WO1991017149A1 - Antagonistes de leucotriene a acide alcanoique substitue oxy ou naphtyle-3-carboxyalkylthio-3 - Google Patents

Antagonistes de leucotriene a acide alcanoique substitue oxy ou naphtyle-3-carboxyalkylthio-3 Download PDF

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WO1991017149A1
WO1991017149A1 PCT/US1991/002889 US9102889W WO9117149A1 WO 1991017149 A1 WO1991017149 A1 WO 1991017149A1 US 9102889 W US9102889 W US 9102889W WO 9117149 A1 WO9117149 A1 WO 9117149A1
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compound
alkyl
pharmaceutically acceptable
phenylpentyl
acid
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PCT/US1991/002889
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James Simpson Frazee
John Gerald Gleason
Ralph Floyd Hall
Irene Nijole Uzinskas
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • A61P11/08—Bronchodilators
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/562—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with nitrogen as the only hetero atom
    • C07C45/565—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with nitrogen as the only hetero atom by reaction with hexamethylene-tetramine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
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    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings

Definitions

  • Scope of the Invention relates to 3-naphtyl-3-carboxyalkylthio or -oxy substiuted alkanoic acid derivatives which are useful for treating diseases associated with 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.
  • Leukotrienenes are a group of eicosanoids formed from arachidonic acid metabolism via the lipoxygenase pathway. These lipid derivatives originate from LTA4 and are of. two types: (1) those containing a sulfidopeptide side chain (LTC4, LTD4, and LTE4), and (2) those that are nonpeptidic (LTB4). Leukotrienes comprise a group of naturally occuring substances that have the potential to contribute significantly to the pathogensis of a variety of inflammatory and ischemic disorders.
  • LTB4 has potent chemotactic actions and contributes to the recruitment and adherence of mobile scavenger cells to endothelial membrane.
  • LTC4, LTD4 and I--TE4 stimulate a variety of types of muscles.
  • LTC4 and LTD4 are p rtent 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 mucous from human airways in vitro. [See Marom, Z. et al., Am. Rev. Respir. Pis.. 126, 449-451 (1982).] The leukotriene antagonists of the prese 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 i a variety of non-pulmonary diseases in the ocular, dermatologic, cardiovascular, renal, trauma, inflammatory, carcinogenic and other areas.
  • 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 enduced renal failure and th effects of the leukotrienes selectively antagonized in this model of renal injury. [See Badr, K.F., et al., Kidney International.
  • LTD4 has been shown to produce local glomerular constrict actions which are prevented by treatment with 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 Punn, M.J. et al., Kidney International. 27. 1, 256 ( ⁇ 985).
  • Leukotriene antagonists thus can be useful in the treatmen of inflammatory liver and bowel disease,
  • the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment o diseases in subjects, including human or animals, in which leukotrienes are a key factor.
  • Leukotriene antagonists based on 3-phenyl-3-carboxyalkylthi alkanoic acids are disclosed in U.S. patent No. 4,820,719.
  • Ri is C8 to C13 alkyl, C7 to C ⁇ 2 alkoxy, C ⁇ to C ⁇ 2 alkylthio, CI Q to Cj2 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to Ci 0 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C ⁇ to C9 alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C ⁇ to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to Cio alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl- C4 to Cio alkyl;
  • P is 0 or S(0) q where q is 0, 1 or 2, with the proviso that ⁇ is not alkylthio or phenylthioalkyl when q is 1 or 2;
  • Y is R2, CH(R 3 )(CH2) m R2, CH(R 3 )-tetrazol-5-yl, or tetrazol-5-yl; m is 0, 1, and 2;
  • R2 is -COR4 where R4 is -OH, -OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group
