CA2379319A1 - Aminobenzophenones as inhibitors of il-1.beta. and tnf-.alpha. - Google Patents
Aminobenzophenones as inhibitors of il-1.beta. and tnf-.alpha. Download PDFInfo
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- CA2379319A1 CA2379319A1 CA002379319A CA2379319A CA2379319A1 CA 2379319 A1 CA2379319 A1 CA 2379319A1 CA 002379319 A CA002379319 A CA 002379319A CA 2379319 A CA2379319 A CA 2379319A CA 2379319 A1 CA2379319 A1 CA 2379319A1
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Abstract
The present invention relates to compounds of formula (I) wherein R1 and R2 independently represent one or more, same or different substituents selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, carbamoyl, phenyl, or nitro;
R2 further being represented by hydrogen; R3 represents hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, phenyl, cyano, carboxy or carbamoyl; R4 represents hydrogen, (C1-C3)alkyl, or allyl; X represents oxygen or sulphur; with the proviso that formula (I) does not comprise the compound 2,2,2-trifluoro-<i>N</i>-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide wherein R1 is a 2-methyl, R2 is 2-chloro, R3 and R4 is hydrogen, and X is oxygen; and a salt thereof with a pharmaceutically acceptable acid, a hydrate or a solvate thereof. The compounds are valuable in the human and veterinary therapy.
R2 further being represented by hydrogen; R3 represents hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, phenyl, cyano, carboxy or carbamoyl; R4 represents hydrogen, (C1-C3)alkyl, or allyl; X represents oxygen or sulphur; with the proviso that formula (I) does not comprise the compound 2,2,2-trifluoro-<i>N</i>-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide wherein R1 is a 2-methyl, R2 is 2-chloro, R3 and R4 is hydrogen, and X is oxygen; and a salt thereof with a pharmaceutically acceptable acid, a hydrate or a solvate thereof. The compounds are valuable in the human and veterinary therapy.
Description
AMINOBENZOPHENONES AS INHIBITORS OF IL-1~ AND TNF-OC
FIELD OF THE INVENTION
This invention relates to a hitherto unknown class of compounds which shows anti-s inflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and prophylaxis of asthma, allergy, arthritis, including rheumatoid arthritis and spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin disorders, such as psoriasis and atopic dermatitis, uveitis, septic shock, AIDS, and acne.
BACKGROUND OF THE INVENTION
Previously, a series of closely related aminobenzophenones (e.g. 4-(2-amino-4-nitro-phenylamino)benzophenone) have been described (Hussein, F.A. et al, Iraqi J.
Sci., 22, 54-66 (1981)). However, there is no description of their uses. PCT/DK98/00008 discloses aminobenzophenone inhibitors of interleukin 1~ (IL-1(3) and tumour necrosis factor a (TNF-a) secretion in vitro, said inhibitors being potentially useful for treatment of inflammatory diseases in which the production of cytokines is involved in the pathogenesis, e.9. asthma, rheumatoid arthritis, psoriasis, contact dermatitis, and atopic dermatitis.
Furthermore the compounds of PCT/DK98/00008 was tested in vivo for anti-inflammatory properties in the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced murine chronic skin inflammation model, (De Young, L.M. et al, Agents Actions, 26, 335-341 (1989); Carlson, R.P. et al, Agents Actions, 17, 197-204 (1985); Alford, J.G. et al, Agents Action, 37, (1992); Stanley, P. L, et al, Skin Pharmacol, 4, 262-271 (1991)). In this chronic skin inflammation model the compounds had the same potency compared to the reference compound hydrocor-tisone.
The purpose of the present invention is to provide further pharmacologically active amino-benzophenone derivatives and related compounds.
This purpose is achieved by providing novel aminobenzophenone derivatives according to the general formula I that are potent inhibitors of interleukin 1(3 (IL-1(3) and tumour necrosis factor a (TNF-a) secretion in vitro, making them potentially useful for treatment of inflammatory diseases, in which the secretion and regulation of cytokines or more specifically interleukin 1(3 (IL-1(3) and tumour necrosis factor a (TNF-a) are involved in the pathogenesis. The inhibition or down regulation of the cytokines is possibly due to an inhibition of MAP kinases.
SUBSTITUTE SHEET (RULE 26) SUMMARY OF THE INVENTION
The compounds of the present invention are represented by the general formula I below X
\ ~ \ /
/ / \
R N F
4 i \
H F
O
wherein R1 and R2 independently represent one or more, same or different substituents selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, carbamoyl, phenyl, or nitro; R2 further being represented by hydrogen;
R3 represents hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, phenyl, cyano, carboxy, or carbamoyl;
R4 represents hydrogen, (C1-C3)alkyl, or allyl;
X represents oxygen or sulphur;
with the proviso that formula I does not comprise the compound 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]acetamide wherein R1 is 2-methyl, R2 is 2'-chloro, R3 and R4 is hydrogen, and X is oxygen, or a salt thereof with a pharmaceutically acceptable acid, a hydrate or a solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferred embodiments of the invention SUBSTITUTE SHEET (RULE 26) In compounds of the invention it is preferred that R1 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C2)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, or -CONH2; R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy;
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, carboxy, or -CONH2;
represents hydrogen, (C1-C2)alkyl, or allyl; and X represents oxygen.
More preferred are compounds of formula I wherein R1 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R3 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R4 represents hydrogen or (C1-C2)alkyl.
Further preferred compounds of general formula I are compounds wherein R1, R2, and R3 represent one substituent. R1 and R2 preferably being in the ortho position.
Even more preferred are compounds of formula I wherein R1 is in the 2-position and represents 2-methyl; wherein R2 is in the 2-position and represents 2-chloro or 2-methyl;
wherein R3 is in the 4-position and represents 4-Br or 4-F; and wherein Rq. is hydrogen.
Specific compounds of the invention are:
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 101), 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-5-fluoro-phenyl]acetamide (Compound 102), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,3-dimethylbenzoyl)-phenylamino]phenyl]acetamide (Compound 103), SUBSTITUTE SHEET (RULE 26) 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-n-butyl-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 104), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 105), 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 106), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 107), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 108), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 109), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(3-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 110), 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 111), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-ethoxy-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 112), 2,2,2-Trifluoro-N-[5-bromo-2-[3-ethoxy-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 113), and salts thereof with pharmaceutically acceptable acids, hydrates and solvates.
As used in the specification, unless specified to the contrary, the following terms have the meaning indicated:
"Alkyl" refers to any univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom, and includes the subclasses of normal alkyl (n-alkyl), and primary, secondary and tertiary alkyl groups respectively, and having the number of carbon atoms specified, including for example (C1-C3)alkyl, methyl, ethyl, n-propyl, isopropyl. Alkane refers to an acyclic branched or unbranched hydrocarbon having the general formula C~HZn+2, and therefore consisting entirely of hydrogen atoms and saturated carbon atoms.
"Olefinic group" refers to a straight or branched acyclic hydrocarbon having one or more carbon-carbon double bonds of either E or Z stereochemistry where applicable, and having the number of carbon atoms specified. The term includes, for example, (C2-C3)olefinic group, preferably a (C2-C3)alkenyl, preferably a vinyl; or allyl. Olefinic groups having SUBSTITUTE SKEET (RULE 26) only one carbon-carbon double bond, herein called alkenyl, are preferred.
"Alkoxy" refers broadly to a radical of the formula -OR, where R is alkyl as defined above, for example (C1-C3)alkoxy, (C1-C2)alkoxy, methoxy, ethoxy, n-propoxy, and the like.
"(C1-C3)alkylthio" refers broadly to a radical of the formula -SR, where R is alkyl as defined above and includes methylthio, ethylthio, n-propylthio, and 2-propylthio.
"(C1-C6)alkylamino" refers broadly to a radical of the formula -NHR or -NR2, where R is alkyl as defined above having from 1-6 carbon atoms and includes, for example, methyl-amino, dimethylamino, di-(n-propyl)amino, and n-butyl(ethyl)amino.
