|Title of Invention||
HYDANTOIN DERIVATIVES FOR THE TREATMENT OF INFLAMMATORY DISORDERS
|Abstract||This invention relates to compounds of formula (l) or a pharmaceutically acceptable salt. Solvate or isomers thereof. which can be useful for treatment of diseases or conditions mediated by MMPs. ADAMs. TACE. TNF- or combinations thereof.|
HYDANTOIN DERIVATIVES FOR THE TREATMENT OF ' INFLAMMATORY DISORDERS
BACKGROUND OF THE INVEMTIOW Fisld of the Invention
This invention relates generally to novel hydantoin derivatives that can inhibit matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs) and/or tumor necrosis factor alpha - converting enzyme (TACE) and in so doing prevent the release of tumor necrosis factor alpha (TNF-Q), pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
Osteo- and rheumatoid arthritis (OA and RA, respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown thai artkxjiar cartilage fron the femoral heads of patients with GA: for example, had a -educed hxooration of radiolabeled sulfate over controls, suaaestina that there mjs; re ar enhanced rate of callage degradation in OA 'Mankr e: a;, c. Szr-e Joint
V • —
enzymes in mammalian ceils: serine, cysteine, aspartic and metalloproteases. The available evidence supports the belief that it is the meialioproteases that are responsible for the degracation of ins sxraoeliuia." ~atrb: o* art'c-jliar cartilage in OA and RA. Increased activities ?■- coiiaoerases a~d stnioetysin have been found in OA carnage and the anvfr/ :x-~iaies ••'■'"- seve"^ o* ihe lesion (Mankinetai. Arthritis Roe urn. 2~\. "~z- ~£'-""5c vvoess^e-' a: a'. Arthritis Rheum, 26: 1983. 52-53 and Ibic. I~. "95^ .3~'5-3"2 - =r-~:o-aggrecanase (a newly identified meialioprelease; ~.as r-een idenir^e: —at provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L S. et al. Arthritis Rheum. 36. 193S. "2^-22
Metalloproteases (MPs) have been implicated as the key e^x/mes in the destruction of mammalian cartilage and bone, it can be expecte:: that the pathogenesis of such diseases can be modified in a beneficiai manner by the administration of MP inhibitors (see Wahl et ai. Ann. Rep. Med. Chem. 25: 175-184, AP, San Diego.. 1990).
\\f\MPs are a family of over 20 different enzymes that are involved in a variety of biological processes important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as RA and OA, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macrogiobuiins and TIMPs (tissue inhibitor of MPs), which form Inactive complexes with the MMPs.
^Tumor necrosis factor alpha (TNF-a) is a cell-associated cytokine that is processed from a 26 kDa precursor form to a 17 kd active form. See Black R.A. Tumor necrosis factor-alpha converting enzyme" Int J Biochem Cell Biol. 2002 Jan; 34(1 ):1 -5 and Moss ML Whirs JM, Lambert MK, Andrews RC.'TACE and other ADAM oroteases as targets for drug discovery" Drug Discov Today. 2001 ADT * :5(S):4"! 7-425. each of which is incorporated by reference herein.
TNF-a has bee" srown ~ 3;sy a orvotal role in immune and infiamnaton. -espr-.ses ~a?z--o"=ze ~" over-expression of TNF-a is a hallmark of a number of diseases, including RA, Crohn's disease, multiple sclerosis, psoriasis and sepsis. Inhibition of TNF-a production has been shown to be bene^cia; r -nary o^eclinlca! models of Infianruatory disease, making inhibit" z~ ~N~-e Dr>o-:oo-. ~- signaling an appealing target for the development c" ~c-e- a~-^f;ar~:~a:o~. orugs.
infection anc snook. Exsees T^r~c. has been shown to be iethaJ. Biookino the effects of TNF-o; with specific antibodies can be beneficial in a variety of conditions, inducing a^toirrvnune znseases such as RA (Feldman et al; Lancet, (1994) 344: 1105;. non-insuur dependent diabetes mellftus (Lohmander L S. et aL Arthritis Rheum. 36 (1993) 1214-22) and Crohn's disease (Macdonaid T. et ai.T Clin. Exp. Immunol. 81 (1990) 301).
Compounds that inhibit the production of TMF-oc are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that metalloproteases, such as TACE, are capable of converting TNF-a from its inactive to active form (Gearing et al Nature, 1994, 370, 555). Since excessive TNF-a production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF-a production may also have a particular advantage in diseases where both mechanisms are involved.
One approach to inhibiting the harmful effects of TNF-a is to inhibit the enzyme, TACE before it can process TNF-a to its soluble form. TACE is a member of the ADAM family of type I membrane proteins and mediates the ectodomain sheddino of various membrane-anchored signaiino and adhesion proteins. TACE has become increasingly important in the study of several diseases,, including inflammatory disease, because of its role in cleaving TNF-a from Its ^staftr sequence and thus releasing the soluble form of the TNF-o: rrasr "Sax RA. :~ J Bbchem Cell Bio!. 2002 34,1-5).
T^BPB are numerous patents and publications which disclose >-rc3=T2H. ?^D~c~a~ae. hydantoin. carboxylate and/or lactam based
US 6,577.355 and US 6.534;491(B2}: describe compounds that are hydroxamlc acki derivatives and MMP inhibitors.
US -5 -55 555 discloses lactam derivatives that are potential inhibitors of MMPs ar-z z~ ~N--c.
~i' — —-[.—v~~ '-— -™~—™ —■-- r-^-^^.-r^—---trzz~ fp2T pre p; client! a I ir~>rj?«~!~.*"■-•"c '"**■" f FCT -Liblicatio^s Vv 02004024698 and W02004024715 disclose sulphonamide derivatives that are potential inhibitors of MMPs,
FC- Publlcaiions WO2004056766.. WO2003053940 and WO2003053941 also describe potential inhibitors of TACE and MMPs.
~here is a need in the art for inhibitors of MMPs, ADAMs. TACE: and "^"NF-a *T>ch can be useful as anti-inflammatory compounds and cartilage D^scsnc therapeutics. The inhibition of TNF-a, TACE and or other MMPs
can prevent the degradation of cartiiage by these enzymes, thereby alleviating the pathological conditions of OA and RA as well as many other auto-immune diseases.
SUMMARY OF THE INVENTION
In its many embodiments, the present invention provides a novel class of compounds as inhibitors of TACE, the production of TNF-a, MMPs, ADAMs or any combination thereof, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with TACE, TNF-a, MMPs, ADAMs or any combination thereof using such compounds or pharmaceutical compositions.
