CA2115349A1 - New 3,5-di-tert-butyl-4-hydroxyphenyl derivatives, processes for their preparation and medicaments - Google Patents

Abstract

Described are compounds of formula (I), in which A is a valency bond or a straight or branched alkyl chain with 1 to 5 C-atoms; X
is an -NR-CO (amide) or -NR-CO-NR- (urea) group in which R is a hydrogen atom or a C1-C4 alkyl group; and Y is a straight or branched, saturated or unsaturated hydrocarbon chain with 1 to 6 C-atoms (which may be substituted by an aryl, hetero-aryl, aryloxy or arylthio group), a C3-C6 cycloalkyl group or an aryl group, whereby the aryl or hetero-aryl group may be substituted in any possible positions on the ring with one to three CN, hydroxymethyl, methylenedioxy, halogen, trifluoromethyl, C1-C4 alkyl, amino, C1-C4 acylamino, di-(C1-C4)-alkylamino, hydroxy, C1-C4 alkoxy, carboxy, oxyacetic acid ethyl ester or nitro groups, with the provision that Y may only be an unsubstituted phenyl group when A is anything other than -CH2- or -CH2-CH2, as well as the pharmacologically acceptable salts of such compounds.
The invention also concerns methods of preparing such compounds, and drugs containing them for the treatment of metabolic disorders.

Description

3 ~

~he present inve~tion concerns n~w di-tert~-but~l-hgdroxyphengl derivatives (BH~) derivatives of the.
ge~r~l ~ormula I

H~ A-~-Y (I) ~ , . .
.i~ wbicb A signifies ~ str~aigh~ or bra~ched~al~yl : chai~ wi~b l ~o 5 C~atoms, X a~ -NR-GO~ (amid~) group ~0 or a~ ~R^GO-~R (.urea) gr~u~ i~ which R repres~ts a bydrog~n ~tom or a Cl-C~-alk~l ra~ical ~nd Y a str~ t chained or bra~cbed, ~aturatedor u~saturat:~d hydrocarbo~
chai~ wi~h 1 ~o 6 C-atoms~ whic~h can be~substitut~d b~
an ar~ betaryl~, ar~ or arylthio ~adical, a ~7Da6-c~cloalk~l:or an aryl radicalp:whereby the srgl an~he:tar~l radical;i~ guestio~ can;,~ in ~ach case~ be sub~ :~
stituted one to tbree eimeS i~ a~ll po6sible positio~s: : - : ~f the ri~g b~ C~ hydr~x~methyl~ me~bylenedi slog~nt~trifLuorDmethgl, Cl-G4-~alkyl,;~am1no,~e ~ l~
20 ~c~lamin~, di (Cl-C~)alkg~amin~,:aL-C~-alkox~g ~rboxgl~ :
~og~acetic acid et~l ester or nitro, with~the: p~oviso ~ :
, that Y o~Ig slgnifies unsubstituted~:p~henyl when A has~
~a~meaning oth~r:t~a~CH2~ or ~-CE2-CH2~-, as~well as t;heir pharmao:euticallg ~ccept~able~sa~ts, prDc~esses :
: : ~ 25:~ror thelr~preparati~n and medicaments which c~ntain : ::these comp~unds9 :

3 fl ~ :

As "bridge " A, there pr~e~ably s~nds t~e -C~2- ,,

2 2 ~ ( H2) 3 -CE2- ,C~- or the -CEI2WC (CH ) C~3 .
gr oup .
In tt~e carbo~mide group in which the h~droxgphenyl 5 radical is con~ected via t~ "b~idge" A with the amide ~itroge~ or i~ the urea gr~uping X~ R pre~-rablg represe~ts a h;~droge~ atom or a mettl~l. group:6.
- Y~r ~, tb~ be~z~l~ phene~h91~ s~gr~l~ the pb~n;~L

a~d th~ naphth~ ~ radioal ~ r~f errad 9 tbe ~r~mstic o:~ -~0 which Gan,, i~ turn, b~ S~titut~d 0~ ~0 :tbree times in all p~sitiotls b~ CNy ~ oro, chloro" hydr~e~h$1"
met~l9 tri~luorometh~ etb~x~ ~itro,~dimat~laminoj~
metbg~enedi ~ , o~yac~tiG ~cid~ ~h~l ester~ oarb~Dl, 2-~rid~1, 3-pgrid~ 4-p~ridyl, p~rid~gl~p~rimid~
~ra~ pr 2-i~dol~ As~pre~erred hetar~l ra~ic~ls there~are~the~2-fur~ 2-thien~l, 2-p~rr~l, 2-pyridgl,~
~as w~ ss~the~3-indol~l radioal.~
St~ucturall~ analogous`;~compounds ~i~d use as addi~tives in~the~c~s~e o~ pol~m~ri~tio~ reaot~io~s ~cY~ U~SO Pat. 4~152~,319,~ U.S~Pat~ ~780,~103)~

3,5-Di-tert.-butyl-4-hydroxyacetanil=i~e~ls~known as:antihyperlipidaemic (ZA 7401080). ::
; The constitutionally isomerlc~amldes~are also des~ribed~:in EP-A-407 20~0 as~antihyperlipidaemics.

29 ~ ~ H0- ~ ~ R

!. 1 ~
~:: . ` ` ; ~, ,~

r~ Jl1 9

-4-Furth~r anti-oxidatively~cting comp~u~ds are d~scribed in ~P;A-407 200 N~ 5-di-~ert~-butyl-~-h~drox~)-phenethglb~n~oic acid amide is alread~ k~own (J~ Am. ~hem~ Soc~ 84 16Z9 ~1962) but onl,y phg~ ch~mic~l properti~s o~
th~ said ~ompou~d are described in ~hi~ w~rk~
Co~pou~ds wit~ two B~ radicals which ~lso 8ct a~ti-o~ativel~ ~re described in EP-A-40~ 039.
In a B~ssia~ w~rg, ~-(3,~rdi;tert.-but~ ~-10 hgdr~ me~ phenrlure~ is ~es~ri~e~ 88~ UB~itive ,, ~Ie~t~ekhimi;5r~ ~"~ (5) ~ 70~
~ h~ comp~u~d~ I o~ t~ l?rese~ atio~ pg~~81ESS
a s~oag ~ti ~xids~t ~Ctivity.D ~l~e 1ip~plbili~ o~ this anki-o:x:ida~t group ha~ th~ resu1t that t~ compou~d~
15 ~ricb in t~e athe~ogeni~ w de~si~g 1ip~op~t~
: ~ a~d ~f~ectiv~ ro~ect the sensitive p8r~ 0~ t~e ~D~
: ag:i~s~ reacti~e~:ox~gen species~ H~we~r, th~
i~to the m~crop~ago~cgtic:foam ~ells ~s t~e~ewitb di~inctly~retsrded; t~he p~stbologicallg i~ore~sed: ;
upta~o~ ~therog~iG LD~ the atbe~ma CQ~ pr8- :;
suppo~ its o~ d~tive modific~tionO ~ ~ ;
: ~ Anti-~xidsnts ar~ substances whiob ;g~nersll~seen -bring ~bout 8 co~siderobl~ retarding o~ t~e oxid~tiv~
~roces~es in th~ e ~ a produ~t to be~protec~ed Probucol R is~a pote~t a~ti-~t~her~scLerotic~ active~
an~I-oxidant wbicb h~s a h~p~lipid~mic ~cti~n in ::
v~rious a~imal species a~d in buma~s~ I~ is ~ æ~ricall~-hinder~d al~ylphenol~wbich accu~ulates in the ~D~

