WO1991008208A1

WO1991008208A1 - Heterocyclic substituted naphthyridinones and methods and compositions employing them

Info

Publication number: WO1991008208A1
Application number: PCT/US1990/006873
Authority: WO
Inventors: David J. Blythin
Original assignee: Schering Corporation
Priority date: 1989-12-04
Filing date: 1990-11-30
Publication date: 1991-06-13
Also published as: JPH04506357A; EP0505434A1; JPH0749430B2; CA2070400A1; AU6960391A

Abstract

Nitrogen-containing heterocyclic substituted naphthyridinones of formula (I), effective in treating allergic reactions, inflammation, inflammatory bowel disease, pepticulcers and hyperproliferative skin disease, and pharmaceutical compositions employing them, are disclosed. Formula (I) or a pharmaceutically acceptable salt thereof, wherein: A is O or S; W represents (a) or (b); R represents H or alkyl; R1 represents alkanediyl; R2 represents a covalent bond or -alkanediyl-O-; R3 represents alkyl, cycloalkyl, benzyl, substituted benzyl or hydroxyalkyl; Q represents phenyl, 1- or 2-naphthyl, 1-,2-,3-,4-,5-,6-, or 7-indenyl or 1-,2-,3-,4-,5-,6- or 7-indanyl, each of which may optionally be substituted with 1 to 3 Y groups as defined below; and each Y is independently selected from alkyl, halo, nitro, alkoxy, alkylthio, -CF¿3?, -CN, cycloalkyl, alkylsulfinyl or alkylsulfonyl.

Description

HETEROCYCLIC SUBSTITUTED NAPHTHYRIDINONES AND METHODS AND COMPOSITIONS EMPLOYING THEM

BACKGROUND OF THE INVENTION

The present invention relates to certain heterocyclic substituted naphthyridinones and to methods and compositions using such compounds.

European published application No. 0 231 709 discloses phenyl naphthyridinones of the formula:

wherein Z is, for example, an amine functional group and X and Y are, for example, H, a halogen atom, a lower alkyl group, a trifluoromethyl, an alkoxy, a methylthio, a nitro or a cyano. Among the amine functional groups described are

where n is 0 to 5 and it is possible for R-j and R2 to form a piperazine ring substituted by an alkyl or an aromatic nucleus which may or may not be substituted, or alternatively to form an imidazole ring. These compounds are disclosed as ulcer-inhibiting drugs.

U.S. Patent No. 4,684,727 discloses zwitterionic bicyclic compounds of the formula:

wherein the substitutents can be among those exemplified below: W and X may be the same or different and each independently represents -CH= or -N=;

Z-i and Z₂ are the same or different and each independently represents -O- or -S-; R¹ , R2, R3_ R4 _and R5 are the same or different and each may be independently selected from the group consisting of, for example, H, alkyl having from 1 to 12 carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, etc.; in addition, two of R¹, R² and R³ can be joined together to represent a ring which can contain from 2 to 8 carbon atoms, such as a pyrrole, piperidine or morpholine ring; m is an integer of from 0 to 3; n is an integer of from 0 to 2;

Q represents an aryl or an aromatic heterocyclic group which can optionally be substituted with 1 to 3 substituents Y; and each Y substituent is independently selected from the group consisting of, for example, hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, NO2, alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, cyano, etc. These compounds are disclosed as being anti-allergic, anti-inflammatory and/or cytoprotective agents.

SUMMARY OF THE INVENTION

We have now surprisingly found that compounds having the structural formula I

or a pharmaceutically acceptable salt thereof have activity useful in the treatment of allergy, inflammation, hyperproliferative skin disease and peptic ulcers, wherein:

R is H or alkyl;

A is O or S;

W represents

R¹ represents alkanediyl;

R² represents a covalent bond or -alkanediyl-O-; R3 represents alkyl, cycloalkyl, benzyl, substituted benzyl or hydroxyalkyl having 2 to 6 carbon atoms between the N atom and the OH group; Q represents phenyl, 1 - or 2-naphthyl, 1 -, 2-, 3-, 4-, 5-, 6- or

7-indenyl or 1-, 2-, 3-, 4-, 5-, 6- or 7-indanyl, each of which may optionally be substituted with 1 to 3 Y groups as defined below; and each Y is independently selected from alkyl, halo, nitro, alkoxy, alkylthio, -CF3, -CN, cycloalkyl, alkylsuifinyl or alkylsulfonyl. Preferably, W is the group

A is preferably O and Q is preferably phenyl or substituted phenyl. W is preferably

more preferably

Particularly preferred compounds include:

r

or a pharmaceutically acceptable salt thereof.

