Note: Descriptions are shown in the official language in which they were submitted.
s~
4-13682/CGC 960/~
N-SUBSTITUTED-2-PYRIDYLINDOLES
United States Patent 3,468,394 disclosed the l-unsubstituted
3-methyl-2-(3- or 4~pyridyl)-indoles as diuretic agents. 2-(2-
Pyridyl)-indole-3-(acetic, propionic) acids are reported e.g. 9 in
Pharm. Bu11.4, 16 (1956) and Chemical Abstracts 64, 19540d (1966)
respectively. Various optionally substituted 2-(3-pyridyl)-indole-3-
acetic acids have been described as chemical intermediates in Bull.
Soc. Chim. France 1966, 771-2 and Bull. Soc. Chim. France 1969,
4154~9. The preparation of l~cyanoethyl~2-(2~pyridyl)-indole is
reported in Pharmazie 23 (10),557~60 (1968).
Surprising]y it was found, that N~(or l)-substitutecl~2~pyridyl~
indoles of formula I represent a novel class of outstanding potent
and highly specific thromboxane synthetase inhibitors.
The foregoing attributes render the N-substituted-2-pyridyl indoles
of this invention particularly useful when administered, alone or
in combination, to mammals, e.g. Eor the treatment or prevention
of diseases responsive to the inhibition of thromboxane synthetase,
comprising cardiovascular disorders such as thrombosis, athero -
sclerosis,coronary spasm, arrhythmias, cerebral ischaemic attacks,
migraine and other vascular headaches, myocardial infarction,
angina pectoris, hypertension; respiratory disorders, such as asthma
and apnea; and inElammatory disorders. Inhibition of thromboxane
synthetase also llas been noted to decrease metastasis in certain
classes of tumors, and the compounds of this invention may be useful
for the treatment of certain carcinomas.
~37;~
-- 2 --
This inverltion concerns therefore l-substituted 2-pyridyl indoles
of ~ormula I
R2
/ ~ \A (I)
CH -A-B
wherein Rl represents hydrogen or lower alkyl; ~r represents pyridyl
unsubstituted or substituted by lower alkyl, carboxy, lower alkoxy
carbonyl or carbamoyl; R2 and R3 independently represent hydrogen,
lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy,
carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carboxy,
lower alkoxycarbonyl, or lower alkyl-(thio, sulEinyl or sul~onyl),
or R2 und R3 together on adjacent carbon atoms represent lower
alkylenedioxy; A represents alkylene of 1 to 12 carbon atoms,
alkenylene o~ 2 to 12 carbon atoms, alkynylene of 2 to 12 carbon
atoms, lower alkylenephenylene lower alkylene, lower alkylene-
phenylene, phenylene lower alkylene, phenylene, a direct bond,
lower alkylene-(thio or oxy)-lower alkylene, (thio- or oxy)-phenylene,
lower alkylene-(thio- or oxy)-phenylene, phenylene-(thio or oxy)-
lower alkylene or phenylene lower alkenylene; B represents carboxy,
lower alkoxycarbonyl, carbamoyl, mono- or di-lower.alkylcarbamoyl,
hydroxymethyl, hydroxycarbamoyl, 5-tetrazolyl or formyl; the N-oxides
thereoE; and salts, especially pharmaceut~cal.ly acceptable salts
thereof, process Eor their manuEacture, pharmaceutical preparations
containing these compounds ancl thei.r therapeutic application.
PreEerred embodiments oE this invention relate to compounds of
:~ormula I wherein Rl represents hydrogen or lower alkyl; Ar re-
presents 2-, 3- or 4-pyridyl optionally substituted by lower alkyl;
R2 is hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy,
72'~
lower alkoxy, lower alkylthio, carboxy lower alkyl or lower alkoxy~
carbonyl lower alkyl; R3 is hydrogen; or R2 and R3 together on ad-
jacent carbon atoms represent lower alkylenedioxy; A represents
alkylene of 1 to 12 carbon atoms, phenylene, lower(alkylenephenylene,
alkylene-thio-phenylene or alkylene-oxy-phenylene) oE 7 to 10 carbon
atoms, or a direct bond; B represents carboxy, lower alkoxycarbonyl,
carbamoyl, hydroxycarbamoyl, 5-tetrazolyl or hydroxymethyl; the N-
oxides thereof; and salts, especially pharmaceutically acceptable
salts thereof.
Further preferred are said compounds of formula I wherein R2 is
attached at the 5-position of the indole nucleus.
Particularly preferred are said compounds of formula I wherein B
represents carboxy, lower alkoxycarbonyl, carbamoyl, 5-tetrazolyl
or hydroxycarbamoyl.
Greatly preferred are the compounds oE formula I wherein A repre-
sents alkylene of 3 to 10 carbon atoms, phenylene, lower alkylene-
thio-phenylene or lower alkylene-oxy-phenylene of 7 to 10 carbon
atoms each.
Very useful are the compounds of Eormula I wherein A represents
alkylene of 1 to 12 carbon atoms or phenylene.
Particularly usef~ll are compounds of formula IL
~ \.,_,./ 1
~n/ \N/ \P
Cl mil2m
COR~
7~
wherein R'L represents hydrogen or lower alkyl; R2 and R3 represent
independently hydrogen, lower alkyl, halogen, trifluoromethyl,
hydroxy, lower alkylthio or lower alkoxy; or R2 and R3 together on
adjacent carbon atoms represent methylenedioxy; Pyr represents 2-,
3- or 4-pyridyl; m represents an integer from 1 to 13; R4 repre-
sents hydroxy, lower alkoxy or amino; and salts, especially pharma-
ceutically acceptable salts thereof.
Preferred are the compounds of formula II wherein R3 represents
hydrogen.
Particularly useful are also compounds of formula III
~- _ /CH3
R6C-C H2 ~ / ~ \p (III)
C H
In 2n
COR5
wherein n represents an interger from 3 to 10; p represents an
integer Erom O to 4; Pyr represents 2-, 3- or 4-pyridyL; R5 and
R6 independently represent hydroxy or lower alkoxy;and, salts,
especiaLly pharmaceutically acceptable salts thereof.
Preferred are compounds of Eormula [:[I wherein Q iS 4 to 8, p is,
1 to 4; Pyr is 3- or 4-pyriclyl; R5 and R6 represent hydroxy.
~lso valuable are compounds of formula IV
- s
5 -
/ 3
Il i1
O
CqH2q (IV)
!x
~ \O
! I!
~OR,
wherein R2 and R3 independently represent hydrogen, lower alkyl,
halogen, lower alkoxy, lower alkylthio or hydroxy; or R2 and R3
together on adjacent carbon atoms represent methylenedioxy; X re-
presents oxygen, sulfur or a direct bond; q represents an integer`
from 1 to 4; R7 represents hydroxy or lower alkoxy; Pyr represents
2-, 3- or 4-pyridyl, and salts, especially pharmaceutically
accepteable salts thereof.
Preerred are the compounds of formula IV wherein X is a direct bond.
~lso preEerred are the compolmds of Eormula IV wherein q is an
integer Erom 2 to 4 and X is oxygen or sulEur.
The general deEinitions used herein have the Eollowing meanings with-
in the scope of the present invention.
~n alkylene representing Cl-C12 alkylene, may have a straight chain
or branched chain, ancl is preEerably propylene, butylene, pen~ylene,
hexylene, or heptylene, said radicals being unsubstituted or sub-
stituted by one or more lower alkyl groups, with the proviso that
the total number of carbon atoms equals no more than 12.
-- 6 --
The term alkenylene representing C2-C12 alkenylene groups, may have
a straight or branched chain, and is preferably propenylene, 1- or
2-butenylene, 1- or 2-pentenylene, 1-, 2- or 3-hexenylene, 1-, 2-,
3- or 4-heptenylene, said groups being unsubstituted or substituted
by one or more lower alkyl groups, with the proviso that the total
number of carbon atoms equals no more than 12.
The term alkynylene representing C2-C12 alkynylene, may have a straightor branched chain, and is pre~erably propynylene, 1- or 2-butynylene,
1- or 2-pentynylene, 1-, 2~ or 3-hexynylene, 1-, 2-, 3- or 4-hepty-
nylene, said radicals being unsubstituted or sub~tituted by one or
more lower alkyl groups with the proviso that the total number oE
carbon atoms equals no more than 12.
The term phenylene represents 1,2-, 1,3- and preferably 1,4-phenylene.
The term pyridyl represents 2-, 3 and 4-pyridyl, preEerably 3-
pyridyl.
The term "lower" when re~erred to above and herelnaEter in connection
with organic groups, radicals or compounds respectively defines
such as with up to and including 7, pre~erably up to and including
4 and advantageously one, two or three carbon atoms.
lower alkylenephenylene group, a phenylene lower alkylene group,
a lower alkylenephenylene lower alkylene group, a lower alkylene-
(thio or oxy)-phenylene group, a phenylene-(thio or oxy)-lower
alkylene group, or a phenylene lower alkenylene group preEerab:ly
contains 1 to ~ carbon atoms and advantageously one or two carbon
atoms in each alkylene or alkenylene portion. The lower alkylene
and alkenylene portions may be straight chain or branched.
lower alkylene-(thio or oxy)-lower alkylene group is straight
chain or branched and may contain a total oE 2 to 12 carbon atoms,
2'~
preferably 2 to 8 carbon atoms.
A lower alkyl group preferably contains 1-4 carbon atoms and repre-
sents for example ethyl, propyl, butyl or advantageously methyl.
A lower alkylenedioxy group represents preferably ethylenedioxy
and methylene-dioxy.
A lower alkoxy group preferably contains 1-4 carbon atoms and re-
presents for example, ethoxy, propoxy or advantageously methoxy.
A lower alkyl-~thio~ sulfinyl or sulfonyl) group represents ad-
vantageously methylthio, methylsulfinyl or methylsulfonyl respectively.
A lower alkoxycarbonyl group preferably contains 1-~l carbon atoms in
the alkoxy portion and represents for example: methoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonyl.
A mono(lower alkyl)-carbamoyl group preferably contains 1-4 carbon
atoms in the alkyl portion and is for example N methylcarbamoyl,
N-propylcarbamoyl, or advantageously N-ethylcarbamoyl. A di(lower
alkyl)-carbamoyl group preferably contains 1-~l carbon atoms in each
lower alkyl portion and represents for example N,N-dimethylcarbamoyl,
N-methyl-N-ethylcarbamoyl and adv~ntageously N,N-diethylcarbamoyl.
Halogen is preferably fluorine and chlorine, but may also represent
bromine or iodine.
Salts are preEe-rably pharmaceutically acceptable salts, e.g. metal
or ammonium salts of said compo~mcls oE formula :t having a free
carboxy group, more particularly alkali or alkaline earth metal
salts, e.~., the sodium, potassLum, magnesium or calcium salt; or
advantageously easily crystallizing ammonium salts derived from
ammonia or organic amines, such as mollo-, di- or tri-lower (alkyl,
cycloallcyl or hydroxyalkyl)-amines, lower alkylenediamines or
-- 8 --
(hydroxy-lower-alkyl or aryl-lower alkyl)-alkylammonium bases, e.g.,
methylamine, diethylamine, triethylamine, dicyclohexylamine, tri-
ethanolamine, ethylenediamine, tris-(hydroxymethyl)-aminomethalle or
benzyl-trimethyla~nonium hydroxide. Said compounds of formula I
form acid addition salts, which are preferably such of pharmaceuti-
cally acceptable inorganic or organic acids, such as of strong mineral
acids, for example hydrohalic, e.g. hydrochloric or hydrobromic
acid; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or
aromatic carboxylic or sulfonic acids, e.g. formic,acetic, propionic,
succinic, glycolic, lactic, malic, tartaric, gluconic, citric,
maleic, fumaric, pyruvic, phenylacetic, benzoic, 4-aminobenzoic,
anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic,
nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic,
benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic
or cyclohexylsulfamic acid, or ascorbic acid.
The compounds of this invention exhibit valuable pharmacological
properties, e.g. cardiovascular eEfects, by selectively decreasing
thromboxane levels through selective inhibition oE thromboxane
synthetase in mammals. The compounds are thus useEul Eor treating
diseases responsive to thromboxane synthetase inhibition in mammals,
primarily cardiovasular disorders such as thrombosis, atherosclerosis,
coronary spasm, cerebral ischaemic attacks, migraine and other vas-
cular headaches, myocardial inEarction, angina pectoris, and
hypertension.
These efEects are demonstrable in in vitro tests or in vivo
animal tests using aclvantageously mammals, e.g. guinea pigs,
mice, rats, cats, dogs, or monkeys. Said compounds can be administered
to them enterally or parenterally, advantageously orally, or sub-
cutaneously, intravenously or intraperitoneally, for example, within
gelatin capsules, or in the form of starchy suspensions or aqueous
7~
_ 9 _
solutions respectively. The applied dosage may range between about
0.01 to 100 mg/kg/day, preferably between about 0.05 and 50 mg/kg/
day, advantageously between about 0.1 and 25 mg/kg/day.
The in vitro inhibition of the thromboxane synthetase enzyme can
be demonstrated, analogous to the method of Sun, Biochem. Biophys.
Res. Comm. 7_, 1432 (1977); the testing procedure is as follows:
C-Arachidonic acid is incubated with an enzyme mixture preparation
consisting of solubilized and partially purified prostaglandin
cyclo-oxygenase from sheep seminal vesicles and a crude microsomal
preparation of thromboxane synthetase from lysed human platelets.
