Note: Descriptions are shown in the official language in which they were submitted.
1~15709 (`
1 BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to new and useful 5-substituted
picolinic acids and salts thereof, 5-substituted picolinic
esters and 5-substituted picolinic acid amides, to a process for
preparing the same, and to pharmaceutical compositions containing
the same.
This invention relates to new and useful compounds,
5-indanyl ester of 5-alkoxy-picolinic acid, to a process for
preparing the same, and to pharmaceutical compositions containing
the same.
Description of the Prior Art
It is known that hypertension o~ten includes apoplexy,
heart trouble, etc., which necessitates extensive research for
new and useful anti-hypertensives.
Fusaric acid (5-n-butylpicolinic acid) is known to be
.,,
useful as an anti-hypertensive agent as disclosed in Jap. J.
Pharmacol., Vol. 25, 188 ~1975~, however, fusaric acid has a
butyl group at the 5-position of the picolinic acid moiety and
has a low LD50 value. As a result, an improved anti-hypertensive
agent is desired.
British Patent 1,502,055 discloses that 3-substituted-
2(IH)-pyridone-6-carboxylic acid can be used as an anti-
hypertensive agent but the anti~hypertensive activity ~i.e.,
maximum depression in blood pressure) thereof is poor and an
..;
; improvement is desired.
The inventors have already synthesized 5-alkoxy-
: picolinic acids and evaluated them as anti-hypertensive agents
as reported in Canadian Patent Application No. 287,913
tcorresponding to U.S. Patent No. 4,189,489~.
.,. ~
--1--
. ' .
~:`'' . .
.,
. . ..
~.~157~9
1 It has now been found that the compounds of the present
invention exhibit anti-hypertensive activity equal or
superior to 5-alkoxypicolinic acids of the Canadian Patent
Application No. 287,913 and have lower toxicity than 5-
alkoxypicolinic acids of the Canadian Patent Application
No. 287,913 and, therefore, the compounds of the present
invention are use~ul compounds for the treatment of hyper-
tension.
;i SUMMARY OF THE INVENTION
; 10 It is a principal object of the present invention to
provide a novel group of anti-hypertensive agents.
It is another object of the present invention to
provide a novel group of anti-hypertensive agents which are less
toxic than 5-alkoxypicolinic acids but equal to or superior to
"
5-alkoxypicolinic acids in their anti-hypertensive activity.
Still another object of the present invention is to
provide novel processes for producing these anti-hypertensive
agents.
Accordingly, the present invention provides 5-
` 20 substituted picolinic acid derivatives represented by theformula (I):
,i? J~ ORl
R2~C ~ (I)
":. :
:; wherein Rl represents a straight or branched chain halogen-
" substituted alkyl group having 2 to 6 carbon atoms or a
substituted phenyl group of the formula ~ wherein R3
R4
and R4, which may be the same or different, each represents a
:"~ .
-2-
, ` .Afl
. . --
,
11~57~
1 hydrogen atom, a halogen atom, a lower alkyl group, a lower
alkoxy group, a nitro group, an amino group, an N-alkyl-
substituted amino group, an acylamino group, an acetyl group,
an acyloxy group, a hydroxyl group or a halogen-substituted
alkyl group, or R3 and R4, when taken together, represent a
polymethylene chain; and R2 represents an -OM chain wherein M
represents a hydrogen atom, a sodium atom, a potassium atom,
a calcium atom, analuminium atom or a magnesium atom, a straight
or branched chain or cyclic alkoxy group having l to 6 carbon
atoms, an aminoalkoxy group, a phenoxy group, a 5-indanyloxy
group, an acyloxyalkyloxy group having the formula
-O-CHOCOR6 wherein R5 represents a hydrogen atom or a methyl
group and R6 represents a lower alkyl group having l to 6
carbon atoms, a phenyl group or a substituted phenyl group, or
R7
an amino group represented by the formula -N whereLn R7
,. R8
and R8, which may be the same or different, each represents a
hydrogen atom, a lower alkyl group or a phenyl group.
DETAILED DESCRIPTION OF THE INVENTION
In the formula (I), Rl represents a straight or
branched chain halogen-substituted alkyl group having 2 to 6
carbon atoms (such as a 4-chlorobutyl group, a 4-bromobutyl
group, a 3-chloropropyl group, a 5,5,5-trifluoropentyl group,
.
a 4,4,4-trifluorobutyl group, a 3,4-dibromobutyl group, a 5-
chloro-3-methyl-pentyl group, etc.); or a substituted phenyl
... .
~ ~ R3
group having the formula ~ R wherein R3 and R4, which may
be the same or diJferent, each repre~ents a hydrogen atom, a
.,
.
': :
lilS7~9
1 halogen atom (such as chlorine, bromine, fluorine, etc.), a
lower alkyl group having 1 to 3 carbon atoms (such as a methyl
group, an ethyl group, a propyl group, etc.), a lower alkoxy
group having 1 to 3 carbon atoms (such as a methoxy group, an
ethoxy group, a propoxy group, etc.), a nitro group, an amino
group, an N-alkyl-substituted amino group wherein the alkyl
moiety has 1 to 3 carbon atoms (such as a dimethylamino group,
a diethylamino group, etc.), an acylamino group having 2 to 4
; carbon atoms (such as an acetamido group, a propionylamino
group, etc.), an acetyl group, an acyloxy group having 2 to 4
, carbon atoms (such as an acetoxy group, a propionyloxy group,
etc.)c a hydroxy group or a halogen-substituted alkyl group
having 1 to 3 carbon atoms (such as a trifluoromethyl group,
etc.), or R3 and R4, when taken together, represent a poly-
methylene chain having 3 to 5 carbon atoms (such as trimethylene,
etc.).
R2 represents an -OM group wherein M represents a
hydrogen atom, a sodium atom, a potassium atom, a calcium atom,
an ~u~inium atom or a magnesium atom; a straight or branched
chain or cyclic alkoxy group having 1 to 6 carbon atoms (such
as a methoxy group, an ethoxy group, a propoxy group, an
isobutoxy group, a cyclohexylox~ group, etc.); an aminoalkoxy
~ group having 2 to 5 carbon atoms (such as dimethylaminoethyloxy
group, etc.); a phenoxy group (including a phenoxy group
substituted as illustrated below for the phenyl group); a 5-
indanyloxy group; an acyloxyalkyloxy group having the formula
-O-CHOCOR6 wherein R5 represents a hydrogen atom or a methyl
group and R6 represents a lower alkyl group having 1 to 6
;`f~ 30 carbon atoms (such as a methyl group, an ethyl group, a propyl
.,~,; ,.
~ -4-
.', .
~ ' ,
l~lS709
1 group, an isobutyl group, a t-butyl group, etc.), a phenyl
group,or a substituted phenyl group wherein the substituent
includes an alkyl group having 1 to 3 carbon atoms and an
alkoxy group having 1 to 3 carbon atoms (such as a p-tolyl group,
a p-methoxyphenyl group, a 3,4,5-trimethoxyphenyl group, etc.);
. ~ 7
or an amino group represented by the formula -N wherein R
R8
and R8, which may be the same or different, each represents a
hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms
(such as a methyl group, an ethyl group, etc.), or a phenyl
group.
Compounds represented by the formula (II-a):
OR 01
I ¦l (II-a)
;HOOc~A~iN~
wherein Rlol represents a straight or branched chain halogen-
substituted alkyl group having 2 to 6 carbon atoms, can be ~.
` prepared by reacting a compound represented by the formula (IV):
. ~ OH
.j R N (IV)
... ..
~ wherein Rg represents a methyl group or a hydroxymethyl group,
:~: with a halide represented by the formula (V):
~`''':' ' '
"'' RlolX (V)
.
wherein Rlol is as defined above and X representS a halogen atom,
.~ 30 in an organic solvent such as dimethylformamide, dimethyl
:" . .
': .
"~', -S-
! ~ , - :
;. ~ : ,
11157Q9
1 sulfoxide, dimethylacetamide and the like in the presence of an
inorganic base such as potassium hydroxide, sodium hydroxide,
potassium carbonate, sodium carbonatel sodium hydrogencarbonate
and the like or an organic base such as triethylaminel N,N-
dimethylaniline and the like to obtain a compound represented
by the formula (VI):
~ 101 ~ ~ '
Rg N (VI)
wherein R9 and Rlol are as defined above.
This substitution reaction takes place selectively
at the 5-position hydroxy group, and no reaction of the
-CH2OH group or by-production of pyridinium salts is observed
under the conditions of the invention. The reaction easily
proceeds at a temperature ranging from about 30 to 100C and
is completed in a relatively short time such as about 1 to 20 -
hours.
The compounds of the formula (II-a) according to this
. - . .
invention can be prepared by oxidizing the intermediate of the ~ ~-
formula (VIj as described above using an oxidizing agent such as
: potassium permanganate, chromic anhydride, selenium dioxide,
~ nitric acid, potassium bichromate and the like in a solvent such
., ~ ~ .
