U.S. patent application number 10/928835 was filed with the patent office on 2005-02-24 for immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene a4 hydrolase inhibitor.
This patent application is currently assigned to Pharmacia Corporation. Invention is credited to Anderson, Gary, Gregory, Susan A., Isakson, Peter C..
Application Number | 20050043355 10/928835 |
Document ID | / |
Family ID | 24404526 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050043355 |
Kind Code |
A1 |
Gregory, Susan A. ; et
al. |
February 24, 2005 |
Immunosuppressive effects of administration of a cyclooxygenase-2
inhibitor and a leukotriene A4 hydrolase inhibitor
Abstract
Treatment with a cyclooxygenase-2 inhibitor and a leukotriene
A.sub.4 hydrolase inhibitor is described as being useful in
reducing recipient rejection of transplanted organs and for
treatment of autoimmune diseases.
Inventors: |
Gregory, Susan A.; (San
Diego, CA) ; Isakson, Peter C.; (Morristown, NJ)
; Anderson, Gary; (Maryland Heights, MO) |
Correspondence
Address: |
SENNIGER POWERS LEAVITT AND ROEDEL
ONE METROPOLITAN SQUARE
16TH FLOOR
ST LOUIS
MO
63102
US
|
Assignee: |
Pharmacia Corporation
|
Family ID: |
24404526 |
Appl. No.: |
10/928835 |
Filed: |
August 27, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10928835 |
Aug 27, 2004 |
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10137231 |
May 2, 2002 |
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10137231 |
May 2, 2002 |
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09489311 |
Jan 21, 2000 |
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6407140 |
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09489311 |
Jan 21, 2000 |
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08600655 |
Feb 13, 1996 |
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Current U.S.
Class: |
514/317 ;
514/408; 514/602 |
Current CPC
Class: |
A61P 37/08 20180101;
A61P 35/00 20180101; A61P 37/06 20180101; A61P 37/00 20180101; A61P
25/00 20180101; A61P 29/00 20180101; A61P 7/00 20180101; A61K 45/06
20130101 |
Class at
Publication: |
514/317 ;
514/602; 514/408 |
International
Class: |
C12Q 001/68; A61K
031/445; A61K 031/40; A61K 031/18 |
Claims
What is claimed is:
1. A method to suppress immune, acute or delayed-type
hypersensitivity response in a subject, said method comprising
treating the subject with a therapeutically-effective amount of a
leukotriene A.sub.4 hydrolase inhibitor and a cyclooxygenase-2
inhibitor selected from the group consisting of
5-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-thi ophene,
N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide, meloxicam,
flosulide and compounds of Formula I 34wherein: A is a 5- or
6-member ring substituent selected from partially unsaturated or
unsaturated heterocyclo and carbocyclic rings; R.sup.1 is at least
one substituent selected from heterocyclo, cycloalkyl, cycloalkenyl
and aryl, wherein R.sup.1 is optionally substituted at a
substitutable position with one or more radicals selected from
alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,
alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; R.sup.2 is
alkyl or amino; and R.sup.3 is selected from the group consisting
of halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl,
heterocyclooxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl,
aryl, haloalkyl, heterocyclo, cycloalkenyl, aralkyl,
heterocycloalkyl, acyl, alkylthioalkyl, hydroxyalkyl,
alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl,
aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino,
N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino,
aminoalkyl, alkylaminoalkyl, Narylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl, and N-alkyl-Narylaminosulfonyl; or a
pharmaceutically-acceptable salt thereof.
2. The method of claim 1 wherein the leukotriene A.sub.4 hydrolase
inhibitor is selected from
[4-[5-(3-phenylpropyl)-2-thienyl]butoxyl]-acet- ic acid and
compounds of Formula II Ar.sup.1-Q-Ar.sup.2--Y--R-Z (II) or a
pharmaceutically-acceptable salt thereof and a
pharmaceutically-acceptabl- e carrier, wherein Ar.sup.1 is an aryl
moiety selected from: (i) phenyl, mono-, di-, or tri-substituted
phenyl with the substituents selected from Cl, Br, F, CF.sub.3,
lower alkyl, lower alkoxy, NH.sub.2, NO.sub.2 and OH; (ii) 2-, 4-
or 5-thiazolyl, (iii) 2-, 3- or 4-pyridinyl, (iv) 2- or 3-thienyl,
and (v) 2- or 3-furyl; wherein Ar.sup.2 is an aryl moiety selected
from: 35wherein Q is selected from: (i) --O--, (ii) --CH.sub.2--,
(iii) --OCH.sub.2--, (iv) --CH.sub.2O--, (v) --NH--, (vi)
--NHCH.sub.2--, (vii) --CH.sub.2NH--, (viii) --CF.sub.2--, (ix)
--CH.dbd.CH--, (x) --CH.sub.2CH.sub.2--, and (xi) carbon-carbon
single bond; wherein Y is selected from: (i) --O--, (ii) --S--,
(iii) --NH--, (iv) --S(O)--, and (v) --S(O.sub.2)--; wherein R is
selected from: (i) linear or branched C.sub.2-C.sub.6 alkylenyl,
and (ii) --C(R.sup.13) (R.sup.14)--(CH.sub.2).sub.m--; wherein Z is
selected from: 36(vii) a monocyclic or bicyclic heteroaromatic
moiety having at least one heteroatom, wherein the heteroatom is
nitrogen, and wherein the monocyclic heteroaromatic moiety
comprises a 5- or 6-membered ring and the bicyclic heteroaromatic
moiety comprises a fused 9- or 10-membered ring; wherein R.sup.4
and R.sup.5 are independently selected from: 37wherein R.sup.6 and
R.sup.7 are independently H or lower alkyl; wherein R.sup.8 and
R.sup.9 are independently selected from 38wherein R.sup.10 is H,
halogen, lower alkyl, lower alkoxy, nitro, or hydroxy, or R.sup.10
taken together with R.sup.13 is an alkylenyl group having one or
two carbon atoms; wherein R.sup.11 and R.sup.12 are independently
H, halogen, lower alkyl, lower alkoxy, NH.sub.2, NO.sub.2 or OH;
wherein R.sup.13 is H, or lower alkyl, or R.sup.13 taken together
with R.sup.10 is an alkylenyl group having one or two carbon atoms;
wherein R.sup.14 is H or lower alkyl; wherein R.sup.15 is selected
from (i) H, (ii) --OH or .dbd.O, (iii)
--(CH.sub.2).sub.aCOR.sup.18, (iv) --(CH.sub.2).sub.aCONH(C-
H.sub.2).sub.bCO.sub.2R.sup.19, and (v) --NHR.sup.20; wherein
R.sup.16 and R.sup.17 are independently hydrogen, or
--(CH.sub.2).sub.aCOR.sup.18, provided that at least one of
R.sup.16 and R.sup.17 is hydrogen; wherein R.sup.18 is --OR.sup.19,
--NHR.sup.19 or --NHNH.sub.2; wherein R.sup.19 is H, lower alkyl or
benzyl; wherein R.sup.20 is H, lower alkkyl, benzyl, --COR.sup.19
or --CONH.sub.2; wherein X.sup.1 is 39--S--, or --O--, wherein
R.sup.21 is H, lower alkyl, --CONH.sub.2, --CSNH.sub.2,
--COCH.sub.3 or --SO.sub.2CH.sub.3; wherein a and b are
independently integers of from 0 to 5; wherein m is 1, 2 or 3;
wherein n is 0, 1, 2 or 3; wherein p is 1 or 2; and wherein q is 1,
2 or 3; provided however that where R is --C(R.sup.13)
(R.sup.14)--(CH.sub.2).sub.m--, and R.sup.13 taken together with
R.sup.10 forms an alkylenyl group having one or two carbon atoms,
then --Ar.sup.2--Y--R-- is 40wherein X is --CH-- or --N--; and
wherein r is 1 or 2; further provided that wherein Z is 41and
either R.sup.4 or R.sup.5, or both R.sup.4 and R.sup.5 are
--(CH.sub.2).sub.aCOR.sup.18, then a is not 0.
3. The method of claim 1 wherein the cyclooxygenase-2 inhibitor is
a compound selected from the group consisting of:
3-(3,4-difluorophenyl)-4--
(4-methylsulfonylphenyl)-2-(5H)-furanone;
3-phenyl-4-4-methylsulfonylpheny- l-2-(5H)-furanone;
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1--
yl]benzenesulfonamide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazo-
l-1-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluorometh-
yl)-1H-pyrazol-1-yl]benzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4--
trifluoromethyl-1H-imidazol-2-yl]pyridine;
2-methyl-5-[1-[4-(methylsulfony-
l)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenes-
ulfonamide; 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-hydroxyethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfonamide;
4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; and
4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfo-
namide; or a prodrug of the compound or a pharmaceutically
acceptable salt of the compound.
4. A combination comprising a therapeutically-effective amount of a
cyclooxygenase-2 inhibitor, a leukotriene A.sub.4 hydrolase
inhibitor and an immunosuppressive drug selected from
antiproliferative agents, antiinflammatory-acting compounds and
inhibitors of leukocyte activation.
5. The combination of claim 4 wherein the cyclooxygenase-2
inhibitor is selected from the group consisting of
5-bromo-2-(4-fluorophenyl)-3-[4-(me-
thylsulfonyl)phenyl]-thiophene,
N-[2-(cyclohexyloxy)-4-nitrophenyl]-methan- esulfonamide,
meloxicam, flosulide and compounds of Formula I 42wherein A is a 5-
or 6-member ring substituent selected from partially unsaturated or
unsaturated heterocyclo and carbocyclic rings; wherein R.sup.1 is
at least one substituent selected from heterocyclo, cycloalkyl,
cycloalkenyl and aryl, wherein R.sup.1 is optionally substituted at
a substitutable position with one or more radicals selected from
alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,
alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; wherein
R.sup.2 is selected from alkyl, and amino; and wherein R.sup.3 is
selected from halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl,
cyanoalkyl, heterocyclooxy, alkyloxy, alkylthio, alkylcarbonyl,
cycloalkyl, aryl, haloalkyl, heterocyclo, cycloalkenyl, aralkyl,
heterocycloalkyl, acyl, alkylthioalkyl, hydroxyalkyl,
alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl,
aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino,
N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino,
aminoalkyl, alkylaminoalkyl, Narylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalky- l, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl, and N-alkyl-Narylaminosulfonyl; or a
pharmaceutically-acceptable salt or prodrug thereof.