The test compound (dissolved in buffer, or if necessary, in a small
amount of ethanol) is added to the incubation medium. ~t the end
of the incubation period (30 minutes), Prostaglandin E2 (PGE2) is
reduced to a mixture of Prostaglandin F2~ and F2~ (PGF2 ~+~) by
addition of sodium borohydride. The radioactive products and excess
substrate are extracted into ethyl acetate; the extract is evaporated
to dryness; the residue is dissolved in acetone, spotted on thin-
layer plates and chromatographed in the solvent system toluene:
acetone: glaeial acetic acid (100 volumes: 100 volumes: 3 volumes).
The radioactive zones are located; those corresponding to Thromboxane
B2 (TxB2) and PGF2 ~ are transferred to liquid scintillatlon vials
and counted. The ratio of eounts for TxB2/PGF2 ~ is calculated for
each concentration of test compound and IC50 values are determined
graphieally as the eoneentration of test compouncl at which the ratio
of TxB2/PGF2 ~ is reduecl to 50% oE the control value.
The in-vitro effect on prostaglanclin eyclooxygenase is measured by
a modification of the method of Takeguchi et al. described in Bio-
chemistry 10, 2372 (1971); the testing procedure is as follows:
Lyophilized sheep seminal vesicle microsomes are utilized as the
prostaglandin-synthesizing enzyme preparation. The conversion of
- 10 -
C-arachidonic acid to PGE2 is measured. Test compounds (dissolvecl
in buffer, or if necessary, in a small amount of ethanol) are addecl
to the incubation mixture. The prostaglandins are extracted and
separated by thin-layer chromatography; the plates are scanned, the
radioactive zones corresponding to PGR2 are transferred to liquid
scintillation vials and counted for radioactivity. IC50 values for
inhibition are determined graphically as the concentration of test
compound causing a 50% reduction in the amount of PGE2 synthesized.
The in-vitro effect on prostacyclin (PGI2) synthetase is measured
analogous to the method of Sun et al., Prostaglandins 14~ 1055 (1977).
The testing procedure is as follows:
14C-Arachidonic acid is incubated with an enzyme mixture consisting
of solubilized and partially purified prostaglandin cyclo-oxygenase
from sheep seminal vesicles and crude PGI2 synthetase in the form
of a microsomal fraction of bovine aorta.
Test compound (dissolved in buffer, or if necessary, in a small amotmt
of ethanol) is placed in the incubation medi~lm. The reaction mixture
is incubated in 100 mM Tris HCl (pil 7.5) for 30 minutes at 37C,
acidified to p~l 3 and extracted into ethyl acetate. The extract is
evaporated to dryness; the residue is dissolvecl in acetone, spotted
on thin-layer plates and chromatographed in a solvent system des-
cribed by Sun et ~11. The radioactive zones are located with a scanner;
those corresponding to 6-keto-PGFl~(a stable end product of prostn-
cyclin biotransformation) and PGE2 are transferred to liquicl scin-
tilLation vials and co~mted. The ratio of counts for 6-keto-PGFl~/
PGE2 is calculated for each concentration of test compounds used.
IC50 values for inhibition are determined graphically as the concen-
tration of test compound at which the ratio of 6-keto-PGFl~/PGE2 is
reduced to 50% of the control value.
~7;~
-- 11 --
The inhibition of the synthesis and the reduction of plasma levels
oE thromboxane is determined in vivo on administration to rats in
the following manner (as adapted from the procedures described by
Tai et al. in ~nal. Biochem. 87:3~3, 1978 and by Salmon in Prosta-
glandins 15:383, 1978):
Rats are dosed wiLh vehicle or test drug and injected intravenously
with ionophore A23187 (0.5 mg/kg) two hours later. Blood is collected
for analysis 2 minutes after the ionophore injection. ~ single
aliquot of each plasma sample is assayed for thromboxane B2 and
another aliquot for 6-keto-PGFl~, the stable metabolites of throm-
boxane A2 and prostacyclin (PGI2) respectively, by radioimmunoassay.
Compounds of the formula I are very potent and selective, thromboxane
synthetase inhibitors. At and above the effective dose levels for
thromboxane synthetase inhi~ition neither the beneficial prostacyclin
synthetase enzyme system nor the prostaglandin cyclooxygenase enzyme
system is signiEicantly inhibited. Surprisingly, the prostacyclin
levels are significantly increased.
Illustrative of the invention, the IC50 Eor 1~(7-carboxyheptyl)-3-
methyl-2-(3-pyridyl)-indole is 1.2X10-8M for thromboxane synthetase
inhibition whereas the IC50 for both inhibition of prostacyclin
synthetase and cyclooxygenflse is several orders oE magnitude higher,
i.e. about lX10 4M.
Furthermore tl~e IC50 Eor thromboxane synthetase inhibition is e.g.
2 X 10 ~IEor l-(S-carboxypentyl)-5-(2-carboxyethyl)-3-methy:L-2-(3-
pyridyl)-indoLe, 5 X 10 8M Eor l-(~l-carboxyben~yl)-3-methyl-2-(3-
pyridyl)-indole, 1 X 10 9M Eor l-(S-carboxypentyl)-5-chloro~3-methyl-
2-(3-pyridyl)-indole, 1 X 10 8M Eor 1--(5-carbamoylpentyl)-5-chloro-
3-methyl-2-(3-pyridyl)-indole, 2.6 x 10- M for 1-[2-(~-carboxy-
phenoxy)-ethyl~-3-methyl-2-(3-pyridyl)-indole and 5.8 x 10-8M for
- 12 -
1-[2-(4-carboxyphenylthio)-ethyl]-3-methyl-2-(3-pyridyl)-indole
hydrochloride.
1-(7-Carboxyhepty1-3-methyl-2-(3-pyridyl)-indole and l-(S-carboxy-
pentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole, as representative
compounds of the invention, decrease the plasma concentration of
thromboxane B2 by over 50% in the rat at an oral dose as low as
0.10 mg/kg; a surprising increase in the plasma level of prostacyclin
is observed at this or a higher dose thereoE.
The aforementioned advantageous properties render the compounds o~
this invention oE great value as specific therapeutic agents
for mammals including man.
The inhibition of variously induced platelet aggregation and
thrombocytopenia by compounds oE this invention, e.g. 1-(7-car-
boxyheptyl)-3-methyl-2-(3-pyridyl)-indole,is indicative of the
utility in thromboembolism. Experimentally, prolongation of bleeding
time in the rat is indicative of a beneficial antithromboeic effect,
e.g. 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole, when
administered orally to rats at a dose oE about 30 mg/kg.
Indicative of the beneficial effect in respiratory disorders is the
fact, that the compounds of this invention afford protection against
sudden death due to arachidonic acid induced pulmonary obstr~lction.
l'hus, for example, 1-(7-carboxyhcptyl)-3-methyl-2-(3-pyridyl)- indole
protects against suclden death when administered orally to mice at a
dose of 100 mg/kg.
In addition to the pharmaceutically acceptable salts cited above,
any prodrug derivatives thereof, e.g., pharmaceutically acceptable
esters and amides of the carboxylic acids of this invention that may
be convertible by solvolysis or under physiological conditions to the
~7~3
- 13 -
said carboxylic acids, represent a further object of this invention.
Said esters are preEerably e.g., the lower alkyl esters unsubsti-
tuted or suitably substituted such as the pivaloyloxymethyl, 2-di-
~ethylaminoethyl, bornyloxycarbonylmethyl, ~-carboxyethyl or suitably
esterified ~-carboxyethyl esters which are prepared by methods well
known to the art.
Said amides are preferably e.g. simple primary and secondary amides
and amides derived from the amino acids or derivatives thereof,
such as the amides derived from alanine or phenylalanine.
The compounds of this invention are prepared according to conventional
methods, advantageously by
1) condensing a compound of the formula V
~ \._.i 1
(v)
~ 0/ ~ \Ar
wherein X is hydrogen, alkaline metal or tri-lower alkyl silyl, Rl,
R2, R3 and Ar have meaning as deEined above, with a reactive
functional derivative oE a compound oE the Eormula VI
~IOC~12-A-B (VI)
wherein A und B have meaning as deEinecl above, or
2) rin~ closing a compouncl oE ormula V[I
~,
- 14 -
R
CH2-Rl
~ I!-N - N = C - Ar (VII)
3 CH2-A-B
' 1' 2' 3' have -~n;np as defined above, or
3) cyclizing a compound of the formula VIII
~ \./ 2 l O
R3 ~ N -C - Ar (VIII)
2 A B
wherein Ar, Rl, R2, R3, A and B have r-~n;ng as defined above;
4) in a compound of the formula Ia
R2
~ \ / 1
~./ ~ \~ (Ia)
R3
CH2-A-C
wherein A, Ar, Rl, R2 and R3 have meaning as deEined above and C
is a gro~lp di:EEering Erom ~ and convert:ible into B, converting said
group C into B, optionally by extencling the chain A within its de-
Einition, or
S) decarboxylating a compound oE the formula IX
7~
- 15 ~
R
~ \._./
~ (IX)
R ~ Ar
CH -A-B
in which A, B, Ar~ R2 and R3 have the meaning as defined above, and,
if desired or necessary, temporarily protecting in each of these
processes on interfering reactive group> and, if desired, converting
any resulting compound of formula I into another compound of the
invention, and/or, if desired, converting a resulting free compound
into a salt or a resulting salt into the free compound or into an-
other salt, and, if required, resolving a mixture of isomers or
racemates obtained into the single isomers or racemates, and, if
required, resolving a racemate obtained into the optical antipodes.
The condensation according to process 1) is preferably carried out
under basic conditions, e.g. with a basic alkali metal salt or a
quaternary ammonium salt such as tetrabutyl ammonium hydroxide.
For example more specifically compounds oE Eormula V, wherein X is
hydrogen, are converted preferably in situ, to reactive organo~
metallic intermediates with a reactive metallizing agent, pre-
ferably about one molar equivalent of e.g. a strong alkali metal
base, such as lithium diisopropylamide, sodium hydride, potassium
t-butoxide,in an inert solvent such as dimethylformamide or tetra-
hydrofuran,at a temperature range between -50 to +75,preferably
between -25 and +50. Condensation oE the resulting reactive organo-
metallic compound of formula V with a reactive functional derivative
of a compound of formula VI proceeds at a temperature range from
about -25 to +50C,preferably at a temperature range of 0 to 30C.
In the case where B represents carboxy, carbamoyl, hydroxycarbamoyl,
,;~,. .~
- 16 -
or mono lower alkylcarbamoyl, additional, e.g. one molar equivalent,
of metallizing agent is required.
For example starting materials of formula V wherein X is hydrogen
are either known to the art (e.g. U.S. Patent 3,468,894; J. Chem.
Soc. 1955, 2865; Bull. Soc. Chim. France 1969, 4154) or are prepared
analogously from the corresponding optionally substituted phenyl-
hydrazines and ketones of the formula ArCOCH2Rl in the presence of a
condensing agent, e.g. ethanolic hydrogen chloride or polyphosphoric
acid by the well-known Fischer indole synthesis.
The starting materials of formula VI or formula VIa hereinafter
are known or if new, are prepared according to conventional methods,
e.g. the methods illustrated in US patent 4,256,757, British patent
application 2,016,~52A or as described in the examples herein.
More specifically, the compounds of formula I are advantageously pre-
pared according to process 1) as follows:
Condensing preEerably under basic conditions a compound oE the
~ormula V
R2
.\ /R]
~ / ~ \~r (V)
wherein X is hydrogen, Rl represents hydrogen or lower alkyl;
~r represents pyridyl or pyridyl substituted by lower alkyl9
carboxy, lower alkoxycarbonyl or carbamoyl; R2 and R3 represent
hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower
alkoxy, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl,
carboxy or lower alkoxycarbonyl;
- 17 -
with a reactive f~mctional derivative of a compound of the formula
VIa
2 (VIa)
wherein ~ represents alky]ene of 1 to 12 carbon atoms, alkenylene
of 2 to 12 carbon atoms, alkynylene of 2 to 12 carbon atoms, lower
alkylenephenylene lower alkylene, lower alkylenephenylene, phenylene
lower alkylene, phenylene or a direct bond; and B' represents carboxy,
lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylcarbamoyl,
hydroxymethyl, etheri~ied hydroxymethyl, halomethyl, trialkoxymethyl
or cyano; and in a resulting compound of formula Ib
~ \o,_,/ 1
~ ! (Ib)
~ / ~ \A
CH -~-BI
wherein B' differs from B, converting said group B' into B,
optionally by extending the chain ~ within its definition, and,
iE desired, converting any resulting compound of Eormula I into
another compound of this invention.
The conversion of an initial product in which B' diEfers from B and
the conversion of the resulting product into another compound of this
invention are performed by chemical methodology known to the art.
The ring-closure of the starting material of formuLa VII according
to process 2) is carried out by the well-known Fischer indole
synthesis [as described in "Heterocyclic Compounds, Indoles Part I"
edited by W.J. Iloulihan pp. 232-317] thermally or preferably in the
presence oE an acid condensing agent, advantageously a hydrogen
halide, e.g. ethanolic hydrogen chloride, or polyphosphoric acid,
~7~
- 18 -
optionally in an inert solvent preferably at a temperature of about
50-100C.
The hydrazone starting materials of formula VII are either isolated
or are preferably prepared in situ by the condensation of a ketone
of the formula ArCOCH2Rl, wherein Ar and Rl have the meaning
given above, with a substituted hydrazine of the formula X
R2~
11
;~ (X)
CH ~A-B
wherein the symbols A, B, R2 and R3 have mean;ng given above,
advantageously in the presence of an acid catalyst.
