CA1193197A - Anti-inflammatory composition - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A pharmaceutical composition containing an interphenylene 9-thia-11-oxo-12-aza prostanoic acid type renal vasodilator and a non-steroidal anti-inflammatory agent and its use are disclosed.

Description

TITLE OF THE INVENTION
ANTI-INFLA~ATORY CO~POS I T I ON

BA~KGROUND OF ~HE INVENTION
S The present invention is concerned wi~h a pharmaceutical composition containing a renal vasodilator and a non-steroidal anti~inflammatory agent.
Non steroidal an~i-inflammatory agents are known (see e.g., U.S. 3,161~6549 U.S. 3,654,349, U.S.
3,547l858). A specific example of this class of compounds is the commercial product known as indomekhacin.
Recentlyr a novel class oE prostanoic acid type compounds having pharmarological activity have been disclosed (U.S. 4,225~609). These compounds are especially effective renal vasodilators.
It has been discovered that the combination of these renal vasodilator compounds and khe non-steroidal anti-inflammatory agents produces a composition having enhanced pharmacological activity.
~,..-.

3~'7

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99e~iY~9~ 3~ ION
A pharmaceutical composition containing an interphenylene-9-thia-11-oxo-12-aza prostanoic acid type renal vasodilato~ and a non-steroidal anti-inflammatory agent~

DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the invention is a pharmaceutical composition useful for treating inflammation containing i) a renal vasodilator compound of the formula ()m Rl ~ (CH2)n- A - R

Rl~ N ` R3 oY R2-oi'~R4 (I) wherein R is carboxy, a carboxy salt, a carboxy ester of the formula CoOR5 wherein R5 is Cl 10 alkyl, or CONHR6 wherein R6 is amino or methylsulfonyl;
A is a p-phenylene or a m-phenylene or substituted phenylene derivative in which one or two of the phenylene hydrogens is replaced by a methyl or a halo substituent, or 2l5-thienylene or 2,5~-furylene;
n is 3 or 4, m is 0, 1, or 2;
Rl is hydrogen, deuterium, or methyl;

~33l~7

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Z is alkylene or unsaturated alkylene having from 2 3 carbon atoms;
R2 is hydrogen or lower alkanoyl;
R3 is hydrogen or straight chain Cl 3 alkyl;
and R4 is lower stra.ight chain or branched alkyl having from 3-7 carbon atoms, an unsaturated alkyl having from 3 7 carbon atoms, or a substituted lower alkyl selected from polyfluoro alkyl of from 3-7 carbon atoms and lower alkoxy methylene; or R3 and R4 taken together with the carbon atom connecting R3 and R is a cyclic substituent selected from a bridged or unbridged alicyclic ring of from 5-9 carbon atoms or a heterocyclic ring containing sulfur or oxygen and from 5-7 ring-forming carbon atoms;
and ii) a non-steroidal anti-inflammatory compo~nd.
A preferred i) compound has the Formula R~ CH2 )~XCOOH

Z - C ~

HO
wherein X is ch'orine or methyl;
r i5 O, 1, or 2;
n is 3 or 4, Rl is hydrogen, de~terium, or methyl;
Z is ethylene, trimethylene, cis or trans-propenylene, or propynylene;
R3 is hydrogen or lower alkyl of 1-3 carbon atoms; and 3~'7

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R4 i.s 4-pentenyl, 5,5,5-trifl.uoropentyl, or lower straight or branched chain alkyl of 3-7 carbon atoms.

or ()m Rl~/Sy (cH2)~cooH

~1 ~ N \ CH ~
,/ CH D
HO
wherein X i5 chlorine or methyl;
r is 0~ 1, or 2;
n is 3 or 4;
m is 0, 1, or 25 Rl is hydrogen, de~terium, or methyl;
Z i5 ethylene, trimethylene, propenylene, or propynylene;
y is 0, 2, or 3; and W is polymethylene of 2 6 carbvn atoms.

