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1. (WO1991017149) 3-NAPHTHYL-3-CARBOXYALKYLTHIO OR OXY SUBSTITUTED ALKANOIC ACID LEUKOTRIENE ANTAGONISTS
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3-Naphtyl-3-carboxyalkylthio or Oxy Substituted Alkanoic
Acid Leukotriene Antagonists

Scope of the Invention
This invention relates to 3-naphtyl-3-carboxyalkylthio or -oxy substiuted 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 challenge. SRS-A has been proposed as a primary mediator in human asthma. SRS-A, in addition to its pronounced effects on lung tissue, also produces permeability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to effect depression of ventricular contraction and potentiation of the cardiovascular effects of histamine.
Leukotrienenes are a group of eicosanoids formed from
arachidonic acid metabolism via the lipoxygenase pathway. These lipid derivatives originate from LTA4 and are of. two types: (1) those containing a sulfidopeptide side chain (LTC4, LTD4, and LTE4), and (2) those that are nonpeptidic (LTB4). Leukotrienes comprise a group of naturally occuring substances that have the potential to contribute significantly to the pathogensis of a variety of inflammatory and ischemic disorders.
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 I--TE4 stimulate a variety of types of muscles. LTC4 and LTD4 are p rtent bronchoconstrictors and effective stimulators of vascular smooth muscle. This vasoconstrictor effect has been shown to occur in pulmonary, coronary, cerebral, renal, and mesenteric vasculatures.
Leukotrienes have been implicated in a number of pulmonary diseases. Leukotrienes are known to be potent bronchoconstrictors in humans. LTC4 and LTD4 have been shown to be potent and selective peripheral airway agonists, being more active than histamine. [See Drazen, J.M. et al., Proc. Nat'l. Acad. Sci. USA. 77, 7, 4354-4358 (1980) LTC4 and LTD4 have been shown to increase the release of mucous from human airways in vitro. [See Marom, Z. et al., Am. Rev. Respir. Pis.. 126, 449-451 (1982).] The leukotriene antagonists of the prese invention can be useful in the treatment of allergic or non-allergic bronchial asthma or pulmonary anaphylaxis.
Leukotrienes have been identified in the nasal secretions of allergic subjects who underwent in vivo challenge with specific antigen. The release of the leukotrienes was correlated with typical allergic signs and symptoms. [See Creticos, P.S. et al., New England J. of Med.. 310. 25, 1626-1629 (1984).] This suggests that allergic rhinitis is another area of utility for leukotriene antagonists.
Leukotrienes have also been directly or indirectly implicated i a variety of non-pulmonary diseases in the ocular, dermatologic, cardiovascular, renal, trauma, inflammatory, carcinogenic and other areas.
Leukotriene antagonists can also be useful in the area of renal ischemia or renal failure. Badr et al. have shown that LTC4 produces significant elevation of mean arterial pressure and reductions in cardiac output and renal blood flow, and that such effects can be abolished by a specific leukotriene antagonist. [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 th effects of the leukotrienes selectively antagonized in this model of renal injury. [See Badr, K.F., et al., Kidney International. 30, 474-48 (1986).] LTD4 has been shown to produce local glomerular constrict actions which are prevented by treatment with a leukotriene antagonist, [See Badr, K.F. et al., Kidnev International. 29. 1, 328 (1986). LTC4 has been demonstrated to contract rat glomerular mesangial cells in culture and thereby effect intraglomerular actions to reduce filtration surface area, [see Punn, M.J. et al., Kidney
International. 27. 1, 256 (ι985). Thus another area of utility for leukotriene antagonists can be in the treatment of glomerulonephri Cysteinyl leukotrienes have also been shown to undergo enterohepatic circulation, and thus are indicated in the area of inflammatory liver disease. [See Penzlinger, C. et al., Prostaglandins Leukotrienes and Medicine. 21. 321-322 (1986).] Leukotrienes can also be important mediators of inflammation in inflammatory bowel disease. [See Peskar, B.M. et al., Agents and Actions. 18. 381-383 (1986).] Leukotriene antagonists thus can be useful in the treatmen of inflammatory liver and bowel disease,
By antagonizing the effects of LTC4, LTP4 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 o diseases in subjects, including human or animals, in which
leukotrienes are a key factor.
Leukotriene antagonists based on 3-phenyl-3-carboxyalkylthi alkanoic acids are disclosed in U.S. patent No. 4,820,719.

PETAILEP PESCRIPπON OF THE INVENTION
The compounds of this invention are represented by formula (


where each substituent may be substituted on any carbon of die naphthyl ring, or a pharmaceutically acceptable salt thereof;
Ri is C8 to C13 alkyl, C7 to C\2 alkoxy, Cη to Cχ2 alkylthio, CI Q to Cj2 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to Ci 0 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-Cβ to C9 alkyl with each phenyl optionally mono substituted with bromo, chloro,
trifluoromethyl, C\ to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to Cio alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to Cio alkyl;
P is 0 or S(0)q where q is 0, 1 or 2, with the proviso that \ is not alkylthio or phenylthioalkyl when q is 1 or 2;
Y is R2, CH(R3)(CH2)mR2, CH(R3)-tetrazol-5-yl, or tetrazol-5-yl; m is 0, 1, and 2;
R2 is -COR4 where R4 is -OH, -OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, R2 is -N(R5)2 where R5 is H, C\ to alkyl, phenylCi-Cβ-alkyl, o the two R5 groups are combined to form a cyclic group having 3 to 5 carbons, -CN, -SO3H, -S02NH2, NHS02R6, -CH(NH2)COR4, NHCH2COR4;
R3 is hydrogen, methyl, Ci to C4 alkoxy, fluoro or hydroxy;

R is -(CH2)nA, -(CH2)nArA or ArA where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and A is -(CH2)nR2- -R2> -tetrazol-5-yl, -CH(NH2)R2, -CN, -SO3H, -SO2NH2, NHSO2R6, -CH(NH2)C0R4, NHCH2COR4;
Re is Ci to Cio-alkyl, phenyl, or phenylCi to C3-alkyl.
This invention also relates to a means for treating diseases pulmonary or non-pulmonary diseases which involve leukotrienes and which can be treated by administering a leukotriene antagonist.