6. The combination of claim 5 wherein the leukotriene A.sub.4
hydrolase inhibitor is selected from
[4-[5-(3-phenylpropyl)-2-thienyl]butoxyl]-acet- ic acid and
compounds of Formula II Ar.sup.1-Q-Ar.sup.2--Y--R-Z (II) or a
pharmaceutically-acceptable salt thereof, and a
pharmaceutically-acceptab- le carrier, wherein Ar.sup.1 is an aryl
moiety selected from: (i) phenyl, mono-, di-, or tri-substituted
phenyl with the substituents selected from Cl, Br, F, CF.sub.3,
lower alkyl, lower alkoxy, NH.sub.2, NO.sub.2 and OH, (ii) 2-, 4-
or 5-thiazolyl, (iii) 2-, 3- or 4-pyridinyl, (iv) 2- or 3-thienyl,
and (v) 2- or 3-furyl; wherein Ar.sup.2 is an aryl moiety selected
from: 43wherein Q is selected from: (i) --O--, (ii) --CH.sub.2--,
(iii) --OCH.sub.2--, (iv) --CH.sub.2O--, (v) --NH--, (vi)
--NHCH.sub.2--, (vii) --CH.sub.2NH--, (viii) --CF.sub.2--, (ix)
--CH.dbd.CH--, (x) --CH.sub.2CH.sub.2--, and (xi) carbon-carbon
single bond; wherein Y is selected from (i) --O--, (ii) --S--,
(iii) --NH--, (iv) --S(O)--, and (v) --S(O.sub.2)--; wherein R is
selected from: (i) linear or branched C.sub.2-C.sub.6 alkylenyl;
and (ii) --C(R.sup.13) (R.sup.14)--(CH.sub.2).sub.m--; wherein Z is
selected from: 44(vii) a monocyclic or bicyclic heteroaromatic
moiety having at least one heteroatom, wherein the heteroatom is
nitrogen, and wherein the monocyclic heteroaromatic moiety
comprises a 5- or 6-membered ring and the bicyclic heteroaromatic
moiety comprises a fused 9- or 10-membered ring; wherein R.sup.4
and R.sup.5 are independently selected from: 45wherein R.sup.6 and
R.sup.7 are independently H or lower alkyl; wherein R.sup.8 and
R.sup.9 are independently selected from 46wherein R.sup.10 is H,
halogen, lower alkyl, lower alkoxy, nitro, or hydroxy, or R.sup.10
taken together with R.sup.3 is an alkylenyl group having one or two
carbon atoms; wherein R.sup.11 and R.sup.12 are independently H,
halogen, lower alkyl, lower alkoxy, NH.sub.2, NO.sub.2 or OH;
wherein R.sup.3 is H, or lower alkyl, or R.sup.13 taken together
with R.sup.10 is an alkylenyl group having one or two carbon atoms;
wherein R.sup.14 is H or lower alkyl; wherein R.sup.15 is selected
from (i) H, (ii) --OH or .dbd.O, (iii)
--(CH.sub.2).sub.aCOR.sup.18, (iv) --(CH.sub.2).sub.aCONH(C-
H.sub.2).sub.bCO.sub.2R.sup.19, and (v) NHR.sup.20; wherein
R.sup.16 and R.sup.17 are independently hydrogen, or
--(CH.sub.2).sub.aCOR.sup.18, provided that at least one of
R.sup.16 and R.sup.17 is hydrogen; wherein R.sup.18 is --OR.sup.19,
--NHR.sup.19 or --NHNH.sub.2, wherein R.sup.19 is H, lower alkyl or
benzyl; wherein R.sup.20 is H, lower alkyl, benzyl, --COR.sup.19 or
--CONH.sub.2; wherein X.sup.1 is 47 --S--, or --O--, wherein
R.sup.21 is H, lower alkyl, --CONH.sub.2, --CSNH.sub.2,
--COCH.sub.3 or --SO.sub.2CH.sub.3; wherein a and b are
independently integers of from 0 to 5; wherein m is 1, 2 or 3;
wherein n is 0, 1, 2 or 3; wherein p is 1 or 2; and wherein q is 1,
2 or 3; provided however that where R is --C(R.sup.13)
(R.sup.14)--(CH.sub.2).sub.m--, and R.sup.13 taken together with
R.sup.0 forms an alkylenyl group having one or two carbon atoms,
then --Ar.sup.2--Y--R-- is 48wherein X is --CH-- or --N--; and
wherein r is 1 or 2; further provided that wherein Z is 49and
either R.sup.4 or R.sup.5, or both R.sup.4 and R.sup.1 are
--(CH.sub.2).sub.aCOR.sup.18, then a is not 0.
7. The combination of claim 6 wherein the leukotriene A.sub.4
hydrolase inhibitor is selected from the group consisting of:
(4-[5-(3-phenylpropyl)-2-thienyl]butoxyl)-acetic acid;
ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazolylpiperidine;
1-[2-[4-(4-(2-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine;
3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoic
acid; methyl-3-[methyl
[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoate;
3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoic
acid;
methyl-3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoate;
3-[methyl [3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;
3-[methyl[3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propanoic
acid; and
3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propanoic
acid.
8. The combination of claim 5 wherein the cyclooxygenase-2
inhibitor is a compound selected from the group consisting of:
3-(3,4-difluorophenyl)-4--
(4-methylsulfonylphenyl)-2-(5H)-furanone;
3-phenyl-4-4-methylsulfonylpheny- l-2-(5H)-furanone;
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1--
yl]benzenesulfonamide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazo-
l-1-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluorometh-
yl)-1H-pyrazol-1-yl]benzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4--
trifluoromethyl-1H-imidazol-2-yl]pyridine;
2-methyl-5-[1-[4-(methylsulfony-
l)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenez-
ulfonamide; 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-hydroxyethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfonamide;
4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; and
4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfo-
namide; or a prodrug of the compound or a pharmaceutically
acceptable salt of the compound.
9. A pharmaceutical composition comprising a
pharmaceutically-acceptable carrier and a therapeutically-effective
amount of a leukotriene A.sub.4 hydrolase inhibitor, a cyclosporin
and a cyclooxygenase-2 inhibitor selected from the group consisting
of: 5-bromo-2-(4-fluorophenyl)-3-[4-(m- ethylsulfonyl)phenyl]-thi
ophene, N-[2-(cyclohexyloxy)-4-nitrophenyl]-meth- anesulfonamide,
meloxicam, flosulide and compounds of Formula I 50wherein A is a 5-
or 6-member ring substituent selected from partially unsaturated or
unsaturated heterocyclo and carbocyclic rings; wherein R.sup.1 is
at least one substituent selected from heterocyclo, cycloalkyl,
cycloalkenyl and aryl, wherein R.sup.1 is optionally substituted at
a substitutable position with one or more radicals selected from
alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,
alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; wherein
R.sup.2 is selected from alkyl, and amino; and wherein R.sup.3 is a
radical selected from halo, alkyl, alkenyl, alkynyl, oxo, cyano,
carboxyl, cyanoalkyl, heterocyclooxy, alkyloxy, alkylthio,
alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclo,
cycloalkenyl, aralkyl, heterocycloalkyl, acyl, alkylthioalkyl,
hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl,
aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl,
aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl,
alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, Narylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-Narylaminosulfonyl;
or a pharmaceutically-acceptable salt or prodrug thereof.
10. The combination of claim 6 wherein the immunosuppressant is
cyclosporin.
11. The combination of claim 6 wherein the immunosuppressant is
selected from the group consisting of macrolide lactone, rapamycin,
a glucocorticoid, 15-deoxyspergulin and cyclosporin.
12. The combination of claim 6 wherein the immunosuppressant is
macrolide lactone.
13. The combination of claim 6 wherein the immunosuppressant is
rapamycin.
14. The combination of claim 6 wherein the immunosuppressant is
15-deoxyspergulin.
15. The combination of claim 6 wherein the immunosuppressant is a
glucocorticoid.
16. The method of claim 1, wherein the cyclooxygenase-2 inhibitor
is selected from
5-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-thi-
ophene, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide,
meloxicam, and flosulide.
17. The method of claim 16 wherein the leukotriene A.sub.4
hydrolase inhibitor is selected from the group consisting of:
[4-[5-(3-phenylpropyl)-2-thienyl]butoxyl]-acetic acid;
ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazolylpiperidine;
1-[2-[4-(4-(2-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine;
3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoic
acid; methyl-3-[methyl
[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoate;
3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoic
acid;
methyl-3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoate;
3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;
3-[methyl[3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propanoic
acid; and
3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propanoic
acid.
18. The method of claim 1, wherein the leukotriene A.sub.4
hydrolase inhibitor is selected from the group consisting of:
[4-[5-(3-phenylpropyl)-2-thienyl]butoxyl]-acetic acid;
ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazolylpiperidine;
1-[2-[4-(4-(2-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine;
3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoic
acid; methyl-3-[methyl
[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoate;
3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoic
acid;
methyl-3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoate;
3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;
3-[methyl [3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propanoic
acid; and
3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propanoic acid,
and the cyclooxygenase-2 inhibitor is selected from the group
consisting of:
3-(3,4-difluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone;
3-phenyl-4-4-methylsulfonylphenyl-2-(5H)-furanone;
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-
-imidazol-2-yl)pyridine;
2-methyl-5-(1-[4-(methylsulfonyl)phenyl]-4-triflu-
oromethyl-1H-imidazol-2-yl]pyridine;
4-[2-(5-methylpyridin-3-yl)-4-(triflu-
oromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[5-methyl-3-phenylisoxaz- ol-4-yl]benzenesulfonamide;
4-[5-hydroxyethyl-3-phenylisoxazol-4-yl]benzen- esulfonamide;
[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzene-
sulfonamide; 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide;
and
4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfo-
namide.
19. The method of claim 18, wherein the cyclooxygenase-2 inhibitor
is
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide and the leukotriene A.sub.4 hydrolase inhibitor is
3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic
acid.
20. The method of claim 18, wherein the cyclooxygenase-2 inhibitor
is
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide and the leukotriene A.sub.4 hydrolase inhibitor is
3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic
acid.
21. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor is
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfo-
namide.
22. A combination comprising a therapeutically-effective amount of
cyclosporin, a cyclooxygenase-2 inhibitor selected from the group
consisting of:
3-(3,4-difluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-f-
uranone; 3-phenyl-4-4-methylsulfonylphenyl-2-(5H)-furanone;
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-
-imidazol-2-yl]pyridine;
2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-triflu-
oromethyl-1H-imidazol-2-yl]pyridine;
4-[2-(5-methylpyridin-3-yl)-4-(triflu-
oromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[5-methyl-3-phenylisoxaz- ol-4-yl]benzenesulfonamide;
4-[5-hydroxyethyl-3-phenylisoxazol-4-yl]benzen- esulfonamide;
[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzene-
sulfonamide; 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide;
and
4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfo-
namide; and a leukotriene A.sub.4 hydrolase inhibitor selected from
the group consisting of:
ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperid-
ine-carboxylate;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazoly-
lpiperidine;
1-[2-[4-(4-(2-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine;
3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoic
acid; methyl-3-[methyl
[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoate; 3-[methyl
[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoic acid;
methyl-3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoate;
3-[methyl [3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;
3-[methyl[3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propanoic
acid; and
3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propanoic
acid.
23. The combination of claim 22 wherein the cyclooxygenase-2
selective inhibitor is
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide.
Description
FIELD OF THE INVENTION
[0001] This invention is in the field of clinical immunology and
relates to compositions having immunosuppressive properties. Of
particular interest is a method of reducing recipient acute or
chronic rejection of transplanted cells or organs, and for
treatment of autoimmune diseases, hypersensitivity reactions of the
acute or delayed type, allergic disorders, granulomas, meningitis,
and septic shock by administering a cyclooxygenase-2 inhibitor and
a leukotriene A.sub.4 hydrolase (LTA.sub.4 hydrolase)
inhibitor.
