Treatment of organ transplantation rejection

4-Quinoline-carboxylic acid derivatives, such as 2-(2'-fluoro-1,1'-biphenyl-4-yl)-6-fluoro-3-methyl-4-quinoline carboxylic acid, in combination with other immunosuppressive agents are useful for the treatment and/or prevention of transplantation rejection, graft vs. host disease, autoimmune diseases, and chronic inflammatory disease.

BACKGROUND OF THE INVENTION 
U.S. Pat. No. 4,680,299 (Hesson), granted Jul. 14, 1987, describes 
4-quinoline-carboxylic acid derivatives as tumor inhibiting agents. 
Commonly assigned European Patent Application Serial No. 89107099.7, 
published Nov. 2, 1989 described 4-quinoline-carboxylic acid derivatives 
as immunomodulatory and anti-inflammatory agents. 
U.S. Pat. No. 4,847,381 (Sutherland et. al.,) teaches substituted 
4-quinoline-carboxylic acid compounds useful for the treatment of 
arthritis and useful as immunosuppressive agents. 
Presently, cyclosporin A, an immunosuppressive agent, used in combination 
with other adjunctive therapies, such as azathioprine (AZA and 
corticosteroids, is the treatment of choice for the prevention of organ 
transplantation rejection. Other immunosuppressive agents, including but 
not limited to azathioprine, corticosteroids (such as prednisone), OKT3, 
FK506, mycophenolic acid or the morpholinethylester thereof, 
15-deoxyspergualin, rapamycin, mizoribine, misoprostol and 
anti-interluekin-2 (IL-2) receptor antibodies have been used or are 
suggested to be useful in the treatment and/or prevention of organ 
transplantation rejection. 
Use of any of these known immunosuppressive compounds, either along or in 
combination, is associated with a high incidence of side effects such as 
nephrotoxicity and/or hepatoxicity. The 4-quinoline-carboxylic acid 
compounds useful in the present invention have a unique mechanism of 
action compared to other known immunosuppressive agents, and therefore 
have not been associated with the nephrotoxicity and hepatoxicity seen 
with other immunosuppressive agents such as cyclosporin A and AZA. In 
addition, the combination of a 4-quinoline-carboxylic acid with known 
immunosuppressive agents has a synergistic effect in terms of inhibition 
of inflammation in animal models. This synergistic effect is seen at 
suboptimal doses of each immunosuppressive agent, thus, suggesting that 
known immunosuppressive agents could be used in combination with a 
4-quinoline-carboxylic acid compound, each at lower doses with an 
associated lower incidence of side effects. 
SUMMARY OF THE INVENTION 
According to the present invention, there are provided methods of treating 
and/or preventing organ transplantation rejection, graft versus host 
disease, psoriasis and autoimmune diseases, including but not limited to 
rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, 
myasthenia gravis as well as chronic inflammatory disease including but 
not limited to Crohn's disease and primary billiary cirrhosis, in a 
mammal, said methods comprising administering to the mammal in an 
effective amount for the treatment of a desired aforesaid disease a 
combination of: (a) at least one immunosuppressive agent preferably 
selected from the group consisting of cyclosporin A, azathioprine, a 
corticosteroid such as prednisone or prednisolone, OKT3, FK506, 
