Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/70—Sulfur atoms
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/55—Acids; Esters

Definitions

• This invention relates to certain substituted pyridyl alkanoic acids and their derivatives which are leukotriene antagonists and thus useful in treating diseases caused by or involving leukotrienes.
• SRS-A Slow Reacting Substance of Anaphylaxis
• SRS-A has been shown to be a highly potent bronchoconstricting substance which is released primarily from mast cells and basophils on antigenic challenge.
• SRS-A has been proposed as a primary mediator in human asthma.
• SRS-A in addition to its pronounced effects on lung tissue, also produces permeability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to effect depression of ventricular contraction and potentiation of the cardiovascular effects of histamine.
• SRS-A derived from mouse, rat, guinea pig and man have all been characterized as mixtures of leukotriene-C4 (LTC4), leukotriene-D4 (LTD4) and leukotriene-E4 (LTE4).
• LTC4 leukotriene-C4
• LTD4 leukotriene-D4
• LTE4 leukotriene-E4
• LTA4 lipid derivatives originate from LTA4 and are of two types: (1) those containing a sulfido- peptide side chain (LTC4, LTD4, and LTE4), and (2) those that are nonpeptidic (LTB4).
• LTC4, LTD4, and LTE4 lipid derivatives
• LTB4 nonpeptidic lipid derivatives
• Leukotrienes comprise a group of naturally occurring substances that have the potential to contribute significantly to the pathogenesis of a variety of inflammatory and ischemic disorders. The pathophysiological role of leukotrienes has been the focus of recent intensive studies.
• LTB4 has potent chemotactic actions and contributes to the recruitment and adherence of mobile scavenger cells to the endothelial membrane.
• LTC4, LTD4 and LTE4 stimulate a variety of types of muscles.
• LTC4 and LTD4 are potent bronchoconstrictors and effective stimulators of vascular smooth muscle. This vasoconstrictor effect has been shown to occur in pulmonary, coronary, cerebral, renal, and mesenteric vasculatures.
• Leukotrienes have been implicated in a number of pulmonary diseases. Leukotrienes are known to be potent bronchoconstrictors in humans. LTC4 and LTD4 have been shown to be potent and selective peripheral airway agonists, being more active than histamine. [See Drazen, J.M. et al., Proc. Nat'l. Acad. Sci. USA. 77, 7, 4354-4358 (1980).] LTC4 and LTD4 have been shown to increase the release of mucus from human airways in. vitro. [See Marom, Z. et al., Am. Rev. Respir. Pis.. 126, 449-451 (1982).] The leukotriene antagonists of the present invention can be useful in the treatment of allergic or non- allergic bronchial asthma or pulmonary anaphylaxis.
• Leukotrienes have been identified in the nasal secretions of allergic subjects who underwent in. vivo challenge with specific antigen. The release of the leukotrienes was correlated with typical allergic signs and symptoms. [See Creticos, P.S. et al., New England J. of Med.. 310. 25, 1626-1629 (1984).] This suggests that allergic rhinitis is another area of utility for leukotriene antagonists. Leukotrienes have also been directly or indirectly implicated in a variety of non-pulmonary diseases in the ocular, dermatologic, cardiovascular, renal, trauma, inflammatory, carcinogenic and other areas.
• leukotriene antagonists are potent coronary vasoconstrictors, they are implicated in a variety of cardiac disorders including arrhythmias, conduction blocks and cardiac depression.
• Synthetic leukotrienes have been shown to be powerful myocardial depressants, their effects consisting of a decrease in contractile force and coronary flow.
• the cardiac effects of LTC4 and LTD4 have been shown to be antagonized by a specific leukotriene antagonist, thus suggesting usefulness of leukotriene antagonists in the areas of myocardial depression and cardiac anaphylaxis.
• Leukotriene antagonists can also be useful in the area of renal ischemia or renal failure.
• Badr et al. have shown that LTC4 produces significant elevation of mean arterial pressure and reductions in cardiac output and renal blood flow, and that such effects can be abolished by a specific leukotriene antagonist.