  • R2 is -N(R5)2 where R5 is H, C ⁇ to alkyl, phenylCi-C ⁇ -alkyl, o the two R5 groups are combined to form a cyclic group having 3 to 5 carbons, -CN, -SO3H, -S0 2 NH 2 , NHS0 2 R6, -CH(NH 2 )COR4, NHCH2COR4
  • R3 is hydrogen, methyl, Ci to C4 alkoxy, fluoro or hydroxy
  • R is -(CH2) n A, -(CH2)nArA or ArA where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and A
  • This invention also relates to a means for treating diseases pulmonary or non-pulmonary diseases which involve leukotrienes and which can be treated by administering a leukotriene antagonist.
  • compositions! which comprise a compound of formula I either alone formulated with a pharmaceutically acceptable excipient.
  • Such compositions may also contain an Hi blocker.
  • phenylthioalkyl is used to mean the thioether radical where -S- is bonded to the phenyl group and the alkyl portion of the radical is bonded to the sulfur as illustrated by the following formul
  • a preferred class of compounds of this invention are the substituted alkanoic acid analogs of formula (I) where P is -S- represented by formula (II)
  • a particularly preferred class of these compounds are the diac derivatives represented by the following general structural formula (III)
  • a further preferred class of compounds of this invention are th 2-hydroxy substituted propionic acid analogs of formula (I) where D is -S- represented by the structural formula (IV)
  • R is the same as described above, but particularly those compounds where Rj is dodecyl or phenyl-C4 to Ci Q-alkyl and R2 is COOH
  • Another preferred class of compounds of this invention are the tetrazolyl substituted analogs of formula (I) where again P is -S- represented by the structural formula (V)
  • Some of the compounds of the formula (I) contain two or even three asymmetric centers.
  • R3 is methyl, methoxy, fluoro or hydroxy, or R is CH(C ⁇ 2H)CH2C ⁇ 2H, or both R3 and R are on of these substituents.
  • R3 and R are on of these substituents.
  • these compound are prepared as a mixture of stereoisomers. Resolution procedures employing, for example, optically active amines can furnish the separated enantiomers.
  • the compounds of the present invention 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 compoun and do not exhibit untoward or deliberous activity.
  • Acceptable acids include inorganic and organic acids, such as hydrochloric, sulfuric, methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and acetic acid.
  • Bases include organic and inorganic bases, such as ammonia, arginine, organic amines, alkali metal bases and alkaline earth metal bases. Piperazine and ethyienediamine salts are particularly useful i this invention.
  • Pharmaceutically acceptable cations are the same as the just recited base-derived pharmaceutically acceptable salts.
  • the compounds of the present invention 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 compoun and do not exhibit untoward or deliberous activity.
  • Acceptable acids include inorganic and organic acids, such as hydrochloric, sulfuric, methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and acetic acid.
  • Bases include organic and inorganic bases, such as ammonia, arginine, organic amines, alkali metal bases and alkaline earth metal bases. Piperazine and ethyienediamine salts are particularly useful this invention. Also preferred are the dipotassium, disodium, dimagnesium, di-zinc, and dicalcium salts of the diacid compounds o formula (I). Pharmaceutically acceptable cations are the same as the just recited base-derived pharmaceutically acceptable salts.
  • the compounds of the formula (I) wherein Y is CH2CO2H are prepared by reacting the appropriate aldehydes of the formula VI, wherein Ri and R2 are as described above 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 use to prepare the 3-hydroxypropionate derivative.
  • compounds of formula (I) are prepared from th aldehydes VI by reaction with lithium diisopropylamide and t-butyl acetate at -78°C to 25°C in a suitable solvent such as, for example, tetrahydrofuran (THF), to provide the precursor esterified 3- hydroxypropionate derivatives which are converted to the thiol acid with a mercaptan in trifluoroacetic acid.
  • THF tetrahydrofuran
  • the appropriate thio product is conveniently oxidized with a weak oxidizing agent such as sodium periodate or metachloroperbenzoic acid to obtain the sulfoxide or sulfone product.
