CA1209586A - Naphthalenecarboxamides, their production and use - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel 2,5-dihydroxy-6-substituted amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide of the formula wherein R is phenyl-C1-6 alkyl, and salts thereof, have intraocular pressure depressant action.
These compounds are prepared by condensing the corresponding primary amine or 2-hydroxy protected derivative thereof under reducing conditions with a compound of the formula .
wherein R1 and R2 are selected so that

Description

-` ~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~:

[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:

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 AO ~ [V~

NH-R
OH

:

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 . ~

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 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.

~ 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

.

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 (%~ =

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

Claims (12)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a compound of the formula:
[I]
wherein R is phenyl-C1-6 alkyl, or a pharmaceutically acceptable salt thereof, which process comprises:
a) condensing under reducing conditions a compound of the formula:
[II]

with a compound of the formula:
[III]
wherein R1 is phenyl-C1-5 alkyl or phenyl, R2 is hydrogen or C1-5 alkyl and the group represented by corresponds to R of the formula [I], or b) condensing under reducing conditions a compound of the formula:

[IV]
wherein A is a hydroxy-protecting group selected from the class consisting of lower alkyl and aralkyl, with the compound of the formula [III] to give a compound of the formula [V]

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) if desired, converting the thus obtained compound of the formula [I] into a pharmaceutically acceptable salt thereof.

2. A compound of the formula:
[I]
wherein R is phenyl-C1-6 alkyl, or a pharmaceutically acceptable salt thereof, whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process according to claim 1, wherein the starting materials and the resulting products are essentially in the form of trans-isomer.

4. A process according to claim 3, wherein the compound of formula [I]
is converted to a pharmaceutically acceptable acid addition salt.

5. A process according to claim 1, 3 or 4, wherein process variant b) is employed using a compound of formula IV wherein A is benzyl.

6. A process according to claim 1, 3, 4, wherein process variant b) is employed using a compound of formula IV wherein A is benzyl, and a complex metal hydride as a reducing agent.

7. A process for producing 2, 5-dihydroxy-6-(1-methyl-3-phenylpropylamino) -5,6,7,8-tetrahydro-1-naphthalenecarboxamide or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
a) condensing 6-amino-2,5-dihydroxy-5,6,7,8-tetrahydro-1-napthalene-carboxamide or 2-hydroxy protected derivative thereof wherein the hydroxy protecting derivative is selected from the class consisting of lower alkyl and aralkyl, or an acid addition salt thereof, with benzylacetone under reducing conditions, b) when required, removing the hydroxy protecting group, and c) if desired, converting to a pharmaceutically acceptable salt.

8. 2,5-Dihydroxy-6-(1-methyl-3-phenylpropylamino)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide, or a pharmaceutically acceptable salt thereof, whenever prepared or produced by the process of claim 7 or by an obvious chemical equivalent thereof.

9. A process according to claim 7, wherein as the starting material the trans-isomer is used.

10. A process according to claim 9, wherein as the starting material, trans-6-amino-2-benzyloxy-5-hydroxy-5,6,7,8-tetrahydro-1-naphthalene-carboxamide or an acid addition salt thereof is employed.

11. A process according to claim 9 or 10, wherein step c) is carried out to convert to the hydrochloride thereof.

12. A process according to claim 10, wherein the benzyl group is removed by catalytic hydrogenolysis.