Note: Descriptions are shown in the official language in which they were submitted.
~55~;3~i
HOECHST AKTIENG~SELLSCHAF~ HOE 90/F 346 Dr.~A/AP
De~cription
Substituted azoles, process for ~heir preparation, agent~
cont~ining them and their use
EP-A-324,377, EP-A-253,310, EP-A-2B,834 ~nd ~P-A 323,841
disclose deri~ative~ of imidazolls, pyrrola, pyrazole and
triazole and their U8e ~8 antagoni~t~ of angiotensin II
receptors.
Novel compounds of the azole type have now been found
which are surprisingly highly active antagonists of
angioten6in II receptoxs both in vitro and in ViYo.
The invention relates to compounds of the formula I
Z~y
R1 ~
--X
L-A-T-E
in which
a) X, Y and Z are identical or di~ferent and are ~ or
CR2,
b) R1 is 1. (C2-C10)-alkyl,
2. ~ C3 Clo ) -alkenyl,
3. (C3-Clo )-alkynyl,
4. ~3,
5 . ( C3_CB )--CYC loalkyl,
6. (C~-Cl0)~cycloalkylalkyl,
7 ( Cs Clo ~ -cycloal~lalkenyl r
8. ~Cs-ClO~cycloalkylalkynyl,
9 . - ( C~Iz ) m~B~ ~ CH2 ~ n~R4
10. ben~yl,
. ~ , -
~55~i3~
11. a radical a~ defin~d under b) 1., 2., 3. or
9., which i~ mono~ub~tituted by CO2R3,
12. a radical defined a~ under b) 1., 2., 3. or
9., in which 1 to all of the hydrogen atoms
are ~ub~tituted by ~luorine, o.r
13. the r~dical define~i undex b~ 10.~ which i~
substituted on the phenyl by 1 or 2 identi-
cal or differen~ radicals from th~ 8erie6
compri~ing halogen, (Cl C4)-alkoxy a~d
nitro;
c) R2 is 1. hydrogen,
2. halogen,
3. nitro,
~. CVF
5. SFs,
6. pentafluorophenyl,
7. cyano,
8. (Cl-C4)-alkoxy, benæyloxy,
9. phenyl,
10. phanyl-(cl-c3 )-alkyl,
11. (Cl-C~ alkyl,
12. (C3-C10)-alkenylO
13. phenyl-( C2 C~ ) -alkenyl,
14. l-imidaz~lY~ 2)~-~
15. 1,2,3 triaZolyl-(c~2)n-t
16. tetraZolyl-~cHz) m~
17. -(CHz)ol-C~R7 oR5
18. -(CH2)~ o-Co-R3,
19 . - ( t::H2 ) o~ R5 ~ ~
20. ~S()
21. -CH=CH-( CH2 ) ~CHR3-oR
22. C~2=CH-(CH~ Co-R3,
23. -CO-RB,
24. -C~-C~-(CH2)~ o-Co-R7,
25. -(C~2)~ CH~CH3)~CO R5,
26. -(C~2lo~CO~R
27. -(CHz)o-O-C-NH-Ra,
,:
- 3 ~ 36
2 8 . - ( CH2 ) o-NR7-C-oR9,
2 9 . - ( CH2 ) o -NR7-CC)-N}IR0 r
3 O ~ ~ ( CH2 ) o~NR -SO2R
31 . - ( CH2 ) o-NR7-C-R~
32 . ~ (CH23n
3 3 . - ( CH2 ) "--N2
3 4 . -CH2-N3 o
35 . ~ (cH2)n-N()2
36 . -CH=N-NRsR7
3 7 . phthali~lido- ( CH2 ~ "~
N\
3 t3 - ( CH2 ) n~~ NH
R10
39. - (CH2)n~~ ~CF
H
1$ 40 (~H2)n~N/~
CH3
41 . ( C~2 ~ ~ ~ - 1- Co- N~
~C~3
42. phenyl-SO2-NH-N=CH-,
~N
4 3 . - CH~N~ /<
N
H
4 4 . - ( CHz ) D-So2-NR7-Co-NR8R~,
45. -(C~)O SO2~9,
46. a radical defined a~ under c) 9. or 10,,
which is ~ubstituted on ~he phenyl by
:
":, . .
.
~ , . . .
~ 4 - 2~ S~
1 or 2 identical or dif~Qrent radicals ~rom
the series compri~ing halogen, hydroxyl,
methoxy, trifluoromethyl, Co2R3 and phenyl,
47. a radical de~ined ,as under c) 11., 12. or
20., in which 1 ~o all of ~he ~ydrogen atoms
are ~ub~tituted by ~luorine, or
48. the radic~l d~fined under c) 15., which i8
sub~tituted by 1 or 2 id~ntical or differ~
ent radicals from the ~erie~ ~omprising
methoxycarbonyl ancl tC1~C4)-al~yl;
d) R3 is 1. hydrogen,
2. (Cl-C~)-alkyl,
3. (C3-C~)-cycloalkyl,
. 4. phenyl,
5. benzyl or
6. the radical de~ined under d) 2., in which 1
to all o~ the hydrogen atom~ are ~ubskitu
ted by fluorine;
e) R4 is 1. hydrogen,
2. (Cl-C6)-alkyl,
3. ( C3-C~ ) -CyC loalkyl,
4. (C2-C4)-alkenyl or
5. ( C2-C4 ) ~ CyTlyl;
f) Rs is 1. hydrogen,
2:5 2. (C1-C6~-alkyl,
3. (C3-Ca)-cycloalkyl,
4. phenyl or
5. benzyl;
: . g) R6 i~ 1. hydrogen,
: ~ 30 2. (C1~C6)-alkyl,
3 ( C3-C0 )~ycloalkyl,
4. ~C6-Cl2)-aryl, p~efera~ly phenyl,
5. benzyl,
:
- 5 - ~55~3~
6. (C1-C~)-heteroaryl which can al~o be
partially or completely hydrogenated,
preferably 2-pyrimidinyl,
7. (Cl-C~)-alkanoyl,
8. (C1-C~)-hateroaryl-(C1-C3)-alkyl, where the
heteroaryl moiety can al80 be partially or
comple~ely hydrogema~ed, or
9. a radical defi~ed a~ under g) 4., 6. or 8.,
substituted by 1 or 2 identical or diffar-
ent radicals ~rom ~he ~eries comprising
halogen, hydro~yl, methoxy, nitro, cyano,
Co2R3, -NR11R12 and trifluoromethyl;
h) R7 is 1. hydrogen/
2. (Cl-C6)-alkyl,
3. (C3-C8)-cycloalkyl,
4- (co-cl2)-aryl-(cl-c~)-alkyl~ prefsrably
benzyl,
S. phenyl ox
6. (C1~Cg)-heteroaryl;
i) R8 is 1. hydrogen,
2. (Cl-C6)~alkyl,
3. (C3-Ca~-cycloalkyl,
4, phenyl-(CH2)q~~
5. oR5,
6. NRl1R12 or
r
7.