Also within the scope of this invention are pharmaceutical composition!? which comprise a compound of formula I either alone formulated with a pharmaceutically acceptable excipient. Such compositions may also contain an Hi blocker.
The term phenylthioalkyl is used to mean the thioether radical where -S- is bonded to the phenyl group and the alkyl portion of the radical is bonded to the sulfur as illustrated by the following formul

o- (CH2)π

A preferred class of compounds of this invention are the substituted alkanoic acid analogs of formula (I) where P is -S- represented by formula (II)


wherein R and Ri are described above.
Particular members of this class of compounds are those represented by the structural formula (II) wherein R is (CH2)i-3R2- A particularly preferred class of these compounds are the diac derivatives represented by the following general structural formula (III)


wherein Ri is described above, and particularly those where R\ is dodecyl or phenyl-C4 to C Q alkyl and R2 is hydrogen.

The compounds of the formula (III) are exemplified by the following compounds:


(1) 3-(2-carboxyethylthio)-3-[7-(5-phenylpentyl)naphth- l yl]propionic acid;

Hθocm2αfcs.^cH2θpoH


(2) 3-(2-carboxyethylthio)-3-(7-dodecylnaρhth- l -yl)-propionic acid;
A further preferred class of compounds of this invention are th 2-hydroxy substituted propionic acid analogs of formula (I) where D is -S- represented by the structural formula (IV)


wherein R is the same as described above, but particularly those compounds where Rj is dodecyl or phenyl-C4 to Ci Q-alkyl and R2 is COOH
The compounds of the formula (IV) are exemplified by the following compounds:


( 1 ) 3 -(2-carboxyethylthio)-3 -(7-dodecylnaphth- l -yl)-2-hydroxypropionic acid; and

(2) 3-(2-carboxyethylthio)-3-[7-(5-phenylpentyl)naphth- l -yl]-2-hydroxypropionic acid.
Another preferred class of compounds of this invention are the tetrazolyl substituted analogs of formula (I) where again P is -S-represented by the structural formula (V)


wherein R is the same as described above.
The most preferred compounds of formula (V) are exemplified by the following compounds:


(1 ) 4-thia-5-(7-dodecylnaphth- l -yl)-6-(tetrazol-5-yl)hexanoic acid; and


(2) 4-thia-5-[l -(7-(5-phenylpentyl)naphth-l - l)]-6-(tetrazo 5-yl)hexanoic acid.
In addition, the 2-hydroxy analogs of the tetrazol-5-yl of the foregoing compounds are preferred.
In parallel with the proceeding preferred compounds, those compounds where P is -0- are preferred. These preferred oxy compounds include the analogs of the structures represented by formulas II thru V. Particlarly preferred compounds of this group are:
3-(2-carboxyethyloxy)-3-[7-(5-phenylpentyl)naphth- l - yl]propionic acid;
3-(2-carboxyethyloxy)-3-(7-dodecylnaphth-l -yl)-propionic acid;
3-(2-carboxyethyloxy)-3-(7-dodecylnaphth-l -yl)-2- hydroxypropionic acid;
3r(2-carboxyethyloxy)-3-[7-(5-phenylpentyl)naphth- l -yl] -2- hydroxypropionic acid;
4-oxy-5-(7-dodecylnaphth-l -yl)-6-(tetrazol-5-yl)hexanoic acid or
4-oxy-5-[l -(7-(5-phenylpentyl)naphth-l -yl)]-6-(tetrazol-5 - yl)hexanoic acid.
All compounds have at least one assymetric center. All stereoisomers are intended to be covered in this invention, including mixtures thereof.
Some of the compounds of the formula (I) contain two or even three asymmetric centers. For example when R3 is methyl, methoxy, fluoro or hydroxy, or R is CH(Cθ2H)CH2Cθ2H, or both R3 and R are on of these substituents. This leads to the possibility of four or more stereoisomers for each such compound. In practice, these compound are prepared as a mixture of stereoisomers. Resolution procedures employing, for example, optically active amines can furnish the separated enantiomers.
The compounds of the present invention, depending on their structure, are capable of forming pharmaceutically acceptable salts with acids and bases according to procedures well known in the art. Such salts are those which match the activity of the parent compoun and do not exhibit untoward or deliberous activity. Acceptable acids include inorganic and organic acids, such as hydrochloric, sulfuric, methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and acetic acid. Bases include organic and inorganic bases, such as ammonia, arginine, organic amines, alkali metal bases and alkaline earth metal bases. Piperazine and ethyienediamine salts are particularly useful i this invention. 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 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 art. Such salts are those which match the activity of the parent compoun and do not exhibit untoward or deliberous activity. Acceptable acids include inorganic and organic acids, such as hydrochloric, sulfuric, methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and acetic acid. Bases include organic and inorganic bases, such as ammonia, arginine, organic amines, alkali metal bases and alkaline earth metal bases. Piperazine and ethyienediamine salts are particularly useful this invention. Also preferred are the dipotassium, disodium, dimagnesium, di-zinc, and dicalcium salts of the diacid compounds o formula (I). Pharmaceutically acceptable cations are the same as the just recited base-derived pharmaceutically acceptable salts.
The compounds of the formula (I) wherein Y is CH2CO2H are prepared by reacting the appropriate aldehydes of the formula VI, wherein Ri and R2 are as described above and an esterified bromoacetate, conveniently t-butyl bromoacetate, with a mixture of diethyl aluminum chloride, zinc dust and a catalytic amount of cuprous bromide at low temperatures in an inert solvent to give the esterified 3-hydroxypropionate derivative which is reacted directly with a substituted thiol in trifluoroacetic acid. Alternatively, a mixture of trimethyl borate and zinc in tetrahydrofuran may be use to prepare the 3-hydroxypropionate derivative.
Alternatively, compounds of formula (I) are prepared from th aldehydes VI by reaction with lithium diisopropylamide and t-butyl acetate at -78°C to 25°C in a suitable solvent such as, for example, tetrahydrofuran (THF), to provide the precursor esterified 3-hydroxypropionate derivatives which are converted to the thiol acid with a mercaptan in trifluoroacetic acid. By employing an esterified

