NZ229305A - Method of treating autoimmune diseases in non-human mammals by administration of quinoline derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £29305 o ■Q o /"""N 22 9 305 MOOMWUffi; Priority Date(s): Complete Specification Filed: Class: Publication Date: .ViV'. P.O. Journal, No: ... 1-&S3, Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION 4-QUINOLINE CARBOXYLIC ACID DERIVATIVES USEFUL AS IMMUNOSUPPRESSIVE AGENTS jC/We, E.I. DU PONT DE NEMOURS AND COMPANY, A corporation organized and existing under the laws of the State of Delaware, USA, of 10th & Market Streets, Wilmington, Delaware, UNITED STATES OF AMERICA hereby declare the invention, for which Jf/we pray that a patent may be granted to n)6/us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) la 229305 This invention relates to nethods of treating imnunaTDdulatory and antiinflammatory diseases and more particularly to nethods of treating such diseases with 4-quinoline carbaxylic acids and derivatives thereof.

U.S. Patent 4,680,299, granted July 14, 1987, to Hesson describes phenylquinoline cabcxylic acids and their derivatives as tumor inhibiting agents.

It has now been found that the ccrpounds described in U.S. 4,680,299 are useful as iranunarodulatory and antiinflanmatory agents.

According to the present invention there is provided a method of treating an autoimmune disease • '* » in a non-human manrnal ccsnprising acfriinigterihg to the mammal an immunosuppressive- amount Of a compound having the fonnula.1; R E * (I) E E 3 wherein N.Z. PATENT OFFICE ia (followed by page 2 - 1 NOV i990 P.ECSIV5D 229305 R iE or JO- phenyl; Rl is CH3CH2(CH3)CH, alkyl of 5-12 carbon atoms, cyclohexyl, er - and when R is SCOW*1- then R* can be in addition alkyl of 3-4 carbon atcms; R2 is - —ocT R3 is H, alkoxy of 1-3 carbon a tans, or alkyl of 1- 2 carbon atoms; R4 is CO2H or OO2R11; R5, R6, R7 and R8 are independently H, F, Cl, Br, I, CH3, CF3, SCH3 or ch2<-^3» least two of R5, R6, R7 and R8 being H; N.Z. PATENT 0"F( "E 1 NOV 19U0 RECEIVED 229305 3 R? and R9A are independently H or alkyl of 1 to 3 carbon atoms; R11 is (CH2)2_4NR9R9A; W, Y and Z are independently H, F, Cl, Br, alkyl of 1-5 carbon atoms, NOg, OH, CF3 or OCH3; in is 0 or 1; or a pharmaceutical^ suitable salt thereof; with the following provisos: (1) R5, R6 and R7 cannot all be H; (2) when R4 is a)2CH2CH2N(CH3)2, R6 is CH2CH3, or R7 is Cl, R1 cannot be cyclohexyl; (3) when R1 is cyclohexyl and R3 is H, R6 mast be Cl or F, but Re and R8 cannot both be Cl; and (4) when R6 is CH3, then R7 cannot be Cl.

Additionally provided is the above-described method wherein the compound is administered in caiibination with a nonsteroidal antiinflammatory drug.

The invention also provides a pharmaceutical composition comprising a compound of formula I (as defined in this specification) together with a nonsteroidal anti-inflammatory drug.

Preferred compounds useful in the method have the formula: 4 (ii) R R b 1 wherein 3 229305 R1 is cyclohexyl; phenyl; phenyl substituted with one halogen, alkyl of 1-5 carbon atans or CF3; phenoxy, or phenoxy substituted with one halogen or alkyl of 1-5 carbon atcms; R3 is H or alkyl of 1-2 carbon atoms; R4 is CO2H, a sodium or potassium salt thereof; or CO2]*11; R5 and R6 are independently H, halogen, CH3 or CF3; R? and R8 are independently H or halogen; R11 is (CH2)2-4nr9r9A; R9 and R^ are independently alkyl of 1 to 3 carbon atcms, or a pharmaceutical^ suitable salt thereof; provided that R5, R® and R7 cannot all be H and that when R1 is cyclohexyl and R3 is H, R6 must be Cl or F, but and R8 cannot both be Cl, and when R6 is CH3, then R7 cannot be Cl.

