Note: Descriptions are shown in the official language in which they were submitted.
L~L ~
4-13454/CGC 945/-~
Substituted Imidazo[1,5-a]pyridines, process for their manufacture,
pharmaceutical preparations containing these compounds and their
therapeutic application
Imidazo[1,5-a]pyridines reported in the literature are for the most
part only functionally substituted on the imidazole portion of the
bicyclic ring system. For example 1- and 3-aminoalkyl subs-tituted
imidazo[l,5-a]pyridines and tetrahydro derivatives are described in
Journal of Medicinal Chemistry 16, 1272-6 (1973).
Surprisingly it was found, that imidazo [1,5-a]pyridine alkanoic
acids and derivatives represent a novel class of outstanding potent
and highly specific thromboxane synthetase inhibitors.
The oregoing advantages and attributes render the imidazo
[1,5-a]pyridine derivatives of this invention particularly useful
when administered, alone or in combination, to mammals, e.g. for the
treatment or prevention of diseases responsive to the inhibition of
thro~boxane synthetase comprising cardiovascular disorders such as
thrombosis, atherosclerosis, cerebral ischaemic attacks, myocardial
infarction, angina pectoris and hypertension; respiratory disorders,
such as asthma; inflammatory disorders; carcinoma, such as tumor
metastasis; and migraine headache.
This invention concers thereEore imidazo[l,5-a]pyridines of formula I
2 --
Rl ~ 2 (I)
CH -A-B
or 5,6,7,8-tetrahydro derivatives thereof, wherein each of Rl and R2
is hydrogen, halogen or lower alkyl, A is alkylene of 1 to 12 carbon
atoms, alkynylene or a].kenylene of 2 to 12 carbon atoms; B represents
carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di-(lower
alkyl) substituted carbamoyl, cyano or hydroxymethyl; or salts,
especially pharmaceutical]y acceptable salts thereof, process for
their manufacture, pharmaceutical preparations containing these
compounds and their therapeutic application.
Preferred embodiments of this invention relate to compounds of
formula I wherein the group CH2-A-B is attached at the 5 position.
Very useful are compounds of formula I wherein A is alkylene of 1 to
12 carbon atoms.
Particularly useful are compounds of formula II
Rl ~ r\ 2
(C~j ~
1 2 n
R3-C-(CH2) -B
R~
or 5,6,7,8-tetrahydroderivatives thereof, wherein Rl, R2, R3 and R4
are hydrogen or lower alkyl of l to 4 carbon atoms, n is 1 to 7, m is
O or l; B represents carboxy, lower alkoxycarbony]., unsubstituted or
mono- or di-(lower alkyl) substituted carbamoyl, cyano or hydroxy-
~2~
methyl; or salts, especially pharmaceutically acceptable salts thereof.
Especially useful are compounds of formula II or 5,6,7,8-tetrahydro
derivatives thereof, wherein Rl, R2, R3 and R~ are hyclrogen, methyl
or ethyl; (CH2) is propylene, butylene, pentylene or hexylene, m is
O or l; B represents carboxy, methoxycarbonyl or ethoxycarbonyl,
unsubstituted carbamoyl, monomethyl or monoethylcarbamoyl, dimethyl or
diethylcarbamoyl, cyano or hydroxymethyl; or salts, especially
pharmaceutically acceptable salts thereof.
Preferred in turn, are the compounds of formula II wherein the group
R3
(CH ) -¢-(CH ) -B
2 n 2 m
R~
is attached at the 5-position.
Exceedi~gly useful are compounds of formula III
0~ \
!~ ~ ~ (III)
(CH2)p-B
or 5,6,7,8-tetrahydro derivatives thereof, wherein p is 3 to 8; B
represents carboxy, lower alkoxycarbonyl, unsubstituted, mono- or di-
(lower alkyl) substituted carbamoyl; cyano or hydroxymethyl; or salts,
especially pharmaceutically acceptable salts thereof.
Especially valuable are compounds of formula IV
.~ \
(IV)
(1H2) COOH
~sv~
or 5,6,7,8-tetrahydro derivatives thereof, wherein q is 4, 5 or 6; or
salts, especial]y pharmaceutically acceptab]e acid or base addition
salts thereof.
The general definitions used herein have the following meanings
within the scope of the present invention.
An alkylene represents Cl 12-alkylene, may have a straight chain or
branched chain, and is preferably propylene, butylene, pentylene or
hexyiene, said radicals 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 alkenylene represents C2 12 alkenylene, which may have a
straight or branched chain, and is preferably propenylene, 1- or
2-butenylene, l- or 2-pentenylene, l-, 2- or 3-hexenylene, said
radicals 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 represents C2-Cl2 alkynylene, which may have a
straight or branched chain, and is preferably propynylene, l- or
2- butynylene, l- or 2-pentynylene, l-, 2- or 3--hexynylene, said
radicals 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 "lower" referred to above and hereinafter in connection with
organic radicals or compounds respectively defines such with up to and
including 7, preferably up and inrluding 4 and advantageously one or
two carbon atoms.
~5~
- 5
A lower alkyl group preEerably contains 1-4 carbon atoms and
represents for example ethyl, propyl, butyl or advantageously methyl.
A lower alkoxycarbonyl group preferably contains 1-4 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 1-4 carbon atoms in each
lower alkyl portion and represents for example N,N-dimethylcarbamoyl,
N-methyl-N-ethylcarbamoyl and advantageously N,N-diethylcarbamoyl.
Salts are preferably pharmaceutically acceptable salts, e.g. metal or
ammonium salts of said compounds of formuIa I when B represents
carboxy, more particularly alkali or alkaline earth metal salts, e.g.,
the sodium, potassium, magnesium or calcium salt; or advantageously
easily crystalli~ing ammonium salts derived from ammonia or organic
amines, such as mono- di- or tri-lower (alkyl, cycloalkyl or
hydroxyalkyl)-amines, lower alkylenediamines or (hydroxy-lower alkyl
or aryl-lower alkyl)-lower-alkylammonium bases, e.g., methylamine,
diethylamine, triethylamine, dicyclohexylamine, triethanolamine,
ethylenediamine, tris-(hydroxymethyl)-aminomethane or benzyl-tri-
methylammonium hydroxide. Said compounds of formula I form acid
addition salts, which are preferably such of therapeutically
acceptable inorganic or organic acids, such as 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, glycollic, lactic, malic, tartaric, gluconic, citric,
maleic, fumaric, hydroxymaleic, pyruvic, phenylacetic, ben70ic,
4-aminoben~oic, anthranilic, 4-hydroxyben~oic, salicylic, 4-amino-
salicylic, pamoic, nicotinic; methanesulfonic, ethanesulfonic,
3~'~
hydroxyetllanesulfonic, benzenesulfonic, p-toluenesulfonic,
naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid, or
ascorbic acid.
The compounds of this invention exhibit valuable pharmacological
properties, e.g. cardiovascular effects, by selectively inhibiting
the release of thromboxane through selective inhibition of thromboxane
synthetase in mammals. The compounds are thus useful Eor treating
diseases responsive to thromboxane synthetase inhibition in mammals
including man.
These effects are demonstrable in vitro assay tests or in vivo
animal testsusing advantageously mammals, e.g. guinea pigs, mice,
rats, cats, dogs or monkeys. Said compounds can be administered to
them enterally or parenterally, advantageously orally, or
subcutaneously, intravenously or intraperitoneally~ for example,
within gelatin capsules, or in the form of starchy suspensions or
aqueous solutions respectively. The applied dosage may range between
about 0.01 and 100 mg/kg day, preferably between about 0.05 and
50 mg/kg/day, advantageously be-tween 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. ~es.
Comm. 74, 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 hyman
platelets. The test compound (dissolved in buffer, or if necessary,
in a small amount of ethanol) is added to the incubation medium. At
the end of the incubation period (30 minutes) Prostaglandin E2 (PGE2)
is reduced to a mixture of Prostaglandin F2~ and E2~ (PGF2(~ )] by
addition of sodium borohydride. The radioactive products and excess
s~lbstrate are extracted into ethyl acetate and 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: glacial acetic acid (100 volumes: 100 volumes:
3 volumes). The radioactive zones are located; those corresponding to
Thromboxane B2 (TxB2) and PGF2 a + ~ are transferred to liquid
scintillation vials and counted. The ratio of counts Eor TxB2/PGF2
+ ~ is calculated for each concentration of test compound and
IC50 values are determined graphically as the concentration of test
compound at which the ratio of TxB2/PGF2 ~ is reduced to 50 % of
the control value.
The in-vitro effect on prostaglandin cyclooxygenase is measured by a
modification of the method of Tekeguchi et al described in
Biochemistry 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
C-arachidonic acid to PGE2 is measured. Test compounds (dissolved
in buffer, or if necessary, in small amount of ethanol) are added to
the incubation mixture. The prostaglandins are extracted and
separated by thin-layer chromatography; the plates are scanned, the
radioactive zones corresponding to PGE2 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 arnount 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:
C-Aracllidonic acid is incubated with an enzyme mixture consisting
of solubilized and partially purified prostaglandin cyclo oxygenase
from sheepseminal 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
amount of ethanol) is placed in the incubation medium.
The reaction mixture is incubated in 100 mM Tris HCl (pH 7.5) for
30 minutes at 37, acidified to pH 3 and extracted into ethyl
acetate. The extract is evaporated to dryness, the residue is
dissolved in acetone, spotted on thin-layer plates and chromatographed
in a solvent system described by Sun et al. The radioactive zones
are located with a scanner; those corresponding to 6-keto-PGF
( a stable end product of prostacyclin biotrasformation) and PGE~
are transferred to liquid scintillation vials and counted. The ratio
of counts for 6-keto-PGFl~/PGE2 is calculated for each concentration
of test compound used. IC50 values for inhibition are determined
graphically as the concentration of test compound at which the ratio
of 6-keto-PGFlo/PGE2 is reduced to 50 % of the control value.
The reduction of plasma levels of thromboxane is determined in vivo
on administration of the test compound to guinea pigs in the
following manner:
Guinea pigs are dosed with vehicle or test drug and injected
intraperitoneal]y with arachidonic acid (40 mg/kg) 2 hours later.
Blood is collected for analysis 1 hour after the arachidonic acid
challenge. A single aliquot of each plasma sample is assayed for
thromboxane B2 and another aliquot Eor 6-keto-PGFl~, the stable
metabolites of thromboxane A2 and prostacyclin (PGI2) respectively.
The compounds of the formula I are very potent thromboxane
synthetase inhibitors. At effective dose levels and greater, the
beneficial prostacyclin synthetase enzyme system is not inhibited9 nor
is the prostaglandin cyclooxygenese enzyme system.
The IC50 for a compound of the invention, e.g. 5-(5-carboxypentyl)-
imidazo[l~5-a]pyridine, is about 3XlO M for thromboxane synthetase
inhibition whereas the IC50 for both inhibition of prostacyclin
synthetase and cyclooxygenase is greater than lX10 M.
A compound of the invention, e.g. 5-(5-carboxypentyl)-imidazo[1,5-a]-
pyridine, also reduces the plasma levels ofthromboxane B2 by over
50 % in the guinea pig at an oral dose as low as 0.25 mg/kg; no
significant decrease with respect to prostacyclin is observed at the
said oral dose or at higher doses.
The aforementioned advantageous properties render the compounds of
this invention of grea-t value as specific therapeutic agents for
mammals including man. For example, in thromboembolism specific
inhibition of the enzyme thromboxane synthetase reduces arachidonic
acid induced platelet aggregation involved in clot formation.
Experimentally, prolongation of bleeding time in the rat is
indicative of a beneficial antithrombotic effect. The imidaæo[l,5-a]-
pyridines of this invention prolong bleeding time, e.g. 5-(5-carboxy-
pentyl3-imidazo[1,5-a]pyridine prolongs bleeding time when
administered to rats at a dose of about 1 mg/kg i.p. or lower.
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 obstruction.
Thus, for example, 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine protects
against sudden death when administered orally to mice at a dose of
100 mg/kg.
~S~?~
-- 10 --
The compounds of tiliS invention are prepared according to
conventional methods, advantageously by
1) condensing a compound of the formula VI
\~ \ ~
I ~ ~ (VI)
C 2M
wherein M is an alkali metal; Rl and R2 represent hydrogen or lower
alkyl, with a reactive functional derivative of a compound of the
formula VII
HO - A - B' (VII)
wherein A has the meaning given above, B' represents carboxy,
trialkoxymethyl, unsubstituted, mono- or di-(lower alkyl) substituted
carbamoyl, cyano, etherified hydroxymethyl or halomethyl9 to yield
a compound of formula Ia
Rl ~ ~ / 2
(Ia)
-A-B'
converting any resulting compound wherein B' differs from B, into a
compound of formula I; and, if desired, converting any resulting
compound of formula I into another compound of this invention.
Reactive organometallic compounds of formula VI wtlerein M is an alkalimetal are obtained bymetallization of the appropriate methyl
substituted imidazo[l,5-a]pyridine, e.g. 5-methylimidazo[1,5-a]-
pyridine, prepared as described in the Journal of Organic Chemistry
40, 1210 ~1975), with a reactive metallizing agent, e.g. butyl
3~
1 1 --
lithium or lithium diisopropylamide in an inert solvent such as
tetrahydrofuran at a temperature below room temperature, preferably
at about -50.