"(C1-C3)alkoxycarbonyl" refers broadly to a radical of the formula -COOK, where R is alkyl as defined above and includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and i-propoxycarbonyl.
"Amino" means the group -NH2.
"Carbamoyl" refers to any one of the groups -CONHZ , -CONHR, and -CONRR' where R and R' represent alkyl as defined above.
"Carboxy" refers to a radical of the formula -COOH.
"Halogen" means the same or different of fluoro, chloro, bromo, and iodo;
fluoro, chloro, and bromo being preferred.
The phenyl group of R1 and RZ may optionally be substituted, e.g. with hydroxy; amino;
nitro; cyano; halogen, preferably fluoro, chloro, or bromo; methyl; or methoxy.
The compounds can be used in the form of their salts which are formed with pharmaceuti-cally acceptable inorganic or organic acids, such as hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid propionic acid, citric acid, tartaric acid, succinic acid, benzoic acid, malefic acid, these examples being considered as non-limiting for the invention.
SUBSTITUTE SI3EET (RULE 26) Pharmacological methods To study the effect of the compound of the present invention in vitro the inhibition of the IL-1~ and TNF-a secretion was measured using the following procedure:
Cytokine production was measured in the media from lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells. The mononuclear cells were isolated from human peripheral blood by Lymphoprep~ (Nycomed, Norway) fractionation and suspended in RPMI 1640 (growth medium) with foetal calv serum (FCS, 2%), at a concentration of 5 x 105 cells/ml. The cells were incubated in 24-well tissue culture plates in 1 ml aliquots.
Test compounds were dissolved in dimethylsulfoxide (DMSO, 10 mM) and were diluted with the medium. Compounds were added to the cells for 30 minutes, then LPS (1 mg/ml final concentration) was added. The plates were incubated for 18 hours, and the concentration of IL-1(i and TNF-a in the medium was determined by enzyme-linked immunosorbent assays. The median inhibitory concentrations (IC50) of the compounds were calculated. The results are shown in Table 1.
The compounds of the present invention also show similar activities in the ability to inhibit PMN (polymorphonuclear) superoxide secretion which is also indicative of potentially useful anti-inflammatory drugs. The compounds were tested using the following p roced a re Human polymorphonuclear (PMN) granulocytes were isolated from human blood by dextran sedimentation, Lymphoprep~ fractionation and hypotonic lysis of contaminating erythrocytes. Superoxide anion generation was measured as the superoxide dismutase inhibitable reduction of ferricytochrome C (Madhu, S.B. et al, Inflammation, 16, 241, (1992)). The cells were suspended in Hanks' balanced salt solution, and incubated for 10 minutes at 37°C with test compounds. The cells were primed by the addition of TNF-a (3 ng/ml final concentration) for 10 minutes, and then ferricytochrome C, (final concentra-tion 750pg/ml), bovine serum albumin (BSA, final concentration 1 mg/ml) and formyl-methionyl-leucyl-phenylalanine (fMLP, final concentration 10-7 M) were added for 3 min-utes. The cells were chilled on ice, and were spun down. The optical densities in the cell-free supernatant was measured in a spectrophotometer. The median inhibitory concentration (IC50) of the compounds was calculated. The results are shown in Table 1.
SUBSTITL'TE SKEET (RULE 26) Table 1. Inhibition of cytokines and PMN-superoxide production in vitro by compounds of the present invention.
The median inhibition concentration (IC50, nM) of Comp. No.; IL-1[i TNF-a PMN-superoxide comp. 101 32 6.3 13 comp. 102 6.3 3.2 25 ref. a) 13 7.1 5.0 ref. b) 20 4.0 13 ref. a): 4-(2-Aminophenylamino)-2-chloro-2'-methylbenzophenone, compound 106 disclosed in PCT/DK98/00008. ref. b): 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide, compound 181 disclosed in PCT/DK98/00008.
These results show that the compounds of the present invention are able to inhibit the production of IL-1~, TNF-a and PMN-superoxide, thus making them potentially useful in the treatment of inflammatory diseases.
To study the compounds of the present invention in vivo the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced murine chronic skin inflammation model can be used (De Young, L.M. et al, Agents Actions, 26, 335-341 (1989); Carlson, R.P. et al, Agents Actions, 17, 197-204 (1985); Alford, J.G. et al, Agents Action, 37, (1992); Stanley, P.L.
et al, Skin Pharmacol, 4, 262-271 (1991)), cf. description of method in PCT/DK98/00008 hereby incorporated by reference. These results shows that the compounds of the present invention are of the same potency compared to known reference compounds, e.g.
hydrocortisone with its known side effects, whereas the compounds of the present invention are well tolerated and are non-toxic. Some members of the present class of compounds show a very low absorption, thus making them especially useful in the treatment of various dermatological diseases. In general, they may be administered by e.g. oral, intravenous, intranasal, topically or transdermal routes.
Method of preparation The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesised using the methods outlined below, together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in SUBSTITUTE SHEET (RULE 26) the art. Preferred methods include, but are not limited to, those described below.
The novel compounds of formula I may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the S reagents and materials employed and are suitable for the transformations being effected.
Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction tempera-ture, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognised by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be compatible with the reagents and reactions proposed. Not all compounds of formula I falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods can be used.
SUBSTITUTE SHEET (RULE 26) X
/
/ / N
z\ /CF3 O Z: CF3C00, OH, CI
Ia Coupling X
/ / N /
H F
I O
and R1, R2, R3, R4 and X have the above meanings.
Scheme 1 Compounds according to the present invention may be prepared by a process comprising coupling of an amine of the formula II with an acid of the formula III or an activated derivative thereof; especially trifluoroacetic anhydride, as shown in scheme 1, where R1, R2, R3, R4, and X are as defined in general formula I, except that any substituents or functional group which are potentially reactive in the coupling reaction may themselves be protected before the coupling reaction is performed and subsequently removed.
In the case where Z stand for OH, the coupling reaction or condensation is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis. These methods include, but are not limited to, use of standard SUBSTITUTE SKEET (RULE 26) coupling procedures such as mixed carbonic anhydride (isobutyl chloroformate) method, carbodiimide (N,N-dimethylaminopropyl-NI-ethyl carbodiimide (EDC)), dicyclohexyl carbodiimide, diisopropyl carbodiimide) method, active ester (pentafluorophenyl ester, p-nitrophenyl ester, N-hydroxysuccinic imido ester) method, cabonyldiimidazole method, 5 azide method, phosphorous reagents such as BOP-CI, azide method , conversion of acid (III) to an acid chloride. Some of these methods (especially carbodiimide) can be enhanced by the addition of 1-hydroxybenzotriazole (HOBt).
Compounds accordingly to the present invention with the general formula II(X=O) may be 10 prepared by several methods known to those skilled in the art of organic synthesis. One useful sequence is shown in scheme 2 were the key process comprising coupling of an amine of the formula VII with an fluoride, chloride, bromide, iodide, or triflate with the formula VIII, as shown in Scheme 2, where R1, R2, R3, and, R4 are as defined in general formula I, to give a coupled product with the general formula VI, except that any substitu-ents or functional group which are potentially reactive in the coupling reaction may themselves be protected before the coupling reaction is performed and subsequently removed. This compound VI may then be reduced to the corresponding amine with the general formula II by treatment with standard reducing agents. Examples of such reducing agents include, but are not limited to, stannous chloride dihydrate; hydrogen, ammonium formiate, or hydrazine hydrate and a catalytic amount of palladium on carbon.
SUBSTITUTE SHEET (RULE 26) O
\ \ /
I / I / \ R3 O
VII + VIII
Coupling O
\ \
/ I / \ R3 Alkylation VI, (R4=H) Y-R
VI, (R4=R) O
\ I \ / R
Reduction R / R / N \
II (X=O) L: Br, I, OS02CF3, or F and CI
Y:CI, Br, I, OS02CF3 , OS02CH3, or OTs FGI: Functional group interconversion and R1, R2, R3, and R4 have the above meanings.