More preferred compounds useful in this invention have the formula: wherein R1 is cyclohexyl, (iii) 4 N.Z. PATENT OFFICE -I NOV 1990 R3 is H or alkyl of 1-2 carbon atcms; R4 is CO2H, a sodium or potassium salt thereof, or OO2R11; R5 and R6 are independently H, halogen or CF3 provided that both R5 and R6 are not* hydrogen; R11 is (CH2)2-4NR9R9A; and R9 and R9a are independently alkyl of 1 to 3 carbon atcms, and W and 2 are independently H, . F, Cl, Br, alkyl of 1-5 carbon atcms or CF3; provided that when R1 is phenyl or phenoxy, and R5 is H, then R® cannot be Br; and that when R1 is cyclohexyl and R3 is H, R® must be Cl or F. Specifically preferred ccnpounds useful in this invention are: (1) 2- (1,1' -biphenyl-4-yl) -5-chloro-3-methyl-4-quinoline carboy lie acid, scxiium or potassium salt (2) 2- (1,1' -biphenyl-4-yl) -6-fluoro-3-methyl-4-quinoline carboxylic acid, sodium or potassium salt (3) 6-fluoro-3~methyl-2- ( 4 -phenoxyphenyl) -4-guinoline carboxylic acid, sodium or potassium salt (4) 2- (4' -brcrro-1,1 '-biphenyl-4-yl )-6-fluoro-3-rnethy 1-4-quinoline carboxylic acid, sodium or potassium salt (5) 2- (2' -f luoro-1,1 '-biphenyl-4-yl)-6-fIuoro-3-methyl-4-qainoline carboxylic acid, sodium or potassium salt. < ■* V The ccnpounds useful in this invention are described in and prepared by methods set forth in U.S. Patent 4,680,299, the disclosure, synthesis, 22 9 3 05 and synthesis examples of which are hereby incorporated by reference.

The invention can be further understood by the following exanples in which parts and percentages 5 are by weight unless otherwise indicated; all tenperatures are in degrees centigrade.

Example 1 Part A: 2-(1,1'-Biphenyl-4-yl)-5-chloro-3-methy1- quinoline-4-carboxylic acid A mixture of 4-chloroisatin (7.28 g, .04 mol), rj. An. Chem. Soc., 1251 (1956)], 4-phenylpropiophenone (8.8 g, .04 mol), diethylamide (4 ml, .04 mol) and ethanol (200 ml) was stirred 15 for a period of 18 hours at roan temperature. The precipitated solids were collected by filtration, washed with ice-cold ethanol and air dried to yield the adduct (9.1 g, 58%) m.p. 209-214° dec.

G 25 Part B: The above described adduct (9.1 g) was added to a mixture of tetrahydrofuran (200 ml), and concentrated HC1 (200 ml) and heated at reflux for 24 hr. The reaction mixture was cooled, water (300 ml) was added and most of the tetrahydrofuran removed by evaporation in vacuo. The aqueous residue was cooled and the sticky solids collected by filtration. Trituration in 150 ml of boiling methanol yielded (4.8 g, 55%) m.p. 295-297° dec.

O 3Q C23H16CINO2 HRMS: 373.0869 Calcd, measured m/e 373.0814.

NMR (EMSO-dg)8.5(m,lH), 7.7-7.85(m,7H), . 7.35-7.55(m,4H), 2.45(s,3H). 6 22 9305 Part C; Sodium 2-(l,l'-Biphenyl-4-yl)-5-chloro- 3-methyl-quinoline-4-carboxylate To a suspension of the above acid (3.7 g, .01 mol) in ethanol 100 ml, sodium hydroxide (IK, 10 5 ml, .01 mol) was added, and gently warmed. The clear solution was then filtered and evaporated to dryness to yield (4.0 g) m.p. 320-330° dec.

