U.S. patent application number 10/489920 was filed with the patent office on 2004-12-02 for combination.
Invention is credited to Klein, Thomas, Kley, Hans-Peter.
Application Number | 20040242597 10/489920 |
Document ID | / |
Family ID | 8176065 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040242597 |
Kind Code |
A1 |
Klein, Thomas ; et
al. |
December 2, 2004 |
Combination
Abstract
The invention relates to the combined administration of
PDE4-inhibitors and NSAIDs for the treatment of an inflammatory
disease and/or an inflammation associated disorder while minimizing
gastrointesti-nal side effects, such as gastric erosions and ulcer,
which are frequently associated with the use of NSAIDs.
Inventors: |
Klein, Thomas; (Konstanz,
DE) ; Kley, Hans-Peter; (Allensbach, DE) |
Correspondence
Address: |
NATH & ASSOCIATES PLLC
1030 FIFTEENTH STREET, N.W.
SIXTH FLOOR
WASHINGTON
DC
20005
US
|
Family ID: |
8176065 |
Appl. No.: |
10/489920 |
Filed: |
March 18, 2004 |
PCT Filed: |
September 17, 2002 |
PCT NO: |
PCT/EP02/10424 |
Current U.S.
Class: |
514/263.3 ;
514/221; 514/269; 514/314; 514/469 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
19/02 20180101; A61P 29/00 20180101; A61K 45/06 20130101; A61K
31/00 20130101; A61P 3/10 20180101; A61P 43/00 20180101; A61P 19/10
20180101; A61P 1/00 20180101; A61K 31/00 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/263.3 ;
514/269; 514/314; 514/469; 514/221 |
International
Class: |
A61K 031/522; A61K
031/513; A61K 031/4709 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 19, 2001 |
EP |
01000473.7 |
Claims
1. A pharmaceutical composition comprising, in admixture, a first
active ingredient which is a PDE4 inhibitor selected from CDC-998,
SH-636, D-4396, IC-485, CC-1088 and
3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)-
quinoline-5-ylcarboxamido]pyridine-1-oxide [Research Code:
SCH351591],
3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-puri-
ne [Research-Code: V11294A],
N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro- pyrrolo[3,2,1-jk]
[1,4]benzo-diazepin-3(R)yl]pyridine-4-carboxamide [Research-Code:
C.sub.1-1018, N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluoro-
benzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research-Code:
AWD-12-281],
N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)--
1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-343],
8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN: CIPAMFYLLINE],
Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2-(1H)-pyrim-
idone [ATIZORAM],
B-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-d-
ioxo-2H-isoindole-2-propanamide [Research-Code: CDC-801],
Methanesulfonic acid
2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:
LIRIMILAST],
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzami- de
[INN: PICLAMILAST],
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cy-
clohexane-1-carboxylic acid [INN: CILOMILAST],
3-Cyclopropylmethoxy-4-difl-
uoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST]
and their pharmaceutically acceptable derivatives, and a second
active ingredient which is a conventional NSAID selected from
glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN:
ACECLOFENAC];
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid
[ACETYLSALICYLIC ACID],
2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylac- etate [Research
Code: AF2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN:
ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN:
ALMINOPROFEN], 2-amino-3-benzoylphenylacetic acid [INN: AMFENAC],
(plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazin-
e-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN:
AMPIROXICAM],
2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate
[INN: AMTOLMETINGUACIL],
(plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H
pyrrolizine-1-carboxylic acid [INN: ANIROLAC],
2-[4-(alpha,alpha,alpha-tr-
ifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7-trifluoromethyl-4-quinolyl)anthr-
anilate [INN: ANTRAFENINE],
5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazol-
o[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE],
4-acetamidophenyl salicylate acetate [INN: BENORILATE],
2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic
acid [INN: BERMOPROFEN],
2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropion- ic acid
[INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid
[INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid
[INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN:
BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC],
butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE],
alpha-ethyl-4-(2-methylpro- pyl)benzeneacetic acid [INN:
BUTIBUFEN], 2-(4-bi-phenylyl)butyric acid,
trans-4-phenylcyctohexylamine salt (1:1) [INN: BUTIXIRATE],
2-(acetyloxy)benzoic acid, calcium salt, compound with urea (1:1)
[INN: CARBASALATE CALCIUM],
(plus/minus)-6-chloro-alpha-methylcarbazole-2-aceti- c acid [INN:
CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid
[INN: CINMETACIN],
N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benz-
othiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM],
6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC],
2-[4(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN:
CLOBUZARIT], 5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN:
DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN],
(+)--(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN:
DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN:
ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID]
salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide
[INN: ETERSALATE],
1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid
[INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid
2-(2-hydroxyethoxy}ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic
acid, ester with
4-butyl-4-(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN:
FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC],
3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN],
[o-(2,4-dichlorophenoxy)phenyl]acetic acid (NN: FENCLOFENAC],
(plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN],
4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC],
(plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl
alcohol [INN: FEPRADINOL],
4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbut- anoic acid [INN:
FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthran- ilic
acid [INN: FLUFENAMIC ACID],
(plus)-2-(p-fluorophenyl)-alpha-methyl-5- -benzoxazoleacetic acid
[INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biph- enylacetic acid
[INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl-
)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL],
2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC],
2-[4-(2'-furoyl)phenyl]propionic acid [INN: FURPROFEN],
2-[2-(1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido]-2-deoxy-
-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic
acid 4-nitrooxybutylester [Research Code: HCT-1026],
(p-isobutylphenyl)acetic acid [INN: IBUFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl
4-(3-thienyl)phenyl-alpha-methylacetate [Research Code: IDPH-8261],
(plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN:
INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-
-acetic acid [INN: INDOMETACIN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H- -indole-3-acetic acid,
3,7,11-trimethyl-2,6,10-dodeca-trienyl ester [INN: INDOMETACIN
FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN:
INDOPROFEN],
2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylide-
ne)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic
acid [INN: KETOPROFEN],
(DL)-5-benzoyl-3H-1,2-dihydropyrrolo[1,2-a]pyrrole-1-c- arboxylic
acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2-(hydroxymethyl-
)cinnamyl]benzofuran [Research Code: L-651896],
N-(2-carboxyphenyl)-4chlor- oanthranilic acid [INN: LOBENZARIT],
3-(p-chlorophenyl)-1-phenylpyrazole-4- -acetic acid [INN:
LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H--
thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN:
LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate
[INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic
acid [Research Code: M-5010], N-(2,3-xylyl)anthranilic acid [INN:
MEFENAMIC ACID],
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-
amide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN:
MESALAZINE],
(2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyr-
rolizin-5-yl)-acetic acid [Research Code: ML-3000],
3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC],
4-(6-methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE],
(plus)-6-methoxyalpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN:
NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE],
alpha-methyl-4-((2oxocyclohex- ylidene)methyl]benzene acetic acid
[INN: PELUBIPROFEN], 2-(p-isobutylphenyl)propionic acid
2-pyridyl-methyl ester [INN: PIMEPROFEN],
4-(p-chlorophenyl)-1-(p-fluorophenyl)pyrazole-3-acetic acid [INN:
PIRAZOLAC],
4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-
-carboxamide 1,1-dioxide [INN: PIROXICAM],
3-chloro-4-(3-pyrrolin-1-yl)hyd- ratropic acid [INN: PIRPROFEN],
2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]pr- opionic acid [INN:
PRANOPROFEN], 2,6-di-tert-butyl-4-(2'-thenoyl)phenol [INN:
PRIFELONE], alpha-cyano-1-methyl-beta-oxopyrrole-2-propionanilide
[INN: PRINOMIDE],
3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L-4-benza-
mido-N,N-dipropylglutaramat
1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3- -acetate (ester)
[INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-phenyl-
-2(1H)quinazolinone [INN: PROQUAZONE],
7-methoxy-alpha,10-dimethylphenothi- azine-2-acetic acid [INN:
PROTIZINIC ACID], 2-[[2-(p-chlorophenyl)-4-methy-
l-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT],
o-hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC
ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester)
[INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN:
SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN:
SALSALATE],
4-[1-(2-fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine
[Research Code: SM-8849],
(Z)-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]in-
dene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid
[INN: SUPROFEN], 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid
[Research Code: TA-601], phthalidyl
2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN:
TALNIFLUMATE], (Z)-5-chloro-3-(2-thenoyl)-2-oxoindole-1-carboxamide
[INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic
acid [INN: TENOSAL],
4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiaz-
ine-3-carboxamide [INN: TENOXICAM],
5-(4-chlorophenyl)-N-hydroxy-1-(4-meth-
oxyphenyl)-N-methyl-1H-pyrazole-3-propionamide {INN: TEPOXALIN],
alpha-(5-benzoyl-2-thienyl)-propionic acid [INN: TIAPROFENIC ACID],
5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzo-thiaz-
olinone [INN: TIARAMIDE],
2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7yl)- -propionic acid
N,N-dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL],
1-Cyclohexyl-2-(2-methyl-4-quinolyl)-3-(2-thiazolyl)guanidine [INN:
TIMEGADINE],
2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridi- ne [INN:
TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC
ACID], 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN:
TOLMETIN], hydroxybis[alpha-methyl-4-(2-methylpropyl)benzene
acetato-O]-aluminium [Research Code: U-18573-G],
N-(3-trifluoromethylphen- yl)-anthranilic acid n-butyl ester [INN:
UFENAMATE], 2-[4-[3-(hydroxyimino)cyclohexyl]phenyl] propionic acid
[INN: XIMOPROFEN],
2-(10,11-dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid
[INN: ZALTOPROFEN], 2-[4-(2-thiazolyloxy)phenyl]propionic acid
[INN: ZOLIPROFEN] and their pharmaceutically acceptable
derivatives.
2. A pharmaceutical composition according to claim 1, wherein the
first and/or second active ingredient is in the form of a
pharmaceutically acceptable salt, solvate, ester, N-oxide, solvate
of a salt, solvate of an ester or solvate of an N-oxide.
3. A pharmaceutical composition according to claim 1 which is a
fixed oral combination.
4. A pharmaceutical composition according to claim 1 wherein the
first active ingredient is a PDE4-inhibitor selected from
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxyiic
acid [INN: CILOMILAST] and
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5--
dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], and the second
active ingredient is a conventional NSAID selected from
2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
[INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphthalineaceti- c acid [INN:
NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothia-
diazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].
5. A pharmaceutical composition according to claim 4, wherein the
first active ingredient is
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichlo-
ropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically
acceptable salt, solvate, N-oxide, solvate of a salt or solvate of
an N-oxide thereof.
6. A pharmaceutical composition according to claim 4, wherein the
second active ingredient is
2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or
a pharmaceutically acceptable salt, ester, solvate, solvate of a
salt or solvate of an ester thereof.
7. A method of treating an inflammatory disease and/or an
inflammation associated disorder in a patient comprising
administering to a patient in need thereof a therapeutically
effective amount of a pharmaceutical composition according to claim
1.
8. A process for the preparation of a pharmaceutical composition as
defined in claim 1 which comprises mixing the first active
ingredient with the second active ingredient.
