Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2~3.~
890307
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8-substituted 4-(heterocyclylmethylamino)quinolines, the
use thereof and drugs prepared therefrom
The present invention relates to novel 8-
substituted 4-(heterocyclylmethylamino)quinolines and to
the use thereof for controlling diseases.
In a general form, 2-alky1-4-aralkylamino-
quinolines ~re mentioned as intermediates in US-P
3 075 984; no pharmacological actions of these inter-
mediates were described. 4-Heteroarylmethylamino-
quinolines with fungicidal activity have been describedin US 4 744 823.
The following 4-aminoquinolines may be mentioned
from among those with pharmacological activity and a wide
variety of substitution patterns on the quinoline moiety:
4-Anilino- and 4-benzylamino-3-quinolyl ketones
and -3-quinolinecarboxylates which are unsubstituted in
the 2 position and inhibit gastric acid secretion
(US 4 343 804, US 4 806 549 and US 4 806 550).
4-Amino-2-methyl-3-quinolyl ketones and -3-
quinolylalkanols for the treatment of Al~heimer's disease
(US 4 789 678 and 4 840 970).
The patent application DE 3 908 767.0 which has
not been prior-published describes 2-alky1-4-benzylamino-
8-methoxyquinolines which inhibit K+/H+-ATPase.
We have now found that the compounds of the
formula I according to the invention
R 4~N--CH 2--R 3
R6~RR12 (I),
R5
where
Rl is hydrogen or Cl-C4-alkyl which can be ~ubstituted
by hydroxyl or Cl-C4-alkoxy,
R2 is hydrogen or Cl-C6-alkyl,
R3 is thienyl, which can be substituted by 1 to 3
~fi~l4~
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Cl-C4-alkyl groups and/or 1 to 2 halogen atoms,
furyl which can be substituted by 1 to 3 Cl-C4-alkyl
groups,
pyrrolyl which can have hydrogen, Cl-C6-alkyl,
phenyl-Cl-C3-alkyl or phenyl on the nitrogen and can
be substituted on the carbon atoms by 1 to 3 Cl-C4-
al~yl groups,
it also being possible for the thienyl, furyl or
pyrrolyl to be benzo-fused,
R4 is hydrogen, Cl-C4-alkyl or -CH2-R3 where R3 has the
abovementioned meaning,
Rs is C1-C6-alkyl which ca.n be substituted by hydroxyl
or Cl-C3-alkoxy, or is hydroxyl, Cl-C6-alkoxy,
phenoxy,phenyl-Cl-C3-alkoxy,Cl-C6-alkylthio,phenyl-
thio,phenyl-Cl-C3-alkylthio,amino,Cl-C4-alkylamino,
di-(Cl-C4-alkyl~amino, phenylamino, N-phenyl-N-(Cl-
C4-alkyl)amino, phenyl-Cl-C4-alkylamino, N-phenyl-Cl-
C4-alkyl-N-(Cl-C4-alkyl)amino, Cl-C4-alkanoylamino,
benzoylamino, phenyl-Cl-C3-alkanoylamino, Cl-C6-
alkanoyl, hydroxycarbonyl, Cl-C6-alkoxycarbonyl,
aminocarbonyl, Cl-C6-alkylaminocarbonyl, di-(Cl-C6-
alkyl)aminocarbonyl, trifluoromethyl or halogen, and
R6 is hydrogen, Cl-C4-alkyl, Cl-C4-alkoxy or halogen
and the physiologically tolerated salts thereof have
valuable pharmacological action
Preferred meanings of Rl are hydrogen and C1-C3-
alkyl which can be substituted by hydroxyl or Cl-C3-
alkoxy. If Rl is Cl-C3-alkyl, it is particularly prefer-
ably methyl which can be substituted by hydroxyl or Cl-
C3-alkoxy, in particular methoxy.
Preferred meanings of R2 are hydrogen or Cl-C3-
alkyl.
In a preferred group of compounds according to
the invention, R1 and R2 are each hydrogen.
