SUBSTITUTED 1,8-NAPHTHYRIDINONES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Substituted 1,8-naphthyridinones of formulae V, VI or VII wherein n is 1 or 2; R¹ and R² may be combined to form a bond, or R¹ is hydrogen and R² is OR, halogen or NR³R⁴; R is hy­ drogen, carboxylic acyl or carbamyl; R³ and R⁴ are indepen­ dently hydrogen or alkyl having from 1 to 6 carbon atoms, or R³ and R⁴ may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piper­ azino ring; R⁵ is hydrogen or carboxylic acyl; and Y is CH or N. The compounds possess anti-allergic, anti-inflammatory, cytoprotective activity and an immuno-suppressing effect.

Description: SUBSTITUTED 1,8-NAPHTHYRIDINONES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention relates to novel tricyclic compounds which possess anti-allergic, antiinflammatory, cytoprotective activity and an immunosuppressing effect. The compounds of the present invention are compounds of the formula EMI1.1 wherein A is a moiety of the formula II, III or IV EMI2.1 wherein n is 1 or 2; R1 and R2 may be combined to form a bond, or R1 is hydrogen and R2 is OR, halogen or NR3R4; R is hydrogen, R6-C(O)-, or R7R8NC(O)-; R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring; R5 is hydrogen or R6-C(O)-; R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl; ; R7 and R8 are independently hydrogen, lower alkyl having from I to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms; X is hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, nitro, halogen, trifluoromethyl or alkyl-S(O)m having from 1 to 6 carbon atoms, and wherein m is zero, 1 or 2; p is 1, 2 or 3; and Y is CH or N; and the acid addition salts thereof. The compounds of formula I can also be represented by formulae V, VI and VII EMI3.1 wherein R1, R2, R5, X, Y, n and p are as defined above. Compounds of formulae V and VI wherein R1 is hydrogen have at least one asymmetric carbon atom, i.e., the carbon indicated with an asterisk(*) in formulae V and VI. The compounds accordingly exist in eantiomeric forms or in racemic mixtures thereof, and all such isomers and racemic mixtures are within the scope of this invention. Separation of the isomers may be accomplished by methods well known to those skilled in the art. The compounds of formulae V, VI and VII can exist in unsolvated as well as solvated forms, including hydrated forms. 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. As used herein, the term "alkyl" refers to straight or branched chain groups, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl and hexyl. Examples of "alkoxy" groups are methoxy, ethoxy, isopropoxy, butoxy and hexoxy. "Halogen" refers to fluorine, chlorine, bromine and iodine. The term "acid addition salts" as used herein refers to salts formed with pharmaceutically acceptable acids such as, for example, hydrochloric, hydrobromic, methane sulfonic and sulfuric acids. Preferred are compounds of formulae V and VI, with compounds of formula V being more preferred. Preferred compounds of formulae V and VI are those wherein n is 1. A third group of preferred compounds is that wherein Y is CH. A fourth group of preferred compounds is that wherein R1is hydrogen and R2 is OR wherein R is hydrogen or R6C(O)-, preferably R being hydrogen or R6C(O)-, wherein R6is alkyl. A further group of preferred compounds is that wherein R1 is hydrogen and R2 is NR3R4, preferably being l-piperidinyl or l-pyrrolidinyl. A further group of preferred compounds is that wherein R1 is hydrogen and R2 is halogen, preferably bromo or iodo. Still another group of preferred compounds is that wherein p is 1 and X is hydrogen, halogen or alkoxy, preferably hydrogen, chloro or methoxy, preferably the substituent being in meta-position. Also contemplated as part of this invention are pharmaceutical compositions which comprise a compound of formula I in combination with a pharmaceutically acceptable carrier. The compounds of this invention are useful for treatinq allergic reactions and inflammation. It is also contemplated that compounds of the invention are useful in the treatment of peptic ulcers. The compounds of this invention are useful for suppressing the immune response in mammals. The compounds of this invention can be prepared according to known methods. In the following equations suitable methods are described. Reactive groups not involved in the described reaction are protected according to standard methods before the reaction and are subsequently deprotected to yield the desired product. The starting compounds used in the described processes can be prepared according to known methods. In the formulae of the following description of the processes, unless stated otherwise, n is 1 or 2; R1 and R2 may be combined to form a bond, or