CA1330999C - Naphthalenepropionic acid derivatives as anti-inflammatory/antiallergic agents - Google Patents

Abstract

NAPHTHALENEPROPIONIC ACID DERIVATIVES
AS ANTI-INFLAMMATORY/ANTIALLERGIC AGENTS
Abstract of the Disclosure There are disclosed compounds of the formula wherein X is N or CR;
Z is , , , , S or O;
R is hydrogen or lower alkyl;
R1 is hydrogen or lower alkyl;
R2 is hydrogen or lower alkyl; or R1 and R2 taken together form a benzene ring;
and the pharmaceutically acceptable salts thereof, and their use in the treatment of leukotriene-mediated naso-bronchial obstructive airpassageway conditions, such as allergic rhinitis, allergic bronchial asthma and the like, in psoriasis, ulcerative colitis, rheumatoid arthritis as well as in other immediate hypersensitivity reactions.

Description

NAPHl~IALENEPROPIONIC ACID DERIVAl~V~S ~ ~ -AS ANT[-lNELAM~q~TORY/ANT~ALLE12GIC AG13NTS

This invention relates to novel naphthalenepropionic acid ~ ;
derivatives possessing lipoxygenase inhibitory and leukotriene antagonist 5activity, which are useful as anti-inflamrnatory and antiallergic agents. ~ ;
It is known that arachidonic acid (AA) is metabolized in mammals by two distinct pathways. The metabolism of arachidonic acid by cyclooxy-genase enzymes results in the production of prostaglandins and thromboxanes.
The physiological activity of the prostaglandins has already been amply 10elucidated in recent years. The other pathway of AA metabolism involves lipoxygenase enzymes and results in the production of a number of oxidative products called leukotrienes. The latter are designated by the LT
nomenclature system, and the most significant products of the lipoxygenase metabolic pathway are the leukotrienes B4, C4, D4 and E4. The substance denominated slow-reacting substance of anaphylaxis (SRS-A) has been shown to consist of a mixture of sulfidopeptide leukotrienes, C4, D4 and E4 [see Bach - -et al., J. Immun., 215, 115-118 (1980); Biochem. Biophys. Res. Commun. 93, 1121-1126 (1980) ] . -~
The significance of these leukotrienes is that a great deal of 20evidence has been accumulated showing that leukotrienes participate in inflammatory reactions, exhibit chemotactic activities, stimulate lysosomal enzyme release and act as important factors in the immediate hypersensitivity reaction. It has been shown that LTC4 and LTD4 are potent broncho~
constrictors of the human bronchi [see Dahlen et al., Nature 288, 484-486 25(1980) and Piper, Int. Arch. Appl. Immunol., 76, suppl. 1, 43 (1985)] which stimulate the release of mucus from airways in vitro [Marom et al., Am. Rev.
Resp. Dis., 126, 449 (1982)], are potent vasodilators in skin [see Bisgaard et al, Prostaglandins, 23, 797 (1982)], and produce a wheal and flare ~esponse [Camp et al., Br. J. Pharmacol" 80, 497 (1983)]. The nonpeptide leukotriene, LTB4, 30is a powerful chemotactic factor for leukocytes [see A.W. Ford-Hutchinson, J.
. Soc. Med.~ 74, 831-833 (1981)], which stimulates cell accumulation and ;
affects vascular smooth aluscle [see Bray, Br. Med. Bull., 39, 249 (1983)]. The activity of leulcotrienes as mediators of inflammation and hypersensitivity is extensively reviewed in Bailey and Casey, Ann. Reports Med. Chem., 17, 203-35217 (1982) and in Bray, Agents and Actions, ~, 87 (1986).

