Anti-inflammatory/anti-allergic compounds

Claim 2

Condensation of a compound of formula II in which X' is -CH 2 Hal, Hal, OH, CH 2 0H, SH, or CH 2 SH; with a compound of formula III in which X" is -CH 2 Hal, Hal, OH, CH 2 OH, SH or CH 2 SH, through elimination of X' and X" with a residue Z remaining after condensation. Such condensation reactions are known and occur between, for example, -CH 2 Hal and -OH with the elimination of hydrogen halide and formation of the bridging group -CH 2 0- between the two rings of the resulting product. Substituting simply halogen in place of -CH 2 Hal- results in the diphenyl ether structure (where X is -0-). This reaction is known an Ullman ether synthesis. Substituting the analogous sulfuric intermediates provides the sulfur analogs of the aforesaid compounds (where X is -S- or -CH 2 S-). A variation of this synthetic route employs the Grignard reagent in place of the halogen-containing substituent.

Claim 3

When X is unsaturated hydrocarbyl [-C(R 1 )=C(R 1 )-or -C≡C-, a compound of formula II in which X' is vinyl or acetylenyl is condensed with a compound of formula III in which X" is halogen, usually in the presence of an active metal (Na, Li, etc.). Alternatively, X' and X" of course can be reversed, i.e., X' can be halogen and X" the unsaturated hydrocarbyl group.

Claim 4

When X is unsaturated hydrocarbyl [-C(R 1 )=C(R 1 )-or -C≡C-, a compound of formula II in which X' is vinyl or acetylenyl is condensed with a compound of formula III in which X" is halogen, usually in the presence of an active metal (Na, Li, etc.). Alternatively, X' and X" of course can be reversed, i.e., X' can be halogen and X" the unsaturated hydrocarbyl group.

Claim 5

When Z is -CH=N-, X' and X" can be -CHO and NH 2 and anil formation will result in production of the final product.

Claim 6

When Z is -CH=N-, X' and X" can be -CHO and NH 2 and anil formation will result in production of the final product.

Claim 7

When Z is an amide or ester linkage, i.e., -COZ-, X' and X", of course, are COOH, and OH or NH on either formula II or formula III, by classical ester or amide formation methods.

Claim 8

When Z is an amide or ester linkage, i.e., -COZ-, X' and X", of course, are COOH, and OH or NH on either formula II or formula III, by classical ester or amide formation methods.

Claim 9

When Z is a carbonyl, i.e., C=O, X' and X" are H and an acylating group on either formula II or formula III by classical ketone formation reaction, e.g., by Friedl-Crafts reaction; or alternatively by oxidation of the compound in which Z is -CHOH-.

Claim 10

When Z is a carbonyl, i.e., C=O, X' and X" are H and an acylating group on either formula II or formula III by classical ketone formation reaction, e.g., by Friedl-Crafts reaction; or alternatively by oxidation of the compound in which Z is -CHOH-.

Claim 11

When Z includes -hR 4 - by classical methods of forming diphenyl amines which include reaction between the compound (either of formula II or III) in which X' or X" is -NR 4 H- with the compound (formula II or III) in which X' or X" is halogen.

Claim 12

When Z includes -hR 4 - by classical methods of forming diphenyl amines which include reaction between the compound (either of formula II or III) in which X' or X" is -NR 4 H- with the compound (formula II or III) in which X' or X" is halogen.

Claim 13

Alternatively, substituent-Z-(R)n' can be added to compounds of formula IV using classical acylation or alkylation condensation reactions, for example, an acylating derivative of an acid with a Friedl-Crafts catalyst to provide compounds in which from which compounds in which R is other than O can be prepared by known reactions, e.g., reduction of the carbonyl oxygen to -OH using lithium aluminum hydride and similar reducing agents. Substituents on Ar l can be present in the starting intermediates in the foregoing synthetic routes or alternatively can be added by suitable substitution reactions using the starting compounds of formula I herein in which Ar 1 is substituted with hydrogen. The described reactions are performed using classical organic reactions known to those skilled in the art. Of course, reactive groups where present are preferably blocked by known methods to avoid competing or secondary reactions. The aforesaid reactions are carried out in an organic solvent for the reactive starting materials at temperatures ranging from room temperature up to the reflux temperature of the reaction mixture. In condensation reactions in which hydrogen halide is formed, a hydrogen halide acceptor, i.e., usually a basic compound such as an organic amine, is present to facilitate the reaction. In those reactions where a Friedl-Crafts catalyst is employed, aluminum chloride or zinc-chloride are generally useful. The final products are recovered from the reaction mixtures and subsequently purified by art-recognized procedures, e.g., column chromatographic techniques. The compounds of the invention containing basic nitrogen form salts with acids, both organic and inorganic acids. Of particular value are salts with pharmaceutically-acceptable acids especially in dosage forms predicated on aqueous systems where the enhanced water solubility of the salts is most advantageous. Salts formed with pharmceutically unacceptable acids are also useful in the isolation and purification of the basic nitrogen-containing present new compounds. Salts include those formed with hydrochloric, sulfuric, nitric, perchloric, benzenesulfonic, toluenesulfonic, phosphoric, acetic, malic, malonic, tartaric and similar such acids. The compounds of the invention also exist in stereoisomeric forms due to the presence of asymmetric centers in the molecule, especially in the group -Z(R) , and in the linkage -X- (where R 1 is other than H) or in other parts of the molecule. This invention contemplates the stereoisomers individually or in mixtures or as the racemic compound. The individual stereoisomers can be obtained by standard resolution procedures known to those skilled in the art or by stereospecific synthesis. The compounds of the present invention can be administered to the host in a variety of forms adapted to the chosen route of administration, i.e., orally, or parenterally. Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelially including transdermal, opthalmic, sublingual and buccal; topically including opthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic. .The active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions; syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg of active compound. The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the doage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations. The active compound may also be administered parenterally or intraperitoneally. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must.be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof. The therapeutic compounds of this invention may be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. The physician will determine the dosage of the present thereapeutic agents which will be most suitable for prophylaxis or treatment and it will vary with the form of administration and the particular compound chosen, and also, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages by small increments until the optimum effect under the circumstances is reached. The therapeutic dosage will generally be from 0.1 to 100µM/day or from about 0.1 mg to about 50 mg/kg of body weight per day and higher although it may be administered in several different dosage units. Higher dosages are.required for oral administration. The following examples are illustrative.

Claim 14

Alternatively, substituent-Z-(R)n' can be added to compounds of formula IV using classical acylation or alkylation condensation reactions, for example, an acylating derivative of an acid with a Friedl-Crafts catalyst to provide compounds in which from which compounds in which R is other than O can be prepared by known reactions, e.g., reduction of the carbonyl oxygen to -OH using lithium aluminum hydride and similar reducing agents. Substituents on Ar l can be present in the starting intermediates in the foregoing synthetic routes or alternatively can be added by suitable substitution reactions using the starting compounds of formula I herein in which Ar 1 is substituted with hydrogen. The described reactions are performed using classical organic reactions known to those skilled in the art. Of course, reactive groups where present are preferably blocked by known methods to avoid competing or secondary reactions. The aforesaid reactions are carried out in an organic solvent for the reactive starting materials at temperatures ranging from room temperature up to the reflux temperature of the reaction mixture. In condensation reactions in which hydrogen halide is formed, a hydrogen halide acceptor, i.e., usually a basic compound such as an organic amine, is present to facilitate the reaction. In those reactions where a Friedl-Crafts catalyst is employed, aluminum chloride or zinc-chloride are generally useful. The final products are recovered from the reaction mixtures and subsequently purified by art-recognized procedures, e.g., column chromatographic techniques. The compounds of the invention containing basic nitrogen form salts with acids, both organic and inorganic acids. Of particular value are salts with pharmaceutically-acceptable acids especially in dosage forms predicated on aqueous systems where the enhanced water solubility of the salts is most advantageous. Salts formed with pharmceutically unacceptable acids are also useful in the isolation and purification of the basic nitrogen-containing present new compounds. Salts include those formed with hydrochloric, sulfuric, nitric, perchloric, benzenesulfonic, toluenesulfonic, phosphoric, acetic, malic, malonic, tartaric and similar such acids. The compounds of the invention also exist in stereoisomeric forms due to the presence of asymmetric centers in the molecule, especially in the group -Z(R) , and in the linkage -X- (where R 1 is other than H) or in other parts of the molecule. This invention contemplates the stereoisomers individually or in mixtures or as the racemic compound. The individual stereoisomers can be obtained by standard resolution procedures known to those skilled in the art or by stereospecific synthesis. The compounds of the present invention can be administered to the host in a variety of forms adapted to the chosen route of administration, i.e., orally, or parenterally. Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelially including transdermal, opthalmic, sublingual and buccal; topically including opthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic. .The active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions; syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg of active compound. The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the doage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations. The active compound may also be administered parenterally or intraperitoneally. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must.be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof. The therapeutic compounds of this invention may be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. The physician will determine the dosage of the present thereapeutic agents which will be most suitable for prophylaxis or treatment and it will vary with the form of administration and the particular compound chosen, and also, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages by small increments until the optimum effect under the circumstances is reached. The therapeutic dosage will generally be from 0.1 to 100µM/day or from about 0.1 mg to about 50 mg/kg of body weight per day and higher although it may be administered in several different dosage units. Higher dosages are.required for oral administration. The following examples are illustrative.

Claim 15

EXAMPLE 1 2-[3-(1-Hydroxy-2-methylhexyl)phenoxymethyl]quinoline A. A solution of the ketone, 2-(3-hexanoylphenoxymethyl) - quinoline (prepared from 3-hexanoylphenol and 2-chloromethyl quinoline) (6 g, 0.018 mol) in dry THF (25 ml) was added slowly to a mildly refluxing suspension of sodium hydride (1.3 g, 0.054 mol) in dry THF (75 ml) containing excess methyl iodide (10.3 g, 0.073 mol). After the addition of the ketone was complete (30 min.), the reaction mixture was refluxed for 4 hours. After cooling the mixture to room temperature, excess NaH was destroyed by adding methanol. All volatiles were removed at the rotary evaporator and the residue was taken up in ethyl acetate. The organic extract was washed with water and brine, and dried over anhydrous magnesium sulfate. Upon removal of all solvent, the mono-methylated ketone (2-[3-(2-methylhexanoyl) phenoxymethyl]quinoline, was obtained as a yellow oil weighing 8 g.

Claim 16

EXAMPLE 1 2-[3-(1-Hydroxy-2-methylhexyl)phenoxymethyl]quinoline A. A solution of the ketone, 2-(3-hexanoylphenoxymethyl) - quinoline (prepared from 3-hexanoylphenol and 2-chloromethyl quinoline) (6 g, 0.018 mol) in dry THF (25 ml) was added slowly to a mildly refluxing suspension of sodium hydride (1.3 g, 0.054 mol) in dry THF (75 ml) containing excess methyl iodide (10.3 g, 0.073 mol). After the addition of the ketone was complete (30 min.), the reaction mixture was refluxed for 4 hours. After cooling the mixture to room temperature, excess NaH was destroyed by adding methanol. All volatiles were removed at the rotary evaporator and the residue was taken up in ethyl acetate. The organic extract was washed with water and brine, and dried over anhydrous magnesium sulfate. Upon removal of all solvent, the mono-methylated ketone (2-[3-(2-methylhexanoyl) phenoxymethyl]quinoline, was obtained as a yellow oil weighing 8 g.

Claim 17

B. This ketone (8 g) was next reduced with sodium borohydride (1.4 g, 0.036 mol) in ethanol (100 ml) at room temperature for about 15 hours. A little water and methanol was added to the reaction mixture, and then most of the volatiles were removed at the rotary evaporator. The residue was thoroughly extracted with ethyl acetate, and the organics were washed with water, brine, and then dried over anhydrous MgSO 4 . All solvent was removed to leave a yellow oil (6 g) which was chromatographed on silica gel using 20% ethyl acetate in hexane as eluent. The desired mono methylated alcohol was obtained as a yellowish solid (1.5 g), mp. 64-67°C.

Claim 18

B. This ketone (8 g) was next reduced with sodium borohydride (1.4 g, 0.036 mol) in ethanol (100 ml) at room temperature for about 15 hours. A little water and methanol was added to the reaction mixture, and then most of the volatiles were removed at the rotary evaporator. The residue was thoroughly extracted with ethyl acetate, and the organics were washed with water, brine, and then dried over anhydrous MgSO 4 . All solvent was removed to leave a yellow oil (6 g) which was chromatographed on silica gel using 20% ethyl acetate in hexane as eluent. The desired mono methylated alcohol was obtained as a yellowish solid (1.5 g), mp. 64-67°C.

Claim 19

EXAMPLE 2 2-[3-(1-Hydroxy-2,2-dimethylhexyl)phenoxymethyl]quinoline A. The ketone 2-(3-(2,2-dimethylhexanoyl)phenoxymethyl)quinoline (4 g) was treated with sodium borohydride (0.9 g) in ethanol (70 ml) at room temperature for about 15 hours. The solution was cooled in an ice bath, and excess of borohydride was destroyed by adding cold, dil HC1 solution dropwise. After all the reducing agent was destroyed, the pH of the solution was adjusted to about 5-6, and then most of the volatiles were removed. The residue was taken up in ethyl acetate, and the organics were washed with water, brine and dried over MgSO 4 . The crude alcohol was isolated by removing all solvents. The pure alcohol (1.6 g, 114-116°C.,), was isolated by chromatography on silica gel using 20% ethyl acetate in hexane as eluent.

Claim 20

EXAMPLE 2 2-[3-(1-Hydroxy-2,2-dimethylhexyl)phenoxymethyl]quinoline A. The ketone 2-(3-(2,2-dimethylhexanoyl)phenoxymethyl)quinoline (4 g) was treated with sodium borohydride (0.9 g) in ethanol (70 ml) at room temperature for about 15 hours. The solution was cooled in an ice bath, and excess of borohydride was destroyed by adding cold, dil HC1 solution dropwise. After all the reducing agent was destroyed, the pH of the solution was adjusted to about 5-6, and then most of the volatiles were removed. The residue was taken up in ethyl acetate, and the organics were washed with water, brine and dried over MgSO 4 . The crude alcohol was isolated by removing all solvents. The pure alcohol (1.6 g, 114-116°C.,), was isolated by chromatography on silica gel using 20% ethyl acetate in hexane as eluent.

Claim 21

B. Preparation of 2-(3-(2,2-dinethylhexanoyl)phenoxy- methvl quinoline (starting compound for A. procedure) : A mixture of 2-chloromethylquinoline (12.1 g), 3-(2,2-dimethylhexanoyl)phenol (15 g), finely powdered anhydrous potassium carbonate (20 g) and potassium iodide (0.05 g) in dry acetone (300 ml) was refluxed overnight. The suspension was filtered, and most of the volatiles were removed at the rotary evaporator. The residue was taken up in ethyl acetate, washed with 5% NaOH solution,water, brine,and the extract was dried. On removal of all solvent, the crude ether was obtained as a yellow oil. This oil was purified on HPLC (Prep. 500, Waters) using 10% ethyl acetate in hexane as eluent. The pure material was isolated in about 48% yield (12 g) as a light yellow oil.