:
;) R9 is 1. (C1-Ca) alkyl,
2. 1-adaman~yl,
3. l-naphthyl,
4. l-naphthylethyl,
5. phenyl-(CH2)~- or
6. the radical defined under ;) 1., in which 1
t,o all of the hydrogen atoms are sub~titu-
ted by ~Iuorine;
:
:
,
~ '55~;3
~ 6 -
or R5 and R8 together wi~h the nitrogen akom
carxying them are
~ R12;
k) R~ cyano, ni~ro or CoaR7;
l~ Rl1 and R12 are identi~l or differenk and are
1. hydrogen,
2. (C1-C4)-alkyl,
~. phenyl,
4. benzyl or
5. ~-methylbenzyl;
lO m) D is NR13, O or CH2;
n) Rl3 is hydrogen, ( Cl-C4 )-alkyl or phenyl;
o) A i~ ~) a (C6-C14)-aryl r~dical or
~) (cl-c9)-heteroaryll
which can either be aromatic, partially
hy~rogenated or comple~ely hydrog~natPd, or
~) the radical of a fused hete~ocycl2 having 8
to lO ring atoms, of which up to 9 are
carbon atoms,
it being po~sible to substituke A in each c~e by up
2G to 3 identical or different radical0 from the ~eries
compri~ing
: 1. halogen,
~ . oxo,
3. nitro~o,
4. nitro,
5. cyano,
6. hydroxyl,
7. I~Cl-C~ lkyl,
: 8. C1-C4)-alkanoyl,
9 ( Cl-C4 ) -alkan
. ~ . . .
- ... . . ~: ~
: : , - . ~ : . ; - . : .:
~ ' . ~ : ~ '', . :
- 7 ~ 3~i
10. Co2R3,
11 . methanesul f onylamino,
12. trifluoxome~hanesulfoTIylamino,
13 . -Co-NH-oR9,
14. -So2-NR6R7,
1 5 . -CH2-OR7,
16 . ( C6-C12 ) -aryl,
17 . t C3~C8 ) -cycloalkyl,
18. (Cl C4)v-alkoxy~
19. (cl-c9)~heteroa~
2 0 . Co2R3,
21. NR6R7,
22. aulfo,
2 3 ~ -So3R3 r
2 4 . -So2-NR7-Co-NR~R9,
2 5 . -NR7-Co-NR6-So2-CH2-R5,
26. -C~CF3)aOH, O
2 7 . pho~phonooxy, ~O-P-OH
2 8 . -PO3H2 r bH
29. -NX-PO(oH)
30. ~S(O)rR6,
31. -Co-R3 and
3 2 . -Co-NR6R3;
p ~ ~ 1. a single bond
2. -CO-,
3. -CH2-,
4 . -O-,
5 . -$-,
6 . -MR21-,
3 0 7 . ~ O-NR21-,
~ . -NR2~-co_,
9. -O-CH2-, :
1 0 . -CH2-C)-,
S-CH2- ~
12. -CH2-S-,
13. -~I-CR20R22_,
14. -NR2l-SO2-,
15 . ~ SO2-NR21-,
,, . ;
.. ~ , :
~S~i~36
16 CR20R22 NH
17 . -CH=CH-,
18. CF-CF-,
l9 . -CH=CF-,
2 0 . -CF=CH-,
21. -CH2-C~z~ ~
2 2 . -CF2-CF2-,
23 . -C}I(OR33~,
24 . -C~(oCoR5) -,
25. ~C-
~R23 ~
2 6 . -C- or
R240 ' 'olR25
27. ~
q ) E is a xadical
R14
1. ~ with ~he proviso that in the ca~e
< 1l where x=~r=cH ~ Rl4 i~ not COOH,
R14
. 2. ~ B
< I
y~X
S ( CH~5< R4
(CH2 )m R~
4- R14
, , . . - , ,
, ' ~. ~ i ;~; , ,
~ C~S~ t~
r) B is 0, NR7 or S;
6) L is (C1-C3)-alkanediyl;
t) R14 i~ -Co2R3, -CH2Co2R3, -PO3H2, -SO3H or tetrazolyl,
u) m is an integer from O tv 5;
v) n is ~n integer from 1 to 5;
w) o is an integer from l to 10;
x) r i5 0 r l or ~, and
y) v is an integer from 1 to 6;
and their physiologically tolerable 8alt~.
Alkyl, alkenyl and alkynyl can be s~raigh~-chain or
branched. The same applie6 to radicals derived therefrom,
such as alkanoyl or alkoxy.
Cycloalkyl is also understosd as meaning alkyl-8ubstitu-
ted rings.
(C6-Cl23-aryl is, for example, phenyl, naphthyl or bi-
phenylyl, pre~erably phenyl. The same ~pplies to r~dical~
: derived therefrom, such ~ aroyl or aralkyl.
(Cl-Cg)-heteroaryl i8 in particular under~tood a~ meaning
radical~ which ~re derived from phe~l or naphthyl, in
which one or more CH groups are replaced ~y nitro~en
and/or in which at lesst two ad~acent CH groups re
replaoed (with the formation o~ a ~ive-me~bered aro~atic
ring) by S, NH or 0. In addition, one or two atom~ of the
condensation ~ite of bicyclic radicals ( ~u~h a6 in
~5 indolizinyl) can also be a nitrogen atom.
These are, for example, furanyl, thienyl, pyrrolyl,
- ,
lo ~ 5~.s3~;
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, pyxidyl, pyraxinyl,
pyrimidinyl, pyridazinyl, indolyl, inda~olyl, quinolyl/
i~oquinolyl, phthalazinyl, guinoxalinyl, quinazolinyl and
cinnolinyl.
The fused heterobicyclic ~ys~em iB understood as meaning,
in particular, a bicyclic ring sy~tem having 8 to 10 rin~
atoms, of which up to 9 are carbon atoms, in which two
adjacent atoms are common componenkR of both ring~ . One
or both of these rings ls/are formally derived from
benzene in which one or more CH groups are repl~ced by N,
O+ and S~ and/or in which two ad;acent CH group are
replaced by S, NH or O (with the formation of a five-
membered aromatic ring).