Condensation of the intermediate of formula VI with reactive
functional derivatives of a compound of formula VII proceeds at a
temperature range preferably from about ~75 to ~ 50~. In the case
where B' represents carboxy or mono(lower-alkyl)carbamoyl, the
appropriate metal salt, e.g. the lithium salt, of the reactive
functional derivative of the corresponding compound of formula VII
is first prepared for the condensation with intermediate VI.
Another process for the preparation of compounds of formula I
consists in
2) condensing a compound of formula VIII
l~o ~R2
i ~7~ (VIII)
~R5
wherein M is an alkali metal, Rl and R2 represent hydrogen or lower
alkyl, and R5 is lower alkyl, with a reactive functional derivative
of a compound of the formula IX
HOCH -A-B' (IX)
wherein A has the meaning given above, B' represents carboxy,
trialkoxymethyl, unsubstituted, mono- or di-(lower alkyl) substituted
carbamoyl, cyano, etherified hydroxymethyl or halomethyl;
converting in any resulting compound wherein B' differs from B, B'
into a group B; desulfurizing the resulting compound; and if desired,
converting any resulting compound into another compound of this
invention.
- 12 -
Preparation of Lhe organometallic intermediate VIII and subsequent
condensations are carried out as described under process l supra and
in Tetrahedron Letters 21, 21g5-6 (1980). Desulfurization is
preferably performed with a desulfuriæation catalyst such as Raney
nickel in a solvent such as ethanol, preferably at elevated
temperature.
A further process for the manufacture of compounds of formula I
consists in
3) condensing under basic catalysis a compound of the formula X
Rl~ ~R2
(X)
C 2R6
wherein Rl and R2 represents hydrogen or lower alkyl and R6
represents lower alkoxycarbonyl or cyano; with a reactive functional
derivative of a compound of the formula VII
H0-A-B' (VII)
wherein A has the meaning given above~ B' represents carboxy,
trialkoxymethyl, unsubstituted, mono- or di-(lower alkyl) substituted
carbamoyl, cyano, etherified hydroxymethyl or halomethyl;splitting off R6,
converting any resulting compound wherein B' differs from B into a
compound of formula I; and, if desired, converting any resulting
compound of formula I into another compound of the invention.
The intermediates of formula X are prepared from the compound of
formula VI supra on treatment with e.g. carbon dioxide and
esterifyingthe resulting carboxylic acid, or with a di-(lower)alkyl
carbonate or with a cyanogen halide.
Another process for tlle preparation of compounds of formula I
consists in
4) cyclizing a compound of formula XI
R~ /R2
~ 0~ ~ H (XI)
C ~ A-B" R2
wherein each of the symbols Rl, R2 ~ and R'2 represents hydrogen or
lower alkyl; A has meaning given above; and B" represents carboxy,
lower alkoxycarbonyl, unsubstituted, mono- or di-(lower alkyl)
substituted carbamoyl, cyano, hydroxymethyl, lower alkanoyloxymethyl,
etherified hydroxymethyl or halomethyl; to yield a compound of
formula Ib
l\ . R2 l
!~ C~ (Ib)
-A-B"
converting any resulting compound wherein B" differs from B into a
compound of formula I; and if desired converting any resulting
compound of formula I into another compound of the invention.
The cyclization of the amide of formula XI is advantageously carried
out with a Lewis acid, such as polyphosphoric acid, phosphorous
oxychloride or polyphosphate ester, optionally in an inert solvent
such as toluene, at a temperature range of 25 to 150, preferably
50 to 120.
The amides of formu]a XI are prepared by acylating a compound of
formula XII
- 14 -
~ N (XII)
C 2-~-B"
wherein Rl, R2, ~ and B" have meaning given above, with a
carboxylic acid of the formula XIII
R'2COOH (XIII)
wherein R'2 has meaning given above, or with a reactive functional
derivative thereof.
Reactive functional derivatives of compounds XIII are preferably acid
halides, simple or mixed anhydrides, such as the acid chloride, the
acid anhydride (R2"CO)20, or a mixed anhydride derived from a lower
alkoxycarbonyl halide, such as ethyl chloroformate, or from a
hindered lower alkanoyl halide, e.g., from pivaloyl chloride, by
methods well-known to the art.
Said condensation of compounds XII and XIII (the acylation of XII)
occurs either spontaneously by e.g. heating with formic acid, or in
the presence of condensing agents, e.g. disubstituted carbodiimides,
such as dicyclohexylcarbodiimide.
The acylation of compounds of formula XII with a reactive functional
derivative of XIII, e.g. acetyl chloride or acetic anhydride, occurs
advantageously in the presence of an organic or inorganic base, e.g.,
potassium carbonate, or triethylamine.
The amines of formula XII may be obtained, e.g. from the
correspondingly substituted 2-(cyano or lower hydroxyiminoalkyl)
pyridines by reduction, e.g. by hydrogenation in the presence of
a catalyst such as palladium on charcoal or by treatment wi~h a
chemical reducing agent such as borane or sodium cyanoborohydride, the
reducing agent being chosen according to the type of other
functional groups present in the molecule. The compounds of formula
XII may also be obtained by amination of the correspondingly
substituted and reactively esterified 2-(hydroxymethyl)-pyridines.
~ further process for the preparation of compounds of formula I
where A represents alkylene consists in
5) hydrogenating a compound of formula XIV
1~
1~-,,~2
I ~ ~ (XIV)
=CH-A'-B
wherein A' represents alkylene, alkenylene
or alkynylene having up to 11 carbon atoms, and, if desired,
converting any resulting compound of formula I into another
compound of the invention.
The reaction is carried out according to methods known per se, e.g.
preferably with hydrogen in the presence of a catalyst, preferably
palladium.
The starting materials of formula XIV may be prepared by e.g.
condensing a compound of formula XV
~1 ~ o\ ~ 2
~,b~ (xv)
o
- 16 -
(obtained e.g. by reacting a compound of formula VIII ~ith dimethyl-
formamide followed by desulfurization with Raney nickel) in a Wittig
reaction, for example, with a tr;(lower)alkyl 4-phosphono-
crotonate in the presence of a strong base, e.g. sodium hydride.
A further process Eor the preparation of compounds of formula I,
advantageously said compounds wherein A represents alkylene, comprises
6) in a compound of formula XVI
Rl~. R2
~7~ (XVI)
CH/ -A-C
or in its 5,6,7,8-tetrahydro derivative, wherein Rl, R and A are
as previously defined and C is a group convertible into a carboxy
group, converting said group C into carboxy, optionally by extending
the chain A within its definition, and, if desired, converting any
resulting compound of formula I into another compound of the inven-
tion.
Groups convertible into a carboxy group are, for example, esterified
carboxy groups, carboxy groups in form of their anhydrides, including
corresponding groups of asymmetrical and inner anhydrides, amidated
carboxy groups, cyano, amidino groups, including cyclic amidino groups
such as 5-tetrazolyl, iminoether groups, including cyclic iminoether
groups, e.gO 2-oxazolinyl or dihydro-2-oxazolinyl groups, substituted
by lower alkyl, and also hydroxymethyl, etherified hydroxymethyl,
lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl,
halomethyl, carboxycarbonyl (COCOOH), methyl, formyl (CtlO),
di(lower)alkoxymethyl, alkylenedioxymethyl, vinyl, or diazoacetyl.
Simultaneously with conversion of C into the carboxy group, the
chain A can be extended within its definition.
~ ~r~ ~3U ~
The conversion into the carboxy group is accomplisllecl by methods
wllich are known per se, and as described herein and in the examples,
e.g. by solvolysis such as hydrolysis or acidolysis, or
by reduction (esterified carboxy groups). For example
trichloroethyl or 2-iodoethyl ester may be converted into the
carboxylic ac-id by reduction, e.g. with zinc and a carboxylic acid
in the presence of water. Benzyl esters or nitrobenzyl esters may
be converted into the carboxy group by catalytic hyclrogenation, the
latter also with chemical reducing agents, e.g. sodium dithionite or
with zinc and a carboxylic acid. In addition, tert- butyl ester may
also be cleaved with trifluoroacetic acid.
In the reduction of the group C, an alkenylene or alkynylene chain A
may be converted into the corresponding alkylene chain.
Furthermore compounds oE formula XVI wherein C represents acetyl
may be oxidatively cleaved to the corresponding compounds of formula
I wherein B represents carboxy by conversion first to a compound
of formula XVI wherein C represents trihaloacetyl, e.g. tribromo or
triiodoacetyl, by treatment e.g. with sodium hypobromite followed
by cleavage with e.g. an aqueous base, such as sodium hydroxide.
The starting material of formula XVI wherein C represents acetyl is
in turn prepared from a compound of formula I(b) wherein B'
represents halomethyl by treatment with an a]ky] ester of acetocetic
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.
- lS -
Compounds of for~lula XVI 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, in tile presence of g]ass powder, or by treating e.g.
with hydrogen peroxide in the presence of a basic agent, e.g. sodium
hydroxide.
The starting materials of formula XVI wherein C represents COCOOH
are prepared by e.g. condensation of a compound of formula Ia
wherein B' represents halomethyl with e.g. 2-ethoxycarbonyl-1,3-
dithiane, and subsequent oxidative hydrolysis, e.g. with N-bromo-
succinimide in aqueous acetone followed by treatment with dilute
aqueous sodium hydroxide.
Compounds of formula XVI 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 or ozone to the corresponding compound of formula I wherein
B represents carboxy.
The starting carboxaldehydes, the compounds of formula XVI wherein
C represents methyl or formyl, may be prepared by oxidizing
compounds of formula I or Ia wherein B or B' represents
respectively hydroxymethy] or ha]omethyl with e.g. dimethylsul~oxide
and a cata]yst, such as a mixture of triethylamine and silver
~ ~r~
tetrafluoroborate. Said carboxaldehydes are converted to the
corresponding acetals, the compounds of formula XVI wherein C
represents di(lower)alkoxymethyl, or alkylenedioxymethyl e.g. a
dimethylacetal, by acid-catalyzed condensation with an alcohol, e.g.
methanol.
Compounds of formula I wherein B represents carboxy may be converted
by the well-known Arndt-Eistert synthesis to compounds of formula I
wherein B represents carboxy and the chain has been extended by 1
carbon atom. More particularly, a reactive functional derivative of
the starting carboxylic acid, e.g. the acid chloride, is treated
with diazomethane in e.g. diethyl ether to yield a compound of
formula XVI wherein C represents diazoacetyl. Rearrangement with e.g.
silver oxide yields said carboxylic acid of formula I wherein the
chain A has been extended by 1 carbon atom.
Compounds of formula XVI wherein C represents vinyl may be converted
to compounds of formula I wherein B represents carboxy by first
ozonolysis to compounds of formula XVI wherein C represents formyl,
which are in turn oxidized to compounds of formula I wherein B
represents carboxy.
Compounds of formula XVI wherein C represents vinyl may also be
treated with nickel carbonyl and carbon monoxide under high pressure
conditions to give compounds of formula I wherein B represents
carboxy and the chain length of A has been extended by 1 carbon atom.
Certain terms used in the foregoing processes have the meanings as
defined below.
Reactive functional derivative of alcohols oE formula VII and IX
are e.g. such esterified by a strong inorganic or organic sulfonic
- 20 -
acid above all a hydrohalic acid, e.g. hydrochloric, hydrobromic or
hydriodic acid, an aliphatic or aromatic sulfonic acid, e.g.
methanesulfonic acid or p-toluenesulfonic acid, and are prepared by
methods known in the art.
Trialkoxymethyl represents preferably tri(lower alkoxy)-methyl,
particularly triethoxy- or trimethoxymethyl.
Etherified hydroxymethyl represents preferably tertiary lower alkoxy-
methyl, lower alkoxyalkoxymethyl such as methoxymethoxymethyl, 2-oxa-
or 2-thiacycloalkoxymethyl particularly 2-tetrahydropyranyloxymethyl.
Halomethyl represents especially chloromethyl but may also be
bromomethyl or iodomethyl.
Lower alkanoyloxyrne-thyl represents preferably acetoxymethyl.
An alkali metal represents preferably lithium but may also be
potassium or sodium.
The indispensable steps of converting in a resulting compound of
aforesaid processes, in which compound B' or B" differs from B, into
a compound of formula I, and the optional conversion of the
resulting produc~ of formula I into another compound of this
invention are performed by chemical methodology known to the art.
Hydrolysis of intermediates wherein B' represents trialkoxymethyl to
compounds of formula I wherein B is carboxy is advantageously carried
out with inorganic acids such as hydrohalic or sulEuric acid.
Hydrolysis of intermediates wherein B' represents etherified
hydroxymethyl to compounds of formula I wherein B represents
hydroxymethyl is preferably carried out with aqueous solutions of
- 21 -
inorganic acids such asahydrollalic acid.
Intermediates of formula Ia or Ib wherein B7 or B'l is halomethyl may
be reacted preferalby with a metal cyanide such as potassium cyanide
in a conventional malmer to yield the compounds of formula I wherein
the chain is extended by 1 carbon atom and B is cyano. These in turn
are converted to compounds of formula I wherein B is carboxy, alkoxy-
carbonyl or carbamoyl using methods known t~ the art.