~ as acetone, dioxane, pyridine, hydrous acetone, hydrous t-
;,
butanol, sulfuric acid and the like. Any impurities by-produced
~d '
during the reaction can easily be removed by solvent extraction, ~-
precipitation, crystallization or a like operation. Reaction
;~` conditions for the oxidation vary with kind of the oxidizing
~.,...................................................................... :
~ agent used and Rg group in the compound of the formula (VI).
.~
When R9 group is hydroxymethyl group, the reaction conditions for
the oxidation are generally mild. For example, when the compound
' .
~"`; -6-
:
~ .
l~lS7Q9
.. .
1 of the formula (VI) having hydroxymethyl group as the Rg group
is oxidized with potassium permanganate, about 1 to 2 mols of
potassium permanganate per mol of the compound of the formula
(VI) is used and the reaction.time and reaction temperature
are about 5 to 20C and about 2 to 20 hours, respectively. In
the case of oxidizing the compound of the formula (VI) having a
methyl group as the Rg group with potassium permanganate,about 2
to 4 mols of potassium permanganate per mol of the compound of
the formula (VI) are needed at the reaction temperature of
about 80 to 100C and for the reaction time of about 4 to 10
hours. In a case of oxidizing the compound of the formula (VI)
having a methyl group as the R9 group with chromic anhydride,
about 2.5 to 3.5 mols of chromic anhydride per mol of the compound
of the formula (VI) is used in the presence of sulfuric acid
at the reaction temperature of about 30 to 70C for the reaction
~ time of about 4 to 10 hours. When selenium dioxide is used as
an oxidizing agent, the oxidation reaction is carried out in
the presence of pyridine in an amount of about 1.8 to 2.5 mols
:~ of selenium dioxide per mol of the compound of the formula (VI)
` 20 at reaction temperature of about 100 to 120C for reaction time
of about 5 to 10 hours.
.~ ~ Compounds represented by the formula (II-f?:
R
302 (II-f)
HOOC N R404
.~wherein R302 and R404, which may be the same or different,
each represents a hydrogen atom, a halogen atom, a lower alkyl
group, a lower alkoxy group, a nitro group, an amino group,
. 30 an N-alkyl-substituted amino group, an acylamino group, an
,--7--
.
.
i:
ll~S7Q9
.
1 acetyl group, or a halogen-subs-tituted alkyl group, or R302 and
R404, when taken together, represent a polymethylene chain can ~ :
be obtained by reacting the compound of the formula (IV) or a
metal salt thereof such as a potassium salt,a sodium salt, etc.,
with a substituted halobenzene derivative represented by the ~.
formula (VII-a): ~
X ~ R302 ~ :
~ R404 (VII-a)
wherein R302 and R404 are as defined above and X is a halogen :.
atom, in an organic solvent such as dimethylformamide,
dim~thlyacetamide, pyridine,collidine and the like preferably
in the presence of a catalyst such as a copper powder, copper
oxide, copper chloride and the like to obtain a compound
represented by the formula (VIII-b):
Rg~ R404 (VIIl-b)
: wherein Rg, R302 and R404 are as defined above. Of the compounds
of the formula (VII-a), those wherein at least one of R302 and ~.
~ R404 isa nitro group and the nitro group is positioned at
ortho- or para-position of the halogen X may be prepared under
mild conditions such as at a reaction temperature of about `
S0 to 100C in a reaction time of about 10 to 15 hours without
catalyst.
. The halobenzene derivative of the formula (VII-a) ;
is used in an amount of about 0.9 to 1.2 mols per mol of the
30 compound of the formula (IV). The reaction requires a higher ;
; . -8-
.'.
. ~:
.','~- ' .
~1157Q9
1 temperature than in the preparation of the compounds of the
formula (II-a) generally ranging from about 90 to 180C and
takes a relatively long reaction time to complete such as
about 8 to 30 hours. The reaction is usually carried out in a
nitrogen stream in order to prevent side reactions such as
oxidation and polymerization. In the case of using copper
powder as the catalyst, about 5 to 15 wt~ of copper powder per
weight of the compound of the formula (IV) is used at a reaction
temperature of about 100 to 150C for a reaction time of about
10 to 20 hours. In the case of using copper oxide or copper
~ chloride as the catalyst, about 0.2 to 0.3 mol of copper oxide
; or copper chloride per mol of the compound of the formula (IV)
is uSed at a reaction temperature of about 130 to 160C for a
reaction time of about 10 to 20 hours. In both cases above,
the reaction is carried out in a nitrogen gas stream.
Then, the compound of the formula (VIII-b) is oxidized
;;~ in a solvent such as acetone, dioxane, hydrous acetone, pyridine,
water, hydous t-butanol, sulfuric acid and the like using an
oxidizing agent such as potassium permanganate, selenium dioxide,
chromic anhydride, nitric acid, potassium bichromate and the
-~ like, thereby to obtain the compound of the formula (II-f).
- The oxidation conditions for this reaction are the same as
those for the oxidation of the compound of the formula (VI)
obtained above.
Of the compounds of the formula (VIII-b), those
wherein at least one of R302 and R404 is a nitro group may be
prepared under the conditions employed in the preparation of
the compounds of the formula (II-a) since the reaction reagent
,~ ,. .
of the formula (VII-a) is active.
Among the compounds of the formula (II-f), those
_9_
~"
i ..,
. ~ ,
.ix,.
. ... .
,
lllS7Q9
1 wherein at least one of R302 and R404 is a nitro group can be
subjected to reduction using tin or stannic chloric in hydro-
chloric acid or an iron powder in hydrochloric acid or
catalytic reduction in an alcohol, a dioxane, a hydrous
alcohol, an ammoniacal alcohol or an ammoniacal hydrous
alcohol in the presence of a catalyst such as platinum oxide,
palladium, Raney nickel and the like to obtain a compound
represented by the formula (II-h) having at least one amino
group on the phenoxy moiety: -
HOOC ~ ~ ~405 ~ h)
wherein R405 represents a hydrogen atom, a halogen atom, a
lower alkyl group, a lower alkoxy group, an amino group, an ~
: N-alkyl-substituted amino group, an acylamino group, an acetyl .
group or a halogen-substituted alkyl group. In the case of
using stannic chloride or iron powder as the reducing agent,
about 3 mols of stannic chloride or 2.5 to 5 atoms of iron
~;~ 20 powder per mol of the compound o the formula (II-f) is used ..
under acidic conditions, generally in hydrochloric acid, at a
reaction temperature of room temperature (about 15C to about
~, .,
~ 30C) to about 70C for a reaction time of about 5 to 20 hours~
f~
~: In the case of catalytic reduction, the catalys~ ~such as
platinum oxide, palladium, Raney nickel) is used in an amount
~: :
of about 5 to 10 wt% based on the compound of the formula (II-f)
and the catalytic reduction is carried out in neutral or
alkaline condition at room temperature (about 15C to about
~ 30C) and atmospheric pressure for a reaction time of about 2
" '4
~. 30 to 5 hours.
., .
j
.`~ `. --10--
.''~.' ' :
~ ' '` .
,: .
-- lllS7~9
1 When the above-described catalytic reduction is
carried out in an acid anhydride or a mixed solvent of an acid
anhydride and an organic acid constituting the same, a compound
represented by the formula (II-i) containing an acylamino
substituent:
~ NHCORlo
HOOC N R405
(II-i)
wherein Rlo represents a lower alkyl group and R405 is the same
as defined above is obtained.
The compounds of the formula (II-h) may also be
easily prepared by hydrolyzing the compound of the formula
(II-i) as described above with an acid or an alkali, followed by
deacylation.
The compound of the formula (II-h) as obtained above
i8 dissolved in an aqueous solution containing a mineral acid
such as hydrochloric acid, sulfuric acid, hydrobromic acid and the
~r~
like, and sodium nitrite is added thereto under ice-cooling to
- 20 form a diazonium salt of the compound (II-h). The diazotization
is usually carried out in the presence of acid such as
hydrochloric acid, sulfuric acid or hydrobronic acid using
i sodium nitrite (NaN02) in an amount of about 1 to 1.2 mols
per mol of the compound of the formula (II-h) at a reaction
~; temperature of O to 10C. The resulting diazonium salt can be
chlorinated or brominated by treating with cuprous chloride
hydrochloric acid or cuprous bromid/hydrobromic acid, iodinated
by adding potassium iodide or fluorinated by adding fluoroboric
acid and heating the resulting diazonium fluoroborate, thereby
to obtain a compound represented by the formula (II-j) having
... . . .
: -.
',` --11-
, ~:
, ...... .
....
::
...
,f,',' ' ~, ' ' . ' '' ` ' ~ ', ` , " '
lllS709
.
at least one halogen atom on the phenoxy moiety:
HOOC ~ ~ R406 (II~
wherein X represents a halogen atom and R406 represents a .
hydrogen atom, a halogen atom, a lower alkyl group, a lower ~ :
alkoxy group, an N-alkyl-substituted -amino group, an acylamino
group, an acetyl group or a halogen-substituted alkyl group. :;
Compounds represented by the formula (II-k) having at
least one hydroxy group on the phenoxy ring:
~ ~ R (II-k~
; HOO N
wherein R4 is the same as defined above, can easily be prepared
~i by dealkoxylation of the compound of the formula (II-f) in a
hydrohalogenic acid under heating or by treating the diazonium
alt of the compound (II-H~ with an aqueous dilute acid.