mycophenolic acid or the morpholinethylester thereof, 15-deoxyspergualin, 
rapamycin, mizoribine, misoprostol and anti-interleukin-2 (IL-2) receptor 
antibodies, and (b) a compound of the formula: 
##STR1## 
or a pharmaceutically acceptable salt thereof wherein: R is 
##STR2## 
R.sup.1 is CH.sub.3 CH.sub.2 (CH.sub.3)CH, alkyl of 5 to 12 carbon atoms, 
cyclohexyl, 
##STR3## 
R.sup.1 can be in addition alkyl of 3 to 4 carbon atoms; R.sup.2 is 
##STR4## 
R.sup.3 is H, alkoxy of 1 to 3 carbon atoms, alkyl of 1 to 2 carbon atoms, 
hydroxy or alkanoyloxy of 2 to 6 carbon atoms; 
when R.sup.3 is hydroxy or alkanoyloxy of 2 to 6 
Carbon atoms, R.sup.1 can be in addition, trifluoromethyl, halogen, 
hydroxy, alkyl of 1 to 6 carbon atoms and cycloalkyl of 1 to 6 carbon 
atoms; 
R.sup.4 is CO.sub.2 H or CO.sub.2 R.sup.11 ; 
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I, 
CH.sub.3, CF.sub.3, SCH.sub.3 or alkyl of 1 to 3 carbon atoms, at least 
two of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 being H; 
R.sup.9 and R.sup.9 A are independently H or alkyl of 1 to 3 carbon atoms; 
R.sup.11 is (CH.sub.2).sub.2-4 NR.sup.9 R.sup.9A ; 
W, Y and Z are independently H, F, Cl, Br, alkyl of 1 to carbon atoms, 
NO.sub.2, OH, CF.sub.3 or OCH.sub.3 ; and 
m is 0 or 1; 
with the following provisos: 
(1) R.sup.5, R.sup.6 and R.sup.7 cannot all be H; 
(2) when R.sup.4 is CO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2, R.sup.6 
is CH.sub.2 CH.sub.3, or R.sup.7 is Cl, R.sup.1 cannot be cyclohexyl; 
(3) when R.sup.1 is cyclohexyl and R.sup.3 is H, R.sup.6 must be Cl or F, 
but R.sup.6 and R.sup.8 cannot both be Cl; and 
(4) when R.sup.6 is CH.sub.3, then R.sup.7 cannot be Cl. 
Current recommended therapy for the prevention of organ transplantation 
rejection and related disorders, including graft versus host disease, 
traditionally involves patient treatment with cyclosporin A and adjunctive 
therapy with corticosteroids and other immunosuppressive drugs (Immune 
Modulation Agents and Their Mechanisms, ISBN 0-8247-7178-8, 1984, pp 
191-228, Jacobs and Elgin "Cyclosporin A, Current Status, Including the 
Cape Town Experience" Transplantation and Clinical Immunology, Volume XX 
Combined Immunosuppressive suppressive Therapy in Transplantation ISBN 
444-81068-4, 1989). Our results indicate that 
2-phenyl-4-quinoline-carboxylic acids and their derivatives will be useful 
as agents to be used in combination with compounds currently used in these 
clinical regimens. 
The significant clinically observed toxicities associated with cyclosporin 
A (nephrotoxicity) and AZA (hepatoxicity), have not been seen with 
2-phenyl-4-quinoline-carboxylic acids and their derivatives. Moreover, 
2-phenyl-4-quinoline-carboxylic acids and their derivatives have a unique 
mechanism of action (inhibition of dihydroorotate dehydrogenase) which is 
distinct from other available immunosuppressive agents. Our results show 
that 2-phenyl-4-quinoline-carboxylic acids and their derivatives have 
synergistic activity when included in the currently accepted regimen of 
drug therapy for the prevention of organ transplantation rejection and 
related complications. More particularly, these 
2-phenyl-4-quinoline-carboxylic acid derivatives should be useful at 
reduced doses of both the quinoline-carboxylic acid compound and other 
immunosuppressive agents used in combination therewith.