In one emDodfment. the present application discloses a comaoand: or pharmaceuiicair. acceptable salts or solvates of said compound, saic compound na^nc the generai structure shown In formula (!):
ar/ls.KY;. saic ar/:., neteroaryi, neterccyc:"/;. cycloalkyL alkylaryl and aryiaikyi being optionally fused with one or more moieties selected from the group consisting of ar/.. -eteroaryi. hsterocyclyL cycloalkyl, alkyiaryi and ar^aikyL wherein each of any of the aforementioned alkyi, alkenyl, aryl. hefercary?. heterocyclyi. cycioaikyl, alkyiaryi and arylalkyi groups of T is unsubstnuied or optionally independently substituted with one to four R10 moieties wrcr can
be the same or different, each R10 moiety being independently selected from the group of R10 moieties below;
U is absent or present, and if present U is selected from the group
consisting of a covalent bond, -N(R >, -N(R4)C(RV. -N(R4)C(0)-, -0-, -N(R4)S(0)r, -N(R4)C(0)N(R >, and -N(R4)C(S)N(R4)-;
V is absent or present, and if present V is selected from the group
consisting of alkyl, aryl, heteroaryl, heterocyclyi and cycloalkyl. said aryl,
heteroaryl, heterocyclyi, cycloalkyl, alkyiaryl and arylalkyl being optionally
fused with one or more moieties selected from the group consisting of aryl,
heteroaiyl, heterocyclyi, cycloalkyl, alkyiaryl and arylalkyl, wherein each of
any of the aforementioned alkyl, aryl. heteroaryl, heterocyclyi and cycloalkyl is
unsubstituted or optionally independently substituted with one to four R1D
moieties which can be the same or different, each R10 moiety being
independently selected from the group of R10 moieties below;
Y is absent or present and if present Y is selected from the group
consisting or a covaien: DOHC; -(C(R")a)n-; -N(R )-. -C(0)N(R K -N(H ;C'0;-: -N(R4)C(0)N(R^-. -3(0)2N(R-}-. -N(R4)-3(0)2. -0-.-S-. -C(OX -S(OK ar-z
Z is aosen: or present. a~c 'if present Z is sesectec f^m tne oro^z
consisting of a covalent bond, -(C(R4)2)n-, -N(R>; -C(0)N(fi>r -N(R*)C;'0)-: -N(R4)C(0MR4k -S(0)2N(R4K -M(R4)-S(0)r. -0--S-. -C-'"Ck -S(0"'- and
n Is 1 TO 3;
r-! is seiectec trom me gno'jp consisting OT n. —^H ~~a:Ope"v ai*~-
IJUOlUClN'i I. d! V ; . . } — tv7- ^' —. >■ ■ . -.^. v'L'vviW. uirvVjU! »i. UlNwIi^Lw -. — : _
2 r\ f' s l'iS~, *\ •' "T~^.•"ni"- ~ ^ ^^ ~~ ~r~~ — ^ -\r- ■ T\: in r^ii^ !u^*,n on/I hof OT-— -~ ~ "~ ~~^.—"v**- - — *
J J r - J J ,
alkyiaryl, alkylhetercaryi and arylalkyl groups of R' is unsubsritursd or optionally independently substituted with one to four R20 moieties which can be the same or different, each R2u moiety being independently se^acteo ^om the group of R2C moieties beicw. with the proviso that when Y is present and Y is N. S or O. then R: is net haioaen:
R is selected from the group consisting of H, -OR4, halogen, allcyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, aiicyiaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fiuoroalkyl, an/I, heteroaryl, heterocyclyl,
alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R20 moieties which can be the same or different, each R2D moiety being independently selected from the group of R20 moieties below, with the proviso that when Z is present and Z is M S or O, then R2 is not halooen:
each R is the same or different and is independently selected from the group consisting of H and alky!;
10 / 4
R is selected from the group consisting of-OR , -N(R )zt -S(O)-,
-3(0)2-, -N(R4)S(0)2-, -S(0)2N(R")-: -0(fiuoroalkyS), halogen, allcyl, fiuoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl. alkylaryl and aiyialkyl, wherein each of the alky!, fiuoroalkyL aryL heteroaryl. heterocyciyi, cycloalkyl, alkylaryl and
arylalkyl groups of R " ;s uns-bs^jsc:- :>: optionally independently substituted with one to ^our F~~ moiety w*ic car- be the same or different, each R3C moiety being hoeoenie^ljy setecsc ~D~ r>e c-oup of R30 moieties below;
R is seiectec from the grouo consisting of halogen, alkyL and fluoroalkyi.
The comoounds c: Form- a ■ :.=_- z~ useful as inhibitors o^ ~-CE anc may be use-u; — ^e trearnen: arc t/e.errrior: c* diseases assooiatec wit" TACE:T'vF-c MW-s -Zr-M= z~ sr ■ comolnaion thereof.
DETAILED DESCRIPTION OF THE INVENTION
in its severai embodiments, trie present invention provides a novel class of inhibitor of TAC-E. the production of TNF-a: MMPs, ADAMs or any combination :nsr50f, Dnarniaeeutteai compositions containing one or more of the compounds methods :r o-rsparing pharmaceutical formulations
comprising one or more such compounds, and methods of treatment, prevention or amelioration of one or more of the symptoms of inflammation.
In one embodiment, the present invention provides compounds which are represented by structural Formula (I) above or a pharmaceutical!^' acceptable salt, solvate or isomer thereof, wherein the various moieties are as described above.
In another embodiment, the isomer referred to the in the preceding paragraph is a stereoisomer.
In one embodiment, T is alkyl or aryl; X is -C(R )r; Y is absent; L is
absent or present; R* is selected from the group consisting, of H, halogen and alkyi; and if Z is present Z is -Q-.
In another embodiment, T is alkyl or aryl; X is -C(R )2-; Y is absent: L
is absent or present and if present Z is -0-: and R is selected from the group consisting of alkyisry! and alkylheteroary!.
In another embodiment, 7 is alkyl or aryl: X is -N(R }-; Y is absent -L ls absent or --resent: R" s se:eoted from the arouo consistina of H. halooen anc
in yet another embodiment, X is -CH?-. in still another embodiment. X is -N(R "\-
tna group of R'~ moieties.
'r. another embcc*-ment: R'C: is halogen.
in yet another embodiment, R10 is heteroaryi.
:-n sz:. another embodiment. R10 is aryi.
in an embocLme" J selected from the group consisting of a covaier.
bond. -HiP'-. -NiP/iC-O'-. and -N(Ff)S(0)2-.
In yet another embodiment U is a covalent bond.
In still another embodiment U is -M(R )-.
in yet still another embodiment, U is -N(R )C(0)-.
In another embodiment, V is selected from the group consisting of aryl, heteroaryl, heterocyclyl and cycloalkyl, said aryl, heteroaryl, heterocyclyl, and cycloalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl. or cycloalkyl, wherein each of any of said aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R10 moieties which can be the same or different, each R10 moiety being independently selected from the group of R10 moieties.
In another embodiment.. Y is selected from the group consisting of a covalent bond, -(C(R4)2)n-, -C(O)- and -O-.
In yet another embodiment Y is -O-.
In still another embodiment, Y is -(C(R4)2)n-.
In yet stil! another embodiment. Y is -C(O)-,
In another embodiment. Y is a covalent bond.
In an embodiment. R :s selected from the arouo consistino zz —OPT. -alkyi. fluorcaiky:. alkyiary:. na'oge^. and hetercaryl.
In another embodiment. R1 is K
In yet another embodiment, R' is alkylaryl.
in stii! another embodiment R1 is aikyL
in yet stilt anotner embodiment, R ■ is fiuoroalkyi.
In s ^.irrh^r ^.fn^'i^'irn^1"^ — : '^ '".p.ir"ic
.'II CI .* L> ; *~ : —-1 -r I ■ i w' —'--J, i ; : w: -. ■ w : ialCJui i.
In anoiner enoocnmen*. -* .3 —-jrxin another embodiment v./here P" is -OR\ P7 is -CH2C=CC-':
in another embodiment where R is -ORt R" is-Cn2C^CC-:0-.
In another embodiment, where R"; is -OR4, R4 is ~CH2 In another embodiment, the alkyi is -CH3.
