CA1314654C - Leukotriene antagonists - Google Patents

Abstract

ABSTRACT

This invention relates to alkanoic acid compounds having phenyl and sulfinyl or sulfonyl substituents which are useful as leukotriene antagonists and pharmaceutical compositions containing such compounds. The invention also relates to the use of such compound for treatment of diseases in which leukotrienes are a factor.

Description

s 131~

LEUKOTRIENE ANTAGONISTS

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 challenge. SRS-A has been propos~d as a primary mediator in h~an 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 5RS-A has reinforced interest i~ SRS-A and other arachidonate metabolites. SRS-A derived from mouse, rat, guinea pig and man have all been ~haracterized as mixtures of leukotriene-C4 (LTC4), leu~otriene-D4 (LTD4) and leukotriene-E4 (LTE4), the structural formulae of which are represen~ed below.

~ Glu o~ I

2~ LTC4 R'' - Cys-Gly 5 11 SR~ LTE4 R" = Cys - 2 - ~3~65~

1 Leukotrienes are a group of eicosanoids formed from arachidonio acid metabolism via the lipo~ygenase pathway. These lipid derivatives originate from LTA4 and are of two types: (1) those containing a 5 sulfidopeptide side chain (LTC~, LTD4, and hTE4), and (2) those that are nonpeptidic (LTB~). 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.
As summarized by Lefer, A.M., Biochemical Pharmacoloqy, 35, 2, 123-127 (1986~ both the peptide and non-peptide leukotrienes exert microcirculatory actions, 15 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 the endothelial membrane. LTC4, LTD~ and LTE4 20 stimulate a variety of types of muscles. LTC4 and LTD~ are potent bronchoconstrictors and effective stimulators of vascular smooth muscle. This vasoconstrictor effect has been shown to occur in pulmonary, coronary, cerebral, renal, ~nd mesenteric vasculatures-Leukotrienes have been implicated in a number of pulmonary diseases. Leukotrienes are known to be potent bronchoconstrictors in humans. hTC 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. ~at'l. ~cad. Sci. U~A, 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., m. Rev. Respir. Dis., 126, 449-451 (1982).] The leukotriene antagonists of the present 3 13:~6~
1 invention can be useful in the treatment of allergic or non-allergic hronchial asthma or pulmonary anaphylaxis.
The presence of leukotrienes in the sputum of patients having cystic fibrosis chronic bro~chitis, and bronchiectasis at levels likely ~o have pathophy~iological efects has been demonstrated by Zakrzewski et al. [See Zakrzewski, J. T. et al., Prostaqlandins, 28, 5, 641 (lg~4).] Treatmen~ of these diseases constitutes additional possible utility for leukotriene antagonists.
Leukotrienes have been identified in the nasal secretions of allergic subjects who underwent ln 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 Enqland J.
of Med., 310, 25/ 1626-1629 (1984).] This suggests that allergic rhinitis is another area of utility for leukotriene antagonists.
The role of leukotrienes and the specificity and selectivity of a particular leukotriene antagonist in an animal model of the adult respiratory distress syndrome was investigated by Snapper et al. [See Snapper, J.R. et al., Abstracts of Int'l Conf. on Prostaqlandins and Related Comp., Florence, Italy, p. 495 (June 1986).]
Elevated concentrations o LTD4 were shown in pulmonary edema fluid of patients with adult respiratory distress syndrome. [See Matthay, M. et al. J. Clin. Immunol., 4, 479-483 (1984).] Markedly elevated leukotriene levels have been shown in the edema fluid of a patient with pulmonary edema after cardiopulmonary bypass. [See Swerdlow, B.N., et al., Anesth. Analq., 65, 306-308, (1986).] LTC and LTD have also been shown to have a direct systemic arterial hypotensive effect and produce ~31~
1 vasoconstriction and increased vasopermeability. ~See Dra~en et al., ibid.] This suggests leukotriene antagonists can also be useful in the areas of adul~
respiratory distress syndrome, pulmonary edema, and hypertension.
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.
Further evidence of leukotrienes as mediators of allergic reactions is provided by the identification of leukotrienes in tear fluids from subjects following a conjunctival provocation test and in skin blister fluids after allergen challenge in allergic skin diseases and conjunctival mucosa. [See Bisgaard, H., et al., Allerqy, 40, 417-423 (1985).] Leukotriene immunoreactivity has also been shown to be present in the aqueous humor of human patients with and without uveitis. The concentrations of leukotri~nes were sufficiently high that these mediators were expected to contribute in a meaningful way to tissue responses. [See Parker, J.A. et al., A h Ophthalmol, 104, 722-724 ~1986).3 It has also besn demonstrated that psoriatic skin has elevated levels of leukotrienes. [See Ford-Hutchinson, J. AllerqY Clin.
Immunol., 74, 437-440 (1984~.]. Local effects of intracutaneous injections of synthetic leukotrienes in human skin were demonstrated by Soter et al. (See Soter et al., J. Clin Invest Dermatol, 80, llS-ll9 (1983).3 Cutaneous vasodilation with edema formation and a neutrophil infiltrate were induced. Leukotriene synthesis inhibitors or leukotriene antagonists can also be useful in the treatment of ocular or dermatological diseases such as allergic conjunctivitis, uveitis, allergic dermatitis or psoriasis.

