Note: Descriptions are shown in the official language in which they were submitted.
~`:
2~33939 - ~
J~ :~ ~erck Patffnt Go~ollochaft ~:
- ~it boochran~t~r ~aftung
6~271 D a r ~ ~ t a d t
1.2-Dlhydro-2-o~pyr$dlnes
5Th~ lnv~nt~on r~lat~s to nov~l 1,2-dlhydro-2-oxo-
pyrldine~ of th- for~ula Is
R-CH
R2
wher~ln
R $8 ~ CH2NR3R~
Rl ~
10 R~ , A, C2-C6-al~onyl or C2-Cc-alkynyl,
R2 1~- 802N~ - CooR5, - 802NI~ - CoR5, - 802N~- 802RS,
-8O2N~-CoNR5RC, -C(N~2).N0~, ~,S-dlhydro-
5-oxo-1,2,~-oxadlazol-3-yl, ~,5-dlhydro-
5-thloxo-1,2,4-oxadlazol-3-yl, 2-oxo-38-
1,2,3,5-oxathladlazol-4-yl, Z,2-dloxo-3~-
1,2,3,5-oxathladlazol-~-yl, 2,3-dlhydro-
3-oxo-1,2,~-oxadlazol-5-yl, a, 5-dlhydro-
2,5-dloxo-1~-lmldazol-~-yl, ~,5-dlhydro- ~;
5-oxo-1~-1,2,~-trlazol-3-yl, ~,5-dlhydro-
5-thloxo-1~-1,2,4-trlazol-3-yl, 2,3-dl- .
hydro-2-oxo-1,3,4-thladlazol-5-yl or ~,5-
dlhydro-5-oxo-1,2,~-thladlazol-3-yl,
R3 1~ ~, A, C3-C8-cycloalkyl-C~2n- or
Ar~Cn~2n~ ' ` - ~ ~ `
25 R~ 1~ A-CO-, Ar'-CO-, Ar'-C.~2~-CO-, R9-gO2-
or Ar'-8O2-, .
, '~'"~
2133939
RS and R6 are oach ~, a Cl-C6-al~yl group, wheroln
on~ C~2 group can aleo bo roplaood by O or
8 or an additional C-C double bond ean bo
containod and whleh can add$tlonally bo
sub~titutod by O~, oR7, Ar, ~t2, NR7a8,
NR7-CooR~, N~7-COO-Ct~2t-Ar, NR7-COO-Ct~12t-
Hot and/or CooR7, or aro C3-C8-cycloalkyl,
Ar or ~-t,
R7 and R~ aro oaeh A, C2-C6-alkonyl, C2-C6-alkynyl,
C3-C~-cycloalkyl-C~2~- or Cl-C6-alkyl,
whoroln ono C~2 group 1~ roplacod by O or
8,
R9 i~ Cl-C6-al~yl, whoroin ono or more
atom~ can al~o bo replacod by F,
15 A i~ Cl-C6-alkyl,
Ar and Ar' ar- o-eh an un~ub~titutod phonyl group or
a phonyl group monosub~titutod or disub-
8tltutod by R~, O~, OR9, COOR, COOA, CN?,
N02, NE~, N~A, N(A)~, N~COR9, N~COOA,
N~8O2R9, ~al and/or lH-tetrazol-5-yl,
a?-t 1~ a fivo- or ~ix-momborod hotoroaromatie
radleal hav~ng 1 to 3 N, O and/or 8
atomJ, ~hieh oan al~o bo fusod wlth a
b-nz n- or pyrldln- rlng,
25 ~al 1~ P, Cl, ~r or I,
i~ 0, 1, 2, 3 or ~,
and n ar- oaeh 1, 2 or 3 and
t 1~ 1, 2, 3 or
nd their salt~
8~1ar eompound- ar- known from ~uropean patent
applieatlon A2-0530702
Th- ob~-et of tho invention was to find nov l
eompound~ w~th valuabl- prop-rt$o~, o~poclally eompound~
~hleh ean bo u~-d for the pr-paratlon of drug~
It ha~ bo-n found that tho compounds of tho
formula I and tholr ~alt- po~os~ vory valuabl- pharmaeo-
logleal prop-rtl-- eoupl-d wlth a good tolerane- In
partleular, th-y ~xhiblt antagoni~tie prop-rtio~ toward~
~ngloton-ln II and e~ thorefor- bo used a~
~ 2133939
- 3 -
pharmacoutlcal actlve lngredienta for the prophylaxis
~ and/or therapy of coronary, cardiovascular and vascular
dlsorders, ln particular for the treatm~nt of aDglotensln
II-dependent hyportenolon, aldo~teron~sm, card~ac lnsuf-
f$clency and increaeed lntraocular preesure, and of
dlsorders of tho central nervou~ eystem, al~o of hyper-
trophy and hyperplasia of the blood vessole and of the
heart, angina pectorle, cardlac $nfarct, stro~o, re-
steno~es after angloplasty or by-pass oporatlons, of
lechaemlc per~pheral clrculatory dl~ordera, artorlo-
sclerosl-, glauc~m~s, macular degenerat~on, hypor-
urica~mla, ~dnoy functlon dlsorders, o.g. ~ldney fall-
ures, dlabotlc nephropathy, diabetlc retinopathy, psor$-
asls, of ga~trolntestlnal dlsorder~, bladdar dlsorders,
lS pulmonary oedema, chronlc bronchlti~, anglotonsln II-
modlatod dlsorder~ ln femalo roproduct~ve organ~, porcep-
tlvo dlsordor~, e.g. domentla, amne~a, memory functlon
disordoro, anxioty stato~, depre~slon, opllepsy,
Par~lnson's Dlseaoe and/or bul~a.
The~- ff~ct~ can bo determined by conventional
ln vltro or ln rlvo methods such as, for examplo, thoso
descrlbod ln ~8 Patent ~ 880 804, US Patont 5 036 0~8 and
Internatlonal Patent Appllcatlon 91/14367 and al~o by
A.T. Chlu ot al., ~. Phar~acol. Exp. Therap. 250, 867-874
(1989), and by P.C. Wong ot al., lbld. ~, 719-725
(199Os ln vlvo, on rate).