Other aspects of the invention involve a pharmaceutical composition comprising a compound of formula I above in combination with a pharmaceutically acceptable carrier and methods of treating allergic reactions, inflammation, inflammatory bowel disease, peptic ulcers and hyperproliferative skin disease in a mammal comprising administering to said mammal an effective amount or a compound of formula I for such purpose.

DETAILED DESCRIPTION OF THE INVENTION

Certain compounds of this invention may exist in isomeric forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.

Certain compounds of the invention of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of the invention.

Certain compounds of the invention e.g., those with a strongly basic amine group, also form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral, sulfonic and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of this invention.

The following terms used in the present specification and claims have the meanings given below, unless otherwise indicated: alkyl (including the alkyl portions of hydroxyalkyl, alkoxy, alkylthio, alkylsuifinyl and alkylsulfonyl) - represents a straight or branched, saturated hydrocarbon chain having from 1 to 10, preferably from 1 to 6, carbon atoms; alkanediyl - represents a divalent, saturated straight or branched hydrocarbon chain, having from 1 to 10, preferably from 1 to 6, carbon atoms; cycloalkyl - represents a saturated carbocyclic ring having from 3 to 10, preferably from 3 to 6 carbon atoms; halo - represents fluoro, chloro, bromo or iodo; substituted phenyl (including the substituted phenyl portion of substituted benzyl) - represents a phenyl group in which 1 to 3 hydrogen atoms thereof are replaced by the same or different substituents independently chosen from alkyl, halo, nitro, alkoxy, alkylthio, -CF₃, -CN, cycloalkyl, alkylsuifinyl or alkylsulfonyl; and substituted benzyl - represents a benzyl group in which the phenyl ring is substituted as defined above. The compounds of the invention can be made by the processes described below with reference to Scheme 1 : SCHEME 1

,CH(OH)Alkyl

^*N ' N WHHQO

VI VI I

In the compound of Formula II, L represents a conventional leaving group such as chloro, bromo, iodo, tosyl, mesyl, etc. and R⁴ can be H or alkyl. In Step A, the compound of Formula II wherein R⁴ is H can be reacted with an amine of Formula QNH2 in aqueous solution with an acid catalyst such as para-toluene sulfonic acid.

In Step A, when R⁴ is alkyl (preferably not methyl), the compound QNH2 can be reacted in excess (preferably more than 2 equivalents) with the compound of Formula II and heated, preferably to about 125°C, for a time sufficient to provide the desired reaction, e.g., by following the reaction with thin layer chromatography. This reaction can be run neat or in a suitable solvent such as toluene, xylene, etc.

If R⁴ in Formula HI is H, it is preferably converted to an ester (i.e., R⁴ is alkyl) by reaction under standard esterification conditions with, for example, potassium carbonate and diethyl sulfate in dimethylformamide.

In Step B, the ester of Formula HI is reduced with a suitable reducing agent such as lithium aluminum hydride, lithium borohydride or lithium triethylborohydride ("Super Hydride^®"). With "Super Hydride^®", the reaction is preferably cooled, e.g., to a temperature of from about -20°C to about room temperature. With lithium aluminum hydride, the reaction is normally performed in an ether such as diethylether under reflux. With lithium borohydride, the reaction is run initially at room temperature, then heated at reflux (e.g., in tetrahydrofuran) until the reaction is complete, e.g., as shown by thin layer chromatography.