~ more preferred i) compound is selected from 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thia-zolidinyl]-propyl]benzoic acid a~d 4-[3 [3-l2(l-hydroxycyclo~exyl!eth~l]
oxo-2 thiazolidinyl]propyl~benzo1c acid.

and individual isomers thereofO A still more pre-ferred i) compound is the (~) enantiomer of 4-[3-~3-~3~

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[2-(1-Hydroxycyclohexyl)ethyl]-4 oxo-2-thiazolidinyl]
propyl]benzoic acid.
Non-steroidal anti~in~lammatory compounds are exemplified by indomethacin, ibuprofen, naproxen, piroxicam and the like~ A preferred non-steroidal antiinflammatory compound is indomethacin.
The composition may contain varying amounts of (i) and (ii). ~he weight ratio of i):ii) may range from 1.7:1 to 1:26; preferably from 1:1 to 1:26; more preferably from 1:7 to 1:26; and most preferably from 1:15 to 1:26~ In addition to the active ingredients i) and ii) the composition may also contain other conventional pharmaceutically acceptable compounding ingredients, as necessary or desired. Such ingredients are generally referred to as carriers or diluents. ~onventional procedures for preparing such compositions in appropriate dosage forms may be utilized. Whatever the dosage form, i~
will contain a therapeutically effective amount of the present composition.
The present compositions may be administered orally or o~her than orally e.g., parenterally, by insufflation, topically, rectally, etc.; using appropriate dosage forms, e.g.~ tablets7 capsules, suspensions, solutions and the like for oral admini-stration, suspension emulsions and the like for parenteral administration; ointments and the like for topical administration.
Treatment dosage for human beings may be varied as necessary. Generally, daily dosages of the present composition may range from about 550 to about '7

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27 mg; preferably rom 400 to about 60 mg; more preferably from about 200 to about 120 mg, using the appropriate dosage form and mode of administration~
The present compositions provide for an improved method of treating inflammation in patients who may have or may develop impaired renal function n It is known that administration of a non-s~eroidal, anti-inflammatory agent such as indomethacin may result in reducing renal function of a human patient~
Where the patient already has renal function impaired, of course, the non-steroidal anti-inflammatory might cause further impairment - andl thus, this patient would be denied the benefit of the inflammation relief offered by the non-steroidal inflammatory.
In vivo testing in test anima]s (dogs) has demonstrated that the present compositions prevent ~or restore) impairment of renal func~ion~
Specifically, indomethacin alone when administered intravenously to test animals decreased effective renal plasma flow (ERPF) by about 37% and glomelular filtration rate (GFR) by about 28%, two criteria of renal unction. When 4-[3-[3-[2-(l hydroxy~yclo-hexyl)ethyl]-4-oxo-2-thiazolidinyl3propyl]benzoic acid7 was administered to the test animals after the indomethacin, GFR was restored to normal within about two hours and the ERPF rose to almost twice the pre-indomethacin treatment level. The restoration of the GFR is especially surprising and coupled with the increase in ERPF indicates that the present compo-sitions can be used in patients; requiring anti-inflammatory therapy without impairing renal function~

The formula I compounds are fully disclosed in U.S. ~,225,609.
A process for preparing the individual enanti-omers of the formula I compounds is illus-tra-ted by the following examples. The underlined numbers in Example l identify -the products as shown in the Flow Sheet.

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Resolution of Racemic A-~3-~3-[2-(1-hydroxycyclohexyl)-ethyl~-4-oxo-2-thiazolidinyl~p_ ~ nzolc Acid FLOW SHEET

S--f ''~3Co2H
N
OH
(+)-1 ~Step A

N
OH
Step B
~ ~ \~ C02CH3 A R IH
o)/-- --~ \~`N'C`N~

o ~
3 Step C 4'' "~' \
~ I , S ~ CO2CH3 j ~ ~ 2 3 M ~ ~ N ~
`?~ ~

(+,-)-3 (-,-)-3 Step D(a) \ / ,Step D(b) ~/--\/\~ C02H S--\ ~ C2H
N ~ O
OH OH
(~) --1 ~--) --1 ~Th.is by-prodllct acylurea 4is separable hychroma-tography.