Tho lnvont~on relat-~ to th- compoundb of the
formula I and tholr salts and to a proce~e for tho
preparation of theso compound~ and thelr salt~, charac~
torlzod ln that
(a) a compound of the formula II
E-CH2- ~ -X-
R2
whereln
E le Cl, Br, I, a froe 0~ group or an 0~ group whlch
has be~n functlonally modlflod to acqulro
2133939 ::
" ~
reactlvlty, and
R2 1~ a~ de~lned in Clalm 1,
1~ roacted with a compound of tho formula III
~-R III
wherein
R 1~ ~ def~nod ln Claim 1,
or
(b) a compound of th- formul~ I 18 froed from one of it~
functlonal derivatlv-~ by troatment with a
~ol~oly~lng or hydrog~noly~ing agont,
(c) to preparo a compound of the formula I whereln R2 ie
-C(NH2).NOH, a compound whlch corro~ponds to formula
I but 1~ replacod by tho radlcal R2 ln whlch a C~
group, 1~ reactod wlth hydroxyl ~ine or
(d) to propar- a compound of tho formula I whorein R2 1
-802NH-COOR5, -802N~-COR5, -So2N~-So2R5 or -S02N~-
CoNR5RC, ~ compound which correspond- to the formula
I but ln whlch th- radlcal R2 ~ replaced by n
-SO~N~2 group, 1D roact-d wlth a compound of th-
for~ul~ ~-CooR5, ~-CoR5, ~-802R5, Æ-CoNR5RC or ~ 3
o-C-NR5
and/or ln that on- or r- radlcal~ R ~nd/or R2 $n a
compound of tho formul~ I ~r- conv-rt-d to one or mor-
differ~nt radlcal~ R and/or R2, and/or a bas- or acld of
th- for Nla I $~ converted to on~ of $ts salt~
Abov- and bolow, unles~ oxpreeely lnd$catod
otherwl~-, th- radical~ or parametor~ R, Rl to R9, A, Ar,
Ar', ~t, Hal, ~, m, n, t and ~, ar- as def$n-d ln
formula~ I ~nd II
In th- abov- formulae, A h~ 6, preferably 1,
2, 3 or ~ C atomJ A $~ proforably mothyl, or els- othyl,
propyl, i~opropyl, butyl, $~obutyl, so~-butyl or tert-
butyl, or 180 pentyl, 1-, 2- or 3-methylbutyl, 1,1-,
1,2- or 2,2-di~ethylpropyl, l-othylpropyl, hoxyl, 1-, 2-,
3- or ~-~ thylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or
3,3-d~^thylbutyl, 1- or 2-othylbutyl, l-ethyl-l-methyl-
propyl, l-othyl-2-~ thylpropyl or 1,1,2- or 1,2,2-trl-
2133939
- 5 -
methylpropyl Al~enyl 1~ preferably ~inyl, prop-l-enyl,
prop-2-onyl or but-1-~nyl, or 1~ pent-l-enyl or
hox-;-enyl Al~ynyl i8 preferably thynyl, prop-1-ynyl or
prop-2-ynyl, or 818~ but-l-ynyl, pent-1-ynyl or hex-l-
ynyl If ~everal radical~ A, al~enyl or al~ynyl arepresent ln a compound of tho formula I, they can be
ldentlcal to or dlfferent from one another
~al i~ proferably P, Cl or Br, or OlBe T-
R lo a radlcal derivod from 1,2-dlhydro-2-oxo-
pyrldln-, r- pr~cl~oly 1,2-dlhydro-2-oxo-3-(R3~N-
methyl)-6-Rl-pyrldin-1-yl
Ar and Ar' are each, lndependently of each other,
preferably un~ub~tltuted or further, a~ lnd~cated,
no~ubstituted phenyl~ in dotall pr-ferably phenyl, o-,
m- or p-tolyl, o-, m- or p-ethylph~nyl, o-, m- or p-
trifluoromethylphenyl, o-, m- or p-m thoxyphenyl, o-, ~-
or p--thoxyph~yl, o, m- or p-difluoro-~ethoxyphenyl, o-,
m- or p-trlfluoro-m~thoxyph-nyl, o-, _- or p-carboxy-
phenyl, o-, ~- or p-~ethoxycarbonylphenyl, o-, m-or p-
ethoxycarbonylphenyl, o-, ~- or p-cyanophenyl, o-, ~- or
p-nltroph nyl, o-, m- or p-~m~noph nyl, o-, m- or p-
m thylaminoph-nyl, o~ or p-dimethyl~m~nophenyl, o-,
m- or p-trifluoroac-tum~dophonyl, o-, ~- or p-m thoxy-
carbonylamino, o-, ~- or p--thoxycarbonyl~m1no, o-, ~- or
p-~-thyl~ulfon midoph nyl, o-, m- or p-trifluoromothyl-
~ulfonamidoph-nyl, o-, ~- or p-fluorophenyl, o-, ~- or
p-chlorophenyl, o-, ~- or p-bro phenyl, o-, m- or p-~
t-trazol-5-yl)ph~nyl, furthermore preferably 2,3-, 2,4-,
2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3- 2,4-, 2,5-
2,6-, 3,4- or 3,5-dim~thoxyphonyl
~et 1~ preferably furan-2- or -3-yl, thi-n-2- or
-3-yl, pyrrol-l-, -2- or -3-yl, imidazol-l-, -2-, -~- or
-5-yl, pyrazol-l-, -3-, -4- or -5-yl, oxazol-2-, -4- or
-5-yl, i~oxazol-3-, -~- or -5-yl, thiazol-2-, -~- or
-5-yl, i~othlazol-3-, -4- or -5-yl, pyridin-2-, -3- or
-4-yl or pyrimidin-2-, -4-, -5- or -6-yl, or l~e
preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-
tr$azol-l-, -3- or -5-yl, 1,2,3-oxadiazol-4- or -5-yl,
1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or
. .
2133939
- 6 -
-5-yl, 1,2,4-th$adlazol-3- or -4-yl, 2,1,5-thladlazol-3-
or -4-yl, pyr~dazin-3- or -4-yl, pyrazinyl, benzo-
f~ran-2-, -3-, -4-, -5-, -6- or -7-yl, benzothlen-2-,
-3-, -4-, -5-, -6- or -7-yl, lndol-l-, -2-, -3-, -4-,
-5-, -6- or -7-yl, ~olndol-l-, -2-, -3-, -4-, -5-, -6-
or -7-yl, b~nzlmldazol-l-, -2-, -4- or -5-yl, benzo-
pyrazol-l-, -3-, -4-, -5-, -6- or -7-yl, bonzoxazol-2-,
-~, -5-, -6- or -7-yl, bonz~eoxazol-3-, -~-, -5-, -6- or
-7-yl, benzothlazol-2-, -~-, -5-, -6- or -7-yl,
bonzl~othlazol-2-, -~-, -5-, -6- or -7-yl, benz-2,1,3-
oxad~azol-~-, -5-, -6- or -7-yl, qulnol-2-, -3-, -4-,
-5-, -6-, -7- or -8-yl, isoqulnol-l-, -3-, -4-, -5-, -6-,
-7- or -8-yl, cinnolln-3-, -~-, -5-, -6-, -7- or -8-yl,
qylnazolln-2-, -~-, -5-, -6-, -7- or -8-yl, l~-lmidazo-
[~,5-blpyrldln-1-, -2-, -S-, -6- or -7-yl, 3~-
l~ldazol~,5-blpyrldln-2-, -3-, -5-, -6- or -7-yl, 1
l~ldazol~,5-clpyrldln-1-, -2-, -~-, -6- or -7-yl or 3
~dazol~,5-clpyrldln-2-, -3-, -~-, -6- or -7-yl
The group- -C~2~-, -C~2,-~ ~Cn~2n~ a~d -Ct~2t-
are proferably stralght-chaln and are thu~ preferably
-(C~2)~-~ -(C~2)~-/ ~(CH2)n~ and -(C~2)t-, ln p-rtlcular
_C~2-, al-o -C~2C82-~ -(C~2)3-, -lC~2)~ C~2)s- or
-(C~2)6-, but also, for oxamplo, -C~(C~3)-, -C~2-C~(C~3)-
or -C(C~3)2- Tho param t-r ~ can proferably al~o be 0,
~o that th- group -C~2~- lo abcent
The radlcal Rl 1~ proforably atralght-chaln and
1~ pr-ferably A, ln partlcular othyl, propyl or butyl,
al~o mothyl, per~tyl or hexyl, furthermoro ln partlcular
al~onyl proferably havlng 3-6 C ato~J, ln partlcular
allyl or l-propenyl, also l-butonyl, l-pontonyl or
l-hexenyl5 al~ynyl proforably having 3-6 C atoms, ln
p~rtlcular propargyl or l-propynyl, al~o l-butynyl,
l-pentynyl or l-hoxy~yl
Th- radical R2 1~ preforably -So~N~-CooR5, ln
partlcular -S02N~-COOA; -802NH-Co-R5, ln partlcular -
S02NH-COAr ~uch a~ -802N~-COC6~5 t -S02N~-CONRSR6, ln
partlcular -802N~-CO-N~Ar ~ucb a~ -S02NH-CO-NHC6~S or -
S02N~-C0-NHC~2~0t2 ~uch a~ -802N~-C0-NHC~2-(2-pyrldyl)
Th- radlcal R2 1- furth~r prof~rably ~,5-dlhydro-5-oxo-
~' ` . ` "; . ; ~ ' :
2133939
. -,
-- 7
1,2,4-oxadlazol-3-yl, or further preferably ~,5-dl~ydro-
5-thloxo-1,2,4-oxadlazol-3-yl, 2-oxo-3H-1,2,3,5-oxathl-
~dlaæol-4-yl, 2,2-dloxo-3H-1,2,3,5-oxathladlazol-4-yl or
4,5-dlhydro-5-oxo-1,2,4-thlad~azol-3-yl
S Ths radlcal R3 lo proferably ~ A, in partlcular
methyl, further othyl, propyl, isopropyl, hutyl or
l~obutyl;, cyclopropylmothyl ?
