Note: Descriptions are shown in the official language in which they were submitted.
-` ~2(~9~B
This invention relates to novel naphthalenecarboxamide compounds
having an excellent pharmacological action and preparation thereof.
More particularly, this invention provides compounds of the formul~:
CONH2
[I]
OH
~herein R is phenyl-Cl 6 alkyl and salts thereof, which have intraocular
pressure depressant action.
~ nited States Patent No. 4,035,512 ~corresponding to Canadian Patent
No. 1,039,297) describes the b~oad concept of tetralol compounds which
encompasses the compound of the formula [I] among other compounds. ~owever,
1~ thi~patent does not concretely disclose the compound ~I] nor does it
contain any statement suggesting the utility of such compounds in the field
of ophthalmology.
The present invention has been accomplished as the result of the
present inventor's intensive research directed ~o the ophthalmologic
application of various salicylic acid derivatives.
Referring to the formula [I], phenyl-Cl 6 alkyl for R is
exemplified by benzyl, phenethyl, 3-phenylpropyl, ~-methylben~ylg
~-methylphenethyl, l-methyl-3-phenylpropyl~ 2-methyl-3-phenylpropyl J
l-methyl-~-phenylbutyl, 3-phenyl-pentyl, 6-phenylhexyl and 1,1-dimethyl-3-
phenylpropyl. Most desirable is l-methyl-3-phenylpropyl.
The present invention also provides a process for preparing the
compound of the formula [I] or a pharmaceutically acceptable salt thereof
by a) condensing under reducing conditions a compound of the formula:
CON~12
HO ~ NH2 [II]
OH
wi~h a compound of the formula
2 \ C =~O [III]
wherein Rl is ph~vnyl-Cl 5 alkyl or phenyl, R2 is hydrogen orC 5 alkyl ~d the
group represented by Rl
~ CH
corresponds to R of the formula [I], or b~ by condensing under reducing.con-
conditions a compound of the formula:
CONH2
AO
~ NH2 ~I~]
OH
wherein A is a hydroxy-protecting group selected from *he class consisting of
lower alkyl and aralkyl, with the compound of the formula ~ to give a
compound of the formula
CONH2
AO ~ [V~
NH-R
OH
-- 2 --
:
il2~
wherein A and R are as defined above, and removing the hydroxy-protecting
group in the thus obtained compound of the formula [V], and c~ i~ desired,
converting the thus obtained compound of the formula [I] into a pharmaceutically
accep~able salt thereof.
Re~erring to the above formulas, phenyl-Cl 5 alkyl for Rl is exem-
plified by benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, ~-methylbenzyl,
~-methylphenethyl and 5-phenylpentyl. Cl 5 alkyl R~ is exemplified by methyl,
ethyl, propyl, isopropyl, butyl and the like. The lower alkyl A is exemplified
by methyl, ethyl, propyl, isopropyl, butyl, etc. and the aralkyl A is exem-
plified by benzyl, phenethyl, 3-phenylpropyl and so on.
The above reaction between [II] and [III] and that between [IV] and
[III] are carried out generally by reducing both compounds inwater or an
organic solvent ~for example, methanol, ethanol, dioxane, ethyl acetate, etc.)
or a mixture thereof. This reduction reaction may for example be catalytic
reduction with the aid of a catalyst such as platinum, palladium, Raney
nickel, etc.; reduction using a complex metal hydride such as lithium
aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohy-
dride, sodium cyanoborohydride, etc.; reduction using metallic sodiumg metallic
magnesium or the like and an alcohol; reduction using zinc dust and a base;
or reduction using a metal such as iron, zinc or the like and an acid such as
hydrochloric acid or acetic acid. Aside from these reduction reactions, any
other reduction method can be employed. While the reaction temperature varies
~ith different reduction methods, it is generally advantageous to conduct the
reduction at a temperature of about -20C to about 100C. This reaction can
be successfully
-- 3 --
. ~
conducted at atmospheric pressure but, if necessary, it
may be conducted at elevated or reduced pressure.