BACKGROUND OF THE INVENTION
[0002] Successful organ transplantation requires effective
physiological and pharmacological intervention of the immune system
of an organ recipient. Immunologic mechanisms are universal within
the human species, but histocompatibility variations between organ
donor and recipient may lead to rejection of donor tissue by
stimulation of the recipient's immune system, except perhaps, in
donor-recipient pairing of the monozygotic type. One approach to
intervention of immune response in an organ transplant recipient,
especially a recipient targeted for an allogenic graft, is by the
use of immunosuppressive drugs. These drugs are used to prolong
survival of transplanted organs in recipients in cases involving,
for example, transplants of kidney, liver, heart, lung, bone marrow
and pancreas.
[0003] There are several types of immunosuppressive drugs available
for use in reducing organ rejection in transplantation. Such drugs
fall within three major classes, namely: antiproliferative agents,
antiinflammatory-acting compounds and inhibitors of lymphocyte
activation.
[0004] Examples of the class of cytotoxic or antiproliferative
agents are azathioprine, cyclophosphamide and methotrexate. The
compound azathioprine acts by interrupting DNA synthesis through
inhibition of purine metabolism. The compound cyclophosphamide is
an alkylating agent which interferes with enzyme actions and cell
proliferation and interrupts DNA synthesis by binding to cellular
DNA, RNA, and proteins. The compound methotrexate is a folic acid
antagonist which interferes with nucleotide and protein synthesis.
Drugs of the antiproliferative class may be effective
immunosuppressives in patients with chronic inflammatory disorders
and in organ transplant recipients by limiting cell proliferation.
These drugs which abrogate mitosis and cell division have severe
cytotoxic side effects on normal cell populations which have a high
turn-over rate, such as bone marrow cells and cells of the
gastrointestinal (GI) tract lining. Accordingly, such drugs often
have severe side effects, particularly, lymphopenia, neutropenia,
bone marrow depression, hemorrhagic cystitis, liver damage,
increased incidence of malignancy, hair loss, GI tract
disturbances, and infertility.
[0005] A second class of immunosuppressive drugs for use in
transplantation is provided by compounds having antiinflammatory
action. Representatives of this drug class are generally known as
adrenal corticosteroids and have the advantage of not exerting
globally systemic cytotoxic effects. These compounds usually act by
preventing or inhibiting inflammatory responses or by reducing
cytokine production, or by reducing chemotaxis, or by reducing
neutrophil, macrophage or lymphocyte activation, or effector
function. Typical examples of adrenal corticosteroids are
prednisone and prednisolone which affect carbohydrate and protein
metabolism as well as immune functions. Compounds of this class are
sometimes used in combination with cytotoxic agents, such as
compounds of the antiproliferative class because the
corticosteroids are significantly less toxic. But the adrenal
corticosteroids lack specificity of effect and can exert a broad
range of metabolic, antiinflammatory and immune effects. Typical
side effects of this class include increased organ-recipient
infections and interference with wound healing, as well as
disturbing hemodynamic balance, carbohydrate and bone metabolism
and mineral regulation.
[0006] A third class of immunosuppressive drugs for use in organ
transplantation is provided by compounds which are immunomodulatory
and generally prevent or inhibit leukocyte activation. Such
compounds usually act by blocking activated T-cell effector
functions or proliferation, or by inhibiting cytokine production,
or by preventing or inhibiting activation, differentiation or
effector functions of platelet, granulocyte, B-cell, or macrophage
actions. The cyclosporin family of compounds is the leading example
of drugs in this class. Such compounds are polypeptide fungal
metabolites which have been found to be very effective in
suppressing helper T-cells so as to reduce both cellular and
humoral responses to newly-encountered antigens. Cyclosporins alter
macrophage and lymphocyte activity by reducing cytokine production
or secretion and, in particular, by interfering with activation of
antigen-specific CD4 cells, by preventing IL-2 secretion and
secretion of many T-cell products, as well as by interfering with
expression of receptors for these lymphokines on various cell
types. Cyclosporin A, in particular, has been used extensively as
an immunosuppressive agent in organ transplantation. Other
microbial metabolites include cyclosporins such as cyclosporin B
and cyclosporin G, and another microbial product known as FK-506.
Cyclosporin A suppresses humoral immunity as well as cell-mediated
reactions. Cyclosporin A is indicated for organ rejection in
kidney, liver, heart, pancreas, bone-marrow and heart-lung
transplants. Cyclosporin A is also useful in the treatment of
autoimmune and inflammatory diseases, including rheumatoid
arthritis, Crohn's disease, Graves' disease, severe psoriasis,
aplastic anemia, multiple-sclerosis, alopecia greata, penphigus and
penphigoid, dermatomyositis, polymyositis, Behcet's disease,
uveitis, pulmonary sarcocidiosis, biliary cirrhosis, myasthenia
gravis and atopic dermatitis.
[0007] Cyclosporins possess several significant disadvantages.
While cyclosporins have provided significant benefits in organ
transplantation, cyclosporins are non-specific immunosuppressives.
Desirable immune reactions may be reduced against foreign antigens.
Tolerated dosages do not provide complete suppression of rejection
response. Thus, immunologic reactions to transplanted tissue are
not totally impeded, requiring concomitant treatment with
prednisone, methylprednisolone, and/or other immunosuppression
agents, including monoclonal antibodies such as anti-CD3 or
anti-CD5/CD7. Cyclosporins can produce severe side effects in many
organ recipients, and show host-variable effects on the liver,
kidney, the CNS and GI tract. Significant among the adverse side
effects are damage to the kidney and liver, hyperplasia of gum
tissue, refractory hypertension and increased incidence of
infections and malignancy.
[0008] Thus, the need remains for efficacious and selective
immunosuppressive drugs in organ transplantation, especially for
grafts between less-than-perfectly matched donor-recipient
pairs.
[0009] Prostaglandins and leukotrienes are lipid mediators produced
in a variety of inflammatory disease states. Both are products of
metabolism of arachidonic acid. Cyclooxygenases (COX-1 and COX-2)
are the enzymes that catalyze the conversion of arachidonic acid to
prostaglandins. 5-Lipoxygenase (5-LO) catalyzes the conversion of
arachidonic acid to leukotrienes. Products of both pathways have
been described in association with transplant rejection in humans
and animal models. Excess production of these mediators may play a
role in accelerating loss of the transplant function, particularly
in the kidney. However, little research has been directed at
determining direct effects of eicosanoids on tissue rejection.
[0010] Compounds which selectively inhibit cyclooxygenase-2 have
been described. U.S. Pat. No. 5,380,738 describes oxazoles which
selectively inhibit cyclooxygenase-2. U.S. Pat. No. 5,344,991
describes cyclopentenes which selectively inhibit cyclooxygenase-2.
U.S. Pat. No. 5,393,790 describes spiro compounds which selectively
inhibit cyclooxygenase-2. WO documents WO94/15932 describes
thiophene and furan derivatives which selectively inhibit
cyclooxygenase-2. WO94/27980 describes oxazoles which selectively
inhibit cyclooxygenase-2. WO95/00501 describes compounds which
selectively inhibit cyclooxygenase-2. WO94/13635 describes
compounds which selectively inhibit cyclooxygenase-2. WO094/20480
describes compounds which selectively inhibit cyclooxygenase-2.
WO94/26731 describes compounds which selectively inhibit
cyclooxygenase-2. WO documents WO95/15316 describes pyrazolyl
sulfonamide derivatives which selectively inhibit
cyclooxygenase-2.
[0011] Compounds which inhibit leukotriene A.sub.4 hydrolase have
been described in co-pending U.S. patent application Ser. No.
08/321,184.
[0012] Combined therapies of NSAIDs and other reagents are known in
the art. Combination analgesics have been reported (W. Beaver, Am.
J. Med., 77, 38 (1984)) although such combinations do not
substantially reduce adverse effects. The combination of NSAIDs and
steroids have been described. A combination of indomethacin,
steroid and lipopolysaccharide has been reported for the treatment
of spinal injury (L. Guth et al., Proc. Natl. Acad. Sci. USA., 91,
12308 (1994)). C. Hughes et al. describe combinations of
corticosteroids with NSAIDs for the treatment of sunburn
(Dermatology, 184, 54 (1992)). C. Stewart et al. (Clin. Pharmacol.
Ther., 47, 540 (1990)) describe the combination of naproxen and
methotrexate as safe, although concurrent administrations of
methotrexate with other NSAIDs have been reported to be toxic and
sometimes fatal. A combination of a dual
5-lipoxygenase/cyclooxygenase inhibitor with a glucocorticoid is
described for the treatment of skin disorders (K. Tramposch,
Inflammation, 17, 531 (1993)). Combinations of NSAIDs and steroids
should be used in the treatment of scleritis only if patients are
not responsive to any other treatment (S. Lightman and P. Watson,
Am. J. Ophthalmol., 108, 95 (1989)). Combinations of cyclooxygenase
inhibitors, lipoxygenase inhibitors, collagenase inhibitors and
cytotoxic agents have been used in the treatment of non-small-cell
lung cancers (B. Teicher et al., Cancer. Chemother. Pharmacol., 33,
515 (1994)). Combinations of naproxen with other NSAIDs have been
described in the treatment of arthritis. R. Willikens and E. Segre
(Arthritis Rheum., 19, 677 (1976)) describe the combination of
aspirin and naproxen as being more effective than aspirin alone for
the treatment of rheumatoid arthritis. Naproxen and acetaminophen
together were described for treating the pain associated with
arthritis (P. Seideman et al., Acta Orthop. Scand., 64, 285
(1993)). However, combinations of naproxen with indomethacin or
ibuprofen offer no advantage in the treatment of arthritis (M.
Seifert and C. Engler, Curr. Med. Res. Opin., 7, 38 (1980)).
[0013] Tenidap has been described as inhibiting cyclooxygenases and
cytokine-modifying [F. Breedveld, Scand. J. Rheumatol., 23 (Supp.
100), 31 (1994).sub.3. WO patent Publication 94/02448, published
Feb. 3, 1994, describes hydroxamic acid derivatives as dual
5-lipoxygenase and cyclooxygenase inhibitors having
immunosuppressant utility. U.S. Pat. No. 4,595,699, to Terada et
al., describes phenyl alkanoic acid derivatives as having
analgesic, antiinflammatory and immune regulating activity. R.
Bartlett et al. describe thiazolo(3,2-b)(1,2,4)triazin-7-ones as
antiinflammatory agents with immunomodulating properties [Drugs
Exptl. Clin. Res., 15, 521 (1989)]. J. Shaw and R. Greatorex [Adv.
Prostaglandin, Thromboxane, Leukotriene Res., 13, 219 (1985)]
describe that whereas aspirin and sodium salicylate prolong graft
survival, a cyclooxygenase inhibitor reduced the survival period.