R1 is hydrogen and R2 is OR, halogen or NR3R4; R is hydrogen, R6-C(O)-, or R7R8NC(O)-; R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring; R5 is hydrogen or R6-C(O)-; R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having .from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl; ; and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms; X is hydrogen, hydroxy, alkyl having from I to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, nitro, halogen, trifluoromethyl or alkyl-S(O)m having from 1 to 6 carbon atoms, and wherein m is zero, 1 or 2; p is 1, 2 or 3; and Y is CH or N; including suitable protecting groups. The processes are particularly useful for the preparation of compounds of formulae V and VI wherein Y is CH and n is 1 and of formula VII wherein Y is CH. (a) For the preparation of compounds of formulae V and VI wherein R1 is hydrogen and R2 is halogen, a compound of formula VIII EMI6.1 or an ester thereof is subjected to halogenation and cyclisation. This procedure is particularly useful for the preparation of compounds wherein Y is CH and n is 1. For example, for the preparation of compounds of formulae V and VI wherein R1 is hydrogen and R is bromo, a compound VIII or its 4-ester is subjected to bromination, which results in spontaneous cyclization of the intermediate dibromo compound. The bromination can be carried out at reduced temperatures (-10 to +320C), by adding bromine to the solution of the compound VIII and letting the reaction mixture come to room temperature. Preferably equimolar amounts of compound VIII and bromine are used. After the isolation of the reaction product compounds V and VI are isolated, for example, by column chromatography. For the preparation of compounds of formulas V and VI wherein R1 is hydrogen and R2 is iodo, a compound of formula VIII or its 4-ester is reacted with N-iodosuccinimide in the presence of perchloric acid at reduced temperature. The compounds V and VI are isolated by e.g., column chromatography. A variant of the process for preparing compounds of formula VI wherein R1 is hydrogen and R2 is iodo comprises reacting a compound of formula VIII with iodine monochloride in a halogenated hydrocarbon as solvent such as, for example, methylene chloride, perferably at room temperature. Equimolar amounts of the compound VIII and iodine monochloride, or preferably, a small excess of iodine monochloride is used. A further variant of the process for preparing compounds of formula VI wherein R1 is hydrogen and R2is iodo comprises reacting a compound of formula VIII with an equimolar amount (or small excess) of iodine in a halogenated hydrocarbon as solvent (e.g., methylene chloride) in an alkaline medium. b) A compound of formula IX EMI8.1 or ester thereof is cyclized to form a compound of formula V wherein R1 is hydrogen and R2 is hydroxy. The cyclization can be carried out by heating, if desired, a solution of compound of formula IX. The compound IX can be obtained by reacting the corresponding compound of formula VIII with peracetic acid in a solvent (e.g., ethylacetate or a halogenated hydrocarbon, e.g., methylene chloride) at 20 to 300C, preferably around room temperature. Without isolation the compound IX the desired end product V can be obtained. c) Compounds of formulae V, VI and VII, wherein R1 is hydrogen, R2 is hydroxy and R5 is hydrogen can be prepared by hydrolysis of a compound of formula V or VI, wherein R1 is hydrogen and R2 is halogen. A compound of formula VI wherein R1 is hydrogen and R2 is halogen, preferably bromo, can be subjected to hydrolysis by refluxing the reaction mixture containing water, sodium hydroxide and, possibly, methanol, yielding, besides possible side products, a compound of formula V wherein R1 is hydrogen, and R2 is hydroxy and (when n is one) of formula VII wherein R5 is hydrogen. The compounds are isolated by techniques known in the art. If the compound of formula VI wherein R1 is hydrogen and R2 is halogen (preferably bromo) is subjected to hydrolysis under very mild conditions (e.g. silver acetate in aqueous methanol at room temperature), the corresponding compound of formula VI is obtained wherein R1 is hydrogen and R2 is hydroxy. d) A compound of formula V or VI wherein R1 is hydrogen and R2 is hydroxy or VII wherein R5 is hydrogen can be esterfied to form the corresponding respective compound of formula V, VI or VII. Therein R1 is hydrogen, R2 is OR, wherein R is R6C(O)- or R7R8NC(O)and R5 is R6C(O)-, wherein R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl and R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms. This process is carried out using acylating processes known in the art, such as reacting the hydroxy compound with the appropriate acid anhydride