The starting hydrazines of formula X are ln turn preferably pre-
pared by e.g. nitrosation of the correspondingly substituted ani-
lines of formula XI
R2~
11
R3 ~lctl2-~-B (~I)
wherein the symbols A, B, R2 and R3 have meaning as previously
defined, and subse~uent reduction oE the N-nitroso derivatives,
e.g. Witil zinc in acetic acid or by other methods well-known to
the art.
If said intermediates contain interfering reactive groups, e.g.
hydroxy or amino groups, such may advantageously be temporarily
protected at any stage with easily removable blocking groups, e.g.
- 19 -
in the form of esters or amicles respectively, by methods well known
to the art.
The cyclization according to process 3) is carried out under con-
ditions of the Madelung indole synthesis as described in "Hetero-
cyclic Compounds, Indoles Part I", edited by W.J. Houlihan, pp. 3~35
396. The intramolecular cyclization is preferably carried out in the
presence of a strong base, e.g. sodium ethoxide, sodium amide or
potassium t-butoxide,advantageously at elevated temperature e.g.
ca. 300 heat or in an inert high boiling solvent such as tetrahydro-
naphthalene.
The starting materials of formula VIII are prepared by acylation
of the substituted anilines of formula XI above with a compound
of the formula ~rCOOH or a reactive functional derivative thereo.
The decarboxylation according to process 5) is carried out in a
conventional manner, e.g. with heat in an inert hig'h boiling
solvent or in the presence of a strong acid, e.g. a mineral acid
such as hydrochlorid acid.
The starting 3-carboxy-substituted indoles are prepared accor~ing
to conventional methods. For example, compounds of formula IX,
wherein the substituent at the 3-position is carboxy and
wherein one oE R2 and R3 represents 5-hydroxy, may be prepared
accorcling to the Nenitæescu synthesis as deseribed in "Hetero-
cyclic Compo~mds",Indoles Part I, page ~139 e.g. by condensing
p-benzoquinone with a Lower alkyl ~-pyridyl-~-(C~12-~-~B-substituted
amino)-aerylate, such as lower alkyl ~-(3-pyridyl-~-(5-ethoxycarbonyl-
pentylamino)-aerylate, and hydrolyæing the resulting lower alkyl
ester of the eorresponcling substituted 5-hydroxy-2-(3-pyridyl)-
indole-3-carboxylic acid (a compound oE formula I wherein Rl is
lower alkoxycarbonyl).
7~
- 20 -
The conversion of a compound of Eormula Ia accorcling to a process l~)
wherein C differs Erom B into a compownd of formula I, and the
o?tional conversion of resulting product of formula I into another
compound of this invention are performed by chemical methodology
known to the art, and/or e.g. as described herein.
Convertible group C preferably represents trialkoxymethyl, esterified
hydroxymethyl, etherified hydroxymethyl, halomethyl, cyano, 2-
oxa~olinyl, dihydro-Z-oxazolinyl, lower alkanoyloxymethyl, acetyl,
methyl, carboxycarbonyl, trihaloacetyl, di(lower)alkoxymethyl,
alkylenedioxymethyl, vinyl, alkynyl, esterified carboxy, amidated
carboxy.
The starting materials of formula Ia are prepared according to
processes 1 to 3 and/or as described herein, using conventional
chemical methodology well known to the art.
Certain terms used in the foregoing processes have the meanings as
defined below:
Reactive functional derivatives of alcoho'ls of forrmula VI or VIa
are e.g. such esteriEied by a strong inorganic or organic acid above
all a hydro'halid acid, e.g. hydrochloric, hydrobroinid or hydriodic
acid, an aliphatic or aromatic su'lfonic acid, e.g. methanesulfonic
acid, p-toluenesu'LEonic acid, and are prcpared by methocls known in
the art.
Trialkoxymethyl represents preferably tri(lower alkoxy)-methyl,
particularly triethoxy- or trimethoxymethyl.
~L~9'7~
- 21 -
EtheriEied hydroxymethyl represents preferably tertiary lower alkyl~
oxymethyl, lower alkoxyalkoxymethyl such as methoxymethoxymethyl,
2-oxa- or 2-thiacycloalkoxymethyl particularly 2-tetrahydropyranyl-
oxymethyl.
Esterified hydroxy-methyl represents preferably lower alkanoyloxy
methyl, advantageously acetoxymethyl.
Halomethyl represents especially chloromethyl but may also be bromo-
methyl or iodomethyl.
An alkali metal represents preferably lithium but may also be
potassium or sodium.
Intermediates of formula Ia or Ib wherein C or B' is halomethyl
may be reacted preferably with an alkali metal cyanide such as
potassium cyanide in a conventional manner to yield the compounds
of formula Ia or Ib wherein the chain is extended by 1 carbon
atom and C or B' is cyano. These in turn are converted to compounds
of formula I wherein B is carboxy, alkoxycarbonyl or carbamoyl using
methods known to the art.
Thus, the compounds oE formula Ia or Ib wherein C or B' represents
cyano (nitriles) are eonverted to eompounds oE formula I wherein B
is earboxy by hydrolysis with inorganie acids, e.g. a hydrohalic
acid such as hydrochloric acid or sulEuric acid in aqueous solution,
or advantageously by hydrolysis with aq-leous alkali metal hydroxide
e.g. potassium hyclroxide at reflux temperature.
The eonversion of said nitriles to eompounds of formula I
wherein B represents lower alkoxycarbonyl is advantageously
carried out by treatment first with a lower alkanol, e.g.
- 22 -
anhydrous ethanol, in the presence of a strong acid, e.g. hydro-
chloric acid preferably at reflux temperature, followed by careful
hydrolysis with water.
Furthermore, the conversion of the said nitriles to compounds of
formula I wherein B represents carbamoyl is preferably carried
out by treatment with an alkali metal hydroxide, e.g. dilute sodium
hydroxide, and hydrogen peroxide, preferably at room temperature.
Furthermore, the intermediates of formula Ia or Ib wherein C or B'
is ha]omethyl, such as chloromethyl, are converted to compounds of
formula I, wherein B is carboxy and the chain length is extended
by two carbons, by first treating with e.g. a di-(lower)~alkyl
malonate, such asdiethyl malonate, in the presence of a base, such
as potassium carbonate or sodîum ethoxide, in a solvent such as di~
methylformamide, preferably at a temperature range from 50 to 100.
The resulting substituted di(lower)alkyl malonate is hydrolyzed,
advantageously with an aqueous base, such as dilute sodium hydroxide,
to the corresponding malonic acid which is decarboxylated under
standard conditions, e.g. by heating in xylene solution, to give
a compound of formula I wherein B is carboxy. Substitution of the
di-(lower)alkyl malonate with a lower alkyl cyanoacetate yields the
corresponding compounds of fc~rmula la or Ib wherein C or B' is
cyano,
Compounds of the invention, wherein ~ represents straight chain or
branched alkenylene with a terminul double bond, may also be pre-
parecl from intermediates oE formuLa Ia or Ib wherein C or B' is
halomethyl. For instance, said intermediates are first treated with
e.g. a lower allcyl ester of an ~-(aryl- or alkyl) thioacetic acid
such as ethyl c~-(phenylthio)-acetate, in the presence of a strong
base such as sodium hydride. Subsequent oxidation of the resulting
c~-arylthio or c~-alkylthio substituted ester to the ~-arylsulfinyl
~7~
- 23 -
or ~-alkylsulinyl ester with e.g. sodium periodate, followed by heat-
induced elimination, by e.g. reEluxing in xylene, yields a compound
of general formula I (an a,~~~msaturated ester) wherein A represents
alkenylene and B represents e.g. lower alkoxycarbonyl, and the chain
length has been extended by two carbon atoms. The same transEormation
is also carried out using e.g. ethyl ~-(phenylseleno)acetate as des-
cribed in J. Am. Chem. Soc. 95, 6137(1973). Similarly, the compounds
of Eormula Ia wherein C represents halomethyl may first be converted
to the corresponding carboxaldehydes with e.g. dimethylsulfoxide in
the presence of triethylamine and silver tetrafluoroborate, or with
chromium trioxide and pyridine in methylene chloride. Subsequent
Wittig condensation e.g. with trimethylphosphonoacetate or ethyl
(triphenylphosphoranylidene)-acetate also yields the above-cited
~,~-unsaturated esters.
Compounds of formula I wherein B is lower alkoxycarbonyl may be
amidized with ammonia, mono- or di-(lower) alkylamines e.g. methyl-
amine, dimethylamine in an inert solvent, e.g. a lower alkanal, such
as butanol, optionally at elevated temperatures to yield compounds
of formula I wherein B represents unsubstituted, mono- or di(lower)
alkylcarbamoyl.
Compounds of formula I wherein A represents straight chain or
branched alkenylene with a terminal double bond, e.g. ~ un-
saturated esters, may also be prepared Erom the corresponding ~
saturated compounds by treatment with e.g. phenylselenyl chloride
in the prescnce of a strong base according to the procedure des-
cribed in ~.~m. Chem. Soc. 95, 6l37 (L973).
Conversion of compounds of formula I or Ib wherein B or B'
respectively is lower alkoxycarbonyl; cyano; unsubstituted, mono~
or di-(loweralkyl) carbamoyl to compounds of formula I wherein B
represents carboxy is advantageously carried out by hydrolysis with
1~72~
- 2~ -
inorganic acids such as hydrohalic or sulfuric acid or with aqueous
alkalies, preferably alkali metal hydroxides such as lithium or
sodium hydroxide.
Compounds of formula I wherein B represents carboxy or lower alkoxy-
carbonyl may be reduced with simple or complex light metal hydrides
such as lithium aluminum hydride, alane or diborane to compounds
of formula I wherein B is hydroxymethyl. Said alcohols are also
obtained by appropriate solvolysis of compounds of formula Ia
wherein C is halomethyl by treatment with e~g. an alkali metal hy-
droxide as lithium or sodium hydroxideL
Said alcohols may in turn be transformed to the compounds of
formula I wherein B is carboxy with conventional oxidizing agents,
advantageously with pyridinum dichromate in dimethylformamide at
room temperature.
Free carboxylic acids may be esterified with lower alkanols such
as ethanol in the presence of a strong acid, e.g. sulfuric acid,
advantageously ~t ele~7atecl temperature or with diazo (lower) alkanes,
e.g. diazomethane in a solvent such as ethyl ether, advantageously
at room temperature, to give the corresponding esters~ namely com-
pounds of formula I wherein B is lower aLkoxycarbonyl~
Furthermore, the ~ree carboxylic acids may 'be converted vla treatment
of a reactive intermediate thereoE, e.g. an acyl halide such as
the acid chloride, or a mixed anhydride, e.g. such derived from
a 'lower alky'l halocarbonate such as ethyl chloroformate, with
ammonia, mono- or di-tlower) alkylamines, in an inert solvent such
as methylene chloride, preferably in the presence of a basic
catalyst such as pyridine, to compounds oE formula I wherein B
represents unsubstituted, mono or di-(lower)-alkylcarbamoyl.
- 25 -
Compounds of formula I wherein B represents mono(Lower)~alkyl-
carbamoyl are converted to compo~mds of formula I wherein B is di-
(lower)alkyl-carbamoyl by treatment of the former with a strong
base e.g. sodium hydride followed by an alkylating agent9 e.g. a lower
alkyl halide in an inert solventJ e.g. dimethylformamider
Furthermore compounds of formula I wherein A represents a straight
chain or branched alkynylene or alkenylene may be converted by
catalytic hydrogenation, advantageously under neutral conditions
e.g. with palladium catalyst at atmospheric pressure in an inert
solvent, e.g. ethanol, tQ compounds of formula I wherein ~ repre-
sents straight chain or branched alkyleneO
~he carboxaldehydes, the compounds of formula I wherein B repre-
sents formyl, may be prepared by oxidizing compounds of formula Ia
wherein C represents respectively hydroxymethyl or halomethyl with
e.g. dimethyl sulfoxide and a catalyst, such as a mixture of
triethylamine and silver tetrafluoroborate, or with chromium tri-
oxide and pyridine or other oxidizing agents known in the art.
Said carboxaldehydes are converted to the correspondlng acetals,
the compounds of formula Ia wherein C represents di(lower)alkoxy-
methyl, or alkylenedioxymethyl e.g. a dimethylacetal~ by acid-
catalyzed condensation with an alcoilol, e.g. methanol.
Compounds of formula I wherein B represents carboxy may be con-
verted by the welL-known ~rndt-Eistert synthesis to compo~mds
of formula I wherein B represents ca-rboxy and the chain has been
extencled by 1 carbon atom. ~ore particularly, a reactive functional
derivative of the starting carboxylic acid, e.g. the acid chloride,
is treated wi.th diazomethane in e.g. diethyl ether to yield a
compound of formula Ia wherein C represents diazoacetyl. Rearrange-
ment with e.g. silver oxide yields said carboxylic acid of formula I
wherein the chain has been extended by 1 carbon atom.
7~
- 26 ~
A specific embodiment of process 4) is for the preparation of com
pounds of formula I wherein B represents carboxy and comprises con-
verting in a compound of the formula Ia in which C represents a
group convertible into a carboxyl group, the group C into carboxy,
optionally by extending the chain A within its definition.