Thus, the compounds of formula I wherein B represents cyano
(nitriles) are converted to compounds of formula I wherein B is
carboxy by hydrolysis with inorganic acids e.g. a hydrohalic acid
such as hydrochloric acid or sulfuric acid in aqueous solution, or
advantageously by hydrolysis with aqeous alkali metal hydroxide e.g.
potassium hydroxideg preferably at reflux temperature.
The conversion of said nitriles to compounds of formula I wherein B
represents lower alkoxycarbonyl is advantageously carried out by
treatment first with a lower alkanol, e.g. anhydrous ethanol, in the
presence of a strong acid, e.g. hydrochloric 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 heydoxide, e.g. dilute sodium
hydroxide, and hydrogen peroxide, preferably at room temperature.
Furthermore, the intermediates of formula Ia or Ib wherein B' or B"
is halomethyl, 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 as diethyl malonate, in the presence of a base such as
potassium carbonate or sodium ethoxide, in a solvent such as
- .'2 -
dime~hylformamide, preferably at a temperature range from 50 to 100.
The resulting substituted cli(lower)alkyl malonate is hydrolyzed,
advantageously with 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 compouncls of formula I wherein B is cyano.
Compounds of formula Ia or Ib wherein B' or B" represents halomethyl
may be converted to a corresponding organometallic intermediate, e.g.
a cuprous or magnesium derivative, under conditions well known to
the art.
Condensation of e.g. the resulting organo magnesium (Grignard) reagent,e.g. a compound of formula Ia wherein B' representing halomethyl is
transformed to e.g. CH2MgCl, with carbon dioxide yields the compound
of formula I wherein B represents carboxy and the chain has been
extended by 1 carbon atom.
Condensation of said Grignard reagent with e.g. a lower alkyl
haloacetate or e.g. ethyl bromoacetate, yields a compound of formula I
wherein B represents lower alkoxycarbonyl and wherein the chain has
been extended by 2 carbon atoms.
Said Grignard reagent may be condensed in the presence of a cuprous
halide, e.g. cuprous chloride, with an ~,~3-unsaturated acid or ester,
e.g. propiolic or acrylic acid, to yield a compound of formula I
wherein B represents carboxy or lower alkoxycarbonyl and wherein the
chain has been extended by 3 carbon atoîns.
Furthermore, compounds of formula Ia or Ib wherein B' and B"
represent halomethyl may be condensed with e.g. the 3-lithio
derivative of propiolic acid (prepared in situ from propiolic acid
with e.g. lithium diisopropylamide) to yield a compound of formula I
wherein A represents a terminal alkynylene, B represents carboxy and
the chain length has been extended by 3 carbon atoms.
Compounds of the invention, wherein A represents straight chain or
branched alkenylene with a terminal double bondS may also be prepared
from intermediates of formula Ia or Ib wherein B' or B"is halomethyl.
~or instance, said intermediates are first treated with e.g. a lower
alkyl ester of an a-(aryl- or alkyl)-thioacetic acid such as ethyl
~-(phenylthio)-acetate, in the presence of a strong base such as
sodium hydride. Subsequent oxidation of the resulting ~-arylthio or
a-alkylthio substituted ester to the ~-arylsulfinyl or a-alkylsulfinyl
ester with e.g. sodium periodate, followed by heat-induced
elimination, by e.gO refluxing in xylene, yields a compound of general
formula I (an ~,~-unsaturated ester) wherein A represents alkenylene
and B represents e.g. lower alkoxycarbonyl, and the chain length has
been extended by two carbon atoms. Similarly, the compounds of
formula Ia wherein B' represents halomethyl may first be converted
to the corresponding carboxaldehydes with e.g. dimethylsulfoxide
in the presence of triethylamine and silvertetrafluoroborate.
Subsequent Wittig condensation e.g. with ethyl (triphenylphosphorany]-
idene)-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. methylamine,
dimethylamine in an inert solvent, e.g. a lower alkanol, such as
butanol, optionally at elevated temperatures, to yield compounds of
formula I wherein B represents unsubstituted, mono- or di-(lower)
alkylcarbamoyl.
The compounds of formula I wherein B represents unsubstituted
carbamoyl may be dehydrated to the corresponding nitrile by treatment
with e.g. triphenylphosphine or thionyl chloride in an inert solvent
such as toluene.
Conversion of compounds of formula I wherein B is lower alkoxycarbonyl,cyano; unsubstituted, mono- or di-(lower alkyl)carbamoyl to compounds
of formula I wherein B represents carboxy is advantageously carried
out by hydrolysis with 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 aluminium 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
or Ib wherein B' or B" is halomethyl by treatment with e.g. an
alkali metal hydroxide such as lithium or sodium hydroxide.
Said alcohols may in turn be transformed to the compounds of
formula I wherein B is carboxy with conventional oxidizingagents,
advantageously with pyridinum dichromate in dimethylformamide at
room temperature.
Said alcohols may also be transformed to the compounds of formula I
wherein B is carboxy and the chain has been extended by 1 carbon
atom, by treatment with nickel carbonyl and carbon monoxide under
high pressure conditions.
Free carboxylic acids may be esteriEied with lower alkanols such as
ethanol in the presence of a strong acid e.g. sulfuric acid
advantageously at elevated 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 compounds of formula I wherein B is lower alkoxycarbonyl.
Furthermore, the free carboxylic acids may be converted via
treatment of a reactive intermediate thereof~ e.g. an acyl halide
such as the acid chloride, or a mixed anhydride, e.g. such derived
from a lower alkyl halocarbonate suchas ethyl chloroformate, with
ammonia, mono- or di-(lower) alkylamines, in an inert solvent such
as methylene chloride, preferably in the presence of a basic
catalyst such as pyridine, to compounds of formula I wherein B
represents unsubstituted, mono or di-(lower)alkylcarbamoyl.
Compounds of formula I wherein B represents mono~lower) alkylcarbamoyl
are converted to compounds 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 agent, e.g. a lower alkyl halide
in an inert solvent, e.g. dimethylformamide.
Compounds of formula I are converted to the corresponding 5,6,7,8-
tetrahydroimidazo[l,5-a]pyridine compounds by reduction with hydrogen
in the presence of a hydrogenation catalyst, e.g. palladium, and an
acid e.g. a mineral acid, for instance hydrochloric acid in an inert
solvent, e.g. ethanol.
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 ca~alyst at atmospheric pressure in an inert
solvent, e.g. ethano], to compounds of formula I wherein ~ represents
straight chain or branched alkylene.
- 26 -
Furthermore compounds of formula I wherein Rl and ~2 represent
hydrogen can be converted to the corresponding halo derivatives by
direct halogenation with chlorine, bromine or iodine.
The above-mentioned reactions are carried out according to standard
methods, in the presence or absence of diluents, preferably such as
are inert to the reagents and are solvents thereof, of catalysts,
condensing or said other agents respectively and/or inert
atmospheres, at low temperatures, room temperature or elevated
temperatures, preferably at the boiling point of the solvents used,
at atmospheric or superatmospheric pressure.
The invetion 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 number of asymmetrical carbon atoms, as pure optical
isomers, such as antipodes, or as mixtures of isomers, such as
racemates, mixtures of diastereoisomers, mixtures of racemates or
mixtures of geometrical isomers.
~ ~r~
Resulting mixtures of diastereoisomers, mixtures of racemates and
geometric isomers can be separated on the basis of the physicochemical
differences of the constituents, in known manner, into the pure
isomers, diastereoisomers, racemates, or geometric isomers for
example by chromatography and/or fract;onal crystallisation.
Resulting racemates can furthermore be resolved into the optical
antipodes by known methods, for example by recrystallisation from an
optically active solvent, by means of microorganisms or by reacting
an acidic end product with an optically active base that forms salts
with the racemic acid, and separating the salts obtained in this
manner, for example on the basis of their different solubilities,
into the diastereoisomers, from which the antipodes can be liberated
by the action of suitable agents. Basic racemic products can
likewise be resolved into the antipodes, for example, be separation
of diastereomeric salts thereof, e.g. by the fractional
crystallization of d- or l-tartrates.
Advantageously, the more active of the two antipodes is isolated.
Finally, the compounds of the invention are either obtained in the
free form, or as a salt thereof. Any 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. A compound of Eormula I
wherein B represents carboxy can thus also be converted into the
corresponding metal or ammonium salts. These or other salts, for
example, the picrates, can also be used for purification of the
bases obtained; the bases are converted into salts, the salts are
- ~8 -
separated and the bases are liberated from the salts. In view of the
close relationship between the free compounds and the compo~mds in
the form of their salts, whenever a compound is referred to in this
context, a corresponding salt is also intended, provided such is
possible or appropriate under the circumstances.
The compounds, including their salts, can also be obtained in the
form of their hydrates, or inculde other solvents used for the
crystallisation.
The pharmaceutical compositions according to the invention are those
suitable for enteral, such as oral or rectal, and parenteral
administration to mammals, including man, for the treatment or
prevention of diseases responsive to inhibition of thromboxane
synthetase, such as peripheral vascular diseases, comprising an
effective amount of a pharmacologically active compound of formula I,
or pharmaceutically acceptable salts thereof, alone or in
combination with one or morepharmaceutically acceptable carriers.
The pharmacologically active compounds of the invention are useful in
the manufacture of pharmaceutical compositions comprising an effective
amount thereof in conjunction or admixture with excipients or
carriers suitable for either enteral or parenteral administration.
Preferred are tablets and gelatin capsules comprising the active
ingredient together with a) diluents, e.g. lactose, dextrose, sucrose,
mannitol, sorbitol, cellulose ancVor glycine, b) lubricants, e.g.
silica, talcum, stearic acid, its magnesium or calcium salt andVor
polyethyleneglycol, for tablets also c) binders, e.g. magnesium
al-minium silicate,starch paste, gelatin, tragacanth, methyl-
cellulose, sodium carboxymethylcellulose ancVor polyvinylpyrrolidone,
if desired, d) disintegrants, e.g. starches, agar, alginic acid or
its sodium salt, or effervescent mixtures and/or e) absorbents,
colorants, flavors and sweetners. Injectable compositions are
preferably aqueous isotonic solutions or suspensions, and
suppositories are advantageously fatty emulsions or suspensions. Said
compositions may be sterilized and/or contain adjuvants, such as
preserving, stabilizing, wetting or emulsifying agents9 solution
promoters, salts ~or regulating the osmotic pressure and/or buffers.
In addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to conventional
mixing, granulating or coating methods, respectively, and contain
about 0.1 to 75 %, preferably about 1 to 50%, of the active
ingredient. ~ unit dosage for a mammal of about 50 to 70 kg may
contain between about 10 to 200 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 about 15 and 100 mmHg.
u~
- 30 -
~xample 1: To a solution oF 50 g of S-methylimidazo[1,5-a]pyridine
[J. Org. Chem. 40, 1210 (1975)] in 625 ml of tetrahydrofuran pre-
cooled to -75 is added under nitrogen atmosphere 175 ml of 2.4 N
n-butyllithium in hexane while maintaining temperature below -53.
The solution of 5-(lithiomethyl)-imidazo[1,5-a]pyridine, is cooled
back to -75 and a solution of 121.8 g of 5-bromo-1,1,1-triethoxy-
pentane in 125 ml of tetrahydrofuran is added rapidly at which time
the temperature rises to -60. The reaction mixture is allowed to
warm to -4 over a 45 minute period and evaporated practically to
dryness. The residue is partitioned between 500 ml of ethyl ether
and 240 ml of 3N hydrochloric acid. The ether solution is further
extracted twice with 60 ml of 3N hydrochloric acid; the combined
aqueous extract is basified with 100 ml of concentrated ammonia
hydroxide and reextracted twice with 200 ml of ethyl ether. The
ether extract is dried over magnesium sulfate and evaporated to dry-
ness to give an oil which is distilled under high vacuum to give
5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine boiling at 180-185/
0.12 mm Hg.
Example 2: A suspension of 26 g of 5-(5-ethoxycarbonylpentyl)-
imidazo[l,5-a]pyridine in 100 ml of lN aqueous sodium hydroxide solu-
tion is heated on a steam bath for two hours; 10 ml of ethanol is
added and heating is continued for 45 minutes. The reaction mixture
is cooled, washed with 300 ml of ether and the solution is adjusted
to pH 5.5 with concentrated hydrochloric acid. The crystallized pro-
duct is collected by filtration and washed with 50 ml of water to
yield 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine melting at 144-147~.
Example 3:
a) To a solution of 39.6 g of 5-bromovaleric acid in 400 ml of tetra-
hydrofuran cooled to -78 is added slowly 93 ml of 2.3N n-butyl
lithium solution in hexane so as to maintain the temperature below
~ ~ 5 ~
- 31 -
-65. The suspension is stirred for 20 minutes. Then a solution of
5-(lithiomethyl)-imidazo[1,5-a]pyridine, prepared from 26.9 g of 5-
methylimidazo[l,5-a]pyridine and 93 ml of 2.3N n-butyl lithium solu-
tion as described in example 1, is added all at once at -75. The
reaction mixture is stirred at -75 for two hours, allowed to warm
to room temperature, treated with 15 ml of 12N hydrochloric acid, and
evaporated under vacuum.