~ 1 1 a ~ 9 th~3 animaL experiment~ i~ was sh~wn t~at Probucol blocks th~ idativ~ modi~icatio~ of ~ t he a~teri~l w~lls ~d dir~ctly prevents th~ athe~Dm~
for~atio~ o~ t~e ~asis ~f the anti-o~:ida~t act~vit;~

5 (D~ ~t~i~berg et ~ Amer . J . C~rdiol ,., 57 ~ l~M (1986) 0 Di~dvant~ges o~ Probucoi R lie in th~ low r~prP~
t~ o~ o~ t~ ~ubst~ce ~ ~ well as the egtre~ y lo~
resi~ce period i~ th~ b~d~ ti~ues~ the exor~io~ of ~obuc~I t3kes pllsce m~ vi~ `t~ ~aecas (c~O M~
a~ " Pltls~ GQl~ ~!h~r~ 9~ ~57 (1985)~
~rth~m~r~ ompou~d~ ~f th~ f~r~uls I -1QW~r ~h~
.. . . ~ .
pl~sma lipids ~ tbat t~e~ blo~k t~e i~testi~sl chol~
e~terol ~sor~tio~" co~eque~ r~duceithe: i~tr~ -~epatic pool c~ 'rree cholesteroL and corraspo~di~
1~; reduc~ th~ ~r~ti6~ utriti~-d~p~d~ lip~protei~s ~rom t~e 11Y~ int3 th~ p~asm~ ~he i~ iti~ o~ tb~
cb~lesterol r~orpti0~ ~epends up~ a~ i~hibiti~ ~f ac~l~coe~z~m~ A~ ~ho~t~r~l tr ~ferse (~CA~ reac~
In th~ ~teroc~ , ACAI? ~ata~ses tbe ~$~ri~iGati~ or ~0 ~e cb~ erol whic~ c~sar;sr in ord~r t~ pa~
c~olestero1 :into c~microns ~nd to i~troduce it; ~a the intesti~1 ~mph ~n~ tb~ thor~ci~ ~uct ~to ~e circu~ati~g blood.
!: . ' ! i ! : , . ! :~
ubstarl~e~ bave ~ g~od resorptio~ ~d i~hibi~
25 t~e ACAl-dep~de~t esterific~ti~ o~ tbe fre~ ~holes~ero~
not on~g i~ :tbe ellterocg~e~ but also in the c~lls o~ th~
~therom~ it~ r~heg th~reby pr~e~t tbeir f ~m ~
cellular de~enera~ion ~s ~ r85ult 0~ overloadi~; with cholester~l esters1, 211 ~ 9

6--The di-tert "-butylphenol deriva~ives of th~ f ormula I c~ be ~btained accordi~g ~ o per s~ known s~nthesis processes, ~or example j b~sr reaction of an amin~ of the f ormula II w~th a carbox~lic ~c~d or a d~rivative o~ a - 5 ca~box;ylic acid o~ the ~:e~eral ï ~rmula III
O :
H~ N~ ~

II III
i~ w.hic~ ~,, R ~d Y lla~e tbè m~a~ ive~ ormu~a I
a~d Z repr~ t~ ~d~o~l~ h~logen, C ~54-alk~g- ~r ~zide-O
~ a rula~ the :r~aeti~ tals:~s pl~ce ~ a~ i~ert solve~t 9 SUO~ a b~droca~o~, dimelih~ rmamide, dicl~lor~metb~ e or i~; s.tb~r~, 0~ prefer~bl~ u6e~ ~egui.molar::~amounts of ami~e: a~d:
cs~o~y~ic aoid in the presellce ~ e~ù~molar amou~ts ~ of 5 :~s~;ba~s~ suc~h as B: tert. org. ~ amineg pr~erablg triet~gl~
ami~e~lka~li m~l bic~rbo~ate, h~dro~ide~or ~arbs~a~
.
B de~i~rati~es~ o~ t~e c~r~ox~li¢ ~c~ ormul~
~: ~ : ; t~ber~ c~n serve t~e; acid balide, azide" anb~drid~ or ester, For t~e reactio~ ~f t~e ~re~ carbox~lio ~cid, ~s :
8 rul~, t~e pr~s~nce ~f P~13~ SOC12 or PCI~; is necesssr~, ~r the reacti~n ~f a carbox~lic: ~cid ~ter with the : 0mine~ a basia c~talyst~, preferBbl~ a~ al~Bli me~B
alcoholate. In man~ oases~ the r~80ti~n ~f the cBrb~
25 oxyliG BCid~ with B~;B~ine a~so tBkes plBce i~ a solv~t 3 such as e,gr~ lene, b~ heating under reflux on a h'llà3-~9 water separatorn The ur~a derivatives of ge~ f ormula I ~X
~R-C-NR ) ~re pr~erabl~ obtairled by addition of lsoc~anate IV ~o a~ smi~e o~ t~e ge~eral ~ormul~
5 car~i~d out in an inert solv~t9 ~3~gO tolu~3n~
~ouben ~e91, V~l ~, VIII r P 0~ I~i7 ~ -. O
.. ~ .~
H~- ~ ~ ~>~ a~ Y
'' ' ~2='~ ' :
~ I
Because o~ t ~eir ~tabiLisi~ acti~a o~ lipo~rokei~
10 ~he com~ou~d~ o~ t~ formu~a I ~i~d use as me~ic~m~at~l, , especiall~ ~8 a~ atberosclsrGtic~
~ urth~rmore~ t~e~ act a~ti~inflammatori1~J ¢~t~-~protectiveLy3 as we11~a~ antIa~tbmatica1I~. H~we~r, tb~ ca~ a1so~ba us~d ~ hibitors ~f th~ p~r~u3ioa-depende~t lipid peroxidatio~ and as ~tsbilis~rs o~ tbe"lung sur~ct~k factor"~
I~ individua1~reacti~n pro~ucts are~ ~ot obtai~ed witb su~icient purit~t the puri~iQsti~ or:the~Grude ~:' :products ca~ tsk~ place:by crgst~ a~io~or ~olum~ :~
: :20 ~hromatograph~. :
~: ~or t~e preparatio~ of saLts wl~h pb~sio~ogica11 1 I compatlbl~organic Dr inorganic bases, 8UC~ ~5 f~r ;: ~ : example, s~dium~ droxide, p~tassium hydroxi~e~::cal~ium hg~o~ide~;~mmonium b~droxide, meth~l~lucamine9 :
morpholine~, triethylamine or ethanolamine, the ~ompounds:
o~ the formula I can be reacted with ~e ~ppropria~e baB~s~