These are, for e~ample, a radical of benzothiophene,
benzo~uran, indole, isoindole, indazole, benzimidaxole,
quinoline, isoquinoline, phthalazine, quinoxaline,
quinazoline, cinnolinel benzothiazole, ben~othiazole-
l,1-dioxide, coumarin, chroman, benzoxazole, benziso-
thiazole, benzodiazines, benzotriazol~, benzotriazine,benzoxazine, imidazopyridine, imidazopyrimidine,
imidazopyrazine, imidazopyridazine, imidazothiazole,
pyrazolopyridine, thienopyridine and pyrrolopyrLmidine.
Said heterobicyclic ~ystem can also be partially or
completely hydrogenated. However, one ring preferably
remains aromatic, a benzo-fu~ed heterobicyclic aystem
being particularly preferred.
In the ca~e of S-containin~ and/or partially saturated
radicals, the bicyclic ~ystem ~an also, for e~ample, be
oxo-substituted, a~ is the ca~ with the radical of the
benzo-1,2,3-triazinone.
Physiologically tolerable ~alt~ of compounds of the
formula I ~re understood a6 meaning both their organic
and their ino:rgani~ salts, such a~ are described in
Remington's Pharmaceutical Sciences, (17th editiont page
, ~
:
'5~
1418 (1985). Owing to phy~ical and chemical ~tability and
solubility, ~odium, potassi~m~ calcium and nmmonium
salts, inter ~lia, are pre~erred for acid group ; ~alt~
with hydrochloric acid, sulfuric ~cid, pho6phoric acid or
S with carboxylic acid~ or sulfoni.c acid~, such as 2cetic
acid, citric acid, benzoic acidg maleic acid, fu~aric
acid, tartaric acid and p-toluenesulfoni~ acid~ inter
alial for basic groups.
Preferred compounds of the ~ormula I are tho~e in which
a) X i~ N, Y is CR2 and Z i8 CR2~
b) X is CR2, Y i8 N and Z i CR2;
c) X is CR2, Y is CR2 and Z 1~ N
or
d) X, Y and Z are in each case N.
Compounds of the formula I are additionally preferred in
which
a) Rl is 1. (~3-Clo)-alkyl,
2. ( C3 Clo ) -alkenyl,
3. ( C3 Clo )-al~ynyl,
4. (C3-C8)-cycloalkyl,
5. benzyl or
6. benzyl which i~ ~ubstituted as defined
above, or
7. -(CH2)~-B-(CH3)n-R4;
~5 b) R2 is 1. hydrosen,
2. halogen,
3. nitro,
4. CvF2~l,
5~ SFs~
6. pen~afluorophenyl,
7. cyano,
8. (Cl-C4~-alkoxy, benzyloxy,
9. phenyl,
10. phenyl-(C1 C3 )-alkyl,
11. (C1-C,0)-alkyl,
.
.~ .': ~ `. ,
-- 12 - 2C,~55~j3~D
12 . ( C3-Clo ) -alkenyl,
13 . phenyl- ( C2 C~ ) -alkenyl,
14 . l-imidazolyl- ( CH2 ) m-
15 . 1, 2, 3~triazolylD ( CH2 ) O-
16 . tetrazolyl ~ ~ CH2 ) m~
17 . --( CH2 ) o 1 -CHR7-oR5
18 . -(CH2)o-o-CoR3,
1g. -COR8,
20. -(CH2~ CO-Ra,
21. -S(O)rR6t
.2 2 . -CH=CH- ( CH2 ) ,"-CHR3- OR6,
X 3 . ~ CH2=CH- ( CH2 ) " Co-~8,
2 4 . - ( CH;I ) o~NH~CO~ORD,
2 5 . - ( CH2 ) O ~H-SO2-R,
26. -(CH2)n~,
2 7 . - ( C~z ) o-SO3R ~
2 8 . - ( CH2 ) n~ SO2-NH- CO-NR6R~ t or
29. a radical defined a~ under b) 9., 10., 11.,
12. or 15., which is ~ub~ti~u~ed as defined
above under c) 45., 47, or 4~. ln each case
a~ described for ~uch a radical;
c ) R8 is hydrogen, ( Cl-C5 ) -alkyl, O~s, ~RllRl2 or
morphollno;
d) T is 1. a ~ingle bond,
2 5 2 . -CO-,
3 . -CONR21-,
4. CH2-CH2-,
5 . -NR71-Co-
6. t)-C:H2
3 0 7 . -CH2-O-
8 . -S~C~a-
9. -CH2-S-,
10. ~ CH2-,
1 1 . -C~2~
12 . -CH=C~I- t or
.
.
- 13 ` ~ i5~
o
13 . _l _
O
and the other radica.ls and variable~ are a~
def ined abs:)v0 .
Particularly preferred compounc1s of the formula I a:re
those in which
a) R1 iS ~C3-C,)-alk~ (C3 C,)-alkenyl or (C3--C,) -alkynyl;
b ) R~ is l . hydrogen
l 0 2 . chlorine,
3. bromine,
4. CVF2V~l where v = 1, 2 or 3,
5 . pentaf luorophenyl,
6 . ( Cl-C4 ) -al3coxy, berlzylc~
7, --S(O)r~
8. SF5,
9 . ( CH2 ) o l-CHR'-t)R5 ~
(CH2)o-O~CO R3,
11. C ORa,
2 0 l 2 . - ( C~I2 ) o-CO-Ra ~
l 3 . -CH2~ CO-R3,
14. -(CH2~ SO2-R ,
15 . -CH--CII-CHR3-OR5
l 6 . tetrazolyl- ( CE~2 ) m'- ~
2 5 l 7 . - ~ CH~ ) I,SOa-NH-CO-NR8R~,
18 . - ( CEI2 ) o-SO3R or
19 . ( Cl-Cs) -alkyl which 16 optionally sub-
stituted by hydroxyl, pref~rably hydroxy-
m~3thyl;
30 c) R3 is hydrogen or ~Cl Cb)-alkyl;
d) R6 is hydrogen, (Cl-C4)-alkyl, (Cl-C:4~allcanoyl! phenyl
which can op~ionally ba sub~tituted by l or 2 . .