9-14. (Canceled)
15. A kit comprising a preparation of a first active ingredient
which is a PDE4 inhibitor selected from CDC-998, SH-636, D-4396,
IC-485, CC-1088 and
3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]py-
ridine-1-oxide [Research Code: SCH351591],
3-[3-(cyclopentyloxy)-4-methoxy-
benzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code:
V11294A],
N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk]
[1,4]benzodiazepin-3(R)yl]pyridine-4-carboxamide [Research-Code:
CI-1018,
N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-y-
l]-2-oxoacetamide [Research-Code: AWD-12-281],
N-(3,5-dichloropyridin-4-yl-
)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide
[Research Code: AWD-12-343],
8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN: CIPAMFYLLINE],
Tetra-hydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phen-
yl]-2-(1H)-pyrimidone [ATIZORAM],
1-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1-
,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide [Research-Code:
CDC-801], Methanesulfonic acid
2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6- -yl ester
[INN: LIRIMILAST], N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-
-methoxybenzamide [INN: PICLAMILAST],
cis-[4-Cyano-4-(3-cyclopentyloxy-4-m-
ethoxyphenyl)cyclohexane-1-carboxylic acid [INN: CILOMILAST],
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzami-
de [INN: ROFLUMILAST] and their pharmaceutically acceptable
derivatives, a preparation of a second active ingredient which is a
conventional NSAID selected from glycolic acid
[o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC];
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-ac- etic acid
carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid
[ACETYLSALICYLIC ACID],
2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylac- etate [Research
Code: AF2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN:
ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN:
ALMINOPROFEN], 2-amino-3-benzoylphenylacetic acid [INN: AMFENAC],
(plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazin-
e-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN:
AMPIROXICAM],
2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate
[INN: AMTOLMETINGUACIL],
(plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H
pyrrolizine-1-carboxylic acid [INN: ANIROLAC],
2-[4-(alpha,alpha,alpha-tr-
ifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7-trifluoromethyl-4-quinolyl)anthr-
anilate [INN: ANTRAFENINE],
5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazol-
o[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE],
4-acetamidophenyl salicylate acetate [INN: BENORILATE],
2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic
acid [INN: BERMOPROFEN],
2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropion- ic acid
[INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid
[INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid
[INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN:
BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC],
butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE],
alpha-ethyl-4-(2-methylpro- pyl)benzeneacetic acid [INN:
BUTIBUFEN], 2-(4-bi-phenylyl)butyric acid,
trans-4-phenylcyctohexylamine salt (1:1) [INN: BUTIXIRATE],
2-(acetyloxy)benzoic acid, calcium salt, compound with urea (1:1)
[INN: CARBASALATE CALCIUM],
(plus/minus)-6-chloro-alpha-methylcarbazole-2-aceti- c acid [INN:
CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid
[INN: CINMETACIN],
N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benz-
othiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM],
6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC],
2-[4(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN:
CLOBUZARIT], 5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN:
DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN],
(+)--(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN:
DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN:
ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID]
salicylic acid acetate, ester with betahydroxy p-acetophenetidide
[INN: ETERSALATE],
1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid
[INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid
2-(2-hydroxyethoxy}ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic
acid, ester with
4-butyl-4-(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN:
FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC],
3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN],
[o-(2,4-dichlorophenoxy)phenyl]acetic acid (NN: FENCLOFENAC],
(plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN],
4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC],
(plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl
alcohol [INN: FEPRADINOL],
4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbut- anoic acid [INN:
FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthran- ilic
acid [INN: FLUFENAMIC ACID],
(plus)-2-(p-fluorophenyl)-alpha-methyl-5- -benzoxazoleacetic acid
[INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biph- enylacetic acid
[INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl-
)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL],
2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC],
2-[4-(2'-furoyl)phenyl]propionic acid [INN: FURPROFEN],
2-[2-(1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido]-2-deoxy-
-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic
acid 4-nitrooxybutylester [Research Code: HCT-1026],
(p-isobutylphenyl)acetic acid [INN: IBUFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl
4-(3-thienyl)phenyl-alpha-methylacetate [Research Code: IDPH-8261],
(plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN:
INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-
-acetic acid [INN: INDOMETACIN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H- -indole-3-acetic acid,
3,7,11-trimethyl-2,6,10-dodecatrienyl ester [INN: INDOMETACIN
FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN:
INDOPROFEN],
2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylide-
ne)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic
acid [INN: KETOPROFEN],
(DL)-5-benzoyl-3H-1,2-dihydropyrrolo[1,2-a]pyrrole-1-c- arboxylic
acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2-(hydroxymethyl-
)cinnamyl]benzofuran [Research Code: L-651896],
N-(2-carboxyphenyl)-4chlor- oanthranilic acid [INN: LOBENZARIT],
3-(p-chlorophenyl)-1-phenylpyrazole-4- -acetic acid [INN:
LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H--
thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN:
LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate
[INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic
acid [Research Code: M-5010], N-(2,3-xylyl)anthranilic acid [INN:
MEFENAMIC ACID],
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-
amide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN:
MESALAZINE],
(2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyr-
rolizin-5-yl)-acetic acid [Research Code: ML-3000],
3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC],
4-(6-methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE],
(plus)-6-methoxyalpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN:
NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE],
alpha-methyl-4-((2oxocyclohex- ylidene)methyl]benzene acetic acid
[INN: PELUBIPROFEN], 2-(p-isobutylphenyl)propionic acid
2-pyridyl-methyl ester [INN: PIMEPROFEN],
4-(p-chlorophenyl)-1-(p-fluorophenyl)pyrazole-3-acetic acid [INN:
PIRAZOLAC],
4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-
-carboxamide 1,1-dioxide [INN: PIROXICAM],
3-chloro-4-(3-pyrrolin-1-yl)hyd- ratropic acid [INN: PIRPROFEN],
2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]pr- opionic acid [INN:
PRANOPROFEN], 2,6-di-tert-butyl-4-(2'-thenoyl)phenol [INN:
PRIFELONE], alpha-cyano-1-methyl-beta-oxopyrrole-2-propionanilide
[INN: PRINOMIDE],
3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L-4-benza-
mido-N,N-dipropylglutaramat
1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3- -acetate (ester)
[INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-phenyl-
-2(1H)quinazolinone [INN: PROQUAZONE],
7-methoxy-alpha,10-dimethylphenothi- azine-2-acetic acid [INN:
PROTIZINIC ACID], 2-[[2-(p-chlorophenyl)-4-methy-
l-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT],
o-hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid (SALICYLIC
ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester)
[INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN:
SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN:
SALSALATE],
4-[1-(2-fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine
[Research Code: SM-8849],
(Z)-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]in-
dene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid
[INN: SUPROFEN], 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid
[Research Code: TA-601], phthalidyl
2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN:
TALNIFLUMATE], (Z)-5-chloro-3-(2-thenoyl)-2-oxoindole-1-carboxamide
[INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic
acid [INN: TENOSAL],
4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiaz-
ine-3-carboxamide [INN: TENOXICAM],
5-(4-chlorophenyl)-N-hydroxy-1-(4-meth-
oxyphenyl)-N-methyl-1H-pyrazole-3-propionamide {INN: TEPOXALIN],
alpha-(5-benzoyl-2-thienyl)-propionic acid [INN: TIAPROFENIC ACID],
5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzothiazo-
linone [INN: TIARAMIDE],
2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7yl)-- propionic acid
N,N-dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL],
1-Cyclohexyl-2-(2-methyl-4-quinolyl)-3-(2-thiazolyl)guanidine [INN:
TIMEGADINE],
2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridi- ne [INN:
TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC
ACID], 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN:
TOLMETIN], hydroxybis[alpha-methyl-4-(2-methylpropyl)benzene
acetato-O]-aluminium [Research Code: U-18573-G],
N-(3-trifluoromethylphen- yl)-anthranilic acid n-butyl ester [INN:
UFENAMATE], 2-[4-[3-(hydroxyimino)cyclohexyl]phenyl] propionic acid
[INN: XIMOPROFEN],
2-(10,11-dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid
[INN: ZALTOPROFEN], 2-[4-(2-thiazolyloxy)phenyl]propionic acid
[INN: ZOLIPROFEN] and their pharmaceutically acceptable
derivatives, and instructions for simultaneous, sequential or
separate administration to the patient in need thereof.
16. A kit according to claim 15, wherein the first and/or second
active ingredient is in the form of a pharmaceutically acceptable
salt, solvate, ester, N-oxide, solvate of a salt, solvate of an
ester or solvate of an N-oxide.
17. A kit according to claim 15 wherein the first active ingredient
is a PDE4-inhibitor selected from
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyph-
enyl)cyclohexane-1-carboxyiic acid [INN: CILOMILAST] and
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzami-
de [INN: ROFLUMILAST], and the second active ingredient is a
conventional NSAID selected from 2-(acetyloxy)benzoic acid
[ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic
acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN:
IBUPROFEN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
[INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN] and
4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-
-3-carboxamide 1,1-dioxide [INN: PIROXICAM].
18. A kit according to claim 17, wherein the first active
ingredient is
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzami-
de [INN: ROFLUMILAST] or a pharmaceutically acceptable salt,
solvate, N-oxide, solvate of a salt or solvate of an N-oxide
thereof.
19. A kit according to claim 17, wherein the second active
ingredient is 2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN:
DICLOFENAC] or a pharmaceutically acceptable salt, ester, solvate,
solvate of a salt or solvate of an ester thereof.
20. A method of treating an inflammatory disease and/or an
inflammation associated disorder which can be treated with a
conventional NSAID while minimizing gastrointestinal side effects
comprising the simultaneous, sequential or separate administration
of i) a first amount of a conventional NSAID or a pharmaceutically
acceptable derivative thereof; and ii) a second amount of a PDE4
inhibitor or a pharmaceutically acceptable derivative thereof,
wherein the sum of the first and the second amount is a
therapeutically effective amount, to a patient in need thereof.
21. A method according to claim 20 wherein the inflammatory disease
is inflammatory bowel disease, Crohn's disease, irritable bowel
syndrome or ulcerative colitis.
22. A method of minimizing gastrointestinal side effects frequently
associated with the use of conventional NSAIDs comprising the
simultaneous, sequential or separate administration of i) a first
amount of a conventional NSAID or a pharmaceutically acceptable
derivative thereof; and ii) a second amount of a PDE4 inhibitor or
a pharmaceutically acceptable derivative thereof, wherein the sum
of the first and the second amount is a therapeutically effective
amount, to a patient in need thereof.
23-24. (Canceled)
25. A pharmaceutical composition according to claim 2 which is a
fixed oral combination.
26. A pharmaceutical composition according to claim 2 wherein the
first active ingredient is a PDE4-inhibitor selected from
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxyiic
acid [INN: CILOMILAST] and
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5--
dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], and the second
active ingredient is a conventional NSAID selected from
2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
[INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphthalineaceti- c acid [INN:
NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothia-
diazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].
27. A pharmaceutical composition according to claim 26, wherein the
first active ingredient is
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichlo-
ropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically
acceptable salt, solvate, N-oxide, solvate of a salt or solvate of
an N-oxide thereof.
28. A pharmaceutical composition according to claim 26, wherein the
second active ingredient is
2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or
a pharmaceutically acceptable salt, ester, solvate, solvate of a
salt of solvate of an ester thereof.
29. A pharmaceutical composition according to claim 3 wherein the
first active ingredient is a PDE4-inhibitor selected from
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxyiic
acid [INN: CILOMILAST] and
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5--
dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], and the second
active ingredient is a conventional NSAID selected from
2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
[INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphthalineaceti- c acid [INN:
NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothia-
diazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].
30. A pharmaceutical composition according to claim 29, wherein the
first active ingredient is
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichlo-
ropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically
acceptable salt, solvate, N-oxide, solvate of a salt or solvate of
an N-oxide thereof.
31. A pharmaceutical composition according to claim 29, wherein the
second active ingredient is
2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or
a pharmaceutically acceptable salt, ester, solvate, solvate of a
salt of solvate of an ester thereof.
32. A method of treating an inflammatory disease and/or an
inflammation associated disorder in a patient comprising
administering to a patient in need thereof a therapeutically
effective amount of a pharmaceutical composition according to claim
2.
