United States Patent [191
`Sutherland et al.
`
`[11]
`[45]
`
`Patent Number:
`Date of Patent:
`
`4,847,381
`Jul. 11, 1989
`
`[54]
`
`[75]
`
`[73]
`
`[21]
`[22]
`[51]
`[52]
`[58]
`
`[56]
`
`2-PHENYL-4-QUINOLINE CARBOXYLIC
`ACIDS
`Inventors: Leslie H. Sutherland, Dallas, Tex.;
`Adolph E. Sloboda; Ralph G. Child,
`both of Rockland, N.Y.; John F.
`Poletto, Bergen, N.J.; Dennis W.
`Powell, Rockland, N.Y.
`Assignee: American Cyanamid Company,
`Stamford, Conn.
`Appl. N0.: 90,996
`Filed:
`Aug. 31, 1987
`
`Int. Cl.4 ................... .. A61K 31/47; C07D 215/20
`US. Cl. ................................... .. 546/156; 548/485
`Field of Search
`546/152, 153, 156, 170,
`546/173; 514/311, 312
`References Cited
`U.S. PATENT DOCUMENTS
`
`2,008,923 7/1935 Ornstein ............................ .. 546/ 173
`2,077,903 4/1937 Schlichenmaier
`546/ 153
`2,524,741 10/1950 Tulagin .............. ..
`546/170
`2,579,420 12/1951 Coles ...... ..
`546/170
`2,886,436 5/1959 Schmidt
`546/156
`2,888,346 5/1959 Tulagin ............................. .. 546/173
`
`514/311
`3,574,840’ 4/1971 Riviere ................... ..
`..... .. 71/94
`4,009,020 2/1977 Starke
`4,680,299 7/1987 Hesson .............................. .. 514/311
`
`FOREIGN PATENT DOCUMENTS
`
`2304270 8/1973 Fed. Rep. of Germany .... .. 546/173
`1109402 8/1984 U.S.S.R. ............................ .. 546/153
`
`OTHER PUBLICATIONS
`John et a1. (1932) J. Prakt. Chem, vol. 133, pp. 259-272.
`Kost et a1. (1971) Khim. Geterotsikl. Soedin., 7 (9), pp.
`1214-1217.
`Munson et a1. (1975) J. Med. Chem, 18 (12), pp.
`1232-1236.
`Primary Examiner-Anton H. Sutto
`Assistant Examiner—Mark W. Noel
`Attorney, Agent, or Firm-Edward A. Conroy; Alan M.
`Gordon
`ABSTRACT
`[57]
`Substituted 4-quino1ine-carboxy1ic acids useful in the
`treatment of arthritis and inhibition of progressive joint
`deterioration are disclosed together with methods of
`use and synthesis thereof.
`
`9 Claims, No Drawings
`
`NOVARTIS EXHIBIT 2030
`Par v Novartis, IPR 2016-00084
`Page 1 of 8
`
`

`
`1
`
`2-PHENYL-4-QUINOLINE CARBOXYLIC ACIDS
`
`BRIEF SUMMARY OF THE INVENTION
`This invention is concerned with methods of (a) treat
`ing arthritis in a mammal by inhibiting the progressive
`joint deterioration characteristic of arthritic disease,
`and (b) inducing immunosuppression in a mammal
`which comprise administering to said mammal an effec- 1O
`tive amount of a compound of the formula:
`
`5
`
`COZH
`
`(1)
`
`4,847,381
`2
`is heated further at re?ux, then cooled and ?ltered and
`the ?ltrate acidi?ed where-upon the desired product (I)
`preciptates. The product (I) is then collected by ?ltra
`tion and, if necessary, recrystallized by conventional
`procedures.
`The compounds of the present invention are active
`immunosuppressive agents when administered to warm
`blooded animals. As such they are effective in treating
`conditions where elevated levels of antibody produc
`tion or monocyte/lymphocyte activity as a result of the
`hyperreactivity of the immunoregulatory network are
`closely associated with the development of autoimmune
`diseases, including rheumatoid arthritis [Mellbye, OJ.
`and Natvig, J.B., Clin. Exp. Immunol., 8, 889 (1971)],
`multiple sclerosis [Tourtellotte, W.W. and Parker, J.A.,
`Science 154, 1044 (1966)], systemic lupus erythematosis
`[Abdu, N. I., et al., Clin. Immunol. Immunopath, 6, 192
`(1976)], thyroiditis [Witebsky, E., et al., J. Immunol.,
`103, 708 (1969)], mixed connective tissue disease [Sharp,
`G. C., et al., Am. J. Med, 52, 148 (1972)], dermato/
`polymyositis [Venables, P.J.W., et al., Ann. Rheum.
`Dis., 40, 217 (1981)], insulin-dependent diabetes
`[Charles, M. A., et al., J. Immunol., 130, 1189 (1983)]
`and in patients undergoing organ transplantation.
`The immunosuppressive activity of the compounds of
`this invention was established in the following test.
`
`wherein R1 is hydrogen, halogen or alkyl(C1-C3); R2 is
`hydrogen, halogen, trifluoromethyl or alkyl(C1—C3); R3
`is hydroxy or alkanlyloxy(C2-C6); R4 is halogen, hy
`droxy, alkyl(C1—C6), tri?uoromethyl, cycloalkyl(
`C3-C6, phenyl, benzyl, phenoxy, phenylthio, 2,4
`dichlorophenoxy or mono-and di-substituted phenyl
`wherein the substituents are halogen or alkoxy(C1-C3);
`and R5 is hydrogen or halogen; in association with a
`pharmacologically acceptable carrier.
