Abstract:
1-Substituted naphthyridines and pyridopyrazines are disclosed which are useful in treating allergic reactions, inflammation, peptic uclers and hyperproliferative skin diseases and in suppressing the immune response in mammals. Pharmaceutical compositions and methods of treatment employing such compounds are also disclosed.

Description:
This application is a continuation-in-part of U.S. application Ser. No. 919,176, filed Oct. 15, 1986, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to certain 1-substituted naphthyridine and pyridopyrazine derivatives which are useful in the treatment of allergies, inflammation, peptic ulcers and hyperproliferative diseases and which suppress the immune response in mammals. 
     Carboni et al. in Farmaco, Ed. Sci., 1973, 28(9), 722-732 disclose 1-benzyl-7-benzyloxy-[1,8]naphthyridin-2-one and other compounds, but indicate that such compounds were tested as antibacterials and found to be inactive. 
     European published Application No. 0 172 058 discloses certain 1-phenyl-3-alkyl-[1,8]naphthyridin-2-ones as having anti-ulcer, anti-inflammatory and analgesic activities. 
     SUMMARY OF THE INVENTION 
     The compounds of this invention have the structural formula I ##STR1## or a pharmaceutically acceptable salt or solvate thereof, wherein: X represents ═CH--, ═CY--{wherein Y is as defined below} or ═N--; 
     A represents O or S; 
     m is an integer of from 0 to 2; 
     n is an integer of from 0 to 2; 
     R 1  is H, alkyl, halogenated alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, halo, or --DZR 5  {wherein D represents alkanediyl, Z is ##STR2##  --S(O) p  -- (wherein p is 0, 1 or 2 with the proviso that p is 0 when R 5  is H) or ##STR3## (wherein R 6  is H or alkyl), and R 5  is H, alkyl, cycloalkyl, phenyl, phenyl substituted by 1 to 3 Y groups as defined below}; 
     R 2  is cycloalkyl, alkenyl, alkynyl, cycloalkenyl, phenyl or phenylalkyl in which the phenyl rings may be substituted with 1 to 3 Y groups as defined below, --D--Z--R 5  {wherein D, Z and R 5  are as defined above}, --Z--R 5  {wherein Z and R 5  are as defined above}, --O--(E--O) q  --R 5  {wherein q is 1, 2, 3 or 4, E represents alkanediyl with the proviso that the two available bonds of the E group are not on the same carbon atom and R 5  is as defined above}, --CO--N(R 7 ) 2  {wherein each R 7  independently is H or alkyl}, or --CN; 
     R 3  and R 4  are the same or different and each is independently H or alkyl; 
     Q represents an aryl group or an aromatic heterocyclic group which can optionally be substituted with from 1 to 3 substituents Y as defined below; and 
     each Y substituent is independently selected from OR 6  {wherein R 6  is as defined above}, alkyl, halo, --NO 2 , --CF 3 , --CN, cycloalkyl, alkenyloxy, alkynyloxy, --S(O) p  --R 8  {wherein R 8  is alkyl and p is as defined above}, --CO--R 9  {wherein R 9  represents R 5 , N(R 7 ) 2  or OR 6   in which R 5 , R 6  and R 7  are as defined above}, --O--D--COR 9  {wherein D and R 9  are as defined above}, --N(R 7 ) 2  {wherein R 7  is as defined above} or --NH(CO)H. 
     Compounds of formula I in which A is oxygen are preferred. Also, X is preferably CH. R 2  is preferably alkenyl, alkynyl, cycloalkenyl, --DZR 5 , --ZR 5 , --O(EO) q  R 5 , CON(R 7 ) 2 , or CN and more preferably one of the latter five groups. Suitable R 2  groups include hydroxyalkyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy or alkanoyloxyalkyl. R 1  is preferably H or alkyl. The letter n preferably represents zero and m is preferably zero. Q is preferably phenyl or Y-substituted phenyl, and in the latter case each Y substituent on the Q phenyl ring is preferably independently selected from halo, hydroxy, nitro, alkoxy, alkylthio, CF 3 , CN or COR 9  and more preferably chloro, nitro, methoxy or trifluoromethyl. The most preferred orientation is in the meta position. 
     A preferred subgenus is represented by the formula II ##STR4## wherein R 1  is H or alkyl having from 1 to 4 carbon atoms; R 2  is selected from hydroxyalkyl, alkoxy, alkanoyloxyalkyl or O--(E--O) q  --R 5  (wherein E, q and R 5  are as defined above}; and Q is phenyl or phenyl substituted with 1 to 3 Y substituents each independently selected from halo, NO 2 , OH, alkoxy, alkylthio, CF 3 , CN or COR 9  {wherein R 9  is as defined above}. 
     When utilized herein, the terms below, unless otherwise indicated, have the following scope: 
     halo-represents fluoro, chloro, bromo and iodo; 
     alkyl (including the alkyl portions of hydroxyalkyl, phenylalkyl and alkoxy and each alkyl portion of alkoxyalkoxy, alkoxyalkoxyalkoxy, and alkanoyloxyalkyl)--represents straight or branched carbon chains and, unless otherwise specified, contain from 1 to 6 carbon atoms; 
     halogenated alkyl--represents an alkyl group as defined above containing from 1 to 5 halo groups, (preferably chloro or fluoro) replacing some or all of the hydrogens thereon depending on the sites of possible halogenation, e.g., CF 3 , --CH 2  Cl, etc.; 
     alkanediyl--represents a divalent, straight or branched hydrocarbon chain having from 1 to 6 carbon atoms, the two available bonds being from the same or different carbon atoms thereof, e.g., methylene, ethylene, ethylidene, ##STR5## etc.; 
     alkenyl and alkenyloxy--represent straight or branched carbon chains having at least one carbon to carbon double bond and having from 3 to 6 carbon atoms, with the proviso that the oxygen of alkenyloxy is not bound to an olefinic bond thereof; 
     alkynyl and alkynyloxy--represent straight or branched carbon chains having at least one carbon to carbon triple bond and having from 3 to 6 carbon atoms, with the proviso that the oxygen of alkynyloxy is not bound to an acetylenic bond thereof; 
     cycloalkyl--represents a saturated carbocyclic ring having from 3 to 7 carbon atoms; 
     cycloalkenyl--represents a carbocyclic ring having from 5 to 8 carbon atoms and one carbon to carbon double bond in such ring; 