h ~ 3 4 9 Mix~ures of the acidic c~mpounds with a suitable alkali metal carbo~at;e or h;srdrogan c~rbonate ~lso come i~to c on~ider~ti~n .
For ~e ~r~p~ration ~f medicaments 1~ the c ompou~d~
5 o~ the ~;eneral formu~a I are mixed in per se k~ow~
m~er with sui~ pharm~ceutica~ carri~r ~ubstar~ces, ~r~ma~ ~lavo~r ng ~nd col~llring materi~l~ and formed2 for ~æsmp~e" ~s t~b~t~ or dr~;e~s or, wit~ addi~ion of ap~ropri~te. ~ v~ u~p~d~d or ~ssol~ .~alter 10 or ~il, suob U8 e~g. olive oil.
o~ ra~ ~r~u~ I can b~ :
admi~ls~r~d or~ll;5r ~d par~ter~ liqui~ or solid form. ~g ~ecti~ medium" w~t~r i~ ~?r~ferabl;y u~d w~ich co~tai~s t~e ~ lisi~g a@;ent~ lubili~i~g L5 ~gellts ~d~or bur~er~ usu~ the oa~e of i~e~tio~
~;olutio~5 e~ha~ol" dimethgl ~ulphoxide~ compleæ ~ormers (such 8S etb~le~e~ami~e~tetraac~tic acid), hig~
mol~ular pol~mer~ (such a~ liguid p~sreth~ene; oxide) . !
for t~e~ vi~co~ r~gula~io~ or pol;st~k~ e deri~-:~` 20 stives ~r s~rbitol a~hgdride~
Solid carrisr ~8teri81~ are ~.g~ star~h, laGtoss~.man~itol, ms~h~l~oellul~se9 t~lc~ bigb~y-dispersed silicic acid~hi~h mo~ulsr ~attg acids; (6uoh a~
stearîc acid~), ge~ati~e~ agar-s~arJ c~lcium phosph~te, ~a~esium~stëar~te, a~imal and vege~bl~ ~ats or selid high mo~ecuIar po~mers ~$u~h as polyethyle~e ~l~cols)~
Co~positions suitable for oral administr~tio~ car, ir l 9 _9_ desir~d9 c~nt~i~ f~avouri~ and s~ tenin~ agentsD
~ he ~min~ster~d dosage depends upon the age" the s~a~e o:E haaltb a~d tbe weight OI the recipient7 th0 exts~t of ~he disease " th~ natur~ of further treat-5 me~t~ possibl~ carried out simultan~usl~y, thefr~que~cy of the t~e~tmen~ a~d th~ nature o~ t~e desire~ actio~G Usuall;sr D the d~il;sr dose o~ th~ active ~omp~u~d amolmts to OD1 tQ 10 m~;/kg o~ bvdy w~ght.
~i~e ~ollowi~g :E%am~les show 80m~ of the proc~s ~:
10 varia~ts wbic~ ca~ be u~d ror the ~;g~hesis o~ t~e ~omp~u~d~ ~c~ordi~; to tbe i~ve~ti~ wev~r~ ~th~ are ~ to re.pr~t ~ ~imit~tio~ o~ the meaai~g of the i~v~ntive co~c~ptO
~ ' :
` .

~ o~
q~O 8 ~olu~ o~ 0 3; ~42 mmol) 3,5-di-~ertO~ :~
but~l-4~:~dr~xybe~xglamin~ HCl (~.,g ~alogouslg~ to ~I0ub~-Weyl, Yol 11~1, p . 502)- and 5~4 m~ ~rieth 5~1-20 ~mi~ i~ 100 ml absolute ~Q~e~e o~e sdd~ d~op~
40 mmo~ 4~c~1~rocin~amic:~ci~ chlorid0 (~rom 7~ g :~40 mmol~ chlorocinnamic ~cid ~n~logolisl;s~ t~
ben-We;5~1s VolO 81~ po 464) diæsolved i~ ~0 m~
to~ue~e ~ 1 hour ~t room ~emperature, A~t~r 1~
;2~ hour~, one pours tbe~ batc~ t~ cold 1~ h~droc~lorîc acid, s eparat~s the phases and shakes tbe organic phase twice with, in each case, 100 ml of wat~r~.
A~ter drgin~ OI tt~e to~uene phase over M~;~04~ ~he 2il~3~1~

--~o solvent is ~emoved i~ ~ vacuum" the resldue tritur-~ted with a little li~roi~ and ~ilter~d o~ with suc~ioll.
8~.7 g Or almos~ col~urless crg~al~ p~ 175C.
a) ~_ ~L~
e~l~
A mixture. Qf 30,90 g (0~ mol~ . 3,5-di-~rt.-buts~l~
4-hDbt~rQ~p~eth~lami~ d 1~i~,4 ml (0,13 mol) bo~z~
?0 ald~h;stde i~ 200 m~ absolut~ l;olue~ is bo~ u~d~r :
r~ a wa~er ~a~ator`until no m~re wat~r o~ ..
reactio~ separat~ ub~u~tl~,~o~ ~v~p~rate i~
vacuum9 ag~ di~solve~ i~ 100 m~ absolute tol~e a~d mi~s this s:~luti~ b:l2~6 ml ~O,l~ m~
dimeth~l sulphate.~A~ter 3 b~ours beati~g, it i~ ~ :
cooled, 150 ml of water ad~e~ th-er~to~ agaîn ~eat~ :
for 1 hour~ 120~.C and agai~ eooled. Tbe aque:o~ua ~ ;
phase is s0par~t;ad o~ th~ orgaaic phase is mi:xe~
` w;lth a Iittle: HG~ ~ono~aad ~ubsegu~tl~;evaporatod 0~ in a~ vacuum~Wa~er~still pros~e~t is rem~ved az~eo- ;
~tr~pically ~ith toluen~ Th~e remaining residue is :~ :
: t~riturated with~a~Lit~le etber/ligroi~ a~d ~ilt~red ~: :
o~ with suc~ion.
2~8 g of ~rvwn~h~c~r~stals, m.p. 200 - 203~C~
b~
.
~-m~th~ c:hlorophen~ acr la~ids :~
mixture of 4`DO g (l5~6 mmol) of the amine ;~ obtained und~er a)y: 2.6 ml (36 mmol) pyridine an~

