United States Patent [191
`Ackerman et al.
`
`[11]
`[45]
`
`Patent Number:
`Date of Patent:
`
`4,968,701
`Nov. 6, 1990
`
`[54]
`
`4-QUINOLINE CARBOXYLIC ACID
`DERIVATIVES USEFUL AS
`IIVIMUNOSUPPRESSIVE AGENTS
`
`[75]
`
`Inventors:
`
`Neil R. Ackerman, Greenville;
`Richard R. Harris, Wilmington; Scott
`E. Loveless, Newark, all of Del.;
`Russell H. Neubauer, West Chester,
`Pa.
`
`[73]
`
`Assignee:
`
`E. I. Du Pont de Nemours and
`Company, Wilmington, Del.
`
`[21]
`
`Appl. No.: 186,243
`
`[22]
`
`Filed:
`
`Apr. 26, 1988
`
`[51]
`[52]
`[53]
`
`Int. Cl.5 . . . . . . .
`
`. . . . . . . . . . . . .. A61K 31/47
`
`US. Cl. ........... .: ..................... .. 514/312; 514/311;
`514/314; 514/825; 514/885
`Field of Search ............. .. 514/311, 314, 312, 825,
`514/885
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,973,022 8/ 1976 Goschke ........................... .. 514/825
`4,407,803 10/1983 Haviv et a1. . . . . . . .
`. . . .. 514/825
`4,680,299 7/1987 Hesson ...................... .. 514/311
`4,847,381 7/ 1989 Sutherland et a1. .............. .. 548/485
`
`FOREIGN PATENT DOCUMENTS
`0190722 8/ 1986 European Pat. Off. .......... .. 514/312
`Primary Examiner-Douglas W. Robinson
`Assistant Examiner-Zohreh A. Fay
`[57]
`ABSTRACT
`4-Quinolinecarboxylic acids and derivatives thereof,
`such as 2-(2’-?uoro-1,l’-biphenyl~4-yl)-6-?uoro-3-meth
`yl-4-quinolinecarboxylic acid, are useful as im
`munomodulatory and anti-in?ammatory agents. Phar
`maceutical formulations containing such compounds
`are useful for the treatment of autoimmune diseases,
`organ transplantation rejection, graft vs. host disease,
`multiple sclerosis, and chronic inflammatory diseases
`such as rheumatoid arthritis.
`
`8 Claims, No Drawings
`
`NOVARTIS EXHIBIT 2031
`Par v Novartis, IPR 2016-00084
`Page 1 of 8
`
`

`
`1
`
`4,968,701
`
`4-QUINOLINE CARBOXYLIC ACID
`DERIVATIVES USEFUL AS
`IMMUNOSUPPRESSIVE AGENTS
`
`BACKGROUND OF THE INVENTION
`This invention 'relates to methods of treating immu
`nological and in?ammatory diseases and more particu
`larly to methods of treating such diseases with 4-quino
`line carboxylic acids and derivatives thereof.
`US. Pat. No. 4,680,299, granted July, 14, 1987, to'
`Hesson describes phenylquinoline caboxylic acids and
`their derivatives as tumor inhibiting agents.
`It has now been found that the compounds described
`in US. Pat. No. 4,680,299 are useful as immunomodula
`tory and antiin?ammatory agents.
`
`SUMMARY OF THE INVENTION
`According to the present invention there is provided
`a method of treating an autoimmune disease in a mam
`mal comprising administering to the mammal an immu
`nosuppressive amount of a compound having the for
`mula:
`
`20
`
`25
`
`O
`
`N
`
`R7
`
`R8
`
`wherein
`
`R is
`
`Y
`
`R1,
`
`0R2,
`
`@smmzk or U-plrenyl;
`
`s
`
`45
`
`W
`
`or -CH;
`
`Z
`
`Z
`
`R3 is H, alkoxy of 1-3 carbon atoms, or alkyl of 1-2
`carbon atoms;
`. R4 is COzH or CO2R11;
`R5, R6, R7 and R8 are independently H, F, Cl, Br, 1,
`CH3, CF3, SCI-I3 or CH2CH3, at least two of R5,
`R6, R7 and R8 being H;
`R9 and R914 are independently H or alkyl of 1 to 3
`carbon atoms;
`
`W, Y and Z are independently H, F, Cl, Br, alkyl of
`1-5 carbon atoms, N02, OH, CF3 or OCH3;
`m is 0 or 1; or
`a pharmaceutically suitable salt thereof;
`with the following provisos:
`(1) R5, R6 and R7 cannot all be H;
`(2) when R4 is CO2CH2CH2N(CH3)2, R6 is
`CH2CH3, or R7 is Cl, Rl cannot be cyclohexyl;
`(3) when R1 is cyclohexyl and R3 is H R6 must be Cl
`or F, but R6 and R8 cannot both be Cl; and
`(4) when R6 is CH3, then R7 cannot be C1.