PREFERRED EMBODIMENTS 
Preferred compounds useful in the present invention have the formula: 
##STR5## 
or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is 
cyclohexyl; phenyl; phenyl substituted with one halogen; alkyl of 1 to 5 
carbon atoms or CF.sub.3 ; phenoxy; or phenoxy substituted with one 
halogen or alkyl of 1 to 5 carbon atoms; and/or 
R.sup.3 is H or alkyl of 1 to 2 carbon atoms; and/or 
R.sup.4 is CO.sub.2 H, a sodium or potassium salt thereof; or CO.sup.2 
R.sup.11 ; and/or 
R.sup.5 and R.sup.6 are independently H, halogen, CH.sub.3 or CF.sub.3 ; 
and/or 
R.sup.7 and R.sup.8 are independently H or halogen; and/or 
R.sup.11 is (CH.sub.2).sub.2-4 NR.sup.9 R.sup.9A ; and/or 
R.sup.9 and R.sup.9 A are independently alkyl of 1 to 3 carbon atoms; 
provided that R.sup.5, R.sup.6 and R.sup.7 cannot all be H; when R.sup.1 is 
cyclohexyl and R.sup.3 is H, R.sup.6 must be Cl or F, but R.sup.6 and 
R.sup.8 cannot both be Cl; when R.sup.6 is CH.sub.3, then R.sup.7 cannot 
be Cl; and when R.sup.4 is CO.sub.2 H, R.sup.1 or R.sup.2 is phenyl, and 
R.sup.5, R.sup.7 and R.sup.8 are H, then R.sup.6 cannot be Br. 
More preferred compounds useful in this invention have the formula: 
##STR6## 
wherein R.sup.1 is cyclohexyl, 
##STR7## 
R.sup.3 is H or alkyl of 1 to 2 carbon atoms; and/or R.sup.4 is CO.sub.2 
H, a sodium or potassium salt thereof, or CO.sub.2 R.sup.11 ; and/or 
R.sup.5 and R.sup.6 are independently H, halogen or CF.sub.3 provided that 
both R.sup.5 and R.sup.6 are not hydrogen; and/or 
R.sup.11 is (CH.sub.2).sub.2-4 NR.sup.9 R.sup.9A ; and/or 
R.sup.9 and R.sup.9 A are independently alkyl of 1 to 3 carbon atoms, 
and/or 
W and Z are independently H, halogen, alkyl of 1 to 5 carbon atoms or 
CF.sub.3 ; 
provided that when R.sup.1 is phenyl or phenoxy, and R.sup.5 is H, then 
R.sup.6 cannot be Br; and that when R.sup.1 is cyclohexyl and R.sup.3 is 
H, R.sup.6 must be Cl or F. 
Specifically preferred compounds useful in this invention are: 
(1) 2-(1,1'-biphenyl-4-yl)-5-chloro-3-methyl-4-quinoline carboxylic acid, 
sodium 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-quinoline carboxylic acid, 
sodium or potassium salt 
(4) 2-(4'-bromo-1,1'-biphenyl-4-yl)-6-fluoro-3-methyl-4-quinoline 
carboxylic acid, sodium or potassium salt 
(5) 2-(2'-fluoro-1,1'-biphenyl-4-yl)-6-fluoro-3-methyl-4-quinoline 
carboxylic acid, sodium or potassium salt. 
DETAILED DESCRIPTION OF THE INVENTION 
The 4-quinoline-carboxylic acid derivatives useful in this invention are 
described in and prepared by methods set forth in U.S. Pat. Nos. 4,680,299 
and 4,847,381, the disclosure, synthesis, and synthesis examples of which 
are hereby incorporated by reference. The isolation of the FK506 natural 
product is described in European Patent Application publication number 
240,773, published 10/14/87 and the chemical synthesis of FK506 is 
described in Jones et al. (1989) J. Am. Chem. Soc. 11:1157-1159. 
The preparation of azathioprine is described in U.S. Pat. No. 3,056,785 
issued to Burroughs Wellcome. LOC Azathioprine is available as 
Imuran.RTM., for which the product information, including dosage and 
administration, is given in Physician' Desk Reference 44th Edition, 1990, 
pp 777-778. 
The preparation of cyclosporin A is described in U.S. Pat. No. 4,117,118 
issued to Sandoz. Cyclosporin A is available as Sandimmune.RTM., for which 
the product information, including dosage and information, is given in 
Physician' Desk Reference 44th Edition, 1990, pp 1950-1952. 
The preparation of prednisone is described in U.S. Pat. Nos. 2,897,216 and 
3,134,718 issued to Schering. Prednisone is available commercially from 
several manufacturers as are other corticosteroids (see generally, 
Physicians' Desk Reference, supra). 