  • a weak oxidizing agent such as sodium periodate or metachloroperbenzoic acid
  • aldehydes of the formula (VI) are known or readily prepared utilizing the general procedures described as follows.
  • the aldehyde precursors to the compounds of the formula (I) wherein Ri is, for example, an alkyl radical containing 8 to 13 carbon atoms are prepared from the appropriate 2-methoxyphenyl-4,4- dimethyloxazoline [see Meyers et al. J. Ore. Chem.. 43. 1372 (1978)].
  • the aldehyde precursors to the compounds of the formula (I) wherein Ri is a 1-alkynyl radical containing 10 to 12 carbon atoms are prepared by coupling a halobenzaldehyde with the appropriate 1 alkyne in the presence of cuprous iodide and (Pd3)2PdCl2- [See Higahara et al., Synthesis. 627 (1980)].
  • the compounds of the formula (I) wherein Y is CH2CO2H are prepared from a propenoate precursor of the alkene of formulas (VII).
  • Rj and R2 are described above, and R Q is an ester protecting group, such as t-butyl.
  • a compound of formula (VII) is reacted with a mixture of alkali metal alkoxide, such as sodium methoxide, and an appropriately substituted thiol or alcohol to give, after removal of the ester protective group, products of formula (I).
  • the propenoate precursors of formula (VII) are prepared from the corresponding aldehydes of formulas (VI) by general procedures such as reaction with an alkyl (triphenylphosphoranylidene)acetate o 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 or from a 3-acetoxypropionate derivative by treatment with l,8-diazabicyclo-[5,4,0]undec-7-ene at elevated temperature, eg. about 90°C. 1 0
  • Rj , R2, and m are defined above, and R is lower alkyl, su as methyl or ethyl.
  • a compound of formula (VIII) is reacted . in an inert solvent with triethylamine and a substituted thiol or alcohol selected to give, after removal of ester protective groups, a product formula (I).
  • the epoxide precursors of formula (VIII) where m is 0 are prepared by reaction of an aldehyde of the formula (VI) with a lowe alkyl chloroacetate and an alkali metal alkoxide, such as sodium methoxide.
  • the compounds of the formula (I) wherein Y is CH(OH)COR2 are prepared from a propenoate precursor of formula (VII) wherein Rn is lower alkyl.
  • the 2-thioimidazole precursors necessary to prepare the R-heterocyclic derivatives of formula (I) are known compounds or a conveniently prepared employing standard chemical reactions.
  • these reactants bearing a carboxyl or carboxymethyl substituent as set forth in Rg and R9 above are employed as the corresponding carboalkoxy derivatives wherein the alkoxy radical contains from one to six carbon atoms.
  • the alkoxy substituent is' subsequently hydrolyzed to give the free carboxyl or carboxymethyl substituted products.
  • 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 vitr
  • Guinea pig (ad male albino • Hartley strain) tracheal spiral strips of approximate dimensions 2 to 3 mm cross-sectional width and 3.5 cm length were bathed in modified Krebs buffer in jacketed 10 ml tissue bath and continuously aerated with 95% 02/5 C02- The tissues were connected via silk suture to force displacement transducers for recording isometric tension.
  • the tissues were equilibrated for 1 hou pretreated for 15 minutes with meclofenamic acid (1 mM) to remov intrinsic prostaglandin responses, and then pretreated for an additional 30 minutes with either the test compound or vehicle control.
  • a cumulative concentration-response curve for LTP4 on triplicate tissues was generated by successive increases in the bath concentration of the LTP4.
  • the contractions elicited by LTP4 were standardized as a percentage of the maximum response obtained to a reference agonist carbachol (10 mM).
  • the compounds of this invention possess useful antagonist activity against leukotrienes, primarily leukotriene P4.
  • the antagonist activity of representative compounds of this invention is tabulated below.
  • the -log Kg values were calculated from the above test protocols.
  • a represented compound, the phenylpentyl- substituted analog, was compared in this assay to the known leukotriene antagonist 2-hydroxy-3-(2-carboxyethylthio)-3-((2- octylphenyl)phenyl)propionic acid.
  • the naphthyl compound gave a pK ⁇ of 6.5 at 10" 5 M.