3~L~3'7 Step A. Preparation of (~)-Methyl 4-[3-[3~[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thia-zolidinyl]Propyl]benzoate (2) To a freshly-prepared solution of (+)-4-[3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidin-yl]propyl]benzoic acid (1) (10 g, 25.6 mmol) in dry N,N-dimethylformamide (86 ml) contained in a 250 ml round bottom flask is added finely-ground potassium carbonate (3.54 g, 25.6 mmol) followed by methyl iodide (1.6 ml~ 25~6 mmol). The resulting su~pension is protected from atmospheric moisture ~ith a magnesium sulfate drying tube and is stirred a~ room temperature for 19.5 hours. The reaction mixture is poured into water (175 ml) contained in a separatory funnel and then is extracted with e~her (3 X 40 ml~.
The organic extracts are combined~ washed with saturated aqueous sodium bicarbonate (3 X 30 ml), dried over sodium sulfate and filtered. Evaporation (in vacuo) of the filtrate leaves the desired ester 2 _._ as a pale yellow oil (10.55 g): tlc, R~ = 0.4 (homogeneous, UV detection) on silica gel with ethyl acetate:hexane (7:3; v:v) as eluent; ir (2% solution in chloroform) 3400 (w), 1710 (c), 1600 (s) and 1280 (s) cm~l.
Step B. Preparation of Methyl 4-[3-[3-[2-(1~
camphanyloxy)cyclohexyl)-ethyl~-4-oxo-2-thiazolidinyl]proPYl]benzoate (3) To a solution of (+)-methyl 4-[3-[3-~2-(1-hydroxycyclohexyl)ethyl~-4-oxo-2 thiazolidinyl]propyl]-benzoate (2) (38.37 g, 94.6 mmol) in methylene chloride (189 ml) are added (-)-camphanic acid (20~64 r~

~t 104~1 mmol) and 4-dimethylaminopyridine (5.77 g~
47.3 mmol)~ The resulting solution is cooled to 0C
and treated with a solution of N,~'-dicyclohexyl-carbodiimide (23.38 g, 113.52 mmol) in methylene chloride (180 ml) added slowly with stirring over 15 minutes. Thereby is obtained a heterogeneous mixture which is ~tirred at ambient temperature for 22 hours.
The reaction mixture is filtered to remove the insoluble solid (~ dicyclohexylurea~. The filtrate is washed with 0.2 N-hydrochloric acid (2 x ~0 ml) -and water (2 x 80 ml), dried over sodium sulfate and filtered. Evaporation ~in vacuo) of the filtra~e affords a brown, oily residue ~semi-solid): tlc on silica gel with chloroform-methanol (98:2; v v) indicates that the product 3, Rf = 0.3, is accom-panied by starting material 2 (ca. 5%) and traces of 4-dimethylaminopyridineO
The oily residue is "flash chromatographed"
on silica gel ~600 9, 230-400 mesh9 Eo ~erck~ using chloroform-methanol (98:2; v:v) as eluent and a flow rate sufficient to move the solvent front at 1" per minute. Thereby is eluted product 3 (ca. 55 g as a yellow solid) which is contaminated with N~
camphanyl)-N,N'-dicyclohexylurea (4). Product 3 is used as such in Step C described below~

Step ~. Separation of ~ixture 3 Into Diastereomeric Com~onents ~ -3_and (+_-~-3 (a) Isolation of (-,-)3 - Yellow solid 3 . __ (ca~ 55 g from Step B above~ is triturated with ethyl acetate hexane (1:1; v:v; 300 ml) at room temperature for 1 hour to provide a heterogeneous mixture which ~3~