or acyl chloride in an inert solvent such as, for example, benzene. e) A compound of formula V or VI wherein R1 is hydrogen and Rê is halogen, preferably bromo, is reacted with an amine HNR R4 (wherein R and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring) or with a reactive derivative of said amine to form the respective corresponding compound V or VI wherein R1 is hydrogen and R2 is NR3R4. The reaction can be carried out at room temperature. f) A compound of formula V or VI wherein R1 is hydrogen and R2 is halogen, preferably iodo, is dehydro halogenated to form the respective corresponding compound V or VI wherein R1 and R2 together form a bond. The reaction can be carried out at room temperature in the presence of a base, preferably an organic base such as, for example, piperidine. g) A compound of formula VI wherein R1 is hydrogen and R2 is bromo can be reacted with sodium iodide to yield a compound of formula V wherein R1 is hydrogen and R2 is iodo. The reaction can be carried out in a solvent such as, for example, acetone. h) A compound of formula V, VI or VII, wherein R1 is hydroqen, R2 is OR, wherein R is R6-C(O)-, or R7R8NC(O)--; R5 is hydrogen or R6-C(O)-; R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl; R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms, can be hydrolyzed to yield the respective corresponding compound of formula V, VI or VII wherein R1 is hydrogen, R2 is hydroxy and R5 is hydrogen. The hydrolysis can be carried out in an aqueous alkaline medium, if desired also containing an alcohol (e.g., methanol). Preferably the hydrolysis is carried out with NaOH (preferably 0.5 NaOH) under reflux of the aqueous alcohol-free medium. (i) A compound of formula V or VI wherein R1 is hydrogen and R2 is hydroxy is dehydrated to form the corresponding respective compound of formula V or VI wherein R1 and R2 together form a bond. The reaction can be carried out with dicyclohexylcarbodiimide (DCC) in the presence of a catalyst such as, for example, CuCl in an organic solvent such as an ether, preferably diethylether. The above processes are followed by isolation of the individual compounds and/or formation of salts and/or solvates. The compounds in their enantiomeric form can be isolated from the racemic mixture according to known methods. Compounds of formula VIII may be prepared by methods known in the art. See, for example, U.S. Patent 4,492,702. An example of such a procedure is provided in Preparation 1. Representative of the compounds of this invention of formulae V, VI and VII are the following: 3,5-dihydro-2-(hydroxymethyl)-5-phenyl furo( 3,2-c) -l , 8-naphthyridin-4( 2H) -one, 5-(3-chlorophenyl)-3,5-dihydro-2 (hydroxymethyl)-furo(3,2-c)-1,8-naphtyridin-4(2H)-one, 2- ( acetyloxymethyl) -3, 5-dihydro-5-phenyl- furo(3,2-c)-1, 8-naghthyridin-4( 2L) -one, 2-(acetoxymethyl)-3,5-dihydro-5-(3methoxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-2-(iodomethyl)-5-phenyl-furo(3,2c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-2-(iodome.thyl)-5-(3-methoxyphenyl)- furo( 3,2-c) -l , 8-naphthyridin-4 ( 2H) -one, 3,5-dihydro-5-phenyl-2-(1-pyrrolidinylmethyl)- furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-5-phenyl-2-(1-piperidinylmethyl) furo(3,2-c)-1, 8-naphthyridin-4-( 2 -one, 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-9-phenyl-2-(1-pyrrolidinylmethyl)- furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3 methoxyphenyl)-furo(2 r 3-b ) -1,8-naphthyridin-4(2H)-one, 3,9-dihydro-2-(iodomethyl)-9-phenyl-furo(2,3b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-2-methylene-9-phenyl-furo(2,3-b)1,8-naphthyridin-4(2H)-one, 3-hydroxy-6-phenyl-2,3,4,6-tetrahydro-5H- pyrano(3,2-c)-1,8-naphthyridin-5-one, 3-acetyloxy-6-phenyl-2,3,4,6-tetrahydr-5H pyrano(3,2-c)-1,8-naphthyridin-5-one, 2-(hydroxymethyl)-3,5-dihydro-5-(3methoxyphenyl)-furo(2,3-c)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3-chlorophenyl)- furo(2,3-b)-1,8-naphthyridin-4(2H)-one, (in the form of the racemic mixtures or the enantiomers) or pharmaceutically acceptable salts or solvates thereof. The compounds of this invention can be used to treat allergy caused diseases and their preferred use is for treating allergic chronic obstructive lun diseases. Chronic obstructive lung disease as used herein means disease conditions in which the passage of air through the lungs is obstructed or diminished such as is the case in asthma, bronchitis and the like. The anti-allergy method of this invention is identified by tests which measure a compound's inhibition of anaphylactic bronchospasm in sensitized rats having antigen induced bronchoconstriction. For example, the compound 3 ,5-dihydro-2-(hydroxymethyl)-5-phenyl-furo- [3,2-c]-1,8-naphthyridin-4(2H)-one was