In still another embodiment, the alkyi is -CH2CH3.
atoms, in which one or mors of ths ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system suhstituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyt pyrimidinyi. pyridone (including N-substituted pyridones). isoxazolyL isothiazofyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyi, 1r2,4-thiadiazofyi, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyL oxindoiyL imidazo[1 ,2~a]pyridinyi, imidazo^i-bfthiazotyl, benzofurazanyl, indofyl. azaindolyi. benzimidazolyl. benzothienyL quinolinyl. imidazolyl. thienopynciyi. quinazolinyL thienopyrimidyl. pyrroiopyridyL Irnidazopyridyl. socrjfeiD&rs'i. benzoazaindofyL 1.2.4-triaziny:. benzothiazolyi and the like. The te~ T*eteroary:r also refers to partially satJrated heteroaryl moieties such as. ~z~ examo
o~=nsthyi and naphthalenylmethy!. The bond to the parent moiety is through
"O r,-. :S TT: r -J •_; 0 "y iPiS G. I VI.
"Cvctoaikvl" means a non-aromatic mono- or multicvclic rino system comDrising about 3 to about 10 carbon atomsr preferably about 5 to about 10 caroon atoms. Preferred cycioalky! rings contain about 5 to about 7 ring atoms. The cycioalky! can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycioalky Is include
cyclopropyl, cyclopentyl. cyciohexyi, cycloheptyl and the lite. Non-limiting examples of suitable multicyciic cycloalkyls include i-decalinyl norbornyL adamantyi and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like.
"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
"Ring system substituenf means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyL aikenyl, alkynyl, aryL heteroaryl, aralkyl, alkyiaryL heteroaraikyi, heteroaryiaikenyl, heteroaryiaikynyl, alkylheteroaryL hydroxy, hydroxyalkyl, afkcxy: aryioxy, aralkoxy. acyi, aroyl, halo, nitro, eyano. carboxy. alkoxycarbonyi, aryloxycarbonyl, aralkoxy carbonyL alkylsuifonyL arylsulfonyl. hetercaryisulfonyl, alkylthio. arylthio. hsteroarytthio: araikytthio. heteroaralkyithio, cycioafkyt '-^=oc\c^ -r-=^?-N:-*vHr -G-=Nr-n-NH2: -C(=NH)-NH(aIkyI): GiG2Nk G-GzN-alKV;-. G-G2NG C - 3-G2NSOr and -
cycioaikyi. and aralkyi. uRing system substituenf' may aiso mean a single moiety which simultaneously replaces two available rrycrogens on two
~~.-r-. ~-r2,;9*;05 such as. Tor 9xarnp-e;
"^ ' r" - arc Heterocyclyl" means a non-aromatic saturated monocyclic or multicyciic ring system comorising about 3 to about 10 rhg atoms: preferably about 5 to about 10 ring atoms r- *vhlch one or more o~ tie axoms in the ring system is an element other than carbon, for example nitrogen, oxygen or suifun aione or in combination ~~*ere are no adjacent oxygen and/or sulfur atoms present in the ring sys:e~ -^e'ereo '-ete-"ccrycly!s contain about 5 to
moiety is through the carbonyl. Preferred acyls contain a lower alio/1. Mon-iimiting examples of suitable acyl groups include formyl. acetyl and propanoyl.
"AroyI" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-iimiting examples of suitable groups include benzoyl and 1- naphthoyL
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-iimiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
"Aryioxy" means an aryl-O- group in which the aryi group is as previously described. Non-limiting examples of suitable arybxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
'"AraJkyioxy" means an aralkyl-O- group in which the aralkyi group is as oreyiousry described. Non-iimiting examples of suitable aralkyloxy groups ;nobde benrvToxy and 1- or 2-naphthalsnernethcyy. The bond to the parent ~z:,=T\- is rrouah the ether oxvaen.
lAi*y(thioL means an a!ky:-S- group r wrch the alky! croup is as
include rnethyithio and ethylthio. The bono to the parent moiety is through the
5 'J :~U r
: Arvithio" means an aryi-S- grcuc —. which ^e a°/' Group is as -~ -,ZB che~vith;o and naphthv:tNc ™-e ~"d tc ~~r _arent mo'stv ;s th:*ougn
berr/'th!0. The bond to the parent rnoistv is throuoh the suifu:*.
i!Aikoxycarbonyi" means an alkyl-O-CO- group. Non-iimiting examples of su^ab'e alkoxycarbony! groups include methoxycarbony! and ethcxycarbony!. The bond to the parent moiety is through the carbonyl.
"An/lo:;ycarbony[l! means an aryl-O-C(O)- group. Non-limiting examples of suitable aiyloxycarbonyl groups include phenorycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
'Araikoxycarbonyl11 means an arallcyl-O-C(O)- group. Non-limiting example of a suitable araikoxycarbonyl group is benzyloxycarbonyL The bond to the parent moiety is through the carbonyl.
"Alicylsulfonyl" means an alkyl-SfOa)- group. Preferred groups are those in which the alkyl group is lower alkyi. The bond to the parent moiety is through the sulfonyl.
"Arylsulfonyl" means an aryl-S(C>2)- group. The bond to the parent moiety is through the sulfonyl.
The term "substituted" means that one or more hydrogens on the Designated atom is replaced with a selection from the indicated group, orovided that the designated atom's normal valency under the existing oirc-umstances is not exceeded, and that the substitution results in a stabfe compound. Combinations of substituents anchor '-^rsses e~ oe—^ssc-e j^"y if such combinations result in stable compo_ncs. By ^siao-e coToojnr .' ^stable structurer is mean: a comDound that is ^•s=.^artr/ -cc_^:t: s-^-r-s
]rno an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or —oieties.
* ."■— 1a!'!'■': .so.a^ec -~ so.a:—c .err. ,w. — ^-_-~^„w.__^ reterc- ~z- ~r~ z~ s:ca^ state o~ said ocr^-oound after beinc isolate- ^o^ s S"."~t~etic cccess
;a.".g ob:ained from a pu~fncatio~ process or oroossss^ describeo ner*e'- c-~ ■vs:! known to the skilled artisan, in sufficient purity zo be characterizable by standard analytical techniques described herein or ive!i known :c the ski!sec a-dsar.
It should also be noted that any carbon as wei: as heieroatcm with --.satisfied valences in the text schemes, examples ard Tabies he~er- s
assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as; for example, T. W. Greene etal, Protective Groups in organic Synthesis (1991), Wiley, New York.
When any variable (e.g., aryl, heterocycie, R2, etc.) occurs more than one time in any constituent or in Formula L its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term Composition" is intended to encompass a product comprising me specified ingredients in the specified amounts, as well as any product which results. cSractry or indirectly. from combination of the specified Ingredients h the specified amounts.
Prodrugs ano SOK'HSS c^ths compounds of the Invention are also contemoiated herein. The te— '"c-odrug1. as employed ^e-er. denotes a
undergoes chemicai conversion by metabolic or chemical processes to yield a compound of Formula ! or a salt and/or solvate thereon A discussion of
'Srva:e= ~ea~s a :n^':a associate:" z~ a ocmcc-no c~ this invention with one :~ —ore solvent ~ojeo^es: This physical association involves varvinc decrees of Ionic and oovaJent bondinq. includinc hvdroaen bondina. in certain instances the so'vate ■&":■ oe caoable of isolation, fo" example when one or more soiverr- molecules are incorporated in the crystal lattice of the crystalline soiid. =Sovate! encompasses both solution-phase and isolatable solvates. Non-limiting examples o* suitable solvates include ethanolates,
methanolates, and the like. 'Hydrate1' is a solvate wherein the solvent molecule is H20.