is filtered. The collected, pale yellow solid (ca~
25 9 of impure t~ 3) is recrystallized six times from ethyl acetate to afford pure diastereomer (-,-)-3 as colorless cry~tals (8.85 g), mp 163 164C;
[~]22 = _47.3o (c 0.58, CHC13) D
(b) Isolation Of t~ 3 - The trituration filtrate from Step C (a) above is evaporated ln vacuo to provide a residue2 (ca. 24 g) consisting essentially of (~,-) 3 and byproduct 4. This residue is "flash chromatographed" in two separate 12 g portions as described below. A 12 g portion is applied in chloroform to a silica gel column (caO 350 g, 230-400 mesh, E. ~erck, 60 mm in diameter x 10" in length) which is eluted first with 30% ethyl acetate in hexane (2.4 L) at a flow rate sufficient to move the solvents front 1" per minute to remove the byproduct 4. Continued elution at the same flow rate with 40% ethyl acetate in hexane (1 L), 50% ethyl acetate in hexane (2 L) and 60% ethyl acetate in hexane (1 L) provides (~ 3. From the two "flash chromatographies" is obtained a pale yellow solid (l5 9)~ [~]22 = ~26.5 (c 0.57, CHC13~. This solid is recrystallized from ethyl acetate to constant rotation. Thereby i5 obtained pure diastereomer _ _ _ 1) Pmr analysis of (-,-)-3 and (+,-) 3 using the Europium shift reagent Fu(fOd)3 shows that each of these materials is a single diastereomerg 2) This residue can be analyzed by tlc: Rf = 0.12 for (~ 3 and Rf = 0.36 for 4 on silica gel with ethyl acetate. hexane (3:7; v:v) elution followed by detection (dipping tlc plate in 5~
sulfuric acid in ethanol and subsequent heating on a hot plate).

3~

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~ )-33 as colorless crystals (10.55), mp 130-132C; ~]22 = +3702~ (c 0.61, CHC13).Step D. Hydrolysis of (~ 3 and ( ,-)-3_ ~a) Preparation of (~)-4- 3-[3-[2-S (l-Hydroxycyclohexyl)ethyl]-4-oxo 2-thiazolidinyl]-~ropyl benzoic Acid To toluene (102 ml) contained in a 250 ml round bottom flask is added crushed solid potassium hydroxide (3.83 g, 68.3 mmol)O The resulting hetero geneous mixture is heated at reflux until ca~ 20 ml of distillate is collected4 and then is cooled to roorn temperature. To the cooled heterogeneous mixture is added (~ )-3 (4 g, 6.83 mmol) followed by dicyclohexyl 18-Crown-6 (12.72 q, 34.2 mmol). The resulting reaction mixture is protected from atmos-pheric moisture with a magnesium sulfate drying ~ube and is vigorously stirred and heated at 40C (oil bath) for 1 hourO Then the drying tube is removed~
water l80 ml) is added ~o the brown reaction mixture and stirring and heating at 40C are continued for 45 hours. After cooling to room temperature, the reac-tion mixture is poured slowly into cold, excess N
hydrochloric acid (200 ml~ with vigorous stirring.
The acidic,5 aqueous mixture is transferred to a separatory funnel and the layers are allowed to separate~ The aqueous layer (acidic phase) is extracted with chloroform (4 x 100 mlj. The toluene 3) See footnote 1) on page llo 4) Azeotropic distillation ensures the removal of traces of moisture.
5) The pH of this aqueous mixture should be checked with Congo red test paper; if not sufficiently acidic, additional O.lN hydrochloric acid should be added prior to separatlon of the layers.

~nd chloroform layers are combined, washed with water (2 x 100 ml), dried over sodium sulfate and filtered.
Evaporation (in vacuo) of the filtrate leaves an oily _.
residue which is triturated with ether at room temper-ature to afford an insoluble, colorless solid. The solid is collected, washed with ether and dried to give 2.04 g (76%) of (~ tlc, Rf = 0.26 (homogeneous, UV detection) with chloroform:methanol (9:1; v:v) on silica gel; identical by tlc to 1.
Recrys~allization from methanol affords pure enantiomer (~)-1 as colorless crystals (1.1 g), mp 139.5-140.5C; [~]22 ~ 70.00 (c 0.47, C~C13~;
ir (KBr pellet) 3270, 1690, 1640 and 1260 cm ; pmr (CD~13) 8.05 (2H, d), 7.28 (2H, d), 6.49 (2H, bs, OH and CO2~), 4.75 (H, bm), 3.56 (2H,s), 2.68 (2H, t) and 1~60 (bc envelope).
Anal. Calcd. for C21H29NO4S:
C, 64.42; H, 7.47; N~ 3.58 Found: C, 64.57; H, 7.81; N, 3.51 (b) Preparation of (-)-4-[3-[3-[2-(l-hydroxycyclohexyl)ethyl]-4-oxo-2-The hydrolysis of the pure diastereomer (-7-)-3 is carried out exactly as described above or (+,-) 3 in Step D (a~. Thereby is obtained pure enantiomer (~
as colorless crystals (1.24 9), mp 140-141C (from CH30H); [~]D -68.7 (C 0.47l CHC13); tlc~
ir and pmr data identical with those recorded for (+)--1 .