The residue is partitioned between water and methylene chloride after
pH is adjusted to 10 with sodium carbonate. The aqueous solution is
further washed with chloroform, acidified to pH l with 12N hydro-
chloric acid and again washed with ether and toluene. After pH is
adjusted to 5.5 with sodium bicarbonate, extraction with chloroform
gives crude 5-(5-carboxypentyl)~imidazo-[1,5-a]pyridine. A solution
of the acid in 30 ml of acetonitrile is treated with 20 ml of 5N
ethanolic hydrochloric acid. After addition oE 25 ml oE ethyl ether,
5-(5-carboxypentyl)-imidazo[1,5-a]pyridine hydrochloride, melting at
201-204, crystallizes. 5-(5-Carboxypentyl)-imidazo[1,5-a]pyridine
(example 2) is obtained on neutralization of a methanolic solution
of the salt to pH 5 with dilute sodium hydroxide solution.
b) Similarly prepared from 6-bromohexanoic acid is 5-(6-carboxyhexyl)-
imidazo[l,5-a]pyridine melting at 137-139.
c) 5-(7-carboxyheptyl)-imidazo[1,5-a]pyridine melting at 97-101 is
similarly prepared from 7-bromoheptanoic acid.
Example 4: A solution of 37 g of 5-(5-chloropentyl)-imidazo[1,5-a]-
pyridine, 21.7 g of potassium cyanide and 3 g of dibenzo-18-crown-6
in 500 ml of acetonitrile is heated under reflux for 20 hours. The
acetonitrile is evaporated under reduced pressure, the residue is
partitioned between water and methylene chloride, and the methylene
- 32 -
chloride extract is evaporated to dryness. Treatment of a solution of
the residue in etiler with ethanolic hydrochloric acid yields 5-(5-
cyanopentyl)-imidazo[1,5-a]pyridine hydrochloride melting at 178 180.
The starting material is prepared as fo]lows:
A solution of 30 g of 1-bromo-4-c}llorobutane in 20 ml of dry tetra-
hydrofuran is added to a solution of 5-(lithiomethyl)-imidazo[1,5-a]-
pyridine (prepared from 22 g of 5-methylimidazo[1,5-a]pyridine and
80 ml of 2.3N solution of n-butyl lithium in hexane according to
example 1) while maintaining the temperature below -50. The reaction
mixture is stirred for 2 to 3 hours at -50, allowed to warm to room
temperature, stirred overnight, and evaporated to dryness.
The solution of the residue in 200 ml of methylene chloride is washed
with water, dried over magnesium sulfate and evaporated to dryness
to give the 5-(5-chloropentyl)-imidazo[1,5-a]pyridine which is used
without further purification.
Example 5: 5-(4-chlorobutyl)-imidazo[1,5-a]pyridine is converted in a
manner analogous to that described for Example 4, to 5-(4-cyanobutyl)-
imidazo[l,5-a]pyridine melting at 72-77.
Example 6: By a procedure analogous to that described for example 4
3,5-dimethylimidazo[1,5-a]pyridine [J. Het. Chem. 3, 33 (1966)] is
converted to 5-(5-chloropentyl)-3-methyl--imidazo[1,5-a]pyridine,
melting at 98-104. Reaction with potassium cyanide, under the con-
ditions of example 4, yields the 5-(5-cyanopentyl)-3-metilylimidazo-
[1,5-a]-pyridine which is converted into its hydrobromide salt by
dissolving the free base in acetonitrile and acidification of the so-
lution with ethanolic hydrogen bromide whereupon the 5-(5-cyano-
pentyl)-3-methyl-imidazo[1,5-a]pyridine hydrobromide crystallizes
and has a melting point of 215-220.
Example 7: A solution of 36 g of 5-(cyanopentyl)-imidazo[l,5-a]
pyridine in 100 ml of methanol and 50 ml of 45 % aqueous potassium
hydroxide solution is heated under reflux for 48 hours. The methanol
is removed by evaporation under reduced pressure, and water is added.
The basic solution is washed with ethyl acetate and acidified to pH
5.5-6 with concentrated hydrochlorid acid.
The crystallized acid is collected, and recrystallized from ethanol
to yield the product of example 2, namely the 5-(5-carboxypentyl)-
imidazo[l,5-a]pyridine melting at 142-145, further recrystallization
raises the melting point to 144-147.
Example 8: Hydrolysis of 5-(4-cyanobutyl)-imidazo[1,5-a]pyridine as
described for example 7 yields 5-(4-carboxybutyl)-imidazo[1,5-a]-
pyridine melting at 161-163.
Example 9: Hydrolysis as described for example 7, of 5-(5-cyano-
pentyl)-3-methyl-imidazo[1,5-a]pyridine yields 5-(5-carboxypentyl)-
3-methyl-imidazo[1,5-a]pyridine melting at 170~173.
Example _ To a solution of 3g oE 5-(5-cyanopentyl)-3-methyl-imidazo-
[1,5-a]pyridine hydrochloride in a mixture of 20 ml of ethanol and
5 ml of lN aqueous sodium hydroxide solution is added 10 ml of 30 %
hydrogen peroxide solution; 5 ml of ethanol and a sufficient volume
of lN sodium hydroxide solution to reach pH lO are then added.
After stirring at room temperature overnight, the ethanol is
evaporated under reduced pressure, water is added and the mixture is
extracted with methylene chloride. The resulting product is
crystallized from ether and recrystallized from acetonitrile to yield
~5~
- 3~1 -
5-(5-carbamoylpentyl)-imidazo[1,5-a]pyridine melting at 131-132.
Example 11: A solution of 3.9 g of 5-(5-ethoxycarbonylpentyl)-imidazo-[1,5-a]pyridine in 40 ml of n-butanol is saturated with methylamine
and heated on a steam bath for 56 hours in a pressure bottle. The
reaction mixture is evaporated to dryness; the resulting product is
first crystallized from ether and then recrystallized from 1:1 ethyl
acetate-ether to yield the 5-[5-(N-methylcarbamoyl)-pentyl]-imidazo-
[1,5-a]pyridine melting at 118-122.
Example 12: A solution of 2.45 g of 5-[5-(N-methylcarbamoyl)-pentyl]-
. .
imidazo[l,5-a]pyridine in 25 ml of dimethylformamide is treated with
0.011 mole of sodium hydride (obtained by washing 0.53 g of 50 ~
sodium hydride dispersion in mineral oil with hexane) and warmed
briefly on a steam bath. Methyl iodide (1.56 g) is added to the cooled
yellow solution. The mixture is stirred at room temperature for
2 hours, diluted with 100 ml oE water and extracted first with 150 ml
of a 1:1 mixture of ethyl acetate and ether and subsequently with
100 ml of chloroform. The residue obtained on evaporation of the
combined extracts to dryness is dissolved in 100 ml of ether and
treated with 20 ml of ethanolic hydrochloric acid. The precipitated
salt is collected, recrystallized first from 50 ml of 1:1 aceto-
nitrile/ethyl acetate and then from 30 ml of 1:1 ethanol/ether to
yield 5-[5--(N,N-dimethylcarbamoyl)-pentyl]-imidazo[1,5-a]pyridine
hydrochloride melting at 166-171.
Example 13: 5-(5-Carboxypentyl)-imidazo[1,5-a]pyridine (1,0 g) is
suspended in 5 ml of tetrahydrofuran. While stirring at room tempera-
ture, 2.35 g of trimethyl borate is added, followed by the slow
addition of 1.0 ml (equivalent to 0.01 mole) of boranemethyl sulfide
complex. The reaction mixture is heated at reflux temperature for
2 hours, cooled and quenched by the addition of 2.6 ml of methanol,
- 35 -
9.5 ml of water and 2 ml of 50 % sodium hydroxide solution. After
heating under reflux for 1 hour, the mixture is diluted with 50 ml
of water and extracted twice with 75 ml aliquots of methylene
chloride. The methylene chloride extract is evaporated to dryness.
The residue is treated with 4 ml of 5N ethanolic hydrochloric acid
in 30 ml of ether to yield the 5-(6-hydroxyhexyl)-imidazo[1,5-a]-
pyridine hydrochloride melting at 174-179.
Example 14: A solution of 11.1 g of 1-tetrahydropyranyloxy-8-bromo-
octane in 15 ml of tetrahydrofuran is added at -70 to a solution of
5-(lithiomethyl)-imidazo[1,5-a]pyridine (prepared from 5 g of 5-
methylimidazo[l,5-a]pyridine and 17.7 ml of 2.3N n-butyl lithium in
hexane according to example 1). The mixture was stirred at -70~ for
1 hour and then stirred overnight without additional cooling. A solu-
tion of the residue (after evaporation to dryness) in 50 ml of 4N
hydrochlorid acid is washed with 2 x 100 ml aliquots of ether,
basified with 75 ml of aqueous sodium hydroxide solution and extracted
twice with 100 ml aliquots of methylene chloride. The methylene
chloride extract is evaporated to dryness. Conversion to the hydro-
chloride salt with etheral hydrogen chloride and recrystallization
from ethanol/ether yields 5-(9-hydroxynonyl)-imidazo[1,5-a]pyridine
hydrochloride melting at 150-153.
Example 15:
a) A solution of 2.7 g of 5-(6-carboxyhexyl)-imidazo[1,5-a]-pyridine
in a mixture of 120 ml of ethanol and 30 ml of concentrated hydro-
chloric acid is hydrogenated at 3 atmospheres in the presence of 1 g
of lO % palladium on charcoal catalyst until 2 moles of hydrogen are
consumed. The mixture is filtered free of catalyst and evaporated to
dryness. The residue is recrystallized from isopropanol-ether to yield
the 5-(6-carboxyhexyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine
hydrochloride melting at 150-L54.
~" ~ t~
b) Similar hydrogenation of 5-(5-carboxypentyl)-imidazo[1,5-a]-
pyridine yields 5-(5-carboxypentyl)-5,6,7,8-tetrahydroimidazo[1,5-a]-
pyridine hydrochloride melting at 146-150.
c) Similar i~ydrogenation of 5-(~-carboxybutyl)-imidazo[1,5-a]pyridine
yields 5-(4-carboxybutyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine
hydrochloride melting at 120-123.
Example 16: A solution of 2.3 g (0.011 mole) of 5-bromo-3,3-dimethyl-
pentanoic acid [J. Org. Chem. 44, 1258 (1979)] in 20 ml of dry tetra-
hydrofuran is cooled to -70 under nitrogen, 5.05 ml of 2.4N n-butyl-
lithium in hexane is added dropwise. After addition is complete the
solution of 5-(lithiomethyl)-imidazo[1,5-a]pyridine in hexane
(prepared from 1.32 g of 5-methylimidazo-[1,5-a]pyridine and 5.05 ml
of 2.4N n-butyllithium in hexane) is added all at once. The mixture
is stirred at room temperature overnight.
The reaction mixture is diluted with 50 ml of water, 10 g of sodium
carbonate is added and the basic solution is then extracted 3 times
with 75 ml aliquots of chloroform. The aqueous phase is washed 3
times with 100 ml of ether after acidification to pH 2 with 12N
hydrochloric acid. Finally the aqueous phase is adjusted to pH 5
with dilute sodium hydroxide solution and extracted with 200 ml of
1:1 ethyl acetate/ether. The extracts are dried and evaporated to give
a yellow oil. ~laterial is crystallized from 50 m] of l:l ethanol/
ether to give 5-(5-carboxy-4,4-dimethylpentyl)-imidazo[1,5-a]pyridine,
melting at 124-129.
Example 17- Iodine crystals (1.9 g) are added to a well-stirred
solution of 1.16 g of 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine and
1.68 g of sodium bicarbonate in 10 ml of water and 1 ml of ethanol.
Additional 4 ml of ethanol are added to dissolve the bulk of the
~ j~ t;~
- 37 -
iodine and stirring is continued for 45 minutes. The reaction
mixture is diluted witll 125 ml of water and extracted twice with
methylene chloride at pH 8 (NaHC03 added if necessary). The aqueous
phase is concentrated in vacuo, charcoaled and adjusted to pH 4.5
with 2H hydrochloric acid. The precipitate is collected, dried and
recrystallized from methanol/ether to give l-iodo-5-(5-carboxy-
pentyl)-imidazo[l,5-a]pyridine melting at 163-165.
Example 18: Preparation of 10,000 tablets each containing 10 ml of
the active ingredient of Example 2:
~ormula:
5-(5-carboxypentyl)-imidazo[1,5-a]pyridine 100.00 g
Lactose 1,157.00 g
Corn starch 75.00 g
Polyethylene glycol 6,00075.00 g
Talcum powder 75.00 g
Magnesium stearate 18.00 g
Purified water q.s.
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 ~0 ml of water and the suspension added to the
boiling solution of the po]yethylene 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 using concave punches with 6.4 mm diameter,
uppers bisected.
- 38 -
Example 19: Preparation of 10,000 capsules each containing 25 mg of
the active ingredient oE Example 3b:
Formula:
5-(6-carboxyhexyl)-imidazo[1,5-a]pyridine 250.00 g
Lactose 1.800.00 g
Talcum powder 100.00 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 Eirst
with the talcum, then with the lactose until homogenous. No. 3
capsules are filled with 215 mg, using a capsule filling machine.