"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting TACE, the production of TNF-a, MMPs, ADAMS or any combination thereof and thus producing the desired therapeutic, ameliorative, inhibitor or preventative effect.
The compounds of Formula I can form salts which are also within the scope of this invention. Referenceio a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)B, as employed herein, denotes acidic salts formed with inoroanic and/or oraanic acids, as well as basic salts formed with inoraanic and/or oraanic bases. In addition, when a compound of Formula i contains both a basic moiety, such as, but not limited to a pyridine or imidazole., and an acidic moiety, such as, but not limited to a carboxyiic acid, zwitterions ("inner salts") may be formed and are included within the term "saitfsV1 as used herein. Pharmaceutical^ acceptable (i.e.. non-toxic, physiologically acceptable; safe are preferred, although other salts are also useful. Salts o"
compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an asueous medium followed by iyophilization.
zenzenesulfcnates. bisuifates: borates: butyrates. crates, camphcratss
oxalates, ohosohates. orociona:es. saiicvlates. Succinates, sulfates. tartarates! thiocyanates. toluenesuifonates (also known as tosylates.) azz the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutical^' useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl eiai Camille G. (eds. Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002: Zurich: Wiley-VCH; S. Berge ei al Journal of Pharmaceutical Sciences (1977)
56(1) 1-19; P. Gould, International J. of Pharmaceutics (A 986) 33 201-217; Anderson etal, The Practice of Medicinal Chemisin/ (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alky! haiides (e.g. methyl, ethyl and butyl chlorides, bromides and iodides), dialky) sulfates (e.g. dimethyl diethyl, and dibutyl sulfates), long chain haiides (e.g. decyl, lauryl, and stearyi chlorides, bromides and iodides), araikyi haiides (e.g. benzyl and phenethyi bromides), and others.
acceptable salts within the soooe of tie fnve~o~ anc ail adz and base salts are considered equivalent :r- r-s ~ee ^—s rr "~e ^c"esoc-,3:^c compounds
Compounds of Formula I, ana salts, solvates and prodrugs thereof, -nay exist in their tautomeric form (for example, as an amide or imino ether). A:: SJC~ tautomeric forms are conrempiated Ha3^ a~ pa-* c~ t^e o^esert
— **-*"_. ~ - " •, . ~ — ■ — — .. —-. — — —. — — w ■■'
absence of asymmetric carbons), rotamericfonr;s. atroolscme^s. and diastereomeric forms, are -oniemp^ed within t~e scope of this invention, as are positional isomers (such as. for examoie. 4-cyridy! and 3-pyridyi). Individual stereoisomers c*—e oo^Dounds o"ine invention may. for example, be substantially free of ore- some's. :~ msv be admixed, for example, as
racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUFAO1974 Recommendations, The use of the terms "salt", nsoivate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
Polymorphic forms of the compounds of Formula I, and of the salts, solvates and prodrugs of the compounds of Formula I, are intended to be included in the present invention.
The compounds according to the invention have pharmacological properties: in particular, the compounds of Formula ! can be inhibitors of TACE, TNF-cc and/or WIMP activity.
In one aspect, the invention provides a pharmaceutical composition comprising as an active ingredient at least one compound of formula 1.
in another aspect, the invention provides a pharmaceutical composition of formula 1 additionally oo^oisrrvr zr. ^asl one ou>arnaceui>oairy acceotable carrier.
In anothe* asoecL the hYerr-" crudes a ~etno:i of seating disorders
said method comprising administering IO a patient in need of such treatment a oharmaceutical composition v/hich comprises therapeutically effective
including but no; -;~hec TO septic shock, "aamodynamlc shock, sepsis syndrome, pest ischaemic reoerfuslon hL:~y. maiaria. mycobacterial infection, meningitis., psoriasis, congssrve hea-~^a:-.-e: fibrotic diseases, cachexia. graft rejection, cancers such -as cutaneous T-ceil lymphoma, diseases involving angiogenesis. ain:o:~mjne diseases, skin inflammatory diseases, inflammatory bowel diseases such as Oc"'s disease and colitis, OA and
RA; ankylosing spondylitis, psoriatic arthritis, aduil Still's disease, ureitis. Wegener's granulomatosis, Behcehe disease, Sjogren's syndroms, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non-insulin dependent diabetes meliitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction,, cerebral stroke, cerebral ischemia,. nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and/or bronchitis, it is contemplated that a compound of this invention may be useful in treating one or more of the diseases listed.
In another aspect the invention provides a method of preparing a "hamaceutioai oomrosftion for treating the disorders associated with TAGE. 7^>r-z, K4MPs. ADAMs or any combination thereof, said method comprising
In another aspect, the invention provides a compound of formula (!) exhibiting 7^CE: TNF-CL MMPSS ADAMs or any combination thereof inhibitory
":'"•;H~~>2■_—~_ ^ajG r:C'—'DO'j^o beino selec^o z"-.'^~ i;~— co""r*c~'_'~ins ^ s^"'^—^-■I'ss
combination thereof in a subject comprising, administering to the subject in need o~ such treatment a therapeutically effective amount of at least one compounc o" formula i or a pharmaceuticaily acceptable sail, solvate or i^r.m-r '^-^reof
;"' another aspect the invention provides a compound of formula 1 in
in another aspect, the invention provides a method of treating a condition or disease mediated by TACE. fvlMPs, TNF-a, aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula i or a pharmaceutical!}/ acceptable salt, solvate or isomer thereof.
in another aspect, the invention provides a method of treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease., multiple sclerosis and psoriasis in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a oharmaceuticaiiy acceotable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease selected from the grouc constrg r^^^er cardiovascular conditions, hemorrhage, coagulation, cachexia, anc-re.ca, aboholism. acute phase response. acute infect!" rox rr=f: ve"=i3 ~s:
administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula * or a pharmaceutical!-/
^^■"rsot^Ms sa^ so.va^ ^ Isomer thereof
--oeii iymDhoma. diseases invoivina anqioaenesls. autoimmune diseases, skin inflammator/ diseases, inflammatory bowe^ diseases such as Crop's disease and colitis, osteo and rheumatoid arthritis- ankylosing spondylitis. psoriatic arthritis, adult StilPs disease, ureitls, Wegener s granulomatosis. Sehcehe disease. Sjogren's syndrome, sarcoidosis zctymyosrtis dermatomyositis. multiple sclerosis, sciatica., ccmr>e-- regic"a; ca* syndrome.
radiation damager hyparchic alveolar injury, periodontal disease, HIV. non-insulin dependent diabetes meliitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary' fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis. psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutical^ acceptable salt, solvate or isomer thereof.
in another aspect, the invention provides a method of treating a condition or disease associated with COPD. comprising: administering to the subject in need of such treatment a therapeutically effective amount -of at least one compound of claim 1 or a phr-rmaceLrDcaiy accectable ear. sovate or isomer thereof.
administering to the subject in need of SUCH treatment a therapeutically effective amount of at least one compound of formula t or a prtamaceuticaily acceptable sait. solvate or isomer thereo*
oc~do:ic"t cr disease associated with Cro~~ s o:sease oo:~or:s:oo:
In another aspect, the invention provides a method entreating a condition or disease associated with psoriasis, comprising: adm;^stering to the subiect in need of such treatment a ther5Joeutoai:\ effective a~o^rtt of at least one compound of formula 1 or a pharmaceuticalK" aoceptaiye salt. solvate or isomer thereof.
in another aspect, the invention provides a method of treating a condition or disease associated with ankylosing spondylitis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula i or a pharmaceutical!^/ acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with sciatica, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutical^ acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with complex regional pain syndrome, comorisina: administerina to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a phajrraceiitically acceptable salt, solvate or isomer thereof.