     aryl--represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one benzene ring, with all available substitutable carbon atoms thereof being intended as possible points of attachment to the (CR 3  R 4 )m group or to the N atom if m is zero. More preferably, aryl is phenyl or Y-substituted phenyl. Suitable aryl groups include, e.g., phenyl, 1- or 2-naphthyl, indenyl, indanyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, etc.; 
     aromatic heterocyclic--represents cyclic groups having at least one O, S and/or N interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-[1,2,4-triazinyl], 3- or 5-[1,2,4-thiadiazolyl], 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, etc., with all available substitutable carbon atoms thereof being intended as a possible point of attachment to the (CR 3  R 4 ) m  group or to the N atom if m is zero. 
     The invention in its pharmaceutical composition aspect comprises a compound of formula I in combination with a pharmaceutically acceptable carrier. 
     The invention also includes a method for treating allergic reactions in a mammal which comprises administering an anti-allergic effective amount of a compound of formula I to the mammal. 
     The invention in a second pharmaceutical method aspect is a method for treating inflammation in a mammal which comprises administering an anti-inflammatory effective amount of a compound of formula I to the mammal. 
     The invention in a third pharmaceutical method aspect is a method for treating peptic ulcers in a mammal which comprises administering a cytoprotective effective amount of a compound of formula I to the mammal. 
     The invention in a fourth pharmaceutical method aspect is a method for treating hyperproliferative skin diseases, e.g. psoriasis, lichenified eczema or seborrhoeic dermatitis, in a mammal which comprises topically administering an effective amount of a compound of formula I to the mammal. 
     The invention in a fifth pharmaceutical method aspect is a method for suppressing the immune response in a mammal which comprises administering an immunosuppressive effective amount of a compound of formula I to the mammal. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The compounds of formula I contain a --(CR 3  R 4 ) m  -- substituent wherein each R 3  group and each R 4  group may vary independently. Thus, for example, when m equals 2, the following patterns of substitution (wherein hydrogen and CH 3  are used to represent any substituent, R 3  or R 4 , are contemplated: --C(CH 3 ) 2  CH 2  --, --CH 2  C(CH 3 ) 2  --, --CH 2  CH(CH 3 )--, --CH(CH 3 )CH 2  --, --(C(CH 3 )H) 2  -- and the like. 
     As noted above, the compounds of the invention may include one to three Y substituents on the fused ring system. Also, the Q group may include up to three Y substituents depending upon the available sites for substitution. In compounds where there is more than one such Y substituent, they may be the same or different. Thus, compounds having combinations of different Y substituents are contemplated within the scope of the invention. Examples of suitable Y substituents include hydroxy, methyl, chloro, bromo, methoxy, cyclohexyl, allyloxy, 2-propynyloxy, methylthio, methylsulfonyl, carboxy, acetoxy, N-methylaminocarbonyl, and the like. 
     Compounds of the invention 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 this invention. 
     Certain compounds of the 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 also form pharmaceutically acceptable salts with organic and inorganic acids, e.g., the pyrido- or pyrazino-nitrogen atoms may form salts with strong acids, while compounds having basic Y substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those 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 the invention. 
     Also, some compounds of this invention are acidic, e.g., when Y is OH, and can form salts with inorganic and organic bases. 
     The compounds of the invention may be prepared by a number of different synthetic routes. For example, compounds of formula I wherein R 1  is other than halo may be prepared by the methods identified as processes A-E below, while compounds of formula I wherein R 1  is halo may be prepared by process F below: 
     A. A compound of formula III below is reacted with a compound or formula IV, preferably in excess: ##STR6## L 1  represents a suitable leaving group such as halo (e.g., chloro or bromo) or alkoxy. Alternatively, R 2  and L 1  in the group ##STR7## together form a lactone ring of the formula ##STR8## wherein D&#39; represents alkanediyl containing from 2 to 4 carbon atoms. Such lactone ring will cleave to form compounds of the invention wherein R 2  is a hydroxyalkyl group. L 2  also represents a suitable leaving group such as halo, e.g., chloro or bromo. The reaction may be performed in an inert solvent such as Dowtherm® (which is a mixture of diphenyl ether and biphenyl) or may be run neat using the amine of formula IV as the &#34;solvent&#34;. The amine is used in equivalent amounts or in excess and any suitable temperature can be employed, e.g., 60° C. to reflux. The reaction (and all the reactions herein described) may be followed by thin layer chromatography to determine the course of the reaction. 
     The compounds of formula III are either known or easily prepared by reacting a compound of formula V with a carbanion of formula VI: ##STR9## This reaction can, for example, be performed in an inert solvent such as tetrahydrofuran (THF) at any suitable temperature e.g., about -100° C. to about -20° C. 
     B. A compound of formula V is reacted with a compound of formula VII in the presence of a base such as potassium tertiary butoxide, NaH/DMF, NaH/DMSO/THF, lithium diisopropylamide (LDA)/THF, lithium hexamethyldisilazide/THF, etc., first at a lower suitable temperature such as about -70° C. to about -20° C. and then at a higher suitable temperature as described below: 
     
