FIVE-MEMBERED RING ALKANOIC ACID LEUKOTRIENE ANTAGONISTS

Abstract: This invention relates to alkanoic acid compounds having a 5-membered heterocyclic ring and a thio substituent which are useful as leukotriene antagonists.

Description: Five-Membered Ring Alkanoic Acid Leukotriene Antagonists Scope of the Invention • This invention relates to heteroaromatic five-memembered ring alkanoic acid derivatives which are useful for treating diseases associated with leukotrienes. Background of the Invention "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 ch lenge. 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. The discovery of the naturally occurring leukotrienes and their relationship to SRS-A has reinforced interest in SRS-A and other arachidonate metabolites. 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). As summarized by Lefer, A.M., Biochemical Pharmacology. 35. 2. 123-127 (1986) both the peptide and non-peptide leukotrienes exert microcirculatory actions, promoting leakage of fluid across the capillary endothelial membrane in most types of vascular beds. LTB4 has potent chemotactic actions and contributes to the recruitment and adherence of mobile scavenger cells to 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. LTC and LTD 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. Res p ir. 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 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. Another area of utility for leukotriene antagonists is in the treatment of cardiovascular diseases. Since peptide leukotrienes are potent coronary vasoconstrictors, they are implicated in a variety of cardiac depression. Synthetic leukotrienes have been shown to be powerful myocardial depressants, their effects consisting of a decrease i 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 cardian anaphylaxis. [See Burke, J.A., et al., J. Pharmacology and Experimental Therapeutics. 221, 1, 235-241 (1982).] 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. [See Badr, K.F. et al.. Circulation Research. 54. 5, 492-499 (1984). Leukotrienes have also been shown to have a role in endotoxin enduced renal failure and the effects of the leukotrienes selectively antagonized in this model of renal injury. [See Badr, K.F., et al., Kidney International. 30, 474-480 (1986).] LTD4 has been shown to produce local glomerular constrictor 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 Dunn, M.J. et al., Kidnev International. 27. 1, 256 (1985). Thus another area of utility for leukotriene antagonists can be in the treatment of glomerulonephritis. By antagonizing the effects of LTC4, LTD4 and LTE4 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. Leukotriene antagonists based on 3-phenyl-3-thiopropionic acids are disclosed in U.S. patent 4,820,719 and EPO application No. 0 202 759 published 26 November, 1986. DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are represented by formula (I) wherein R \ is not substituted on A or B; X is 0 or S(0) q where q is 0, 1 or 2 with the proviso that Rj is not alkylthio or phenylthioalkyl when q is 1 or 2; Rl is C8 to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, Cχ o to C12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to Ci 0 alkyl, phenyl-C3 t0 C9 alkoxy, phenylthio-C3 to Co alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, Ci to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C to C12 alkyl or cyclohexyl- C4 to C10 alkyl; A is S, O, or N; B is CH or NR2; R2 is H, Ci to C 1 3 .alkyl, C10 to C \ 2 - 1-alkynyl, 11 -docedynyl, phenyl-C4 to C 10 alkyl with phenyl optionally monosubstituted or X-R the dotted line between A and B indicates a single bond in one position and a double bond in the other; Y is R3, CH(R4)(CH2) m R 3> CH(R4)-tetrazol-5-yl, or tetrazol-5-yl; R3 is -COR5 where R5 is -OH or OX where X is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R7, -CH(NH 2 )COR 5 , or -NHCH2COR5, or R3 is -N(Rg)2 where Re is H, Ci to Cβ alkyl, phenylCi-Cβalkyl, or the two R$ groups are combined to form a cyclic group having 3 to 5 carbons; R4 is hydrogen, methyl, Cj to C4 .alkoxy, fluoro or hydroxy; R7 is Ci to Cio-alkyl, phenyl or substituted phenyl; m is 0, 1, or 2; R is -(CH2) n D, -(CH2) n AτD or ArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2) n R3, -COR3, tetrazol-5-yl, -CH(NH2)Rs, -NHCH2COR5, -NHSO2R7, -SO3H, -CN, or -SO2NH2; or a pharmaceutically acceptable salt. The term phenylthioalkyl is used to mean the thioether radical where phenyl is bonded to sulfur which is bonded to the alkyl moiety, the radical of the formula A preferred class of compounds of this invention are the substituted alkanoic acid analogs of formula (I) where X is S(0) q where q is 0 and Y is -(CH2 θ-3 OOH represented by formula (II) wherein R and R are the same as described above, A is S, O or N and B is CH or NR2. The most preferred class of these compounds are those where X is S, R is -(CH2) n D, -(CH2) n ArD or ArD, Y is -CH2COOH, A X-R is S, O, or N, and B is CH or -NR2 where the group -^ " ^Y is not R2, and R l is Cδ to Ci3-alkyl or phenyl-C 4 to Cio-alkyl. The most preferred X-R compounds in this category are where *"^Y is at the 2-position: (1 ) 3-(2-carboxyethylthio)-3-(3-dodecylthien-2-yl)propionic acid; (2) 