Claim 22

B. Preparation of 2-(3-(2,2-dinethylhexanoyl)phenoxy- methvl quinoline (starting compound for A. procedure) : A mixture of 2-chloromethylquinoline (12.1 g), 3-(2,2-dimethylhexanoyl)phenol (15 g), finely powdered anhydrous potassium carbonate (20 g) and potassium iodide (0.05 g) in dry acetone (300 ml) was refluxed overnight. The suspension was filtered, and most of the volatiles were removed at the rotary evaporator. The residue was taken up in ethyl acetate, washed with 5% NaOH solution,water, brine,and the extract was dried. On removal of all solvent, the crude ether was obtained as a yellow oil. This oil was purified on HPLC (Prep. 500, Waters) using 10% ethyl acetate in hexane as eluent. The pure material was isolated in about 48% yield (12 g) as a light yellow oil.

Claim 23

C . Synthesis of 3-(2,2-dimethyl hexanoyl)phenol

Claim 24

C . Synthesis of 3-(2,2-dimethyl hexanoyl)phenol

Claim 25

The benzyl ether of the desired phenol (26 g) was taken in methanol (l50 ml) and this solution was hydrogenated in a Parr apparatus under an atmosphere of hydrogen (45-50 lbs./sq.in.) in the presence of 10% palladium on charcoal (10 g ). After 20-24 hours, the suspension was filtered on celite all methanol was removed to obtain the desired phenol in about 83% yield (15.4 g) as a coloress liquid.

Claim 26

The benzyl ether of the desired phenol (26 g) was taken in methanol (l50 ml) and this solution was hydrogenated in a Parr apparatus under an atmosphere of hydrogen (45-50 lbs./sq.in.) in the presence of 10% palladium on charcoal (10 g ). After 20-24 hours, the suspension was filtered on celite all methanol was removed to obtain the desired phenol in about 83% yield (15.4 g) as a coloress liquid.

Claim 27

The benzyl ether starting compound was prepared by oxidation of 3-(1-hydroxyhexyl)phenyl benzyl ether to the corresponding ketone followed by alkylation with methyl iodide to form the 2,2-dimethyl compound. In similar manner, using appropriate starting materials and reagents, the following compounds and the corresponding ketones are prepared:

Claim 28

The benzyl ether starting compound was prepared by oxidation of 3-(1-hydroxyhexyl)phenyl benzyl ether to the corresponding ketone followed by alkylation with methyl iodide to form the 2,2-dimethyl compound. In similar manner, using appropriate starting materials and reagents, the following compounds and the corresponding ketones are prepared:

Claim 29

2-[3-(1-hydroxy-2-isobutylhexyl)phenoxymethyl]benzofuran; 2-(3-(1-hydroxy-2,2-diethylpentyl)phenoxymethyl]thiophene; and 2-[3-(1-hydroxy-2-methylhexyl)phenoxymethyl]benzothiophene.

Claim 30

2-[3-(1-hydroxy-2-isobutylhexyl)phenoxymethyl]benzofuran; 2-(3-(1-hydroxy-2,2-diethylpentyl)phenoxymethyl]thiophene; and 2-[3-(1-hydroxy-2-methylhexyl)phenoxymethyl]benzothiophene.

Claim 31

EXAMPLE 3 2-[3-(1-Hydroxyhoxyl)phenoxy]methyl]pyridine hydrochloride

Claim 32

EXAMPLE 3 2-[3-(1-Hydroxyhoxyl)phenoxy]methyl]pyridine hydrochloride

Claim 33

A suspension of 3.3 g of picolyl chloride hydrochloride (Aldrich 16,270-1), 1-(3-hydroxyphenyl)-1-hexanol (3.9 g), cesium carbonate (16.3 g), cesium iodide (trace) and acetonewere refluxed for 40 hours.

Claim 34

A suspension of 3.3 g of picolyl chloride hydrochloride (Aldrich 16,270-1), 1-(3-hydroxyphenyl)-1-hexanol (3.9 g), cesium carbonate (16.3 g), cesium iodide (trace) and acetonewere refluxed for 40 hours.

Claim 35

The reaction was filtered through a pad of celite and silica gel and the solvent removed in vacuo. The remaining oil was dissolved in ethyl ether, filtered through celite and silica gel and treated with ethereal hydrochloric acid. The resulting white precipitate was filtered, washed (ethyl ether) and dried giving 4.2 g (66% yield) of solid, m.p. 164-165°C.

Claim 36

The reaction was filtered through a pad of celite and silica gel and the solvent removed in vacuo. The remaining oil was dissolved in ethyl ether, filtered through celite and silica gel and treated with ethereal hydrochloric acid. The resulting white precipitate was filtered, washed (ethyl ether) and dried giving 4.2 g (66% yield) of solid, m.p. 164-165°C.

Claim 37

In like manner as above using appropriate starting materials and reagents, the following compounds were prepared:

Claim 38

In like manner as above using appropriate starting materials and reagents, the following compounds were prepared:

Claim 39

3-[[3-(1-Hydroxyhexyl)phenoxy]methyl]pyridine hydrochloride, m.p. 162-163°C;

Claim 40

3-[[3-(1-Hydroxyhexyl)phenoxy]methyl]pyridine hydrochloride, m.p. 162-163°C;

Claim 41

2-[[3-(l-Hydroxyhexyl)phenoxy]methyl]quinoline hydrochloride, m.p. 90-95°C; and

Claim 42

2-[[3-(l-Hydroxyhexyl)phenoxy]methyl]quinoline hydrochloride, m.p. 90-95°C; and

Claim 43

4-[[3-(1-Hydroxyhexyl)phenoxy]methyl]pyridine hydrochloride, m.p. 160-160.5°C.

Claim 44

4-[[3-(1-Hydroxyhexyl)phenoxy]methyl]pyridine hydrochloride, m.p. 160-160.5°C.

Claim 45

EXAMPLE 4

Claim 46

EXAMPLE 4

Claim 47

Methyl 6-[[3-(1-hydroxyhoxyl) phenoxy]methyl]picolinate

Claim 48

Methyl 6-[[3-(1-hydroxyhoxyl) phenoxy]methyl]picolinate

Claim 49

A solution of 6-[[3-(1-hydroxyhexyl)phenoxy]-methyl]picolinyl nitrile (1.1 g), methanol (50 ml) and cesium carbonate was stirred at room temperature overnight. The reaction mixture was diluted with 0.1N hydrochloric acid. After stirring for three hours, the methanol was removed in vacuo and the remaining suspension was extracted with chloroform. The organic extract was dried (MgSO 4 ) and concentrated to an oil (7.6 g, 94% yield).

Claim 50

A solution of 6-[[3-(1-hydroxyhexyl)phenoxy]-methyl]picolinyl nitrile (1.1 g), methanol (50 ml) and cesium carbonate was stirred at room temperature overnight. The reaction mixture was diluted with 0.1N hydrochloric acid. After stirring for three hours, the methanol was removed in vacuo and the remaining suspension was extracted with chloroform. The organic extract was dried (MgSO 4 ) and concentrated to an oil (7.6 g, 94% yield).

Claim 51

In like manner as above, using appropriate starting materials and reagents, the following compounds were prepared:

Claim 52

In like manner as above, using appropriate starting materials and reagents, the following compounds were prepared:

Claim 53

Ethyl 2-(3-(2-quinolinylmethoxy)phenoxy)propionic acid; Ethyl 2-(3-(2-quinolinylmethoxy)phenyl)propionic acid.

Claim 54

Ethyl 2-(3-(2-quinolinylmethoxy)phenoxy)propionic acid; Ethyl 2-(3-(2-quinolinylmethoxy)phenyl)propionic acid.

Claim 55

EXAMPLE 5

Claim 56

EXAMPLE 5

Claim 57

2-(3-(2-(2-Hydroxy)heptyl)phenoxymethyl)quinoline hvdrochloridc

Claim 58

2-(3-(2-(2-Hydroxy)heptyl)phenoxymethyl)quinoline hvdrochloridc

Claim 59

A mixture of 2-chloromethyl quinoline hydrochloride (3.1 g) and 2-(3-hydroxyphenyl)-2-heptanol (3 g) in acetone (300 ml) containing potassium carbonate (20 g) and potassium iodide (0.2 g) was refluxed overnight. The reaction mixture was cooled, and most of the volatiles were removed at the rotary evaporator.

Claim 60

A mixture of 2-chloromethyl quinoline hydrochloride (3.1 g) and 2-(3-hydroxyphenyl)-2-heptanol (3 g) in acetone (300 ml) containing potassium carbonate (20 g) and potassium iodide (0.2 g) was refluxed overnight. The reaction mixture was cooled, and most of the volatiles were removed at the rotary evaporator.

Claim 61

The residue was taken up in ethyl acetate, and was washed with sodium hydroxide solution (5%) and brine. The organic layer was dried over magnesium sulfate and all solvent was removed to leave the crude product (weighing about 6 g), which was purified by chromatography (silica gel; 20% ethyl acetate in hexanes). The free base, isolated as an oil, was dissolved in dry ether, and treated with hydrogen chloride gas to give the pure desired salt as a white solid, m.p. 125°C. (dec.).

Claim 62

The residue was taken up in ethyl acetate, and was washed with sodium hydroxide solution (5%) and brine. The organic layer was dried over magnesium sulfate and all solvent was removed to leave the crude product (weighing about 6 g), which was purified by chromatography (silica gel; 20% ethyl acetate in hexanes). The free base, isolated as an oil, was dissolved in dry ether, and treated with hydrogen chloride gas to give the pure desired salt as a white solid, m.p. 125°C. (dec.).

Claim 63

In like manner as described above, using appropriate starting materials and reagents, 2-(3-(2-(2-hydroxy)heptyl)phenoxymethyl)pyridine hydrochloride, m.p. 160-165°C., was prepared.

Claim 64

In like manner as described above, using appropriate starting materials and reagents, 2-(3-(2-(2-hydroxy)heptyl)phenoxymethyl)pyridine hydrochloride, m.p. 160-165°C., was prepared.

Claim 65

EXAMPLE 6

Claim 66

EXAMPLE 6

Claim 67

2-13-(l-Hexenvl)phenoxymethyllquinoline

Claim 68

2-13-(l-Hexenvl)phenoxymethyllquinoline

Claim 69

Sodium ethoxide was prepared by dissolving sodium metal (0.9 g) in absolute ethanol (50 ml). 3-Hydroxy-benzaldehyde (5 g) in alcohol (50 ml) was added to sodium ethoxide and the mixture was refluxed for one hour. The reaction mixture was cooled, and a solution of 2-chloromethyl quinoline (7.3 g) in alcohol (50 ml) was added. The mixture was refluxed for one dav.

Claim 70

Sodium ethoxide was prepared by dissolving sodium metal (0.9 g) in absolute ethanol (50 ml). 3-Hydroxy-benzaldehyde (5 g) in alcohol (50 ml) was added to sodium ethoxide and the mixture was refluxed for one hour. The reaction mixture was cooled, and a solution of 2-chloromethyl quinoline (7.3 g) in alcohol (50 ml) was added. The mixture was refluxed for one dav.

Claim 71

All volatiles were removed, and the residue was taken up in ethyl acetate. The organic extract was washed with aqueous sodium hydroxide (5%) solution, water and brine. After drying, all solvent was removed. The residual oil was chromatographed on silica gel using 15% ethyl acetate in hexane as eluent and the pure aldehyde was isolated.

Claim 72

All volatiles were removed, and the residue was taken up in ethyl acetate. The organic extract was washed with aqueous sodium hydroxide (5%) solution, water and brine. After drying, all solvent was removed. The residual oil was chromatographed on silica gel using 15% ethyl acetate in hexane as eluent and the pure aldehyde was isolated.

Claim 73

N-pentyl-triphenylphosphonium bromide (3.1 g), prepared by refluxing a toluene solution of 1-bromo- pentane and triphenylphosphine, and filtering the white phosphonium salt, was dissolved in tetrahydrofuran (100 ml.) The solution was cooled to 0°C., and n-butyl lithium (7.6 mmol; 2.3 M solution in hexane) was added. The mixture was stirred at room temperature for one hour, then cooled again to 0°C., and a solution of the above aldehyde (2 g) in tetrahydrofuran (35 ml) was added. The reaction mixture was stirred at room temperature overnight. Most tetrahydrofuran was removed, and the residue was taken up in ethyl acetate. The organic layer was washed with water, brine, and dried over magnesium sulfate. All solvents were removed, and the crude product was purified on silica gel using 15% ethyl acetate in hexane as eluent. The desired compound was isolated as a light yellow liquid (0.8 g).

Claim 74

N-pentyl-triphenylphosphonium bromide (3.1 g), prepared by refluxing a toluene solution of 1-bromo- pentane and triphenylphosphine, and filtering the white phosphonium salt, was dissolved in tetrahydrofuran (100 ml.) The solution was cooled to 0°C., and n-butyl lithium (7.6 mmol; 2.3 M solution in hexane) was added. The mixture was stirred at room temperature for one hour, then cooled again to 0°C., and a solution of the above aldehyde (2 g) in tetrahydrofuran (35 ml) was added. The reaction mixture was stirred at room temperature overnight. Most tetrahydrofuran was removed, and the residue was taken up in ethyl acetate. The organic layer was washed with water, brine, and dried over magnesium sulfate. All solvents were removed, and the crude product was purified on silica gel using 15% ethyl acetate in hexane as eluent. The desired compound was isolated as a light yellow liquid (0.8 g).

Claim 75

EXAMPLE 7

Claim 76

EXAMPLE 7

Claim 77

2-[3-(1-Hydroxyethyl)phenoxymethyl]quinoline

Claim 78

2-[3-(1-Hydroxyethyl)phenoxymethyl]quinoline

Claim 79

A mixture of 3-(1-hydroxyethyl)phenol (7 g), 2-chloromethylquinoline (9 g), potassium carbonate (7 g) and potassium iodide (0.3 g) in acetone (75 ml) was refluxed overnight. The reaction mixture was poured into water, and then thoroughly extracted with ethyl acetate (3 x 30 ml). The organic extract was washed with NaOH solution (1 N), water, brine, and then dried over MgSO 4 . All volatiles were removed to obtain a dark brown liquid, which was chromatographed on silica gel (12% ethyl acetate in hexanes) to leave the desired product as a light yellow liquid.

Claim 80

A mixture of 3-(1-hydroxyethyl)phenol (7 g), 2-chloromethylquinoline (9 g), potassium carbonate (7 g) and potassium iodide (0.3 g) in acetone (75 ml) was refluxed overnight. The reaction mixture was poured into water, and then thoroughly extracted with ethyl acetate (3 x 30 ml). The organic extract was washed with NaOH solution (1 N), water, brine, and then dried over MgSO 4 . All volatiles were removed to obtain a dark brown liquid, which was chromatographed on silica gel (12% ethyl acetate in hexanes) to leave the desired product as a light yellow liquid.

Claim 81

EXAMPLE 8

Claim 82

EXAMPLE 8

Claim 83

2-[3-(1-N-methylaminohexyl)phenoxymethyl]quinoline

Claim 84

2-[3-(1-N-methylaminohexyl)phenoxymethyl]quinoline

Claim 85

A solution of 2-[3-(hexanoyl)phenoxymethyl]-quinoline (2.8 g), 40% aqueous methylamine (1.5 ml) and methanol adjusted to pH 6 with 5% aqueous hydrochloric acid is treated with a methanolic solution of sodium cyanoborohydride. The reaction is stirred overnight. The methanol is removed in vacuo and the remaining mixture is extracted with methylene chloride. The organic extract is dried (MgS0 4 ) and concentrated to an oil.