`In addition, this invention is also concerned with
`novel compounds of the formula (I) wherein R1, R2, R3,
`R4 and R5 are as therein de?ned but with the provisio
`that when R1 is hydrogen, R2 is other than ?uoro, and
`R3 is hydroxy then R4 may not be chloro, bromo, iodo,
`methyl or phenyl.
`
`20
`
`35
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The compounds of formula (I) may be readily pre
`pared in accordance with the following reaction
`scheme:
`
`(1)
`
`45
`
`50
`
`55
`
`(2)
`
`R5
`
`wherein R1, R2, R4 and R5 are as hereinbefore de?ned
`and R5 is —C2H5 O1‘ ——CH2OCO-alkyl(C1—C5). With
`reference to the above reaction scheme, an appropri
`ately substituted 2,3-indolinedione (l) in aqueous solu
`tion made basic with an alkali metal hydroxide and
`warmed, is mixed with a lower alkanolic solution of an
`appropriately substituted acetophenone (2), and the
`resulting reaction mixture is held at the re?ux tempera
`ture for several hours. During this process, a portion of
`the lower alkanol is removed by distillation, the residue
`
`65
`
`ACUTE GRAFT-VS.-HOST REACTION
`An acute graft-vs-host (GvH) reaction was induced
`in normal B6D2Fl male mice by the intravenous injec~
`tion of 30-5OX l06 parental spleen cells of the C57BL/ 6
`parent. Ten days post GvH induction the B6D2F1 mice
`were acutely immunosuppressed. On day 10, spleen
`cells from the B6D2F1 mice were removed ascepti
`cally, placed in tissue culture and stimulated with T-cell
`mitogen [Concanavalin-A (Con-A)]at a concentraion of
`2 pig/ml. The ability of the spleen cells to proliferate in
`response to the mitogen was determined by pulse label
`ing of dividing cells with 3H-thymidine for the last 24
`hours of the 72 hour tissue culture period. The labeled
`cells were harvested on millipore ?lters and the amount
`of 3H radioactivity was quantitated with a liquid scintil
`lation spectrometer. Drug dosing began on the day of
`GvH induction and continued through the 10 day in
`vivo protocol. The test compounds were administered
`orally in a phosphate buffer pH 7.4 vehicle containing
`0.025M phosphate, 0.075M sodium chloride and 0.002%
`polysorbate 20. The data from drug dosed mice was
`compared with GvH mice dosed with vehicle and with
`normal mice. A compound is considered active if it
`reduced the degree of suppression seen in the Con-A
`proliferative response of vehicle treated GvH mice
`compared with normal mice.
`The results of this test on representative compounds
`of this invention appear in Table I.
`TABLE I
`Graft-vs.-Host Reaction
`
`Compound
`
`None
`Vehicle
`2-(4-ChlorophenyD-3-
`hydroxy-6-iodo-4-quino
`linecarboxylic acid
`
`None
`Vehicle
`2-[l,l’-Biphenyl]-4-yl-
`
`Dose
`(mg/kg)
`
`GvI-I
`
`Percent
`Con-A
`Response Suppres
`3H cpm
`sion
`
`—
`—-
`50
`
`—
`-—
`50
`
`—
`+
`+
`
`—
`+
`+
`
`120386
`32428
`96487
`
`295315
`169220
`278001
`
`—
`73
`20
`
`—
`43
`6
`
`NOVARTIS EXHIBIT 2030
`Par v Novartis, IPR 2016-00084
`Page 2 of 8
`
`

`
`4,847,381
`
`3
`TABLE I-continued
`Graft-vs.-Host Reaction
`
`25
`
`30
`
`Dose
`(mg/kg)
`
`Gvl-I
`
`Percent
`Con-A
`Response Suppres~
`31-1 cpm
`sion
`
`LII
`
`—
`—
`50
`
`—
`-
`50
`
`—
`—
`50
`
`—
`-—
`25
`
`—
`+
`+
`
`—
`+
`+
`
`—
`+
`+
`
`—
`+
`+
`
`181886
`17161
`128187
`
`295315
`169220
`285448
`
`157509
`74145
`139289
`
`248699
`28206
`183441
`
`—
`91
`29
`
`-
`43
`3
`
`—
`53
`12
`
`—
`89
`26
`
`Compound
`6-bromo-3-hydroxy-4
`quinolinecarboxylic
`acid
`
`None
`Vehicle
`3-(Acetyloxy)-2-[l,l'-
`
`linecarboxylic acid
`
`None
`Vehicle
`3-Hydroxy-6-methy1-2-
`
`quinolinecarboxylic
`acid
`
`None
`Vehicle
`6-F1uoro-3-l1ydroxy-2-
`
`4-quinolinecarboxylic
`acid
`
`None
`Vehicle
`2-(4-Cl1lorophenyl)-6»
`fluoro-S-hydroxy-4
`quinolinecarboxylic
`acid
`
`None
`
`‘ Vehicle
`
`—
`
`—
`
`-—
`
`+
`
`157509
`
`74145
`
`-
`
`53
`
`[l,l'-biphenyl]—4-yl)—
`3-hydroxy-4_quinoline
`carboxylic acid
`
`In addition these compounds are effective in treating
`in?ammation and joint destruction associated with ar
`thritic disease in warm-blooded animals as established in
`the following test.
`
`35
`
`INDUCTION OF ADJUVANT ARTHRITIS
`Outbred, male, Royalhart Wistar rats (Royalhart
`Farms, New Hampton, N.Y.), weighing approximately
`165 g, were injected intradermally in the right hind paw
`with killed and dried Mycobacterium tuberculosis
`emulsi?ed in mineral oil (adjuvant) at a dose of 2 mg/ kg
`of body weight. This protocol for induction of arthritis
`45
`has been described in detail by A.E. Sloboda and A.C.