Compounds represented by the formula (VIII): -
~ ~ ~VIII)
wherein R3, R4 and Rg axe the same as defined above, which are
intermediates for the compounds represented by the formula (II-b):
,,.~ ~;
R3
~;~ ~ R4 (II-b)
.~` HOOC N
~t wherein R3 and R4 are the same as defined above, may also be
~ obtained by the following process:
`:.. 30
., :
-12- -
.
.: . . ,
, ~.
.': .
.. .
,, . . , , ~ - ~ . .
1115709
1 That is, the compounds of the formula (II-b) can be
prepared by reacting a compound represented by the formula (IX):
,~X ' ' :'
Rg N (IX)
wherein X represents a halogen atom and Rg is as defined above,
with a substituted phenol represented by the ormula ~X-a):
;.
HO~ 302 .
404 (X-a)
wherein R302 and R404 are the same as defined above. The
reaction proceeds under the same conditions as described in the
$
condensation reaction between the compound of the formula (IU)
and the compound of the formula (VII-a).
The 5-substituted picolinic acids as above obtained
can easily be converted to pharmaceutically acceptable salts
thereof such as calcium salts, sodium salts, aluminium salts,
magnesium salts and potassium salts.
This invention provides a process for preparing a
.~ .
5-substituted picolinio acid ester or amide represented by the
formula (III):
i~,,j ~ : ,
201 ~ ORl (III)
.
. ~i, , ~
wherein Rl represents a straight or branched chain halogen-
substituted alkyl group having 2 to 6 carbon atoms or a
substituted phenyl group represented by the formula ~ 3
R4
-13-
,. ,. :,
~'`' .
~lS7~9
.
1 wherein R3 and R4 are defined as above; and R201 represents a
straight or branched chain or cyclic alkoxy group having 1 to -~
6 carbon atoms, an aminoalkoxy group, a phenoxy group, a sub- -
stituted phenoxy group, a 5-indanyloxy group, an acyloxy- ~-
: `
alkyloxy group represented by the formula -O-CHOCOR6 wherein
R5 and R6 are defined as above, or an amino group represented
/ 7
by the formula -N \ wherein R7 and R8 are defined as above,
R8 ~ :
which comprises: -
(i) reacting a 5-substituted picolinic acid or a ;~
metal salt thereof represented by the formula (II-g):
~ 102 (II-g)
MOOC~ N
wherein R102 represents a straight or branched chain halogen-
substituted alkyl group (containing a halogen atom such as ~:
chlorine, bromine,iodine and fluorine) or a substituted phenyl : :
~ R302 . -~`
s:: group represented by the formula ~ R404 wherein R302 and
~: R404 are defined as above; and M represents a hydrogen atom or
a metal atom (such as sodium, potassium, calciumj aluminium :
and magnesium), with one of an aliphatic alcohol having 1 to
~ . 6 carbon atoms, 5-indanol, phenol, substituted phenols and
.~` amineslrepresented by the formula (XI):
;; / R7 --.
~ R (XI)
.,. . :
.~.` 30
~, . . .
i~ -14-
'~ `', '' ' ' ' '
., :
"~. :
57Q9
1 wherein R7 and R8 are defined as above, in the presence of an
acid catalyst or a condensation agent; or
(ii) reacting a 5-substitute~ picolinic acid or a
metal salt of the formula (II-g) with an ac~loxyalkyl halide
represented by the formula (XII):
: I (XII)
X--CHOCOR6 ~
wherein R5 and R6 are as deined above, and X represents a
halogen atom, in the presence of a base. .
More specifically, of the compounds having the
formula (III) according to the present invention, lower alkyl
~ esters such as methyl, ethyl, propyl and isobutyl esters and ;
~` the like can easily be obtained by reacting a 5-substituted
picolinic acid represented by the formula (II): ~
: ~ 1 (II) ~ ~ .
. MOOC N . .
:i.l wherein Rl and M are as defined above, with the corresponding
;~ aliphatic alcohoI having 1 to 6 carbon atoms in the presence
of an acid catalyst such as hydrochloric acid, sulfuric acid,
p-toiuenesulfonic acid and the like at a temperature of from
40C to 100C.
5-Indanyl esters, phenyl esters and substituted
phenyl esters having the formula (III) can be obtained by ~ :
reacting the 5-substituted picolinic acid f the formula (II)
~'i.`. with S-indanol, phenyl or substituted phenol (such.as p-
ethylphenyl, p-methylphenol, o-methylphenol and the like),
~ ., .
.u respectively, in an organic solvent such as chlorororm, dioxane,
dimethylformamide, pyridine and the like in the presence of a
`.;. 30 condensation agent such as dicyclohexylcarbodiimide and the like.
;~ ." '.
~,,' , ,
. 15
:'~.,,'. .
'`,.'' '~ ,
57Qg
1 Acyloxyalkyl esters of the 5-substituted picolinic
acid such as acetoxymethyl es~ers, pivaloyloxymethyl esters,
~-pivaloyloxyethyl esters, ~-benzoyloxyethyl esters, ~-
(isovaleroyloxy)ethyl esters, ~-(3,4,5-trimethoxybenzoloxy)- :
ethyl esters and the like can be prepared by reacting the 5-
substituted picolinic acid of the formula (II) with an
acyloxyalkyl halide represented by the formula (XII) in a
solvent such as dimethylformamide, dimethyl sulfoxide and the
like in the presence of a base such as pyridine, triethylamine
and the like in an amount of about 1 to 1.5 mols per mol of
5-substituted picolinic acid of the formula (II). The reac-
tion is performed at a temperature of from -20 to 80C for a ;
period of from 4 to 20 hours.
Alternatively, the compound of the formula ~III) can
be prepared by reacting an acid halide of a 5-substituted
picolinic acid represented by the formula (XIII):
~: ~ ORl .
XOC (XIII)
wherein Rl is the same as defined above and X represents a
halogen atom, which is obtained by reacting a 5-substituted
.: picolinic acid represented by the formula ~II) with an acid
. halogenating reagent,.with one of an aliphatic alcohol having 1
to 6 carbon atoms, 5-indanol, phenol, substituted phenols,
. . ,
amines represented by the formula (XI) and acyloxyalkanols
represented by the formula (XIV):
(XIV)
,`., HO--CHOCOR6
wherein R5 and R6 are the same as defined above, in the
presence of a base.
, .,
. .
",,,
. . .
r
. .
. .
'
11157Q9
1 5-Indanyl esters, phenyl esters and substituted
phenyl esters can be obtained by reacting the acid halide of
the formula (XIII) with 5-indanol, phenyl and a substituted
phenol, respectively, in pyridine or in the presence of a
base such as triethylamine, N,N-dimethylaniline and the like in
an organic solvent such as methylene chloride, ethyl ether, -f
dimethylformamide, dioxane and the like. Both reactions are
conducted at a temperature ranging from -10 to 5~C for a
period of from 2 to 10 hours.
The acyloxyalkyl esters may also be obtained by
reacting the acid halide of the formula (XIII) with an
acyloxyalkanol of the formula (XIV) in an organic solvent such
as methylene chloride, chloroform, dioxane, dimethylformamide and
~ the like in the presence of a base such as triethylamine and the
; like or in pyridine. In this case, the reaction temperature
ranges from -30 to 50C and the reaction time ranges from 1
to 10 hours.
~` Amide derivatives of the 5-substituted picolinic
f acid can be prepared by reacting the 5-substituted picolinic
20 acid of the formula (II) with an amine of the formula (XI) in
f
; an organic solvent in the presence of a condensation agent such
~-~ as dicyclohexylcarbodiimide and the like or by reacting an
' acid halide of a 5-substituted picolinic acid of the formula
, .
` (XIII) with an amine of the formula (XI) in a solvent such as
~;~ methylene chloride, ethyl ether, chloroform, dioxane and the
like.
~mide derivatives of the formula (III-b):
NOC ~ ORl (III-b)
R8 /
. y
~ -17-
:' .;
.: .
lllS7~9
1 wherein Rl is as defined above and R7 and R8 may be the same or
different and represent a hydrogen atom, a lower alkyl group,
or a phenyl group, may also be prepared by reacting the 5-
substituted picolinic ester of the formula ~ a):
~OR
~ (III-a)
202 N
,
wherein Rl is as defined above and R202 represents a straight,
branched or cyclic alkoxy group having 1 to 6 carbon atoms, an
aminoalkoxy group, a phenoxy group, a substituted phenoxy
group, a 5-indanyloxy group or an acyloxyalkyloxy group-having
f~ 1 5
the formula -O-CHOCOR6 wherein R5 represents a hydrogen atom or
~` a methyl group and R6 represents a lower alkyl group having 1
;~ to 6 carbon atoms, a phenyl group or a substituted phenyl group,
S with an amine of the formula (XI) with or without an appropriate
solvent.