Claim 86

A solution of 2-[3-(hexanoyl)phenoxymethyl]-quinoline (2.8 g), 40% aqueous methylamine (1.5 ml) and methanol adjusted to pH 6 with 5% aqueous hydrochloric acid is treated with a methanolic solution of sodium cyanoborohydride. The reaction is stirred overnight. The methanol is removed in vacuo and the remaining mixture is extracted with methylene chloride. The organic extract is dried (MgS0 4 ) and concentrated to an oil.

Claim 87

In like manner as above, using appropriate starting materials, the following compounds can be prepared:

Claim 88

In like manner as above, using appropriate starting materials, the following compounds can be prepared:

Claim 89

2-[3-(1-n-butylaminohexyl)phenoxymethyl]quinoline; and 2-[3-(l-N,N-dimethylaminonexyl)phenoxymethyl]pyridine.

Claim 90

2-[3-(1-n-butylaminohexyl)phenoxymethyl]quinoline; and 2-[3-(l-N,N-dimethylaminonexyl)phenoxymethyl]pyridine.

Claim 91

EXAMPLE 9

Claim 92

EXAMPLE 9

Claim 93

2-[3-(2-hydroxy-2-heotyl)phenoxymethyl]quinoline

Claim 94

2-[3-(2-hydroxy-2-heotyl)phenoxymethyl]quinoline

Claim 95

To an ethereal solution of 2-(3-hexanoyl- phenoxymethyl)quinoline (3.2 g) (prepared by oxidation of the corresponding alcohol'with pyridinium chlorochromate in CH Cl ) is added slowly an excess of a 3M solution of methylmagnesium bromide (2.5 g; 7.0 ml) in ether and the mixture stirred overnight. A saturated solution of ammonium chloride is added dropwise to the well-stirred reaction mixture until the solution became clear, and a gray-white solid coagulated to form a hard cake. The liquid was filtered, and the residue was washed with more ether. The ether layer was separated from the aqueous layer, washed with brine, and dried over. magnesium sulfate. All volatiles were removed to give an oil, which was purified by chromatography on silica gel (6% ethyl acetate in hexane) to get the desired tertiary alcohol as a clear, colorless liquid.

Claim 96

To an ethereal solution of 2-(3-hexanoyl- phenoxymethyl)quinoline (3.2 g) (prepared by oxidation of the corresponding alcohol'with pyridinium chlorochromate in CH Cl ) is added slowly an excess of a 3M solution of methylmagnesium bromide (2.5 g; 7.0 ml) in ether and the mixture stirred overnight. A saturated solution of ammonium chloride is added dropwise to the well-stirred reaction mixture until the solution became clear, and a gray-white solid coagulated to form a hard cake. The liquid was filtered, and the residue was washed with more ether. The ether layer was separated from the aqueous layer, washed with brine, and dried over. magnesium sulfate. All volatiles were removed to give an oil, which was purified by chromatography on silica gel (6% ethyl acetate in hexane) to get the desired tertiary alcohol as a clear, colorless liquid.

Claim 97

In the same manner, using appropriate starting materials and reagents, the following compounds are prepared:

Claim 98

In the same manner, using appropriate starting materials and reagents, the following compounds are prepared:

Claim 99

2-[3-(2-hydroxy-2-heptyl)phenoxymethyl]pyridine; and 2-[3-(1-hydroxy-2,2-dimethylbutyl)phenoxymethyl]quinoline.

Claim 100

2-[3-(2-hydroxy-2-heptyl)phenoxymethyl]pyridine; and 2-[3-(1-hydroxy-2,2-dimethylbutyl)phenoxymethyl]quinoline.

Claim 101

EXAMPLE 10

Claim 102

EXAMPLE 10

Claim 103

3-(3-(1-Hydroxyhexyl) phenoxymethyl)quinoline

Claim 104

3-(3-(1-Hydroxyhexyl) phenoxymethyl)quinoline

Claim 105

To a solution of 3-chloromethylquinoline (10 g, 0.056 mol; prepared from 3-hydroxymethylquinoline and thionyl chloride) and 3-(l-hydroxyhexyl)phenol (12 g, 0.062 mol) in DXSO (200 ml) was added a 2N solution of sodium hydroxide (31 ml, 0.062 mol). The solution became warm (40-45°C.). This was allowed to stir at room temperature for 5 hours. The dark reaction mixture was poured into water, and the aqueous solution was thoroughly extracted (4 x 50 ml) with ethyl acetate. The organic extract was washed with IN NaOH solution, water and then brine. After drying over anhydrous magnesium sulfate, all volatiles were removed. The dark residual liquid on trituration with ether-petroleum ether (1:2) yielded a beige colored solid, which on recrystallization from hexane-ethyl acetate gave the desried material (12.9 g, 69%) as an off-white solid.

Claim 106

To a solution of 3-chloromethylquinoline (10 g, 0.056 mol; prepared from 3-hydroxymethylquinoline and thionyl chloride) and 3-(l-hydroxyhexyl)phenol (12 g, 0.062 mol) in DXSO (200 ml) was added a 2N solution of sodium hydroxide (31 ml, 0.062 mol). The solution became warm (40-45°C.). This was allowed to stir at room temperature for 5 hours. The dark reaction mixture was poured into water, and the aqueous solution was thoroughly extracted (4 x 50 ml) with ethyl acetate. The organic extract was washed with IN NaOH solution, water and then brine. After drying over anhydrous magnesium sulfate, all volatiles were removed. The dark residual liquid on trituration with ether-petroleum ether (1:2) yielded a beige colored solid, which on recrystallization from hexane-ethyl acetate gave the desried material (12.9 g, 69%) as an off-white solid.

Claim 107

In a similar manner, starting from 6-chloromethylquinoline and 3-(l-hydroxyhexyl)phenol, the other isomeric compound,6-(3-(l-hydroxyhexyl)phenoxymethyl) quinoline, can be prepared.

Claim 108

In a similar manner, starting from 6-chloromethylquinoline and 3-(l-hydroxyhexyl)phenol, the other isomeric compound,6-(3-(l-hydroxyhexyl)phenoxymethyl) quinoline, can be prepared.

Claim 109

EXAMPLE 11

Claim 110

EXAMPLE 11

Claim 111

2-(3-(2-Quinolinylmethoxy)phenoxy)propionic acid (hvdro- chloride salt)

Claim 112

2-(3-(2-Quinolinylmethoxy)phenoxy)propionic acid (hvdro- chloride salt)

Claim 113

Ethyl 2-(3-(2-quinolinylmethoxy)phenoxy)propionate (3.6 g; m.p. 58-60° C .) was taken up in 10% hydrochloric acid solution (180 ml), and the mixture was heated at 100°C, for 26 hours. On cooling the reaction mixture in an ice bath, the desired carboxylic acid crystallized as a hydrochloride salt (3.6 g), which was recrystallized from ethanol to give the desired acid, as its hydrochloride salt, as colorless crystals, (2.2 g; m.p. 184-185°C.).

Claim 114

Ethyl 2-(3-(2-quinolinylmethoxy)phenoxy)propionate (3.6 g; m.p. 58-60° C .) was taken up in 10% hydrochloric acid solution (180 ml), and the mixture was heated at 100°C, for 26 hours. On cooling the reaction mixture in an ice bath, the desired carboxylic acid crystallized as a hydrochloride salt (3.6 g), which was recrystallized from ethanol to give the desired acid, as its hydrochloride salt, as colorless crystals, (2.2 g; m.p. 184-185°C.).

Claim 115

In a similar manner, starting from ethyl 2-(3-(2-quinolinylmethoxy)phenoxy propionate (2.5 g) and hydrochloric acid (90 ml, 4N), 2-(3-(2-quinolinylmethoxy)-phenoxypropionic acid (hydrochloride salt; 1.3 g;

Claim 116

In a similar manner, starting from ethyl 2-(3-(2-quinolinylmethoxy)phenoxy propionate (2.5 g) and hydrochloric acid (90 ml, 4N), 2-(3-(2-quinolinylmethoxy)-phenoxypropionic acid (hydrochloride salt; 1.3 g;

Claim 117

m.p. 136-138°C.) can be prepared.

Claim 118

m.p. 136-138°C.) can be prepared.

Claim 119

EXAMPLE 12

Claim 120

EXAMPLE 12

Claim 121

2-(3-(1-Hydroxyhexyl)benzyloxymethyl)quinoline

Claim 122

2-(3-(1-Hydroxyhexyl)benzyloxymethyl)quinoline

Claim 123

A mixture of 2-hydroxymethylquinoline (8 g, 0 05 mol) and 3-(1-hydroxyhexyl)benzyl p-toluenesulfonate (18.2 g, 0.05 mol; in methylene chloride (200 ml) containing triethylamine (15 ml) was stirred at 0°C. for 4 hours, and then allowed to warm up to room temperature. This mixture was stirred for two more hours at this tmperature, and then poured into water. The organic layer was separated and washed with dilute sodium hydroxide solution, water and brine. After drying the organics, all volatiles were removed to obtain the crude product as a yellowish brown liquid. This was purified by chromatography on silica gel using 15% ethyl acetate in hexanes to get the pure product as a clear, light yellow liquid (9 g, 52% yield).

Claim 124

A mixture of 2-hydroxymethylquinoline (8 g, 0 05 mol) and 3-(1-hydroxyhexyl)benzyl p-toluenesulfonate (18.2 g, 0.05 mol; in methylene chloride (200 ml) containing triethylamine (15 ml) was stirred at 0°C. for 4 hours, and then allowed to warm up to room temperature. This mixture was stirred for two more hours at this tmperature, and then poured into water. The organic layer was separated and washed with dilute sodium hydroxide solution, water and brine. After drying the organics, all volatiles were removed to obtain the crude product as a yellowish brown liquid. This was purified by chromatography on silica gel using 15% ethyl acetate in hexanes to get the pure product as a clear, light yellow liquid (9 g, 52% yield).

Claim 125

EXAMPLE 13

Claim 126

EXAMPLE 13

Claim 127

3-(2-Quinolinylmethoxy)phenylacetic acid

Claim 128

3-(2-Quinolinylmethoxy)phenylacetic acid

Claim 129

A mixture of 2-chloromethyl quinoline (2.3g, 13.3 mmol), 3-hydroxyphenyl acetate (2.2g, 13.3 mmol), excess powdered potassium carbonate (lOg) and a catalytic amount of potassium iodide (0.1g) in dry acetone (150 ml) was refluxed overnight (18 hr.). The reaction mixture was filtered, and the filtrate was concentrated, taken up in ethyl acetate, and the organic extract was washed with a 5% NaOH solution and brine. After drying over NgSO 4 , all volatiles were removed from the organic extract, and the crude oil was chromatographed on silica gel (20% ethylacetate in hexanes) to obtain the methyl ester of the desired product (3.0g).

Claim 130

A mixture of 2-chloromethyl quinoline (2.3g, 13.3 mmol), 3-hydroxyphenyl acetate (2.2g, 13.3 mmol), excess powdered potassium carbonate (lOg) and a catalytic amount of potassium iodide (0.1g) in dry acetone (150 ml) was refluxed overnight (18 hr.). The reaction mixture was filtered, and the filtrate was concentrated, taken up in ethyl acetate, and the organic extract was washed with a 5% NaOH solution and brine. After drying over NgSO 4 , all volatiles were removed from the organic extract, and the crude oil was chromatographed on silica gel (20% ethylacetate in hexanes) to obtain the methyl ester of the desired product (3.0g).

Claim 131

The above ester (3.0g) was dissolved in 4N HC1 solution, and this was refluxed for 4 hours. On cooling in an ice bath, the product crystallized out as the hydrochloride salt. This salt was purified further by recrystallization twice from ethanol. The desired product was obtained as the hydrochloride salt, as slightly pink crystals (2.5g), and slowly decomposes with nelting above 180 0 C.

Claim 132

The above ester (3.0g) was dissolved in 4N HC1 solution, and this was refluxed for 4 hours. On cooling in an ice bath, the product crystallized out as the hydrochloride salt. This salt was purified further by recrystallization twice from ethanol. The desired product was obtained as the hydrochloride salt, as slightly pink crystals (2.5g), and slowly decomposes with nelting above 180 0 C.

Claim 133

EXAMPLE 14

Claim 134

EXAMPLE 14

Claim 135

2-(3-(6-Phenoxy-l,2,2-trimethyl-l-hydroxyhexyl)phenoxymethyl) quinoline

Claim 136

2-(3-(6-Phenoxy-l,2,2-trimethyl-l-hydroxyhexyl)phenoxymethyl) quinoline

Claim 137

To a solution of the ketone, 2-(3-(6-phenoxy-2,2-dimethyl hexanoyl)phenoxymethyl) quinoline (3.6g) in dry ether (100 ml) at 0°C, was added dropwise, an ethereal solution of methyl magnesiumbromide (7.7 ml, 23.8 mmol, 3 eqv.) under an atmosphere of nitrogen. The clear orange solution was stirred overnight at room temperature. To this solution, a saturated ammonium chloride solution was added when the magnesium salts precipitated. The ether layer was separated, washed with water and brine, and then dried over MgSO 4 . All volatiles were removed to obtain the crude product (4.2g). This was purified by chromatography on silica gel (25% ethyl acetate in hexanes, 20% ethyl acetate in hexanes and finally 10% ethyl acetate in hexanes) to obtain the pure product as a yellow liquid (0.9g).

Claim 138

To a solution of the ketone, 2-(3-(6-phenoxy-2,2-dimethyl hexanoyl)phenoxymethyl) quinoline (3.6g) in dry ether (100 ml) at 0°C, was added dropwise, an ethereal solution of methyl magnesiumbromide (7.7 ml, 23.8 mmol, 3 eqv.) under an atmosphere of nitrogen. The clear orange solution was stirred overnight at room temperature. To this solution, a saturated ammonium chloride solution was added when the magnesium salts precipitated. The ether layer was separated, washed with water and brine, and then dried over MgSO 4 . All volatiles were removed to obtain the crude product (4.2g). This was purified by chromatography on silica gel (25% ethyl acetate in hexanes, 20% ethyl acetate in hexanes and finally 10% ethyl acetate in hexanes) to obtain the pure product as a yellow liquid (0.9g).

Claim 139

EXAMPLE 15

Claim 140

EXAMPLE 15

Claim 141

2-(3-Hexyl p henox y )meth y l quinoline

Claim 142

2-(3-Hexyl p henox y )meth y l quinoline

Claim 143

A solution of 99% pure 2-(3-(l-hexenylphenoxy) methyl) quinoline (1.5g) in ethanol (20 ml) containing 10% Pd-C catalyst (0.5g) was exposed to an atmosphere of hydrogen at 10 psig for one hour. The catalyst was filtered through a bed of celite, and all ethanol was removed to obtain the pure desired saturated compound (l.lg) as a yellow liquid.

Claim 144

A solution of 99% pure 2-(3-(l-hexenylphenoxy) methyl) quinoline (1.5g) in ethanol (20 ml) containing 10% Pd-C catalyst (0.5g) was exposed to an atmosphere of hydrogen at 10 psig for one hour. The catalyst was filtered through a bed of celite, and all ethanol was removed to obtain the pure desired saturated compound (l.lg) as a yellow liquid.