In another preferred group, R2 is C~-C3-alkyl and
Rl is hydrogen or C1-C3-alkyl which can be substituted by
hydroxyl or Cl-C3-alkoxy. If R2 is C~-C3-alkyl, R1 is
particularly preferably hydrogen or unsubsti~uted
_ 3 _ 890307
O.Z. 0050~40846
Cl-C3-alkyl, in particular methyl.
In a particularly preferred group of compounds
according to the invention, R2 is hydrogen and R1 is Cl-
C3-alkyl which can be substituted by hydroxyl or Cl-C3-
alkoxy.
R3 is preferably thienyl or pyrrolyl which can be
substituted and/or benzo-fused, in particular thienyl
which can be substituted and/or benzo-fused.
The furyl, thienyl or pyrrolyl is preferably
substituted one to three times.
A substituent in R3 is preferably in the position
ortho to the point of attachment to the quinolinamino
methyl group.
If R3 is thienyl which is substituted by 1 to 3
Cl-C4-alkyl groups and~or 1 to 2 halogen atoms, it is
preferably substituted by 1 to 3 C1-C3-alkyl groups, in
particular methyl groups, and/or 1 to 2 halogen atoms.
Halogens are fluorine, chlorine, bromLne and
iodine; chlorine and bromine are preferred.
If R3 is furyl substituted by 1 to 3 Cl-C4-alkyl
groups, it is preferably substituted by 1 to 3 C~-C3-alkyl
groups, in particular methyl groups.
If R3 is substituted pyrrolyl, the following
substituents on the nitrogen are preferred: C1-C4-alkyl,
benzyl or phenyl, in particular C1-C4-alkyl. Preferred
substituents on the carbon atoms of the ring are 1 to 3
methyl groups.
R4 is preferably hydrogen or methyl, in particu-
lar hydrogen.
If R5 is halogen, it can be fluorine, chlorine or
bromine. R5 is preferably C1-C3-alkyl which can be
substituted by hydroxyl or methoxy, or i hydroxyl or Cl-
C3-alkoxy, in particular R5 is C1-C3-alkoxy or Cl-C3-alkyl,
with methoxy and methyl being particularly preferred.
R6 is preferably methyl, methoxy, fluorine,
chlorine or bromine, in particular hydrogen.
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The compounds according to the invention are
prepared by reacting a quinoline of the formula II
~N~R I ( I I ),
R~
where X is a nucleofugic leaving group such as chlorine
or bromine or phenoxy, and Rl, R2, R5 and R6 have the above
meanings, and where, if R1 or R5 is a hydroxyl-substituted
Cl-C4-alkyl or/and R5 is primary or secondary amino, the
hydroxyl and amino can be modified by a suitable conven-
tional protective group, with an amine of the formula
R3-CH2-NH-R4 where R3 and R4 have the above meanings, in a
conventional manner, and eliminating the hydroxyl- or
amino-protective group, where present.
The reaction can be carried out in the presence
of a solvent such as toluene, xylene, phenol, ethanol,
butanol, dimethyl sulfoxide, dimethylethyleneurea,
dimethylpropyleneurea, pyrrolidone or N-methyl-
pyrrolidone, in mixtures of the~e solvents or in the
absence of solvents, in the presence or absence of a
cataly~t such as copper or bronze powder or copper(I)
chloride, at from 50 to 250C, under atmospheric or
superatmospheric pressure. The amines R3CH2NHR4 can be
used in equimolar amounts or in excess.
The reaction of the compounds of the formula II
with the amine~ R3CH2NHR4 is preferably carried out in the
ratio 1:1 to 1:10 in the presence of phenol at from 60 to
160~C.
The preparation of 4-aminoquinolines by the above
process has been described, inter alia, in the following
citations:
G. Jones, Quinolines, Part I, John Wiley & Sons, London,
New York, 1977, pp. 547-550 and literature cited therein;
J. Indian Chem. Soc. 51 (1974) 880-882; J. Med. Chem. 14
(1971) 1060-1066; Chim. Therap. 1 (1966) 339-346;
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Eur. J. Med. Chem. 11 (1976) 561-565.
