Note: Descriptions are shown in the official language in which they were submitted.
~268~i
HOECHST AKTIENGESELLSCHAFT HOE 87/F 242 K Dr.~I/je
aescription
Substituted th;eno;midazole derivatives, processes for
their preparat;on, pharmaceutical formulations contain;ng
them and the;r use as gastric acid secretion inhibitors.
Thienoimidazole derivatives ~ith a gastric acid secre-
tion-inhibit;ng action are kno~n from EP-A1-234,485,
EP-A2-201,094 and EP-A-237,248.
The present invention r~lates to novel thienoimidazole
derivatives of the for~ula I
R7
R4 R ~ R~
C l~
R5
R3
in ~hich
R1 R1
R2 R~
T denotes -S-, -SO- or -S02-,
R1 and RZ are identical or different and denote hydrogen,
halogen, cyano, nitro, trifluoromethyl~ tC1-C6)-
alkyl, tC1-e6)-hydroxyalkyl, (C1-C~)-alkoxy,
~~[CH~O~cpHt2p~1-4)Halq~ preferabLy tC1-C8)-
fluoroalkoxy~ tC1-Cg)-fluoroalk~nyloxy, tC1-Cg)-
fluoroalkynyloxy, -OCFzCl or -0-CF2-CHFClr tC1-C6)-
alkylmercapto, tC1-C~)-alkylsulfinyl, tt1 C6)-
alkylsulfonyl, (C~-C6)-alkylcarbonyl, tC1-C6)-
alkoxycDrbonyl, carbamoyl, N-tC1-C4)-alkylcarba~oyl,
N,N-di-tC1-1:4~-alkylcarb3moyl, tC1-C6)-alkylcarbonyl-
oxy, tC3-Cg)-cycloalkyl, phenyl~ benzyl, phenoxy,
, ~
:
, . ;: ..
-- ~26~346
-- 2 --
benzyloxy, anil;no, N-methylaniLino, phenylmercapto,
phenylsulfonyl, phenylsulf;nyl, sulfamoyl, N-(C1-C4)-
alkylsulfamoyl or N,N-di-~C1-C4)-alkylsulfamoyl, or,
;f A is as def;ned above under (a) or (c), can also
together denote -[CH2]n- or -CH-CH-CH=CH-, ~here;n
one CHz group ;s optionally replaced by NR', 0, S,
S0 or S02, or denote a substituted (C6-C12)-aryloxy,
(C7-C~ aralkyloxy, (C6-C~2)-aryL or (C7-C11)-
aralkyl radical, ~hich carr;es in the aryl part 1, 2,
3, 4 or 5 ident;cal or d;fferent substituents from
the ser;es compr;s;ng halogen, cyano, n;tro, tr;-
fluoromethyl, (C1-C6~-alkyl, tC1-C6)-alkoxy,
CCH2]o CpH(2p+1-q)Halq~ -OCF2Cl, -O-CF2-CHFCl,
(C1-C6)-alkylmercapto, (C1-C~)-alkylsulfinyl,
(C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl,
(C1-C6)-alkoxycarbonyl, carbamoyL, N-(C1-C~)-alkyl-
carbamoyl, N,N-d;-(C1-C4)-alkylcarbamoyl, (C1-C6)-
alkylcarbonyloxy, (C3-Cg)-cycloalkyl, NR'R"~ sulfamoyl,
N-(C~-C4)-alkylsulfamoyl or N~rl-di-(c1-c4)-alkyl
sulfamoyl,
R3denotes hydrDgen, (C1-C6)-alkanoyl, (C1-C~-alkyl-
carbamoyl, (C1-C6)-aLkoxycarbonyl, ben~yloxycarbonyl
or ~nother phys;olog;cally tolerated Nim-protective
group, uhich can preferably be spl;t off in an acid
~ed;um and/or under physiolog;cal conditions, such
as, for example, (C1-C1o)-acyloxy-(C1-C6)-alkyl,
preferably tC1-C10)-alkanoyloxy-tC1-C6)-alkyl,
benzoyloxy-(C1-CO)-alkyl, benzyloxycarbonyloxy-
(C1-C6)-alkyl or tC1-C6)-alkoxycarbonyloxy-(C1-C6)
alkyl~
R4 and R5 are identical or different and denote hydrogen
or (C1-C3)-alkyl,
a) R6 denotes hydrogen and
R8 denotes f~uorine, chlorine or bromine, or
b) R6 denotes (C1-C3)-alkyl and
" ~ .
:.,,: , -
8 - 3 -
R denotes fluorine, or
c) R6 denotes fluorine or bromine and
R8 denotes hydrogen, or
d) R6 denotes fluorine and
R8 denotes tC1-C3)-alkyl, or
e) one of the substituents R6 ancl RB denotes the radical
-0-CCH2~O-CpHt2p+1_q)Halq and the other denotes
hydrogen, halogen, (C1-C3)-alkyl or ~he radical
-0-lCH2~O-CpH(2p~1_q)Halq, or
f) one of the substituents R6 and R8 denotes a substitu-
ted (CS-C12)-aryloxy radical or ~C7-C11~-aralkyloxy
radical, Yhich carries in the aryl part 1, 2~ 3, 4 or
S identical or different substituents from the ~eries
co~prising halogen, cyano, nitro, trifluoromethyl,
(C1-C6)-alkyl, (C1-C6)-alkoxy,
-O-CCH2]0-CpH(2p+1_q)Halq, -OCF2Cl, -O-CF2-CHFCl,
(C1-C6~-alkylmercapto, (C1-C6)-alkylsulfinyl,
(C1-C6)-alkylsulfonyl, (Cl-C6)-alkylcarbonyl,
(C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkyl-
carbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl, (C1-C6)-
alkylcarbonyloxy, (C3-Cg)-cycloalkyl~ sulfamoyl,
N-tC1-C4)-alkylsulfamoyl or N,N-di-(C1-C4)-alkyl-
sulfamoyl,
and the other denotes hydrogen, halogen, (C1-C3)-
alkyl, the radical -0-tCH2]O-CpH(2p~ )Halq or a
substituted (C6-C12)-aryloxy radical or (C7-C11)-
aralkyloxy radical~
Hal denotes halogen, for example fluorine, chlorine or
bromine, preferably fluorine,
30 R7 denotes hydrogen, halogen, (C1-C12)-alkYl~ (C1-C12)-
alkoxy, -0-~SH~]o-cpH(~ +1-q)Halq~ -NR'R",
(cl-c12)-alk9xy-~c1-cl2)-a~kyl~ (c1-c12)-alk
.. .. . ,. ..
~26~3461
-- 4 --
tCl-C12)-alkoxy, (C7-C11)-aralkyloxy, (C1-C12)-
alkylmercapto, (C1-C12)-alkylsulfinyl or (C1-C12)-
alkylsulfonyl, or
;f at Least one o~ the substituents R6 and ~8 denotes
a substitu~ed (C6-C12)-aryloxy radical or (C7-C11)-
aralkyloxy radical, R7 can lilte~ise denote a (C6-C1~)-
aryloxy radical or (C7-C11)-3ralkyloxy radical sub-
stituted as defined above under f),
R5 and R6 together stand for -~CHi~]j-,
R' and R" are ;dentical or different and denote hydrogen,
(C6-C12)-arYl or (C1-C12)-alkylf or
R' and R" together stand for -~CH2]h-, in ~hich one CH2
group can be replaced by 0, S, N-(C1-C4)-alkanoylimino
or N-(C1-C4)-alkoxylcarbonylimino~
h is 3, 4, 5 or 6, preferably 4 to 6,
i is 1, 2, 3 or 4, preferably 1 to 3,
n is 3 or 4,
o is 0, 1, 2 or 3, preferably 0 or 1,
p is 1, 2, 3, 4, S~ 6, 7 or 8, preferably 1 to 5, and
q is 0 or 1 to (2pl1),
and physiologicalLy tolerated salts thereof, vith the
proviso that the compounds
5-methyl-2-(2-pyridylmethylthio)-3H-thienot2,3-d~imida-
zole,
S-methyl-2-((4-methoxy-2-pyridyl)methyl~hio)-3H-th;eno-
t2,3-d~imidazole,
2-(pyridyl)methylthio-3H-thieno~2,3-dJimidazole,
2-t~4-methoxy-2--pyridyl)methylth;o)-3H-~hieno~2,3-d]-
. -
!; :.
1.26~3~6~
imida~ole,
5-acetyl-2-(t4-methoxy-3,5-dimethyl-2-pyr;dyl)methylthio)-
3H-th;eno-t2,3-d~;m;dazole,
methyl 2-((4-~ethoxy-3,5-d;methyl-2-pyr;dyl)methylth;o)-
5 3H-th;enol2,3-d~imidazole-5-carboxylate,
5-acetyl-2-((4-~ethoxy-2-pyr;dy~)methylth;o)-3H-thieno-
t2,3-d]im;dazole,
5-acetyl-2-(2-pyr;dyl)methylthio-3H-thieno~2,3-d~i0;da-
zole,
and the correspond;ng sulfinyl compounds are excluded.
1H-Th;eno~3,4-d~imidazole derivatives of the formula I
in ~hich A is as defined ~bove under (b) are preferred.
T is preferabLy an -S0- group.