The above-mentioned deprotection reaction for [V]
may be carried out in any known manner. For example,
solvolysis, hydrogenolysis, etc~ can be utilized with
advantage. More particularly, -there may preferably be
employed such reactions as (1) catalytic reduction with
the aid of a catalyst such as platinum, palladium, rhodium,
Raney nickel, etc.; (2) reduction using liquid ammonia or
alcohol ~e.g. ethanol, butanol, etc.~ and a metal (e.g.
sodium metal, potassium metal, etc.); (3) reaction with a
Lewis acid such as aluminum chloride, aluminum bromide,
zinc chloride~ magnesium iodidej iron chloride, boron
trichloride, boron trifluoride, etc.; (4) reaction with an
acid such as a hydrogen halide (e.g~ hydrogen fluoride,
48~ hydrobromic acid, hydrogen fluoride-acetic acidt
hydrochloric acid, hydrogen iodide, etc~), sulfuric acid,
nitric acid, phosphoric acid~ perchloric acid, boric acid,
etc. or a solution thereof in water, alcohol or the like;
(5) reaction with an organic acid such as trifluoroacetic
acid, acetic acid, oxalic acid, p-toluenesulfonic acid,
formic acid, etc. or an aqueous solution thereof; (6)
reaction with an inorganic base such as sodium hydroxi~e,
potassium hydroxide, barium hydroxide, potassium carbonate,
sodium hydrogen carbonate, aqueous ammonia, hydrazine
hydrate, etc., or an organic base such as pyridine hydro-
chloride, tetramethylammonium hydroxide, collidine-lithium
iodide, etc. The reaction temperature varies with kinds
of reaction but generally speaking, the range of about
30 -40C to about 150C is desirable~ While these reactions
are generally conducted at atmospheric pressure, they may
be carried out at reduced or elevated pressure.
The resulting contemplated compound [I~ can be
isolated by the conventional isolation procedures such as
e~traction, concentration, neutralization, filtration,
recrystallization, column chromatography, thin layer
~L2~
chromatography, etc.
Since the compound of the formula [I] contains
asymmetric carbon within its molecule, it e~ists as
several optical isomers but, of course, all of these
individual isomers as well as a racemic mixture thereof
fall within the scope of -the present invention. While
the compound of formula ~I] is generally obtained as a
mixture of isomers, it can be separated into individual
component isomers by the per se conventional separation
procedures such as the method of producing a salt with an
opticall~ active base (e.g. cinchonine, cinchonidine,
quinine, quinidine, etc.), various chromatographic
procedures, fractional cr~stallization, etc.
The contemplated compound [I~ of this invention may
also be isolated after it has been converted to salts,
especially to physiologically acceptable salts such as
acid addition salts and alkaline metal salts in the
conventional manner; for example, an inorganic acid salt
(such as hydrochloride, hydrobromide, sulfate, etc.), an
organic acid salt (such as maleate, fumarate, tartrate,
toluenesulfonate, naphthalenesulfonate, methanesulfonate,
etc.~, and a metal salt tsuch as sodium salt, potassium
salt, etc.2
The compound of the present invention exhibits intra-
ocular pressure depressant acti~ity ;n mammalian animalsinclusive of man and is low in toxicity. Therefore, it is
of value as a drug for the treatment o glaucoma, for
instance. The administration routes include oral and
parenteral but it is generally preferable to use the
compound locally as an ophthalmic solution. In ophthal-
mological application, it is desirably used as a 0.01 to 1%
(w/v~ ophthalmic solution and administered at a frequency
of 3 to 5 times daily, one to a few drops per dose.
An ophthalmic solution containing the compound [I]
or a salt thereof may be prepared by per se conventional
techniques using suitable pharmaceutically acceptable
carrier, vehicle or diluent.
The ophthalmic solution may, if desired, contain
other and conventional ophthalmic ingredients such as
; boric acid, preservatives, salts, antibiotics, vitamins,
amino acids and so forth.
The starting compound [II] for use in the practice
of the present invention can be prepared, for example by
the following reactions:
~ CH20 ~ 1) PC15 ~ 2
` ~ CEzO ~ ~H3- ~ S0zC
~X
~ CE20 ~ C2H~OK
N-0-SOz ~ CH3
~ ~' N~z ~ N~2
H2 > ~II]
The following reference, working and preparation
examples are given to illustrate the present invention in
further detail and should by no means be construed as
limiting the scope of the invention.