Example 20: A solution of 5-methylimidazo~175-a]pyridine (4.0 g) and
tetramethylethylene diamine ~4.9 g) in 100 ml of tetrahydrofuran is
cooled to 0 under nitrogen and 26.5 ml of 1.6N n-butyllithium in
hexane is added dropwise maintaining the temperature below 2. After
30 minutes this solution is transferred under nitrogen over 45 minutes
to an ice-cold solution of 5-bromovaleronitrile (4.86 g) in 80 ml
of tetrahydroEuran. After 15 minutes the solvent is evaporated and
the residue is partitioned between water and ethyl acetate. The
organic phase is reextracted with 2N hydrochloric acid (3x15 ml).
Basification of the aqueous phase to pH=10 with 50 % sodium hydroxide,
extraction with ethyl acetate (2x75 ml), drying over magnesium
sulEate, evaporation and chromatography (SiO2, ethyl acetate) yields
5-(5-cyanopentyl)-imidazo[1,5-a]pyridine.
Example 21: To a solution of ~I g of 5-(~-ethoxycarbonylbutyl)-3-
ethylthio-imidazo[1,5-a]pyridine in 100 ml of ethanol is added
approximately 5 g of Raney nickel.Thesolution is heated under reflux
for 18 hours. The Raney nickelisremoved by filtration and the filter
- 39 -
cake washed with 100 ml of ethyl acetate. The filtrate is evaporated
to dryness under reduced pressure to yield the product as a heavy oil.
This material is purified by column chromatography on silica gel
usingan ether-hexane mixture (1:3) as eluent. Evaporation of the
solvent under reduced pressure yields 5-(4-ethoxycarbonylbutyl)-
imidazo[l,5-a]pyridine as a yellow oil; NMR (CDC13) 1.25 (t, 3H),
4.15 (q, 2H), 8.1 (s, lH).
The starting material is prepared as follows:
17.8 g of 3-ethylthio-imidazo[1,5-a]pyridine is dissolved in 200 ml
of teteahydrofuran (dried) and cooled to -70. 80 ml of 1.6M n-butyl
lithium in hexane is added dropwise to the stirred solution over a
period of 15 minutes . On completion of the addition, the reaction
mixture is allowed to stir at -70 for a further 30 minutes. To the
reaction mixture is added dropwise a solution of 20 g of ethyl 4-bromo-
pentanoate in 75 ml of tetrahydroFuran. The reaction mixture is
allowed to warm up to -10 where it is maintained for 30 minutes and
subsequently is allowed to stand for 1 hour at room temperature. To
the reaction mixture is added 400 ml of diethyl ether and 400 ml of
4N hydrochlorid acid. The aqueous layer is separated and the ethereal
layer is washed with water. The combined aqueous extracts are
rendered basic with ammonium hydroxide and extracted with 3x200 ml of
ether. The ethereal extract is dried over anhydrous magnesium sulfate
and the solvent evaporated under red~lced pressure to yield the crude
product as a heavy oil. This material is purified by column chromato-
graphy on silica gel using a 4-1 mixture of pentane-diethyl ether as
eluent. On evaporation of the solvent the product was distilled to
give 3-ethylthio-5-(5-ethoxycarbonylbutyl)-imidazo[1,5-a]pyridine,
boiling at 170/0.3 mln Hg; NMR (CDC13) 1.25(t,3H), 1.30 (t,3~1),
3.15 (q,2H), 4.15 (q,2H).
. c~ ~. 5 U ~
- 40 -
Example 22: A solution of 3 g of 5-[5-ethoxycarbonyl~5-(phenyl-sul-
finyl)-pentyl]-imidazo[1,5-a]pyridine in 50 ml xylene is heated at
reflux temperature for 30 minutes under an atmosphere of nitrogen.
The xylene is then removed by distillation under reduced pressure,
the residue is dissolved in 15 ml of diethyl ether and purified by
column chromatography on silica gel. The product is eluted using a
2:1 mixture of diethyl ether and ethyl acetate as eluent. Evaporation
of the solvent yields 5-(5-ethoxycarbonylpent-4-enyl)-imidazo[1,5-a]-
pyridine as an oil; NMR (CDC13) 1.29 (t,3H), 4.25 (q,2H), 5.88 (d,lH).
The starting material is prepared as follows:
To an ice-cooled, magnetically stirred slurry of 0.96 g of sodium
hydride in 50 ml dimethylformamide is added 3.92 g of ethyl 2-(phenyl-
thio)acetate in a dropwise manner over a period of 15 minutes. The
suspension is stirred at room temperature for 2 hours and then cooled
to 5 by means of an ice-bath. To this suspension is added 4.16 g
of 5-(4-chlorobutyl)-imidazo[1,5-a]pyridine in a dropwise manner over
a period of 1 hour. On completion of the addition, 3.2 g of sodium
iodide is added to the reaction mixture which is then allowed to stir
overnight at room temperature.
The reaction mixture is poured into 150 ml of ice water and
extracted with 3xlOO ml aliquots of a 1:1 mixture of diethyl ether
and ethyl acetate. The organic phase is washed with 2xlOO ml of
saturated aqueous sodium chloride solution and then extracted with
3x50 ml portions of lN hydrochLoric acid. The acidic aqueous extracts
are combined, basified with ammonium hydroxide and extracted with
3x150 ml portions of a 1:1 mixture of diethyl ether and ethyl acetate.
These organic extracts are dried over anhydrous magnesium sulfate,
filtered and the solvent concentrated under reduced pressure to yield
the product as an oil, which is purified by column chromatography on
- 41 -
silica gel using diethyl etiler as eluent. Evaporation of the solvent
yields 5-[5-ethoxycarbonyl-5 (phenylthio)pentyl]-imidazo[1,5-a]-
pyridine as a heavy oil; N~IR (CDC13) 3.3-3.8 (lll); IR 1720 cm
To a solution of 3.8 g of 5-[5-ethoxycarbonyl-5-(phenylthio)-pentyl]-
imidazo[l,5-a]pyridine in lO0 ml of methanol is added 2.8 g of sodium
metaperiodate. The reaction mixture is allowed to stir at room tem-
perature for 18 hours. The solvent is evaporated under reduced
pressure and 150 ml of water is added to the residue, which is
extracted with 3xlO0 ml of ethyl acetate. The organic phase is
extracted with 2x50 ml portions of lN hydrochloric acid followed by
basification of the aqueous extract with ammonium hydroxide and re-
extraction into 2xlO0 ml portions of ethyl acetate. These combined
ethyl acetate extracts are dried over anhydrous magnesium sulfate,
filtered and the solvent concentrated under reduced pressure to yield
an oil which is purified by column chromatography on silica gel using
ethyl acetate, diethyl ether (1:1) as eluent. Evaporation of the
solvent yields 5-[5-ethoxycarbonyl-5-(phenylsulfinyl)-pentyl]-imidazo-
[1,5-a]pyridine as an oil; IR 1720 cm , 1040 cm
Example 23: To a solution of 300 mg of 5-(5-ethoxycarbonylpent-4-
enyl)-imidazo[1,5-a]pyridine in 20 ml methanol is added 5 ml of lN
sodium hydroxide. The reaction mixture is stirred at room temperature
for 18 hours. The methanol is evaporated under reduced pressure and
an additional 5 ml of water is added to the aqueous residue, which is
then extracted with 3x5 ml aliquots of ethyl acetate. The basic
aqueous layer is then adjusted to pH 5 and extracted with 3x5 ml
portions of ethyl acetate. These extracts are dried over anhydrous
magnesium sulfate, filtered and the solvent evaporated under reduced
pressure to yield 5-(5-carboxypent-4-enyl)-imidazol[1,5-a]pyridine
melting at 142-14~.
- 42 -
l~ample 24: To a solution of 2.75 g of 5-(5-formylpentyl)-imidazo[1,5-
a]pyridine in 180 ml of chloroform is added 6.5 g of carbethoxy-
methylene-triphenylphosphorane. The reaction mixture is stirred at
room temperature for l8 hours. The solvent is then evaporated under
reduced pressure to yield 5-(7-ethoxycarbonyl-hept-6-enyl-imidazo-
[1,5-a]pyridine as an oil.
The starting material is prepared as follows:
To a cooled (-60) solution of 4.9 g of 5-(5-methoxycarbonylpentyl)-
imidazo[l,5-a]pyridine (obtained by esterification of 5-(5-carboxy-
pentyl)-imidazo[1,5-a]pyridine of Example 2 with diazomethane in
methylene chloride) in 140 ml of methylene chloride is added 40 ml
of a 1.75 M solution of di-isobutyl aluminium hydride in hexane in
a dropwise manner over a 20 minute period. On completion of the
addition, the reaction mixture is allowed to stir at -60 for a
further 20 minutes. Then, 10 ml of methanol, followed by 100 ml of
water, are added to quench the reaction. The reaction mixture is
stirred at room temperature for 15 minutes, the methylene chloride
layer is separated and the solvent evaporated under reduced pressure
to yield 5-(5-formylpentyl)-imidazo[1,5-a]pyridine as an oil; NMR
(CDCl ) 9.7 (m,lH); IR (CH2C12) 1710 cm 1.
Example 25: To a solution of 2.8 g of 5-(7-ethoxycarbonyl-hept-6-
enyl) - imidazo[l,5-a]pyridine in 30 m]. of methanol is added 15 ml of
lN sodium hydroxide. The reaction is stirred at room temperature for
3 hours. The methanol is evaporated under reduced pressure and the
residue diluted with 30 ml of water and the solution adjusted to pH 7
with lN hydrochloric acid. The solution is extracted with 2x50 ml
of ethyl acetate. The combined ethyl acetate extracts are dried over
anhydrous magnesium sulfate, filtered and the solvent evaporated under
reduced pressure to yield 5-(7-carboxyhept-6-enyl)-imidazo[1,5-a]-
pyridine melting at 110-111.
~'t~?~
- 43 -
Example 26: To a solution of 150 mg of 5-(5-carboxypent~~l-enyl)-
imidazo[l,5-a]pyridine in 7 ml methanol is added 100 ml of 10 %
palladium on carbon as catalyst. The reaction mixture is hydrogenated
at atmospheric pressure for 3 hours. The catalyst is removed by
filtration and the solvent evaporated under reduced pressure to yield
5-(5-carboxypentyl)-imidazo[1~5-a]?yridine melting at 144-147, and
identical to the product of Example 2.
Example 27: To a solution of 180 mg of 5-(7-carboxyhept-6-enyl)-
imidazo[l,5-a]pyridine in 30 ml of methanol is added 200 mg of 10 %
palladium on carbon as catalyst. The reaction mixture is sub;ected to
hydrogenation at atmospheric pressure for 3 hours. The catalyst is
removed by filtration and the solvent evaporated under reduced pressure
to yield the product melting at 69-71, consisting of a mixture of
5-(7-carboxyheptyl)-imidazo[1,5-a]pyridine (the compound oE example 3c)
and 5-(7-carboxyheptyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.
Example 28: A solution of 0.1 g of 2-aminomethyl-3-(4-methoxycarbonyl-butyl)-pyridine in 0.6 ml of formic acid is heated at 90 for 18 hours.
The mixture is cooled to 0, made basic with saturated aqueous
ammonium hydroxide solution and extracted with methylene chloride
(4xlO ml). Drying, filtration and evaporation of extracts yields
2-(N-formylaminomethyl)-3-(4-methoxycarbonylbutyl)~pyridine, melting
at 43-45 which is redissolved in 1 ml of toluene and heated at 90
for 17 hours with 75 -ng of phosphorus oxychloride. Evaporation of
excess phosphorus oxychloride with toluene, basification at 0 with
saturated aqueous ammonium hydroxide solution, extraction with
methylene chloride (~x15 ml), drying of the extract over sodium
sulfate and evaporation yields an oil, which is chron~atographed
(silica gel, ethyl acetate) to yield as an oil, 8-(4-methoxycarbonyl-
butyl)-imidazo[1,5-a]pyridine; Rf 0.29; NMR (CDC13) 3.70 (s, 3H),
6.50 (d, 2H), 7.43 (s, lH), 7.83 (t, lH), 8.22 (s, lH); IR (CH2C12)
1725 cm
The starting material is prepared as follows:
A solution of 3-bromopyridine (7.9 g), methyl 4-pentenoate (7~15 g),
palladium acetate (0.11 g) and tri-o-tolylphosphine (0.6 g) in 50 ml
of triethylamine is refluxed for 24 hours under argon and the solvent
evaporated. The residue is taken up in methylene chloride (50 ml) and
washed with water (2x40 ml). The organic phase is dried and evaporated
to yield 3-(4-methoxycarbonylbut-1-enyl)-pyridine as a colorless
liquid; NMR (CDC13) 3.72 (s, 3H), 6.40 (S, lH); IR (film) 1725 cm
3-(4-21ethoxycarbonylbut-1-enyl)-pyridine (9.5 g) is hydrogenated in
100 ml of methanol at 3 atmospheres for 3.5 hours with 0.5 g of 5 %
palladium on charcoal to yield, after filtration and evaporat;on,
3-(4-methoxycarbonylbutyl)-pyridine as an oil; NMR (CDC13) 3.80
(s, 3H); IR (CH2C12) 1730 cm
Peracetic acid (40 %, 8.3 ml) is added dropwise to 3-(4-methoxy-
carbonylbutyl)-pyridine (10.81 g) so as to mainta;n the reaction
temperature between 80 and 85. After the addition is complete, the
temperature is allowed to fall to 30 and excess peracid is destroyed
wi~h aqueous sodium sulfite. The acetic acid is distilled at reduced
pressure, and the residue is taken up in methylene chloride (50 ml),
filtered and evaporated. The residue consisting of 3-(4-methoxy-
carbonylbutyl)-pyridine-N-oxide is treated with dimethyl sulfate
(7.7 g) in 40 ml of toluene at 90 for 1 hour and the solvent is
evaporated. The 3-(4-methoxycarbonylbutyl)-1-methoxypyridinillm methyl
sulfate salt is dissolved in 16.7 ml of ice-cold water and 8.3 ml of
lN sodium hydroxide, and a solution of potassium cyanide (11.21 g) in
16.7 ml of ice-cold water is added slowly so as to keep the reaction
temperature below 0. After 24 hours at 0, extraction with methylene
chloride (3x30 ml), drying over sodium sulfate and evaporation of
solvent yields a mixture of isomeric cyanopyridines from whi~h
- ~,5 -
2-cyano-3-(4-methoxycarbonylbutyl)-pyridine having Rf = 0.56 and NMR
(CDC13) 8.52 (m, lH), and 2-cyano-5-(4-methoxycarbonylblItyl)-pyridine
having Rf = 0.50 and N~IR (CDCl3) 8.72 (s, lH) were separated by chroma-
tography (silica gel, ether-pentane 3:2).