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Acco~dingly, the biological activity of the leukotrienes and SRS's, and of lipoxygenase as the enzyme leading to the metabolism of AA to leukotrienes, indicates that a rational approach to drug therapy to prevent, remove or ameliorate the symptoms of allergies, anaphyIaxis, asthma and 5 inflammation must focus on either blocking the release of mediators of these conditions or antagonizing their effects. Thus compounds, which inhibit the biological effects of the leukotrienes and SRS's and/or which control the biosynthesis of these substances, as by inhibiting lipoxygenase, are considered to be of value in treating such conditions as allergic bronchial asthma, allergic 10 rhinitis, as well as in other immediate hypersensitivity reactions.
It has now been found that certain noveI naphthalenepropionic acid derivatives inhibit lipoxygenase and antagonize products of the lipoxygenase pathway, and so are useful as antiinflammatory and anti-allergic agents. The present invention provides novel compounds having the following formula~

;~ CHCOOH

~CH20 ~1 wherein X is N or CR;
Z is -Cl - I -, -C=N-, -N= IC-, -N-, S or O;
R R R R R
R is hydrogen or lower alkyl;
Rl is hydrogen or lower alkyl;
R2 is hydrogen or lower aL'cyl; or Rl and R2 taken together form a benzene ring;
and the pharmaceutically acceptable salts thereof. ~ ;
The term "lower alkyl" refers to moieties having 1 to 6 carbon 25 atoms in the carbon chain.

1 3 3 ~

The compounds of the invention can be readily prepar~d according to the following reaction sequence~
f H3 CHCOOH :
R2~C--Z ~ NaOCH

', "-~

2 ~C Dl~ I OC--HCOOH
NnOII > ~ ~CN20 R.
The starting materials used in the above reaction sequence are available commercially or can be prepared by known methods conventional in ~` ~ the art. Thus, for example, the benzo-fus:e: heterocyclic compounds such as l-methyl-2-chloromethylbenzimidazole, 2-chloromethylbenzthiazole and 2-10 chloromethylbenzoxazole can be prepared by the following reaction scheme:

~ Cl 112C--OCR3 ~ ~C112CI

wherein X is O, S or NCH3. The reaction is preferably carried out at a ;
controlled low temperature in an organic solvent, such as methylene chloride. .:
,; ;~
., ~ .-,.
: -:.-: : :.
~'.,~

~ ~ 3 3 ~

Compounds of the invention which contain a basic nitrogen are capable of forming pharmaceutically acceptable salts, including the salts of pharmaceutically acceptable organic and inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, methanesulfonic, benzenesulfonic, 5 acetic, citric, fumaric, maleic, succinie and the like.
The compounds of the invention, by virtue of their ability to inhibit the activity of lipoxygenase enzyme and to antagonize mediators arising from this enzymatic pathway, are useful in the treatment of inflammatory conditions. Accordingly, the compounds are indicated in the treatment of such 10 diseases as rheumatoid arthritis, osteoarthritis, tendinitis, bursitis and similar conditions involving inflammation. Moreover, by virtue of their ability to inhibit the activity of lipoxygenase enzyme and by their ability to antagonize the effect of LTC4, LTD4 and LTE4 which are the constituents of SRS-A, they are useful for the inhibition of symptoms induced by these leukotrienes.
15 Accordingly, the compounds are indicated in the prevention and treatment of those disease states in which LTC4, LTD4 and LTE4 are causative factors, for example allergic rhinitis, allergic bronchial asthma and other leukotriene mediated naso-bronchial obstructive air-passageway conditions, as well as in other immediate hypersensitivity reactions, such as allergic conjunctivitis 20 The compounds are especially valuable in the prevention and treatment of allergic bronchial asthma.
When the compounds of the invention are employed in the treatment of allergic airway disorders and/or as antiinflammatory agents, they can be formulated into oral dosage forms such as tablets, capsules and the 25 like. The compounds can be administered alone or by combining them with conventional carriers, such as magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl~
cellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. Diluents, flavoring agents, solubilizers, lubricants, suspending agents, 30 binders, tablet-disintegrating agents and the like may be employed. The compounds may be encapsulated with or without other carriers. In all cases, the proportion of active ingredients in said compositions both solid and liquid will be at least to impart the desired activity thereto on oral administration.
The compounds may also be injected parenterally, in which case they are used 35 in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic. For administration by :. .,' ,, .,', ', ~`~
~ 3 3 ~ 9 - 5 ~
inhalation or insufflation, the compounds may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
The dosage requirements vary with the particular compositions 5 employed, the route of administration, the severity of the symptoms presented and the particular subject being treated Treatment will generally be initiated with small dosQges less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. In general, the compounds of the invention are most desirably 10 administered at a concentration that will generally afford effective results without causing any harmful or deleterious side effects, and can be administered either as a single unit dose, or if desired, the dosage may be divided into convenient subunits administered at suitable times throughout the day.
The lipoxygenase inhibitory and leukotriene antagonist effects as well as the antiinflammatory effects of the compounds of the invention may be demonstrated by standard pharmacological procedures, which are described more fully in the examples given hereinafter.
These procedures illustrate the ability of the compounds of the 20 invention to inhibit the polymorphonuclear leukocyte synthesis of the lipoxy~genase product 5-HETE; the in vivo ability of the compounds to inhibit bronchospasm induced by exogenously administered mediators of bronchocon~
striction; and measure the in vivo activity of the compounds as anti-inflammatory agents in the rat carrageenan paw edema assay.
The following examples show the preparation and pharmacological testing of compounds within the invention.