This invention also provides an anti-hypertensive
composition containing, as an active ingredient, a therepeu- -~
20 tically effective amount of at least one 5-substituted picolinic
~, acid derivative having the formula (I) described above.
.;. - :,
In one embodiment of this invention, this invention
provides 5-indanyl ester of 5-alkoxy-picolinic acid represented
by the formula (A): -
.
RaO ~ _ COO ~ (A)
wherein Ra represents an alkyl group having 1 to 6 carbon atoms.
The term "alkyl group having 1 to 6 carbon atoms" as
30 used herein for Ra includes straight or branched chain alkyl
-18-
~,,.,,~ .
, . . .:
~, ..
. ' ~ .
.;, .
.
i:,~^
ll~S7Q9
.
1 groups and specific examples include methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl
and the like.
In another embodiment of this invention, this
invention provides a process for preparing a 5-indanyl ester of
5-alkoxy-picolinic acid represented by the formula (A):
R O~ ~ ~ (A)
wherein Ra represents an alkyl group having 1 to 6 carbon atoms;
which comprises reacting a 5-alkoxy-picolinic acid or metal
salt thereof represented by the formula (B): -
RaO ~
(B)
N COOM
~ wherein Ra is as described above and M is a hydrogen atom or
"~
a metal atom, with a 5-hydroxyindane (i.e., ~ ), in an
H0
organic solvent (such as dimethylformamide, dimethylsulfoxide
and the like) in the presence of a base (such as pyridine,
~ .
triethylamine, etc.), with a suitable reaction temperature
ranging ~bout 0C to about 40C and the reaction time generally
ranging from about 3 to 10 hours.
Also, an additional embodiment of this invention
provides a process for preparing a 5-indanyl ester of 5-alkoxy-
picolinic acid represented by the formula (A):
, ~ C00 ~ (A)
.~, , --1 9--
: ',
, ....................................................... .
11~57~9
1 wherein Ra represents an alkyl group having l to 6 carbon atoms;
which comprises reacting an acid halide of 5-alkoxy-picolinic
acid represented by the formula ~C):
RaO
~ (C)
~ N "~`COX
wherein Ra is as described above and X represents a halogen
atom, with 5-hydroxyindane, in an organic solvent (such as
chloroform, methylene chloride, dimethylformamide, dioxane,
etc.) in the presence of a base (such as pyridine, triethylamine,
etc.), with a suitable reaction temperature ranging from about
-10C to about 40C and the reaction time generally ranging from
about 3 hours to about lO hours.
~ The above synthesis will be illustrated in greater ~
; detail by reference to the following Examples which should not ~-
be considered as limiting the present invention. Unless -
otherwise indicated, all percents, parts, ratios and the like
are by weight.
EXAMPLE 1
.:
4.86 g of a potassium salt of 5-hydroxy-2-hydroxy-
methylpyridine was suspended in 80 mQ of dimethylformamide,
and 5.7 g of tetramethylene chloride and l g of potassium
carbonate were added to the suspension, followed by sbirring
at 70C for 15 hours to effect the reaction. The reaction~ ;
mixture was concentrated to dryness, and to the residue were
.... .
added 150 mQ each of ethyl acetate and water to form two layers.
The ethyl acetate layer was separated and dried with anhydrous
sodium sulfate, immediately followed by concentration to obtain
$ .::
5.4 g of a syrup of 5-(4-chlorobutoxy)-2-hydroxymethylpyridine.
The unreacted materials were found to remain in the aqueous
,' ,~
~ layer.
., . ~ .
;, -20-
:,,
~, '' ' ,
~' , ,
11~5709
4.1 g of the thus-obtained product was dissolved in
a mixed solvent of 35 mQ of t-butanol and 12 mQ of water, and
30 mQ of an aqueous solution containing 3.5 g of potassium
permanganate was added dropwise thereto for 1 hour. The reaction
was further continued at a temperature of 5 to 10C for 2 hours
while stirring. The reaction mixture was filtrated, and the
filter cake was washed with 50 mQ of a warm 50% aqueous methanol
solution (adjusted to a pH of 10 with sodium hydroxide). The
filtrate and the washing were combined, the mixture was concen-
trated to a volume of about 30 mQ, and the solvent distilled
off. The resulting aqueous layer was adjusted to a pH of 1!5
with 5N hydrochloric acid and extracted with 50 mQ of chloroform.
The chloroform layer was dried with anhydrous sodium sulfate
and concentrated to a volume of about 3 mQ. 10 mQ of ethanol
was then added to the concentrate, and the mixture was allowed
to stand at a low temperature, and the product crystallized.
The crystals thus-obtained were separated by filtration to
obtain 3.5 g of white crystals of 5-(4-chlorobutoxy)picolinic
acid.
Melting Point: 96--97C
..... .
Elemental Analysis for CloH12N3NC
~; C H N 0 CQ
~j ~ Calcd.(%): 52.29 5.23 6.1029.92 15.47
Found (%): 52.18 5.92 6.15 15.32
~ EXAMPLE 2
?,,''~ 4.3 g of a potassium salt of 5-hydroxy-2-hydroxy-
,....
methylpyridine was suspended in 50 mQ of dimethylsulfoxide, and
4.4 g of 1,3-dichloropropane and 500 mg of potassium carbonate
were added to the suspension, followed by stirring at 60C for
:~ 30 10 hours to effect the reaction~ The reaction mixture was
. ;, .
." j '
~ , --21--
. ~ . . . .
';~' '
:
1~15709
, . . .
t concentrated to dryness, and 100 mQ each of chloroform and water
were added to the residue to form two layers. The chloroform
layer was separated, dried with anhydrous sodium sulfate and
immediately concentrated to dryness to obtain 4.5 g of a syrup
of 5-(3-chloropropoxy)-2-hydroxymethylpyridine.
The thus-obtained product was oxidized in 50 mQ of a
70% aqueous acetone with potassium permanganate in the same
manner as described in Example 1 to obtain 3.7 g of white
crystals of 5-(3-chloropropoxy)picolinic acid.
Melting Point: 120-121C
Elemental Analysis for C9H10O3NCQ:
C H N O CQ
:.
Calcd.t%): 50.12 4.64 6.50 22.~7 16.47
Found (%): 50.07 4.72 6.58 16.33
EXAMPLE 3
.
4.9 g of a potassium salt of 5-hydroxy-2-hydroxy-
methylpyridine was suspended in 90 mQ of dimethylformamide, and
6.1 g of 4-bromoni~nbenzene and 0.5 g of potassium carbonate
were added to the suspension, and the reaction was effected
20 at 80C for 18 hours. The reaction mixture was immediately
concentrated to dryness, and 200 mQ of chloroform and 100 mQ of
water were added to the residue to form two iayers. The
i chloroform layer was separated, drîed with anhydrous sodium
.
sulfate and immediately concentrated to obtain a crystalline
` residue. The resulting residue was recrystallized from
chloroform to obtain 5.7 g of crystals of 5-(p-nitrophenoxy)-
2-hydroxymethylpyridine having a melting point of 129-130C.
5 g of the thus-obtaîned product was dissolved in
` 150 mQ of acetone, and 80 mQ of an aqueous solution containing
3.8 g of potassium permanganate was added dropwise to the
-22-
.,;
:, .
.,
1~15709
1 solution over a 1 hour period. The reaction was further
continued at room temperature for 3 hours, and the reaction
mixture was filtered. The filter cake was washed with 80 mQ of
a warm 50% aqueous methanol (adjusted to a pH of 10 with
sodium hydroxide). The filtrate and the washing were combined,
concentrated to a volume of about 40 mQ, adjusted to a pH of
1.5 with 5N hydrochloric acid and extracted wi~h 100 mQ of
chloroform. The extract was dried with anhydrous sodium
sulfate, concentrated to a volume of about 30 mQ and allowed to
stand at a low temperature to crystallize the product. The
thus-formed crystals were separated by filtration to obtain
4.2 g of crystals of 5-(p-nitrophenyl)picolinic acid.-
Melting Point: 188-189C
s Elemental Analysis for C12H8O5N2:
C H N O
, Calcd.(~): 55.38 3.08 10.77 30.77
Found (%~: 55.47 3.12 10.68
EXAMPLE 4
7.35 g of a potassium salt of 5-hydroxy-2-methyl-
pyridine was suspended in 20 mQ of dimethylformamide, and
9.6 g of bromochlorobenzene and 800 mg of a copper powder were
added to the suspension. The reaction was effected at a
temperature of 120C for a period of 18 hours in a nitrogen
stream while stirring. After allowing the reaction mixture to
5 `;
i cool, the reaction mixture was diluted with 50 mQ of methanol
and then filtered. The filtrate was immediately concentrated
; to dryness, and 200 mQ of chloroform and loO mQ of water were .:
1~ added to the dried material, and the mixture adjusted to a pH j
~`~'
~ !, of g with 5N sodium hydroxide. The insoluble matter was again
, " i
h,~' 30 separated by filtration. The resulting chloroform layer was
. ~ , .