found to inhibit anaphylactic bronchospasm in such a test procedure when qiven at an oral dose of 2 mg/kg. Said compound was also found to inhihit allergen-induced histamine release from guinea pig sensitized tissue. The compounds are effective non-adrenergic, non-anticholinergic antianaphylactic agents. When administered orally they are active at doses from about 0.1 to 10 mg/kg of body weight; when administered parenterally, e.g., intravenously, the compounds are active at dosages of from about 0.05 to 5 mg/kg body weight; when administered by inhalation (aerosol or nebulizer) the compounds are active at dosages of about 0.25 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. The anti-inflammatory use of the compounds of the present invention may be demonstrated by the Reversed Passive Arthus Reaction (RPAR) Rat Paw technique as set forth below. The potency of the compounds is determined using indomethacin as the standard. On the basis of the test results, an oral dosage range of about 5 milligrams per kilogram of body weight per day to about 50 milligrams per kilogram 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. RPAR Rat Paw Technique 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), obtained 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 a 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 so as to provide a dose for a 200 gram animal which is equivalent to the mg/kg dose for the 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 into the penile vein with 0.2 ml of PFS containing 1.0 mg of BSA. One hour later, the animals are "challenged" in the right rear paw with subplantar injections of 0.2 ml of PFS containing 0.1 mg of anti-BSA. Immediately after the subplantar injection, the right paw is dipped (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 also 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 (n 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. When administered parenterally, e.g. intravenously, the compounds are administered at a dosage range of about 0.01-10 mg/kg of body weight in single or multiple daily doses. The compounds are also useful in the treatment of auto immune 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 Bl/6XA/J(B6AFl) male mice were injected intravenously with parental (C57B1/6J) spleen and lymph node cells. The compound 3,5-dihydro-2hydroxymethyl-5-phenyl-furo(3,2-c)-1,8-naphthyridin -4(2H)-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'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 Compound A 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. In this test Compound A reduced spleen weight by 138% as compared to the untreated animals at a dose of 100 mg/kg. 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 a 25% and 48% spleen weight decrease at a dosages level of 25 mg/kq and 50 mg/kg, respectively, indicating an ED50 of between 25 mg/kg and 50 m/kq. As mentioned above, the subject compounds also possess anti-allergy and anti-inflammatory activities. For example, Compound A has an ED50 value of below about 2 mg/kg p.o. in tests measuring the inhibition of anaphylactic bronchospasm in sensitized guinea pigs having antigen-induced bronchoconstriction and an ED50 value of below about 25 mg/kg p.o. in tests measuring the reverse passive Arthus reaction in the paw of rats (as described above). These results for Compound A indicate that an immunosuppressive effective dose for the compounds of formula I is about 5 times or more their anti-allergy effective doses (ED505). The usual dosage range for the compounds of formula I in a 70 kg mammal is an oral dose of about .1 to 250 mg/kq, preferably .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 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. 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. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can 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 or 10 to about 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" 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 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 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, flavors, 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. 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. Alternately, sufficient solid may be pro vided 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. When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decomposition. 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 water, ethanol, glycerine, propylene glycol and the like as well as mixtures thereof. Naturally, the solvent utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use. 