The compounds of the general formula II can be
obtained in a similar manner to known compounds. For the
preparation of compounds of the formula Il, see, for
example, J. Indian Chem. Soc. 51 (1974), 880-882 and
G. Jones (Ed.) Quinolines, Part I, John Wiley & Sons,
London, 1977: X = Cl: pp. 391-398, X = Br: pp. 404-406,
X = OC6H5: pp. 577-579. 4-Phenoxyquinolines can also be
detected as intermediates in the reaction of 4-chloro-
quinolin~s with amines R3CH2NHR4 in the presence of
phenol.
The amines R3CH2NHR4 are known from the literature
or can be prepared in a similar manner to known compounds
(Houben Weyl, ~ethoden der Organischen Chemie vol. 11/1,
4th edition 1957, G. Thieme-Verlag Stuttgart).
The compounds according to the invention can be
converted into the addition salt with a physiologically
tolerated acid. A compilation of conventional physio-
logically tolerated acids is to be found in Fortschritte
der Arzneimittelforschung 1966, Germany, Switzerland,
BirXhauser Verlag, vol. 10, pp. 224-285 and
J. Pharm. Sci. 66 (1977) 1-5.
The acid addition salts are usually obtained in
a conventional manner by mixing the free base or solu-
tions thereof ~ith the appropriate acid or soIutions
thereof in an organic solvent, for example a lower
alcohol such as methanol, ethanol or propanol, or a lower
ketone such as acetone, methyl ethyl ketone or methyl
isobutyl ketone, or an ether such as diethyl ether,
tetrahydrofuran or dioxane. Mixtures of these solvents
can be used to improve crystallization. It is also
possible to prepare pharmaceutically acceptable aqueous
solutions of acid addition compounds of the amino com-
pounds of the formula I by dissolving the free bases in
an aqueous acid solution.
The compounds according to the invention and the
salts thereof with physiologically tolerated acids have
valuable pharmacological actions. In particular, they
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inhibit gastroitltestinal K~/H -A'rPase and gastric acid
secretiQn~ The compounds according to the invention c~n
~herefore be used for the therapy of all disorders in
which a reduction in gastric acid secretion has a bene-
S ficial effect on healing, e.g. gastric ulcer, duodenalulcer, gastritis, reflux esoph~gitis and
Zollinger-Ellison syndrome (cf. re~iew on inhibitors of
R+/H+-ATPase, G. Sachs et al., Ann. Rev. Pharmacol.
Toxicol. 28 (88) 269-284 and literature cited therein).
The present invention also relates to drugs for
oral, re~tal or intxa~enous administration, which contain
the compounds of the formula I or the acid addition salts
thereof as active substance, in addition to conventional
carriers and dil~ents, and to the use of the noYe
compounds and the physiologically tolerated salts thereof
for the treatment of ~he said diseases.
The drugs of the present invention are prepared
with ~he conventional solid ox liquid carriers or dilu-
ents and the auxiliaries conventionally used in pharma-
ceutical technology, in accordance with the desired modeof administration, with a suitable dosage, in a con-
ventional manner. The preferred presentations are
suitable for oral administration. ~xamples of such
presentations are tablets, which may be (film) coated,
capsules, pill5, powders~ solutions or su~pensions, or
depot fonms. Also suitable, of course, are parenteral
formulations such as solutions for injection. An example
of another formul~tion is the suppository.
Appropriate tablets can be obtained, for example,
b~ mixing the acti~e substance with conventional auxili-
aries/ for example inert diluents such as dextrose,
sucro~, sorbitol, mannitol and polyvinylpyrrolidone,
disintegran~s such as corn starch or alginic acid,
binders such as starch or gelatin, lubricants such as
magnesium stearate or talc and/or agents to achieve a
depot effect such as carboxypolymethylene, carboxymethyl-
ce lulose, cellulose acetate phthalate or polyvinyl
acetateO The tablets can also be composed of several
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la~e~-s.
Appropriate coated tablets can be prepared from
cores which are prepared in a similar mannex to the
tablets and coated with the material conventionally used
for this purpose, e.g. polyvinylpyrrolidone or shallac,
gum arabic, talc, titanium dioxide or sucrose. This
coating can al~o be composed of several layers, and it is
possible to use the auxiliaries mentioned above for the
tablets.