The compound of Formula IV is oxidized in Step C with a suitable oxidizing agent such as activated manganese dioxide in a suitable solvent, such as benzene, toluene, xylene, chloroform, etc., at elevated temperature (e.g., about 50°C to about 120°C), preferably with removal of water formed in the reaction.

In Step D, the compound of Formula V is reacted with a compound of the Formula W-CH2-C0₂alkyl in the presence of a catalytic amount of a suitable base. Exemplary bases include potassium t- butoxide, sodium ethoxide, etc. The reaction can be performed in a suitable solvent such as tetrahydrofuran (preferably containing a small quantity of a protic solvent such as t-butanol) or an alcohol solvent, preferably corresponding to the alcohol portion of the ester W-CH₂-C0₂alkyl. Other possible solvents include ether type solvents such as dioxane, dimethoxyethane, etc. The reaction can be run at any suitable temperature, preferably at room temperature or below.

In Step E, the compound of Formula V is reacted with a suitable alkyl organometallic agent MAIkyl, wherein M is, for example, a magnesium halide or lithium. This reaction is run in a suitable solvent such as an ether , e.g., diethylether or tetrahydrofuran. The reaction is preferably run at or below room temperature, e.g. from about 25°C to about -20°C. The reaction is neutralized with a mineral acid to provide the compound of Formula VI. The conditions and reactants for Steps F and G are essentially the same as those set forth above for Steps C and D, respectively.

The compounds of this invention wherein A is sulfur may be obtained by treating the purified 2-carbonyl compound of formula I with thiating reagents well known in the art. Lawesson's Reagent {2,4- bis(4-methoxyphenyl-1 ,3-dithia-2,4-diphosphetane-2,4-disulfide} or one of its analogues, in toluene, or phosphorus pentasulfide in pyridine are suitable for this purpose.

The compounds of formula I wherein W represents

can be prepared by reacting a compound of formula I wherein W represents

with a compound R³ L wherein L represents a suitable leaving group such as chloro, bromo, iodo, tosyl, mesyl, etc. The reaction is carried out in an inert solvent such as toluene or xylene at elevated temperatures, e.g. from about 50°C to about 140°C. The compounds of this invention may be employed as anti- allergy agents in the treatment of, for example, asthma, allergic or seasonal rhinitis, and/or chronic bronchitis. The anti-allergy method of this invention is identified by tests which measure a compound's ability to inhibit leukotriene release.

In one such test procedure, the anti-allergy method of this invention is identified by tests which measure a compound's inhibition of leukotriene release in sensitized guinea pigs. Male Hartley guinea pigs (250-300 g) are sensitized with 5 mg ovalbumin injected i.p. and 5 mg injected s.c. in 1 ml saline on day 1 and 5 mg ovalbumin injected i.p. on day 4. The sensitized animals are used 3-4 weeks later at which time they weigh 450-500 g. Sensitized guinea pigs are killed by a blow to the head and the lungs removed and cleaned of visible connective tissue, trachea and large blood vessels. The lungs from individual animals are sliced into fragments approximately 1 mm in thickness using a Mcllwain tissue chopper and then washed with oxygenated Tyrode's buffer. Weighed aliquots (approximately 400 mg wet weight) of lung are transferred into vials containing 2 ml of fresh Tyrode's solution

(containing 10 mM cysteine) and incubated in the presence or absence of test compound for 12 min at 37°C. The tissues are then challenged with 20 μg ovalbumin/ml (final concentration) and incubated for 15 min. To measure leukotriene release, an aliquot of supernatant fluid is extracted with 4 volumes of 100% ethanol. After removal of the precipitated protein, the leukotriene content is measured by a radioimmunoassay using [³H]LTC4 and antiserum obtained from New England Nuclear. The cross-reactivity of the antiserum for LTD4 is 55%. Percent inhibition of lekotriene release is calculated by comparing for each lung the release in the presence of the test compound to that in the absence of test compound. Representative compounds of the invention at a dose of 10 μM are found to inhibit leukotriene release in the test procedure as indicated below in Table 1 :