Scheme 2 The coupling reaction is carried out using any of the methods for the formation of diphenylamines known to one skilled in the art of organic synthesis. The preferred method is the nucleophilc aromatic substiution method which comprising coupling of an amine with an arylfluoride or arylchloride in the presence of a base, in an suitable solvent.
Especially potassium-tert-butoxide (KOt-Bu), sodium-tert-butoxide (NaOt-Bu), sodium SUBSTITUTE SHEET (RULE 26) hydrid (NaH), and potassium hydride (KH) have proven to be the best bases in this process, but other bases may be used as well.
The reaction is typically performed at ambient temperature (20-25 °C) in dipolar aprotic solvents like dimethylsulfoxide (DMSO), dimethylformamide (DMF), or N-methylpyrroli-done (NMP) under an inert atmosphere like argon or nitrogen.
Alternatively, the coupling reaction can be done by the palladium catalysed amination method which comprising coupling of an amine with an arylhalogenide (iodide, bromide, triflate, or in some cases chloride) in the presence of a base, a suitable Pd source, and a suitable phosphine ligand in an inert solvent.
The palladium compound used in the process is not particularly limited, and as specific examples are palladium(II) acetate, palladium(II) chloride, palladium(II) bromide, dichlorobis(triphenyl-phosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylidene-acetone)dipalladium(0). The preferred ligand include, but are not limited to, racemic or non-racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as BINAP), tri-o-tolylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)-ferro-cene, bis[(2-diphenylphosphino)phenyl~ether (DPEphos), 2-dicyclohexylphosphanyl-2'-dimethylaminobiphenyl, 2-(di-tert-butylphosphino)biphenyl, and 9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene (Xantphos). The amount of palladium and ligand used in this process is typically in the range 0.1 to 10 % by mole relative to the amount of the aromatic halide (or triflate) used. Especially sodium-tert-butoxide (NaOt-Bu) and caesium carbonate (Cs2C03) have proven to be the best bases in this process, but other bases may be used as well. The reaction is typically performed at elevated temperature (80-120 °C) in inert solvents like 1,4-dioxane, toluene, benzene and tetrahydrofurane under an inert atmosphere like argon or nitrogen.
Compounds according to the present invention in which R4 is not hydrogen may be prepared by a process comprising coupling of an amine of the formula VI (R4=
H) with an alkylating agent, as shown in scheme 2, where R1, R2, R3, and, R4 are as defined in general formula I, except that any substituents or functional group which are potentially reactive in the coupling reaction may themselves be protected before the coupling reaction is performed and subsequently removed.
SUBSTITUTE SHEET (RULE 26) Typically alkylating agents of the general formula R-Y include, but are not limited to, iodides (Y=I), bromides (Y=Br), chlorides (Y=CI) and sulfonates (Y=OS02R', where R' represents methyl, trifluoromethyl or 4-methylphenyl).
Compounds according to the present invention may in special cases be prepared by a simple functional group interconversion (FGI), meaning a standard process, known to those skilled in the art of organic synthesis, where a functional group in compounds with the general formula I (or any other intermediate described herein) is transformed into a different functional group in one or more synthetic steps, leading to a new compound with the general formula I. Examples of such processes are, but are not limited to, hydrolysis of an ester to give an acid under basic conditions; deprotection of an methylether to give an phenol by treatment with e.g. borontribromide (BBr3); and catalytic hydrogenation of an olefin to give an saturated hydrocarbon.
Compounds according to the present invention in which C=X represents -(CS)-may be prepared from compounds of the invention (or any other intermediate described herein) in which C=X represents -(CO)- by a process using an appropiate thiocarbonylating agent such as phosphorous pentasulfide (P4S1~), or Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide) or the like.
SUBSTITUTE SHEET (RULE 26) O
Hal CI
X XI
Coupling O O
~ Reduction R R / N02 R / R ~ NH2 IX VII
hal: Br, I
and R1, and R2 have the above meanings.
Compounds accordingly to the present invention with the general formula VII
may be prepared by several methods known to those skilled in the art of organic synthesis. One useful sequence is shown in Scheme 3. The key step comprises coupling of a bromide (or iodide) with the general formula X with an acid chloride with the general formula XI to afford the benzophenone with the general formula IX. This compound IX may then be reduced to the corresponding amine with the general formula VII by treatment with stan-dard reducing agents. Examples of such reducing agents include, but are not limited to, stannous chloride dihydrate; hydrogen, ammonium formiate, or hydrazine hydrate and a catalytic amount of palladium on carbon. The coupling reaction is done by transforming the bromide (X) into a reactive organometallic intermediate, e.g. by treatment with butyllithium to afford the lithium derivative or by treatment with magnesium to afford the magnesium derivative. The reactivity of this intermediate is then modulated by transme-SUBSTITUTE SHEET (RULE 26) WO 01!05745 PCT/DK00/00388 tallation to e.g. zinc, by treatment with ZnCl2, ZnBr2, or ZnI2. This organozinc compound is then coupled with the acid chloride, with the general formula XI, under the influence of a palladium(0) complex in catalytic amount. Examples of such catalyst include but are not particularly limited to tetrakis(triphenylphosphine)palladium(0), tetrakis(triphenylarsine)-5 palladium(0), dichlorobis(triphenylphosphine)palladium(II), or benzylchlorobis(triphenyl-phosphine)palladium(II).
It may be more advantageous in some cases to alter the sequence of the processes described above. The described sequence of processes is not considered as being limited 10 for the preparation of the compounds of the present invention with the general formula I
and alteration of the reaction sequence is an obvious alternative for those skilled in the art of organic synthesis.
FIELD OF THE INVENTION
This invention relates to a hitherto unknown class of compounds which shows anti-s inflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and prophylaxis of asthma, allergy, arthritis, including rheumatoid arthritis and spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin disorders, such as psoriasis and atopic dermatitis, uveitis, septic shock, AIDS, and acne.
BACKGROUND OF THE INVENTION
Previously, a series of closely related aminobenzophenones (e.g. 4-(2-amino-4-nitro-phenylamino)benzophenone) have been described (Hussein, F.A. et al, Iraqi J.
Sci., 22, 54-66 (1981)). However, there is no description of their uses. PCT/DK98/00008 discloses aminobenzophenone inhibitors of interleukin 1~ (IL-1(3) and tumour necrosis factor a (TNF-a) secretion in vitro, said inhibitors being potentially useful for treatment of inflammatory diseases in which the production of cytokines is involved in the pathogenesis, e.9. asthma, rheumatoid arthritis, psoriasis, contact dermatitis, and atopic dermatitis.
Furthermore the compounds of PCT/DK98/00008 was tested in vivo for anti-inflammatory properties in the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced murine chronic skin inflammation model, (De Young, L.M. et al, Agents Actions, 26, 335-341 (1989); Carlson, R.P. et al, Agents Actions, 17, 197-204 (1985); Alford, J.G. et al, Agents Action, 37, (1992); Stanley, P. L, et al, Skin Pharmacol, 4, 262-271 (1991)). In this chronic skin inflammation model the compounds had the same potency compared to the reference compound hydrocor-tisone.
The purpose of the present invention is to provide further pharmacologically active amino-benzophenone derivatives and related compounds.
This purpose is achieved by providing novel aminobenzophenone derivatives according to the general formula I that are potent inhibitors of interleukin 1(3 (IL-1(3) and tumour necrosis factor a (TNF-a) secretion in vitro, making them potentially useful for treatment of inflammatory diseases, in which the secretion and regulation of cytokines or more specifically interleukin 1(3 (IL-1(3) and tumour necrosis factor a (TNF-a) are involved in the pathogenesis. The inhibition or down regulation of the cytokines is possibly due to an inhibition of MAP kinases.