Solutions or suspensions containing the acti~e
substance according to the invention can additionally
contain flavor-improvers such as saccharin, cyclamate or
suc~ose and, for examp1e, flavorings s~ch as vanillin or
orange extract. They can additionally contain suspending
auxiliaries such as sodi~m carbo~ym~thylcellulose or
preservatives such as p-hydro~ybenzoates. Capsules
containing active substances can bP prepared, for ex~
ample, by the active substance being mixed with an inert
carrier, such as lactose or ~orbitol, and encapsulated in
?0 gelatin capsules.
Suitable suppositories can be prepared, for
example, by mi~ing with carriers intended for ~his
purpose, such as neutral fats or polyethylene glycol or
deri~atives thereof.
The single dose for h~mans on oral or rectal
administration is from 10 to 1000 mg and on i.Y. ad-
ministration is from 0.01 to 1.0 mg/kg of body weight.
The action of the compounds according to the
invention has been determined in the following design of
assayo
The mucosa of a freshly removed pig stomach was
nomogenized in 0.25 M sucrose, 20 ~ tris (tris(hydroxy-
methylamino)methane), 1 I~MEGTA ~ethyl~nebis(oxyethylene-
nitrilo~etraacetic acid), pH 7.0, in an ice bath and
centrifuged at 20,000 xg for 20 minO The supern~tant was
centrifuged at 100,000 xg for 60 min. The resulting
microsomal pellet wa~ homogenized with 50 mM tris ~ 2 mM
MgCl2 + 0~1 mM E~TA, pH 7.5, and frozen in portions at
y ~
B90307
O.~. 005~0846
-'0 C. The ~ /H -ATPase activity was assayed in
1 ml mixtures of the follo~ing composition: 50 mM
tris~HC1 buffer, pH 7.5, 2 mM MgCl2, 20 ~g of membrane
protein with or without addition of 5 mM RCl. The ATPase
reaction was started by addition of Na2ATP, final con-
centration 2 mM, reaction time 15 min at 37 C. The
reaction was then 5topped by adding 1 ml of 20 % tri-
chloroacetic acid. The liberated phosphate was deter-
mined by the method of Sanui (Analyt. Biochem. 60
(1974) 489-50~)~
The IC50 for inhibition of K~/H+-ATPase wa~ de~er-
mined by adding ~arious concentrations of the compounds
according to the invention in the above design of assay.
Examples
General method:
A mixture of 1 equivalent of a compound of the
formula II, 1 to 11 equivalents of an amine of the
formula R3CH2NHR4 and 5 to 20 equivalents of phenol w~s
heated at 60 to 140 C under reflux or in an autoclave
for 2 ~o 8 h. The excess amine and the phenol were
removed by distillation under reduced pressure, then
ethyl ace~ate was added ~o the residue, and the mixture
was extracted several times with aqueous tartaric acid
solution. The aqueous phase was made alkaline with con-
~5 centrated NH3 or dilute NaOH and extracted several times
withethyl acet~te, and the orga~ic phase was washed seve-
ral tLmes with dilute NaOH and H20, dried over Na2SO4 and
evaporated in a rotary evaporator. The crude products
were boiled with ether, and th product was filtered off
with suction.The products were further purified by
recrystallization from a suitable solvent (see Table).
The compounds of Examples 1 to 6 were obtained by
this method.
Example~ 1 ~o Ç, compounds of the general formula I, R1 =
CH3, R2 = R4 = R8 = H, R5 = OCH3
v 9~
9 .. 890307
E~mpl~ R Yield Recrystal~- M.p. ( C)
in % lization
of theory f~om
1 2-thieny~ 40 1) ethanol
2) ethyl
ceta~e 233-234
3-thienyl 66 ethanol 201-202
3 3-methyl-2-
thienyl 70 214-215
4 2-furyl 22 ~ 215-216
5-methyl-2-
furyl lS~) ethanol 179-180
6 1-methyl-2-
pyrroiyl 10a)b~ ethanol 219-220
a) Purification by colu~n chromatography on silica gel
with 95/5 CH2Cl2/CH3OH
b~ The reaction was carried out in the presen~e of 3
equi~alents of N-methylmorpholine.