Th- radlcal R~ 18 pr-forably R9-S02-
Tho radlcal R5 1~ preforably A, ln partlcular
methyl, ethyl, propyl or butyls Ar, ln part~cular phsnyl;
~et-al~yl, 1~ partlcular 2-, 3- or 4-pyrldylmothyl; or
cycloal~yl, ln partlcular cyclopropyl
Th- radical R6 1~ prof-rably ~, or further A
Th- radlcal~ R7 and R~ aro preferably oach A
Tho radlcal R9 1- pr-forably A, ln partlcular
methyl, furth-r othyl, propyl, lsopropyl, butyl or
l~obutyl `
Tho paramot~r ~ 1~ prof-rably 0 or 1 Tho para-
~etor m 1~ prof-rably 1 or 2 Tho parameter~ n and t are
20 pref-rably 1, or furthor pr-f-rably 2, 3 or ~ -
Th- compo~nd~ of th- for~ula I can po~ ono or
moro chlral c-ntr-- ~nd can t~ r-for- exi~t ln dlff-r-nt
formJ (optlcally activ- or optlcally lnactlv ) Pormula
I lncludo~ all th-~- formu
Accordlngly th- lnv-ntlon r-lat-s sp-cl-lly to
tho~- compound- of tho for~ul- I ln ~hlch at lea~t ono of
sald radlcal~ has on- of th- pr-f-rr-d meaning~ lndlcated
abo~- Somo pr-forrod group- of compound~ can be ~-~
~pr-ssod by th- follo~lng partlal formNla- Ia to Ic,
whlch correspond to formNla I and whereln th radlcals
~ot de~crlbed r- precls-ly aro a~ doflnod ln for~ula I,
excopt thats
ln Ia Rl 1~ A;
~n Ib R2 1~ ~,5-dlhydro-5-oxo-1,2,~-oxadiazol-3-ylt
in Ic Rl 1~ A and R2 1~ ~,S-dlhydro-5-oxo-1,2,~-oxa-
dlazol-3-yl
Th- followlng ar- also prof-rrod
oo~pound~ of th- formula- Id and Iad to Icd, wh~ch
corrospond to tho co~pound~ of th- formulao I and Ia to
2133939
- 8 -
Ic, except that in addltlon R3 1~ A or cyclopropylmethyl;
compound~ of the formulae I-, Ia~ to Ido and Iade to
Icde, whlch corro~pond to formulae I, Ia to Id and Iad to
Icd, except that ln addltlon R~ 1~ A-SO2-
~h- oompounds of the formula I and also the
etartlng materlal~ for thelr preparation are mcreover
prspared by msthod~ ~nown per -, 0uch a~ those de~cribod
ln th- llterature (for exampl- ln the ~tandard wor~ e
~oubon-Woyl, Methoden der organl~chen Chemi- (Methodc of
Organlc Ch d ~try), Georg-Thl~ -V~rlag, Stuttgart, but
especlally ln Buropoan patent appllcatlon A2-0 ~30 709
and U8 patont ~ 880 804), under condltlonc whlch are
~nown and suitabl~ for eald reactlon~, it al~o being
posclble to ma~- u~- of varlant- ~fiown per ~e, whloh are
not montloned ln greater detall h~ro
If de~lred, th- ~tart~g material~ can also be
form d ln ~ltu, ~o that th-y are not l~olated from the
reactlon mlxture but ~medlately roacted furth-r to g~-
th- compound~ of th- for~ula I
(a) Th- compound~ of the formula I can b~
obtaln-d by reactlng compound~ of the
formula II wlth co pound~ of the formwla
III
In th- compound~ of th- formula II, ~ lc
as pref-rably Cl, Br, I or an 0~ group whlch
ha~ been functlonally modlflod to acguir-
r-actlvlty, uch a- al~ylsulfonylo~y
having 1-6 C atom~ (preferably methylsul-
fonyloxy) or arylsulfonyloxy havlng 6-lO
C atom~ (pr-ferAbly ph-nyl- or p-tolyl-
sulfonyloxy).
Th- reactlon of II wlth III 1- con-
venlently carrled out by flrct convertlng
III to a salt by tr-atment with a ba~-,
for exampl- wlth ~n al~all metal
alcoholate` ~uch a~ C~30Na or pota~-lu~
t-rt-butylat- ln an alcohol cuch ac
methanol or tert-butanol, or wlth an
al~all m tal carbonate cuch a~ ~2CO3, or
2133939
~ .