• Leukotrienes have also been shown to have a role in endotoxin-induced renal failure and the effects of the leukotrienes selectively antagonized in this model of renal injury. [See Badr, K.F., et al., Kidnev International. 30.
• LTD4 has been shown to produce local glomerular constrictor actions which are prevented by treatment with a leukotriene antagonist.
• a leukotriene antagonist See Badr, K.F. et al., Kidnev International. 29. 1 , 328 (1986).
• LTC4 has been demonstrated to contract rat glomerular mesangial cells in culture and thereby effect intraglomerular actions to reduce filtration surface area. [See Dunn, M.J. et al., Kidney International. 27, 1, 256 (1985).]
• Another area of utility for leukotriene antagonists can be in the treatment of glomerulonephritis.
• Cysteinyl leukotrienes have also been shown to undergo enterohepatic circulation, and thus are indicated in the area of inflammatory liver disease. [See Denzlinger, C. et al., Prostaglandins Leukotrienes and Medicine. 21. 321-322 (1986).] Leukotrienes can also be important mediators of inflammation in inflammatory bowel disease. [See Peskar, B.M. et al., Agents and Actions. 18. 381-383 (1986).] Leukotriene antagonists thus can be useful in the treatment of inflammatory liver and bowel disease.
• leukotriene antagonists can have utility because leukotrienes are indicated as mediators.
• prevention of premature labor See Clayton, J.K. et al., Proceedings of the BPS. 573P, 17-19 Dec. 1984]; treatment of migraine headaches [See Gazzaniga, P.P. et al., Abstracts Int'l Conf. on Prostaglandins and Related Comp.. 121, Florence, Italy (June 1986)]; and treatment of gallstones [See Doty, J.E. et al., Amer. J. of Surgery. 145. 54-61 (1983) and Marom, Z. et al., Amer. Rev. Respir. Pis.. 126. 449-451 (1982).
• 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 compounds of formula (I): where neither of the two pyridyl substituents are substituted on the pyridyl nitrogen, or a pharmaceutically acceptable salt thereof wherein X is O or S(0) q where q is 0, 1 or 2 with the proviso that Ri is not alkylthio or phenylthioalkyl when q is 1 or 2;
• Rl is C ⁇ to Ci3 alkyl, C ⁇ to C12 alkoxy, C ⁇ to C12 alkylthio, C10 to C1 2 1-alkynyl, 10-undecynyloxy, 11 -dodecynyl, phenyl-C4 to C1 0 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl, phenyl-C3 to C 9 alkylthio with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C ⁇ to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to CJ Q alkyl, trifluoromethyl-C to C1 2 alkyl or cyclohexyl-C4 to C10 alkyl;
• Y is R2, CH(R3)(CH2) m R2- CH(R 3 )-tetrazol-5-yl, or tetrazol-5-yl;
• R2 is -COR4 where R4 is -OH, -OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R6, -CH(NH )COR4, or -CONHCH2COR4, or R2 is -CON(R5)2 where R5 is H, Ci to C6 alkyl, phenylCi-C ⁇ alkyl, or the two R5 groups are combined to form a cyclic group having 3 to 5 carbons;
• R3 is hydrogen, methyl, C ⁇ to C4 alkoxy, fluoro or hydroxy
• R6 is Ci to Cio-alkyl, phenyl or substituted phenyl; m is 0, 1, or 2;
• R is -(CH2) n D, -(CH2) n ArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2).R2. where 1 is 10-3, or tetrazol-5-yl.
• This invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier or diluent.
• This invention also relates to pharmaceutical compositions for inhibiting antigen-induced respiratory anaphylaxis comprising an effective amount of a compound of formula (I) alone or in combination with a pharmaceutically acceptable excipient; an Hi blocker may also be present in this composition.
• a method of treating a disease in which leukotrienes are a factor which method comprises administering to a subject in need thereof an effective amount of a compound of claim 1 alone or in combination with a pharamceutically acceptable excipient.
• esters may be formed from those compounds having a carboxylic acid function.