Particularly preferred co~pounds of the formula I are
those in ~hich
A is preferably as def;ned above under tb),
T preferably denotes an -S0- group,
R1 and R2 are identical or different and denote hydrogen,
(C1-C3)-alkyl, halogen, (C1-C4)-alkoxy or (C1~C4)-
alkoxycarbDnyl,
R3 is as defined above,
R4 and R5 each denote hydrogen,
R6 and R8 are identical or different and are as defined
above under a) - e) and
R7 denotes hydrogen, (C1-C3)-alkyl or a halogenated
alkoxy, alkenyloxy or alkynyloxy radical of the
formula ~o-~cH2~o-cpH~2p~l-q)Halqo ~C1-C7)-
alkoxy, benzyloxy or (C1-C7~-alkoxy-(C~-C3)-alkyl,
and in ~hich halogen preferably denotes fluorine,
~684~,~
-- 6 --
chlorine or brom;ne, o is 0 or 1, p is 1 to 8 and q
is 0 or 1 to ~2p+1), and
but in part;cular those compounds of the formula I in ~hich
A js preferably as defined abovl- under (b~,
T preferably denotes an -S0- group,
R1 and R2 are identical or different and denote hydrogen
or (C1-C3)-aLkyl,
R3 is as defined above,
R4 and R5 each denote hydrogen,
R~ and R8 are ;dentical or different and are as defined
above under a) - e) and
R7 denotes hydrogen, (C1-C4)-alkoxy, a fluorinated n-alkoxy
radical of the formula ~o-tcH2]o-cpHt2p+1-q)Halq
or (C1-C3)-aLkyl, in ~hich halogen denotes fluorine,
o is 1, p is 1 to 5 and q is 0 or 1 tD t2p~1).
Compounds ~hich are of particular importance are
2-t3-methoxy-4-(2,2,2-trifluoroethoxy)-2-picolylsulfinyl~-
1~-thienoC3,4-d~imidazole,
2-[3-methoxy-4-t2,2,3,3~tetrafluoropropoxy)-2-picolyl-
suLfinyl]-1H-th;eno~3,4-d]imidazols,
2-C3-methoxy-4-t2,2,3,3,3-pentafluoropropoxy)-2-picolyl-
sulfinyl]-1H-th;enoC3,4-d3îmidazole,
2-C3-methoxy-4-t2,2r3,3,4,4,4-heptafluorobutoxy)-2-
picolylsulfinyl:l-lH-thieno~3,4-d~imidazole,
2-~3-bromo-4-mel:ho~y-2-picolylsulfinyl)-1H-thienoC3,4-d~-
imidazole,
2-(4-methoxy-5-bromo-2-picolylsulfinyl)-1H-thienoC3,4-d~-
imidazole, ~nd
- ~ `, '` .,~'.: :, . ............... .
: : , : ::
~: :::. - . .
126~
-- 7 --
2-t4-methoxy-5-chloro-2~picolylsulfinyl)-1H-thieno[3,4-d~-
i~idazole.
Alkyl and rad;cals derived therefrom, such as, for
example, alkoxy, alkylmercapto, alkylsulf;nyl, alkyl-
sulfony~, aralkyl or alkanoyl, can be straight-chain or
branched.
(C6-C12)-Aryl is, for example, phenyl, naphthyl or
biphenylyl, and phenyl is preferred.
(C7-C~ Aralkyl is, for example, benzyl or phenethyl,
preferably benzyl. This correspondingly applies to
radicals derived therefrom, such as aralkyloxy.
Halogen stands for fluorine, chlorine, bromine or iodine.
Suitable Nim-protective groups R3 are described, for
example, in connection ~ith substituted picolylsulfinyl-
benzimidazoles in EP-A-176,308 and EP-A2-221,041, and for
~hienoimidazole compounds in EP-A-234,485.
Preferred Nim-protective groups are those ~hich can be
split off in the presence of acid, preferably in a pH
range of about 1 - ~ and/or under physiological eondi-
tions.
Any ch;ral C and S ato~s present can occur both in theR- and in the S-configuration. In such cases, the com-
pounds of the formula I are in the form of the pure
enantiomers or as a stereoisomer mixture tsuch as an
enantiomer mixture and diastereomer m;xture).
Possible salts ~re, in particular, alkali metal and
alkaline eareh ~etal salts and salts ~ith physiologically
tolerated amines.
The invention turthermore relates to a process for the
:
.: : . .
i268461
preparation of compounds of the formula I, which com-
prises
a) reacting compounds of the formula II
~ ~ x~ tII)
R3
in ~hich A, R1, R2 and R3 are as defined above and
x1 ;. denotes a Leaving group or
ii. denotes -SH, -S M or -SOz-M ,
with compounds of the formula III
~ a
X 2 C~
RS
10 in ~hich R4, R5, R6, R7 and R8 are as defined above
and
x2 in the abovementioned case i. denotes -SH, -S M or
-SO~-Mt and
in the above~entioned case ii. preferably denotes a
leaving group or OH, or
b) reacting eompounds of the for~ula IV
NH2
tIV)
~ NH-R3
in which A~ R1, R2 and R3 are as defined above,
with compounds of ~he formula V
~C ~ ~ tV)
R9- 0 RS
i h h R4 R5 R6 R7 and R8 are as defined above
and R stands for an ester;fying group,
:
,. . ..
1;~6~34~1
i. if desired oxidizing any -S- groupts) present in
compounds of the formula I to ~the) -S0- or -S02-
group(s),
;i. if desired oxidi2;ng any -S0- groupts) present in
compounds of the formula I to (the) -S02- group(s),
;;;. if desired acylating, alkylat;ng or aralkylating
compounds of the formula I in ~hich R3 stands for
hydrogen,
iv. if desired hydrolysing compounds of the for~ula I in
~hich R3 does not denote hydrogen, and
v. if desired converting compounds of the formula I
into their physiologically tolerated salts,
it also being possible for t~o or ~ore of the ~easures
i.-iv. to be carried out in a se~uence other than that
sho~n.
M stands for cstions, such as, for example, aLkali
netal, alkaline earth ~etal, ammonium or alkyla~monium
ions, in particular sodium or potassium ions.
If in accordance ~ith the process variant (a) preferred
here compounds of the formula II are reacted ~ith com-
pounds of the formula III, X1 or x2 stands ~or a leaving
group ~hich can be detached nucleoph;lically, such as Cl,
9r, I, -0-S02-CH3, -0-S02-CF3 or -0-S02-tC6H4-pCH3).
The reaction of a compound of the formula ~1 ~ith a com-
pcund of the for~ula lII or salts thereof is carried outin an inert solvent, such as, frr example, ~ater, methyl-
ene chloride, methanol, ethanol, acetone, ethyl acetate,
toluene, tetrahydrofuran, acetonitrile, dimethylfor~-
am;de, dimethyl~cetamide, dimethyl sulfoxide or mixtures
of these solvents, advantageously in the presence of an
: : ,.:, . ~ . - , ., . :, ,
~268~
- 10 -
inorganic or organic base, such as, for example, sodium
or potassium hydrox;de, carbonate, aLkoxide, hydride or
amide, ammonia, triethylamine, tributylamine or pyridine,
at -20 to ~150C, preferably at 0 - 80C.
The compounds of the formula lI are known compounds (see,
for example, Gronowitz, "The Chemistry of Heterocyclic
Compounds", Volume 44, "Th;ophene and its Derivatives",
Parts 1-3, NeY York 1985-6) or they can be prepared analo-
gously to kno~n processes, for example by cyclization of
correspondingly substituted 2,3-, 3,4- or 4,5-diamino-
thiophenes of the formula IV defined above ~ith corre-
sponding sulfur compounds, such as carbon disulfide (for
example DE-A-3,132,167).
The 2,3-, 3,4- or 4,5-diaminothiophenes required for this
are either kno~n from the literature or can be prepared
analogously to kno~n processes. They are obta;ned, for
example, by reduction o~ correspondingly substituted
aminonitrothiophenes.
In the esters of the formula V used in process variant
~b), R9 stands for an esterifying group, preferably
lC1-C6)-alkyl or benzyl.
The reaction o~ a compound of the formula IY ~;th a com-
pound of the formula V in 3ccordance ~ith process variant
~b) is carried out analogously to the procedures de-
scribed in Preston et al., Benzimidazoles and CongenericTricyclic Compounds, Part 1, New York, pages 10-13.
If R3 denotes hydrogen, the compounds of the for~ula I
thus obtained can be converted into physiologically
tolerated salts.
Compounds of the formula I where T = -S- can furthermore
be converted inlto those uhere T - -S0- or -S02- ~ith
suitable oxidizing agents. -S- groups in the substituents
- : :;: , ,
' :,
~ 26~3~6~
- 11 -
R1, R2 and R7 can also be oxidized in the same ~ay.
This reaction is carried out in a suitable inert solvent,
such as, for example, ~ethylene chloride, chloroform,
carbon tetrachloride, 1~2-dich~oroethane, toluene, ethyl
acetate, acetic acid, trifluoroacetic acid, water~
0ethanol, ethanol or mixtures thereof, at -~0C to
+150C, preferably at -1ûC to t40C.
Possible oxidizing agents are, fol example: hydrogen
persxide, peracids and peresters, such as peracetic acid,
trifluoroperacetic acid, monoperphthalic acid, m-chloro-
perben~oic acid and esters thereof, ozone, d;nitrogen
tetroxide, iodosobenzene, N-chlorosuccinimide, 1-chloro-
ben~otriazole, sodium hypochlorite, sodium bromite,
potassium peroxodisulfate, t-buty~ hypochlorite, tetra-
butylammonium periodate or permanganate, sodium ~eta-
periodate, selenium dioxide or ~anganese dioxide, cerium
ammonium nitrate, chromic acid, chlorine, bro~ine, diaza-
bicycloC2,~,2~octane-bromine complex, d;oxane dibromide,
pyridinium perbromide, sulfur~l chloride, 2-arylsulfonyl-
3-aryloxaziridines and titanium teeraisopropylate/tert~
butyl hydroperoxide (if appropriate Yith the addition of
dialkyl esters of (D)- or (L)-tartaric acid and a defined
amount of ~ater).