33. A kit according to claim 16 wherein the first active ingredient
is a PDE4-inhibitor selected from
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyph-
enyl)cyclohexane-1--carboxyiic acid [INN: CILOMILAST] and
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzami-
de [INN: ROFLUMILAST], and the second active ingredient is a
conventional NSAID selected from 2-(acetyloxy)benzoic acid
[ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic
acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN:
IBUPROFEN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
[INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN] and
4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-
-3-carboxamide 1,1-dioxide [INN: PIROXICAM].
34. A kit according to claim 33, wherein the first active
ingredient is
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzami-
de [INN: ROFLUMILAST] or a pharmaceutically acceptable salt,
solvate, N-oxide, solvate of a salt or solvate of an N-oxide
thereof.
35. A kit according to claim 33, wherein the second active
ingredient is 2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN:
DICLOFENAC] or a pharmaceutically acceptable salt, ester, solvate,
solvate of a salt of solvate of an ester thereof.
Description
FIELD OF APPLICATION OF THE INVENTION
[0001] The invention relates to the combination of certain known
active compounds for therapeutic purposes.
[0002] The substances used in the combination according to the
invention are known active compounds from the PDE4-inhibitor class
and active compounds from the non-steroidal anti-inflammatory drug
(NSAID) class.
KNOWN TECHNICAL BACKGROUND
[0003] In the International Patent Application WO01/58441 the
treating of an inflammatory disease by administering a
phosphodiesterase 4 inhibitor in combination with an inhibitor of
prostaglandin synthesis, NSAIDS being exemplary, is disclosed.
DESCRIPTION OF THE INVENTION
[0004] The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is
often associated with the development of gastrointestinal (GI) side
effects such as gastric erosions and ulcer, which limit their
widespread clinical use.
[0005] Investigations into the role of several NSAIDs in inhibiting
the phosphodiesterase 4 and 5 in vitro showed that in partially
purified or recombinant PDE4 and PDE5, NSAIDs with preferential
COX-2 selectivity (for example, nimesulide [INN], CGP28238
[Research Code], L-745337 [Research Code], and the highly selective
drug celecoxib [INN]) possess PDE4 and PDE5 activity in the .mu.M
range, whereas conventional NSAIDs (for example, acetylsalicylic
acid, diclofenac [INN] or indometacin [INN]) show only minor
effects.
[0006] In isolated guinea pig Langendorff hearts, celecoxib
selectively increased coronary heart flow at doses consistent with
its inhibitory potency on PDE4 and 5, but had no effect on left
ventricular pressure and heart rate, thereby excluding inhibition
of PDE3.
[0007] In mice, diclofenac (3-100 mg/kg, p.o.) induced
gastrointestinal bleeding (ED.sub.50=56 mg/kg), assessed by
spectrophotometric determination of fecal hemoglobin. Treatment
with diclofenac (10-100 mg/kg, p.o. t=0 h) in the presence of the
selective PDE5 inhibitor sildenafil (3-100 mg/kg, p.o. t=-48 h to
+7 h) demonstrated no protection from NSAID-induced blood loss,
whereas treatment in the presence of several selective PDE4
inhibitors significantly reduced the amount of detectable
hemoglobin.
[0008] In summary, one can say that NSAIDs with preferential COX-2
selectivity possess PDE4 and PDE5 inhibitory potency on isolated
enzymes, an effect which was confirmed in the Langendorff heart by
an increase in coronary flow. It seems that the intrinsic PDE4--but
not the intrinsic PDE5--inhibitory component of NSAIDs with
preferential COX-2 selectivity most likely contribute to the
gastrointestinal safety of these drugs. Furthermore,
gastrointestinal side effects of conventional NSAIDs can be
attentuated or even prevented, if these class of compounds is
applied in combination with a compound from the class of selective
PDE4 inhibitors.
[0009] The invention thus relates to the combined use of a PDE4
inhibitor and a conventional NSAID in the treatment of an
inflammatory disease and/or an inflammation-associated disorder
while minimizing gastrointestinal side effects, such as gastric
erosions and ulcer, which are frequently associated with the use of
conventional NSAIDs.
[0010] "Combined use" in the context of the invention means the
simultaneous, sequential or separate administration of the
conventional NSAID on the one hand and of the PDE4 inhibitor on the
other hand.
[0011] Simultaneous administration includes--aside from the
simultaneous uptake of two separate dosage forms containing the
conventional NSAID in the one and the PDE4 inhibitor in the other
dosage form--pharmaceutical compositions containing both active
ingredients in one single dosage form (fixed unit dose form).
[0012] Simultaneous administration also includes the oral
administration of the PDE4 inhibitor during i. v. administration
(e.g. by infusion) of the conventional NSAID, or shortly after
intramuscular or intravenous injection of the conventional
NSAID.
[0013] Sequential administration in the context of the invention
means the administration of the conventional NSAID on the one hand
and of the PDE4 inhibitor on the other hand in separate dosage
forms within less than 12 hours, more preferably within less than
one hour, most preferably within 5 minutes or less, including
regimen where the PDE4 inhibitor is administered first.
[0014] Separate administration within the context of the invention
means the administration of the conventional NSAID on the one hand
and of the PDE4 inhibitor on the other hand in separate dosage
forms within 12 hours or more, including administration regimen
where the PDE4 inhibitor is administered first, and including
regimen where e.g. the conventional NSAID is administered twice or
three times daily and the PDE4 inhibitor is administered once or
twice daily.
[0015] Sequential and separate administration also include the oral
administration of the PDE4 inhibitor and the i. v. administration
(e.g. by infusion) or intramuscular or intravenous injection of the
conventional NSAID.
[0016] "Combined use" in the context of the invention also includes
a pharmaceutical product comprising both the conventional NSAID and
the PDE4 inhibitor as discrete separate dosage forms, in separate
containers or e.g. in blisters containing both types of drugs in
discrete solid dosage units, preferably in a form in which the
dosage units which have to be taken together or which have to be
taken within one day are grouped together in a manner which is
convenient for the patient. Said pharmaceutical product itself or
as a part of a kit may contain instructions for the simultaneous,
sequential or separate administration of the discrete separate
dosage units, to a patient in need thereof.
[0017] By the expression "PDE4 inhibitor" is meant a
phosphodiesterase inhibitor, which selectively inhibits the type 4
phosphodiesterase when compared to other known types of
phosphodiesterase, e.g. type 1, 2, 3, 5 etc., whereby the compound
has a lower IC.sub.50 (more potent) for the type 4
phosphodiesterase, such as where the IC.sub.50 for PDE4 inhibition
is about factor 100 lower compared to IC.sub.50 for inhibition of
other known type of phosphodiesterase, e.g. type 1, 2, 3, 5
etc.
[0018] By "conventional NSAID" is meant a cyclooxygenase inhibitor
which inhibits both, the constitutive form (COX-1) and the
inducible form (COX-2) of the cyclooxygenase and does not contain
any of the following residues: --S(O).sub.2NH.sub.2,
--S(O).sub.2CH.sub.3, --S(O).sub.2N(H)C(O)CH.sub.2CH.sub.3 and
--N(H)--S(O).sub.2--CH.sub.3.
[0019] PDE4 inhibitors within the meaning of the present invention
are those which are named expressis verbis as an example or
described and/or claimed generically in the following patent
applications and patents: EP0428302, EP0731099, WO9212961,
WO9319749, WO9402465, WO9500516, WO9501338, WO9611690, WO9603399,
WO9636625, WO9636626, WO9723457, WO9728131, WO9735854, WO9743288,
WO9807715, WO9808841, WO9809946, WO9821207, WO9821209, WO9822453,
WO9831674, WO9905111, WO9905112, WO9905113, WO9931090, WO9957115,
WO9964414, WO0001695, WO0026208, WO0042017, WO0042018, WO0042019,
WO0042020, WO0042034, WO0130766, WO0130777, WO0151470, WO0206239,
WO0206270, WO0205616 and WO0206238 and additionally the following
compounds identified by their research codes: CDC-998, D4396,
IC-485, CC-1088 and KW-4490. Substances having good oral
availability are preferred here.
[0020] Preferred PDE4 inhibitors which are selected from the
above-defined PDE4 inhibitors are the compounds with the research
codes CDC-998, SH-636, D-4396, IC-485, CC-1088 and
3,5-dichloro-4-[8-methoxy-2-(trifluor-
omethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide [Research Code:
SCH351591],
3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopr-
opyl-3H-purine [Research-Code: V 11294A],
N-[9-methyl-4-oxo-1-phenyl-3,4,6-
,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carbo-
xamide [Research-Code: Cl-1018,
N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluor-
obenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research-Code:
AWD-12-281],
N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)--
1H-indol-3-yl]-2-oxoacetamide [Research-Code: AWD-12-343],
8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN: CIPAMFYLLINE],
Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimi-
done [INN: ATIZORAM],
.beta.-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihy-
dro-1,3-dioxo-2H-isoindole-2-propanamide [Research-Code: CDC-801],
Methanesulfonic acid
2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6- -yl ester
[INN: LIRIMILAST], N-(3,5-dichloropy-rid-4-yl)-3-cyclopentyloxy--
4-methoxybenzamide [INN: PICLAMILAST],
cis-[4-Cyano-4-(3-cyclopentyloxy-4--
methoxyphenyl)cyclohexane-1-carboxylic acid [INN: CILOMILAST] and
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzami-
de [INN: ROFLUMILAST].
[0021] Particularly preferred PDE4-inhibitors are
cis-[4-Cyano-4-(3-cyclop-
entyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid [INN:
CILOMILAST] and
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-ben-
zamide [INN: ROFLUMILAST].