2-Cyano-3-(4-methoxycarbonylbutyl)-pyridine (2.40 g) is dissolved in
92 ml of methanol containing 2.4 ml of conc. hydroch]orid acid and
hydrogenated at atmospheric pressure with 1.2 g of 10 % palladium on
charcoal for 3 hours. Filtration, evaporation and recrystallization
from ether-rnethylene chloride yields 2-aminomethyl-3-(4-methoxy-
carbonylbutyl)~pyridine hydrochloride, m.p. 7g-81.
Example 29: A solution of 8-(4-methoxycarbonylbutyl)-imidazo[1,5-a]-
.
pyridine (30 mg) in 0.3 ml of ethanol and 0.3 ml of lN sodium
hydroxide is refluxed for 2 hours, cooled, diluted with 2 ml of
water and extracted with ethyl acetate (lx5 ml). The aqueous phase is
brought to pH=6 is extracted with methylene chloride (4xlO ml). The
extracts are dried and evaporated to yield 8-(4-carboxybutyl)-imidazo-
[1,5-a]pyridine, melting at 195-197.
Example 30: 2-Aminomethyl-5-(4-methoxycarbonylbutyl)-pyridine (0.20 g)is heated at 90 in 0.6 ml of formic acid for 18 hours. The mixture
is cooled to 0, made basic with saturated aqueous ammonium hydroxide
solution and extracted with methylene chloride (4x15 ml). Drying,
filtration and evaporation oE the extracts yields 2-(N-formylamino-
methyl)-5-(4-methoxycarbonylbutyl)-pyridine as an oil (IR 1720,
1675 cm ) which is redissolved in l ml of toluene and heated at 90
for 18 hours with phospllorus oxychloride (0.166 g). Evaporation of
excess phosphorus oxychloride with toluene, basification at 0 with
saturated ammonium hydroxide solution, extraction with methylene
chloride (4x15 ml) and drying of the extract over sodium sulfate
yields an oil which is chromatographed (silica gel, ethyl acetate) to
- 46 -
yield (6-(4-methoxycarbonylbutyl)-imidazo[1,5-a]pyridine; Rf = 0,26;
N~IR (CDC13) 3.58 (s, 3H), 6.45 (d, lH), 7.25 (d, lH), 7.38 (s, lH),
7.62 (s, lH), 7.94 (s, lH); IR (CH2C12) 1730 cm
The starting material is prepared as follows:
2-Cyano-5-(4-methoxycarbonylbutyl)-pyridine (1.48 g, see Example 28)
is dissolved in 56 ml of methanol containing 1.5 ml of concentrated
hydrochloric acid and hydrogenated at atmospheric pressure with 0.75 g
of 10 % palladium on charcoal for 18 hours. Filtration, evaporation,
chromatography on 20 g of silica gel with 1:1 methanol-ethyl acetate,
and crystallization from ether-methylene chloride yields 2-amino-
methyl-5-(4-methoxycarbonylbutyl)-pyridine as its carbonate melting at
79-80; NMR (CDC13) 3.67 (s, 3H), 4.24 (s, 2H); I~ (CH2C12) 1725 cm
Example 31: A solution of 92 mg of 6-(4-methoxycarbonylbutyl)-imidazo-[1,5a~pyridine in 0.3 ml of ethanol and 0.8 ml of lN sodium hydroxide,
is refluxed gently for 2 hours, cooled, diluted with 2 ml of water and
extracted with ethyl acetate (5 ml~. The aqueous phase is brought to
pH = 6 and is extracted with chloroform. The extracts are dried and
evaporated to yield 6-(4-carboxybutyl)-imidazo[1,5-a]pyridine, melting
at 168-171~.
Example 32: 2-(N-formylaminomethyl)-4-(3-methoxycarbonylpropyl)-
pyridine (33 mg) is dissolved in 1 ml of toluene and heated at 90
with phosphorus oxychloride (44 mg) for 18 hours under nitrogen. The
solvent is evaporated and the residue is suspended in methylene
chloride, cooled to 0 and made basic with saturated ammonium
hydroxide solution. The aqueous phase is extracted with methylene
chloride (4x15 ml) which is dried over sodium sulfate and evaporated
to yield 7-(3-methoxycarbonylpropyl)-imidazo[1,5-a]pyridine as an oil,
after purification by preparative thin layer chromatography (silica
gel, 3:1 ethyl acetate-methanol); ~MR (CDC13) 3.70 (s, 3 H), 6.45
(q, 1 H), 7.2 (s, 1 H), 7.32 (s, 1 H), 7.90 (d, 1 H), 8.08 (s, 1 H);
IR (CH2C12) 1730 cm
The starting material is prepared as follows:
Potassium cyanide (11.18 g) and dibenzo-18-crown-6 (1.0 g) are added
to a solution of 4-(3-chloropropyl)-pyridine (6.68 g) (prepared from
4-(3-hydroxypropyl)-pyridine), in 300 ml oE dry acetonitrile under
nitrogen. The mixture is refluxed for 24 hours, the solvent evaporated
and the residue partitioned between methylene chloride and water. The
aqueous phase is further extracted with methylene chloride (3xlO0 ml)
and the combined extracts are dried over sodium sulfate, decolorized
with charcoal and evaporated to yield 4-(3-cyanopropyl)-pyridine as
a colorless oil.
Hydrogen chloride is bubbled slowly into an ice-cooled methanolic
solution of 4-(3-cyanopropyl)-pyridine (5.5 g) for 2 hours and 100 ml
of water is added carefully. The solution is stirred for 15 minutes
and the solvent is evaporated. The residue is made basic with
saturated aqueous sodium bicarbonate solution and extracted with
methylene chloride (3xlO0 ml) which is dried over sodium sulfate.
Evaporation oE the solvent and filtration through 50 g of silica gel
in ether yields 4-(3-methoxycarbonylpropyl)-pyridine as an oil; NMR
(CDC13) 3.68 (s, 3 H), 7.05-7.25 (m, 2 H), 8.45-8.65 (m, 2 H); IR:
1725 cm
Peracetic acid (40 ~, 2.9 ml) is added to 4-(3-methoxycarbonylpropyl)-
pyridine (3.20 g) at room temperature. The mixture is heated at 80
for 1 hour and the acetic acid is evaporated after a test for peroxide
is negative. The residue is taken up in methylene chloride (50 ml),
filtered, and the solvent evaporated. The resulting 4-(3-methoxy-
~ 48 -
carbonylpropyl)-pyridine-N-oxide is treated with dimethylsulfate
(2.8 g, 22.2 mmol) in 12 ml of toluene at 80~ for 1 hour. The solvent
is evaporated to yield 5.45 g of the 4-(3-methoxycarbonylpropyl)-1-
rmethoxypyridinium methyl sulfate salt which is added at 0 to a solu-
tion of 89.75 g potassium cyanide in 20 ml of water. The reaction
mixture is stirred at 0 for 1 hour and 25 for 3 hours and then
extracted with methylene chloride (lx30 ml). The aqueous phase is re-
extracted after standing for 24 hours, wi.th methylene chloride
(lx30 ml) and the combined extracts are dried over sodium sulfate
and evaporated to yield a red oil. Chromatography on 70 g of silica
gel with ether as the eluent yields 2-cyano-4-(3-methoxycarbonyl-
propyl)-pyridine as an oil; NMR (CDC13) 3.67 (s, 3 H), 7.42 (d, 1 H),
7.60 (s, 1 H), 8.60 (d, 1 H); IR (CH2C12) 1725 cm
2-Cyano-4-(3-methoxycarbonylpropyl)-pyridine (0.83 g) is hydrogenated
at 3 atmospheres for 3 hours in 9 ml of methanol with 0.4 g of 10 %
palladium on charcoal. Filtration, evaporation, and preparative thin
layer chromatography on silica gel with 1:1 methanol-ethyl acetate
yields 2~aminomethyl-4-(3-methoxycarbonylpropyl)-pyridine; Rf = 0.37
(EtOAc-MeOH 1:1, 1 % NH40H~; NMR (CDC13) 3.67 (s, 3 }1), 4.15 (s, 2 H).
2-Aminomethyl-4-(3-methoxycarbonylpropyl)-pyridine (0.11 g) is heated
at 90 in 0.5 ml of 97 % formic acid for 18 hours. The reaction
mixture is cooled to room temperature, made basic with ammonium
hydroxide solution and extracted with methylene chloride (4 x 20 ml).
The organic extracts are dried over sodium sulfate and evaporated to
yield 2-(N-formylaminomethyl)-4-(3-methoxycarbonylpropyl)-pyridine;
IR (CH2C12) 1735, 1685 cm
Example 33: 7-(3-methoxycarbonylpropyl)-imidazo[1,5-a]pyridine
(Example 32, 8.0 mg) is dissolved in 0.3 ml of methanol and 0.1 ml of
lN sodium hydroxide is added. The mixture is stirred at 25 for
~r~5~
- 49 -
5 ho~lrs, evaporated, and the residue is redissolvecL in 5 ml of water.
The aqueous solution is washed with 2 ml of ethyl acetate, brought to
pH=6 with 2N sulfuric acid and extracted with methylene chloride
(3x5 ml). The organic extracts are dried over sodium sulfate/magnesium
sulfate and evaporated to yield 7-(3-carboxypropyl)-imidazo[1,5-a]-
pyridine, IR (CHC13) 1720 cm
Example 34: A solution of 7 [4,4-(bis-methoxycarbonyl)-butyl]-imidazo-[1,5-a]pyridine (65 mg) in 0,8 ml of lN sodium hydroxide and 0.5 ml
of ethanol is heated at reflux for 2 hours. The solvent is evaporated
and 0.8 ml of lN hydrochloric acid is added. After the water is
evaporated, the residue is redissolved in 3 ml of xylene and heated
at 137 for 4 hours. The xylene is evaporated and replaced with 2 ml
of lN sodium hydroxide. Extraction of the aqueous phase with ethyl
acetate (5 ml), acidification to pH=6, reextraction with chloroform
~3x15 ml) and evaporation yields 7-(4-carboxybutyl)-imidazo[1,5-a]-
pyridine, melting at 158-161.
The starting material is prepared as follows:
According to procedures previously described (e.g., Examples 28, 32),
4-(3-chloropropyl)-pyridine is converted to 4-(3-chloropropyl)-2-
cyanopyridine; NMR (C~C13) 3.56 (t, 2 H), 7.40 (d, 1 H), 7.57 (s, 1 H),
8.60 (d, 1 H ).
A solution of borane-dimethylsulfide (0.83 ml, 7.7 mmol) in 7 ml of
tetrahydrofuran is added slowly to a refluxing solution of 4-(3-
chloropropyl)-2-cyanopyricline (1.24 g, 6.9 mmol) in 7 ml of tetrahydro-
furan while dimethylsulfide simultaneously distills off. The mixture
is refluxed for 15 minutes after the addition is complete, cooled to
30 and 6 ml of 6N hydrochloric acid is added. After hydrogen evolu-
tion ceases, the mixture is refluxed for 30 minutes, cooled to 0 and
saturated with solid sodium carbonate beEore extracting with methylene
- 50 -
chloride (4x50 ml). The or~anic extracts are dried over sodium sulfate
and evaporated to yield an oil which is filtered through 10 g of
silica gel (1:1 EtOAc-~leOil) to yield 2-aminomethyl-4-(3 chloropropyl)-
pyridine as a yellow oil; NMR (CDC13) 3.55 (t, 2 H), 4.20 (s, 2 H).
