Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D215/14—Radicals substituted by oxygen atoms

Definitions

• This invention relates to disubstituted quinolines which are useful as leukotriene antagonists. More particularly, these quinolines are 2,7-disubstituted compounds which have utility in treating diseases related to leukotriene B wherein the treatment is affected by virtue of the antagonist activity of these 2,7-disubstituted quinolines.
• the family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems.
• the leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C4, D4 and E4) and the hydroxyleukotrienes (leukotriene B4) .
• This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes.
• the peptidoleukotrienes are implicated with the biological response associated with the "Slow Reacting
• SRS-A Substance of Anaphylaxis
• This response has been expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses.
• the pharmacology of the peptidoleukotrienes include smooth muscle contractions, myocardial depression, increased vascular permeability and enhanced mucous production.
• LTB4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs) . It is critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.
• PMNs polymorphonuclear leukocytes
• Leukotriene B4 was first described by Borgeat and Samuelsson in 1979, and later shown by Corey and co- workers to be 5(S) , 12 ⁇ R)-dihydroxy-(Z,E,E,Z)- ⁇ ,8,10,14- eicosatetraenoic acid ( Figure I) .
• LTB4 It is a product of the arachidonic acid cascade that results from the enzymatic hydrolysis of LTA4. It has been found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB4 has been shown to be a potent stimulus in vivo for PMN leukocytes, causing increased chemotactic and chemokinetic migration, adherence, aggregation, degranulation, superoxide production and cytotoxicity. The effects of LTB4 are mediated through distinct receptor sites on the leukocyte cell surface which exhibit a high degree of stereospecificity.
• LTB4 has been established as an inflammatory mediator in vivo. It has also been associated with airway hyper- responsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction. In addition, as with the other leukotrienes, LTB4 has been implicated in inflammatory bowel disease, rheumatoid arthritis, gout, and psoriasis. By antagonizing the effects of LTB4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a key factor.
• This invention relates to disubstituted quinolines of formula I
• Rl is CH3(CH2)nHOHC- or
• n 3-20, m is 1-6 and R3 is lower alkyl, lower alkoxy or halo;
• this invention covers pharmaceutical compositions containing the instant compounds and a pharmaceutically acceptable excipient.
• Treating diseases related to or caused by leukotrienes, particularly LTB4, or related pharmacologically active mediators at the end organ are within the scope of this invention.
• This treatment can be effected by administering one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient.
• this invention relates to a method for making a compound of formula I which method is illustrated in the Schemes given below and in the Examples set forth in this specification.
• this case relates to a method for making a compound of formula I which method comprises: a) forming a salt, or b) hydrolyzing an ester to the salt or free acid, or c) forming an ester, or d) forming an amide, or e) alkylating the quinoline, or f) inserting an R2 group at position 2 by means of a triflate intermediate, or g) reducing a double bond in the R2 group.
• lower alkyl means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form.
• Lower alkoxy means the group lower alkyl-O-.
• Halo means fluoro, chloro, bromo or iodo.
• An ester-forming group is any group where an oxygen is covalently bonded to a carbonyl carbon and a second carbon atom wherein the resulting group is denominated an ester.
• an amide-forming group is one where a nitrogen is bonded to a carbonyl carbon and otherwise has one or two hydrogens or one or two bonds to a carbon atom, resulting in a group which is identified as an amide. All esters or amides made thereby will retain some useful activity in treating a disease or for some other industrial application.
• esters or amides which can be used in the medicinal arts, either the human or animal medicinal arts.
• the preferred esters are those having of the formula CH3 (CH2)u ⁇ 0- where u is 0-6.
• the most preferred amides are those where the nitrogen is substituted with just hydrogen or one or two lower alkyl groups.
• the diethylamide is particularly preferred.
• this invention is intended to cover such a salt having industrial application. If the phrase "a pharmaceutically acceptable salt” is used, that is intended to cover salts which have use and application in the human and animal medicinal arts.
• Salts are prepared in a standard manner, in a suitable solvent.
• the parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of a basic functionality, or an excess of organic or inorganic base where X is OH.
• N-oxides may also be prepared by means of selected oxidizing agents. These oxides are useful as intermediates in prepar ng t e compoun s o ormu a I an may ave use n and of themselves. Hence, for example, one can administer the N-oxides of formula I to a subject who is susceptible to or is suffering from a disease related to or caused by LTB4 or similar leukotrienes.