• Such an ester, or diester as the case may be will be any ester which, as with pharmacuetically acceptable salts, gives an ester which retains the activity of the parent compound and does not impart to the parent acid any unacceptable untoward pharmacological or toxic effects in the context of its intended use and application.
• esters derived from the following radicals: C ⁇ to C ⁇ alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl.
• the compounds of the present invention depending on their atomic components, are capable of forming pharmaceutically acceptable salts with acids and bases according to procedures well known in the art.
• Such salts are those which match the activity of the parent compound and do not exhibit untoward or deleterious activity.
• Acceptable acids include inorganic and organic acids, such as hydrochloric, sulfuric, methanesulfonic, benzenesulfonic, p- toluenesul ⁇ nic acid and acetic acid.
• Bases include organic and inorganic bases, such as ammonia, arginins, organic amines, alkali metal bases and alkaline earth metal bases. Piperazine and ethylenediamine salts are particularly useful in this invention. Also preferred are the dipotassium, disodium, magnesium, zinc, and calcium salts of the diacid compounds of formula (I).
• a preferred subgeneric class of compounds of this invention are those where the two pyridyl substituents are interchangeably in the 2 and 3 positions and X is S or O. More preferred are those compounds where X is S, Y is -R2 or CH(R3)(CH 2 ) m R2 where R2 is -COOH, R3 is H or -OH and m is 0 and R is -(CH 2 ) n D where n is 1, 2, or 3, or R is -(CH2) ⁇ ArD where n is 0 or 1 and Ar is phenyl or tetrazol-5-yl.
• the preferred Ri groups are C ⁇ to C ⁇ 2 alkylthio, C to C13 - alkyl, phenyl-C3 to C9 -alkylthio and phenyl-C4 to C10 -alkyl.
• the nitrogen of the pyridyl ring may be oxidized to the nitrous oxide form by means of an appropriate oxidant.
• Such oxides will be limited to those compounds of formula (I) where D is O or S(0) 2 -
• a compound of formula (II) is treated with trimethylsilyl cyanide in the presence of zinc iodide at low temperatures in an inert solvent to form the trimethylsilyl-protected cyanohydrin. Treatment of this with gaseous . hydrogen chloride in methanol provides the methyl 2-hydroxyacetate derivative which is converted to the 2-chloroacetate with thionyl chloride. This valuable intermediate is then reacted with a substituted thiol selected to give, a compound of formula (I). The ester may be hydrolyzed to give the salt or the free acid.
• CH(R3)COR4 wherein R4 is OH or an ester, R3 is H, methyl, or alkoxy are prepared by reacting the appropriate aldehyde of the formula (II) and an esterified bromoacetate, conveniently t-butyl bromoacetate, with a mixture of diethyl aluminum chloride, zinc dust and a catalytic amount of cuprous bromide at low temperatures in an inert solvent to give the esterified 3-hydroxypropionate derivative which is reacted directly with a substituted thiol in trifluoroacetic acid.
• a mixture of trimethyl borate and zinc in tetrahydrofuran may be used to prepare the 3-hydroxypropionate derivative.
• an aldehyde of formula (II) may be reacted at low temperature with the ⁇ -lithio salt prepared from an esterified ⁇ -halo acetic acid, conveniently t-butylacetate, in an inert solvent to give the esterified 3-hydroxypropionate derivative.
• the compounds of formula (I) wherein Y is CH(CH3)COR4 where R4 is OH or an ester are obtained.
• Rj is described above, R4 is an alkyl ester protective group, such as t-butyl, and R ⁇ ⁇ is H, methyl, alkoxy, or fluoro.
• a compound of formula (III) is reacted with a mixture of alkali metal alkoxide, such as sodium methoxide, and substituted thiol or alcohol to give and ester of formula (I) which can be saponified to obtain a salt or the acid.
• the propenoate precursors of formula (III) are prepared from the corresponding aldehydes of formula (II) by general procedures such as reaction with an alkyl (triphenylphosphoranylidene)acetate or by conversion of the aldehyde to a 3-hydroxypropionate derivative, as described above, followed by an elimination reaction to form the double bond. Additionally, the propenoate precursor is obtained from a 3-methanesulfonyloxypropionate derivative by treatment with triethylamine.