Example 2 - Part A: 2-(2-Fluoro-l,l'-biphenyl-4-yl)-6-fluoro- 3-methyl-4-quinoline carboxylic acid 5-Fluoroisatin (72.6 g, 0.44 mole) and 4-(2-fluorophenyl)propiophenone (100 g, 0.44 mole) were suspended in 720 ml of ethanol and stirred 15 mechanically as a solution of KQH (147.8 g, 2.64 mole) in 300 nil of water was added dropwise over 15 minutes. The reaction mixture was heated at reflux for 12 hours, cooled and the ethanol evaporated under reduced pressure. The resulting solid was 20 dissolved in water and washed with ethyl ether.

The aqueous layer was cooled to 5° and acidified with glacial acetic acid. The resulting precipitate was filtered, washed 2 times with 300 ml of ethyl ether and dried. Recrystallization frcm diraefchylfontBCTri.de and water gave 84 g of a white 2- (2' -Fluoro-1,1' -biphenyl-4-yl) -6-fluoro-3-methyl-4-quinoline carboxylic acid, m.p. 315°-317°.

G Part B: Sodium 2-(2'-Fluoro-1,l'-biphenyl-4-yl)-30 6-fluoro-3-methylquinoline-4-carboxylate The ccrpound of Part A (37.5 g, 0.10 mole) was suspended in 1,000 ml of ethanol and treated with IN NaOH (100 ml, 0.10 mole). The mixture was warmed and stirred until clear; the ethanol and 35 water were evaporated at reduced pressure to give 7 ■*««< * v? * r> 22 9 3 05 39.6 g of the white solid sodium 2-(2'-fluoro-1,1'-biphenyl-4-yl) 6-fluoro-3-nethylquinoline-4-carboxylate, m.p. >360°.

Following the procedures of Exanples 1 and 2 o 5 or the synthesis procedures described in U.S. 4,680,299, the ccnpounds set forth in Table 1 were prepared. kO 10 0 8 uEwTin "S* * V n t - y ■•} © O' Ex. No. 3 4 6 7 8 11 R1 R2 F Na F Na CH3 Na F Na Cl Na Cl K F Na F Na F Na 9 Table 1 22 9 3 05 co2r2 12 Cl Na r3 r4 ch3 °-o >350 ch3 -0"Br >350 ch3 -o >350 ch3 -s-ch(ch3)2 339-343 ch3 -~o 319-324 ch3 -s-0 310-325 h -O >360 ch3 251-260 och3 —o 345-349 ch3 >360 r> o 22 9 3 0 5 Utility Results of the biological tests described below establish that the ccrpounds useful in this invention have the ability to suppress/inhibit: S the contact sensitivity response to 2,4- dinitrofluorobenzene (DNFB) in mice, the hunan mixed lymphocyte reaction, and adjuvant-induced arthritis in rats.

Contact sensitivity to DNFB has been exten-10 sively studied and characterized in the mouse to determine the regulatory mechanisms involved in cell mediated imnune responses (Claman, et al,, Immunol Rev 50:105, 1980). This is an antigen-specific T-cell mediated inf lanmatory response that 15 represents delayed-type hypersensitivity reactions seen in both humans and other nenrals. The primary use of the human mixed lymphocyte reaction is for the determination of transplantation ccnpatibility between the donor (graft) and the recipient (Park 20 and Good, p. 71. In Yunis, et al., Tissue typing and organ transplantation. 1973 Academic Press Inc., N.Y.).

Rat adjuvant-induced arthritis represents a (2) systemic inflammatory disease with bone and cartilage changes similar to that observed in rheumatoid arthritis, but in an accelerated time span (Pearson, Arth Rheum 7:80, 1964).