Murine monoclonal antibody to the human T3 antigen (herein referred to as 
OKT3) is available as Orthoclone OKT.RTM.3, for which the product 
information, including dosage and administration and references to methods 
of preparation, is given in PDR, 1990, pp 1553-1554. 
The preparation of mycophenolic acid is described in British patents 
1,157,099; 1,157,100; and 1,158,387 issued to ICI. 
15-dioxyspergualin is a derivative of spergualin discovered in culture 
filtrates of the bacterial strain BGM162-aFZ as reported in Ochiai, T., 
Hori, S., Nakajimak, et. al. Prolongation of Rat Heart Allograft Survival 
by 15-desoxyspergualin, J. Antibiot (Tokyo) 1987; 40:249. 
Mizoribine is described in U.S. Pat. No. 3,888,843 issued to Toyo Jozo. 
Misoprostol, a prostaglandin (PGEl) analog, is described in U.S. Pat. No. 
3,965,143 assigned to Searle and U.S. Pat. No. 4,132,738 assigned to 
Miles. Rapamycin is described in U.S. Pat. Nos. 4,650,803; 4,316,885; 
4,885,171; 3,993,749 and U.S. Pat. No. 3,929,992, all assigned to Ayerst. 
Antibodies to the IL-2 receptor protein are described in U.S. Pat. Nos. 
4,578,335 and 4,845,198 (Immunex) and U.S. Pat. No. 7/341,361 and U.S. 
Pat. No. 4,892,827 issued to Pastan et. al. 
Utility 
Contact Sensitivity Response to DNFB in Mice 
Balb/c female mice (.perspectiveto.20 g, Charles River) were sensitized on 
the shaved abdomen with 25 .mu.l 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 .mu.l of 0.2% DNFB in a vehicle of 4:1 
acetone:olive oil on day 5. An identical segment of the ear was measured 
immediately before challenge 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.sup.-4 inches.+-.SEM. Percent 
suppression was calculated as: 
##EQU1## 
Compounds were administered orally from day 0 through day 6 and were 
prepared in 0.25% Methocel.RTM. (Dow Chemical Co.). Control animals 
received only vehicle (0.25% Methocel.RTM.). 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 are shown in Tables 
1-4. 
Results of the biological tests described below establish that the 
combination of (1) a 4-quinoline-carboxylic acid derivative and (2) at 
least one additional immunosuppressive agent, such as cyclosporin A, 
azathioprine or prednisone, has the effect of suppressing or inhibiting 
the contact sensitivity response to 2,4-dinitrofluorobenzene (DNFB) in 
mice. 
Contact sensitivity to DNFB is a form of delayed-type hypersensitivity 
which has been extensively studied to gain an understanding of the 
regulation of immunologic processes (Claman et. al. (1980), Immunological 
Rev. 50:105-132). This reaction is mediated by T lymphocytes that become 
sensitized to antigen by proliferating and developing into mature effector 
cells (Claman et. al. (1980), Immunological Rev. 105-132). This 
cell-mediated immune response (T-cell mediated immunity) is central to 
many disease states such as organ transplantation rejection and graft 
versus host disease (Benacerraf and Unanue (1979), Textbook of Immunology, 
Williams & Wilkins Co.,; Eisen (1980), Immunology, An Introduction to 
Molecular and Cellular Principles of the Immune Responses, Harper & Row, 
Inc.; Loveland and McKenzie (1982), Inflammation, Basic Principles and 
Clinical Correlates, Raven Press). 
A representative 4-quinoline-carboxylic acid derivative, 
2-(2'-fluoro-1,1'-biphenyl-4-yl)-6-fluoro-3-methyl-4-quinoline carboxylic 
acid (Example 28, U.S. Pat. No. 4,680,299; hereinafter referred to as 
Example 28), was tested individually (Table 1) as was cyclosporin A (Table 
1) and in combination with cyclosporin A in the DNFB contact sensitivity 
model (Table 2). 