Isolated and if appropriate immobili~ed oxid; ing enzymes
or microorganisms can also be used as the oxid;zing
agent.
The oxidizing agents are used in equimolar amounts, and
also if appropriate in a slight excess of 5 - 10 mol X
in the case of oxidation to T - -S0- or in a larger
excess and/or at a higher reaction temperature it oxida-
tion to T = -S02- is required.
The invention ~urthermore relates to novel intermediates
of the formula III. They can be prepared by methods
. .: ..,' :' , ' :
,
~26~3~61
- 12 -
~hich are kno~n to the expert, such as ar~e descr;bed, for
exa~ple, in "The Chemistry of Heterocyclic Compounds -
Pyridine and its Derivatives", pts. 2 and 3, E. Klings-
berg Ed. Interscience Publishers, 1962.
In addition to the synthesis of the compounds of the for-
~ula III, in which x2 denotes a leaving group, from com-
pounds of ehe formula III, in ~hich x2 denotes a hydroxyl
group, the compounds of the formula III, in ~hich x2
deno~es chlorine or bromine, can be prepared, for example,
by haLogenation of the corresponding 2-picolines ~ith N-
bro~osucc;nimide, trichloroisocyanuric acid (Chem. ~er.
120, 649-651 (1987)) or o~her N-halogenoamides, ~uch as
N-chlorophtha~i~ide.
~ithout limiting the invent;on to the follow;ng examples,
ssme preparat;on processes for $he compounds of the
~ormula III ;n wh;ch x2 denotes hydrDxyl are described
belo~. They are converted ;nto compounds of the formula
III, ;n wh;ch x2 denotes a leaving group, by standard
methods.
Co~pounds of the formula III in ~hich x2 denotes a
hydroxyl group, one of the substituents R6 and R8 denotes
~romine and the other denotes hydrogen can be obtained in
accordance ~ith equation 1.
A mixture of the conpounds of the formula VII/VIII ;s
obta;ned by brominat;on of 2-picol;ne by known processes
(cf., for example, ~ull. Soc. Ch;m. France 2466, 1972).
After N-ox;dat;on, for example w;th m-chloroperbenzoic
ac;d, and nitration, the compounds IX and X 3re separated
by crystall;~ation or chromatography and prepared ;n a
pure form.
The compounds of the formuLae XI and XlII in ~hich R7
denotes alkoxy are ;n each case obta;ned from the
.
' .
: . .
..
: . , . .:
;84
-- 13 --
compounds of the formulae IX and X and the corresponding
alcoholates MR7, in ~hich M is as defined on page 9,
S and are reacted, for example, ~ith acetic anhydride or
(CF3CO)20 ~ith subsequent hydrolysis of the aceta~es
to give the compounds of the for~ulae XII and XIV.
Equation 1:
R6,R3-r 1-1250-1i503 )~R8 R6 E3,.
(VI) tVII) ~VIII)
1 . m~C~35 er~R8 R6 ~E3
Z. HNO3 /H2504 C~3 ~J CH3)~
O O
~IX) (X)
5;7 R7
> ~ C2 / ~ ~c O~ ) ar ~Ra
CH3 1 2. NoOH HOCH2
( lX)
(Xl ) tXI )
MR7 ~ c20/~cO>) ~8
~XIII) (XIV)
The synthesis of compounds of the formula III in which
x2 denotes a hydroxyl group, R6 denotes hydrogen and R8
denotes chlorine is shown in equation 2. The 5-amino-2-
picoline XV obtainable by known processes via degradation
reactions of carboxylic acid der;vat;ves of S-~ethyl-
nicotinic acid (cf. J. Prakt. Chem. 133 t1932] 19) is
reacted by reactions fam;liar to the expert (5andmeyer
. . ,
~.. , . ,, , ' . . . .
6~4~1
- 14 -
reaction, N-oxidation, nitrat;on, reaction with alcohol-
a~es, rearrangement with acetic anhydride, acetate hydroly-
sis) to give compounds of the formula XX.
Equation 2:
R ~ NoNO2/HCI R ~ Cl R ~ C
H3C ~ CuCI ~ll ~ m~ CPEIS> ,,~!~
S (XV) tXVI) (XVII)
NO R7 R7
HNO3/H25O4 R ~ Cl M~ R ~ 1. ~c~ cOH~ ~ C
C 1 H3C ~ HOH2C
O o
tXVIII) (XIX) tXX)
Compounds of the formuLa lII in ~hich x2 denotes a
hydroxyL group, R6 denotes hydrogen or ~ethyl and R8
denotes fluorine can be obtained as sho~n in equation 3.
The compounds of the formula VIII can be converted into
5-amino-2-picolines XY under the conditions of the
Ullmann reaction tcf. Rec. Trav. Chim. 84 t7), 951-64
11965)).
The compounds XV are ~ike~ise accessible via degradation
reactions of carboxylic acid derivatives of 6-~ethyl-
nicotinic acid of the formula XXI. The synthesis of the
fluorine derivatives XXII is advantageously carried out
under the conditions of the Schiemann reaction, as is
known for XXII tR6 = ~) tcf. J. Med. Chem. 13, 1124
~1970)).
The 4-nitro 5-fluoro-2-picolines of the for~ula XXIII
are reduced, as is kno~n for the analogous 3-fluorine
isomers, to the a~ino derivatives XXIV (cf. Rocz. Chem.
41 t2), 279-87 t1967)) and these are converted into
.. . .
::,
.
. ,,,, : ~ . ~ ..
6846
- 15 -
the dihalides XXV.
Equation 3: R6 = H, CH3
R~ V 1 1 1 ) H3C~/ / X ~ N3 ~ NH2 od-r NHNH2 )
NH3 1 /
CUSO~
R~ ~ ~ 1 m~CPE3~i> ~ F- /~cO~I
2 HNO~ / d >
C N- H3C H250~ H3C
~XV) ~XXlI) ~XXI11)
R~ NoN02/HCI ~ R~ 1 . m~CPE15) R~
od. NN02~HElr4 ~ 2. MR H3C)`lN
~XX1V) ~XXV~ Y ~ F~ Cl) ~XXVI )
F
l ~C2 R~
2 . N o O
HQH2C N~
~XXV~ I ) , '
After N-oxidation, replacement of the 4-halogen by alco-
S holate R7 and rearrangement, preferably with acetic
anhydride or trifluoroacetic anhydride, and acetate
hydrolysis, the picolyl alcohols of the formula XX~II are
obta;ned.
The corresponding compounds ~here R6 = fluorine and
R8 = H or ~C1-C3)-alkyl can be prepared in an analogous
manner.
Compounds of the formula III in ~hich X denotes a
hydroxyl group and both R6 and R8 denote fluorine or
~L26~
- 16 -
chlorine can be obtained, for e~ample, ;n accordance ~ith
equat;on 4:
quation 4:
R~R8 ~ R6 7 RB R ~.
od . R ~ ~ . E3 . Li~:l I H4 ,~H
Y ~ F~ Cl) (XXIX) / (XXX)
R6 R7 RE1 R6 R R9 2 ~-CPE15 R6 R7 R8
3 . NoOH > ~f
RO2C ) 2HC H H3C~H HOH2C~H
~XXXI) ~XXXII) ~XXXIII)
Replacement react;ons Yith nucleoph;les, such as, for
example, amines and alcoholates, on the halogen der;va-
tives XXVIII lead to compounds of the formula XXIX,
reduction of ~hich gives XXX, cf. J. Chem. Soc. 1965,
10 575. Esters of the formula XXXI can be obtained by
reaction of tompounds of the formula XXX ~ith salts of
malonic acid diesters, and these decarboxylate following
acid or alkaline hydrolysis in an acid medium to give the
substituted 3,5-dihalogeno-2-picolines of the formula
15 XXXII.
The compounds of the formula XXX can also be reacted
directly ~ith organometallic reagents, such as, for
example, methylmagnesium halides or methyllith;um, to
give XXXII.
20 Useful substances can also be obtained from compounds of
the formula XXX by nucleophil;c replacement ~ith C1-
synthones, such as, for example, salts of dithianes or
cyanides, and these lead to co~pounds of the formula
XXXIII via further reactions.
., ~ , . . .
- , ~ -: - . .: ,
,~
- ~ .: : ., : :
. ............. . :
:.. - ; ,
~26~4i~
- 17 -
Compounds of the formula III ;n which x2 denotes a
hydroxyl group, R6 denotes an alkoxy radical and R8
denotes hydrogen can be prepared in accordance with
equation 5:
Equation 5:
HO~ 20/R' X R 0~ _ 3
H3CJ~ 2 . NH3 o~ JJ 2 . m~CPE~S
(XXX~V) ~XXXV) ~)X
xxxvlo; X - O)
1.~2.: ~XXXVI~; X - 1)
R 0~ 1 ~c20 R 0
H3C 1 H01-12C
O O
~XXXVlI) ~XXXVII1)
Maltol XXXIV is alkylated Yith an alkyl halide R'X in the
presence of silver oxide to give 3-alkoxy-pyran-4-ones,
1û uhich are reacted ~ith aqueous ammonia to give 2-methyl-
3-alkoxy-4-pyridones of the formula XXXV (J. Org~ Chem.