Most clinically effective drugs exhibit activity in these biological tests similar to that 30 observed with the ccrpounds useful in this invention (Fenichel and Chirigos, ed, Iranune 22 9 3 li O \ modulation agents and their mechanisms, 1984 Dekker, Inc, N.Y., and Billingham, 21:389, 1983).

Contact Sensitivity Response to DNFB in Mice 5 Balb/c female mice (- 20g, Charles River) were sensitized on the shaved abdomen with 25 jil of 0.5% 2,4-dinitrofluorobenzene (DNFB, Eastman Kodak Co.) in a vehicle of 4:1 acetone:olive oil on days 0 and 1. Mice were ear challenged with 20 fil of \±) 10 0.2% DNFB in a vehicle of 4:1 acetone:olive oil on day 5. A constant area of the ears was neasured imnediately before challenge and 24 hours later with an engineer's micrometer. Ear swelling was expressed as the difference in ear thickness before 15 and after challenge in units of 10-4 inches ± SEM.

Percent suppression was calculated as: % Suppression = 1- compound treated-neqative control x 100 positive control-negative control Ccrpounds were administered orally from days - 2 through day 6 and were prepared in 0.25% Methocel® (Dow Chemical Co.). Control animals received only vehicle (0.25% Methocel®). Negative controls were not sensitized on days 0 and 1 but were ear 25 challenged on day 5. 'Ben mice were used per group.

Results with caxpounds of invention and drugs used clinically are shown in-Tables 2 and 3. 11 *V5' ' : 3" 12 Table 2 22 9 3 05 o Dose Ear Swelling3 % (rag/kg) (units ± SEM) Suppression ED50 Treatment O Negative Positive Dexamethasone Vehicle 0.7410.52 Vehicle 74.1H3.78 0.2 1.0 5.0 10.0 Cyclosporin A 2.0 10.0 50.0 100.0 Methotrexate Exarnple 1 Example 2 0.4 2.0 10.0 20.0 0.4 2.0 10.0 20.0 0.4 2.0 10.0 20.0 52.95±3.39 41.60±2.46 23.79±2.71 15.50±2.10 56.1513.74 66.58±3.75 47.90±3.76 7.8012.04 71.30*2.96 60.80il.99 36.10±3.23 27.4514.99 66.0514.32 56.94±4.80 6.10±0.75 5.2011.17 51.9512.33 25.6113.39 6.40ll.09 4.7511.20 28.84 44.31 68.58 79.88 24.48 .27 35.72 90.37 3.83 18.14 51.80 63.59 .99 23.40 92.69 93.92 .20 66.10 92.28 94.53 1.50 70.00 9.00 3.50 0.95 a Increase in ear thickness frcm day 5 to day 6, unit = 10~4 inches u 12 ."•* \\ - r"}-' " : 13 table 3 22 9 3 05 n © 0 Dose Ear Swelling® % Treatment (mg/kg) (units t SEM) Suppression Negative Vehicle 2.60±0.73 Positive Vehicle 73.1H3.69 Dexamethasone 1.0 42.20i2.61 Cyclosporin A 20.0 Methotrexate 20.0 Example 3 20.0 Exanple 4 20.0 Exanple 5 20.0 Exanple 6 20.0 Exanple 7 20.0 Exanple 8 20.0 Exanple 9 20.0 Exanple 10 20.0 Exanple 11 20.0 Exanple 12 20.0 74.3012.86 16.9412.10 14.2511.49 ll.80ll.03 35.4712.31 58.2014.63 62.9513.40 63.2513.58 42.6012.68 57.2812.36 20.8512.53 54.5813.21 0 43.83 -1.69 79.66 83.48 86.95 53.37 21.14 14.40 13.98 43.27 22.45 74.12 26.28 a increase in ear thickness frctn day 5 to day 6, unit = 10-4 13 \~$i . ' • . * \, - '; r.' •• - 0^ n 14 22 9 3 05 Human Mixed Lymphocyte Reaction Blood was obtained by venipunture from two nonrelated human donors. Peripheral blood mononuclear cells (PBMS) were isolated from these 5 samples ty using the Leuco Prep procedure (Becton- Dickinson). PBMC were washed twice in phosphate buffered saline (without calcium and magnesium) and the separate cell isolations were adjusted to the appropriate concentrations in media (RFMI 1640) 10 supplemented with 20% human SB serum and "50 pl/ml gentamicin. Cells frcm donor A (2 x 105) were incubated with cells frcm donor B (2 x 105) in 96 well round bottcm microliter plates at 37 0C, 5% CO2 for 6 days. Eighteen hours prior to harvesting 15 cells frcm the plates, all wells were pulsed with 1 fiCi of 3H-thymidine. Cells frcm the plates were harvested on day 6 and 3H-thymidine incorporation was determined using a scintillation counter. Test results are shown in HJable 4.