S~J

Anal. Calcd. for C21H29NO4S:
C, 64.42; H, 7.47; N, 3.58 Found: C, 64~48; H, 7.72; N, 3.72 EXA~PLE 2 A) Preparation of ~ethyl 4~[3~[3-hydroxyoctyl)-4-oxo-2-t.hiazolidinyl]propyl] benzoat enzolc A solution of racemic 4-[3-[3-(3-hydroxy-octyl)-4-oxo-2-thiazolidinyl]propyl] benzoic acid (13~13 g; 0.03335 mole) in dimethylformamide (66 ml) is ~reated with potassium carbonate (9.22 g; 0.06672 mole) and methyliodide (5.68 g; 0.04003 mole) and the resulting mixture is stirred at room temperature for 22 hours.
The reaction mixture is poured into cold water (330 ml). The oily layer is ex~racted with ether. The combined extracts are washed well with water and dried over magnesium sulfatec The solvent is removed under vacuum to give the methyl 4-[3 [3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoate racemate as an orange oil, yield 13~60 g.
B) Separation of the Two Racemic Modifications of Methyl 4-13-[3-(3-hydroxyoctyl)-4-oxo-2-thiazoli-din 13 ro l]benzoate ~_ P PY _ The two racemic modifications that comprise methyl 4-[3-[3 (3-hydroxyoctyl-4 oxo-2-thiazolidinyl]-propyl] benzoate as ob~ained above in A are separated by liquid chromatography using a Prep LC~System 500 liquid chromatograph manufactured by Waters Associate, Inc. The chromatographic column in this instrument is a Prep PAK-500/('18 silica cartridge ~ith dimensions 5.7 x 30 cm. The solvent mixture 3~
~ q used is hexane-isopropyl alcohol, 95 5 (v/v).
Thirteen g of the mixed racemates of the methyl ester after elution with 60 L of the solvent system gives 4.8 g of a front running fraction designated Racemate B-methyl ester and 6.9 g of a slower running rac~ion -designated Racemate -methyl ester. ~he ~wo fractions can also be differentiated by thin layer chromato-graphy on silica with 2% methanol in chlorofoxm (v/v) as the mobile phase. In this system, Racemate B-methyl ester has Rf 0~32~ and Racemate A-methyl ester has R~ 0.28 C-l) Preparation of Diastereomeric Camphanates from Racemate A of ~ethyl 4-[3-[3-(3 hydroxyoctyl) 4-oxo-2-thiazolidinyl]propyl] benzoate __ N,N'-Dicyclohexylcarbodiimide (6.2 g, 30 mmole) in C~2Cl~ is added to a solu~ion at 0C of Racemate A of methyl 4[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoate (10.0 g, 24.6 mmole), (15)~ camphanic acid (5.39 g, 27.2 mmole~ and 4-dimethylaminopyridine (1.5 9, 1203 mmole) in CH2C12 (25 ml). The mixture is stirred at 27C
for 6 hours. Precipitated dicyclohexylurea is removed by filtration. The filtrate is washed with 0.1 N hydrochloric acid and dried. Removal o~ sol-vent gave the crude mixed diastereomeric camphanates of Racemate A-methyl ester.
C-2) Preparation of Diastereomeric Camphanates rom Racemate B o ~ethyl 4-[3-[3 (3 hydroxyoctyl)-4 oxo-2-thiazolidinyl]propyl~ benzoate . .
By following the procedure described in 5tep C 1 but substituting Racemate B-methyl ester for the Racemate A-methyl ester there i~ obtained the crude 3~

