the pulverulent sub~ulces, and the whole is mixed and gran~ te~
if .-Pcesc~.y with the addition of water. The granulate is dried overnight at 35~C, forced 20 through a sieve of 1.2 mm mesh width and co~ ;ssed to form tablets of d~ox;ll~ ly 10 mm .li,.,.,.,t~ ~ which are concave on both sides and have a breaking notch on the upper side.
FY~n~ple 12 Gelatin dry-filled c~rs~les, each co..~;n;.-~ 100 milli~r~ of active ingredient, can be ~a~cd in the following ll~lllcl.
Co~osi~ n (for 1000 ç~rs~ s) active ingredient 100.0 grams llliC~Cl ~:~lline ce~ lose30.0 grams sodium lauryl s~ h~tP 2.0 grams g~ A;.llll stearate 8.0 grams W O 97108143 PCT~US96/14077 The sodium lauryl slllph~te is sieved into t_e active illgl~diel-l through a sieve of 0.2 mm mesh width and the two com~ul~llL~ are i..~ Ply mixed for 10 ...;..~ . The micro-;ly~L~lline celll-lose is then added Lllluu~h a sieve of 0.9 mm mesh width and the whole is again i..li...,.lely mixed for 10 ...;..~ s. Finally, the m~ stearate is added thluugh a S sieve of 0.8 mm width and, after mixing for a furt~er 3 ~nimlt~s~ the llliAlUlC, iS introduced in portions of 140 milligram~ each into size 0 (elong~ttq(l) gelatin dry-fill ç~ps~ os.
F.x~ml~le 13 A 0.2% injection or infilsi~ solution can be pl~ d, for example, in the following llla"ll~ .
active ill~;lcdien~5.0 grams sodium chloride22.5 grams phosph~te buffer pH 7.4 300.0 grams de---;-,- .. lized waterto 2500.0 millilher.~
The active i~lediell~ is dissolved in 1000 milliliters of water and filtered through a microfilter or slurried in 1000 mL of H20. The buffer solution is added and the whole is made up to 2500 millilit.or~ with water. To prepare dosage unit forms, portions of 1.0 or 2.5 milliliters each are illLlu~luced into glass ampoules (each u~ .g lespe~lively 2.0 or 5.0 rnilligrams of active hl~lediellL).
Ba~ d of the I~v~ ol~
The present invention relates a method of re~vring levels of TNFa in a ~ 1 and to cu~ vunds and compositions useful therein.
TNFa, or tumor nec.osis factor a, is a cytokine which is released primariIy by ~o~ l.r1e~r phagocytes in l~s~G,~e to various ;.~ o~ tnr.s. When a~l...in;~t~red to animals or 1 nlm~n~ it causes i--n~-.---.~ion~ fever, cal~iov~ lar effects, h~ o, .1.5~ge7 Co~ tio7t and acute phase r~s~ollscs similar to those seen during acute infections and shock states.
FX~s~ive or unregulated TNFa production has been implicated in a l.ullll)el of disease con~1itit)nc These include endoto~Pmi~ and/or toxic shock ~ylld~ulllc {Tracey et al., Nature 330, 662-664 (1987) and Hinshaw et al., Circ. Shock 30, 279-292 (1990)}; c~rl~ {Dezube et al., Lancet, 335(8690), 662 (1990)}; and Adult Re~ildL~ly Distress Syl~lr~lue where TNFa collcc~ dlion in excess of 12,000 pglmillilit~rs have been ~I~?tected in p~ n~ y- asl.hd~s from ARDS patients {Millar et al., Lancet 2(8665), 712-714 (1989)}. Sy~l~.nic infil~icn of recombinant TNFa also resulted in c~ g~s typically seen in AR~S {Ferrai-Baliviera et al., Arch.
Surg. 124(12), 1400-1405 (1989)}.
TNFa appears to be involved in bone resorption ~ e5, in-~ln~ a,~ is where it hasbeen ~ lr~ " ~ FA that when a~;Liv~ d, leukocytes will ~lc luc~ a bone-l~s~ll,illg activity, and data sug~est that TNFa cc,llLLil,ul~s to this activity ~Bertolini et al., Nature 319, 516-518 (1986) and Johnson et al., Endocrinology 124(3), 1424-1427 (1989)}. It has been r1~ t~""i~ that TNFa stim~ t~ bone resorption and inhibits bone form~tion in vitro and in vivo through stim~ tion of osteoclast forrnation and activation colllbhled with inhibition of osteoblast fimrtion Although TNFa may be involved in many bone resorption ~ s, inr~ arthritis, the most coInpellin~
link with disease is the association be~ l production of TNFa by tumor or host tissues and m~ n~nry associatedhyperc~ {Calci. TissueInt. (US) 46(Suppl.), S3-10 (1990)}. InGraft versus Host ~ction~ increased serum TNFa levels have been ~soci~l~d with major complications following acute allogenic bone lnallUW transplants ~Holler et al., Blood, 75(4), 1011-1016 (1990)}.
~ Cerebral malaria is a lethal hypela~;u~ neurological ~ylldlull~c ~csoci~t~-i with high blood levels of TNFa and the most severe complication oc~;ulling in malaria p~ti~ntc Levels of serum TNFa coll~lalc;d directly with the severiy of the disease and the plu~llosis in pà~iellLs with acute malaria attacks {Grau et al., N. Engl. J. Med. 320(24), 1586-1591 (1989)}.
W O 97/08143 PCTrUS96/14077 TNFa also plays a role in the area of chronic plll.,,on~y ;..n ~ y ~ c~s ~hedepQ.~ition of silica particles leads to ~iliro.~ a disease of yluglessi~e l~SpuaLuly failure caused by a fibrotic re~rtinn Antibodies to TNPa completely blocked the silica-in~ re~l lung fibrosis in mice {Pignet et al., Nature, 344:245-247 (1990)}. High levels of TNFa y~u~ n (ill the 5 serum and in isolated ,~a~oyllages) have been delnul~Lialed in animal models of silica and asbestos i..rl.~red fibrosis ~Bisso~ e et al., ~nflammation 13(3), 329-339 (1989)}. Alveûlar macl~hages from pUlll~l)~y sarcoidosis patients have also been found to yun~e-ou~.ly release massive qn~ntities of TNFa as coll-ydl~d with macrophages firom normal donors {R?~nghm~n et al., J. Lab. Clin. Med. 115(1), 36~2 (1990)}.
TNFa is also implicated in the i-~n~ .y response which follows rC~Clru~iOn, called L~elÇu~ion injury, and is a major cause of tissue damage after loss of blood flow {Vedder er al., PNAS 87, 2643-2646 (1990)}. TNFa also alters the ~lo~cl~ies of endothelial cells and has various pro-coagulant activities, such as producing an increase in tissue factor pro-co~ nt activity and ~uyylt;SSiOn of the ~ntit~s~ulant protein C L~aLllway as well as down-regulating the tAyl~,ssion of ll.rul,ll,o.. -d-llin {Sherry et al., J. Cell Biol. 107, 1269-1277 (1988)}. TNFa has pro-infl~ ..ly ac;LiviLies which tog~LI~l with its early procl~ction (during the initial stage of an infli~ ly event) make it a likely .n~ or of tissue injury in several illlyOl~lll disu-~
in-ln~lin~ but not limited to, llly~aldial infarction, stroke and circulatory shock. Of ~.e~;l;c i~yOl~lCC may be TNFa-in-lllred e~l~ ion of adhesion molecules, such as intercellular adhesion molecule (ICAM) or endothelial leukocyte ~lh~sion molecule (ELAM) on endothelial cells {Munro et al., Am. J. Path. 13~(1), 121-132 (1989)}.