TABLE 1 
______________________________________ 
Ear.sup.a 
Dose Swelling % Sup- ED.sub.50 
Treatment (mg/kg) (units .+-. SEM) 
pression 
mg/kg 
______________________________________ 
Negative Vehicle 0.74 .+-. 0.52 
-- -- 
Positive Vehicle 74.11 .+-. 3.78 
0 -- 
Cyclosporin A 
2.0 56.15 .+-. 3.74 
24.48 70.00 
10.0 66.58 .+-. 3.75 
10.27 
50.0 47.90 .+-. 3.76 
35.72 
100.0 7.80 .+-. 2.04 
90.37 
Example 28 
0.4 51.95 .+-. 2.33 
30.20 0.95 
2.0 25.61 .+-. 3.39 
66.10 
10.0 6.40 .+-. 1.09 
92.28 
20.0 4.75 .+-. 1.20 
94.53 
______________________________________ 
.sup.a Increase in ear thickness from day 5 to day 6, unit = 10.sup.-4 
inches 
TABLE 2 
__________________________________________________________________________ 
Immunosuppressive Effect (% Suppression of Ear Swelling) 
of the Combination of Example 28 and Cyclosporin A in a 
Mouse DFNB Contact Sensitivity Model 
Cyclo- 
sporin A 
Cyclosporin A (mg/kg) ED.sub.50 
0 6.3 12.5 25.0 30.0 50.0 70.0 100.0 (mg/kg) 
__________________________________________________________________________ 
Ex. 28 
(mg/kg) 
0 0 -9.9 .+-. 7.2 
-4.0 .+-. 2.6 
0.1 .+-. 3.5 
4.2 .+-. 4.9 
33.6 .+-. 5.7 
68.9 .+-. 1.2 
92.5 
60.02.0 
0.1 6.5 .+-. 2.9 
7.4 .+-. 13.2 
1.5 .+-. 8.0 
8.7 .+-. 9.6 
-- 28.8 .+-. 11.4 
-- -- &gt;50.0 
0.3 7.3 .+-. 2.4 
10.2 .+-. 17.6 
15.2 .+-. 7.5 
3.8 .+-. 7.1 
-1.7 .+-. 13.4 
44.7 .+-. 7.7 
66.7 .+-. 3.6 
-- 52.0 
1.0 31.4 .+-. 3.3 
51.9 .+-. 4.6 
62.1 .+-. 3.4 
77.0 .+-. 8.5 
84.6 .+-. 3.3 
90.8 .+-. 1.7 
94.6 .+-. 4.0 
-- &lt;6.3 
3.0 91.9 .+-. 2.3 
97.0 .+-. 1.4 
99.1 .+-. 3.8 
95.7 .+-. 3.2 
93.6 .+-. 4.3 
93.9 .+-. 4.5 
92.0 .+-. 6.2 
-- &lt;6.3 
10.0 93.9 .+-. 2.4 
-- -- -- 91.5 .+-. 8.0 
88.3 .+-. 9.0 
86.5 .+-. 7.1 
-- &lt;6.3 
Ex. 28 
1.4 1.0 0.8 0.7 0.4 0.4 &lt;0.3 
ED.sub.50 
(mg/kg) 
__________________________________________________________________________ 
As shown in Table 2, test results with mice receiving the combination 
treatment of Example 28 and cyclosporin A (CSA) demonstrate that the 
coadministration of suboptimal doses of each agent (Example 28 at 1.0 
mg/kg and CSA at 30.0 mg/kg) produced strong suppression of this 
T-cell-mediated immune response. These data demonstrate a remarkable 
synergistic effect of the two compounds using this combination therapy. 
Whereas Example 28 alone at 1.0 mg/kg results in a 31.4% suppression of 
this immune response and cyclosporin A alone at 30.0 mg/kg results in only 
a 4.2% suppression of immune response, when these agents are administered 
in combination at these suboptimal doses (1.0 mg/kg Ex. 28 and 30 mg/kg 
CSA), an 84.6% suppression of the immune response was observed. Thus, the 
immunosuppressive effect of the agents used in combination greatly exceeds 
the simple addition of the effect of each agent used alone. As shown in 
Table 2, treatment with Example 28 at a dose of 1.0 mg/kg reduced the 
effective ED.sub.50 of cyclosporin A from 60 mg/kg to &lt;6.3 mg/kg. 