3-(2-carboxyethylthio)-3-[3-(8-ρhenyloctyl)thien-2-yl] propionic acid; (3) 3-(2-carboxyethylthio)-3-( l -dodecyl- lH-imidazol-2-yl) propionic acid; (4) 3-(2-carboxyethylthio)-3-[l -(8-phenyloctyl)- lH-imidazol 2-yl]propionic acid, (5) 3-(2-carboxyethylthio)-3-[3-(8-phenyloctyl)fur-2-yl] propionic acid, and ' (6) 3-(2-carboxyethylthio)-3-(3 -dodecylfur-2-yl)propionic acid. A further particular group of compounds of this invention are those where X is S, Y is -C(OH)HCOR3, R is -(CH2) n D, -(CH2) π ArD or ArD Rl is Cδ to Ci3-alkyl or phenyl-C4 to Cio-alkyl, A is S, 0, or N and B is X-R CH or -NR2 where the group '"' r is not R2. The most preferred X-R compounds of this group are those where "^Y is at the 2-position: 3 -(2-carboxyethylthio)-3-(3 -dodecylthien-2-yI)-2- hydroxypropionic acid; 3-(2-carboxyethylthio)-3-(3 -(8-phenyloctyl)thien-2-yl)-2- hydroxypropionic acid, 3-(2-carboxyethylthio)-3-(l -dodecyl- lH-imidazoi-2-yl)-2- hydroxypropionic acid, 3-(2-carboxyethylthio)-3-(l -(8-phenyloctyl)- l H-imidazoI-2- yl)-2-hydroxypropionic acid, 3-(2-carboxyethylthio)-3 -(3 -dodecylfur-2-yl)-2- hydroxypropionic acid; and 3-(2-carboxyethylthio)-3 -(3-(8-phenyloctyl)fur-2-yI )-2- hydroxypropionic acid. Another preferred class of compounds of this invention are the compounds where Y is (CH2)o-i-tetrazol-5-yl or -CH(OH)-tetrazol-5-yl. X is S, R is -(CH 2 ) n D. -(CH 2 ) n ArD or ArD, A is O, S or N, B is -CH- or NR X-R where the group " τ is not R2 and Ri is Cg to C13 -alkyl or phenyl-d X-R to Cio-alkyl. The most preferred compounds are those where '" ' Ύ is at the 2-position, : 4-thia-5-(3-dodecylthien-2-yl)-6-(tetrazol-5-yI)hexanoic acid; 4-thia-5-(l -dodecyl-lH-imidazol-2-yl)-6-(tetrazol-5- yl)hexanoic acid; 4-thia-5-(3-(8-phenyloctyl)thien-2-yl)-6-(tetrazol-5 - yl)hexanoic acid; 4-thia-5-( l -(8-phenyloctyl)-lH-imidazol-2-yl)-6-(tetrazoi-5 - yl)hexanoic acid 4-thia-5-(3-dodecylfur-2-yl)-6-(tetrazol-5-yl)hexanoic acid; 4-thia-5-(3-(8-phenyloctyl)fur-2-yl)-6-(tetrazol-5-yl)hexanoic acid; 4-thia-5-(3-dodecylthien-2-yl)-6-hydroxy-6-(tetrazol-5- yl)hexanoic acid; 4-thia-5-(l -dodecyl-lH-imidazol-2-yl)-6-hydroxy-6-(tetrazol- 5-yl)hexanoic acid; 4-thia-5-(3-(8-phenyloctyl)thien-2-yl)-6-(tetrazoi-5 - yl)hexanoic acid; 4-thia-5-(l -(8-phenyloctyl)- l H-imidazol-2-yl)-6-hydroxy-6- (tetrazol-5-yl)hexanoic acid 4-thia-5-(3-dodecylfur-2-yl)-6-hydroxy-6-(tetrazol-5-yl)- hexanoic acid; and 4-thia-5-(3-(8-phenyloctyl)fur-2-yl)-6-hydroxy-6-(tetrazol-5 - yl)hexanoic acid. A second class of preferred compounds are those where X is O, particularly those paralleling the preferred and most preferred definitions for the case where X is S given above. Most preferred compounds of this group are the following compounds: 3-(2-carboxyethyloxy)-3-(3-dodecylthien-2-yl)propionic acid: 3-(2-carboxyethyloxy)-3-[3-(8-phenyloctyl)thien-2-yl] - propionic acid; 3-(2-carboxyethyloxy)-3-( l -dodecyl- lH-imidazol-2-yl) propionic acid; 3-(2-carboxyethyloxy)-3- [l -(8-phenyloctyl)- l H-imidazol-2- yl]propionic acid. 3-(2-carboxyethyloxy)-3 -(3-dodecylthien-2-yl)-2- hydroxypropionic acid; 3-(2-carboxyethyloxy)-3-(l -dodecyl-lH-imidazol-2-yl)-2- hydroxypropionic acid; 4-oxy-5-(3-dodecylthien-2-yl)-6-(tetrazol-5-yl)hexanoic acid; 4-oxy-5-(3-(8-phenyloctyl)thien-2-yl)-6-(tetrazol-5- yl)hexanoic acid; 4-oxy-5-(l -(8-phenyloctyl)- l H-imidazol-2-yl)-6-(tetrazol-5- yl)hexanoic acid; and 4-oxy-5-( l -dodecyl-lH-imidazol-2-yl)-6-(tetrazol-5- yl)hexanoic acid. All compounds of this invention have at least one assymetric center due to X being sulfur or oxygen. Some of the compounds of th formula (I) contain two asymmetric centers, such as when R4 in the sustituent is other than hydrogen, such as is methyl, methoxy, fluoro or hydroxy. Other asymetric centers may also be present in these molecules depending on the selection of substituents in any given compound. In practice, these compounds are prepared as a mixture stereoisomers. all steroisomers, as mixtures or resolved isomers, are included in this invention. Resolution procedures employing, for example, optically active amines furnish the separated enantiomers. Pharmaceutically acceptable esters may be formed from those compounds having a carboxylic acid function ie when R has the -COR3 terminal group. Such an ester, or di-ester as the case may be will be any ester which, as with pharmacuetically acceptable suits, gives an ester which retains the activity of the parent compound and does not impart to the parent acid any unacceptable untoward pharmacologic or toxic affects in the context of its intended use and application. While it is expected that any carboxylic acid ester may be used, it is preferred to employ certain esters derived from the following radicals: Ci to Cβ alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl. The compounds of the present invention, depending on their structure, are capable of forming pharmaceutically acceptable salts with acids and bases according to procedures well known in the an. Such salts are those which match the activity of the parent compound 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 ethylenediamine salts are particularly useful in this invention. Also preferred are the dipotassium, disodium, dimagnesium, dizinc, and dicalcium salts of the diacid compounds of formula (I). Pharmaceutically acceptable cations are the same as the just recited base-derived pharmaceutically acceptable salts. The compounds of die formula (I) wherein Y is CH2CO2H are prepared by reacting the appropriate aldehydes of the formula VI or VII, wherein R , R2 and A 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. Alternatively, a mixture of trimethyl borate and zinc in tetrahydrofuran may be used to prepare the 3-hydroxypropionate derivative. Preferably, compounds of formula (I) are prepared from the aldehydes VI or VII by reaction with lithium diisopropylamide and t-butyl acetate at - 78°C to 25°C in a suitable solvent such as, for example, THF, to provide the precursor esterified 3-hydroxypropionate derivatives which are converted to the thiol acids with a mercaptan in trifluoroacetic acid. By employing an esterified 2-bromopropionate in the above reaction with an aldehydes VI or VII, the compounds of the formula (I) wherein Y is CH(CH3)C02H are obtained. To prepare the compounds of formula (I) wherein q is 1 or 2, the appropriate thio product is conveniently oxidized with sodium periodate or metachloroperbenzoic acid to obtain the sulfoxide or sulfone product. The aldehydes of die formula (VI) .and (VII) 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. Or?. 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 (Pθ3)2PdCl2- [See Higahara et al., Synthesis. 627 (1980)]. The catalytic hydrogenation of these alkynyl containing precursors under standard conditions affords the aldehyde precursors of the compounds of the formula (I) wherein R i is an alkyl or phenylalkyl radical. Alternatively, the compounds of the formula (I) wherein Y is CH2CO2H are prepared from a propionate precursor of the following structural formulas (VIII) and (IX). wherein Ri , R2 and A are described above, and R\ $ is an ester protective group, such as t-butyl. A compound of formula (VIII) or (IX) is reacted with a mixture of alkali metal alkoxide, such as sodium methoxide, and substituted thiol to give, after removal of the ester protective group, products of formula (I). The propionate precursors of formula (VIII) or (IX) are prepared from the corresponding aldehydes of formulas (VI) and (VII) 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-methane- sulfonyloxypropionate derivative by treatment with triethylamine or from a 3-acetoxypropionate derivative by treatment with 1,8- diazabicyclo-[5,4,0]undec-7-ene at elevated temperature, eg. about 90°C. The compounds of the formula (I) wherein Y is CH(OH)(CH2)mC02H are prepared from an epoxide precursor of the following structural formulas (X) and (XI) wherein R\ , R2, A and m are the same as described above, and R g is C i to C alkoxy. A compound of formula (X) or (XI) is reacted in an inert solvent with triethylamine and a substituted thiol selected to give, after removal of ester protective groups, a product of formula (I). The epoxide precursors of formula (X) or (XI) where m is 0 are prepared by reaction of an aldehyde of the formula (VI) or (VII) with a lower alkyl chloroacetate and an alkali metal alkoxide, such as sodium methoxide. Alternatively, the compounds of the formula (I) wherein Y is CH(OH)COR 6 .are prepared from a propenoate precursor of formula (VIII) or (IX) wherein R g is lower alkyl. The 2-thioimidazole precursors necessary to prepare the R- heterocyclic derivatives of formula (I) are known compounds or are conveniently prepared employing standard chemical reactions. Preferably 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. When present, the alkoxy substituent is subsequently hydrolyzed to give the free carboxyl or carboxymethyl substituted products. Appropriate modifications of the general processes disclosed, and as further described in the Examples provided hereinbelow, furnish the various compounds defined by formula (I). 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: In vitro: Guinea pig (adult 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 CO2. The tissues were connected via silk suture to force displacement transducers for recording isometric tension. The tissues were equilibrated for 1 hr, pretreated for 15 minutes with meclofenamic acid (1 mM) to remove 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 LTD4 on triplicate- tissues was generated by successive increases in the bath concentration of .the LTD4. In order to minimize intertissue variability, the contractions elicited by LTD4 were standardized as a percentage of the maximum response obtained to a reference agonist, carbachol (10 mM). Calculations: The averages of the triplicate LTD4 concentration- response curves both in the presence and absence of the test compound w- ^ re plotted on log graph paper. The concentration of LTD4 needed to elicit 30% of the contraction elicited by carbachol was measured and defined as the EC30. The -log Kg value for the test compound was determined by the following equations: 1- EC30 ( " presence of test compound) = dose ratio = X EC30 (presence of vehicle control) 2. Kβ = concentration of test compound/(X-l) The compounds of this invention possess antagonist activity against leukotrienes, primarily leukotriene D4. The antagonist activity of representative compounds of this invention is tabulated below. The -log Kβ values were calculated from the above test protocols. Where compounds were tested more than once, the -log Kβ values given herein represent the current average data. Compound 3- (2-carboxyethylthio-3-(3-dodecylthien-2-yl)propionic acid at a molar concentration of 10' 5 showed a pKβ of 6.5 in comparison to a pKβ of 7.3 for a 10' 6 molar concentation of 2-hydroxy-3(R)-2- carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propionic acid, a known leukotriene antagonist. Likewise, methyl 2-hydroxy-3-(2- carboxyethylthio)-3-(3-dodecylimidazol-2-yl)propionate was tested against the afore mentioned phenylpropionic acid, the imidazole having a pKβ of 5.9 at a molar concentration of 10 -5 and the phenylpropionic acid having a pKβ of 8.3 at a molar concentration of 10-5. 