- 5 - 1 31~

1 ~nother area of utility for leukotriene antagonists is in the trea-tment of cardiovascular diseases. Since peptide leukotrienes are potent coronary vasoconstrictors, they are implicated in a variety of cardiac disorders including arrhythmias, conduction blocks and cardlac depression. Synthetic leukotrienes have been shown to be powerul myocardial depressants, their Qffects consis~ing of a decrease in contractile force and coronary flow. The cardiac effects of LTC4 and LTD4 have been shown to be antagonized by a speciic leukotrien~
antagonist, thus suggesting usefulness of leukotriene antagonists in the areas of myocardial depression and cardiac anaphylaxis. [See Burke, J.A., et al., J.
Pharmacolo~y_and ExPerimental Therapeutics, 221, 1, 235-241 (1982).]
LTC4 and LTD4 have been measured in the body fluids or rats in endotoxic shock, but are rapidly cleared from the blood into the bile. Thus leukotrienes are formed in ischemia and shock. Specific inhibitors of leukotriene biosynthesis reduce the level of leukotrienes and therefore reduce manifestations of traumatic shock, endotoxic ~hock, and acute myocardial ischemia.
Leukotriene receptor antagonists have also been shown to reduce manifestations o endotoxic shock and to reduce extension of infarct si~e. Administration of peptide leukotrienes has been shown to produce significant ischemia or shock. [See Lefer, A.M., Biochemical Pharmacoloqy, 35, 2, 123-1~7 (1986~.] Thus further areas of utility for leukotriene antagonists can be the treatment of myocardial ischemia, acute myocardial infarction, salvage of ischemic myocardium, angina, cardiac arrhythmias, shock and atherosclerosis.

- 6 - .~ 3~ll6 ~

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-induced 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., KidneY International, 29, 1, 328 (1986). LTC4 has been demonstrated to contract rat glomerular mesangial cells in culture and thereby effect intraglomerular actions to reduce fiItration surface area. [See Dunn, M.J. et al., Kidnev International, 27, 1, 25S ~19B5). Thus another area of utility for leukotrie~e antagonists can be in the treatment o glomerulonephritis.
Leukotrienes have also been indicated in the area of transplant rejsction. An increase in cardiac and renal allograft survival in the presence of a leukotriene receptor antagonist was documented by Foegh et al. [See Foegh, M.L. et al. Advances in Prostaqlandin, Thromboxane, and Leukotriene Research, 13, 209-~17 ~1985).] Rejection of rat renal allografts was shown ~o produce increased amounts of LTC4. [See Coffman, T.M.
et al., Kidney International, 29, 1, 332 ~1986).
A further area of utility for leukotriene antagonists can be in treatment of tissue trama, burns, or fractures. A significant increase in the production of - 7 - -1 3 1 ~

cysteinyl leukotrienes was shown after mechanical or thermal trauma sufficient to induce tissue edema and circulatory and respiratory dysfunction. [See Denzlinger, C. et al., Science, 230, 330-332 (1985).]
Leukotrienes have also been shown to have a role in acute in1ammatory actions. LTC~ and LTD4 have potent effects on vascular caliber and permeability and LTB4 increases leukocyte adhesion to the endothelium.
The arteriolar constriction, plasma leakage, and leukocyte adhesion bear close resemblence to the early events in acute inflammatory reactions. [See Dahlen, S.E. et al., Proc. Natl. Acad. Sci. USA, 78, 6, 3a87-3891 (1981).]
Mediation of local homeostasis and inflammation by leukotrienes and other mast cell-dependent compounds was also investigated by Lewis et al. [See Lewis, R.A. et al., Nature, 293, 103-108 (1981). Leukotriene antagonists can therefore be useful in the treatment of inflammatory diseases including rheumatoid arthritis and gout.
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., Prostaqlandins Leukotrienes and MedicinQ, 21, 321-32~ ~1986).] Leukotrienes can also be important mediators of inflammation in inflammatory bowel disease. [See Peskar, B.M. et al., Aqents and Actions, lB, 381-383 (1986).] Leukotriene antagonists thus can be useful in the treatment of i~flammatory liver and bowel disease.
Leukotrienes have been shown to modulate IL-l production by human monocytes. [See Rola-Pleszczynski, M.
et al., J. of Immun., 135, 6, 3958-3961 (1985). This suggests that leukotriene antagonists may play a role in IL-l mediated functions of monocytes in inflammation and immune reactions.

~31~6~
LTA4 has been shown to be a factor in inducing carcinogenic tumors and is considered a link between acute immunologic defense reactions and carcinogenesis.
Leukotriene antagonists can therefore possibly have utility in treatment of some types of carcinogenic tumors. [See Wischnewsky, G.G. et al. Anticancer Res. 5, 6, 639 (1985).]
Leukotrienes have been implicated in gastric cytodestruction and gastric ulcers. Damage of gastro intestinal mucosa because of potent vasoconstric-tion and stasis of blood flow is correlated with increased levels of LTC4. Functional antagonism of leukotriene effects may represent an alternative in treatment of mucosal injury. [See Dreyling, K.W. et al., British J.
Pharmacoloqy, 88, 236P ~1986), and Peskar, B.M. et al.
Prostaqlandins, 31, 2, 283-293 (1986).] A leukotriene antagonist has b~en shown to protect against stress-induced gastric ulcers in rats. [See Ogle, C.W. et al., IRCS Med. Sci., 14, 114-115 (1986).]
Other areas in which leukotriene antagonists can have utility because leukotrienes are indicated as mediators include 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 Prosta~landins and Related Comp., 121, Florence, Italy (June 1986)]; and treatment of gallstones [See Doty, J.E.
et al., Amer. J. of Surqery, 145, 54-61 (1983) and Marom, 3 Z. et al., Amer. Rev. Respir. Dis., 126, 449-451 (19B2).
o 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 invertion are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a key f actor.