Moreover, it is now known that TNFa is a potent activator of retrovirus replication activation of HIV-l. {Duh et al., Proc. Nat. Acad. Sci. 86, 597~5978 (1989); Poll et al.~ Proc. Nat. Acad. Sci. 87, 782-785 (1990); Monto et al., Blood 79, 2670 (1990); Clouse et 2'S al., J. Imm~nol. 142, 431~38 (1989); Poll et al., AIDS Res. Hum. Retrovirus, 191-197 (1992)} .
AIDS results from the illre~Lion of T ly~ ho-;yles with Human Tllllll~ rriri~ y Virus (HIV).
At least three types or strains of HIV have been i~ rird~ i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV ;--Lcl;u~-, T-cell ...eA;~ ;ly iS il~ ailcd and infected individuals .-.~,.ir. ~l severe V~ulLulli:~ic infections and/or unusual neoplasms. HIV entry into the T
30 lymphocyte requires T Iymphocyte activation. Other viruses, such as HIV-1 and HIV-2, infect T lymphocytes after T cell activation and such virus protein e~l.r~,s:,ion and/or replication is mP.~ ted or ...~ ;.;..rd by such T cell activation. Once an activated T lymphocyte is inf~ctetl -PCTrUS96/14077 with HIV, the T lymphocyte must co~ we to be m~int~inpd in an activaled state to permit HIV
gene e~ies~ion and/or HIV rep1i~-~tiQn. Cytokines, slJEcirlr~lly TNFo~, are implicated in acti-vated T-cell ...Fdi~ HIV protein e~ ssion andlor virus replication by playing a role in T Iymphocyte activation. Th~.~ro,e, hlL~lr.,~ ce with cytokine activity such as by 5 pl~v~.lLion or inhibition of cytokine production, notably TNE~a, in a HIV-infPctP~ illdividùal aids in l;...il;l,g the Ill~;lllrl~nre of T Iymphocyte activation caused by HIV infection.
Mo~ y~s, n aclopha~,es, and related cells, such as kupffer and glial cells, have also been implicated in ~n~ e of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activatio~ state of the cells 10 {Rosellbelg et al., The Immunopat~logenesis of HIV Infection, A~lv~ces in Tlll~llology, ~7 (1989)}. Cytokines, such as TNFa, have been shown to activate HIV replication in l.~ono-~t~s and/or macrophages ~Poli et al. Proc. Natl. Acad. Sci., 87, 782-784 (1990)}, lll.,.cr~
prevention or inhibition of cytokine production or activity aids in limitin~ HIV pL~ i,sion as stated above for T cells. A(lditic-n~l studies have j~lpntifipd TNFa as a common factor in the activation of HIV in vitro and has provided a clear mP~h~ni~m of action via a nuclear regulatory protein found in the cytoplasm of cells (Osborn, et al., PNAS 86, 2336-2340). This evidence suggests that a reduction of TNFa synthesis may have an antiviral effect in HIV infections, by re~1ncin~ the L~sc~ ion and thus virus production.
AIDS viral replication of latent HIV in T cell and macrophage lines can be in~ red by TNFa {Folks et al., PNAS 86, 2365-2368 (1989)}. A molecular ",Prl.~ ", for the virus in-lncing activity is suggested by TNFc~s ability to activate a gene regulatory protein (NFlcB) found in the cytoplasm of cells, which plOmO~t;S EIIV replication through binding to a viral regulatory gene seq~l~nre (LTR) {Osborn et al., PNAS 86, 2336-2340 (1989)}. TNFoc in AIDS
~csori~tPrlc~rh~yi~is suggested by elevated serum TNFcc and high levels of spontaneous TNFx production in peripheral blood monocytes from patients {Wright et al. J. Immunol. 141(1),99-104 (1988)}.
TNFcc has been implicated in various roles wi~ other viral infections, such as the ~y~ Fg~ virus (CMV), inflllen7~ virus, adenovirus, and the herpes family of viruses for similar reasons as those noted.
Pl~e.~ g or inhibi~ g the production or action of TNFx (e.g. with ~r~tll.f ~,l with the compounds of this illvcll~ioll) is, Ll,~.crole, predicted to be a potent ~ e~ LldLcgy for many ;.,n5.-.. ~,c~ly~ infectious, immlmnlogical or m~lign~nt r1ice~es These include but are not W O 97/08143 PCT~US96/14077 ~ i.;Lc;d to septic shock, sepsis, Glldvlu~c shock, hemo lyl~lic shock and sepsis sy,lLo~e, post i~r1.~.n;r ~ ruiion injury, malaria, mycobacterial il~Lion, ~ ;e, IJ~O1;~;C, congci~liv~
heart failure, fibrotic disease, cacl.- Y ;A, graft rejection~ cancer, aulù;l.~ disease, o~olLuni~Lic infections in AIDS, .~ oid ~l~h.ilis"l. ~.~ uid spondylitis, o~o~iLis, other a~ ilic 5 cU~ io~ Crohn's disease, ulcerative colids, multiple sclerosis, ~y~t-,,llic lupus e,yLl~ lu~;c, ENL in leprosy, radiation damage, and hyperoxic alveolar injury. Efforts directed to the su~ s~ion of the effects of TNFc~ have ranged from the nfili7~tion of steroids such as dexa-lllcillasol~ and pl~,dnisolone to the use of both polyclonal and monoclonal antibodies {Beutler et al., Science 234, 470-474 (1985); WO 92/11383}.
The nuclear factor lcB (NFKB) is a pleiotropic ~.d~ Lional activator (Lenardo, et al.
Cell 1989, 58, 227-29). NFl~B has been implicated as a Llailscli~Lional a~;~ivalor in a variety of disease and ;.,n~ states and is thought to regulate cytokine levels in~ln(lin~ but not limited to TNFa and also to be an a.;Li~dlul of HIV tlansclil.~ion (Dbaibo, et al. J. Biol. Chem. 1993, 17762-66; Duh et al. Proc. Natl. Acad. Sci. 1989, 86, 5974-78; Ba~ ie et al. Nature 1991, 350, 709-12; Boswas et al. J.. Acquired T.. ,.~"~ Deficiency Sy~ ome 1993, 6, 778-786; Suzulci et al. Biochem. And Biophys. Res. Comm. 1993, 193, 277-83; Suzuki et al. Bior~lPrll- And Biophys. Res Comm. 1992, 189, 1709-15; Suzuki et al. Biochem. Mol. Bio. Int. 1993, 31(4), 693-700; Shak'hov et al. 1990, 171, 3547; and Staal et al. Proc. Natl. Acad. Sci. USA 1990, 87, 9943~7). Thus, inhibition of NFIcB binding can regulate ~ ~cliL,lion of cytokine gene(s) and 20 ~lru~ll this mn~ tioIl and other ",P~ c be useful in the i~ .oll of a mllltihl~ito of disease states. The culll~uullds claimed in this patent can inhibit the action of NFlcB in the mlclPllc and thus are useful in the ~ I of a variety of di~ce,c inr~]~din~ but not lirruted to .l-. ~ foicl a~ is"l.~ id spondylitis, osteoa,LLuilis, other arthritic colldiLions, septic shock, septis, ~n-loto~ic shock, graft versus host rlice~ce, waSLillg, Crohn's disease, ulcerative colitis, mnl~irle 25 scl~o~is, ~y~ lic lupus e.yllu~ cic, ENL in leprosy, HIV, AII:)S, and oppu,Lulli~Lic infections in AIDS.