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. Pharmaceutical 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. When the pharmaceutical composition is employed in the form of a solution or suspension, 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. Also, in addition to the pharmaceutical carrier or diluent, 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. In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer. Alternatively 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 die solid active ingredient diluted with a solid diluent for administration from a powder inhalation device. In the above compositions, 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. For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampul or an aqueous or nonaqueous liquid suspension. • For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, and drops suitable for administration to the eye, ear, or nose. For oral administration the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup. liquid, or emulsion. Usually 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. When employed in this manner, the dosage of the composition is selected from the range of from 350 mg to 1000 mg of active ingredient for each administration. For convenience, 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. The pharmaceutical preparations thus described are made following the conventional techniques of the phamaceutical chemist as appropriate to the desired end product. Included within the scope of this disclosure is the method of treating a disease which comprises administering to a subject a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition. For example, inhibiting the symptoms of an allergic response resulting from a mediator release by administration of an effective amount of a compound of formula I is included within the scope of this disclosure. The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this memod 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 so forth. Compounds of this invention, alone and in combination with a histamine Hi -receptor antagonist, inhibit antigen-induced contraction of isolated, sensitized guinea pig trachea (a model of respiratory anaphylaxis as described by Weichman, B.M., Wasserman, M.A., Holden, D.A., Osborn, R.R., Woodward, D.F., Ku, T.W., and Gleason, J.G., J. Pharmacol. Exp. Ther., 227, 700-705, 1983. Pharmaceutical 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 Hi - receptor 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 H -receptor antagonist. The methods of administration described above for the single active ingredient can similarly be employed for the combination with a histamine Hi -receptor antagonist. The following examples illustrate the preparation of the compounds of this invention and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto. Example 1 S-^-Carboxyethylthio^-fS-dodecyl thien- 2-yDpropionic acid (i) 3-methyl-2-thiophenecarboxylic acid chloride. A mixture of 3-methyl-2-thiophenecarboxylic acid (10 g, 0.07 mole) and thionyl chloride (20 mL) was heated at 50°C for 2 hours. IR analysis indicated complete conversion to the acid chloride. Excess thionyl chloride was evaporated and the residue was azeotroped with dry toluene (3 times). The crude product was dissolved in ether, stirred with activated charcoal, filtered and concentrated to provide 3-methyl-2-thiophenecarbox lic acid chloride as an oil which was not purified further. (ii) 4.4-dimethyl-2-r2-r3-methylthienvmoxazoline. A solution of 3-methyl-2-thiophenecarboxylic acid chloride (9 g. 0.056 mole) in dichloromethane (50 mL) was treated dropwise below 20°C with a solution of 2-amino-2-methyl-l-propanol (9.98 g, 0.112 mole) in dichloromethane (20 mL). The resulting solution was then stirred at ambient temperature for 2 hours, extracted with water and the organic phase was dried (MgSθ4) and concentrated. This concentrate was suspended in toluene (100 mL), and thionyl chloride (13.5 mL, 0.18 mole) was added dropwise to the stirred suspension below 30°C. After being stirred at 25°C for 18 hours, the solvent was removed and the residue was partitioned between water and ether. The aqueous layer was extracted with additional ether, and the combined organic layer was washed \. ith brine, dried (MgSθ4) and concentrated to 11.9 g of crude material. This was purified by flash chromatography over silica gel with 9: 1 petroleum ether/ether to provide 4,4-dimethyI-2-[2-(3-methylthienyl)]oxazoline as an oil; 90 MHz iH NMR (CDCI3): 1.3 ppm (s, 6H), 2.55 (s, 3H), 4.05 (s, 2H), 6.85 (d, IH), 7.25 (d, IH). (iii) 4.4-dimethyl-2-r2-f3-dodecvIthienvmoxazoline To a solution of 4,4-dimethyl-2-[2-(3-methylthienyl)]oxazoline (2 g, 10.2 mmole) in ethyl ether (15 mL) cooled to -78°C was added dropwise n.