         V+Q--(CR.sup.3 R.sup.4).sub.m --NHCO--CH.sub.2 R.sup.2 →I (wherein A=O)                                                      VII 
    
     wherein L 2  of the compound of formula V is as defined above. The base generates an anion in the compound of formula VII. The reaction is normally run in a suitable inert solvent such as dimethyl acetamide (DMA), hexamethyl phosphoric triamide, or those mentioned above with regard to process A. The higher temperature can be, e.g., about 60° C. to about 180° C. 
     The compounds of formula VII are known or can be prepared by conventional techniques from the appropriately substituted amines of the formula 
     
         Q--(CR.sup.3 R.sup.4).sub.m --NH.sub.2                     (IV) 
    
     by reaction with an appropriately substituted acid derivative of the formula 
     
         L.sup.3 COCH.sub.2 R.sup.2                                 VIIb 
    
     wherein L 3  is a suitable leaving group, e.g., compound VIIb is the acid chloride or anhydride derivative. 
     C. A compound of formula VIII is reacted with a compound of formula IX to produce a compound of formula I wherein R 1  represents H and A is O: ##STR10## wherein L 1  is as defined above. The reaction is performed in the presence of base such as tertiary butoxide, sodium ethoxide, etc. The reaction may be performed neat (i.e., with the compound of formula IX as &#34;solvent&#34;) or in an inert solvent such as toluene and any suitable temperature may be employed, e.g., 0° to 80° C. 
     The compounds of formula VIII can be prepared by reacting a compound of formula X with an appropriate substituted amine of formula XI: ##STR11## wherein L `  is a leaving group as defined above such as chloro or bromo and R is H or alkyl. The compound of formula XII is reduced to the alcohol of formula XIII below by reaction with a strong reducing agent which will reduce a carboxylic acid or ester to the corresponding alcohol, such as Super Hydride (which is triethylborohydride in THF). ##STR12## The compound of formula XIII is then oxidized to the aldehyde of formula XIV below by reaction with a suitable oxidizing agent such as MnO 2  in benzene or toluene, for example, at about 80° C. ##STR13## 
     D. A compound of the formula XV is reacted with a strong acid to eliminate --OH and --R 2a  from the indicated 4- and 3-positions, respectively, wherein R 2a  is a group which will eliminate in preference to the desired R 2  group. ##STR14## For example, R 2a  may be a group of formula XVI ##STR15## wherein each R may be H or alkyl and W is H, alkyl or a group which enhances the lability of the hydrogen on the beta-carbon atom (thus potentiating the elimination of the R 2a  group) W can thus be, for example, ##STR16## etc. In general, if R 2  and R 2a  both include a hydrogen on the carbon atom beta relative to the naphthyridine or pyridopyrazine nucleus, i.e., both have the basic partial structure ##STR17## the group with the most labile hydrogen on such beta carbon atom will eliminate in preference to the other group, but a mixture of compounds having R 2  or R 2a  in the 3-position may be obtained. If R 2  is allyl (or a similar alkenyl group having the carbon-carbon double bond beta to the naphthyridine or pyridopyrazine nucleus), the hydrogen on the beta carbon will be less labile and therefore elimination of such an R 2  group is minimized. Also, if R 2  has an oxygen or carbonyl carbon (e.g., as in ZR 5 , --O--(E--O) q  --R 5 , CON(R 7 ) 2 , etc.) connecting the R 2  group to the 3-position of the naphthyridine or pyridopyrazine nucleus, the reaction will proceed by a non-competing elimination of the R 2a  group. 
     The reaction may be conducted at any suitable temperature, e.g., -20° C. to 40° C. It can be run neat using the acid as a solvent or in an inert solvent such as CH 2  Cl 2 . The acid is preferably a strong acid such as a super acid. Suitable acids include CF 3  SO 3  H, Eaton&#39;s reagent, polyphosphoric acid, HF/BF 3 , etc. 
     The compounds of formula XV above in which R 1  is H (referred to below as formula XVa) may be prepared, for example, by reacting a compound of formula XVIIa or XVIIb ##STR18## (which are either known or can be prepared by the processes described in U.S. Pat. No. 4,492,702) with a compound of the formula R 2a  L 5  or R 2  L 5 , respectively: ##STR19## wherein L 5  is a suitable leaving group such as halo, e.g., bromo or chloro. The compound of formula XVIII is formed possibly along with its O-alkylated isomers (where R 2  or R 2a  is an alkyl group) which isomers may be separated by chromatography and/or crystallization. The carbonyl in the 4-position of formula XVIII is then reduced to a hydroxy group by employing a suitable reducing agent such as t-butylamine borane to provide a compound of formula XVa. 
     Alternatively, a compound of formula XV wherein R 1  is H and R 2  represents R 2b  and R 2b  is --ZR 5  or O(EO) q  R 5  may be prepared by reacting a compound of formula XVIIa or XVIIb with, for example, a halogen (X 2 ) such as Cl 2  or Br 2 , to provide a compound of formula XIX(a) or XIX(b) ##STR20## The compound of formula XIX(b) may then be reacted with a compound of formula HR 2b  such as methanol, methoxyethanol or methoxyethoxyethanol to produce a compound of formula XXa: ##STR21## The 4-carbonyl group of the compound of formula XXa above is then reduced as described above to produce a compound of the formula XVb: ##STR22## 
     For preparing compounds of formula XV wherein R 1  represents a group R 1a  and R 1a  is as defined for R 1  except omitting H, a compound of the formula XVIII above is reacted with a suitable Grignard reagent and then dilute acid: ##STR23## The compound of formula XXI is then reacted with strong acid as described above to eliminate --R 2a  and --OH. 
     E. A compound of the formula XXII is reacted with a strong acid so as to rearrange the R 1  group (wherein R 1  is R 1a  as defined above) from the indicated 3-position to the 4-position with elimination of H 2  O: ##STR24## Preferably, if R 1a  and R 2  in this rearrangement reaction comprise alkyl chains of 2 or more carbons, they do not contain a hydrogen on the carbon atom beta to the naphthyridine or pyridopyrazine nucleus, i.e., the R 1a  or R 2  group preferably does not have a partial structure ##STR25## If such a hydrogen is present on such a beta carbon atom, preferably the other substituents on the R 1a  or R 2  group deactivate the lability of such hydrogen so that the elimination reaction of Process D above is avoided or minimized, e.g., R 2  is allyl. If there is a hydrogen on such a beta carbon atom, the elimination reaction of process D above will compete with the rearrangement described in this process E and a mixture of compounds of formula I from the elimination and rearrangement will result. The rearrangement reaction can also be potentiated, when R 1a  contains a hydrogen on such a beta-carbon atom, by employing an R 2  group having an oxygen or sulfur adjacent to the basic heterocyclic ring nucleus, e.g., R 2  is alkoxy, alkoxyalkoxy, alkylthio, etc., such as ethoxy, methoxyethoxy, propoxy, propylthio, etc. The reaction conditions for process E are basically as described above for process D. 
     F. To prepare compounds of formula I wherein R 1  represents halo, a compound of formula XXIII is reacted with a halogenating reagent such as POCl 3 , POBr 3 , PCl 5 , PCl 3 , PBr 3 , etc: ##STR26## wherein halo is, for example, chloro or bromo. The reaction may be performed at any suitable temperature, but preferably at reflux. An inert solvent may also be employed, if desired. A basic catalyst such as dimethyl aniline may be added. The compounds of formula XXIII are known or easily prepared by conventional methods, e.g., see U.S. Pat. No. 4,492,702. 
     The compounds of the 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&#39;s Reagent {2,4-bis(4-methoxyphenyl-1,3-dithia-2,4-diphosphetane-2,4-disulfide} or one of its analogs, in toluene, or phosphorus pentasulfide in pyridine are suitable for this purpose. 
     In the above processes, it is sometimes desirable and/or necessary to protect certain R 1 , R 2  and/or Y groups during reactions. Conventional protecting groups are operable. For example, the groups in column 1 of the following table may be protected as indicated in column 2 of the table. 
     