TABLE 4 Compound IC50 (M) (?) Tndcnethacin Cyclosporin A Methotrexate Exanple 1 Example 2 > ID-6 1.6 X -® 2.5 X -9 9.6 X -9 2.5 X ~B 14 22 9 3 05 Adjuvant-Induced Arthritis Male Lewis rats (Charles River) weighing 160-210 grams were injected subcutaneously with 0.1 ml of Freund's Coiplete Adjuvant containing 5 irg of M. 5 butyricum/ml of paraffin oil (Difco Laboratories) into the plantar region of the right hind paw. Paraffin oil was injected for non-arthritic controls. Ten rats were used per group. Compounds were prepared in 0.25% Methocel® (Dow Chemical Co) G' 10 with one drop of Tween® 80 per 10 ml of Methocel®.

Animals were dosed every day beginning on the day of paw injection until day 18. The weight of each animal was recorded every other day beginning on the day of the paw injections. On day 18 the 15 animals were weighed, and the non-injected hind paw volume was measured using a Ugo Basile Volume Differential Plethysmometer. The results are shown in Table 5. 0 W 16 TABLE 5 22 9 3 05 0 Group (AA) Gonpound (mg/kg) Weight Gain <g> Non-Injected Hind-Paw Volume (ml) « Suppression A - Vehicle 85.6±4.8 1.1210.01 - B + Vehicle -20.3±2.9 1.8810.05 - © C + Exanple 1 (10.00) -14.0±4.2 1.8710.08 1.4 D + Exanple 1 (17.5) 2.8±5.3 1.7210.08 .8 E + F + Exanple 1 (25.0) Exanple 2 (2.0) .6±6.3 - 1.513.6 1.3410.10 1.6210.05 70.6 34.5 G + Exanple 2 (10.0) 65.615.2 1.1510.02 96.2 H + Exanple 2 (25.0) * Exanple 1: ED50 = 21 mg/kg (T) Exanple 2: ED50 < 10 mg/kg *Toxic by day 7 16 4^ o 17 22 9 3 05 In sunmary, test results show that the carpounds useful in this invention have both irmrancmodulating and anti-inflaimatory effectiveness. Based on these data, the ccrpounds 5 useful in this invention should be efficacious in treating autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, and irryastenia gravis; all of which involve T lynphocyte mediated components similar to 20 those known in the contact sensitivity model.

Activities in the human mixed lynphocyte reaction indicate that the compounds of invention should be effective in preventing transplantation rejection and graft vs. host disease. These compounds were 15 also effective in the adjuvant-induced arthritis model and should therefore be useful antiinflammatory agents for the treatment of chronic inf lanmatory diseases such as rheumatoid arthritis, psoriasis, and inf lanmatory bowel disease.

DOSAGE FORMS The antitumor compounds (active ingredients) of this invention can be administered to inhibit tumors by any means that produces contact of the 25 active ingredient with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic active ingredients or in a 30 combination of therapeutic active ingredients.