`Osterberg, In?ammation, 1, 415 (1976).
`'
`Seven days subsequent to immunization with the
`adjuvant, the rats were divided into groups and treated
`daily by gavage with various doses of the test com
`pounds. Control groups of rats were immunized with
`adjuvant, but then treated only with starch vehicle.
`At the end of 23 days post adjuvant immunization,
`the left hin paw diameters of all the rats were measured
`around the ankle joint with a Vernier caliper.
`The results of this test on representative compounds
`of this invention are shown in Table II.
`The statistical signi?cance of differences between
`control and treated group were calculated using Stu
`dents test.
`
`50
`
`55
`
`60
`
`TABLE II
`Treatment of Adjuvant Induced Arthritis
`Final
`Rat
`Wt.
`(gm)
`244
`
`Daily Number
`Dose
`of
`mg/kg Animals
`— 446
`
`Compound
`Arthritic Controls
`pooled)
`
`Arthritic
`Paw
`Diameter
`(mm)
`11.8
`
`5
`
`4
`TABLE II-continued
`Treatment of Adjuvant Induced Arthritis
`Final
`Rat
`Wt.
`(gm)
`276
`
`Daily
`Number
`of
`Dose
`mg/ kg Animals
`15
`50
`
`Arthritic
`Paw
`Diameter
`(mm)
`
`5
`12.
`
`25
`
`8
`
`15
`
`17
`
`11
`
`15
`
`275
`
`303
`
`291
`
`910*
`
`267
`
`244
`
`314
`
`
`
`12. 5
`
`14
`
`319
`
`317
`
`5
`12.
`
`13
`
`301
`
`14
`
`269
`
`8.1"
`
`325
`
`273
`
`14
`
`322
`
`10.5*
`
`50
`
`50
`
`50
`
`50
`
`25
`
`50
`
`50
`
`Compound
`2-(4-Chlorophenyl)-3
`hydroxy-6-iodo-4<quino
`linecarboxylic acid
`6-Chloro-2-(4-chloro
`phenyl)-3-hydroxy-4
`quinolinecarboxylic acid
`2-[l,l’-Biphenyl]-4-yl~
`3-hydroxy-4-quinoline
`carboxylic acid
`2-(4-Chlorophenyl)-3
`hydroxy-4-quinoline
`carboxylic acid
`2-[1,1’-Biphenyl]—4-yl
`6-bromo-3-hydroxy4
`quinolinecarboxylic acid
`2-(4-Bromophenyl)~3
`hydroxy-6-iodo-4-quino
`linecarboxylic acid
`3-Hydroxy-2-(4-iodo
`phenyl)-4-quinolinecar
`boxylic acid
`3-(Acetyloxy)-2-[1,l'
`biphenyl]-4-y1-4-quino
`linecarboxylic acid
`3-Hydroxy-6-methyl-2
`[1,1’-biphenyl]-4-yl-4
`quinolinecarboxylic
`acid
`6,8-Dich1oro-3-hydroxy
`2-[1,1'-biphenyl]-4-yl
`4-quinolinecarboxylic
`acid
`3-Hydroxy-8-methy1-2
`[1,1'-biphenyl]-4-y1-4
`quinolinecarboxylic acid
`6-Fluoro-3-hydroxy-2
`[1, l'-biphenyl]-4-yl-4
`quinolinecarboxylic acid
`2-(3,4-Dichlorophenyl)
`3-hydroxy-6-methyl-4
`quinolinecarboxylic acid
`2-(4-Ch1orophenyl)-6
`?uoro-3-hydroxy-4
`quinolinecarboxylic acid
`3-(Acetyloxy)-2-[l , 1 ’~
`biphenylI-4-y1-6-bromo
`~4-quinolinecarboxylic
`acid
`6-F1uoro-2-(2’-?uoro
`[1, l'-biphenyl]-4-yl)-3
`hydroxy-4-quinolinecar
`boxylic acid
`6-Bromo-2-(4~chloro
`phenyl)-3-hydroxy-4
`quinolinecarboxylic acid
`6,8-Dichloro-2~(4
`ch1orophenyl)-3-hydroxy
`4-quinolinecarboxylic
`acid
`2-(4-Chlorophenyl)-3
`hydroxy-6-methy1-4
`quinolinecarboxylic acid
`6-Bromo-3-hydroxy-Z~(4~
`iodophenyl)-4-quinoline
`carboxylic acid
`6-Fluoro-2-(4-?uoro
`phenyl)-3-hydroxy-4
`quinolinecarboxylic acid
`6'-Bromo-3-hydroxy-2~(4'
`methoxy[l,l’-biphenyl]
`4-yl)-4-quinolinecar
`boxylic acid
`6-Bromo-2-(4-fluoro
`pheny1)-3-hydroxy-4
`quinolinecarboxylic acid
`2-(2,4-Di?uorophenyl)
`
`NOVARTIS EXHIBIT 2030
`Par v Novartis, IPR 2016-00084
`Page 3 of 8
`
`

`
`4,847,381
`
`5
`TABLE II-continued
`Treatment of Adjuvant Induced Arthritis
`Arthritis
`Final
`‘Paw
`Rat
`wt D‘ameter
`(gm)
`(mm)
`
`Daily Number
`D055
`of
`mg/kg Animals
`
`6
`TABLE III-continued
`Inhibition of Induced Joint Deterioration
`Daily
`—X-_R_am_res—
`No. of
`Dose
`Cartilage
`mg/kg Animals Erosions
`Space
`_
`:0
`
`1.57"
`
`2.00"
`
`5
`
`Compound
`
`15
`
`5O
`
`50
`
`15
`
`15
`
`270
`
`8.9“
`
`269
`
`7-3‘
`
`12.5
`
`14
`
`L64:
`
`L64:
`
`12.5
`
`17
`
`203*
`
`197*
`
`25
`
`17
`
`286
`
`8.4‘
`
`12.5
`
`13
`
`246*
`
`2.38“
`
`25
`
`7
`
`298
`
`8.1t
`
`50
`
`12
`
`1.95:
`
`2.32::
`
`5O
`
`12
`
`276
`
`8.6‘
`
`.