g
~lth an al~all motal hydrldo ~uch ae Na~,
or wlth ~n al~all motal alcoholato ln
dlmethylformamfdo (DM~), and thon
roactlng sald salt wlth II In au lnort
solvont, for oxa~plo an amldo euch a~
DNF, N-methylpyrrolldono or dimothylacet-
amldo, or a sulfoxlds such a~ d~methyl
~ulfoxldo (DMSO), convonlontly at tem-
porature- of between -20 and 100 , pro-
forably of betwaen 10 nd 30 Otb~r
sult blo baso~ aro al~all metal hydrogen
oarbonatoo ~uch a~ Na~C03 or ~HC03 ~-~
~b) It 1~ furthermoro po~lblo to froo a
compound of the formula I fro~ ono of lts
lS functional dorlvatlves by solvolyei~ (for
oxampl- hydrolysi~) or hydrogonoly~is ;~
Thu~ carboxyllc aclde of th- forrula I ;
whlch conta~n (at loaet) ono COO~ group ~ ~ i
can b- obtalnod by tho saponlflcatlon of `
corro~pondlng al~yl stor~, for oxampl~
wlth NaOH or ~0~ in aquooue ~olutlon,
with or wlthout tho addlt$on of n inort ~
organlc ~olvont ~ueh a~ othanol, ~-
thanol, T~F or dloxan-, at t _ oraturo~
of b~two-n O and 100', or by th~
hydrogonoly~l~ of corroqpondlng b nzyl -~
o~tor~, for xamplo on Pd-on-charcoal at
proe~uro~ of botwoon 1 and 200 bar and at ~ -
t-~p-raturo~ of botwoon O and 100 , ln
on- of th- ln-rt solvent~ lndicatod
It 1- al~o po~slblo to cleavo wlth al~all
a eo~pound whleh ha~ tho formula I but in
~hleh th- radleal R2 i~ replacod by S~
trlchloro~othyl-1,2,4-oxadlazol-3-yl
group (whleh ean bo obtained by r-actlng
a earboxa~ido oximo of tho for ula I,
R2 . -C(N~2).NO~, with trichloroacotle ~-
anhydrldo), for ~xamplo wlth NaO~ ln
~at-r/dlox no at 0-10 , tho corroepondlng
,
r ~
2133939
' '' -- 10 -
eompound I, R2 . 4,5-dthydro-5-oxo-1,2,4-
oxad~azol-3-yl, bolng obtained
(c) Roaction of a nltr~lo which correeponde
to formula I but instead of the radical R2
contain~ a CN group, with hydroxylam~ne
ylolds th- eorre~po~ding carboxamlde
oxlmo I, R2 . -C(NH2)~N~ Thle reactlon
le convenlontly carrlod out ln an lnert
solvent such as THF at temporatures
b-t~een 20 and 100
(d) Co~pound~ of th- formula I wherein R2 le
-802N~-CooR5, -So2N~-CoR5, -S02NH-S02R5 or
-So2N~-CoNR5R6 ean bo obta~ned by n-
acylation of eompounde whleh correepond
to th- formula I but ln whieh th- radical
R2 1~ roplaced by an -S02N~2 group
Sultabl- aeylatlng agent~ aro, for
exampl-, co~pound~ of the formula- ~-
cooa5, for e~amplo mothyl ehloroformat-
and ethyl chloroformate; E-CoR5, for
exampl- ae-tyl ehlorido, eyelopropano-
earbonyl ehlorld- or b~nzoyl ahlorld-; ~-
802R5, for xampl- methan-sulfo~yl
ehlorld-, p-tolu nosulfonyl ehlorld-s ~-
C0-NRSR~, for oxamplo dlphonylcarba~oyl
ehlorld-; 0-C-NRs, for oxa~pl- phonyl
leocyanato
Normally, th- reaetlon le performed ~n
tho pro~once of a ba~o, proforably of a
tort~ary a~ln-, for oxample
trlothylumin-, pyrid~n- or 4-dimethyl-
amlnopyrldlnQ, convenlontly at tempor-
atur-~ b-tw en 0 and 100 An exe-e~ of
th- amin- e n al~o b- ueod ae a eolver,t
Th- reaet~on with ~soeyanates of the
formula 0-C.NR5 to glve th~ correopond~ng
sulfonylur-as 1- pref-rably perforred at
tomp~ratur-r botwe-n 50 and 100 , an
r~e-~ of th l~oey-nat- ~-1ng u~-d ~ -
2133939
~.
11 -
solv nt
Somo of tho etarting materiale, eopoeially tho~c
of the formula II, are ~nown If they are not ~nown, they
ean be prepared by ~nown methode analogouely to ~nown
eub~tances
.
It ~ 8 aloo poeeibl- to eonvert one eompound of
the formula I to another compound of tho formula I by
converting on~ or moro of the radiealo R a~d/or R2 to
oth-r radleals a and/or R2, for exa~ple by roaeting a
eompound of th- formul- I(R3 . ~) with a compound of tho
formula ~-R3 (ln which R3 le different from ~) or by
reducing nitro groupe to amino groupo (for examplo by
hydrogonation on Raney nie~-l or Pd-on-ehareoal in an
inert oolvent eueh ae mothanol or ethanol), and/or
funetlonally dlfying free amlno and/or hydroxyl groupe,
and/or fre-lng funetlonally modifiod amlno and~or
hydroxyl groupo by colvolyele or hydrogonolyoi-, and/or
hydroly~lng nitrll- groupe to C008 group~, and/or
eet-rlfylng a carboxylle aeld group, for examplo by
reaetion with an aleohol of th- formula A-0~ and/or
eonv-rting a earbamidoxim group to a ~,5-dihydro-5-oxo-
1,2,~-oxadlazol-3-yl group by roaetlor~ (a) with 1,1'-
earbonyldlimidazol- or an al~yl chlorofor~ato, (b) to a
~,5-dihydro-5-oxo-1,2,~-thladlasol-3-yl group u~lng 1,1'-
thiocarbonyldiimldazol-, ~c) to a 2-oxo-3~-1,2,3,5-
oxathiadiazol-~-yl group usi~g SOC12 or (d) to a 2,2-
dioxo-3~-1,2,3,5-oxathladlazol-~-yl group uelng S02Cl2,
and/or eonvorting an S02N~-COOR5 group to an -~02N~-CO-
NR5RC group by amidation wlth a compound of th formul~
HNR5R6
Compou~ds of tho formula I (R3 . H) ean thue b-
al~ylatod by r~actlon ~lth eompoundo of th~ for~ul~ ~-R3
(~horoln R3 le diff-rent fro~ ~) Th~ roaetlon le profor-
ably carrl~d out ln an lnert solv~nt, for oxa~pl- an aeld
a id eueh ao DM~, N-methylpyrrolidon-, 1,3-dim thyl-2-
oxohexahydropyrimldin- or hox~mothylphoephora~ldo, an
aleohol ueh a~ m thanol or t-rt-butanol, an eth-r eueh
ae T%P or ~ halog nat-d hydroearbon sueh ae dlehloro-
methano or mixturoe thoreof ae eolv~nto and/or lu tho