Inhibition of SRS-A release

_____ w in vitro -Guinea Pig Lung 10 μM

-N phenyl 34%

m-CF3- phenyl 46%

m-CN phenyl 43%

phenyl 65%

m-CN-phenyl 66%

m-CN-phenyl 46%

The anti-allergy activity of the compounds of the invention may also be demonstrated by the following protocol:

Male Hartley guinea pigs (250-300 g) are sensitized with 5 mg ovalbumin injected i.p. and 5 mg injected s.c. in 1 ml saline on day 1 and 5 mg ovalbumin injected i.p. on day 4. The sensitized animals are used 3-4 weeks later at which time they weigh 450-500 g. The sensitized guinea pigs are fasted overnight and the following morning are anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/ml diallybarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane). The trachea are cannulated and the animals are ventilated by a Harvard^® rodent respirator at 50 strokes/minute with a stroke volume of 5 ml. A side arm to the tracheal cannula is connected to a pressure transducer (Harvard) to obtain a continuous measure of intratracheal pressure which is recorded on a polygraph (Harvard). The jugular vein is cannulated for the i.v. administration of substances. The sensitized guinea pigs are injected i.v. with 1 mg/kg propranolol, 5 mg/kg indomethacin and 2 mg/kg mepyramine given together in a volume of 1 ml/kg. The animals are challenged with antigen (0.5% ovalbumin) as an aerosol generated from a DeVilbiss^® Model 65 ultrasonic nebulizer and delivered through the tracheal cannula for 30 seconds.

Bronchoconstriction is measured as the peak increase in intratracheal pressure occurring within 15 minutes after antigen challenge.

Test compounds are administered orally 2 hours before challenge with ovalbumin. Suppression of anaphylactic bronchospasm is expressed as a percent inhibition of the peak increase in intratracheal pressure by comparison to a vehicle-treated control group.

Results from the above procedure for two compounds of the invention are listed in Table 2 below.

Inhibition of anaphylactic bronchospasm

_Ω_ _____ Pose mg/kg % Inhibition

phenyl 61

phenyl 93

The compounds of this invention are also useful for the treatment of inflammation. Thus, they are useful in the treatment of arthritis, bursitis, tendonitis, gout and other physical conditions characterized by inflammation. The anti-inflammatory use of the compounds of this invention may be demonstrated by the Reversed Passive Arthus Response Technique, as described below.

Reversed Passive Arthus Response (RPAR) Animals. Materials and Methods

Male Lewis inbred albino rats weighing 180-200 grams obtained from Charles River Breeding Laboratories are used in these experiments. The rats are housed 3 animals/cage and food and water are allowed ad libitum. The animals are numbered 1-3 in each cage and color marked for identification purposes. Drug and Reagent Preparation All reagents and drugs are prepared just prior to the study. Crystallized and lyophilized bovine serum albumin (BSA), available from Sigma Chemical Company, is solubilized without shaking in cold, sterile, pyrogen-free saline (10 mg/ml). Lyophilized anti-bovine serum albumin (IgG fraction), obtained from Cappel Laboratories, is suspended in sterile distilled water and diluted with cold, pyrogen-free saline (PFS) just prior to use. The final concentration of anti-bovine serum albumin is 0.5 mg/ml of PFS. Both BSA and anti-BSA solutions are iced during use. Drugs are suspended or solubilized in an aqueous solution of methyl cellulose (MC) with an homogenizer just prior to administration.

Drug Administration and Induction of Inflammation

Groups of animals (6/group) are dosed with drug in MC by gavage once daily for 3 days. The last dose is administered one hour prior to sensitization with BSA. Controls are given MC alone and a drug-standard is usually included in each assay for verification purposes. Drugs are prepared and diluted so as to provide a dose for a 200 gram animal which is equivalent to the mg/kg dose for each experiment. Thus each rat receives an oral dose in a volume of approximately 2.0 cc. One hour after the last dose the animals are , lightly anesthetized with ether and "sensitized" by injection of 0.2 ml of PFS containing 1.0 mg of BSA into the penile vein. One hour later, the animals are "challenged" in the right rear paw with subplantar injections of 0.2 ml of ml of PFS containing 0.1 mg of anti-BSA. Immediately after the subplantar injection, the right paw is dipped (up to the lateral malleolus) into the mercury well of a plethysmograph. The volume of mercury displaced is converted to weight and recorded. This value is considered to be the control reading for the animal. Paw volumes are subsequently recorded with a plethysmograph during the development of the inflammation at 2 and 4 hours post-challenge. Results