`Additionally provided is the above-described method
`wherein the compound is administered in combination
`with a nonsteroidal antiin?ammatory drug.
`
`_
`
`PREFERRED EMBODIMENTS
`Preferred compounds useful in the method have the
`formula:
`
`R6
`
`R7
`
`R5
`
`R4
`
`(11)
`
`R3
`
`N
`
`R8
`
`R 1
`
`R1 is CH3CH2(CH3)CH, alkyl of 5-12 carbon atoms,
`cyclohexyl,
`
`Z
`
`or CH;
`
`Z
`
`W
`
`W
`
`when R is
`
`R1 can be in addition alkyl of 3-4 carbon atoms; R2 is
`
`wherein
`R1 is cyclohexyl; phenyl; phenyl substituted with one
`halogen; alkyl or 1-5 carbon atoms or CF3; phe
`noxy; or phenoxy substituted with one halogen or
`alkyl of l-5 carbon atoms;
`R3 is H or alkyl of 1-2 carbon atoms;
`R4 is COZH, a sodium or potassium salt thereof; or
`CO2R11;
`R5 and R6 are independently H, halogen, CH3 or CF3;
`R7 and R8 are independently H or halogen;
`R11 is (CH2)24NR9R9A; and R9 and R9A are indepen
`dently alkyl of 1 to 3 carbon atoms,
`or a pharmaceutically suitable salt thereof; provided
`that R5, R6 and R7 cannot all be H and that when
`R‘ is cyclohexyl and R3 is H, R6 must be C1 or F,
`but R6 and R8 cannot both be Cl, and when R6 is
`CH3, then R7 cannot be C1.
`More preferred compounds useful in this invention
`have the formula:
`
`65
`
`NOVARTIS EXHIBIT 2031
`Par v Novartis, IPR 2016-00084
`Page 2 of 8
`
`

`
`3
`
`R3
`
`R5
`
`R4
`
`R6
`
`N
`
`wherein
`R1 is cyclohexyl,
`
`R l
`
`w
`
`z
`
`w
`
`or —0
`
`Z
`
`(III)
`
`4,968,701
`4
`ethanol and air dried to yield the adduct (9.1 g,
`58%) m.p. 209°-214° dec.
`PartB
`The above described adduct (9.1 g) was added to a
`mixture of tetrahydrofuran (200 ml), and concentrated
`HCl (200 m1) and heated at re?ux for 24 hr. The reac
`tion 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 ?ltration. Trituration in 150 mol of
`boiling methanol yielded (4.8 g. 55%) m.p. 295°-297°
`dec.
`C23H16CINOZHRMS: 373.0869 Calcd, measured m/ e
`373.0814.
`
`R3 is H or alkyl of 1-2 carbon atoms;
`R4 is CO2H, a sodium or potassium salt thereof, or
`COZRH;
`R5 and R6 are independently H, halogen or CF 3 pro
`vided that both R5 and R6 are not hydrogen;
`
`20
`
`7.35-7.55(m,4H), 2.45(s,3H).
`Part C: Sodium
`2-(1, l’-Biphenyl-4-yl)-5-chloro-3-methyl-guinoline-4
`carboxylate
`‘
`To a suspension of the above acid (3.7 g, 0.01 mol) in
`ethanol 100 ml, sodium hydroxide (IN, 10 ml, 0.01 mol)
`was added, and gently warmed. The clear solution was
`then ?ltered and evaporated to dryness to yield (4.0 g)
`m.p. 320°-330° dec.
`
`EXAMPLE 2
`Part A:
`2-(2-F1ouro-l,1'-biphenyl-4-y1)-6-?uoro-3-methyl-4
`quinoline carboxylic acid
`S-Fluoroisatin (72.6 g, 0.44 mole) and 4-(2-fluoro
`pheny1)propiophenone (100 g, 0.44 mole) were sus
`pended in 720 ml of ethanol and stirred mechanically as
`a solution of KOH (147.8 g, 2.64 mole) in 300 ml of
`water was added dropwise over 15 minutes. The reac
`tion mixture was heated at re?ux for 12 hours, cooled
`and the ethanol evaporated under reduced pressure.