2-bromoρroρionate in the above reaction with the aldehydes VI, th compounds of the formula (I) wherein Y is CH(CH3)Cθ2H are obtaine


To prepare the compounds of formula (I) wherein q is 1 or 2, the appropriate thio product is conveniently oxidized with a weak oxidizing agent such as sodium periodate or metachloroperbenzoic acid to obtain the sulfoxide or sulfone product.
The aldehydes of the formula (VI) are known or readily prepared utilizing the general procedures described as follows.
The aldehyde precursors to the compounds of the formula (I) wherein Ri is, for example, an alkyl radical containing 8 to 13 carbon atoms are prepared from the appropriate 2-methoxyphenyl-4,4-dimethyloxazoline [see Meyers et al. J. Ore. Chem.. 43. 1372 (1978)]. The aldehyde precursors to the compounds of the formula (I) wherein Ri is a 1-alkynyl radical containing 10 to 12 carbon atoms are prepared by coupling a halobenzaldehyde with the appropriate 1 alkyne in the presence of cuprous iodide and (Pd3)2PdCl2- [See Higahara et al., Synthesis. 627 (1980)]. The catalytic hydrogenation o these alkynyl containing precursors under standard conditions afford the aldehyde precursors of the compounds of the formula (I) wherein Rl is an alkyl or phenylalkyl radical.
Preferably, the compounds of the formula (I) wherein Y is CH2CO2H are prepared from a propenoate precursor of the alkene of formulas (VII).


wherein Rj and R2 are described above, and R Q is an ester
protecting group, such as t-butyl. A compound of formula (VII) is reacted with a mixture of alkali metal alkoxide, such as sodium methoxide, and an appropriately substituted thiol or alcohol to give, after removal of the ester protective group, products of formula (I).
The propenoate precursors of formula (VII) are prepared from the corresponding aldehydes of formulas (VI) by general procedures such as reaction with an alkyl (triphenylphosphoranylidene)acetate o by conversion of the aldehyde to a 3-hydroxypropionate derivative, as described above, followed by an elimination reaction to form the double bond. Additionally, the propenoate precursor is obtained from a 3-methanesulfonyloxypropionate derivative by treatment with triethylamine or from a 3-acetoxypropionate derivative by treatment with l,8-diazabicyclo-[5,4,0]undec-7-ene at elevated temperature, eg. about 90°C.

The compounds of the formula (I) wherein Y is
CH(OH)(CH2)mCθ2H are prepared from an epoxide precursor of the following structural formula (VIII)


wherein Rj , R2, and m are defined above, and R is lower alkyl, su as methyl or ethyl. A compound of formula (VIII) is reacted . in an inert solvent with triethylamine and a substituted thiol or alcohol selected to give, after removal of ester protective groups, a product formula (I).
The epoxide precursors of formula (VIII) where m is 0 are prepared by reaction of an aldehyde of the formula (VI) with a lowe alkyl chloroacetate and an alkali metal alkoxide, such as sodium methoxide.
Alternatively, the compounds of the formula (I) wherein Y is CH(OH)COR2 are prepared from a propenoate precursor of formula (VII) wherein Rn is lower alkyl.
The 2-thioimidazole precursors necessary to prepare the R-heterocyclic derivatives of formula (I) are known compounds or a conveniently prepared employing standard chemical reactions.
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 vitr The following methodology was employed: In vitro: Guinea pig (ad male albino Hartley strain) tracheal spiral strips of approximate dimensions 2 to 3 mm cross-sectional width and 3.5 cm length were bathed in modified Krebs buffer in jacketed 10 ml tissue bath and continuously aerated with 95% 02/5 C02- The tissues were connected via silk suture to force displacement transducers for recording isometric tension. The tissues were equilibrated for 1 hou pretreated for 15 minutes with meclofenamic acid (1 mM) to remov intrinsic prostaglandin responses, and then pretreated for an additional 30 minutes with either the test compound or vehicle control. A cumulative concentration-response curve for LTP4 on triplicate tissues was generated by successive increases in the bath concentration of the LTP4. In order to minimize inter-tissue variability, the contractions elicited by LTP4 were standardized as a percentage of the maximum response obtained to a reference agonist carbachol (10 mM).
Calculations: The averages of the triplicate LTP4 . concentration response curves both in the presence and absence of the test compound were plotted on log graph paper. The concentration of

LTP4 needed to elicit 30% of the contraction elicited by carbachol wa measured and defined as the EC30. The -log Kβ 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. Kg = concentration of test compound/(X-l)