Results are expressed by the change in paw volume (Δ paw volume) from the control reading for each animal to that recorded 2 and 4 hours post-challenge. All drug treated groups are compared to the MC control for significant differences with an analysis of variance. The compounds of this invention are also useful in the treatment of peptic ulcers and stress ulceration, and to promote healing of gastric and/or duodenal ulcers. The antiulcer activity of the compounds of this invention is identified by standard tests which measure the cytoprotective effect in rats, e.g., by inducing gastrointestinal damage with ethanol prior to administering a compound of the invention. The compounds may be used as conjunctive therapeutic agents for coadministration with such anti- inflammatory/analgesic agents as aspirin, indomethacin, phenylbutazone, ibuprofen, naproxen, tolmetin and other agents. The compounds of this invention prevent the untoward side effects of irritation and damage to the gastrointestinal tract caused by such agents.

The compounds of formula I are useful in the treatment of hyperproliferative skin disease, e.g., psoriasis, which utility may be demonstrated by the Arachidonic Acid Mouse Ear Test as described below.

Arachidonic Acid Mouse Ear Test, Materials and Methods

Charles River, female, CD, (SD) BR mice, 6 weeks old, are caged 8/groups and allowed to acclimate 1-3 weeks prior to use. Arachidonic acid (AA) is dissolved in reagent grade acetone (2 mg/.01 ml) and stored at -20°C for a maximum of 1 week prior to use. Inflammatory reactions are induced by applying 10 μl of AA to both surfaces of one ear (4 mg total).

Test drugs are dissolved in either reagent grade acetone or aqueous ethanol (only if insoluble in acetone) at the same doses selected by Opas eial-, Fed. Proc. 43. Abstract 2983, p. 1927 (1984) and Young filal., J. Invest. Dermatol. 82. pp. 367-371 (1984). These doses are employed to ensure maximum responses and to overcome any difference in topical absoφtion which could occur with any drug applied in an aqueous ethanol vehicle. The test drug is applied 30 minutes prior to challenge with AA.

The severity of the inflammation is measured as a function of increased ear weight. A 6 mm punch biopsy is removed 1 hour after AA challenge and weighed to the nearest 0.1 mg. Mean ± standard error and all possible comparisons are made via Duncan's Multiple Range Statistic.

As a result of the topical administration of a compound of formula I, a remission of the symptoms of the psoriatic patient, in most cases, can be expected. Thus, one affected by psoriasis can expect a decrease in scaling, erythema, size of the plaques, pruritus and other symptoms associated with psoriasis. The dosage of medicament and the length of time required for successfully treating each individual psoriatic patient may vary, but those skilled in the art of medicine will be able to recognize these variations and adjust the course of therapy accordingly. The activity against inflammatory bowel disease of the compounds of the invention can be demonstrated by the protocols described in G.P. Morris, L Rebeiro, M. M. Herridge, M. Szewczuk, and W. Eepew, Gastroenterologv. fiβ, 1188 (1984) and J.L Wallace, Can. J. Physiol. Pharmacol.. 66. 422 (1988). Administration of the dose can be intravenous, intranasal, parenteral, oral, subcutaneous, intramuscular, topical, transdermal or any other acceptable method. The compounds of the present invention can be administered in any number of conventional dosage forms. Solid dosage forms include capsules, tablets, pills, powders, suspensions, solutions, cachets or suppositories. Parenteral preparations include sterile solutions or suspensions. Inhalation administration can be in the form of a nasal or oral spray, or by insufflation. Topical dosage forms can be creams, ointments, lotions, transdermal devices (e.g., of the conventional reservoir or matrix patch type) and the like.