`The resulting solid was dissolved in water and washed
`with ethyl ether. The aqueous layer was cooled to 5°
`and acidi?ed with glacial acetic acid. The resulting
`precipitate was ?ltered, washed 2 times with 300 ml of
`ethyl ether and dried. Recrystallization from dimethyl
`formamide and water gave 84 g of a white 2-(2’-Fluoro
`1,1’-biphenyl-4yl)-6-fluoro-3-methyl-4quinoline carbox
`ylic acid, m.p. 315°-317°.
`Part B: Sodium
`2-(2’-F1uoro- l , l ’-biphenyl-4-yl)~6-?uoro-3-methy1g
`quinoline-4-carboxylate
`The compound of Part A (37.5 g, 0.10 mole) was
`suspended in 1,000 ml of ethanol and treated with 1N
`NaOH (100 ml, 0.10 mole). The mixture was warmed
`and stirred until clear; the ethanol and water were evap
`orated at reduced pressure to give 39.6 g of the white
`solid sodium 2-(2'-?uoro-l,1’-biphenyl-4-y1)6-?uoro
`3fluoro-3-methylquinoline-Lcarboxylate, m.p. >360".
`Following the procedures of Example 1 and 2 or the
`synthesis procedures described in U.S. Pat. No.
`4,680,299, the compounds set forth in Table l were
`prepared.
`
`R9 and R94 are independently alkyl or 1 to 3 carbon
`atoms, and
`W and Z are independently H, halogen, alkyl of 1-5
`carbon atoms or CF3;
`provided that when R1 is phenyl or phenoxy, and R5
`is H, then R6 cannot be Br; and that when R1 is
`cyclohexyl and R3 is H, R6 must be C1 or F. Speci?
`cally preferred compounds useful in
`this invention are:
`(1) 2-(l,l’-biphenyl-4-yl)-5-chloro-3-methyl-4-quino
`line carboxylic acid, sodium or potassium salt
`(2) 2-(1,l’-biphenyl-4yl)-6-?uoro-3-methyl-4-quino
`line carboxylic acid, sodium or potassium salt
`(3) 6-?uoro-3-methyl-2-(4-phenoxyphenyl)-4-quino
`line carboxylic acid, sodium or potassium salt
`(4) 2-(4’-bromo-1,1'-biphenyl-4yl)-6-?uoro-3-methyl
`4-quinoline carboxylic acid, sodium or potassium
`salt
`(5) 2-(2’-fluoro- 1, 1 '-biphenyl-4yl)-6-?uoro-3-methyl
`4quinoline carboxylic acid, sodium 0 r potassium
`salt.
`DETAILED DESCRIPTION OF THE
`INVENTION
`The compounds useful in this invention are described
`in and prepared by methods set forth in U.S. Pat. No.
`4,680,299, the disclosure, synthesis, and synthesis exam
`ple of which are hereby incorporated by reference.
`The invention can be further understood by the fol
`lowing example in which parts and percentages are by
`weight unless otherwise indicated; all temperatures are
`in degrees centigrade.
`EXAMPLE 1
`Part A:
`2-(1, 1’-Biphenyl-4yl)-5-chloro-3-methylguinoline-4car
`boxylic acid
`A mixture of 4-chloroisatin (7.28 g, 0.04 mol), [.I. Am.
`Chem. Soc, 1251 (1956)], 4-henylpropiophenone
`(8.8 g, 0.04 mol), diethylamine (4 ml, 0.04 mol) and
`ethanol (200 ml) was stirred for a period of 18
`hours at room temperature. The precipitated solids
`where collected by ?ltration, washed with ice-cold
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`NOVARTIS EXHIBIT 2031
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`Page 3 of 8
`
`

`
`5
`TABLEI
`C0211z
`\ R3
`
`/
`N
`
`R4
`
`R1
`
`Ex.
`No. R1
`3
`F
`
`R3
`R2
`Na c113
`
`4
`
`F
`
`Na c113
`
`R4
`
`m.p.(°)
`>350
`
`>350
`
`0Q
`QB‘.