SUBSTITUTE SHEET (RULE 26) SUMMARY OF THE INVENTION
The compounds of the present invention are represented by the general formula I below X
\ ~ \ /
/ / \
R N F
4 i \
H F
O
wherein R1 and R2 independently represent one or more, same or different substituents selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, carbamoyl, phenyl, or nitro; R2 further being represented by hydrogen;
R3 represents hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, phenyl, cyano, carboxy, or carbamoyl;
R4 represents hydrogen, (C1-C3)alkyl, or allyl;
X represents oxygen or sulphur;
with the proviso that formula I does not comprise the compound 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]acetamide wherein R1 is 2-methyl, R2 is 2'-chloro, R3 and R4 is hydrogen, and X is oxygen, or a salt thereof with a pharmaceutically acceptable acid, a hydrate or a solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferred embodiments of the invention SUBSTITUTE SHEET (RULE 26) In compounds of the invention it is preferred that R1 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C2)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, or -CONH2; R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy;
represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, carboxy, or -CONH2;
represents hydrogen, (C1-C2)alkyl, or allyl; and X represents oxygen.
More preferred are compounds of formula I wherein R1 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R3 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, or methoxy; R4 represents hydrogen or (C1-C2)alkyl.
Further preferred compounds of general formula I are compounds wherein R1, R2, and R3 represent one substituent. R1 and R2 preferably being in the ortho position.
Even more preferred are compounds of formula I wherein R1 is in the 2-position and represents 2-methyl; wherein R2 is in the 2-position and represents 2-chloro or 2-methyl;
wherein R3 is in the 4-position and represents 4-Br or 4-F; and wherein Rq. is hydrogen.
Specific compounds of the invention are:
2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 101), 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-5-fluoro-phenyl]acetamide (Compound 102), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,3-dimethylbenzoyl)-phenylamino]phenyl]acetamide (Compound 103), SUBSTITUTE SHEET (RULE 26) 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-n-butyl-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 104), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 105), 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 106), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 107), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 108), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 109), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(3-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 110), 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 111), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-ethoxy-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 112), 2,2,2-Trifluoro-N-[5-bromo-2-[3-ethoxy-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 113), and salts thereof with pharmaceutically acceptable acids, hydrates and solvates.
As used in the specification, unless specified to the contrary, the following terms have the meaning indicated:
"Alkyl" refers to any univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom, and includes the subclasses of normal alkyl (n-alkyl), and primary, secondary and tertiary alkyl groups respectively, and having the number of carbon atoms specified, including for example (C1-C3)alkyl, methyl, ethyl, n-propyl, isopropyl. Alkane refers to an acyclic branched or unbranched hydrocarbon having the general formula C~HZn+2, and therefore consisting entirely of hydrogen atoms and saturated carbon atoms.
"Olefinic group" refers to a straight or branched acyclic hydrocarbon having one or more carbon-carbon double bonds of either E or Z stereochemistry where applicable, and having the number of carbon atoms specified. The term includes, for example, (C2-C3)olefinic group, preferably a (C2-C3)alkenyl, preferably a vinyl; or allyl. Olefinic groups having SUBSTITUTE SKEET (RULE 26) only one carbon-carbon double bond, herein called alkenyl, are preferred.
"Alkoxy" refers broadly to a radical of the formula -OR, where R is alkyl as defined above, for example (C1-C3)alkoxy, (C1-C2)alkoxy, methoxy, ethoxy, n-propoxy, and the like.
"(C1-C3)alkylthio" refers broadly to a radical of the formula -SR, where R is alkyl as defined above and includes methylthio, ethylthio, n-propylthio, and 2-propylthio.
"(C1-C6)alkylamino" refers broadly to a radical of the formula -NHR or -NR2, where R is alkyl as defined above having from 1-6 carbon atoms and includes, for example, methyl-amino, dimethylamino, di-(n-propyl)amino, and n-butyl(ethyl)amino.
"(C1-C3)alkoxycarbonyl" refers broadly to a radical of the formula -COOK, where R is alkyl as defined above and includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and i-propoxycarbonyl.
"Amino" means the group -NH2.
"Carbamoyl" refers to any one of the groups -CONHZ , -CONHR, and -CONRR' where R and R' represent alkyl as defined above.
"Carboxy" refers to a radical of the formula -COOH.
"Halogen" means the same or different of fluoro, chloro, bromo, and iodo;
fluoro, chloro, and bromo being preferred.
The phenyl group of R1 and RZ may optionally be substituted, e.g. with hydroxy; amino;
nitro; cyano; halogen, preferably fluoro, chloro, or bromo; methyl; or methoxy.
The compounds can be used in the form of their salts which are formed with pharmaceuti-cally acceptable inorganic or organic acids, such as hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid propionic acid, citric acid, tartaric acid, succinic acid, benzoic acid, malefic acid, these examples being considered as non-limiting for the invention.
SUBSTITUTE SI3EET (RULE 26) Pharmacological methods To study the effect of the compound of the present invention in vitro the inhibition of the IL-1~ and TNF-a secretion was measured using the following procedure:
Cytokine production was measured in the media from lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells. The mononuclear cells were isolated from human peripheral blood by Lymphoprep~ (Nycomed, Norway) fractionation and suspended in RPMI 1640 (growth medium) with foetal calv serum (FCS, 2%), at a concentration of 5 x 105 cells/ml. The cells were incubated in 24-well tissue culture plates in 1 ml aliquots.
Test compounds were dissolved in dimethylsulfoxide (DMSO, 10 mM) and were diluted with the medium. Compounds were added to the cells for 30 minutes, then LPS (1 mg/ml final concentration) was added. The plates were incubated for 18 hours, and the concentration of IL-1(i and TNF-a in the medium was determined by enzyme-linked immunosorbent assays. The median inhibitory concentrations (IC50) of the compounds were calculated. The results are shown in Table 1.
The compounds of the present invention also show similar activities in the ability to inhibit PMN (polymorphonuclear) superoxide secretion which is also indicative of potentially useful anti-inflammatory drugs. The compounds were tested using the following p roced a re Human polymorphonuclear (PMN) granulocytes were isolated from human blood by dextran sedimentation, Lymphoprep~ fractionation and hypotonic lysis of contaminating erythrocytes. Superoxide anion generation was measured as the superoxide dismutase inhibitable reduction of ferricytochrome C (Madhu, S.B. et al, Inflammation, 16, 241, (1992)). The cells were suspended in Hanks' balanced salt solution, and incubated for 10 minutes at 37°C with test compounds. The cells were primed by the addition of TNF-a (3 ng/ml final concentration) for 10 minutes, and then ferricytochrome C, (final concentra-tion 750pg/ml), bovine serum albumin (BSA, final concentration 1 mg/ml) and formyl-methionyl-leucyl-phenylalanine (fMLP, final concentration 10-7 M) were added for 3 min-utes. The cells were chilled on ice, and were spun down. The optical densities in the cell-free supernatant was measured in a spectrophotometer. The median inhibitory concentration (IC50) of the compounds was calculated. The results are shown in Table 1.
SUBSTITL'TE SKEET (RULE 26) Table 1. Inhibition of cytokines and PMN-superoxide production in vitro by compounds of the present invention.
The median inhibition concentration (IC50, nM) of Comp. No.; IL-1[i TNF-a PMN-superoxide comp. 101 32 6.3 13 comp. 102 6.3 3.2 25 ref. a) 13 7.1 5.0 ref. b) 20 4.0 13 ref. a): 4-(2-Aminophenylamino)-2-chloro-2'-methylbenzophenone, compound 106 disclosed in PCT/DK98/00008. ref. b): 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide, compound 181 disclosed in PCT/DK98/00008.
These results show that the compounds of the present invention are able to inhibit the production of IL-1~, TNF-a and PMN-superoxide, thus making them potentially useful in the treatment of inflammatory diseases.
To study the compounds of the present invention in vivo the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced murine chronic skin inflammation model can be used (De Young, L.M. et al, Agents Actions, 26, 335-341 (1989); Carlson, R.P. et al, Agents Actions, 17, 197-204 (1985); Alford, J.G. et al, Agents Action, 37, (1992); Stanley, P.L.
et al, Skin Pharmacol, 4, 262-271 (1991)), cf. description of method in PCT/DK98/00008 hereby incorporated by reference. These results shows that the compounds of the present invention are of the same potency compared to known reference compounds, e.g.
hydrocortisone with its known side effects, whereas the compounds of the present invention are well tolerated and are non-toxic. Some members of the present class of compounds show a very low absorption, thus making them especially useful in the treatment of various dermatological diseases. In general, they may be administered by e.g. oral, intravenous, intranasal, topically or transdermal routes.