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Example 1 ~ -.
ethyl~2~oinolinylmethoy~2-naphthaleneacetie acid - n - ~
.
To a solution of 6-hydroxy-o~-methyl-2-naphthaleneacetic acid (10.8 g, 50 mmol) in methanol (100 ml) is added sodium methoxide (100 mmol).
5 After 10 minutes the solvent is removed and replaced with dimethylformamide (250 ml). 2-(Chloromethyl)quinoline (17.8 g, 100 mmol) is then added and the reaction mixture is stirred for 8 days at room temperature. The reaction mixture is partitioned between water and methylene chloride, the organic layer is washed with water and evaporated to yield 27 g of an oil.
10 Recrystallization of this oil twice from acetonitrile gives 10.6 g of white ~;
crystals of intermediate ether ester (4296 yield, m.p. 106-108C).
The ether ester from above is hydrolyzed as follows: a solution of the ether ester (14.4 g, 28.9 mmol) in a mixture of 110 ml of lN NaOH and 110 ml tetrahydrofuran is refluxed for 1 hour. The organic solvent is then ~; 15 removed and 2-(hydroxymethyl)quinoline is filtered off. The aqueous solution ~; is acidified to pH 6 and the precipitate is filtered and recrystallized from -~
ethanol to afford 2.2 g of white crystals (21% yield, m.p. 186-187C).
Analysis for: C23HlgNO
Calculated: C, 77.30; H, 5.36; N, 3.92. ;~
20 Found: C, 77.69; H, 5.36; N, 3.93.

Example 2 a-Methyl~6~phenylmetho2~y~2-naphthaleneaceti~ acid -.,: .: ~- . .
To a solution of 6-hydroxy-~ -methyl-2-naphthaleneacetic acid (6.48 g, 30 mmol) in methanol (100 ml) is added sodium methoxide (60 mm).
25 After 10 minutes the solvent is removed and replaced with dimethylformamide (100 ml). Benzyl chloride (7.6 g, 60 mm) is then added and the reaction mixture is stirred overnight at room temperature. The reaction is then heated ; at 150 C for 1 hour. The solvent is then removed and the residue is partitioned between water and methylene chloride. The organic layer is 30 washed with water, dried over magnesium sulfate and evaporated to 11.5 g of crude product. This crude product is extracted with 100 ml hot hexane which affords 3.5 g of white crystals. A final recrystallization from methanol affords 2.5 g of white crystals of the intermediate ethyl ester (21% yield, m.p.76-78C).
` `,',~,..
'~'` ' ;'';"'~'' ~l 3 3 ~

The ether ester (~.2 g, 5.56 mmol) ;s hydrolyzed using the method of Example 1. Recrystallization from ethanol affords 1.1 g of white crystals (65% yield, m.p. 149-151C).
AnalysiS for: C20H183 Calculated: C, 78.40; H, 5.92.
Found:G, 78.31; H, 6.02.