• a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are intended to be covered herein. These compounds may be used as a racemic mixture or the racemates may be separated and the individual enantiomer used alone.
• these compounds can be used in treating a variety of diseases associated with or attributing their origin or affect to leukotrienes, particularly LTB4.
• these compounds can be used in treating pulmonary and non-pulmonary allergic diseases.
• these compounds will be useful in treating antigen-induced anaphylaxis. They are useful in treating asthma and allergic rhinitis.
• Ocular diseases such as uveitis, and allergic conjunctivitis can also be treated with these compounds. They also are expected to have anti- inflammatory activity and be useful in treating psoriasis.
• Preferred compounds are those where Rl is
• n 7, 8 or 9, or is
• R2 is one of
• R4 is COOH or a salt thereof and is substituted at the 3 or 4 position, most preferably the 3 position.
• Preferred compounds include pharmaceutically acceptable salts thereof as well, provided such salts can be prepared from a given compound.
• the most preferred compounds are:
• These compounds may be made by the starting materials, intermediates and reagents set out in the reaction flow charts given below. These flow charts are intended to act as a road map to guide one from known starting materials to the desired products. These specific starting materials, intermediates and reagents are given only to illustrate the general case and are not intended to limit the chemistry illustrated thereby. Reagents, intermediates, temperatures, solvents, reaction times, work-up procedures, all may be varied to accommodate differences in the processes needed to optimize the particular conditions for making a given . will not require more than minimal experimentation to optimize conditions and reagents for a particular step.
• Scheme I illustrates a method for making useful intermediates and for converting them into several of the compounds of this invention.
• the 7-methylquinoline is known. It is oxidized to the aldehyde 2 by means of an oxidizing agent, for example by using selenium dioxide at elevated temperature.
• Compounds of 3 are prepared from the aldehyde by means of a Grignard reagent employing the appropriate 1-haloalkane needed to form 3.
• the alcohol group is then protected (4) by some means such as that of a silyloxy group.
• the preferred silyloxy group is t-butyldimethylsilyloxy.
• Preferred starting material, the reagent used to form the silyloxy adduct is t-butyldimethylsilyltri- fluoromethansulfonate.
• Compound 8 is derived from 6 by causing it to undergo loss of water, accomplished by means of treatment with ammonium chloride at about room temperature followed by removal of the silyloxy protecting group on the 7-position substituent as well as the ester on the 2-position substituent. Catalytic hydrogenation gives the fully saturated side chain of quinoline 9.
• Compound 8 can also be prepared by treating 6 with tetrabutylammonium fluoride through an initial lactone formation followed by elimination and opening the lactone to give the corresponding acid (8) . hydroxyl group of an a,w-alkanediol, then oxidizing the other hydroxyl group to the aldehyde.
• 1,5- pentane-diol is treated with a siloxane such as t- butyldiphenylsilyl chloride under conditions which form 5-t- butyldiphenlylsilyloxy-1-pentanol.
• An oxidizing agent is then used to prepare the corresponding aldehyde.
• a chromate such as pyridinium chlorochromate may be used, the reaction being carried out under an inert atmosphere such as argon for a time sufficient to effect the reaction.
• This aldehyde is then added to a solution of 5 to which has been added a base such as n-butyl lithium.
• reagents are usually added at reduced temperature, e.g. -78°C, under an inert atmosphere, then the solution is allowed to warm to about room temperature after which the product is isolated. This process gives 10.
• the triflate 11 To form the triflate 11, one first prepares the necessary triflurormethylsulfonyl-substituted benzaldehyde from the corresponding hydroxybenzaldehyde and N- phenyltrifluoromethane sulfonimide. This triflate is then added to an already prepared solution of 5 to which has been added n-butyl lithium. Reduced temperature (e.g. -78°C) and an inert atmosphere are used to mix the reactants and to affect the reaction, though the temperature may be increased after the triflate is added.
• Reduced temperature e.g. -78°C
• an inert atmosphere are used to mix the reactants and to affect the reaction, though the temperature may be increased after the triflate is added.
• a triflate can be converted to an ester by bubbling carbon monoxide through a solution of the triflate in the presence of Pd(0Ac)2 and 1,1- bis (diphenylphosphino)propane. Fluoride anion is then used to remove the protecting group (tetrabutylammonium fluoride) and the salt is obtained by saponifying the ester with a base such as lithium hydroxide.