iden~ical or di~ferent radicals from the s~rie~
- 14 ~ 5~
compri~ing halogen, hydxoxyl, metho~y, nitro,
cyano, Co2R3 and trifluoromethy1, or tC1-C~)-
heteroaryl which can al80 be partially or
completely hydrogenated, preferably
2-pyrimidyl;
e) R7 is hydrogen, (Cl-C")-alkyl., (Cl-C~)-hetç!roaryl, or
( C6-Cl2 ) -aryl - ( Cl-C4 ) -allcyl;
f ) RB i8 hydrogen, ( Cl-c4 ) -allcyl ~ oR5 or ms:~rpholino;
g) R~ is CF3, (Cl-C6)-alkyl or phenyl;
h) A is ct) a (C6-C10~-aryl radical or
) ( Cl-C4 ) -heteroaryl which can aither ba
aromatic, paxtially hydrogenated or com-
plately hydrogenated, or
~ the radical of a fused heterobicyclic
~ystem having 8 to 10 ring a~oms, o~ which
up to 9 are carbon atoms;
where
A in each case can be 6ubs~ituted by up to 3
identical or different radical~ from the series
comprising halogen, nitro, cyano, hydroxyl,
-NR~R7, phenyl, -S(O) rR6 and -Co2R3;
1) T is a single bond, -O-, CO-, N~CO-, OCH2- or -S-
11 ~.
and the other radioals and v~riable~ are as defined
above.
Very particula:rly preferred compounds of the ~onmula I
are those ln which ~.
a) ~1 is (C3-~5)-
b) R~ is hydrogen, chlorine, methoxy, -S(O)rR~ or
-- 15 --
$3
henzyloxy,
c ) R3 i~ hydrogen or ( C~ 4 ) -alkyl,
d) R4 and R5 axe idenkical or diff~erent and are
hydrogen or ( Cl~ 4 ) -alkyl,
e~ R5 is hydrogan, (cl-c4)-alkyll phenyl or 4-tolyl,
f) R14 is-COOH, ~PO3Hz~ -S~3~ or S-tetrazolyl,
g) A is phenyl or the radical o~ a fu~ed heterocyclic
system having 8 to lO ring atom~, o~ which up
to 9 are c~rbon atoms~ it being po~ible,
however~ ~or A to be sub~tituted by up to 2
identical or di~ferenk radic~ rom the
~eries comprising halogen, nitro, cyano,
phenyl, -S(O)rR~ and -CO2~ ,
h) B i8 0, NH or S,
i) L is CH2-,
; ) r is 0, 1 or 2,
k) q is 0,
a ~ingle bond,
m ) m is a, 1, 2 or 3 and
n) n i8 1, 2 or 3
and X, Y and Z are as defined above.
Th~ invention al80 x~late~ to a process for the prepara-
tion of compolmd~ of the formula I, which compri~es
aIkylating ~Qmpound~ of the or~ula II
Y ~II) -~
X
H
.
. .
16 - 2~5~3~
in which R1, X, Y and Z ~ra a~ defined above, with com-
pounds of the formula III
U-L-A~'r-E (II~)
in which L, A, T and E are a~ de~fined above, and U i~ a
leaving group, i~ appropriatel removing temporarily
introduced protec~ive groups and converting the co~pound~
of the formula I ob~ained, i~ ,appropriate, into their
physiologically tolerable alts.
Suitable leaving ~roups U ~re preferably a nucleofugic
group (cf. Angew. Chem. 72 [1960] 713 such a~ halogen,
o-toluenesulfonate, mesyl~te or triflate.
Processes for the preparation of the precur~ors of the
formula (II) are known, inter alia, from ~S Patent No.
4,355,044, EP-A-324,377 snd EP-A-323,841.
lS Other processes are described in G. L'abbe Chem. Rev. 69,
345 (1969); T. Srodsky in ~The Chemis~ry of ~he Azido
~roup", Wiley, Nsw York, 1971, p. 331; H. W~mhof~ in
"Comprehensive Heterocyclic Chemi~try", S. ~atxi~zky Ed.,
Pergamon Press, New York (1984).
To alkyla~s the azole~ o~ the ~ormula II, suitable
alkylating agents are, for ex~mple, appropri~te benzyl
halides, tosylate~, me~ylate~ or trifla~e~ or appropriate
alkyl halides, to8ylat08~ mesylates or trlflate~
~ he synthesis of derivatives such a~ benzofuran~, benzo-
thioph0ne and indole~ havlng a ben3yllc -CH3 group wa~
described, inter aIia, by R.P. Dick~on,o et al. in J. ~ed.
Chem. 29, 1637 (1986)~ and ibid. 29, 16~3 (1986). The
preparation o~ benzimidazoles, benzothiazole~, b~nzo-
diazines, benzopyrone~, benzothlazolones, benzotria~ines,
b~nzoxazines and benzo~azoles i~ ou~lined in ~he edi~ion
"Comprehensive Heterocyclic Chemistry~, S. Ratrit2ky Ed.
Pergamon Pres~ New York (1984) cited above.
:: : .
~ .
- -:
- 17 ~ 5~3~
The alkylation is carried out in an analogous manner to
proce~ses which are known in principle.
The azole deri~ati~e of the formula II i~ metalated, for
ex~mple, in ~he pre~ence of a ba~e. Preferred base~ ~re
metal hydrides of the formula ~1 ~uch as, for example,
lithium hydride, 80dlum hydride or pota~ium hydride in,
for example, D~F or DM~O 88 a solvent or metal alkoxides
of the formula MOR, where R i8 methyl, ethyl or ~butyl~
and ~he reaction i5 carried out in the corre~ponding
alcohol, DMF or DNSO. The 8al~8 of the azoles thus formed
are dissolved in an apro~ic ~olvent such as D~F or DMSO
and treated with a suitable amount of alkylating reagent.
An alternative pofi~ibility for the deprotonation of the
a201e derivatives is, for example, r~action with potas-
15 6ium carbonate in DM~I or DMSO.
The reaction~ are carried out at temperature~ below roomtemperature up to the boiling poin~ of the reaction
mixture, preferably between ~20C and the boiling point
of the reaction mix~urel for about 1 to 10 hour~.
Fragments of the fonmula II
R14
A - T ~ (II)
are synthe6ized via the addition of metalated ~sonitriles
~Angew. Chem. 86, 878 (1974), 89, 351 (1977) to acid
chlorides of the formula III
A - ~ - CO-C:l (~II)
in inert solvents at -78C up to the boiling point cf the
solvent, preferably in diethyl ether or THF at 78C to
OC.
18 - ~ ~ SS~ ~6
The synthe~i~ of ~ragment~ of the fo.rmulaa IV and V
R14 ~H2~ R4
A - T ~ m "' X R5 IV)
R14 ~V)
A - T ~ R
R5
is carrisd out by means of tha ~l~ylation, which i~ known
in principle, of arylacetic acid derivative~ or aryl-
acetonitrile~ in an nnalogous m~nner, elkher in ethers
such as diethyl ether, ~HF or dimethoxyethane with LDA at
-78C or with ROtBu at room tempera~ure in t butanol.