29, 776 (1~64)).
Substituted 3-benzyloxy derivativçs can be obtain~d in
an analogous manner by alkylation of ~al~ol ~ith the
corresponding benzyL halides.
The compounds isomeric to the compounds of the formula
XXXVIII ~here R6 = hydrogen and R8 = alkoxy are obtained
by analogous react;ons ~ith 5-hydroxy-2-methyl-4-pyranone,
prepared from Kojic acid.
The compounds of the formula XXXV are converted into
2-methyl-3-alkoxy-4-chloropyridines ~ith a halo~enating
agent, for example POCl3, and 4-alkoxy derivatives are
obtained from these ~ith an alcohol R7H in the presence
of a base.
. ,~,
, ' . : ,.,~ :' -. . : .
- ., ., - . . -
.. ~.. - ,, .,. , ~
,
1268~61
- 18 -
The reaction of the analogous N-oxides XXXVIb with alco-
holates to give compounds of the formula XXXVII is advan-
tageous.
Co~pounds of the formula XXXV can also be alkylated
directly in the presence of silver ox;de to give com-
pounds of the formula XXXIX.
R3CO ~ H3C
xxxv~ ~xxxlx
R7 - ~c~^c7)-~lkoxY)
Processes for the preparation of 3,4-dialkoxy-2-picolines
and 4,5-dialkoxy-2-picolines are described in EP-A-
166,287 and EP-A-208,452.
Co~pounds of the for~ula III in ~hich x2 denotes a
hydroxyl group, one of the substituents R6 and R8 denotes
an alkoxy substituent nr a halogenated, preferably
fluorinated, alkoxy radical R~ and the other can be -
hydrogen, halogen, alkyl, alkoxy or a halogenated,
preferably f~uorinated alkoxy radical Rf, can be prepared
in accordance ~ith equation 6:
:: ~ . ~.- . . ......... . :
: .:.. ....
... .....
~Z~46~
- 19 -
Equation 6:
HO R0 RrO~R9 ~ . m~CPeS
~ 1 2. nitrat;on
H3C ~ ~3C ~ ~N03/~25
~xxxx) txxxx1)
R F~ ~, R B R ~ 0~ R9
H~C ~ H3C ~, 2. NoOH oq,
O O
(XXXXlI) (XXXX~I1)
R~O ~ R8
~ ~ R~- ~CH2)O CpH( 2P~ 1 ~q )
-lCH2c o 'O, 1 J
~XXXXIV)
S Compounds of the formula XXXXI are obtained by adding
3-hydroxy-2-picolines of the formuLa XXXX onto correspond-
ingly halogenated olefins (for example CF2=CF2 or
rFz=cClF).
Halogenated carbenes can furthermore be produced from
aLkyl halides and a base, for example CF~ from CHCLF2,
and these likewise lead to compounds of the formula XXXXI
by insertion into the OH bond of the 3-hydroxy-2-pico-
lines (cf. J. Org. Chem. 25~ Z009 (1960)). S-Tr;-
fluoromethoxy-2-picollne is obtained as is described, for
example, in J. Org. Chem. 29, 1 (1964) and J. Med. Chem.
13, 1124 (1970).
The isomeric 5-hydroxy-2-picolines can be reacted in an
analogous manner.
In the preparation processes shown in the above equations,
- , . .
.
~2~ 4~jl
- 20 -
the substituents and variables have the definitions given
above, unless defined otherw;se ;n an ;ndividual case.
In add;t;on to the th;enoim;dazole der;vat;ves descr;bed
;n the ;~lustrat;ve ~xampLes, the compounds of the general
formula I ~hich are summar;zed ;n the foll~ing Table 1
and salts thereof, for example, are also obtained accord-
ing to th~ invention.
Abbreviations used:
methyl (Me), ethyl (Et), propyl (F'r), butyl (Bu), hexyl
(Hex), acetyl (Ac), phenyl (Ph), cyclo (c), iso (;).
Table
R
~ '~(
>~ , T = SO
R2
Rl R2 R3 R4 R5 R6 R7 ~~~ R3
H H H H H H OEt Cl
H H H H H H OPr Cl
H H H H H H OiPr Cl
H H H H H H OCH~Ph C:l
H H H H H H 1)(~H2)20Me t:l
H H H H H H OC:H2CF3 Cl
H H H H H H OcH2cF2cF3 Cl
H H H H H H OEt Br
H H H H H H OPr E~r
. H H H H H H OCH2Ph Br
H H H H H H I:S(CH2)20Me Br
H H H H H H OCH2CF3 Br
H H H H H H OcH2cF2cF3 13r
H H H H H H OCH2Ph F
H H H H H H O(CH2)20~e
,. : .,, . . ~ : .
~2~8~3~
- 21 -
Table, Continuati~n
Rl
'5 ( , T c SO
R2
Rl R2 R3 R4 ~ 5 R16 R7-- -- R8
H H H H H H OCH2CF3 F
ff H H H H F OMe H
H H H H H F OEt
H H H M H F OPr H
H H H H H F OCH2Ph
H H H H H F O(cH2)2~)Me H
H H H H H F OM~ Me
H H H H H F OEt Me
H H H }I H F OPr Me
H H H H H F OiPr Me
H H H H H F OCH2Ph Me
H H H H H F O(CH2)2oMe Me
H H H H H F OCH2~F3 Me
H H H H H Me OEt F
H H H H H Me OPr F
H H H H H Me OCH2Ph F
H H H H H Me O ( CH2 ) 20Me
H 3I H H H Me OCH2CF3 F
H H ~ H H H OMe F
H H H H H H O t F
H H H ~I H H O~r F
H H H H ~I N O~Pr F
; , ~: ' " ' ~ ~ '
- . - , ..
.~
12~84~
-- 22 --
Table, Continuation
Rl
T = SO
R2
2 R3 ~4 ~5 R6 R7 R8
H H H ~ H Br OEt
H H H H H Br OPr H
H H H H H Br OCH2Ph H
H H H H H Br O(CH2)20Me H
H H H H H 8r ocH2cF3 H
H H H H H OC~3 OMe H
H H H H H OCF3 OEt H
H H H H H OCF3 OPr H
H H H H H ~CF3 OCH2Ph H
H H H H H OCF3 OtCH2)20Me H
H H H H H OCF3 0CH2CF3
H H H H H OCF2H OMe H
H H H H H OCF2H OEt H
H H H H H OCF2R OPr H
H H H H H OCF2H O ( CH2 ) 20Me H
H H H H H OCF2CFzH OMe
H H H H H OCF2CF2H i:Me Me
H H H H H OCF2CF2H OEt ~e
CH3 CH3 H H H OCF2CF2N OMe
CH3 CH3 H H H OCF2CF2H OMe Me
OCH2CF3 H H H ~I OCF2CF2H OMe H
OCH2~::F3 H H ~l H OCF2CF2H OMe Me
126~a~61
-- 23 --
TabLe, Cont inuat ion
Rl
~( , T = SQ
R
Rl R2 R3 R4 R5 R~; R7 R8
OCH2CF3 H H H H OCF2CF2H OCH2Ph H
OCH2CF3 H H H H H OMe OCF2CF2H
OCH2CF3 H H H H M~ . t)Me OCF2CF~H
OCH2CF3CF3 H H H H OCF2CF2H OMe H
OCH2CF2CF3 ~ H H H O ::F2CF2H OPr H
OCF2CF2X H H H H OCF2CF2H OMe
9CF2CF2H X H H H OCF~CF2H OEt H
OCF2CF2H H H H E~ OCF2cF2H OCH2Ph H
OCF2CF~H H H H H OMe OMe OCF2CF2H
H H H H H H OMe OCHF2
H H H H H H OEt OCHF2 ::
}I H H H H H OCH2Ph OCHF2
H H H H H H 0 ~ t:H2 ) 20Me OCF3
H H H H H H OMe OC:F3
H H H H H H OEt OCF3
H H H H H F OMe F
H H H H H F OEt F H
H H H H H F OCH2Ph F
H H H H H F O(CH2)2C~Me F
H H H H H Cl N~Me H
H H H H H Cl N~'hMe Me
- :.
:. :....... .
~ '' ',':, ~ '~- ,' -
126846:1
-- 24 --
TableO Cont inuat ion
R1
~ ~ ( , T = SG
R2>~
___ R2 R3 R4 R5 R6 R7 - - R8
H H H H H H NPhMe Cl
H H H H H Me NPhMe Cl
H H H H H F --NMe2 F
H H H H H F - ~ F
H H H H H F -N~-~O F
H H X H H Cl -NMe2 Cl
~_,
H H H H H Cl - V . Cl
H H H -H H Cl -N ~ 'Cl
CH3 CH3 ~ H H OCH3OCH2CF3
CH3 C~3 H H H OCH3OcH2cF2cF2H
CH3 CH3 H H H OCH3O~H2CF2CF3 H
CH3 CH3 ~ H H OCH3 OCH?CF2CF2CF3 H
CH3 CH3 H H H O~H3 OCH2cF2~F2~F2cF2H H
H H H H H H OC~2~F3 OCH3
H H H H H H ocH2cF2GF2H OCH3
H H H H H H OCH2CF2CF3 O~H3
H H H H H H oCH2CF2CF2~F3 O~H3
H H H H H H OcH~cF2eF2~F2c~2H OCH3
CH3 CH3 H H X H OCH2CF3OC~3
CH3 . CH3 H ~ H H . OCH2CF2C~2~ ~CH3
- . :. - .