         ______________________________________1. Group tobe Protected      2. Protected Group______________________________________COOH       COOalkyl, COObenzyl, COOphenyl ##STR27##       ##STR28## ##STR29##       ##STR30##OH       ##STR31##NH.sub.2       ##STR32##______________________________________ 
    
     Of course, other protecting groups well known in the art may be used. After the reaction or reactions, the protecting groups may be removed by standard procedures. 
     Also, certain R 1 , R 2  and Y groups may be converted to other R 1 , R 2  and Y groups by means conventional in the art for such conversions. For example, the R 2  group --CH 2  CH 2  OH may be converted to --CH 2  COOH by conventional oxidation with, e.g., pyridinium dichromate. 
     For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers are admixed with the active compounds. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can he one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it may also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound In the tablet, the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to about 70% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl-cellulose, a low melting wax, cocoa butter and other materials typically used in the pharmaceutical industries. The term &#34;preparation&#34; is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. 
     For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify. 
     Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution or suspension in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavoring, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. 
     Formulations for topical application may include creams, aerosols, sprays, dusts, powders, lotions and ointments which are prepared by combining an active ingredient according to this inventions with conventional pharmaceutical diluents and carriers commonly used in topical dry, liquid, cream and aerosol formulations. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Such bases may, thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as peanut oil or castor oil. Thickening agents which may be used according to the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, woolfat, hydrogenated lanolin, beeswax, etc. 
     Lotions may be formulations with an aqueous or oily base and will, in general, also include one or more of the following, namely, stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes and the like. 
     Powders may be formed with the aid of any suitable powder base, e.g. talc, lactose, starch, etc. Drops may be formulated with an aqueous base or nonaqueous base also comprising one or more dispersing agents, suspending agents, solubilizing agents, etc. 
     The topical pharmaceutical compositions according to the invention may also include one or more preservatives or bacteriostatic agents, e.g., methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, etc. 
     The topical pharmaceutical compositions according to the invention may also contain other active ingredients such as antimicrobial agents, particularly antibiotics, anesthetics, analgesics and antioruritic agents. 
     Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternatively, sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon or other volumetric container. The solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. The solvent utilized for preparing the liquid form preparation may be water, isotonic aqueous salt solutions, ethanol, glycerine, propylene glycol and the like, as well as mixtures thereof. The solvent utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not generally suitable for parenteral use. 
     The compounds of the invention may also be deliverable transdermally for systemic distribution. The transdermal compositions can take the form of creams, lotions and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. 
     Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active components. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation such as packaged tablets, capsules and powders in vials or ampules. The unit dosage form can also be a capsule, cachet or tablet itself, or it may be the appropriate number of any of these in a packaged form. 
     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&#39;s inhibition of anaphylactic bronchosoasm in sensitized guinea pigs having antigen induced broncho-constriction. 
     In one such test procedure, 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 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 5 minutes after antigen challenge. 
     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. Fifteen minutes later the animals are challenged with nebulized ovalbumin. 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. 
     Representative compounds of the invention tested in the above procedure were found to inhibit anaphylactic bronchospasm as indicated in Table 1 below: 
     
                                           TABLE 1__________________________________________________________________________ ##STR33##                    Dose p.o.Compound R.sup.1     R.sup.2   Q    (mg/kg)                         % Inhibition__________________________________________________________________________A     H   CH.sub.2 CH.sub.2 OH               phenyl                    5    78B     H   CH.sub.2 CH.sub.2 OH               3-chloro-                    2    79               phenylC     CH.sub.3     OCH.sub.2 CH.sub.3 OCH.sub.3               phenyl                    5    25__________________________________________________________________________ 
    