-23-
.
:
, ~ '' - :`, : .~' ,.
1:1157Q9
1 dried with anhydrous sodium sulfate and immediately concentrated
to dryness to obtain 8.2 g of oily 5-(p-chlorophenoxy)-2-
methylpyridine. Gas chromatoyraphy revealed that the thus-
obtained product contained no 5-(p-bromophenoxy)-2-methylpyridine.
4.7 g of the above product was dissolved in 25 mQ of
pyridine, and 4.5 g of selenium dioxide was added to the
solution, followed by stirring at 120C for 12 hours to effect
oxidation. The reaction mixture was filtered, and the filtrate
was concentrated to dryness. The concentrate was dissolved in
200 mQ of chloroform and then washed successively with 100 mQ of
an aqueous hydrochloric acid solution at pH 2 and 50 mQ of
water. The chloroform layer was dried with anhydrous sodium
sulfate and immediately concentrated to crystallize the product,
which were then recrystallized from ethanol to obtain 4.2 g of
crystals of 5-~p--chlorophenoxy)picolinlc acid.
Melting Point: 158-159.5C
Elemental Analysis for C12H8O3NCQ:
C H N O CQ
Calcd.(~): 57.72 3.21 5.61 19.24 14.23
Found (%): 57.63 3.26 5.53 14.19
EXAMPLE 5
., .
2.0 g of the 5-(p-chlorophenox~)-2-methylpyridine as
obtaîned in Example 4 was suspended in 60 mQ of water, and a
1.53 g portion of potassium permanganate was added four times
to the suspension while stirring at 100C over a 10 hour period
to effect oxidation. The reaction mixture was filtered, and the
filter cake washed with 30 mQ of warm water. The filtrate and
the washin~ were combined, adjusted to a pH of 9.5 with 5N
. ~ .
sodium hydroxide and washed with 30 mQ of chloroform. The
aqueous layer was adjusted to a pH of 1.5 with a 5N aqueous
, ` ~ .
-24-
;;, -
:'
,
'~
11157~19
hydrochloric acid solution, extracted with 50 m~ of chloroform.The chloroform layer was worked up in the same manner as
described in Example 4 to obtain 1.2 g of crystals of 5-~p-
chlorophenoxy)picolinic acid.
EXAMPLE 6
7.4 g of a potassium salt of 5-hydroxy-2-methyl-
pyridine, 8.5 g of p-bromotoluene and 500 mg of a copper
powder were suspended in 25 mQ of dimethylformamide, and the
mixture was allowed to react in a nitrogen gas stream at 130C
for 14 hours under stirring. The reaction mixture was dlluted
with 70 mQ of methanol and filtered. The filtrate was
immediately concentrated, and to the residue was added 150 mQ
of chloroform. The mixture was washed with 100 mQ of a O.OlN
aqueous sodium hydroxide solution, whereby the unreacted 5-
hydroxy-2-methylpyridine shifted to the aqueous layer. The
; chloroform layer was washed with water, dried with anhydrous
sodium sulfate and immediately dried to obtain 8.9 g of oily ~-
5-(p-methylphenoxy)-2-methylpyridine.
4 g of the thus-obtained product was dissolved in
~o 20 mQ of pyridine, and 4.3 g of selenium dioxide was added
, .
;~ thereto, followed by stirring at 120C for lS hours to effect
Xj oxidation. The reaction mixture was worked up in the same
manner as described in Example 4 to obtain 3.1 g of crystals of
5-(p-methylphènoxy)picolinic acid.
~ ~ Melting Point: 165-166C --
`' Elemental AnalySiS for C13HllO3N:
;~ C H N O
, ~ .
"t' Calcd.(~): 68.12 4.80 6.11 20.96
, . ,
Found (%): 68.17 4.72 6.19
-25-
.,
., ,
.~ - .
', :
. .
' . ' : . ~.' ': .
s7Q9
1 EXAMPLE 7
2.84 g of a potassium salt of 5-hydroxy-2-methyl-
pyridine, 4.7 g of p-dibromobenzene and 400 mg of cuprous
oxide were suspended in 10 m of dimethylacetamide, and the ;~
mixture was allowed to react in a nitrogen gas stream at 150C
for 15 hours. The reaction mixture was diluted with 30 mQ of
methanol and then filtered. The filtrate was immediately
dried, and the residue was taken into 100 mQ of chloroform and
washed successively with a 3% aqueous sodium carbonate solution
~ 10 and 50 mQ of water. The chloroform layer was dried with
; anhydrous sodium sulfate and immediately concentrated to
dryness to obtain 2.1 g of oily 5-(p-bromophenoxy)-2-methyl-
; pyridine.
2.0 g of the thus-obtained product-was then subjected
to oxidation in pyridine with selenium dioxide in the same manner
as described in Example 6 to obtain 1.4 g of crystals of 5-
!~
(p-bromophenoxy)picolinic acid.
;, Melting Point: 139-141C ;
~ Elemental Analysis for C12H803NBr:
,' 20 C H N 0 Br
Calcd.(%): 49.00 2.72 4.76 16.33 27.19
, ~ .
Found (%): 49.13 2.64 4.81 26.83
EXAMPLE 8
... ~
2.2 g of the 5-(p-nitrophenoxy)picolinic acid as
obtained in Example 3 was added to a solution of 6.1 g of
stannous chloride in 16.2 mQ of concentrated hydrochloric acid
~' cooled at 5C, followed by stirring at room temperature for
16 hours. The resulting crystalline precipitate was separated
by filtration and dissolved in 12 mQ of warm water. To the
. ~
~ 30 immediately solidified crystals was added 12 mQ of water, and
~''.'`'' ' . '.
-26-
.
-~
.: . , :.
11157~9
1 the resulting suspension was filtered. The resulting crude
crystals were washed with 25 mQ of water, recrys~allized from
75 mQ of a mixed solvent system of concentrated hydrochloric
acid/ethanol (3:5 by volume), washed with 15 mQ of ethanol and
dried under reduced pressure to obtain 1.0 g of colorless
crystals of 5-(p-aminophenoxy)picolinic acid dihydrochloride.
Melting Point: 221-230C (decomposition)
Elemental Analysis for C12Hl N O 2HCQ:
C H N O CQ
; 10 Calcd.(~): 47.52 3.96 9.2415.84 23.43
Found (%): 47.61 3.72 9.36 23.40
EXAMPLE 9
1.4 g of the 5~(p-aminophenoxy)picolinic acid
dihydrochloride as obtained in Example 8 was suspended in 22 mQ
of concentrated hydrochloric acid, and 3 mQ of an aqueous
solution containing 828 mg of sodium nitrite was added dropwise
~ to the suspension over a period of 1 hour under ice-cooling.
;~ 5.4 mQ of an aqueous solution containing 760 mg of
sodium metabisulfite and 480 mg of sodium hydroxide was added
to 11 mQ of a warm aqueous solution containing 3.4 g of copper
sulfate pentahydrate and 2.9 g of sodium chloride to prepare a
' cuprous chloride solution. The cuprous chloride solution was
added to the diazonium salt solution as above obtained to form
~i a solution, and 15 mQ of concentrated hydrochloric acid was
~hen added to the resulting solution, followed by stirring at
10C for 2 hours and then at room temperature for 16 hours
to effect the reaction. The reaction mixture was diluted with
50 mQ of water, adjusted to a pH of 1.5 with 5N sodium hydroxide
and extracted with 100 mQ of chloroform. The extract was dried
with anhydrous sodium sulfate, concentrated to a volume of about
'':' '
-27-
.'~ .
~i~S7Q9
. .
1 10 m~ and allowed to stand at 3C to form crystals, which were
then separated by filtration to obtain 0.91 g of crystals of
5-(p-chlorophenoxy)picolinic acid.
EXAMPLE 10
3.68 g of a potassium salt of 5-hydroxy-2-methyl-
pyridine was suspended in 10 mQ of dimethylformamide, and
5.65 g of m-bromobenzotrifluoride and 300 mg of copper powders
were added to the suspension, followed by allowing the mixture
to react in a nitrogen stream at 120C for 15 hours while -~
; 10 stirring. After cooling, the reaction mixture was diluted with
,.~
40 m~ of acetone and filtered. The filtrate was im~ediately
,, :
dried to solidify, and 100 mQ of chloroform and 50 mQ of water
were added thereto. The mlxture was adjusted to a pH of 9
with 5N sodium hydroxide, and any insoluble matter was again
,~ separated by filtration. The resulting chloroform layer was
;~ dried with anhydrous sodium sulfate and immediately concentrated
to dryness to obtain 4.1 g of oily 5-(m-trifluoromethylphenoxy)-
2-methylpyridine.
The thus-obtained product was subjected to oxidation
in pyridine using selenlum dioxide in the same manner as
described in Example 4. The product was crystallized from 20
:',`1 ~
~- mQ of ethyl acetate to obtain 2.7 g o crystals of 5-(m-
trifluoromethylphenoxy)picolinic acid.