The compounds of this invention possess useful antagonist activity against leukotrienes, primarily leukotriene P4. The
antagonist activity of representative compounds of this invention is tabulated below. The -log Kg values were calculated from the above test protocols. A represented compound, the phenylpentyl-substituted analog, was compared in this assay to the known leukotriene antagonist 2-hydroxy-3-(2-carboxyethylthio)-3-((2-octylphenyl)phenyl)propionic acid. In this asasay, the naphthyl compound gave a pKβ of 6.5 at 10"5M. The
2-(octylphenyl)phenylpropionic acid compound gave a pKβ of 7.7 at 10"6M. Where compounds were tested more than once, the log Kβ values given herein represent the "current average data.
The specificity of the antagonist activity of a number of the cδmpounds 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 alkal metal salt thereof, sufficient to produce the inhibition of the effects o 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 n have a detrimental effect on the therapeutic action of the instant compositions.
The nature of the composition and the pharmaceutical carrier o diluent will, of course, depend upon the intended route of
administration, whether it be parenterally, topically, orally or by inhalation.
In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administratio by inhalation. Thus the compositions will comprise a suspension or solution of the active ingredient in water for administration by mean 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 composition may also comprise the 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 o the active ingredient. When the diluent is a solid it may be present lesser, equal or greater amounts than the solid active ingredient.

For parenteral administration the pharmaceutical composition may be in the form of a sterile injectable liquid such as an ampule an aqueous or nonaqueous liquid suspension.
For topical administration the pharmaceutical composition ma be in the form of a cream, ointment, liniment, lotion, pastes, and dr suitable for administration to the eye, ear, or nose.
For oral administration the pharmaceutical composition will b in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syr liquid, or emulsion.
Sustained release formulations may also be prepared. Refere is made to Remington's Pharmaceutical Sciences for detailed information on the preparation of such formulations, and for assistance in preparing all other formulations indicated by the practice of this invention.
Usually a compound of formula I is administered to a subject i a composition comprising a therapeutically effective amount, a nontoxic amount, sufficient to produce an inhibition of the symptom of a disease in which leukotrienes are a factor. When employed in this manner, the dosage of the composition is selected from the rang 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 appropriate to the desired end product.
Included within the scope of this disclosure is the method of treating a disease comprising administering to a subject a
therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition. For exampl 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 disclosur The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically required. However the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the condition or disease being treated, and forth.
Compounds of this invention, alone and in combination with a histamine Hi -receptor antagonist, inhibit antigen-induced contractio of isolated, sensitized guinea pig trachea (a model of respiratory anaphylaxis as described by Weichman, B.M., Wasserman, M.A., Holden, P.A., Osborn, R.R., Woodward, P.F., Ku, T.W., and Gleason, J.G., 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 H -receptor antagonist in amounts sufficient to inhibit antigen-induced respiratory anaphylaxis. The above-defined dosage of a compound o formula I is conveniently employed for this purpose and the known effective dosage for the histamine H -receptor antagonist. The methods of administration described above for the single active ingredient can similarly be employed for the combination with a histamine H -receptor antagonist.
The following examples illustrate the preparation of the compounds of this invention and their incorporation into
pharmaceutical compositions these examples are not to be intended nor should be considered as limiting the invention set forth in the claims appended hereto.

Example 1
3- 2-CaτboxyethylthioV3-r7-('5-phenylpentyl )naphthyl1propionic ac l( ) 4-f4-bromophenyl)butanoic acid.
To a solution of 3-(4-bromobenzoyl)propionic acid (4.75 g, 18. mmole) and potassium hydroxide (3.51 g, 62.6 mmole) in diethylen glycol (25 mL) was added 85% hydrazine hydrate (2.5 mL), and the resulting solution was refluxed for 1.5 hours. Then the temperature (pot) was raised to 195°C, and heating was continued for an additio 4 hours. After cooling, water (100 mL) was added and the mixture was acidified with 6 N HC1. The separated solid was filtered, dissolv in ethyl ether, and the organic layer was washed with water, dried (MgSθ4) and concentrated to give 4-(4-bromophenyl)butanoic acid;

mp 50-55°C; 90 MHz iH NMR (CPCI3): δ 2.0 ppm (m, 2H), 2.4 (t, 2H),

2.65 (t, 2H), 7.05 (broad d, 2H), 7.4 (d, 2H), 9.1 (s, IH).
Kiϊ) 7-bromo-α-tetralone.
4-(4-Bromophenyl)butanoic acid (3 g, 12.3 mmole) was treate with the complex formed from equivalent amounts of methane sulfonic acid and phosphorus pentoxide (prepared according to J. Or Chem. (1973), 2&, 4071), (30 g), and this mixture was heated at 70° for 1 hour. The reaction mixture was poured onto ice water, the pH was adjusted to 12 with NaOH solution and the product was extracte into ether. The extracts were washed with brine, dried and
concentrated to a crystalline solid. Trituration with petroleum ether afforded crystalline 7-bromo-α-tetralone; mp 76-78°C; i H NMR (CPCI3): δ 2.15 ppm (m, 2H), 2.65 (t, 2H), 2.9 (t, 2H), 7.15 (d, IH), 7.5

(dd, IH), 8.15 (d, IH).
l fiii) 7-Bromo-3.4-dihydro-l -methylnaphthalene.
A solution of methyl magnesium bromide (14 mL of 2.9 M in diethyl ether, 41 mmole) under an argon atmosphere was treated at 15° to 20°C with a solution of 7-bromo-α-tetralone (9 g, 40 mmole) i diethyl ether (100 mL). The resulting solution was refluxed for 10 minutes, cooled, and water (15 mL) was added, concentrated HCl (15 mL) was introduced and the organic layer was separated". The ether layer was washed with dil HCl, 5% NaHCθ3 solution and brine, and then dried (MgS04). The solvent was evaporated at water aspirator pressure, and the residue was heated at 180-190°C for 1 hour. The oily residue of 7-bromo-3,4-dihydro-l-methylnaphthalene was use without further purification; -H NMR (CPCI3): δ 2.20 ppm (s, 3H), 2.3