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 component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules and powders in vials or ampoules. The unit dosage¯ form can also be a capsule, cachet or tablet itself or it can be the appropriate number of any of these in packaged form. The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient. The compositions can, if desired, also contain other therapeutic agents. The dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which 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. PREPARATION AND EXAtIPLES PREPARATION 1 4-HYDROXY-1-PHENYL-3-(2-PROPENYL)- 1,8-NAPHTHYRIDIN-2(1H)-ONE (A) 4-Hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one, To a stirred solution of I kg. of methyl 2phenylamino-3-pyridine carboxylate in 3.97 liters of nbutyl acetate there is added portionwise, 1.1 kg. of potassium tertiary butoxide. After the addition of the potassium tertiary butoxide, there is added an additional 1.32 liters of n-butyl acetate. The reaction mixture is heated to reflux for 20 hours during which the internal temperature of the reaction mixture rises from 900C to 1220 C. During this period, 1.8 liters of liquid is removed from the reaction via a Dean-Stark trap. Xylene (3.0 liters) is added to the reaction mixture and the remainder of the n-butyl acetate is removed via the Dean Stark trap. The reaction mixture is cooled and the potassium salt is collected by filtration, washed with toluene and air dried. The crude potassium salt is dissolved in 12 liters of water, the aqueous solution is extracted with toluene, acidified to pH 2 and the product filtered and dried; weight 937 g., m.p. 3lI-3l30C. (B) 4-Acetyloxy-1-phenyl-3-(2-propenyl) 1,8-naphthyridin-2(1H)-one 1.) l-phenyl-4-C 2-propenyloxy)-l ,8-naphthyridin- 2(111)-one: To a mixture of 62 g. of 4-hydroxy-1-phenyl 1,8-naphthyridin-2(1H)-one, 39.6 g. of anhydrous potassium carbonate and 1,800 ml of acetone, there is added dropwise, with stirring, 37.5 g. of allyl bromide. The reaction mixture is refluxed for 22 hours, concentrated in vacuo, and the residue extracted with 600 ml. of chloroform. The organic extracted is washed with water, 1N sodium hydroxide solution and again with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid is triturated with 3 x 400 ml of boiling isopropyl ether and filtered, yielding the insoluble product, wt. 38.5 g., m.p. 171-174 . Recrystallization from methanol produces the product as a colorless solid, m.p. 176-1770C. 2.) 4-Acetyloxy-1-phenyl-3-(2-propenyl)-1,8 naphthyridin-2(1H)-one: A mixture of 33.8 g. of 1-phenyl-4-(2 propenyloxy)-1,8-naphthyridin-2(1H)-one and 35 ml. of acetic anhydride is refluxed for four hours. On cooling, the reaction mixture solidified. Trituration with isopropyl ether and filtration yields the product, 36.1 g., as a colorless solid, m.p. 189-1950C. Recrystallization from ethanol provides the product with m.p. 195 1960C. (C) 4-Hydroxy-l-phenyl-3-(2-propenyl) 1 ,8-naphthyridin-2( 111)-one A mixture of 6.0 g. of 4-acetyloxy-l-phenyl-3 (2-propenyl)-1,8-naphthyridin-2(1H)-one, 200 ml. of ethanol and 40 ml. of 1N sodium hydroxide solution is stirred at room temperature for 22 hours. The ethanol is removed in vacuo and the remaining aqueous solution acidified with 1N hydrochloric acid. The product is filtered, washed with water and dried, weight 5.3 g., m.p. 248-250 C. Recrystallization from chloroform yields the product of this preparation as a colorless solid, m. p. 250-252 C. In a similar manner, substitute 4-bromo-lbutene for allyl bromide in part B(1) of Preparation 1 to prepare 3-(3-butenyl)-4-hydroxy-l-phenyl-1,8 naphthyridin-2(lH)-one. EXAMPLE 1 2-(BROMOMETHYL)-3,9-DIHYDRO-9-PHENYL-FURO(2,3-b)-1,8- NAPHTHYRIDIN-4(2H)-ONE To a cooled (50) solution of 24.5 g. (0.076 moles) of 4-(acetyloxy)-1-phenyl-3-(2-propenyl)-1,8 naphthyridin-2(1H)-one in 350 ml. of dry chloroform there is added dropwise, 12.2 g. (0.076 moles) of bromine. The reaction mixture is allowed to come to room temperature, stirred for 18 hours, concentrated in vacuo, and the solid product is triturated with 3 x 150 ml. of isopropyl ether and filtered. The crude hydrobromide salt melts at 209-2110(dec), and on recrystallization from ethanol melts at 2l2-2I30Cdec). The hydrobromide salt is readily treated with cold 0.1 N sodium hydroxide solution, then recrystallized from ethyl acetate to yield the title compound, m.p. 187 1880C. EXAMPLE 2 3,5-DIHYDRO-2-(HYDROXYMETHYL)-5-PHENYL-FURO(3,2-c)- 1,8-blAPHTHYRIDIN-4(2H)-ONE A solution of 15.0 g. of 2-(bromomethyl)-3,9dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one hydrobromide in 200 ml of methanol, 160 ml of 1.0 N sodium hydroxide solution and 150 ml. of water is stirred and refluxed on a steam bath for 21 hours. The reaction is concentrated to a volume of 200 ml in vacuo and