Example 3 ~-Nethyl~-l(l-methyl-lH~enz:imida~:ol-2-yl) methoy ]-2-naphthaleneacetic acid -10 The procedure of Example 2 is followed on a 10 mmol scale, substituting 2-chlormethyl-N-methyl-benzimidazole for benzyl chloride. ~-Normal workup affords 2.5 g of white crystals of ether ester (50% yield, m.p.
228-230C). This material is analytically pure and needs no recrystallization.
The ether ester (2.5 g, 4.9 mmol) is hydrolyzed according to the 15 method of Example 1. Recrystallization from ethanol affords 0.75 g of white -~
crystals (43% yield, m.p. 216-219C).
Analysis for: C22H20N2o3 3/4 H2O
Calculated: C, 70.66; H, 5.79; N, 7.49.
Found: C, 70.89; H, 5.72; N, 7.28.

Example 4 -Methylff~2-pyridinylmethoy~2-n~phthaleneaceti~ acid To a solution of 6-hydroxy-u-methyl-2-naphthaleneacetic acid (10.8 g, 50 mmol) in methanol (100 ml) is added sodium methoxide (100 mmol).
After 10 minutes the solvent is removed and replaced with hexamethyl- -25 phosphoric triamide (250 ml). 2-Chloromethyl-pyridine (100 mmol) is then ~ ~ :
added and the reaction is stirred for 5 days. The reaction is worked up by partitioning between water and methylene chloride, and the organic extract is evaporated to a crude oil which is chromatographed on silica gel (eluant: ~ -methylene chloride - ethyl acetate) to afford 6.0 g of ether ester as an oil.
The ether ester is hydrolyzed using the method of Example 1.
Recrystallization from ethanol affords 5.5 g of white crystals ~36% yield, m.p.
185-187 C). ~ -.~ ' -~::'' '~
.~.,,:

- 3 3 3 a ~

Analysis for: ClgH17NO3 Calculated: C, 74.24; H, 5.57; N, 4.56.
Pound: C, 74.49; H, 5.63; N, 4.49.

13xample 5 The compounds 5- and 12-hydroxyeicosatetraenoic acid (5-HETE
and 12-HETE) and 5,12-dihydroxyeicosatetraenoic acid (5,12-diHETE;) are early arachidonic acid oxidation products in the lipoxygenase cascade, which have been shown to mediate several aspects c>f inflammatory and allergic response.
The assay of this Example measures the ability of the compounds of the invention to inhibit the synthesis of 5-HETE by rat glycogen elicited poly-morphonuclear leukocytes.
The assay is carried out as follows: -~
Peritoneal PMN are obtained from female Wistar rats (150-250 g) that received an i.p. injection of 6% glycogen (10 ml). After 24 hours, rats are killed by CO2 asphyxiation and peritoneal cells are harvested by peritoneal lavage using Ca++and Mg++ free Hanks' balanced salt solution (HBSS). The peritoneal exudate is centrifuged at 400 g for 10 minutes. After centrifugation, the lavaged fluid is removed and the cell pellet is resuspended in HBSS containing Ca++ and Mg++ and 10 mM L-cysteine at a concentration ~ `
of 2 x 107 cells/ml. To 1 ml portions of cell suspension, test drugs or vehicle are added and incubated at 37C fsr 10 minutes. Following this preincubation, the calcium ionophore (10 ,uM), A23187, is added together with 0.5 llCi ~14C]
~ -arachidonic acid and further incubated for 10 minutes. The reaction is stopped by the addition of ice cold water (3 ml) and acidifying to pH 3.5. Lipoxygenase -~
products are then extracted twice into diethyl ether. The pooled ether ~
extracts are evaporated to dryness under nitrogen and the residue is ~ - ;
redissolved in a small volume of methanol and spotted on aluminum backed pre-coated thin layer chromatographic plates. The samples are then cochromatographed with authentic reference 5-HETE in the solvent system hexane: ether: acetic acid (50:50:3). After chromatography, the areas associated with 5-HETE standard are identified by autoradiography, cut out and quantitated by liquid scintillation.
-The compounds of the invention, when tested in this assay at the ;
~` level of lO uM, gave the following results in inhibiting the synthesis of the arachidonic acid lipoxygenase oxidation product 5-HETE.