:: , : ,., . : .~ :. ,, - ,
~, .- , , : .. ., :
12~84f~L
- 25 -
TabLe, Continuation
>~
T = SO
R2
Rl R2 R3 R4 R5 R6 _ R7 ~ 8
CH3 CH3 ~ H H HOCH2CF2CF3 oc~3
CH3 CH3 H H H XOCH2CF;~CF2CF3 OCH3
CH3 CH3 H H H HOCtl2CF2CF2CF2CF2H OCH3
OCH2CF3 H H H H OCH3 OCH2CF3 H
OCH2CF3 ~ ~ H H OCH3 Ol:H2CF2CF3
H H H H H 4-chloroben- CX:H3 H
zyLoxy
H H H H H - 4-fluoroben- OCH3 H
zyloxy
H H H H 2,4-difluoro- OCH3 H
benzyloxy
H H H H H 3,5-difluoro- OCH3 H
benzyloxy
H H H H H 4,6-dichloro- OCH3
benzyloxy
H H H H H 4,5-dichloro- OCH3 H
benzyloxy
H H H H H 4-trifLuoro- OCH3
methylben-
zyloxy ,
H H H H H 3,5-bis-tri- OCH3 H
flunromethyL-
benzyloxy
H H H H H 4-fluoroben- OCH2CF3 H
, zyloxy
H H H H H 4-chloroben- OCH2CF3 H
ZylOXy
H H H H H 4-trifluoro- OCH2CF3
benzyloxy
..
, . .:; .
: - : ~,:
. ::
; ~` : : ;' . ~
:
3461
- 26 -
Table, Continuation
R1
R2 ' T = SO
Rl R2 R3 R4 R5 R6 R7 R8
_ _
H H H H ~ 3,5-bis-tri- OCH2CF3 H
fluoromethyl-
benzyloxy
CH3 CH3 ~ H H 4-tr;fluoro- OC~2CF3 H
methyl-
benzyloxy
H H H H H ~ O~H3 4-fluoro-
benzyl-
oxy
H H H H H H Q~H3 4-tr;-
fluoro-
methyl-
benzyl-
oxy
H H H H H H OCH2CF3 4-fluoro-
benzyl-
oxy
H H H H H H OCH2CF3 ~-tr;-
fluoro-
methyl-
benzyl-
oxy
The novel compounds of the formula I and their salts have
useful pharmacological propert;es.
S They clearly inhibit gastric acid secretion and moreover
have an excellent effect of protection of the stom3ch and
intestine.
"Protection of ~he stomach and in~estine" in this connec-
tion is understood as the prevention and treatment of
gastrointestinaL diseases, in particular gastrointestinal
inflammatory dis;eases and Lesions (such as, for examPle,
~;~68461
-- 27 --
Ulcus ventriculi, Ulcus duodeni, gastritis, irriSated
stomach of hyperacid or medicamentous or;gin~, ~hich can
be caused, for example, by microorganisms, bacterial
toxins, ~edicaments (for example antiinflammatories and
antirheumatics), chemicals ~for example ethanol), gastric
acid or stress situations.
On the basis of their excellent properties, the substitu-
ted thienoimidazoles of the formula I and their pharma-
cologically tolerated salts are outstandingly suitable
for use in human and veterinary medicineO and they are
used in particular for the treatment and prophylaxis of
diseases of the stomach and intestine and those diseases
based on excessive gastric acid secretion.
It has been found that colon H~/K~-ATPase (cf. ~ustin,
Goodman, J. ~iol. Chem. 256 C1981~ 10651-10656~ is also
greatly inhibited in vitro by compounds ~hich are formed
~hen the compounds of the formula I according to the
invention are treated ~ith acid (for sxample ~ith sodium
acetate/HCl buffer ~ith a pH of about 4-5.5). Such con-
version products can also be formed in vivo during pas-
sage of the co~pounds o~ the formula I through the gastro-
intestinal tract. The extent to ~hich they are formed
depends on the substitution pattern and on the pH.
Colon H+lK~-ATPase is attributed a decisive influence
on the electrolyte equilibrium on the intestinal ~ucosa.
Colon H /K~-ATPase inhibitors, such as those mentioned
above, can therefore intervene in this equilibrium and
be used for the treatment of diseases ~i~h disturbed
electrolyte equilibrium.
The inven~ion thus also relates to the ~se of compounds
of the formula I or acid conversion products thereof in
the treatment of diarrhea diseases. Examples of such
diseases are inflammatory intestinal diseases, such as
cholera, paratyphoid, travellers` diarrhea or other forms
.~ .
. .
.
' ~ .: ' ' ' .
~268461
- 28 -
of secretory diarrhea, and also other ;ntestinal d;seases,
such as Morbus Crohn, CoLit;s ulcerosa and regional
enteritis.
The invent;on further~ore relates to conversion products
~hich are formed ~hen compounds o1 the formula I are
treated ~ith acid.
The invention thus also relates to the compounds of the
formula I according to the invent;on for use in the treat-
~ent and prophylaxis of the abovementioned d;seases.
The invention like~ise relates to ehe use of the com-
pounds according to the invention in the preparation of
~edicaments ~hich are used for ehe treatment and prophyl-
axis of the abovementioned diseases.
The invention furthermore relates to medicaments contain-
ing one or more compounds of the general formuia I and/or
pharma~ologically tolerated salts thereof.
The med;caments are prepared by processes which are known
per se and vith ~hich the expert is familiar~ The
pharmacologic3lly active compounds ~= active compounds)
according to the invention are used as medicaments either
as such or, preferably, in comb;nation with suitable
pharmaceutical auxiliaries in the form of tablets, coated
tablets, capsules, suppositories, emulsions, suspensions
or solutions, the active compound content advantageously
being bet~een 0.1 and 96X.
The expert is familiar, on the basis of his kno~ledge,
~ith the auxiliaries vhich are suieable for the desired
medicament fornulations7 In ~ddition to solvents, gel-
forming agents, suppository bases~ tablet auxiliaries
and other active compound excipients, it i5 also possible
to use, for ex~Mple, antioxidants, dispersing agents,
emulsifiers, foilm suppressants, flavor correctants,
~Z6~4~i1
-- 29 --
preservatives, solubilizing agents or dyestuffs.
The active compounds can be administered orally or paren-
terally, oral administration being preferred.
In general, it has proved advantageous in human ~edicine
to administer the active compound or compounds, in the
case of oral administration, in a daily dose of about
0.01 to about 20 mg/kg of body ~e;ght, if appropriate in
the form of several, preferably 1 to 4, individual doses,
in order to achieve the desired result. In the case of
parenteral administration, similar or tespecially in the
case of intravenous administratiorl of the active com-
pounds) as a rule lower dosages can be used. The parti-
cular optimum dosage required and the mode of adm;nistra-
tion of the active soMpounds can easily be specified by
any expert on the basis of his ~echnical kno~ledge.
If the compounds according to the invention and/or their
salts are to be used for the treatment ot the abovemen-
tioned diseases, the pharmaceutical formulat;ons can also
contain one or more phar~acologically artive constituents
from other groups of medicaments, such as antibiotics,
for example ofloxacin, ~ntacids, for example aluminum
hydroxide, magnesium aluminate, sucralfate and Bi salts,
tranquillizers, such as benzodiazepines, for example
diazepam; spasmolytics, such as, for examPle, bietamiver-
;ne and camylofin; anticholinergics, such as, forexample, pirenzepine, telenzepine, oxyphencyclimine and
phencarbam;de; local anesthetics, such as~ for example,
tetracaine and procaine; and if appropriate also gastr;n
antagonists, enzymes, vitamins or amino acids.
For the oral use form, the active compounds are mixed with
the additives customary for this, such as exçipients, stabi-
lizers or inert diluents, and are brought into suitabLe
presentation fotms, such as tablets, coated tablets~ push-
fit capsules, a~ueous, alcoholic or oily suspensions or
. : ' :': :: ``
.
',: ': ::' ` `. `'
126~4~
-- 30 -
aqueous, alcoholic or oily solutions, by customary methods.
lnert excipients which can be used are, for example, gum
arabic, ~agnesia, Magnesium carbonate, lactose, ~ucose or
starch, in particular ~aize starch. The Nixtures can there-
by be formulated either as dry or as moist granules. Pos-
sible oily excipients or solvents are, for ex~mple, vegetable
and an;~al oils, such as sunflo~er oil or cod-liver oil.
For subcutaneous or intravenous administration, the active
coopounds or phys;ologically tolerated salts thereof are
dissolved, suspended or emulsified, if appropriate ~ith the
substances customary for this, such as solubilizing agents,
emulsifiers or other auxiliaries. Possible soLvents for the
novel active compounds and the corresponding physiolog;cally
tolerated salts are, for example: water, physiological
saLine solutions or alcohols, for example ethanol, propanol
or glycerol, and in add;tion also sugar solutions, such as
glucose solutions or ~annitol solutions, or also a mixture
of the various solvents nentioned.
The following examples are intended to illustrate the
procedures according to the invention ~ithout limiting
the invent;on to the substances Rentioned here as repres-
entatives.
The melting points and decomposition points stated are
not corrected or standardi2ed.