the solid filtered and washed with water. Recrystallization of the crude solid from methanol yields the title compound, m.p. 267-268 . EXAMPLE 3 2-(ACETYLOXYMETHYL)-3,5-DIHYDRO-5-PHENYL-FURO(3,2-c)-1,8 NAPHTHYRIDIN-4(2H)-ONE The product of Example 2 is refluxed with acetic anhydride in benzene, and the resultant product is recrystallized from isopropyl acetate to give the title compound, m.p. 207-208"C. EXAMPLE 4 3-ACETYLOXY-2,3,4,6-TETRAHYDRO-6-PHENYL-5H-PYRANO(3,2-c)- 1,8-NAPHTHYRIDIN-5-ONE A solution of 51.0 g. of 2-(bromomethyl)-3,9dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 680 ml. of methanol, 545 ml. of 1.0 N sodium hydroxide solution and 510 ml. of water is stirred and refluxed on a steam bath for 18 hours. The solution is concentrated in vacuo to a volume of 600 ml., cooled, and the solids filtered and washed with water. Spectral data and chromatography indicated the presence of two compounds, the product of Example 2 ("compound 2") and the title compound of example 5. After separation of most of "compound 2" the mother liquor is acetylated with acetic anhydride in refluxing benzene, yielding a mixture of the acetates which are separated by chromatography, yielding the title compound, m.p. 224-2260. EXAMPLE 5 3-HYDROXY-2,3,4,6-TETRAHYDRO-6-PHENYL-5H-PYRANO(3,2-c)- 1,8-NAPHTHYRIDIN-5-ONE Hydrolysis of the product of Example 4 with methanol:l.0 N sodium hydroxide solution followed hy recrystallization of the resultant product from methanol yields the title compound, m.p. 296-2980C. EXAMPLE 6 2-(BROMOMETHYL)-3,9-DIHYDRO-9-(3-METHOXYPHENYL)-FURO(2,3b)-1,8-NAPHTHYRIDIN-4(2H)-ONE Treat 4-hydroxy-1-(3-methoxyphenyl)-3-(2- propenylö)-1,8-naphthyridin-2-(1H)-one according to the procedure described in Example 1, recrystallizing from methanol:ethyl acetate to obtain the title compound, m.p. 196-1980C. EXAMPLE 7 2-(ACETYLOXYMETHYL)-3,5DIHYDRO5-(3-tIETHOXYPHENYL)-FURO- (3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE Treat 2-(bromomethyl)-3,9-dihydro-9-(3 methoxyphenyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one according to the procedure of Example 2 to prepare the 2hydroxymethyl analog of the title compound. Treat this 2-hydroxymethyl compound according to the procedures of Example 3 to obtain the title compound, m.p. 183-184 C. EXAMPLE 8 3,9-DIHYDRO-2-(IODOMETHYL)-9-PHENYL-FURO(2,3-b)-1,8 NAPHT11YRIDIN-4C 211)-ONE To a solution of 4.0 g. (0.014 moles) of 4 hydroxy-l-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(1H)- one in 380 ml. of tetrahydrofuran, there is added, dropwise, with stirring at 3-50C, 4.0g. of 70% perchloric acid in 11.5 ml. of water, followed by the slow addition of 10.2g. of N-iodo-succinimide over a period of 45 minutes. The reaction is stirred at room temperature for three hours, treated with a saturated solution of sodium sulfite, and extracted with 2 x 250 ml. of ether. The organic layer is dried over magnesium sulfate, filtered and concentrated to a solid residue. The crude products are separated on a 60G silica gel column with methanol: chloroform (5:95). The desired fraction is recrystallized from ethyl acetate to yield the title compound, m. p. 178-180 C. EXAMPLE 9 3,5-DIHYDRO-2(IODOMETHYL)-5-PHENYL-FURO(3,2-c)-1,8 NAPHTHYRIDIN-4 ( 2H) -ONE The desired fraction comprising the compound of this example isolated from the column chromatography carried out in Example 8 is recrystallized from acetonitrile to yield the title compound, m.p. 238-240 C. EXAMPLE 10 3,9-DIHYDRO-2-METHYLENE-9-PHENYL-FURO(2,3-b)-l,8- NAPHTHYRIDIN-4 ( 2H ) -ONE A solution of 2 g. of 3,9-dihydro-2-(iodomethyl)-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one in 4 g. of dry piperidine is stirred at room temperature for 72 hours. The reaction mixture is diluted with 80 ml. of water, filtered and the solids washed well with water. The aqueous filtrate is made strongly basic with sodium hydroxide solution and filtered. The combined solids are purified on a grade 62 silica gel column using 5 pts MéOH, 95 pts ethyl acetate as solvent. Fraction III is triturated with 2 x 50 ml. of hot isopropyl ether yielding the title compound, m.p. 259-261 C. EXAMPLE 11 3,9-DIHYDRO-9-PHENYL-2-(1-PYRROLIDINYLMETHYL)-FURO(2,3b)-1,8-NAPHTHYRIDIN-4(2H)-ONE HYDROCHLORIDE A mixture of 10.0 g. of 2-(bromomethyl)-3,9 dihydro-9-phenyl-furo(2,3-b)-l,8-naphthyridin-4(211)-one and 22g. of pyrrolidine is stirred at room temperature for three hours. The reaction mixture is diluted with 180 ml. of water, the solids washed well with water and air dried. The crude product is treated with excess 1 N hydrochloric acid solution, extracted with methylene chloride and the aqueous acidic layer separated. The acidic layer is basified with dilute sodium hydroxide solution, cooled and