`
`s
`
`e
`
`7
`
`CH3 Na c113
`
`: >350
`
`F
`
`c1
`
`Na c113
`
`—'S-CH(CH3)2
`
`Na cu;
`
`339-343
`
`319-324
`
`4,968,701
`6
`mune responses (Claman, et al., Immunol Rev 50:105,
`1980). this is an antigen-speci?c T-cell mediated in?am
`matory response that represents delayed-type hypersen
`sitivity reactions seen in both humans and other mam
`‘mals. The primary use of the human mixed lymphocyte
`reaction is for the determination of transplantation com
`patibility between the donor (graft) and the recipient
`(Park 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 systemic
`in?ammatory 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 observed with the
`compounds useful in this invention (Fenichel and Chiri
`gos, ed, Immune modulation agents and their mecha
`nisms, 1984 Dekker, Inc., NY. , and Billingham, 21:389,
`1983).
`‘
`Contact Sensitivity Response to DNFB in Mice
`Balb/c female mice (=20 g, Charles River) were
`sensitized on the shaved abdomen with 25 11.1 of 0.5%
`2,4-dinitrofluorobenzene (DNFB, Eastmen Kodak Co.)
`in a vehicle of 4:1 acetonezolive oil on days 0 and 1.
`Mice were are challenged with 20 pl of 0.2% DNFB in
`a vehicle of 4:1 acetonezolive oil on day 5. A constant
`area of the ears was measured immediately before chal
`lenge and 24 hours later with an engineer’s micrometer.
`Ear swelling was expressed as the difference in ear
`thickness before and after challenge in units of 10-4
`inchesiSEM. Percent suppression was calculated as:
`
`10
`
`15
`
`25
`
`30
`
`35
`
`8
`
`01 K CH3
`
`310-325
`
`9
`
`F
`
`Na n
`
`: >360
`
`compound treated — negative control
`positive control -— negative control
`
`X 100
`
`% Suppression = 1 —
`
`10
`
`F
`
`Na CH3
`
`0
`
`251-260
`
`-s
`
`11
`
`F
`
`Na OCH; : 345-349
`
`12
`
`c1
`
`Na 0113
`
`>360
`
`UTILITY
`Results of the biological tests-described below estab
`lish that the compounds useful in this invention have the
`ability of suppress/inhibit: the contact sensitivity re
`sponse to 2,4-dinitro?uorobenzene (DNFB) in mice, the
`human mixed lymphocte reaction, and adjuvant
`induced arthritis in rats.
`Contact sensitivity of DNFB has been extensively
`studied and characterized in the mouse to determine the
`regulatory mechanisms involved in cell mediated im
`
`45
`
`55
`
`60
`
`65
`
`Compounds 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 challenged
`on day 5. Ten mice were used per group. Results with
`compounds of invention and drugs used clinically are
`shown in Tables 2 and 3.
`TABLE 2
`%
`Ear Swelling“
`Dose
`(mg/kg) (units i SEM) Suppression ED50
`Vehicle
`0.74 i 0.52
`—
`—
`Vehicle
`74.11 i 3.78
`0
`—
`0.2
`52.95 i 3.39
`28.84
`1.50
`1.0
`41.60 i 2.46
`44.31
`5.0
`23.79 i 2.71
`68.58
`10.0
`15.50 i 2.10
`79.88
`2.0
`56.15 i 3.74
`24.48
`10.0
`66.58 i 3.75
`10.27
`50.0
`47.90 i 3.76
`35.72
`100.0
`7.80 i 2.04
`90.37
`0.4
`71.30 i 2.96
`3.83
`2.0
`60.80 i 1.99
`18.14
`10.0
`36.10 i 3.23
`51.80
`20.0
`27.45 i 4.99
`63.59
`0.4-
`66.05 i 4.32
`10.99
`2.0
`56.94 i 4.80
`23.40
`10.0
`6.10 i 0.75
`92.69
`20.0
`5.20 i 1.17
`93.92
`0.4
`51.95 i- 2.33
`30.20
`2.0
`25.61 i 3.39
`66.10
`
`Treatment
`Negative
`Positive
`Dexarnethasone
`
`Cyclosporin A
`
`Methotrexate
`
`Example 1
`
`Example 2
`
`70.00
`
`9.00
`
`3.50
`
`0.95
`
`NOVARTIS EXHIBIT 2031
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`
`

`
`4,968,701
`8
`Ugo Basile Volume Differential Plethysmometer. The
`results are shown in Table 5.