Groups convertible into a carboxy group are, for example, esterified
carboxy groups, carboxy groups in form of their anhydrides, in-
cluding corresponding groups of asymmetrical and inner anhydrides,
amidated carboxy groups, cyano, amidino groups, including cyclic
amidino group such as 5-tetrazolyl,' iminoether groups, including
cyclic iminoether groups, e.g., 2-oxazolinyl or dihydro-2-oxaæolinyl
groups substituted by lower alkyl, and also methyl, hydroxymethyl,
etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl,
acetyl, trihaloacetyl, halomethyl, carboxycarbonyl (COCOOH), formyl
(CHO), d-(Lower)alkoxymethyl, alkylenedioxymethyl, vinyl, ethynyl
or diazoacetyl.
Simultaneously with conversion of C into the carboxy group, the
chain A can be extended within its definition.
Esterified carboxy groups are preferably in form of the lower alkyl
esters, e.g. the methyl, ethyl, n- or i-(propyl or butyl) esters;
substituted lower alkyl esters e.g. the ~-amino, ~-mono- or di-
methylamino, ~-carboxy or ~-carbethoxy-(ethyl, propyl or butyl)
esters; aryl(lower)alkyl esters, e.g. benæyl, ~methyl-, methoxy-,
chloro-)substitllted benxy'L, and pyridylmethyl esters; lower alkanoyl-
oxy-(lower)alkyl esters, e.g. pivaloy'loxymethyl estcrs; 3-phthalidyl
and (methyl-, methoxy-, chloro-)substituted 3-phthalidyl esters,
derived from the corresponding 3-hydroxyphthalides, (hydroxy-,
Iower alkanoyloxy-, lower alkoxy-) substituted lower alkoxymethyl
esters e.g. ~-(hydroxy-, acetyloxy-~ methoxy-) ethoxymethyl esters;
bicycloalkyloxy-carbonyl-(lower) alkyl esters, e.g. those derived
7Z'~S~
- 27 -
from bicyclic monoterpenoid alcohols, such as unsubstituted or lower
alkyl substituted bicyclo [2,2,1]heptyloxycarbonyl-(lower)alkyl
esters~ advantageously bornyloxycarbonylmethyl esters; halo substi~
tuted lower alkyl esters, e.g. trichloroethyl or iodoethyl esters.
Amidated carboxy groups are preferably carboxy groups in form of
their unsubstituted amides; N-mono or di-lower alkylamides, e.g.
mono- or di-methylamides; tertiary amides derived from e.gO pyrroli-
dine, piperidine or morpholine; a-(carbo loweralkoxy)- or carboxy-
substituted lower alkylamides, e.g. mono N-(carboethoxymethyl)-
amides, and mono N-(carboxymethyl)-amides; ~-(carbo loweralkoxy)- or
carboxy-substituted aryl(lower) alkylamides, e.g. (carboethoxy or
carboxy) substituted phenethylamides; amino(lower)-alkylamides,
e.g. ~-aminoethylamides and ~-(carbobenzyloxy-amino)-ethylamides.
The conversion into the earboxy group is aeeomplished by methods
whieh are known per se, and as deseribed herein and in the examples,
e.g., by solvolysis sueh as hydrolysis or acidolysis as previously
described, or by reduction (esterified carboxy groups). For example,
a triehloroethy] or 2-iodoethyl ester may be eonverted into the
earboxylic acid by reduetion, e.g. with zine and a earboxylie aeid
in the presenee of water. Benzyl esters or n;trobenzyl esters may
be eonverted into the earboxy group by eatalyLie hydrogenation,
the latter also with ehemieal redueing agents, e.g., sodium dithionite
or with zlne and a earboxylie aeid. In addition, tert-butyl esters
may also be cleavecl with trifluoroaeetie aeid. During the reduetion
oE the group C, an a]kenylene or alkynylene chain A may be con-
verted into the corresponcling alkylene ehain.
Furthermore, eompocmds oE formula Ia wherein C represents aeetyl
may be oxidatively eleaved to the eorresponding eompounds of formula I
wherein B represents earboxy by eonversion first to a eompouncl
of formula Ia wherein C represents trihaloacetyl, e.g. tribromo or
7~4~3
triiodoacetyl, by treatment e.g. with sodium hypobromite followed
by cleavage with eO~. an aqueous base, such as sodium hydroxide.
The starting materials oE formula Ia wherein C represents acetyl are
in turn prepared from compounds of formula Ia wherein C represents
halomethyl by treatment with an alkyl ester of acetoacetic acid, e.g.
ethyl acetoacetate, in the presence of a base, e.g. sodium hydride,
followed by hydrolysis with a strong base, e.g., aqueous sodium
hydroxide.
Said compounds are also prepared by condensing a compound of formula
Ia wherein C is cyano with eOg. a Grignard or other organometallic
reagent~ e.g. methyl magnesium bromide under standard conditions~
Compounds of formula Ia wherein C represents carboxycarbonyl
(COCOOH) are converted thermally or by oxidation to compounds of
formula I wherein B represents carboxy by heating at elevated
temperature e.g., at about 200 degrees, in the presence of glass
powder, or by Lreating e.g., with hydrogen peroxide in the presence
of a basic agent, e.g. sodium hydroxicle.
The starting materials of formula Ia wherein C represents COCOOll
are prepared by e.~. condensation of a compound of formula Ia
wherein C represents halomethyl with e.g. 2-ethoxy-carbonyl-1,3-
dithiane, and subsequent oxidative hydrolysis, e.g. with N-bromo-
succinimide in aqueous acetone followed by treatment with dil.ute
aqueous sodium hydroxide.
Compo~mds of Eormula Ia wherein C represents formyl, di(lower)-
alkoxymethyl or alkylenedioxymethyl (formyl protected in the form
of an acetal), e.g. the dimethyl acetal, are oxidized with e.g.
silver nitrate, pyridinium dichromate or ozone to the corresponding
compound of formula I wherein B represents carboxy.
2'~L~
Compounds of formula Ia wherein C represents vinyl may be converted
to compounds of formula I wherein B represents carboxy by first
ozonolysis to compounds of formula I wherein B represents formyl,
which are in turn oxidized to compounds of formula I wherein B re-
presents carboxy.
Compounds of formula Ia wherein C represents vinyl may also be treated
with nickel carbonyl and carbon monoxide under high pressure con-
ditions to give compounds of formula I wherein B represents carboxy
and the chain A contains a double bond adjacent to the carboxyl
group.
Compounds of formula Ia wherein C represents ethynyl may be treated
with a strong base, e.g. butyl lithium followed by condensation with
carbon dioxide or condensation with a lower alkyl haloforma~te, e.g.
ethyl ch]oroEormate followed by hydrolysis to give compounds of
formula I where;n B represents carboxy and the chain A contains
a triple bond adjacent to the carboxyl group.
Compounds oE formula Ia wherein C represents halomethyl may be COtl-
verted to a corresponding organometallic intermediate, e.g. a
cuprous or magnesium derivative, under conclitions well known to the
art.
Condensation of e.g. the resulting organomagnesium ~Grignard) reagent,
e.g. a compo~md oE Eormula Ia wherein C is transformed to e.g.
Cil2MgCl, with carbon dioxide yields a compound of Eormuln I wherein
B represents carboxy atld the ch~in has been extencled by L carbon
atom.
Condensation o;E said Grignarcl reagent with e.g. a lower alkyl halo-
acetate or e.g. ethyl bromoacetate and subsequent hydrolysis yields
a compound of formula I wherein B represents carboxy and wherein the
chain has been extended by 2 carbon atoms.
~72~9
- 30 -
Said Grignard reagent may be condensed in the presence of a cuprous
halide, e.g. cuprous chloride,with an ~ unsaturated acid, e.g.
propiolic or acrylic acid to yield a compound of formula I wherein
B represents carboxy and wherein the chain has been extended by 3
carbon atoms.
Furthermore, compounds of formula Ia wherein C represents halomethyl
may be condensed with e.g. the 3-lithio derivative of propiolic
acid (prepared with e.g. lithium diisopropylamide) to yield a com-
pound of formula I wherein A contains a terminal alkynylene, B re-
presents carboxy and the chain length has been extended by 3 carbon
atoms.
Compounds of formula I wherein A represents lower alkylene or a
direct bond and B represents hydroxymethyl, as reactive functional
derivatives thereof, may be condensed with a lower alkanol tor thiol),
or a phenol (or thiophenol) appropriately substituted by B, pre-
ferably in the presence of a strong base, to give compounds of
formu].a I wherein A represents lower alkylene-tthio or oxy)-phenylene,
phenylene-(thio or oxy)-lower alkylene or lower alkylene-(thio or
oxy)-lower alkylene.
The above-mentioned reactions are carried out according to standard
methods, in the presence or absence of diluents, preferàbly such as
are inert to the reagents and are solvents thereof, of catalysts,
condensing or sai~l other agents respectively and/or inert atmospheres,
at low temperatures, room temperature or elevated temperatures
preferably at the boiLing point oE the solvents used, and at atmos-
pheric or super-atmospheric pressure. The preferred solvents,
catalysts and reaction conditions are set Eorth in the appended
illustrative examples.
7~
- 31 -
The invention further includes any variant of the present processes,
in which an intermediate product obtainable at any stage thereof
is used as starting material and the remaining steps are carried out,
or the process is discontinued at any stage thereof, or in which the
starting materials are formed under the reaction conditions, or in
which the reaction components are used in the form of their salts
or optically pure antipodes.
Mainly those starting materials should be used in said reactions,
that lead to the formation of those compounds indicated above as
being especially useful.
The invention also relates to novel starting materials and processes
for their manufacture.
Depending on the choice of starting materials and methods, the new
compounds may be in the form of one of the possible isomers or
mixtures thereof, for example, depending on the presence of a double
bond and the mlmber of asymmetrical carbon atoms, as pure optical
isomers, such as antipodes, or as mixtures oE optical isomers such
as racemates, mixtures of diastereoisomers,mixtures of racemates
or mixtures of geometrical isomers. The aforesaid possible isomers
or mixtures thereof are within the purview oE th;s invention;
certain particular isomers may be preferred.
Any resulting mixtures oE diastereoisomers, mixtures oE racemates
and geometric isomers can be separated on the basis oE the physico-
chemicclL diferences of the constituents, in known manner, into the
pure isomers, diastereoisomers, racemates, or geometric isomers,
Eor example by chromatography and/or Eractional crystallisation.
Any resulting racemates can be resolved into the optical antipodes
by known methods, for example by e.g. reacting an acidic end product
with an optically active base that forms salts with the racemic
~ ~7;29L~
- 32 -
acid, and separating the salts obtained in this manner, Eor example
by fractional crystallization, into the diastereoisomeric salts from
which the optically active carboxylic acid antipodes can be
liberated on acidification. The basic racemic products can likewise
be resolved into the optical antipodes, e.g. by separation of the
diastereoisomeric salts thereof, with an optically active acid, and
liberating the optically active basic compound by treatment with a
standard base. Racemic products of the invention can thus be resolved
into their optical antipodes, e.g., by the fractional crystallisation
of d- or l-(tartrates, mandelates, camphorsulfonates) or of d- or
~ methylbenzylamine, cinchonidine,cinchonine, quinine, quinidine,
ephedrine, dehydroabietylamine, brucine or strychnine) salts.
AdvantageGusly, the more active of the two antipodes is isolated.
Finally the compo~mds of the invention are either obtained in the
free form~ or as a salt thereof. ~ny resulting base can be converted
into a corresponding acid addition salt,preferably with the use
of a therapeutically useful acid or anion exchange preparation, or
resulting salts can be converted into the corresponding free bases,
for example, with the use of a stronger base, such as a metal or
ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide
or carbonate, or a cation exchange preparation. ~ compound of
formula I wherein B represents carboxy can thus also be converted
into the corresponding metal or ammonium salts. These or other salts,
Eor example, the picrates, can also be used Eor purificltion of the
bases obtained; the bases are convertecl into salts, the salts are
separated and the bases are liberated from the ~salts.
In view of the close relationship between the free compounds and the
compounds in the form of their salts, whenever a compound is re-
ferred to in this context, a corresponcling salt is also intended,
provided such is possible or appropriate under the circumstances.
~972~5~
- 33 -
The compounds, including their salts, can also be obtained in the form
of their hydrates, or include other solvents used for their erystalli-
zation.
The pharmace~tical compositions according to the invention are those
suitable for enteral, such as oral or rectalg and parenteral admini-
stration to mammals, including man, for the treatment or prevention
of diseases responsive to inhibition of thromboxane synthetase, com-
prising an effective amount of a pharmacologically active compound of
formula I, or a pharmaceutically acceptable salt thereof, alone or
in combination with one or more pharmaceutically accep-table carriers.
The pharmacologically active compounds of the invention are useful
in the manufacture of pharmaceutical eompositions eomprising an
effeetive amount thereof in eonjunction or admixture with exeipients
or carriers suitable for either enteral or parenteral applieation.
Preferred are tablets and gelatin eapsules eomprising the active
ingredient together with a) diluents, e.g. laetose, dextrose, suerose,
mannitol, sorbitol, eellulose and/or glyeine; b) lubrieants, e.g.
siliea, talcum, stearie acid, its magnesium or ealeium salt and/or
polyethyleneglycol; for tablets also e) binders, e.g. magnesium
alumin;unsilicate, stareh paste, gelatin, tragaeanth7 methyleellu-
lose, sodium carboxymethyleellulose and/or polyvinylpyrrolidone;
iE desired d) disintegrants, e.g. starehes, agar, alginie aeid or its
sodium salt, or efferveseent mixtures; and/or e) absorbents,
eolorants, flavors and sweeteners. ~.njeetable eompositions are pre-
ferably aqueous isotonie so1utions or suspensions, ancl suppositories
a-re aclvantageously prepared from Eatty Qmulsions or suspensions. Said
eompositions may be sterilized ancVor eontain acljuvants, sueh as
preserving, stabilizing, wetting or emulsifying agents, solution
promoters, saLts for regulating the osmotie pressure and/or buffers.