:r another aspect, the invention orovides a method of treating a co~dtio~ or disease associated with psoriatic arthritis, comprising: a™r-is-erhc to the subject in need of such treatment a therapeutically
acceptabie salt, solvate or isomer thereof.
:r another aspect, the invention provides a method of treating a cc-i:t]cr :~ ~;sease associated with ~u;tip;e scie^os^s. oomDrising:
zs~" compounds indicated for the treatme^: o~ rru'tipie so>e"s;s
Additionally, a comoound of the present invent!": mav be co-administered or used in combination with dissase-modnvino antirheumatic crugs ;DMARDS) such as methotrexate, azathioprine., iefiunomids. pencitlinamine. gold salts, mycophenolate mofeti!. cyclophosphamide and other similar drugs. They may also be co-administered with or used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) such as
piro?;icam. naproxen, indomeihacin, ibuprofsn and the like; cycbxygenase-2 selective (COX-2) inhibitors such as Vioxx® and Celebrex©; immunosuppressives such as steroids, cyclosporin, Tacrolimus, rapamycin and the like; biological response modifiers (BRMs) such as Enbrel®. Rernicade®, IL-i antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the like; and other anti-inflammatory agents such as p33 kinase inhibitors, PDE4 inhibitor other chemically different TACE inhibitors, Ghemokine receptor antagonists, Thalidomide and other small molecule inhibitors of pro-inflammatory cytokine production.
Also, a compound of the present invention may be co-administered or used in combination with an Hi antaaonist for the treatment of seasonal allergic rhinitis and/or asthma. Suitable Hi antagonists may be, for example. Claritin®, Clarinex®, Aliegra®, orZyrtec®.
in another aspect, the invention provides a method of treating a condition or disease mediated by TACE, MMPs. TNF-c: aggreoanase. or any combination the'eo^ in. a subject comp~s:-r ao—r;a^-" -z ~ tre sjr^ect :* need of such treatment a therapeutically effective a.":u" z' a: .-eas: ore
least one medicament selected from the group consisting of disease modifying antirheumatic drugs (DMARDS), NSAiDs. COX-2 innlfcrtc-3 COX-1 r-hibfiors. immunosuppressives, bioioglca^ -esoo^se m coders f5=x~s: a^o-:"*'!a"T£::7 ace-ts and Hi antagonists
- a~c™e~ aspect, the invention prcvioes a r-i&zr.oz oJ rear- : a.
Z"Z'\\Z" EZ~Z *r_™z" "vaS'Cn uy seconocirv :;.~-n^-.^.c:^^. . rr^vci^v--—.c: OiCLuooma. inflammatory ccwel disease, multiple sclerosis and osoriasis in a subject comprising: administering to the subject r ~eec 0* suoH treatment a therapeutically effective amount cf ai least one comoouna cf Cia;rr " cr a pharmaceutically acceptable sa!t. solvate c Lscrr.9' tnereof \r combination with a therapeutically effective amount of a: east one msdksme^t selected from the group consisting of DMARDS. NS-.:I>s. OCX-I mioses. COX-
inhibitors, immunosuppressives, BRi/is, anti-inflammatory agents and Hi antaooniste.
In another aspect, the invention provides a method of treating a condition or disease selected from the group consisting of septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureltis, Wegener's granulomatosis. Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hypercxic alveolar injury, periodontal disease, HIV. non-insulin dependent diabetes melirtus. systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic DuL7>>nary nbross bronchopulmonary -dysplasia, retinal disease, scleroderma, osteopc-Dss. ~enai ischemia! myocardial infarction. cerebraJ sv'oke. ce~ec"a: Is^he—:ia. nephritis, heoatitis. gbmerulcoepnrltis. erotogenic-b'cs'n:; a.'e::'t= zsz'.as's. :-ans:~;a:~: rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respirator disirsss syndrome, asthma, onronic obstructive pulmonary zls^as% ;CCPD; and crc-c^tis in a subjee:
. . _;. . , .! 1 ~ ' J : w O L- L# —■ M S ! O U t i U O ■ i—' - - - - - —' ■— -'— ~.: — !r - -_' w ' . L. .. .; ^■:: \j. £ . ■_' w' /'■.
inhibitors, immunosuppressives 3R!-/:s: ar-::-inf!ar;"r=:c7 agents and H" antaaonists.
In another aspect, the invention oroides a method for treating RA comorisina administerina a comoour-.c rJ the :orPJ:a ' "- combination with compound selected from the class consisting c" a CCX-2 inhibitor e.g.
Gelebre;:® or Via.^®; a COX-i inhibitor e.g. Feidene'l1; an immunosuppressive e.g. methotrexate or cyclosporin; a steroid e.g. j3-methasone; and anti-TNF-o; compound, e.g. Enbrei® or Remicade®; a PDE IV inhibitor, or other classes of compounds indicated for the treatment of RA.
In another aspect, the invention provides a method for treating multiple sclerosis comprising administering a compound of the formula I in combination with a compound selected from the group consisting of Avonex®, Beiaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.
TACE activity is determined by a kinetic assay measuring the rate of increase in fluorescent intensity generated by TACE catalyzed cleavage of an internally quenched peptide substrate (SPDL-3). The purified catalytic-domain of recombinant human TACE (rhTACEc, Residue 215 to 477 with two mutation (S2S6A and N!452Q) and a oxHis tai!) is used in the assay. It is purified from the bac?uicMrjs/Hl5 cells expression system using affinity r-'c^Hrr-^r^ —-^ vjbstrais 5-DL-3 is an htemal'y quenched peptide 'MC^-Prc-^-~j£-3;r-A;a-v/arArg-Ser-Ser-Ser"Dpa-Arg-NH2)r with its
A 50 Lti assay mature contains 20 mM HEPES. DH 7.3: 5 mM CaCk IOC J-J ZnC>. 2 --r DM80 0.04-= Methyice!!u!ose. 30 u^' SPD_-3. 7C cl-A —.T&C-Ez- anc| £ T8S- ——rc_:m. -"TACEc is pre-incjtatec \i-:zr. the testmg
■/3HEMIN- >.'S ^c^acu^r Devices:, Rate cf enzymatic "eac^o^ ;s shown as Units oar seccnc. Effect of a test compound is shown as % of TACE activity
useful compounds for TACE inhibitory activity can exhibit K; values of :sss than about '000 nm: preferably about 0.01 nm to about 1000 nm, more cefsraoy aoou: 0." nm to about 100 nm: and most preferably less than about * 5 nm ~~e "ACE inhibitory activity (Ki values) of some representative
compounds of the present invention are listed in the "EXAMPLES" section hereinbelow.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft-capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutical^ elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutical!}/ acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegraSnc agents, for example, com starch, or alginio acfcr c—cfmg agarrz 'or examcfe starch, gelatin or acacia, and lubricating agents. fe~ example magnes~_— s^arate. stearic acid or tab. ~~e Tablets may be _~ccaier v ™—Y """£■ ~— rcated bv kncv."" "ec^'C-'e^ ~r ce'av d'^^te"*"'" E.~Z absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as giycery: "o^-stea-aie cr giycsr\ri olszeasazs may be employed. They may aiso be
a~z - 253 £"- to ^crr: osmotic t~e~aneji:e :ab;ets for controi>eb re:eas9.