     The compounds of the invention also inhibit allergen-induced histamine release from guinea pig and human sensitized tissue. 
     The compounds are effective non-adrenergic, non-anticholinergic, antianaphylactic agents. They may be administered by any conventional mode of administration by employing an antiallergic effective amount of a compound of formula I for such mode. For example, when administered orally they are active at doses from about 0.5 to 25 mg/kg of body weight, preferably 0.5 to 10 mg/kg; when administered parenterally, e.g., intravenously, the compounds are active at dosages of from about 0.1 to 5 mg/kg body weight preferably 0.1 to 2.5, and when administered by inhalation (aerosol or nebulizer) the compounds are active at dosages of about 0.1 to 5 mg per puff, and one to four puffs may be taken every 4 hours. 
     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 kept near 0° C. 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 gavace 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 &#34;sensitized&#34; by injection of 0.2 ml of PFS containing 1.0 mg of BSA into the penile vein. One hour later, the animals are &#34;challenged&#34; 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 dioped (up to the lateral maleolus) 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 chance 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. Differences from control in drug-treated groups are expressed as percent change from control are determined. Compound C above in this procedure showed a 74% inhibition after 2 hours and a 36% inhibition after 4 hours at a dose (p.o.) of 25 mg/kg. 
     Another procedure for testing for acute anti-inflammatory activity measures the reverse passive Arthus reaction in the pleural cavity of rats as described in Myers et al., Inflammation, Vol. 9, No. 1, 1985, pp. 91-98. Compound A provided an ED 50  value (fluid) of about 5.0 mg/kg p.o. in such procedure. 
     The compounds can be administered by any conventional mode of administration to obtain the anti-inflammatory activity by employing an anti-inflammatory effective amount of a compound of formula I for such mode. For example, on the basis of the test results, an oral dosage range of from about 5 mg/kg of body weight per day to about 50 mg/kg of body weight per day in divided doses taken at about 4 hour intervals is recommended. The dosage to be administered and the route of administration depends upon the particular compound used, the age and general health of the patient and the severity of the inflammatory condition. Thus, the dose ultimately decided upon must be left to the judgment of a trained health-care practitioner. 
     The compounds of this invention are also useful in the treatment of peptic ulcers. They display chemotherapeutic activity which enables them to relieve the symptoms of peptic ulcer disease 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 this invention may be evaluated for their antiulcer activity characteristics by the procedures which measure the cytoprotective effect in rats e.g., as described in Chiu et al., Archives Internationales de Pharmacodynamie et de Therapie, 270, 128-140 (1984). 
     In the treatment of peptic ulcer disease, and the prevention and treatment of drug-induced gastric ulceration, the active compounds of this invention can be administered in conventional dosage forms such as tablets, capsules, pill, powders, granules, sterile parenteral solutions or suspensions, suppositories, mechanical delivery devices, e.g., transdermal, and the like, again employing a cytoprotective effective amount of a compound of formula I for the mode of administration selected. For example, the compounds of this invention may be administered orally at doses of about 0.3 to about 30 mg/kg, preferably, from about 2 to about 15 mg/kg, of body weight per day. Preferably, the total dosages are administered 2-4 divided doses per day. 
     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/group and allowed to acclimate 1-3 weeks prior to use. 
     Arachidonic acid (AA) is dissolved in reagent grade acetone (2 mg/0.01 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 et al., Fed. Proc. 43, Abstract 2983, p. 1927 (1984) and Young et al., J. Invest. Dermatol. 82, pp 367-371 (1984). These doses are employed to ensure maximum responses and to overcome any difference in topical absorption 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&#39;s Multiple Range Statistic. 
     When administered for the treatment of hyperproliferative skin disease, the compounds of formula I may be administered topically, orally, rectally or parenterally. When administered topically, the amount of compound administered varies widely with the amount of skin being treated, as well as with the concentration of active ingredient applied to the affected area. When administered orally, the compounds of formula I are effective for the treatment of hyperproliferative skin disease at daily doses ranging from about 0.1 mg/kg to about 100 mg/kg, preferably from about 5 mg/kg to about 50 mg/kg, which may be administered in divided doses. When administered rectally, the compounds of formula I may be administered in daily doses ranging from about 0.1 mg/kg to about 100 mg/kg. When administered parenterally, the compounds of formula I are effective for the treatment of hyperproliferative skin disease in daily doses ranging from about 0.1 mg/kg body weight to about 10 mg/kg body weight which may be administered in divided doses. 
     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. 
     Included within the invention are preparation for topical application to the skin whereby the compounds having structural formula I are effective in the treatment and control of skin diseases characterized by rapid rates of cell proliferation and/or abnormal cell proliferation, e.g. psoriasis. 
     In a preferred method of carrying out the invention, a pharmaceutical formulation comprising a compound of formula I together with a non-toxic, pharmaceutically acceptable topical carrier, usually in concentrations in the range of from about 0.001 percent to about 10 percent, preferably from about 0.1 percent to about 5 percent, is applied several times daily to the affected skin until the condition has improved Topical applications may then be continued at less frequent intervals (e.g. once a day) to control mitosis in order to prevent return of severe disease conditions. 
     The compounds of the invention are also useful in the treatment of autoimmune and other immunological diseases including graft rejection in which T cell proliferation is a contributing factor to the pathogenesis of disease. The effectiveness of these compounds as immunosuppressing agents may be demonstrated by the following tests which involve the inhibition of T cell functions using these compounds. 
     GRAFT VS. HOST REACTION (GVHR) 
     To induce a GVHR, C57 B1/6XA/J(F6AF1) male mice were injected intravenously with parental (C57B/6J) spleen and lymph node cells. 3-(2-Hydroxyethyl)-1-phenyl-1,8-naphthyridin-2(1H)-one (Compound A) was then administered orally for 10 days beginning on the day prior to the cell transfer. On the day following the last treatment, the animals were sacrificed, and their spleens were excised and weighed. The enlargement of the spleen of the host is a result of a GVHR. To some extent it is the host&#39;s own cells which infiltrate and enlarge the spleen although they do this because of the presence of graft cells reacting against the host. The amount of spleen enlargement, splenomegaly, is taken as a measure of the severity of the GVHR. 
     In carrying out the GVHR the animal in the experimental group is injected with parental cells, cells of the same species but of different genotype, which cause a weight increase of the spleen. The animal in the control group is injected with syngeneic cells, genetically identical cells which do not cause a weight increase of the spleen. The effectiveness of the compounds administered to the mice in the experimental group is measured by comparing the spleen weight of the untreated and treated GVH animal with that of the syngeneic control. Compound A in this test procedure reduced spleen weight by 92% at a dose of 100 mg/kg as compared to the untreated animals. 
     SPLENIC ATROPHY 
     The immunosuppressive activity of the compounds may also be shown by a decrease in spleen weight after dosing BDF1 mice orally with the drug for seven (7) consecutive days. The mice are sacrificed on the eighth day. The percent decrease in spleen weight is measured for each dosage level. In this procedure, Compound A provided an ED 30  of less than 25 mg/kg. 
     The usual dosage range for the immuno-suppressive method of the invention with the compounds of formula I in a 70 kg mammal is an oral dose of about 0.1 to 250 mg/kg, preferably 0.1 to 150 mg/kg, in 3 or 4 divided doses per day. Of course, the dose will be regulated according to the potency of the compound employed, the immunological disease being treated, and the judgment of the attending clinician depending on factors such as the degree and the severity of the disease state and age and general condition of the patient being treated, with an effective amount of a compound of formula I being employed for the particular mode of administration selected. 