Method of preparation The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesised using the methods outlined below, together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in SUBSTITUTE SHEET (RULE 26) the art. Preferred methods include, but are not limited to, those described below.
The novel compounds of formula I may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the S reagents and materials employed and are suitable for the transformations being effected.
Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction tempera-ture, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognised by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be compatible with the reagents and reactions proposed. Not all compounds of formula I falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods can be used.
SUBSTITUTE SHEET (RULE 26) X
/
/ / N
z\ /CF3 O Z: CF3C00, OH, CI
Ia Coupling X
/ / N /
H F
I O
and R1, R2, R3, R4 and X have the above meanings.
Scheme 1 Compounds according to the present invention may be prepared by a process comprising coupling of an amine of the formula II with an acid of the formula III or an activated derivative thereof; especially trifluoroacetic anhydride, as shown in scheme 1, where R1, R2, R3, R4, and X are as defined in general formula I, except that any substituents or functional group which are potentially reactive in the coupling reaction may themselves be protected before the coupling reaction is performed and subsequently removed.
In the case where Z stand for OH, the coupling reaction or condensation is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis. These methods include, but are not limited to, use of standard SUBSTITUTE SKEET (RULE 26) coupling procedures such as mixed carbonic anhydride (isobutyl chloroformate) method, carbodiimide (N,N-dimethylaminopropyl-NI-ethyl carbodiimide (EDC)), dicyclohexyl carbodiimide, diisopropyl carbodiimide) method, active ester (pentafluorophenyl ester, p-nitrophenyl ester, N-hydroxysuccinic imido ester) method, cabonyldiimidazole method, 5 azide method, phosphorous reagents such as BOP-CI, azide method , conversion of acid (III) to an acid chloride. Some of these methods (especially carbodiimide) can be enhanced by the addition of 1-hydroxybenzotriazole (HOBt).
Compounds accordingly to the present invention with the general formula II(X=O) may be 10 prepared by several methods known to those skilled in the art of organic synthesis. One useful sequence is shown in scheme 2 were the key process comprising coupling of an amine of the formula VII with an fluoride, chloride, bromide, iodide, or triflate with the formula VIII, as shown in Scheme 2, where R1, R2, R3, and, R4 are as defined in general formula I, to give a coupled product with the general formula VI, except that any substitu-ents or functional group which are potentially reactive in the coupling reaction may themselves be protected before the coupling reaction is performed and subsequently removed. This compound VI may then be reduced to the corresponding amine with the general formula II by treatment with standard reducing agents. Examples of such reducing agents include, but are not limited to, stannous chloride dihydrate; hydrogen, ammonium formiate, or hydrazine hydrate and a catalytic amount of palladium on carbon.
SUBSTITUTE SHEET (RULE 26) O
\ \ /
I / I / \ R3 O
VII + VIII
Coupling O
\ \
/ I / \ R3 Alkylation VI, (R4=H) Y-R
VI, (R4=R) O
\ I \ / R
Reduction R / R / N \
II (X=O) L: Br, I, OS02CF3, or F and CI
Y:CI, Br, I, OS02CF3 , OS02CH3, or OTs FGI: Functional group interconversion and R1, R2, R3, and R4 have the above meanings.
Scheme 2 The coupling reaction is carried out using any of the methods for the formation of diphenylamines known to one skilled in the art of organic synthesis. The preferred method is the nucleophilc aromatic substiution method which comprising coupling of an amine with an arylfluoride or arylchloride in the presence of a base, in an suitable solvent.
Especially potassium-tert-butoxide (KOt-Bu), sodium-tert-butoxide (NaOt-Bu), sodium SUBSTITUTE SHEET (RULE 26) hydrid (NaH), and potassium hydride (KH) have proven to be the best bases in this process, but other bases may be used as well.
The reaction is typically performed at ambient temperature (20-25 °C) in dipolar aprotic solvents like dimethylsulfoxide (DMSO), dimethylformamide (DMF), or N-methylpyrroli-done (NMP) under an inert atmosphere like argon or nitrogen.
Alternatively, the coupling reaction can be done by the palladium catalysed amination method which comprising coupling of an amine with an arylhalogenide (iodide, bromide, triflate, or in some cases chloride) in the presence of a base, a suitable Pd source, and a suitable phosphine ligand in an inert solvent.
The palladium compound used in the process is not particularly limited, and as specific examples are palladium(II) acetate, palladium(II) chloride, palladium(II) bromide, dichlorobis(triphenyl-phosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylidene-acetone)dipalladium(0). The preferred ligand include, but are not limited to, racemic or non-racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as BINAP), tri-o-tolylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)-ferro-cene, bis[(2-diphenylphosphino)phenyl~ether (DPEphos), 2-dicyclohexylphosphanyl-2'-dimethylaminobiphenyl, 2-(di-tert-butylphosphino)biphenyl, and 9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene (Xantphos). The amount of palladium and ligand used in this process is typically in the range 0.1 to 10 % by mole relative to the amount of the aromatic halide (or triflate) used. Especially sodium-tert-butoxide (NaOt-Bu) and caesium carbonate (Cs2C03) have proven to be the best bases in this process, but other bases may be used as well. The reaction is typically performed at elevated temperature (80-120 °C) in inert solvents like 1,4-dioxane, toluene, benzene and tetrahydrofurane under an inert atmosphere like argon or nitrogen.
Compounds according to the present invention in which R4 is not hydrogen may be prepared by a process comprising coupling of an amine of the formula VI (R4=
H) with an alkylating agent, as shown in scheme 2, where R1, R2, R3, and, R4 are as defined in general formula I, except that any substituents or functional group which are potentially reactive in the coupling reaction may themselves be protected before the coupling reaction is performed and subsequently removed.
SUBSTITUTE SHEET (RULE 26) Typically alkylating agents of the general formula R-Y include, but are not limited to, iodides (Y=I), bromides (Y=Br), chlorides (Y=CI) and sulfonates (Y=OS02R', where R' represents methyl, trifluoromethyl or 4-methylphenyl).
Compounds according to the present invention may in special cases be prepared by a simple functional group interconversion (FGI), meaning a standard process, known to those skilled in the art of organic synthesis, where a functional group in compounds with the general formula I (or any other intermediate described herein) is transformed into a different functional group in one or more synthetic steps, leading to a new compound with the general formula I. Examples of such processes are, but are not limited to, hydrolysis of an ester to give an acid under basic conditions; deprotection of an methylether to give an phenol by treatment with e.g. borontribromide (BBr3); and catalytic hydrogenation of an olefin to give an saturated hydrocarbon.
Compounds according to the present invention in which C=X represents -(CS)-may be prepared from compounds of the invention (or any other intermediate described herein) in which C=X represents -(CO)- by a process using an appropiate thiocarbonylating agent such as phosphorous pentasulfide (P4S1~), or Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide) or the like.
SUBSTITUTE SHEET (RULE 26) O
Hal CI
X XI
Coupling O O
~ Reduction R R / N02 R / R ~ NH2 IX VII
hal: Br, I
and R1, and R2 have the above meanings.