~ $ ~ ~
~ r ' '~
~ 2133939
- 12 -
pre~ence of ~n al~ali motal alcoholate ~uch a~ sodium
methylat~ or potaeei~m tort-butylate, ~ al~all motal
hydrldo euch a~ sodiu~ hydrido or pota~lum hydrldo, an
al~all metal carbo~ato ~uch as eodlum carbonato or
S potae~um carbonate, àn al~all metal blcarbonato ~uch as
~od~um blcarbonate or potaeeium blcarbonate or a tertlary
amin~ such a~ triethyla~i~e or ethyldii~opropylamine at
temporaturo~ botwoon about -30 and 200, proferably
betwoen 20 and 60
Further~oro, freo ~mino groupe can bo acylated ln
con~ontlonal manner wlth an acld chlorld- or anhydr~do,
or al~ylatod wlth an un~ub~tituted or cub~tltuted al~yl
halido, convonlontly ln an lnort ~olvent ~uch as ~ethyl-
eDe chlorlde or TEP, and/or in the prosonco of a ba~o
~uch ac triethylamtne or pyrid~ne, at temperature~ of
betwoon -60 and ~30
If deelrod, a functlonally modlfiod amlno and/or
hydroxyl group ln a co~pound of tho formula I can be
frood by solvolyele or hydrogenolyele uelng conventlonal
methode Thu~, for examplo, a compound of th- fo ula I
contalnlng an N~COR9 or COOA group can ~o conv-rtod to
thc ¢orreepondtng compound of th- formula I containl~g an
N9~ or ~OCC group instead COOA groupa can b- ~apontfled
for oxa~pl- wlth ~aO~ or ~O~ ln wator, water/TEF or
wator/dloxan-, at tomporatur-~ of botween 0 and 100
Th- abovemontionod eonv-relon8 of a earbamidoxt~o
group (I, ~2 . -C(NE~).NO~) to varlous abov~mentloned
hotoroeycllc radieal~ 1~ proforably earri~d out in th-
pre~enco of an inert ~olvont, for example of an othor
cuch a~ T~, of a hydroearbon ~ueh a~ toluon~, of an
~do ~ueh a~ DMF, of a halogenated hydrocarbon ~ueh a~
dlchloromothan- or of a ba~- ~ueh a~ pyridin- or of
m$xt~so of two of thoso ~olv~nt~ at temporaturoa botwoon
O and 100
A ba~o of tho formula I ean be conv0rtod with an
aeid to th~ corrosponding aeld addition salt, for oxample
by reactlon of oguivalont amount~ of tho ba~o and of tho
ae$d ln an inort aolvont oueh aD othanol and eub~oguent
ovaporation Po~siblo aeld~ for thi~ roaction aro
':
2133339
. ~
- 13 -
eepeclally thoso ~hlch yl~ld physlologically acceptabl~
- ealte ~hu~ lt 18 poseibl- to ue~ lnorganlc aclde, for
example sulfuric acld, nltric acid, hydrohalic aclde euch
as hydrochloric acld or hydrobromic acld, phoephorlc
aclde euch ae orthophoephoric acld, and eulfamlc acld, ae
woll ao organlc aclds, espoclally allphatic, allcyclic,
arallphatlc, aromatlc or hetorocycllc monobaeic or
polybaelc carboxylic, sulfonic or eulfurlc acld-, for
oxamplo for~lc acid, acotic acid, prop~onic acld, plvalic
acid, diothylac-tlc acid, malonlc ac~d, euc¢lnlc acld,
pimellc acld, fumar~c acld, mal-lc acld, lactic acid,
tartaric acld, mallc acid, citric acid, gluconlc acld,
aecorbic acld, nlcotinic acid, ieonlcotinlc acld,
mothano- or othan--eulfonic acid, ethanedleulfonlc acld,
2-hydroxy~than~eulfonlc acld, b-nzeneeulfonlo acld, p-
toluon-sulfonlc acld, naphthal-no- noeulfonlc and
-dlsulfonlc acid~ and lauryleulfuric acld 8alt~ wlth
phy~lologlcally unacc-ptabl- acld~, for xampl- plcrat~,
oan b- ue-d for l~olatlng and/or purlfylng th~ compound
of tho for~ula I
On tho oth-r hand, compound~ of th- formula I
contalnlng C00~ or, for xa~pl-, 1,2,~-oxadiazol- group~
can b- oonv-rted wlth ba~ for xa~pl- eodlu~ or
pota~lu~ hydroxid- or carbonat-) to th- oorro~ponding
m tal ~alt~ p-cially al~ali m tal or al~alln arth
m~tal ~alt~, or to th- oorr-~pondlng ammonlu~ ealt~ Th
potaselu~ ealto of th- 1,2,~-oxadlazolo dorlvatlve~ ar-
partloularly preforred
Th- nov-l compound~ of the for~ula I and th-ir
phyelologioally acooptabl- calts oan b- ueot for th
manufaoturo of pha-mAo-utical preparation~ by
incorporatlon lnto a ~ultablo doeag- fon~ tog~th r wlth
at leaet ono exolplont or ad~unot and, lf deelr-d,
together wlth on- or ~oro othor aotlvo lngredlent~ Th
r-eultlng formulation~ ca~ bo ueod a~ drugs ln human or
~otorlnary ~odioin- Poe~lbl- oxoipient~ ar- organic or
lnorganlc ~ub~tanc-~ whlch ar- ~ultabl- for onter-l (for
examplo oral or root-l) or parentoral ~lnlstratlon or
for ad~lnl-tratlon ln tho form of an inhalation epray,
2133939
. ,~.,
and whlch do not roact wlth tho novol cQ~pound~ ple-
belng wator, vegetablo oll-, be~zyl alcohols,
polyothylone glycol~, glycorol trlacotato and other fatty
acld glycorldo~, golatin, ~oya leclthln, carbohydrate~
~uch a~ lactoso or atarch, magne~lum ~tearat~, talc and
celluloso Tablets, coatod tabloto, cap~ulee, syrupo,
~uices or drop~, ln partlcular, aro ueed for oral
admlnlotratlons ~pocl-l lacquorod tablet- and cap~ulos
wlth coatlng~ or sh-ll~ rooletant to ga~trlc ~ulce- ar~
of lntor~t ~uppo~ltorlo~ ar- used for rectal adblnl~-
tratlon and ~olutlon-, proforably olly or aqueou~ aolu-
tlon~, a~ woll a~ ~u~pon~lon~ uls~onc or lmplant~, ar-
u~ed for paronteral adm~nl~trat$on For admlnlotratlon as
lnhalatlon ~pray~, lt ~ po~lblo to uso opray~ contaln-
lng tho actlv~ ingr-dlent olth-r d~s~olved or su~pended
ln a propollant ga- ~lxtur- It 1~ con~onlont hor- to u~e
tho actlv- lngr-dl-nt ln lcronl~od for~, lt bolng