Melting Point: 151-152C
Elemental Analysis for C13H803NF3:
~ C H N
; Calcd.(~):55.12 2.83 4.95
Found (%):53.68 2.72 4.79
EXAMPLE 11
~'."
`~ 30 3 g of a potassium salt of 5-hydroxy-2-methylpyridine,
: ~ .
.
,
-28-
..
:~"''.', `
. .
.
,; .
. . .. :. ::
~1~57Q9
.
1 3.83 g of m-bromochlorobenzene and 200 mg of a copper powder
were suspended in 8 mQ of dimethylformamide, followed by
allowing the mixture to react in a nitrogen gas stream at 130C
for 13 hours while stirring. The reaction mixture was diluted
with 40 mQ of ethanol and filtered. The filtrate was immediately
concentrated, and 80 mQ of chloroform was added to the residue.
The mixture was washed with a O.OlN aqueous sodium hydroxide
solution. The chloroform layer was washed with water, dried
with anhydouus sodium sulfate and dried to solidify to obtain
2.96 g of oily 5-(m-chlorophenoxy)-2-methylpyridine.
The thus, obtained product was subjected to oxidation A, '"t:~
using potassium permanganate in the same manner as described
in Example 5 to obtain 1.43 g of crystals of 5-(m-chlorophenoxy)-
/ picolinic acid.
; Melting Point: 138-139C
. j . .
Elemental Analy~is for C12H8O3NCQ:
C H N CQ
-~ Calcd.t%): 57.72 3.21 5.61 14.23
Found (~): 57.58 3.29 5.38 13.82
,~ 2Q EXAMPLE 12
;~ 4 g of a potassium salt of 5-hydroxy-2-methyl-
pyridine was suspended in 10 mQ of dimethylacetamide, and 5.1 g
of p-methOxybromobenzene and 450 mg of a copper powder were
added to the suspension, followed by allowing the mixture to
~; react in a nitrogen stream at 140C for 14 hours. The reaction
mixture was diluted with 50 mQ of methanol and filtered, and
the filtrate was immediately dried to a solid. 100 mQ of ethyl -
acetate was added to the résidue, and the mixture was washed
~` with 50 mQ of an aqueous sodium hydroxide solution at pH 9.
The ethyl acetate layer was washed with water, dried with
~`'`~,', ' .
29
.. ~
j,,.
. ~,, .
:-." . . ,; , ~ .
11~;57Q9
1 anhydrous sodium sulfate and immediately dried to obtain 3.9 g
of oily 5-(p-methoxyphenoxy)-2-methylpyridine.
The thus-obtained product was subjected to oxidation
in pyridine with selenium dioxide in the same manner as
described in Example 4 to obtain 1.8 g of crystals of 5-(p-
methoxyphenoxy)picolinic acid.
Melting Point: 170 172C
Elemental Analysis for C13HllO4N:
C H N ~ -
Calcd.(%): 63.67 4.49 5.71
Found (~): 63.25 4.62 5.76
EXAMPLE 13
, 4 g of a potassium salt of 5-hydroxy-2-methylpyridine,
;i 5.2 g of o-bromochlorobenzene and 250 mg of a copper powder
were suspended i~ 10 mQ of dimethylformamide, and tbe mixture
was allowed to react in a nitrogen gas stream at 115C for 23
" hours under stirring. The reaction mixture was diluted with
~; 70 mQ of methanol and filtered. The filtrate was dried to a
L
solid, and 120 mQ of chloroform was added to the residue. The
mixture was washed with 70 mQ of an aqueous sodium hydroxide
solution at pH of 9. The solvent layer was washed with water,
dried with anhydrous sodium sulfate and immediately dried to
obtain 2.8 g of oily 5-(o-chlorophenoxy)-2-methylpyridine.
~he thus-obtained product was subjected to oxidation
i
in pyridine with selenium dioxide in the same manner as
described in Example 4 to obtain 1~82 g of crystals of 5-(o-
chlorophenoxy)picolinic ccid.
Melting Point: 178-179C
- Elemental Analysis for Cl2H8o3NcQ:
C H N CQ
Calcd.(~): 57.72 3.21 5.61 14.23
Found (%): 57.67 3.15 5.73 13.82
.`''' ,
~ -30-
, . . .
~;,
~1~57~9
1 EXAMPLE 14
4 g of a potassium salt of 5-hydroxy-2-methyl-
pyridine was suspended in 10 mQ of dimethylformamide, and
6.15 g of p-bromobenzotrifluoride and 500 mg of a copper powder
were added to the suspension, followed by stirring in a nitrogen
; stream at 125C for 18 hours to effect the reaction. The
reaction mixture was allowed to cool, diluted with 50 mQ of ;
methanol and then filtered. The filtrate was immediately dried
to a solid, and 150 mQ of chloroform and 100 mQ of water were
added to the residue. The resulting mixture was adjusted to a
pH of 9.5 with 5N sodium hydroxide-and any insoluble matter
again separated by filtration. The chloroform layer was dried `~
with anhydrous sodium sulfate and immediately concentrated to
,,
" dryness to obtain 5.6 g of oily 5-(p-trifluoromethylphenoxy)-2-
methylpyridine.
The thus-obtained product was subjected to oxidation
; ~
' in pyridine with selenium dioxide in the same manner as described
in Example 4 to obtain 3.8 g of crystals of 5-(p-trifluoromethyl-
phenoxy)picolinic acid.
, .. ..
;~ 20 Melting Point: 150-151C
:
Elemental Analysis for C13H8O3NF3:
;~ C H N
;1~ Calcd.(%): 55.12 2.83 4.95
Found (%): 54.63 3.02 4.81
EXAMPLE 15
0.8 g of sodium hydroxide was added to a suspension
.~ - ,. .
` of 4.63 g of 5-(3-chloropropoxy)picolinic acid in 180 mQ of
water, followed by stirring to obtain an aqueous solution of
!
the sodium salt of 5-(3-chloropropoxy)picolinic acid. Ta this
'~ 30 solution was added 20 mQ of an aqueous solution containing 1.8 g
~ -31
. . .
~ ' ' , '
~,
, .- .
. . , ~, .. : ~ .
11~57~9
,, . ",
1 of calcium acetate monohydrate to form a white precipitate.
The thus-formed precipitate was separated by filtration, washed
with water and dried over phosphorus pentoxide to obtain 4.7 g
of a calcium salt of 5-(3-chloropropoxy)picolinic acid as white
powder.
Melting Point: above 220C
Elemental Analysis for CgHl0o3NcQ 1/2Ca:
C H N CQ
Calcd.(%): 45.86 4.25 5.94 15.07
Found (%): 44.72 4.31 5.73 14.25
EXAMPLE 16
8.15 g of a potassium salt of 5-hydroxy-2-hydroxy-
methylpyridine was suspended in 120 mQ of dimethylformamide,
and 10.5 g of 1,1,1-trifluoro-5-bromopentane was added to the
; suspension, followed by stirring at 65C for 18 hours to
effect the reaction. The reaction mixture was immediately
concentrated to dryness, and 200 mQ each of chloroform and
water were added to the residue to form two layers. The
chloroform layer was washed with water, dried with anhydrous
sodium sulfate and immediately ddred to obtain 12.83 g of a
syrup of 5-(5,5,5-trifluoropentyloxy)-2-hydroxymethylpyridine.
- 12.73 g of the thus-obtained product was dissolved in
150 mQ of a mixed solvent system of t-butanol-water (3:1 by
volume), and 110 mQ of an aqueous solution containing 9.4 g of
potassiurn permanganate was added dropwise thereto under ice-
; cooling over a period of 1.5 hours. The reaction mixture
was further stirred at 10 to 20C for an additional 2 hour -`
period and filtered. The filter cake was washed with 150 mQ of
a warm 50% aque~us methanol (adjusted to a pH 10 with sodium
hydroxide). The filtrate and the washlng were combined,
.
-32-
: . .
;'' ''
.
l~ls7~a
1 concentrated to a volume of about 100 mQ, adjusted to a pH of
1.5 with a 5N aqueous hydrochloric acid solution and extracted
with 200 mQ of chlorof~rm. The chloroform layer was dried with
anhydrous sodium sulfate, concentrated to a volume of about
20 mQ, mixed with 30 mQ of ethanol and allowed to stand at a
low temperature to form crystals, which were separated by
filtration to obtain 9.1 g of white crystals of 5-(5,5,5-
trifluoropentyloxy)picolinic acid.
Melting Point: 99-101C
10 Elemental Analysis for CllH12NO3F3:
C H N O F
Calcd.(%): 50.19 4.56 5.32 18.25 21.67
; Found (%): 49.92 4.67 5.19
EXAMPLE 17
5 g of 5-(4-chlorobutoxy)picolinic acid was suspended
in 30 mQ of benzene, and 14 mQ of thionyl chloride was added to
the suspension, ~ollowed by heat-refluxing for 3 hours. The
reaction mixture was immediately concentrated to dryness, and
20 mQ of benzene was added to the residue. The mixture was
again dried to solidify to remove the by-produced hydrogen
-~ chloride and sulfurous acid gas, thereby preparing an acid
chloride of 5-(4-chlorobutoxy)picolinic acid (hydrochloride).