The following compounds of the formula I can be
obtained similarly by reaction of the appropriate 4-
chloro-, 4-b~omo- or 4-phenoxyquinolines with the amines
R3_~HZ-NHR4 -
Example 7
R4 = R~ 5 - OCH3
Ex. Rl RZ R3
7a C2H5 ~ 3-methyl-2-thienyl
7b i-C3H7 H 2-thie~yl
7c n-C4H9 H 2-methyl-3-thienyl
7d CH2OH H 3-methyl-2 thienyl
7e CH2OCH3 H l-methyl-2-pyrrolyl
7f CX2OCH3 H 3-methyl-2-thienyl
7g CHz~CH3 H 2~methyl-3-thienyl
7h CH3 CH3 2~thienyl
-- 10 - 890307
E.';. R ! R2 R3
7 i c~3 CH3 3-thienyl
7j CH3 c~3 3-methyl-2-thienyl
7k CH3 CH3 5 methyl-2-furyl
71 CH3 CH3 2 - furyl-
7m CH3 CH3 1-methyl-2-pyrrolyl
7n CH20CH3 CH3 3-thienyl
~H3 C2H5 2 thienyl
7p CH3 i-C3H7 2-thie~yl
7q CH3 n-C4Hg 3-methyl-2-thienyl
7r CH3 n-C6H13 3-thienyl
7s H CH3 3-methyl-2-thienyl
7t X C2Hs 2-methyl-3-thienyl
7u H i-C3H7 2-fu~yl
7v H n-C~Hg 2-thienyl
7w H n C6H13 3-methyl-2-thienyl
7x H H 3-methyl-2-thienyl
7y ~ H 1-methyl-2-pyrrolyl
Exa~ple 8
R' = CH3 r R2 = H) R5 - CH30, R6 = H
Ex. R3 R~
8a 3- thienyl CH3
8D 2-thienyl 2-thienylmethyl
8c 2-methyl~3-thienyl CH3
8d 3-methyl-2-thienyl 3-methyl-2-thienyl-methyl
8e 1-methyl 2-pyrrolyl 1-methyl-2-pyrrolyl-methyl
8~ l~methyl-2-pyrrolyl 2-thienylmethyl
8g 1-methyl-2-pyrrolyl CH3
8h 3-methyl-2 thienyl CH3
11 - 890307
Ex~ple ~
R~ = CH3, Ri = R~ = H~ R5 = CH30
Ex. ~?. R3
9a EI 4 methyl-2 thienyl
9b H 5-methyl-2-thienyl
9c CH3 5-rnethyl-2-thienyl
9d H 4,5-dimethyl-2-thienyl
9e H 4,5-dichloro-2-thienyl
9f CH3 2-chloro-3-thienyl
9g H 2-chloro-3-thienyl
9h H 3-methyl-2-furyl
9i CH3 3-methyl-2-furyl
9j H 4-methyl-2-furyl
9k El 2~methyl-4-furyl
91 CH3 2-methyl-4-furyl
9m H 2-methyl-3-furyl
9n H 2,5~dimethyl-3-:Euryl
9o CH3 2,5-dimethyl-3-furyl
9p CH3 1-methyl-2-pyrrolyl
9q H l-isopropyl-2-pyrrolyl
9r H l-n~butyl-2-pyrrolyl
9s H l-benzyl-2-pyrrolyl
9t H l-phenyl 2-pyrrolyl
9u H 1-(4-chlorophenyl)-2-pyrrolyl
9v H 1 ( 2-methoxyphenyl ~ -2-
pyrrolyl
9w H 1,3-dimethyl 2-pyrrolyl
9x H 1,2-dirnethyl-3-pyrrolyl
9y H 1-methyl-3-pyrrolyl
9z CH3 1-me~hyl-3-pyrrolyl
9z~ H l-isopropyl-3-pyrrolyl
9zb H 1-phenyl-3 -pyrrolyl
9zc H 1-benzyl-3-pyrrolyl
gzd H 2-benzofuranyl
3ze H 3-benzofuranyl
9zf H 3-methyl-2-ben~ofuranyl