mixed diastereomeric camphanates of Racemate B-methyl ester.
D-l) Isolation of the Levorotatory Diastereomeric Camphanate of Racemate A of Methyl 4-~3-[3-(3 hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]-benzoate The crude mixed diastereomeric camphanates of Racemate A-methyl ester (Step C-l) are triturated with 1:1 ethyl acetate-hexane (100 ml of solvent mixture per 15 g of esters). The insoluble material is collected on a filter. The filtrate containing the bulk of the dextrorotatory diastereomer is set aside. The solid is recrystallized three times from ethyl acetate to give the levorotatory diastereomeric camphanate of Racemate A-methyl ester (chemical name~ diastereomer of racemate A methyl 4-[3-[~-(153- -camphanyloxy)octyl)-4-oxoT2-thiazolidinyl~-propyl] benzoate~.
D-2~ Isolation of the Dextrorotatory Diastereomeric Camphanate of Racemate A of Methyl 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2 thiazolidinyl~propyl]
benzoate .. . . ~ . _ _ .
Evaporation of solvents from the filtrate obtained by trituration of mixed diastereomeric camphanate of racemate A-methyl ester gives an oil which crystallizes on standing. This solid is recrystallized three times from ethyl aceta~e to yield the dextrorotatory diastereomeric camphanate of racemate A-methyl esterO (Chemical name~
diastereomer of racemate A methyl 4-~3-[3-(3-((153- -camphanyloxy-octyl)-4-oxo-2-thiazolidinyl~propyl3 benzoate).

3~ t~

D-3) Isolation of the Levorotatory Diastereomeric Camphanate of Racemate B of ~ethyl 4-[3-[3-l3~
hydroxyoctyl)-4-oxo-2-thiazolidinylJpropyl]-benzoate . _ . . _ _ .
Treatment of the crude mixed diastereomeric camphanates of Racemate B methyl ester (Step C-2) exactly as in D-l yields the levorotatory diastereo-meric camphanate of Racemate B-methyl ester (chemical name~ diastereomer or racemate B-methyl 4-[3-[3-(3-((lS)- -camphanyl-oxy)octyl-4-oxo-2-thiazoli dinyl]propyl benzoate).
D-4) Isolation of the Dextrorotatory Diastereomeric Camphanate of Racemate B of Methyl 4-13-[3-(3-hydroxyoctyl~-4-oxo-2-thiazolidinyl]propyl]
benzoate Treatment of the filtrate from the isolation of the camphanate of ~-3 exactly as described in Step D-2 yields the dextrorotatory diastereomeric campha-nate of Racema~e B-methyl ester (chemical name~
diastereomer or racemate B-methyl 4-~3-[3 (3-((15)- -camphanyloxy)octyl)-4-oxo-2-thiazolidinyl]propyl] ben-zoate.
E~l) Preparation of the (-)-Enantiomer of Racemate A
of 4-[3-[3-(3-hydroxyoctyl-4-oxo-2-thiazoli-dinyl]~ropYl] benzoic acid Potassium hydroxide (finely crushed pellets) (3.83 g/, 68.3 mmoles) is added to toluene (100 ml).
The mixture is stirred and treated with the levo-ro~a~ory diastereomeric camphanate of Racema~e A methyl ester ~D-1)(4 g, 6.82 mmoles) and dicyclo-hexyl-18-crown-6 (12.7 g, 34.2 mmole). The mixture is then stirred and heated at 40C for 1 hourn Water 3~