`
`uoro- - y roxy
`
`_
`
`_ ‘
`
`'_
`
`.
`
`.
`
`.
`
`.
`
`.
`
`acid
`
`3.13
`
`16
`
`1.94‘
`
`2.13"
`
`so
`
`25
`
`6-25
`
`14
`
`13
`
`‘7
`
`229*
`
`221*
`
`111*
`
`L42"
`
`III
`
`L71
`
`1*
`
`L06
`
`25?
`
`153,‘
`
`Compound
`_
`3-Hydroxy-2-(4-iodo-
`6-?uoro-3-hydroxy-4-
`phenyl)-4-quino1inecar
`quinolinecarboxylic acid
`boxylic acid
`6-Bromo-2-(2,4-di?uoro-
`3_(Acetyloxy)_z_[lyll_
`PhEnY1)'3'hYdr°XY'4'
`1O bipheny1]-4-yl-4-quino
`quinolinecarboxylic acid
`linecarboxylic acid
`?-chloro-3-hydroay-l-
`3-Hydroxy-6-methy1-2-
`(4'-methoXyl1.1’-b}-
`[1,1’-biphenyl]-4-yl-4
`Pheny114'yD'4'q‘11m‘
`quinolinecarboxylic
`linecarboxylic acid
`acid
`6-Fluoro-3-hydrox'y-2-
`15 6,8-Dichloro-3-hydroxy-
`(4’-rnethoxy[l, l'-b_l-
`2-[1, l'-biphenyl]-4-yl—
`phenyl]-4-yl)-4-quino-
`4-quinolinecarboxylic
`linecarboxylic acid
`acid
`6,3-DiCh10l'0-2-(3A-di-
`3_HydrOxy_8_methy1_2_
`chlo_r0pl_1enyl)-3-hyqrOXi/-
`[1,l'-biphenyl]-4-yl-4
`4-<_lumollnecal'boxyllc
`2O quinolinecarboxylic acid
`acid
`6-Fluoro-3-hydroxy-2-
`6,8-Dichloro-3-hydroxy-
`[lyll_biphenyl]_4_yl_4_
`2-(f1*-i°_d°Phenyl)+
`_
`quinolinecarboxylic acid
`qumolmecarboxyhc wd
`2-(3,4-Dichloropheny1)-
`‘Statistically signi?cant suppression of arthritic paw diameter relative to the ar-
`3-hYdr0Xy-6-methyl-4—
`thritic controls. p = <.05 by students t test.
`25 quinolinecarboxylic acid
`p The inhibition of progressive joint deterioration was
`é-(4*ch3h§°ghen>l)i6'
`demonstrated by the followlng test.
`quino?necarboxy?c acid
`INHIBITION OF PROGRESSIVE JOINT
`gig;§§‘y{]‘jf§{_§_£1r§mo_
`DESTRUCTION
`30 4-quinolinecarboxylic
`Thls protocol is Identical to the experiment whose
`6_Flu°r°_2_(2,_?uow_
`results were described In Table I. At the end of 23 days
`[1, 1'_bipheny1]_4_y1)_
`the rats were killed, their left hind paws amputated and
`3-hydroxy-4-quinoline
`radiographic evaluation was made as follows: Joint
`carboxylic acid
`roentgraphs of the left hind paws were prepared on 35
`quinolinecarboxylic
`Polaroid x-ray ?lm (type 55) using a F axit‘ron i‘t-ray unit
`acid
`(Model 43805-N, Hewlett Packard, McMlnnville, OR).
`6,3-DiChIOYO-Z-(‘P
`The focus to ?lm distance was 45cm and the exposure
`chloropheny‘?:
`to the x-ray source was 5 minutes at 60KVP. Each
`hydroxy-4»qumoline
`d.
`h
`d d b1. d f
`h
`d
`ra lo'grap was gra e ( lIl ) or t e presence an 40 carboxylic acid
`severity of the following parameters:
`2-(4-Chlorophenyl)-3-
`(a) juxtaarticular erosions of the tarsal bones; and
`hyf1rw§y-6-methylj4~
`(b) cartilage space narrowing.
`gsi‘gmmecarbmyhc
`A grade of
`to 4 (w1th-norma1 and 4 severe
`6_Bmm°_3_hydrmy_2_
`changes) was assigned to each of the parameters.
`45 (44odophgnyD-4
`Again the statistical signi?cance between arthritic
`quinolinecarboxylic
`controls and treated rats were determined by the use of
`23;:
`2 M1
`Students t test. The results of this test on representative
`d
`compounds of this invention are shown in Table III.