TNFa and NFKB levels are infll~en~ed by a reci~rocàl feedb~cl~ loop. As noted above, the compounds of the present invention affect the levels of both TNF~ and NFlcB. It is not known at this time, however, how the compounds of the present invention regulate the levels of 30 TNFoc, NFlcB, or both.
Many cellular ~ln-~tio~c can be "--o~ ttod by levels of ~ nosillF 3',5'-cyclic ullul~ho~l~h~(cAMP). Such cellular functions can collLlibule to infl~"...._lo.,y conditions and W O 97/081~3 PCTAUS96/14077 e~ces including a~thm~ ;oll, and other colldi~iolls ~Lowe and Cheng, Drugs of the Future, 17(9), 799-807, 1992). It has been shown that the elevation of cAMP in i~
l~uko~;yLcs inhibits their a;Livalion and the su~sc~luent release of i"n;.,.,~ tOl,~ ...P(~ ,J i.
Illcreased levels of cAMP also leads to the re~ tion of airway smooth muscle.
The ~ cellular ~-.Pr~ --- for the inacLivaLioll of cAMP is the breakdown of cAMP
by a family of isoe.~yl~les lefclled to as cyclic nucleotide ph-)srh~ iPstPr~ces(PDE). There are seven known lll~lll~LS of the family of PDEs. It is leCO~l~i2e;i, for e~i~...ple, that the inhibition of PDE type IV is particularly crfeclive in both the inhibition of ;.. nZ.. ,.~Oly me~i~tQr release and the rel~ tion of airway smooth muscle. Thus, COlll~oul ds that inhibit PDE IV ~I,~ircally, 10 would exhibit the desirable inhibition of ;~.n~".,~ ;on and rela~cation of airway smooth muscle with a ...i..i....~." of u~w~lltd side effects, such as cardio-vascular or anti-platelet effects.
Cullclllly used PDE IV inhibitors lack the sel~;livt; action at arcept~hle lhel~euLic doses.
The com~u~lds of the present invention are useful in the i~ iLion of phncpho.l;~ ,L~ s, particularly PDE III and PDE IV, and in the ~ l"e.,l of disease states mPAi~terl thereby.
15 Detailed Des~.;ylion The present invention is based on the discovery that a c,lass of non-polypeptide imides more fully described herein appear to inhibit the action of TNFc~.
The present h.-,e.-lioll ~e~ s to co.n~u~..ds of the formula:
o R~ ~N ~ H-(CH2)~Y
R~ ~,7 in which:
Y is -C--N or -C(CH2)mCH3;
m is 0-3;
R5 is: (i) o-phenylene, lln~llb~ "lP(1 or sn'c stitllt~d with one or more s~lbstit lent~ each select~d independently from nitro, cyano, trifluolo~ llyl, carbethoxy, ca~ l-o~y, ~bo~lopo~Ly, acetyl, ca.ballloyl, ca~ lloyl ..~ Pd with and aLIcyl of 1 to 3 carbon atoms, acetoxy, ca.bo~Ly, hydlo~y, amino, amino ~ ed witn an allyl of 1 to 3 carbon atoms, allyl PCT~US96/14077 of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; (ii) the divalent residue of pyridine, pyrrolidine, imidizole"~ h~ lf n~, or thiophene, W~ till the divalent bonds are on vicinal ring carbon atoms; (iil~ a divalent cycloaL~cyl of 4 - 10 carbon atoms, u~ub~ u~d or ,SI;I~ (1 with one or more ~ e~ ; each select~d ii~ lly of the other from the group 5 co...~ of nitro, cyano, trifluoromethyl, cal~hoxy, c~lJv~ lloxy, c~bo~lu~u~y, acetyl, calb~ulloyl, acetoxy, carboxy, hydroxy, amino, ~.lb~ A. amino, aL~yl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iv) di-~ stihlt-f~d vinylene, sllk,~ (l with nitro, cyano, trifluoromethyl, carbethoxy, Ca1bV111ClhOXY~ ca~bv~lv~o~y, acetyl, callJ~vyl~
~l,~lloyl snhstihltPA with and aL~yl of 1 to 3 carbon atoms, acetoxy, c~l,o,Ly, hydroxy, amino, 10 amino sul,~ lecl with an alkyl of 1 to 3 carbon atoms, aLkyl of 1 to 4 carbon atoms, aIkoxy of 1 to 4 carbon atoms, or halo; or (v) ethylene, ~h.~lb5l;l~ or ~ub~ /r~ with 1 to 2 ~ b~ t~;
each scl~ct-d indepen~lfntly from nitro, cyano, trifluolulll~,~yl, carbethoxy, cdllJol..~ y, callJv~lu~o~y, acetyl, ca~ uloyl~ carbamoyl sllbstit~lt-f d with and alkyl of 1 to 3 carbon atoms, acetoxy, c~l,o~y, hydlu~Ly, armino, amino, ~ with an aL~cyl of 1 to 3 carbon atoms, alkyl 15 of 1 to 4 carbon atoms, aLkoxy of 1 to 4 carbon atoms, or halo;
R6 is -CO-, -CH2-, -CH2CO-, or -SO2-;
R7 is (i) straight or l..~ f d aLlcyl of 1 to 12 carbon atoms; (i~ cyclic or bicyclic aLlcyl of 4 to 12 carbon atoIns; (iil~ pyridyl; (iv) phenyl subsLiLulcd with one or more sllbstitll~.nt~ each sel~tfA~ f~ fntlyoftheotherfromnitro,cyano,Lli~luClu~ ,Lllyl,c~l,~w~y, c~l,.. ~ y, 20 CO1IJO~1OPO~Y~ acetyl, c~lJdllluyl, acetoxy, carboxy, Ly~u~Ly, amino, straight, blallched, cyclic, or bicyclic aLkyl of 1 to 10 carbon atoms, straight, bl,..~rl-~(l, cyclic, or bicyclic aLkoxy of 1 to 10 carbon atoms, CH2R where R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms, or halo;
(v) benzyl ~bs~ with one to three ~ "l~i each selff~te~ d~,pendclllly from the group cc....~ of nitro, cyano, trifluolo..l~hyl, call~cllloky, c~bu...~ nxy, calllo~lupoxy, acetyl, . 25 c~l,~luyl, acetoxy, carboxy, hy~lloxy, amino, allyl of 1 to 4 carbon atoms, aLkoxy of 1 to 10 carbon atoms, or halo; (vi) l~l)hlllyl; or (vii) benzyloxy;
and, where n has a value of 0, 1, 2, or 3;
A first pl~rcllcd sllbcl~cc p~.~i,ls to compounds in which:
Y is -C-N;
Rs is o-phenylene, ~ubsl;l~ ,cl or ...~.~ub~
R6 is -CO- or -CH2-;
R7 is an aryl; and nis 1.