[0022] Conventional NSAIDs within the meaning of the present
invention are glycolic acid
[o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC];
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid
[ACETYLSALICYLIC ACID],
2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylac- etate [Research
Code: AF-2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN:
ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN:
ALMINOPROFEN], 2-amino-3-benzoylphenylacetic acid [INN: AMFENAC],
(plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazin-
e-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN:
AMPIROXICAM],
2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate
[INN: AMTOLMETINGUACIL],
(plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H
pyrrolizine-1-carboxylic acid [INN: ANIROLAC],
2-[4-(alpha,alpha,alpha-tr-
ifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7-trifluoromethyl-4-quinolyl)anthr-
anilate [INN: ANTRAFENINE],
5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazol-
o[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE],
4-acetamidophenyl salicylate acetate [INN: BENORILATE],
2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic
acid [INN: BERMOPROFEN],
2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropion- ic acid
[INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid
[INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid
[INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN:
BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC],
butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE],
alpha-ethyl-4-(2-methylpro- pyl)benzeneacetic acid [INN:
BUTIBUFEN], 2-(4-biphenylyl)butyric acid,
trans-4-phenylcyclohexylamine salt (1:1) [INN: BUTIXIRATE],
2-(acetyloxy)-benzoic acid, calcium salt, compound with urea (1:1)
[INN: CARBASALATE CALCIUM],
(plus/minus)-6-chloro-alpha-methylcarbazole-2-aceti- c acid [INN:
CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid
[INN: CINMETACIN],
N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benz-
othiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM],
6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC],
2-[4-(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN:
CLOBUZARIT],5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN:
DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN],
(+)-(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN:
DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN:
ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID]
salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide
[INN: ETERSALATE],
1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid
[INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid
2-(2-hydroxyethoxy)-ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic
acid, ester with
4-butyl-4-(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN:
FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC],
3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN],
[o-(2,4-dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC],
(plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN],
4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC],
(plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl
alcohol [INN: FEPRADINOL],
4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbut- anoic acid [INN:
FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthran- ilic
acid [INN: FLUFENAMIC ACID],
(plus)-2-(p-fluorophenyl)-alpha-methyl-5- -benzoxazoleacetic acid
[INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biph- enylacetic acid
[INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl-
)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL],
2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC],
2-[4-(2'-furoyl)phenyl]propionic acid [INN: FURPROFEN],
2-[2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido]-2-deoxy-
-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic
acid 4-nitrooxybutylester [Research Code: HCT-1026],
(p-isobutylphenyl)acetic acid [INN: IBUFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl
4-(3-thienyl)phenyl-alpha-methylacetate [Research Code: IDPH-8261],
(plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN:
INDOBUFEN], 1-(4-chlorobenzoyl)-5 methoxy-2-methyl-1H-indole-3-
-acetic acid [INN: INDOMETACIN],
1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-- indole-3-acetic acid,
3,7,11-trimethyl-2,6,10-dodecatrienyl ester [INN: INDOMETACIN
FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN:
INDOPROFEN],
2-(10-methoxy-4H-benzo[4,5]-cyclohepta[1,2-b]thiophen-4-ylid-
ene)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic
acid [INN: KETOPROFEN],
(DL)-5-benzoyl-3H-1,2-dihydropyrrolo[1,2-a]pyrrole-1-c- arboxylic
acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2-(hydroxymethyl-
)cinnamyl]benzofuran [Research Code: L-651896],
N-(2-carboxyphenyl)-4-chlo- roanthranilic acid [INN: LOBENZARIT],
3-(p-chlorophenyl)-1-phenylpyrazole-- 4-acetic acid [INN:
LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-
-thieno-[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN:
LORNOXICAM], 2-[4-(2-oxocyclopentan-1-yl-methyl)phenyl]-propionate
[INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic
acid [Research Code: M-5010], N-(2,3-xylyl)anthranilic acid [INN:
MEFENAMIC ACID],
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-
amide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN:
MESALAZINE],
(2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyr-
rolizin-5-yl)-acetic acid [Research Code: ML-3000],
3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC],
4-(6-methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE],
(plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN), 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN:
NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE],
alpha-methyl-4-[(2-oxocyclohe- xylidene)methyl]benzene acetic acid
[INN: PELUBIPROFEN], 2-(p-isobutylphenyl)propionic acid
2-pyridyl-methyl ester [INN: PIMEPROFEN],
4-(p-chlorophenyl)-1-(p-fluorophenyl)pyrazole-3-acetic acid [INN:
PIRAZOLAC],
4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-
-carboxamide 1,1-dioxide [INN: PIROXICAM],
3-chloro-4-(3-pyrrolin-1-yl)hyd- ratropic acid [INN: PIRPROFEN],
2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]pr- opionic acid [INN:
PRANOPROFEN], 2,6-di-tert-butyl-4-(2'-thenoyl)phenol [INN:
PRIFELONE], alpha-cyano-1-methyl-beta-oxopyrrole-2-propionanilide
[INN: PRINOMIDE],
3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L4-benzam-
ido-N,N-dipropylglutaramat
1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-- acetate (ester)
[INN: PROGLUMETACIN], 7-methyl-1-(1-methyl-ethyl)-4-phenyl-
-2(1H)quinazolinone [INN: PROQUAZONE],
7-methoxy-alpha,10-dimethylphenothi- azine-2-acetic acid [INN:
PROTIZINIC] ACID], 2-[[2-(p-chlorophenyl)-4-meth-
yl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT],
o-hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC
ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester)
[INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN:
SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN:
SALSALATE],
4-[1-(2-fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine
[Research Code: SM-8849],
(Z)-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]in-
dene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid
[INN: SUPROFEN] 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid
[Research Code: TA-60], phthalidyl
2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN:
TALNIFLUMATE], (Z)-5-chloro-3-(2-thenoyl)-2-oxoindole-1-carboxamide
[INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic
acid [INN: TENOSAL],
4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiaz-
ine-3-carboxamide [INN: TENOXICAM],
5-(4-chlorophenyl)-N-hydroxy-1-(4-meth-
oxyphenyl)-N-methyl-1H-pyrazole-3-propionamide [INN: TEPOXALIN],
alpha-(5-benzoyl-2-thienyl)propionic acid [INN: TIAPROFENIC ACID],
5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzothiazo-
lin one [INN: TIARAMIDE],
2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7-yl- )-propionic acid
N,N-dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL],
1-Cyclohexyl-2-(2-methyl-4-quinolyl)-3-(2-thiazolyl)guanidine [INN:
TIMEGADINE],
2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridi- ne [INN:
TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC
ACID], 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN:
TOLMETIN], hydroxybis[alpha-methyl-4-(2-methylpropyl)benzene
acetato-O]-aluminium [Research Code: U-18573-G],
N-(3-trifluoromethylphen- -yl)-anthranilic acid n-butyl ester [INN:
UFENAMATE], 2-[4-[3-(hydroxyimino)cyclohexyl]phenyl]propionic acid
[INN: XIMOPROFEN],
2-(10,11-dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid
[INN: ZALTOPROFEN] and 2-[4-(2-thiazolyloxy)phenyl]-propionic acid
[INN: ZOLIPROFEN].
[0023] Preferred conventional NSAIDs which are selected from the
above-defined group of conventional NSAIDs are 2-(acetyloxy)benzoic
acid [ACETYLSALICYLIC ACID],
2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid [INN: DICLOFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN],],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
[INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphthalineaceti- c acid [INN:
NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothia-
diazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].
[0024] An particularly preferred conventional NSAID is
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN:
DICLOFENAC].
[0025] In the context of the present invention, unless otherwise
stated, a pharmaceutically acceptable derivative of an active
ingredient means a pharmaceutically acceptable salt or solvate
(e.g. hydrate), a pharmaceutically acceptable solvate of such salt,
a pharmaceutically acceptable N-oxide or a pharmaceutically
acceptable salt or solvate of the latter.
[0026] Suitable pharmacologically tolerable salts here are on the
one hand in particular water-soluble and water-insoluble acid
addition salts with acids such as, for example, hydrochloric acid,
hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,
acetic acid, citric acid, D-gluconic acid, benzoic acid,
2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic
acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic
acid, oxalic acid, tartaric acid, embonic acid, stearic acid,
toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic
acid, the acids being employed in salt preparation--depending on
whether it is a mono- or polybasic acid and depending on which salt
is desired--in an equimolar quantitative ratio or one differing
therefrom. Furthermore, the active compounds mentioned can also be
present as pure enantiomers or as enantiomer mixtures in any mixing
ratio.
[0027] On the other hand, salts with bases are also suitable.
Examples of salts with bases which may be mentioned are alkali
metal (lithium, sodium, potassium) or calcium, aluminum, magnesium,
titanium, ammonium, meglumine or guanidinium salts, where here too
the bases are employed in salt preparation in an equimolar
quantitative ratio or one differing therefrom.
[0028] Certain of the active ingredients used in the present
invention are capable of existing in stereoisomeric forms. The
invention encompasses all stereoisomers of the active ingredients
and mixtures thereof including racemates. Tautomers and mixtures
thereof of the active ingredients are also part of the present
invention.
[0029] In accordance with the present invention, there is provided
in a first aspect a pharmaceutical composition comprising, in
admixture, a first active ingredient which is a PDE4-inhibitor
selected from CDC-998, SH-636, D-4396, IC-485, CC-1088 and
3,5-dichloro-4-[8-methoxy-2-(trifluor-
omethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide [Research Code:
SCH351591],
3-[3-(cyclopentyloxy)-4-methoxybenz-yl]-6-(ethylamino)-8-isop-
ropyl-3H-purine [Research-Code: V-11294A],
N-[9-methyl-4-oxo-1-phenyl-3,4,-
6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carb-
oxamide [Research-Code: Cl-1018,
N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluo-
robenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacet-amide [Research-Code:
AWD-12-281],
N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)--
1H-indol-3-yl]-2-oxoacetamide [Research-Code: AWD-12-343],
8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN: CIPAMFYLLINE],
Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimi-
done [INN: ATIZORAM],
.beta.-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihy-
dro-1,3-dioxo-2H-isoindole-2-propanamide [Research-Code: CDC-801],
Methanesulfonic acid
2-(2,4-dichlorophenyl-carbonyl)-3-ureidobenzo-furan-- 6-yl ester
[INN: LIRIMILAST], N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy--
4-methoxybenzamide [INN: PICLAMILAST],
cis-[4-Cyano-4-(3-cyclopentyloxy-4--
methoxyphenyl)-cyclohexane-1-carboxylic acid [INN: CILOMILAST],
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzami-
de [INN: ROFLUMILAST] and their pharmaceutically acceptable
derivatives, and a second active ingredient which is a conventional
NSAID selected from glycolic acid
[o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC];
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid
[ACETYLSALICYLIC ACID],
2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylac- etate [Research
Code: AF-2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN:
ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN:
ALMINOPROFEN], 2-amino-3-benzoylphenylacetic acid [INN: AMFENAC],
(plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazin-
e-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN:
AMPIROXICAM],
2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate
[INN: AMTOLMETINGUACIL],
(plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H
pyrrolizine-1-carboxylic acid [INN: ANIROLAC],
2-[4-(alpha,alpha,alpha-tr-
ifluoro-m-tolyl)-1-piperazinyl]-ethyl-N-(7-trifluoromethyl-4-quinolyl)anth-
ranilate [INN: ANTRAFENINE],
5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazo-
lo[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE],
4-acetamidophenyl salicylate acetate [INN: BENORILATE],
2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic
acid [INN: BERMOPROFEN],
2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropion- ic acid
[INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid
[INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid
[INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN:
BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC],
butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE],
alpha-ethyl-4-(2-methylpro- pyl)benzeneacetic acid [INN:
BUTIBUFEN], 2-(4-biphenylyl)butyric acid,
trans-4-phenylcyclohexylamine salt (1:1) [INN: BUTIXIRATE],
2-(acetyloxy)-benzoic acid, calcium salt, compound with urea (1:1)
[INN: CARBASALATE CALCIUM],
(plus/minus)-6-chloro-alpha-methylcarbazole-2-aceti- c acid [INN:
CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid
[INN: CINMETACIN],
N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benz-
othiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM],
6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC],
2-[4-(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN:
CLOBUZARIT], 5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN:
DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN],
(+)--(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN:
DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN:
ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID]
salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide
[INN: ETERSALATE],
1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid
[INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid
2-(2-hydroxyethoxy)ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic
acid, ester with
4-butyl-4-(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN:
FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC],
3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN],
[o-(2,4-dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC],
(plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN],
4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC],
(plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl
alcohol [INN: FEPRADINOL],
4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbut- anoic acid [INN:
FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthran- ilic
acid [INN: FLUFENAMIC ACID],
(plus)-2-(p-fluorophenyl)-alpha-methyl-5- -benzoxazoleacetic acid
[INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biph- enylacetic acid
[INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl-
)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL],
2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC],
2-[4-(2'-furoyl)phenyl]propionic acid [INN: FURPROFEN],