`quinolinecarboxylic
`acid
`so 6-Bromo-3-hydroxy-2-
`(4’-methoxy[1,l'-bi
`FheHYlLA‘YIEMQglO'
`6-BrOmO-Z-(4'?‘IOm-
`phenyl)-3-hydroxy~4
`55 quinolinecarboxylic
`acid
`2-(2,4-Di?uor0pheny1)~
`6-?uoro-3-hydroxy-4
`quinolinecarboxylic
`acid
`6O 6-Bromo—2-(2,4-di-
`?uorophcnyl)-3-hy
`droxyA-quinolinecar
`boxylic acid
`6-Ch1oro-3-hydroxy-2-
`(4'-methoxy[l, 1'-bi
`65 phenyl]-4-yl)-4—quino
`linecarboxylic acid
`6-Fluoro-3-hydroxy-2-
`
`Com ound
`p
`Arthritis Controls
`(historical)
`2-(4-Chl0rophenyD-3-
`hydroxy-6-iodo-4-quino-
`linecarboxylic acid
`6-Chloro-2-(4-ch1oro-
`phenyl)-3-hydroxy-4-
`quinolinecarboxylic acid
`2-[1,l’-Biphenyl]-4-yl-
`3-hydroxy-4-quinoline-
`carboxylic acid
`2-(4-Chl0rophenyl)-3-
`hydroxy-4-quinoline-
`carboxylic acid
`2-[ l , l'-Bipheny1]-4—yl-
`6-bromo-3-hydroxy-4
`quinolinecarboxylic acid
`
`50
`
`50
`
`12.5
`
`5O
`
`15
`
`8
`
`15
`
`17
`
`1.86‘
`
`2.29‘
`
`1. 17’
`
`1.67‘
`
`2.07‘
`
`1.67‘
`
`1.53*
`
`1.94‘
`
`12.5
`
`17
`
`1.64‘
`
`2.16“
`
`‘
`
`__
`
`Q
`
`TABLE In
`Inhibition of Induced Joint Deterioration
`Daily
`X-Ray Scores
`nlijgjske
`:iimgs Erosions casniife
`g
`p
`- 9,668
`3.27
`
`-
`
`3.12
`
`615
`
`17
`
`50
`
`5O
`
`so
`
`50
`
`25
`
`14
`
`12
`
`14
`
`14
`
`17
`
`‘
`2'19
`
`*
`1'69
`
`117*
`
`175*
`
`207*
`
`1.43*
`
`207..
`
`L86.
`
`2 6‘
`'
`
`2 8
`'
`
`5O
`
`17
`
`1.65‘
`
`1.59“
`
`5O
`
`12
`
`2'17‘
`
`242‘
`
`50
`
`14
`
`2.5‘
`
`1.79‘
`
`50
`
`15
`
`1.0‘
`
`1.67*
`
`5O
`
`15
`
`1.67‘
`
`0.60‘
`
`25
`
`17
`
`222*
`
`0.89‘
`
`mecar oxy 10 act
`
`NOVARTIS EXHIBIT 2030
`Par v Novartis, IPR 2016-00084
`Page 4 of 8
`
`

`
`7
`TABLE III-continued
`Inhibition of Induced Joint Deterioration
`Daily
`X-Ray Scores
`No. of
`Dose
`Cartilage
`mg/ kg Animals Erosions
`Space
`
`Compound
`linecarboxylic acid
`‘Statistically signi?cant suppression of arthritic paw diameter relative to the ar
`thritic controls. p = <.O5 by students t test.
`
`5
`
`10
`
`4,847,381
`8
`The invention will be described in greater detail in
`conjuncton with the following speci?c examples,
`EXAMPLE 1
`2-(4-Chlorophenyl)-3-hydroxy-6-iodo-4
`quinolinecarboxylic acid
`This compound was prepared by the method of Mar
`shall and Blanchard, J. PharmacoL, 95, 185 (1949), mp
`199.5°-200° C.
`The compounds of Examples 2-12, named below,
`were made by the same procedure.
`
`The compounds of this invention may be orally ad
`ministered to treat arthritis, for example, with an inert
`diluent, or with an assimilable edible carrier, or they
`may be enclosed in hard or soft shell capsules, or they
`may be compressed into tablets, or they may be incor
`porated directly with the food of the diet. For oral
`therapeutic administration, these active compounds
`may be incorporated with excipients and used in the
`form of tablets, capsules, elixirs, suspensions, syrups,
`and the like. Such compositions and preparations should
`contain at least 0.1% of the active compound. The per
`centage of active compound in these compositions may,
`of course, be varied and may conveniently be between
`about 2% to about 60% of the weight of the unit. The
`amount of active compound in such therapeutically
`useful compositions is such that a suitable dosage will be
`obtained. Preferred compositions according to this in
`vention are prepared so that an oral dosage unit con»
`tains between about 50 and 250 mg of active compound.
`The tablets, capsules and the like may also contain a
`binder such as gum tragacanth, acacia, corn starch or
`gelatin; excipients such as dicalcium phosphate; a disin
`tegrating agent such as corn starch, potato starch or
`alginic acid; a lubricant such as magnesium stearate; and
`a sweetning agent such as sucrose, lactose or saccharin.
`When the dosage unit form is a capsule it may con
`tain, in addition to materials of the above type, a liquid
`carrier such as a fatty oil.
`Various other materials may be present as coatings or
`to otherwise modify the physical form of the dosage
`unit. For instance, tablets may be coated with shellac,
`sugar or both. A syrup or elixir may contain, in addition
`to the active ingredient, sucrose as a sweetening agent,
`methyl and propylparabens as preservatives, a dye and
`?avoring such as cherry or orange ?avor.
`These active compounds may also be administered
`parenterally. Solutions or suspensions of these active
`compounds can be prepared in water suitably mixed
`with a surfactant such as hydroxypropylcelllose. Dis
`persions can also be prepared in glycerol, liquid poly
`ethylene glycols and mixtures thereof in oils. Under
`ordinary conditions of storage and use, these prepara
`tions contain a preservative to prevent the growth of
`microorganisms.