In addition, they may also eontain other therapeutieally valuable
substances. Said compositions are prepared aeeording to eonventional
~97;~
- 34 -
mixing, granulating or coating methods, respectively, and contain
about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
A unit dosage for a mammal of about 50 to 70 kg may contain between
about 10 to 100 mg of the active ingredient.
The following examples are intended to illustrate the invention and
are not to be construed as being limitations thereon. Temperatures
are given in degrees Centigrade, and all parts wherever given are
parts by weight. If not mentioned otherwise, all evaporations are
performed under reduced pressure, preferably between abou~ 15 and
100 mn~lg.
~7Z~
- 35
Example l: Dimethylformamide (1640 ml) is chargecl into a 76 li~re
glass kettle along with 430 g oE potassium t butoxide. This solution
is stirred under nitrogen and cooled to -8. A solution of 682 g
of 3-methyl-2-(3-pyridyl)-indole in 3280 ml of dimethylformamide
i5 added over 0.75 hour while the temperature is maintained below
0. After 2 hours of stirring at -10, 1640 ml of a solution of
780 g of methyl 8-bromooctanoate in dimethylformamide is added
over 1 hour. Reaction temperature is maintained below 0. After
2 hours stirring, the reaction mixture is allowed to warm to room
temperature overnight. Teh rust-coloured mixture is then cooled
to about 5 and treated with 19700 ml of ice-water. The temperature
rises to 25. After 0.5 hour stirring, the mixture is extracted
with 2 x 8000 ml of ether.
The extracts are dried over magnesium sulfate and concentrated in
vacuo to give the 1-(7-methoxycarbonylheptyl)-3-methyl-2-(3-py-
ridyl)-indole as an oil; 1293 g of this oil is treated with 6530 ml
of lN sodium hydroxide and warmed over steam to 90 for 2.5 hours.
After cooling to room temperature, the solution is washed with 3 x
3000 ml of ether. The aqueous layer is cooled to 10 and acidified
to pH 3.5 with 3400 ml of 2N hydrochloric acid. The heavy suspension
which results is extracted with 4 x 4000 ml of methylene chloride.
The combined extracts are washed once with 4000 ml of water and
dried over magnesium sulfate. After filtration and evaporation of
solvent in vacuo at 60, the residue is triturated with ether
(2000 ml) and dr;ed to give 1-(7-carboxyheptyl)-3-methyL-2-(3-py-
ridyl)-indole, m.p. 113-115. Recrystallization from ethanol raises
the melting point to 114-116.
The starting 3-methyi-2-(3-pyridyl)-indole is prepared essentially
as described in U.S. patent 3,468,8~
Methyl 8-bromooctanoate is prepared from azelaic acid essentially as
described in U.S. patent 3,852,419, or by direct esterification of
7~
- 36 -
8-bromooctanoic acid as follows: Methanol (4700 ml), 8-bromooctanoic
acid (912 g) and sulfuric acid (912 ml) are charged into a suitable
reactor and the mixture is heated at reflux temperature for 5 hours
and is then stirred at ambient temperature overnight. The solvent is
removed at reduce(l (3 mm Hg) pressure and the oily residue is dis-
solved in ether (~lO00 ml). The solution is washed with water (3 x
2000 ml), saturated sodium hydrogencarbonate solution (1000 ml) and
saturated aqueous sodium ch]oride solution (1000 ml). The ether
portion is dried over magnesium sulfate and filtered. Evaporation
of solvent followed by distillation of the crude oil gives met~hyl
8-bromooctanoate, b.pl 73-76/O.OS mm Hg, nD23 = 1.4614.
Example 2: To a suspension obtained by diluting 4.8 g of a 50 %
sodium hydride suspension in mineral oil with 40 ml of dimethyl-
Eormamide under nitrogen, there is added dropwise a solution of
13.5 g of 3-methyl-2-(3-pyridyl)-indole in 80 ml of dimethylform-
amide. After addition is completed, the greenish yellow mixture
is stirred at room temperature for about 1 hour. ~thyl bromoacetate
(11.2 ml, 0.10 mole) is added dropwise to the reaction mixture which
is cooled to 0-5 and stirred at room temperature for 4 hours.
The reaction mixture is poured into 1000 ml of ice-water and is
extracted with 3 x 300 ml oE ether. The ether layer is extracted
with 3 x 300 ml of lN hydrochloric acid. The acldic extract is
adjusted to pH 9-10 with concentrated ammonium hydroxide and ex-
tractecl with 3 x 250 mL of ether. The combined ether extracts are
dried over magnes;um sulEate, E;ltered, ancl concentrated under
vacuum to give l-ethoxycarbonylmethyl-3-methyl-2-(3-pyridyl)-indole
as an oil.
This oil is heated at reflux for 4 hours in 500 ml of lN hydro-
chloric acid. After standing at room temperature overnight a yellow
solid is collected and dried at 60-80C/30 mm Hg for 12 hours.
2~
- 37 -
Xecrystallization from e~hanol gives l-carboxymethyl-3-methyl-2-
(3-pyridyl)-indole hydrochloride, m.p. 204-207.
If the free amino acid is desired, it may be obtained by adjusting
the pH of the hydrolysis medium to 3,5.
Examples 3 - 6: Utilizing the procedures of examples l and 2, the
following compounds of formula II in which Rl'= CH3, ~2' and R3' = H,
and R~= OH are prepared:
Recrystalli~ation
Example Starting Ester C H2m Pyr M.P- solvent
3 Br(CH2)5CEt (CH2)5 3-pyridyl 113-4 acetonitrile
4 Br(CH2)6COOMe (CH2)6 3-pyridyl 106-7.5 acetonitrile
5 Br(CH2)4CM (CH2)4 3-pyridyl 123-5 ethanol
6 Br(CH2)5COOEt (CH2)5 4-pyridyl 186-8 acetonitrile
The starting 2-(3- and ~-pyridyl)-indoles are prepared according to
U.S. patent 3,468,894.
The starting ethyl or methyl ~-bromo esters are obtained commercial-
ly or are prepared Erom the commercially available ~-bromoacids as
illustrated below for methyl 6-bromohexanoate. ~ solution of 6-bromo-
hexanQic acid (10 g) in 50 ml of methanol to which is added 1.0 ml
of concentrated sulfuric acid, is heated llnder reElu~ Eor 8 hours.
The methanol is distilled off, the residue is dissolved in ether.
The ether solution is washed Eree oE acid with water, dried over
sodium sulEate and e.vaporated to dryness. ~istillation at 0.8 mm ~Ig
give~s methyl 6-bromohexanoate, b.p. 85-90/0.8 nlm ~Ig.
1-(7-Carboxyheptyl)-3-methyl-2-(2-pyridyl)-indole is prepared
analogous to the procedure of example 1 using as starting material
the 3-methyl-2-(2-pyridyl)-indole described in ~. Chem. Soc. 1955,
2865.
2~
- 38 -
The ccrresponding compounds of Eormula II wherein Rl' = hydrogen,
Pyr = 2-,3-, or 4-pyridyl and R2' = fluoro, hydrogen or methyl, and
R3' = hydrogen, are similarly prepared, using the procedures of
examples 1 and 2, from the prerequisite ~bromo ester and the fol-
lowing known starting 2-(pyridyl)-indoles: the 2-(2-,3- and 4-py-
ridyl)-indoles described in Pharm. Bull. Japan 4, 16 (1956); and
5-(fluoro and methyl)-2-(3-pyridyl)-indoles described in Bull. Soc.
Chim. France 1969, 4154.
__
Examples 7 and 8: The following compounds of formula II in which
Rl = CH3; R3 = H; Pyr = 3-pyridyl; Cmll2m = (CH2)5 and R4 = OH
are prepared using analogous procedures to those described in previous
examples.
Example R2' M.P. Salt
7 5-C1 143-5
8 5-OCH3 175-8 tlCl
The compound of example 7 is prepared as Eollows: To a suspension
obtained by diluting i.39 g of a 50 % sodium hydride suspension in
mineral oil with 30 ml of dimethylE~rmamide, there is added under
nitrogen at 0-5 dropwise while stirring a solution oE 6.59 g Oe
5-chloro-3-methyl-2-(3-pyridyl)-indole (prepared as described in
US patent 3,468,894) in 60 ml of dimethylEormamide. ~fter addition
is complete the suspension is stirred at 0 for 1/2 hour. While
maintaining the temperature at 0, a solution oE 6.06 g of methyl
6-bromohexanoate in 10 ml of climethyLEormamide is added dropwise.
The reaction mixture is allowed to reach room temperature, stirred
at room temperature Eor 5 hours and poured into 400 ml of ice-water.
The resulting mixture ;s extracted with ethyl acetate (3 x 300 ml).
The extract is washed with saturated aqueous sodium chloride solution,
dried over magnesium sulfate and evaporated to dryness to give l-
(5-methoxycarbonylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole
as an oil.
~97~
A solution of 3.2 g of the above ester in 30 ml of 3N sodium hydroxide
is heated under reflux for 17 hours. After cooling, the resulting
product is collected by filtration, and dissolved in 50 ml of water.
Acidification with 2N hydrochloric acid to pH 4-5 precipitates the
product which is purified by suspending in ether to give 1-(5-carboxy-
pentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole, m.p. 143-5.
Similarly preparecl is 1-(5-carboxypentyl)-5-methoxy-3-methyl-2-
(3-pyridyl)-indole, obtained as an oil. Treatment with ethanolic
hydrochloric acid in ethanol and crystallization by addition oE
ethyl ether yields compound of example 8, namely 1-(5-carboxypentyl)-
5-methoxy-3-methyl-2-(3-pyridyl)-indole hydrochloride, m.p. 175-178.
1-(5-carboxypentyl)-5-hydroxy-3-methyl-2-(pyridyl)-indole is pre~-
pared as follows: A solution of 1.70 g of 1-(5-carboxypentyl)-5-
methoxy-3-methyl-2-(3-pyridyl)-indole in 85 ml of 48 % hydrobromic
acid is heatecl under reflux for 0.5 hour. The reaction mixture is
evaporated to dryness, diluted with water and adjusted to pH 6 with
diluted sodium hydroxide. The precipitate is collected and recrystal-
lized from acetone/ethyl ester3 to yield 1-(5-carboxypentyl)-5-
hydroxy-3-methyl-2-(3-pyridyl)-indole.
Examples 9 and LO: The following examples oE formula III in which
C H2 represents CH2CH23 and Pyr represents 3-pyriclyl are prepared
essentially according to the proceclure of example 2. Condensation
Oe ethyl 3-methyl-2 (3-pyridyl)-indole-5-propionate with ethyl 6-
bromohexanoate and methyl 8-bromooctanoate respectively yields the
esters of exampLes 9a and lOa. Hydrolysis with hydrochloric acid
gives the corresponding diacids oE examples 9 and 10.
~xample C HM.P. R R Recrystallization
n 2n 5 6 solvent
9a (CH2)5 oil OC2H5 OC2H5 --
9 (CH2)5 143-5 OH OH acetonitrile
lOa (CH2)oil OCH OC H --
(CH2)7 128-30 OH 3 oH2 5 acetonitrile
7Z~
- 40 -
l-Carboxyheptyl-3-methyl-2-(4-pyridyl)-indole-5-propionic acicl is
similarly prepared.
The starting indoles are prepared as follows: To a suspension of
p-hydrazinohydrocinnamic acid [Manske and Kulka, J. Can. Res., 25B:
376 (1947), 4.50 g] in 50 ml of absolute ethanol under nitrogen at
room temperature is added while stirring 10 ml of a saturated
ethanolic hydrogen chloride solution. A solution results in approxi-
mately 5 minutes. To the red-orange solution is added 3-propionyl-
pyridine (3.37 g, 0.025 mole), the reaction mixture is heated to
reflux and maintained at reflux for 18 hours. The resulting solution
is cooled in an ice-water bath and the resulting yellow crystals of
ethyl 3-methyl-2-(3-pyridyl)-indole-5-propionate hydrochloride are
collected, m.p. 249-51. The free base, ethyl 3-methyl-2-(3-pyridyl)-
indole-5-propionate is prepared by suspending the hydrochloride
salt in water, basifying with 3N sodium hydroxide and extracting
with ether.
Simi]arly prepared is ethyl 3-methyl-2-(4-pyridyl)-indole-5-
propionate hydrochloride, m.p. greater than 275, and the correspond-
ing free base.
Heating a suspension oE 7.5 g of ethyl 3-methyl 2-(3-pyridyl)-
indole-5-propionate hydrochloride in 450 ml of 2N hydrochloric acid
at reflux temperature for 2 hours, cooling and collecting the result-
ing solid gives 3-methyl-2-(3-pyridyl)-indole-5-propionic acid hydro-
chloride, m.p. 290. Similar hydrolysis oE ethyl 3-methyl-2-(~l-
pyridyl)-indole-5-propionate hydrochloride yields 3-methyl-2-(~-py-
rldyl)-indole-5-propionic acid hydrochloride, melting above 305.
Example 11:
a) A solution of 1-(~ cyanobenzyl)-3-methyl-2-(3-pyridyl)-indole
(5.8 g) in 100 ml of a 1:1 mixture of 20 % aqueous hydrochloric
acid and glacial acetic acid is heated at reflux for 20 hours. After
~9~
cooling, the solution is poured into ice-water (100 ml) and the pH
is adjusted to 4.5-5 with saturated aqueous sodium bicarbonate
solution. The resulting precipitate is extracted with ethyl acetate,
the extract is was~ed with water and evaporated to dryness to give
1-(4-carboxybenzyl)-3-methyl-2-(3-pyridyl)-indole, m.p. 273-275.