2-[2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido]-2-deoxy-
-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic
acid 4-nitrooxybutylester [Research Code: HCT-1026],
(p-isobutylphenyl)acetic acid [INN: IBUFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl
4-(3-thienyl)phenyl-alpha-methylacetate [Research Code: IDPH-8261],
(plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN:
INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-
-acetic acid [INN: INDOMETACIN],
1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-- indole-3-acetic acid,
3,7,11-trimethyl-2,6,10-dodecatrienyl ester [INN: INDOMETACIN
FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN:
INDOPROFEN],
2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylide-
ne)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic
acid [INN: KETOPROFEN],
(DL)-5-benzoyl-3H-1,2-dihydropyrrolo[1,2-a]pyrrole-1-c- arboxylic
acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2-(hydroxymethyl-
)cinnamyl]benzofuran [Research Code: L-651896],
N-(2-carboxyphenyl)-4-chlo- roanthranilic acid [INN: LOBENZARIT],
3-(p-chlorophenyl)-1-phenylpyrazole-- 4-acetic acid [INN:
LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-
-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN:
LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate
[INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic
acid [Research Code: M-5010], N-(2,3-xylyl)anthranilic acid [INN:
MEFENAMIC ACID],
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-
amide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN:
MESALAZINE],
(2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyr-
rolizin-5-yl)-acetic acid [Research Code: ML-3000],
3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC],
4-(6-methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE],
(plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN:
NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE],
alpha-methyl-4-[(2-oxocyclohe- xylidene)methyl]benzene acetic acid
[INN: PELUBIPROFEN], 2-(p-isobutylphenyl)propionic acid
2-pyridyl-methyl ester [INN: PIMEPROFEN],
4-(p-chlorophenyl)-1-(p-fluorophenyl)pyrazole-3-acetic acid [INN:
PIRAZOLAC],
4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-
-carboxamide 1,1-dioxide [INN: PIROXICAM],
3-chloro-4-(3-pyrrolin-1-yl)hyd- ratropic acid [INN: PIRPROFEN],
2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]pr- opionic acid [INN:
PRANOPROFEN], 2,6-di-tert-butyl-4-(2'-thenoyl)phenol [INN: PRIFELON
E], alpha-cyano-1-methyl-beta-oxopyrrole-2-propionanilide [INN:
PRINOMIDE],
3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L-4-benza-
mido-N,N-dipropylglutaramat
1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3- -acetate (ester)
[INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-phenyl-
-2(1H)quinazolinone [INN: PROQUAZONE],
7-methoxy-alpha,10-dimethylphenothi- azine-2-acetic acid [INN:
PROTIZINIC] ACID], 2-[[2-(p-chlorophenyl)-4-meth-
yl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT],
o-hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC
ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester)
[INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN:
SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN:
SALSALATE],
4-[1-(2-fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine
[Research Code: SM-8849],
(Z)-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]in-
dene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid
[INN: SUPROFEN] 2-(4-(3-methyl-2-butenyl)phenyl)-propionic acid
[Research Code: TA-60], phthalidyl
2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN:
TALNIFLUMATE], (Z)-5-chloro-3-(2-thenoyl)-2-oxoindole-1-carboxamide
[INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic
acid [INN: TENOSAL],
4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiaz-
ine-3-carboxamide [INN: TENOXICAM],
5-(4-chlorophenyl)-N-hydroxy-1-(4-meth-
oxyphenyl)-N-methyl-1H-pyrazole-3-propionamide [INN: TEPOXALIN],
alpha-(5-benzoyl-2-thien-yl)propionic acid [INN: TIAPROFENIC ACID],
5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzo-thiaz-
olin one [INN: TIARAMIDE],
2-(2-methyl-5H-[i]benzopyrano[2,3-b]pyridin-7-y- l)-propionic acid
N,N-dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL],
1-Cyclohexyl-2-(2-methyl-4-quinolyl)-3-(2-thiazolyl)guanidine [INN:
TIMEGADINE],
2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridi- ne [INN:
TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC
ACID], 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN:
TOLMETIN], hydroxybis[alpha-methyl-4-(2-methylpropyl)benzene
acetato-O]-aluminium [Research Code: U-18573-G],
N-(3-trifluo-romethylphe- nyl)-anthranilic acid n-butyl ester [INN:
UFENAMATE], 2-[4-[3-(hydroxyimino)cyclohexyl]phenyl]propionic acid
[INN: XIMOPROFEN],
2-(10,11-dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid
[INN: ZALTOPROFEN], 2-[4-(2-thiazolyloxy)phenyl]-propionic acid
[INN: ZOLIPROFEN] and their pharmaceutically acceptable
derivatives.
[0030] In a second aspect--which is an embodiment of the first
aspect--there is provided a pharmaceutical composition comprising,
in admixture, a first active ingredient which is a PDE4-inhibitor
selected from
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carbo-
xylic acid [INN: CILOMILAST],
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,-
5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and their
pharmaceutically acceptable derivatives, and a second active
ingredient which is a conventional NSAID selected from
2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN],],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
[INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphthalineaceti- c acid [INN:
NAPROXEN], 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadia-
zin-3-carboxamide 1,1-dioxide [INN: PIROXICAM] and their
pharmaceutically acceptable derivatives.
[0031] In a third aspect--which is another embodiment of the first
aspect--there is provided a pharmaceutical composition comprising,
in admixture, a first active ingredient which selected from
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzami-
de [INN: ROFLUMILAST] and its Pharmaceutically acceptable
derivatives, and a second active ingredient which is selected from
2-[(2,6-dichlorophenyl)- amino]benzeneacetic acid [INN: DICLOFENAC]
and its pharmaceutically acceptable derivatives.
[0032] In a forth aspect the invention provides a pharmaceutical
product comprising, in combination, a preparation of a first active
ingredient which is a PDE4-inhibitor selected from CDC-998, SH-636,
D4396, IC485, CC-1088 and
3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylca-
rboxamido]pyridine-1-oxide [Research Code: SCH351591],
3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-puri-
ne [Research-Code: V-11294A],
N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydr-
opyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide
[Research-Code: Cl-1018,
N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzy-
l)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research-Code:
AWD-12-281],
N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl-
]-2-oxoacetamide [Research-Code: AWD-12-343],
8-Amino-1,3-bis(cyclopropylm- ethyl)xanthine [INN:CIPAMFYLLINE],
Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-
-norbornyloxy]phenyl]-2(1H)-pyrimidone [INN: ATIZORAM],
.beta.-[3-(Cyclopentyloxy).sub.4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H--
isoindole-2-propanamide [Research-Code: CDC-801], Methanesulfonic
acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester
[INN: LIRIMILAST],
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzami- de
[INN: PICLAMILAST],
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cy-
clohexane-1-carboxylic acid [INN: CILOMILAST],
3-Cyclopropylmethoxy-4-difl-
uoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST]
and their pharmaceutically acceptable derivatives, and a
preparation of a second active ingredient which is a conventional
NSAID selected from glycolic acid
[o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC];
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid
[ACETYLSALICYLIC ACID],
2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylac- etate [Research
Code: AF-2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN:
ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN:
ALMINOPROFEN], 2-amino-3-benzoylphenylacetic acid [INN: AMFENAC],
(plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazin-
e-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN:
AMPIROXICAM],
2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamidoacetate
[INN: AMTOLMETINGUACIL],
(plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H
pyrrolizine-1-carboxylic acid [INN: AN IROLAC],
2-[4-(alpha,alpha,alpha-t-
rifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7-trifluoromethyl-4-quinolyl)anth-
ranilate [INN: ANTRAFENINE],
5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazo-
lo[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZON E],
4-acetamidophenyl salicylate acetate [INN: BENORILATE],
2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic
acid [INN: BERMOPROFEN],
2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropion- ic acid
[INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid
[INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid
[INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN:
BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC],
butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE],
alpha-ethyl-4-(2-methylpro- pyl)benzeneacetic acid [INN:
BUTIBUFEN], 2-(4-biphenylyl)butyric acid,
trans-4-phenylcyclohexylamine salt (1:1) [INN: BUTIXIRATE],
2-(acetyloxy]benzoic acid, calcium salt, compound with urea (1:1)
[INN: CARBASALATE CALCIUM],
(plus/minus)-6-chloro-alpha-methylcarbazole-2-aceti- c acid [INN:
CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid
[INN: CINMETACIN],
N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benz-
othiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM],
6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC],
2-[4-(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN:
CLOBUZARIT], 5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN:
DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN],
(+)--(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN:
DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN:
ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID]
salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide
[INN: ETERSALATE],
1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid
[INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid
2-(2-hydroxyethoxy)-ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic
acid, ester with
4-butyl(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN:
FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC],
3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN],
[o-(2,4-dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC],
(plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN],
4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC],
(plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl
alcohol [INN: FEPRADINOL],
4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbut- anoic acid [INN:
FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthran- ilic
acid [INN: FLUFENAMIC ACID),
(plus)-2-(p-fluorophenyl)-alpha-methyl-5- -benzoxazoleacetic acid
[INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biph- enylacetic acid
[INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl-
)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL],
2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC],
2-[4-(2'-furoyl)phenyl]propionic acid [INN: FURPROFEN],
2-[2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido]-2-deoxy-
-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic
acid 4-nitrooxybutylester [Research Code: HCT-1026],
(p-isobutylphenyl)acetic acid [INN: IBUFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl
4-(3-thienyl)phenyl-alpha-methylacetate [Research Code: IDPH-8261],
(plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN:
INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-
-acetic acid [INN: INDOMETACIN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H- -indole-3-acetic acid,
3,7,11-trimethyl-2,6,10-dodecatrienyl ester [INN: INDOMETACIN
FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN:
INDOPROFEN],
2-(10-methoxy-4H-benzo[4,5]-cyclohepta[1,2-b]thiophen-4-ylid-
ene)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic
acid [INN: KETOPROFEN],
(DL)-5-benzoyl-3H-1,2-dihydropyrrolo[1,2-a]pyrrole-1-c- arboxylic
acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2-(hydroxymethyl-
)cinnamyl]benzofuran [Research Code: L-651896],
N-(2-carboxyphenyl)-4-chlo- roanthranilic acid [INN: LOBENZARIT],
3-(p-chlorophenyl)-1-phenylpyrazole-- 4-acetic acid [INN:
LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-
-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN:
LORNOXICAM], 2-[4-(2-oxocyclopentan-1-yl-methyl)phenyl]-propionate
[INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic
acid [Research Code: M-5010], N-(2,3-xylyl)anthranilic acid [INN:
MEFENAMIC ACID],
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-
amide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN:
MESALAZINE],
(2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyr-
rolizin-5-yl]acetic acid [Research Code: ML-3000],
3,4-bis(4-methoxyphenyl- )-5-isoxazoleacetic acid [INN: MOFEZOLAC],
4-(6-methoxy-2-naphthyl)-2-buta- none [INN: NABUMETONE],
(plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN:
NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE],
alpha-methyl-4-[(2-oxocyclohexylidene)methyl]benzene acetic acid
[INN: PELUBIPROFEN], 2-(p-isobutylphenyl)propionic acid
2-pyridyl-methyl ester [INN: PIMEPROFEN],
4-(p-chlorophenyl)-1-(.beta.-fluorophenyl)pyrazole-3-a- cetic acid
[INN: PIRAZOLAC], 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzoth-
iadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM],
3-chloro-4-(3-pyrrolin-1-yl)hydratropic acid [INN: PIRPROFEN],
2-[5H--(1)benzopyrano]2,3-b]pyridin-7-yl]propionic acid [INN:
PRANOPROFEN], 2,6-di-tert-butyl-4-(2'-thenoyl)phenol [INN:
PRIFELONE], alpha-cyano-1-methyl-beta-oxopyrrole-2-propionanilide
[INN: PRINOMIDE],
3-[4-(2-hydroxyethyly)-1-piperazinyl]-propyl-D,L-4-benzamido-N,N-dipropyl-
glutaramat 1-(p-chloro-benzoyl)-5-methoxy-2-methylindole-3-acetate
(ester) [INN: PROGLUMETACIN],
7-methyl-1-(1-methyl-ethyl)-4-phenyl-2(1H)quinazoli- none [INN:
PROQUAZONE], 7-methoxy-alpha,10-dimethylphenothiazine-2-acetic acid
[INN: PROTIZINIC] ACID],
2-[[2-(p-chlorophenyl)-4-methyl-5-oxazolyl]-
methoxy]-2-methylpropionic acid [INN: ROMAZARIT],
o-hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC
ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester)
[INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN:
SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN:
SALSALATE],
4-[1-(2-fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine
[Research Code: SM-8849],
(Z)-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]in-
dene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid
[INN: SUPROFEN] 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid
[Research Code: TA-60], phthalidyl
2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN:
TALNIFLUMATE], (Z)-5-chloro-3-(2-thenoyl)-2-oxoindole-1-carboxamide
[INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic
acid [INN: TENOSAL],
4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiaz-
ine-3-carboxamide [INN: TENOXICAM],
5-(4-chlorophenyl)-N-hydroxy-1-(4-meth-
oxyphenyl)-N-methyl-1H-pyrazole-3-propionamide [INN: TEPOXALIN],
alpha-(5-benzoyl-2-thienyl)propionic acid [INN: TIAPROFENIC ACID],
5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzothiazo-
lin one [INN: TIARAMIDE],
2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7-yl- )-propionic acid
N,N-dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL],
1-Cyclohexyl-2-(2-methyl-4-quinolyl)-3-(2-thiazolyl)guanidine [INN:
TIMEGADINE],
2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridi- ne [INN:
TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC
ACID], 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN:
TOLMETIN], hydroxybis[alpha-methyl-4-(2-methylpropyl)benzene
acetato-O]-aluminium [Research Code: U-18573-G],
N-(3-trifluoromethylphen- yl)-anthranilic acid n-butyl ester [INN:
UFENAMATE], 2-[4-[3-(hydroxyimino)cyclohexyl]phenyl]propionic acid
[INN: XIMOPROFEN],
2-(10,11-dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid
[INN: ZALTOPROFEN], 2-[4-(2-thiazolyloxy)phenyl]-propionic acid
[INN: ZOLIPROFEN] and their pharmaceutically acceptable
derivatives, for simultaneous, sequential or separate use in
therapy.