-butyl lithium (8.8 mL of 2.5 M in hexanes). The resulting solution was stirred an additional 20 minutes at -78°C, and then stirred for 30 to 40 minutes at 0°C. The reaction mixture was recooled to -78°C, and a solution of 1-bromodecane (2.58 g, 11 mmole) in ether (10 mL) was added slowly. The coolant was removed, and the mixture was stirred at ambient temperature for 18 hours. The reaction was quenched with saturated NH4CI solution. The product was extracted with additional ether, and the organic phase was then washed with brine, dried and was concentrated. Chromatography over silica gel with 5% ethyl ether in petroleum ether afforded the 4,4-dimethyI-2-[2-(3-dodecylthienyl)]oxazoline as an oil; 90 MHz * H NMR (CDCI3): 0.4-1.8 ppm (m, 23H), 1.32 (s, 6H), 2.95 (broad t, 2H), 4.1 (s, 2H), 6.9 (d, IH), 7.3 (d, IH). (iv) 2-r2--f3-dodecylthienyD]-3.4.4-trimethyloxazoIinium iodide. A mixture of 4,4-dimethyl-2-[2-(3-dodecylthienyl)]oxazoline (6.2 g, 31.7 mmole) and methyl iodide (70 mL) was refluxed for 24 hours under an argon atmosphere. Excess methyl iodide was evaporated, the semi-solid residue was suspended in petroleum ether and filtered. The solid was stirred in diethyl ether and filtered to obtain solid 2-[2-(3-dodecylthienyl)]-3,4,4-trimethyloxazolinium iodide; mp 148-154°C; 90 MHz -H NMR (CDCI3): 0.65-1.75 ppm (m. 23H), 1.75 (s, 6H), 2.95 (broad t, 2H), 3.65 (s, 3H), 5.1 (broad s, 2H), 7.2 (d, IH), 8.1 (d, IH). (v) 3-dodecyl-2-thiophenecarboxaIdehvde. A solution of sodium bis-(2-methoxyethoxy)aluminum hydride in toluene (15 mL of 0.34 M solution, 5.1 mmole) was cooled to -20°C under an argon atmosphere, and was treated dropwise with a solution of 2-[2-(3-dodecylthienyl)]-3,4,4-trimethyloxazolinium iodide (4 g, 8.1 mmole) in THF (20 mL) while maintaining the temperature below -5°C. Then the mixture was stirred at -5°C to 10°C for 4 hours. Exces hydride reagent was quenched by the slow addition of dilute HC1, and the mixture was then stirred at 25°C for- 18 hours. The separated organic layer was washed with sodium sulfite solution and water, and the coi centrated, dried product was flash chromatographed over silic gel with 5% ether in petroleum ether to afford 3-dodecyl-2- thiophenecarboxaldehyde as an oil; 90 MHz * H NMR (CDCI3): 0.75-1.9 ppm (m, 23H), 3.0 (broad t, 2H), 7.0 (d, IH), 7.65 (d, IH), 10.1 (s, IH). (vi) t-butyl 3-r2-C3-dodecylthienyl ' )l -3-hydroxypropionate. Lithium diisopropyl amide was prepared by the addition of n-butyl lithium (1.1 mL of 2.5 M in hexanes) to a solution of diisopropylamine (288 mg, 2.85 mmole) in THF (5 mL) held at -78 °C under an argon atmosphere. After being stirred for 5 minutes, t-butyl acetate (330 mg, 2.85 mmole) in THF (5 mL) was then added dropwise, and the resulting solution was stirred at -78°C for 15 minutes. Then a solution of 3-dodecyl-2-thiophenecarboxaldehyde (799 mg, 2.85 mmole) in THF (5 mL) was added slowly, and the resulting mixture was stirred an additional hour at -78°C. The mixture was allowed to slowly warm to ambient temperature, and stirring was men continued for another hour. Saturated NH4C I solution and ether were added, and the organic phase was washed with brine, dried, concentrated and flash chromatographed over silica gel with an elution system of 15% of ethyl ether and 85% of petroleum ether to afford t-butyl 3-[2-(3-dodecylthienyl)]-3-hydroxypropionate as an oil; 270 MHz iH NMR (CDCI3): 0.89 ppm (t,3H), 1.5 (broad s, 18H), 1.49-1.65 (m and s, 11H), 2.55-2.85 (m,4H); 3.44 (s,lH), 5.4 (dd, I H), 6.88 (d,lH), 7.19 (d,lH). (vii) 3-C2-carboxyethylthio -3-f3-dodecylthien -2-yl ' )propionic acid . A solution of t-butyl 3-[2-(3-dodecylthienyl)]-3- hydroxypropionate (400 mg, 1 mmole) in dichloromethane (6 mL) . was cooled to -10°C and 3-mercaptopropionic acid (634 mg, 6 mmole) was added. Then trifluoroacetic acid (8 mL) was added dropwise at -10°C. After being stirred at -10°C for 45 minutes and at 0°C for 5 hours, the mixture was partitioned between dichloromethane and water. The organic extract was washed with water, dried, concentrated and chromatographed over silica gel with a solution of 80:20 hexanes/ethyl acetate containing 0.25% of formic acid to provide 3-(2-carboxyethylthio)-3 -(3-dodecylthien-2-yl)propionic acid (oily); 270 MHz *H NMR (CDCI3): 0.86 ppm (t,3H), 1.25 (broad s, 18H). 1.54 (m,2H), 2.42 (t,2H), 2.46-2.65 (m,4H), 2.68 (dd, l H), 2.82 (dd,l H), 3.34 (s,2H), 4.61 (t,lH), 6,82 (d,lH), 7.32 (d,lH). Anal. Calcd. for 22H36θ4S2:C, 61.64; H, 8.47. Found: C, 62.03; H, 8.14. Exa pl ? 