3 ll 9 ' -Ll-100 ml dichloromethan0 is mixed at room temper~tur~
within 30 mi~ with a s~ution of 1~ mmol 4~c~10ro-ci~namic acid chloride (from 209 g (15 mmol) 4-ch~oroci~llamic ~cid anal~gousl~ t~ ~ouben-Weyl~
5 Vol. 83, p. 464~ in 20 m~ dichlorometban~, ~ pter 6 hour~ stirring, o~e pours i~to ~o~d ~
~Cl, sep~a;t~3 the phases a~d shake~ bUi; the or3a~ic plla~. twice wit~ wat~r,. A~ter dr;lring o~ th~ dicbl~ro~
ms1;h~ne pba~ ver 1~280~,,. the ~olve~t i~ r~moved in ~0 a ~a¢uum. ~er triturati~n w~h ligroi~/tolu0 o~ obtai~ a cr~stalli~e product. 1~ f colourl~æ~
~gs~ 15 .. . . . ....... . .. . .. .. . . . . . . . . . .
~' ' ~
~5 ~ .
~ 0 a s~olution~o~:2~7 g (10 mmol~ ~5-di~ort~-bu~4-b~drox~be~æ~l~mi~e b~drochloride (pr~pared a~a~go~ly:~tp: ~oube~Weyl~,. Vol. 11/1~ p~5~2 ~r~m 3,5-di-te~t~-butyl~4-hydrox~Qnzaldox~m~ 50 ml 2~ t~tr~h~drofura~ one.add~ 4~2 ml ~:riet~ ine~a~d, a~t~r 2 hour~ 6~irri~ ilter~ off witb suctio~
t~ trieth~lamine h~dr~chloride:~orm~d~For the dis801~i~g ef:tbe base,. 2~ ~ (10 mmol) 3~4~met~g~en~-diox~phe~ crylic acid azide in 50 ml~tetrabydro-furan are~sdded thereto with ice cvoli~ ~nd ~llowedto,stir over~ight at room:temperature~, A~ter evaporatiOn o~ the tetrahgdrofuran soIutio~, it is ta~e~ up in water and eth~l acet~te, the org~nic ~ .

s;~

-~2~
ph~e is separatedoff . a~d further sbaken out twice with eth;yl acekate" A~ter dr~ing o~ the ekh~rl acetate pha~ over Na2S04, it is distill~bf~ d the residue triturated with eth~r/isobex~ne ànd filkered ~ff 5 ~rith suctiorlc There remai~ 1,,4 g o~ colourless or~stals r m .p ID ~94 ~ 197QC .
'` '.
.

.
:
~0 ~ ~olutio~ of ~pO g (8 mmol) ~ di-~srt~-but~-~dro~phe~ b;srlami~e (~.~0 ~ording to J.~ Am. Chem, ~30c~ 84, 1629 (1962) in 30 m:L tolue~e i8 mi:ced dropw~s~ witb 0~87 ml (~ mm~ pheny~ i~oc~Late~
A~r 2 h~ur~ stirring~ ` the ~olvent is subst~tiall~
~5~ ~em~ed~ the residue ~ ered o~ wit~ suckio~ a~d recr9~s~allised ~rom etb~ol~toluene. (1~3). 20~3 g . .
~ c~lourle~s cr~st~1s, m~>pO 181 183t)CD

20~ b~ I~o~do 4"9 g (30 mmol~ ~tra~s-4-bgdroxgcin~amic~: aoid are~
~ ~ susp~ded: i~ 50 ml ~n~gdr~u~ ~ceto~ snd mi~:ed ~rit~
1 12.6 jm~ ~9~ mmol) trietbiDlamine. O~e c~ols i~ ~n ~ce-bath to ab~ut ~5C and ~dds ~dropwi~e thereto a 25 ~oluti~o~ 11.7~g (90 mm~l) isobutsll~chloro~ormate~
in 12 ml acQtone. A~ter 2 hours stirring wlth ice co~ling, a solution of 6.,3 ~; (96 mmol3 sodium azide .. . . . . ....... , .. ,, .. ... ,, ,,,, . , . , , ., .,,, .. ", . . , .. . ,, ~ .. ..... ... ...... . .... .. . ... ... .....
.... . ..... . ...... . ..... ... .. ............ ........ . .. . . .. ...... .

~ L~34~
:

13_ i~ 24 ml o~ water is ~ldQd dropwise thereto and further stirred f ~r a furth~r 2 h~urs ~ hout cooling" One dilu~es with sb~ut ~00 m~ ~f water alld ~tr~cks the azide f~rme~ se~ersl times with ~thyl ~-5 acetate . A~t~r ev~poration ~, there is obtai~ed a crys~ e pro~u~t of t~e m.p~ ?4- 76~c"
~ h~ aæide i~ i~t~duced ~lid int~ 100 ml of tatr~drofuran ~oluti~ 0~ 20 mmb~ 3,5~ tert.~
butgl-4~drD~be~z;srl~mi~e (pr~pared a~ des~rib~d Exam~ ) a~d~ st~r~ ~or 2 m~ t r00m t~mp~r- :
ature~ tb~ additi~ o~-300 ml o~ wak~r ~
~æ~raction wit~ e~h~l ~Cet;~lti63D 0~ obt~ias lO g o~ :
the iso~u~c~r~o~gl c~m~ou~d~ ~b~ e~er is ~p~ni~ie~ b~ di~ol~iag ~tb 75 ml t~tra~dr~fu~a~
15 a~d ~d~iti~ f: ~25~ml co~ ammo~ia~ ~he solukioll is~
, distill~d~ disso1ved i~wst~r aRd eth~ Gebat~
tbe~ org~ic pbase dried ~over ~2SO~ a~d rem~Yed i~
a ~ vacuum., ~ter ~ triturstion~ -~otio~ ~ ~iltr~tio~
ne obtai~s 2,6 g o~ almost~ colourle~s :~r~sta~s;~
20 ~ m.p. 205 - 2Q~

: , :

-14` -., .._ A R Y l~C]
~ . _ ~ _ _ 5.1 CH2 H OCH3 158-161 -CH=CH- ~ -OCH3 .

~ . ~ ~ ...
5.2 c~2 H . OCH3 193-195 ~.

-CH=CH- ~ -OH
... _ .. ... _. _. _ _ _ _ .. ~ i, 5.3 C~2 H ~H=CH ~ 214-216 N . .
l .
c:oo~:2Hs ~.
.... .. ___ _ _ _ ~ _ . .. ._ ~, ~
~.4 ~2 ~ :~ . 1~8 15~ :.
-C~=C~ ,) , ~:
~ . . .. _ _ . ~ :
5~5 CH2 H ~ CH3 185-188 . : -CH=CH~
~: : C~3 : : ~ :-. . .. _ _ _ _ . -~ 5.6~ ~:CH2 H ~ ~ CIH3 : 232-234 : ~
~ ~ _L I ~ -CH=~H~
5.7~ ~ H: ~ OCOCH3~ ~ :~`i98-200 j~ ; ~ : ~ -CH=CH- ~ -OCOC~3 ~: ~ :
~ ~-- ~ ~ ~ ~
~5.~8 ~CH2 ` H ~ : o ~ ~ : 128-13~0 ;~ : -C~-CH~ : :
~` I . -- . j ~ ~ ~ ~ ... ~ _ ~ . .. ~.:-.--- `':

.:
", ::

::: ~
~.

-- ~:5 - .