`
`5
`
`10
`
`15
`
`TABLE 5
`Non-Injected
`%
`Hind-Paw
`volume (ml) suppresslon
`1.12 i 0.01
`—
`1.88 i 0.05
`—
`1.87 i 0.08
`1.4
`
`Weight Gain
`(g)
`85.6 i 4.8
`-20.3 i 2.9
`-14.0 -+_- 4.2
`
`2'8 i 5'3
`20.6 i 6.3
`
`—1.5 i 3.6
`
`65.6 :- 5.2
`
`L72 i 0'08
`1.34 i 0.10
`
`1.62 i- 0.05
`
`1.15 t 0.02
`
`20'8
`70.6
`
`34.5
`
`96.2
`
`Group Compound
`(AA)
`(mg/kg)
`A — Vehicle
`B + Vehicle
`c + Example 1
`(1000)
`D + 5:33pm 1
`E + Example 1
`(25.0)
`F + Example 2
`(2.0)
`G + Example 2
`(10.0)
`H + Example 2‘
`(25.0)
`Example 1: ED” : 21 Ins/kg
`20 Example 2: EDSO < 10 mg/kg
`‘Toxic by day 1
`
`7
`TABLE 2_cominued
`.
`%
`Dose
`Ear Swelling“
`(mg/kg) (units : SEM) Suppression ED50
`10.0
`6.40 i 1.09
`92.28
`20.0
`4.75 i 1.20
`94.53
`"Increase in ear thickness from day 5 to day 6, unit = 10-4 inches
`
`Treatment
`
`Treatment
`Negative
`Positive
`Dexamethasone
`Cyclosporin A
`Methotrexate
`Example 3
`Example 4
`Example 5
`Example 6
`Example 7
`Example 8
`Example 9
`Example ‘0
`xample 11
`Example 12
`
`TABLE 3
`Dose
`Ear Swelling“
`(mg/kg)
`(units i SEM)
`Vehicle
`2.60 i 0.73
`' Vehicle
`73.11 i 3.69
`1.0
`42.20 i 2.61
`20.0
`74.30 i 2.86
`20.0
`16.94 :1: 2.10
`20.0
`14.25 t 1.49
`20.0
`11.80 i 1.03
`20.0
`35.47 i 2.31
`20.0
`58.20 i 4.63
`20.0
`62.95 i 3.40
`20.0
`63.25 i 3.58
`20.0
`42.60 i 2.68
`zo'o
`57'28 i 2'36
`20.0
`20.85 i 2.53
`no
`5458 i 311
`
`%
`Suppression
`-—
`0
`43.83
`—1.69
`79.66
`83.48
`86.95
`53.37
`21.14
`14.40
`13.98
`43.27
`22'“
`74.12
`2528
`
`25
`
`"increase in ear thickness from day 5 to day 6, unit = 10“4
`Human Mixed Lymphocyte Reaction
`Blood was obtained by venipunture from two non
`related human donors. Peripheral blood mononuclear
`cells (PBMC) were isolated from these samples by using
`the Leuco Prep procedure (Becton-Dickinson). PBMC
`30
`were washed twice in phosphate buffered saline (with
`out calcium and magnesium) and the separate cell isola
`tions were adjusted to the appropriate concentrations in
`media (PRMI 1640) supplemented with 10% human AB
`35
`serum and 50 pl/ml gentamicin. Cells from donor A
`(2X 105) were incubated with cells from donor B
`(2 X 105) in 96 well round bottom microliter plates at 37°
`C., 5% CO2 for 6 days. Eighteen hours prior to harvest
`ing cells from the plates, all wells were pusled with 1
`“Ci of 3H-thymidine. Cells from the plates were har
`vested on day 6 and 3H-thymidine incorporation was
`determined using a scintillation counter. Test results are
`shown in Table 4.
`
`TABLE 4
`
`Compound
`lndomethacin
`Cyclosporin A
`Methotrexate
`Example 1
`Example 2
`
`1C5Q (M)
`> 10‘6
`1.6 X 10"8
`2.5 X 10-9
`9.6 x 10-9
`2.5 X lo-8
`
`45
`
`50
`
`Adjuvant-Induced Arthritis
`Male Lewis rats (Charles River) weighing 160-210
`grams were injected subcutaneously with 0.1 ml of
`Freund’s Complete Adjuvant containing 5 mg of M.