Claim 145

EXAMPLE 16

Claim 146

EXAMPLE 16

Claim 147

1-(3-(2-Quinolinylmethoxy)phenyl)-3-methyl-1,3-butane diol

Claim 148

1-(3-(2-Quinolinylmethoxy)phenyl)-3-methyl-1,3-butane diol

Claim 149

A mixture of 2-chloromethyl quinoline hydrochloride (10g, 47 mmol), 3-hydroxybenzaldehyde (6.3g, 52 mmol), powdered potassium carbonate (14.5g, 105 mmol), catalytic amounts of cesium carbonate (1.5g) and sodium iodide (0.7g) in dry acetone (150 ml) was refluxed for 14 hours. The solid residue was filtered off, and the filtrate was concentrated and dissolved in ethyl acetate. The organic solution was washed successively with 10% NaOH solution, water and brine and then dried over MgSO 4 . All volatiles were removed to leave a yellowish solid weighing 14.8g. This was recrystallized from hexanes-ethanol mixture to obtain 4-(3-(2-quinolinylmethoxy)phenyl-4-hydroxy-2-butanone as off-white crystals (11.8g), mp 116-9°C.

Claim 150

A mixture of 2-chloromethyl quinoline hydrochloride (10g, 47 mmol), 3-hydroxybenzaldehyde (6.3g, 52 mmol), powdered potassium carbonate (14.5g, 105 mmol), catalytic amounts of cesium carbonate (1.5g) and sodium iodide (0.7g) in dry acetone (150 ml) was refluxed for 14 hours. The solid residue was filtered off, and the filtrate was concentrated and dissolved in ethyl acetate. The organic solution was washed successively with 10% NaOH solution, water and brine and then dried over MgSO 4 . All volatiles were removed to leave a yellowish solid weighing 14.8g. This was recrystallized from hexanes-ethanol mixture to obtain 4-(3-(2-quinolinylmethoxy)phenyl-4-hydroxy-2-butanone as off-white crystals (11.8g), mp 116-9°C.

Claim 151

To a solution of the above hydroxy-ketone (2.5g) in dry THF (150 ml) was added dropwise, an ethereal solution of methyl magnesium bromide (17.1 mmol, 2.2 eqv.). The reaction mixture was stirred overnight, and then a saturated ammonium chloride solution was added. The precipitated magnesium salts were filtered, and the filtrate was concentrated in vacuo. The desired material was isolated after purification by chromatography on silica gel using 40% ethyl acetate in hexanes, as asyellowish crystalline solid, mp l17-124°C (1.2g).

Claim 152

To a solution of the above hydroxy-ketone (2.5g) in dry THF (150 ml) was added dropwise, an ethereal solution of methyl magnesium bromide (17.1 mmol, 2.2 eqv.). The reaction mixture was stirred overnight, and then a saturated ammonium chloride solution was added. The precipitated magnesium salts were filtered, and the filtrate was concentrated in vacuo. The desired material was isolated after purification by chromatography on silica gel using 40% ethyl acetate in hexanes, as asyellowish crystalline solid, mp l17-124°C (1.2g).

Claim 153

EXAMPLE 17

Claim 154

EXAMPLE 17

Claim 155

2-(3-(6,6,6-Trifluorohexanoyl)phenoxymethyl) quinoline

Claim 156

2-(3-(6,6,6-Trifluorohexanoyl)phenoxymethyl) quinoline

Claim 157

A mixture of 3-(5,5,5-trifluorohexanoyl)phenol (6.8g, 27 mmol) and 2-chloromethylquinoline (4.4g, 25 mmol) in DMSO (75 ml) containing 2N NaOH solution (14 ml) was stirred at room temperature overnight (13 hrs.). The dark reaction mixture was poured into water (200 ml) and the aqueous solution was extracted with ethyl acetate (4 x 30 ml). The organic extract was washed with 1N NaOH solution, water and brine and then dried over MgS0 4 . After removal of all volatiles, a dark liquid was obtained which solidified on standing (7.2g). This solid was chromatographed (3% ethanol in toluene on silica gel) to obtain a beige color solid (4.5g; mp 83-4°C), which was chromatographed again (15% acetone in hexanes on silica gel) to get a white solid (3.1g; mp 86-87°C). This pure material was recrystallized from hexanes-acetone (trace) to leave the desired compound as a colorless, crystalline solid (2.4g), mp 88-88.5°C (first crop; second crop mp 87-88°C).

Claim 158

A mixture of 3-(5,5,5-trifluorohexanoyl)phenol (6.8g, 27 mmol) and 2-chloromethylquinoline (4.4g, 25 mmol) in DMSO (75 ml) containing 2N NaOH solution (14 ml) was stirred at room temperature overnight (13 hrs.). The dark reaction mixture was poured into water (200 ml) and the aqueous solution was extracted with ethyl acetate (4 x 30 ml). The organic extract was washed with 1N NaOH solution, water and brine and then dried over MgS0 4 . After removal of all volatiles, a dark liquid was obtained which solidified on standing (7.2g). This solid was chromatographed (3% ethanol in toluene on silica gel) to obtain a beige color solid (4.5g; mp 83-4°C), which was chromatographed again (15% acetone in hexanes on silica gel) to get a white solid (3.1g; mp 86-87°C). This pure material was recrystallized from hexanes-acetone (trace) to leave the desired compound as a colorless, crystalline solid (2.4g), mp 88-88.5°C (first crop; second crop mp 87-88°C).

Claim 159

EXAMPLE 18

Claim 160

EXAMPLE 18

Claim 161

2-(3-(5,5,5-Trifluoropentanoyl) p henoxvmethyl) quinoline

Claim 162

2-(3-(5,5,5-Trifluoropentanoyl) p henoxvmethyl) quinoline

Claim 163

This material was synthesized by refluxing a mixture of 2-chloromethyl quinoline (2.6g, 14.5 mmol), 3-(5,5,5-trifluoropentanoyl)phenol (3.7g, 15.9 mmol), powdered potassium carbonate (6.0g, 43.5 mmol) and a catalytic amount of potassium iodide (0.1g) in dry acetone (50 ml) for 14 hours. After this period, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in ether, and the ethereal solution was washed with brine, dried over MgS0 4 , and then concentrated in vacuo. The pure desired ketone was isolated by chromatography on silica gel using 20% ethyl acetate in hexanes as eluent. The product was obtained in 62% yield (3.4g), had a melting point 80-82°C and was a yellowish solid.

Claim 164

This material was synthesized by refluxing a mixture of 2-chloromethyl quinoline (2.6g, 14.5 mmol), 3-(5,5,5-trifluoropentanoyl)phenol (3.7g, 15.9 mmol), powdered potassium carbonate (6.0g, 43.5 mmol) and a catalytic amount of potassium iodide (0.1g) in dry acetone (50 ml) for 14 hours. After this period, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in ether, and the ethereal solution was washed with brine, dried over MgS0 4 , and then concentrated in vacuo. The pure desired ketone was isolated by chromatography on silica gel using 20% ethyl acetate in hexanes as eluent. The product was obtained in 62% yield (3.4g), had a melting point 80-82°C and was a yellowish solid.

Claim 165

EXAMPLE 19

Claim 166

EXAMPLE 19

Claim 167

2-(3-(6-Benzyloxy-1-hydroxyhexyl)phenoxymethyl) quinoline

Claim 168

2-(3-(6-Benzyloxy-1-hydroxyhexyl)phenoxymethyl) quinoline

Claim 169

2-Chloromethyl quinoline (3.6g) was refluxed with 3-(6-benzyloxy-l-hydroxyhexyl)phenol (4.2g), powdered potassium carbonate (8g) and potassium iodide (0.2g) in dry acetone (150 ml) overnight (16 hrs.). The suspension was filtered, the filtrat was concentrated in vacuo and then taken up in ethyl acetate. This solution was washed with 5% NaOH solution, water and brine and then dried.

Claim 170

2-Chloromethyl quinoline (3.6g) was refluxed with 3-(6-benzyloxy-l-hydroxyhexyl)phenol (4.2g), powdered potassium carbonate (8g) and potassium iodide (0.2g) in dry acetone (150 ml) overnight (16 hrs.). The suspension was filtered, the filtrat was concentrated in vacuo and then taken up in ethyl acetate. This solution was washed with 5% NaOH solution, water and brine and then dried.

Claim 171

All solvent was removed to obtain the crude product which was purified by chromatography (silica gel; 30% ethyl acetate in hexanes). The pure compound was dissolved in ether, and was precipitated as the hydrochloride salt with dry ethereal solution of HC1. The pure salt was filtered, washed with cold water, and dried in vacuo to yield a tan powder (1.5g), mp 86-89°C.

Claim 172

All solvent was removed to obtain the crude product which was purified by chromatography (silica gel; 30% ethyl acetate in hexanes). The pure compound was dissolved in ether, and was precipitated as the hydrochloride salt with dry ethereal solution of HC1. The pure salt was filtered, washed with cold water, and dried in vacuo to yield a tan powder (1.5g), mp 86-89°C.

Claim 173

EXAMPLE 20

Claim 174

EXAMPLE 20

Claim 175

Methvl 3-(3-(2-quinolinylmethoxy)benzoyl)propanoate

Claim 176

Methvl 3-(3-(2-quinolinylmethoxy)benzoyl)propanoate

Claim 177

A mixture of pure methyl 4-(3-(2-quinolinyl- methoxy) phenyl-4-hydroxy butyrate (l.lg) and activated manganese dioxide (6.2g) in methylene chloride (25 ml) was stirred at room temperature. After 20 hours, no starting material was detected by thin layer chromatography. The manganese dioxide was filtered through celite, and the methylene chloride solution was concentrated in vacuo.

Claim 178

A mixture of pure methyl 4-(3-(2-quinolinyl- methoxy) phenyl-4-hydroxy butyrate (l.lg) and activated manganese dioxide (6.2g) in methylene chloride (25 ml) was stirred at room temperature. After 20 hours, no starting material was detected by thin layer chromatography. The manganese dioxide was filtered through celite, and the methylene chloride solution was concentrated in vacuo.

Claim 179

The residue was purified by chromatography on silica gel using 15% ethyl acetate in hexanes containing 1% acetic acid.as eluent. The desired keto-ester was obtained (0.22g) as an off-white solid, mp 80-81°C.

Claim 180

The residue was purified by chromatography on silica gel using 15% ethyl acetate in hexanes containing 1% acetic acid.as eluent. The desired keto-ester was obtained (0.22g) as an off-white solid, mp 80-81°C.

Claim 181

EXAMPLE 21

Claim 182

EXAMPLE 21

Claim 183

Synthesis of 5-phenoxvnentvl bromide

Claim 184

Synthesis of 5-phenoxvnentvl bromide

Claim 185

To a well-stirred suspension of sodium hydride (15.3g, 0.32 mol; 50% oil dispersion) in dry DMF (500 ml) containing (25g, 0.26 mol), was added dropwise 1,5-dibromopentane (122.2g, 0.53 mol). After the addition was complete, the reaction mixture was stirred at 60-70°C for 4 hours. Most of the DMF was next removed under reduced pressure, and the residue was dissolved in ethyl acetate (250 ml). The organic extract was washed successively with a 5% sodium hydroxide solution, water and brine. After drying the organics over anhydrous magnesium sulfate, all volatiles were removed. The residual yellow liquid was then distilled under reduced pressure, and the pure product was collected at 118-125°C/1 mm as a clear colorless liquid (26g, 40% yield).

Claim 186

To a well-stirred suspension of sodium hydride (15.3g, 0.32 mol; 50% oil dispersion) in dry DMF (500 ml) containing (25g, 0.26 mol), was added dropwise 1,5-dibromopentane (122.2g, 0.53 mol). After the addition was complete, the reaction mixture was stirred at 60-70°C for 4 hours. Most of the DMF was next removed under reduced pressure, and the residue was dissolved in ethyl acetate (250 ml). The organic extract was washed successively with a 5% sodium hydroxide solution, water and brine. After drying the organics over anhydrous magnesium sulfate, all volatiles were removed. The residual yellow liquid was then distilled under reduced pressure, and the pure product was collected at 118-125°C/1 mm as a clear colorless liquid (26g, 40% yield).

Claim 187

Synthesis of 3-(6-phenoxy-1-hydroxyhexyl)phenol

Claim 188

Synthesis of 3-(6-phenoxy-1-hydroxyhexyl)phenol

Claim 189

To gently refluxing.dry tetrahydrofuran (70 ml) containing magnesium turnings (l.lg, 44 mmol) and a small crystal of iodine, was added dropwise from a dropping funnel a solution of 5-phenoxypentyl bromide (11.0g, 45 mmol) in dry THF (50 ml). After about 5-7 minutes, the Grignard reaction started as indicated by the disappearance of the brown iodine color. The heating was adjusted so that the solution refluxed gently. After the addition of the halide was complete (ca. 30 min.), the clear solution was refluxed for about 1 hour. This solution of the Grignard reagent was cooled to room temperature.

Claim 190

To gently refluxing.dry tetrahydrofuran (70 ml) containing magnesium turnings (l.lg, 44 mmol) and a small crystal of iodine, was added dropwise from a dropping funnel a solution of 5-phenoxypentyl bromide (11.0g, 45 mmol) in dry THF (50 ml). After about 5-7 minutes, the Grignard reaction started as indicated by the disappearance of the brown iodine color. The heating was adjusted so that the solution refluxed gently. After the addition of the halide was complete (ca. 30 min.), the clear solution was refluxed for about 1 hour. This solution of the Grignard reagent was cooled to room temperature.

Claim 191

A solution of 3-hydroxybenzaldehyde (5.0, 41 mmol) in dry THF (50 ml) was added dropwise to a well-stirred suspension of sodium hydride (2.5g, 52 mmol; 50% oil dispersion) in dry THF (50 ml) at room temperature. The temperature was not allowed to go above ca. 40°C. After the addition of 3-hydroxybenzaldehyde was complete (ca. 30 min.) the slightly cloudy solution was warmed to 45-50°C and stirred for 1 hour at this temperature. The resulting clear solution of sodium 3-formyl phenoxide was cooled to room temperature and added dropwise using a cannula, to the well-stirred solution of the Grignard reagent (whose preparation was described above). A thick precipitate immediately formed. This mixture was maintained at 40-45°C during the addition of the sodium salt. After the addition was complete (ca. 2 hours), the reaction mixture was stirred at this temperature for another hour, and then cooled in an ice bath. The excess reactive materials (sodium hydride, Grignard reagent, etc.) were destroyed slowly by carefully adding methanol (30 ml), and then a saturated ammonium chloride solution (350 ml) was added to dissolve all solids. The organic layer was separated, and the aqueous layer was extracted with ether (2 x 75 ml). The combined organics were washed with water, brine, and then dried over anhydrous magnesium sulfate. After drying the extract, all volatiles were removed to obtain a dark liquid. This oil was titurated with a 1:1 mixture of ether and petroleum ether (35-55°C) when an off-white solid was obtained tl2g). This can be crystallized from methanol-ethyl acetate to give a white solid, mp 148-9°C.

Claim 192

A solution of 3-hydroxybenzaldehyde (5.0, 41 mmol) in dry THF (50 ml) was added dropwise to a well-stirred suspension of sodium hydride (2.5g, 52 mmol; 50% oil dispersion) in dry THF (50 ml) at room temperature. The temperature was not allowed to go above ca. 40°C. After the addition of 3-hydroxybenzaldehyde was complete (ca. 30 min.) the slightly cloudy solution was warmed to 45-50°C and stirred for 1 hour at this temperature. The resulting clear solution of sodium 3-formyl phenoxide was cooled to room temperature and added dropwise using a cannula, to the well-stirred solution of the Grignard reagent (whose preparation was described above). A thick precipitate immediately formed. This mixture was maintained at 40-45°C during the addition of the sodium salt. After the addition was complete (ca. 2 hours), the reaction mixture was stirred at this temperature for another hour, and then cooled in an ice bath. The excess reactive materials (sodium hydride, Grignard reagent, etc.) were destroyed slowly by carefully adding methanol (30 ml), and then a saturated ammonium chloride solution (350 ml) was added to dissolve all solids. The organic layer was separated, and the aqueous layer was extracted with ether (2 x 75 ml). The combined organics were washed with water, brine, and then dried over anhydrous magnesium sulfate. After drying the extract, all volatiles were removed to obtain a dark liquid. This oil was titurated with a 1:1 mixture of ether and petroleum ether (35-55°C) when an off-white solid was obtained tl2g). This can be crystallized from methanol-ethyl acetate to give a white solid, mp 148-9°C.