The starting nitrile is prepared as follows: To a suspension of
2.9 g (0.06 mole) of 50 % sodium hydride in mineral oil in ~0 ml of
dimethylformamide under nitrogen at 0-5 is added dropwise over 20
minutes a solution of 10.4 g (0.05 mole) of 3-methyl-2-(3-pyridyl)-
indole in 60 ml of dimethylformamide. The reaction mixture is stirred
for 0.5 hour at 0-5 followed by dropwise addition of 9.8 g (0.05
mole) of p-cyanobenzyl bromide in 50 ml of dimethylformamide. After
stirring at 0-10 for 1 hour and at room temperature for 0.5 hour,
the reaction mixture is poured into ice-water (600 ml). The result-
ing solid is collected, dried, washed with petroleum ether and
redissolved in ether (500 ml). The ether solution is first washed
with water, then with saturated aqueous sodium bicarbonate solution,
dried over magnesium sulfide, treated with charcoal and filtered.
Rvaporation of the ether solution to dryness yields a yellow solid.
This product is slurried in hot cyclohexane and collected by filtra-
tion to give l-(~i-cyanobenzyl)-3-methyl-2-(3-pyridyl)-indole, m.p.
127-129.
b) Similarly prepared is l-(~i-carboxybenzyl)-5-chloro-3-methyl-2-(3
pyridyl)-indole hydrochlor;de, m.p. 217-220.
~xample 12: a) To a suspension of O.~i9 g o~ lithium alumini-lm hydride
in 50 ml of anhydrous tetrahydrofuran under nitrogen is added drop-
wise at room temperature a solution of 3.92 g of 1-(5-methoxy-car-
bonylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole in 30 ml of
anhydrous tetrahydrofuran. After addition is complete the suspension
is stirred for 1 hour at room temperature and 50 ml of a saturated
aqueous ammonium chloride solution is added. The reaction mixture
g
~ 42 -
is allowed to stand at room ternperature overnight and the organic
layer is separated. The aqueous layer is filtered to remove salts
and extracted with ethyl acetate (2 x 50 ml). The combined organic
layers are washed with saturated aqueous sodium chloride solution,
dried over magnesium sulfate and concentrated in vacuo. The crude
product is purified by trituration with hexane/ether and dissolved
in ethanol. Ethanolic hydrochloric acid is added to acidity and the
solution diluted with anhydrous ether ~o crystallize the product.
1-(6-Hydroxyhexyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole hydro-
chloride hemihydrate, m.p. 115-118, is obtained.
b) Similarly prepared is 1-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)-
indole as an oil; NMR (CDC13) ~3.50 (t,2H), 3.98 (t,2H).
Example 13: To a suspension of 1.52 g of 1-(5-carboxypentyl)-5-chloro-
3-methyl-2-(3-pyridyl)-indole in 50 ml of toluene under nitrogen is
added dropwise at room temperature 0.31 ml of thionyl chloride. The
resulting mixture is heated under reflux Eor 1 hour. ~n additional
0.10 ml portion of thionyl chloride is added and the solution is
stirred at room temperature overnight. The resulting suspension is
evaporated to dryness to give crude 1-(5-chlorocarbonylpentyl)-5-
chloro-3-methyl-2-(3-pyridyl)-indole which is used directly without
further purification.
A suspension of 0.86 g of the above 1-(5-chlorocarbonylpentyl)-5~
chloro-3-methyl-2-(3-pyridyl)-indole in 20 ml of concentrated am-
monium hydroxide is stirred at room temperature overnight. Filtra-
tion of the suspension and slurrying of the resulting solid in
ethyl ether yields 1-(5-carbamoylpentyl)-5-chloro-3-methyl-2-(3-py-
ridyl)-indole, m.p. 137-140.
Example 14: To a suspension of 2.9 g (0.06 mole) of 50 ~ sodium
hydride in mineral oil in 40 ml of dimethylformamide under nitrogen
at 0-5 is added dropwise over 20 minutes a solution of 10.4 g of
~7;~9
- ~3 -
3-methyl-2-(3-pyridyl)-indole in 60 ml of dimethylformamide. The
mixture is stirred for 0.5 hour at 0-5 followed by the dropwise
addition of l7.6 g (0.06 mole) of 1-tetrahydropyranyloxy-8-bromo-
octane in 50 ml of dimethylformamide. After stirring at 0-10 for
1 hour and at room temperature for 0.5 hour, the reaction mixture
is poured into ice-water and extracted with ether. The ether ex-
tract is washed with water, dried over magnesiumsulfate and evapor-
ated to dryness. The residue is dissolved in 100 ml of 3N hydro-
chloric acid, the resulting solution is kept at room temperature for
0.5 hour, washed with ether, basified with aqueous 3N sodium hydroxide
solution and extracted with methylene chloride. The methylene chloride
solution is evaporated to dryness to give 1-(8-hydroxyoctyl)-2-
(3-pyridyl)-3-methylindole.
Example 15: A solution of 4 g of 1-(7-methoxycarbonylheptyl)-3-
methyl-2-(3-pyridyl)-indole in ~0 ml of n-butanol is saturated with
methylamine and heated on a steam bath in a pressure bottle for 3
days. The reaction mixture is evaporated to dryness and the product
is crystalli~ed from ethyl ester to yield the 1-[7-(N-methylcarba-
moyl)-heptyl~-3-methyl-2-(3-pyridyl)-indole.
Example 16: Preparation of 10,000 tablets each containing 10 mg of
the active ingredient of Example 1:
Formula:
1-(7-carboxyheptyl)-3-methyl-2-(3~pyridyl)-indole 100 g
Lactose 1,157 g
Corn starch 75 g
Polyethylene glycol 6,000 75 g
Talcum powder 75 g
Magnesium stearate 18 g
Purified water q.s.
2~
- 44 -
Procedure: All the powders are passed through a screen with openings
of 0.6 mm. Then the drug substance, lactose, talcum, magnesium
stearate and half of the starch are mixed in a suitable mixer. The
other half of the starch is suspended in 40 ml of water and the
suspension added to the boiling solution of the polye-thylene glycol
in 150 ml of water. The paste formed is added to the powders which
are granulated, if necessary, with an additional amount of water.
The granulate is dried overnight at 35, broken on a screen with
1.2 mm openings and compressed into tablets with 6.4 mm diameter,
uppers bisected.
Example 17: Preparation of 10,000 capsules each containing 25 mg
of the active ingredient of Example lla:
Formula:
1-(4-carboxyben~yl)-3-methyl-2-(3-pyridyl)-indole 250 g
Lactose 1,650 g
Talcum powder 100 g
Procedure: All the powders are passed through a screen with openings
of 0.6 mm. Then the drug substance is placed in a suitable mixer and
mixed first with the talcum, then with the lactose until homogenous.
No. 3 capsules are filled with 200 mg, using a capsule filling machine.
Similarly prepared are tablets and capsules comprising about 10-
100 mg oE other compouncls oE the invention, e.g. oE 1-(5-carboxy-
pentyl)-5-(chloro, fluoro, methoxy or methyl)-3-methyl-2-(3-pyridyl)~
indole, 1-(5-carboxypentyl)-5,6-dichloro-3-methyl-2-(3-pyridyl)-
indole, or any other compound given in the examples herein.
Example 18: A solution of 50 mg of 1-(5-carbamoylpentyl)-5-chloro-3-
methyl-2-(3-pyridyl)-indole in 1 ml of 6N hydrochloric acid ls heated
at reflux temperature for 3 hours. On cooling the hydrochloride salt
- 45 -
precipitates. The suspension is concentrated to dryness and the
residue basified with saturated aqueous sodium hydrogencarbonate
solution. This solution is washed with ether and neutralized to pH
6-7 with 2N hydrochloric acid. The crude free acid, 1-(5-carboxy-
pentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole, m.p. 137-141, is
obtained.
Example 19: To a mixture of 4.17 g of 3-methyl-2-(3-pyridyl)-indole~
0.64 g of tetra-n-butyl ammonium bromide and 1.02 g powdered
potassium hydroxide in 500 ml of acetonitrile, while stirring at room
temperature under nitrogen, is added 5.06 g of ethyl p-(2-bromoethoxy)-
benzoate [for preparation see U.S. Patent 2,790,825 (1957)]. The
suspension is stirred for five days. After filtration to remove
potassium bromide, the filtrate is concentrated to an oil which is
dissolved in ethyl acetate and extracted with 3N hydrochloric acid.
The acid layer is separated and treated with 3N sodium hydroxide.
This suspension is extracted with ethyl acetate (3 x 100 ml) and the
organic extract is separated, dried over magnesium sulfate and con-
centrated to give as an oil 1-[2-(4-ethoxycarbonylphenoxy)-ethyl]-2-
(3-pyridyl)-3-methylindole.
Example 20: ~ mixture of ~.7 g of 1-[2-(~-ethoxycarbonylphenoxy)-
ethyl]-2-(3-pyridyl)-3-methylindole in 2N hydrochloric acid (220 ml)
is heated under reElux for 6 hours. ~Eter cooling the solution is
made basic with 3N sodium hydroxide and extracted with ethyl acetate.
The basic solution is Eiltered and acidiEied to p~l 6-7 with 5N hydro-
chloric acid. The solid is collected, dried ancl recrystallized from
acetone to give 1-[2-(4-carboxyphenoxy)-ethyl]-2-(3-pyridyl)-3--
me.thylindole, m.p. 190-193.
Example 21: A solution of 5.9 g of p-mercaptobenzoic acid ethyl ester
(prepared according to J. Chem. Soc., 1963, 1947-1954) in 30 ml of
dimethylformamide is added dropwise to a slurry of 1.55 g of 50 %
sodium hydride-mineral oil in 30 ml of dimethylformamide. This mixture
- 46 -
is stirred at room temperature for 0.5 hour under nitrogen atmosphere.
This solution is added dropwise to a solution of 9.78 g of 1-(2-methyl-
sulfonyloxyethyl)-2-(3-pyridyl)-3-methylindole in 60 ml of dimethyl-
formamide at -10~. This mixture is stirred at room temperature over-
night and poured into 1000 ml of ice-water. This is extracted several
times with ether (_ . 1000 ml total). The ether extract is washed
with water (3 x 200 ml), dried over magnesium sulfate and evaporated
in vacuo yielding 1-[2-(4-ethoxycarbonylphenylthio)-ethyl]-2-(3-py-
ridyl)-3-methylindole as an oil; NMR (CDC13) confirms the structure.
The starting material is prepared as follows: To 11.77 g of 1-(2-
ethoxycarbonylethyl)-2-(3-pyridyl)-3-methylindole in 400 ml of dry
tetrahydrofuran at 0 is added 60 ml of a 1 M solution of lithium
aluminium hydride in tetrahydrofuran. This is allowed to stir at
room temperature for 1 hour, then cooled by an ice bath and quenched
successively with 2.26 ml of water, 2.26 ml of a 15 % sodium hydroxide
solution, and 6.78 ml of water. The mixture is filtered, concentrated
in vacuo, and the residue dissolved in ether, washed with a saturated
sodium hydrogencarbonate solution, ~ried over magnesium sulfate and
concentrated in vacuo. There is obtained the semi-solid 1-(2-hydroxy-
ethyl)-2-(3-pyridyl)-3-methylindole which is used directly in the
next step.
Methanesulfonyl chloride (2.70 ml) is added dropwise to a solut;on
of 7.5 g 1-(2-hydroxyetllyl)-2-(3-pyridyl)-3-methylindole and 10.3
ml of triethylamine in 150 ml oE methylene chloride at -10. This
mixture is stirred at room temperature for 0.5 hour and poured into
600 ml of ice-water. The resuLt;ng slurry is extractecl with methylene
chloride, the extract is washed with saturated sodi~lm hydrogencar-
bonate solution, dried over magnesium sulfate and evaporated in vacuo.
There is obtained 1-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-3-
methylindole which is used directly in the above reaction.
7~g9
- 47 -
Example 22: A mixture of 6.39 g of 1-[2-(~i-ethoxycarbonylphenylthio)-
ethyl]-2-(3-pyridyl)-3-methylindole in 260 ml of 2N hydrochloric acid
is heated at reflux temperature for 6 hours. After cooling the pH is
adjusted to 6-7 with saturated sodium hydrogencarbonate, (ca. 500 ml).
~bout 200 ml of ether is added and the mixture is stirred for 0.5
hour. A solid is collected, first washed with water, then ether, and
then dissolved in 100 ml hot absolute ethanol. The solution is fil-
tered, and while still hot treated with 1.68 ml of 6.5 N ethanolic
hydrogen chloride. The solution is cooled and diluted with ca. 100 ml
ether. The resulting product is collected to yield 1-[2-(4-carboxy-
phenylthio)-ethyl]-2-(3-pyridyl)-3-methylindole hydrochloride, m.p.
222-224.