• a compound of formula (IV) is reacted in a protic solvent with triethylamine and a substituted thiol or alcohol selected to give the diester of formula (I).
• This diester can be hydrolyzed to the salt or the free acid by conventional means, for ezample basic hydrolysis.
• the epoxide precursors of formula (IV) where n is 0 are prepared by reaction of an aldehyde of formula (II) with a lower alkyl chloroacetate and an alkali metal alkoxide, such as sodium methoxide.
• the compounds for formula (I) wherein Y is CH(OH)CH2COOH can also be prepared from an ester of formula (V) where R is -(CH2)2 OR4 and Y is CH(OH)CH 2 COR4:
• a compound of formula (VI) is reacted with a mixture of zinc iodide and a substituted thiol in an inert solvent or with a substituted thiol in trifluoroacetic acid to give, after removal of any ester protective group, a compound of formula (I).
• the tetrahydro-4H-pyran-2-one precursors of formula (VI) are prepared by reaction of the Grignard derivative of the bromopyridine compound of formula (IV) with chloro titanium tri-isopropoxide followed by reaction with 5-oxovalerate alkyl ester.
• aldehydes of the formula (II) are known or readily prepared utilizing the general procedures described below.
• the aldehyde precursors to the compounds of formula (I) wherein Ri is, for example, an alkyl radical containing 8-13 carbons are prepared from ethyl nicotinate-2-carboxaldehyde by reaction with the appropriate alkyltriphenylphosphonium bromide followed by catalytic reduction.
• the ester is then reacted with lithium aluminium hydride in tetrahydrofuran followed by reaction with manganese dioxide in methylene chloride to give the corresponding 2- alky 1-3 -formy lpyridine.
• the ethyl nicotinate-2-carboxaldehyde precursor is prepared from the commercially available ethyl-2-methylnicotinate by reaction with selenium dioxide or benzene selenic anhydride.
• the alkylthio containing aldehyde precursors of the compounds of formula (I) are prepared from 2-mercapto-3-carboxypyridine.
• the acid is reacted with an alkyl halide in an appropriate aprotic solvent such as dimethylformamide in the presence of potassium carbonate, followed by addition of diazomethane to yield a 2-alkylthio-3- carbomethoxypyridine.
• the ester is then reacted with lithium aluminum hydride in tetrahydrofuran followed by reaction with oxalyl chloride in dimethylsulfoxide and triethylamine in methylene chloride to yield the corresponding 2-alkylthio-3-formy lpyridine.
• heteroaryl mercaptan precursors necessary to prepare the compounds of formula (I) are known compounds and are conveniently prepared employing standard chemical reactions.
• the mercapto derivatives of these precursors are prepared according to known methods. These mercaptans are reacted as described above to yield compounds of formula (I).
• the compound of formula (I) containing an ester function at the Y position are prepared from the corresponding diacid compound having a carboxylic acid group at the Y and R positions of formula (I) by reacting the diacid with an appropriately alcohol according to processes known in the art.
• the compounds of formula (I) containing an ester function at the R position are prepared from the above described corresponding diacid compound by reacting the diacid with an alcohol in the presence of an acid catalyst according to processes known in the art.
• a process for the preparation of the compounds of formula (I) of known chirality comprises reacting a diester with a strong base to generate a thiol which is then reacted with an alkylating agent or Michael acceptor to yield the desired compound.
• An appropriate diester for example one having an -OH group on the Y substitutuent, is treated with a suitable strong base such as sodium methoxide, sodium hydride, sodium amide, or lithium diisopropyl amide.
• a suitable strong base such as sodium methoxide, sodium hydride, sodium amide, or lithium diisopropyl amide.
• the reaction is conducted in an aprotic solvent such as tetrahydrofuran, dimethylsulfoxide, or
• Suitable alkylating agents include alkyl halides such as alkyl bromide or alkyl iodide. Benzyl halides are especially suitable to prepare compounds of Formula (I). The reaction is conducted in an aprotic solvent at ambient temperature and pressure.