The formulations and pharmaceutical compositions contemplated by the above dosage forms can be prepared with conventional pharmaceutically acceptable excipients and additives, using conventional techniques. Such pharmaceutically acceptable excipients and additives include carriers, binders, flavorings, buffers, thickeners, color agents, dispersing agents, suspending agents, perfumes, preservatives, lubricants, etc. When used orally or parenterally for the treatment of allergy, inflammation, peptic ulcers and/or hyperproliferative skin diseases, the compounds of the invention can be administered in an amount ranging from about 0.1 mg/kg body weight to about 25 mg/kg body weight, preferably from about 0.1 mg/kg body weight to about 5 mg/kg body weight per day. A typical recommended dosage regimen is oral administration of from 10 mg/day to 1500 mg/day, preferably from 10 mg/day to 250 mg/day, in two to four divided doses to achieve relief of the symptoms of inflammation.

Determination of the proper dosage of a compound of the invention for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound, Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The amount and frequency of administration of the compounds of formula I and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptom being treated.

The invention disclosed herein is exemplified by the following examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.

Preparative Example 1

Preparation of 2-{3-cvanophenvnamino-3-pvridinemethanol.

A 1 L 3-neck flask was equipped with an addition funnel with a glass stopper, a reflux condenser closed with a drying tube, and a dry N₂ inlet. An excess of LiBH₄ (3g) was added to dry tetrahydrofuran (THF; 35mL) contained in the flask. The mixture was stirred magnetically. Ethyl 2-(3-cyanophenyl)aminonicotinate (30g) was dissolved in dry THF (250mL) in the dropping funnel, and then this solution was added dropwise to the solution in the flask. After all had been added, the mixture was heated gradually to the reflux point (ca. 70°C). After heating at reflux for 2h an additional 1.0g of reducing agent was added, and later, a further 0.5g. The reaction was followed by TLC until all the starting material had disappeared. The reaction mixture was then allowed to cool and was stirred at room temperature overnight. Solvent was removed under vacuum, and the product was poured over ice. The pH of the solution was adjusted to ca. 2 and it was allowed to stand for 3h. The product was then extracted into ethyl acetate (3 x 200mL). The combined ethyl acetate layers were washed with water (2 x 300mL) then with saturated NaCI solution (2 x 250mL). The separated organic layer was dried (Na₂S0₄), filtered and evaporated. The crude product was recrystallized from isopropanol to yield the desired product, 18.9g (75%), mp 132-133°C. Found, C, 69.23; H, 5.06; N, 18.72.

Calcd. (for

C, 69.32; H, 4.92; N, 18.66.

Preparative Example 2

Pre^paration of 2-⁽3-trifluoromethvlphenynamino-3-pvridinemethanol.

In a 3-neck 1 L flask, equipped with a reflux condenser closed by a drying tube, a dropping funnel with a septum cap on top, and a dry N₂ inlet, was placed ethyl 2-(3-trifluoromethylpheny!)amino- nicotinate (30g) and dry tetrahydrofuran (THF) (150mL). The solution was stirred magnetically in an ice-salt bath for 20 minutes after which time the inside temperature had reached about -5°C. A solution of

Super Hydride™ (lithium triethylborohydride; 250mL of a 1 M solution in THF) was transferred in the absence of air, using a double-ended needle, into the dropping funnel. This solution was added to the flask dropwise, keeping the temperature around 0°C. After all had been added the reaction mixture was allowed to warm to room temperature and was stirred overnight. Thin layer chromatography was used to follow the course of the reaction. Reaction was completed by the addition of a further 100mL of the Super-Hydride™ solution at room temperature. The total product was poured over ice (400g), with stirring, and the pH was adjusted to 5 with cone. HCI. Solid NaCI was added to salt out the organic layer which was separated. The aqueous layer was extracted with ethyl acetate (2 x 100mL) and the organic layers were combined. The combined organic layer was washed with saturated NaCI solution (2 x 100mL), dried (Na2S0₄), filtered, and evaporated to a yellow oil. A small quantity of this crude product was purified by flash chromatography over silica gel eluting with hexane:ethyl acetate (80:20 -> 67:33). Fractions containing the desired product were combined and evaporated to a light yellow solid, mp 105.5 - 107°C

Found, C, 58.26; H, 4.24; N, 10.17.