z"s -.::. ":- c 3n£rmac5Lit!ca!fy aotve agents such as; ^or exa^~:e a compo:--"o :~ d~e present invention, and an additional agent selected fror~ the lists of the additional agents described herein, along with any onanrnace-^cany inactive excipients. ^ne bulk composition arc eao1' md:vidua- oosage unit can contain fixed amounts of the afore-eaio =more than cne ohamace-tically active agents". The bulk composition is ~a^ia: the: has no: sBi oeer. formed into individual dosage units. An iilustrar-e dosage
unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating, a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredients is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules where in the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylceliuiose, methylcellulose, hydrcxypropyimethy!-ceiyossr sodium alginate, polyvinylpyrrolidone, gum tagacarrth arri gum acacia: dispersing or wetting agents may oe a ^arj^rv-occj^-ng ohosohatide. to: example, lecithin, or condensation products of ar alkyle-e rxlde with fatty acids; for example polyoxyethylene stearate. o- oonde-tsadc~ z-oducts of ethylene oxide with iong chain aiio-at:t- aJc:-~-: s -:- e-:a~r e heptadecaethylene-oxycetanol. or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol SUCH as polycxyethyiene sorbitol monooieate c- corc'e-satior o reduces of etnyle-e sx;de "-:>;rr. oartia! esters derived ^*t~ ^r airs arc -s^tr a—yd-des. ™--: example, oolyethytene sorbitan mc~OG:eate ~~-e a-cuecs suspensions ma*.
ano one cr ^cre sweetening agents s_:- as s_o~ose saoc~a— o: aspartame.
Oily suspensions may be formulated by susoerdho tue active ingredient in a vegetable oil. for exanole. aracnjs oii. crve o sesame oil or coconut oil. or in mineral oil such as liquid pararK The oily suspensions may contain a thickening agent, for examole. beeswax, "arc oa^af^n or cetyl alcohol. Sweetening agents such as these se: -orth above aro flavoring
agents may be added io provide a palatable oreJ preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing, or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, e.g., sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil. e.g., olive oil or arachis oil, or a mineral oil. e.g.. liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, e.g., soy beans, lecithin, and esters or partial esters derived from fairy acids and ^xib' a~rm*dhdes. tor example, sorbftan monooieate, and condensation p~od-C3 ~ re said oatla: esters with ethylene oxide: e.g.. oovoxyethylens so~ota—c~poJeate. ~he emulsions may also contain sweetening and
Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations ma\ also coniaj^ a demulcent, a preservative and fiavcr-p a" co!o^nc
"he p~a'~~~aoeutioa; compositions may be ;" t^e ~':~~ c~ e ster\e
Ari-iC ace— anc Suspending agents -h;cu ^ave bee* ~-enrc-eo above, "he stsriie :njec:able preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, e.g.. as a solution in * .S-ouiane dioi. Among the acceptable vehicles and solvents that nay be employed are water. Ringers solution and isotonic sodium chloride solution, ir addition, steriie fixed oils are conventionally employed as a sovem 2' suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectabies.
Compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. The compositions can be prepared by mixing the drug with a suitable non-irritating sxcipisnt which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc.. containing the compounds of the invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.)
The compounds for the present invention can be administered in the intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administrator "■=*. o~ ■rrrrse re xniirrjoLJS rather than intermittent throughout the dosage -egims":.
vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
""re dosage reg;me^ utilizing the compounds of the ceserr: inventlor =:
amour: cf the druo reouired to prevent, counter, arrest or reverse tr^e orocress of the condition. Optima! precision in achieving concentration of dn>g within the range that yields efficacy without toxicity :~z^;.res a ^egimen based on the kinetics of the druaTs availability to taraei sf^s. Tnis invokes a consideration of the distribution: equilibrium, and elimrnai?" of a cnjg. Pre'e^abiv, doses of the compound of Formula 1 usefu: r me nsro: e-- re
present invention range from 0.01 to 1000 rng per day. More preferably, dosages range from 0.1 to 1000 mg/day. Most preferably, dosages range from 0.1 to 500 mg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 5.0, 10.0,15.0, 25.0, 50.0,100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
Advantageously, the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four time daily.
The amount of active ingredient that may be combined vvfth ths carrier materials to produce single dosage form will van/ depending UDO~ the host treated and the particular mode of administration.
It will be understood: however, thai the specific dose lsve. for ar:: particular patient will depend uoon a variety of factors Inc-uirc the age. ore.'
administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
^ne oo-ioounds of the invention may be croducsd z: recesses ---Ovvr
AcOH Acetic acid
BOC20 BOC Anhydride
0 degrees Celsius
CBZC-I Benzyl chloroformate
DEAD Diethyl azodicarboxyiate
(DHQ)2PHAL Hydroquinine 1,4-phthalazinediyl diether
Dl PEA Diisopropylsthylamine
DMA N, N-Dimethylacetamids
DWIFDMA N.N-Dimethylforrnamide dimethylacetai
DMSO Dirnetny! sulfoxide
EDC! 1 -i'3-D?: ~==rl ivK^r^l^DD""^r'^-?-^^^c^jt>3xJ2!rrjide hydrochloride
~i Eiec-t^"* '■'*^^!zat3">-"~i
HPLC High pressure hquid chrornaiograpny
LAH Lithium aluminum hydride
LDA Lithiu™ ~::soprory;anice
MPLC Medium Pressure Liquid Chromatography
NMR Nuclear Magnetic Resonance
MS Mass Spectroscopy
NM P 1 -msthyi-2-pyrroiidone
PQG Pyridinium Chioro&hrcoaie
FTLO Preparaitve tnh iaye~ on-o1—atograp^v
PyBrOP 5romc-trisi?y^~ondr:>Drosphonium hexafborophosphate
sgc Silica gel 60 chromatography
TACE ~~\r-alpha converting enzyme
NMR scecra '.'/ere acQuirec on me miicwlnq hstnjments: 400 MHZ NMR (3ruker, 300 MHZ NMR (Brukem ^00 MHz NMR (Variar;.. 300 MHZ NMR (Varian) using CD3OD. CDC;- o- DMSO-d5 as solvents. LC-MS data were obtained using a ?5Sc:ex AP " dOEX quadropoie mass spectrometer using electroscopy ionization..
Purification via reverse phase cn'omatography (Gilson) was accomplished using a C!£ reverse ohase column with a gradient of (0.1 %
formic acid) 5:9b to 90:10 acetonitriis:water, at a flow rate of 14 mL/min. Samples were collected usina UV detection. Alternatively an ISCO Companion with (0.1% formic acid) 5:95 to 95:5 acetonitrils:water5 at a flow rate = 10-55 mL/min.
Normal phase silica gel chromatography was either accomplished on a Biotage instrument using, a 60 A 12/M, 25/M, or 4Q/M flash cartridges, or on a Jones Flash Master Personal instrument using. Isoiute flash SI 5g, iOg, 20g, 50g, or 70 g cartridges.
The compounds of formula (I) may be produced by processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below. These preparations and examples should not be construed to limit the scope of the disclosure. Alternate mechanistic pathways and analogous structures may be apparent to those skilled in the art. Some of the compounds made by these processes-are listed in the tables below. AH kinds of isomeric forms of the compounds are considered to be within the scope o~ this invention.