  • the specificity of the antagonist activity of a number of the c ⁇ mpounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, carbachol, histamine and PGF2.
  • 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 alkal metal salt thereof, sufficient to produce the inhibition of the effects o 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 aerosol systems, dichlorodifluoromethane, 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 n have a detrimental effect on the therapeutic action of the instant compositions.
  • compositions and the pharmaceutical carrier o diluent will, of course, depend upon the intended route of administration, whether it be parenterally, topically, orally or by inhalation.
  • the compositions will be in a form suitable for administratio by inhalation.
  • the compositions will comprise a suspension or solution of the active ingredient in water for administration by mean 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 composition 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 o the active ingredient.
  • the diluent When the diluent is a solid it may be present lesser, equal or greater amounts than the solid active ingredient.
  • the pharmaceutical composition may be in the form of a sterile injectable liquid such as an ampule an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical composition for topical administration the pharmaceutical composition may be in the form of a cream, ointment, liniment, lotion, pastes, and dr suitable for administration to the eye, ear, or nose.
  • the pharmaceutical composition will b in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syr liquid, or emulsion. Sustained release formulations may also be prepared. Refere is made to Remington's Pharmaceutical Sciences for detailed information on the preparation of such formulations, and for assistance in preparing all other formulations indicated by the practice of this invention.
  • a compound of formula I is administered to a subject i a composition comprising a therapeutically effective amount, a nontoxic amount, sufficient to produce an inhibition of the symptom of a disease in which leukotrienes are a factor.
  • the dosage of the composition is selected from the rang of from 350 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 350 mg to about 5000 mg.
  • a disease comprising 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. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the condition or disease being treated, and forth.
  • compositions, as described hereinabove, of the present invention also comprise a pharmaceutical carrier or diluent and a combination of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and an histamine H - receptor antagonist in amounts sufficient to inhibit antigen-induced respiratory anaphylaxis.
  • a pharmaceutical carrier or diluent and a combination of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and an histamine H - receptor antagonist in amounts sufficient to inhibit antigen-induced respiratory anaphylaxis.
  • the above-defined dosage of a compound o formula I is conveniently employed for this purpose and the known effective dosage for the histamine H -receptor antagonist.
  • the methods of administration described above for the single active ingredient can similarly be employed for the combination with a histamine H -receptor antagonist.
  • Example 1 3- 2-Ca ⁇ boxyethylthioV3-r7-( ' 5-phenylpentyl )naphthyl1propionic ac l( ) 4-f4-bromophenyl)butanoic acid.
  • 3-(4-bromobenzoyl)propionic acid (4.75 g, 18. mmole) and potassium hydroxide (3.51 g, 62.6 mmole) in diethylen glycol (25 mL) was added 85% hydrazine hydrate (2.5 mL), and the resulting solution was refluxed for 1.5 hours.
  • 4-(4-Bromophenyl)butanoic acid (3 g, 12.3 mmole) was treate with the complex formed from equivalent amounts of methane sulfonic acid and phosphorus pentoxide (prepared according to J. Or Chem. (1973), 2&, 4071), (30 g), and this mixture was heated at 70° for 1 hour.
  • the reaction mixture was poured onto ice water, the pH was adjusted to 12 with NaOH solution and the product was extracte into ether. The extracts were washed with brine, dried and concentrated to a crystalline solid.