(~0 ml) is added to the reaction mixture and stirring at ~0C is continued for 45 hours. The mixture is then poured into lN hydrochloric acid (200 ml~. The toluene layer is separated, washed with water and dried. The solvent is evaporated at reduced pressure.
The residual oil is triturated with acetonitrile to give the waxy solid (-)-enantiomer of racemate A of 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2 thiazolidinyl]propyl]-ber,zoic acid. 0 E-2) Preparation of the (~)-Enantiomer of Racemate A
of 4-[3-[3-(3-hydrQxyoc~yl)-4-oxo-2-thiazol-idin 1] ro 1 benzoic acid Y P PY __ ~ ydrolysis of the dextrorota~ory diastereo-meric camphanate of Racemate A-methyl es~er (Step D-2) exactly as described in Step E~l yields the waxy solid (+)-enantiomer of Racema~e A of 4-[3-[3-t3-hydroxy octyl-4-oxo-2-thiazolidinyl]propyl] benzoic acid~
E-3) Preparation o~ the (-)-Enantiomer of Racemate B
of 4~[3-[3-(3-hydroxyoctyl)-A-oxo-2-~hiazol idinyl]propyl] benzoic acid_ _ ~ydrolysis of the levorotatory diastereo-meric camphanate of Racema~e B-me~hyl ester (Step D-3) exactly as described in Step E-l yields the waxy solid ~ enantiomer of Racemate B of 4-[3-[3-(3-hydroxy-octyl-4-oxo-2-thiazolidinyl]propyl~ benzoic acid~
E-4) Preparation of the ~-Enantiomer of Racemate B
of 4-[3-[3~(3-hydroxyoctyl)-4-oxo-2-thiazo-lidinyl]propyl]benzoic acid _ _ Hydrolysis of the dextrorotatory diastereo-meric camphanate of Racemate B-methyl ester (Step ~-4) exactly as described in Step E-l yields the waxy solid (+)-enantiomer o~ Racemate B of 4 [3 [3-(3-hydroxy-octyl) 4-oxo-2-thiazolidinyl]propyl3 benzoid acid.
Claims to the invention follow,

Claims (8)

IN THE CLAIMS:

1. A pharmaceutical composition useful for treating inflammation containing i) a renal vasodi-lator compound of the formula wherein R is carboxy, a carboxy salt, a carboxy ester of the formula COOR5 wherein R5 is C1-10 alkyl, or CONHR6 wherein R6 is amino or methylsulfonyl;
A is a p-phenylene or a m-phenylene or substituted phenylene derivative in which one or two of the phenylene hydrogens is replaced by a methyl or a halo substituent, or 2,5-thienylene or 2,5-furylene;
n is 3 or 4;
m is 0, 1, or 2;
R1 is hydrogen, deuterium, or methyl;
Z is alkylene or unsaturated alkylene having from 2-3 carbon atoms;
R2 is hydrdogen or lower alkanoyl;

R3 is hydrogen or straight chain C1-3 alkyl;
and R4 is lower straight chain or branched alkyl having from 3-7 carbon atoms, an unsaturated alkyl having from 3-7 carbon atoms, or a substituted lower alkyl selected from polyfluoro alkyl of from 3-7 carbon atoms and lower alkoxy methylene; or R3 and R4 taken together with the carbon atom connecting R3 and R4 is a cyclic substituent selected from a bridged or unbridged alicyclic ring of from 5-9 carbon atoms or a heterocyclic ring containing sulfur or oxygen and from 5-7 ring-forming carbon atoms.
and ii) a non-steroidal anti-inflammatory compound.

2. The composition of Claim 1 wherein said ii) compound is indomethacin.

3. The composition of Claim 1 wherein said i) compound has the formula wherein X is chlorine or methyl r is 0, 1, or 2;
n is 3 or 4;
R1 is hydrogen, deuterium, or methyl;
Z is ethylene, trimethylene, cis or trans-propylene, or propynylene;
R3 is hydrogen or lower alkyl of 1-3 carbon atoms; and R4 is 4-pentenyl, 5,5,5-trifluoropentyl, or lower straight or branched chain alkyl of 3-7 carbon atoms.
or wherein X is chlorine or methyl r is 0, 1, or 2;
n is 3 or 4;
m is 0, 1, or 2;
R1 is hydrogen, deuterium, or methyl Z is ethylene, trimethylene, propenylene, or propynylene;
y is 0, 2, or 3; and W is polymethylene of 2-6 carbon atoms.

4. The composition of Claim 3 wherein said i) compound is 4-[3-[-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl)propyl]benzoic acid.

5. The composition of Claim 3 wherein said i) compound is 4-[3-[3-(2-(1-hydroxycyclohexyl)-ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoic acid.

6. The composition of Claim 5 wherein said i) compound is the (+) enantiomer.

7. The composition of Claim 3 wherein said ii) compound is indomethacin.

8. The composition of Claim 6 wherein said ii) compound is indomethacin.