     To treat immunological diseases, the active compounds of formula I can be administered in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, suppositories, transdermal compositions and the like. Such dosage forms are prepared according to standard techniques well known in the art. 
     In all of the above modes of treatment, the dosage to be administered and the route of administration depends upon the particular compound selected, the age and general health of the subject, and the severity and type of condition to be controlled. Thus, the dose ultimately provided must be left to the judgment of a trained health-care practitioner. 
     The quantity of active compound in a unit dose preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient and the intended treatment. The composition may, if desired, also contain other therapeutic agents. 
     When administered parenterally, e.g. intravenously, the compounds are administered at a dosage range of about 0.1 to 5 mg/kg of body weight in single or multiple daily doses. 
     The invention disclosed herein is exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of applicants invention, may be apparent to those skilled in the art. 
     PREPARATIVE EXAMPLE 1 ##STR34## 
     The compound 4-hydroxy-3-methyl-1-phenyl-1,8-naphthyridin-2(1H)-one(15 grams) was suspended in CH 2  Cl 2  (1.5 L) under nitrogen. To the suspension was added Br 2  (3.5 grams) in CH 2  Cl 2  (60 ml) over a period of about 30 minutes. The mixture was stirred at room temperature for about 2 hours until TLC showed the reaction was complete. Water (2.5 liters) was added and the pH was adjusted to about 5. The organic layer was separated and washed twice with water. The organic layer was dried over Na 2  SO 4 , filtered and concentrated to low volume. Addition of ether caused a solid product to precipitate. The product of formula B was filtered off, and recrystallized from isopropanol, m.p. 188°-190° C. 
     PREPARATIVE EXAMPLE 2 ##STR35## 
     The product of Preparative Example 1 (formula B) above (11.5 grams) was suspended in 2-methoxyethanol (60 ml) under nitrogen. To the suspension was added DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (5.7 ml). The mixture was stirred at room temperature for about 11/2 hours and then poured into water (200 ml) containing acetic acid (5.7 ml). After about 15 minutes the solvent was filtered off and the solid product of formula C was washed with water and dried, m.p., 116°-118° C. 
     PREPARATIVE EXAMPLE 3 ##STR36## 
     The product of the Preparative Example 2 above (formula C) (9 grams) was dissolved in a 1:1 mixture of THF/ethanol (250 ml) under nitrogen. Acetic acid (3.6 ml) was added, followed by t-butylamine-borane (4.4 grams). The reaction was followed by HPLC. After about 11/2 hours water (200 ml) was added, the pH was adjusted to about 4.5, and then the mixture was concentrated to a total of about 200 ml. Water (200 ml) was added and the solution was extracted twice with CH 2  Cl 2 . The organic layer was separated and washed twice with saturated sodium chloride solution and the combined organic extracts were dried over Na 2  SO 4 , filtered and concentrated to an oil to provide the desired product of formula D as an oil which was a mixture of diastereomers. 
     EXAMPLE 1 ##STR37## 
     The mixture of diastereomers of formula D above from Preparative Example 3 (5.9 grams) was dissolved in CF 3  SO 3  H (35 ml) and the mixture was stirred and cooled to about 10° C. for 1 hour. The mixture was then warmed to and maintained at room temperature for 2 days. The reaction mixture was poured into ice water, and the pH was adjusted to between 4 and 5 with aqueous KOH. After stirring for 15 minutes, the precipitate was filtered off and washed with water. The product (formula E) was recrystallized from isopropanol, m.p., 148°-150° C. 
     By basically the same procedures as described in Preparative Examples 2 and 3 and Example 1 above but employing CH 3  OH in place of CH 3  OCH 2  CH 2  OH in the procedure of Preparative Example 2, the following compound was prepared: ##STR38## 
     PREPARATIVE EXAMPLE 4 ##STR39## 
     In dry DMF (500 ml) was dissolved 4-hydroxy-3-hydroxyethyl-1-phenyl-1-8-naphthyridine-2(1H)-one (formula F) (19.4 grams) and K 2  CO 3  (30 grams) was added. The mixture was cooled to 5° C. and allylbromide (7 ml) was added dropwise. The mixture was stirred for about 3 hours at 5° C. and allowed to warm to room temperature. About after about 21/2 days HPLC showed that no starting material remained The reaction mixture was poured into H 2  O (2 liter) containing acetic acid (30 ml). The solution was extracted three times with CH 2  Cl 2  (1 liter). The organic layers were separated, combined, and washed three times with H 2  O(500 ml) and then dried over Na 2  SO 4  and evaporated. The product mixture was heated in an oil bath at about 230° C. for about 1 hour which resulted in a solid of formula G which was crystallized from CH.sub. 3 CN/H 2  O, yielding the desired product, m.p.=156°-158° C. 
     PREPARATIVE EXAMPLE 5 ##STR40## 
     Dissolve the product from Preparative Example 4 above (formula G) in dry THF under a nitrogen atmosphere and cool to about 5° C. Add dropwise 2.2 equivalents of CH 3  MgI in THF with vigorous stirring. Continue stirring until TLC shows no starting material remaining. Add water and adjust the pH to about 5. Extract with CH 2  Cl 2 , wash the extract with H 2  O, dry the extract with Na 2  SO 4 , and then filter and evaporate the extract to dryness to yield the desired product of formula H. 
     PREPARATIVE EXAMPLE 6 ##STR41## 
     Dissolve the product of Preparative Example 5 above (formula H) (4.5 grams) in 20 ml of ethanol and add 5% Pd/C (100 mg) in a Paar vessel and hydrogenate for about 1 hour. Add an additional 400 mg of the 5% Pd/C catalyst and continue for about 4 hours, filter through diatomaceous earth, wash with ethanol and concentrate and recrystallize to yield the desired product of formula J. 
     EXAMPLE 2 ##STR42## 
     Treat the compound of formula J above in accordance with the procedure set forth in Example 1 above to yield the desired end product of formula K. 
     PREPARATIVE EXAMPLE 7 ##STR43## 
     Lithium bis(trimethylsilylamide) 1 M in THF (180 ml) was added to a flask under nitrogen. The solution was cooled to about -60° C. To the flask was added a solution of butyrolactone (13.7 grams) in THF (40 ml) dropwise while maintaining the temperature between -60° C. and -55° C. The solution was stirred for 45 minutes and then a solution of 2-chloronicotinic aldehyde in dry tetrahydrofuran (THF) (40 ml) was added dropwise, while maintaining the temperature at about -60° C. After about 1 hour no starting remained as shown by TLC. Acetic acid (about 25 ml) was added to the reaction mixture, which was allowed to warm to room temperature and was concentrated almost to dryness. CH 2  Cl 2  (300 ml) was added, the mixture was stirred for about 1/2 hour, filtered and the solid residue was washed with more CH 2  Cl 2 . The filtrate was concentrated to about 100 ml and chromatographed over silica gel, eluting with increasing concentrations of CH 3  CN in CH 2  Cl 2 . The desired product (formula L) was obtained by concentrating the eluant in the relevant fractions to dryness followed by recrystallization from CH 2  Cl 2  -isopropyl ether, m.p., 153°-155° C. 
     EXAMPLE 3 ##STR44## 
     The compound of formula L (1 gram) was dissolved in aniline (2 ml) under nitrogen and the reaction mixture was heated to 140° C. for 16 hours. The reaction was cooled and the residue was dissolved in methylene chloride. The methylene chloride was mixture poured into water, and the methylene chloride was separated and washed again with water. The methylene chloride layer was separated and concentrated to dryness. The residue was dissolved in isopropanol, charcoal treated, concentrated and then filtered. The filtrate was chromatographed on silica gel, eluting with methylene chloride containing 5% methanol. The fractions containing the desired compound of formula Q were collected and evaporated, and the solid formed was recrystallized from a methylene chloride/isopropanol mixture. The product of formula M had a melting point of 213°-214° C. 
     By essentially the same process as described employing meta-chloro aniline in place of aniline, the compound of formula N below was also prepared, m.p., 158°-160° C. ##STR45## 
     By employing the aldehyde compound listed in the first column of Table 2 below in the procedure of Preparative Example 7 above in place of the 2-chloronicotinic aldehyde where indicated (i.e. where X=N) and the amino compound listed in the second column of Table 2 in place of the aniline in the procedure of Example 3 above, the products listed in the third column of Table 2 may be prepared. 
     