  • the title compound is prepared by the procedure of Example l(x-xii) by using 7-(l -dodecyl)- 1-naphthaldehyde in place of 7-(5- phenylpentyl)-l -naphthaldehyde.
  • Example 3 3-r2-Carboxyethylthio >-3-r7-r5- ⁇ henylDentvn-l - naphthv ⁇ -2-hvd ⁇ oxypropionic acid
  • the title compound is prepared from 7-(5-phenylpentyl)-l- naphthaldehyde via the derived methyl [l-(7- ⁇ 5-phenylpentylI naphthyl] -2,3 -epoxypropionate following the procedure given in EP application 0 202 759 published November 26, 1986.
  • Example l(x-xii) The procedure of Example l(x-xii) is followed by using " 2-dodecyl-l-naphthaldehyde in place of 7-(5-phenylpentyl)-l - naphthaldehyde.
  • the title compound was a syrup.
  • Example 6 3-f2-CarboxyethylthioV3-r2- ⁇ -dodecyl-2-na ⁇ hthvm- pfQpionic acid
  • the title compound was prepared by the procedure of Exampl 5 using 2-(l-methoxy-2-naphthyl)-4,4-dimethyloxazoline in place o 2-(2-methoxynaphth-l-yl)-4,4-dimethyloxazoline.
  • the title compound is prepared by the method described in Example 3 using 2-dodecyl-l-naphthaldehyde in place of 7-(5- phenylpentyl)-l -naphthaldehyde.
  • the 5 phenylpentyl bromide was prepared from 5-phenylpentanol, carbo tetrabromide and triphenylphosphine in dichloromethane.] After being stirred for 24 hours, the reaction mixture was similarly work up to yield 2-[2-(5-phenylpentyl)naphthyl]-4,4-dimethyloxazoline an oil. This product was converted to 2-(5-phenylpentyl)-l- naphthaldehyde by the procedure entirely analogous to Example 5(i iii). ⁇ fin 3-f2-carboxyethylthio-3-r2-C5- ⁇ henylpentvnnaphth-l -yll ⁇ propionic acid.
  • Example 9 3-f2-CarboxyethylthioV-3-r2-f8- phenyloctyl ' .naphth-1-v ⁇ propionic acid ⁇ 1 ⁇ ) 2-f 8- ⁇ henvioctvn-l -naphthaldehvde.
  • the procedure of Example 8(i) was followed by using 8- phenyloctylmagnesium bromide in place of 5-phenylpentylmagnesium bromide.
  • reaction mixture is diluted with ether, cooled to 0°C, and ice-cold NH4 ⁇ H/water/ glycerine is added dropwise with stirring.
  • the organic layer is washed with wat and brine, dried (MgS04), concentrated and flash chromatographed over silica gel eluting with 5% ethyl acetate in hexanes to give t-buty
  • the resultant oil is flash chromatographed on silica with 20% ethyl acetate in hexanes containing 0.5% of formic acid.
  • the homogeneous fractions (1.2 mmole) are swirled with aqueous potassium carbonate (2.87 mmole) for 80 minutes.
  • This is flash chromatographed on HPLC with a C-18 reverse phase support using 1 : 1 acetonitrile/water to provide after lyophilization the dipotassium salt; mp >250°C.
  • the title compound is prepared by the method described in Example 3 using 1 -dodecyl-2-naphthaldehyde in place of 7-(5- phenylpentyl)-l -naphthaldehyde.
  • Example l(x-xii) The procedure of Example l(x-xii) is followed, using 2- undecyloxy-1-naphthaldehyde in place of 7-(5-phenylpentyl)-l- naphthaldehyde.
  • Example 3 The procedure of Example 3 is followed by using 2-undecylox 1 -naphthaldehyde in place of 7-(5-phenylpentyl)-l -naphthaldehyd
  • Example l l(i) was followed replacing the 2- hydroxy-1 -naphthaldehyde with 2-methyl-l -naphthaldehyde.
  • the title compound is an oil.
  • Example 14 3-( 2-carboxyethylthio')-3-r2-( f 8-undecyloxy)- naphthyllpropionic acid
  • the title compound is prepared by the procedure of Example 1 (i-v) by using 7 -methyl- 1-naphthol in place of 2-methyl-l-naphthol
  • 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 belo
  • Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitab mixer/blender. 25
  • Step 2 Add sufficient water portionwise to the blend from Step with careful mixing after each addition. Such additions o water and mixing until the mass is of a consistency to permit its conversion to wet granules.
  • Step 3 The wet mass is converted to granules by passing it mrough an oscillating granulator using a No. 8 mesh (2.3 mm) screen.
  • Step 4 The wet granules are then dried in an oven at 410°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. Pissolve 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.
  • Example 17 As a specific embodiment of a composition of this invention, an active ingredient of Example 7-11 is dissolved in 25 mM sodium carbonate at a comcentration of 0.4 percent weight/volume and delivered from a nebulizer operating at an air flow adjusted to delive the desired amount of drug in aerosol form.