The compounds of the formula I according to the invantion
have antagonistic action on an~iot2nsin II receptor~ and
can therefoxe ~e u~ed for the treatment of angiotensin
II-dependent hypertension. Po~sibilities of application
furthermore exist in cardiac in~ufficiency, cardioprotec-
tion, myocardial infarct, cardiac hypertrophy, arterio-
sclerosis, nephropathy, kid~ey failure ~nd v~culardiseases of the brain such as transitory ischemic attack~
and stroke.
Renin is a proteolytic enzyme o~ the aspartylprotease
cla~s, which is ~ecr~t~d into the bl~d circulation ~y
the juxtaglomerular cell~ of the kid~ey as a consequence
of various stimuli tvolume depletion, 30dium deficiency,
~-receptor:~timulation). In ths blood, it clea~es the
; ~ decapeptide angiotenBin I from th~ an~ioten~inogen
excreted from the liver. ~he former is conver~ed into
angio~ensin II by the "an~iotensin convertin~ ~nzyme~
(ACE). Angiotensin~ plays an essential role in ~lood
pressure regula~ion,~a~ it directly increases ~he ~lood
: pre sure by ~ans~ of vascular contraction. It addi-
~ioDally ~timulates the secretion of aldos~erone from ~he
adrenal gland and in this w~y increa~es the extracellular
: ~ : :
- 19
fluid volume via the inhibitlon of sodium excr~atio~,
which for it_ part contribute~ to an increa~e in blood
pressure.
Post-receptor actionq are inter alia 6timulation of
pho~phoinositol conversion (CaZ+ release), activa~ion of
protein kinase C) and facilitation of ~A~æ-dependenk
hormone receptors.
The affinity of the compounds of the ~ormula I ~or the
angiotensin II r~ceptor can be deater~ined by measurement
of 125I-angiotensin II or 3H-angiotensin II displacement
from receptor6 on Zona glomerulosa membranes o~ bovine
adrenal glands. For this purpose, the prepared me~rane~
are su6pended in buffer at pH 7.4. Aprotinln, a p~ptidase
inhibitor, i8 added in order to prevent the degradation
of the radioligand during the incubation. About 14000 cpm
of a tracer having a specific activity of 74 T~q/mmol
(available from Amersham Buchler~ and a guantity of
receptor protein which binds 50% of the tracer are
additionally used. The reaction i8 begun by addition of
50 ~1 of membrane su6pension to a mixture of 100 ~1 of
buffer + aprotinin, 50 ~1 of buffer with or without
angiotensin II or r~ceptor antagonist and 50 ~1 of
tracer. After an incubatio~ time of 60 minutes at a
temperature of 25C, bound and free radioligand are
~eparated on a Skatron0 cell collector using ~hatmann
GFIC filtars by means o~ a filtration as~ay.
Non-specific bindin~ is prevented by treatment of the
filter with 0.3% polyethyleneimine pH=10 (Sigma, NoO
3143). The amount of displacement of the radioligand from
3~ the receptor i5 determined by measurement of the radio-
activity in a gamma scintillation counter. ~he IC50
values, which denote the concentrativn of inhibitor for
displacing 50% of the ligand, are de~ermin~d according to
Chem. et al. .J. Theor. Biol. 59, 253 ~1970). For the
compound~ of the formula (I) ~hey are in the range from
10-4-10~ M.
,
3~;
~ 20 -
rro dete~nine the antagoni~tic ac~ion of the cumpound~ of
the formula (I), their e~fect on the Angio^ten~in II-
induced blood pre~ure ri~e in ane~the~ized Sprague-
Dawley rats can be mea~ured. Na thiobarbital (Trapanal,
Byk Gulden) i8 used a~ an ane~thetic in the dose
100 mg/kg i.p. I.~. administrakion i8 carried out in the
jugular vein. The blood pre~sure i~ mea~ured in the
carotid artery. The animals arle firat pretreated with
pentolinium ~artrate (10 mg/kg i.m.) 80 that a lower
blood pxessure level i8 achieved (ganglia blockada). ~N~
II (~yperten~in, CIBA) i~ a~mini3tered i.v. in the volume
O.1 ml~100 g at 10 minute intervals. ~he do~e is
0.5 ~g/kg. The compounds of the formula (I) are di~solved
in distilled water and administered intra~enously or
intraduodenally in the doses 0.1; 1; 10 and 100 mg/kg.
The compounds o~ ths formula ~I) are ef~e~tive in the
range from 0.1-100 mg/kg.
The invention also relates to pharmaceutical compositions
comprising a compound of the formula I and other acti~e
compounds, ~uch as, ~or example, diuretics or non-~teroi-
dal anti-inflammatory active compound~. The compounds of
the formula I can al80 be u~ed as diagnostics for the
renin-angioten~in Gystem.
Pharma~eutical preparation~ cont~in an effective amount
o the active compound of the formula T and if nscessary
other active compounds together with an inorganic or
organic pharmaceutically utilizable e~cipient. A*minis-
tration can be carried out intranasally, intravenously,
subcutaneou~ly or orally. The do~age of the active
compound depends on the mammalian 6pecies, the body
weight, the age and the manner of administration.
The pharmaceut.ical preparations of the present invention
are prepared in a dissolving, mixing, ~ranulating or
coatin~ process known per ~e.
.
. .
- 21
For a form for oral at~minigtra~ion~ the active compounds
are mixed with the addi~ives cu~tomary ~.herefor such a6
excipien~s, s~abilizers or iner~ diluen~i and brought by
means of customary method~ into ~uitable admini~tration
forms, such as tablets, coa~ed tableks, hard gelatin
capsules, aqueous, alcoholic or oily ~uspension~ ox
aqueousl alcoholic or oily solutions. ~nert excipients
which can be used are, for examplle, gum ~rabic, magnesia,
magnesium carbonate, pota~si~n phosphate, lactose,
gluco~e, magnesium stearyl fumarate or ~tarch, in parti-
cular maize ~tarch. The preparation in thiEt cas~ can be
both a~ dry and moist granule~. Suitable oily excipients
or solvents are, for example, vegetable or animal oils,
such as sunflower oil and cod liver oil.
For subcutaneous or intravenous administration, the
active compounds or their phy6iologically tolerable salts
are brought into solutions, suspensions or emul~ions, if
appropria~e with the substances customary therefor such
as ~olubilizer~, emulsifiers or other auxiliaries.