                                           TABLE 2__________________________________________________________________________ ##STR46##  NH.sub.2QCompoundAmino                 ##STR47##X =        Q =       X =   Q =__________________________________________________________________________CH       ##STR48##                CH                       ##STR49##CH       ##STR50##                CH                       ##STR51##CH       ##STR52##                CH                       ##STR53##       ##STR54##                N                       ##STR55##N       ##STR56##                N                       ##STR57##__________________________________________________________________________ 
    
     EXAMPLE 4 ##STR58## 
     To 1 gram of 2-chloronicotinic aldehyde and an equimolar amount of cyclohexylacetanilide dissolved in dimethylforamide (DMF), add 2.2 equivalents of sodium hydride (50% suspension in oil). Heat the mixture gradually and follow the reaction by TLC until complete. Pour the reaction mixture into ice water, adjust the pH to about 5, filter and wash to provide the product of formula P. Recrystallize the product from isopropanol. 
     EXAMPLE 5 ##STR59## 
     A flask containing 4 grams of 2-phenylaminonicotinic aldehyde in 32 ml of gamma-butyrolactone was purged with nitrogen and 8 grams of potassium tertiary butoxide were added. The mixture was stirred at room temperature for about 3 days. A small amount of water was added to the flask and the resulting slurry was then poured into excess water. The pH was adjusted to between 4 and 5, the precipitate formed was filtered, washed and dried, and the solid was recrystallized from isopropanol to provide the compound of formula M. 
     The following formulations exemplify some of the dosage forms of the compositions of this invention. In each, the term &#34;active compound&#34; designates 3-(2-hydroxyethyl)-1-phenyl-1,8-naphthyridin-2(1H)-one (Compound A). It is contemplated, however, that this compound may be replaced by equally effective amounts of other compounds of formula I. 
     Pharmaceutical Dosage Form Examples 
     EXAMPLE A 
     