,~
5-Chloro~2~p;coli-ns ~a~/e
a) 5-Chloro-2-picoline N-oxide
21.3 9 of m-chloroPerbenzoic acid (m-CP8A) are added
in portions to 13.0 9 of 5-chloro-2-picoline in 250 ml
of methylene chloride at room temperatureO ~ith
stirring. After 2 hours, the m;xture ;s extracted
twice by shaking with 20D m~ of saturated aqueous
NaHC03 solution each time and then three times by
,, - ,
. .., : . ' .`' ~' :, . . ~ ' : '
. :: . ' . -
'' ',.. ;'"' ;-
~684~,~
- 31 -
shaking ~ith 200 mL of saturated aqueous NaHS03
solution each time. The bicarbonate solution is
extracted three times ~ith 100 ml of methylene chLor-
ide each time and the combined organic phases are
dried and freed from the solvent. After trituration
~ith petroleum ether, the crystalline eitle comp~und
is obtained, melting point 73-76C.
b) 4-Nitro-5-chloro-2-picoline H-oxide
12 9 of 5-chloro-2-picoline ~-oxide are introduced in
portions into a mixture of 40 nll of concentrated sul-
furic acid and 40 ml of fuming nitric acid, with
cooling. The mixture is then heated at 35 to 40C
for 1 hour and at 65 to 70C for 2 houre. After
cooling, it is stirred ~ith 250 9 of ice, brought to
pH 10 to 11 with 10 N sodium hydroxide solution and
extracted ~ith ethyl acetate. After being freed from
~he solvent, the residue is treated ~i~h diisopropyl
ether, melting point 115-117C.
c) 4-~ethoxy-5-chloro-2-picoline N-oxide
2D 3.5 9 of 4-nitro-5-chloro-~-picoline N-oxide in 50 ml
of anhydrous nethanol are added at -10C to a sodium
methylate solution prepared ~rom 1.5 9 of sodium and
150 ~l of ~ethanol. The mixture is allo~ed to ~arm
slo~ly to room temperature and is then heated under
reflux for 1 hour. The solvent is no~ distilled off
under reduced pressure, water is added to the residue,
the mixture is extracted ~ith ~ethylene chloride and
the solvent is stripped off. Colorless crystals from -
diisopropyl e~her, melting point 137-139C.
d) 5-ChLoro-2-hydroxy~ethyL-4--ethoxypyridine
8.5 g of 3-chloro-4-~ethoxy-Z-picoline N-oxide are
dissolved in 16 ml of glacial acetic acid, and 24 ml
of acetic anhydride are added at 80C, with stirring.
The ~ixture is heated at 110 to 120C for 1.5 hours
and then allowed to cool to 80C and 40 ml of
. . - . .- . .
.:
~268461
- ~2 -
methanol are added drop~ise. The mixture is then
concentrated under reduced pressure, 35 ml of ~ater,
13.6 9 of eaust;c soda, in smalL poreions~ and 15 ml
of dioxane are then added to the residue and this mix-
ture is heated under reflux for 2 hours. After cool-
ing, it is extracted with methylene chloride, the soL-
vent is driven off and the res;ldue is made to crystal-
lize ~ith diisopropyl ether. S~lid, ~elting point 78-
80C
e) 5-ChLoro-2-chloro~ethyl-4-oethoxypyridine hydroehloride
A solueion of 8.0 ml of thionyl chloride in 20 ml of
~ethylene chloride is added drop~ise to a ~ixture of
4.5 9 of 5-chloro-2-hydroxymethyl-4-methoxypyridine
and 100 ml of methylene chloride at 0C and the mix-
ture is then stirred at room temperature for 2 hours.The sol~ent is driven off and the residue is ~ade to
crystallize ~ith diethyl ether. Colorless crystals,
melting point 136-137C.
f) 2-14-~ethoxy-5-chloro-2-picolyl~ercapto)-1H-thieno-
~3,~-d]i-idazole dih~droehloride
1.56 9 of 2-çercapto-thienol3,4-d~imidazole and 2.3 9
of 4-methoxy 5-chloro-2-picolyl chloride hydrochloride
are heated at 60C ;n 100 ml of ethanol for about 1
hour and then hea~ed under reflux for 1.5 hours. After
filtration, the crystalline substance is suspended in
acetone, the suspension ;s stirred at room temperature
for 1 hour and the crystals are filtered off ~ith
suct;on and dried in air, melting point ~ 260C.
The filtrate is treated ~ith animal charcoal and con-
centrated in vacuo and the residue is ~ade to trystal-
lize ~ith acetone, ~elting point > 260C~
9) 2-(4-~lethoxy-5-rhloro-2-picolyloerc~pto~-1H-thieno-
C3,4-d~i-idazole
1.4 9 of the title compound from Example 1 f) are
. :~ ., "
~L~68461
- 33 -
suspended in 70 ml of ethanol and 2 ml of triethyl-
amine are added at room temperature, ~ith stirring~
The solution thus obtained is stirred at room tempera-
ture for about 1 hour, a suspension is formed ~ith
S active charcoal, the ~ixture is filtered and ths fil-
trate is concentrated in vacuo. ~ater is added to the
residue and the mixture is extracted with methylene
chloride. After evaporation of the solven~, the
residue is made to crystallize ~ith diisopropyl ether,
melting point 135-137C.
h) 2-(4-~ethoxy-5-chLoro-2-picolylsulfinyL)-1H-~hieno-
C3,4-d~i0idazole
0.308 g of n-chloroperbenzoic acid (85~ pure) in 10 ml
of methylene chloride is added drop~ise to 0.44 9 of
the title compound of Example 1 9) in a t~o-phase
mixture of 70 ml of methylene chloride and 4Q ~l of
aquPous KH2P04/Na2HP04 buffer solution (pH = 7.5)
at 0 to 5C, ~ith stirring. After about 3D minutes,
the organ;c phase is concentrated and the residue ;s
chromatographed on silica gel using methyLene chLor-
ide/ethyl acetate~ The product is ~ade to crystallize
from the corresponding fractions with ethyl acetate,
melt;ng po;nt 159C tdecompos;t;on~, or is recrys-
tall;zed from ethanol.
Exa-ple 2
a) 3-8rooo-2-piGoline N-oxide and 5-bro~o-2-picoline N-
oxide
The title compounds are obta;ned analogously to
Example 1 a) from 43 9 of a mixture cons;st;ng of 3-
bromo-2-picoline and 5-bromo-2-p;coline ~ith 60 g o~
m-chloroperbenzoic acid ~85X pure). The mixture of
the title compounds is made to crystallize ~ith diiso-
propyl ether, ~elting point 65-80C tnot sharp)~
.
: . - - .
~68~6~
b) 3-~roao-4-nitro-2-picoline N-oxide and 5-bro~o-~-
nitro-2-picoline N-oxide
26.3 9 of the t;tle compounds from Example 2 a) are :
stirred in 50 ml of H2504 / Sû ml of HN03 at 60 to
65C for 7 hours, analogously to Example 1 b).
The 5-;somer, mslting point 133-135C, is preferen-
tially crystaLli.ed from the evaporation residue with
a mixture of ethyL acetate and di;sopropyl ether t1 :
1). On chromatographic separation of the ~other
liquor uith toluene / ethyl acetate (1 : 1) on s;lica
gel, further 5-bro~o-4-nitro-2-picoline N-oxide is
first eluted, follo~ed by 3-bromo-4-nitro-2-picoline
N-oxide, melting point 111-113C (from petroleum
ether).
Exa~ple 3
a~ e~hoxy-S-bro~o-2-picoline N-oxide
The title compound is obtained from 8.2 g of 4-nitro-
5-bromo-2-picoline N-oxide and 0.87 9 of Na in
nethanol analogously to Example 1 c). After evapora-
tion of the methylene chloride, the residue is ~ade tocrystallize ~ith diisopropyl ether, melting point 146-
148C.
b) ~-Wethoxy-5-bro~o-2-hydroxy~ethylpyridine
6.6 9 of 4-methoxy-5-bromo-2-picoline N-oxide are
reacted with 7 ml of glacial acetic atid, 15 ml of
acetic anhydride, 20 ml of me~hanol, 20 ml of ~ater,
8 9 of NaOH and 20 ml of dioxane analogously to
Example 1 d). The crude product is made to crystal-
lize ~ith diisopropyl ether, melting point 80-~2C.
c) 4-~ethoxy-5-bro~o-2-chloro~ethylpyridine h~drochloride
The title compound is obtained fro~ 4.3 9 of the title
compound from Example 3 b) and 5.0 ml of thionyl
chloride analogously to Example 1 e), melting point
.
. ~ -, . . ~ .
. ' - . ' ''i':
., . . ~ .
. .. ~ ~ .
, .,. ..... :~ :; ; :
.,, . ,.... .. :
~L268461
- 35
> 300C (from d;isopropyl ether~.
d) 2-(4-Methoxy-5-brooo-2-picolyloercapto)-1H-thieno[3,4-
d]ioidazole dihydrochloride
1.2 9 of 2-mercapto-thienor3,4-d]imidazole are suspen-
ded in 50 ml of ethanolO 2.0 g of 4-methoxy-5-bromo-
2-chloromethylpyridine hydrochloride are added and the
mixture is stirred at 60C for 1 hour. It is freed
from the solvent and the res;due is Made to crystal-
li~e ~ith diethyl ether, melting po;nt ~ 300C.
10 ~) 2-(4-~ethoxy-5-brooo-2-pitoLyl~ercapto)-1H-thienor3~4-
d~i-idazole
7 nl of triethylamine are added to 2.15 9 of the title
compound from Example 3 d) in 50 ml of Methanol.