,.. _ , R [~pC ~
_ _ - ' - C~l . ~-5. 9 CH2 H 3 195-1~6 -~H=s~ QtCH3 _ CH3 _ 5 . 10 CHz H ~\ h~ 117--118 . -CH--CH-<~ --O ~CH2 ~=~
__. , . . __ ~ :~:
5~11 CH2 H ~ ~ 173-174 ~ CH=C~H~
___ _ _ . ::
5 .12 CH2 H ~ 2 13 -2 15 ~CH--CE~ N
~=~ , :
-5~3 C~2 ._ _ _ __ 3 21~-2~21 -CH=C .
: H
__ _ _ ._, . . . ~ :-5 . 14 ~ - C~2 ~ -C~C~ 231-~233 ~
~ ~ ~ : ,-: ~ .
.`
: : . : ~
_ ~ , _ ~
5~.15 ~ C~H~ H : ~ ,C2~I5 134-135 :~: ;
: : : ~ N ~ : ~ :

~ ~ ~ : ~ -CH2-~ ~ ~ ~ ~ : :
~ : _ _ _ _ _ _ _ _ : -- ~ ~ ~ ~
; ~ 5.16 ~ CH2 H ~ : ~ ; 1~36--13a ~ ~
~ , ,, ~ _ : __ _ ~ ~ ~ ~
5.17 Cll~ EI ~ ~ lB9--190 ~
":,, ;

, ~

: ,,:

.
, ~ l l S t~

_ ..
. _ __ R _ t P ~
5 . 18 CH2 H -~N 213~215 , ~ , .~
5.19 c~2 ~I _~. 220-222- I ~
_ ' . _ 5 . 2 0 CH2 H _ ~ 153--16 0 .

_~ . _ . ~ _ _ C"' ~ ~r,~
~ !
:
!. 'I ~'` . . ' - ' - - -'-' - - .. -.- .. --_.__.. __,.. __ .,.. _ . _.. __ _ _ .___,, _, ,_. _.. _._ .. _ __, .............. , , ,, ~ ,_, _ _,. .... _ ...... .' .' ' I ~ I ".
_ ,, _,,,,: _ _ : . . . .. - ' ' ' '-- ' " ., .. . " .. ... , . _: .. .. . . , . ........... , , .. ... . .. .. _ . ; .
.~ amino~ eo~Proe~ hen~ox~J ac~t~c. ~cid e~
.' ;~
e~t~r ~
. . .
; ~ 5 5~6 ~ (15 mmol)~N-(3,5-ldi-tert~-but~ 4-b~dr ~ -; be~z~ 3~(4-h~dro~p~n~13-~Gr~lamide are disso~vea in 150 ml~ace~v~e-,:~4~2 g potas~iu~ e~rbonate~adas~
t~he~ato:a~d~mi~æ:ed with 3.4 ml ~30~mol) brom~ac~t~o~
acid ~th~l~estsr.~ Aft~r 2~ hours ~ti:rri~g~ at ~ro;o~
~:~temperatura~ iB :~v~p~rated i~ a vacu~m~, dissolve~
~er a~d ~athyl ace~at~, th~: eth~l acetBte~pha~se~
I separ~t~ O~drie~with NB2SO~4 a~d ~istilled o~f~
! ~he solid reBidue~is triturat~d with;~et~her:and ter~d ~:f:wi~h suction. Th~re remai~ 4~5 g :
COlour~esB Grgstals~m~p~ 144 ~ ~47~C. ~ ~ ~

:: :: : : :
:
~ :
:

:

17~
3~ g (20 mm~L) 4-dimet~;ylaminocinnamic ~cid are dissolved in 75 m~~ tetrah;ydro:Eur~n~, 0c4 ml (6() mmol) ~ri~th;yl~mi~e ~dded th~reto and y whil~ c~oli~g . at about 5~C, 2~ ml (22 mmol) cb~or~f~rmic ~cid i~obut~l 5 estffr ~dded dropwi~ thar~toe, O~e ~ ws to a~te~-stir for a fu~th~r 1 hour in the ice-bath a~lLd Ior 1 hour ~t room temperature. Subse~ue~tlgD 2~8 g (10 mmol) 3~5~-d~-t~3rt~-but h~srdrQ~be~zylamiaa ~drocblori~e are a~ s~ orm at r~om ~em~arat~re a~ all~wed 10 ~o s~r Purt~r ~r 2~ ~ur~ ad~ o~ o~
~.0~) ml o~ w~ter, i~ i~ extra~ted~3 ~ime~ ~:Ltb ~tb;~l aGeta~e~, ~he orga~ic E~a~e i~ dried; w~th ~a~ , a~
IEIiS t;;i i3.ed Drr ~, ~h~ r~ g r~idue i~3 puri~i~ia over a ~ilica gel 60 ¢~1~ (60 x 6~ m)~ w~th i~ohQ~
15 ~1 a~Q~ e ~r~G~ b: the p~re ~mpou~d , i9 distill0d oP~ tb~ re~idlle ~ritur~ted wi~th e~her aa~ filtere~ oP~ with ~uction~ ~h~r~ remai~. 2.6 g o~
col~rleæ~ c~stals,~ 195 - 197~a"~
~.

20 ~ q!he ~llowin~: oo~pou~d~ ar~. pr~P~r~d in a ma ana1ogous t;s~ t desc~ d i~ E~ample l; : ~:

X~ ¦
. - - - . ...... , - .. .. .... - . ,.. ~
A ~ R : ~ ~ y : ~ poc3:
.... _. ~ : ~ - - . .. :~
8 . 1 CH2 H ~ 2 0 9 -11 : C~=CH O
~ _ __ .... ~ . _ ........ _ 8 . 2 CH2 H - J~l 194-96 :~
: _ _ CH=~H S _ ... .. ,, . . .. . ... , . . ...... ,, . . , . .. .. , " . . .. ... ... ... , . .. , .. . .. , .. .,, ........... " . .....
... ....... ....... .. . ... ... .. ..... .. ... . . . . . ... .....

_ ....... ~ I [~p C] , tC t -t = ~ ~ 19~

. Cl~=C~? ~SJ

~e~ac2H~ . ' :.
~ " ~1 Ic~J=cJ~

, ,'~/: -' b~ oll~wi~g compou~ds, ar~ pr~?~red i~ m~r :~ aCI81Qg~U33 to that de~cribed in ~ mpl~ 4: :

~ ~ R R

.'~O-~-A-~-CO-N--Y

_ _ : ~ ' :: : ~ : A ~ Y ~ ¦:Cr~P;C3 ~: ~ _ _ ~ ~_ .
: ~ 9 . 1 C~I2 H i -C3H7 : 161- 62 ~ I

1~ ~ . ' , ~ :' ~ _ ~ _ _ g . 2 CH2 IH : :2 o o 02 ~
- Phenyl - ~ ~ ~ :
.