V. Fimiani, et al. describe some NSAID's that may have activity in
the treatment of autoimmune diseases [EOS-Revista di Immunologia
and Immunofarmacologia, 13, 58 (1993)]. A. Badger et al. describe
an indomethacin enhancement of suppressor cell population
[Immunopharm., 4, 149 (1982)]. J. Shelby et al. [Transplantation
Proc., 19, 1435 (1987)] describe indomethacin as reversing
transfusion-induced graft prolongation. D. Latter et al. indicate
that indomethacin was effective as an immunomodulator following
burns [J. Surg. Res., 43, 246 (1987)]. J. Tarayre et al. describe
indomethacin as having an effect in their delayed hypersensitivity
models [Arzneim.-Forsch./Drug Res., 40, 1125 (1990)]. D. Braun et
al indicate that a prostaglandin synthetase inhibitor may help
prevent chemotherapy-induced decline in immune reactivity [Proc.
Am. Soc. Clin. Oncol., 4, 21 Meeting, 223 (1985)]. Administration
of tepoxalin (dual 5-LO and COX inhibitor) and cyclosporine has
been described [Fung-Leung, et al., Transplantation, 60, 362
(1995)] in suppression of graft versus host reaction although the
effect of tepoxalin did not appear to be related to the inhibition
of arachidonic acid metabolism.
[0014] There have been no reports of combinations of a
cyclooxygenase-2 selective inhibitor and a leukotriene A.sub.4
hydrolase inhibitor having a significant prolongation of graft
survival.
DESCRIPTION OF THE INVENTION
[0015] Reduction in recipient rejection of a transplanted organ, or
treatment of an autoimmune or inflammatory disease, or a
hypersensitivity reaction of the acute or delayed type, an allergic
reaction or asthmatic disorder, or treatment of dermatitis,
arthritis, meningitis, granulomas, vasculitis, septic shock or
graft vs. host response may be accomplished by a method to prevent
or suppress immune responses in a recipient or treatment subject,
which method comprises treating the subject with a
therapeutically-effective amount of an immunosuppressive
combination of a cyclooxygenase-2 inhibitor and a leukotriene
A.sub.4 hydrolase inhibitor.
[0016] In addition, the invention describes a combination
comprising a therapeutically-effective amount of a leukotriene
A.sub.4 hydrolase inhibitor and a cyclooxygenase-2 inhibitor
selected from Dupont Dup 697, Taisho NS-398, meloxicam, flosulide
and compounds of Formula I 1
[0017] wherein A is a 5- or 6-member ring substituent selected from
partially unsaturated or unsaturated heterocyclo and carbocyclic
rings;
[0018] wherein R.sup.1 is at least one substituent selected from
heterocyclo, cycloalkyl, cycloalxenyl and aryl, wherein R.sup.1 is
optionally substituted at a substitutable position with one or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo,
alkoxy and alkylthio;
[0019] wherein R.sup.2 is selected from alkyl, and amino; and
[0020] wherein R.sup.3 is a radical selected from halo, alkyl,
alkenyl, alkinyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclooxy,
alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl,
heterocyclo, cycloalkenyl, aralkyl, heterocycloalkyl, acyl,
alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl,
aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl,
aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl,
alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalky- l, aryloxy, aralkoxy, arylthio,
aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,
alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl,
N-alkyl-N-arylaminosulfonyl; or a pharmaceutically-acceptable salt
thereof.
[0021] The invention would be useful for, but not limited to, organ
transplantation procedures and a variety of disease states. For
example, combinations of the invention would be useful to treat a
recipient of a graft of a transplanted organ to reduce recipient
rejection of the graft or to reduce a donor leukocyte response
against the recipient's tissues. Such combinations would be useful,
in particular, for transplants of bone marrow, kidney, liver,
heart, heart-lung and pancreas organs. Combinations of the
invention would also be useful in suppressing immune response in a
human or animal subject susceptible to or afflicted with an
autoimmune disease or inflammatory disease. Examples of such
treatable disease are graft vs. host disease, systemic lupus
erythematosis, multiple sclerosis, myasthenia gravis, thyroiditis,
Graves' disease, autoimmune hemolytic anemia, aplastic anemia,
autoimmune thrombocytopenia purpura, mixed connective tissue
disease, idiopathic Addison's disease, Sjogren's syndrome, insulin
dependent diabetes mellitus, rheumatoid arthritis, osteoarthritis,
skin and muco-epithelial diseases such as psoriasis (in all its
forms) lichen, chronic eczema, and pityriasis, glomerulcnephritis,
inflammatory bowel disease, Crohn's disease, alopecia greata,
pemphigus and pemphigoid, dermatomyositis, polymyositis, Behcet's
disease, uveitis, pulmonary sarcocidiosis, biliary cirrhosis, and
atopic dermatitis. Combinations of the invention would also be
useful in suppressing immune response in a human or animal subject
susceptible to or afflicted with an allergy, such as an asthmatic
condition or reaction, urticaria or with airway hypersensitivity.
The invention would also be useful in suppressing immune response
in a human or animal subject afflicted with or susceptible to
septic shock. Combinations of the invention would also be useful in
preventing or suppressing acute or delayed-type hypersensitivity
responses or conditions resulting from or associated with
hypersensitivity responses such as contact dermatitis, hemolytic
anemias, antibody-induced thrombocytopenia, Goodpasture's syndrome,
hypersensitivity, pneumonitis, glomerulonephritis, granulomas,
thyroiditis, encephelomyelitis, and meningitis. The invention would
also be useful in the treatment of cancer, including leukemia,
lymphoma and solid tumors, including pancreatic, breast, colon,
lung, epithelial and melanoma tumors.
[0022] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of mammals, including
companion animals and farm animals, such as, but not limited to,
horses, dogs, cats, cows, sheep and pigs.
[0023] Compositions of the invention would be useful in treating
organs prior to transplant. For example, an organ removed from a
donor could be stored or transported in a bath containing an
immunosuppressive composition of the invent-on. The
immunosuppressive composition would act to inhibit donor leukocyte,
reactivity.
[0024] Compositions of the invention would also be useful in
adjunct therapy involving, typically, coadministration with an
additional immunosuppressive agent, such as a cyclosporin compound,
or Fujisawa FK-506 (macrolide lactone) compound, or rapamycin, or a
glucocorticoid, or an antiproliferative agent, or a monoclonal
antibody such as an anti-CD3 (anti-T cell receptor antibody) or
anti-CD5/CD7 or anti-CD4 agent, or an anti-IL-2 receptor
(anti-cytokine receptor antibody) agent or an anti-IL-2
(anti-cytokine antibody), or Nippon NKT-01 (15-deoxyspergualin) or
Syntex RS-61443.
[0025] The term "cyclooxygenase-2 inhibitor" embraces compounds
which selectively inhibit cy cyclooxygenase-2 over
cyclooxygenase-1. Preferably, the compounds have a cyclooxygenase-2
IC.sub.50 of less than about 0.5 .mu.M, and also have a selectivity
ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1
inhibition of at least 50, and more preferably of at least 100.
Even more preferably, the compounds have a cyclooxygenase-1
IC.sub.50 of greater than about 1 .mu.M, and more preferably of
greater than 20 .mu.M. Such preferred selectivity may indicate an
ability to reduce the incidence of common NSAID-induced side
effects.
[0026] The term "leukotriene A.sub.4 hydrolase inhibitor" embraces
compounds which selectively inhibit leukotriene A.sub.4 hydrolase
with an IC.sub.50 of less than about 10 .mu.M. More preferably, the
leukotriene A.sub.4 hydrolase inhibitors have an IC.sub.50 of less
than about 1 .mu.M.
[0027] The phrase "combination therapy" (or "co-therapy"), in
defining use of a cyclooxygenase-2 inhibitor agent and a
leukotriene A.sub.4 hydrolase inhibitor agent, is intended to
embrace administration of each agent in a sequential manner in a
regimen that will provide beneficial effects of the drug
combination. The phrase also is intended to embrace
co-administration of these agents in a substantially simultaneous
manner, such as in a single capsule having a fixed ratio of these
active agents or in multiple, separate capsules for each agent.
[0028] The phrase "therapeutically-effective" is intended to
qualify the amount of each agent for use in the combination therapy
which will achieve the goal of improvement in severity and the
frequency of incidence over treatment of each agent by itself,
while avoiding adverse side effects typically associated with
alternative therapies.
[0029] A preferred class of compounds which inhibit
cyclooxygenase-2 consists of compounds of Formula I wherein A is
selected from oxazolyl, isoxazolyl, thienyl, dihydrofuryl, furyl,
pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl,
cyclopentenyl, phenyl, and pyridyl; wherein R.sup.1 is selected
from 5- and 6-membered heterocyclo, lower cycloalkyl, lower
cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl,
wherein R.sup.1 is optionally substituted at a substitutable
position with one or more radicals selected from lower alkyl, lower
haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower
hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,
phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo,
lower alkoxy and lower alkylthio; wherein R.sup.2 is selected from
lower alkyl and amino; and wherein R.sup.3 is a radical selected
from halo, lower alkyl, oxo, cyano, carboxyl, lower cyanoalkyl,
heteroaryloxy, lower alkyloxy, lower cycloalkyl, phenyl, lower
haloalkyl, 5- or 6-membered heterocyclo, lower hydroxylalkyl, lower
aralkyl, acyl, phenylcarbonyl, lower alkoxyalkyl, heteroaryloxy,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino,
aminoalkyl, alkylaminoalkyl, aryloxy, and aralkoxy; or a
pharmaceutically-acceptable salt thereof.
[0030] A more preferred class of compounds which inhibit
cyclooxygenase-2 consists of compounds of Formula I wherein A is
selected from oxazolyl, isoxazolyl, dihydrofuryl, imidazolyl, and
pyrazolyl; wherein R.sup.1 is selected from 5- and 6-membered
heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected
from phenyl, biphenyl and naphthyl, wherein R.sup.1 is optionally
substituted at a substitutable position with one or more radicals
selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower
alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy,
amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl,
lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
wherein R.sup.2 is amino; and wherein R.sup.3 is a radical selected
from oxo, cyano, carboxyl, lower alkoxycarbonyl, lower
carboxyalkyl, lower cyanoalkyl, halo, lower alkyl, lower alkyloxy,
lower cycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered
heterocyclo, lower hydroxylalkyl, lower aralkyl, acyl,
phenylcarbonyl, lower alkoxyalkyl, 5- or 6-membered heteroaryloxy,
aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, lower
aminoalkyl, lower alkylaminoalkyl, phenyloxy, and lower aralkoxy;
or a pharmaceutically-acceptable salt thereof.