A similar synergism was observed when Example 28 was administered in 
combination with azathioprine at suboptimal doses (Table 3). Thus, Example 
28 at 1.0 mg/kg and azathioprine at 12.5 mg/kg in combination resulted in 
a 62.5% immunosuppressive, whereas when used individually these agents at 
these suboptimal doses only resulted in 31.4% suppression and 15.9% 
suppression, respectively. 
TABLE 3 
__________________________________________________________________________ 
Immunosuppressive Effect (% Suppression of Ear Swelling) 
of the Combination of Example 28 and Azathioprine in a 
Mouse DFNB Contact Sensitivity Model 
Azathioprine (mg/kg) Azathioprine 
0 6.3 12.5 25.0 50.0 100.0 ED.sub.50 (mg/kg) 
__________________________________________________________________________ 
Ex. 28 
(mg/kg) 
0 0 2.5 .+-. 4.2 
15.9 .+-. 3.3 
29.7 .+-. 4.1 
72.1 .+-. 3.1 
97.7 .+-. 1.6 
38.0 
0.1 6.5 .+-. 2.8 
11.5 .+-. 10.2 
20.9 .+-. 6.1 
33.6 .+-. 5.6 
78.5 .+-. 3.0 
-- 42.0 
0.3 7.3 .+-. 2.4 
1.7 .+-. 7.7 
25.9 .+-. 7.5 
30.0 .+-. 9.2 
72.0 .+-. 3.7 
101.2 .+-. 0.5 
43.0 
1.0 31.4 .+-. 3.3 
38.4 .+-. 3.8 
62.4 .+-. 3.8 
71.6 .+-. 3.8 
90.3 .+-. 3.4 
99.6 .+-. 3.3 
7.5 
3.0 91.9 .+-. 2.3 
94.0 .+-. 2.8 
96.3 .+-. 2.7 
97.3 .+-. 1.9 
99.2 .+-. 4.3 
100.5 .+-. 0.2 
&lt;6.3 
10.0 93.9 .+-. 2.4 
-- -- 100.1 .+-. 2.2 
101.4 .+-. 4.4 
101.5 .+-. 3.8 
&lt;6.3 
Ex. 28 
1.4 1.3 0.8 0.7 &lt;0.1 &lt;0.1 
ED.sub.50 
(mg/kg) 
__________________________________________________________________________ 
As the data in Tables 2 and 3 suggest, a lower dose of each 
immunosuppressive agent can be used in the combination of the present 
invention while maintaining an effective level of suppression. The dose of 
the combination to be administered could be reduced on a single dose basis 
or on a cumulative basis. For example, the number of days on which dosing 
occurs may be reduced. This is shown in Table 4, wherein dosing was only 
at day 0 and 1, whereas in previous examples, dosing was on day 0-6. 
TABLE 4 
______________________________________ 
Immunosuppressive Effect (% Suppression of Ear Swelling) 
of the Combination of Example 28 and Cyclosporin A in a 
Mouse DNFB Contact Sensitivity Model 
% Sup- 
Group.sup.a /Treatment 
mg/kg .DELTA.Ear Swelling.sup.b 
pression 
______________________________________ 
Negative Control.sup.c 
-- 5.8 .+-. 0.6 
-- 
Positive Control 
-- 68.6 .+-. 3.7 
-- 
Ex. 28 20.0 59.6 .+-. 2.5 
14.4 
CSA 100.0 71.8 .+-. 3.2 
-5.1 
Ex. 28 & CSA 
20.0 + 100.0 
10.8 .+-. 1.5 
92.0 
______________________________________ 
.sup.a Group of 10 Balb/c female mice were sensitized on days 0 & 1 (0.5% 
DNFB). 
.sup.b All mice were ear challenged on day 5 (0.2% DNFB) and measured on 
day 6. 
.sup.c Nonsensitized control. 