Typical compolmds of this invention include:
S -CO- 3,4~imrthc)xyphenyl -CO- 3~tho7cy~-methoxyphenyl -CH2CO- 3,4~imPthoxyphenyl -CH2CO- 3-ethoxy~-methoxyphenyl -CO- 3-propoxy4-metho~y~h.,.lyl -CH2CO- 3-propoxy4-me~oxyphenyl -CO- 3-cyclopentoxy-4-methoxyphenyl (cyclopentoxy = cyclic C5HgO-) -CH2CO- 3-cycl~ycllLu~y4-methoxyphen -CO- 3,4~1iule~hylyhenyl -CO- 3-ethoxy4~y~ hellyl -CH2- 3,4-dimetho~yyhe~lyl -CH2- 3-ethoxy4-methoxyphenyl -CH2- 3,4-diul~lylyhellyl Tbe term alkyl as used herein denotes a univalent 5,,l.. ".~ clled or str~i~ht hydrocarbon chain. Unless uLll~. wi~e stated, such chains can contain from 1 to 18 carbon atoms.
Re~,lf,sf~ e of such alkyl groups are methyl, ethyl, propyl, isoyrvyyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoyc,.llyl, u~oycLlLyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, uu~euyl, dodecyl, tridecyl, tetradecyl, pf nt~(ltocyl~ hf-Y~-1.ocyl, heptadecyl, octadecyl, and the like. When ~u~liftto~ by "lower", the alkyl group will contain from 1 to 6 carbon atoms. The same carbon content applies to the parent term "aLkane" and to de~ivative terms such as "aL~coxy".
The term cycloalkyl (or cyclic aLkyl) as used herein denotes a univalent saturated cyclic hydrocarbon chain. Unless oLlleL~ise stated, such chains can contain from 1 to 18 carbon atoms.
R~yl~se~ e of such cycloaLkyl groups are methyl, ethyl, ~;y~lopluy~l, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclo~odff~yl, cycloLIide.;yl, cyclotetradecyl, cyclop~n~ cyl, cyc~hrY~fl.ocyl, cycloheptadecyl, cyclooctadecyl, cyclic l~y~ 5, and the like. When q~ fird by "lower", the cycloaLkyl group will contain from 3 to 6 carbon atoms. The same carbon content applies tO the parent term "cycloalkane" and to d~Li~a~ e terms such as "cyclo~lkoxy".
The colllyuu~ds can be used, under the supervision of qualified ylor~sionals~ to ~nhibit the undesirable effects of TNFa and/or phrt~phf llircl~, ce~. The collly-)uuds can be ~ ;";~ d 3~ orally, rectally, or y~e~lh~dlly~ alone or in col.. bi~ion with other ~ .a~culic agents inr.llltlin~
W O 97/08143 PCT~US96/14077 antibiotics, steroids, etc., to a ...~ 1 in need of L~ o,ll Oral dosage forms include tablets, c~rs111Ps, dragees, and similar shaped, co~ ressed ph~rm~re11tir~1 forms. Isotonic saline solutions co.~ ;n~ 20-100 milligrams/mi11ilitPr can be used for ~alullL~làl ~r1.n;n;~l.aLion which inr~lrlPs illLl~ r, illLlaLIlecal, intravenous and intra-arterial routes of ~ il aLion. Rectal S a~ .aLion can be effecteri through the use of supposiLclics forrn111~te(l from col~ lLiorlal carriers such as cocoa butter.
Dosage l~;"~r ~ must be titrated to the particular inriir~tir)n the age, weight, and genersl physical conrlitir)n of the patient, and the lc~onse desired but generally doses will be from about 1 to about 1000 milligramslday as needed in single or multiple daily ~h..;..;~alion. In general, 10 an initial Ll~n~ f .1 Lc~hnell can be copied from that known to be erre-;l~ve in hl~f .Ç~.i~ with TNFa activity for other TNFoc IllP~ lrcl disease states by the compounds of the present h~ Lioll.
Treated individuals will be regularly rhPc~pA for T cell numbers and T4/T8 ratios and/or easul~s of vh~,nia such as levels of reverse ~à~,cli~Lase or viral ~lolchls, and/or for progression of cytokine~ lrd disease associated problems such as c~rhPYi~ or muscle 15 dcge.l.,.dlion. If no effect is observed following the normal L.~ ..f~ , then the amount of cytokine activity hlLf .Ç~.,ng agent ~ d is illulf ascd, e.g., by fifty percent a week.
The compounds of the present invention can also be used topically in the Lle~l~..f..l or prophylaxis of topical disease states mPflj~tPcl or exacerbated by excessive TNFa production, such as viral infections, for example those caused by the herpes viruses or viral conj~ ;LiviLis, psoriasis, other skin disorders and ~iic~P~cesJ etc.
The compounds can also be used in the vt;~ inaly ll.~l.. l.. l of .. i.. ~1~ other than h-1m~nc in need of ~lcve~.Lion or inhibition of TNFa pro.1.~r! ion TNFoc mPAi~tf ~ P~cf~c for f ~~ a~wuLically or ~lo~hylactically, in animals include disease states such as those notcd above, but in particular viral illr~Lions. Examples include feline immnnn~PfiriPnry virus, equine 25 inff ctiollc ~n~Pmi~ virus, caprine a,Ll~ is virus, visna virus, and maedi virus, as well as other lentiviruses.
~ ertain of these coll~o~ ds possess centers of chirality and can exist as optical isomers.
Both the r~f ~..~lf s of these isomers and the individual isc.ll~ tll.,~sclves, as well as dia~ ,oisol"~ when there are two chiral centers, are within the scope of the present invention.
30 The ~ e-.~lf,, can be used as such or can be sr~ alp~l into their individual isomers ,~.fLrl~ 11y as by cl~,ll-aLography using a chiral abso-l,e~lt. ~ ly, the individual isomers can be ~a~ed in chiral form or se~al~led cl.~ lly from a mixture by r~"lllin~, salts with a chiral W O 97J08143 PCT~US96/14077 acid, such as the indi\~i~lual en~ntil~m~r~ of lO~l~hoi~..lforir. acid, cam~hulic acid, alpha-c~...phrJric acid, methokyaceLic acid, tartaric acid, ~liac~yl~i~ acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, and then freeing one or both of the resolved bases, optionally ~ the process, so as to obtain either or both isomers subst~nri~lly free of the S other, i. e., in a form having an optical purity of > 95 % .
F~ ion or inhibition of ~ l ion of TNF~ by these co~ u~ds can be CU11~G~ 1Y
assayed using methods known in the art. For e~r~mple, TNF~ Inhibition Assays in LPS
stim~ trd PBMC have been ~c~rull-led as follows:
PBMC ;~Q1~t;~n~ PBMC from normal donors were ol~ .ed by Ficoll-Hypaque density cellllir.lgation. Cells were culhlred in RPMI ~u~)k ~-r ~lrd with 10% AB~
serum, 2mM L-~ 100 U/rnL penicillin and 100 ~g/mL ~ olllycill.