[0031] An even more preferred class of compounds which inhibit
cyclooxygenase-2 consists of compounds of Formula I wherein A is
selected from oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl;
wherein R.sup.1 is phenyl optionally substituted at a substitutable
position with one or more radicals selected from methyl, ethyl,
isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl,
dichloroethyl, dichloropropyl, cyano, carboxyl, methoxycarbonyl,
hydroxyl, hydroxmethyl, trifluoromethoxy, amino, N-methylamino,
N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino,
N-methyl-N-ethylamino, phenylamino, nitro, methoxymethyl,
methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy,
n-butoxy, pentoxy, and methylthio; wherein R.sup.2 is amino; and
wherein R.sup.3 is a radical selected from oxo, cyano, carboxyl,
methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl,
carboxyethyl, cyanomethyl, fluoro, chloro, bromo, methyl, ethyl,
isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl,
dichloroethyl, dichloropropyl, methoxy, ethoxy, propoxy, n-butoxy,
pentoxy, cyclohexyl, phenyl, pyridyl, thienyl, thiazolyl, oxazolyl,
furyl, pyrazinyl, hydroxylmethyl, hydroxylpropyl, benzyl, formyl,
phenylcarbonyl, methoxymethyl, furylmethyloxy, aminocarbonyl,
N-methylaminocarbonyl, N,N-dimethylaminocarbonyl,
N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, 1-butylamino,
N-methyl-N-ethylamino, aminomethyl, N,N-dimethylaminomethyl,
N-methyl-N-ethylaminomethyl, benzyloxy, and phenyloxy; or a
pharmaceutically-acceptable salt thereof.
[0032] A family of specific compounds of particular interest within
Formula I consists of compounds and pharmaceutically-acceptable
salts thereof as follows:
[0033]
3-(3,4-difluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone;
[0034] 3-phenyl-4-4-methylsulfonylphenyl)-2-(5H)-furanone;
[0035]
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0036]
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0037]
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl
benzenesulfonamide;
[0038]
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]-
pyridine;
[0039]
2-methyl-5-(1-[4-(methylsulfonyl)phenyl)-4-trifluoromethyl-1H-imida-
zol-2-yl]pyridine;
[0040]
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0041] 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
[0042]
4-[5-hydroxyethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
[0043]
[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfona-
mide;
[0044] 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; and
[0045]
4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzen-
esulfonamide.
[0046] Preferred leukotriene Ad hydrolase inhibitors include
Rhone-Poulenc Rorer RP-64966 and compounds of Formula II
Ar.sup.1-Q-Ar.sup.2--Y--R-Z (II)
[0047] or a pharmaceutically-acceptable salt thereof, and a
pharmaceutically-acceptable carrier,
[0048] wherein Ar.sup.1 is an aryl moiety selected from:
[0049] (i) phenyl, mono-, di-, or tri-substituted phenyl with the
substituents selected from Cl, Br, F, CF.sub.3, lower alkyl, lower
alkoxy, NH.sub.2. NO.sub.2 and OH;
[0050] (ii) 2-, 4- or 5-thiazolyl,
[0051] (iii) 2-, 3- or 4-pyridinyl,
[0052] (iv) 2- or 3-thienyl, and
[0053] (v) 2- or 3-furyl;
[0054] wherein Ar.sup.2 is an aryl moiety selected from: 2
[0055] wherein Q is selected from:
[0056] (i) --O--,
[0057] (ii) --CH.sub.2,
[0058] (iii)--OCH.sub.2--,
[0059] (iv) --CH.sub.2--,
[0060] (v) --NH--;
[0061] (vi) --NHCH.sub.2--,
[0062] (vii) --CH.sub.2 NH--,
[0063] (viii)--CF.sub.2--,
[0064] (ix) --CH.dbd.CH--,
[0065] (x) --CH.sub.2CH.sub.2--, and
[0066] (xi) carbon-carbon single bond;
[0067] wherein Y is selected from:
[0068] (i) --O--,
[0069] (ii) --S--,
[0070] (iii) --NH--,
[0071] (iv) --S(O)--, and
[0072] (v) --S(O.sub.2)--;
[0073] wherein R is selected from:
[0074] (i) linear or branched C.sub.2-C.sub.6 alkylenyl; and
[0075] (ii) --C(R.sup.13) (R.sup.14)--(CH.sub.2).sub.m--;
[0076] wherein Z is selected from: 3
[0077] (viii) a monocyclic or bicyclic heteroaromatic moiety having
at least one heteroatom, wherein the heteroatom is nitrogen, and
wherein the monocyclic heteroaromatic moiety comprises a 5- or
6-membered ring and the bicyclic heteroaromatic moiety comprises a
fused 9- or 10-membered ring;
[0078] wherein R.sup.4 and R.sup.5 are independently selected from:
4
[0079] wherein R.sup.6 and R.sup.7 are independently H or lower
alkyl;
[0080] wherein R.sup.8 and R.sup.9 are independently selected from
5
[0081] wherein R.sup.10 is H, halogen, lower alkyl, lower alkoxy,
nitro, or hydroxy, or R taken together with R.sup.13 is an
alkylenyl group having one or two carbon atoms;
[0082] wherein R.sup.11 and P.sup.12 are independently H, halogen,
lower alkyl, lower alkoxy, NH.sub.2, NO.sub.2 or OH;
[0083] wherein R.sup.13 is H, or lower alkyl, or R.sup.13 taken
together with R.sup.10 is an alkylenyl group having one or two
carbon atoms;
[0084] wherein R.sup.14 is H or lower alkyl;
[0085] wherein R.sup.15 is selected from
[0086] (i) H,
[0087] (ii) --OH or .dbd.O,
[0088] (iii) (CH.sub.2).sub.aCOR.sup.18
[0089] (iv) (CH.sub.2).sub.aCONH(CH.sub.2).sub.bCO.sub.2R.sup.19,
and
[0090] (v) --NHR.sup.20;
[0091] wherein R.sup.16 and R.sup.17 are independently hydrogen, or
--(CH.sub.2).sub.aCOR.sup.18, provided that at least one of
R.sup.16 and R.sup.17 is hydrogen;
[0092] wherein R.sup.18 is --OR.sup.19 NHR.sup.19 or
--NHNH.sub.2;
[0093] wherein R.sup.19 is H, lower alkyl or benzyl;
[0094] wherein R.sup.20 is H, lower alkyl, benzyl, --COR.sup.19 or
--CONH.sub.2;
[0095] wherein X.sup.1 is 6
[0096] --S--, or --O--, wherein R.sup.21 is H, lower alkyl,
--CONH.sub.2, --CSNH.sub.2, --COCH.sub.3 or --SO.sub.2CH.sub.3;
[0097] wherein a and b are independently integers of from 0 to
5;
[0098] wherein m is 1, 2 or 3;
[0099] wherein n is 0, 1, 2 or 3;
[0100] wherein p is 1 or 2; and
[0101] wherein q is 1, 2 or 3;
[0102] provided however that where R is
--C(R.sup.13)(R.sup.14)--CH.sub.2)- .sub.m, and R.sup.13 taken
together with R.sup.10 forms an alkylenyl group having one or two
carbon atoms, then --Ar.sup.2--Y--R-- is 7
[0103] wherein X is --CH-- or --N--; and wherein r is 1 or 2;
further
[0104] provided that wherein Z is 8
[0105] and either R.sup.4 or R.sup.5, or both R.sup.4 and R.sup.5
are --(CH.sub.2).sub.aCOR.sup.18, then a is not 0.
[0106] More preferred leukotriene A.sub.4 hydrolase inhibitors
include compounds of Formula II wherein Ar.sup.1-Q-Ar.sup.2--Y-- is
9
[0107] wherein Q is --O--, --CH.sub.2--, --CF.sub.2-- or
--CH.sub.2O--; and R.sup.11 and R.sup.22 are independently H, lower
alkyl, lower alkoxy, halogen, NH.sub.2 or NO.sub.2.
[0108] Other more preferred 5-lipoxygenase inhibitors include
leukotriene A.sub.4 hydrolase inhibitors include compounds of
Formula II wherein Ar.sup.1-Q-Ar.sup.2--Y-- is 10
[0109] wherein X.sup.2 is --S--, or --CH.dbd.N--; and Wherein Q is
--CH.sub.2--, --CF.sub.2--, --O-- or --CH.sub.2O--.
[0110] A family of specific compounds of particular interest within
Formula II consists of compounds and pharmaceutically-acceptable
salts thereof in Table A:
1TABLE A 11 12 13 14 15 16 17 18 19 20 21
[0111] The term "hydrido" denotes a single hydrogen atom (H). This
hydrido radical may be attached, for example, to an oxygen atom to
form a hydroxyl radical or two hydrido radicals may be attached to
a carbon atom to form a methylene (--CH.sub.2--) radical. Where
used, either alone or within other terms such as "haloalkyl",
"alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", the term "alkyl"
embraces linear or branched radicals having one to about twenty
carbon atoms or, preferably, one to about twelve carbon atoms. More
preferred alkyl radicals are "lower alkyl" radicals having one to
about ten carbon atoms. Most preferred are lower alkyl radicals
having one to about six carbon atoms. Examples of such radicals
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The
term "alkenyl" embraces linear or branched radicals having at least
one carbon-carbon double bond of two to about twenty carbon atoms
or, preferably, two to about twelve carbon atoms. More preferred
alkenyl radicals are "lower alkenyl" radicals having two to about
six carbon atoms. Examples of alkenyl radicals include ethenyl,
propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term
"alkynyl" denotes linear or branched radicals having at least one
carbon-carbon triple bond, and having two to about twenty carbon
atoms or, preferably, two to about twelve carbon atoms. More
preferred alkynyl radicals are "lower alkynyl" radicals having two
to about ten carbon atoms. Most preferred are lower alkynyl
radicals having two to about six carbon atoms. Examples of such
radicals include propargyl, butynyl, and the like. The terms
"alkenyl" and "lower alkenyl", embrace radicals having "cis" and
"trans" orientations, or alternatively, "E" and "Z" orientations.
The term "cycloalkyl" embraces saturated carbocyclic radicals
having three to about twelve carbon atoms. More preferred
cycloalkyl radicals are "lower cycloalkyl" radicals having three to
about eight carbon atoms. Examples of such radicals include
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term
"cycloalkenyl" embraces partially unsaturated carbocyclic radicals
having three to twelve carbon atoms. More preferred cycloalkenyl
radicals are "lower cycloalkenyl" radicals having four to about
eight carbon atoms. Examples of such radicals include cyclobutenyl,
cyclopentenyl and cyclohexenyl. The term "halo" means halogens such
as fluorine, chlorine, bromine or iodine. The term "haloalkyl"
embraces radicals wherein any one or more of the alkyl carbon atoms
is substituted with halo as defined above. Specifically embraced
are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A
monohaloalkyl radical, for one example, may have either an iodo,
bromo, chloro or fluoro atom within the radical. Dihalo and
polyhaloalkyl radicals may have two or more of the same halo atoms
or a combination of different halo radicals. "Lower haloalkyl"
embraces radicals having one to six carbon atoms. Examples of
haloalkyl radicals include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl and dichloropropyl. The term
"hydroxyalkyl" embraces linear or branched alkyl radicals having
one to about ten carbon atoms any one of which may be substituted
with one or more hydroxyl radicals. More preferred hydroxyalkyl
radicals are "lower hydroxyalkyl" radicals having one to six carbon
atoms and one or more hydroxyl radicals. Examples of such radicals
include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl
and hydroxyhexyl. The terms "alkoxy" and "alkyloxy" embrace linear
or branched oxy-containing radicals each having alkyl portions of
one to about ten carbon atoms. More preferred alkoxy radicals are
"lower alkoxy" radicals having one to six carbon atoms. Examples of
such radicals include methoxy, ethoxy, propoxy, butoxy and
tert-butoxy. The term "alkoxyalkyl" embraces alkyl radicals having
one or more alkoxy radicals attached to the alkyl radical, that is,
to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy"
radicals may be further substituted with one or more halo atoms,
such as fluoro, chloro or bromo, to provide haloalkoxy radicals.