• Suitable Michael acceptors include compounds which undergo nucleophilic addition. Examples include compounds containing carbonyl, carboalkoxy, or cyano groups conjugated with a double or triple bond. Carbonyl compounds or alkynes represented by the following structural formulae are especially suitable.
• R13, R14, and Ri6 are independently selected from hydrogen or C i - ⁇ alkyl; and R15 and R17 are independently selected from H, aryl, or C ⁇ _6alkyl.
• the reaction is conducted in an aprotic solvent at ambient temperature and pressure.
• the leukotriene antagonist activity of the compounds of this invention is measured by the ability of the compounds to inhibit the leukotriene induced contraction of guinea pig tracheal tissues in vitro. The following methodology was employed:
• EC30 presence of test compound
• EC30 presence of vehicle control
• Kg concentration of test compound/(X-l).
• the compounds of this invention possess antagonist activity against leukotrienes, primarily leukotriene D4.
• the antagonist activity of represen-tative compounds of this invention is listed ' in Table I.
• the -log Kg values were calculated from the above proto ⁇ col. Where compounds were tested more than once, the -log Kg values represent the current average data.
• compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of formula (I) or a pharmaceutically acceptable salt, such as an alkali metal salt thereof, sufficient to produce inhibition of the effects of leukotrienes, such as symptoms of asthma and other hypersensitivity diseases.
• 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 paraffins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
• 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 compositions.
• compositions and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, i.e. orally, parenterally, topically or by inhalation.
• the compositions will 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.
• 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 solution or an aqueous or nonaqueous liquid suspension.
• the pharmaceutical composition will be in the form of a cream or ointment.
• a compound of formula I is administered to an animal subject in a composition comprising a nontoxic amount of the compound sufficient to produce an inhibition of the symptoms of an allergic response.
• the dosage of the composition is selected from the range of from 1 ⁇ g to 700 mg. of active ingredient for each administration.
• equal doses will be administered 1 to 4 times daily with the daily dosage regimen being selected from about 1 ⁇ g. to about 2800 mg. per day.
• the pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
• the method of inhibiting the symptoms of an allergic response resulting from a mediator release which comprises administering to an animal subject a therapeutically effective amount for producing said inhibition of a compound of formula I, preferably in the form of an antagonist in amounts sufficient to inhibit antigen-induced respiratory anaphylaxis.
• a therapeutically effective amount for producing said inhibition of a compound of formula I preferably in the form of an antagonist in amounts sufficient to inhibit antigen-induced respiratory anaphylaxis.
• the above-defined dosage of a compound of formula I is conveniently employed for this purpose and the known effective dosage for the histamine Hi -receptor antagonist.
• the methods of administration described above for the single active ingredient can similarly be employed for the combination with a histamine Hj -receptor antagonist.
• Example 1 (a) The compound of Example 1 (a) (7.1 lg, 0.22M) was dissolved in 125 ml of dry tetrahydrofuran under an argon atmosphere and cooled to 0°.
• Diisobutyl aluminum hydride (33.6 ml, 1.5m in toluene, .05 M) was added dropwise and the solution was stirred and allowed to warm to room temperature overnight.
• the reaction mixture was then cooled in an ice bath, quenched by addition of 10% aqueous NH4CI solution; allowed to warm to room temperature, and warmed for 10 minutes at 35°.
• Triethylamine (11 ml, .079 M) dissolved in 15 ml methylene chloride was added over a period of 2 minutes and the cooling bath was removed. After the reaction mixture had warmed to room temperature, 100 ml of 10% ammonium chloride solution was added. The methylene chloride layer was separated and washed once with 10% ammonium chloride once with water, once with 5% sodium bicarbonate, once with brine and dried over MgS04. Filtration and evaporation yielded a red oil which was further purified by flash chromatography (Baker Si ⁇ 2, 28% ethyl acetate/hexane) to yield the titled compound. l fd ⁇ Methyl 2.3-e ⁇ oxy-3-( ' 2-r3-f7-phenylhe ⁇ tylthio ' )l- pyridyOpropanoate
• the compound of example 1(e) (.96 g, 1.9 mm) was dissolved in 15 ml of methanol and stirred under an Ar atmosphere. KOH (.375 g, 5.7 mm) in 5 ml of water was added dropwise. After stirring for 2 hours, the reaction mixture was diluted with water and the solution was washed twice with ethyl acetate. The aqueous was then layered with ethyl acetate and acidified with 3N HC1 to pH 2.0. The organic layer was separated and the aqueous layer was extracted once with ethyl acetate. The acidic organic extracts were combined and washed once with water, once with brine and dried over MgS ⁇ 4.