Calcd. (for C₁₃H₁₁N₂OF₃), C, 58.21; H, 4.13; N, 10.44.

Preparative Example 3

Preparation of 2-(3-cyanophenyl)amino-3-pvridinecarboxaldehyde.

2-(3-trifluoromethylphenyl)amino-3-pyridinemethanol (1 g) was dissolved in toluene (50mL) contained in a flask. The flask was attached to a Dean and Stark water-separator and a reflux condenser. To the reaction flask was added activated Mn0₂ (4g) and it was heated, • with magnetic stirring, to about 80°C. The reaction was followed by thin layer chromatography and was complete after about 1.5h. The product was filtered through a bed of celite which was washed with fresh ethyl acetate. The clear solution was evaporated to a yellow solid. The crude product was purified by running it through a flash column of silica gel, eluting with CH₂CI₂:ethyl acetate (90:10) to yield the desired product,

0.56g (57%), m.p. 152-154°C.

Found, C, 69.58; H, 3.90; N, 18.96.

Calcd. (for. C₁₃H₉N₃0), C, 69.94; H, 4.06; N, 18.83. By essentially the same procedures described in Preparative Examples 1 , 2 and/or 3 above, the compounds listed below were also prepared:

2-(3-trifluoromethyl phenyl) amino-3-pyridine- carboxaldehyde, mp 75-77.5°C; and

2-phenylamino-3-pyridinecarboxaldehyde.

Example 1

Preparation of 3-(1-pyrrolidinyl)-1-phenyH ,8-nap t yridin-2(1H)-. n.

2-Phenylamino-3-pyridinecarboxaldehyde (2.0g) and ethyl 2-pyrrolidinylacetate (1.65g) were mixed together in dry tetrahydrofuran (THF) (5mL) and t-butanol (1mL) under N₂. To the mixture was added fresh potassium t-butoxide (KOt-Bu; 0.1g). After 24hr. a further 0.1 g of KOt-Bu was added, then at 25hr and 48hr. additional amounts of 0.1 g were added. After a total of 2.5 days an additional 0.436g of KOt-Bu was added and the mixture was allowed to stir for a further 2.5 days. The solvent was removed and the residue was dissolved in CH₂CI₂. Water was added and the pH of the aqueous layer was adjusted to about 7 with 1 N-H₂S0₄. The organic layer was separated and chromatographed on silica gel. Fractions containing the product were combined and evaporated to an off-white crude product which was recrystallized from isopropanol to yield the desired product, m.p. 201.5- 202.5°C.

Found, C, 74.23; H, 5.88; N, 14.30.

Calcd. (for C₁₈H₁₇N₃0), C, 74.20; H, 5.88; N, 14.42 Example 2

Preparation of 3-π-pyrrolidinyn-1-f3-trifluoromethvlphenvl.-1.8- naphthvridin-2(1 H .-one

2-(3-Trifluoromethylphenyl)amino-3-pyridine- carboxaldehyde (1g) and ethyl 2-pyrrolidinyl-acetate (0.6g) were dissolved in a mixture of THF (10mL) and t-BuOH (2mL). The solution was stirred under N₂ and to it was added fresh KOt-Bu (0.42g). After 3hr an additional 0.1 g of KOt-Bu was added, then after 4hr the solvents were removed under vacuum. Water (10mL) was added and the pH was adjusted to about 7 with 1 N-H₂S0₄. The product was extracted with 2 x 10mL of CH₂CI₂. The organic layer was washed with saturated NaCI solution (2 x 10mL), dried (Na₂S0₄), and evaporated under vacuum. The product was purified by chromatography on silica gel and the light yellow product was then recrystallized from methanol to yield the desired product, mp 168.5-170°C, after drying overnight under vacuum. Found, C, 63.32; H, 4.22; N, 11.60; F, 16.28. Calcd. (for C₁₉H₁₆N₃OF₃), C, 63.50; H, 4.49; N, 11.69; F, 15.86. By basically the same procedures as described above in Example 1 and 2, the following compounds were also prepared:

3-(1 -Pyrrolidinyl)-1 -(3-cyanophenyl)-1 ,8-naphthyridin-2- (1H)-one; mp >250°C.