`butyricurn/ml of paraffin oil (Difco Laboratories) into
`the planter region of the right hind paw. Paraffin oil
`was injected for non-arthritic controls. Ten rate were
`used per group. Compounds were prepared in 0.25%
`Methocel® (Dow Chemical Co) 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
`ever other day beginning on the day of the paw injec
`tions. On day 18 the animals were weighed, and the
`non-injected hind paw volume was measured using a
`
`65
`
`In summary, test results show that the compounds
`.
`.
`.
`.
`.
`.
`useful in this lnventlon have both lmmunornodulatlng
`an anti-in?ammatory effectiveness. Based on these data,
`the compounds useful in this invention should be effica
`cious in treating autoimmune diseases such as rheuma
`toid arthritis, systemic lupus erythematious, multiple
`sclerosis, and myastenia gravis; all of which involve T
`lymphocyte mediated components similar to those
`known in the contact sensitivity model. Activities in the
`human mixed lymphocte reaction indicate that the com
`pounds of invention should be effective in preventing
`organ transplantation rejection and graft vs. host dis
`ease. These compounds were also effective n the adju
`vant-induced arthritis model and should therefore be
`useful anti-inflammatory agents for the treatment of
`chronic in?ammatory diseases such as rheumatoid ar
`thritis, psoriasis, and in?ammatory 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 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 combination of therapeutic active ingredients. They
`can be administered alone, but are generally adminis
`tered with a pharmaceutical carrier selected on the basis
`of the chosen route of administration and standard phar
`maceutical practice.
`The dosage administered will be a tumor-inhibiting
`amount of active ingredient and will, of course, vary
`depending upon known factors such as the pharmaco
`dynamic characteristic of the particular active ingredi
`ent, and its mode and route of administration; age,
`health, and weight of the recipient; nature an extend of
`symptoms; kind of concurrent treatment, frequency of
`treatment, and the effect desired, usually a daily dosage
`of active ingredient can be about 0.1 to 400 milligrams
`per kilogram of body weight. Ordinarily l 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
`
`NOVARTIS EXHIBIT 2031
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`Page 5 of 8
`
`

`
`4,968,701
`these pharmaceutical compositions the active ingredi
`ent will ordinarily be present in an amount of about
`05-95% by weight based on the total weight of the
`composition.
`the active ingredient can be administered orally in
`solid dosage forms, such as capsules, tablets, and pow
`ders, or in liquid dosage forms, such as elixirs, syrups,
`and suspensions, it can also be administered parenter
`ally, in sterile liquid dosage forms.
`The. active ingredient can be administered orally in
`solid dosage forms, such as capsules, tablets, and pow
`ders, or in liquid dosage forms, such a elixirs, syrups,
`and suspensions, it can also be administered parenter
`ally, in sterile liquid dosage forms.
`Gelation capsules contain the active ingredient and
`powdered carriers, such as lactose, sucrose, mannitol,
`starch, cellulose derivatives, magnesium stearate, stea
`ric acid, and the like. Similar diluents can be used to
`make compressed tablets. Both tablets and capsules can
`be manufactured as sustained release products to pro
`vide for continuous release of medication over a period
`of hours, compressed tablets can be sugar coated or ?lm
`coated to mask any unpleasant taste and protect the
`tablet from the atmosphere, or enteric coated for selec
`tive disintegration in the gastrointestinal tract.
`Liquid dosage forms for oral administration can con
`tain coloring and ?avoring to increase patient accep
`tance.
`In general, water, a suitable oil, saline, aqueous dexe
`trose glucose), and related sugar solutions and glycols
`such as propylene glycol or polyethylene glycols are
`suitable carriers for parenteral solutions. Solutions for
`parenteral administration contain preferably a water
`soluble salt of the active ingredient, suitable stabilizing
`agents, and if necessary, buffer substances. Antioxidiz
`ing agents such as sodium bisul?te, sodium sul?te, or
`ascorbic acid either alone or combined are suitable
`stabilizing agents. Also used are citric acid and its salts
`and sodium 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. 0501, a stan
`dand reference text in this ?eld.
`
`10
`INJECTABLE
`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 made isotonic with sodium
`chloride and sterilized.
`SUSPENSION
`AN aqueous suspension is prepared for oral adminis
`tration so that each 5 milliliters contain 100 milligrams
`of finely divided active ingredient, 200 milligrams of
`sodium carboxymethyl cellulose, 5 milligrams of so
`dium benzoate, 1.0 grams of sorbitol solution, U.S.P.,
`and 0.025 milliliters of vanillin.