Compounds accordingly to the present invention with the general formula VII
may be prepared by several methods known to those skilled in the art of organic synthesis. One useful sequence is shown in Scheme 3. The key step comprises coupling of a bromide (or iodide) with the general formula X with an acid chloride with the general formula XI to afford the benzophenone with the general formula IX. This compound IX may then be reduced to the corresponding amine with the general formula VII by treatment with stan-dard reducing agents. Examples of such reducing agents include, but are not limited to, stannous chloride dihydrate; hydrogen, ammonium formiate, or hydrazine hydrate and a catalytic amount of palladium on carbon. The coupling reaction is done by transforming the bromide (X) into a reactive organometallic intermediate, e.g. by treatment with butyllithium to afford the lithium derivative or by treatment with magnesium to afford the magnesium derivative. The reactivity of this intermediate is then modulated by transme-SUBSTITUTE SHEET (RULE 26) WO 01!05745 PCT/DK00/00388 tallation to e.g. zinc, by treatment with ZnCl2, ZnBr2, or ZnI2. This organozinc compound is then coupled with the acid chloride, with the general formula XI, under the influence of a palladium(0) complex in catalytic amount. Examples of such catalyst include but are not particularly limited to tetrakis(triphenylphosphine)palladium(0), tetrakis(triphenylarsine)-5 palladium(0), dichlorobis(triphenylphosphine)palladium(II), or benzylchlorobis(triphenyl-phosphine)palladium(II).
It may be more advantageous in some cases to alter the sequence of the processes described above. The described sequence of processes is not considered as being limited 10 for the preparation of the compounds of the present invention with the general formula I
and alteration of the reaction sequence is an obvious alternative for those skilled in the art of organic synthesis.
15 The present compounds are intended for use in pharmaceutical compositions which are useful in the treatment of the above mentioned diseases.
The amount required of a compound of formula I (hereinafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. A suitable dose of a compound of formula I for systemic treatment is 0.1 to 200 mg/kg bodyweight, the most preferred dosage being 0.2 to 50 mg/kg of mammal bodyweight, administered one or more times daily.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. Conveniently, the active ingredient comprises from 0.1% to 100% by weight of the formulation.
Conveniently, dosage units of a formulation contain between 0.07 mg and 1 g of the active ingredient.
For topical administration, the active ingredient preferably comprises from 1%
to 20% by weight of the formulation but the active ingredient may comprise as much as 50% w/w.
Formulations suitable for nasal or buccal administration may comprise 0.1% to 20% w/w.
for example about 2% w/w of active ingredient.
By the term ~~dosage unit" is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
SUBSTITUTE SHEET (RULE 26) The formulations, both for veterinary and human medical use, of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s). The carriers) must be ~~accep-table" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
The formulations include those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular, topical, nasal, or buccal administration.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a prede-termined amount of the active ingredient; in the form of a powder or granules;
in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, electuary or paste.
Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.
Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra articular and ophthalmic administration.
SUBSTITUTE SHEET (RULE 26) Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
Formulations suitable for administration to the nose or buccal cavity include powder, self-propelling and spray formulations, such as aerosols and atomizers.
In addition the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients.
The compositions may further contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, for instance glucocorticoids, vitamin D's, anti-histamines, platelet activating factor (PAF) antagonists, anticolinergic agents, methyl xanthines, ~i-adrenergic agents, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, and salicylazosulfapyridin (Salazopyrin).
The novel compounds of the invention are of value in the human and veterinary practice as systemic and topical therapeutic agents for the treatment and prevention of diseases.
The novel compounds show anti-acne properties and, i.a., anti-inflammatory and cytokine regulating effects possibly due to MAP kinase inhibition, and are useful in the treatment and prophylaxis of asthma, allergy, arthritis, including rheumatoid arthritis and spondylo-arthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin disorders, such as psoriasis, atopic dermatitis, uveitis, septic shock, AIDS, and osteoporosis.
The invention will now be further described in the following non-limiting general procedures, preparations and examples.
EXAMPLES
General procedures, preparations and examples The exemplified compounds I are listed in table 2. All melting points are uncorrected. For 1H and 13C nuclear magnetic resonance (NMR) spectra (300 MHz) chemical shift values (8) (in ppm) are quoted, unless otherwise specified, for deuteriochloroform and hexadeuterodimethylsulfoxide solutions relative to internal tetramethylsilane (8 0.00) or SUBSTITUTE SHEET (RULE 26) chloroform (1H NMR 8 7.25, 13C NMR 8 76.81). The value for a multiplet (m), either defined (doublet (d), triplet (t), quartet (q)) or not at the approximate mid point is given unless a range is quoted (s singlet, b broad). The organic solvents used were anhydrous.
The term "chromatography" refers to column chromatography using the flash technique and was performed on silica gel.
The following abbreviations have been used throughout:
CDC13 Deuteriochloroform DMF N,N-Dimethylformemide DMSO-d6 Hexadeuterodimethylsulfoxide Et3N Triethylamine EtOAc Ethyl acetate Et20 Diethylether HMPA Hexamethylphosphorous triamide NMM N-Methylmorpholine TH F Tetra hyd rofu ra ne TLC Thin layer chromatography HOBt 1-Hydroxybenzotriazol BOP-CI Bis(2-oxo-3-oxazolidinyl)phosphinic chloride EDC N,N-dimethylaminopropyl-NI-ethyl carbodiimide Table 2 Compounds of general formula I
Comp. Example X R1 R2 R3 R4 No. No.
101 1 O 2-CH3 2-CI 4-Br H
103 3 O 2-CH3~ 3-CH3 2-CI 4-Br H
104 4 O 2-CH3~ 4-(CH2)3CH3 2-CI 4-Br H
SUBSTITUTE SI3EET (RULE 26) Comp. Example X R1 R2 R3 R4 No. No.
105 5 O 2-CH3~4-CI 2-CI 4-Br H
106 6 O 2-CH3 2-F 4-Br H
107 7 O 2-CH3~4-CH3~ 5-CH32-CI 4-Br H
108 8 O 2-CH3~4-F 2-CI 4-Br H
109 9 O 2-CH3~5-CH3 2-CI 4-Br H
110 10 O 2-CH3~3-CI 2-CI 4-Br H
111 11 O 2-CH3~4-OCH3 2-F 4-Br H
112 12 O 2-CH3~4-OCH2CH3 2-CI 4-Br H
113 13 O 2-CH3 2-OCH2CH3 4-Br H
The numbering in table 2 refers to the numbering in the formula below X
\~ ' \ / 4 / ~N 1\ F
R R2 ~ 2 F~ N F
H F
O
General procedure 1:
Coupling of compounds of the general formula II with compounds of the general formula III (Z=OOCCF3) to give compounds of the general formula I, or a protected derivative thereof.
To a cooled (0 °C) solution of an amine (2.0 mmol), with the general formula II, and pyridine (6.0 mmol) in CH2C12 (10 ml) was added trifluoroacetic anhydride (2.2 mmol).
After stirring for 30 minuttes, the reaction mixture was poured into water and extracted with ethyl acetate twise. The organic phases were dried (MgS04), filtered and concentrated in vacuo to afford the crude product. This was further purified either by crystallization or chromatography to afford the anilide with the general formula I, or a protected derivative thereof.