More preferred haloalkoxy radicals are "lower haloalkoxy" radicals
having one to six carbon atoms and one or more halo radicals.
Examples of such radicals include fluoromethoxy, chloromethoxy,
trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
The term "aryl", alone or in combination, means a carbocyclic
aromatic system containing one, two or three rings wherein such
rings may be attached together in a pendent manner or may be fused.
The term "aryl" embraces aromatic radicals such as phenyl,
naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties
may also be substituted at a substitutable position with one or
more substituents selected independently from alkyl, alkoxyalkyl,
alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro,
alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and
aralkoxycarbonyl. The term "heterocyclo" embraces saturated,
partially unsaturated and unsaturated heteroatom-containing
ring-shaped radicals, where the heteroatoms may be selected from
nitrogen, sulfur and oxygen. Examples of saturated heterocyclo
radicals include saturated 3 to 6-membered heteromonocylic group
containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl,
imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to
6-membered heteromonocyclic group containing 1 to 2 oxygen atoms
and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to
6-membered heteromonocyclic group containing 1 to 2 sulfur atoms
and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of
partially unsaturated heterocyclo radicals include
dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
The term "heteroaryl" embraces unsaturated heterocyclo radicals.
Examples of heteroaryl radicals include unsaturated 3 to 6 membered
heteromonocyclic group containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.)
tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
unsaturated condensed heterocyclo group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoquinolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.),
etc.; unsaturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to
6-membered heteromonocyclic group containing a sulfur atom, for
example, thienyl, etc.; unsaturated 3- to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
etc.) etc.; unsaturated condensed heterocyclo group containing 1 to
2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl,
benzoxadiazolyl, etc.); unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.)
etc.; unsaturated condensed heterocyclo group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl,
benzothiadiazolyl, etc.) and the like. The term "heteroaryl" also
embraces radicals where heterocyclo radicals are fused with aryl
radicals. Examples of such fused bicyclic radicals include
benzofuran, benzothiophene, and the like. Said "heterocyclo group"
may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy,
oxo, amino and alkylamino. The term "alkylthio" embraces radicals
containing a linear or branched alkyl radical, of one to about ten
carbon atoms attached to a divalent sulfur atom. More preferred
alkylthio radicals are "lower alkylthio" radicals having alkyl
radicals of one to six carbon atoms. Examples of such lower
alkylthio radicals are methylthio, ethylthio, propylthio, butylthio
and hexylthio. The term "alkylthioalklyl" embraces radicals
containing an alkylthio radical attached through the divalent
sulfur atom to an alkyl radical of one to about ten carbon atoms.
More preferred alkylthioalkyl radicals are "lower alkylthioalkyl"
radicals having alkyl radicals of one to six carbon atoms. Examples
of such lower alkylthioalkyl radicals include methylthiomethyl. The
term "alkylsulfinyl" embraces radicals containing a linear or
branched alkyl radical, of one to about ten carbon atoms, attached
to a divalent --S(.dbd.O)-- radical. More preferred alkylsulfinyl
radicals are "lower alkylsulfinyl" radicals having alkyl radicals
of one to six carbon atoms. Examples of such lower alkylsulfinyl
radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and
hexylsulfinyl. The term "sulfonyl", whether used alone or linked to
other terms such as "alkylsulfonyl", denotes a divalent radical,
--SO.sub.2--. "Alkylsulfonyl" embraces alkyl radicals attached to a
sulfonyl radical, where alkyl is defined as above. More preferred
alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having
one to six carbon atoms. Examples of such lower alkylsulfonyl
radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The "alkylsulfonyl" radicals may be further substituted with one or
more halo atoms, such as fluoro, chloro or bromo, to provide
haloalkylsulfonyl radicals. The terms "sulfamyl", "aminosulfonyl"
and "sulfonamidyl" denote NH.sub.2O.sub.2S--. The term "acyl"
denotes a radical provided by the residue after removal of hydroxyl
from an organic acid. Examples of such acyl radicals include
alkanoyl and aroyl radicals. Examples of such lower alkanoyl
radicals include formyl, acetyl, propionyl, butyryl, isobutyryl,
valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl. The term
"carbonyl", whether used alone or with other terms, such as
"alkoxycarbonyl", denotes --(C.dbd.O)--. The term "aroyl" embraces
aryl radicals with a carbonyl radical as defined above. Examples of
aroyl include benzoyl, naphthoyl, and the like and the aryl in said
aroyl may be additionally substituted. The terms "carboxy", or
"carboxyl", Whether used alone or with other terms, such as
"carboxyalkyl", denotes --CO.sub.2H. The term "carboxyalkyl"
embraces alkyl radicals substituted with a carboxy radical. More
preferred are "lower carboxyalkyl/" which embrace lower alkyl
radicals as defined above, and may be additionally substituted on
the alkyl radical with halo. Examples of such lower carboxyalkyl
radicals include carboxymethyl, carboxyethyl and carboxypropyl. The
term "alkoxycarbonyl" means a radical containing an alkoxy radical,
as defined above, attached via an oxygen atom to a carbonyl
radical. More preferred are "lower alkoxycarbonyl" radicals with
alkyl portions having one to six carbons. Examples of such lower
alkoxycarbonyl (ester) radicals include substituted or
unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl and hexyloxycarbonyl. The terms "alkylcarbonyl",
"arylcarbonyl" and "aralkylcarbonyl" include radicals having alkyl,
aryl and aralkyl radicals, as defined herein, attached to a
carbonyl radical. Examples of such radicals include substituted or
unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and
benzylcarbonyl. The term "aralkyl" embraces aryl-substituted alkyl
radicals such as benzyl, diphenylmethyl, triphenylmethyl,
phenylethyl, and diphenylethyl. The aryl in said aralkyl may be
additionally substituted with halo, alkyl, alkoxy, halkoalkyl and
haloalkoxy. The terms benzyl and phenylmethyl are interchangeable.
The term "heterocycloalkyl" embraces saturated and partially
unsaturated heterocyclo-substituted alkyl radicals, such as
pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals, such
as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and
quinolylethyl. The heteroaryl in said heteroaralkyl may be
additionally substituted with halo, alkyl, alkoxy, halkoalkyl and
haloalkoxy. The term "aralkoxy" embraces aralkyl radicals attached
through an oxygen atom to other radicals. The term "aralkoxyalkyl"
embraces aralkoxy radicals attached through an oxygen atom to an
alkyl radical. The term "aralkylthio" embraces aralkyl radicals
attached to a sulfur atom. The term "aralkylthioalkyl", embraces
aralkylthio radicals attached through a sulfur atom to an alkyl
radical. The term "aminoalkyl" embraces alkyl radicals substituted
with amino radicals. More preferred are "lower aminoalkyl"
radicals. Examples of such radicals include aminomethyl,
aminoethyl, and the like. The term "alkylamino" denotes amino
groups which are substituted with one or two alkyl radicals.
Preferred are "lower alkylamino" radicals having alkyl portions
having one to six carbon atoms. Suitable lower alkylamino may be
monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such
as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino
or the like. The term "arylamino" denotes amino groups which are
substituted with one or two aryl radicals, such as N-phenylamino.
The "arylamino" radicals may be further substituted on the aryl
ring portion of the radical. The term "aralkylamino" embraces amino
groups which are substituted with one or two aralkyl radicals. The
terms "N-arylaminoalkyl" and "N-aryl-N-alkyl-aminoalkyl" denote
aminoalkyl groups which are substituted with one aryl radical or
one aryl and one alkyl radical, respectively. Examples of such
radicals include N-phenylaminomethyl and
N-phenyl-N-methylaminomethyl. The term "aminocarbonyl" denotes an
amide group of the formula --C(.dbd.O)NH.sub.2. The term
"alkylaminocarbonyl" denotes an aminocarbonyl group which has been
substituted with one or two alkyl radicals on the amino nitrogen
atom. Preferred are "N-alkylaminocarbonyl" and
"N,N-dialkylaminocarbonyl", radicals. More preferred are "lower
N-alkylaminocarbonyl" and "lower N,N-dialkylaminocarbonyl" radicals
with lower alkyl portions as defined above. The term
"alkylaminoalkyl" embraces radicals having one or more alkyl
radicals attached to an aminoalkyl radical. The term "aryloxyalkyl"
embraces radicals having an aryl radicals attached to an alkyl
radical through a divalent oxygen atom. The term "arylthioalkyl"
embraces radicals having an aryl radicals attached to an alkyl
radical through a divalent sulfur atom.
[0112] The present invention comprises a pharmaceutical composition
comprising a therapeutically-effective amount of a leukotriene
A.sub.4 hydrolase inhibitor and a cyclooxygenase-2 inhibitor
compound in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent.
[0113] The present invention also comprises a method of treating
immune-associated disorders in a subject, the method comprising
treating the subject having or susceptible to such disorder with a
leukotriene A.sub.4 hydrolase inhibitor and a cyclooxygenase-2
inhibitor compound. The method of the present invention also
includes prophylactic treatment.
[0114] Also included in the family of compounds of Formula I are
the pharmaceutically-acceptable salts thereof. The term
"pharmaceutically-acceptable salts" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases. The nature of the salt is not critical, provided that
it is pharmaceutically-acceptable. Suitable
pharmaceutically-acceptable acid addition salts of compounds of
Formula I may be prepared from an inorganic acid or from an organic
acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclo, carboxylic and
sulfonic classes of organic acids, example of which are formic,
acetic, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,
p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic,
cyclohexylaminosulfonic, algenic, .beta.-hydroxybutyric, salicylic,
galactaric and galacturonic acid. Suitable
pharmaceutically-acceptable base addition salts of compounds of
Formula I include metallic salts made from aluminum, calcium,
lithium, magnesium, potassium, sodium and zinc or organic salts
made from N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. All of these salts may be prepared by conventional means
from the corresponding compound of Formula I by reacting, for
example, the appropriate acid or base with the compound of Formula
I.
General Synthetic Procedures
[0115] The cyclooxygenase-2 inhibitor compounds of the invention
can be synthesized according to the following procedures of Schemes
I-XII, wherein the R.sup.1-R.sup.5 substituents are as defined for
Formulas I-II, above, except where further noted. 22
[0116] Synthetic Scheme I shows the preparation of cyclooxygenase-2
inhibitor compounds, as described in U.S. patent application Ser.
No. 08/223,629, which is incorporated by reference, embraced by
Formula I. In step 1, ketone 1 is treated with a base, preferably
NaOMe or NaH, and an ester, or ester equivalent, to form the
intermediate diketone 2 (in the enol form) which is used without
further purification. In step 2, diketone 2 in an anhydrous protic
solvent, such as absolute ethanol or acetic acid, is treated with
the hydrochloride salt or the free base of a substituted hydrazine
at reflux to afford a mixture of pyrazoles 3 and 4.