`The pharmaceutical forms suitable for injectable use
`include sterile aqueous solutions or dispersions and
`sterile powders for the extemporaneous preparation of
`sterile injectable solutions or dispersions. In all cases,
`the form must be sterile and must be ?uid to the extent
`that easy syringability exits. It must be stable under the
`conditions of manufacture and storage and must be
`preserved against the contaminating action of microor
`ganisms such as bacteria and fungi. The carrier can be a
`solvent or dispersion medium containing, for example,
`water, ethanol, polyol (e.g., glycerol, propylene glycol
`and liquid polyethylene glycol), suitable mixtures
`thereof, and vegetable oils.
`
`20
`
`Example
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Name
`6-Chloro-2-(4-chlorophenyl)
`3-hydroxy-4-quinolinecarbox
`ylic acid
`2-[1, l'-Biphenyl]-4-yl-3
`hydroxy-4-quinolinecarbox
`ylic acid
`2-(4-ChlorophenyD-3-hy
`droxy-4-quinolinecarboxylic
`acid
`2-[l,l’-Biphenyl]-4-yl-6
`bromo-3-hydroxy-4-quinoline
`carboxylic acid
`3-Hydroxy-6-methyl-2~(4
`methylphenyl)-4-quinoline
`carboxylic acid
`2-(4-Bromophenyl)-3-hydroxy
`6-iodo-4-quinolinecarboxylic
`acid
`2-(4-Bromophenyl)-3-hydroxy
`4-quinolinecarboxylic acid
`S-Hydroxy-6-iodo-2-(4-iodo
`phenyl)-4-quinolinecarbox
`ylic acid
`6-Bromo-2-(4-bromopheny1)-3
`hydroxy-4-quinolinecarbox
`ylic acid
`6,8-Dibromo-2-(4-bromophen
`yl)-3-hydroxy-4-quinoline
`carboxylic acid
`3-Hydroxy-2-(4-iodophenyl)
`4-quinolinecarboxy1ic acid
`
`MP“ C.
`
`212-214
`
`196-201
`
`225
`
`155-157
`
`214.5-215.5
`
`248-249
`
`228-230
`
`216-217
`
`212-213
`
`253-255
`
`EXAMPLE 13
`3-(Acetyloxy)-2-[1- 1'-bipheny1]-4-yl-4-quinolinecar
`boxylic acid
`A 10.4 g portion of 2-[1,1'-biphenyl]-4-yl-3-hydroxy
`4-quinolinecarboxylic acid was treated with 50 m1 of
`acetic anhydride and 20 drops of concentrated sulfuric
`acid. The mixture was heated for 1% hour on a steam bath
`with occasional swirling, then poured into 300 ml of ice
`water, stirred and treated with sodium bicarbonate solu
`tion until weakly acid. The solid was collected, washed
`with water, dried and recrystallized from 400 ml of
`ethanol, giving 6.0 g of the desired product as yellow
`orange crystals, mp 199°14 200° C.
`
`EXAMPLE 14
`2-[1,1’-biphenyl]-4-yl-6-fluoro-3-[(l-oxohexyl)oxy]-4
`quinolinecarboxylic acid
`3.59
`of
`A
`suspension
`6-fluoro-3-hydroxy1-2-( 1 , 1’-biphenyl)-4-
`-quinolinecarboxylic acid in 17 mL of hexanoic anhy
`dride was treated with 6 drops of sulfuric acid. The
`mixture was stirred (over-head) and heated at 100° C.
`(steam-bath) for 3 hours. The reaction mixture was
`cooled and poured over 100 g. of ice. The aqueous
`suspension was neutralized to pH=7 with 5N NaOH.
`After stirring for 15 min., the ester was extracted from
`
`of
`
`g.
`
`55
`
`65
`
`NOVARTIS EXHIBIT 2030
`Par v Novartis, IPR 2016-00084
`Page 5 of 8
`
`

`
`4,847,381
`10
`9
`A suspension of 3.0 g of 3-hydroxy-2-(l,l’-biphenyl)
`the aqueous phase with ethyl acetate (200 mL). The
`4-quinolinecarboxylic acid in 15 mL of butyric anhy
`organic extract was washed with brine, dried over mag
`dride was treated with 6 drops of sulfuric acid. The
`nesium sulfate, ?ltered and then concentrated to ap
`proximately 25 mL. The resulting crystalline solid was
`mixture was stirred (over-head) and heated at 100° C.
`collected, washed with cold ethylacetate and air-dried
`(steam-bath) for 3 hours. The reaction mixture was
`cooled and resulting crystalline solid was collected,
`to afford 2.2 g of the desired product, rn.p. l79°—206° C.
`washed with cold ethylacetate and air-dried to afford
`2.0 g of the de sired product, m.p. l95°~l96° C.
`
`g.
`
`of
`
`EXAMPLE 15
`2-[ l , l’-biphenyl]-4-yl-6-fluoro-3-[( l -oxopentyl)oxy]
`4-quinolinecarboxylic acid
`3.59
`A
`suspension
`of
`_
`6-fluoro-3-hydroxy-2-(l , l’-biphenyl)-4--
`-quinolineacarboxylic acid in 17 mL of valeric anhy
`dride was treated with 6 drops of sulfuric acid. The
`mixture was stirred (over-head) and heated at 100° C.
`(steam-bath) for 3 hours. The reaction mixture was
`cooled and poured over 100 g of ice. The aqueous sus
`pension was neutralized to pH=7 with 5N NaOH.
`After stirring for 15 min., the ester was extracted from
`the aqueous phase with ethyl acetate (200 mL). The
`organic extract was washed with brine, dried over mag
`nesium sulfate, ?ltered and then concentrated to ap
`proximately 25 mL. The resulting crystalline solid was
`collected, washed with cold ethylacetate and air-dried
`to afford 3.0 g. of the desired product, m.p. 2l4°—2l7° C.