filtered to yield a crude product, m.p. 159-1600. Recrystallization from ethyl acetate yields the title compound, m.p. 161-163 ; hydrochloride salt as a hydrate, m.p. 187-1900C from ethanol:ether. EXAMPLE 12 3,5-DIHYDRO-5-(3-CHLOROPHENYL)-2-(HYDROXYMETHYL)- FURO(3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE In a manner similar to that described in Example 2, treat 2-(bromomethyl)-9-(3-chlorophenyl)-3,9dihydro-furo(2,3-b)-1,8-naphthyridin-4(2H)-one to yield the title compound, m.p. 243-245 C. EXAMPLE 13 3,9-DIHYDRO-2-tIODOMETHYL)-9-PHENYL-FURO(2,3-b)-1,8- NAPHTHYRIDIN-4(2H)-ONE To a solution of 2 mmole of 4-hydroxy-l-phenyl3-(2-propenyl)-1,8-naphthyridin-2(1H)-one in 100 ml of methylene chloride there is added a solution of 2.2 mmole of iodine monochloride. The solution is stirred at room temperature until starting material could no longer be detected (e.g. by thin layer chromatography). The methylene chloride was removed in vaccuo and the title compound recrystallized from ethyl acetate, m.p. 178 1800C. EXAMPLE 14 3,9-DIHYDRO-2-(IODOMETHYL)-9-PHENYL-FURO(2,3-b)-1,8- NAPHTHYRIDIN-4(2H)-ONE To 2.3 mmole of 4-hydroxy-1-phenyl-3-(2- propenyl)-l ,8-naphthyridin-2( 111)-one in 100 ml of methylene chloride was added 2.3 Trimol of anhydrous potassium carbonate and 2.76 mmol. of iodine. The reaction mixture was stirred for 15 hours at room temperature, quenched with water and the organic layer dried and concentrated to yield the title compound (m.p. 178-1800C). The following Formulation Examples are intended to illustrate, but not to limit, the present invention. In the examples the term "Compound A" refers to 3,5 dihydro-2-hydroxymethyl-5-phenyl-furo(3,2-c)-1,8- naphthyridin-4(2H)-one. It is contemplated, however, that this compound may be replaced by equally effective quantities of other compounds of formula I as defined above. Formulation 1 Tablets No. Ingredient mg/tablet mg/tablet 1. Compound A 100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade, 30 40 as a 10% paste in Purified Water 4. Corn Starch, Food Grade 45 40 5. 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 if needed. Dry the damp granules. Screen the dried granules if needed and mix with the Items No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate the size and weight on a suitable tablet machine. Formulation 2 Capsules No. Ingredient mg/capsule mg/capsule 1. Compound A 100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4. 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. Formulation 3 Parenteral Ingredient mg/vial mg/vial Compound A Sterile Powder 100 500 Add sterile water for injection or bacteriostatic water for injection, for reconstitution. Formulation 4 Injectable No. Ingredient mg/vial mg/vial 1. Compound A 100 500 2. Methyl para-hydroxybenzoate 1.8 1.8 3. Propyl para-hydroxybenzoate 0.2 0.2 4. Sodium Bisulfite 3.2 3.2 5. Disodium Edetate 0.1 0.1 6. Sodium Sulfate 2.6 2.6 7. Water for Injection q.s. ad 1.0 ml 1.0ml method for Manufacture 1. Dissolve the hydroxybenzoate compounds in a portion (85% of the final volume) of the water for injection at 65-700C. 2. Cool to 25-35 C. Charge and dissolve the sodium bisulfite, disodium edetate and sodium sulfate. 3. Charge and dissolve drug. 4. Bring the solution to final volume by added water for injection. 5. Filter the solution through 0.22 membrane and fill into appropriate containers. 6. Finally sterilize the units by autoclaving.

Claims: Claims: 1) A compound of the formula EMI33.1 wherein A is a moiety of the formula II, II or IV EMI33.2 wherein n is 1 or 2; R1 and R2 may be combined to form a bond, or R1 is hydrogen and R2 is OR, halogen or NR3R4; R is hydrogen, R6-C(O)-, or R7R8NC(O)-; R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring; R5 is hydrogen or R6-C(O)-; R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl; ; R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms; X is hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, nitro, halogen, trifluoromethyl or alkyl-S(O)m having from 1 to 6 carbon atoms, and wherein m is zero, 1 or 2; p is 1, 2 or 3; and Y is CH or N; and the acid addition salts and/or solvates thereof. 2) A compound according to claim 1, wherein A is the moiety of formulae II or III, preferably of formula II. 3) A compound according to claim 2, wherein Y is CH and n is 1. 4) A compound according to claims 2 or 3, wherein R1 is hydrogen and R2 is OR, wherein R is hydrogen or 6C(O)-, preferably R being hydrogen or R6CtO)-, wherein R6 is alkyl or R2 is NR3R4, preferably beinq 1piperidinyl or l-pyrrolidinyl. 5) A compound according to claim 2 or 3, wherein R1 is hydrogen and R2 is halogen, preferably bromo or iodo. 6) A compound according to any one of claims 1 to 5 wherein p is 1 and X is hydrogen, halogen or alkoxy, preferably hydrogen, chloro or methoxy. 