• the other chemistries illustrated in Scheme II use the same type of reagents and processes described in Scheme I for introducing the 7- position substituent, except that the specific reagents are changed to match the substituent being introduced.
• Introducing the 2-, 3-, and 4- (1-hydroxyethyl)benzoic acid group tracks the same chemistries as are described for making 12, 14 and 16.
• 19 can be made by adding methyl-3-ethynylcarboxylate to a solution of the triflate, then introducing bis (triphenylphosphine)- palladium (II) chloride and copper iodide. This reaction can be carried out at room temperature under an inert atmosphere. Catalytic hydrogenation is used to reduce the ethynyl group after which 20 is prepared as before by first removing the silyloxy protecting group and then hydrolyzing the ester with an alkali metal base . The acid can be prepared instead of the salt by acidifying the solution following the saponification reaction.
• n 0,1 ,2
• a reducing agent is used to reduce the ester 21 to the aldehyde 22.
• di-isobutyl aluminum hydride can be employed using standard conditions for this reagent.
• the aldehyde 22 is treated with a reducing agent such as sodium borohydride using standard conditions.
• Converting the alcohol to the bromide (24) is effected using carbon tetrabromide and (Ph)3P. This reaction is carried out at about 0°C.
• the mercapto group is introduced by treating 24 with a mercaptobenzoate in an inert solvent.
• the reaction can be carried out at a slightly reduced temperature, such at between about -10° to +10°C.
• the protecting group on the 7-position substituent is then removed and the ester on the benzene ring may be hydrolized with base to recover the salt or, the solution is acidified, the free acid.
• a mild oxidizing reagent such as m-chloroperbenzoic acid can be use to oxidize the thio ether to the corresponding sulfinyl or sulfonyl forms.
• the acid salt 27 can be made by treating 21 with a base to hydrolyze the ester. The salt is obtained unless the solution is acidified, which gives the free acid.
• compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the formula I or a pharmaceutically acceptable salt, such as an alkali metal salt thereof, sufficient to produce the inhibition of the effects of leukotrienes.
• examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aeroso sys ems, c oro uorome ane, chlorotrifluoroethane and compressed carbon dioxide.
• the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
• the nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
• the compositions may be in a form suitable for administration by inhalation.
• the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer.
• the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container.
• the compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device.
• the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.
• the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
• a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
• the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, paste, and drops suitable for administration to the skin, eye, ear, or nose. will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
• a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor.
• the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration.
• equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 100 mg to about 5000 mg.
• a disease mediated by LTB4 which comprises administering to a subject a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition.
• a therapeutically effective amount of a compound of formula I preferably in the form of a pharmaceutical composition.
• the administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically required. However, the method is also usefully carried out as continuous or prophylactic treatment.
• compositions and their method of use also include the combination of a compound of formula I with Hi blockers where the combination contains sufficient amounts of both compounds to treat antigen-induced respiratory anaphylaxis or similar allergic reaction.
• Hi blockers useful here include cromolyn sodium, compounds from the ethanolamines (diphenhydramine) , ethylenediamines (pyrilamine) , the alkylamines (chlorpheniramine) , the piperazines (chlorcyclizine) , and the phenothiazines (promethazine) .
• Hi blockers such as 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5- [ ( 6- methylpyrid-3-yl) ethyl ] -4-pyrimidone are particularly useful in this aspect of the invention .
• the specificity of the antagonist activity of a number - of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, carbachol, histamine and PGF2.
• the receptor binding affinity of the compounds used in the method of this invention is measured by the ability of the compounds to bind to [3H]-LTB binding sites on human U937 cell membranes.
• the LTB4 antagonists activity of the compounds used in the method of this invention is measured by their ability to antagonize in a dose dependent manner the LTB4 elicited calcium transient measured with fura-2, the fluorescent calcium probe. The methods employed were as follows: U937 Cell Culture Conditions
• U937 cells were obtained from Dr. John Bomalaski (Medical College of PA) and Dr. John Lee [SmithKline & French (SK&F), Dept. of Immunology] and grown in RPMI-1640 medium supplemented with 10% (v/v) heat inactivated fetal calf serum, in a humidified environment of 5% CO2, 95% air at 37°C. Cells were grown both in T-flasks and in Spinner culture. For differentiation of the U937 cells with di ethylsulfoxide to monocyte-like cells, the cells were seeded at a concentration of 1 x 105 cells/ml in the above medium with 1.3% dimethylsulfoxide and the incubation continued for 4 days. The cells were generally at a density of 0.75-1.25 x 106 cells/ml and were harvested by centrifugation at 800 x g for 10 min.