PBMC ~ -.c- Drugs were dissolved in DMSO ~Sigma ChloTnir~l), further dilutions were done in supplem~ntPd RPMI. The final DMSO co..rP~ ;on in the ~l~SG.lCc or ~hs~onre of drug in the PBMC sllsI~pn~ n~ was 0.25 wt %. Drugs wereassayed at half-log dilutions starting at 50 ~g/mL. Drugs were added to PBMC (106 cells/mL) in 96 wells plates one hour before the ~1dition of LPS.
Cell ~ PBMC (1O6 cells/mL) in the ~lcs~"~ce or ~hsenre of drug were stim~ t~l by ~ I with 1 ~g/mL of LPS from Salmonella minnesota R595 (List Biological Labs, Campbell, CA). Cells were then i~rub~tP~I at 37~C for 18-20 hours.
S~ f .l~i were then ha~ ~d and assayed ;............ l;;.l~ly for TNFa levels or kept frozen at -70~C (for not more than 4 days) until assayed.
TNFa D~ lion: The col-~r~-l-aLion of TNFa in the SU~f~ WâS
de~ ...;.)rd by human TNFa ELISA kits (ENDOGEN, Boston, MA) accol-l.~ to the m~nnf~r.hlrer's dih~.liulls.
2~ The compounds can be ~ aled using mPthorlc which are known in general for the .dl;nl~ of nitriles. General reaction srh.omrs are illllctr~t~ by the formulas:
lil) R6 ~N--CO2E t ~ ~CO2H ' R~ ,Nl~CO2EI
or R~ HN~L(CEI2)1rX ~ ~ R7 1) Acti~rate 0 7 ~ R7 CDI or U R
R6 2 ) NH3 Rs/\N~CONH2 or 3) R5RNl~CoNEI Dehydrate R 1~C=N
5 where X is CO2H, CONH2, or CN
The following e~ pl- s will serve tO filrther ~pify lhe na~re of ltbis ill~ ion but should not be construed as a limit~tion in the scope thereof? which scope is defined solely by the ~ppPn-l~P~l claims.
W O 97/08143 PCT~US96/14077 Fx~n~ple 1 3-Phth~ 3-(3,4d;~thoxyphe ,~I)pr~ ;~ile.
To an ice bath cooled stirred ~ e-l~;;oll of 3-phth~limiflo-3 (3,4-diethoxyphenyl)propion~mi~1~ (0.96 g, 2.5 mmol) and 4~ yllllorpholine (0.66 mL, 6 mmol) S in DMF (9 mL) under nitrogen, was added thionyl chloride (0.35 mL, 4.8 mmol) dlc,yw~e.
There was a slight exotherm after which the lllL~ lC was stirred at 0 - 5~C for 30 l~ ~c and at room Lel,l~claLulc for 2 hours. The led~iLion was ~ u~d by HPLC (Waters Nova-PaklC-18 column, 3.9xlS0 mm, 4 micron, 1 mL/min, 240 nm, 50/50 CH3CN/H3PO4 0.1%(aq)). Thel~a~liull ll~lule was poured into a llfuL~ of NaHCO3 (8.5 mL) and ice (40 g) and stirred until the ice had lmelted. The ~ lule was filtered and the solid was washed with copious amounts of H20. The wet solid was dissolved in C~CI2 (25 mT ) and the organic layer was se~ P~ and dried over MgSO4 and cf ~ i in vacuo to a sticly semi-solid. The solid was ~ulirled twice by flash column elll~ o~ hy (silica gel, 3% ethyl acetate/methylene chloride) to afford a solid which was dried in vacuo (50~C, < 1 mm) to afford 0.5 g (55%) of ~lO-lU~;I, as a pale yellow solid; 'H NMR (CDCl3) o 7.91-7.65(m, 4EI), 7.12-6.98(m, 2EI), 6.90-6.78(m, lH), 5.61(dd, J
= 6.4, 10.3 Hz, lH), 4.19-3.96(m, 4H), 3.83(dd, J = 10.3, 16.8 Hz, lH), 3.26(dd, J = 6.4, 16.8 Hz, lH), 1.55-1.30(m, 6H); 13C NMR (CDC13) o 167.7, 149.2, 148.9, 134.3, 131.5, 129.1, 123.6, 120.2, 116.9, 113.2, 112.9, 64.7, 64.5, 51.1, 21.1, 14.7; HPLC 98.4 %. Anal. Calcd for C2~H20N~O4. Theo.cLical: C, 69.22; H,5.53; N,7.69. Found: C, 69.06; H, 5.48; N, 7.58.
F.Y~m~ple 2 3 ph~hs~ 3 (3,/1 "l;... ~ y~lh..yl)propionitrile To an ice bath cooled stirred ~ el-~ion of 3-phth~limit1Q-3-(3,4-~im.oth~ y~ lyl)~r~;.~ (1.77 g, 5.00 mmol) and 4-1llt~hllu~ oline (1.3 mL, 12 mmol) in DMF (17 mL) under N2, was added thionyl cloride (0.7 mL, 9.6 mmol) dr~ise via a 25 syringe. There was a slight exotherm and after 30 minutes the cooling bat_ was ~ ved and the reaction llli~LIUl~, was stirred for 2 hours at room hm~lalule~ The reaction llliAIUlC; was poured into a mixture of NaHC03 (17 g) and 75 mL of ice water and stirred until the ice h-ad melted. The slurry was filtered and the solid was washed with copious ~ of H20. The wet solid was dissolved in CH2Ck (50 mL) and the organic layer was s~d,dted, dried over2Na4SO, and co.lc~,l.LldLed in vacuo to afford an orange solid. The solid was purified by flash column clllolllatography (silica gel, 5/95 EtOAc/CH2C12, 50 mm id column) to afford 1.32 g (79%) of S the product as a white solid: IH NMR (CDCl3) ô 7.9-7.6(m, 4H), 7.10 (m, 2H), 6.83 (m, lH), 5.64 (dd, J = 6.5, 10.2 Hz, lH), 3.88 (s, 3H), 3.85 (s, 3H), 3.82 (dd, lH), 3.30 (dd, J = 6.5, 16.8 Hz, 1 H); '3C NMR (CDC13) ô 167.7, 149.5, 149.2, 134.4, 131.5, 129.1, 123.6, 120.1, 116.9, 111.1, 110.7, 56.0, 55.9, 51.1, 21.1. Andl. Calcd for Cl9H,6N204-0.18 ~ O.
The~"~,Li-,al: C, 76.2; H,4.85; N,8.25. Found: C, 67.23; H, 4.79; N, 8.27.