Recrystallization or chromatography affords 3 usually as a solid.
Similar pyrazoles can be prepared by methods described in U.S. Pat.
Nos. 4,146,721, 5,051,518, 5,134,142 and 4,914,121 which also are
incorporated by reference. 23
[0117] Scheme II shows the four step procedure for forming
cyclooxygenase-2 inhibitor pyrazoles 8 as described in U.S. patent
application Ser. No. 08/278,297 (where R.sup.a is hydrido or alkyl)
from ketones 5. In step 1, ketone 5 is reacted with a base, such as
lithium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA)
to form the anion. In step 2, the anion is reacted with an
acetylating reagent to provide diketone 6. In step 3, the reaction
of diketone 6 with hydrazine or a substituted hydrazine, gives
pyrazole 7. In step 4, the pyrazole 7 is oxidized with an oxidizing
reagent, such as Oxone.RTM. (potassium peroxymonosulfate),
3-chloroperbenzoic acid (MCPBA) or hydrogen peroxide, to give a
mixture of the desired 3-(alkylsulfonyl)phenyl-pyrazole 8 and the
5-(alkylsulfonyl)phenyl-pyrazole isomer. The desired pyrazole 8,
usually a white or pale yellow solid, is obtained in pure form
either by chromatography or recrystallization.
[0118] Alternatively, diketone 6 can be formed from ketone 5 by
treatment with a base, such as sodium hydride, in a solvent, such
as dimethylformamide, and further reacting with a nitrite to form
an aminoketone. Treatment of the aminoketone with acid forms the
diketone 6. Similar pyrazoles can be prepared by methods described
in U.S. Pat. No. 3,984,431 which is incorporated by reference.
24
[0119] Cyclooxygenase-2 inhibitor diaryl/heteroaryl thiophenes
(where T is S. and Rb is alkyl) can be prepared by the methods
described in U.S. Pat. Nos. 4,427,693, 4,302,461, 4,381,311,
4,590,205, and 4,820,827, and PCT documents WO 95/00501 and
WO94/15932, which are incorporated by reference. Similar pyrroles
(where T is N), furanones and furans (where T is C) can be prepared
by methods described in PCT documents WO 95/00501 and 094/15932.
25
[0120] Cyclooxygenase-2 inhibitor diaryl/heteroaryl oxazoles can be
prepared by the methods described in U.S. Pat. Nos. 3,743,656,
3,644,499 and 3,647,858, and PCT documents WO 95/00501 and
WO94/27980, which are incorporated by reference. 26
[0121] Cyclooxygenase-2 inhibitor diaryl/heteroaryl isoxazoles can
be prepared by the methods described in U.S. application Ser. No.
08/387,680, PCT documents WO92/05162, and WO92/19604, and European
Publication EP 26928 which are incorporated by reference.
Sulfonamides 24 can be formed from the hydrated isoxazole 23 in a
two step procedure. First, hydrated isoxazole 23 is treated at
about 0.degree. C. with two or three equivalents of chlorosulfonic
acid to form the corresponding sulfonyl chloride. In step two, the
sulfonyl chloride thus formed is treated with concentrated ammonia
to provide the sulfonamide derivative 24. 27
[0122] Scheme VI shows the three step preparation of the
cyclooxygenase-2 inhibitor imidazoles 29 of the present invention.
In step 1, the reaction of substituted nitrites (R.sup.1CN) 25 with
primary phenylamines 26 in the presence of alkylaluminum reagents
such as trimethylaluminum, triethylaluminum, dimethylaluminum
chloride, diethylaluminum chloride in the presence of inert
solvents such as toluene, benzene, and xylene, gives amidines 27.
In step 2, the reaction of amidine 27 with 2-haloketones (where X
is Br or Cl) in the presence of bases, such as sodium bicarbonate,
potassium carbonate, sodium carbonate, potassium bicarbonate or
hindered tertiary amines such as N,N'-diisopropylethylamin- e,
gives the 4,5-dihydroimidazoles 28 (where R.sup.b is alkyl). Some
of the suitable solvents for this reaction are isopropanol, acetone
and dimethylformamide. The reaction may be carried out at
temperatures of about 20.degree. C. to about 90.degree. C. In step
3, the 4,5-dihydroimidazoles 28 may be dehydrated in the presence
of an acid catalyst such as 4-toluenesulfonic acid or mineral acids
to form the 1,2-disubstituted imidazoles 29 of the invention.
Suitable solvents for this dehydration step are e.g., toluene,
xylene and benzene. Trifluoroacetic acid can be used as solvent and
catalyst for this dehydration step.
[0123] In some cases (e.g., where R.sup.3=methyl or phenyl) the
intermediate 28 may not be readily isolable. The reaction, under
the conditions described above, proceeds to give the targeted
imidazoles directly.
[0124] Similarly, imidazoles can be prepared having the
sulfonylphenyl moiety attached at position 2 and R.sup.1 attached
at the nitrogen atom at position 1. Diaryl/heteroaryl imidazoles
can be prepared by the methods described in U.S. Pat. No.
4,822,805, U.S. application Ser. No. 08/282,395 and PCT document WO
93/14082, which are incorporated by reference. 28
[0125] The subject imidazole cyclooxygenase-2 inhibitor compounds
36 of this invention may be synthesized according to the sequence
outlined in Scheme VII. Aldehyde 30 may be converted to the
protected cyanohydrin 31 by reaction with a trialkylsilyl cyanide,
such as trimethylsilyl cyanide (TMSCN) in the presence of a
catalyst such as zinc iodide (ZnI.sub.2) or potassium cyanide
(KCN). Reaction of cyanohydrin 31 with a strong base followed by
treatment with benzaldehyde 32 (where R.sup.2 is alkyl) and using
both acid and base treatments, in that order, on workup gives
benzoin 33. Examples of strong bases suitable for this reaction are
lithium diisopropylamide (LDA) and lithium hexamethyldisilazane.
Benzoin 33 may be converted to benzil 34 by reaction with a
suitable oxidizing agent, such as bismuth oxide or manganese
dioxide, or by a Swern oxidation using dimethyl sulfoxide (DMSO)
and trifluoroacetic anhydride. Benzil 34 may be obtained directly
by reaction of the anion of cyanohydrin 31 with a substituted
benzoic acid halide. Any of compounds 33 and 34 may be used as
intermediates for conversion to imidazoles 35 (where R.sup.2 is
alkyl) according to chemical procedures known by those skilled in
the art and described by M. R. Grimmett, "Advances in Imidazole
Chemistry" in Advances in Heterocyclic Chemistry, 12, 104 (1970).
The conversion of 34 to imidazoles 35 is carried out by reaction
with ammonium acetate and an appropriate aldehyde (R.sup.3CHO) in
acetic acid. Benzoin 36 may be converted to imidazoles 38 by
reaction with formamide. In addition, benzoin 36 may be converted
to imidazoles by first acylating with an appropriate acyl group
(R.sup.3CO--) and then treating with ammonium hydroxide. Those
skilled in the art will recognize that the oxidation of the sulfide
(where R.sup.2 is methyl) to the sulfone may be carried out at any
point along the way beginning with compounds 35, and including
oxidation of imidazoles 38, using, for examples, reagents such as
hydrogen peroxide in acetic acid, m-chloroperoxybenzoic acid
(MCPBA) and potassium peroxymonosulfate (OXONE.RTM.).
[0126] Diaryl/heteroaryl imidazoles can be prepared by the methods
described in U.S. Pat. Nos. 3,707,475, 4,686,231, 4,503,065,
4,472,422, 4,372,964, 4,576,958, 3,901,908, U.S. application Ser.
No. 08/281,903 European publication EP 372,445, and PCT document WO
95/00501, which are incorporated by reference. 29
[0127] Diaryl/heteroaryl cyclopentene cyclooxygenase-2 inhibitors
can be prepared by the methods described in U.S. Pat. No.
5,344,991, and PCT document WO 95/00501, which are incorporated by
reference. 30
[0128] Similarly, Synthetic Scheme 1.times.shows the procedure for
the preparation of 1,2-diarylbenzene cyclooxygenase-2 inhibitor
agents 44 from 2-bromo-biphenyl intermediates 43 (prepared similar
to that described in Synthetic Scheme VIII) and the appropriate
substituted phenylboronic acids. Using a coupling procedure similar
to the one developed by Suzuki et al. (Synth. Commun., 11, 513
(1981)], intermediates 43 are reacted with the boronic acids in
toluene/ethanol at reflux in the presence of a Pd.degree. catalyst,
e.g., tetrakis(triphenylphosphine)palladium(0), and 2M sodium
carbonate to give the corresponding 1,2-diarylbenzene
antiinflammatory agents 44 of this invention. Such terphenyl
compounds can be prepared by the methods described in U.S.
application Ser. No. 08/346,433, which is incorporated by
reference. 31
[0129] Diaryl/heteroaryl thiazole cyclooxygenase-2 inhibitors can
be prepared by the methods described in U.S. Pat. Nos. 4,051,250,
4,632,930, U.S. application Ser. No. 08/281,288, European
Application EP 592,664, and PCT document WO 95/00501, which are
incorporated by reference. Isothiazoles can be prepared as
described in PCT document WO 95/00501.
[0130] Diaryl/heteroaryl pyridine cyclooxygenase-2 inhibitors can
be prepared by the methods described in U.S. Pat. Nos. 5,169,857,
4,011,328, 4,533,666, U.S. application Ser. No. 08/386,843 and U.S.
application Ser. No. 08/387,150 which are incorporated by
reference. 32
[0131] Scheme XI shows a general method for the preparation of
phenols of the formula Ar.sup.1--O--Ar.sup.2--OH wherein Ar.sup.1
is a substituted phenol. Ar.sup.1 may be any substituted arylphenol
which is capable of reacting with 4-iodoanisole in an Ullman
coupling reaction. See, A. Moroz, et al., Russ. Chef. Rev. 43, 679
(1974). The Ullman reaction is carried out conventionally in the
presence of activated copper or copper iodide at a temperature of
about 150.degree. C. to 200.degree. C. A particularly preferred
substituted phenol for providing compounds of the present invention
having a substituted Ar.sup.1 moiety is 4-fluorophenol. 33
[0132] Scheme XII describes yet another method for preparation of
compounds of Formula II in which compound 48 is alkylated with a
bromodimethyl acetal 52 in DMF in the presence of NaH to afford
acetal 49. Subsequent deprotection with toluene-4-sulfonic acid in
THF/H.sub.2O affords intermediate aldehyde 50 which is reductively
aminated (EtOH, KOH, NaBH.sub.3CN) with an amine of the formula
H.sup.4R.sup.5 to afford compound 51 which is a compound of Formula
II.
[0133] The leukotriene A.sub.4 hydrolase inhibitor compounds of
Formula II can be synthesized according to the other methods
described in U.S. patent application Ser. No. 08/321,184 which is
incorporated by reference.
[0134] The following examples contain detailed descriptions of the
methods of preparation of combinations with compounds of Formula I.