• [ 3 H]-LTB4 binding assays were performed at 25°C, in 50mM Tris-HCl (pH 7.5) buffer containing lOmM CaCl2, 10mM MgCl2, [ 3 H]-LTB4, U937 cell membrane protein (standard conditions) in the presence (or absence) of varying concentrations of LTB4, or SK&F compounds. Each experimental point represents the means of triplicate determinations. Total and non-specific binding of [ 3 H]-LTB4 were determined in the absence or presence of 2 ⁇ M of unlabeled LTB4, respectively. Specific binding was calculated as the difference between total and non-specific binding.
• the radioligand competition experiments were performed, under standard conditions, using approximately 0.2nM [ 3 H]-LTB4, 20-40 ⁇ g of U937 cell membrane protein, increasing concentrations of LTB4 (O.lnM to lOnM) or other competing ligands (O.l ⁇ M to 30 ⁇ M) in a reaction volume of 0.2ml and incubated for 30 minutes at 25°C.
• LTB4 O.lnM to lOnM
• competing ligands OF.l ⁇ M to 30 ⁇ M
• the cells were centrifuged at 800 x g for 10 minutes and resuspended in cold fresh buffer B at 5 x 10 ⁇ cells/ml. Cells were maintained on ice in the dark until used for fluorescent measurements. Fluorescent Measurement-. Calcium Mobilization
• the fluorescence of fura-2 containing U937 cells was measured with a fluorometer designed by the Johnson Foundation Biomedical Instrumentation Group. Fluorometer is equipped with temperature control and a magnetic stirrer under the cuvette holder. The wave lengths are set at 339nm for excitation and 499nm for emission. All experiments were performed at 37°C with constant mixing.
• U937 cells were diluted with fresh buffer to a concentration of 1 x 106 cells/ml and maintained in the dark on ice. Aliquots (2ml) of the cell suspension were put into 4ml cuvettes and the temperature brought up to 37°C, (maintained in 37°C, water bath for 10 min) . Cuvettes were transferred to the fluorometer and fluorescence measured for about one minute before addition of stimulants or antagonists and followed for about 2 minutes post stimulus. Agonists and antagonists were added as 2 ⁇ l aliquots.
• Antagonists were added first to the cells in the fluorometer in order to detect potential agonist activity. Then after about one minute lOnM LTB4 (a near maximal effective concentration) was added and the maximal Ca ⁇ -f- mobilization [Ca ⁇ +]i was calculated using the following formula:
• [Ca 2 +]i 224 ⁇ E __JIl__I. ⁇ ⁇ Fmax-F ⁇
• F was the maximum relative fluorescence measurement of the sample. Fmax was determined by lysing the cells with lO ⁇ l of 10% Triton X-100 (final Concentration 0.02%) . After F max was determined 67 ⁇ l of lOOmM EDTA solution (pH 10) was added to totally chelate the Ca 2+ and quench the fura-2 signal and obtain the Fmin .
• the [Ca 2+ ]i level for lOnM LTB4 in the absence of an antagonist was 100% and basal [Ca 2+ ]i was 0%.
• the IC50 concentration is the concentration of antagonist which blocks 50% of the lOnM LTB4 induced [Ca 2+ ]i mobilization.
• the EC50 for LTB4 induced increase in [Ca 2+ ]i mobilization was the concentration for half maximal increase.
• the Ki for calcium mobilization was determined using the formula:
• Example 1 Preparation of 7- ( -h ⁇ droxypentane-5-r.arboxy1ate.-7- (1- hydroxynonyl.quinoline. lithium salt 1A. 7-Formy1 ⁇ .inol ne. 7-Methylquinoline (26.Og, O.l ⁇ mol) was heated to 160°C and selenium dioxide (13.Og, 0.117mol) was added.