FY~m~ple 3 3-(3'-Nitrophthalimido)-3-(3'-ethoxy-4'-metho~y~ I)propionitrile A stirred ~- .~e. ~ n of 3-niLIulJl .~ lic anhydride (0.24 g, l .13 rnmol) and 3-amino-3-(3 '-ethoxy-4'-methoxyphenyl)propionitrile (0.25 g, l .13 rnmol) in 6 mL of acetic acid was heated to reflux under nitrogen for 12 hours. The acetic acid was removed in vacuo to afford an orange 15 gum which was dissolved in methylene chloride (10 rnL) and was washed with a s~tl~r~tP~1 aqueous solution of sodium bicarbonate (2 x 10 mL). The organic layer was s~ rd and the aqueous layer was extracted with methylene chloride (10 mL). The combined organic extracts were dried over m~nP~ m sulfate, filtered and con- P.ntr~t~d in vacuo to afford a yellow oil. The crude product was purified by flash column cl~ollldlography (silica gel, 5% ethyl 20 acetate/methylene chloride) and the resulting solid was dried in vacuo (60~C, < I rnm) to afford 0.25 g (56%) ofthe product as a yellow solid: mp 155.5-157 ~C; 'H NMR (CDCl3) o 8.20-8.09 (m, 2 H), 8.02-7.86 (m, l H), 7.15-7.02 (m, 2 H), 6.88-6.76 (m, 1 H), 5.64 (dd, J = 6.3, 10.6 Hz, 1 H), 4.09 (q, J = 7 Hz, 2 H), 3.85 (s, 3 H), 3.84 (dd, J = l0.6, 16.7 Hz, l H), 3.26 (dd, J = 6.3, 16.7 Hz, 1 H), 1.46 (t, J = 7 Hz, 3 H); ~3C NMR (CDC13) o 165.3, 162.3, 150.1, 148.7, 144.9, 135.7, 133.5, 129.0, 128.1, l27.4, 123.2, 120.3, 116.6, 112.1, 111.5, 64.6, 55.9, 51.9, 20.9, 14.7;
Anal. calcd for C2oHI7N306. Theoretical: C, 60.76, H, 4.33; N, l0.63. Found: C, 60.59, H, 4.22;
N, 10.65.
W O 97/08143 PCTnJS96/14077 Fx~n~?le 4 3-(3'-Aminop~ o)-3-(3~-ethoxy-4~ etho~lJh; ~I)propionitrile To a solution of 3-(3'-1~,llo~.~"l,~limi(lQ)-3-(3'-ethoxy- 4'-methoxyphenyl)propionitrile (0.2 g, 0.5 mmol) in 30 mL of ethyl acetate was added 0.05 g of 10% p~ m on carbon catalyst. The S ~ Lulc was hydrogenated in a Parr-Shaker ~ aLus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was cOl~'r~ in vacuo to afford a yellow oil. The crude product was purified by flash column cl,~ rhy (silica gel, 3% ethyl acetate/methylene chloride). The rP~nltin~ yellow solid was then dried in vacuo (60~C, < 1 mm) to afford 0.09 g (50%) of the product: mp 171 -172.5 ~C; 'H NMR (CDCl3) 8 7.47-7.35 (m, 1 H);
7.19-7.00 (m, 3 H), 6.90-6.29 (m, 2 H), 5.56 (dd, J = 6.6, 10 Hz, 1 H), 5.24 (s, 2H), 4.09 (q, J = 7 Hz, 2 H), 3.84 (s, 3 H), 3.77 (dd, J = 10, 16.8 Hz, 1 H), 3.27 (dd, ~ = 6.6, 16.8 Hz, 1 H), 1.45 (t, J
= 7 Hz, 3 H), ~3C NMR (CDCl3) o 169.4, 167.9, 149.6, 148.5, 145.5, 135.5, 132.1, 129.4, 121.3, 120.0, 117.1, 113.0, 112.2, 111.4, 110.6,64.5,55.9,50.7,21.1, 14.7;HPLC(WatersNova-Pak C,8 column, 3.9 x 150 mm, 4 micron, 1 mL/min, 240 nm, 40/60, CH3CN/0.1% H3PO4(~q~) 4.5 min, 100%; Anal. calcd. for C20HIgN3O4. Theoretical: C, 65.74, H, 5.24, N, 11.50. Found: C, 65.54; H, 5.23; N, 11.23.
FY~m,ple S
3 ph" -I ~'o 3-(3'-ethoxy-4'-metho~y~ I)propionitrile Oxalyl ~hlori-le (0.49 mL, 5.64 mmol) was added dropwise to an ice bath cooled stirred solution of DMF (0.48 mL, 6.16 mmol) i~ accLo~JiL,ile (10 mL). A white plc~ipiL~c formed imm~ t~:ly and was accn.,.p~ l by gas evolution. The mixture was stirred for 30 mimlt~ at 2-3 ~C and then a solution of 3-phth~limi-1O-3-(3'-ethoxy-4'-metho~y~,hc,l~l)propionarnide ~1.89 g, 5.13 mmol) in DMF (15 mL) was added slowly. After 10 ~ s pyridine was added and the ll~ e was stirred for 30 minllt~s at 2-3 ~C. The reaction mixture was then poured into 60 mL of ice 25 and stirred for 20 ,;~ es. The slurry was filtered and the solid was washed with water, air dried and then dried in vacuo (60 ~C, < 1 mmHg) to afford 1.7 g (95%) of the product as a white solid:
mp 135-137 ~C; 'H NMR (CDCl3) ~ 7.86-7.71 (m, 4 H), 7.08-7.05 (m, 2 H), 6.84-6.81 (m, 1 H), 5.63 (dd, J = 6.5, 10.3 Hz, 1 H), 4.11 (q, J - 7 Hz, 2 H), 3.88-3.77 (m, 1 H), 3.84 (s,3 H), 3.32-W O 97/08143 PCTrUS96/14077 3.23 (m, 1 H)7 1.45 (t, J = 7 Hz, 3 H); 13C NMR (DMSO-d6) o 167.4, 149.0, 147.8, 134.9, 130.8, 129.2, 123.5, 119.4, 118.2, 112.1, 111.7, 63.8, 55.4, 50.0, 20.5, 14.6; Anal. calcd. for C20H,8N2O4. Theoretical: C, 68.56, H, 5.18, N, 8.00. Found: C, 68.46; H, 5.37; N, 8.02.
F.Y~mple 6 S l-(l'-Oxo-isoindoline)-1-(3', 4'-dimetho~yp~ ~I)propic lle To an ice cooled stirred ~ ion of 1-(1 '-oxo-isoin-loline)-1-(3', 4'-im~thn~y~ ellyl)propion~mi-l~ (1.7 g, 5.0 mmol) and 4-n~elhyll~orpholine (1.3 mL, 12 mmol) in DMF (20 mL) under N2, was added thionyl chloride (0.7 mL, 9.6 mmol) dropwise via a syringe. There was a slight exotherm and after 1 hour the cooling bath was removed and the reaction mixture was stirred for 1 hour at room It;nl~e~alule. The reaction l.lixlLIle was poured into 100 mL of ice and stirred until the ice had melted. The slurry was filtered and the solid was washed with copious amounts of water. The solid was purified twice by flash column chrom~fo~T~rhy (silica gel, 1/9 and 24/76, EtOAc/CH2C12). The reclllting solid was dried in vacuo to afford 0.97 g (60%) of the product as an orange tan solid: mp 119-121 ~C; 'H NMR
(CDCl3) ~ 7.94-7.85 (m, 1 H), 7.61-7.30 (m, 3H), 7.05-6.85 (m, 3 H), 5.73 (t, J = 7 Hz, 1 H), 4.46 (d, J = 16.7 Hz, lH), 4.19 (d, J = 16.7 Hz, 1 H), 3.89 (s, 3H), 3.8~ (s, 3H), 3.23(m, 2 H); '3C
NMR(CDCl3) o 168.5, 149.5, 149.4, 141.1, 131.9, 131.8, 128.7, 128.2, 123.9, 122.9, 119.1, 117.4, 111.2, 111.0, 56.0, 55.9, 51.6, 47.3, 21.1; Anal. calcd for ClgHlgN2O3. Theoretical: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.26; H, 5.56; N, 8.47.