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Abstract

Composés d'acide alcanoïque possédant un anneau naphtyle et des substituants thio utiles en tant qu'antagonistes de leucotriène.
PCT/US1991/002889 1990-05-01 1991-04-26 Antagonistes de leucotriene a acide alcanoique substitue oxy ou naphtyle-3-carboxyalkylthio-3 WO1991017149A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP91508401A JPH05506662A (ja) 1990-05-01 1991-04-26 ３―ナフチル―３―カルボキシアルキルチオまたはオキシ置換アルカン酸ロイコトリエン拮抗剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US51858390A 1990-05-01 1990-05-01
US518,583 1990-05-01

Publications (1)

Publication Number Publication Date
WO1991017149A1 true WO1991017149A1 (fr) 1991-11-14

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EP (1) EP0527175A4 (fr)
JP (1) JPH05506662A (fr)
AU (1) AU7769491A (fr)
CA (1) CA2081480A1 (fr)
WO (1) WO1991017149A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0630895A1 (fr) * 1993-06-24 1994-12-28 Bayer Ag Dihydropyridines substituées en position 4 par un groupe bicyclique, procédé pour leur préparation et utilisation dans les médicaments
US6410562B1 (en) * 1998-12-18 2002-06-25 Eli Lilly And Company Hypoglycemic imidazoline compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4009197A (en) * 1967-01-13 1977-02-22 Syntex Corporation 2-(6-Substituted-2'-naphthyl) acetic acid derivatives and the salts and esters thereof
US4954513A (en) * 1988-12-23 1990-09-04 Smithkline Beecham Corporation Leukotriene antagonists
US4968711A (en) * 1987-04-22 1990-11-06 Lilly Industries Limited Tetrazole compounds and use as anti-allergics

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931269A (en) * 1973-12-06 1976-01-06 William H. Rorer, Inc. Alpha-acyl substituted naphthylacetic acids
US4513005A (en) * 1981-06-18 1985-04-23 Lilly Industries Limited SRS-A antagonists
ATE53991T1 (de) * 1985-04-19 1990-07-15 Smithkline Beecham Corp Leukotrien-antagonisten.
JPS63139148A (ja) * 1986-11-29 1988-06-10 Tokuyama Soda Co Ltd フエノキシ酢酸誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4009197A (en) * 1967-01-13 1977-02-22 Syntex Corporation 2-(6-Substituted-2'-naphthyl) acetic acid derivatives and the salts and esters thereof
US4968711A (en) * 1987-04-22 1990-11-06 Lilly Industries Limited Tetrazole compounds and use as anti-allergics
US4954513A (en) * 1988-12-23 1990-09-04 Smithkline Beecham Corporation Leukotriene antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0527175A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0630895A1 (fr) * 1993-06-24 1994-12-28 Bayer Ag Dihydropyridines substituées en position 4 par un groupe bicyclique, procédé pour leur préparation et utilisation dans les médicaments
US5545646A (en) * 1993-06-24 1996-08-13 Bayer Aktiengesellschaft 4-bicyclically substituted dihydropyridines and their use in medicaments
US5721248A (en) * 1993-06-24 1998-02-24 Bayer Aktiengesellschaft 4-bicyclically substituted dihydropyridines, and their use in medicaments
US6410562B1 (en) * 1998-12-18 2002-06-25 Eli Lilly And Company Hypoglycemic imidazoline compounds

Also Published As

Publication number Publication date
AU7769491A (en) 1991-11-27
JPH05506662A (ja) 1993-09-30
CA2081480A1 (fr) 1991-11-02
EP0527175A1 (fr) 1993-02-17
EP0527175A4 (en) 1993-05-05

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