[0033] In a fifth aspect--which is an embodiment of the forth
aspect--the invention provides a pharmaceutical product comprising,
in combination, a preparation of a first active ingredient which is
a PDE4-inhibitor selected from
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-
e-1-carboxylic acid [INN: CILOMILAST],
3-Cyclopropylmethoxy-4-difluorometh-
oxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and
their pharmaceutically acceptable derivatives, and a preparation of
a second active ingredient which is a conventional NSAID selected
from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID],
2-[(2,6-dichlorophenyl)- amino]benzeneacetic acid [INN:
DICLOFENAC], alpha-p-isobutylphenylpropioni- c acid [INN:
IBUPROFEN],], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-
e-3-acetic acid [INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphth- alineacetic acid [INN:
NAPROXEN], 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-be-
nzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM] and their
pharmaceutically acceptable derivatives, for simultaneous,
sequential or separate use in therapy.
[0034] In a sixth aspect--which is another embodiment of the forth
aspect--the invention provides a pharmaceutical product comprising,
in combination, a preparation of a first active ingredient which is
selected from
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-be-
nzamide [INN: ROFLUMILAST] and its pharmaceutically acceptable
derivatives, and a preparation of a second active ingredient which
is selected from 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid
[INN: DICLOFENAC] and its pharmaceutically acceptable derivatives,
for simultaneous, sequential or separate use in therapy.
[0035] In a seventh aspect, the invention provides a kit comprising
a preparation of a first active ingredient which is a
PDE4-inhibitor selected from CDC-998, SH-636, D-4396, IC-485,
CC-1088 and
3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]py-
rdine-1-oxide [Research Code: SCH351591],
3-[3-(cyclopentyloxy)-4-methoxyb-
enzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code:
V-11294A],
N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzod-
iazepin-3(R)-yl]pyridine-4-carboxamide [Research-Code: Cl-1018,
N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-y-
l]-2-oxoacetamide [Research-Code: AWD-12-281],
N-(3,5-dichloropyridin-4-yl-
)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide
[Research-Code: AWD-12-343],
8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN: CIPAMFYLLINE],
Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy-
]phenyl]-2(1H)-pyrimidone [INN: ATIZORAM],
1-[3-(Cyclopentyloxy)-4-methoxy-
phenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide
[Research-Code: CDC-801], Methanesulfonic acid
2-(2,4-dichlorophenylcarbonyl)-3-ureidoben- zo-furan-6-yl ester
[INN: LIRIMILAST], N-(3,5-dichloropyrid-4-yl)-3-cyclop-
entyloxy-4-methoxybenzamide [INN: PICLAMILAST],
cis-[4-Cyano-4-(3-cyclopen-
tyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid [INN:
CILOMILAST],
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzami-
de [INN: ROFLUMILAST] and their pharmaceutically acceptable
derivatives, a preparation of a second active ingredient which is a
conventional NSAID selected from glycolic acid
[o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC];
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-ac- etic acid
carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid
[ACETYLSALICYLIC ACID],
2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylac- etate [Research
Code: AF-2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN:
ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN:
ALMINOPROFEN], 2-amino-3-benzoylphenylacetic acid [INN: AMFENAC],
(plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazin-
e-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN:
AMPIROXICAM],
2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate
[INN: AMTOLMETINGUACIL],
(plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H
pyrrolizine-1-carboxylic acid [INN: ANIROLAC],
2-[4-(alpha,alpha,alpha-tr-
ifluoro-m-tolyl)1-piperazinyl]ethyl-N-(7-trifluoromethyl-4-quinolyl)anthra-
nilate [INN: ANTRAFENINE],
5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazolo-
[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE],
4-acetamidophenyl salicylate acetate [INN: BENORILATE],
2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic
acid [INN: BERMOPROFEN],
2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropion- ic acid
[INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid
[INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid
[INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN:
BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC],
butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE],
alpha-ethyl-4-(2-methylpro- pyl)benzeneacetic acid [INN:
BUTIBUFEN], 2-(4-biphenylyl)butyric acid,
trans-4-phenylcyclohexylamine salt (1:1) [INN: BUTIXIRATE],
2-(acetyloxy)-benzoic acid, calcium salt, compound with urea (1:1)
[INN: CARBASALATE CALCIUM],
(plus/minus)-6-chloro-alpha-methylcarbazole-2-aceti- c acid [INN:
CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid
[INN: CINMETACIN],
N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benz-
othiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM],
6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC],
2-[4-(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN:
CLOBUZARIT], 5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN:
DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN],
(+)--(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN:
DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN:
ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID]
salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide
[INN: ETERSALATE],
1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid
[INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid
2-(2-hydroxyethoxy)-ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic
acid, ester with
4-butyl-4-(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN:
FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC],
3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN],
[o-(2,4-dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC],
(plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN],
4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC],
(plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl
alcohol [INN: FEPRADINOL],
4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbut- anoic acid [INN:
FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthran- ilic
acid [INN: FLUFENAMIC ACID],
(plus)-2-(p-fluorophenyl)-alpha-methyl-5- -benzoxazoleacetic acid
[INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biph- enylacetic acid
[INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl-
)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL],
2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC],
2-[4-(2'-furoyl)phenyl]propionic acid [INN: FURPROFEN],
2-[2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido]-2-deoxy-
-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic
acid 4-nitrooxybutylester [Research Code: HCT-1026],
(p-isobutylphenyl)acetic acid [INN: IBUFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl
4-(3-thienyl)phenyl-alpha-methylacetate [Research Code: IDPH-8261],
(plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN:
INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-
-acetic acid [INN: INDOMETACIN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H- -indole-3-acetic acid,
3,7,11-trimethyl-2,6,10-dodecatrienyl ester [INN: INDOMETACIN
FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN:
INDOPROFEN],
2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylide-
ne)-acetic acid [Research Code: IX-207-887], m-benzoyl-hydratropic
acid [INN: KETOPROFEN],
(DL)-5-benzoyl-3H-1,2-dihydropyrrolo[1,2-a]pyrrole-1-c- arboxylic
acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2-(hydroxymethyl-
)cinnamyl]benzofuran [Research Code: L-651896],
N-(2-carboxyphenyl)-4-chIo- roanthranilic acid [INN: LOBENZARIT],
3-(p-chlorophenyl)-1-phenylpyrazole-- 4-acetic acid [INN:
LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-
-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN:
LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate
[INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic
acid [Research Code: M-5010], N-(2,3-xylyl)anthranilic acid [INN:
MEFENAMIC ACID],
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-
amide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN:
MESALAZINE],
(2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyr-
rolizin-5-yl)-acetic acid [Research Code: ML-3000],
3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC],
4-(6-methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE],
(plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN:
NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE],
alpha-methyl-4-[(2-oxocyclohe- xylidene)methyl]benzene acetic acid
[INN: PELUBIPROFEN], 2-(p-isobutylphenyl)propionic acid
2-pyridyl-methyl ester [INN: PIMEPROFEN],
4-(p-chlorophenyl)-1-(p-fluorophenyl)pyrazole-3-acetic acid [INN:
PIRAZOLAC],
4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-
-carboxamide 1,1-dioxide [INN: PIROXICAM],
3-chloro-4-(3-pyrrolin-1-yl)hyd- ratropic acid [INN: PIRPROFEN],
2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]pr- opionic acid [INN:
PRANOPROFEN], 2,6-di-tert-butyl-4-(2'-thenoyl)phenol [INN:
PRIFELONE], alpha-cyano-1-methyl-beta-oxopyrrole-2-proplonanilide
[INN: PR1-NOMIDE],
3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L-4-benz-
amido-N,N-dipropylglutaramat
1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-- 3-acetate (ester)
[INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-pheny-
l-2(1H)quinazolinone [INN: PROQUAZONE],
7-methoxy-alpha,10-dimethylphenoth- iazine-2-acetic acid [INN:
PROTIZINIC] ACID], 2-[[2-(p-chlorophenyl)-4-met-
hyl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT],
o-hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC
ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester)
[INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN:
SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN:
SALSALATE],
4-[1-(2-fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine
[Research Code: SM-8849],
(Z)-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]in-
dene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid
[INN: SUPROFEN] 2-(4-(3-methyl-2-butenyl)phenyl)-propionic acid
[Research Code: TA-60], phthalidyl
2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN:
TALNIFLUMATE], (Z)-5-chloro-3-(2-thenoyl)-2-oxoindole-1-carboxamide
[INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic
acid [INN: TENOSAL],
4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiaz-
ine-3-carboxamide [INN: TENOXICAM],
5-(4-chlorophenyl)-N-hydroxy-1-(4-meth-
oxyphenyl)-N-methyl-1H-pyrazole-3-propionamide [INN: TEPOXALIN],
alpha-(5-benzoyl-2-thien-yl)propionic acid [INN: TIAPROFENIC ACID],
5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzo-thiaz-
olin one [INN: TIARAMIDE],
2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7-y- l)-propionic acid
N,N-dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL],
1-Cyclohexyl-2-(2-methyl-4-quinolyl)-3-(2-thiazolyl)guanidine [INN:
TIMEGADINE],
2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridi- ne [INN:
TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC
ACID], 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN:
TOLMETIN], hydroxybis[alpha-methyl-4-(2-methylpropyl)benzene
acetato-O]-aluminium [Research Code: U-18573-G],
N-(3-trifluoromethylphen- yl)-anthranilic acid n-butyl ester [INN:
UFENAMATE], 2-[4-[3-(hydroxyimino)cyclohexyl]-phenyl]propionic acid
[INN: XIMOPROFEN],
2-(10,11-dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid
[INN: ZALTOPROFEN], 2-[4-(2-thiazolyloxy)phenyl]-propionic acid
[INN: ZOLIPROFEN] and their pharmaceutically acceptable
derivatives, and instructions for the simultaneous, sequential or
separate administration of the preparations to a patient in need
thereof.