Suitable solvents are, for example, water, physiological
saline solu~ions or alcoholt~, for exa~ple ethanol,
propanediol or glycerol, in addition al~o ~ugar solutions
such as glucose or mannitol solutions or alternatively a
mixture of the different ~aid solvents.
List of abbreviations:
DMF N,N-dimethylformamide
NBS N-bromosuccinimide
AIBN ~ azobi~isobutyronitrile
EI electron impact
DCI desorption-chemical ionization
RT room temperakure
EA ethyl atetate (EtOAc)
DIP diisoprt?pyl ether
THF tetrahydrofuran
M.p. melting point
~TB methyl t-butyl ether
:: .
~ ~2 ~
B.p.~ boiling point at xx torr
Et3N triethylamine
MS ma~s spectrum
FAB fast atom bombardment
LDA lithium diisopropylamide
~he following examples illu~trate the inven~ion withou~
restrictin~ ~he invention theretoo
Example 1
1-[4~ Carboxy-1-cyclopentyl)benzyl] 2-n-butyl-4-chloro-
5-formylLmidazole
a) Ethyl 1-(p-tolyl)~yclopentanecarboxylate
g of 1-(p-~olyl)cyclopentanecarboxylic acid are
su~pended in 200 ml of ethanol, and the 301ution iQ
slowly treated with 4.3 ml of SOCl~ and heated to reflux
for 24 h. ~xces~ SOc12 i8 remoYed in vacuo, and the
residue is taken up with 100 ml of EA, wa~hed twice with
50 ml of ~atd. aq. Na2SO3 solution and dried over ~a2SO
The solvent is then removed in vacuo and 11.3 g of th~
title compound are obtained a~ light br~wn cry~tal~
melting point: 47C.
b) Ethyl 1-(4-bromomethyl)phenylcyclopentanecarboxylate
: 2.5 g of ethyl l-~p-tolyl)cyclopentanecarboxyl~te, 1094 g
of NBS and 200 mg of benzoyl peroxide are heated to
reflux in 50 ml of ~hlorobenzene ~or 3 h. The solvant i8
then removed in vacuo, and the re~idue i~ t~ken up in
300 ml of EA, wa~hed once with S% strength ~q. Na2SO3
solu~ion and twice wi~h 5atd. aq~ NaHCO3 ~olution ~nd
dried over Naa~O4~ ~he sol~ent iz finally remo~ed in vacuo
and 3.2 g of the title compound are obtained as an oil.
30: R~ (SiO2; EA/heptane 1:4) - 0.50 M5 (DCI) : 311 (N~1)
-. : , ~
.. ..
, : ' : .
..
., ~ . ,
- ~3 ~ r~
c) 1-[4~ ethoxycarbonyl-1-cyclopentyl)b~nzylJ-~-n-butyl
-4-chloro-5-formylimidazole
342 my of ethyl 1-(4-bromomethyl)phenylcyclopentane-
carboxylate, 187 mg of 2-n-butyl-4-chloro~5-~ormyl-
Lmidazole and 138 mg of R2C03 are stirred in 10 ml of DNF
at RT for 22 h. The mixture is dilu~ed with 100 ~1 of ~,
washed once with 50 ml of }120 and once with 5% strength
aq. NaCl solution and dried over Na2SO4, and the ~olvent
is removed in vacuo. Chromatogr~lphy on ~ilica gel ~sing
DIP yields 240 mg of the title compound a~ a colorle~s
oil.
R~ (SiO2; DIP/MTB 1~ 0.68 MS (DCI) : 417 ~M~
d) 1-[4~ carboxy-1-cyclopentyl3benzyl~-2-n-butyl-4-
chloro-5-formylimidazole
115 mg of 1-[4-(1-etho~ycarbonyl-1-cyclopentyl)benæyl]~
2-n-butyl-4-chloro-5-~ormylimidazole snd 415 ~1 of 1 N
NaOH are heated to reflux in 8 ml of EtOH for 29 h~ ~he
e~hanol is removed in vacuo, and the residue i~ dilu~ed
with 30 ml Of ~2 and washed with 10 ml vf DXP. It i~ then
adju~ted to pH = 1-2 and extracted twice with SO ml of EA
each tLme. The extracts are dried oYer Na2SO4 and the
solvent is removed in vacuo. Chromatoqraphy on ~ilica gel
using MT~ yields 68 mg of the title compound as a light
brown solid.
M.p: 134~C
R~ (SiO2; N~B3 = 0.30 MS ~DCI) : 389 (M+13
The title compounds o Examples 2 and 3 axe synthesised
~ia the methyl e~ter analogously to Example 1: :
Example 2
30: 1-[4-(1-Carboxy-l-cyclohexyl)benzyl]-2-n-butyl-4 chloro-
S-formylimida~ole
':
,
: '
~'5S~i3~
- 24 -
Ex~nple 3
1-~4~ carboxy~l-cyclohexyl)benzyl~-2-n-butyl 4-me~hoxy-
5-formylimidazole
670 m~ of 1 [4~ methoxycar~onyl-1-cyclohexyl)benzyl]-
2-n-butyl~4-chloro 5-formylimidazole are reacted a~ de~-
cribed under ~xample ld). 300 m~ of the title compound of
Example 2
R~ (SiO2; ~TB/DIP 1:1) = 0.35 MS (DCI) : 403 (M + 1)
malting point 147C
and 160 mg of the title compound of Example 3
R~ (SiO2; M~B/DIP 1~ 0.25 MS (DCI) s 399 (M ~ 1)
melting point 167 DC
are obtained, and can be ~eparated by chromatogr~phy on
silica gel using MTB/DIP lsl.
Example 4
1-~4~ caxboxy~ 4~4-dimethyl)cyclohe~l]benzyl)-2-n-
butyl-4~chloro-5-formylimidazole
a) l-p-Tolyl-4,4-dimethylcyclohexanecarbonitrile
27.S g of potas~ium t-butylate are taken up in 200 ml of
t-butanol and the mixture i~ heatad to reflux. A solution
of 32 g of 195-dibromo-3,3-dimethylpentane and 16.3 ml of
4-tolylacetonitrile in 100 ml o~ t-butanol is then added
dropwi~e in the course of 1 h. The miscture i~ heated
under reflux for 4 h, the solvent i~ removed in ~acuo and
the residue is taken up ln 200 ml of ~atd. a~. ~aHC03 and
200 ml of ~B. It is extr~cted twice with 200 ml o~ NTB
each time and dried over Na25O4, and the solvent is
removed in vacuo. Di~tillation in a fine vacuum yields
9 . 7 g of a colorless oil .