9 :~3~5~

DETAILEV DESCRIPTION OF THE INVENTION

The compounds o this invention are represen~ed by the following general stru~tural ormula (I~

(O)~ ~R

~2 ~ (I) Rl wherein q is 1 or 2;
1 C8 to C13 alkyl, C7 to C12 alkoxy, C10 to C12 l-alkynyl, 10-undecynyloxy, ll-dodec-~nyl, phenyl-C4 to C10 alkyl, phenyl-C3 to Cg alkoxy with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, ~1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;
R2 is hydrogen, bromo, chloro, methyl, trifluoromethyl, hydroxy, Cl to C4 alkoxy or nitro; or Rl is hydrogen and R~ is C8 to C13 alkyl, C7 to 12 xy, C10 to C12 l-alkynyl, 10-undecynylo ll-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-C3 to Cg alkoxy with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, Cl to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to ClO
alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl:

- lO - 13~

3 1 2)mCR3' or (C~2~0-1-c-tetraZolyl;

R3 is hydroxy, amino, or Cl to C~ alkoxy;
R4 is hydrogen, methyl, Cl to C4 alkoxy, fluoro or hydroxy;
m is O, 1, and 2;
R is (CH2)~CHCOR6, CH(CO~H)CH2CO2H, CH2CH2Z or R8 ~ Rg N ~ N

n is 0 to 6;
R5 is hydrogen, amino, or NHCOCH2CH2CH(NH2)C02H;
R6 is hydroxy, amino, NHCH2C02H, or Cl to C6 alkoxY;
Z is SO3H, SO2NH2 or CN;
R7 is hydrogen, Cl to C4 alkyl or C3 to C4 alkenyl;
R8 is hydrogen, Cl to C4 alkyl, carboxyl or carboxamido, or (CH2)pCO2Rl~, wherein p is 1 or 2, R12 is Cl to C6 alkyl, or hydrogen, when R7 and Rg are hydrogen or Cl to C~ alkyl; and Rg is hydrogen, Cl to C4 alkyl or CH2CO2R13 wherein R13 is Cl to C6 alkyl, o hydrogen, with the proviso that when n is 0, R5 is hydrogen and further that R7, R8 and Rg are not all hydrogen; or a pharmaceutically acceptable salt thereof.
The ester and diester compounds of Formula (I) are subject to the further proviso that R3 and R6 are not both hydroxy or R3 is not hydroxy if both R12 and R13 are hydrogen A particular class of compounds of this invention 3~l~6~
1 are the substituted alkanoic acid analogs of formula ~I) represented by the s~ructural formula (II) R2~( CH2 ) 0-3C02H

~l (II) wherein q, Rl, R2 and R are described above.
Particular members of this class of compounds are those represented by the stru~tural formula (II) wherein R
is (CH2)1_3CO2H or R8 Rg and R~, R2, R7, R8 and Rg are described above.
A subgeneri~ class of these compounds are the diacid derivatives represented by the following general structural formula (III) ~cHzcH

Rl wherein q~ Rl and R2 are described above, and particularly where Rl is phenylalkyl.

- 12- ~31~6~

A second subgeneric class o compounds of formula ~II) are the diacid derivatives represented by the following structural ormula (IV) ~CH2CH2 C02tl (o~q R2~ C 2 H ~ I V
R

wherein q, Rl and R2 are described above, and particularly where R1 is phenylalkyl.
A third subgeneric class of compounds of formula (II) are the heterocyclic derivatives represented by the following general structural formula (V) R7 -~N ~ R8 (O)q ~\ N lRq R2~ C02H (V) Rl q, Rl, R2, R7, R8 and Rg are described above.
A further particular class of compounds of this invention are the hydroxy substituted alkanoic acid analogs of formula (I) represented by the structural formula (VI~

() S ~CH2cH2c2 R2 ~ CH COH ~CO2~
1 (VI) 1 wherein q, Rl and R2 are described above, and particularly where Rl is phenylalkyl.
The compounds of the formula (VI) are exemplified by the following compounds:
(1) ~(S)-hydroxy-3~R)-(2-~arboxyethylsulfinyl)-3-[2-(8-phenyloctyl~phenyl]propionic acid; and (2) 2(S)-hydroxy-3(R)-(2-carboxyethylsulfonyl)-3-[2-(8-phenyloctyl)phenyl]propionic acid.
A further class of compounds of this invention are the tetxazolyl substituted analogs of formula ~I) represented by the structural formula (VII) ()qS ~ ~H2CH2co2H
R2--X( CH2 ) O_l-C -tetrazo lyl 1 (VII) wherein q, Rl and R2 are described above.
Some of the compounds of the formula (I) con~ain two asymmetric centers, such as when R4 is methyl, methoxy, fluoro or hydroxy, or R is CH(CO2H)CH2CO2H.
This leads to the possibility of four stereoisomers for each such compound. In practice, these compounds are prepared as a mixture of two stereoisomers. Resolution procedures employing, for example, optically active amines furnish the separated enantiomers.
The compounds o the present invention, depending on their structure, are capable of forming salts with pharmaceutically acceptable acids and bases, according to procedures well known in the art. Such acceptable acids include inorganic and organic acids, such as hydrochloric, :~3~46~