Analogously to Example 1 9), ~he product crystallizes
on addition of water, melt;ng po;nt 165C ~decomposi-
tion].
f) 2-t4-~ethoxy-5-bro~o-2-picol~lsulfinyl)-1H-thieno~3,4-
d~i~idazole
The title co~pound is obtained analogously to ExampLe
1 h) from 1.1 9 of the title compound from Example
~ ~ Orv ~ e ~ ~Of ~
' 3 e) and 0.725 9 of ~r~t~P~ ~e~-acid. On tr~at-
~ent of the residue, the tiele compound crystallizes
frDm a Little diethyl ether/ethyl acetate t1 ~ 1),
melting point 140C ldecomposit;on].
Further product is obtained from the mother liquor,
~hich becomes dark in color, by evaporation and
immediate treatment ~ith ~ little ethyl acetate.
Exa-pLe 4
a) 3-~romo-4--ethoxy-2-picoline N-oxide
The title compound is obtained analogously ~o Examples
1 c) and 3 a) fro~ 4.6 9 of 3-bromo-4-nitro-2-picoline
N-ox;de in 40 ml of methanol with a sodium methylate
. :. ::,
:' ~ .. i'; : ' .
- - - :
.- .~
.. ~. ~ , :
- . . :
~2~846
-- 36 -
so~ution prepared from 0.5 9 of sodium and 20 ml of
~ethanol, melting point 80-82C (from diisopropyl
ether).
b) 3-8ro-o-4-~ethoxy-~-hydroxy~ethylpyridine
3.8 9 of the title compound from Example 4a) are
stirred ~ith 30 ml of acetic anhydride at 80-85C for
1 hour. 25 ml of methanoL and, after concentration,
30 ~l of 5 N sodium hydroxide solution and 10 mL of
dioxane are added, analogously to Examples t d)/3 b).
The product crystallizes from diisopropyl ether, melt-
ing point 109-111C.
c) 3-Bro~o-~-~e~hoxy-2-chloro-ethy~prridine hydrochloride
1.9 9 of the ~itle compound of Example 4 b~ are reac-
ted ~ith 2.5 ml of thionyl chloride analogously to
Examples 1 e) and 3 c). The product is made to
crystallize vith diisopropyl ether, ~elting point 142-
144C
d) 2-(3-Bro-o-4-~ethoxy-2-picolyl-ercapto)-1H-thienoC3,4-
d3i-idazole dihydrochloride
2.3 9 of 3-bromo-4-methoxy-2-chloromethyl-pyridine
hydrochloride are added to 1.3 9 of 2-mercapto-thieno-
C3,4-d]imidazole in 50 ~l of ethanol, with stirring,
and the ~ixture is kept at 60C for 30 minutes. The
product is filtered off with suct;on and dr;ed in
vacuo, melting po;nt > 300C.
e) 2-(3-Bro~o-~ ~ethoxy-2-pieolyl~ercaPto)-1H-thienoC3,4-
d~i-;dazole
2.9 ml of triethylamine are added to 2~4 9 of the di-
hydrochloride from Example 4 d) in 50 ml of methanol
analogously to Example 1 9). Af~er concentration and
additicn of a litt~e ~ater, the residue crystallizes,
melting point 168C Zdecoeposition~.
~- '- . .~ ,, :~
'. :. : ' ''
1;~6~'~6~L
-- 37 --
f) 2-(3-Bro-o-4-~ethoxy-2-picolylsulfinyl)-1H-thieno~3,4-
d]i~idazole
0.44 9 of m-chloroperbenzoic acid (85X pure) in 15 ml
of methylene chloride are added drop~ise to 0.72 g of
the title compound from Example 4 e) in 120 rl of
methylene chloride and 50 ml of aqueous KH2P04/Na2HP04
buffer solution (pH = 7.5) analogously to Example 1 h).
After concentration of the organic phase, the residue
is made to crystallize with ethyl acetate, melting
point 160C (polymerization?).
xa-ple 5
a) 2-~ethy~-3-~ethox~-4-ch~oro-pyridine N-oxide
11.2 9 of 3-methoxy 2-methyl-4(1H)-pyridone are heated
under reflux in 100 ~l of phosphorus oxychloride for
10 hours. The ~ixture is then concentrated, 2 por-
tions of 30 ml each of toluene are added and the 0ix-
ture is concentrated each time, the residue is taken
up in 150 ml of ~ater, the mixture is brought to pH 11
~ith K2C03 and extracted ~ith methylene thloride and
the organic phase is ~ashed ~ith water, dried and
freed from the sol~ent.
The ti~le conpound is obtained from the pale bro~n oil
(9 9) ~ith m-chloroperben~oic ac;d in methylene chlor-
ide under standard condit;ons, melting point 88-89C
(from petroleum ether).
b~ 2-~ethyL-3,4-di~ethoxy-pyridine N-o~ide
A sodium methylate solution prepared from 1.14 9 of
sodium and 50 ml of methanol is added dropwise to 8 9
of the title compound from Example 5 a) in 100 ml of
anhydrous methanol, the mixture is heated at the boil-
ing point for 20 hours and concentrated, ~ater is
added, the mixture is extracted with methylene chlor-
ide ~nd the extract is concentrated to give the title
compound, melt;ng point 111-113C.
: -,:
:. ~ ;: ..
' . '' :.~ . . . .:.
:,,~ :
1~6~3461
- 38 -
c) 3,4-Di~lethoxy-2-hydroxy~ethrl-pyridine
5.8 9 of the product described above are reacted in
10 ml of glac;al acetic acid, 15 ml of acetic anhyd-
ride, 20 ml of ~ethanol, 20 ~l of ~ater, 8 9 of NaOH
and 20 ml of dioxane analogously ~o Example 1 d),
melting point 86-88C (from diisopropyl ether).
d) 3,4-Di~ethoxy-2-chloro~ethy~-pyridine hydrochloride
3.4 9 of the above product are reacted w;th 5 ml of
thionyl chloride analogously to Example 1 e). Melting
point 150-151C ldecomposition~ (from diethyl ether).
e) Z-(3,~-Di-ethoxy-2-picolyl-ercDpto~-1H-thieno~3,4-d~-
i~idazole
1.56 9 of 2-~ercaptsthieno~3,4^d~im;dazole in 70 ml of
ethanol are reacted ~ith 2.3 9 of 3,4-dimethoxy-2-
chloromethy~-pyridine hydrochloride analogously to
Example 1 f).
Melting point 148-150C Cdecomposition].
The product is then treated ~ith 2.5 ml of triethyl-
amine in 60 ml of ~ethanol analogously to Example 1 9).
Melting point 141-142C ~decomposit;on~.
f) 2-(3,~-Di-ethoxy-2-pico~ylsulfinyl)-1H-thienoC3,~]-
i~idazole
- 0.75 9 of the titLe compound from Example 5 e) is
oxidized ~;th 0.55 9 of m-chloroperbenzoic arid in
100 ml of ~ethylene chloride and 50 ml of
Na2HP04/KH2P04 buffer solut;on (pH = 7.5)
analogously to Example 1 h)r After the mixture has
been concentrated, the residue is ~ade to crystaLlize
uith diethyl ether, ~elting point 13g-140C.
Exa-p~e 6
a) 2-~rovo~ethyl-3-fluoropyri~ine
1.11 9 of 3-fluoro-2-p;coline are dissolved in 50 ml
of CCl4, 3.6 9 of ~-bromosuccinim;de and 0.1 g of
-: ~ . . - ...
.
....
" ,.~ -
1268~61
- - 39 - ;
~20bisisobuSyronitrile ~re sdded ~nd the ~ixture ix l~
stirred for 2 hours ~hile boiling under reflux. After
cooling and tiltr~tion, the solvent is removed in
v~cuo. The crude product shous the expected ~ol~cular
pe3k of 189 ~/e in the ~ass spectrum.
b) 2-(3-Fluoro-2-picolyl~ercapto-1H-thienoC3,~-dJi-id~role
~ of 2--crc~pto-thienot3,4-d~iMidJzol~ 2nd 1.9 9
of 2-bro~o~ethyl-3-fluoropyridin~e are stirred w;th
2.8 g of po~dered anhydrous K2C03 in 3bout 100 ~l of
~cetone for ~ hours, uithouS cooling. Aft~r filtration
and re~ov~l of the solvent in vacuo, the crude product
is purified by colu~n chromatography on silica gel with
a ~obile phase oixture of cyclohexane/ethyl acetate.
The product fraction h~s ~n Rf of about 0.95.
e) 2-~3-Fluoro-2 picolylsulfinyl-1N-thieno~3,4-~]i~id3~ole
530 ~9 of the coopound from the precedin~ st~ge are
dissolved in S0 ~l of CH2Cl2 and the solution is
stirred ~ith ~44 mg of ~-chloroperbenzoic ~cid at room
temperatur~ for 4 hours. The solution is ~ashed
2D successively ~ith NaHS03 solution, NaHC03 solut;on ~nd
H20 and dried ~ith Na2S04. The crude product
obtained ~fter re~oval of the solvent is subjected to
colu~n chrooatogr3phy ~SiO2: CH2Cl2: ~cetone = 7/3).
The product fractions are concentrated ~nd the residue
is stirred ~ith diisoprop~l ether and filtered off.
~eltin~ point 145C; MS gives a ~olecu~ar peak of
282 m/e; (M~H)~.