7) A compound according to claim 1 which is 3,5-dihydro-2-(hydroxymethyl)-5-phenyl furoC 3,2-c) -l ,8-naphthyridin-4( 211)-one, 5-(3-chlorophenyl)-3,5-dihydro-2 (hydroxymethyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2- ( acetyloxymethyl) -3, 5-dihydro-5-phenyl- furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2-(acetyloxymethyl)-3,5-dihydro-5-(3methoxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-2-(iodomethyl)-5-phenylfuro(3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-2-(iodomethyl)-5-(3-methoxyphenyl)- furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 3 ,5-dihydro-5-phenyl-2-( 1-pyrrolidinylmethyl)- furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-5-phenyl-2-(1-piperidinylmethyl)furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-phenylfuro(3,2-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-9-phenyl-2-(1-pyrrolidinylmethyl) furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3methoxyphenyl)-furo(3,2-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-2-(iodomethyl)-9-phenyl furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3 ,9-dihydro-2-methylene-9-phenyl-furo( 2,3-b)- 1,8-naphthyridin-4(2H)-one, 3-hydroxy-6-phenyl-2,3,4,6-tetrahydro-5H- pyrano(3,2-c)-1,8-naphthyridin-5-one, 3-acetyloxy-6-phenyl-2,3,4,6-tetrahydro-5H pyrano(3,2-c)-1,8-naphthyridin-5-one, 2-(hydroxynethyl)-3,5-dihydro-5-(3- methOxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3-chlorophenyl)- furo(2,3-b)-1,8-naphthyridin-4(2H)-one, (in the form of the racemic mixtures or the enantiomers) or pharmaceutically acceptable salt thereof. 8) Process for the preparation of a compound of the formula I or its acid addition salt and/or solvates as defined in any one of claims 1 to 7, characterized in that a) a compound of formula VIII EMI36.1 or an ester thereof is subjected to halogenation and cyclization to form compounds of formulae V and VI, EMI37.1 wherein R1 is hydrogen and R2 is halogen; or b) a compound of formula IX EMI37.2 is cyclized to form a compound of formula V EMI38.1 wherein R1 is hydrogen and R2 is hydroxy; or c) a compound of formula V or VI wherein R1 is hydrogen and R2 is halogen is hydrolized to give a compound of formula V and/or VI and/or VII EMI38.2 wherein R1 is hydrogen, R2 is hydroxy and R5 is hydrogen; or d) a compound of formula V or VI wherein R1is hydrogen, R2 is hydroxy) or VII (wherein R5 is hydrogen) is esterified to yield the respective corresponding compound of formula V, VI or VII wherein R1 is hydrogen, R2 is OR wherein R is R6C(O)- or R7R8NC(O)- and R5 is R6C(O)-, wherein R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl and R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms; or e) a compound of formula V or VI wherein R1 is hydrogen and R2 is halogen, preferably bromo, is reacted with an amine HNR3R4 (wherein R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring) or with a reactive derivative of said amine to form the respective corresponding compound V or VI wherein R1 is hydrogen and R2 is NR3R4 or f) a compound of formula V or VI wherein R1 is hydrogen and R2 is halo is dehydrohaloqenated to form the respective corresponding compound V or VI wherein R1 and R2 together form a bond; g) a compound of formula VI wherein R1 is hydrogen and R2 is bromo is reacted with sodium iodide to yield a compound of formula V wherein R1 is hdyrogen and R2 is iodo; or h) a compound of formulae V, VI or VII, wherein R1 is hydrogen, R2is OR, wherein R is R6-C(O)-, or R7R8NC(O)-; R5 is hydrogen or R6-C(O)-; R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl; R7 and R8 are independently hydrogen, lower alkyl having from I to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms, is hydrolyzed to yield the respective corresponding compound of formula V, VI or VII wherein R1 is hydrogen, R2 is hydroxy and R5 is hydrogen; i) a compound of formulae V or VI wherein This hydrogen and R2 is hydroxy is dehydrated to yield the respective corresponding compound V or VI wherein R1 and R2 together form a bond; whereby each of the processes is followed, if desired, by isolation of the individual compound and/or formation of the salt and/or solvate of the compound(s). 9) A pharmaceutical composition which comprises a compound of any one of claims 1 to 7 in combination with a pharmaceutically acceptable carrier. 10) A compound of any one of claims 1 to 7 for use in eliciting an anti-allergic and/or anti-nflammatory and/or cytoprotective and/or immunosuppressing effect.

Inventors: SHERLOCK, MARGARET HAGAR, SIEGEL, MARVIN IRA, SMITH, SIDNEY RANDAL
Applicants: SCHERING CORPORATION
Application year: 1986
Main classification: C07D491
IPC codes: A61K31, C07D491