SUBSTITUTE SKEET (RULE 26) Example 1 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 101) 5 General procedure: 1 Starting compound II: 4-[(2-Amino-4-bromo-phenyl)amino]-2-chloro-2'-methylbenzophenone Purification: Chromatography using EtOAc/pentane 1:9 as eluant 13C NMR (CDCI3): 8 196.8, 155.9, 155.4, 154.9, 154.4, 147.9, 138.4, 138.3, 134.9, 10 133.1, 132.1, 131.5, 131.4, 130.8, 130.7, 130.5, 130.1, 127.6, 125.6, 125.5, 120.1, 117.4, 116.7, 113.5, 113.1, 20.6 Example 2 15 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-5-fluoro-phenyl]acetamide (Compound 102) General procedure: 1 Starting compound II: 4-[(2-Amino-4-fluoro-phenyl)amino]-2-chloro-2'-methylbenzophenone 20 Purification: Chromatography using EtOAc/pentane 1:7 as eluant 13C NMR (DMSO-d6): 8 195.2, 159.9, 156.7, 155.4, 154.9, 149.1, 139.2, 136.4, 133.3, 133.2, 131.3, 131.2, 131.0, 130.7, 130.3, 130.2, 128.7, 126.7, 126.3, 126.2, 125.5, 117.6, 115.0, 114.8, 114.7, 114.3, 113.9, 113.8, 111.9, 19.7 Example 3 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,3-dimethylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 103) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-chloro-2',3'-dimethylbenzo-phenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 197.2, 155.1, 148.0, 139.7, 138.1, 135.9, 135.3, 133.8, 132.5, 132.2, 130.7, 130.6, 130.5, 127.7, 126.9, 125.5, 125.1, 120.2, 116.8, 115.4, 113.0, 20.3, 16.5 SUBSTITUTE SHEET (RULE 26) Example 4 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-n-butyl-2-methylbenzoyl)-phenylamino]phenyl]acetamide (Compound 104) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-4'-n-butyl-2-chloro-2'-methylbenzophenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 196.5, 155.1, 147.5, 147.2, 139.0, 135.4, 134.5, 132.7, 132.2, 131.9, 131.6, 131.1, 130.8, 130.5, 127.6, 125.5, 120.1, 116.7, 115.5, 113.2, 35.6, 33.2, 22.4, 20.9, 13.9 Examele 5 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 105) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2,4'-dichloro-2'-methyl-benzophenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 196.5, 155.1, 147.5, 147.2, 139.0, 135.4, 134.5, 132.7, 132.2, 131.9, 131.6, 131.1, 130.8, 130.5, 127.6, 125.5, 120.1, 116.7, 115.5, 113.2, 35.6, 33.2, 22.4, 20.9, 13.9 Example 6 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 106) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-fluoro-2'-methylbenzo-phenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 194.4, 163.3, 155.1, 150.4, 139.7, 136.7, 134.0, 132.3, 131.1, 130.6, 130.4, 128.5, 128.0, 125.5, 120.5, 119.4, 115.4, 113.5, 110.7, 102.2, 20.0 Example 7 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 107) General procedure: 1 Starting compound II: 4'-(2-Amino-4-bromophenylamino)-2'-chloro-2,4,5-SUBSTITUTE SHEET (RULE 26) trimethylbenzophenone Example 8 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 108) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-chloro-4'-fluoro-2'-methylbenzophenone Example 9 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 109) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-chloro-2',5'-dimethyl-benzophenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 196.8, 155.1, 147.7, 138.3, 135.2, 135.0, 134.9, 133.1, 132.1, 131.4, 131.0, 130.6, 130.5, 130.5, 127.6, 125.5, 120.2, 116.7, 115.5, 113.1, 20.8, 20.1 Example 10 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(3-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 110) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2,3'-dichloro-2'-methyl-benzophenone 13C NMR (CDC13): S 195.5, 155.1, 148.5, 141.5, 136.1, 135.6, 135.2, 134.0, 132.2, 131.6, 130.7, 130.4, 129.6, 127.8, 127.1, 126.4, 125.7, 120.4, 116.8, 115.4, 113.0, 17.1 Example 11 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)-phenylamino)-phenyl]acetamide (Compound 111) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-fluoro-4'-methoxy-2'-methyl-benzophenone Purification: Crystallization from a mixture of ethanol and water SUBSTITUTE SHEET (RULE 26) 13C NMR (CDC13): S 193.3, 162.5, 161.7, 155.1, 149.7, 140.9, 133.5, 132.5, 132.3, 131.5, 130.6, 130.5, 127.8, 125.6, 120.4, 120.3, 116.9, 115.4, 110.8, 110.4, 102.2, 55.3, 21.0 Example 12 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-ethoxy-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 112) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-chloro-4'-ethoxy-2'-methyl-benzophenone 13C NMR (CDC13): 8 195.6, 161.8, 155.1, 147.2, 142.5, 134.2, 134.0, 132.1, 132.1, 132.0, 131.0, 130.5, 130.0, 127.4, 125.5, 119.8, 117.8, 116.5, 115.5, 113.3, 110.9, 63.6, 21.7, 14.7 Example 13 2,2,2-Trifluoro-N-[5-bromo-2-[3-ethoxy-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 113) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-ethoxy-2'-methyl-benzophenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 197.3, 160.6, 155.1, 149.6, 141.9, 136.0, 133.4, 132.1, 131.1, 130.5, 130.3, 129.6, 127.7, 127.5, 125.5, 125.1, 121.8, 119.7, 115.5, 107.5, 98.9, 63.9, 19.9, 13.8 Example 14 Tablet containing compound Compound 101 (active substance) 50 mg Lactose 125 mg Starch 12 mg Methyl cellulose 2 mg Sodium carboxymethyl cellulose 10 mg Magnesium stearate 1 mg The active substance, lactose and starch are mixed to a homogeneous state in a suitable mixer and moistened with a 5 per cent aqueous solution of methyl cellulose 15 cps. The mixing is continued until granules are formed. If necessary, the wet granulation is passed SUBSTITUTE SHEET (RULE 26) through a suitable screen and dried to a water content of less than 1% in a suitable drier, e.g. fluid bed or drying oven. The dried granules are passed through a 1 mm screen and mixed to a homogeneous state with sodium carboxymethyl cellulose. Magnesium stearate is added, and the mixing is continued for a short period of time. Tablets with a weight of 200 mg are produced from the granulation by means of a suitable tabletting machine.
Example 15: Formulation for injection containing compound 101.
Compound 101 (active substance) 1%
Sodium chloride q.s.
Ethanol 10%
Water for injection to make 100%
The active substance is dissolved in ethanol (10%) then water for injection made isotonic with sodium chloride is added to make 100%. The mixture is filled into ampoules and sterilized.
Example 16 Cream formulation containing compound 101.
Compound 101 (10 g) was dissolved in Octyldodecyl myristate (250g) to form Part A.
Methyl paraben (1 g) and propylparaben (0.2 g) were dissolved in phenoxyethanol (6 g) and mixed with a 0.025 M Phosphate buffer pH = 7.5 (632,8 g) to form Part B.
Cetostearyl alcohol (50 g) and ARLACEL 165~ (50 g) was melted in a vessel at 70° to 80 °C. Part A
was added and heated to 60-70°C. The aqueous phase was likewise heated to 60-70 °C
and slowly added to the melted oil phase under high speed stirring. The homogenized components were cooled to room temperature.
SUBSTITUTE SHEET (RULE 26)
The amount required of a compound of formula I (hereinafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. A suitable dose of a compound of formula I for systemic treatment is 0.1 to 200 mg/kg bodyweight, the most preferred dosage being 0.2 to 50 mg/kg of mammal bodyweight, administered one or more times daily.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. Conveniently, the active ingredient comprises from 0.1% to 100% by weight of the formulation.
Conveniently, dosage units of a formulation contain between 0.07 mg and 1 g of the active ingredient.
For topical administration, the active ingredient preferably comprises from 1%
to 20% by weight of the formulation but the active ingredient may comprise as much as 50% w/w.
Formulations suitable for nasal or buccal administration may comprise 0.1% to 20% w/w.
for example about 2% w/w of active ingredient.
By the term ~~dosage unit" is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
SUBSTITUTE SHEET (RULE 26) The formulations, both for veterinary and human medical use, of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s). The carriers) must be ~~accep-table" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
The formulations include those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular, topical, nasal, or buccal administration.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a prede-termined amount of the active ingredient; in the form of a powder or granules;
in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, electuary or paste.
Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.
Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra articular and ophthalmic administration.
SUBSTITUTE SHEET (RULE 26) Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
Formulations suitable for administration to the nose or buccal cavity include powder, self-propelling and spray formulations, such as aerosols and atomizers.
In addition the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients.
The compositions may further contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, for instance glucocorticoids, vitamin D's, anti-histamines, platelet activating factor (PAF) antagonists, anticolinergic agents, methyl xanthines, ~i-adrenergic agents, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, and salicylazosulfapyridin (Salazopyrin).
The novel compounds of the invention are of value in the human and veterinary practice as systemic and topical therapeutic agents for the treatment and prevention of diseases.
The novel compounds show anti-acne properties and, i.a., anti-inflammatory and cytokine regulating effects possibly due to MAP kinase inhibition, and are useful in the treatment and prophylaxis of asthma, allergy, arthritis, including rheumatoid arthritis and spondylo-arthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin disorders, such as psoriasis, atopic dermatitis, uveitis, septic shock, AIDS, and osteoporosis.