A solution of 2-aminomethyl-4-(3-chloropropyl)-pyridine (0.47 g) in
1 ml of formic acid is heated at 90 for 18 hours, cooled to 0 and
made basic by the addition of saturated aqueous ammonium hydroxide
solution. ~xtraction with methylene chloride (4xlO mL), drying over
sodium sulfate and evaporation yields 2-(N-formylaminomethyl)-4-(3-
chloropropyl)-pyridine (IR 1674 cm ) which is heated at 90 in
phosphorus oxychloride (0.75 g) for 15 hours. Excess phosphorus oxy-
chloride is evaporated with toluene and the residue is suspended in
methylene chloride (15 ml), cooled to 0 and made basic with saturated
ammonium hydroxide. Extraction with methylene chloride (4x15 ml),
drying over sodium sulfate and preparative thin layer chromatography
(silica gel, EtOAc) of the residue yields 7-(3-chloropropyl)-imidazo-
[1,5-a]pyridine (Rf = 0.24, EtOAc) as a gum; NMR (CDC13) 3.58
(t, 2 H), 6,42 (q, 1 H), 7.21 (s, 1 H), 7.32 (s, 1 H), 7.88 (d, 1 H),
8.07 (s, 1 H).
A solution of 7-(3-chloropropyl)-imidazo[1,5-a]pyridine (50 mg), di-
methyl malonate (0.14 g) and potassium carbonate (144 mg) in 2 ml of
dimethylformamide is heated between 80 and 90 under nitrogen for
9 hours. The solvent is evaporated and the residue taken up in 10 ml
of water and extracted with ethyl acetate (2xlO ml). The organic
extracts are washed with 2N hydrochlorid acid (2xlO ml). Basification
of the aqueous extracts with solid sodium bicarbonate, extraction with
methylene chloride (3xlO ml), drying over sodium sulfate and evapora-
tion yields 7-[4,~-(bis-methoxycarbonyl)-butyl]-imidazo[1,5-al-
pyridine, NMR (CDC13) 3.40 (s, 6 H), 6.06 (d, 1 H); IR (CH2Cl~)
1725 cm
Example 35: A solution of 5-[5,5-(bis-ethoxycarbonyl)-pentyl]-imidazo-~1,5-a]pyridine (0.60 g) in 6.5 m] oE 1 N sodium hydroxide and 4 ml
of ethanol is refluxed for 2 hours. The solvent is evaporated and
6.5 ml of lN hydrochloric acid is added. The water is then evaporated
and the resulting 5-[5,5-(bis-carboxy)-pentyl]-imidazo[1,5-a]pyridine
is heated at 137 for 4 hours in 25 ml of xylene. The xylene is
replaced with 16 ml of lN sodium hydroxide. Extraction of the aqueous
phase with ethyl acetate (15 ml), acidification to pH=6, reextraction
with chloroform (3x40 ml), drying over magnesium sulfate and evapor-
ation yields 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine melting at
146-147 (compound of Example 2).
The starting material is prepared as follows:
A solution of 5-(4-chlorobutyl)-imidazo[1~5-a]pyridine (0.42 g),
diethyl malonate (1.34 g) ancl potassium carbonate (1.15 g) in 20 ml
of dimethylformamide is heated between 80 and 90 under nitrogen for
10 hours. The solvent is evaporated and the residue taken up in 50 ml
of water. The aqueous phase is extracted with ethyl acetate (3x40 ml).
The extracts are washed with cold 2N hydrochloric acid (3xlO ml).
~asification of the aqueous phase with solid sodium bicarbonate,
extraction with methylene chloride (3x20 ml), drying over sodium
sulfate and evaporation yields the 5-[5,5-(bis-ethoxycarbonyl)-pentyl]-
imidazo[l,5-a]pyridine, melting at 59-61.
The starting material, 5-(4-chlorobutyl)-imidazo[1,5-a]pyridine, is
prepared by the procedure described for the starting material in
Examp-Le 4, using 1-bromo-3-chloropropane as the reagent instead of
l-bromo-4-chlorobutane therein.
Example 36: l'yridinium dichromate (0.94 g) is added as a solid to
a solution of 5-(6-hydroxyhexyl)-imidazo[1,5-a]pyridine (123 mg) in
- s~ -
10 ml of N,N-dimethylformamide at 25 under nitrogen. The solution is
stirred for 6 hours, poured into 150 ml of water and extracted with
methylene chloride (5x20 ml). The organic extracts are washed with lN
sodium hydroxide. Acidification of the aqueous phase to pH=6, extrac-
tion with methylene chloride, drying over sodium sulfate/magnesium
sulfate and evaporation yields 5-(5-carboxypentyl)-imidazo[l,j-a]-
pyridine of Example 2 melting at 145-146.
Example 37: 5-Methylimidazo[1,5-a]pyridine [J. Org. Chem. _, 1210
(1975), 424.7 g] is charged into a 12 liter flask equipped with
mechanical stirrer, thermometer and nitrogen atmosphere. Dry tetra-
hydrofuran (3,000 ml) is charged into the flask and the resulting
solution is cooled to -65 in a dry ice/acetone bath. N-Butyllithium
(1.0 mole, 2.4N in hexane) is poured into the flask all at once under
a nitrogen atmosphere. The temperature rises to -32. The mixture is
recooled to -50 and a second mole of n-butyllithium is charged in
the same manner. A second temperature rise occurs and after again
cooling to -50, a third mole of the n-butyl-lithium is charged into
the reactor. The reaction mixture is then stirred for twenty minutes,
the temperature drops to -65. To this stirring solution a cold (-67)
solution of 5-bromo-1,1,1-triethoxypentane (606.9 g) in 500 ml of
tetrahydrofuran is added as repidly as possible, raising the tempera-
ture to -25. The reaction mixture is then warmed to -15 and stirred
for 2 hours. Acetic acid (50 ml) is added and most of the solvent is
removed under vacuum. The resiclue is taken up in 2,000 ml of ethyl
ether; acetic acid (100 ml) and 12N hydrochloric acid (100 ml) are
added while the reaction mixture is cooled to 0. After 15 to 20
minutes, ice-cold 7.5N ammonium hydroxide (lOOO ml) is added. The
organic phase is separated and the aqueous is washed with ethyl ether
(500 ml). The pH of the aqueous layer is adjusted to 9 with ammonium
hydroxide and extracted again with ethyl ether (500 ml). The combined
ether extracts are washed with a dilute sodium chloride solution and
- 53 -
basified to pH 13-14 with potassium hydroxide. The ether extract is
treated with charcoal and magnesium sulfate. The mixture is filtered
and evaporated to give a dark oil which is dried at 2mm llg. The oil
is distilled under high vacuum to give 5-(5-ethoxycarbonylpentyl)-
imidazo[l,5-a]pyridine of Example 1, boiling at 220/0.2 mm Hg.
The starting 5-bromo-1,1,1-triethoxypentane is prepared as follows:
5-Bromovaleronitrile (1,200 g) is charged into a 5 liter 3 neck
flask under nitrogen atmosphere. The complete reaction vessel is then
placed in an ice bath. Then hydrogen chloride gas (287 g) is slowly
bubbled into the reaction vessel. The reaction mixture is then diluted
with ethyl ether (3,200 ml) and stirred at 4 overnight. The resulting
suspension is cooled to -30 in a dry ice/acetone bath. The solid is
collected, washed with ethyl ether and dried in a vacuum dessicator
over potassium hydroxide and phosphorous pentoxide for 3 days to give
ethyl 5-bromoimidovalerate hydrochloride which is used in the next
step without further purification.
Ethyl 5-bromoimidovalerate hydrochloride (556 g) is charged into a 12
liter flask equipped with a mechanical stirrer under a nitrogen
atmosphere. ~nhydrous ethanol (836 g) is added and the reaction
mixture is stirred at room temperature for 2 hours, at which time
a clear solution is obtained. Ethyl ether (3700 ml) is charged into
the flask and stirring is continued for 3 days at room temperature.
The solution is cooled to -30 and filtered to remove ammonium
chloride. The filtrate is evaporated to dryness in a rotary evaporator
under vacuum. The residue is distilled under high vacuum (0.2 mm Hg),
using a 12 cm fractionation column. The main fraction distilling at ca
71-82 is collected, and redistilled with a 46 cm column to yield
5-bromo-1,1,1-triethoxypentane, b.p. 60-2/0.2 mm Hg.
- s~, -
5-(5-Ethoxycarbonylpentyl)-imidazo[l~5-a]pyridine can also be prepared
from 2-(N-formylaminomethyl)-6-(5-ethoxycarbonylpentyl)-pyridine
essentially according to the cyclization procedure described in
Examples 28, 30 and 32.
rxample 38: 5-(5-Ethoxycarbonylpentyl)-imidazo[l,S-a]pyridine
(1091 g) is charged into a 12 liter round bottom flask under a
nitrogen atmosphere. Ethyl alcohol (95 %, 420 ml) is added while
stirring. ~ith continued stirring9 2N sodium hydroxide (2100 ml) is
added in portions. After complete addition the mixture is warmed at
70~ for 20 minutes, at which time a solution is obtained, and heating
is continued for 2 hours. Additional sodium hydroxide (50 % solution,
21 ml) is added and heating is continued for 40 more minutes. The
reaction mixture is cooled, 12 N hydrochloric acid (30 ml) is added,
and the ethyl alcohol ls partially removed by evaporation under
reduced pressure. The resulting solution is washed with ethyl ether
(1700 ml), decolorized with charcoal, filtered, and acidified with
acetic acid (300 ml). The product that crystallizes at 4 overnight
is collected, washed first with water, then with ethyl ether (1000 ml),
and dried to give 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine, melting
at 146-148C, and identical to the product of Example 2.
Example 39: The following compounds are prepared analogously to the
procedures described in the previous examples.
a) 5-(4-ethoxycarbonyl-but-3-enyl)-imidazo[1,5-a]pyridine by conden-
sation of 5-methylimidazol[1,5-a]pyridine with ethyl 4-bromo-
crotonate;
b) 5-(9-hydroxynorl-7-ynyl)-imidazo[1,5-a]pyridine by condensation of
l-tetrahydropyranyloxy-8-bromooct-6-yne with 5-methylimidazo[1,5-a]-
pyridine and subsequent hydrolysis.
~f~ 3~ ~
I.xample 40: A solution of 5-(6-oxoheptyl)-imidazo[1,5-a]pyridine
(0.35 g) in 10 ml of dioxane is added slowly to a vigorously stirred
aqueous solution (3 ml) of sodium hypobromite (5.2 mmol) at 22-25
(ice-bath cooling, if necessary). After 3 hours the unreacted sodium
hypobromite is destroyed with sodium bisulfite and the solvent is
evaporated. The residue is redissolved in 10 ml of 0.5N sodium
hydroxide, extracted with ether (2x5 ml) and brought to pH=6 with
concentrated sulfuric acid. Extraction with methylene chloride
(3xlO ml), drying over sodium sulfate/magnesium sulfate and evapora-
tion yields 5-(5-carboxypenty])-imidazo[1,5-a]pyridine of Example 2.
The starting material is prepared by treatment of 5~ -chlorobutyl)-
imidazo[l,5-a]pyridine with ethyl acetoacetate in the presence of
sodium hydride, followed by hydrolysis with dilute sodium hydroxide.
Example _ A single crystal of iodine is added to a mixture of
magnesium turnings (36.1 mg, 1.5 mmol) and 5-(~-chlorobutyl)-imidazo-
[1,5-a]pyridine (3l3 mg) in 0.2 ml of dry tetrahydrofuran under nitro-
gen. When the magnesium turnings have dissolved, an additional 2 ml
of anhydrous tetrahydrofuran are added, followed by ethyl bromoacetate
(0.43 g). The reaction mixture is stirred at room temperature for
1 hour, refluxed for 30 minutes, cooled to 25, diluted with 20 ml
of ethyl acetate and washed with water (2xlO ml). Drying, filtration
and evaporation of the organic phase yields 5-(5-ethoxycarbonylpentyl)-
imidazo[l,5-a]pyridine as an oil which is refluxed for 3 hours in 10 ml
of methanol and 5 ml of LN sodium hydroxide. The methanol is evaporated
and the residue is redissolved in 10 ml oE water, washed with 10 ml
of ethyl acetate and brought to pll=6 with concentrated hydrochloric
acid. Extraction with methylene chloride (5xlO ml), drying over sodium
sulfate/magnesium sulfate and evaporation yields 5-(5-carboxypentyl)-
imidazo[l,5-a]pyridine of Example 2.
- 56 -
Example 42: A single crystal of iodine is added to a mixture of
magnesium turnings (36.5 mg) and 5-~5-chloropentyl)-imidazo[1,5-a]-
pyridine (3l3 mg) in 0.2 ml of anhydrous tetrahydrofuran under nitro-
gen. I~len the magnesium turnings have dissolved, an additional 2 ml
of tetrahydrofuran is added. The solution is cooled to -5 9 and dry
carbon dioxide is bubbled through the solution wi.th vigorous stirring
for 30 minutes. The solvent is evaporated and the residue is dissolved
in 10 ml of 25 % sulfuric acid~ washed with 5 ml of ether. Acidifica-
tion to pH=6, extraction with methylene chloride (4x15 ml), drying
of the extract over magnesium sulfate and evaporation oE the solvent
yields 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine of Example 2.