The data show that the combination when dosed on days 0 and 1 yielded 92% 
suppression, whereas cyclosporin A used alone at 100 mg/kg (its optimal 
dose when administered on days 0-6), when dosed on day 0 and was 
ineffective (-5.1% suppression). 
Current recommended therapy for the prevention of organ transplantation 
rejection and related disorders, such as graft versus host disease, 
involves patient treatment with cyclosporin A and adjunctive therapy with 
corticosteroids and other immunosuppressive drugs. The present results 
show that 4-quinoline-carboxylic acid derivatives, such as 
2-(2'-fluoro-1,1'-biphenyl-4-yl)-6-(fluoro-3-methyl-4-quinoline carboxylic 
acid, will be useful as drugs to be used in conjunction with current 
clinical regimens in synergistically effective amounts. The clinically 
observed toxicities associated with cyclosporin A (nephrotoxicity), and 
AZA (hepatoxicity), have not been seen with the 4-quinoline-carboxylic 
acid derivatives useful in this invention. Moreover, the 
4-quinoline-carboxylic acids derivatives useful in this invention, such as 
Example 28, have a unique mechanism of action, i.e., inhibition of 
dihydroorotate dehydrogenase and consequent inhibition of pyrimidine 
nucleotide biosynthesis (Chen et. al. (1986) Cancer Research, 
46:5014-5019). By combining a 4-quinoline-carboxylic acid compound of the 
present invention with another immunosuppressive agent, lower doses of 
each agent or less frequent administration of each agent, can be used with 
comparable effectiveness and lower potential for toxic side effects. 
The present results show that Example 28 and related 4-quinoline-carboxylic 
derivatives should be useful when included in combination with other drugs 
used in current regimens of drug therapy for the prevention of organ 
transplantation rejection and related disorders (Jacobs and Elgin (1984) 
"Cyclosporin A, Current Status, Including the Cape Town Experience", in 
Immune Modulation Agents and Their Mechanisms, pp 191-228, Transplantation 
and Clinical Immunology, Volume XX Combined Immunosuppressive Therapy in 
Transplantation ISBN 0-444-81068-4, 1989. 
DOSAGE FORMS 
The immunosuppressive compounds (active ingredients) of this invention, 
including at least one -quinoline-carboxylic acid compound and at least 
one immunosuppressive agent preferably selected from the group consisting 
of, but not limited to: cyclosporin A, azathioprine, corticosteroids such 
as prednisone, OKT3, FK506, mycophenolic acid or the morpholinethylester 
thereof, 15-dioxyspergualin, rapamycin, mizoribine, misoprostol and 
anti-interleukin-2 (IL-2) receptor antibodies, can be administered to 
treat immunomodulatory disorders and inflammatory diseases and 
particularly to prevent/treat organ transplantation rejection, graft 
versus host disease, psoriasis and related disorders, by any means that 
produces contact of the active ingredient(s) with the agent's site of 
action in the body of a mammal. The combination therapy can be 
administered by any conventional means available for use in conjunction 
with pharmaceuticals; either as individual therapeutically active 
ingredients or in a combination of therapeutically 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. 
The dosage administered will be an immunosuppressive effective amount of 
active ingredient(s) and will, of course, vary depending upon known 
factors such as the pharmacodynamic characteristics of the particular 
active ingredient, and its mode and route of administration; age, health, 
and weight of the recipient; nature and extent 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 1 to 100, and 
preferably 0.1 to 10 milligrams per kilogram per day is effective to 
obtain desired results. 
Pharmaceutical compositions containing the immunosuppressive agents of this 
invention alone or in combination, can be made by those skilled in the 
art, using references such as Remington's Pharmaceutical Sciences, A. 
Osol, a standard reference text in this field. The active ingredients can 
be administered (alone or in combination) orally in solid dosage forms 
such as elixirs, syrups, and suspensions, or can also be administered 
parenterally in sterile liquid dosage forms. 
These dosage forms can generally be used when the compounds of this 
invention are 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 compatibility with both drugs.