,'~', ~
~"'''''" "'' . :

1 3 ~

g .
TQble 1 Compound of % Inhibition of 5-LO
Example No. (as 5-HETE) 100 :: .

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These results show that the compounds of the invention exhibit very significant activity in inhibiting the enzyme, lipoxygenase.

. . ~:
El~ample fi The procedure of Example 5 is also employed for the determination of the ability of the compounds of the invention to inhibit the synthesis of thearachidonic acid cyclooxygenase oxidation product TxB2.
In this assay, the procedure of Example 5 is carried out as 15 described. EIowever, in order to determine cyclooxygenase activity, the samples are cochromatographed with authentic reference TxB2 in the solvent system ethyl acetate:formic acid (80:1) and the upper phase of ethyl acetate: isooctane: acetic acid: water (110:50:20:100). After chromato~
graphy, the areas associated with the TxB2 standard are identified by 20 autoradiography, cut out and quantitated by liquid scintillation techniques.
The results are calculated as in Example 5.
When tested in this assay the compounds of the invention, at a level of lO uM gave the following results in inhibiting the synthesis of the arachidonic acid cyclooxygenase oxidation product TxB2.
Table 2 Compound of % Inhibition of CO
(as TxB2) : . :: .
~ ~:

~ 3 ~

These results show that the compounds of the invention are virtually devoid of cyclooxygenase inhibitory activity, having activity substantially only on the lipoxygenase pathway of arachidonic acid oxidation.

Exam~le 7 The assay of this Example measures the in vivo ability of the compounds of the invention to inhibit the bronchospasm induced in guinea pigs by the exogenously administered leukotrienes C4 and/or D4.
This assay is carried out as follows:
Male Hartley strain guinea pigs (350-600g) are anesthetized with pentobarbital sodium (50 mg/kg, i.p.). The jugular vein is cannulated for~
injection of drugs and the carotid artery for monitoring blood pressure. The trachea is cannulated for artificial ventilation by a miniature Starling pump and for indirect measurement of respiratory volume changes. The animals are then pretreated with succinylcholine (2 mg/kg i.v.) and indomethacin (10 mglkg i.v. in trizma 8.3 buffer, 9 minutes prior to~ leukotriene challenge).
Submaximal bronchoconstrictor responses are established in control animals by varying the dose-levels of leuko~riene. Intravenous dose-levels for LTC4 range from 0.4 to 0.6 ~Ig/kg and for I.TD4 the range is from 0.3 to 0.5 llg/kg. Th~e aerosol bronchoprovocation dose for LTC4 is generated from 1.6 tlM solution and for LTD4 from a 2.0 ~IM solution.
Test drugs (dissolved in a solvent such as propylene glycol, polyethylene glycol 400 or saline) are administered either intraduodenally, by aerosol or intragastrically at 2 or l0 minutes before induction of bronchospasm by administration of either LTC4 or LTD4 at the predetermined dose-levels.
Aerosols of soluble drugs or leukotrienes are produced in-line for l0 seconds only by actuation of an ultrasonic nebulizer (Monaghan). Aerosolized drug dosage is expressed in terms of solution concentration and by a fixed aerosol ~` exposure time (approximately 10 seconds). Control animals receive solvent (2 ml/kg i.d. or appropriate aerosol) in place of drug.
Respiratory volume changes are determined by a calibrated piston whose travel is recorded, ~via a linear transducer, on a Beckman- Dynograph ` ~ ` re~order. Maximal bronchoconstrictor volume is determined by clamping off the trachea at the end of the experiment. Overflow volumes ~t 1, 3 and 5 minutes are obtained from the recorded charts.