• Example 2(a) The compound of Example 2(a) (16 g, .049M) was dissolved in 200 ml of dry tetrahydrofuran and treated with di-isobutyl aluminum hydride (100 ml, 1.5 M in toluene, 0.15M) in the same manner as Example 1(b) to yield the titled compound.
• Example 2(b) The compound of Example 2(b) (13.75 g, .0447 M) was reacted with DMSO (6.45 ml, .0984 M), oxalyl chloride (4.1 ml, .047 mm) and triethylamine (31 ml, .224 M) in 300 ml dry methylene chloride in in the same manner as Example 1(c) to afford the captioned compound.
• DMSO 6.45 ml, .0984 M
• oxalyl chloride 4.1 ml, .047 mm
• triethylamine 31 ml, .224 M
• Example 2(c) The compound of Example 2(c) (11 g, .035 M) was dissolved in 100 ml dry methylene chloride and reacted with methylchloroacetate (4.25 ml; .049 M) and sodium methoxide solution (9.46 ml, .042 M,
• Example 1(d) 25% in MeOH in the same manner as Example 1(d).
• the crude product was purified by flash chromatography (Baker Si ⁇ 2, 25% ethyl acetate/hexane) to yield the titled compound.
• Example 2(d) The compound of Example 2(d) (8.68 g, 22.5 mm) was dissolved in 8 ml of methanol and treated with methyl-3-mercapto propionate (5 ml, 45 mm) and triethylamine (12.5 ml, 90 mm) in the same manner as Example 1(e).
• the retro aldol condensation to degrade the undesired regioisomer was accomplished by the same method by dissolving the crude product in 16 ml MeOH and treating it with sodium methoxide solution (25% NaOMe/methanol, 5.14 ml, 22.5 mm). Final purification was accomplished by flash chromatography. (Baker Si ⁇ 2, 18% ethyl acetate/hexane) to provide the titled compound. 2ffl 2-Hvdroxy-3-f2-carboxyethylthioV3-f3-r2-( 7-phenyl- heptylthio ⁇ pyridv ⁇ propionic acid
• Example 2(e) The compound of Example 2(e) was dissolved in 21 ml of methanol under an Ar atmosphere and treated dropwise with a solution of KOH (58g, 8.85 mm) in 7 ml of water. After 4 hours the reaction was diluted with water, layered with ethyl acetate and acidified to pH 2.0. The organic layer was separated and the aqueous extracted twice with ethyl acetate. The combined organic extracts were washed once with water, once with brine and dried over MgS ⁇ 4.
• KOH 58g, 8.85 mm
• Example 3(a) (2.0g, 7.2mm) was oxidized using the procedure of Example 1(c) using dimethyl sulfoxide (1.2 g, 1.1 ml, 15.6 mm), oxallyl chloride (.99 g, 68 ml, 7.8 mm) and triethylamine (3.58 g, 4.59 ml, 35.5 mm) in 100 ml methylene chloride. This yielded the titled compound.