FY~m~le 7 l-(l'-Oxo ~ linc)-1-(3'-ethoxy-4'-metho~p!r ~ ic it~ile To an ice cooled stirred ~u~l~ion of 1~ oxo-isoindoline)-1-(3'-ethoxy-4'-metho~y~ yl)propion~mi~llo (1.0 g, 2.8 mmol) and 4-1llc~lyhnGll~lloline (0.75 mL, 6.8 mmol) in DMF (10 mL) under N2, was added thionyl chloride (0.4 mL, 5.5 mmol) d~ vise via a 25 syringe. There was a slight t Aolll~nl and after 1 hour the cooling bath was removed and the reaction llliAlul~ was stirred for 1 hour at room ~ a~ule. The reaction lllixlul~ was poured into 100 mL of ice and stirred until the ice had melted. The slurry was filtered and the solid was washed with copious amounts of water. The solid was purified by flash column chromatography (silica gel, 1.5/8.5, EtOAc/CH2Cl2). The r~snltin~ solid was dried in vacuo to afford 0.57 g (60%) of the product as an ivory solid: mp 125-125.5 ~C; 'H NMR (CDCI3) ô 7.88 (d, J = 7 Hz, 1 S H), 7.60-7.30 (m, 3H), 7.05-6.80 (m, 3 H), 5.71 (t, J = 6.9 Hz, 1 H), 4.45 (d, J = 14 Hz, lH), 4.20-4.00 (m, 3 H), 3.87 (s, 3H), 3.23 (m, 2 H), 1.44 (t, 7 Hz, 3 H); 13C NMR (CDCl3) o 168.5, 149.7, 148.8, 141.2, 131.9, 131.8, 128.6, 128.2, 123.9, 122.9, 119.2, 117.4, 112.4, 111.5,64.6, 55.9, 51.6, 47.3, 21.1, 14.6; Anal. calcd for C20H20N2O3. Theoretical: C, 71.41; H, 5.99; N, 8.33.
Found: C, 71.11; H, 5.91; N, 8.17.
F~an~le 8 Tablets, each cont~inin~ 50 milligrams of active hly,ledie~llL~ can be plG~al~d in the following ~
Con~thll~nt~ (for 1000 tablets) active hlgl.,diellL 50.0 grams lactose 50.7 grams wheat starch 7.5 grams polyethylene glycol 6000 5.0 g;rarns talc 5.0 grams g~f~ stearate 1.8 grams de~ i7e~1 water q.s.
The solid iny,lGd;ellL. are first forced through a sieve of 0.6 mm mesh width. The active hl~ , the lactose, the talc, the m~ stearate and half of the starch then are mixed. The other half of the starch is .~ .d/od in 40 milliliters of water and this suspel~io is added to a boiling solution of the polyethylene glycol in 100 milli1it.ors of water. The 25 resllhin$ paste is added to the pulverulent ..ub~.L~ilces and the llli~LlUle iS gramllatt~d, if ~.PC~ .y with the a~ hion of water. The gramll~t~ is dried ovel~ight at 3~C, forced through a sieve of 1.2 mm mesh width and culll~r~ssed to forrn tablets of approximat~ly 6 mm ,1i .. ~ ~ which are coll~ave on both sides.
W O 97/08143 PCT~US96/14077 F.Y~n~l?le 9 Tablets, each CO..~ .;,.g 100 milligrams of active hlgl~,diGllL, can be ~ al~d in the following ~I1~1eL.
CO~ P..I!~ (for 1000 tablets) S active ingl~dienL100.0 grams lactose 100.0 grams wheat starch 47.0 grams m~.r~ stearate 3.0 grams All the solid hl~lGdiGllL~ are first forced through a sieve of 0.6 mm mesh width. The 10 active hlgledien~, the lactose, the m~ r~ , stearate and half of the starch then are mi~ed.
The other half of the starch is sllc~enrlPd in 40 millilitrrs of water and this ~ e~.~ion is added to 100 millilit~rs of boiling water. The reslllfing paste is added to the pulverulent s~ r~s and the mixlule is gr~mll~t.orl, if ..rce~.y with the addition of water. The granulate is dried overnight at 35~C, forced through a sieve of 1.2 mm mesh width and collll)lGs~ed to form 15 tablets of a~loxilllatGly 6 rnm rli~.... r~l which are CO11C~VG on both sides.
F.Y~ le 10 Tablets for ch~..illg, each co..l;~;.-;..g 75 milligrams of active h~ .lielll, can be ~,d in the following lll~e~.
Co~ osil;or (for 1000 tablets) active ingredient75.0 grarns ,n~ .;lol 230.0 grams lactose 150.0 grams talc 21.0 grams glycine 12.5 grarns stearic acid 10.0 grams ~ ~cch~ 1.5 grams 5% gelatin solutionq.s.
All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The ........ ilol and the lactose are mixed, gr~mll~tPd with the addition of gelatin solution, forced through a sieve of 2 mrn mesh width, dried at 50~C and again forced through a sieve of 1.7 mm mesh width. The active ingredient, the glycine and the s~rl-~. ;.. are carefully mixed, the In~ ;lrJl~ the lactose granulate, the stearic acid and the talc are added and the whole is W O 97/08143 PCT~US96/14077 mixed thoroughly and col~ essed to form tablets of ~plo~Li~ately 10 mm ~ which are concave on both sides and have a breaking groove on the upper side.
F.x~ ple 1 1 ,~
Tablets, each co,~ 10 miltigr~m.c of active ingredient. can be p~ cd in the S following lllam~
Co~position (for 1000 tablets) active ingl~dielll 10.û grams lactose 328.5 grams corn starch 17.5 grams polyethylene glycol 6000 S.0 grams talc 25.0 grams m~.. Pc;.. , stearate 4.0 grams 11~ .1l;nf'r.~li7Prl water q.s.
The solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the lS active i-lgrediclll, lactose, talc, m~.,P~ , stearate and half of the starch are i..l;ln-lely mixed. The other half of the starch is ~ çn~lpcl in 65 millilhPr.~ of water and this s~ Pncio.-is added to a boiling solution of the polyethylene glycol in 260 millilitPrs of water. The resllltin~ paste is added to the pulverulent sub~ulces, and the whole is mixed and gran~ te~
if .-Pcesc~.y with the addition of water. The granulate is dried overnight at 35~C, forced 20 through a sieve of 1.2 mm mesh width and co~ ;ssed to form tablets of d~ox;ll~ ly 10 mm .li,.,.,.,t~ ~ which are concave on both sides and have a breaking notch on the upper side.
FY~n~ple 12 Gelatin dry-filled c~rs~les, each co..~;n;.-~ 100 milli~r~ of active ingredient, can be ~a~cd in the following ll~lllcl.