`The same dosage forms can generally be used when
`the compounds of this invention are administered step
`wise in conjunction with another therapeutic agent.
`When the drugs are administered in physical combina
`tion, the dosage form and administration route should
`be selected for compatibility with both drugs. Suitable
`dosages, dosage forms and administration routes are
`illustrated in Table 6.
`
`15
`
`20
`
`25
`
`Drug
`Indomethacin
`
`Meclofenamate
`
`Tablet Oral
`
`Tablet Oral
`
`Tablet Oral
`
`Tablet Oral
`
`Tablet Oral
`
`TABLE 6
`Examples of NSAID's that can be combined with the
`4-quinolinecarboxylic acids used in this invention
`Dose
`Formu
`(mg)
`lation Route
`25
`Tablet Oral
`('3’ times daily)
`50-100
`(§ times daily)
`300400
`(2 times daily)
`10-20
`(i ties daily)
`150-200
`(2 times daily)
`200-500
`(2 times daily)
`
`Ibuprofen
`
`Piroxicam
`
`Sulindac
`
`Azapropazone
`
`35
`
`45
`
`What is claimed is:
`1. A method of treating rheumatoid arthritis, systemic
`lupus erythematour, multiple sclerosis, myasthernia
`gravis, organ transplantation rejection, or a chronic
`in?ammatory disease in a mammal comprising adminis
`tering to the mammal in an amount effective for the
`treatment of a desired aforesaid disease a compound
`having the formula:
`
`CAPSULES
`A large number of unit capsules are prepared by
`?lling standard two-piece hand gelatin capsules each
`with 100 milligrams of powdered active ingredient, 175
`milligrams of lactose, 24 milligrams of talc, and 6 milli
`grams magnesium stearate.
`A mixture of active ingredient in soybean oil is pre
`pared and injected by means of a positive displacement
`pump into gelatin to form soft gelatin capsules contain
`ing 100 milligrams of the active ingredient. The cap
`sules are washed and dried.
`
`TABLES
`A large number of tablets are prepared by conven
`tional procedures so that the dosage unit is 100 milli
`grams of active ingredient, 0.2 milligrams of. colloidal
`silicon dioxide, 5 milligrams of magnesium stearate, 275
`milligrams of microcrystalline cellulose, 11 milligrams
`of cornstarch and 98.8 milligrams of lactose. Appropri
`ate coatings may be applied to increase palatability or
`delay absorption.
`
`R5
`
`R4
`
`'
`
`(I)
`
`R3
`
`N
`
`R
`
`R8
`
`R6
`
`R7
`
`60
`
`wherein
`
`65
`
`R is
`
`Y
`
`R‘.
`
`0R2.
`
`NOVARTIS EXHIBIT 2031
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`Page 6 of 8
`
`

`
`11
`-continued
`
`S
`
`S(O)mR1, or Uphenyl;
`
`4,968,701
`12
`noxy; or phenoxy substituted with one halogen or
`alkyl of 1-5 carbon atoms;
`R3 is H or alkyl or l-2 carbon atoms;
`R4 is COzH, a sodium or potassium salt thereof; or
`COZRII;
`R5 and R6 are independently H, halogen , CH3 or
`CFs;
`R7 and R8 are independently H or halogen;
`
`5
`
`-R1 is CH3CH2(CH3)CH, alkyl of 5-12 carbon atoms,
`cyclohexyl,
`
`Z
`
`Z
`
`‘Q or CH2
`
`W
`
`w
`
`when R is
`
`l0
`
`15
`
`R9 and R94 are independently alkyl of 1 to 9 carbon
`atoms,
`or a pharmaceutically suitable salt thereof;
`provided that R5, R6 and R7 cannot all be H, then
`when R4 is COZH, R1 is phenyl or phenoxy, and R5,
`R7 and R8 and H, then R6 cannot be Br. and that
`when R1 is cyclohexyl and R3 is H, R6 must be C1
`or F, but R6 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:
`
`R1 can be in addition alkyl of 3-4 carbon atoms;
`
`W
`
`@ or —CH2—< 3
`
`Z
`
`25
`
`E E
`
`W
`
`Z ,
`
`R3 is H, alkoxy of 1-—3 carbon atoms, or alkyl of 1-2
`carbon atoms;
`R4 is COZH or COR“;
`R5, R6, R7 and R8 are independently H, F, Cl, Br, I,
`CH3CF3, SCH3 or CH2CH3, at least two of R5, R6,
`R7 and r8 being H;
`R9 and R914 are independently H or alkyl of l to 3
`carbon atoms;
`
`W, Y and Z are independently H, F, Cl, Br, alkyl of
`40
`1-5 carbon atoms, N02, OH, CF3 or OCH3;
`m is O or 1; or
`a pharmaceutically suitable salt thereof;
`with the following provisions:
`(1) R5, R6 and R7 cannot all be H;
`(2) when R4 is CO2CH2CH2CH2N(CH3)2, R6 iS
`CH2CH3, or R7 is Cl, R1 cannot be cyclohexyl;
`(3) when R1 is cyclohexyl and R3 is H, R6 must be
`C1 or F, but 1'6 and R8 cannot both be Cl;
`(4) when R6 is CH3, then R7 cannot be Cl; and
`(5) when R4 is CO2H, R1 or R2 is phenyl, and R5,
`R7 and R8 are H, then R6 cannot be Br.