sulfuric, metha~esulfonic, benzenesulfonic, p-toluene-sulfonic and acetic acid. Such acceptable bases include organic and inorganic bases, such as ammonia, arginine, organic amines, alkali metal bases and alkaline ear~h metal bases. Of particular utility are the dipotassium, disodium, dimagnesium, diammonium, and dicalcium salts of the diacid compounds of formula (I).
The compounds of the formula (I) wherein Y is 1 C02H are conveniently prepared from an aldehyde precursor of the following structural formula (VIII) ~ Rl (VIII) wherein Rl and R2 are described above. A compound of formula ~VIII) 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, after removal of ester protective groups, a sulfide analogue of formula (I~.
The compounds of the formula (I) wherein Y is CH2C02H are prepared by reacting the appropriate aldehyde of the formula (VIII) 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 1 3 ~

l with a substituted thiol in trifluoroacetic acid.
Alternatively, a mixture of trimethyl borate and zinc in tetrahydrofuran may be used to prepare the 3-hydroxypro-pionate derivative. By employing an esterified 2-bromo-propionate in the above reaction with an aldehyde (VIII~,the sulfide compounds wherein Y is CH(CH3~CO~H are obtained.
To prepare the desired compounds of formula ~I) wherein q is l 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 the formula (VIII) are known or readily prepared utilizing the gen~ral procedures described as follows.
ThP aldehyde precursors to the compounds of the formula (I) wherein Rl is, for example, an alkyl radical containing 8 to 13 carbon atoms are prepared from ~he appropriate 2-metho~yphenyl 4,4-dimethyloxazoline [s~e Meyers et al. J. Orq. Chem., 43 1372 (1978)~.
The aldehyde precursors of the`compounds of the formula (I) wherein Rl is, for example, an alkoxy radical containing 7 to 12 carbon atoms are prepared by the O-alkylation of the appropriate 2-hydroxybenzaldehyde with the corresponding alkylating agent.
The aldehyde precursors to the compounds of the formula (I) wherein Rl is a l-alkynyl radical containing 10 to 12 carbon atoms are prepared by coupling a 2-halo-benzaldehyde with the appropriate l-alkyne in the presence of cuprous iodide and (P03)~PdC12. [See Hagihara, et al.
Synthesis, 627, (1980)]. The catalytic hydrogenation of these alkynyl containing precursors under standard condi-tions affords the aldehyde precursors of the compounds of the formula (I) wherein Rl is an alkyl or phenylalkyl radical.

- 16 - 1 3~ ~ ~5~

l Alternatively, the compounds of the formula (I) wherein Y is CH2CO2H are prepared from a propenoate precursor of the following structural formula ~IX) R2 ~CO~Rlo (IX) ~ Rl wherein Rl and R2 are described above, and Rlo is an ester protective group, such as t-butyl. A compound of formula (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, sulfide analogs of formula (I). These are oxidized as previously described to obtain the desired products of formula (I).
The propenoate precursors of formula (IX) are prepared from the corresponding aldehydes of formula ~ ~VIII) by general procedures such as reaction with an alkyl (triphenylphosphoranylidene)acetate or by conversion of the aldehydP to a 3-hydroxypropionate derivative, as described above, followed by an elimination reaction to form the double bond. Additionally, the propionate precursor is obtained from a 3-methanesulfonyl-oxypropionate derivative by treatment with triethylamine.
The compounds of the formula (I) wherein Y is CH(OH)(CH2)mCO2H are prepared from an epoxide 17 - 131L16~4 1 precursor of the following structural formula (X) ~2~ ~ ,(C~2)m C2R11 (X) wherein Rl, R2 and m are described above, and Rll is lower alkyl, such as methyl or ethyl. A compound of formula (X) is reacted in an inert solvent with triethylamine and a substituted thiol selected to give, after removal of ester protective groups and oxidation, a product of formula (I).
The epoxide precursors of formula (X~ where m is 2 are prepared by reaction of the Grignard derivative of a bromobenzene compound of the formula (XI) ~ ~ r Rl with ~crolein to give the corresponding enol derivative which is treated with a trialkylorthoacetate, followed by epoxidation using metachloroperbenzoic acid.
The epoxide precursors of formula ~X) where m is 0 are prepared by reaction of an aldehyde of the formula ~VIII) with a lower alkyl chloroacetate and an alkali metal alkoxide, such as sodium methoxide.

13~5~
l Alternatively, the compounds of the formula (I) wherein Y is CH(OH)COR3 are prepared from a propenoate precursor o formula ~IX) wherein Rlo is lower alkyl.
The compounds of the formula ~I) wherein Y is (CH2~3CO2H are prepared from a tetrahydro-4H-pyran-2-one precursor of the followiny structural formul~ (XII) o R2,~) (Xll) .

~ Rl wherein Rl and R2 are described above. A compound of formula ~XII) 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 and oxidation, a product of formula (I).
The tetrahydro-4H-pyran-2-one precursors of formula (XII) are prepared by reaction of the Grignard derivative of the bromoben~ene compound o formula (XI) with chloro titanium tri-isopropoxide followed by reaction with 5-oxovalerate alkyl ester.
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 R8 and R3 above are employed as the corresponding carboalkoxy derivatives wherein the alkoxy radical contains from one to six carbon atoms. When present, the alkoxy substitutent is subsequently .