:

:: ~

: ' -- -A R [~C ]
_ ~ _ ~ _ _ _ 9 ' 3 CH2 H 43CH~ 216~17 . . ~
9 . 4 CH~ H ~ F 190-92 _. _ _ . _ , _ _. __ ~' 9 . 5 CH2 H ~ Cl 217-18 _ _ _ _ _ _ _ _ _ 9. 6 CH~ H ~ CF3 :16~i--66 4~3 .
'.
_ ____ _ _ _ _-- , 9.7 CH2-C}l2 H ~ ~H5 160-61 __ . _ _ _ _ .
9 . 8 CH2~H2 H i~C3E7 : 188--90 , . . . : .- ' . _ , _ . _ __ . _ , . _ _~
9. 9: CH2CH2 H ~ ~3 ~ li9-90 : :

. _ __ _ _ ___, _ . :,:
~ 9 .10 ~e~2C~2 H ~ F ~ 71-72 :. _ ~ ~
~ ~ 9.11 CE7CH2 H ~ ~ ~ Cl ~ ~200-0l ~ ~ ~

~ _ ~ ~ ~ : ~:
9 . 12 C~2CE2 H p9 ~ ~164-65 ~ ~
\=~C~3 ~ : ~ ~ ~: :`
: ~ _ :
: ::
,, .

.

, .

:

_. ._ ._ . . , . .
A R Y L~p C ]
_ .

9 . 13 CH2 H C~=CH~ 175~77 . _ .. . __ __ 9 .1 4 CH2 H ~ 17 4 -7 6 CH=CH~ Cl \=~
_ . ._ . . . .
9 . l~i CH2 H ~ 202 05 CH--CH~ ~3 . . _ _ _ _ ~ .
9.16 C~12 H . ~ 188 C~=C~ OC~3 . ~
. _ . _ ~ . . _ _ _. _ _ 9.17 C}I2 H C~=C~ NOz i76--78 .
. _ .. ._ . _ 9 . 18 CH2 H ~ . 191--93 CH-CH ~ F' ;~
. . : ~
~ __ . __ ~
9 .19 CH2 ~ Cl : 16 9--7 ~
~ : :.
: _ _ , CX=C~-~ ) ~

~9''0l C~2 I I ~c~ ~17 ~ I ~
: : _ . ~ _ _ .~
~ c~ ~ 8=~ C~7 ~ L ~ ~

: ::
::
`:

:: : : : : ~
: ::: : , :

:, `21 -._ ~ . _ , :, A R Y ~ ~pC
9 . 2 2 CEI ~ . ~ =CA -~ ~_ 9. 23 CH CH=Clr ~ 191-94 . . , . . . `:
9 . 2 4 CH2 H l~3 174--7 6 .
. ~-C~' O .
_ . _ . ,. _. _ _ _ _ 9 . 2 5 CH2 ~C~=~J~I 16 6--6 9 . _ _ _ 9 . 2 6 CH2 HC~=CHJ~ ~ !J 14 9--5 O
. I . ~: ~' . COOC~
._ _ . . __ . _ _~___~
9.~71 .C~2 ~ IC~5C~3 1 11 (Z) : :~-~- ~ _ =~ _ 9 ~ 28 : :-C~-= H 168-170 ; ~ : ~ ~ : ~ ~-CH=CX~ :
: .: ~ - ~ ~ ~ .
9 .: 2 9 -~H2 -ÇH-- H :: 17 0 ~ C}13 ~ ~ ~ i-C3-~7 : - ; ~ ~ --- - ~- -: :

- ;22.

= A R . [~lpC]
g . 3 0-CH2--çH- X 102 CH3 Phenyl , _ _.
9. 31 -CU~ fEl-- H CH3 13 7-1311 9 . 3 2 -C~/, f EI H _ __ _ . . 12 9--13 1 9 . 33 --CH2 fN3 H -~-Cl 159-160 . _ e ~~ _ ___ _ _ 1 9~3~ ~Cll~~clI~ L ~ ~^~
9 . 35 fN3 H . 192 194 .~
-CH2~f-- i-c3H7 CE3 --- - _ : _ `-9.36 fX3 ~ 157 15~ ~
-CN~-f- Phenyl __ C~3 : ~_. :

. 1'~
'~
,:i` ~ ' ' : ~

--2~;--= A R _~ _ ~1~ pC ~
9 . 38 -CH2-fCH-3 _~3-F ~ 89-190 _ ~ ~ _ _ . _ ............. :-~
~ f ~ -~-cl 173 174 ~ ~
~

--I . - _ __ ~ ~
; I 9 40 fH3 H _~ 131-132 ~fCI-13 L___ __~ __ -,' :-... . . _ . . ~ . , ~r~ ~Icr~io ~ériv~tives a~ bav~ tb~
c ~ urati~

~h~ ~oll~wi~g c~mp~u~ds are pre~ared i~ a ma~ner . ~ ~ -. , : a~al~g~u~ t~ that described in :E:xam~
~: .

~la343 H0~ ~ -A-N-CO-Y
>~
. _ _ _ _ . . _ ~
A R Y _ _ _ ~ ...... _ .. _.
10.1Valen~ H Phenyl 194~195 .. .

10.2 l~ ~ -CH2 ~ 160-161 10-3 It -CH2~CH2 ~ ~ 132:
'.~`'' ~
10.4 ., " -(CH2)3~ ~ 116 ~

7, 10 . 5 CH2 H Phenyl 188-1~9 ~ ; . : .
10.6: ~ " ~ ~ 133-134 I 10.7 ~ ; : ~CH2-O ~ 135-137 10.8 ~ ;~ ~ ~CH2-S~ : 117-118 10.9 1 ¦ ¦ -CH=C ~ ¦ 1 1-161~¦~ 10.~10~ ~ ,, -C~=CE ~ -CH3 ~ 153 ::: ~ 10.11~ " .. ~ -CH=CH ~ -F ~ ~ ~:173-174 :
. . .- ~

: : ~ '' : ~ : ~ .. ;

;

~11J~4~ ~;

' ' ' _ __.. . ~:
A R Y L~poC] _ ~:
. _ . ~ ., 10 .12 I- ,. -CX--CH~--OCH3 15 6-lS7 ~1 ~.
10. 13 I. ll -C~=C~I~) 153-1~5 _~3 :~

10 . 14 ,l ,l C~CH~ 178-180 1 . lS ¦ " ~ 135-137 10 . 16 ll I~ -C~IzC~ 197-lg9 ~
- C~3 ~ .
10.17 ll t~ -C~ H--~--N0~: ~ 184-187 : :
~CX-C~$~ ~ 192-194 10. 18 :: 1~ I~ ~ :~ -] 0 .;19 ~ t~ l -CH=C (C~3 )~ : ~154- 156 10.~20 ~ ~C~2--CH~ ~ H ~ ~Cl~ ~ ~'53~ ~ ~ ;~

10.21 ~ ~ " ~; ~ C(CX3~)3 ~ : ~153~-155 10.~22 : ~ ~ ~ ~CH2~ ~ ~ ~138-139 '10~.23~ ~ : ; : ~ `~ C~12~-C~2~ ~ 06-107 _ ~ :: ~ ~ :~

:

. . .
R [~ p~C ]
..... . _ ...
10.24 ll ll -tC~X2~3~3 75 10 . 2 5 .~ ,l -CH=C~I~ 17 6 10 . 2 6 ,l I- -CH=(:~H~3--F 17 6 10027 ll - -C~C~I~ 157 10. 2t~ l n ~=CH--~--Cl 178.