Claim 193

Synthesis of 2-[3-(6-phenoxy-1-hydroxyhexyl)phenoxymethyl) quinoline

Claim 194

Synthesis of 2-[3-(6-phenoxy-1-hydroxyhexyl)phenoxymethyl) quinoline

Claim 195

A mixture of 2-chloromethyl quinoline (l.lg; 6.3 mmol), 3-(6-phenoxy-l-hydroxyhexyl)phenol (1.8g, 6.3 mmol) and finely powdered anhydrous potassium carbonate (1.74g, 12.6 mmol) in acetone (40 ml) containing catalytic amounts of finely powdered, anhydrous cesium carbonate (0.4, 1.3 mmol) and sodium iodide (0.05g, 0.33 mmol) was refluxed overnight (15 hours). The reaction mixture was cooled to the room temperature and filtered. The solid residue was washed thoroughly with acetone (3 x 15 ml), and all the filtrates were combined. All volatiles were removed from the combined acetone filtrate to leave a light yellow viscous liquid which solidifed to an off-white solid on tituration with a 1:1 mixture of ether and petroleum ether (35-55°C). This solid was chromatographed on silica gel with 35% ethylacetate in hexanes to yield the desired product (1.6g, 60%) as a white crystalline solid, mp 83-84.5°C.

Claim 196

A mixture of 2-chloromethyl quinoline (l.lg; 6.3 mmol), 3-(6-phenoxy-l-hydroxyhexyl)phenol (1.8g, 6.3 mmol) and finely powdered anhydrous potassium carbonate (1.74g, 12.6 mmol) in acetone (40 ml) containing catalytic amounts of finely powdered, anhydrous cesium carbonate (0.4, 1.3 mmol) and sodium iodide (0.05g, 0.33 mmol) was refluxed overnight (15 hours). The reaction mixture was cooled to the room temperature and filtered. The solid residue was washed thoroughly with acetone (3 x 15 ml), and all the filtrates were combined. All volatiles were removed from the combined acetone filtrate to leave a light yellow viscous liquid which solidifed to an off-white solid on tituration with a 1:1 mixture of ether and petroleum ether (35-55°C). This solid was chromatographed on silica gel with 35% ethylacetate in hexanes to yield the desired product (1.6g, 60%) as a white crystalline solid, mp 83-84.5°C.

Claim 197

EXAMPLE 22

Claim 198

EXAMPLE 22

Claim 199

2-[3-(1-Hydroxyhexyl)phenoxymethyl]-1,2,3,4-tetrahydro- naphthalane

Claim 200

2-[3-(1-Hydroxyhexyl)phenoxymethyl]-1,2,3,4-tetrahydro- naphthalane

Claim 201

A mixture of 4.0 g (0.018 mol) 2-(iodomethyl)-1,2,3,4-tetrahydronaphthalene, 3.4 a (0.018 mol) 3-(1-hydroxyhexyl)phenol and 3.4 ml NaOH (5K) in 50 ml DMSO and 20 ml THF was stirred at room temperature for a period of 48 hours. The reaction mixture was concentrated under reduced pressure. The concentrated reaction mixture was poured into water and extracted with ether. The ether extract was washed with water, dried over MgS0 4 and concentrated to dryness under reduced pressure. The residue was passed through a silica gel column using hexane/ethyl acetate (3:1) as eluent. Evaporation of eluent gave an oily product (1.3 g).

Claim 202

A mixture of 4.0 g (0.018 mol) 2-(iodomethyl)-1,2,3,4-tetrahydronaphthalene, 3.4 a (0.018 mol) 3-(1-hydroxyhexyl)phenol and 3.4 ml NaOH (5K) in 50 ml DMSO and 20 ml THF was stirred at room temperature for a period of 48 hours. The reaction mixture was concentrated under reduced pressure. The concentrated reaction mixture was poured into water and extracted with ether. The ether extract was washed with water, dried over MgS0 4 and concentrated to dryness under reduced pressure. The residue was passed through a silica gel column using hexane/ethyl acetate (3:1) as eluent. Evaporation of eluent gave an oily product (1.3 g).

Claim 203

The product was evaluated for 5-lipoxygenase pathway inhibition (5-LOX/I 50 µM) and a value of 6.0 µM obtained.

Claim 204

The product was evaluated for 5-lipoxygenase pathway inhibition (5-LOX/I 50 µM) and a value of 6.0 µM obtained.

Claim 205

LXAMPLE 23

Claim 206

LXAMPLE 23

Claim 207

2-(3-(1-Hydroxyhexyl)phenoxymethyl)naphthalene

Claim 208

2-(3-(1-Hydroxyhexyl)phenoxymethyl)naphthalene

Claim 209

A suspension of 2-bromomethyl naphthalene (5 g, 0.023 mol), 3-(1-hydroxyhexyl)phenol (5 g, 0.026 mol), powdered potassium carbonate (4.5 g, 0.033 mol), sodium iodide (0.4 g, 0.0023 mol) and cesium carbonate (0.7 g, 0.0021 mol) in dry acetone (75 ml) was refluxed overnight (14 hours). The reaction mixture was filtered, the filtrate was concentrated, dissolved in ether, and then washed successively with IN NaOH solution 6N HC1 solution, water and brine. After drying the organics over anhydrous MgS0 4 , all volatiles were removed. The crude product (5 g) was further purified by chromatography, using 8% ethylacetate in hexanes on silica gel, to yield 3.5 g of the pure desired compound as a colcrless liquid.

Claim 210

A suspension of 2-bromomethyl naphthalene (5 g, 0.023 mol), 3-(1-hydroxyhexyl)phenol (5 g, 0.026 mol), powdered potassium carbonate (4.5 g, 0.033 mol), sodium iodide (0.4 g, 0.0023 mol) and cesium carbonate (0.7 g, 0.0021 mol) in dry acetone (75 ml) was refluxed overnight (14 hours). The reaction mixture was filtered, the filtrate was concentrated, dissolved in ether, and then washed successively with IN NaOH solution 6N HC1 solution, water and brine. After drying the organics over anhydrous MgS0 4 , all volatiles were removed. The crude product (5 g) was further purified by chromatography, using 8% ethylacetate in hexanes on silica gel, to yield 3.5 g of the pure desired compound as a colcrless liquid.

Claim 211

The compound was evaluated for 5-lipoxygenase pathway inhibition (5-LOX/I 50 µM) and a value of 5.0 µM obtained.

Claim 212

The compound was evaluated for 5-lipoxygenase pathway inhibition (5-LOX/I 50 µM) and a value of 5.0 µM obtained.

Claim 213

EXAMPLE 2 4

Claim 214

EXAMPLE 2 4

Claim 215

2-(3-Hexanoylphenoxy)methyl naphthalene

Claim 216

2-(3-Hexanoylphenoxy)methyl naphthalene

Claim 217

A mixture containing 2-bromomethyl naphthalene (3.0 g, 13.5 mmol), 3-hexanoylphenol (2.6 g, 13.5 mmol), powdered potassium carbonate (19.0 g, l35 mmol) and potassium iodide (0.1 g) in dry acetone (100 ml) was refluxed for two days. Most of the solvent was removed after filtering off the solid residue. The oil was purified by chromatography on silica gel using a 5% ethylacetate in hexane solution as eluent to leave the desired product as a clear, colorless liquid (2.6 g).

Claim 218

A mixture containing 2-bromomethyl naphthalene (3.0 g, 13.5 mmol), 3-hexanoylphenol (2.6 g, 13.5 mmol), powdered potassium carbonate (19.0 g, l35 mmol) and potassium iodide (0.1 g) in dry acetone (100 ml) was refluxed for two days. Most of the solvent was removed after filtering off the solid residue. The oil was purified by chromatography on silica gel using a 5% ethylacetate in hexane solution as eluent to leave the desired product as a clear, colorless liquid (2.6 g).

Claim 219

When evaluated, the product showed some 5-lipoxygenase inhibition (5-LOX/I 50 µM).

Claim 220

When evaluated, the product showed some 5-lipoxygenase inhibition (5-LOX/I 50 µM).

Claim 221

The following protocol describes an assay to detect inhibitors of the lipoxygenase pathway. Such inhibitors are believed to be capable of modulating the biosynthesis of the leukotrienes, a property believed to be useful in treating asthma and inflammatory disease states.

Claim 222

The following protocol describes an assay to detect inhibitors of the lipoxygenase pathway. Such inhibitors are believed to be capable of modulating the biosynthesis of the leukotrienes, a property believed to be useful in treating asthma and inflammatory disease states.

Claim 223

Protocol for Detecting Inhibitors of the Lipoxygenase Pathway A suspension of rat neutrophils in buffer is incubated for 3 minutes at 30°C with [ l4 C]-arachidonic acid (AA) and Calcium lonophore A23187. Citric Acid (2M) is used to quench the reaction. Following the addition of a trace amount of ( 3 H )-5-HETE together with an excess of unlabeled 5-HETE to each tube, the mixture is extracted with chloroform/methanol. The organic layer is washed with dilute acid and an aliquot is transferred to glass tubes and dried. The residue is dissolved in a small volume of chloroform and an aliquot is spotted on silica gel TLC sheets, which are developed with an ethyl acetate/isoctane/water/acetic acid solvent system. The 5-HETE spots are visualized with iodine, cut out and placed in scintillation vials for counting. After adjusting for the extraction efficiency, the amount (pmole) of [ 14 C)-5-HETE in each of the tubes is quantitated. The net pmoles of 5-HETE are obtained by substracting the.pmoles of 5-HETE in the tubes containing buffer alone (blank) from the pmoles of 5-HETE in the tubes containing buffer and cells (control). The ability of the test compounds to modulate the activity of this enzyme is determined by a decrease or increase in the net amount of 5-HETE produced.

Claim 224

Protocol for Detecting Inhibitors of the Lipoxygenase Pathway A suspension of rat neutrophils in buffer is incubated for 3 minutes at 30°C with [ l4 C]-arachidonic acid (AA) and Calcium lonophore A23187. Citric Acid (2M) is used to quench the reaction. Following the addition of a trace amount of ( 3 H )-5-HETE together with an excess of unlabeled 5-HETE to each tube, the mixture is extracted with chloroform/methanol. The organic layer is washed with dilute acid and an aliquot is transferred to glass tubes and dried. The residue is dissolved in a small volume of chloroform and an aliquot is spotted on silica gel TLC sheets, which are developed with an ethyl acetate/isoctane/water/acetic acid solvent system. The 5-HETE spots are visualized with iodine, cut out and placed in scintillation vials for counting. After adjusting for the extraction efficiency, the amount (pmole) of [ 14 C)-5-HETE in each of the tubes is quantitated. The net pmoles of 5-HETE are obtained by substracting the.pmoles of 5-HETE in the tubes containing buffer alone (blank) from the pmoles of 5-HETE in the tubes containing buffer and cells (control). The ability of the test compounds to modulate the activity of this enzyme is determined by a decrease or increase in the net amount of 5-HETE produced.

Claim 225

Table I shows the concentration required for 50% inhibition of the 5-lipoxygenase pathway (5-LOX/I 50 µM) for representative compounds according to the present invention.

Claim 226

Table I shows the concentration required for 50% inhibition of the 5-lipoxygenase pathway (5-LOX/I 50 µM) for representative compounds according to the present invention.