2 2fR.SVHvdroxy-3fS.R 2-carboxyethylthio'>- 3-Cl-dodecyl-lH-imidazol-2-yπpropionic acid (i) 1 -dodecylimidazole A mixture of 18-crown-6 (0.8 g) and potassium t-butoxide (3.9 g, 0.035 mmole) in benzene (50 mL) was stirred for 15 minutes. Then imidazole (2.04 g, 0.03 mole) was added, and, after 30 minutes at 25°C, the mixture was heated to 60°C and dodecyl bromide (8.71 g, 0.035 mole) in benzene (20 mL) was added over 15 minutes. This mixture was heated at 60°C for one hour, then cooled, diluted with water, and the layers were separated. The water- washed, dried organic layer was concentrated and the residue was flash chromatographed over silica gel with 4:1 ethyl acetate/methanol to provide 1-dodecylimidazole. iH NMR (CDCI3): 0.82-1.02 ppm (m,3H), 1.16-1.54 (m,18H), 1.78 (t,2H), 3.96 (t,2H), 6.92 (s,lH), 7.06 (s,lH), 7.46 (s,lH). (ϋ) l -dodecylimidazole-2-carboxaldehyde. A solution of 1-dodecylimidazole (2.77 g, 11.7 mmole) in ethyl ether (100 mL) was cooled to -50°C and n-butyl lithium (5 mL of 2.6 M in hexanes) was added. After one hour of stirring at -50°C, dimethylformamide (2 mL) was then added and the mixture .was allowed to warm to ambient temperature over 30 minutes. The reaction was diluted with saturated NH4CI solution, the ether layer was separated and washed with brine, dried and concentrated. This crude product was chromatographed over silica gel with 50% ethyl acetate in hexanes to afford l -dodecylimidazole-2-carboxaldehyde as an oil; l_ft NMR (CDCI3): 0.78-0.96 ppm (m,3H), 1.15-1.50 (m,18H), 1.58-2.02 (m,2H), 440 (t,2H), 7.16 (s,lH), 7.26 (s,lH), 9.85 (s,lH). (iϋ) trans-2-carbomethoxy-3-π -dodecylimidazol-2-yl ' .oxirane. A solution of l-dodecyiimidazole-2-carboxaldehyde (1.4 g, 5.3 mmole) in dichloromethane (25 mL) was cooled to -20°C and treated with methyl chloroacetate (763 mg, 7.03 mmole) followed by sodium methoxide in methanol (1.27 mL of 25% NaOMe). The temperature was raised to 0°C, stirred for 2.5 hours at 0°C, and then poured into cold 0.5N HC1. The layers were separated, and the organic phase was dried, concentrated and the residue was flash chromatographed over silica gel with ethyl acetate to yield of the oily trans-2-carbomethoxy- 3-(l-dodecylimidazol-2-yl)-oxirane; *H NMR (CDCI3): 0.72-0.90 ppm (m,3H), 1.05-1.40 (m,18H), 1.54-1.94 (m,2H), 3.67 (s,lH), 3.82 (s,3H), 3.92 (s,lH), 4.10 (t,2H), 6.88 (s,lH), 6.92 (s,lH). Civ methyl 2-hvdroxy-3-f2-carbomethoxyethylthio-3-π - dodecylimidazol-2-vDpropionate. A solution of trans 2-carbomethoxy-3-(l -dodecylimidazol-2- yl)oxirane (1.06 g, 3.16 mmole), methyl 3-mercaptopropionate (4.16 mg, 3.47 mmole), triethylamine (0.47 mL, 3.47 mmole) in methanol (10 mL) was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was chromatographed over silica gel with 7:3 hexanes/ethyl acetate to give methyl 2-hydroxy-3- (2-carbomethoxyethylthio-3-(l -dodecylimidazol-2-yl)propionate (oil). iH NMR (CDCI3): 0.80-0.94 ppm (t,3H), 1.10-1.50 (m,14H), 1.60- 1.92 (m,2H), 2.22-2.50 (m,2H), 2.72-2.96 (m,2H), 3.67 (s,6H), 3.88- 4.20 (m,2H), 4.40 (d,lH), 4.75 (d,lH), 6.57 (broad s, IH), 6.88 (s,2H). (v) 2fR.S)-hvdroxy-3fS.RW2-carboxyethylthio)-3-π - dodecvlimidazol-2-vnpropionic acid. A solution of methyl 2-hydroxy-3-(2-carbomethoxyethylthio)- 3-(l -dodecylimidazol-2-yl)propionate (400 mg, 0.88 mmole) in methanol (12 mL) was treated with a solution of sodium hydroxide (96 mg, 2.4 mmole) in water (4 mL). This mixture was stirred at ambient temperature for 28 hours. The solvents were evaporated, the residue was dissolved in water (20 mL) and the aqueous solution was acidified with 3.0 N HC1 (0.8 mL). The product was extracted into 1 :1 methyl ethyl ketone and ethyl acetate. The washed extracts were dried, and the solvent was evaporated to afford homogeneous, oily 2(R,S)-hydroxy-3(S,R)-(2-carboxymethylthio)-3 -( l -dodecylimidazol- 2-yl)propionic acid; iH NMR (Me2CO-Dό): 0.70-1.01 ppm (m,3H), 1.06-1.60 (m,14H). 1.67-2.13 (m,2H), 2.36-3.06 (m,4H), 4.20 (t,2H), 4.68 (d,lH), 4.78 (d,lH), 7.21 (s,lH), 7.36 (s,lH), 10.18 (broad, 3H). Example 3 3-( 2-Carboxyethylthio')-3-f2-dodecylthien-3-vPproρionic acid The title compound is prep.ared by the method described in Example l(i-vii) by using 2-methyl-3-thiophenecarboxylic acid in place of 3-methyl-2-thiophenecarboxylic acid. Example 4 3-f2-Carboxyethylthio-3-C2-dodecvIfur-3-vPpropionic acid The title compound is prepared by the method described in Example l(i-vii) by using 2-methyl-3-furancarboxylic acid in place of 3-methyl-2-thiophenecarboxylic acid. Example 5 3-('2-CarboxyethylthioV3-r3- 8-phenyloctyl ' )thien-2-vI1propionic acid The title compound is synthesized from 3-(8-phenyloctyI)-2- thiophenecarboxaldehyde, prepared from 4,4-dimethyl-2-[2-(3- methoxythienyl oxazoline and 8-phenyloctyl bromide following the procedure given in EPO application No. 0 202 759 published 26 November, 1986. Example 6 -f2-Carboxyethylthio-3-π -dodecyl-l H-imidazoI-2-yl)propionic acid The title compound is prepared by using l -dodecylimidazol-2- carboxaldehyde [Example 2(ii)] in the method outlined in Example l(vi-vii) for 3-dodecyl-2-thiophenecarboxaldehyde. Example 7 3-f2-carboxyethylthio-3-ri -C8-phenyloctvO- l H-imidazol-2- yllpropionic acid The title compound is prepared by the method described in Example l(vi-vii) by using 1 -(8-phenyloctyl)- lH-imidazole-2- carboxaldehyde [which is prepared by the methods outlined in Example 2(i-ii) using 8-phenyloctyl bromide] in place of dodecyl bromide in place of 3-dodecyl-2-thiophenecarboxaldehyde. Example 8 3-f2-Carboxyethylthio)-3-π -dodecylthien-2-yl- 2-hvdroxypropionic acid The title compound is prepared by the method described in Example 2(iii-v) by using 3-dodecyl-2-thiophenecarboxaldehyde in place of l -dodecylimidazole-2-carboxaldehyde. Example 9 