`
`EXAMPLE l9
`3-Hydroxy-6-methyl-2-[ l , l’-biphenyl]-4-yl-4
`quinolinecarboxylic acid
`A mixture of 30 g of 5-methyl-2,3-indolinedione in
`200 ml of water and 30.6 g of sodium hydroxide in 100
`ml of water was reacted with a solution of 47.4 g of
`acetoxyacetylbiphenyl in 500 ml of ethanol. The mix
`ture was re?uxed for 3 hours, then 250 m1 of ethanol
`was removed by distillation. A 500 ml portion of water
`was added, The mixture was stirred, cooled to room
`temperature and ?ltered through diatomaceous earth.
`The ?ltrate was acidi?ed with 60 ml of concentrated
`hydrochloric acid and 20 ml of glacial acetic acid. The
`resulting solid was collected, taken up in dilute ammo
`nia and the insoluble portion collected. This solid was
`dissolved in 7.4N ammonia, ?ltered and precipitated
`with glacial acetic acid, giving 32.0 g of the desired
`product, mp 236°~238° C.
`
`EXAMPLE 20
`6, 8-Dichloro-3-hydroxy-2-[ l , 1’-biphenyl]-4-yl-4
`quinolinecarboxylic acid
`A suspension of 21 g of 5,7-dichloro-2,3‘indolined
`ione in 120 ml of water was treated with a suf?cient
`amount of a solution of 16.6 g of sodium hydroxide in 55
`ml of water to provide solution. A warm solution of
`25.4 g of acetoxyacetylbiphenyl in 350 ml of ethanol
`was added, followed by the balance of the alkali solu
`tion. The mixture was re?uxed for 2.5 hours. During the
`last % hour 50 ml of ethanol was distilled off. A 300 ml
`portion of water was added, the mixture was stirred,
`cooled and ?ltered through diatomaceous earth. The
`solid was taken up in 1500 ml of water containing 100
`ml of 10N sodium hydroxide, ?ltered and the ?ltrate
`treated with 32 ml of concentrated hydrochloric acid
`and 10 ml of glacial acetic acid. The resulting solid was
`dissolved in 400 ml of hot cellosolve, ?ltered and pre
`cipitated with water, giving 18.5 g of the desired prod
`uct, mp 2l5°-217° C.
`
`EXAMPLE 21
`3-Hydroxy-8-methyl-Z-[ l , l'-biphenyl]-4-yl-4
`quinolinecarboxylic acid
`A suspension of 16.1 g of 7-methyl-2,3-indolinedione
`in 120 ml of water was treated with a suf?cient amount
`of a solution of 16.6 of sodium hydroxide in 55 ml of
`water to provide solution. A warm solution of 25.4 g of
`acetoxyacetylbiphenyl in 350 ml of ethanol was added,
`followed by the balance of the alkali solution. The mix
`ture was refluxed for 2.5 hours. During the last 1,: hour
`50 ml of ethanol was distilled off. A 300 ml portion of
`water was added, the mixture was stirred, cooled and
`?ltered through diatomaceous earth. The ?ltrate was
`treated with 34 ml of concentrated hydrochloric acid
`and 12 ml of glacial acetic acid. The resulting solid was
`collected and recrystallized from ethanol/ water, giving
`13.6 g of the desired product, mp l78°~180° C.
`
`g.
`
`30
`
`of
`
`EXAMPLE l6
`2-[l,l’-biphenyl[-4-yl-3-(2,2-dimethyl—l-oxopropoxy
`)-6-fluoro--4~quinolineacarboxylic acid
`A
`suspension
`of
`3.59
`6-?uoro-3-hydroxy-2-( 1 , 1-biphenyl)-4-
`-quinolinecarboxylic acid in 17 mL of trimethylacetic
`anhydride was treated with 6 drops of sulfuric acid. The
`mixture was stirred (over-head) and heated at 100° C.
`(steam-bath) for 3 hours. The reaction mixture was
`cooled and poured over 100 g. of ice. The aqueous
`suspension was neutralized to pH=7 with 5N NaOH.
`After stirring for 15 min., the ester was extracted from
`the aqueous phase with ethylacetate (200 mL). The
`40
`organic extract was washed with brine, dried over mag
`nesium sulfate, ?ltered and then concentrated to ap
`proximately 15 mL. The resulting crystallilne solid was
`collected washed with cold ethylacetate and air-dried
`to afford 2.8 g of the desired product, m.p. 2l5°-2l7° C.
`
`45
`
`g.
`
`of
`
`50
`
`EXAMPLE 17
`2-[l, l’-biphenyl]-4-yl-3-(2-methyl-1-oxopropoxy)-6
`?uoro-4-quinolinecarboxylic acid
`2.5
`A
`suspension
`of
`6-fluoro3-hydroxy-2-(1, l’-biphenyl)-4-
`-quinolinecarboxylic acid in 20 mL of isobutyric anhy
`dride was treated with 6 drops of sulfuric acid. The
`mixture was stirred (over-head) and heated at 100° C.
`(steam-bath) for 3 hours. The reaction mixture was
`cooled and poured over 100 g. of ice. The aqueous
`suspension was neutralized to pH=7 with 5N NaOH.
`After stirring for 15 min., the ester was extracted from
`the aqueous phase with ethylacelate (200 mL). The
`organic extract was washed with brine, dried over mag
`nesium sulfate, ?ltered and then concentrated to ap
`proximately 15 mL. The resulting crystalline solid was
`collected, washed with cold ethylacetate and air-dried
`to afford 0.7 g of the desired product, m.p. 201°-204° C.