:
:
- 25 - 2 ~ ~ S6
B.P.02 - 135-140C MS (DCI) 5 228 (M~1)
b) l-p-Tolyl-4,4 dimethylcyclohexanscarbo~ylic acid
4.0 g ~f 1-p-tolyl~4,4-dLmethy:Lcyclohexanec~rbonitrile
and 3.0 g of ROH are heated under reflux in 50 ml of
diethyl~ne glycol ~or 3 h. The mixture is allowed to
cool, and .is poured into 100 ml of 0.1 ~ NaOH and washed
twice with 30 ml of DIP each time. It i8 then adju~ted to
pH = 1-2 wi~h HCl and ex~rac~ed 3 times wi~h 100 ml of
diethyl ethçr each time. The extrac~s ~re dried over
Na2SO4 and the solvent i8 removed in vacuo. 4.0 g of pale
yellow cxystals are obtained.
Melting point: 128C MS (DCI) : 241 (~)
c) Ethyl l-p-tolyl-4,4-dLmethylcyclohexanecarboxylate
4.0 g o~ l~p-tolyl-4,4-dLmethylcyclohexanecarboxylic acid
are dissolved in 50 ml of ethanol and trea~ed with l.S ml
of SOCl2. The mixture i~ stirred at 50C for 3 h, then at
reflux for 3~5 h. The ~olvent is removed in vacuo, and
the residue is taken up in ~00 ml of EA and washed 3
tLmes with 50 ml of ~atd. aq. Na2CO3 ~ach time. The
extracts are dried o~er Na2SOq and the solvent 1~ removed
in vacuo. 5.0 g of a slightly con~aminated bxown oil are
obtained, which is employed again without purification.
~S ~DCI) : 275 (M+l~
d) Ethyl 1-(4-bromomethyl)phenyl-4,4-dimethylcyclohaxane-
~5 carboxylate
5.0 g of ethyl 1-p-tolyl-4,4-dLmethylryclohexane-
carboxyla~e, 2.g g of NBS and 50 mg o~ benzoyl p~roxi~e
are heated to reflux in 50 ml of chlorobenzene ~or 1.5 h.
The ~olvent is then removed in vacuo, and the residue is
taken up in 200 ml of EA, and washed once with 100 ml of
satd. aq. Na2SO3 and once wlth NaCl solution. The ~olution
is dried over Na2SO4 and the solvent i~ removed in vacuo.
.
- 26 - HOE 90/F' ~
Z ~ ~4~>~6
5.4 g of a brown oil ar~ obtained.
R, (SiO2; EA/hep~ane 1:8) = 0.39 MS (DCI) : 353 (M~l)
Further reaction is carried out analogously to Examples
lc and ld to give 1-(4~ carboxy-1 (4,4-dimethyl)cyclo-
hexyl]benæyl)-2-n-butyl-4-chloro--5-formyl~idazole
R, (SiO2; DIP) = 0.16 ~S (DCI) : 431 (~+1)
Example 5
1-(4-~1-(5-tetrazolyl)cyclohex~l]benzyl) 2-n-butyl-
4-chloro-5-hydroxymethylLmidazole
z) 1-(4-Tolyl)cyclohexanecarbonitrile
mhs co~ound was sy~lthesized analogously to Example 3a)
3 ? ~3 = 9S-100C u~ (D~ 200 (Y~l)
b) 1-(4-Bromo~ethylphenyl)cyclohexanecarbonitrlle
The compound was synthesized analogously to Example 3 d)
Rf (SiO2; EE/Hep 1:4) = 0,~6 MS (DCI) : 278 ~M~l)
c) 1-[4-(1-Cyano-l-cyclohexyl)benzyl]-2-n-butyl-4-chloro-
5-formylimi~azole
~he compound was synthesized analogously to Example lc).
R~ (SiO2; DIP) = 0.33 ~S ~DCI) : 384 (~+1)
d) l-[4~ Cyano-l-cyclohexyl)benzyl~-2-n-butyl-4-chloro-
5-hydroxymethylimidazole
1.0 g of l-[4-~1-cyano-1-cyclohexyl)benzyl]-2-n~butyl-4-
chloro-5-formylLmidazole and 400 mg of NaBH~ arP dis~olved
in 25 ml of ethanol and the solution is ~tiTred at R~ for
18 h. 5~ aq. NaHSO4 soluti2n is then slowly added to pH =
2, the ethanol is removed in vac~o and the resldue is
extracted 3 tLmes with 5~ ml of EA. Th~ extracts are
dried over Na2SO4 and the solvent is removed in vacuo. 1.0
g of a colorless oil is obtai~ed.
.
,
, ~ ~
- ' .:
- : .
~S~4
- 27 -
R~SiO2; NT~) - 0.54 ~S (DCI s 386 ~
e) 1-(4~ (2-Trim~thyl~tanny;L-5-~e~razolyl)-1-
cyclohexyl]benzyl-2-n-butyl-4 chloro-5-hydroxymethyl
imidazole
1.1 g of 1-[4~ yano-1-cycloh~yl)ben~yl]-2-n-butyl-
4chloro-5~hydxo~methylimidazol~ ~nd 1.1 ~ of trimethyl-
tin azide are h~ated ~o re~lux in 25 ml o~ tolueno ~or
48 h. The solvent $ 8 removed in ~cuo ~nd th3 re~idue i~
employed again with~ut pur~icatio~.
f) 1-(4-[1-(1-Triph~nylm0thyl-5-tekr~olyl)-1-cyclo-
hexyl~benzyl-~-n-butyl-4-chloro~S-hydroxy~ethyl-
Lmidazole
~he unpurified title compound of Example Se) is dis~olved
in 7 ml o~ CH2C12 and 1.5 ml o~ ~HF, ~reated wi~h 0.35 ~1
of 10 N NaOH and ~irred a~ RT ~or 5 min. The ~ixture is
then treated with 9~0 ~g of trityl ~hloride and ~tirred
at RT for 3 days. It is diluted with 100 ml of ~A, w~h~d
twice with 10 ml of 0.1 N NaO~ e~ch time and tw~ce with
10 ml o satd. ~g. NaCl ea~h ti~e ~nd dried sver Ma2SO~,
and the solvent i~ removed in vacuo. Chromato~raphy on
~ilica gel usin~ NTB/DIP 1:1 yield~ ~00 mg of tho t~tle
compound a~ white fOamJ
Rf (SiO2~o DIP/NTB 1~ 0,32 ~S (F~) ~ 677 (~+Li)
g) 1-(4-~1 (5-Tetrazolyl)-l-cyclohe~yl~benzyl)~2 n-~utyl-
4-chloro-5 hydroxymethylimidazole
400 mg of 1-(4~ (1 Triph~nylmPthyl-5-tetrazolyl~-
l-cyclohexyl~benzyl) 2-n-butyl 4-~hloro-5-hydro~y~*thyl-
imidazole and 300 ~1 of 4 N ag. HCl are dissolved i~ 4 ml
of methanol and the mixtur~ tirred ~t RT ~or 2 h~ It
is then diluted with 10 ml Of ~2~ the methanol i~ r~mo~d
in ~acuo and the xe~idu~ i~ ad~usted to pH ~ 13 with 2 N
NaOH. It i~ wa hed 3 times with 5 ml of So~u~ne each
,
.; ~ -' , , ~
., ,. .