10 ~ 29 " . . -C~C~--Cl~ 167 ¦10-30 ¦ ~ l , ¦ CH=~---CH3 ¦ 1 5-176¦
10 . 31 ~ 3, -~=C~--~3_ COOEt ~ 180 1~1 10 . 2 : : -CN=C~3--COOH ~2 46-;~4 8 10 . 3 3 : 13 -CH~CH~--OH 153 ¦ 10 ~ 3 4 ¦ " ¦ " -CH=CH~ CC~3 ~ 1 8--16 9 : ~ 10. 35 : ~ :C~I2--CH2--~F 80-81 ; ~ :

10 . 3 6 ~ ~ -CH2-CH2~3--CH3 88-89 ~ ~ ~ : : - ~ ~: ~

:
, ~ :

4 ~ :

,_ I __ R _ . _ 10 . 37 .. .. -CH2 CH2~9--COOEt 120-121 10. 38 . 11 C~2~cH-cH2--~2-- 91-93 ~:

10.39 ll . " -C-~ 135 `

10 . 4~)ll ll ~ Cl 138 :~

10. 41 c~2 H -C~H2--o_~3 CH3 111 . ~.
10 . 42 ll " -CH2-- ~ OC~I3 141-143 ~:~

10 ~13 .. C 3 10. 44 Isil ~ . - ~ ~ 12~ -131 : : : ;~ c~ o~3-- - CH3 ~; .

:

:

e~
- 2~ -A R ~ C]
_ ~ __ 0.461 " ¦ " ¦ -CH2~ 113-114 10.47 tl ,l -CH2-O- ~ -Cl 122-124 ~3 ¦10.48¦ " I " ~ -CH2-O- ~ I 10 -103 '~ ' ' ~ ;', -CH2-O-<' )-NO~
10.4g ~. l \==/ ~ ~43 I44 , 10.50 l CH3 ~10.51 : " ~ ~H3~ ~ 168-169 : ~ 3 ~
: ~ ; L ~ - ( cH~)3-o ~ o 1 7~
:
: ~ ~ :-`- - ~ ~

:

~: :
: ~

:

:

R ~ C'C]
CF3 :
10 . 53 ll ~. -CH~-O~ 99--100 -C~I2 -0-~--CN
10 . 54 ll .l 160-162 ,'., ' ~ O . 55 n - CH=CH~ COO~ 2~5 149 ~150 J~ -1~:1 o 56 ll ~l ~ 1J7-178 . -C~=C~H~ OC~I3 ¦
1 ~
10 . 57 l ll C~I3 0~ : 160-161 ~
~ : ~ ~ :`' 10.58~ ~ ~ " "~ ~ ~S~ ~ ~220-222 : ~ ~ ~ ~ ~ ' 10~59 ~ ~CH2-CH:2 H; : ~ 141-142:
~ ~ ~ ~ ~ ~; ~H3C 0 ,10 . 60 ~ 2 -130 ~10. 61~ ;~ ~ : : ~ ~ -H2C /~ : ~127-128 ---- -- - ~ _ : ~ - -, :

- ~io ~- l . A R ~_ ____ _ =~
N ~ --10~62 ll ll-~3 128 .

. ~J . -10.63 71 ~1~ ) 153 ~ :
10. 64 ll I.~N 131 l, h~N ~ I -110. 65 l " ¦ I -ca2~ S
¦ 10. 66 ~ ca~-cH2~ 13 10 . 67 1 1 " I ~/ 1 16 I~L :: ~ ~ I ~ ~ 1 13~

h~ ~ollowi~e compou~d~ sre~ pr~ared ~ a~ ma~er a~ gous So thab :described ~ E:l~amele 2~

, ;

4 ~ ~

X R
ffO--~-A--N-C0- Y

~ .
A R Y [~;~?C
___ _ _. _ 11. 1 CH2 -CH2 CH3 ~ C ( C~3 ~ 3 151-153 111, 2 .. .. --ClI2--CH2~F 133 .

11. 3 l .- -CH2-CH2~ C~3 124-125 .

11. 4 l ,l l -CX2--CH~ CooEt 1 8--119 ¦

11. ~i - ol -C~=CEI~ 133 .. i-~ ~ . ~ .
11.6 ~ ~ : ~ 150 ~ 11. 7 ! I I -CH=CH~ ~Cl ¦ 12 -124 ¦
11. 8 " ~ -c}~=ca~ -C~3 115-116 : ~

1~1:. 9 ~ I : ~ ; -CK--CH~Cl:)O~:t118-119 :~

~}1.10 : " ~ -CH=CH~3 FooH~ ~l99-Z01 ¦ 11.~ =CH~ OCH3 ¦ I -1 S7 . ~ 2 ~ " ~ : 119 11.13 ll : ~ : ~ -C-C ~1 ~ ~ 6 ' __ ~ ~ ~ ~ : : ~ :
' ::
:

3 3 ll ~

E~amp~e_12 .. . . . .. . . . ..

5~8 ~; (0.0124 mol) N ~,,5-di5 tert,,~but;~l-4-h~drox;sr-5 bell~gl)_3~(4-ptl~no:~yacetic ~cid eth~ ter)-acr~lamide (Exampl~ 6~ are stirred ~or 2~ h at room témpera~r~
i~ 50 ml ~tlla~ol; ~nd 50 ml of wat~r with 1~06 g;
(O.C)~9 m~1) EOH~ Oue ~isti~s ~f~ the ~lcohol, ~ci~
i~e~ with dil. ~drochl~ric acid an~` extra~ts ~rith 10 eth~l acleta~. A~ter ~a~orati~ o~ the et c~tat~
~he ~roduct i~ ~s~llisa~ ~om ~ie.~h~ ~t~er/i~-~xa~ o O~ç~. obtai~s 1,,1 g o~ t~ mO~ 125~1~;0C ~, A~alo~ 9 o~e obtai~2 1201 ~ ,5-di~t~r~-b~lt;~ hy~rox~b~gl-3-(3"4 ~i~gd;r~ h~ acr~ mid~,, almo~ col~url~
~ ~ sta~s, m~p,. 233 ~ rom ~(3;y-di~tert.
but~ h~ro~ b~n~y~ 3~4 diac~t~æ~phe~
acr~lamide (Exampl~ 5~7) ` ~ :
12~2 ~ 5~ tert~but~1-4-~ydroxybe~ægI) 3-(4-~0 h~drox~¢arbo~lphen~ acryla~ide ~rom N 3,5~
tert~ b~t~1~4-bydroxybe~z~1) 3~C4-ethn~c~rbo~gl-p~e~yl~-~cr~lamid~ (.Ex~mple~10~5)~
.
~ ' .
- . . .. .
~ dro~benz~ (4-~ivalo~
. . ... .
25 ~ : -3~ g g~O mmol) N~ di-tert.-butgl-4-hydroxy-~enz~ 3~(4-hgdro~phe~ acr~lamide (Exampla 5~
are dissolv~d in 100 m~ tetrahydrofuran and 2~8 ml h .1 1 i 3 '~ ~

--3~
(20 mmol) triethylamine ~dded the~et~. While coo~ing, betweea~ 5 ~n.d lC)~C 1~,5 m~ (12 mmol) pivàlic ~cid chloride, di~solved i~ 5 ml ~etra~idrofuran ~ ~r~ ;
added dropwise. ~her~toO A~er 24 h s~ir~i~g ~t room 5 temperature ~. :Lt is diluted wit~ water ~d e~tracted ~ith eth~l sc~t~te,, ~he e~ c~t~te; r~sidue is purified ~ver a ~ilica gel c~lum~ ~G 60) with i~
h~a~ th~ ¢~tat~D ~ft~r tritur~tion wi~h ~th~r"
ther~ ~m~ olourl~ cr;~r~tals ~ t~e m"plb 172-~7~G~
.
... ... .
~0 ~4 .... _ _ . .
.. .. ... , .. . .. .... ~ . , . ~ . . ...... , .. . , . .. , ~, .. . ........ ......... . .. . . . .. .. .