Found, C, 72.13; H, 5.06; N, 17.81.

Calcd. (for C₁₉H₁₆N₄0), C, 72.13; H, 5.10; N, 17.71.

3-(4-Morpholinyl)-1 -phenyl-1 ,8-naphthyridin-2(1 H )-one; mp 167-168°C.

Found, C, 70.32; H, 5.55; N, 13.70.

Calcd. (for C₁₈H₁₇N₃θ2), C, 70.34; H, 5.58; N, 13.67. 3-[3-(Hexahydro-1 H-azepin-1 -yl)-1 ,2-dihydro-2-oxo-1 ,8- naphthyridin-1-yl]-benzo-nitrile; mp 194-196°C.

Found, C, 73.08; H, 5.57; N, 16.36.

Calcd. (for C₂ιH₂oN₄0), C, 73.23; H, 5.85; N, 16.27.

3-[1 ,2-Dihydro-3-(4-morpholinyl)-2-oxo-1 ,8-naphthyridin-1 ^• yljbenzonitrile, mp 215-217°C.

Found, C, 68.63; H, 4.73; N, 16.74. Calcd. C, 68.67; H, 4.85; N, 16.85.

The following formulations exemplify some of the dosage forms of the compositions of this invention. In each, the term "active compound" refers to 3-(4-morpholinyl)-1 -phenyl-1 ,8-naphthyridin-2(1 H)- one. However, this compound may be replaced by equally effective amounts of other compounds of formula I.

Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No.

4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes.

Compress the mixture to appropriate size and weigh on a suitable tablet machine.

Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weigh on a suitable tablet machine.

EXAMPLE B

Capsules

____. Ingredient mg/capsule mg/capsule

1. Active compound 25 100

2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4. Magnesium Stearate NF -A _Z

Total 175 300

Method of Manufacture

Mix Item Nos. 1 , 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

CLAIMS:

1. A compound having the structural formula I

or a pharmaceutically acceptable salt thereof, wherein: A is O or S; W represents

R represents H or alkyl;

R¹ represents alkanediyl;

R² represents a covalent bond or -alkanediyl-O-;

R3 represents alkyl, cycloalkyl, benzyl, substituted benzyl or hydroxyalkyl having 2 to 6 carbon atoms between the N atom and the OH group;

Q represents phenyl, 1- or 2-naphthyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl or 1-, 2-, 3-, 4-, 5-, 6- or 7-indanyl, each of which may optionally be substituted with 1 to 3 Y groups as defined below; and each Y is independently selected from alkyl, halo, nitro, alkoxy, alkylthio, -CF3, -CN, cycloalkyl, alkylsuifinyl or alkylsulfonyl.

2. A compound according to claim 1 , wherein W is the group

3. A compound according to claim 2, wherein A is O.

4. A compound according to claim 3, wherein R is H.

5. A compound according to claim 4, wherein Q is phenyl or substituted phenyl.

6. A compound according to claim 5, wherein W is

7. A compound according to claim 5, wherein W is

8. A compound according to claim 1 , having the following structural formula:

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 in combination with a pharmaceutically acceptable carrier.

10. A method of treating allergic reactions in a mammal comprising administering to said mammal an antiallergic effective amount of a compound of formula I as defined in claim 1.

11. A method of treating inflammation in a mammal comprising administering to said mammal an antiinflammatory effective amount of a compound of formula I as defined in claim 1.

12. A method of treating hypeφroliferative skin disease in a mammal comprising administering to said mammal an effective amount of a compound of formula I as defined in claim 1.

13. A method of treating peptic ulcers in a mammal comprising administering to said mammal a cytoprotective amount of a compound of formula I as defined in claim 1.

14. A method of treating inflammatory bowel disease in a mammal comprising administering to said mammal an effective amount of a compound of formula I as defined in claim 1.