:
i3~i
- 2B -
time, then adjusted to pH - 4 with 10~ R~2PO~ ~olu~ion ~nd
extracted 3 ~imeR with 50 ml o ~ each t.i~. The ex-
tract~ are ~ried over NazSO4 and the ~olvent is r~movad in
vacuo. The residue is then dige~ted ~ikh 20 ml of ~A ~n
an ultrasoni~ ~ath~ erad off ~ld wa~hed ~wic~ with
2 ml of EA e~ch tim~. ~be residue i~ dried i~ ~ ~lne
vacuum and 170 mg of the titlo compou~d ~re obt~ined a
colorlea~ cry~tal~.
Melting point: 179C/dec.
R~ (SiO2; EA/M~OH 10~ 3.44 ~S (FAB) ~ 4~9 (~
Example 6
1-~4-(4-Carboxy-5-oxazolyl)benzyl]-2-n-butyl-4-chloro-
5-formylLmidazole
a) Methyl 4-bromQmethyl~enzoate
50 g of methyl p-tolylc~rboxylate, 60 g of N~S ~nd 200 mg
of benzoyl peroxide are suspended in 300 ml of chloro-
benzene and the mixture is cautiou~ly h~ted to r~lux.
The reaction ~tart~ vigorou~ly. The-~ixture i~ directly
allowed to eool ~gain, the chlorobenzene is removed in
vacuo and the re~idue is di~tilled. 6B g o~ the title
compound are obtained as colorless cry~t 1
B.p.5 = 145C
R~ (SiO2; E~/heptane 1s4) ~ 0.50 ~S (DCI) ~ 299 (~+1)
b~ 4-Bromomethylbenzoic ~id
5.0 g of methyl 4 br~momethylbenzo~t~ ~re su~pandad in
15 ml of 48% ~q. 8Br ~nd he~ted to reflu~ for 30 min, ~he
mixture i~ ad~u~ted to pH ~ 8 with NaHCO3 and wa~hed twice
with DIP. ~he agueous pha~e i~ then ad~u~ted to pH ~ 2
with NaHSO~ and extra~ted 3 time~ with 150 ml of ~4 The
extra~s are driecl o~er ~a~SO~ and ~he ~olvent i~ r~movQd
in vacuo. 3.8 g of the title compound ars obt~ine~ as
2~ 3~
- 29 -
colorless hygroscopic crystal~.
Meltin~ point- 45C
R~ (5iO2; EA) a 0.43 MS (DCI) : 215 (M~1)
c) 4-Bromomethylb0nzoyl chloride
3.8 g o~ 4-bromomethylbenzoic acid are su~pended in 10 ~1
of SOCl2 and ~he mixture i~ hea~ted to reflux for 1 h.
Excess SOC12 i~ removed in vacuo, and the re3idue i~ dried
in a fine vacuum and employed again in crude form.
d) 5-(4-Bromomethyl)benzyl-4-methoxycarbonyloxa201e
The ~rude product from Example 5c) i~ di~solvad in 50 ml
of anhyd~ous THF togsther with 5.4 ml of Et3N~ 1.8 ml of
methyl .isocyanoacetate are adde~ dropwi~e at 5C and the
mixture i~ stirred at R.T. for 3 days. It i~ then dill~ted
with 300 ml of EA, washed 3 times with 100 ml of 0.7 M
KH2PO4 each time, 3 times with 100 ml of satd. aq. NaHC03
and once with 100 ml of NaCl ~olution and dried over
Na2S04, and the solvent is removed in v~cuo. Chroma-
tograph~ on silica ~el u~iny MTB yields 2.~ ~ of yellow
crystals.
Meltin~ point: 79C
Rf (SiO2; ~TB) = 0.36
e) 1-~4-~4-~etho~ycarbonyl-5-ox~zolyl~banzyl]-2-n-butyl-
4-chloro-5-fonnylimidazolQ
2~6 mg of 5-(4-bromomethyl)benzyl-4 metho~ycarbonyl-
oxazole~ 187 mg of 2-n-butyl-4-chloro-5-fo~m~limidazole
and 139 mg of R2CO3 are ~tirred i~ 10 ml o~ D~ at RT for
21 h. Th~ mixture i~ then dilu~ed with 150 ml of EA,
wa~hed twice w.;th 50 ml of satd. aq. Na~CO3 ~olution eaoh
time and once with 50 ml of aq. NaCl ~olution and dried
over Na2SO4, ~nd th~ solvent is remo~ed in vacuo. Chroma-
tography on ~ilica gel using MT~DIP 1:1 yields 250 mg of
.
, ,, ~
a colorle~s oil. ~ 5~3~
R~ (SiO2; NTB/DIP 1:1) ~ 0.35 ~S (DCI) s 402 (~
f) 1-[4-(4-Carboxy-5-oxazolyl)benzyl]-2-n-hutyl 4-chloro-
S-formylLmidazale
240 mg of 1-[4-(4 methoxycarbonyl-5-oxazolyl)benzyl]~2-
n-butyl-4-chloro-5-~oxmylimidazole are dis~ol~ed in 15 ml
of methanol, treated with 2.5 ml of 1 ~ a~. NaOH and
stirred at RT for 20 h. The methanol i~ removed in ~cuo,
and the residue iB diluted with 20 ml of H2O and wa~hed
twice with 10 ml of DIP each time. It i8 then ad~u~ted to
pH = 2, extract2d 3 times with 50 ml of EA each kime, the
extracts are dried over Na2SO4 and khe solvent i~ removed
in vacuo. Chromakography on silica gel using ~A/glacial
acetic acid 10:1 yields 90 mg of a light yellow ~oam.
R~ (SiO2; EA/glacial acetic acid 10:1) = 0.16
MS (DCI): 38~(M~l)
::
, ': ' ' ~ .
,
.