G^nsrsii proo&dixres for Enampie ©
In step i; 4-Bromo-2-nitro-benzoic acid (compound 8A) was dissolved in a suitable solvent such as DMF, and reacted with methyl iodide in the presence of cesium carbonate at room temperature tor 2-16 hours. Water and EtOAc were added and the organic phase was washed by water 1-5 times to remove DMF. The organic phase was washed with brine, dried, concentrated, and dried to give the crude product (compound SB) which used without further purification.
In step 2T the methyl ester (compound 3E) was mixed with Pd(OAc)2, C32C03: and an appropriate iigand, such as racernic^Di-f-butylphosphinoJ-i.l'-
blnaphthyl The mixture was placed under vacuum for i to i 0 minutes to remove oxygen, and refilled with N2. An alcohol and toluene were added and the solution was stirred at 50 °C to reflux temperature for 12 to 72 hours. After ooosnc to room temperature, the solid was removed by finraibn and the sorven: was removed. Tne product couio oe purifieo by cnrc-marecraorv. Durinc onis "eaciion, the methyl ester may be partially convener :c the es:er r tne aoo~c-" jsed. ^txs side product was also col;ec:ec ar-z w-o"~ o^-o -
;- stec 3 compound 6C was dissolved In Dloxane/water (3:1.- and treated with
acidic o. aod~:o- of IN HC: so;udon anc subjected to aqueous EiOAo work _o ~"e :--cd-c:s ^compound 5D" ,vere erthsr USBO without xu"e^ p_r^caticn
!n step -. compound 6D was dissolved in a suitable solvent such as DMR ana coup-ec Atti compound 6E under EDCi and HOBT cc~acons a: room temperature overnight. After an aqueous/EtOAc work UP. tne oroouct '.compound SR could be isolated by chromatography.
■Ssroral procedure ior Example S
in step i, Compound 8£ was dissolved in a suitable solvent, such as DMF, and reacted with methyl iodide in the presence of cesium carbonate at room temperature for 2-16 hours. Water and EtOAc were added and the organic phase was washed by water 1-5 times to remove DMF. The organic phase was washed with brine, dried, concentrated, and dried to give the crude product (compound BE) which was used without further purification.
In step 2: when alcohol was used, the reaction was operated in a similar manner as step 2 in example 5. When an aromatic or heterocyclic stannane was used, the reaction was operated in the following manner. The aromatic-or heterocyclic stannane was added into a dry flask, followed by addition of the 4-B:omo-2-methyi-benzoic acid methyl ester (compound SE')r a base, such as Cs2CQs; K3PC-. and a palladium oasSst such as Pd(PPrh)2Ci2. Tne flask was placed unde~ vacuum ~:>- ~ :c ~Z ~rrjtes to -e^-c^e oxvgen and was refilled with N2. Ar. app-opnace sch/e~c s^ch as dry CHsCNL was added and tne solution was sd~ec a: ?~ "C 1c rsfiw" :e*~:oera:ure ove~';:r: :c 3 cays. The so!;d was "emovec cy "d'scc anc :~e s-c e~* ".as "e~c ec 3-c~C'C^~c 8C was isolated by chromatography.
In step 3. compound 3C -.vas dissolved :n a su:tab!e inert so:ve~;. sucr as
8D v;rb~ was usee v/zr :_: tv~e~ c^'cacc--
in step 4r me benzyl bromide (compound 8D; was mixed with hydantcin methyl amine 8E; K2CG3. anc DN;:F. ""he sc-.jiior, was stirred at room temperature for 12 to 24 hours. Tnen the solid was removed by filtration. The product could be purified by reverse ohase ~D_C Compounds 8F and 8G could be obtained in a variable ratio.
Compound 22B: Compound 22A (7.3 g, SI rnrnol) was treated with BOC-ON (21.9 g, SB mmol} in dichloromethane for 3 hr. Solvent was removed and the crude material was purified via sgc (10% NHs^eQH/Ch^Ci?) to give 6.5 (42%) of compound 22E*.
Compound 22C: Compound 225 (1.5g, 7.9 mmol) was dissolved in dichloromethane (50 mL) at 0 °C. CbzCi (1.24 ml, 8.7 mmol) and DIPEA (1.52 ml, 8.7 mmol) were added and the reaction was stirred at 0 °C for 30 min. The reaction mixture was washed by HCI (1N, 50 mL) and brine (50 mL). The organic layer was dried and concentrated to give crude compound 22C (2.6 g, 99%) which was used without further purification.
Compound 22D: Compound 22C (2.78g? 8.57 mmol) was dissolved in methylene chloride (IX mL), PCC (4.52 g, 21.4 mmol) and cefrte (4.3 c^ ivere added and the -eacdon mixture was stirred at 25 DC overnight. Anot^e-0.5 sq. -of PCC (325 ":. 4.3 mmo!) was added and It was stirred for 3 nr a: ^oon temperature. ~ne solid was filtered off and the resulting solution was
-oncDuOu 2^E. '^r..-0'j: iO 22D i i ,oo. c.s mrric:., r\^;\ (.O.oo cT 8.ot> nc. .
Corr-oound 22F: Co—^una 22E (1.45 g. 3.68 mmoi) was treated with Pd;C :~ methar:;: :- a oar 5~^
Compound 22Q; Compound 22F (150 ma 0.58 RIIDO!':, compound 22vA (170 mg, 0.64 mmol) and DIPEA (0.22 mL, i .28 mmol) were mixed in DWiF (5 mL). The solution was stirred at 70 °C overnight. Solvent was removed and the crude material was and purified via sgc (5% NH30MeOH/CH2Cl2) to give 166 mg (71%) of compound 22Q.
Compound 22K: Compound 22G (166 mg) was suspended in methanol (10 mL) and HCI (4M in dioxane, 4 mL) was added. The solution was stirred at 25 °C for 2 hours. Ethyl ether (50 ml) was added. Solvent was removed and give compound 22H (0.14 g, 99%).
Compound 221: Compound 22H (42 mg, 0.12 mmol) and compound 22J (26 mg: 0.16 mmol) were dissolved in DtviF (20 mL). EDC1 (30 mg, 0.16 mmol), HOST (21 mgr 0,16 mmol) and DIPEA (0.05 mL 0.28 mmol) were added and the reaction mixture was stirred at room temperature for 2 hr. Solvent was removed and the crude materia! was and ourified via soc j'10c>= :vH3^MeOH/CH2Cl2) to give 7 mg (13%) of compound 221.
(7.5 mg: 0.088 mmol) were stirred in methylene chloride (5 mL,'. 7itan:urr; ietraisopropoxide '0.043 mL. 0.15 mmol) was added followed by adcnc" z~ D!?EA (O.C-'c ~L. C05S ~mci\ Tne reaction mixture was stirred a: ~:~~
to dryness. Tne crude material was purified via PTLC (1C=-= NHs^MeOK/CHzCIs? tc give 7 mg ^25%) of compound 22L.
Compound 22K: Compound 22H (20 mg: 0.06 mmol) and isooropyi sulphonyl (27 mg, 0.18 mmoi) were dissolved in methylene chloride (10 mL). D!DE£ (0.04 mL 0.26 mmol) were added and the reaction mixture 'was stirreo a
To a solution of compound 1001A (1.S5 g, 3.95 mmoi) in anhydrous Dk'iF (35 mL) was added 2-(trim©thyisilyI)ethQ;cymsthyl chloride (SEiviCL 0.83 mL 4,73 mrnol) and DIPEA (0.8 mL, 5.14 mmol). The solution was stirred at 25 °C for overniaht. DiviF was removed under vacuum. The product 1001E was purified by SGC (Hexane/EtQAc, 2:1. yield: 1.6 g, 74%).