-lg ~31~

1 hydrolyzed to give the free carbo~yl or carbo~ymethyl substituted products.
Appropriate modifications of the general process-es disclosed 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 and to inhibit leukotriene induced bronchoconstriction in guinea pigs in vivo. The following methodologies were 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 continously aerated with 95% 2/5% CO2. The tissues were connected v~a 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 ~M) 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 gen~rated by ~5 successive increases in the bath concentration of the LTD4. In order to minim.ize intertissue variability, the contractions elicited by LTD4 were standardized as a percentage of the maximum response obtained to a reference agonist, carbachol (10 ~M).
Calculations: The averages of the triplicate LTD4 concentration-response curves both in the presence and absence of the test compound were 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 KB

-- ~ O -- ~ a ~; ~

1 value for the test compound was de~ermined by the following eq~lations:
1 EC30 (presence of test compound) = dose ratio = X
EC30 ~presence of vehicle control) 2. KB = concentration of test compound/(X-l) In vivo: Anesthetized, spontaneously breathing guinea pigs (Adult male albino Hartley strain) were monitored on a Buxco pulmonary mechanics computer. Changes in airway resistance ~RL) were calculated by the computer on a breath-by-breath basis at isovolumic points from signals measuring airflow and transpulmonary pressure using differential pressure transducers. Animals were pretreated with 1 mg~kg of propranolol, iv, followed by 100 puffs of an aqueous solution of test compound or vehicle control ~y aerosol via a Monaghan nebulizer.
LTD4 was then aerosolized into the airway. The bronchocons~riction produced was reflected by % changes in airways resistance relative to the baseline values obtained prior to injec~ion of the test compound or vehicle control. Each guinea pig received either vehicle control or test compound.
Calculations: The average of 3 - 6 animals per treatment was calculated using the % changes in the pulmonary parameters for control and test compound-treated animals. The average % inhibition by the test compound was calculated from the following equatlon:
% Inhibition =
(vehicle control) - (test comPound) x 100 RL

(vehicle control) - 2:L -11 3 ~
1 The compounds of this invention possess biosignificant antagonist activity against leukotrienes, primarily leukotriene D~. The antagonist activity of representative compounds of this inventioll is tabulated below (other data appears in the preparative examples).
The -log KB values and the RL values were calculated from the above test protocols. Where compounds were tested more than once, the -log KB values given herein represent the current average data.

ComPounds of the Formula (VI) Rl R2 ~ In Vitro , .. ..
-Log KB

-C8H16PhenYl H 1 7.6 -C8H16 phenyl H 2 7.7 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, - 22 - ~3~

1 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, dichlorodifluoro-methane, chlorotrifluoroethane and compressed carbondioxide. 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, i.e.
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 com-positions will comprise a suspension or solution of theactive 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 the solid active ingredient diluted with a solid diluen~ 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.

~ 3 ~
1 For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampul or an aqueuus or nonaqueous liquid suspens ion .
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 doszge 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 50D0 mg.
The pharmaceutical preparations thus described are made following the conventional techniques of the pharma-ceutical chemist as appropriate to the desired end product.
Included within the scope of this disclosure isthe method of treating a disease, pulmonary or non-pulmonary, in which leukotrienes are a factor which comprises administering to a subject a therapeutically effective amount of a compound o formula I, preferably in the form of a pharmaceutical composition. For example, inhibitins the symptoms of an allergic response resulting rom 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 - 2~ 3~ 6 ~
l carried out in dosage units at suitable lntervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically reguired. However, the method is also usefully carried ou~
as continuous or prophylactic treatment. It is within ~h~
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 Hl-receptor antagonist, inhibit antigen-induced contraction of isolated, sensitized guinea piy trachea (a model o respiratory anaphylaxis).
Exemplary of compounds of this invention are 2(S)-hydroxy-3(R)-(2-carboxyethylsulfinyl)-3-[2-(8-phenyloc~yl)phenyl]-propanoic acid. Exemplary of histamine Hl-receptor antagonists are mepyramine, chlorpheniramine, and 2-[4-(5-bromo-3-methyl-pyrid-2-yl)butylamino]-5-[(6-methyl-~ pyrid-3-yl)methyl]-4-pyrimidone and other known Hl-receptor antagonists.
Pharmaceutical compositions, as described herein-above, of ~he present invention also comprise a pharma-ceutical carrier or diluent and a combination of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and an histamine Hl-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 Hl-receptor antagonist. The methods of administration described above for the single active ingredient can similarly be employed for the combination with a histamine Hl-receptor antagonist.

~ 3 ~
1 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.

Preparation of 2-Hydroxy-3-(2-carboxyethylthio~-3-[2 (8-phenYloctyl)phenyl]~ropionic acid (a) 2-(8-PhenYloctYl)benzaldehyde A solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml~ was reduced with diborane in tetrahydrofuran (30 ml, 29Ol mmol~ at 0C for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml~ and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtra~e was evaporated and distilled to afford 8-phenyloctyl bromide as an oil.
To 8-phenyloctylmagnesium bromide (from 24.25 mmol of 8-phenyloctyl bromide and ~1.27 mmol of magnesium) in distilled tetrahydrofuran ~40 ml~ was added 2-(2-methoxyphenyl)-4,4-dimethyloxa7.oline (17.10 mmol3 [A.I.
Meyers et al., J. Orq. Chem., 43, 1372 (1978~] in tetrahydrofuran (20 ml~. After stirring for 24 hours, the reaction mixture was worked up to yield 2-[2-(8-phenyl-octyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyl- oxazolinium iodide as a white solid (mp 76.5-78C).