The resulting acid chloride was dissolved in 40 mQ of benzene,
and the solution was added dropwise to 40 mQ of a benzene
~ solution containing 2~81 g of 5-hydroxyindane and 10.5 mQ of
i- triethylamine u~er ice-cooling over aperiod of 15 minutes while
` stirring. The reaction was further continued at 5 to 10C for
!~l 2 hours and then at room temperature for 2 hours. The reaction
`j~t~ mixture was dried to solidify, andthe residue was taken into
200 mQ of chloroform. The mixture was washed successively with
-33-
i ' :
- 11157~9
~
1 50 mQ each of an aqueous hydrochloric acid solution at a pH o~
3, an aqueous alkali solution at a pH of 9 and distilled water.
The chloroform layer was dried with anhydrous sodium sulfate,
concentrated to dryness and recrystallized from a mixed solvent
of ethyl ether and hexane to obtain 5.6 g of crystals of a
5-indanyl ester of 5~(4-chlorobutoxy)picolinic acid.
Melting Point: 62-63C
Elemental Analysis,for ClgH20NO3C :
C H N CQ
.
Calcd.(%): 65.99 5.79 4.05 10.27
Found (%): 65.28 5.83 3.97 10.56
EXAMPLE 18
1.5 g of 5-(p-chlorophenoxy)picolinic acid was
dissolved in 40 mQ of dried ethanol, and 0.15 mQ of concentrated
sulfuric acid was added to the solution, followed by heat-
refluxing for 6 hours. The reaction mixture was neutralized
with sodium hydrogencarbonate and concentrated to dryness. The
,: :
~' residue was dissolved in 50 mQ of chloroform and washed with i~
~ 30 mQ of water~ The chloroform layer was decolored with a
'~ 20 small amount of carbon powder, immediately dried to solidify,
dissolved in diethyl ether and allowed to stand at a low
` temperature to form crystals. The thus-formed crystals were
, separated by filtration to obtain 1.62 g of white crystals of
an ethyl ester of 5-(p-chlorophenoxy)picolinic acid.
:
Melting Point: 75-76C
Elemental Analysis for C14H12NO3C :
C H N CQ
^ Calcd.(%):60.54 4.325.05 12.79
Found (~):60.42 4.515.13 13.02
i 30 ~ -,
-34-
.,~ ' . .
~ ' .
11~57~)9
1 EXAMPLE 19
14 mQ of 28~ aqueous ammonia was added to 30 m~ of
a chloroform solution containing 2.37 g of the acid chloride
of 5-(o-trifluoromethylphenoxy)picolinic acid (hydrochloride),
and the resulting mixture was vigorously stirred for 2 hours.
The aqueous layer was removed, and the chloroform layer was
washed with two 20 mQ portions of water, dried with anhydrous
sodium sulfate and concentrated to dryness to obtain a crystal-
line residue. Recrystallization from a mixed solvent system
of ethanol-diethyl ether afforded 2.1 g of white crystals of
5-(o-trifluoromethylphenoxy)picolinic acid amide.
Melting Point: 137-138C -~
Elemental Analysis for C15H12NO3F3:
C H N F ~;
Calcd.(%): 57.88 3.86 4.50 18.33 -
Found (%): 57.69 3.92 4.~1
EXAMPLE 20
1 g of 5-(p-chlorophenoxy)picolinic acid was
dissolved in 20 mQ of dimethylformamide, and 1.22 g of -
zo pivaloyloxyethyl chloride and 1.12 mQ of triethylamine were
added to the solution, followed by stirring at room temperature
for 20 hours. 3 mQ of ice-water was added to the reaction
mixture, and the mixture was allowed to stand for 1 hour,
'~ followed by concentration to dryness. 70 mQ of ethyl acetate
was added to the residue, and the mixture was washed succes-
sively with 40 mQ each of an aqueous hydrochloric acid solution
at pH 3, a 5% aqueous sodium bicarbonate and water. The ethyl
acetate layer was dried with anhydrcussodium sulfate, dried to
solidify and dissolved in 5 mQ of diethyl ether. 10 mQ of
hexane was added to the solution, followed by allowing the
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' .
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:
~1~57~)9
1 mixture to stand at a low temperature to crystallize the
product. The thus-formed crystals ~ere separated by filtration
to obtain 1.2 g of white crystals of an ~-pivaloyloxyethyl
ester of 5-(p-chlorophenoxy)picolinic acid.
Melting Point: 120-122C
Elemental Analysis for C18H20NO5CQ:
C H N CQ
Calcd.(%): 59.10 5.473.83 9.71
Found (%): 59.02 5.533.78 10.02
EXAM2LE 21
10 m of a dichloromethane solution containing the
acid chloride of 5(o-chlorophenoxy)picolinic acid (hydrochloride)
; was added dropwise to 20 mQ of a dichloromethane solution
containing 0.43 g of 5-hydroxyindane and 1.6 mQ of triethylamine
under ice-cooling while stirring over a period of 5 minutes.
The reaction was continued at 0 to 5C for 1 hour and then at
room temperature for 2 hours. The reaction product was dried ~;
to solidify and further worked up in the same manner as
described in Example 17 to obtain 1.32 g of white crystals of
`~ 20 an indanyl ester of 5-(o-chlorophenoxy)picolinic acid.
Melting Point: 100-102C
Elemental Analysis for C21H16NO3CQ:
; C_ H N CQ
~` Calcd.(%): 68.95 4.38 3.83 9.71
'
~,~ Found ~%): 68.82 4.41 3.95 9.86
EXAMPLE 22
1.3 g of the ethyl ester of ~(p-chlorophenoxy)-
picolinic acid was dissolved in 6 mQ of acetone, and 15 mQ of
28% aqueous ammonia was added to the solution, followed by
allowing the mixture to stand at room temperature for 23 hours.
,
- 36
.`',~ , .
., - .`' ` `
~ " ~
~ lilS7(~9
1 The reaction mixture was cooled, and the precipitated crystals
were separated by filtration and recrystallized from a mixed
solvent of ethanol-diethyl ether to obtain 1.1 g of crystals -~
of 5-(p-chlorophenoxy)picolinic acid amide. -
Melting Point: 173-174C
Elemental Analysis for C12HgN202CQ:
C H N CQ
Calcd.(%): 57.95 3.6311.27 14.29
Found (%): 58.02 3.7111.25 14.18
EXAMPLE A
3 g of 5-n-butyloxy-picolinic acid was suspended
30 mQ of benzene and 8 mQ of thionyl chloride was added to the
~ suspension followed by stirring the mixture at 70C for 3
; hours. The resulting solution was then concentrated to dryness.
10 mQ of benzene was then added to the residue and the resulting
solution was concentrated to dryness. The addition of benzene
y (10 mQ) and the concentration to dryness was further repeated
two times so as to remove hydrogen chloride and sulfur dioxide ; ;~
~ by-produced and, thereby, the acid chloride of 5-n-butyloxy-
,~ 20 picolinic acid (hydro~hloride) was obtained. The acid chloride
thus-obtained was dissolved in 20 mQ of benzene and, then, the 3
resulting solution was added dropwise to a solution of 2.1 g of
5-hydroxyindane, 7.7 mQ of triethylamine and 30 mQ of benzene
for 10 minutes under cooling with ice-water while stirring~
The solution was stirred for 1.5 hours at 5-10C and further
stirred for 4 hours at room temperature to complete the reaction.
.. ~ .
The reaction solution was then concentrated to dryness. 100 mQ -
, of ethyl acetate was then added to the residue and the resulting
solution was washed with 50 mQ of cooled (at 5C) hydrochloric
` 30 acid solution (pH 2), 50 mQ of alkaline aqueous solution of
`` ' ~,
i -37-
~. .
: . . .
! ~
1 sodium bicarbonate (pH 9) and 50 mQ of water, respectively.
The ethyl acetate solution was dried over anhydrous sodium
sulfate, and, then, concentrated to dryness to obtain a
crystallize residue. Recrystallization from diethylether- -
hexane provided 4.5 g of crystals of the 5-indanyl ester of
5-n-butvloxy-picolinic acid.
Melting Point: 58-59C
Elemental Analysis for ClgH2lNO3:
C H N
Calcd.(~): 73.31 6.75 ~.50 ;
Found (%): 73.28 6.86 4.35
In clinical use, the compounds of this invention may
be administered orally in the form of tablets, capsules or dry
syrups usually employed as vehicles. The compounds may also
be administered in the form of a subcutaneous injection. In
this case, derivatives having an increased water solubility, e.g.
a dimethylaminoethyl ester of 5-(4-chlorobutoxy)picolinic acid
hydrochloride, are suitably used.
The compounds of this invention can be used as the
sole active agent or can be used in combination with one or
more other physiologically active agents, particularly diuretic
anti-hypertensive agents.
A dosage amount of the compounds of this invention is
about 200 to about 500 mg in one or two doses per day.