Claim 227

Using the procedures of the foregoing examples, the following compounds are prepared: 2-[3-(1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(1-methyl-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(1,2-dihydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(2,2-dimethyl-1-hydroxyhexyl)phenoxymethyl]oyridine; 2-[3-(l,2,2-trimethyl-l-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(1-methyl-1-hydroxyhexyl)phenoxymethyl]pyridine; 2-[3-(6-[3-chlorophenoxy]-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(6-phenoxy-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(6-phenoxy-2,2-dimethyl-l-hydroxyhexyl)phenoxymethyl]-quinoline 2-[3-(6-[3-trifluoromethylphenoxy]-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(1-hydroxyhexyl)phenoxymethyl]benzofuran; 2-[5-(1-hydroxyhexyl)-2-furyloxy)methyl]pyridine; 4-[5-(l-hydroxyhexyl)-2-thienylmethoxy]quinoline; 2-[6-(1-hydroxyhexyl)-3-pyridyloxy]quinoline; 3-[3-(1-hydroxyhexyl)phenoxymethyl]pyridine; 2-[3-(1-hydroxyethyl)benzylthio]pyridine; and 2-[3-(6-[3-chlorophenoxy]-l-methyl-l-hydroxyhexyl)phenoxymethyl]quinoline; 2-(3-(l-hydroxy-2,2-dimethyl-5,5,5-trifluoropentyl)-phenoxymethyl)quinoline; 2-(3-(1,2,2,-trimethyl-5,5,5-trifluoro-1-hydroxypentyl)phenoxymethyl)quinoline; 2-(3-(2,2-dimethyl-6,6,6-trifluoro-l-hydroxyhexyl)-phenoxymethyl)quinoline; 2-(3-(l,2,2-trimethyl-6,6,6-trifluoro-l-hydroxyhexyl)-phenoxymethyl)quinoline; 2-(3-(2,2-dimethyl-6,6,6-trifluoro-1-hydroxyhexyl)-phenoxymethyl)pyridine; 3-(3-(2,2-dimethyl-6,6,6-trifluoro-1-hydroxyhexyl)-phenoxymethyl)pyridine; 4-(3-(2,2-dimethyl-6,6,6-trifluoro-l-hydroxyhexyl)-phenoxymethyl)quinoline; 2-(3-(6-methoxyhexyl)phenoxymethyl)quinoline; 2-(3-(4-methoxybutyl)phenoxymethyl)quinoline; 2-(4-(4-methoxybutyl)phenoxymethyl)quinoline; 2-(3-(6-phenoxyhexyl)phenoxymethyl)quinoline; 2-(3-(4-methoxybutyl)phenoxy)quinoline; 2-(3-(1,1,1-trimethylacetoxyhexyl)phenoxymethyl)-quinoline; 2-(3-(1-acetoxy-5,5,5-trifluoropentyl)-phenoxymethyl)-quinoline; 2-(3-(1,1,1-trimethylacetoxy-5,5,5-trifluoropentyl)-phenoxymethyl)quinoline; 2-(3-(1,1,1-trimethylacetoxy-6,6,6-trifluorohexyl)-phenoxymethyl)quinoline; 2-(3-(2,2-dimethyl-1,1,1-trimethylacetoxyhexyl)phenoxymethyl)quinoline; 2-(3-(2,2-dimethyl-6,6,6-trifluoro-1,1,1-trimethyl- acetoxyhexyl) phenoxymethyl)quinoline. 3-(3-(2-quinolinylmethoxy)benzoyl)propanoic acid; 5-(3-(2-quinolinylmethoxy)benzoyl)pentanoic acid; methyl 5-(3-(2-quinolinylmethoxy)benzoyl)pentanoate; methyl 4-(3-(2-quinolinylmethoxy)phenyl)-4-hydroxy butyrate; 4-(3-(2-quinolinylmethoxy)phenyl)-4-hydroxy butyric acid (and the corresponding lactone); methyl 6-(3-(2-quinolinylmethoxy)phenyl)-6-hydroxy hexanoate; 6-(3-(2-quinolinylmethoxy)phenyl)-6-hydroxy hexanoic acid (and the corresponding lactone); 5-(3-(2-quinolinylmethoxy)phenyl)-5-hydroxy pentanoic acid (and the corresponding lactone); methyl 5-(3-(2-quinolinylmethoxy)phenyl)-5-hydroxy pentanoate; methyl 4-(3-(2-quinolinylmethoxy)benzoyl)butyrate; 4-(3-(2-quinolinylmethoxy)benzoyl)butyric acid; 6-(3-(1-hydroxyhexyl)phenoxymethyl)-1,4-benzodioxan; 2-(3-(l-hydroxyhexyl)phenoxymethyl)-1,4-benzodioxan; 2-(3-(l-hydroxyhexyl)phenoxymethyl)quinoxaline 2-(3-(1-hydroxyhexyl)phenoxymethyl)-3-methyl quinoxaline; 7-(3-(1-hydroxyhexyl)phenoxymethyl)-5-methyl-1,8-naphthyridin-2-ol; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)quinoxaline; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)-1,5-naphthyridine; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)-l,6-naphthyridine; 2-(3-(l-hydroxyhexyl)phenoxymethyl)pyrido(2,3-b)pyrazine; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)pyrido(3,4-b) pyrazine; 2-(3-(1-hydroxyhexyl)phenoxymethyl)pyrido(3,4-d)pyrimidine; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)pyrido(4,3-d) pyrimidine; 3-(3-(1-hydroxyhexyl)phenoxymethyl)piperazine-2,5-dione; and 3-(3-(6-phenoxy-l-hydroxyhexyl)phenoxymethyl)-2,5-dimethoxy-3,6-dihydropyrazine. 1-(3-phenoxyphenyl)-1-hexanol; 3-(1-hydroxyhexyl)phenyl-3-trifluoromethylbenzyl ether; 2-(3-(l-hydroxyhexyl)phenoxy methyl naphthalene; 3-(3-hexanoylphenoxy) methyl benzamide; 3-(3-hexanoyl phenxoy) methyl benzonitrile; benzyl-3-(l-hydroxy-2-methyl hexyl)phenyl ether; 2-[2-(1-hydroxy hexyl)-5-pyridyloxy]benzene; 2-[2-(2-hydroxy hexyl)-3-pyranyloxy]benzene; 2-[2-(2-hydroxy heptyl)-4-thiopyranyloxy] benzene; 2-[2-(2-hydroxy heptyl)-5-quinolyloxy]benzene; 2-(3-(1-hydroxy-6,6,6-trifluorohexyl)phenoxymethyl)-1,4-naphthaquinone; l-(3-(l-hydroxy-l-methylhexyl)phenoxymethyl)-2-methoxy naphthalene; l-(3-(6-phenoxy-l-hydroxyhexyl)phenoxymethyl)-4-methoxy naphthalene; 2-(1-(3-(1-hydroxy-2,2-dimethylhexyl)phenoxy) ethyl)naphthalene; 9-(3-(1-hydroxyhexyl)phenoxymethyl)anthracene; 9-(3-(1-hydroxyhexyl)phenoxymethyl)phenanthrene; Methyl-3-[[3-(1-hydroxyhexyl)phenoxy]methyi]benzoate; Methyl-2-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate; Methyl-4-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate; Methyl-3-[[2-(1-hydroxyhexyl)phenoxy]methyl]benzoate; Methyl-3-[[3-(l-hydroxyhexyl)phenoxy]methyl]phenylacetate; 3-[[3-(1-Hydroxyhexyl)phenoxy]methyl]benzonitrile; Methyl-2-[4-[[3-1-hydroxyhexyl)phenoxy]methyl]phenoxy]acetate; Benzyl-3-[1-(hydroxy)hexyl]phenyl ether; Methyl-3-[[3-l-methyl-l-hexenyl)phenoxy]methyl benzoate; Methyl-3-[[4-(1-hexenyl)phenoxy]methyl benzoate; Phenyl-3-cyanobenzyl ether; 3-(1-Hydroxyhexyl)phenyl-3-trifluoromethylbenzyl ether; 2-(3-(1-Hydroxyhexyl)phenoxy methyl naphthalene; 2-[[3-(1-hydroxyhexyl]phenoxy]methyl]benzoic acid; 3-[[3-1-hydroxyhexyl)phenoxy]methyl]benzoic acid; 5-[[3-1-hydroxyhexyl)phenoxy]methyl]benzoic acid; 4-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoic acid; 3-[[3-(1-hydroxyhexyl)phenoxy]methyl]phenyl acetic acid; methyl-3-[[3-(1-acetoxyhexyl)phenoxy]methyl]benzoate; methyl-3-[[3-(1-methoxyhexyl)phenoxy]methyl]benzoate; methyl-3-[[3-[l-(tetrahydro-2H-pyran-2-yloxy)-hexyl]phenoxy] methyl]benzoate; methyl-2-[[3-[1-(tetrahydro-2H-pyran-2-yloxy)-pentyl] phenoxy]methyl]benzoate; 2-[3-(1-hydroxypentyl)phenoxy]methyl]benzenemethanol; 3-[[3-(1-hydroxyhexyl)phenoxy)methyl]benzaldehyde; phenyl-3-formylbenzyl ether; 3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzyl amine hydrochloride; 3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzamide; 3-[3-hexanoyl phenoxy]methyl benzamide; benzyl-3-(hexanoyl)phenyl ether; 3-[3-hexanoyl phenoxy]methyl benzonitrile; benzyl-3-[1-(N-methylamino)hexyl]phenyl ether; 3-chlorobenzyl-3-[l-(n-butylamino)hexyl]phenyl ether; 2-trifluoromethyl-3-[1-(N,N-dimethylamino)hexyl]-phenyl ether; benzyl-3-[l-hydroxy-2,2-(dimethyl)hexyl]phenyl ether; 2,4-dibromobenzyl-3-[1-(hydroxy)2-(isobutyl)hexyl] phenyl ether; 4-fluorobenzyl-3-[l-(hydroxy)2-(diethyl)heptyl]-phenyl ether; benzyl 3-(1-hydroxy-2-methyl hexyl) phenyl ether; 3-(l-hydroxyhexyl)benzyl alcohol; tolyl-3-(l-hydroxyhexyl)genzyl sulfonate; methyl-3-[[3-(l-hydroxyhexyl)anilinyl]methyl]benzoate; ethyl-2-[[3-(1-hydroxybutyl)anilinyl]methyl]benzoate; isopropyl-4-[[3-(1-hydroxybutyl)anilinyl]methyl]-benzoate; methyl-3-[[2-(1-hydroxyhexyl)anilinyl]methyl]benzoate; phenyl-3-[1-(hydroxyhexyl]benzyl thioether; 3-methoxyphenyl-3-[1-(hydroxy)hexyl]benzyl thioether; 4-nitrophenyl-3-[1-(hydroxy)hexyl]benzyl thioether; methyl-2-[[3-(1-hydroxyhexyl)thiophenoxy]methyl]-benzoate; methyl 3-[3-(l-hydroxyhexyl) phenyl)amino]carbonyl] benzoate; 2-(3-(1-hydroxy-6,6,6-trifluorohexyl)phenoxymethyl)-1,4-naphthaquinone; 1-(3-(1-hydroxy-1-nethylhexyl)phenoxymethyl)-2-methoxy naphthalene; 1-(3-(6-phenoxy-1-hydroxyhexyl)phenoxymethyl)-4-methoxy naphthalene 2-(1-(3-(1-hydroxy-2,2-dimethylhexyl)phenoxy)-ethyl) naphthalene; 9-(3-(l-hydroxyhexyl)phenoxymethyl)anthracene; 9-(3-(l-hydroxyhexyl)phenoxymethyl)phenanthrene; 3-(3-(l-hydroxyethyl)phenoxy)methyl benzoic acid; 3-(2-phenylethyl) hexanophenone; methyl 3-(3-(1-hydroxyethyl)phenoxy)methyl benzoate; 3-hexanoyl diphenyl acetylene; cis-3-(1-hydroxyhexyl) stilbene; 1-(3-(2-phenylethyl)phenyl-1-hexanol; 3-(l-hydroxyhexyl)diphenylacetylene; trans-3-(l'hydroxyhexyl) stilbene; trans-3-hexanoyl stilbene; methyl 3-[3-[l-hydroxy-2,2-dimethylhexyl]phenoxy]-methyl]benzoate; cis-3-hexanoyl stilbene; 2-(3-hexanoylphenoxy) methyl naphthalene; methyl 3-[3-(1-hydroxyhexyl) phenyl)amino]-carbonyl] benzoate; 3-(2- q uinolinylmethoxy)acetophenone; 2-(3-(1-hydroxy-5,5,5-trifluoropentyl)phenoxymethyl)-quinoline; 2-[3-(6-phenoxy-1-hydroxy-1-methylhexyl)phenoxymethyl]quinoline; 2-[3-(6-(3-chlorophenoxy)-l-hydroxy-l-methylhexyl)-phenoxymethyl]quinoline; 2-[3-(6-(3-trifluoromethylphenoxy)-l-hydroxy-l-methylhexyl)phenoxymethyl]quinoline; 3-[6-phenoxy-1-hydroxyhexyl]phenol; 3-[6-(3-trifluoromethylphenoxy)-1-hydroxyhexyl]phenol; 3-[6-(3-chlorophenoxy)-1-hydroxyhexyl]phenol; 2-[3-(6-(3-chlorophenoxy)-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(6-phenoxy)-3-l-hydroxyhexyl)phenoxymethyl]-quinoline; 2-[3-(6-(3-trifluoromethylphenoxy)-l-hydroxyhexyl)-phenoxymethyl]quinoline; 2-[3-(1-acetoxyhexyl)phenoxymethyl]quinoline; 2-[3-(1-methoxyhexyl)phenoxymethyl]quinoline; l-(2-thienyl)-2-(3-hexanoylphenyl)acetylene; 1-(2-thienyl)-2-[3-(1-hydroxyhexyl)phenyl]acetylene; 1-(2-quinolyl)-2-[3-(1-hydroxyhexyl)phenyl]acetylene; 1-(2-indolyl)-2-[3-(1-hydroxyhexyl)phenyl]acetylene; 1-(2-furyl)-2-[3-(1-hydroxyhexyl)phenyl]acetylene; 1-(2-thienyl)-2-[3-(1-hydroxyhexyl)phenyl]ethylene; 1-(2-quinolyl)-2-[3-(1-hydroxyhexyl)phenyl]ethylene; 1-(2-indolyl)-2-[3-(1-hydroxyhexyl)phenyl]ethylene; 1-(2-furyl)-2-[3-(1-hydroxyhexyl)phenyl]ethylene; 1-(2-thienyl)-2-(3-hexanoylphenyl)ethylene; N-[3-(1-hydroxyhexyl)phenyl)pyridine-2-carboxamide; 2-[3-(1-hydroxyhexylbenzylamino]pyridine; 2-[3-(1-hydroxybutyl)anilinylmethyl]thiophene; 4-[3-(1-hydroxybutyl)anilinylmethyl]quinoline; 2-[2-(l-hydroxyhexyl)anilinylmethyl]quinoline; 3-methoxyphenyl-3-[l-(hydroxy)hexyl]benzyl thioether; 4-nitrophenyl-3-[1-(hydroxy)hexyl]benzyl thioether; methyl-2-[[3-(l-hydroxyhexyl)thiophenoxy]methyl]-benzoate; 2-(3-hexanoylphenoxymethyl)quinoline; 2-[2-(l-hydroxyhexyl)-5-pyridyloxy]quinoline; 4-[2-(1-hydroxyhexyl)-5-thienylmethoxy]quinoline; 2-[5-(1-hydroxyhexyl)-2-furylmethoxy]pyridine; 2-[5-(1-hydroxyhexyl)-2-pyridyloxymethyl]indole: 2-[4-(1-hydroxyhexyl)phenoxymethyl]pyrrole;