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E.~. R- R3
9æg H 2-benzothienyl
9 zh H 3-benzothienyl
9~i H 3-methyl-2-ben~othienyl
3 z j H 3 - indo lyl
9z)i ~ l-methyl-3-indolyl
9zl CH3 2-benzothienyl
9zm H 2-methyl-3-benzothienyi
9zn H 3-chloro-2-benzothienyl
3~o H 3-bromo-2-benzothiellyl
9zp H 3-iodo-2-benzothienyl
gzq ~ 2-bromo 3-benzothienyl
9~r H 2, 4, 5-trimethyl-3-thieny~
9zs H 3, 4, 5-trimethyl-2-thienyl
9zt H 2, 4, 5-trimethyl-3-furyl
9 ~ H 3, 4, 5 -trimethyl - 2 - f uryl
9zv }~ 1, 2, 5-trimethyl-3-pyrrolyl
9zw H 1, 2, 4-trimethyl-3~pyrrolyl
9zx H 1, 2, 4, 5-tetramethyl-3-
pyrrolyl
9zy ~ 1, 3, 4-t:rimethyl-2-pyrrolyl
9~z H 1, 3 / 5-trime~hyl-2-pyrrolyl
Exa.nple 1 0
~ = ~H3, ~ = ~
2 5 Ex . R2 ~3 R5 R6
lOa H 3-methyl-2-thienyl O~2H5 H
lQb c~3 3-methyl-2-thienyl OC2H5 H
lOc H 3-methyl-2-thienyl O-nC4H9 H
lOd H 2- thienyl O-nC6~13 H
lOe H l-methyl-2-pyrrolyl OCH2C6H5 H
lOf CH3 1-methyl-2-pyrrolyl OCH2C6H5
lOg H 5-methyl-2-furyl OCH2C6~I5
lOh ~H3 ~methyl-2-thienyl Oc:H2c6H5 H
lQi H 3-methyl-2-thienyl OcH2c6~ls H
- 13 - ~90307
0050/a~0846
E ~ . R- ~' R5 R6
10i H 3-thienyl SCH3 H
lOk H 3-methyl-2-thienyl N(CH3) 2 H
101 H 3-methyl-2-thienyl NHCH2C6H5
lOm H 3-methyl 2-thienyl NHCOC6Hs ~I
lOn H 2-thienyl CF3 H
lOo H 3-methyl-2-thienyl Cl ~
lCp CH3 3-methyl-2-thienyl Cl H
lOq H 1-methyl-2-pyrxolyl Br H
lOr H ~-methyl-2-thienyl OCH3 6-OCH3
105 H 3-methyl-2-thienyl OCH3 5-OCH3
lOt H 2-methyl-3-thienyl OCH3 5-OC~3
lOu H 3-methyl-2-thienyl OCH3 6-Cl
lOv H 3-methyl-2-thienyl OCH3 5-CH3
lOw ~ 3-methyl-2-thienyl OCH3 6-~h3
lOx H 3-methyl-2-thienyl OCH3 7-C~3
lOy H 2-methyl-3-thienyl OCH3 5-CH3
10~ H 2-methyl-3-thienyl oc~3 6-CH3
Example 11
Rl = CH3/ R2 _ R4 = ~6 = H, ~5 = OCH3
Ex, ~3
lla 3-ethyl-2-thienyl
llb 3-isopropyl-2-thienyl
llc 3 cyclopropyl-2-thienyl
lld 5-ethyl-2 thienyl
lle 5-isopropyl-2-thienyl
llf 5-tert. butyl 2-thienyl
llg 3,5-di~lethyl-2-thienyl
llh 3,4-dimethyl-2-thienyl
lli 3,4,5-trimethyl 2-thienyl
llj 2~methyl~3-thienyl
llk 4~methyl-3-thienyl
111 5-methyl-3-thienyl
llm 2,4-dLm~thyl-3-thienyl
lln 2,5 d~nethyl-3-thienyl
E`;. R3
llo 4,5~dimethyl-3 thienyl
llp 2,4,5-trimethyl-3-thienyl
Example 12
Rl = CH3, R2 - R4 = R = H, R5 = OCH3