EXAMPLE 23
The composition of this Example is a tablet. A
granulation was prepared of:
Lactose 65 parts
Corn Starch30 parts
Polyvinyl pyrrolidone 5 parts
WaterA sufficient quantity
.
-38-
1 , The granulation was dried and screened. The follow-
ing ingredients were then mixed well together and compressed
into tablets weighing 250 mg and containing 100 mg of the
calcium salt.
Calcium 5-(4-chlorobutoxy)picolinate 100 g
Lactose granulation 97.5 g
Magnesium Stearate 2.5 g ~-
EXAMPLE 24
The composition of this Example is a capsule. The
following ingredients were blended and then introduced into
standard clear gelatin capsules.
Calcium 5-(5,5,5-trifluoropentyloxy)picolinate 100 g ' '`
Lactose 98 g
Magnesium Stearate 2 g
The resulting capsules contained 100 mg of the
calcium salt per dosage unit.
All the compounds of this invention represented by -; ,
the formula (I) above exhibit an anti-hypertensive activity by
oral or nonoral administration and can be regarded as useful ,
pharmaceutical agents as illustrated in the Examples 25 and 26
given below.
EXAMPLE 25
Each of the compounds of the invention as indicated
below was suspended in a 5% aqueous gum arabic solution and
the suspension was administered orally (100 mg/kg) to groups
consisting of three spontaneously hypertensive rats (18-23
weeks old; blood pressure before administration: 170-190 mmHg).
' Blood pressure changes were determined according to a Direct
Blood Pressure Measuring Method and the results obtained ar,e
shown in Table 1 below.
1 Each of the test compounds was administered intra-
peritoneally to male mice (ICR strain, 5 week old) and LD50
value was observed 1 week after administration, and the results
of acute toxicity are also shown in Table 1 below. -~
TABLE 1
Maximum
Acute Depression
ChemicalToxicity n
Test Compound Formula (Ln50) Pressure
(mg/kg) (%)
Fusaric Acid CloH13 2 75-100 15.8 ~ -
s-n-Butoxy-picolinic C10 13 3 100-150 16.6
5-(4-Chlorobutoxy)- Clo 12 3 150-200 23.0
picolinic Acid
5-(3-Chloropropoxy)- CgHloNO3CQ 150-200 18.2 ~
picolinic Acid -
s~(p-chlorophenoxy)- C12H8 3 150-200 28.3
picolinic Acid
s-(p-MethylPhenXY)~ C13HllN 3 200-300 17 0
picolinic Acid
5-(p-Aminophenoxy)- C12 10 2 3 8.3
picolinic Acid 2HCQ
Dihydrochloride
20 5-(m-Trifluoromethyl- C13H8NO F500-600 - 20.8
phenoxy)picolinic 3 3
Acia
5-(p-Bromophenoxy)- C12H8N 3150-200 27.5
picolinic Acid
5-(p-Methoxyphenoxy)- C13H lN 4500-600 14~2
picolinic Acld
5-(m-Chlorophenoxy)- C12H8NO3CQ 300-400 16.7
picolinic Acid
5-(o-Chlorophenoxy)- C12H8NO3CQ 150-200 30.1
picolinic Acid
5-(p-Acetylphenoxy)- C14HllNO4 400-500 17.3
picolinic Acid
s-(p-Trifluoromethyl- C13H8N 3 3 2Q0-250 29.3
phenoxy)picolinic
Acid
.
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1 Table 1 - cont'd Maximum
Depression
Acute in
Chemical ToxicityBlood
Test Compound Formula 50Pressure
5-(2,4-Dimethyl- C14H13N3 250-300 16.9
phenoxy)picolinic
Acid
5-(o-Trifluoro- C13 8 3 3 150-200 27.6
methylphenoxy)-
picolinic Acid
5-(2,4-Dimethoxy- C14H13 5 19.2
phenoxy)picolinic
Acid
lO 5-(p-Nitrophenoxy)- C12H8N2 5 500-600 15.1
picolinic Acid
5-(2,6-Dichloro- C12H7NO3cQ2 150-200 23.7
phenoxy)picolinic
Acid
5-(2,4-Ditrifluoro- C14H7NO3F6 200-250 25.5
methylphenoxy)-
picolinic Acid
5-(2,4-Dichloro- C12H7NO3cQ2 150-200 24.6
phenoxy)picolinic
Acid
5-(5,5,5-Trifluoro- CllHl2NO3F3 150-200 28.7
pentyloxy)picolinic
Acid
Calcium Salt of 5-(4- CloHllNO3CQ- 800-1000 22.8
Chlorobutoxy)picolinic 1/2Ca
Aci
Calcium Salt of 5-(p- C12H7NO3CQ 350 400 23.5
Chlorophenoxy)- 1/2C
picolinic Acid
Calcium Salt of 5- CllHllNO3F3 800-900 26.9
(5,5,5-Trifluoro- 1/2Ca
pentyloxy)picolinic
Acid
EXAMPLE 26
Each of the compounds of the invention as indicated
below was s~spended in a 5% aqueous gum arabic solution and the
suspension was administered orally to groups consisting of
three spontaneously hypertensive rats (17-23 week old; blood
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.. ~1~9
-
1 pressure before administration: 170-190 mmHg~. Blood pressure
changes were determined according to a Tail Cuff Method and the
results obtained are shown in Table 2 below.
TABLE 2
Maximum
Depression
in
Blood
Test Compound Dose Pressure
(mg/kg) (%) ;
Indanyl Ester of 5-(4-Chlorobutoxy)- 100 26.3
picolinic Acid
5-(4-Chlorobutoxy)picolinic Acid 100 21.5
Amide
Ethyl Ester of 5-(p-Chlorophenoxy)- 100 23.3
picolinic Acid
Indanyl Ester of 5-(p-Chlorophenoxy)- 100 27.5
picolinic Acid
~ Pivaloyloxyethyl Ester of 5-(p- 100 21.8
Chlorophenoxy)picolinic Acid
5-(p-Chlorophenoxy)picolinic Acid 100 23.7
Amide
Indanyl Ester of 5-~o-trifluoro- 100 26.3 ~-
methylphenoxy)picolinic Acid
5-(o-Trifluoromethylphenoxy)picolinic 10020.7
~ Acid Amide
Indanyl Ester of 5-(-Chlorophenoxy)- 100 29.0
; picolinic Acid
5-(o-Chlorophenoxy)picolinic Acid 100 19.6
Amide
The oral LD50 f free acids according to the present
invention was 900 mg/kg for 5-(4-chlorobutoxy)picolinic acid
; and 400 to 600 mg/kg for 5-(p-chlorophenoxy)picolinic aCid,
5-(o-chlorophenoxy)picolinic acid and 5-(o-trifluoromethyl-
phenoxy)picolinic acid. On the other hand, the oral LD50 f
the indanyl esters, acyloxyalkyl esters and amide derivatives
Of the present invention were improved, for example, 1600-1800
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1 m~/kg for the indanyl ester of 5-(4-chlorobutoxy)picolinic acid,
700-800 mg/kg for the indanyl ester of 5-(p-chlorophenoxy)-
picolinic acid, 900-1,000 mg/kg for the ~-pivaloyloxyethyl
ester of 5-(p-chlorophenoxy)picolinic acid, 1,500-1,600 mg/kg
for 5-(4-chlorobutoxy)picolinic acid amide and 950 mg/kg for
5-(o-trifluoromethylphenoxy)picolinic acid amide.
All the compounds of this invention represented by -
the formula (A) above exhibit a long-lasting antihypertensive
activity by oral administration and can be regarded as useful `
lO pharmaceutical agents as illustrated in the Reference Example ~;
hereinafter.
EXAMPLE B
Each of the compounds indicated below was suspended in
a 5% aqueous gum arabi~ solution containing-2~ Tween 80, an~ the
suspension was administered orally to groups of spontaneously
hypertensive rats (15-20 weeks old; 3 rats per group; blood
pressure before administration: 175-190 mmHg). Arterial blood
pressure of concious SHR was recorded from the caudal artery via
a pressure transducer (NIHON KOHDEN MP-24T) on a polygraph
20 (NIHON KOHDEN RM-85). '
The results obtained are shown in the table below.
Maximum
Depression
in Blood
Test Compound DoSe Pressure
~ (mg/kg) (%)
5-Indanyl Ester of 5-n- 100 21.8
Butyloxy-picolinic Acid
Fusaric Acid* (control) 100 10.5
* ~ C4H9
HOOC N
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57~g
1 The oral LD50 of the fusaric acid (control~ was
180 mg/kg and the oral LD50 of free 5-alkoxy-picolinic acids,
such as 5-n-propyloxy-picolinic acid and 5-n-butyloxy-picolinic
acid, was 300-500 mg/kg. On the other hand, the oral LD50 of the
esters of 5-alkoxy-picolinic acid of the present invention were
improved, for example 800-1,000 mg/kg for the indanyl ester.
While the invention has been described in detail and
with reference to specific embodiments thereof, it will be
apparent to one skilled in the art that various changes and ~ :
modifications can be made therein without departing from the
spirit and scope thereof.
~.
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