Claim 228

Using the procedures of the foregoing examples, the following compounds are prepared: 2-[3-(1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(1-methyl-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(1,2-dihydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(2,2-dimethyl-1-hydroxyhexyl)phenoxymethyl]oyridine; 2-[3-(l,2,2-trimethyl-l-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(1-methyl-1-hydroxyhexyl)phenoxymethyl]pyridine; 2-[3-(6-[3-chlorophenoxy]-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(6-phenoxy-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(6-phenoxy-2,2-dimethyl-l-hydroxyhexyl)phenoxymethyl]-quinoline 2-[3-(6-[3-trifluoromethylphenoxy]-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(1-hydroxyhexyl)phenoxymethyl]benzofuran; 2-[5-(1-hydroxyhexyl)-2-furyloxy)methyl]pyridine; 4-[5-(l-hydroxyhexyl)-2-thienylmethoxy]quinoline; 2-[6-(1-hydroxyhexyl)-3-pyridyloxy]quinoline; 3-[3-(1-hydroxyhexyl)phenoxymethyl]pyridine; 2-[3-(1-hydroxyethyl)benzylthio]pyridine; and 2-[3-(6-[3-chlorophenoxy]-l-methyl-l-hydroxyhexyl)phenoxymethyl]quinoline; 2-(3-(l-hydroxy-2,2-dimethyl-5,5,5-trifluoropentyl)-phenoxymethyl)quinoline; 2-(3-(1,2,2,-trimethyl-5,5,5-trifluoro-1-hydroxypentyl)phenoxymethyl)quinoline; 2-(3-(2,2-dimethyl-6,6,6-trifluoro-l-hydroxyhexyl)-phenoxymethyl)quinoline; 2-(3-(l,2,2-trimethyl-6,6,6-trifluoro-l-hydroxyhexyl)-phenoxymethyl)quinoline; 2-(3-(2,2-dimethyl-6,6,6-trifluoro-1-hydroxyhexyl)-phenoxymethyl)pyridine; 3-(3-(2,2-dimethyl-6,6,6-trifluoro-1-hydroxyhexyl)-phenoxymethyl)pyridine; 4-(3-(2,2-dimethyl-6,6,6-trifluoro-l-hydroxyhexyl)-phenoxymethyl)quinoline; 2-(3-(6-methoxyhexyl)phenoxymethyl)quinoline; 2-(3-(4-methoxybutyl)phenoxymethyl)quinoline; 2-(4-(4-methoxybutyl)phenoxymethyl)quinoline; 2-(3-(6-phenoxyhexyl)phenoxymethyl)quinoline; 2-(3-(4-methoxybutyl)phenoxy)quinoline; 2-(3-(1,1,1-trimethylacetoxyhexyl)phenoxymethyl)-quinoline; 2-(3-(1-acetoxy-5,5,5-trifluoropentyl)-phenoxymethyl)-quinoline; 2-(3-(1,1,1-trimethylacetoxy-5,5,5-trifluoropentyl)-phenoxymethyl)quinoline; 2-(3-(1,1,1-trimethylacetoxy-6,6,6-trifluorohexyl)-phenoxymethyl)quinoline; 2-(3-(2,2-dimethyl-1,1,1-trimethylacetoxyhexyl)phenoxymethyl)quinoline; 2-(3-(2,2-dimethyl-6,6,6-trifluoro-1,1,1-trimethyl- acetoxyhexyl) phenoxymethyl)quinoline. 3-(3-(2-quinolinylmethoxy)benzoyl)propanoic acid; 5-(3-(2-quinolinylmethoxy)benzoyl)pentanoic acid; methyl 5-(3-(2-quinolinylmethoxy)benzoyl)pentanoate; methyl 4-(3-(2-quinolinylmethoxy)phenyl)-4-hydroxy butyrate; 4-(3-(2-quinolinylmethoxy)phenyl)-4-hydroxy butyric acid (and the corresponding lactone); methyl 6-(3-(2-quinolinylmethoxy)phenyl)-6-hydroxy hexanoate; 6-(3-(2-quinolinylmethoxy)phenyl)-6-hydroxy hexanoic acid (and the corresponding lactone); 5-(3-(2-quinolinylmethoxy)phenyl)-5-hydroxy pentanoic acid (and the corresponding lactone); methyl 5-(3-(2-quinolinylmethoxy)phenyl)-5-hydroxy pentanoate; methyl 4-(3-(2-quinolinylmethoxy)benzoyl)butyrate; 4-(3-(2-quinolinylmethoxy)benzoyl)butyric acid; 6-(3-(1-hydroxyhexyl)phenoxymethyl)-1,4-benzodioxan; 2-(3-(l-hydroxyhexyl)phenoxymethyl)-1,4-benzodioxan; 2-(3-(l-hydroxyhexyl)phenoxymethyl)quinoxaline 2-(3-(1-hydroxyhexyl)phenoxymethyl)-3-methyl quinoxaline; 7-(3-(1-hydroxyhexyl)phenoxymethyl)-5-methyl-1,8-naphthyridin-2-ol; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)quinoxaline; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)-1,5-naphthyridine; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)-l,6-naphthyridine; 2-(3-(l-hydroxyhexyl)phenoxymethyl)pyrido(2,3-b)pyrazine; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)pyrido(3,4-b) pyrazine; 2-(3-(1-hydroxyhexyl)phenoxymethyl)pyrido(3,4-d)pyrimidine; 2-(3-(l-hydroxy-6-phenoxyhexyl)phenoxymethyl)pyrido(4,3-d) pyrimidine; 3-(3-(1-hydroxyhexyl)phenoxymethyl)piperazine-2,5-dione; and 3-(3-(6-phenoxy-l-hydroxyhexyl)phenoxymethyl)-2,5-dimethoxy-3,6-dihydropyrazine. 1-(3-phenoxyphenyl)-1-hexanol; 3-(1-hydroxyhexyl)phenyl-3-trifluoromethylbenzyl ether; 2-(3-(l-hydroxyhexyl)phenoxy methyl naphthalene; 3-(3-hexanoylphenoxy) methyl benzamide; 3-(3-hexanoyl phenxoy) methyl benzonitrile; benzyl-3-(l-hydroxy-2-methyl hexyl)phenyl ether; 2-[2-(1-hydroxy hexyl)-5-pyridyloxy]benzene; 2-[2-(2-hydroxy hexyl)-3-pyranyloxy]benzene; 2-[2-(2-hydroxy heptyl)-4-thiopyranyloxy] benzene; 2-[2-(2-hydroxy heptyl)-5-quinolyloxy]benzene; 2-(3-(1-hydroxy-6,6,6-trifluorohexyl)phenoxymethyl)-1,4-naphthaquinone; l-(3-(l-hydroxy-l-methylhexyl)phenoxymethyl)-2-methoxy naphthalene; l-(3-(6-phenoxy-l-hydroxyhexyl)phenoxymethyl)-4-methoxy naphthalene; 2-(1-(3-(1-hydroxy-2,2-dimethylhexyl)phenoxy) ethyl)naphthalene; 9-(3-(1-hydroxyhexyl)phenoxymethyl)anthracene; 9-(3-(1-hydroxyhexyl)phenoxymethyl)phenanthrene; Methyl-3-[[3-(1-hydroxyhexyl)phenoxy]methyi]benzoate; Methyl-2-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate; Methyl-4-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate; Methyl-3-[[2-(1-hydroxyhexyl)phenoxy]methyl]benzoate; Methyl-3-[[3-(l-hydroxyhexyl)phenoxy]methyl]phenylacetate; 3-[[3-(1-Hydroxyhexyl)phenoxy]methyl]benzonitrile; Methyl-2-[4-[[3-1-hydroxyhexyl)phenoxy]methyl]phenoxy]acetate; Benzyl-3-[1-(hydroxy)hexyl]phenyl ether; Methyl-3-[[3-l-methyl-l-hexenyl)phenoxy]methyl benzoate; Methyl-3-[[4-(1-hexenyl)phenoxy]methyl benzoate; Phenyl-3-cyanobenzyl ether; 3-(1-Hydroxyhexyl)phenyl-3-trifluoromethylbenzyl ether; 2-(3-(1-Hydroxyhexyl)phenoxy methyl naphthalene; 2-[[3-(1-hydroxyhexyl]phenoxy]methyl]benzoic acid; 3-[[3-1-hydroxyhexyl)phenoxy]methyl]benzoic acid; 5-[[3-1-hydroxyhexyl)phenoxy]methyl]benzoic acid; 4-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoic acid; 3-[[3-(1-hydroxyhexyl)phenoxy]methyl]phenyl acetic acid; methyl-3-[[3-(1-acetoxyhexyl)phenoxy]methyl]benzoate; methyl-3-[[3-(1-methoxyhexyl)phenoxy]methyl]benzoate; methyl-3-[[3-[l-(tetrahydro-2H-pyran-2-yloxy)-hexyl]phenoxy] methyl]benzoate; methyl-2-[[3-[1-(tetrahydro-2H-pyran-2-yloxy)-pentyl] phenoxy]methyl]benzoate; 2-[3-(1-hydroxypentyl)phenoxy]methyl]benzenemethanol; 3-[[3-(1-hydroxyhexyl)phenoxy)methyl]benzaldehyde; phenyl-3-formylbenzyl ether; 3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzyl amine hydrochloride; 3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzamide; 3-[3-hexanoyl phenoxy]methyl benzamide; benzyl-3-(hexanoyl)phenyl ether; 3-[3-hexanoyl phenoxy]methyl benzonitrile; benzyl-3-[1-(N-methylamino)hexyl]phenyl ether; 3-chlorobenzyl-3-[l-(n-butylamino)hexyl]phenyl ether; 2-trifluoromethyl-3-[1-(N,N-dimethylamino)hexyl]-phenyl ether; benzyl-3-[l-hydroxy-2,2-(dimethyl)hexyl]phenyl ether; 2,4-dibromobenzyl-3-[1-(hydroxy)2-(isobutyl)hexyl] phenyl ether; 4-fluorobenzyl-3-[l-(hydroxy)2-(diethyl)heptyl]-phenyl ether; benzyl 3-(1-hydroxy-2-methyl hexyl) phenyl ether; 3-(l-hydroxyhexyl)benzyl alcohol; tolyl-3-(l-hydroxyhexyl)genzyl sulfonate; methyl-3-[[3-(l-hydroxyhexyl)anilinyl]methyl]benzoate; ethyl-2-[[3-(1-hydroxybutyl)anilinyl]methyl]benzoate; isopropyl-4-[[3-(1-hydroxybutyl)anilinyl]methyl]-benzoate; methyl-3-[[2-(1-hydroxyhexyl)anilinyl]methyl]benzoate; phenyl-3-[1-(hydroxyhexyl]benzyl thioether; 3-methoxyphenyl-3-[1-(hydroxy)hexyl]benzyl thioether; 4-nitrophenyl-3-[1-(hydroxy)hexyl]benzyl thioether; methyl-2-[[3-(1-hydroxyhexyl)thiophenoxy]methyl]-benzoate; methyl 3-[3-(l-hydroxyhexyl) phenyl)amino]carbonyl] benzoate; 2-(3-(1-hydroxy-6,6,6-trifluorohexyl)phenoxymethyl)-1,4-naphthaquinone; 1-(3-(1-hydroxy-1-nethylhexyl)phenoxymethyl)-2-methoxy naphthalene; 1-(3-(6-phenoxy-1-hydroxyhexyl)phenoxymethyl)-4-methoxy naphthalene 2-(1-(3-(1-hydroxy-2,2-dimethylhexyl)phenoxy)-ethyl) naphthalene; 9-(3-(l-hydroxyhexyl)phenoxymethyl)anthracene; 9-(3-(l-hydroxyhexyl)phenoxymethyl)phenanthrene; 3-(3-(l-hydroxyethyl)phenoxy)methyl benzoic acid; 3-(2-phenylethyl) hexanophenone; methyl 3-(3-(1-hydroxyethyl)phenoxy)methyl benzoate; 3-hexanoyl diphenyl acetylene; cis-3-(1-hydroxyhexyl) stilbene; 1-(3-(2-phenylethyl)phenyl-1-hexanol; 3-(l-hydroxyhexyl)diphenylacetylene; trans-3-(l'hydroxyhexyl) stilbene; trans-3-hexanoyl stilbene; methyl 3-[3-[l-hydroxy-2,2-dimethylhexyl]phenoxy]-methyl]benzoate; cis-3-hexanoyl stilbene; 2-(3-hexanoylphenoxy) methyl naphthalene; methyl 3-[3-(1-hydroxyhexyl) phenyl)amino]-carbonyl] benzoate; 3-(2- q uinolinylmethoxy)acetophenone; 2-(3-(1-hydroxy-5,5,5-trifluoropentyl)phenoxymethyl)-quinoline; 2-[3-(6-phenoxy-1-hydroxy-1-methylhexyl)phenoxymethyl]quinoline; 2-[3-(6-(3-chlorophenoxy)-l-hydroxy-l-methylhexyl)-phenoxymethyl]quinoline; 2-[3-(6-(3-trifluoromethylphenoxy)-l-hydroxy-l-methylhexyl)phenoxymethyl]quinoline; 3-[6-phenoxy-1-hydroxyhexyl]phenol; 3-[6-(3-trifluoromethylphenoxy)-1-hydroxyhexyl]phenol; 3-[6-(3-chlorophenoxy)-1-hydroxyhexyl]phenol; 2-[3-(6-(3-chlorophenoxy)-1-hydroxyhexyl)phenoxymethyl]quinoline; 2-[3-(6-phenoxy)-3-l-hydroxyhexyl)phenoxymethyl]-quinoline; 2-[3-(6-(3-trifluoromethylphenoxy)-l-hydroxyhexyl)-phenoxymethyl]quinoline; 2-[3-(1-acetoxyhexyl)phenoxymethyl]quinoline; 2-[3-(1-methoxyhexyl)phenoxymethyl]quinoline; l-(2-thienyl)-2-(3-hexanoylphenyl)acetylene; 1-(2-thienyl)-2-[3-(1-hydroxyhexyl)phenyl]acetylene; 1-(2-quinolyl)-2-[3-(1-hydroxyhexyl)phenyl]acetylene; 1-(2-indolyl)-2-[3-(1-hydroxyhexyl)phenyl]acetylene; 1-(2-furyl)-2-[3-(1-hydroxyhexyl)phenyl]acetylene; 1-(2-thienyl)-2-[3-(1-hydroxyhexyl)phenyl]ethylene; 1-(2-quinolyl)-2-[3-(1-hydroxyhexyl)phenyl]ethylene; 1-(2-indolyl)-2-[3-(1-hydroxyhexyl)phenyl]ethylene; 1-(2-furyl)-2-[3-(1-hydroxyhexyl)phenyl]ethylene; 1-(2-thienyl)-2-(3-hexanoylphenyl)ethylene; N-[3-(1-hydroxyhexyl)phenyl)pyridine-2-carboxamide; 2-[3-(1-hydroxyhexylbenzylamino]pyridine; 2-[3-(1-hydroxybutyl)anilinylmethyl]thiophene; 4-[3-(1-hydroxybutyl)anilinylmethyl]quinoline; 2-[2-(l-hydroxyhexyl)anilinylmethyl]quinoline; 3-methoxyphenyl-3-[l-(hydroxy)hexyl]benzyl thioether; 4-nitrophenyl-3-[1-(hydroxy)hexyl]benzyl thioether; methyl-2-[[3-(l-hydroxyhexyl)thiophenoxy]methyl]-benzoate; 2-(3-hexanoylphenoxymethyl)quinoline; 2-[2-(l-hydroxyhexyl)-5-pyridyloxy]quinoline; 4-[2-(1-hydroxyhexyl)-5-thienylmethoxy]quinoline; 2-[5-(1-hydroxyhexyl)-2-furylmethoxy]pyridine; 2-[5-(1-hydroxyhexyl)-2-pyridyloxymethyl]indole: 2-[4-(1-hydroxyhexyl)phenoxymethyl]pyrrole;

Claim 229

WHAT IS CLAIMED IS 1. A compound of the formula: and the pharmaceutically acceptable salts thereof, wherein Ar 1 is a nitrogen, sulfur or oxygen heterocyclic ring or an aromatic ring; Ar is a phenyl ring or a nitrogen, oxygen or sulfur heterocyclic ring; Ar and Ar 1 may be fully substituted or.less than fully substituted with H, CH 3 , lower alkyl, aryl, aralkyl, halo, hydroxy, lower alkoxy, CF 3 , carboxy, alkylcarboxy, arylcarboxy, alkylcarbalkoxy, alkanoyl, formyl, oxo, nitrilo, amino, aminoalkyl, alkylamine, carboxamide, aryloxy, nitro, sulfonyl, sulfonamide, thio, alkylthio, hydroxyalkyl or oxyalkylcarboxy; X = -O(CHR 1 ) n -, -NR 2 (CHR 1 ) n -alkylene of up to 2 carbon atoms in the principal chain and up to a total of 4 carbon atoms, -C(R 1 )=C(R 1 )-, -C≡C-, Z is an alkylene chain containing up to 10 carbon atoms in the principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds and the said alkylene chain may be attached to Ar through an oxygen, sulfur or amino nitrogen atom, and when n' 7 2, one of the R substituents may be halogen on an omega carbon of the alkylene chain Z; when n'=l, R is a substituent attached to one of the carbon atoms of Z selected from the group consisting of =O, OR 3 , SR 3 , N(R 2 ) 2 , R 1 , and -COR 4 and when n'=2 one R is as previously defined, and the additional R is a substituent attached to one of the carbon atoms of Z selected from the group consisting of =O, OR 3 , SR 3 , N(R 2 ) 2 , -COR 4 , lactone and halo; R 1 is H or CH 3 ; R 2 is H, lower alkyl, aryl or aralkyl; R 3 is H, lower alkyl, lower alkanoyl, aryl, aralkyl or substituted aryl in which the substituent is halo, lower alkyl or lower alkoxy; R4 is OR 2 or N(R 2 ) 2 ; n = 0 or 1; n' = 1 to 7 and n" = 0, 1 or 2.

Claim 230

A compound of claim 1 of the formula: Ar 1 - X - Ar - Z - (R) n , and salts thereof, wherein Ar 1 is quinolyl; Ar is a phenyl, pyridyl or quinolyl ring; X = -O(CHR 1 ) n -, NR 2 (CHR 1 ) n -, alkylene of up to 2 carbon atoms in the principal chain and up to a total of 4 carbon atoms, -C(R 1 )=C(R 1 )-, -C = C-, Z is an alkylene chain containing up to 10 carbon atoms in the principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds; each R is a substituent, attached to one of the carbon atoms of Z selected from the group consisting of =O, OR 3 , SR 3 , N(R 2 ) 2 and -COR 4 ; R 1 is H or CH 3 ; R2 is H, lower alkyl, aryl or aralkyl; R 3 is H, lower alkyl, lower alkanoyl, aryl or aralkyl; R 4 is OR 2 or N(R 2 ) 2 ; n = 0 or 1; n' = 1 to 7; and n" = 0, 1 or 2.