They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. 17 o 22 9 3 05 The dosage administered will be a tumor-inhibiting amount of active ingredient and will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the 5 particular active ingredient, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of synptcms; kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of 10 active ingredient can be about 0.1 to 400 milligrams per kilogram of body weight. Ordinarily 1 to 100, and preferably 10 to 50 milligrams per kilogram per day is effective to obtain desired results.

Dosage forms (compositions) suitable for internal administration contain from about 10-500 milligrams to about 500 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily 2o be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, (T) tablets, and powders, or in liquid dosage forms, V—S such as elixirs, syrups, and suspensions, it can also be administered parenteral ly, in sterile liquid dosage forms.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions, it can also be administered parenteral ly, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient 35 and powdered carriers, such as lactose, sucrose, 18 --iTn.t4._j!*" 19 22 9 3 05 o mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make caipressed tablets. Both tablets and capsules can be manufactured as 5 sustained release products to provide for continuous release of medication over a period of hours. Ccnpressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet frcm the atmosphere, or enteric 10 coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral 20 administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, (^) sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents. Also used are citric acid and its salts and sodiinn EDTA. In addition parenteral solutions can contain preservatives, such as benzalkonium chloride, (^) methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

CAPSULES A large number of unit capsules are prepared 35 by filling standard two-piece hard gelatin capsules 19 Vj o 22 9 305 each with 100 milligrams of powdered active ingredient, 175 milligrams of lactose, 24 milligrams of talc, and 6 milligrams magnesium stearate. ^ 5 A mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement punp into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried. 10 TABLETS A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of 15 magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. 20 TM IHI " i 'abt* A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is 25 irade isotonic with sodium chloride and sterilized.

SUSPENSION AN aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 30 200 milligrams of sodium carbaxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of • vanillin.

The same dosage forms can generally be used 35 when "the ccrpounds of this invention are

Claims (11)

. v> '. ■ " i" • " n 0 25 30 22 9 3 05 21 administered stepwise in conjunction with another therapeutic agent. When the drugs are administered in physical combination, the dosage form and administration route should be selected for 5 compatibility with both drugs. Suitable dosages, dosage forms and administration routes are illustrated in Table 6. Table 6 10 Exanples of NSAID's that can be combined with the 4-quinolinecarboxylic acids used in this invention Dose Forrnu- Druq (mq) lation Route 15 Indamethacin 25 Tablet Oral (2/3 times daily) Meclofenanate 50-100 Tablet Oral 20 (2/3 times daily) Ibuprofen 300-400 Tablet Oral (3/4 tiroes daily) Piraxicam 10-20 Tablet Oral (1/2 times daily) Sulindac 150-200 Tablet Oral (2 times daily) Azapropazone 200-500 Tablet Oral (3/4 times daily) 35 21 22 what We claim rs> MHM* IS PAD CD ISi-

1. A method of treating an autoijnmune disease in a non-human manimal ccnprising administering to the inanmal an ajirnunosuppressive amount of a ccrrpound having the formula: (I) wherein R is Y or JO- phenyl: R1 is CH3CH2(CH3)CH, alkyl of 5-12 carbon atoms, cyclohexyl, or —ch2 , and when R is then r! can be in addition alkyl of 3-4 carbon atoms; 22 N.Z. PATENT OFFJCE -INQV icld(J RECEIVED © 229305 23 R2 is O -aC ■■ -~oc! R3 is H, alkoxy of 1-3 carbon atcms, or alkyl of 1-2 carbon atcms; ^ 10 R4 is OO2H or CXD2R11; R5, R6, R7 and R8 are independently H, F, Cl, Br, I, CH3, CF3, SCH3 or CH2CH3, at least two of R5, R6, R7 and R8 being H; R9 and R9A are independently H or alkyl of 1 to 3 15 carbon atcms; R11 is (CH2)2-4NR9R9A; W, Y and 2 are independently H, F, Cl, Br, alkyl of 1-5 carbon atcms, NO2, OH, CF3 or OCH3; m is 0 or 1; or 20 a pharmaceutical^ suitable salt thereof; with the following provisos: (1) R5, R6 and R7 cannot all be H; (2) when R4 is C02CH2CH2N(CH3)2r R6 is O* CH2CH3, or R7 is Cl, R1 cannot be 25 cyclohexyl; (3) when R1 is cyclohexyl and R3 is H, R6 mast be Cl or F, but R6 and R8 cannot both be Cl; and O (4) when R6 is CH3, then R7 cannot be Cl. 30 35 23 229305 24