• 3Cd Methyl 2.3-epoxy-3-f3-[2-undecylthio1pyridyl )p ⁇ opan ⁇ ate
• Example 3(c) The compound of Example 3(c) (1.55 g, 5.29 mm) was reacted with methyl chloroacetate (.84 g, .65 ml, 7.4 mm) and sodium methoxide (.337 g, 6.24 mm; 1.43 ml of 25% sodium methoxide in methanol) in 65 ml methylene chloride according to the procedure of Example 1(d). Flash chromatography (Baker Si ⁇ 2- 10% ethyl acetate/hexane) yielded the titled product. 3(e) Methyl 2-hvdroxy-3-C2-rcarborne.thoxylethylthioV3-G-r2- undecylthiolpyridyPpropanoate
• Example 3(d) The compound of Example 3(d) (1.6 g, 4.38 mm) was dissolved in 3 ml methanol and a solution of methyl-3-mercaptopropionate (1.05 g, 9.67 ml, 8.76 mm) and triethylamine (1.77 g, 2.45 ml, 17.52 mm) in 2 ml MeOH was added. The reaction mixture was stirred at room temperature under an argon atmosphere for 48 hours. The solvent was evaporated to yield an oil. The oil was flash chromatographed (Baker Si ⁇ 2, 15% ethyl acetate/hexane) to yield the desired isomer. 3 • 2-Hvdroxy-3-r2-carboxyethylthioV3-( ' 3-r2-undecylthiol- pyridvDpropionic acid, dipotassium salt.
• Example 3(c) The compound of Example 3(c) (270 mg, .557 mm) was dissolved in 2.5 ml of methanol and potassium hydroxide (110 mg. 1.67 mm) in 1 ml water was added dropwise. The reaction was stirred at room temperature for 2 hours, the methanol was evaporated and the reaction mixture was diluted with water, washed with diethylether (2x), layered with ethyl acetate and acidified to pH 2.0 with dilute HC1. The organic layer was separated and the aqueous was extracted with ethyl acetate (2x). The combined organic extracts were washed with water (lx), brine (lx) and dried over MgS ⁇ 4.
• This material was flash chromatographed (Baker Si ⁇ 2, 3.5% methanol/chloroform - 3.5% trifluoroacetate acid) to yield an oil.
• the oil was further dissolved in 1 ml H2O and treated with 230 mg (8 eq) of potassium hydrogen carbonate.
• the resulting solution was applied to a column of octadecyl silane silica gel (Baker ODS) and eluted sequentially with water (200 ml), 60% methanol/H2 ⁇ (125 ml) and 70% methanol/H2 ⁇ (100 ml).
• Methyl 2,3-epoxy-3- ⁇ 3-[2-(8-phenyloctyl)]pyridyl ⁇ propionate (0.64 g, 1.7 mmol) was dissolved in methanol under an argon atmosphere. To this was added a solution of methyl 3-mercaptopropionate (0.42 g, 3.5 mmol) and triethylamine (0.7 g, 7.0 mmol) in methanol. The resulting solution was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in CH2CI2 and washed successively with H2O, 5% aqueous NaHC03 and saturated aqueous NaCl and dried (MgS ⁇ 4).
• Example 8 2-(4-Carboxyphenoxy)-2-[3-(2-undecylthio)py ⁇ idyl] acetic acid 8(i) methyl 2-chloro-2-[3-(2-undecylthio)pyridylacetate.
• the title compound is prepared from 3-formyl-2- (undecylthio)pyridine [3(c)] following the procedure given in U.S. Patent No. 4,820,719 for the preparation of methyl 2-chloro-2-(2- dodecylphenyl)acetate from 2-dodecylbenzaldehyde.
• Example 9 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
• Inhalant Formulation A compound of formula I, 1 to 10 mg/ml, ' is dissolved in isotonic saline and aerosolized from nebulizer operating at an air flow adjusted to deliver the desired amount of drug per use.
• Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
• Step 2 Add sufficient water portion-wise to the blend from Step
• Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
• Step 4 The wet granules are then dried in an oven at 110°F
• Step 5 The dry granules are lubricated with ingredient No. 5.
• Step 6 The lubricated granules are compressed on a suitable tablet press.
• Step 1 Melt ingredient No. 2 and No. 3 together and stir until uniform.
• Step 2 Dissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform.
• Step 3. Pour the molten mass from Step 2 into supository moulds and chill.
• Step 4. Remove the suppositories from moulds and wrap.

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• 1991
  • 1991-09-10 WO PCT/US1991/006494 patent/WO1992005156A1/en not_active Application Discontinuation
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