3-f2-CarboxycthylthioV3-(3 -dodecylfur-2-vn- 2-hydroxypropionic acid The title compound is prepared by the method described in Example 2(iii-v) by using 3-dodecyl-2-furancarboxaldehyde in place of 1 -dodecylimidazole-2-carboxaldehyde. Example 10 4-Thia-5-f3-d odecylthien-2-vn-6- (tetrazol-5-vOhexanoic acid The title compound is prepared from 3-dodecyl-2- thiophenecarboxaldehyde by condensation with ethyl 2-(tetrazol-5- yl) acetate (as per EPO application No. 0 202 759 published 26 November, 1986) after which the condensation product is oxidized to methyl 3-(3-dodecylthien-2-yl-3-keto-2-(tetrazol-5-yl)propionate by manganese dioxide in refluxing toluene. This β-keto acid is decarboxylated in hot acetic acid/hydrochloric acid as described in the above reference, the resulting (3-dodecylthien-2-yl)-5- methyltetrazolketone is reduced with sodium borohydride in methanol to provide the 3-hydroxy derivative, and the title compound is obtained on treatment with 3-mercaptopropionic acid in trifluoroacetic acid as described in Example l(vii). Example 11 4-Thia-5-π -dodecyl- l H-imidazol-2-yl ' .-6-ftetrazol-5-yDhexanoic acid The title compound is prepared by the method described in Example 10 by using l -dodecylimidazole-2-carbσxaldehyde in place of 3-dodecyl-2-thiophenecarboxaldehyde. Example 12 2-f4-Carbosvphenoxy)-2-f3-dodecylthien-2-vOacetic acid (i) methyl 2-chloro-2-(3-dodecylthien-2-yl)acetate. 22 The title compound is prepared from 3-dodecyl-2-thio- phenecarboxaldehyde l(v) following the procedure given in U.S. Patent No. 4,820,719 for the preparation of methyl 2-chlqro-2-(2- dodecyl-phenyl)acetate from 2-dodecylbenzaldehyde. (ii) 2-(4-Carboxyphenoxy)-2-(3-dodecylthien-2-yl)acetic acid The title compound is prepared from methyl 2-chloro-2-(3- dodecylthien-2-yI)acetate by reaction with methyl 4-hydroxy- benzoate and potassium carbonate in dimethylformamide followed by saponificatioπ of the diester. Exam le 13 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. Tablets Ingredients Per Tablet 101.3 mg 1013 g Procedure for tablets: Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender. S ep 2 Add sufficient water portion- wise to the blend from Step 1 with careful mixing after each addition. Such additions of 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 through an oscillating granulator using a No. 8 mesh (2.3S mm) screen. 23 Step 4 The wet granules are then dried in an oven at 410°F (60°C) until dry. Step 5 The dry granules are lubricated with ingredient No. 5. Step 6 The lubricated granules are compressed on a suitable tablet press. S ppositories: Iπ gredjeηtS Per Supp. Per 1000 SUDD. 1. Formula I compound 40.0 mg 40 g Active ingredient 2. Polyethylene Glycol 1350.0 mg 1,350 g 1000 3. polyethylene glycol 450.0 mg 450 g 4000 1840.0 mg 1,840 g Procedure: 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.

Claims: CLAIMS: 1. The compounds of formula (I) wherein Ri is not substituted on A or B; 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 C8 to C13 alkyl, Cη to C12 alkoxy, Cη to C 2 alkylthio, C1 0 to C12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to Ci 0 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C to C4 alkoxy, methyl thio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl- C4 to C10 alkyl; A is O, or N; B is CH or NR2; R2 is H, Ci to C 1 3 alkyl, C 1 0 to Ci2-l -alkynyl, 11 -docedynyl, phenyl-C4 to C10 alkyl with phenyl optionally monosubstituted or X-R ^ ; the dotted line between A and B indicates a single bond in one position and a double bond in the other; Y is R3, CH(R4)(CH2) m R3. CH(R 4 )-tetrazol-5-yl, or tetrazol-5-yl; R3 is -COR5 where R5 is -OH or OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R7, -CH(NH 2 )COR 5 , or -CONHCH2COR5, or R3 is -CON(R 6 )2 where Re is H, Ci to C 6 alkyl. phenylC i-Cβalkyl, or the two Re groups are combined to form a cyclic group having 3 to 5 carbons; R4 is hydrogen, methyl, Ci to C4 alkoxy, fluoro or hydroxy; R7 is C] to Cio-alkyl, phenyl or substituted phenyl; m is 0, 1, or 2; R is -(CH2) n D, -(CH2) n ArD or ArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2) n R3, -COR3, tetrazol-5-yl, -CH(NH2)R3, -CONHCH2COR5, -NHSO2R7, -SO3H, -CN, or -SO2NH2; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 where X is S(0) q where q is 0 and Y is -(CH2)θ-3COR5 represented by formula (II) where R and Ri are the same as described in claim 1, A is 0 or N and B is CH or NR2. 3. A compound of claim 2 where X is S, R is -(CH2) n D, -(CH2) n ArD or ArD, Y is -CH2COR5, A is 0, or N, and B is CH or -NR2 X-R where the group "^Y is not R2, and Ri is Cs to Ci3-alkyl or phenyl-C4 to Cio-alkyl. 4. A compound of claim 3 where X is S, A is N, B is NR2 and Y is -CH2COR5 represented by the formula: X-R with the proviso that R2 is not '" ' 1 , or a pharmaceutically acceptable salt thereof. X-R 5. A compound of claim 4 wherein ^ Y is at the 2-position, and R2 is Cg to C13 alkyl or a phenyl-C4 to Cio-alkyl radical. 6. A compound of claim 5 which is 3-(2-carboxyethylthio)-3- (1 -dodecyl- lH-imidazol-2-yl)propionic acid or a pharmaceutically acceptable salt thereof. 7. A compound of claim 6 which is 2-(2-carboxyethylthio)-3- [1 -(8-phenyloctyl)- lH-imidazol-2-yl]propionic acid or a pharmaceutically acceptable salt thereof. 