2. The method of Claim 1 wherein the ccrrpound has the formula: (ii) wherein R* is cyclohexyl; phenyl; phenyl substituted with one halogen, alkyl of 1-5 carbon atcrns or CF3; phenaxy;' or phenaxy substituted with one halogen or alkyl of 1-5 carbon atcms; R3 is H or alkyl of 1-2 carbon atoms; R4 is CO2H, a sodium or potassium salt thereof; or CCpR11; R5 and R6 are independently H, halogen, CH3 or CF3; R7 and R8 are independently H or halogen; R11 is (CH2)2-4NR9R9A; and R9 and R9a are independently alkyl of 1 to 3 carbon atans, or a piharmaceutically suitable salt thereof; provided that R5, R6 and R7 cannot all be H and that when R* is cyclohexyl and R3 is H, R® mast be Cl car F, but R® and R8 cannot both be Cl, and when R6 is CH3,. then R7 cannot be Cl.

3. The method of Claim 1 wherein the compound has the formula: (iii) N.Z. PATEtMT OrFJCE NOV 1990 e o 25 wherein R1 is cyclohexyl, r, or —o- R3 is H or alkyl of 1-2 carbon atoms; 10 R4 is CX^H, a sodium or potassium salt thereof, or CO2R11; R5 and R6 are independently H, halogen or CF3 provided that both R5 and R6 are not hydrogen; r11 is (ch2)2-4nr9r9a#" a™* 15 Tp and R5A are independently alkyl of 1 to 3 carbon atcms, and W and Z are independently H, F, Cl, Br, alkyl of 1-5 carbon atcms or CF3; provided that when R1 is phenyl or phenaxy, and R5 20 is H, then R6 cannot be Br; and that when R* is cyclohexyl and R3 is H, R6 must be Cl or F.

4. The method of Claim 1 wherein the ccrrpound (/j) is 2-(1,1 '-biphenyl-4-yl) -5-chloro-3-methyl-4- 25 guinoline carboxylic acid, sodium or potassium salt.

5. Hie nethod of Claim 1 wherein the ccrrpound is 2-(l,l'-biphenyl-4-yl)-6-fluoro-3-methyl-4-30 quinoline carboxylic acid, sodium or potassium salt. 35 25 N.Z. PATENT OFFICE - 1 NOV 19S0 rGCEIVSD 26

6. The method of Claim 1 wherein the ccrrpound is 6-fluoro-3-methyl-2- (4 -phenaxyphenyl) -4-quinoline carboxylic acid, sodium or potassium salt.

7. The method of Claim 1 wherein the ccrrpound is 2- (4 '-brcmo-1,1 '-biphenyl-4-yl)-6-fluoro-3-irethyl-4-qainoline carboxylic acid, sodium or potassium salt.

8. The method of Claim 1 wherein the ccrrpound is 2- (2' -fluoro-1,1 '-biphenyl-4-yl) -6-fluoro-3-insthyl-4-guincline carboxylic acid, sodium or potassium salt.

9. The method of any one of claims 1 to 8 wherein the carpound is " administered in coribination with a -nonsteroidal antiinflantnatory drug.

10. A pharmaceutical composition suitable for treating immunomodulatory and anti-inflammatory diseases, the composition comprising a compound of the formula I as defined in any one of claims 1 to 9 together with a non-steroidal anti-inflammatory drug.

11. A pharmaceutical composition according to claim 10 and substantially as described in this specification. AND COMPANY 26