The compounds of the formula I(A as defined ab~ve under (b))
in the following Examples 7 to 22 are obtained by procedures
analogous to those described in Examples 1 to 6:
:
i
:': ' ,:
126~34~.1
-- 40 --
Ex. T R3 ~6 _ R7 X8 Melti,n~ D~int
7 S H CH3 OCH3 F . 170-173 C
8 SO H CH3 O~H3 F ab 145~C tdecomp.
9 S H H H OCHF2 (MS: M~=313
SO H H H OCHF2 116C rdecomp.~
MS(Dl~ M~41=329
11 S H H H Cl 160C ~decomp.
1~ SO H H H Cl 15'7~C tdecomP-~
13 S H OCH3 H H 180C rdecomp.
14 SO H OCH3 H ~1 85- 90C rdecomp.
S H H H OCH 3 112-114C
16 SO H H H OCH3 152-154CIdecomp.]
17 S ~1 9CHF2 ~ H 103C ldeco~p~];M+=313
18 SO H OCHF2 H H 78C ~decomp.~;M+H+-330
19 S H OCH2CF3 0CH2CF3 H 145C tdecomP.~;M~=443
SO H OCH2CF3 OCH2CF3 H 154l: rdecomp.~;M+H~=460
21 S H OCF2CF2H OCH3 H Ol ;M~H~=394
22 SO H OCF2CF2H OCH3 H ~38C [deco;:p.~ ;M~H~C410
Rl, R2, R4 and R5 are in each case hydrogen
Exa-ple 23
a~ 2-~ethyl-3--ethoxy-4-(2,2,2-trifluoroethoxy~pyridine
N-oxide
6.7 9 of potassium tert.-butylate are added in por-
tions to 20 ml of tr;fluoroethanol at -20C, w;th
stirring and under a nitrogen atmosphere~ After the
mixture has been ~armed ~o 0C, 5.2 9 of 2-methyl-
3-methoxy-4-chloro-pyridine N-oxide (~itle compound
from Example 5 a) are added in port;ons. The mixture
is heated under reflux for 3 hours and allo~ed to cool
to room temperature, a further 3.45 9 of potassium
tert.-butylate are added and the mixture is heated
under reflux for 2 hours. After cooLing, 40 ml of
~ater are added to the reaction mixture, the mixture
. ~
~Z6~34~
- 41 -
is extracted ~ith methylene chlor;de and the extract
is dried over MgS04 3nd freed from the solvent in
vacuo. The oily crude product obtained is reacted
further.
b) 3-~ethoxy-4-(2,2,2-trif~uoroethoxy)-2-hydroxy-~ethyl-
pyridine
8 9 of the title compound from Example 23 a) are dis-
solved in 16 ml of glacial acetic acid, and 24 ml of
acetic anhydride are added at ~0C, with stirring.
The mixture is heated at 110C for 2 hours and then
cooled to 80C, and 40 ml of methanol are added
drop~ise to the reaction mixture. The mi~ture is then
concentrated in vacuo, the oily residue is ~dded to
75 ~l of 2 N methanolic NaOH and the ~ixture is
stirred for 30 minutes. After treatment ~ith active
charcoal and fil~ration, the filtrate is concentrated
in vacuo, 50 ml of ~ater are added to the residue, ~he
mixture is extracted ~ith methylene chloride, the
extract is dried tMgS04) and concentrated and the
residue is treated ~ith diisopropyl ether. Colorless
crystals, meleing point 107-108C.
c) 3-~ethoxy-4-t2,2,2-~rifluoroethoxy)-2-chloro~ethyl-
Prridine hydrochloride
A solution of 6.0 ml vf thionyl ehloride in 15 ml of
methylene chloride tS added drop~ise to a mixture of
3.9 g of the above product and 1~0 ml of methylene
chloride at 0C and the mixture is then stirred at
roon temperature for 2 hours. The solvent is driven
o~f and the residue is made to crystallize ~ith d;iso-
propyl ether. Colorless crystals, melting point 166-
168C.
d) 2-t3-~ethoxy-4-t2,2~2-trifluoroethoxy)-2-pico~yl-er-
capto)-1H-thienoC3,~-d~i~idazole dihydrochloride
1.0 9 of 2-~ercapto-thienoC3,4-d~im;dazole and 1.9 9
of the above product are heated at 60C in 60 ~l of
.. ,...... - ; ,.
~2~8
-- 42 --
ethanol for about 1 hour, and the m;xture is then
heated under reflux for 1.5 hours. After treatment
with active charcoal, f;ltra~ion and concentration,
the res;due is made to ~rystall;~e with acetone~
Melting point from 188C (decompos;tion).
e~ 2-(3-~ethoxy-4-~2,2,2-trifluoroethoxy)-2-pico~ylmer-
capto)-1H-thieno~3,4-d~i-ida~ole
2.1 9 of the title compound from Example 23 d) are
suspended in 80 ml of methanol, and 4 ml of triethyl-
amine are added at room te~perature, ~;th stirring.The solution thus obtained is stirred at room tempera-
ture for about 1 hour, a suspension is formed vith
active charcoal, the suspension ;s filtered and the
filtrate is contentrated in vacuo. On adding ~ater~
the colorless product crystallizes. Melting point
147-148C.
f) 2-t3-~ethoxy-~-~2,2,2-trifluoroethoxy)-2-picoly~sulf-
inyl)-1H-thienoC3,$-d3i~idazole
0.42 9 of ~-chloroperben oic aciJ t85% pure) in 10 ml
of ~ethylene chloride is added dropwise to 0.75 9 of
the title compound from Example 23 e) in a t~o-phase
mixture of 80 ~l of ~ethyLene ~hloride and ~0 ml of
aqueous KHzPO4/Ha2HPO4 buffer solution (pH = 7.5)
at O to 5C, ~ith stirring. Af~er about 30 minutes,
the organic phase is separa~ed off, dried and concen-
trated and the residue is ~ade to crystalli~e ~ith
diethyl ether. Melting point 135-137C.
The following inter~ediates of the formulae XXXXVI-
XXXXYIII can be prepared, for example, analogously to
Equation 5:
, . . . .
.:
. .
68461
-- 43 --
R7
C~130
Xxxxv~
Exalple
_Meltir~3 point
24 0cH2cF2cF2H 40- 42 C
0CH2CF2CF3 138 C
26 oCH2CF2CF2~F3 128-130 C
27 ocH2cF2cF2cF2cF2H 0 i l
R7
CH30~,~
HOH2 C
XXXXV1
Exalple
No. R7 PRlting point
.
28 0cH2cF2c F2H 45-47 C
29 0cH2cF2cF3 Oi l
0CH2CF2CF2CF3 68- 70 C
31 OCH2CF2CE'2CF2CF2H Oi l
.
~as reacted directly
- : ::: .: ~ : ,:
~2~84
-- 44 --
CH30
CIH2C
l-IC
XXXXVl~I
i~xanple
ting point
32 O~H2CF2CF2H 133 C decomposition
33 OC~2cF2cF3 155 C
34 OCH2CF2CF21::F~ 161-163 C
OCH2CF2CF2CF2CF2H 132 C
The following compounds of the for~ul3 1 are obt~ined
anaLogously to Examples 5 and 23:
~ \)- T - C ~ R El
R2 i H
Exalple
N~. . T Rl R2 R6 R7 R8 Melting i int(C)
36 S H H OCH3 OCH2CF2CF2H ~ 127-129
37 S H H OCH3 0~2cF2~F3 ~ 142
38 S ~ H OCH3 OcH2cF2~F2cF3 H 133-135
39 S H H ~ ~r}~3 OcH2cF2cF2cF2~F2~ ~ 110
SO H H ~CH3 O~H2~ F2CF2H ~ 133-135
41 SO ~1 H OCH3 0C~2CF2~F3 ~ 137 decomposi~;on
42 SO H H OCH3 Ot ~2CE~2~ F2c~3 H 113-115 ~ :
43 SO H H OCH3 OCH2CF2CF2CF2CF2H H 103 decomposit;on
44 S HPhenyl H ~I ~ 153-157
~henyl ~ OCH3 H 1~2-185
.,.
.: , : . ,, ~ -
. ~ - ..
:. .
- . ,. ~ : .,; :
~;~68~
-- 45 --
Exaple T ~1 R2 R6 R7 R8 (C)
No. _ _ _ _
46 S H Phenyl CH3 OCH3 CH3 192-195
47 S H 4-Methoxy- H H ~ 141-143
phenyl
48 S H " H OC~3 H 170-173
49 S H " CH3 OCH~ CH3 151-154
S H Phenyl H OCH2CF2CF2CF3 H 216
51 S H 4-Methoxy- H OCH2CF2CF2CF3 H 203
phenyl
52 S OCH3 C~2CH3 H H H 106-110
53 S H CON(C2Hs)2 H H ~ 102-104
~Cl
54 SO H Phenyl H H H 137-141
SO H n H OCH3 H 130-135
56 SO H n CH3 OCH3 CH3 160-165
57 SO ~ 4-Methoxy- H ~ H 164^167
phenyl decompos;t;on
58 SO H ~ H OCH3 H 162-165
59 S0 H n CH3 OCH3 CH3 162-165
decompos;tion
SO X Phenyl ~ ocH2cF2cF2cF3 ~ 80
61 SO H 4-Methoxy- H OCH~CF2CF2CF3 H 79
phenyl
R2~ ~ C~
R3
Exalple T Rl ~2 R6 R7 ~8 ~ CC:)
No. _ __ ~__ __ __
62 S -CH2SCH2- H H H lB6-188
63 S C2~H3 CO2CH3 H OCH3 H 156-159
64 SO CO2CH3 CO2CH3 H OCH3 H ~40 decompos;t;on
S0 C02CH3 C02CH3 H H H 146-149
.,.. - . : . . , . :
...: .
, ,.. ,~ ~,. . ,
`~ ; . . ~, : .:
.... .. .
:` : . ~ :- : .. ~