2.55 (m, 2H), 2.85 (t, 2H), 6.05 (m, IH), 7.10 (d, IH), 7.40 (m, 2H). lfiv 7-bromo-l-methylnaphthalene.
7-Bromo-3,4-dihydro-l-methylnaphthalene (8 g, 35 mmole) and tetrachlorobenzoquinone (18 g, .73.2 mmole) in toluene (250 mL were refluxed for 18 hours. The cooled mixture was filtered, the filtrate was concentrated, the residual product was treated with petroleum ether, the. solid was filtered and the filtrate was
concentrated in vacuum. The crude residual oil was flash
chromatographed over silica gel to afford the oily 7-bromo-l-methylnaphthalene; * H NMR (CPCI3): δ 2.60 ppm (s, 3H), 7.05-7.75 (

5H), 8.15 (broad s, IH).
l (v) 7.1 -dibromo-l -methylnaphthalene.

To a solution of 7-bromo-l-methylnaphthalene (0.55 g, 2.5 mmole) in chloroform (10 mL) was added N-bromosuccinimide (0.48 g, 2.75 mmole) and benzoyl peroxide (2.5 mg), and this mixture was refluxed under argon with a light source for 30 minutes. The mixtur was concentrated and partitioned between ether and water, and the organic phase was washed with brine, dried, concentrated and the residue was purified by flash chromatography over silica gel with petroleum ether to provide as a white crystalline material 7,1-dibromo-1-methylnaphthalene; mp 108-110°C; *H NMR (CPCI3): δ 4.85 ppm (s, 2H), 7.20-7.85 (m, 5H), 8.30 (broad s, IH).
lCvi". 7-bromo-l-naphthaldehvde.
A solution of 7,1-dibromo-l-methylnaphthalene (1.5 g, 5 mmole) in glacial acetic acid (10 mL) was treated with
hexamethylenetetramine (1.5 g, 11 mmole) in water (10 mL), and th mixture was refluxed for 18 hours. The mixture was then
concentrated under reduced pressure, the residue taken up in ether and water and the organic layer was washed with brine, dried and concentrated to a solid that was triturated with petroleum ether to yield the captioned compound as a crystalline solid; mp 110-111°C; * NMR (CPCI3): δ 7.30-8.15 (m, 5H), 9.50 .(broad d, IH), 10.35 (s, IH). lfvii 7-(5-phenylpent-l -ynylVl-naphthaldehvde.
A mixture of 7-bromo-l-naphthaldehyde (235 mg, 1 mmole), 5-phenylpent-l-yne (173 mg, 1.2 mmole), triethylamine (5 mL), bis(triphenylphosphine) palladium chloride (14 mg, 0.02 mmole) an cuprous iodide (1 mg, 0.005 mmole) was heated at 80-90°C for one hour. The cooled mixture was then concentrated, the residue was taken up in ether, washed with HCl and water, and the concentrated, dried product was flash chromatographed over silica gel with 15% of diethyl ether in petroleum ether to afford the oily 7-(5-phenyl-l-pentynyl)-l-naphthaldehyde material; -K NMR (CPCI3): δ 2.00 ppm

(m, 2H), 2.45 (t, 2H), 2.80 (t, 2H), 7.20 (broad s, 5H), 7.45-8.10 (m, 5

9.35 (s, IH), 10.4 (s, IH).
lfix) 7-(r5-phenylpentyO-l -naphthaldehyde.
A solution of 7-(5-phenylpent-l-ynyl)-l-naphthaldehyde (0.7 g, 2.3 mmole) and ethyl acetate (50 mL) was shaken with 10% palladium on carbon (0.1 g) on a Parr hydrogenator apparatus at atomospheric hydrogen pressure until the uptake of hydrogen was complete. The filtered, concentrated, crude product (0.7 g, 2.3 mmo of l-hydroxymethyl-7-(5-phenylpentyl)naphthalene was dissolved methylene dichloride (30 mL) and manganese dioxide (7 g, 0.08 mol was added, and the mixture was stirred at ambient temperature for 18 hours. The filtered and concentrated filtrate was stirred in ether over MgS04, and die solution was concentrated to the crude product that was purified by flash chromatography with 10% of diethyl ethe in petroleum ether to yield 7-(5-phenylpentyl)-l-naphthaldehyde a an oil.
l (x) t-butyl 3-ri -C7-f 5-phenylpentyl lnaphthvDlpropionate.
A solution of 7-(5-phenylpentyl)-l-naphthaldehyde (0.1 g, 0.3 mmole) and t-butyl 2-triphenylphosphoranylideneacetate (0.12 g, 0.32 mmole) in toluene (25 mL) was refluxed for 18 hours. The concentrated reaction mixture was chromatographed over silica gel using 5% of diethyl ether in petroleum ether to afford an oily t-buty 3-[l-(7-(5-phenylpentyl)naphthyl]propionate; - NMR (CPCI3): δ 1.20-1.90 ppm (m, 6H), 1.55 (s, 9H), 2.45-2.90 (m, 4H), 6.40 (d, IH), 7.05-8.01 (m, 11H), 8.40 (d, IH).
l rxi") t-butyl 3-f2-carbomethoxyethylthioV3-π -r7-f 5-phenylpentyl l naphthympropionate.
A mixture of t-butyl 3-[l -(7-[5-phenylpentyl}naphthyl)]-propionate (60 mg, 0.15 mmole), methyl 3-mercaptopropionate (0.1 g, 1.5 mmole) and tetra N-butylammonium fluoride (3 mL of 1 M solution in tetrahydrofuran) was stirred at ambient temperature for 18 hours. The THF was evaporated, the residue was taken up in eth and water, the ether layer was washed with water and dried and th product was flash chromatographed over silica gel with 9:1
hexanes/ethyl acetate to t-butyl 3-(2-carbomethoxyethylthio)-3-[l -(7-{5-phenylpentyl}naphthyl)]propionate as a syrup; iH NMR (CPCI3 δ 1.15-2.0 ppm (m, 6H), 1.25 (s, 9H), 2.3-3.1 (m, 10H), 3.65 (s, 3H),