Co~osi~ n (for 1000 ç~rs~ s) active ingredient 100.0 grams llliC~Cl ~:~lline ce~ lose30.0 grams sodium lauryl s~ h~tP 2.0 grams g~ A;.llll stearate 8.0 grams W O 97108143 PCT~US96/14077 The sodium lauryl slllph~te is sieved into t_e active illgl~diel-l through a sieve of 0.2 mm mesh width and the two com~ul~llL~ are i..~ Ply mixed for 10 ...;..~ . The micro-;ly~L~lline celll-lose is then added Lllluu~h a sieve of 0.9 mm mesh width and the whole is again i..li...,.lely mixed for 10 ...;..~ s. Finally, the m~ stearate is added thluugh a S sieve of 0.8 mm width and, after mixing for a furt~er 3 ~nimlt~s~ the llliAlUlC, iS introduced in portions of 140 milligram~ each into size 0 (elong~ttq(l) gelatin dry-fill ç~ps~ os.
F.x~ml~le 13 A 0.2% injection or infilsi~ solution can be pl~ d, for example, in the following llla"ll~ .
active ill~;lcdien~5.0 grams sodium chloride22.5 grams phosph~te buffer pH 7.4 300.0 grams de---;-,- .. lized waterto 2500.0 millilher.~
The active i~lediell~ is dissolved in 1000 milliliters of water and filtered through a microfilter or slurried in 1000 mL of H20. The buffer solution is added and the whole is made up to 2500 millilit.or~ with water. To prepare dosage unit forms, portions of 1.0 or 2.5 milliliters each are illLlu~luced into glass ampoules (each u~ .g lespe~lively 2.0 or 5.0 rnilligrams of active hl~lediellL).
Claims (5)
- Claim 1. A composition having the formula:
wherein:
m is 0-3;
R5 is: (i) o-phenylene unsubstituted or substituted with one or more substituents each selected independently from nitro, cyano, trifluoromeyhyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; (ii) the divalent residue of pyridine, pyrrolidine, imidizole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; (iii) a divalent cycloalkyl of 4 - 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iv) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; or (v) ethylene, unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl,carbethoxy carbomethoxy, carbopropoxy,acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino, substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo;
R6 is -CO-, -CH2-, -CH2CO-, or -SO2-;
R7 is (i) straight or branched alkyl of 1 to 12 carbon atoms; (ii) cyclic or bicyclic alkyl of 4 to 12 carbon atoms; (iii) pyridyl; (iv) phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight, branched, cyclic, or bicyclic alkyl of 1 to 10 carbon atoms, straight,branched, cyclic, or bicyclic alkoxy of 1 to 10 carbon atoms, CH2R where R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms, or halo; (v) benzyl substituted with one to three substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; (vi)naphthyl; or (vii) benzyloxy;
and, where n has a value of 0, 1, 2, or 3. - Claim 2. The method of reducing levels of TNF.alpha. in a mammal which comprises administering thereto an effective amount of a compound of Claim 1.
- Claim 3. A pharmaceutical composition comprising an amount of a compound according to claim 1 effective upon single or multiple dosage to inhibit TNF.alpha..
- Claim 4. The method of inhibiting phosphodiesterase in a mammal which comprises administering thereto an effective amount of a compound of Claim 1.
- Claim 5. A pharmaceutical composition comprising an amount of a compound according to claim 1 effective upon single or multiple dosage to inhibit phosphodiesterase.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/520,710 US5728845A (en) | 1995-08-29 | 1995-08-29 | Immunotherapeutic nitriles |
| US08/520,710 | 1995-08-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2230487A1 true CA2230487A1 (en) | 1997-03-06 |
Family
ID=24073769
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002230487A Abandoned CA2230487A1 (en) | 1995-08-29 | 1996-08-29 | Inhibitors of tumor necrosis factor alpha |
Country Status (20)
| Country | Link |
|---|---|
| US (3) | US5728845A (en) |
| EP (3) | EP0851857B1 (en) |
| JP (2) | JP2000500118A (en) |
| KR (2) | KR100440874B1 (en) |
| AT (1) | ATE259787T1 (en) |
| AU (1) | AU716775B2 (en) |
| CA (1) | CA2230487A1 (en) |
| CZ (1) | CZ291613B6 (en) |
| DE (1) | DE69631592T2 (en) |
| DK (1) | DK0851857T3 (en) |
| ES (1) | ES2216059T3 (en) |
| FI (1) | FI980038A (en) |
| HK (1) | HK1022692A1 (en) |
| HU (1) | HUP9901410A3 (en) |
| NZ (1) | NZ318212A (en) |
| PL (1) | PL329107A1 (en) |
| PT (1) | PT851857E (en) |
| RU (1) | RU2196134C2 (en) |
| SK (1) | SK284144B6 (en) |
| WO (1) | WO1997008143A1 (en) |
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-
1995
- 1995-08-29 US US08/520,710 patent/US5728845A/en not_active Expired - Fee Related
-
1996
- 1996-08-29 KR KR10-1998-0701029A patent/KR100440874B1/en not_active IP Right Cessation
- 1996-08-29 EP EP96930664A patent/EP0851857B1/en not_active Expired - Lifetime
- 1996-08-29 ES ES96930664T patent/ES2216059T3/en not_active Expired - Lifetime
- 1996-08-29 WO PCT/US1996/014077 patent/WO1997008143A1/en active IP Right Grant
- 1996-08-29 DK DK96930664T patent/DK0851857T3/en active
- 1996-08-29 DE DE69631592T patent/DE69631592T2/en not_active Expired - Fee Related
- 1996-08-29 KR KR10-2003-7015515A patent/KR20030097902A/en not_active Application Discontinuation
- 1996-08-29 CZ CZ1998609A patent/CZ291613B6/en not_active IP Right Cessation
- 1996-08-29 PT PT96930664T patent/PT851857E/en unknown
- 1996-08-29 NZ NZ318212A patent/NZ318212A/en unknown
- 1996-08-29 AU AU69632/96A patent/AU716775B2/en not_active Ceased
- 1996-08-29 JP JP9510629A patent/JP2000500118A/en not_active Ceased
- 1996-08-29 EP EP99200946A patent/EP0957091B1/en not_active Expired - Lifetime
- 1996-08-29 RU RU98105689/04A patent/RU2196134C2/en not_active IP Right Cessation
- 1996-08-29 CA CA002230487A patent/CA2230487A1/en not_active Abandoned
- 1996-08-29 EP EP03077311A patent/EP1367051A3/en not_active Withdrawn
- 1996-08-29 PL PL96329107A patent/PL329107A1/en unknown
- 1996-08-29 SK SK272-98A patent/SK284144B6/en unknown
- 1996-08-29 HU HU9901410A patent/HUP9901410A3/en unknown
- 1996-08-29 AT AT96930664T patent/ATE259787T1/en not_active IP Right Cessation
-
1998
- 1998-01-09 FI FI980038A patent/FI980038A/en unknown
- 1998-01-14 US US09/007,135 patent/US5968945A/en not_active Expired - Lifetime
-
1999
- 1999-06-11 US US09/330,701 patent/US6180644B1/en not_active Expired - Lifetime
-
2000
- 2000-03-20 HK HK00101665A patent/HK1022692A1/en not_active IP Right Cessation
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2008
- 2008-02-25 JP JP2008043383A patent/JP2008133303A/en active Pending
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| FZDE | Discontinued |