• the reaction mixture was maintained at 150 - 155°C for 12 hr and then cooled to room temperature, diluted with CH2CI2, and filtered. Hexanes were added to the filtrate and the resulting precipitate was filtered and washed with hexanes. The combined organic filtrates were concentrated in vacuo and the residue was purified by flash column chromatography (silica, 15 - 30% ethyl acetate/hexanes) to afford the aldehyde.
• Tetramethylethylenediamine (4.5ml, 29.8mmol) and tetrahydrofuran (100ml) were cooled to 0°C under an argon atmosphere and methyl lithium (1.4M, 21.4ml, 30.0mmol) was added.
• methyl lithium 1.M, 21.4ml, 30.0mmol
• 7-(l-t- butyldimethylsilyloxy-nonyl)quinoline 3.85g, 2.60mmol
• tetrahydrofuran (75ml) was added dropwise and the reaction mixture warmed to room temperature and then exposed to air. Oxygen was bubbled into the solution for 1 hr, and the mixture partitioned between H2O and ethyl acetate.
• Titanium chloride triisopropo ide Titanium tetra- isopropoxide (23.66g, O.O ⁇ mol) was cooled to 0°C under an argon atmosphere and titanium tetrachloride (5.28g, 0.03mol) was added over a 5 min period and then warmed to room temperature. Purification was achieved by distillation (10.5 torr) collecting the product fraction between 95 - 100°C. The desired product crystallized on standing.
• reaction mixture was warmed to room temperature, stirred for 12h, cooled to -78°C and quenched with H2O.
• the reaction mixture was partitioned between H2O and ethyl acetate, the organic layer separated, washed with NaCl (sat) and dried (MgS ⁇ 4) .
• the ester was dissolved in tetrahydrofuran (1ml) under an argon atmosphere, cooled to 0°C, and treated with tetrabutylammonium fluoride (1M in tetrahydrofuran, 210 ⁇ l, 2.2 eq) . Following the addition, the cooling bath was removed and the reaction was stirred at room temperature for 3h. The reaction solution was diluted with ethyl acetate and washed with water, NaCl (sat) and dried (Na2S04) . Flash column chromatography (silica, CH2CI2) gave the desired product.
• the methyl ester (250mg, 0.5mmol) was hydrolized (LiOH, tetrahydrofuran, MeOH, water) as previously described and purified by MPLC (RP-18 silica, 0-40% CH3OH, H2O) to afford a lyophilized solid: ---H NMR (250MHz, CD3OD) : ⁇ 8.15 (d,
• Carbon monoxide was bubbled through the reaction mixture for 5 min and the reaction heated to 65°C and maintained at this temperature for 3h, cooled to room temperature, and diluted with diethyl ether. The resulting solution was washed with H2O, NaHC03 and NaCl (sat) and dried (MgS04) .
• Methyl 7- (1-t-butyldimethylsilyloxynonyl)quinoline-2- carboxylate (0.7g, 1.6mmol) was dissolved in CH2CI2 (8ml) and cooled to -78°C. To this solution was added diisobutylaluminumhydride (1M in CH2CI2, 2.7ml, 2.7mmol) over a 20 min period and the resulting solution stirred for lh, quenched with ethyl acetate and a potassium sodium tartrate solution. The organic phase was separated and washed with tartrate solution, NaCl (sat) and dried (MgS ⁇ 4) .
• the ester (0.065g, 0.144mmol) was dissolved in CH3OH (0.5ml) and tetrahydrofuran (0.5ml), degassed with a stream of argon, and treated with a 1M aqueous solution of LiOH (0.43ml, 0.43mmol) .
• a compound of Example 1-11 is dissolved in isotonic saline at a concentration of 1 to 10 mg/ml and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired aerosolized weight of drug.
• a preparation which contains 20 mg of a compound of any of the foregoing Examples 1-11 as a sterile dry powder is prepared as follows: 20 mg of the compound is dissolved in 15 ml of distilled water. The solution is filtered under sterile conditions into a 25 ml multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume.
• D5W dextrose in water
• Subsequent dilution may be made by addition of a metered volume of this dosage unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system.
• a capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Examples 1-11 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
• Example 15 Oral Dosa ⁇ e Unit Composit on A tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of any of the foregoing Examples 1-11 with a 10% gelatin solution. The wet granules are screened, dried, mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid, and compressed into a tablet.

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