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Area under the volume overflow curve (AUC) is estimated, using the overflow values at 1, 3 and 5 minutes, and expressed as a percentage of the maximal overflow AUC (equation l):
3 (l min) + 4 (3 min) -~ 2 (5 min) % max AUC = - -- X lO0 (l ~ :~
l0 (max) 5 Drug effects are reported as percent inhibition of % max AUC values obtained from appropriate control animals (equation 2):
% max AUC control- % max AUC treated % inhibition = X 100 (2 ~: % max AUC control Student's t-test for unpaired data is used to determine statistical significance (p < 0.05). ICso values can also be determined by inverse 10prediction from linear regression lines through points between 10 and 90% ~ ~ :
inhibition. .
The results for compounds of the invention are as follows: ~-Table 3 ~: Compound administered at 10 minutes before induction of bronchospasm .
15using LTD4 :~ Compound of Dose*
Example Number mg/kg% Inhibition ~ :~
l 25 ~5 :

4 25 52 : ~

* = intraduodenally administered - : ::: ~:

The results show that compounds of the invention have significant :
in vivo activity against LTD4 induced bronchoconstriction. ~

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E~cample ~
The compounds of the invention are further tested in the rat carrageenan paw edema assay to determine their ability to inhibit the acute inflammatory response.
This assay is carried out as follows: ;~
140-180 gm male Sprague-Dawley rats, in groups of 6 animals are -injected subcutaneously in the right paw with 0.1 ml of 1% carrageenan at -~
zero time. Mercury plethysmographic readings (ml) of the paw are made at zero time and 3 hours later. Test compounds are suspended or dissolved in 0.5% methylcellulose and given perorally 1 hour prior to carrageenan administration.
The increase in paw volume (edema in ml.) produced by the carrageenan is measured. Paw edema is calculated (3 hour volume minus zero -time volume), and percent inhibition of edema is determined. Unpaired ~ ~ -Student's t-test is used to determine statistical significance. -The activity of standard drugs in this assay is as follows:
Dru~ Oral EDso (95% C.L.~ m~/kF ~- -Indomethacin 3-7 t0.6, 23.8) Aspirin * 145.4 (33.1, 645.6) Phenylbutazone 26.2 (2.3, 291.0) When tested in this assay, the compounds of the invention gave the following results:
Table 4 Compound of% Inhibition at 25 ExamDle No.50 mg/kg (peroral) ` ~ 1 42 ~: :
The results show that the compounds tested have activity in the rat carrageenan paw edema assay, evidencing an effect on the acute inflammatory ~ ~ `
response.
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Claims (5)

1. A compound having the formula;
wherein X is N or CR;
Z is , , , , S or O;
R is hydrogen or lower alkyl;
R1 is hydrogen or lower alkyl;
R2 is hydrogen or lower alkyl; and further when X is N and Z is , R1 and R2 may be taken together to form a benzene ring;
and the pharmaceutically acceptable salts thereof.

2. The compound of Claim 1, having the name .alpha.-methyl-6-(2-quinolinylmethoxy)-2-naphthaleneacetic acid.

3. The compound of Claim 1, having the name .alpha.-methyl-6-(phenylmethoxy)-2-naphthaleneacetic acid.

4. The compound of Claim 1, having the name .alpha.-methyl-6-[(1-methyl-1H-benzimidazol-2-yl)methoxy]-2-naphthaleneacetic acid.

5. The compound of Claim 1, having the name .alpha.-methyl-6-(2-pyridinylmethoxy)-2-naphthalaneacetic acid.