8. A compound of claim 2 where X is S, A is O and B is CH. 9. A compound of claim 1 where Y is -C(OH)HCOR5, R is -(CH2) n D, -(CH2) n ArD or ArD, Ri is Cg to Ci3-alkyl or phenyl-C 4 to C10- X-R alkyl, A is O, or N and B is CH or -NR2 where the group "^^Y is not R2. 10. A compound of claim 9 where A is N, B is NR2 where R2 is 8-phenyloctyl or dodecyl, and R is -CH2CH2COOH or a pharmaceutically acceptable salt hereof. 11. A compound of claim 11 which is 3-(2-carboxyethylthio)- 3-(l-dodecyl-lH-imidazol-2-yl)-2-hydroxypropionic acid or 3-(2- carboxyethyIthio)-3-(l -(8-phenyloctyl)- l H-imidazol-2-yl)-2- hydroxypropionic acid or a pharmaceutically acceptable salt thereof. X-R 12. a compound of claim 9 where A is O, B is CH, ^^ is at the 2-position, R is CH2CH2COOH and Ri is 3-(8-phenyloctyl) or 3-dodecyI, or a pharmaceutically acceptable salt thereof. 13. A compound of claim 1 where Y is (CH2)o- l -tetrazol-5-yl or -CH(OH)-tetrazol-5-yl, X is S, R is -(CH2) n D, -(CH2) n ArD or ArD, A is X-R O, S or N, B is -CH- or NR2 where the group ^ Ύ is not R2. 14. A compound of claim 13 where A is N, B is NR2 where Ro is 8-phenyloctyl or dodecyl, and R is -CH2CH2COOH or a pharmaceutically acceptable salt hereof. x-R 15. A compound of claim 13 where A is O, B is CH, "^Y is at the 2-position, R is CH2CH2COOH and Ri is 3-(8-phenyloctyl) or 3- dodecyl or a pharmaceutically acceptable salt thereof. . 16. A compound of claim 1 where X is O. 17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula 1 according to claim 1. 18. A pharmaceutical composition according to claim 17 in which the active ingredient is 2(S)-hydroxy-3(R)-(2-carboxyethyl- thio)-3-(l-dodecyl-lH-imidazol-2-yl)propionoic acid or 2(S)-hydroxy- 3(R)-(2-carboxyethylthio)-3-( l -(8-phenyloctyl)- lH-imidazol-2- yl)propionoic acid or a pharmaceutically acceptable salt thereof. 19. A method of treating a pulmonary disease in which leukotrienes are a factor in a subject in need thereof comprising administering to such subject an effective amount of a compound of claim 1 either alone or in combination with a pharmaceutically acceptable carrier. 20. A method of treating a non -pulmonary disease in which leukotrienes are a factor in a subject in need thereof comprising administratering to such subject an effective amount of a compound of claim 1 either alone or in combinatin with a pharmaceutically acceptable carrier. 21. The compounds of formula (I) wherein Ri is not substituted on A or B; X is O or S(O)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 Cδ to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C1 0 to C12 1 -alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to Ci 0 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, Ci to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl- C4 to C10 alkyl; A is S; B is CH or NR2; R2 is H, Ci to C13 alkyl, C10 to Ci 2- 1-alkynyl, 11 -docedynyl, phenyl-C4 to C10 alkyl with phenyl optionally monosubstituted or x-R -^Y; the dotted line between A and B indicates a single bond in one position and a double bond in the other; Y is R3, CH(R4)(CH2) m R3, CH(R 4 )-tetr.azol-5-yl, or tetrazol-5-yl; R3 is -COR5 where R5 is -OH or OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R7, -CH(NH 2 )COR5, or -CONHCH2COR5, or R3 is -CON(Rό)2 where R is H, to Ce alkyl, phenylCi-Cόalkyl, or the two Re groups are combined to form a cyclic group having 3 to 5 carbons; R4 is hydrogen, methyl, Ci to C4 alkoxy, fluoro or hydroxy; R7 is Ci to Cio-alkyl, phenyl or substituted phenyl; m is 0, 1, or 2; R is -(CH2) n D, -(CH2) n ArD or ArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2) n R3, -COR3, tetrazol-5-yl, -CH(NH2)R3, -CONHCH2COR5, -NHSO2R7, -SO3H, -CN, or -Sθ2NH 2; or a pharmaceutically acceptable salt. 22. A compound of claim 21 where X is S(0) q where q is 0 and Y is -(CH2)θ-3COR5 represented by formula (II) where R and Ri are the same as described in claim 24, A is S and B is CH or NR2. 23. A compound of claim 22 where X is S, R is -(CH2) n D , -(CH2) n ArD or ArD, Y is -CH2COR5, A is S, O, or N, and B is CH or -NR2 X-R where the group Y is not R2, and Ri is Cs to Ci 3 -alkyl or phenyl-C 4 to Cio-alkyl. 24. A compound of claim 23 where R is -CH2CH2COR5, A is S and B is -CH-, represented by the formula: or a pharmaceutically acceptable salt thereof. 25. A compound of claim 24 wherein Ri is C% to C13 alkyl or phenyl-C4 to C10 alkyl. 26. A compound of claim 25 which is 3-(2-carboxyethylthio)- 3-(3-dodecylthien-2-yl)propanoic acid or a pharmaceutically acceptable salt thereof. 27. A compound of claim 26 which is 3-(2-carboxyethylthio)- 3-[3-(8-phenyloctyl)thien-2-yl]propanoic acid or a pharmaceutically acceptable salt thereof. X-R 28. A compound of claim 23 where ^" Ύ is at the 2-position, X is S(0) q , Y is C(OH)COR 5 , and R is -CH2CH2COR3 . 29. A compound of claim 28 where Ri is 3-(8-phenyloctyI) or 3-dodecyl or a pharmaceutically acceptable salt thereof.

Inventors: FRAZEE JAMES SIMPSON, GLEASON JOHN GERALD, HALL RALPH FLOYD, UZINSKAS IRENE NIJOLE, FRAZEE, JAMES, SIMPSON, GLEASON, JOHN, GERALD, HALL, RALPH, FLOYD, UZINSKAS, IRENE, NIJOLE
Applicants: SMITHKLINE BEECHAM CORP, SMITHKLINE BEECHAM CORPORATION
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P9, A61P37, A61P43, C07D233, C07D257, C07D307, C07D333, C07D403, C07D409, C07D413