Ex. R3
12a 3-chloro-2-thienyl
12b 4-chloro-2-thienyl
12c 5-chloro-2-thienyl
12d 3,4-dichloro-2-~hienyl
12e 3,4,5-trichloro-2-thienyl
12f 5-chloro-3-methyl-thienyl
12g 2-chloro-3-thienyl
12h 4-chloro-3-thienyl
12i 5-chloro-3-thienyl
12j 2,5-dichloro-3-thienyl
12k 4,5~dichloro-3-thienyl
121 4-chloro-2,5-dimethyl-2-thienyl
12m 2 chloro-5-methyl-2-thienyl
12n 3-bromo-2-thienyl
120 4~bromo-2-thienyl
12p 5-bromo-2-thienyl
12q 3,4-dibromo-2-thienyl
12r 3,5-dibromo-2-thienyl
12s 4,5-dibromo-2-thienyl
12t 3 bromo-5-methyl-2-thienyl
12u 4-bromo-3-methyl-2-thienyl
12v 5-bromo-3-methyl-2-thienyl
12w 2-bromo-3-thienyl
12x 4-bromo-3-thienyl
12y 5-bromo-3-thienyl
12z 2,4-dibromo-3-thienyl
12za 2,5-dibromo-3-thienyl
12zb 4,5-dibromo-3-thierlyl
12zd 2,4,5 tribromo-3-thienyl
- 15 -
.Y, ~,~
l~e 5-bromo-~-methyl-3-thienyl
12~f 2-bromo-5-methyl-3-thienyl
12~g 4-bromo-2-methyl-3 thienyl
12zh 2-bromo-4-methyl-3-thienyl
12~i 3-iodo-2~hienyl
12zj 4-iodo-2-thienyl
12zk 5-iodo-2-thienyl
12zl 3-iodo-5-methyl-2~thienyl
12zm 5-iodo-3 methyl-2-thienyl
12~n 2-iodo-3-thienyl
l~o 5-iodo-3-thienyl
12~p ~-iodo-4-methyl-3-thienyl
12z~ 4-iodo-2-methyl-3-thienyl
12zr 5-iodo-2-methyl-3-thienyl
12~s 2,5~dimethyl-4-iodo-3-thienyl
Example 13
Rl = CH3, R2 - R~ - R6 = H
Ex, R3 R5
13a 3-methyl-2-thienyl NHCOcH3
13b 3 methyl-2-thienyl o-iC3~7
13c 3-methyl-2-thienyl o-nC3~7
13d 3 methyl-2-thienyl NHCH3
13e 3-methyl 2-thienyl COCH3
13f 3-methyl-~-thienyl COOH
13g 3-methyl-2-thienyl COOC2H5
13h 3-methyl-2-thienyl CONH2
13i 3-methyl-2-thienyl CON(cH3)z
13j 3-methyl-2-thienyl CH2OH
13k 2 methyl-3-thlenyl CH2OH
131 1-methyl-2-pyrrolyl CH2OH
13m 3-methyl-2~thienyl CH(OH~ C~3
13n 2-methyl-3-thienyl CH(OH) C~3
13O 2-thienyl CH3
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O.Z~ 00.50~4~5
E~. R3 ~5
13p 3 -thienyl C~13
13q 3-methyl-2-thienyl CH3
13r 2-methyl-3 thienyl CH3
13s 1-methyl-2-pyrrolyl CH3
13t 1-isopropyl-2-pyrrolyl CH3
13u 1, 2,5-tri.~ethyl-3-
pyrrolyl CH3
13v 3-methyl-2-thienyl C2Hs
13w 2~methyl-3thienyl C2H5
13x 3-methyl-2-thienyl nC3~7
13y 3-methyl 2-thienyl iC3~1
13z 3 rnethy~-2-thienyl CH2OCH3
13~a 3 methyl-2-thienyl CH2OC2~5
13~b 3~methyl-2~thienyl CH2OiC3~7