1 To an ice cold solution of the iodide (9.46 mmol~
in methanol (35 ml) was added in portions sodium borohydride (9.20 mmol). The reaction mixture was allowed to stir for 30 minutes and was then quenched with 5 percent sodium hydroxide (50 ml). The reaction mixture was extracted with diethyl ether (2 x 50 ml~ and the extract was washed with brine (50 ml) and dried over anhydrous magn2sium sulfate and filtered. E~aporation of the filtrate afforded an oil which was dissolved in acetone (50 ml) and 3N hydrochloric acid (10 ml) was added. The mixture was flushed with argon and stirred for 16 hours at ambient temperature. The volatiles were removed under vacuum and the residue partitioned between diethyl ether (50 ml) and water (50 ml). The aqueous phase was extracted with more diethyl ether (50 ml). The combined organic phase was washed with brine (50 ml) and dried over anhydrous magnesium sulfate. Evaporation o the organic phase yielded an oil which was purified by flash chromatography over silica gel with 2 percent ethyl aceta~e in hexane as eluant to afford the desired product as a colorless oil.
Analysis for C21H~60: Calculated: C, 85.67;
H, 8.90. Found: C, 85.12, 85.22; H, 8.94, 8.96.
(b) Alternative preparation of 2-(8-phenyloctyl)-benzaldehYde A solution of 5-hexynyl alcohol (102 mmol) in pyridine (150 ml), under argon, was cooled to OC and p-toluenesulfonyl chloride (204 mmol) was added. The reaction mixture was kept at about 4C for 18 hours, poured into ice-water and then taken up in ether. The ether extract was washed with cold 10% hydrochloric acid, water and brine. The organic layer was dried and concen-trated ln vacuo to give 5-hexynyl p-toluenesulfonate. A
solution of phenylacetylene (97 mmol) in tetrahydrofuran - 27 - ~3~

1 (200 ml) containing a trace of ~riphenylmethane was cooled to 0C and then n-butyl lithium (37.3 ml of 2.6 mol in hexane) was added dropwise. The resulting solution was stirred at 0C for 10 minutes and hexamethylphosphoramide (21 ml) was added dropwise. After stirring for 10 minutes a solution of 5-hexynyl p-toluenesulfonate (97.~ mmol) in ~etrahydrofuran (200 ml) was added. The reaction mix-ture was stirred at room temperature for 18 hours, diluted with ether and the organic layer was washed with water and brine. The dried organic solution was concentrated and the product was purified by flash chromatography to give l-phenylocta-1,7-diyne. A mixture of this compound (43 mmol), 2-bromobenzaldehyde ~35.8 mmol), cuprous iodide (0.5 mmol) and bis(triphenylphosphine) palladium (II) chloride (0.7 mmol) in triethylamine (100 ml) was heated in an oil bath (95C) for onP hour. The reaction mixture was cooled to 0C, filtered and the filtrate was concen-trated. The residue was dissolved in ether, washed with 10% hydrochloric acid, water and brine. The organic layer was dried and concentrated to give a product which was purified by flash chromatography to yield 2-(8-phenyl-1,7-octadiynyl)benzaldehyde. A solution of this compound (24.1 mmol) in ethyl acetate (100 ml) and 10% palladium on charcoal (1 g) was hydrogenated (40 psi of hydrogen) at room temperature for 15 minutes. The ca~alyst was filtered off and the filtrate concentrated to give the 2-(8-phenyloctyl)benzaldehyde.
(c) Methyl trans-3-[2-~8-PhenyloctYl)phenyl]-2,3-epoxS7proPionate The compound of Example l(a) or (b~ (2.94 g, 10 mmol) was dissolved in diethyl ether (25 ml) and the solution was stirred under argon at OC. Methyl chloro-acetate (1.32 ml, 15 mmol) was added, followed by the addition of sodium methoxide (810 mg, 15 mmol). The mixture was stirred for 2.5 hours at ice bath temperature.