         ______________________________________ TabletsNo.   Ingredient       mg/tablet  mg/tablet______________________________________1.    Active compound  100        5002.    Lactose USP      122        1133.    Corn Starch, Food Grade,                   30         40 as a 10% paste in Purified Water4.    Corn Starch, Food Grade                   45         405.    Magnesium Stearate                   3          7 Total            300        700______________________________________ 
    
     Method of Manufacture 
     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&#34;) if needed. Dry the damp granules. Screen the dried granules if needed 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 weight on a suitable tablet machine. 
     EXAMPLE B 
     
         ______________________________________ CapsulesNo.   Ingredient       mg/capsule mg/capsule______________________________________1.    Active compound  100        5002.    Lactose USP      106        1233.    Corn Starch, Food Grade                   40         704.    Magnesium Stearate NF                   4          7 Total            250        700______________________________________ 
    
     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. 
     EXAMPLE C 
     
         ______________________________________ Nasal Spray               mg/ml______________________________________Active Compound       10.0Phenyl Mercuric Acetate                 0.02Glycine USP           3.7Sorbitol Solution, USP                 57.0Benzalkonium Chloride Solution                 0.2Sodium Hydroxide 1N Solution to                 --adjust pHWater Purified USP to make                 1.0 ml______________________________________ 
    
     The following formulations exemplify some of the dosage forms in which the anti-psoriatic agents of the invention may be employed. 
     EXAMPLE D 
     
         ______________________________________ OintmentFormula                mg/g______________________________________Active Compound        1.0-20.0Benzyl Alcohol, NF     20.0Mineral Oil, USP       50.0White Petrolatum, USP to make                  1.0      g______________________________________ 
    
     Method of Manufacture 
     Disperse active compound in a portion of the mineral oil. Mix and heat to 65° C., a weighed quantity of white petrolatum, the remaining mineral oil and benzyl alcohol, and cool to 50°-55° C. with stirring. Add the dispersed active compound to the above mixture with stirring. Cool to room temperature. 
     EXAMPLE E 
     
         ______________________________________ CreamFormula                 mg/g______________________________________Active Compound         1.0-20.0Stearic Acid, USP       60.0Glyceryl Monostearate   100.0Propylene Glycol, USP   50.0Polyethylene Sorbitan Monopalmitate                   50.0Sorbitol Solution, USP  30.0Benzyl Alcohol, NF      10.0Purified Water, USP to make                   1.0      g______________________________________ 
    
     Method of Manufacture 
     Heat the stearic acid, glyceryl monostearate and polyethylene sorbitan monopalmitate to 70° C. In a separate vessel, dissolve sorbital solution, benzyl alcohol, water, and half quantity of propylene glycol and heat to 70° C. Add the aqueous phase to oil phase with high speed stirring. Dissolve the active compound in remaining quantity of propylene glycol and add to the above emulsion when the temperature of emulsion is 37°-40° C. Mix uniformly with stirring and cool to room temperature. 
     EXAMPLE F 
     
         ______________________________________ GelFormula                mg./g______________________________________Active Compound        1.0-20.0Propylene Glycol, USP  300.0Butylated Hydroxytoluene                  5.0Carbomer 940           5.0Sodium Hydroxide (added as a 1% w/w                  0.7solution in propylene glycol)Polyethylene Glycol 400, USP                  669.3-688.______________________________________ 
    
     Method of Manufacture 
     Prepare a 1% solution of the sodium hydroxide in propylene glycol. Add approximately one-half the remaining propylene glycol and the polyethylene glycol 400 to a suitable vessel and mix. Dissolve the butylated hydroxytoluene in this mixture. Disperse the carbomer 940 in the above mixture with vigorous agitation. Add the solution of sodium hydroxide with high speed agitation to bring pH up to 7 and mix until a thick gel forms. Dissolve the active compound in the remaining propylene glycol and add to the gel slowly as the gel is continuously mixed. 
     EXAMPLE G 
     
         ______________________________________ LotionFormula                 mg/g______________________________________Active Compound         1.0-20.0Carbomer 940            3.0Sodium hydroxide (charged as 4% w/w                   0.05aqueous solution)Isopropyl Alcohol       40.00Purified Water, USP to make                   1.0      g______________________________________ 
    
     Method of Manufacture 
     Prepare a 4% solution of sodium hydroxide in water. Heat the purified water to 60° C. Add carbomer 940 and mix at high speed until dispersed. Cool the above mixture to room temperature and slowly charge sodium hydroxide solution until uniform. Add 80% of isopropyl alcohol to the above with mixing. Dissolve the active compound in remaining isopropyl alcohol. Add this to the mixture with stirring Adjust pH to 5.0 to 5.5 with sodium hydroxide, if necessary. 
     EXAMPLE H 
     
         ______________________________________ Topical AerosolFormula                mg/g______________________________________Active Compound        1.0-20.0Caprylic/Capric Triglyceride                  50.00Mineral Oil            20.00Denatured Alcohol      150.00Hydrocarbon Aerosol Propellant                  1.0      gq.s. ad.______________________________________ 
    
     Method of Manufacture 
     Add and mix the caprylic/capric triglyceride mineral oil and specially denatured alcohol in a suitable compounding tank. Add the active compound and continue mixing until the active compound is dissolved or dispersed uniformly. Fill the concentrate into cans and then fill the required amount of hydrocarbon aerosol propellent. 
     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 within the spirit and scope of the present invention.