Example 43: A mixture of 5-(6-carboxy-6-oxohexyl)-imidazo[1,5-a]-
pyridine (0.52 g) and 0.5 g of glass powder is heated gradually
to 240. The reaction mixture is maintained at 240 for 1 hour and
cooled to room temperature. The residue is taken up in methylene
chloride and the solid filtered. Evaporation and recrystallization
yields 5-(5-carboxypentyl)-imidazo[1,5-a]-pyridine of Example 2.
The starting material may be prepared as follows:
5-(5-chloropentyl)-imidazo[1,5-a]pyridine is dissolved in dimethyl-
formamide and reacted with 2-ethoxycarbonyl-1,3-dithiane and sodium
hydride followed by treatment with ~-brorno-succinirnide in aqueous
acetone and hydrolysis with dilute sodium hydroxide yields the 5-(6-
carboxy-6-oxohexyl)-imidazo[1,5-a]pyridine.
Exarnple 44: A solution of 5-(4-carboxybutyl)-imidazo[1,5-a]pyridine
(0.22 g) and oxalyl chloride (0.2 g) in 10 ml of chloroform is refluxed
for 1.5 hours. The solvent is evaporated, the residue is redissolved
in 15 ml of freshly distilled dry dioxane, and the solution is added
to an equimoLar ethereal solution of diazomethane with external
cooling to keep the reaction at or below 0. The mixture is allowed
- 57 -
to stand at room temperature overnight and the ether is evaporated
carefully. A solution of silver oxide (0.14 g) in 1 ml of 0,84 M
sodium thiosulEate is added to the dioxane so]ution of the resulting
diazo compound. Tile mixture is stirred for 3 hours at room tempera-
ture while additional silver oxide (0.14 g) is added portionwise, then
stirred for l hour at 50, cooled, filtered and extracted with 1 %
aqueous sodium hydroxide solution. Acidification of the aqueous phase
with concentrated sulfuric acid, extracting with methylene chloride,
drying of the extract over magnesium sulEate and evaporation yields
5-(5-carboxypentyl)-imidazo[1,5-a]pyridine oE Example 2.
Example 45: A mixture of 4.1 g of 5-(5-hydroxypentyl)-imidazo[1,5-a]-
pyridine, 1.5 ml of water, 1.7 g of nickel carbonyl, 0.5 g of nickel
chloride hexahydrate and 0.3 ml of concentrated hydrochloric acid is
heated under a high pressure of carbon monoxide for 10 hours. All
volatile material is evaporated. The remaining aqueous phase is
washed with ether (5 ml), made basic (pH=10) with 6N sodium hydroxide
and reextracted with ether (10 ml). Acid;fication to pH=6, extraction
with methylene chloride, evaporation and recrystallization from chloro-
form/ether yields 5-(5-carboxypentyl) imidazo[l,5-a]pyridine of
Example 2.
Similar treatment of 5-(4-pentenyl)-imidazo[1,5-a]pyridine with nickel
carbonyl also yields 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine.
Example 46: A mixture of silver nitrate (0.34 g) in 10 ml of water
and 5-(5-formylpentyl)-imidazo[1,5-a]pyridine (0.2 g in 10 ml of
dioxane is brought to pH=10 with lN sodium hydroxide and warmed gently
between 70 and 80 for 1 hour. The precipitated silver is filtered
through celite and the volume reduced by 50%. The remainign aqueous
base is extracted with ethyl acetate, brought to pH=6 with concentrated
sulfuric acid and extracted with methylene chloride (5xlO ml). Drying
~/~ 2 ~ L~
- 58 -
over sodium sulfate/magnesium sulfate and evaporation yields 5-(5-
carboxypentyl)-imidazo[1,5-a]pyridine.
The starting material 5-(5-formylpentyl)-imidazo[1,5-a]pyridine is
prepared as follows:
5-(6-Chlorohexyl)-imidazo[1,5-a]pyridine is treated with dimethyl-
sulfoxide, triethylamine and silver tetrafluoroborate according to
the method described in Tetrahedron Letters 1974, 917.
Example 47: Ozone is bubbled through a solution of 5-(6,6-dimethoxy-
hexyl)-imidazo[1,5-a]pyridine (0.456 g) in 20 ml of methylene chloride
at -50 for 4 hours. Excess ozone is driven off with nitrogen and 1 ml
of dimethyl sulfide is added at 78 and the reaction mixture is
allowed to warm slowly to room temperature. The solvent is evaporated,
the residue is taken up in 10 ml of methanol and ref:Luxed with 10 ml
of lN sodium hydroxide for 2 hours. The methanol is evaporated and the
residue is washed with ethyl acetate (5 ml) and brought to pH=6 with
concentrated sulfuric acid. Extraction with methylene chloride
(SxlO ml), drying over magnesium sulfate and evaporation yields 5-
(5-carboxypentyl)-imidazo[1,5-a]pyridine.
Example 48: 2-(N~Formylaminomethyl)-6-(5-ethoxycarbonylpentyl)-
-
pyridine (1.0 g) is heated at 90 for 15 hours with 0.25 ml of
phosphorus oxychloride in 10 ml of toluene. Evaporation of excess
phosphorus oxychloride with toluene, basification at 0 with saturated
ammoni~m hydroxide solution, extraction with methylene chloride
(4x50 ml), drying over sodium sulfate and chromatography (40 g silica
gel, EtOAc) yields 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine.
The starting material is prepared via 6~(5-ethoxycarbonylpentyl)-2-
cyano-pyridine according to procedures described in the previous
examples.
- 59 -
Example 49: A solution of lithi-ml diisopropylamide (from 1.0 g of
diisopropylamine and 6.9 ml of 1.6N n butyllithium) and hexamethyl-
phospiloramide (1.8 g) in 50 ml of tetrahydrofuran, is coo]ed to -50,
and propiolic acid (0.35 g) is added dropwise. The reaction mixture
is allowed to warm s]owly (2 hours) to -15 and 5-(chlorobutyl)-
imidazo[l,5-a]pyridine (1.04 g) in 10 ml of tetrahydrofuran is added
dropwise over 15 minutes. External cooling is removed and the reaction
mixture is stirred for 90 minutes at room temperature before pouring
into 100 g of ice. The aqueous phase is separated, washed with ethyl
acetate (20 ml), brought of pH=2 with concentrated sulfuric acid and
washed again with ethyl acetate (20 ml). The aqueous phase is adjust-
ed to pH=6 and extracted with methylene chloride (5x30 ml). Drying of
the extracts over Na2S04/~gS04, filtration and evaporation yields
5-(6-carboxyhex-5-ynyl)-imidazo[l,S-a]pyridine.
Example 50: A solution of 5-methylimidazo[1,5-a]pyridine (4.0 g, 0.03
mole) and tetramethylethylene diamine (4.9 g) in 100 ml of tetra-
hydrofuran is cooled to 0 under nitrogen and 26.5 ml of 1.6N n-butyl-
lithium is added dropwise so as to maintain the temperature below 5.
After 40 minutes this solution is added to an ice-cold solution of
ethyl 4-bromocrotonate (7.02 g) in 90 ml of tetrahydrofuran. After
15 minutes the reaction mixture is quenched with excess saturated
ammonium chloride solution and partitioned between water (100 ml) and
ethyl acetate (150 ml). The organic phase is dried over sodium sulfate,
filtered and evaporated to yield 5-(4-ethoxycarbonyl-but-3-enyl)-
imidazo[l,5-a]pyridine.
Example 51: A solution of 5-methylimidazo[1,5-a]pyridine (4.0 g) and
tetramethylethylene diamine (4.9 g) in 100 ml of tetrahydrofuran is
cooled to 0 under nitrogen and 26.5 ml of 1.6N n-butyl-lithium is
added dropwise so as to maintain t~e temperature below 5. After 40
minutes this solution is added to an ice-cold solution of l-tetrahydro-
- 60 -
pyranyloxy-8-bromo-oct-6-yne (10.4 g) in 80 ml of tetrahydrofuran.
After 30 minutcs the reaction is quenched with 50 ml of 2N hydrochloric
acid and stirred an additional 2 hours at room temperature. The layers
are separated and the aqueous phase is brought to pH=10 with 50 %
of sodium hydroxide solution. Extraction with methylene chloride
(3x30 ml), drying over sodium sulfate, filtration, evaporation, and
chromatography (silica gel, EtOAc) yields 5-(9-hydroxynon-7-ynyl)-
imidazo[l,5-a]pyridine.
Example 52: To a solution of 150 mg of 5-(4-carboxybuta-1,3-dienyl)-
imidazo[l,5-a]pyridine in 9 ml of methanol is added 100 mg of 10 %
palladium on carbon as catalyst. The reaction mixture is hydrogenated
at atmospheric pressure for 2 hours. The catalyst is removed by
filtration and the solvent evaporated under reduced pressure to yield
5-(4-carboxybutyl)-imida~o[1,5-a]pyridine identical to the compound
of Example 8.
The starting material is prepared as follows.
To a solution of 18 g of 3-ethylthioimidazo[1,5-a]pyridine [Blatcher
and Middlemiss~ Tet.~ett. (21) 2195 (1980)] in 200 ml of tetrahydro-
furan at -50 is added a solution of 80 ml of 1.6 M n-butyl lithium
in hexane in a dropwise manner over a period of 30 minutes. On
completion of the addition, the reaction mixture is allowed to stir
at -50 for a further 45 minutes and 10 ml of dimethylformamide is
added dropwise to the cooled solution over a period of 10 minutes.
On completion of the addition, the reaction mixture is allowed to
warm to room temperature and is poured into 500 ml of ice water.
The mixture is extracted with 500 ml of diethyl ether and the ethereal
extract is dried over anhydrous magnesium sulfate, filtered and the
solvent evaporated under reduced pressure to yield an oily residue.
This is purified by column chromatography on silica gel using a
- 61 -
mixture of diethyl ether and hexane (1:2) as eluent. Evaporation of
the solvent yields 5-formyl-3-ethylthioimidazo[1,5-a]pyridine melting
at 41-42.
To a solution of 20 g of 5-formyl-3-ethylthioimidazo[1,5-a]pyridine
in 200 ml of isopropanol is added approximately 15 g of Raney nickel.
The reaction mixture is stirred and heated at reflux temperature for
16 hours. The catalyst is removed by filtration through celite. The
filtrate is evaporated under reduced pressure to yield an oily residue.
This is purified by column chromatography on silica gel using a
mixture of diethyl ether and ethyl acetate (2:1) as eluent. Evaporation
of the solvent under reduced pressure yields 5-formylimidazo[1,5-a]-
pyridine melting at 138-140.
To a stirred suspension of 150 ml of sodium hydride in 25 ml of
toluene is added 550 mg of triethyl 4-phosphonocrotonate in a drop-
wise manner over a 10-minute period. The reaction mixture is maintained
at 5 by cooling in an ice-water bath. On completion of the addition,
300 mg of 5-formylimidazo[1,5-a]pyridine is added to the reaction
mixture which is then allowed to stir at room temperature for 1 hour.
The reaction mixture is poured into 100 ml of ice water and extracted
with 2xlOO ml of ethyl acetate. The ethyl acetate extracts are combined
and dried over magnesium sulfate, filtered and evaporated to dryness
to yield an oily residue. This is purified by column chromatography
on silica gel using a mixture of diethyl ether and ethyl acetate as
eluent. Evaporation of the solvent under reduced pressure yields 5-(4-
ethoxycarbonylbuta-1,3-dieny])-imidazo[1,5-a]pyridine melting at
101-103.
To a solution of 200 mg of 5-(~l-ethoxycarbonylbuta-1,3-dienyl)-
imidazo[l,5-a]pyridine in 20 ml of methanol is added 4 ml of lN sodium
hydroxide. The reaction mixture is stirred at room temperature for
~5~
- 62 -
18 hours. The methanol is evaporated under reduced pressure and the
residue diluted with 20 ml of water and the solution adjusted to pH 5
with hydrochloric acid. The precipitate is collected to give 5-(4-
carboxybuta-].,3-dienyl)-imidazo[1,5-a]pyridine, melting at 2L3-245.
- G3 -
~ffect on thrombo~ane synthetase from human platelets
The method is carried out according to the description given above,
i.e. the in vitro inhibition of the thromboxane synthetase enzyme is
demonstrated analogous to the method of Sun, Biochem. Biophys. Res.
Comm. 74, 1432 (1977).
Results:
Compounds of the formula
~a~
CH -A-B
are represented in the table given below.
Compound of 2 50
Example No. in cell-free test system
Thromboxane Synthetase
8 -(CH2)4COOH 41
2 -(CH2)5COOH 3
3/b -(CH2)6COOH 5
3/c -(CH2)7COOH 21
16 -(CH2)3C(CH3)2CH2COOH 18
-(CH2) CONH 77
11 -(CH2)5CoNHCH3 270
12 -(CH2)5CON(CH3)2550
-(CH2)4-CN 1'500
4 -(CH2)5-CN 630
13 -(CH2)5CH2OH 280
1 -(CH2)5COOC2H~ 330
15/c 5,6,/,8-Tetrahydro-290
-(CH2)4COOH
15/b 5,6,/, -Tetrahydro-85
-(CH2)5COOH
15/a 5,6,7,8-Tetrahydro-14
- (CH2) 6COOH _
_ _