Example 1
In 200 ml of benzene was dissolved 27 g of 2-
benzyloxy-5-oxo-5,6,7-8-tetrahydro-1-naphthoic acid and
after addition of 22.7 g of phosphorus pentachloride,
the solution was refluxed for 1 hourO The solvent was
then distilled off and the residue was dissolved in 200 ml
of dioxane. Ammonia gas was bubbled khrough the dioxane
solution at room temperature or 1 hour, after which the
solution was poured into 500 ml of water and extracted
with 300 ml of ethyl acetate. The extract was washed with
water, dried and distilled to give 20 g of 2-benzyloxy-5-
oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxamide.
Recrystallization from ethyl acetate gave crystals melting
at 192-194C.
-Example 2
To a mixture of 20 ml of methanol and 2 ml of water
were added 3 g of 2-benzyloxy-5-oxo-5,6,7,8-tetrahydro-1-
naphthalenecarboxamide, 2 g of potassium carbonate and
2.8 g of hydroxylamine hydrochloride, and the solution
was refluxed ur.der stirring for 3 hours. After cooling,
the reaction mixture was poured into 50 ml of water and
the crystals separating out were collected and recrystal-
lized from 50% methanol~ whereby 3 g of 2-benzyloxy-5-
25 hydroxyimino-5,6,7,8-tetrahydro-1 naphthalenecarboxamide,
m.p. 244-246C, was obtained.
Example 3
In 10 ml of pyridine was dissolved 3 g of 2-
30 benzyloxy-5-hydroxyimino-5,6,7~8-~etrahydro-1-naphthalene-
carboxamide and, then, 4 g of p-toluenesulfonyl chloride
was added in small portions under ice-cooling. The mixture
was stirred at 5C for 30 minutes and, further, at room
temperature for 1 hour, The raaction mixture was poured
into 100 ml of ice-water and the crystals separating out
were collected by filtration and recrystallized from
-- 8 --
methanol. The above procedure yielded 2.8 g of 2-
benzyloxy-5-p~toluenesulfonyloxyimino-5,6,7,8-tetrahydro-
l-naphthalenecarboxamide as colorless crystals, m.p. 149-
151C.
~ Example 4
A solution of 15 g of 2-benzyloxy-S-p-toluene-
sulfonyloxyimino-5,6,7,8-tetrahydro-1-naphthalenecarbox-
amide in 300 ml of benzene was ice-cooled and a solution
of potassium ethoxide prepared from an equivalent of
potassium metal in anhydrous methanol was added under a
nitrogen gas stream. The mixture was stirred under ice-
cooling for 5 hours and, then, allowed to stand in a
refrigerator for 1 week. The precipitates were filtered
off and 25 ml o~ concentrated hydrochloric acid was added
to the filtrate. The crystals separating out were
collected by filtration and recrystallized from 200 ml of
ethanol. The procedure yielded 7 g of 6-amino-2-benzyloxy-
5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydro~
chloride melting at 227-230C.
Example 5
In 5Q ml of methanol was dissolved 2 g of 6-amino-
2-benzyloxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarbox-
amide followed by addition of 2 g of sodium borohydrideat room temperature. The mixture was stirred for 30
minutes, after which it was diluted with 300 ml of water
and extracted three times with 50 ml portions of chloroform.
The extract was washed with water, dried and distilled,
and the residue was dissolved in sa ml of ethyl ether,
followed by addition of 5 ml of 20% ethanolic hydrochloric
acid. The resulting crystals were recrystallized from
methanol-ethylether to give 1.5 g of trans-6-amino-2-
benzyloxy-5-hydroxy-5,6,7,8-tetrahydro-1-naphthalene-
carboxamide hydrochloride, m.p. 220-222C.
- 9 -
~ Example 6
In 30 ml of methanol was dissolved 1 g of trans-6-
amino-2-benzyloxy-5-hydroxy-5,6,7,g-tetrahydro-1-
naphthalenecarboxamide hydrochloride, followed by addition
of 5 g of benzylacetone. Then, under ice-cooling, 1 g of
sodium cyanoborohydride was added and the mixture was
allowed to stand at room temperature overnight. The re-
action mixture was diluted with 300 ml of water and
extracted 3 times with 30 ml of CHC13 The CHC13 layers
were combined, washed with water, dried and concentrated
under reduced pressure. The residue was dissolved in 50 ml
of ethyl ether, followed by addition of 5 ml of 20%
ethanolic hydrochloric acid, whereby 0.84 g of trans-~-
benzyloxy-5-hydroxy-6-(1-methyl-3-phenylpropylamino~-
15 5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride
was ohtained as colorless crystals, m.p. 215-218C.