~ 3 ~

l A small ~uantity of water was added, the ether phase separated, dxied over anhydrous sodium sulfate, filtered and evaporated. The residue was 1ash chromatographed on 80 grams of silica gel eluted with 5-30~ ethyl acetate/
hexane to give the product.
(d) Methyl 3-(2-Carbomethoxyethylthio)-3-[2-(8-phenyloctyl)phenyl]-2-hydroxypropionate The compound of Example l(c) (1.2 g, 3.28 mmol~
was dissolved in me~hanol (20 ml) containing 2% triethyl-amine and stirred under argon at room temperature. Methyl3-mercaptopropionate (0.623 ml, 5.45 mmoles) and triethyl-amine (1.45 ml, 9.84 mmol) were dissolved in methanol (15 ml) and added dropwise. The mixture was stirred for 18 hours. The solvent was stripped and the residue eluted with 20% ethyl acetate/hexane to give a mixture of the desired product and its regioisomer, methyl 2--S2-carho-methoxyethylthio)-3-[2-(8-phenyloctyl)phenyl]-3- hydroxy-propionate. The mixture was rechromatographed on lOOg of neutral alumina to separate the desired product.
(e) Erythro-3-(2-carboxYethylthio)-3-[2-(8 phenyloctyl)phenyl]-2-hYdroxy-propionic acid The desired product of Example l(d) (320 mg, 0.66 mmol~ was dissolved in methanol (10 ml~ and stirred under argon at ice bath temperature. A lN solution of sodium hydroxide (2.5 ml, 2.5 mmol~ was added dropwise, the ice bath removed, the mixture stirred at room temperature for 2.5 hours~ and then cooled for 18 hours. After an additional l hour of stirring at room temperature, the methanol was stripped, the residue diluted with water and the pH adjusted to 3.5 with dilute hydrochloric acid.
Extraction with ethyl acetate followed by drying over anhydrous sodium sulfate, filtration and evaporation gave the crude product which was flash chromatographed on 20 - 29 - ~3 1 grams of silica gel eluted with 30:70:0.5 ethyl acetate:hexane:formic acid to yive the free acid product.
(f) Resolution of 3-(2~-carboxyethylthio)~3-[2-(8-phenyloctyl)phenylJ-2-hydro~ypro~ionic acid The racemic diacid of Example l(e) (63.5 g, 0.138 mol~ in 700 ml of isopropanol was treated with a solution of (R)-4-bromo-a-phene~hylamine (57.1 g, 0.286 mol) in 200 ml of isopropanol at 25C. The resulting solution was stirred for 3 hours, causing crystallization of the 2S,3R
diamine salt. The suspension was cooled to 5C, filtered, and the salt recrystallized twice from ethanol to give 37.7 g (72%) of 2S,3R diamine salt, m.p. 146-147C;
[a]24 C =-15.8 (C=l, CH30H).
The diamine salt (37.7 g, 0.0497 mol) was. added in portions to 400 ml of cold 0.5N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the ethyl acetate solution washed three times with 0.5N
hydrochloric acid. The ethyl acetate solution was washed with saturated sodium chloride solution, dried, and ~o concentrated to give 19.5 g (97%) of the desired 2(S)-hydroxy-3(R)-(2-carboxyethylthio)-3-[2-(8-phenyloctyl)-phenyl]-propionic acid; ~a]24 = -40.8 (C=l, CHC13).
(g) 2(S)-Hydroxy-3(R)-( -carboxyethylsulfinyl)-3-[2-t8-phenyloctyl)phenyl]propionic acid A suspension of the compound of Example l~f) (870 mg, 1.9 mmole) in 15 ml of water was treated with NaOH
(152 mg, 3.8 mmol), stirred until solution was complete, and cooled to 0. A solution of NaIO4 (500 mg) in 8 ml of water was added. Stirring was continued at 0 for 45 minutes and at 23 for 1 hour. The reaction was acidified and extracted with ethyl acetate. The extracts were dried and the solvent evaporated. The residue was chromatographed over a silica gel column, and the product eluted with a mixture of ethyl acetate: hexane: acetic acid (80:20:3), and gave 470 g (52%). nmr . _ _ . _ _ . . .. . , . _ _ _ . . . ... . ..

- 30 - ~ 31~

1 (CDC13~Me2C0) on the mixture of diastereomers: 8.72 (broad, 3H), 7.62 (d~ and 7.96(d3 (together lH~, 7.20 ~s, 8H), 5.12 (m, lH), 4.82 (m, lH), 2.48 to 2.92 (m, 8H), 1.20 to 1.86 (m, 12H).

2($)-Hydroxy-3(R)-~2-carboxyethylsulfonyl)-3-[2-(8-phenyloctyl)phenyl]~ropionic acid.
A solution of the compound of Example l(f) (930 mg) in 75 ml of CHC13 was treated over 15 minutes with m-chloroperbenzoic acid (1 g). After 1-1/2 hours at 23, 3 ml of saturated aqueous NaHS03 was added. After 5 minutes 3N HCl was added. The organic layer was separated, washed with water, dried, and the solvent removed. The residue ~as chromatographed over a silica gel column, and eluted with a mixture of ethyl acetate:
chloroform: acetic acid (50:50:1). After a forerun containing m-chlorobenzoic acid, the product was collected in the later fractions, and gave 740 g (75~).
nmr ~CDC13/Me2CO) 10.0 ~broad 3H), 8.10 (d, lH), 7.03 to 7.33 (m, 8H), 5.29 (d, lH), 5.03 Sd, lH), 3.24 to 3.60 (m, 2H) 2.46 to 2.92 (m, 6H), 1.16 to 1.88 (m, 12H).