po~lbl- for ono or ~or- addltlonal phyclologlcally
compatlbl- ~olvont-, for oxa pl- othanol, to bo pro~ont
Inhalatlon ~olutlon~ c~u bo admlnlatorod wlth th- ald of
conventlonal lnhalor~ Tho nov-l compounds can bo lyo-
phllla-d nd th- r--ultlng lyophlllrat-- u~od for oxa~pl-
for th- nuf-ctur- of ln~-ctabl- proparatlon~ Th
lndlcat-d for~ul-tlon- c~n b- ~t-rllleod and/or can
contaln ad~unet~ ~uch a- pr---rv tlvoc, ~tablll~or~
nd/or ~ ttlng ago~t-, ooulclfl-ra, a~lta for l~flu~ncing
th- o-~otle pr-a-ur-, buff-r ubat ncoa and eolouro
a~d/or flavourlnga If doalrod, th-y ean al80 coutaln ono
or moro oth-r actlv- lngrodlont-, for oxamplo ono or ~oro
vltamlna, dlur-tlea or antlphloglatlea
Th- aub~tanc-a aecordlng to tho lnvention ar-
normally admln~atorod nalogoualy to oth~r known,
coomorclally avallablo pr-paratlon~, for exumpl- cap-
toprll or nalaprll, but ln p rtlcular nalogoualy to th~
compounda d-acrlb-d ln ~ patent ~ 880 80~, pr-forably lu
dos-a of bot~oon about 1 ~g and 1 g, o~p~c~ally of
botwoon 50 nd 500 m~ por aoaag- unlt Th~ dally do~o 1
prof-rably b-t~-on bout 0 1 and 50 mg/~g, ~p-clally
botwoon 1 and 10 ~g/~g of body ~$ght ~ow v~r, th-
2133933 : ~:
~ 15 -
partlcular dose for each ~ndividu~l patient deponds on a
very wide variety of factor~, for example on the eficacy
of tho partlcular compound u~ed, age, body weight,
genoral ~tate of health, sox, diot, time and mode of
adminietration, rat- of excretlon, drug co~bination and
soverity of th- particular disea~e to which the therapy
ie applied Oral administration ~ preferred
Above and below, all temporatures aro givon in
C ~n the following examples, ~conventional wor~ing-up~
mean~ Water i8 add-d if noc-soary, the p~ is ad~usted to
between 2 and 10 if necessary, depending on the
con~titution of th- end product, extraction 1~ carried
out with ethyl ac-tate or ~ethylen- chlorlde and the
organic phase i8 ~eparat-d off, dried ovor sodium
~ulfate, evaporated and purifi~d by chromatography on
eillca g-l and/or by cry~talllzation FAB ~ molecul-r ion
pea~ (M~ ~ 1) obtain-d ~a~ pectroecoplcally by the
~fa~t ato~ bombardment~ mothod
Exampl- 1
A olutlon of 2 72 g of 1,2-dihydro-2-oxo-3-N-
m thyl-N-~ethyl~ulfonylamino~ thyl-6-butylpyrldln- (PAB
273~ obtalnable by r-actlon of 1,2-dlhydro-2-oxo-6-
butylpyrldln--3-carboxald-hyd- wlth ~ethylam~n-/E~ to
glve 1,2-dlhydro-2-oxo-3-~ethylaminomethyl-6-butyl-
pyrldln- and ~ub~-gu-nt roactlon wlth methan-~ulfonyl
chlorld-) ln 30 ~1 of DMP 1~ treated wlth 1 12 g of
t-rt-butoxld- and th- mixtur- 1- stlrred at 20 for
1 hour A eolutlon of 3 31 g of ~-bromomethyl-2'-~,5-
dlhydro-5-oxo-1,2,~-oxodlazol-3-yl)blphenyl (obtalnable
by reactlon of 4-methyl-2'-cyanobiphenyl with
hydroxylamin- to glv- ~-~ethyl-2'-(am~nooxtminomethyl)-
blph-nyl, reaotlon wlth ethyl chloroformat- to glve
~-~othyl-2'-(~,5-dlhydro-5-oxo-1,2,~-oxadlazol-3-yl)-
blphenyl and brom$nat$on) ln 35 ml of DM~ lo then added
dropw~s- at 0 wlth ~tirrlng The m~xture lo otirr~d at
20 for 16 hour- and evaporat-d, and the re~ldu~
wor~ed up ln th- cu-tomary m~nn-r and 1,2-dihydro-1-(2~-
(~,5-dlhydro-S-oxo-1,2,~-oxad~azol-3-yl)biphenyl-~-
.r~ 2133939
- 16 -
ylmethyl)-2-oxo-3-N-methyl-N-methylsulfonyl~nomethyl-6-
butylpyridino ~Ix~), m p 207 i8 obtained ~ salt, Rf
0 27 on silica gol (ethyl acetate)
ExamDl- 2
S 1 5 ml of 1 N NaO~ are added dropwlee w$th lce
cooling to a ~olutlon of 1 g of 1,2-dihydro-1-(2'-(5-
trichloromethyl-1,2,~-oxadiazol-3-yl)biphenyl-4-yl-
methyl)-2-oxo-3-N-~ethyl-N-methylsulfonylaminomethyl-6-
butylpyrid~n- (obtalnable from 3-(4'-bromomethyl-2-bi-
ph-nylyl)-5-trichloromethyl-1,2,~-oxadiazole
(~P-A2-520423, ~xamplo 22 c) and 1,2-dihydro-2-oxo-3-N-
methyl-N-methylsulfonylaminomethyl-6-butylpyrldine
analogously to Bxampl- 1) in a mixtur~ of 8 ml of dioxane
and 2 ml of water, and the d xture ~8 stlrred for 30 min
w~th lce-coollng, wor~-d up ln the customary manner
(dllute hydrochlor~c ac$d/othyl acetate) and ~Ix~ i~
obtaln-d, m p 207
ExamDle 3
(a) A ~olution 7 1 g of hydroxylammonium chloride ln
30 ml of DMSO 1~ tr-ated wlth 14 4 ml of tri-thylamln- ln
40 ml of T~F Th- solut~on 1~ filt-red, and th- flltrat-
i~ vaporat-d and tr-at-d with 4 63 g of 1,2-dihydro-1-
(2'-oyanoblph-nyl-~-ylmothyl)-2-oxo-3-N-methyl-N-m thyl-
~ulfonylaminom thyl-6-butylpyrldln- (Rf 0 35 (p-troleum
ther/othyl acetat- ~ 6); obtalnabl- by reaction of 1,2-
dihydro-2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-
butylpyrldin- with ~'-bromom thyl-2-cyanobiphenyl) and a
furth-r 3 5 ~1 of tri-thylamine The solution ia stirr-d
for 16 hour- at 75 It 18 cooled, poured into water, and
the proolpltat-d 1,2-dihydro-1-(2'-( d noox~nomethyl)-
biphenyl-~-ylmethyl)-2-oxo-3-N-methyl-N-methyl~ulfonyl-
aminomothyl-6-butylpyridine (~A ) is filtered off and
drl-d
(b) A suspension of ~ 96 g of A (crude) in 32 ml of
~EF ie treat-d with 2 ~ g of l,l'-carbonyldilmldazolo and
h-atod wlth ~tlrrlng for 7 hour~ Ths mi~ture 18 e~apor-
atod and wor~ed up ln th- cu~tomary (ethyl acetate/dilute
~ ~133939
- 17 -
H2S0~, and ~Ix~ i~ obtained m.p. 207.