`2. The method of claim 1 wherein the compound has
`the formula:
`
`45
`
`R6
`
`R7
`
`R5
`
`R4
`
`(II)
`
`R3
`
`N
`
`R8
`
`R1
`
`wherein
`R1 is cyclohexyl; phenyl; phenyl substituted with one
`halogen; alkyl of l-5 carbon atoms or CF3; phe
`
`(III)
`
`R5
`
`R4
`
`R3
`
`N
`
`R6
`
`.
`
`wherein
`R1 is cyclohexyl,
`
`W
`
`or —0
`
`Z
`
`R 1
`
`Z
`
`R3 is H or alkyl of l-2 carbon atoms;
`R4 is COZH, a sodium or potassium salt thereof, or
`COzR“;
`R5 and R6 are independently H, halogen or CF3 pro
`vided that both R5 and R6 are not hydrogen;
`
`R9 and R914 are independently alkyl of l to 3 carbon
`atoms, and
`W and Z are independently H, halogen, alkyl of 1-5
`carbon atoms or CF3;
`provided that when R4 is COZH R1 is phenoxy, and
`R5 is H, then R6 cannot be'Br; and that when R1 is
`cyclohexyl and R3 is H, R6 must be C1 or F.
`4. The method of claim 1 wherein the compound is
`2-(1, 1’-biphenyl-4-yl)-5-chloro-3-methyl-4-quinoline
`carboxylic acid, sodium or potassium salt.
`5. The method of claim 1 wherein the compound is
`2-(1,1’-biphenyl-4yl)-6-fluoro-3-methyl-4-quinoline car
`boxylic acid, sodium or potassium salt.
`6. The method of claim 1 wherein the compound is
`6-fluoro-3-methyl-2-(4-phenoxyphenyl)-4-quinoline
`carboxylic acid, sodium or potassium salt.
`7. The method of claim 1 wherein the compound is
`2-(4’-bromo- l , l’-biphenyl-4-yl)-6-?uoro-3-methyl-4
`quinoline carboxylic acid, sodium or potassium salt.
`8. The method of claim 1 wherein the compound is
`2-(2’-?uoro- 1 , 1 ’-biphenyl-4-y1)-6-?uoro-3-methyl-4
`quinoline carboxylic acid, sodium or potassium salt.
`Ill
`* i * i
`
`NOVARTIS EXHIBIT 2031
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`Page 7 of 8
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`4, 968, 701
`PATENT N0. :
`November 6, 1990
`DATED
`:
`Neil Richard Ackerman, Bruce Donald Jaffee,
`INVENTOR(S) :
`Scott Edward Lovelees, Russell Howard Neupauer
`_
`_
`_
`It IS certlfled that error appears I" the above-rdentlfled patent and that sad Letters Patent as hereby
`corrected asshown below:
`
`On the title page:
`[75] Inventors:
`delete "Richard R. Harris" and
`insert ——Bruce D. Jaffee--.
`
`Signed and Sealed this
`
`Thirtieth Day of June, 1992
`
`Arrest:
`
`Attesting O?icer
`
`Acting Cummissioner of Patents and Trademarks
`
`DOUGLAS B. COMER
`
`NOVARTIS EXHIBIT 2031
`Par v Novartis, IPR 2016-00084
`Page 8 of 8