Claim 231

A compound of claim 1 of the formula: and salts thereof, wherein Z is an alkylene chain containing up to 10 carbon atoms in the principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds; n = 0 or 1; n' = 1 to 7; and Each R is a substituent, attached to one of the carbon atoms of Z selected from the group consisting of = 0, OR 3 , SR 3 N(R 2 ) 2 and -C O R 4 ; R 1 is H or CH 3 : R2 is H, lower alkyl, aryl or aralkyl; R3 is H, lower.alkyl, lower alkanoyl, aryl or aralkyl; R 4 is OH, OR 2 or N(R 2 ) 2 ; n = 0 or 1; n' = 1 to 7; with the proviso that one R is on the carbon atom of Z attached to the phenyl group.

Claim 232

The compound according to Claim 1 which is 2-[3-(1-methyl-1-hydroxyhexyl)phenoxymethyl]quinoline, 2-[3-(2,2-dimethyl-1-hydroxyhexyl)phenoxymethyl]pyridine, 2-[3-(1,2,2-trimethyl-1-hydroxyhexyl)phenoxymethyl]quinoline, 2-[3-(1-methyl-1-hydroxyhexyl)phenoxymethyl]pyridine, 2-[3-(6- (6-[3-chlorophenoxyl]-1-hydroxyhexyl)phenoxymethyl]quinoline or 2-[3-(6-phenoxy-l-hydroxyhexyl)-phenoxymethyl]quinoline.

Claim 233

The compound according to Claim 1 which is 2-[3-(6-phenoxy-2,2-dimethyl-1-hydroxyhexyl)phenoxymethyl]quinoline, 2-[3-(6-[3-trifluoromethylphenoxy]-1-hydroxyhexyl)phenoxymethyl]quinoline, 2-[6-(1-hydroxyhexyl)-3-pyridyloxy]quinoline, 2-[3-(6-[3-chlorophenoxy]-1-methyl-1-hydroxyhexyl)phenoxymethyl]quinoline, 2-(3-(1-hydroxy-5,5,5-trifluoropentyl)phenoxymethyl)-quinoline or 2-(3-(1-hydroxy-5,5,5-trifluoropentyl)-phenoxymethylpyridine.

Claim 234

The compound according to Claim 1 which is 2-(3-(1-hydroxy-6,6,6-trifluorohexyl)phenoxymethyl)-quinoline, 2-(3-(1-hydroxy-6,6,6-trifluorohexyl)phenoxymethyl)pyridine, 2-(3-(1-hydroxyheptyl)phenoxymethyl)-quinoline, 2-(3-(l-hydroxyheptyl)phenoxymethyl)pyridine, 4-(3-(1-hydroxy-5,5,5-trifluoropentyl)phenoxymethyl)-quinoline, 4-(3-(6-phenoxy-l-hydroxyhexyl)phenoxymethyl quinoline or 2-(3-(6-phenoxy-l-hydroxyhexyl)phenoxymethyl) pyridine.

Claim 235

The compound according to Claim 1 which is 2-(3-(l-hydroxy-l-methyl-5,5,5-trifluoropentyl)-phenoxymethyl)quinoline, 2-(3-(1-hydroxy-2,2-dimethyl-5,5,5-trifluoropentyl)-phenoxymethyl)quinoline, 2-(3-(1,2,2-trimethyl-5,5,5-trifluoro-l-hydroxypentyl)-phenoxymethyl)quinoline, 2-(3-(1-methyl-1-hydroxy-5,5,5-trifluoropentyl)-phenoxymethyl)quinoline, 2-(3-(2,2-dimethyl-6,6,6-trifluoro-l-hydroxyhexyl)phenoxymethyl)-quinoline, 2-(3-(1,2,2-trimethyl-6,6,6-trifluoro-1-hydroxyhexyl)phenoxymethyl)quinoline, 2-(3-(2,2-dimethyl-6,6,6-trifluoro-1-hydroxyhexyl)-phenoxymethyl)pyridine, 3-(3-(2,2-dimethyl-6,6,6-trifluoro-l-hydroxyhexyl)-phenoxymethyl)pyridine, 4-(3-(2,2-dimethyl-1-1-hydroxyhexyl)phenoxymethyl)quinoline or 2-(3-(6-methoxyhexyl)-phenoxymethyl)quinoline.

Claim 236

The compound according to Claim 1 which is 2-(3-(4-methoxybutyl)phonoxymethyl)quinoline, 2-(4-(4-methoxybutyl)phenoxymethyl)quinoline, 2-(3-(6-phenoxy- hexyl)phenoxymethyl)quinoline, 2-(3-(4-methoxybutyl)-phenoxy)quinoline, 2-(3-(l-acetoxyhexyl)phenoxymethyl)-quinoline, 2-(3-1-(1,1,1-trimethylacetoxy)hexyl)phenoxymethyl)quinoline, 2-(3-(l-acetoxy-5,5,5-trifluoropentyl)-phenoxymethylquinoline, 2-(3-1-(1,1,1-(trimethylacetoxy)-5,5,5-trifluoropentyl)phenoxymethyl)quinoline, 2-(3-1-(1,1,1-(trimethylacetoxy)-6,6,6-trifluorohexyl)-phenoxymethyl)quinoline, 2-(3-(2,2-dimethyl-1-(1,1,1-trimethylacetoxy)hexylphenoxymethyl)quinoline, 2-(3-(2, 2-dimethyl-6,6,6-trifluoro-1-(1,1,1-trimethylacetoxy)-hexyl)phenoxymethyl)quinoline or ethyl 2-(3-(2-quinolinyl- methoxy)phenoxy)propionate.

Claim 237

The compound according to Claim 1 which is 2-(3-(2-quinolinylmethoxy)phonoxy)propionic acid, ethyl 2-(3-(2-quinolinylmethoxy)phenyl)propionate, 2-(3-(2-quinolinylmethoxy)phenyl)propionic acid, 3-(3-(1-hydroxyhexyl)phenoxymethyl)quinoline, 6-(3-(1-hydroxyhexyl)phenoxymethyl)quinoline, 2-(3-(1-hydroxyhexyl)benzyloxymethyl)quinoline, 2-[3-(6(3-chloro- phenoxy)-l-hydroxyhexyl)phenoxymethyllquinoline, 2-[(3-(6-phenoxy)-l-hydroxyhexyl)phenoxymethyl]quinoline, 2-(3-(6(3-trifluoromethylphenoxy)-1-hydroxyhexyl)-phenoxymethyl]quinoline, 3-[6-(3-chlorophenoxy)-l-hydroxyhexyl]-phenol, 3-[6-phenoxy-l-hydroxyhexyl]phenol, 3-[6-(3-trifluoromethylphenoxy)-1-hydroxyhexyl]phenol, 2-[3-(6-phenoxy-l-hydroxy-l-methylhexyl)phenoxymethyl]-quinoline or 2-[3-(6-(3-chlorophenoxy)-1-hydroxy-1-methylhexyl)phenoxymethyl]quinoline.

Claim 238

The compound according to Claim 1 which is 2-[3-(6-(3-trifluoromethylphenoxy)-l-hydroxy-l-methylhexyl)phenoxymethyl]quinoline, 3-(2-quinolinylmethoxy) acetophenone, 2-[3-(1-Hydroxyhexyl)phenoxymethyl]quinoline, (2-quinolinylmethoxy)phenylacetic acid, 2-(3-(6-phenoxy- l,2,2-trimethyl-l-hydroxyhexyl)phenoxymethyl)quinoline, 2-(3-hexylphenoxy)methyl quinoline, 1-(3-(2-quinolinyl- methoxy)phenyl)-3-methyl-1,3-butane diol, 2-(3-(6,6,6-trifluorohexanoyl)phenoxymethyl)quinoline, 2-(3-(5,5,5-trifluoropentanoyl)phenoxymethyl)quinoline, 2-(3-(6-benzyloxy-1-hydroxyhexyl)phenoxymethyl)quinoline, methyl(3-(3-(2-quinolinylmethoxy)benzoyl)propionoate or 2-[3-(6-phenoxy-1-hydroxyhexyl)phenoxymethyl]quinoline.

Claim 239

A compound of Claim 1 of the formula: Ar 1 - X - Ar - Z - (R) n , and salts thereof, wherein Ar 1 is a phenyl or naphthyl group: Ar is a phenyl, pyridyl or quinolyl group; X = -O(CHR 1 ) n -, NR 2 (CHR 1 ) n -, alkylene of up to 2 carbon atoms in the principal chain and up to a total of 4 carbon atoms, -C(R 1 )=C(R 1 )-, -C = C-, Z is an alkylene chain containing up to 10 carbon atoms in the principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds each R is a substituent, attached to one of the carbon atoms of Z selected from the group consisting of =O, OR 3 , SR 3 , N(R2)2 and -COR 4 ; R 1 is H or CH 3 ; R 2 is H, lower alkyl, aryl or aralkyl; R 3 is H, lower alkyl, lower alkanoyl, aryl or aralkyl or an 0-heterocyclic group; R 4 is OR 2 or N(R 2 ) 2 ; n = 0 or 1; n' = 1 to 7; and n" = 0, 1 or 2.

Claim 240

A compound of Claim 1 of the formula: and salts thereof; wherein Ar 1 is a phenyl or naphthyl group; Ar is a phenyl group; X = -O(CHR 1 ) n -, -NR 2 (CHR 1 ) n - , alkylene of up to 2 carbon atoms in the principal chain and up to a total of 4 carbon atoms; -C(R 1 )=C(R 1 )-, -C≡C-, -CH=N-, -C-N(R 1 )-; O Z is alkylene chain containing up to 10 cabon atoms in the principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds and the each R is a substituent, attached to one of the carbon atoms of Z selected from the group consisting of =O, OR 3 , N(R2)2 and -CO R 4 ; R 1 is H or CH3; R 2 is H, lower alkyl, aryl or aralkyl; R 3 is H,.lower alkyl, lower alkanoyl, aryl or aralkyl and said 0-heterocyclic group is a pyran group or tetrahydropyran group; R 4 is OR 2 or N(R 2 ) 2 ; n = 0 or 1; n' = 1 to 7; and n" = 0, 1 or 2.

Claim 241

13 . The compound according to Claim 1 which is methyl 3-[ [ 3-(1-hydroxyhexyl)phenoxy]methyl]benzoate, methyl 2-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate, 3[[3-(1-hydroxyhexyl)phenoxy[methyl[benzamide, methyl-3-[3-(1-methyl-1-hexenyl)phenoxy]methy]benzoate, l-(3-phenoxyphenyl)-l-hexanol, 1-(3-benzyloxphenyl)-1-methyl-1-pentanol, 2-(3-hexanoylphenoxy)methyl naphthalene, 2-(3-(1-hydroxyhexyl)phenoxymethyl)naphthalene or 2-(3-(1-hydroxyhexyl)-phenoxymethyl)-1,2,3,4-tetrahydronaphthalene.

Claim 243

A process for the production of a compound as in Claim 1, which includes at least one of the following: (a) condensation of a compound of formula II and III herein in which X' and X" are -CH 2 Hal, Hal, OH, CH 2 0H, SH or CH 2 SH, the nature of X' and X" being such to permit formation of Z on condensing to a compound of formula I herein; (b) condensation of compounds of formula II and III herein in which X' and X" are -CH=CH 2 -, -C≡CH, or Hal, the nature of X' and X" being such to permit formation of Z on condensing to a compound of formula I herein; (c) condensing compounds of formulas II and III herein in which X' and X" are -CHO or -NH 2 -, the nature of X' and X" being such to permit formation of Z on condensing to a compound of formula I herein; (d) condensing compounds of formula II and I I I herein in which X' and X" are COOH, or NH, the nature of X' and X" being such to permit formation of Z on condensing to a compound of formula I herein;

Claim 244

The process of Claim 15 where the compounds of Formula I are: and salts thereof, wherein Ar 1 is quinolyl; Ar is a phenyl, pyridyl or quinolyl ring , NR 2 (CHR 1 ) n -; alkylene of up to 2 carbon atoms in the principal chain and up to a total of 4 carbon atoms, -C(R 1 )=C(R 1 )-, -C≡C-, Z is an alkylene chain containing up to 10 carbon atoms in the principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds each R is a substituent, attached to one of the carbon atoms of Z selected from the group consisting of =O, OR 3 , SR 3 , N(R 2 ) 2 and -COR 4 ; R 1 is H or CH 3 ; R 2 is H, lower alkyl, aryl or aralkyl; R 3 is H, lower alkyl, lower alkanoyl, aryl or aralkyl; R 4 is OR 2 or N(R 2 ) 2 ; n = 0 or 1; n' = 1 to 7; and n" = 0, 1 or 2.

Claim 245

The process of Claim 15 where the compounds of Formula I are: and salts thereof, wherein Z is an alkylene chain containing up to 10 carbon atoms in the principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds; n = 0 or 1; n' = 1 to 7; and Each R is a substituent, attached to one of the carbon atoms of Z selected from the group consisting of =O, OR 3 , SR 3 N (R 2 ) 2 and -COR 4 ; R 1 is H or CH 3 ; R 2 is H, lower alkyl, aryl or aralkyl; R 3 is H, lower.alkyl, lower alkanoyl, aryl or aralkyl; R 4 is OH, OR 2 or N(R 2 ) 2 ; n = 0 or 1; n' = 1 to 7; with the proviso that one R is on the carbon atom of Z attached to the phenyl group.

Claim 246

The process of Claim 15 where the compounds of Formula I are: and salts thereof, wherein Ar 1 is a phenyl or naphthyl group; Ar is a phenyl, pyridyl or quinolyl group; X = -O(CHR 1 ) n -, NR 2 (CHR 1 ) n -, , alkylene of up to 2 carbon atoms in the principal chain and up to a total of 4 carbon atoms, -C(R 1 )=C(R 1 )-, -C = C-, Z is an alkylene chain containing up to 10 carbon atoms in the principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds each R is a substituent, attached to one of the carbon atoms of Z selected from the group consisting of =O, OR 3 , SR 3 , N(R 2 ) 2 and -COR 4 ; R 1 is H or CH 3 ; R 2 is H, lower alkyl, aryl or aralkyl; R 3 is H, lower alkyl, lower alkanoyl, aryl or aralkyl or an 0-heterocyclic group; R 4 is OR 2 or N(R 2 ) 2 ; n = 0 or 1; n' = 1 to 7; and n" = 0, 1 or 2.

Claim 247

The process of Claim 15 wherein the compounds of Formula I are: and salts thereof; wherein Ar 1 is a phenyl or naphthyl group; Ar is a phenyl group; X = -O(CHR 1 ) n , , -NR 2 (CHR 1 ) n -, alkylene of up to 2 carbon atoms in the principal chain and up to a total of 4 carbon atoms, -C(R 1 )=C(R 1 )-, -C≡C-, -CH=N-, Z is alkylene chain containing up to 10 cabon atoms in the principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds and the each R is a substituent, attached to one of the carbon atoms of Z selected from the group consisting of =0, OR 3 , N(R 2 ) 2 and -COR4; R 1 is H or CH3; R 2 is H, lower alkyl, aryl or aralkyl; R 3 is H,-lower alkyl, lower alkanoyl, aryl or aralkyl and said 0-heterocyclic group is a pyran group or tetrahydropyran group; R 4 is OR 2 or N(R 2 ) 2 ; n = 0 or 1; n' = 1 to 7; and n" = 0, 1 or 2.