These detailed descriptions fall within the scope, and serve to
exemplify, the above described General Synthetic Procedures which
form part of the invention. These detailed descriptions are
presented for illustrative purposes only and are not intended as a
restriction on the scope of the invention. All parts are by weight
and temperatures are in Degrees centigrade unless otherwise
indicated. All compounds showed NMR spectra consistent with their
assigned structures.
EXAMPLE 1
4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami-
de
[0135] Step 1: Preparation of
4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-- 1,3-dione
[0136] Ethyl trifluoroacetate (23.52 g, 166 mmol) was dissolved in
methyl tert-butyl ether (75 mL). To the stirred solution was added
25 weight % sodium methoxide (40 mL, 177 mmol).
4'-Chloroacetophenone (23.21 g, 150 mmol) was dissolved in methyl
tert-butyl ether (20 mL) and added to the reaction dropwise. After
stirring overnight (15.75 hours), 3N HCl (70 mL) was added. The
organic layer was collected, washed with brine (75 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo to give a
yellow-orange solid. The solid was recrystallized from isooctane to
give the dione (31.96 g, 85%): mp 66-67.degree. C.
[0137] Step 2: Preparation of
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-
-pyrazol-1-yl]benzenesulfonamide.
[0138] 4-Sulphonamidophenyl hydrazine hydrochloride (982 mg, 4.4
mmol, 1.1 equiv.) was added to a stirred solution of
4,4,4-trifluoro-1-[4-(chloro)p- henyl]-butane-1,3-dione from Step 1
(1.00 g, 4.0 mmol) in ethanol (50 mL). The reaction was heated to
reflux and stirred for 20 hours. After cooling to room temperature,
the reaction mixture was concentrated in vacuo. The residue was
taken up in ethyl acetate and washed with water and brine. The
residue was dried over MgSO.sub.4, filtered, and concentrated in
vacuo to give a light brown solid. The solid was recrystallized
from ethyl acetate and isooctane to give the pyrazole (1.28 g,
80%): mp 143-145.degree. C.; EI GC-MS M.sup.+=401.
EXAMPLE 2
4-[5-(3-Fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide
[0139] Step 1: Preparation of
3'-fluoro-4'-methoxy-acetophenone.
[0140] Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a
stirred solution of aluminum chloride (80.0 g, 0.6 mol) and
chloroform (750 mL), maintaining the temperature between
5-10.degree. C. The mixture was stirred for 10 minutes at 5.degree.
C. before the dropwise addition of 2-fluoroanisole (62.6 g, 0.5
mol). The mixture was stirred at 0-10.degree. C. for 1 hour and
poured into ice (1 L). The resultant layers were separated and the
aqueous layer was extracted with dichloromethane (2.times.250 mL)
The combined organic layers were washed with water (2.times.150
mL), dried over anhydrous MgSO.sub.4, filtered and concentrated in
vacuo to a volume of 300 mL. Hexanes were added and a white solid
formed which was isolated by filtration and air dried. This
material was recrystallized from a mixture of dichloromethane and
hexanes to afford material suitable for use in the next step (77.2
g, 92%): mp 92-94.degree. C.
[0141] Step 2: Preparation of
4,4-difluoro-1-(3-fluoro-4-methoxyphenyl)-bu- tane-1, 3-dione.
[0142] Ethyl difluoroacetate (4.06 g, 32.7 mmol) was dissolved in
methyl tert-butyl ether (50 mL). To the stirred solution was added
25 weight % sodium methoxide (7.07 g, 32.7 mmol) followed by
3'-fluoro-4'-methoxyacet- ophenone from Seep 1 (5.0 g, 29.7 mmol).
After stirring for 16 hours, 1N HCl (50, mL) was added. The organic
layer was collected and washed with water (2.times.50 mL), dried
over anhydrous MgSO.sub.4, filtered, and added to hexanes to
precipitate a tan solid (7.0 g, 96%): mp 70-72.degree. C.
[0143] Step 3: Preparation of
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluorom-
ethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
[0144] 4,4-Difluoro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione
from Step 2 (7.0 g, 28.4 mmol) was dissolved in ethanol (150 mL).
To the stirred mixture was added 4-sulphonamidophenyl hydrazine
hydrochloride (7.4 g, 33 mmol) and stirred at reflux overnight (16
hours). The mixture was cooled and water was added until crystals
slowly appeared. The product was isolated by filtration and air
dried to provide the desired product as a light tan solid (9.8 g,
87%): mp 159-161.degree. C. Anal. Calc'd. for
C.sub.17H.sub.14N.sub.3SO.sub.3F.sub.3: C, 51.38; H, 3.55; N,
10.57. Found: C, 51.46; H, 3.52; N, 10.63.
EXAMPLE 3
3-[Methyl(3-[4-phenylmethyl)phenoxy]propyl]-amino]propanoic
acid
[0145] 3-[Methyl[3-[4-phenylmethyl)phenoxy]propyl]-amino]propanoic
acid is prepared by a four step method. 4-Hydroxydiphenylmethane is
alkylated with 3-chlorobromopropane at 70.degree. C. in the
presence of potassium carbonate for 16 hours to form the
1-chloro-3-[4-phenylmethyl)phenoxy]pro- pane. The chloropropane is
condensed with methylamine at 60.degree. C. in a Parr bomb at 200
psi for 20 hours. The secondary amine is isolated as the
hydrochloride salt. Condensation of the secondary amine ith benzyl
acetate in ethanol at room temperature for 3 ours affords the
.beta.-amino acid derivative. The derivative is directly
hydrogenated (Pd/C, H.sub.2, ethanol, 2 psi) to afford
3-[methyl[3-[4-phenylmethyl)phe- noxy]propyl]-amino]propanoic
acid.
Biological Evaluation
[0146] A combination of a cyclooxygenase-2 inhibitor and a
LTA.sub.4 hydrolase inhibitor is evaluated as described in the
following tests.
[0147] Transplantation and Evaluation of Graft Rejection
[0148] The method of skin grafting used has been previously
described [D. Steinmuller, Skin Grafting. Surgical Techniques in
Immunology, Methods Enzymol. 108, 20 (1984)]. Briefly, a tailskin
from an 8-12 week old male B10.Br mouse is removed and stored in
cold saline. Male C57BL/10 mice are anesthetized, and their backs
are shaved. The backs are scrubbed with alcohol, and a 1 cm.sup.2
piece of skin is removed. A similar size piece of skin is cut from
the tailskin of the B10.Br mouse and placed in the excised area on
the C57BL/10 animal's back. A petroleum jelly coated bandage is
placed over the graft and held in place by a bandage. Compounds are
prepared as a suspension in 0.5% methylcellulose (Sigma, St. Louis,
Mo.), and 0.025% Tween.RTM. 20 (Sigma). The compounds are
administered by i.p. injection in a volume of 0.1 ml beginning on
the day of skin grafting and continuing until transplant rejection.
Cyclosporin A (csa) is purchased as "Sandimmune Injection" at a
pharmacy. Compounds are administered alone or as combinations of a
COX-2 and LTA.sub.4 hydrolase inhibitor. Bandages are left in place
until 8 days post grafting. At that time they are removed, and the
grafts are observed daily for signs of rejection. Rejection is
determined by complete blackening or scabbing of the grafted skin.
The animals are dosed at one of the following dosing ranges:
[0149] Example 1 @ M,W,F @ 10 mpk/day;
[0150] Example 2 @ 30 mpk/day, q.d.;
[0151] Example 3 @ 10 mpk/day, q.d.;
[0152] csa @ 5 mpk/day, b.d.
[0153] The combinations of a COX-2 inhibitor or the LTA.sub.4
hydrolase inhibitor should be active in delaying graft rejection at
a dosage of about 10-20 mg per kg body weight. The coadministration
of a COX-2 inhibitor or the LTA.sub.4 hydrolase inhibitor with a
low dose of the immunosuppressant Cyclosporin A should enhance
prolongation of graft survival and may have additive or synergistic
effects when combined with cyclosporin.
EXAMPLE 4
[0154] A formulation is prepared having the following
components:
[0155] 700 mg of a cyclooxygenase-2 inhibitor and 700 mg of a
LTA.sub.4 hydrolase inhibitor.
EXAMPLE 5
[0156] A formulation is prepared having the following
components:
[0157] 350 mg of
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyr-
azol-1-yl] benzenesulfonamide and 700 mg of
3-[methyl[3-[4-phenylmethyl)ph- enoxy]propyl]-amino]propanoic
acid.
[0158] Also embraced within this invention is a class of
pharmaceutical compositions comprising the active compounds of this
combination therapy in association with one or more non-toxic,
pharmaceutically-acceptable carriers and/or diluents and/or
adjuvants (collectively referred to herein as "carrier" materials)
and, if desired, other active ingredients. The active compounds of
the present invention may be administered by any suitable route,
preferably in the form of a pharmaceutical composition adapted to
such a route, and in a dose effective for the treatment intended.
The active compounds and composition may, for example, be
administered orally, intravascularly, intraperitoneally,
subcutaneously, intramuscularly or topically.
[0159] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
The active ingredient may also be administered by injection as a
composition wherein, for example, saline, dextrose or water may be
used as a suitable carrier.
[0160] The amount of therapeutically active compounds that are
administered and the dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
depends on a variety of factors, including the age, weight, sex and
medical condition of the subject, the severity of the disease, the
route and frequency of administration, and the particular compound
employed, and thus may vary widely. The pharmaceutical compositions
may contain active ingredients in the range of about 0.1 to 2000
mg, preferably in the range of about 0.5 to 500 mg and most
preferably between about 1 and 100 mg. A daily dose of about 0.01
to 100 mg/kg body weight, preferably between about 0.05 and about
20 mg/kg body weight and most preferably between about 0.1 to 10
mg/kg body weight, may be appropriate. The daily dose can be
administered in one to four doses per day.
[0161] In the case of psoriasis and other skin conditions, it may
be preferable to apply a topical preparation of compounds of this
invention to the affected area two to four times a day.
[0162] For disorders of the eye or other external tissues, e.g.,
mouth and skin, the formulations are preferably applied as a
topical ointment or cream, or as a suppository, containing the
active ingredients in a total amount of, for example, 0.075 to 30%
w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
When formulated in an ointment, the active ingredients may be
employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with an oil-in-water cream base. If desired, the aqueous phase of
the cream base may include, for example at least 30% w/w of a
polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs. The compounds of this invention can also be administered
by a transdermal device. Preferably topical administration will be
accomplished using a catch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane.
[0163] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others.
[0164] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0165] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients. The antiinflammatory active ingredients are
preferably present in such formulations in a concentration of 0.5
to 20%, advantageously 0.5 to 10% and particularly about 1.5%
w/w.
[0166] For therapeutic purposes, the active compounds of this
combination invention are ordinarily combined with one or more
adjuvants appropriate to the indicated route of administration. If
administered per os, the compounds may be admixed with lactose,
sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate,
magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose. Formulations for parenteral administration may be in the
form of aqueous or nonaqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules having one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
[0167] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations.
* * * * *