[0036] In a eigth aspect--which is an embodiment of the seventh
aspect--the invention provides a kit comprising a preparation of a
first active ingredient which is a PDE4-inhibitor selected from
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic
acid [INN: CILOMILAST],
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dic-
hloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and their
pharmaceutically acceptable derivatives, a preparation of a second
active ingredient which is conventional NSAID selected from
2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN],],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
[INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphthalineaceti- c acid [INN:
NAPROXEN], 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadia-
zin-3-carboxamide 1,1-dioxide [INN: PIROXICAM] and their
pharmaceutically acceptable derivatives, and Instructions for the
simultaneous, sequential or separate administration of the
preparations to a patient in need thereof.
[0037] In a ninth aspect--which is another embodiment of the
seventh aspect--the invention provides a kit comprising a
preparation of a first active ingredient which is selected from
3-Cyclopropylmethoxy-4-difluorom-
ethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and
its pharmaceutically acceptable derivatives, a preparation of a
second active ingredient which is selected from
2-[(2,6-dichlorophenyl)amino]benzeneace- tic acid [INN: DICLOFENAC]
and its pharmaceutically acceptable derivatives, and instructions
for the simultaneous, sequential or separate administration of the
preparations to a patient in need thereof.
[0038] It has been found that the choice of active ingredients
according to the invention is advantageous because it results in a
beneficial antiinflammatory effect while simultaneously minimizing
gastrointestinal side effects which are Inevitably associated with
the use of the conventional NSAIDs.
[0039] The pharmaceutical composition of the present invention may
be prepared by mixing the first active ingredient with the second
active ingredient.
[0040] In the above-mentioned mixing process the first active
ingredient and the second active ingredient can
[0041] a) in a first step be mixed as such, afterwards be processed
with pharmaceutically acceptable auxiliaries and/or excipients and
finally pressed to tablets or caplets
[0042] or
[0043] b) in a first step separately be processed with
pharmaceutically acceptable auxiliaries and/or excipients to give
granules or pellets containing each only one of the two active
ingredients; the pellets or granules for their part then can be
mixed in an appropriate ratio and either be pressed--optionally
with further pharmaceutically acceptable auxiliaries and/or
excipients--to give for example, tablets or caplets, or can be
filled in more or less loose form in capsules.
[0044] Therefore, in a tenth aspect of the present invention, there
is provided a process for the preparation of a pharmaceutical
composition which comprises mixing a first active ingredient which
is a PDE4-inhibitor selected from CDC-998, SH-636, D-4396, IC-485,
CC-1088 and
3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]py-
ridine-1-oxide [Research Code: SCH351591],
3-[3-(cyclopentyloxy)-4-methoxy-
benzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code:
V-11294A],
N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo--
diazepin-3(R)-yl]pyridine-4-carboxamide [Research-Code: Cl-1018,
N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-y-
l]-2-oxoacetamide [Research-Code: AWD-12-281],
N-(3,5-dichloropyridin-4-yl-
)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide
[Research-Code: AWD-12-343],
8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN:CIPAMFYLLINE],
Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]-
phenyl]-2(1H)-pyrimidone (INN: ATIZORAM],
.beta.-[3-(Cyclopentyloxy)-4-met-
hoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide
[Research-Code: CDC-801], Methanesulfonic acid
2-(2,4-dichlorophenylcarbo- nyl)-3-ureidobenzo-furan-6-yl ester
[INN: LIRIMILAST],
N-(3,5-dichloropyrid-4-yl-3-cyclopentyloxy-4-methoxybenzamide [INN:
PICLAMILAST],
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-
e-1-carboxylic acid [INN:
CILOMILAST1,3-Cyclopropylmethoxy-4-difluorometho-
xy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and
their pharmaceutically acceptable derivatives, with a second active
ingredient which is a conventional NSAID selected from glycolic
acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN:
ACECLOFENAC];
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid
[ACETYLSALICYLIC ACID],
2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylac- etate [Research
Code: AF-2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN:
ALCLOFENAC], p-[(2-methylallyl)amino]-hydratropic acid [INN:
ALMINOPROFEN], 2-amino-3-benzoylphenylacetic acid [INN: AMFENAC],
(plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazin-
e-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN:
AMPIROXICAM],
2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate
[INN: AMTOLMETINGUACIL],
(plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H
pyrrolizine-1-carboxylic acid [INN: ANIROLAC],
2-[4-(alpha,alpha,alpha-tr-
ifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7-trifluoromethyl-4-quinolyl)anthr-
anilate [INN: ANTRAFENINE],
5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazol-
o[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE],
4-acetamidophenyl salicylate acetate [INN: BENORILATE],
2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic
acid [INN: BERMOPROFEN],
2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropion- ic acid
[INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid
[INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid
[INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN:
BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC],
butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE],
alpha-ethyl-4-(2-methylpro- pyl)benzeneacetic acid [INN:
BUTIBUFEN], 2-(4-biphenylyl)butyric acid,
trans-4-phenylcyclohexylamine salt (1:1) [INN: BUTIXIRATE],
2-(acetyloxy)-benzoic acid, calcium salt, compound with urea (1:1)
[INN: CARBASALATE CALCIUM],
(plus/minus)-6-chloro-alpha-methylcarbazole-2-aceti- c acid [INN:
CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid
[INN: CINMETACIN],
N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benz-
othiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM],
6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC],
2-[4-(p-chlorophenyl)benzyloxy]-2-methyl-propionic acid [INN:
CLOBUZARIT], 5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN:
DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN],
(+)--(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN:
DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN:
ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID]
salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide
[INN: ETERSALATE],
1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid
[INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]-amino]benzoic acid
2-(2-hydroxyethoxy]ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic
acid, ester with
4-butyl-4-(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN:
FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC],
3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN],
[o-(2,4-dichlorophenoxy)phenyl]acetic acid [INN: FENCLOFENAC],
(plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN],
4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC],
(plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl
alcohol [INN: FEPRADINOL],
4-(2',4'-difluorobiphenylyl)-4-oxo-2-methylbut- anoic acid [INN:
FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthran- ilic
acid [INN: FLUFENAMIC ACID],
(plus)-2-(p-fluorophenyl)-alpha-methyl-5- -benzoxazoleacetic acid
[INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biph- enylacetic acid
[INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl-
)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL],
2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC],
2-[4-(2'-furoyl)phenyl]propionic acid [INN: FURPROFEN],
2-[2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido]-2-deoxy-
-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic
acid 4-nitrooxybutylester [Research Code: HCT-1026],
(p-isobutylphenyl)acetic acid [INN: IBUFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl
4-(3-thienyl)phenyl-alpha-methyl-acetate [Research Code:
IDPH-8261], (plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric
acid [INN: INDOBUFEN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3- -acetic acid
[INN: INDOMETACIN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-
-indole-3-acetic acid, 3,7,11-trimethyl-2,6,10-dode-catrienyl ester
[INN: INDOMETACIN FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic
acid [INN: INDOPROFEN],
2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylide-
ne)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic
acid [INN: KETOPROFEN],
(DL)-5-benzoyl-3H-1,2-dihydro-pyrrolo[1,2-a]pyrrole-1-- carboxylic
acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2-(hydroxymethy-
l)cinnamyl]benzofuran [Research Code: L-651896],
N-(2-carboxyphenyl)-4-chl- oroanthranilic acid [INN: LOBENZARIT],
3-(p-chlorophenyl)-1-phenylpyrazole- -4-acetic acid [INN:
LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2-
H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN:
LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate
[INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic
acid [Research Code: M-5010], N-(2,3-xylyl)anthranilic acid [INN:
MEFENAMIC ACID],
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-
amide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN:
MESALAZINE],
(2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyr-
rolizin-5-yl)-acetic acid [Research Code: ML-3000],
3,4-bis-(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC],
4-(6-methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE],
(plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN:
NIFLUMIC ACID], 5,5'-azodisalicylic acid [INN: OLSALAZINE],
alpha-methyl-4-[(2-oxocyclohe- xylidene)methyl]benzene acetic acid
[INN: PELUBIPROFEN], 2-(p-isobutylphenyl)propionic acid
2-pyridyl-methyl ester [INN: PIMEPROFEN],
4-(p-chlorophenyl)-1-(p-fluorophenyl)pyrazole-3-acetic acid [INN:
PIRAZOLAC],
4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-
-carboxamide 1,1-dioxide [INN: PIROXICAM],
3-chloro-4-(3-pyrrolin-1-yl)hyd- ratropic acid [INN: PIRPROFEN],
2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]pr- opionic acid [INN:
PRANOPROFEN], 2,6-di-tert-butyl-4-(2'-thenoyl)phenol [INN:
PRIFELONE], alpha-cyano-1-methyl-beta-oxopyrrole-2-propionanilide
[INN: PRINOMIDE],
3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L-4-benza- mido
N,N-dipropylglutaramat
1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3- -acetate (ester)
[INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-phenyl-
-2(1H)quinazolinone [INN: PROQUAZONE],
7-methoxy-alpha,10-dimethylphenothi- azine-2-acetic acid [INN:
PROTIZINIC] ACID], 2-[[2-(p-chlorophenyl)-4-meth-
yl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT],
o-hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC
ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester)
[INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN:
SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN:
SALSALATE],
4-[1-(2-fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine
[Research Code: SM-8849],
(Z)-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]in-
dene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid
[INN: SUPROFEN] 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid
[Research Code: TA-60], phthalidyl
2-(al-pha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN:
TALNIFLUMATE], (Z)-5-chloro-3-(2-thenoyl)-2-oxoindole-1-carboxamide
[INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic
acid [INN: TENOSAL],
4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiaz-
ine-3-carboxamide [INN: TENOXICAM],
5-(4-chlorophenyl)-N-hydroxy-1-(4-meth-
oxyphenyl)-N-methyl-1H-pyrazole-3-propionamide [INN: TEPOXALIN],
alpha-(5-benzoyl-2-thienyl)propionic acid [INN: TIAPROFENIC ACID],
5-chloro-3-(4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzo-thiaz-
olin one [INN: TIARAMIDE],
2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7-y- l)-propionic acid
N,N-dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL],
1-Cyclohexyl-2-(2-methyl-4-quinolyl)-3-(2-thiazolyl)guanidine [INN:
TIMEGADINE],
2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridi- ne [INN:
TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC
ACID], 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN:
TOLMETIN], hydroxybis[alpha-methyl-4-(2-methylpropyl)benzene
acetato-O]-aluminium [Research Code: U-18573-G],
N-(3-trifluoromethylphen- yl)-anthranilic acid n-butyl ester [INN:
UFENAMATE], 2-[4-[3-(hydroxyimino)cyclohexyl]phenyl]propionic acid
[INN: XIMOPROFEN],
2-(10,11-dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid
[INN: ZALTOPROFEN], 2-[4-(2-thiazolyloxy)phenyl]-propionic acid
[INN: ZOLIPROFEN] and their pharmaceutically acceptable
derivatives.
[0045] In an eleventh aspect--which is an embodiment of the tenth
aspect--there is provided a process for the preparation of a
pharmaceutical composition which comprises mixing a first active
ingredient which is a PDE4-inhibitor selected from
cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic
acid [INN: CILOMILAST],
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dic-
hloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and their
pharmaceutically acceptable derivatives, with a second active
ingredient which is a conventional NSAID selected from
2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID],
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC],
alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN],
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
[INN: INDOMETACIN],
(plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN:
NAPROXEN],
4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3--
carboxamide 1,1-dioxide [INN: PIROXICAM] and their pharmaceutically
acceptable derivatives.