..
.. . . ...

- 4~1 g (i~ mmol) 3~ $a di-ter~ but;g~1~4~drox~-be~z;s~ 3-(4-~itrop~e~l)-acr~lamid~ ~:Ex~m~le lO~L7) 15 are ~is~ol~e~ ia 250~ml:~thaaol a~d mi~a wi~ ~.,5 g ~:
. . . .
(lOS~ mmol~ s~itlG dus~ 00 ml 2 mo~Lar t~gdr~chloric ~cld -ar~ a~de~ dropwi~ wît~i~ 1 h with vigorous stirring.
A~ter 3 hours stirri~g, :~he reaction is~ e~ded. It is ~ilter~d ~o~f wi~h ~u¢tio~, tbe ~iltra~e distilled of~
2C) a~d ta~ up i~ etbyl ~tat~: and wa~er. ~be ~th~
~: : ac~tat~ residue is puri~ied over ~ silioa gel column~
(XG ~0), A~er ~ritur~ti~ with isobe~ane, there~are obta~ned 1~5 g ~f pr~duct o~ the m~p~ 80~ ~sin~er~)O
i - .

he~o~va~e~ic acid amid~
P~_ : ~ 105 g 3~2 mmol N-(3,4-di-tertO-bu~yl~4-h~dr~
: be~zyl)-4~benzyi~xgphenox~ace~ic acid amid~ ~Exampl~

:

.

211~349 -~4-10050) are dissolved i~ 50 ml meths~ly mixed wit~
0~5 g 10 percent Pd~charco~l a~d h~dro~nat~d ~or 3 h at room ~emperature ~nd normal pressureO After ~ ering o~f the catalyst with suction and ~vapor-ation of tbe s~lva~t~ there is obtained 1~2 gcol~ur~ess cr~stals o~ the m~p, 114 - 116C~
A~alo~ou~ly to Example ~5, o~ ~btai~s: -T~O~ A~ CO--q ~, ~

~ . . . l :
_ ~ :E~ ~ ~ p . C 1~ ' ~ ,~
_ . _ 11.1 CX2~ H -c~-0- ~ ~2 1a _ _ : _ _ _ - ~ /==N

11.2 2 _ , _ ~ ~ ~ 140-141 . . , : .

--- . ~ :
~5 2~7 g 6 mmol N-(3~5-di-tert~-but~1-4-h~dro~y benægl)-3-(4-eth~xgcarbonDlpbe~yl) ~crg1amide :
~a~æle ~0.55) are stirred for 24 h ~t room temp~r-ature with LiBH4 (prepared from 1~4 g Na:13H4 37 mmol and 1.6 g ~iCl, 37 mmol) in 100 ml ~th~rleDe: glgcoI
àimethgl ether and subs~u~ntly stirred for 4 h at : 50C. ~he reductio~ complex is de~omposed with watsr s~d 2 m~l ~ulphuric acid and the pro~uc~ extrac~ed :

-35~ .
with ethgl aoet~tet. A~ter evap~ration of the etbyl ac~tate phase ~nd tri~uration wi~ ether~is~hexa~e, there are ~tained 1.~ ~; of colourl~ss cr;y~t~l~ of the mDpO 177 - 179C.

:
~. ~

:
: ~ ` :: :

':

:
:

Claims (4)

1. Compounds of the formula I
(I) in which A signifies a straight or branched alkyl chain with 1 to 5 C-atoms, X an -NR-CO- (amide) or an -NR-CO-NR- (urea) group in which R represents a hydrogen atom of a C1-C4-alkyl radical and Y a straight-chained or branched, saturated or unsaturated hydrocarbon chain with 1 to 6 C-atoms, which can be substituted by an aryl, hetaryl, aryloxy or arylthio radical, a C3-C6-cycloalkyl or an aryl radical, whereby the aryl or hetaryl radical in question can, in each case, be substituted one to three times in all possible positions on the ring by CN, hydroxymethyl, methylenedioxy, halogen, trifluoromethyl, C1-C4-alkyl, amino, C1-C4-acylamino, di-(C1-C4)alkyl-amino, C1-C4-alkoxy, carboxyl, oxyacetic acid ethyl ester or nitro, with the proviso that Y only signifies unsubstituted phenyl when A has a meaning other than -CH2- or -CH2-CH2-, as well as their pharmacologically acceptable salts.

2. Process for the preparation of compounds of the formula I
(I) in which A signifies a straight or branched alkyl chain with 1 to 5 C-atoms, X an -NR-CO- (amide) or an -NR-CO-NR- (urea) group in which R represents a hydrogen atom of a C1-C4-alkyl radical and Y a straight-chained or branched, saturated or unsatur-ated hydrocarbon chain with 1 to 6 C-atoms, which can be substituted by an aryl, hetaryl, aryloxy or arylthio radical, a C3-C6-cycloalkyl or an aryl radical, whereby the aryl or hetaryl radicals in question can, in each case, be substituted one to three times in all possible positions of the ring by CN, hydroxymethyl, methylene-dioxy, halogen, trifluoromethyl, C1-C4-alkyl, amino, C1-C4-acylamino, di-(C1-C4)alkylamino, C1-C4-alkoxy, carboxyl, oxyacetic acid ethyl ester or nitro, with the proviso that Y only signifies unsubstituted phenyl when A has a meaning other than -CH2- or -CH2-CH2-, as well as their pharmacologically acceptable salts, character-ised in that, in per se known manner, one a) for the case that X represents a -CO-NR- group, reacts a compound of the formula II
(II) in which A and R have the given meaning, with a compound of the formula III
(III) in which Y has the given meaning and Z represents hydroxyl, halogen, C1-C4-alkoxy or azide; and b) in the case that X represents an -NR-CO-NR group, reacts a compound of the formula II
(II) in which A and R have the given meaning, with an isocyanate of the formula IV
O=C=N-Y (IV) in which Y has the given meaning, and subsequently, if desired, converts the compounds obtained of the formula I by suitable measures into other compounds of the formula I of converts the compounds into pharmacologically acceptable salts.

3. Medicaments containing a compound according to claim 1, besides usual carrier and adjuvant materials.

4. Use of compounds according to claim 1 for the treatment of metabolic diseases.