5.21 (t, IH), 7.1-8.1 (m, 11H).
l f i 3-r2-carboxyethylthio >-3-r7-r5-phenylpentvnnaphth- l -ylΗpropionic acid.
A mixture of t-butyl 3-(2-carbomethoxyethylthio)-3-[l -(7-[5-phenyipentyl} naphthyl)]propionate (40 mg, 0.08 mmole) in acetone mL) and 1 N HCl (1 mL) was refluxed for 3 days. The solvent was evaporated, the residue was taken up in ether, washed with brine, dried (MgS04) and the crude product was purified by HPLC on
Pynamax silica gel (21.2 mm x 25 cm) using 20:30:0.5 of hexane/eth acetate/formic acid at 20 mL/min (RT 15.2) to provide 3-(2-carboxyethylthio)-3-[l -(7-[5-phenylpentyl } naphthyl)]propionic acid (syrupy); 270 MHz *H NMR (PMSO-dg): δ 1.40 ppm (m, 3H), 1.55-1.8 (m, 5H), .2.4-2.7 (m, 6H), 2.81 (t, 2H), 2.95 (broad d, 2H), 5.2 (s, IH), 7.15 (m, 5H), 7.30 (d, IH), 7.37 (d, IH), 7.65 (d, IH), 7.70 (d, IH), 7.7 (d, IH), 7.9 (s, IH); Mass Spec. (PCI, NH3) m/e 468.

Example 2
3-C2-CarboxyethylthioV3-f7-dodecyl-l - paphthyDpropionic acid
2m 7-α -dodecvn-l-naphthaldehvde.
The title compound is prepared by the procedure of Example l(viii-ix) by using 1-dodecyne in place of 5-phenyl-l-pentyne.(ii) 3 (2-carboxyethylthio)-3-(7-dodecyl)naphth-l -yl)propionic acid.
The title compound is prepared by the procedure of Example l(x-xii) by using 7-(l -dodecyl)- 1-naphthaldehyde in place of 7-(5-phenylpentyl)-l -naphthaldehyde.

Example 3
3-r2-Carboxyethylthio >-3-r7-r5-ρhenylDentvn-l - naphthvπ-2-hvdτoxypropionic acid
The title compound is prepared from 7-(5-phenylpentyl)-l-naphthaldehyde via the derived methyl [l-(7-{5-phenylpentylI naphthyl] -2,3 -epoxypropionate following the procedure given in EP application 0 202 759 published November 26, 1986.

Example 4
3-C2-Carboxyethylthio )-3-r-r7-dodecylnaphth-l -vn- 2-hvdroxypropionic acid
The title compound is- prepared according to Example 3 by usi 7-(l-dodecyl)-l-naphthaldehyde in place of 7-(5-phenylpentyl)-l - naphthaldehyde.

Example 5
3-f2-CarboxyethylthioV3-r i-f2-dodecvn- naphthyllpropionic acid
5(1) 2-f2-dodecylnaphthylV4,4-dimethyloxazoline.
To freshly prepared dodecylmagnesium bromide (from 30.1 mmoles of dodecyl bromide and 26.2 mmoles of magnesium) in distilled tetrahydrofuran (50 mL) was added 2-(2-methoxynaρhth- yl)-4,4-dimethyloxazoline [prepared by the method of A.I. Meyers al., J. Org. Chem. (1978), 41, 1372] (17.9 mmole) in tetrahydrofuran (30 mL). The resultant yellow solution was stirred under argon at ambient temperature for 20 hours. The solution was cooled in an ice water bath and quenched with aqueous NH4CI (100 mL). The reacti

5 product was extracted into diethyl ether (100 mL) and the organic phase was washed with brine and then dried (MgSθ4). The organic phase was concentrated to a colorless oil which was purified by flash chromatography over silica gel with 5% ethyl acetate in hexanes as eluant to provide the title compound as a pale yellow oil.
0 5fii'. 2-f 2-dodecylnaphth-l -v'0-3.4.4-trimethyloxazolinium iodide.
A solution of 2-(2-dodecylnaphth-l -yl)-4,4-dimethyloxazoline (16 mmoles) in methyl iodide (20 mL) was refluxed under argon for 18 hours. The reaction was concentrated under vacuum and the soli residue triturated with ethyl acetate (25 mL) to afford the desired 5 product as white crystals; mp 82-87°C.
5fiiP 2-dodecyl-l -naphthaldehvde.
To an ice cold solution of 2-(2-dodecylπaphth-l-yl)-3,4,4- trimethyloxazolinium iodide (10 mmole) in methanol (50 mL) was added sodium borohydride (10 mmole) over a period of 15 minutes, 0 and the mixture was then stirred an additional 30 minutes. The mixture was diluted with 5% NaOH (50 mL) and extracted well with ether. The washed, dried, concentrated product was an oil, and was dissolved in acetone (50 mL) and 3N HCl (10 mL) was added. The solution was stirred under argon for 16 hours at 25°C, the volatiles 5 were evaporated and the residual aqueous mixture was diluted with additional water. The product was extracted into ether, washed with brine, dried, and concentrated to an oil which was purified by flash chromatography over silica gel with 2% ethyl acetate in hexanes to provide 2-dodecyl-l-naphthaldehyde as a pale yellow oil.
0 5 iv) 3-f2-carboxyethylthio)-3-ri -('2-dodecyl)naphthyl1 propionic acid.
The procedure of Example l(x-xii) is followed by using"
2-dodecyl-l-naphthaldehyde in place of 7-(5-phenylpentyl)-l - naphthaldehyde. The title compound was a syrup.
5 Example 6
3-f2-CarboxyethylthioV3-r2-π -dodecyl-2-naρhthvm- pfQpionic acid
The title compound was prepared by the procedure of Exampl 5 using 2-(l-methoxy-2-naphthyl)-4,4-dimethyloxazoline in place o 2-(2-methoxynaphth-l-yl)-4,4-dimethyloxazoline.