Analogou~ly to a~, fro~ tho 1,2-dlhydro-1-(2'-
cyanobiphenyl-4-ylmsthyl)-2-oxo-3-N-R3-N-mothyleulfonyl-
aminomethyl-6-butylpyridino~ below (obtainable by
S reaction of 1,2-dihydro-2-oxo-6-butylpyridine-3-carbox-
aldehydo with amine~ of the formula R3-NH2/H2 to give 1,2-
dlhydro-2-oxo-3-N-R3-aminomethyl-6-butylpyridines, reac-
tion with methane~ulfonyl chloride/pyridino to give 1,2-
dihydro-2-oxo-3-N-R3-N-~ethyl~ulfonylamlnomethyl-6-butyl-
pyridino- and reaction with ~'-bromomethyl-2-cyano-
biphenyl):
-3-N-ethyl-
-3-N-propyl-
-3-N-i~opropyl-
-3-N-butyl-
-3-N-i~obutyl-
-3-N-cyclopropylmothyl-
wlth hydroxyla~monium chloride/trlethylam~ne th- 1,2-
dihydro-1-(2'-(aminooxim~no~thyl)blphenyl-4-ylmethyl)-2-
oxo-3-N-R3-N-methyl-ulfonylaminomethyl-6-butylpyridlne~
below aro obtain-d: -~
-3-N-othyl-
-3-N-propyl-
-3-N-l~opropyl-
-3-N-butyl-
-3-N-i-obutyl-
-3-N-cyclopropylmethyl-
and from tho~o analogou~ly to b) wlth 1,1'-carbonyldi-
imldazolothol,2-dihydro-1-(2'-(4,5-dlhydro-S-oxo-1,2,4- ;
oxadiazol-3-yl)biphenyl-4-ylmethyl)-2-oxo-3-N-R3-N-meth- -~
yl~ulfonylamlnomethyl-6-butylpyridines below: -~ ~-
-3-N-othyl-
-3-N-propyl-
-3-N-isopropyl-
-3-N-butyl- ~ --
-3-N-isobutyl-
-3-N-cyclopropylmothyl.
. 2133939
- le-
Exampl~ ~
(a) 550 ~g of ethyl chloroformato ar~ added to a 801u-
tion of 527 ~g of 1,2-dlhydro-1-(2'-amino~ulfo~yl-
biphenyl-4-yl~ethyl)-2-oxo-3-N-mothyl-N-methyl-
~ulfonylamlnomothyl-6-butylpyrldine(~B~;obtainabls
by roaction of 1,2-dihydro-2-oxo-3~N-msthyl-N-
methylsulfonylaminomethyl-6-butylpyr~d~no with N-
tort-butyl-4~-bromomethylblphenyl-2-sulfonamide to
g~e 1,2-d~hydro-1-(2'-N-tert-butylaminosulfonyl-
biphenyl-~-ylmethyl)-2-oxo-3-N-mothyl-N-methyl-
sulfonylAm~nomethyl-6-butylpyrid~ne and remo~al of
tho t-rt-butyl group using CF3COO~/anl~ole) and
360 ~ of 4-d~methylaminopyr~dine in 12 ml of
pyridine, the mixture 1B stirred for 48 hours at
20, 8 ml of methanol are addod and it i~ wor~ed up
in th- customary manner 1,2-D~hydro-1-(2'-(N-
etho~cycarbonyl~m~no~ulfonyl)blphonyl-4-ylmethyl)-2-
oxo-3-N-thyl-N-m-thyl~ulfonylaoino~et~yl-6-butyl-
pyridin- 1B obtained
1,2-Dihydro-1-(2'-(N-buto~ycarbonylamino-
~ulfonyl)blph nyl-4-ylm-thyl)-2-oxo-3-N-mothyl-N-methyl-
~ulfonylaminomethyl-6-butylpyridin~ 1~ obtalnsd analo-
gously from ~ and butyl chlorofor~ate
The 1,2-dlhydro-1-(2'-R2-biphenyl-4-ylmethyl)-2-
oxo-3-N-m~thyl-N-methyl~ulfonylaminomethyl-6-butyl-
pyridlne~ b-low ar- obtalned analogou~ly using acetyl
chloride, propionyl chlorld~, butyryl chlorlde, cyclo-
propylcarbonyl chlorld~, cyclopropylacotyl chlorld-,
cyclopsntylcarbonyl chlorid-, bsnzoyl chlorids, p-meth-
oxybsnzoyl chlorid-, p-chlorobonzoyl chlorld~ or 2-
thlenylcarbonyl chloride inst-ad of ethyl chloroformat-
-3-(2'-(acetylaminosulfonyl)blphenyl-4-ylm~thyl)-
-3-(2'-(propionylaminosulfonyl)biphenyl-4-ylmethyl)-
-3-(2'-(butyrylaminosulfonyl)blphenyl-4-ylmet~yl)-
-3-(2'-(cyclopropylcarbonylaminosulfonyl)blphenyl-4-
ylmothyl)-
-3-(2'-(cyclopropylacetyl~nosulfo~yl)blphsnyl-~-
ylmethyl)-
2133939
f~
.~.;,~............................ g
-3-(2'-(cyclopentylcarbonylam~nosulfonyl)biphenyl-4-
ylmethyl)-
-3-(2'-(benzoylaminosulfonyl)b$phenyl-4-ylmethyl)-
-3-(2'-(p-methoxybenzoylaminosulfonyl)blphenyl-4-
ylmethyl)-
-3-(2'-(p-chlorobenzoylamlnosulfonyl)biphenyl-4-
ylmethyl)-
-3-(2'-(2-thienylcarbonylaminosulfonyl)b~phenyl-4-
ylmethyl)-. ~-
10 (b) A solution of 598 mg of the ethoxycarbonyl ~ A''
compound obtalned a~ in (a) and 108 mg of 2-aminomethyl-
pyridine ln 30 ml of tolue~e i~ heated for 2 hours,
cooled and wor~ied up in th- customary manner. 1,2-Di-
hydro-1-(2~-N-(N-2-pyridylmethylcarbamoyl)amlnosulfonyl-
biphenyl-4-ylmethyl)-2-oxo-3-N-methyl-N-methylsulfonyl-
aminomethyl-6-butylpyridine 18 obtained.
Example 5
A mlxture of 527 mg of ~B~ and 7 ml of phenyl
lsocyanate i~ heated for 4 hour~ at 80. It i8 cooled,
the exces~ phenyl isocyanato 18 di~tilled off and 1,2-
dihydro-1-(2'-N-(N-phenylcarbaooyl)ami~osulfonylbiphenyl-
4-ylmethyl)-2-oxo-3-N-methyl-N-m~thylsulfonyl-amino-
methyl-6-butylpyrldine is obtained aft~r chromatographic
puriflcation.
xample 6
496 mg of A- are suspended under argon ln 7 ml
of pyridlne and treated dropwise at 0 wlth ~tlrrlng with
a ~olution of 0.09 ml of ~OC12 in 3.5 ml of CH2C12. The
mixture ~ 8 stirred for a further 2 hours at 0, poured
into 500 ml of water and wor~ed up ln tho customary
manner, and 1,2-dlhydro-1-(2'-(2-oxo-3~-1,2,3,5-oxathia-
diazol-4-yl)biphenyl-4-ylmethyl)-2-oxo-3-N-m-thyl-N-
mothylsulfonylaminomethyl-6-butylpyrldine is obtalned.
Bxample 7
1,2-Dlhydro-1-(2'-(2,2-dioxo-3~-1,2,3,5-oxa-
thiadiazol-4-yl)biphe~yl-~-ylmothyl)-2-oxo-3-N-methyl-N-
~ ~r
2133933
.
- 20 -
methylsulfonylami~omethyl-6-butyl-pyr$dine i8 obtained
analogou~ly to Example 6 from A- and S02C12.