Example 23: A solution of lithium diisopropylamide (LDA) is prepared
by adding n-butyl lithium (7.66 mmol, 1.6M in hexane) to a solution
of diisopropylamine (7.6 mmol) in tetrahydrofuran (THF, 12 nl) at
-20. The LDA solution is cooled to -78 and 1-(5-methoxycarbonyl-
pentyl)-2-(3-pyridyl)-3-methylindole (2.48 g) in THF (24 ml) is
added dropwise over 5 minutes. The mixture is stirred at -78 for
20 minutes, followed by addition of phenylselenyl chloride (1.5 g)
in THF (12 ml). ~Eter 5 minutes the cooling bath is removed and the
mixture allowed to warm to 0. Saturated aqueous sodium bicarbonate
(60 ml) is added, followed by ether extraction (3 x 50 ml). The com-
bined organic phases are washed with saturated flqueous sodium bi-
carbonate, saturated aqueous sodium chloride and then dried over
anhydrous magnesium sulfate. Concentration in vacuo gives the crude
1-(5-methoxycarbonyl-5-phenylselenyl-2-t3-pyridyl)-3~methylindole
as a yellow oil. The crucle selenide is dissolved in dichloromethane
(40 ml) and 30 % hydrogen peroxide (1.8 g, 16 mmol) in water (1.8 ml)
is added dropwise. An exotherm reaction begins after the addition
of ca. 10 % of the hydrogen peroxide. The temperature rises to 30
by completion of the addition. Stirring is continued for an additional
30 minutes, then 5 % aqueous sodium carbonate (40 ml) is added. The
dichloromethane layer is separated. The aqueous phase is extracted
~7;~
~ 4~ -
with dichloromethane (25 ml). The combined organic phases are washed
with 5 % aqueous sodium carbonate, water, saturated aqueous sodium
chloride solution, and dried over anhydrous magnesium sulfate. Con-
centration in vacuo yields 1-(5-methoxycarbonylpent-4-enyl)-2-(3-py-
ridyl)-3-methylindole as a light yellow oil. Further purification is
achieved by flash chromatography (Sio2) using ethyl acetate :hexane
(2:3) as the eluent. NMR ~CDC13) ~5.53 (d, lH), 6.65 (m, lH); IR
(neat) 1720 cm~l
Example 24: To a solution of the ~,j3-unsaturated ester 1-(5-methoxy-
carbonylpent-4-enyl)-2-(3-pyridyl)-3-methylindole (84 mg) in
methanol (1 ml) is added lN aqueous lithium hydroxide (1 ml). The
mixture is stirred at room temperature overnight, then evaporated
to dryness in vacuo. The residue is dissolved in water (2 ml) and
washed with diethyl ether (5 ml). The aqueous phase is acidified
to pH 6.6-7.0 and extracted with dichloromethane. The organic ex-
tract is washed with saturated aqueous sodium chloride solution
and dried over magnesium sulfate, then concentrated in vacuo to a
pale yellow oil which solidifies upon trituration wibh chloroform
to give 1-(5-carboxypent-4-enyl)-2-(3-pyridyl)-3-methylindole, m.p.
1~i5-147.
Example 25: To a solution of Collins ~eagent prepared with chromium
trioxide (5.6 g) and pyridine (8.~6 g, 112 mmol) in dichloromethane
(150 ml) at 0-5 under a nitrogen atmosphere is added all at once
1.8 g of 1-(6-hy~lroxyhexyL)-3-methyl-2-(3-pyridyl)-indole in
dichloromethane (15 ml). The mixture is stirred Eor 25 minutes,
then Eilterecl through celite5 The EiLtrate is then passed through
a silica gel coLumn. The product is eluted from the silica gel
with a 1:1 mixture of ethyl acetate:dichloromethane (500 ml).
Concentration in vacuo yields the desired 1-(5-Eormylpentyl)-2-
(3-pyridy])-3-methylindole as a pale yellow oil; NMR (CDC13)
~9.7 (t, lH); IR (neat) 2710, 1720 cm~l.
~7;~
- 49 ~
Example 26: Trimethyl phosphonoacetate (328 mg) is added dropwise to
a solution of potassium tert-butoxide (220 mg) in THF (5 ml) of 0
under a nitrogen atmosphere. The solution is stirred at 0 for 20
minutes, then cooled to -78. ~ solution of the l-(5-formylpentyl)-2~
(3-pyridyl)-3-methylindole (450 mg) in THF (5 ml) is added dropwise
over 15 minutes. The mixture is kept at -78 for 15 minutes, then
the cooling bath is removed. The mixture is stirred overnight at
room temperature, then diluted with water (25 ml) and extracted with
diethyl ether (3 x 25 ml). The combined extracts are washed with
saturated aqueous sodium bicarbonate, then saturated aqueous sodium
chloride solution, and dried over magnesium sulfate. Concentration
in vacuo yields the 1-(7-methoxycarbonylhept-6-enyl)-2-(3-pyridyl)-3-
methylindole as a pale yellow oil; IR (neat) 1735 cm~l.
ExampLe 27: Hydrolysis of 50 mg of 1-(7-methoxycarbonylhept-6-enyl)-2-
(3-pyridyl)-3-methylindole according to the procedure of example 24
yields 1-(7-carboxyhept-6-enyl)-2-(3-pyridyl)-3-methylindole, m.p.
144-146 (recrystallized from dichloromethane/hexane).
Example 28: 1-(7-Carboxyhept-6-enyl)-3-methyl-2-~3-pyridyl)-indole
(10 mg) is dissolved in 1 ml of absolute ethanol with a catalytic
amount of 10 % palladium on charcoal and hydrogenated at 1 atmos-
phere pressure. ~ter 3.5 hours~ the catalyst is removed by
filtration and washed with a few milliliters of ethanol. The com-
bined Eiltrfltes are concentrated in vacuo to yield a colourless
oil which crystalLiæes to give 1-(7-carboxyheptyl)-3-methyl-2-
(3-pyridyl)-indole oE Example 1 (crude product has m.p. 110-113).
Example 29: 1-(4-Cyanobutyl)-8-methyl-2-(3-pyridyl)-indole (578 mg)
is heated at 185 for 0.5 hour with 450 mg of powdered sodium
hydroxide and 5 ml of ethylene glycoL; there is obtained, after
pouring the reaction solution into 50 ml water, washing with ether,
and adjusting the pH to 6 with 2N hydrochloric acid, an oily soLid
which crystallizes to give 1-(4-carboxybutyl)-3-methyl-2-(3-pyridyl)-
- 50 ~ 7Z~3
indole of Example 5 (m.p. 127-129).
The starting material is prepared as follows: A solution of 3-methyl-
-2-(3-pyridyl)-indole (2.09 g) in 12 ml of DMF is added to a suspen-
sion of 0.528 g of 50 ~ sodium hydride-mineral oil in 6 ml of DMF
at 0. The mixture is stirred at 0 for 0.5 hour and is treated with
a solution of 1.78 g of 5-bromovaleronitrile in 4 ml of DMF. This
mixture is stirred at room temperature overnight and is poured into
125 ml of water. This is extracted with 2 x 50 ml of ether, the
extract is washed with 3 x 20 ml of water and dried over magnesium
sulfate to give 1-(4-cyanobutyl)-3-methyl-2-(3-pyridyl)-indole as
an oil.
Example 30: A mixture of 578 mg of 1-(4-cyanobutyl)-3-methyl-2-
(3-pyridyl)-indole, 173 mg of sodium azide, 142 mg of ammonium
chloride and 5 mg of lithium chloride in 2 ml of DMF is heated at
120 overnight. After cooling the mixture is filtered and the fil-
trate diluted with ca. 25 ml of water. After the p~l is adjusted to
10-11 with 3N sodium hydroxide, the solution is washed wit`h ether
to remove unreacted nitrile. The aqueous phase is adjusted to p~l
5-6 with 2N hydrochloric acid and extracted with ether. The ether
extract is washed with water, dried over magnesium sulfate and
concentrated _ vacuo. The solid residue is slurried in petroleum
ether and collected to give 1-[4-(5-tetrazolyl)-butyl]-3-methyl-2-
(3-pyridyl)-indole, m.p. 177-179.
Example 31: A solution of 3-methyl-2-(3-pyridyl)-indole (2.08 g)
in 12 mL o DMF is added to a suspension of 0.528 g oE 50 % sodium
hydride-mineral oil in 6 ml oE DMF under nitroge~ at 10-15. AEter
complete addition the mixture is stirred at room temperature for
0.5 hour and is treated with a solution of 2.39 g of ethyl 3-
(p-chloromethylphenyl)-2-methylacrylate in 5 ml of DMF dropwise.
The resulting mixture is stirred at room temperature overnight and
poured in 100 ml of water. The resulting mixture is extracted with
- 51 ~
ethyl acetate (2 x 50 ml) and the organic layer is washed with lO0 ml
of saturated aqueous sodium chloride solution, driecl over magnesium
sulfate and evaporated to yield l-[p-(2-ethoxycarbonylpropen-1-yl)-
benzyl]-3-methyl-2-(3-pyridyl)-inclole.
Hydrolysis with 2M aqueous hydrochloric acid yields l-[p-(2-carboxy-
propen-l-yl)-ben~yl]-3-methyl-2-(3-pyridyl)-indole.
The starting material is prepared as follows: To a suspension of
10.0 g of a 50 % sodium hydride in mineral oil in freshly distilled
dimethoxyethane (DME, 350 ml) stirred under nitrogen at 10 is added
53.6 ml of triethyl 2-phosphonopriopionate in ca. 40 minutes. The
mixture is stirred for 0.5 hours at 10 and for an additional 1.5
hours during which time the temperature is allowed to rise to room
temperature. This solution is transferred under nitrogen by cannula
to a 500 ml addition funnel and is added dropwise to a solution of
terephthalaldehyde (33.53 g) in dry DME (475 ml) over a period of
1 hour at 22-34. After addition is complete the reaction mixture
is stirred mechanically at room temperature for 2 hours, poured into
1000 ml of water and cxtracted with 4 x 500 ml of ether. The ether
extract is washed with a saturatèd sodium chloride solution (700 ml),
dried over magnesium sulfate, filtered, and concentrated in vacuo
to give a yellow oil which partially crystallizes on standing. This
crude mixture is puriEied by suspending in petroleum ether and
ethyl acetate (93:7). The Eiltrate, after removal of unreacted cli-
aldehyde, is concentrated in vacuo to give a mixture which is further
puriEied by high pressure liquid chromatography (using petroleum
ether/ethyl acetate 93:7). There is obtained pure ethyl 4-formyl-~-
methylcinnamate. ~ solution of the aldehyde (34.80 g) in 820 ml of
absolute ethanol is treated with 12.11 g of granular sodium boro-
hydride at room temperature under nitrogen. The resulting mixture
is stirred at room temperature for 3 hours (or until all borohydride
has dissolved) and then concentrated to ca. 200 ml volume, diluted
with 400 ml of water, and extracted with 3 x 200 ml of ether. The
~7~
- 52 -
ether extract is washed with 100 ml of water and saturated aqueous
sodium chloride solution (100 ml), is dried over Magnesium sulfate,
Eiltered, and the Eiltrate concentrated in vacuo to give ethyl 3-
(p-hydroxymethylphenyl)-2-methylacrylate. To a solution oE this
product in 350 ml of methylene chloride is added at room temperature
11.53 ml of thionyl chloride dropwise over 25 minutes. The clear,
colourless solution is stirred for 2 hours. The solution is washed
with 100 ml of water, 200 ml of saturated sodium bicarbonate, 100
ml of water, and 100 ml of saturated aqueous sodium chloride solution.
The organic layer after drying and removal of solvent yields ethyl
3-(p-chloromethylphenyl)-2-methylacrylate, used without further
purification.
Example 32: 1-(5-Formylpentyl)-3-methyl-2-(3-pyridyl)-indole (127
mg) is dissolved in DMF (0.66 ml) and pyridinium dichromate (298 mg)
added all at once. The mixture is stirred overnight at room tem-
perature, then diluted with ether:ethyl acetate (25 ml, 4:1) and
filtered. The solid is washed with hot chloroform and the combined
filtrates concentrated in vacuo to yield a dark brown gum which is
slurried in ether:ethyl acetate (4:1) and extracted with 0.1 N
aqueous sodium hydroxide (2 ml). The aqueous extract is acidified
to pH 5.5-6.0 and extracted with chloroform. The chloroEorm extract
is dried and concentratecl in vacuo yieLding a yellow oil; thln
layer chromatography (= TLC); (SiO2, ethyl acetate:hexane l:L)
;ndicates the presence oE the desired acid. Further purification
by chromatography on silica gel using ethyl acetate: hexane (1:1)
as the eluent yields the desired 1-(5-carboxypentyl)-3-methyl-2-
(3-pyridyl)-indole oE Example 3.
~xample 33: Bromine (0.344 ml) is added to a solution of 692 mg of
sodium hydroxide in 4 ml of water with ice bath cooling. The result-
ing solution is added to 400 mg of 1-(5-oxohexyl)-3-methyl-2-
(3-pyridyl)-indole and this mixture is stirred for 2 hours at room
temperature. The mixture is washed with ether. The aqueous solution
97~
53 -
is filtered and acidified to pll 5-6 with 2N hydrochloric acid. A
crude white solid is collected which melts in the range of 108-120.
TLC (silica gel; methylene chloride/methanol 9:1) separation gives
1-(4-carboxybutyl)-3-methyl-2-(3-pyridyl)-indole of Example 5.
The starting material is prepared as follows: 1-(4-cyanobutyl)-3-
mett,yl-2-(3-pyridyl)-indole (1.5 g) in 15 ml of ether is added to
a solution of 0.0103 mole of methyl magnesium bromide in 15 ml of
ether , and this mixture is heated at reflux temperature for 3 hours.
After cooling, 10 ml of 6N hydrochloric acid is added dropwise and
this mixture refluxed for several hours. The reaction mixture is
washed with ether, and basified to p.H. 10-11 with 3N sodium
hydroxide. Ether extraction and evaporation oE the solvent yields
the 1-(5-oxohexyl)-3-methyl-2-(3-pyridyl)-indole; IR 1720 cm 1.