[0046] In an twelfth aspect--which is another embodiment of the
tenth aspect--there is provided a process for the preparation of a
pharmaceutical composition which comprises mixing a first active
ingredient which is selected from
3-Cyclopropylmethoxy-4-difluoromethoxy--
N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and its
pharmaceutically acceptable derivatives, with a second active
ingredient which is selected from
2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC]
and its pharmaceutically acceptable derivatives.
[0047] The present invention further provides the use of a
pharmaceutical composition, or pharmaceutical product according to
the invention in the manufacture of a medicament for the treatment
of an inflammatory disease and/or an inflammation associated
disorder.
[0048] In a further aspect the present invention provides a method
of an effective treatment of an inflammatory disease and/or an
inflammation associated disorder which can be treated with a
conventional NSAID while minimizing gastrointestinal side effects
comprising the simultaneous, sequential or separate administration
of i) a first amount of a conventional NSAID or a pharmaceutically
acceptable derivative therof; and ii) a second amount of a PDE4
inhibitor or a pharmaceutically acceptable derivative thereof,
wherein the sum of the first and the second amount is a
therapeutically effective amount, to a patient in need thereof.
[0049] In a still further aspect the present invention provides a
method of minimizing gastrointestinal side effects frequently
associated with the use of conventional NSAIDs comprising the
simultaneous, sequential or separate administration of i) a first
amount of a conventional NSAID or a pharmaceutically acceptable
derivative therof; and ii) a second amount of a PDE4 inhibitor or a
pharmaceutically acceptable derivative thereof, wherein the sum of
the first and the second amount is a therapeutically effective
amount, to a patient in need thereof.
[0050] Said methods also include a pharmaceutical product or kit
containing a conventional NSAID and a written description which
discloses that said conventional NSAID can be administered together
with a PDE4 inhibitor (a) for the treatment of an inflammatory
disease and/or an inflammation associated disorder while minimizing
gastrointestinal side effects or (b) for the attenuation of
gastrointestinal side effects frequently associated with the use of
conventional NSAIDs. Likewise, said methods include a
pharmaceutical product or kit containing a PDE4 inhibitor and a
written description which discloses that said PDE4 inhibitor can be
administered together with a conventional NSAID (a) for the
treatment of an inflammatory disease and/or an inflammation
associated disorder while minimizing gastrointestinal side effects
or (b) for the attenuation of gastrointestinal side effects
frequently associated with the use of conventional NSAIDs.
[0051] "Inflammatory diseases" which may be mentioned in particular
are arthritis, including but not limited to rheumatoid arthritis,
osteoarthritis, systemic lupus erythematosus and juvenile
arthritis; gastrointestinal conditions such as inflammatory bowel
disease, Crohn's disease, irritable bowel syndrome and ulcerative
colitis; asthma, bronchitis and skin related disorders such as
psoriasis, eczema, burns and dermatitis.
[0052] "Inflammation associated disorders" which may be mentioned
are, for example, pain, migraine, fever and headaches.
[0053] The active ingredients may, and indeed will, as part of the
pharmaceutical composition, the pharmaceutical product or
preparation, be used in admixture with one or more pharmaceutically
acceptable auxiliaries and/or excipients.
[0054] The person skilled in the art is familiar on the basis of
his/her expert knowledge with which excipients or auxiliaries are
suitable for the desired pharmaceutical composition, product or
preparation. In addition to solvents, gel-forming agents, tablet
excipients and other active compound carriers, it is possible to
use, for example, antioxidants, dispersants, emulsifiers,
antifoams, flavor corrigents, preservatives, solubilizers,
colorants or permeation promoters and complexing agents (e.g.
cyclodextrins).
[0055] Within the meaning of the present invention, "combined use"
is preferably understood as meaning the oral administration of both
active ingredients. Further methods of administration, which may be
mentioned are the parenteral (for example intravenous injection or
infusion or intramuscular or intraarticular injection) and the
topical administration of the active ingredients.
[0056] For oral administration the pharmaceutical compositions or
products according to the invention are preferably in the form of
tablets, coated tablets, chewing tablets, lemonade tablets,
dragees, capsules, caplets, suppositories, emulsions, (sterile
parenteral) suspensions or solutions, the active ingredient content
advantageously being between 0.1 and 95% and by appropriate choice
of the excipients and the auxiliaries, it being possible to achieve
a pharmaceutical administration form precisely tailored to the
active ingredient(s) and/or to the desired onset of action (e.g. a
sustained release form or an enteric form).
[0057] For the treatment of diseases of the arthritic type or skin
related disorders, the compounds according to the invention also
can be used in form of pharmaceutical compositions or products
which are suitable for topical application. For the production of
those pharmaceutical compositions or products, the compounds
according to the invention (=active ingredients) are preferably
mixed with suitable pharmaceutical excipients and further processed
to give suitable pharmaceutical formulations. Suitable
pharmaceutical formulations which may be mentioned in this
connection are, for example, ointments, fatty ointments, creams,
pastes or gels. The pharmaceutical compositions or products for
topical application can preferably also be in form of a patch (e.g.
as TTS).
[0058] For the above-mentioned therapeutic uses the dosages
administered will, of course, vary with the first and second active
ingredients employed, the mode of administration, the treatment
desired and the disorder indicated.
[0059] However, in general, satisfactory results will be obtained
when the total daily dosage of first active ingredient(s), the PDE4
inhibitor(s), when taken oral is in the range from 1-2000 .mu.g/kg
of body weight. In the case of the especially preferred PDE4
inhibitor ROFLUMILAST, the daily dosage is in a range from 2-20
.mu.g/kg of body weight.
[0060] The total daily dosage of the second active ingredient(s),
the conventional NSAIDs also can vary within a wide range. In the
case of the especially preferred NSAIDs Diclofenac the daily doses
are in a range from 100-2000 .mu.g/kg.
Pharmacology
[0061] Investigations into the role of several NSAIDs in inhibiting
the phosphodiesterase 4 and 5 in vitro (Table 1 below) showed that
in partially purified or recombinant PDE4 and PDE5, NSAIDs with
preferential COX-2 selectivity (for example, nimesulide [INN],
CGP28238 [Research Code], L-745337 [Research Code], and the highly
selective drug celecoxib [INN]) possess PDE4 and PDE5 activity in
the .mu.M range, whereas conventional NSAIDs (for example,
acetylsalicylic acid, diclofenac [INN] or indometacin [INN]) show
only minor effects:
1TABLE 1 (IC.sub.50, .mu.M) ASS Diclofenac Indometacin Nimesulide
CGP28238 L-745337 Celecoxib PDE4 >100 >100 .about.100 58 23
31 6 PDE5 >100 >100 62 25 14 24 12
[0062] ASS, acetylsalicylic acid; diclofenac,
2-[(2,6-dichlorophenyl)amino- ]benzeneacetic acid; indomethacin,
1-(4-chlorobenzoyl)-5-methoxy-2-methyl-- 1H-indole-3-acetic acid;
nimesulide, 4'-nitro-2'-phenoxymethansulfonamide; CGP28238,
6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone; L-745337
5-methanesulfonamido-6-(2,4-difluorophenylthio)-1-indanone);
celecoxib,
(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide.
[0063] In isolated guinea pig Langendorff hearts, celecoxib
selectively increased coronary heart flow at doses consistent with
its inhibitory potency on PDE4 and 5, but had no effect on left
ventricular pressure and heart rate, thereby excluding inhibition
of PDE3.
[0064] In mice, diclofenac (3-100 mg/kg, p.o.) induced
gastrointestinal bleeding (ED.sub.60=56 mg/kg), assessed by
spectrophotometric determination of fecal hemoglobin. Treatment
with diclofenac (10-100 mg/kg, p.o. t=0 h) in the presence of the
selective PDE5 inhibitor sildenafil (3-100 mg/kg, p.o. t=-48 h to
+7 h) demonstrated no protection from NSAID-induced blood loss,
whereas treatment in the presence of several selective PDE4
inhibitors significantly reduced the amount of detectable
hemoglobin.
[0065] Influence of PDE4 Inhibition on Diclofenac Induced Blood
Loss in Mice
[0066] Methods
[0067] In Vivo Experiments
[0068] Male NMRI mice (Charles River Laboratories, Sulzfeld,
Germany) weighting 23-25 g were housed in groups of 5 under
standard conditions at a temperature of 22.degree. C.+/-2.degree.
C. and a 12 h light-dark cycle. If not otherwise stated animals had
free access to tap water and standard food pellets. Diclofenac was
administrated at doses from 1-100 mg/kg p.o.; rolipram, roflumliast
and RP73401 were given at doses from 1-100 mg/kg p.o. Preventive
treatment: Diclofenac was given at time point 0h. At time points
-24, -16, 0 h, +7 h one of the selective PDE4 inhibitors was
administered. Curative treatment: Diclofenac was given at time
point 0h. At time points +1 h and +7 h one of the selective PDE4
inhibitors was administered. The drugs used were dissolved in 4%
aqueos methyl cellulose. The animals were food reduced 24 h prior
diclofenac administration. For each experiment 5 animals were used
for one experimental point. Following 24 h administration of drugs
animals were weighted and stool was collected quantitatively and
homogenized as described below:
[0069] Detection of Hemoglobin in Feces
[0070] The modified method of Welch (Clin. Chem. 29/12, 2022-2025,
1983) was used. The amount of hemoglobin was determined by the heme
catalyzed oxidation of tolidine in the presence of hydrogen
peroxide. Feces was homogenized in destilled water in a
concentration with 1g feces/6.6 ml H.sub.2O with an ultra-turrax
(IKA-Werke, Germany). 500 .mu.l aliquots from two different areas
of the stool were taken to minimize error due to inhomogenous
distribution of blood in the feces and heated 10 min at 95.degree.
C. to inactivate peroxidases and than diluted with 500 .mu.l of
acetic acid/H.sub.2O (30/70 vol/vol). Hemoglobin was extracted in
2.5 ml of acetic acid/H.sub.2O (30/70 vol/vol) by the addition of
4.5 ml ethyl acetate. The sample was rigorously shacked and the
supernatant was used following a centrifugation step for optical
detection of hemoglobin. Tolidine was prepared freshly from a stock
solution (0.4 g tolidine in 10 ml ethanol) by mixing equal volumes
of stock solution, H.sub.2O and acetic acid and equilibrated at
room temperature. 20 .mu.l of extracted supernatant was diluted to
100 .mu.l ethyl acetate in a 96er crystall plate and incubated with
50 .mu.l of the working solution. The reaction was initiated by the
injection of 25 .mu.l hydrogen peroxide (6%) in a Wallac Victor
spectro-photometer (Turku, Finnland). The increase of OD 690 was
monitored by a kinetic analysis and expressed as
.DELTA..largecircle.D690/min.
[0071] Results
[0072] Table 2 shows the % reduction of the .DELTA.OD.sub.690/min
when a PDE4 inhibitor was administered (preventive or curative)
compared to the .DELTA.OD.sub.690/min obtained without the
administration of a PDE4-inhibitor.
2TABLE 2 [% reduction of .DELTA.OD.sub.690/min] NSAID: 30 mg/kg
NSAID: 100 mg/kg diclofenac indomethacin Rolipram 30 90% mg/kg
(prevent- ive) Rollpram 10 82% mg/kg (cur- ative) Roflumilast 10
95% mg/kg (prevent- ive) Roflumilast 3 95% mg/kg (cur- ative)
Rolipram 100 65% mg/kg (cur- ative) RP73401 100 96% mg/kg (cur-
ative)
* * * * *