Claims (11)

1. A process for the preparation of compounds of the following structural formula (I):
(I) wherein q is 1 or 2;
R1 is C8 to C13 alkyl, C7 to C12 alkoxy C10 to C12 l-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl- C3 to C9 alkoxy with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;
R2 is hydrogen, bromo, chloro, methyl, trifluoromethyl, hydroxy, C1 to C4 alkoxy or nitro; or R1 is hydrogen and R2 is C8 to C13 alkyl, C7 to C12 alkoxy, C10 to C12-l-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to alkyl, phenyl-C3 to C9 alkoxy with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10- alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;

Y is COR3, or (CH2)0-1-C-tetrazolyl;

R3 is hydroxy or amino;
R4 is hydrogen, methyl, C1 to C4 alkoxy, fluoro or hydroxy;
m is 0, 1, or 2;
R is (, CH(CO2H)CH2CO2H, CH2CH2Z or n is 0 to 6;
R5 is hydrogen, amino, or NHCOCH2CH2CH(NH2)CO2H;
R6 is hydroxy, amino or NHCH2CO2H;
Z is SO3H, SO2H2 or CN;
R7 is hydrogen, C1 to C4 alkyl or C3 to C4 alkenyl;
R8 is hydrogen, C1 to C4 alkyl, carboxyl or carboxamido, or (CH2)pCO2H, wherein p is 1 or 2, when R7 and R9 are hydrogen or C1 to C4 alkyl; and.
R9 is hydrogen, C1 to C4 alkyl or CH2CO2H, with the proviso that when n is 0, R5 is hydrogen and further that R7, R8 and R9 are not all hydroyen; or a pharmaceutically acceptable salt thereof.
which comprises reacting an appropriately protected substituted thiol, RSH, wherein R is as defined above, with, (a) a compound of the general formula:
wherein R1, R2 and m are as defined in Claim 1, and R11 is lower alkyl, to form compounds wherein Y
is CH(OH)(CH2)mCO2H;
(b) a compound of the general formula:

wherein R1 and R2 are as defined in claim 1 to form compounds wherein Y is (CH2)3CO2H;
and (c) a compound of the general formula:
wherein R1 and R2 are as defined in claim 1 and R10 is an ester protective group, to form compounds wherein Y is CH2CO2H;
followed by deprotection of any group, optionally resolving any diastereomeric mixture of compounds oxidizing the sulfide group, and optionally forming a pharmaceutically acceptable salt.

2. A process for the preparation of 3-(2-carboxyethylsulfinyl)-3-[2-(8-phenyloctyl)phenyl]-2-hydroxy-propionic acid which comprises reacting methyl

3-2-[8-phenyloctyl)phenyl]-2,3-epoxypropionate with methyl 3-mercaptopropionate, followed by deprotection of the ester groups, and oxidation of the sulfur moiety.

3. A process for the preparation of 2(S)-hydroxy-3(R)-(2-carboxyethylsulfinyl)-3-[2-(8-phenyl-octyl)phenyl]propionic acid which comprises resolving the erythro mixture of diastereomers prior to oxidation of the sulfur moiety.

4. A process for the preparation of 3-(2-carboxyethylsulfonyl)-3-[2-(8-phenyloctyl)phenyl]-2-hydroxy-propionic acid which comprises reacting methyl 3-[2-(8-phenyloctyl)phenyl]-2,3-epoxypropionate with methyl .angle. followed by deprotection of the ester groups, and oxidation of the sulfur moiety.

5. A process for the preparation of 2(S)-hydroxy-3(R)-(2-carboxyethylsulfonyl)-3-[2-(8-phenyl-octyl)phenyl]propionic acid which comprises resolving the erythro mixture of diastereomers prior to oxidation of the sulfur moiety.

6. A compound of the general formula:
(I) wherein q is 1 or 2;
R1 is C8 to C13 alkyl, C7 to C12 alkoxy C10 to C12 l-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl- C3 to C9 alkoxy with the phenyl optionally mono subsituted with bromo, chloro, trifluoromethyl, C1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;
R2 is hydrogen, bromo, chloro, methyl, trifluoromethyl, hydroxy, C1 to C4 alkoxy or nitro, or R1 is hydrogen and R2 is C8 to C13 alkyl, C7 to C12 alkoxy, C10 to C12-l-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to alkyl, phenyl-C3 to C9 alkoxy with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10- alkyl, trifluoromethyl C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;

Y is COR3, or (CH2)0-1-C-tetrazolyl;
R3 is hydroxy or amino;
R4 is hydrogen, methyl, C1 to C4 alkoxy, fluoro or hydroxy;
m is 0, 1, or 2;
R is , CH(CO2H)CH2CO2H, CH2CH2Z or n is 0 to 6;
R5 is hydrogen, amino, or NHCOCH2CH2CH(NH2)CO2H;;
R6; is hydroxy, amino or NHCH2CO2H;
Z is SO3H, SO2NH2 or CN;
R7 is hydrogen, C1 to C4 alkyl or C3 to C4 alkenyl;
R8 is hydrogen, C1 to C4 alkyl, carboxyl or carboxamido, or (CH2)pCO2H, wherein p is 1 or 2, whern R7 and R9 are hydrogen or C1 to C4 alkyl; and Rg is hydrogen, C1 to C:4 alkyl or CH2CO2H, with the proviso that when n is 0, R5 is hydrogen and further that R7, R8 and R9 are not all hydrogen; or a pharmaceutically acceptable salt thereof.

7. 3 - (2-carboxyethylsulfinyl)-3-[2-(8-phenyloctyl)phenyl]-2-hydroxy-propionic acid.

8. 3 - (2-carboxyethylsulfonyl)-3-[2-(8-phenyloctyl)phenyl]-2-hydroxy-propionic acid.

9. A composition comprising a pharmaceutically effective amount of the compound of claim 6 and a pharmaceutically acceptable carrier therefor.

10. A composition comprising a pharmaceutically effective amount of the compound of claim 7 and a pharmaceutically acceptable carrier therefor.

11. A composition comprising a pharmaceutically effective amount of the compound of claim 8 and a pharmaceutically acceptable carrier therefor.