Example 7
3-C2-Carboxyethylthio )-3-C2-dodecylnaphth-l -vπ - 2-hvdτoxypropionic acid
The title compound is prepared by the method described in Example 3 using 2-dodecyl-l-naphthaldehyde in place of 7-(5-phenylpentyl)-l -naphthaldehyde.

Example 8
3-f2-Carboxvethvlthio >-3-r2-f5- phenylpentvDnaphth-1 -yllpropionic acid
Sd) 2-C5-phenylpentylVl-naphthaldehyde.
Following the procedure of Example 5(i-iii), to 5-phenylpentyl bromide (24.3 mmole) and magnesium (21.3 mmole) in
tetrahydrofuran was added 2-(2-methoxynaphth-l -yl)-4,4-dimethyloxazoline (17.1 mmole) in tetrahydrofuran (20 mL). [The 5 phenylpentyl bromide was prepared from 5-phenylpentanol, carbo tetrabromide and triphenylphosphine in dichloromethane.] After being stirred for 24 hours, the reaction mixture was similarly work up to yield 2-[2-(5-phenylpentyl)naphthyl]-4,4-dimethyloxazoline an oil. This product was converted to 2-(5-phenylpentyl)-l-naphthaldehyde by the procedure entirely analogous to Example 5(i iii).
δfin 3-f2-carboxyethylthio-3-r2-C5-ρhenylpentvnnaphth-l -yll propionic acid.
The title compound is prepared by the method described in Example l(x-xii) by using 2-(5-phenylpentyl)-l-naphthaldehyde in place of 7-(5-phenylpentyl)-l-naphthaldehyde.

Example 9
. 3-f2-CarboxyethylthioV-3-r2-f8- phenyloctyl'.naphth-1-vπpropionic acid
^1^) 2-f 8-ρhenvioctvn-l -naphthaldehvde.
The procedure of Example 8(i) was followed by using 8- phenyloctylmagnesium bromide in place of
5-phenylpentylmagnesium bromide.
9fii') t-butyl 3-r2- 8-phenyloctvnnaphth-l -yn-3-hvdroxypropionate A solution of 2-(8-phenyloctyl)-l-naphthaldehyde (6.8 mmole in tetrahydrofuran (7 mL) and trimethyl borate (7 mL) is added dropwise with stirring to zinc metal (8.8 mmole) at 25°C. After 5 minutes, t-butyl bromoacetate is added and the mixture is stirred at ambient temperature for 36 hours. The reaction mixture is diluted with ether, cooled to 0°C, and ice-cold NH4θH/water/ glycerine is added dropwise with stirring. The organic layer is washed with wat and brine, dried (MgS04), concentrated and flash chromatographed over silica gel eluting with 5% ethyl acetate in hexanes to give t-buty

3-[l -(2- { 8-phenyloctyl} naphthyl] -3 -hydroxypropionate.
9(^11 3-f2-caτboxyethylthio')-3-ri -r2-f 8-phenyloctvn naphthvni-propionic acid.
A solution of t-butyl 3-[2-(8-ρhenyloctyl)naρhth-l -yl]-3-hydroxypropionate (5.5 mmole) was dissolved in dichlorome thane (25 mL) under argon and cooled to -15°C as 3-mercaptopropionic aci (16.6 mmole) is added. Trifluoroacetic acid (25 mL) is added dropwise over 30 minutes, the reaction is then maintained at -15°C for an additional 30 minutes, and then the temperature is allowed to rise to 0°C for 6 hours. The reaction mixture is concentrated in vacuo at 0°C, the residue dissolved in dichloromethane, washed with water until neutral, dried and concentrated. The resultant oil is flash chromatographed on silica with 20% ethyl acetate in hexanes containing 0.5% of formic acid. The homogeneous fractions (1.2 mmole) are swirled with aqueous potassium carbonate (2.87 mmole) for 80 minutes. This is flash chromatographed on HPLC with a C-18 reverse phase support using 1 : 1 acetonitrile/water to provide after lyophilization the dipotassium salt; mp >250°C.

Example 10
3-f2-CarboxyethylthioV3-r2-π -dodecvnnaρhthvn - 2-hvdτoxypτopionic acid
The title compound is prepared by the method described in Example 3 using 1 -dodecyl-2-naphthaldehyde in place of 7-(5-phenylpentyl)-l -naphthaldehyde.

gxqmpl? U
3-f 2-CarboxyethylthioV3-r 1 -C2-undecyloxy1naphthyllpropionic aci 1 UP 2-undecyloxy-l -naphthaldehyde.
To a stirred suspension of sodium hydride (10 mmole) in dry dimethylformamide (10 mL) is added dropwise a solution of
2-hydroxy-l -naphthaldehyde (10 mmole) in dimethylformamide (2 mL). To the reaction mixture is then added undecyl bromide (10 mmole) and the mixture is stirred for 16 hours at ambient
temperature under argon. The product is taken up in 1:1
hexanes/ethyl acetate, washed with 10% NaOH and brine, dried over MgS04 and charcoal and concentrated. The crude liquid is
chromatographed by flash column chromatography over silica gel with 2% ethyl acetate in hexanes as eluant to give 2-undecyloxy-l-naphthaldehyde as an oil.
l iP 3-C2-carboxyethylthioV3-['l -f2-undecyloxy')naphthyπpropion acid.
The procedure of Example l(x-xii) is followed, using 2-undecyloxy-1-naphthaldehyde in place of 7-(5-phenylpentyl)-l-naphthaldehyde.