`
`55
`
`EXAMPLE l8
`2-[ l, 1’-biphenyl]-4-yl-3-( l-oxobutoxy)-4
`quinolinecarboxylic acid
`
`65
`
`NOVARTIS EXHIBIT 2030
`Par v Novartis, IPR 2016-00084
`Page 6 of 8
`
`

`
`11
`
`4,847,381
`
`‘EXAMPLE 22
`6-Fluoro-3-hydroxy-2-[ 1 , l’-biphenyl]-4-y1-4-=
`quinolinecarboxylic acid
`A suspension of 6.6 g of 5-?uoro-2,3-indolinedione in
`48 ml of water was treated with a suf?cient amount of
`a solution of 6.62 g of sodium hydroxide in 22 ml of
`water to provide solution. A warm solution of 10.17 g of
`acetoxyacetylbiphenyl in 80 ml of ethanol was added,
`followed by the balance of the alkali solution. The mix
`ture was re?uxed for 3 hours. During the last 12* hour 10
`ml of ethanol was distilled off. A 103 ml portion of
`water was added, the mixture was stirred, cooled and
`?ltered through diatomaceous earth. The ?ltrate was
`treated with 13.6 ml of concentrated hydrochloric acid
`and 4.39 ml of glacial acetic acid and stirred for 30
`minutes. The resulting precipitate was collected,
`washed with water and ether and air dried. The result
`ing solid was stirred and heated in 400 ml of ethanol.
`The solid was collected, washed with water and dried
`giving 11.2 g of the desired product, mp 25220 -254‘’ C.
`
`1.0
`
`20
`
`12
`EXAMPLE 23
`2-(3,4-Dichlorophenyl)-3-hydroxy-6-methyl-4
`quinolinecarboxylic acid
`A suspension of 16.1 g of 5-methyl-2,3-indolinedione
`in 120 ml of water was treated with a suf?cient amount
`of a solution of 16 g of sodium hydroxide in 60 ml of
`water to provide solution. A warm solution of 24.7 g of
`3,4-c1ichloro-2-hydroxyacetophenone, acetate in 250 ml
`of ethanol was added followed by the balance of the
`alkali solution. The mixture was refluxed for 3 hours
`and 75 ml of alcohol was distilled off. The mixture was
`cooled, treated wth 300 ml of water, stirred and ?ltered
`through diatomaceous earth. The ?ltrate was acidi?ed
`with 33 ml of concentrated hydrochloric acid and 12 ml
`of glacial acetic acid, cooled for 3 hours and the result
`ing solid collected. This solid was dissolved in 800 ml of
`boiling methyl cellosolve, treated with charcoal, ?l
`tered and cooled. This solid was collected, giving 10.2 g
`of the desired product, mp 250° C. (dec.).
`Following the general procedures described in Ex
`amples 13-23, the compounds listed in the following
`Table IV as Examples 24-56 were prepared.
`TABLE IV
`Acetyl Derivative
`Product
`4-Chloro-2-hydroxyaceto-
`2-(4-Chlorophenyl)~6-?uoro-3-
`phenone, acetate
`hydroxy-4-quinolinecarboxylic acid
`Acetoxyacetylbiphenyl
`3-(Acetyloxy)-2-[l,l’-biphenyl]-4-
`yl,-6-bromo-4-quinolinecarboxylic
`acid
`6-Fluoro-2-(2'-?uoro[1,1’-bi-
`pheny1]-4-y1)-3-hydroxy~4-quino
`linecarboxylic acid
`6-Bromo-2-(4-chlorophenyl)-3-
`hydroxy-4-quinolinecarboxylic acid
`6,8-Dichloro-Z-(4-chlorophenyl)-
`3-hydroxy-4-quinolinecarboxylic
`acid
`2-(4-Chlorophenyl)-3-hydroxy-6-
`methyl-4-quinolinecarboxylic acid
`6-Bromo-3-hydroxy-2-(4-iodophen-
`y1)-4-quinolinecarboxylic acid
`6-Fluoro-2-(4-?uoropheny1)-3-
`hydroxy-4-quinolinecarboxylic acid
`6-Bromo-3-hydroxy-2-(4’-methoxy-
`[1,l’-biphenyl]-4-y1)-4-quinoline
`carboxylic acid
`6-Bromo-2-(4-?uorophenyl)-3-
`hydroxy-4-quinolinecarboxylic acid
`2-(2,4-Di?uoropheny1)-6-?uoro-3-
`hydroxy-4-quinolinecarboxylic acid
`6-Bromo-2-(2,4-di?uorophenyl)-3-
`hydroxy-4-quino1inecarboxylic acid
`6~Chloro-3-hydroxy~2-(4’-methoxy-
`[1,1’—biphenyl]-4-yl)-4-quinoline
`carboxylic acid
`6-F1uoro-3-hydroxy-2-(4'-methoxy-
`[1,1'-bipheny1]-4-yl)-4-quinoline
`carboxylic acid
`6,8-Dichloro-2-(3,4-dichlorophen-
`yl)-3-hydroxy-4-quino1inecarbox
`ylic acid
`6,8-Dichloro-3-hydroxy-2-(4-iodo
`pheny1)-4-quinolinecarboxylic acid
`6-Fluoro~3-hydroxy-2-(4-phenoxy-
`phenyl)-4-quinolinecarboxylic acid
`3-Hydroxy-2-(4—phenoxyphenyD-4-
`quinolinecarboxylic acid
`3-l-lydroxy-6-methyl-2-(4-phenoxy-
`pheny1)-4-quinolinecarboxylic acid
`6-Bromo-3-hydroxy-2-(4-phenoxy-
`pheny1)-4-quinolinecarboxylic acid
`6-Fluoro-3-hydroxy-2-[4-(phenyl-
`methyl)phenyl]-4-quino1inecar
`boxylic acid
`6-Fluoro-3-hydroxy-2-[4-(phenyl-
`thio)phenyl]-4-quinoline