Compound 1001S was resolved by Chiralcel OD column (Mobile phase: Hexane/2-propano! 3:1). The first peak was collected and concentrated to give compound 10010.
To a dry flask was added compound 1001C (1.5 g. 2.73 mmol) and 4-pyridyI boronic acid (570 mg. 5.50 mmol). The flask was vacuumed and refilled with ~~TOGS~ 1r™3e times. ^d/dDpfiC!? (220 mo. 0.30 mmol) was added and foi'owe-c by addrtkr. zr CHSCN (20 mL) and aq. K2C03 (1 IvL 15 mL"-. The so:uro~ wa£ sd~~e_ a: 5u :"C 'oil bath) for 16 ^O'j^s. Afte- coo;wg down.
aqueous layer was seoarated and extracted with EtOAc (20 mL) once. The orcar-ie solution was combined and concentrated. The product was ourified ;y SGC (CH^G-^sO-^-jD-: 20:1:0.1) to give co-pound 1001D.
5-- "C ;o:- oa~r -ne~ T-e solution was cooled, the soiutio^ was ™r.s~s"rec ln:c a 250 mL round bottom flask. It was concentrated and dried under vacuum. The crude mixture was dissolved in methanol (50 mU and Et3N f0.5 mL was added ana stirred overnight at 25 CC. The solvent was then removed a.nu the oroduct was purified by C18 reverse phase chromatography
To a flamed dried flask was added compound 1003A (100 mg, 0.182 mmo!)f [1,4-bis(diphenylphosphino)butane] paliadium(II) dichioride [Pd(dppb)Ck 12 mg., 0.02 mmoi], and copper (I!) oxide (15 mg, 0.18 mmol). The flask was vacuumed and refilled with nitrogen. 2-Tri-n-butyistannylpyridine (0.075 mL 0.237 mmoi) and DfvlF (1 mL) were added. The solution was stirred at 100 °C Di: hzzr- for 5 hours. After cooling, the DMF was removed by rotary evaporator. The product was purified by SGC (Hexane'EiOAc >~ ~ cr-^ 10O3B E^mg. 84%).
— L-r '-
Compound 10145- was reacted with carbonyi compound under reductive amination conditions to give compound 1014E. Alternatively, compound 1014B was treated with a suitable eiectrophile and a base to give compound 1014E, which was purified by silica gel chromatography.
Compound 1014B was reacted with isocyanate compound and DIPEA to give compound 1014F. which was purified by silica gei chromatography.
temperature overnight. Solvent was removed and the crude material was purified via sgo (5% HKs^'teOK/Gb^GI?) to give 2.2 mg (3%) of compound 1Q15B.
Compound 1015E: Compound 101 SB (40 mg, 0.11 mmol) and compound 10151 (0.024 mL, 0.22 mmol) were dissolved in DMF (1 mL). K2CQ3 (46 mg, 0.33 mmol) was added and the reaction mixture was stirred at 90 °C ovemight. Solvent was removed and the crude material was purified via sgc (5% NH3*K>ieOH/CH2C!2) to give 2.6 mg (5%) of compound 1015E.
Compound 1015F: Compound 1Q15B (46 mg, 0.13 mmo!) and cyciobutanone (0.2 mL; were stirred in methylene chloride (1 mL). Titanium tetraisopropoxide (0.045 mL, 0.15 mmol) was added followed by addition of DiPEA (0.027 mL 0.16 mmol). The reaction mixture was stirred at room ternpsrsire for 2 h. Then, NaCNBH3 (41 mg, 0.65 mmol) was added and the -~br_-e *■*== strec* at r overnight. The solvent was removed. The crude m=ie-;=L: rvas -jrrfieri -/.a PTLC (10% NrVMeOK/CH2Cy to give 3.1 mg (6%)
Comr;-GL.'"-J 1015G: Compound 1015B (30 ~g: 0.24 mmol) and ethy! "he *oi:owing compounds were prepared as describee ;n Examples 1012 tc
Compound. 1017E: Compound 1017D (210 mg, 0.32 mmol) was heated In a sealed tube with NhVHH* (0.2 mL 6.2 mmol) and EtOK (2 mL) ai SO °C overnioht. Solvent was removed and aave crude material 1017E (210 mo,, 99%) which was used without further purification.
Compound 1017F: Compound 1017E (210 mg, 0.62 mmol) and ethyl isocyanate (59 |xL, 0.74 mmol) were dissolved in CH2C12 (10 mL). The reaction mixture was stirred at room temperature overnight. To this mixture was added Et3N (0.43 mL 3.1 mmo!)r DWiAP (15 mg, cat.) and p-TsCl (141 mg, 0.74 mmol). Tne reaction was stirred at rt overnight. Solvent was removed and the crude material was purified via sgc (10% NK3-M9OH/GH2CI2) to give SO mg (25%) of compound 1Q17F.
Compound 10175: Compound 1017F (SO mg, 0.15 mmoi) was heated in a sealed tube with HC! :'3 mL 4N in dicxane^ at 55 GC for ^-8 hr. Solvent was
mmol). and (NH^zCOs (30 mg. 0.3 mmo1; were suspended in a mixture of NH3*H2C (- T-L a^d etrano; ?1mL. Tne solution was stirreo at 90 Z'C
DK'iF ( 100 mL). cesium carbonate (41.13 g, 125 mmol), and 2-ch!oro-5-methylphenol (1021 A) (15.0 g} 105 mmol) were added to a flask. Methyl iodide (17.S2 g, 126 mmol) was added dropwise via addition funnel. The reaction mbcture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, washed with water and brine, and dried with Na2S04- The resulting material was filtered, and concentrated to dryness. The crude product was purified via flash sgc using 1:4 EtOAc: hexanes as the mobile phase to aive 15.93 o of 1Q21B.
A flask containing AIC!3 (2.55 g, 19.1 mmol), and UCI (0.41 g, 9.6 mmo!) was placed in a -30 3C cold bath. A solution of 1021B (1.0 g, 6.3S mmol) and acetyl chloride (0.75 g: 3.5 mmo!) in 20 mL of CH^CI* was added dropwise. "Hie reaction mbcture was stirred for 1 h at -30 CG. then allowed to warm to r.
oe ana EtOAc. The organic layer was wasnec with ware". sat^^atec aq Stec 3
let: stirrino overnicnt. The reaction mixture was heatec at 40 rC for > n.
-esultina materia! was diluted with 10% aa NaOn and extracted with ErOAoto --move starting material. The aqueous iaye-~ -A-as adiustec :c z~ ' and extracteo with additional EtOAc. The organic ^aye: was one- w~- Na^O^ "^tersd. and concentrated to dryness to give 12.2" : of 1021D
|Indian Patent Application Number||174/CHENP/2007|
|PG Journal Number||32/2010|
|Date of Filing||16-Jan-2007|
|Name of Patentee||SCHERING CORPORATION|
|Applicant Address||2000 GALLOPING HILL ROAD, KENILWORTH, NEW JERSERY 07033|
|PCT International Classification Number||C07D 401/14|
|PCT International Application Number||PCT/US05/24771|
|PCT International Filing date||2005-07-13|