Example 12
3-f2-CarboxyethylthioV3-ri -f2-undecyloxy naphthyl1 - 2-hvdroxypτopionic acid
The procedure of Example 3 is followed by using 2-undecylox 1 -naphthaldehyde in place of 7-(5-phenylpentyl)-l -naphthaldehyd

Example 13
3-<'2-carboxyethylthioV3-r2-(' l -undecyloxy naphthyl1propionic aci 13(P 2-methyl- l -undecyloxynaphthalene
The procedure of Example l l(i) was followed replacing the 2- hydroxy-1 -naphthaldehyde with 2-methyl-l -naphthaldehyde. The title compound is an oil.

13HP l -undecyloxy-2-naphthaldehvde
The title compound is prepared by the procedure described in Example 1 (v-vi) but using 2-methyl-l-undecyloxy naphthalene in place of 7-bromo-l -methylnaphthalene.
13fiiP t-butyl 3-r2-π-undecyloxyynaphthvπpropionate
A solution of l-undecyloxy-2-naphthaldehyde (32 mmole) is dissolved in toluene (50 ml) and cooled to 0°C in an ice-water bath under argon. t-Butyl (triphenylphosphoranylidene)acetate (32 mmole) is added in one portion. The mixture is brought to reflux, an then heated at 100°C for 24 hours, The mixture is concentrated in vacuum and the resulting residue flash chromatographed over silica gel using 5% ethyl acetate in hexanes to provide t-butyl 3-[2-(l - undecyloxy)naphthyl]propionate as an oil.
lSfiv') t-butyl 3-(,2-carboxyethvIthio>)-3-r2-π -undecyloxy')naphthvn propionate
Sodium (156 mmole) was added slowly to methanol (200 ml) under an argon atmosphere. The mixture was cooled to 0°C and 3-mercaptopropionic acid (78 mmole) was added dropwise. This mixture was stirred for 30 minutes, and a solution of t-butyl 3-[2-(l undecyloxy)naphthyl]propenoate (7.8 mmole in methanol (4 mL) is added dropwise. After being stirred for 18 hours at ambient temperature, the solvent is evaporated, residue taken up in ice water acidified with 10% H3PO4 to pH 6.5 and the product is extracted into ethyl acetate. The extracts are washed with brine, dried, concentrate and the crude product is flash chromatographed over silica gel with

1% methanol in dichloromethane containing 1% formic acid to afford the oily t-butyl 3-(2-carboxyethylthio)-3-[2-(l-undecyloxy)-naphthyl]propionate.
13(v) 3-f2-carboxyethylthio')-3-r2-π -undecyloxy')naphthvnpropioni acid
t-Butyl 3-(2-carboxyethyithio)-3-[2-(l -undecyloxy)naphthyl]-propionate (5.6 mmole) is cooled to -10°C, and cold trifluoroacetic aci (15 mL) is added. The mixture is stirred under argon for 2.5 hours a the temperatures is raised to 0 to 5°C. Evaporation in vacuo at room temperature provides the low melting solid 3-(2-carboxyethylthio)-3

[2-(l-undecyloxy)naphthyl]propionic acid.

Example 14
3-( 2-carboxyethylthio')-3-r2-(f8-undecyloxy)- naphthyllpropionic acid
The title compound is prepared by the procedure of Example 1 (i-v) by using 7 -methyl- 1-naphthol in place of 2-methyl-l-naphthol

ampl? }5
2-f4-Carboxyphenoxy')-2-fl-f2-dodecvPnaphthyl1acetic acid

(i) methyl 2-chloro-2-[l-(2-dodecyl)naphthyl]acetate.
The title compound is prepared from 2-dodecyl-l-naphthaldehyde [5 (iii)] following the procedure given in U.S. Patent

No. 4,820,719 for the preparation of methyl 2-chloro-2-(2-dodecyl-phenyl)acetate from 2-dodecylbenzaldehyde.
(ii) 2-(4-Carboxyphenoxy)-2-[l -(2-dodecyl)naphthyl]acetic acid
The title compound is prepared from methyl 2-chloro-2- [l-(2 dodecyl)naphthyl]acetate by reaction with methyl 4-hydroxy-benzoate and potassium carbonate in dimethylformamide followed, saponification of the diester if desired.

Example 16
Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given belo

Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitab mixer/blender.

Step 2 Add sufficient water portionwise to the blend from Step with careful mixing after each addition. Such additions o water and mixing until the mass is of a consistency to
permit its conversion to wet granules.
Step 3 The wet mass is converted to granules by passing it
mrough an oscillating granulator using a No. 8 mesh (2.3 mm) screen.
Step 4 The wet granules are then dried in an oven at 410°F
(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.
Example 16
Suppositories:


Procedure:
Step 1. Melt ingredient No. 2 and No. 3 together and stir until
uniform.
Step 2. Pissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform.
Step 3. Pour the molten mass from Step 2 into supository moulds and chill.
Step 4. Remove the suppositories from moulds and wrap.

Example 17
As a specific embodiment of a composition of this invention, an active ingredient of Example 7-11 is dissolved in 25 mM sodium carbonate at a comcentration of 0.4 percent weight/volume and delivered from a nebulizer operating at an air flow adjusted to delive the desired amount of drug in aerosol form.