Elemental analysis: C28H32~2O3
Calcd.: C, 69.91, H, 6.91; N, 5~82
Found . C, 70.11; H, 7.15; N, 5.6g
NMR spectrum, ~d6-DMSO~: 4.75(1H, d, J=9HZ,
C
Example 7
In 50 ml of methanol was dissolved 1 g of trans-2-
benzyloxy-5-hydroxy-6-(1-methyl-3-phenylpropylamino)-
5,6,7,~-tetrahydro-1-naphthalenecarboxamide hydrochloride
and catalytic reduction was carried out in the presence of
1 ~ o~ 10% palladium-on-carbon at atmospheric temperature
and pressure. After the absorption of hydrogen was
completed, the catalyst was filterd off and the filtxate
was distilled under reduced pressure. To the residue was
added 50 ml of ethyl ether, whereby 0.56 g of trans-2,5-
dihydroxy-6-(1-methyl-3-phenylpropylamino)-5,6,7,8-tetra-
hydro-l-naphthalenecarboxamide hydrochloride was obtained
as colorless powder.
Elemental analysis: C21H26N2O3-HC
.
-- 10 --
Calcd.: C, 64.52; H, 6.96; N, 7.17
Found : C, 64.12; H, 6.75; N, 7.05
NMR spectrum ~(d6-DMSo): 1.33(3H, d, J=6Hz,
CH3), 1.70-2.20(4H, m), 2.50-2.85(4H, m),
3,20-3.45(2H, m~. 4.85(1H, d, J=9Hz, Cl-H),
7.00(lH, d, J=6Hz, phenyl protons),
7.40-7.53(6H, m, phenyl protons)
.
Preparation Example
An exemplary opthalmologic formula for use of the
compound o~ the present invention as an ophthalmic solution
is as follows:
Boric acid 1.8%
lN sodium hydroxide Suitable amount
Adjusted to pH 7.0
Benzalkonium chloride 0.005%
Trans-2,5-dihydroxy-6-
(l-methyl-3-phenylpropylamino~-
5,6,7,8-tetrahydro-1-naphthalene-
carboxamide hydrochloride 0.5%
Pure water Suitable amount
Total 100 ml
Test Example
The intraocular pressure depressant action of trans-
2,5-dihydroxy-6-(1-methyl-3-phenylpropylamino)-5,6,7,8-
tetrahydro-1-naphthalenecarboxamide hydrochloride [here-
inafter referred to briefly as compound (1)] was studied
in healthy white rabbits~
50 ~1 of a 0.5 to 0.05 w/v~ solution of compound (1)
; in physiological saline was instilled into rabbit eyes and
the intraocular pressure was measured with a pneumatic
applanation tonometer ~R.E. Walker et al~, Experimental
Eye Research 13, 187 (1972?]. The intraocular pressure
measurement was carried out immediately before
~IL2~
. .
instillation and thereafter repeatedly up to 5.5 hours
after instillation and the ra-te of pressure drop (%) was
calculated by means of the following equation:
Rate of intraocular pressure drop (%~ =
P 0 P
po ~ g x 100
[where P0 is the intraocular pressure immediately before
instillakion~ P is the average intraocular pressure after
instillation, and the numeral 9 is the value set as the
theoretical lower limit of intraocular pressure]
The rate of intraocular pressure drop for each
concentration l`evel of compound (1) is given in Table 1.
Table 1
_ _
Concentra- Rate of pres- Number
tion (w/v%) 0 (mmHg) P (mmHg) sure d (%) of eyes
_
0.05 16.2+1.4 14.0-~1.3 27.6+25.6 8
0.10 16.7+1.5 13.3+1.g ~0.3+21.0 8
0.25 16.3+1.7 13.0+1.5 45.4+13.9 10
2Q 0.5 17.0+2.1 11~2+0.6 6~.7+18.5 8