.. . '.
Example 8
A mixture of 496 ~g of A-, 10 ~1 of TaP and
S 180 mg of l,l'-thiocarbonyldlimidazole i8 st$rred for 30
min at 20 and evaporated. The re~idue i~ dissolved in
ethyl ac~tate, washed with dilute hydrochlor$c acid and
then with water, dried and evaporated agaln. The resldue ;~
thu~ obtalned i~ d~s~olved in a m$~tur~ of 60 ml of
chloroform and 12 ml of methanol. 3.5 g of silica gel are
added to thi~ solutlon, th~ mlxture 1~ stirred for 48
hours at 20, filtered and ovaporated and the residue ~e
purified by chromatography on ~$1$ca gel. 1,2-Dihydro-l-
(2'-(4,5-dihydro-5-oxo-1,2,4-thlad$azol-3-yl)blphenyl-4-
ylmethyl)-2-oxo-3-N-methyl-N-metbylsulfonylamln~m^thyl-6-
butylpyr$dine i~ obta$ned.
' ' : ~ . :-
Example 9
4.96 g of A- are d$scolved in 50 ml of dichloro-
mothane, 1.15 g of tr$etbylamine and 1.15 g of acetic
anbydride ar- add-d and th- mlxtur- is stirred for
2 hours at 20. It ic evaporat-d and the res$due $e
wor~ed up in the cu~tomary manner (ethyl acetat-/water;
washing with NaHC03 solution) and th- result$ng crude
acetyl derivativ- ia d$ssolved ln 30 ~1 of DMP. 4 g of
CS2 are added f$rct, then, ln the cour~e of 10 m~nutee,
NaH (60 %, ln o$1; 1.4 g) and th~ mixture $8 stirred for
2 hours at 20. After cuotomary wor~ng up (pH 3, lce
water), 1,2-dihydro-1-(2'-(4,5-dlhydro-5-thloxo-1,2,4-
oxad$azol-3-yl)b$phenyl-4-ylmethyl)-2-oxo-3-N-metbyl-N-
methyleulfonylamlnomethyl-6-butylpyrld$ne 18 obta$ned.
~, 21 2133939
E~ample 10
a) Analogously to E~arnple 3a), 1,2-dihydro 1-(2'-(a nino-oximino-methyl)-
biphenylyl4-methyl)-2- o~o-3-N-methyl-N-methylsulfonyl-aminomethyl-
~
propyl-pyridineisobtainedfrom 1,2-dihydro-1~2'-cyano-biphenylyl4- ~ ~ -
methyl)-2-oxo-3-N-methyl-N-methylsulfonyl-aminomethyl-~propyl-pyridine
(obtainable by reaction of 1,2-dihydr~2-oxo-3-N-methyl-N-methylsulfonyl-
aminornethyl-~propyl-pyridine with 4'-bromomethyl-2-cyano-biphenyl)
with hydro~ylammoniumchoride/triethylamine.
b) Analogously to E-~ample 3b), 1,2-dihydr~1-(2'-(4,5-dihydro-5-oxo-1,2,4-
o~adiazol-3-yl)-biphenylyl-4-methyl)-2-oxo-3-N-methyl-N-methylsulfonyl-
aminomethyl-~propyl-pyridine is obtained from the compound prepared
according to a) with 1,1 carbonyldiimidazole.
Analogously to there are obtained from the following 1,2-dihydro-1-(2'-
cyano-biphenylyl4-methyl)-2-o~o-3-N-R3-N-methylsulfonyl-amjnomethyl- .
~propyl-pyridines (obtainable by reaction of 1,2-dihydro-2-o~lo~propyl-
pyridine-3 carbo~caldehyde with amines of formula R3-NH2/H2 to 1,2-
dihydro-2-o~o-3-N-R3-aminomethyl-~propyl-pyridines, conversion with
methanesulfonyl chloride/pyridine to 1,2 dihydro 2-oxo-3-N-R3-N-methyl-
sulfonyl-aminomethyl~propyl-pyridines and reaction with 4'-bromomethyl-
2-cyano-biphenyl):
-3-N~yl-
-3-N-propyl-
-3-N-isopropyl-
-3-N-butyl-
-3-N-isobutyl-
-3-N-cyclapropylmethyl-
wi~ hydrw~ylarnmonjum chloride/triethylamine the following 1,2-dihydro-1-
(2'-an~ino-o~imino-methyl)-biphenylyl~-methyl~2-o~o-3-N-R3-N-
methylsulfonyl-aminomethyl-~propyl-pyridines:
~ , .
"` -22- 2133939
... -. ~.
-3-N-ethyl- .; .. :.
-3-N-propyl-
-3-N-isopropyl- ,
-3-N-butyl-
-3-N-isobutyl
-3-N-cyclopropylmethyl-
,. . ;.
and from these, in analogy to b), with l,1'4arbonyldiimidazole the following
1,2-dihydr~1-(2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenylyl-4-
methyl)-2-oxo-3-N-R3-N-methylsulfonyl-aminomethyl-~propyl-pyridines~
-3-N-ethyl-
-3-N-propyl- ~: ::
-3-N-isopropyl-
-3-N-butyl-
-3-N-isobutyl-
-3-N-cyclopropylmethyl-, oil.
Th- followlng axampl-- rol~t~ to pharmac-utlc~
for~ul~tlon~ contalnlng actlv lngredl-nt~ of th- formula ;~
I or tholr ~lt~
ExamDl- A Ta~l-tc and coat d tabl-t~
Tabl~t~ of tho follo~lng co~po~lt~on aro produc-d
.:
2133939
.
,~ .
- 23 -
by compr-aaion in conventional mannor and, whero
rogulr-d, are provlded with a conventional eucrose-baaed
coating
Activo lngredient of tho formula I100 mg
5 Microcry~talline celluloae 278 8 mg
Lactoao 110 mg
~alze atarch 11 mg
Magnoaium atearat- 5 mg
Finely divlded eilicon dloxido0 2 mg
~xamplo ~ ~ard golatin cap~ulea
Convent$onal two-part hard gelatin cap~ules are
each filled with
Actlvo lngrediont of tho formula I100 mg
~actoao 150 mg
15 Celluloao 50 mg
Magnealum atearat- 6 mg
Exampl- Cs Soft gelatin cap~uloa
Conv-ntional aoft gelatin capaule~ aro filled
with a mixturo of 50 mg of actlve ~ngrediont and 250 mg
of ollvo oll ln oach ca~e
Exampl- D~ Ampoul-a
A ~olutlon of 200 g of actlvo lngredlent in 2 ~g
of propano-1,2-diol 1~ mado up to 10 1 with ~at-r and
flllod into a~pouloa ~o that oach ampoulo containa 20 mg
of activo lngrodient
~xampl- ~ Aquooua au-penaion for oral adminiatration
An aquooua au~pension of the activo ingrodient iB
propared i~ conventional manner Tho unit doao (5 d )
containa 100 mg of active lngr-dlent, 100 mg of Na
carboxymothylcolluloao, 5 mg of Na benzoato and 100 mg of
sorbitol
.,
'~ . '