NMR (CDC13) o, 2Ø
Example 34: 1-(7-carboxyheptyl)-5-chloro-3-methyl-2-(3-pyridyl)-
indole hydrochloride (421 mg) dissolved in 7 ml oE tetrahydrofuran
is warmed and treated with 202 mg (0.278 ml) of triethylamine. This
solution is added dropwise to a solution of 108 mg (0.096 ml) of
ethyl chloroformate in 1 ml of tetrahyclrofuran which is cooled to
0-5. The reaction mixture is stirred 1 hour at this temperature
and filtered to remove triethylamine hydrochloride. The filtrate
is treated with a solution of hydroxylamine hyclrochloride (69 mg)
and sodium hydroxide (~0 mg) in 10 ml bE methanol. This mixture is
stirred 0.5 hour and concentrated in vacuo. The residue is treated
with 25 ml oE ether-methanol (10:1) and filtered. The filtrate is
evaporated in vacuo leaving a thick oil which ls dissolved in acetone
and treated with 6.5 N ethanolic hydrogen chloride to give 1-(7-
hydroxycarbamoyl-heptyl)-3-methyl-2-(3-pyridyl)-indole hydro-
chloride, m.p. 170-173.
Example 35: Ethanolic hydrogen chloride (7.1 N, 0.14 ml) is added
to 236 mg of N-phenyl-N-(5-methoxycarbonylpentyl)-hydrazine in 2 ml
72~g
- 54 ~
of absolute ethanol followed by 135 mg of 3-prop;onylpyridine. The
mixture is heated at reflux temperature overnight. Additional
ethanolic hydrogen chloride (0.62 ml) is àdded and heating is con-
tinued for an additional 2~l hours. After cooling the mixture is
filtered and the filtrate evaporated in vacuo. The residue is
stirred in 10 ml of water and basified to pH 10-11 with 1 N sodium
hydroxide; this mixture is extracted with ether. The extract after
washing with water and drying over magnesium sulfate gives on
evaporation of solvent an oil which is identified as 1-(5-ethoxy-
carbonylpentyl)-3-methyl-2-(3-pyridyl)-indole.
This ester is hydrolyzed with 10 ml of 2N hydrochloric acid at reflux
temperature followed by adjustment of the p~l to ca. 6 with saturat-
ed sodium bicarbonate and extraction with ether. Work-up of the
organic extract gives 1-(5-carboxypentyl)-3-methyl-2-(3-pyridyl)-
indole of Example 3 (crude m.p. 111-113.
The start;ng material is prepared as follows: ~niline (2.79 g,
2.73 ml~, 6.27 g of methyl 6-bromohexanoate and 12.24 g (0.09 mole)
of sodlum acetate trihydrate are heated at 80-100 overnight ln 15
ml of absolute ethanol. ~fter cooling, the mixture is poured into
75 ml of ice-water and extracted with ether. The organic extract is
washed with water, dried over magnesium sulfate and evaporated in
vacuo to give N-(5-methoxycarbonylpentyl)-aniline.
solution of 1.4 g of sodium nitrite in 5 ml of water is added
dropwise at 0-10 to a mixture of 4.~2 g of N-(5-methoxycarbonyl-
pentyl)-aniline, ~.9 ml of concentrated hydrochloric acid, and ice
as needed to maintain the desired temperature. The mixture is then
allowed to stir at ambient temperature for 1 hour and is then ex-
tracted with ether. The extract is washed with water, dried over
magnesium sulfate, and evaporated in vacuo to give N-nitroso-N-(S-
methoxycarbonylpentyl)-aniline as an oil.
2~
- 55 -
The above N-nitroso clerivative (3.6 g) in 4 ml of glacial acetic
acid is added dropwise to 3.94 g of zinc powder in 6 ml of water.
After an exothermic reaction to 35, the mixture is stirred at room
temperature for 2 hours. After filtration to remove zinc, the fil-
trate is washed with ether and basified to pH 10-11 with 40 % sodium
hydroxide and extracted with ether. The extract is dried over
magnesium sulfate and evaporated in vacuo to give a crude oil.
After flash chromatography through silica gel with hexane-acetic
acid (5:1), N-phenyl-N-(5-methoxycarbonylpentyl)-hydrazine of about
80 ~ purity is obtained, which is used directly in the Fischer
cyclization described above.
Example 36: 1-[7,7-(bis-methoxycarbonyl)-heptyl]-3-methyl-2-(3-
pyridyl)-indole (273 mg) is dissolved in methanol (0.5 ml) and 1 N
aqueous lithium hydroxide (1.95 ml) added. The mixture is stirred
at room temperature for 1 hour, then refluxed for 2.5 hours. The
clear solution is concentrated to dryness, the residue dissolved in
water and the pH adjusted to 6-6.2. A yellow gummy solid precipitates
which is extracted into chloroform. Concentration of the chloroform,
which is dried over magnesium sulfate, yields crude 1-[7,7-(bis-
carboxy)-heptyl]-3-methyl-2-(3-pyridyl)-indole; NMR (CDC13)
c~10.60 (2H).
A sample of the crude dicarboxylic acid (28 mg) is heated with
p-xylene (3 ml) containing 0~1 N hydrochloric acicl (0.1 ml) Eor
0.5 hour. The clear solution ;5 allowed to cool to room temperature.
A gum prec;pitates and iB extracted into aqueous sodium hydroxide.
The aqueous phase is separatecl, and aEter acljustment of the pH to
6-6.2, extracted with ethyl acetate:ether (8:2). The organic phase
is dried over magnesium sulEate and concentrated to give a colourless
oil which solidiEies on standing to yield 1-(7~carboxyheptyl)-3-
methyl-2-(3-pyridyl)-indole, identical by NMR and TLC to the com-
pound of Example 1.
The starting material is prepared as follows: Thionyl chloride
(0.36 ml) is combined with 1-(6-hydroxyhexyl)-3-methyl-2-(3-py-
ridyl~-indole (1.37 g) at 0. The mixture is then stirred at room
temperature for 1 hour. Saturated aqueous sodium bicarbonate is
added and the mixture is extracted with dichloromethane. The ex-
tract is washed with saturated aqueous sodium chloride solution
and dried over magnesium sulfate. Concentration in vacuo yields
the crude chloride as an oil. PuriEication by silica gel chroma-
tography (methylene chloride/ethyl acetate 19:1) gives 1-(6-
chlorohexyl)-3-methyl-2-(3-pyridyl)-indole as a light yellow oil;
NMR (CDC13) ~3.30 (t, 2E~), 3.92 (t, 2H).
The 1-(6-chlorohexyl)-3-methyl-2-(3-pyridyl)-indole (0.5 g) is
combined with dimethyl malonate (792 mg), potassium carbonate
(790 mg) and dimethylformamide (11.6 ml) and the mixture heated
at 30-90 for 18 hours under nitrogen. The mixture is poured into
ice-water (80 ml), acidified with lN hydrochloric acid and washed
with ether. The aqueous layer is adjusted to pH 6 and extracted with
ether which is then dried over magnesium sulEate and concentrated to
yield a yellow oil. Purification by preparative TLC (chloroEorm-
ethyl ester 9:1) gives 1-[7,7-(bis-methoxycarbonyl)-heptyl~-3-
methyl-2-(3-pyridyl)-indole; NMR (CDC13) c~3.32 (t, lH), 3.78
(s, 6H), ~.03 (t, 2H): IR (neat) 1750 cm 1.
Example 37: 1-(6-chlorohexyl)-3-methyl-2-(3-pyridyl)-indole (165 mg)
in dry THF (2 mL) is added dropwise to magnesium turnings (12 mg)
in dry THF (2 mL) uncler a nitrogen atmnsphere. ~ crystal of iodine
is added during tlle addition to initiate the reaction. The mixture
is refluxed for ~hours after the addition is completed, then
cooled to 0, and dry carbon dioxide gas bubbled into the flask
with stirring for 15 minutes. The cloudy mixture is poured into
5 ml lN sodium hydroxide and extracted with ether. The aqueous phase
is adjusted to pH 6-6.2 and extracted with ethyl acetate. The or-
ganic phase is dried over magnesium sulfate and concentrated in vacuo
:~9~9
yielding a white solid, crude m.p. 106-107, being L-(6-carboxy-
hexyl)-3-methyl-2-t3-pyridyl)-indole, identical by TLC and NMR to
the compound of Example 4.
Example 38: 1-(Prop-2-ynyl)-3-methyl-2-(3-pyridyl)-indole (90 mg)
is dissolved in THF (2 ml) under a nitrogen atmosphere and the re-
sulting solution cooled to -78. A solution of n-butyl lithium
(0.024 ml, 1.6M in hexane) is added dropwise via syringe over 1
minute. After stirring at -78 for an additional 10 minutes the
orange coloured mixture is quenched with methyl chloroformate
(0.031 ml) and allowed to warm to room temperature. The mixture is
then poured into saturated aqueous soclium chloride solution and ex-
tracted with ether. The extract is washed with water and dried over
magnesium sulfate. Concentration in vacuo yields an oil which is
purified by prepaxative TLC using (1:1) ethyl acetate:hexane as
the developing solvent. The 1-(3-methoxycarbonyl-prop-2-ynyl~-3-
methyl-2-(3-pyridyl)-indole is isolated as an oil; NMR (CDC13)
~3.73 (s, 3H), 4.83 (s, 2H); IR (CHC13) 1715, 2245 cm~l.
The starting material is prepared as follows: Sodium hydride (50 %
mineral oil dispersion, 53 mg) is washed with petroleum ether under
nitrogen. The washed sodium hydride is suspended in dry DMF (2 ml)
and 3-methyl-2~(3-pyridyl)-indole (208 mg) in DMF (2 ml) added drop-
wise. The mixture is stirred an additional 30 minutes followed by
the dropwise addition of propargyl bromide (220 mg). The mixture
is stirred for an additional 2 hours, poured into ice-water, acidi-
fied with lN hydrochloric aci.d and extractecl with ether. The aqueous
pilase is macle baslc with sodium bicarbonate and extracted with ether.
The ether extract i9 washed with water, saturated aqueous sodium
chloride solution and dried over magnesium sulfate. Concentra-
tion in vacuo yields l-(prop-2-ynyl)~3-methyl-2-(3-pyridyl)-indole;
NMR (CDC13) ~ 2.20 (s, 4H), 4.70 (d, 2H, J=3Hz); IR (neat) 3200,
2120 cm~l; m.p. 104-105 after purification with silica gel flash
chromatography using ethyl acetate:hexane (1:1).
- 58 -
Example 39: Treatment of 33 mg of 1-(3-methoxycarbonylprop-2-yny])~
3-methyl-2-(3-pyridyl)-indole in 1 ml of methanol with 0.3 ml o~ lN
lithium hydroxide at room temperature yields 1-(3-carboxyprop-2-
ynyl)-3-methyl-2-(3-pyridyl)-indole; 'LR 1720 cm~10
Example 40: Preparation by methods analogous to those described in
the previous examples of additional compounds of formula II wherein
Rl = CH3, Pyr = 3-pyridyl and R4 = OH.
Compound R21 R3' C H2 Salt m.pO
40/1 5-Cl H (CH2)7 HCl 173-176
40/2 5-OCH3 H (CH2)5 HBr 188-189
40/3 5-C1 6-Cl (CH2)5 HCl 178-80
40/4 5-F H (CH2)5 HCl 216-219
40/5 5-CH3 H (CH2)5 HCl 185-8Q
40/6 5-CH3 ( 2)7 124-125
40/7 H H (CH2)10 100-102
40/8 5-0-CH2-0-6 ( 2)5
40/9 5-OH (CH2)5 168-170
40/10 5-~CH3 ( 2)5 135-7~
The starting N-unsubstituted indoles are known. The new starting ma-
terial ior compound ~O/lOl 5-methylthio-3-methy'l-2-(3-pyridyl)-indole,
has m.p. oE 160-L62.
The compound oE example 40/9 is prepared by hydrogeno'Lysis of 1-(5-
carboxypentyl) 5-benzyloxy-3-meLhyL-2-(3-pyridyl)-indole, m.p. 176-
178. The starting 5-benzyloxy-3-methyl-2-(3-pyridyl)-indole has the
m.p. 164-166.
72~
- 59 -
Example 41: Preparation by methods analogous to those described in
the previous examples of additional compounds of formula I wherein
Rl = CH3, Ar = 3-pyridyl, and B = COOH
Example R2 R3 A B
41/1 H H C-C-(CH ) COOH
41/2 H H CH2S(CH2)2COOH
4L/3 H H (CH2)20(CH2)2 COOH
4L/4 H H (CH2)20(CH2)3 COOH
The alkylating starting materials for compounds 41/2, 4L~3 and
41/4 are prepared as described in J. Org. Chem. 34, 2955 (1969) 9
U.S. Patent 3,984,459 and Chem. Abstr. 83, 166177b respectively.
Effect on thromboxane synthetase from human platelets
The method is carried out accroding to the description given above,
i.e. the in vitro inhibition of the thromboxane synthetase enæym~
is demonstrated analogous to the method of Sun, Biochem. Biophys.
Res. Comm. 74, 1432 (1977).
Results:
Compound of Example No. IC50 (~u M) Tromboxane Synthetase
3 0.003
1 0.012
2 1.800
~ 0.008
0.007
9 0.021
0.069
11
6 3.400
7 0.001
12 0.260
13 0.013