The invention will now be further described in the following non-limiting general procedures, preparations and examples.
EXAMPLES
General procedures, preparations and examples The exemplified compounds I are listed in table 2. All melting points are uncorrected. For 1H and 13C nuclear magnetic resonance (NMR) spectra (300 MHz) chemical shift values (8) (in ppm) are quoted, unless otherwise specified, for deuteriochloroform and hexadeuterodimethylsulfoxide solutions relative to internal tetramethylsilane (8 0.00) or SUBSTITUTE SHEET (RULE 26) chloroform (1H NMR 8 7.25, 13C NMR 8 76.81). The value for a multiplet (m), either defined (doublet (d), triplet (t), quartet (q)) or not at the approximate mid point is given unless a range is quoted (s singlet, b broad). The organic solvents used were anhydrous.
The term "chromatography" refers to column chromatography using the flash technique and was performed on silica gel.
The following abbreviations have been used throughout:
CDC13 Deuteriochloroform DMF N,N-Dimethylformemide DMSO-d6 Hexadeuterodimethylsulfoxide Et3N Triethylamine EtOAc Ethyl acetate Et20 Diethylether HMPA Hexamethylphosphorous triamide NMM N-Methylmorpholine TH F Tetra hyd rofu ra ne TLC Thin layer chromatography HOBt 1-Hydroxybenzotriazol BOP-CI Bis(2-oxo-3-oxazolidinyl)phosphinic chloride EDC N,N-dimethylaminopropyl-NI-ethyl carbodiimide Table 2 Compounds of general formula I
Comp. Example X R1 R2 R3 R4 No. No.
101 1 O 2-CH3 2-CI 4-Br H
103 3 O 2-CH3~ 3-CH3 2-CI 4-Br H
104 4 O 2-CH3~ 4-(CH2)3CH3 2-CI 4-Br H
SUBSTITUTE SI3EET (RULE 26) Comp. Example X R1 R2 R3 R4 No. No.
105 5 O 2-CH3~4-CI 2-CI 4-Br H
106 6 O 2-CH3 2-F 4-Br H
107 7 O 2-CH3~4-CH3~ 5-CH32-CI 4-Br H
108 8 O 2-CH3~4-F 2-CI 4-Br H
109 9 O 2-CH3~5-CH3 2-CI 4-Br H
110 10 O 2-CH3~3-CI 2-CI 4-Br H
111 11 O 2-CH3~4-OCH3 2-F 4-Br H
112 12 O 2-CH3~4-OCH2CH3 2-CI 4-Br H
113 13 O 2-CH3 2-OCH2CH3 4-Br H
The numbering in table 2 refers to the numbering in the formula below X
\~ ' \ / 4 / ~N 1\ F
R R2 ~ 2 F~ N F
H F
O
General procedure 1:
Coupling of compounds of the general formula II with compounds of the general formula III (Z=OOCCF3) to give compounds of the general formula I, or a protected derivative thereof.
To a cooled (0 °C) solution of an amine (2.0 mmol), with the general formula II, and pyridine (6.0 mmol) in CH2C12 (10 ml) was added trifluoroacetic anhydride (2.2 mmol).
After stirring for 30 minuttes, the reaction mixture was poured into water and extracted with ethyl acetate twise. The organic phases were dried (MgS04), filtered and concentrated in vacuo to afford the crude product. This was further purified either by crystallization or chromatography to afford the anilide with the general formula I, or a protected derivative thereof.
SUBSTITUTE SKEET (RULE 26) Example 1 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 101) 5 General procedure: 1 Starting compound II: 4-[(2-Amino-4-bromo-phenyl)amino]-2-chloro-2'-methylbenzophenone Purification: Chromatography using EtOAc/pentane 1:9 as eluant 13C NMR (CDCI3): 8 196.8, 155.9, 155.4, 154.9, 154.4, 147.9, 138.4, 138.3, 134.9, 10 133.1, 132.1, 131.5, 131.4, 130.8, 130.7, 130.5, 130.1, 127.6, 125.6, 125.5, 120.1, 117.4, 116.7, 113.5, 113.1, 20.6 Example 2 15 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-5-fluoro-phenyl]acetamide (Compound 102) General procedure: 1 Starting compound II: 4-[(2-Amino-4-fluoro-phenyl)amino]-2-chloro-2'-methylbenzophenone 20 Purification: Chromatography using EtOAc/pentane 1:7 as eluant 13C NMR (DMSO-d6): 8 195.2, 159.9, 156.7, 155.4, 154.9, 149.1, 139.2, 136.4, 133.3, 133.2, 131.3, 131.2, 131.0, 130.7, 130.3, 130.2, 128.7, 126.7, 126.3, 126.2, 125.5, 117.6, 115.0, 114.8, 114.7, 114.3, 113.9, 113.8, 111.9, 19.7 Example 3 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,3-dimethylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 103) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-chloro-2',3'-dimethylbenzo-phenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 197.2, 155.1, 148.0, 139.7, 138.1, 135.9, 135.3, 133.8, 132.5, 132.2, 130.7, 130.6, 130.5, 127.7, 126.9, 125.5, 125.1, 120.2, 116.8, 115.4, 113.0, 20.3, 16.5 SUBSTITUTE SHEET (RULE 26) Example 4 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-n-butyl-2-methylbenzoyl)-phenylamino]phenyl]acetamide (Compound 104) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-4'-n-butyl-2-chloro-2'-methylbenzophenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 196.5, 155.1, 147.5, 147.2, 139.0, 135.4, 134.5, 132.7, 132.2, 131.9, 131.6, 131.1, 130.8, 130.5, 127.6, 125.5, 120.1, 116.7, 115.5, 113.2, 35.6, 33.2, 22.4, 20.9, 13.9 Examele 5 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 105) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2,4'-dichloro-2'-methyl-benzophenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 196.5, 155.1, 147.5, 147.2, 139.0, 135.4, 134.5, 132.7, 132.2, 131.9, 131.6, 131.1, 130.8, 130.5, 127.6, 125.5, 120.1, 116.7, 115.5, 113.2, 35.6, 33.2, 22.4, 20.9, 13.9 Example 6 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 106) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-fluoro-2'-methylbenzo-phenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 194.4, 163.3, 155.1, 150.4, 139.7, 136.7, 134.0, 132.3, 131.1, 130.6, 130.4, 128.5, 128.0, 125.5, 120.5, 119.4, 115.4, 113.5, 110.7, 102.2, 20.0 Example 7 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 107) General procedure: 1 Starting compound II: 4'-(2-Amino-4-bromophenylamino)-2'-chloro-2,4,5-SUBSTITUTE SHEET (RULE 26) trimethylbenzophenone Example 8 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 108) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-chloro-4'-fluoro-2'-methylbenzophenone Example 9 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 109) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-chloro-2',5'-dimethyl-benzophenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 196.8, 155.1, 147.7, 138.3, 135.2, 135.0, 134.9, 133.1, 132.1, 131.4, 131.0, 130.6, 130.5, 130.5, 127.6, 125.5, 120.2, 116.7, 115.5, 113.1, 20.8, 20.1 Example 10 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(3-chloro-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 110) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2,3'-dichloro-2'-methyl-benzophenone 13C NMR (CDC13): S 195.5, 155.1, 148.5, 141.5, 136.1, 135.6, 135.2, 134.0, 132.2, 131.6, 130.7, 130.4, 129.6, 127.8, 127.1, 126.4, 125.7, 120.4, 116.8, 115.4, 113.0, 17.1 Example 11 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)-phenylamino)-phenyl]acetamide (Compound 111) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-fluoro-4'-methoxy-2'-methyl-benzophenone Purification: Crystallization from a mixture of ethanol and water SUBSTITUTE SHEET (RULE 26) 13C NMR (CDC13): S 193.3, 162.5, 161.7, 155.1, 149.7, 140.9, 133.5, 132.5, 132.3, 131.5, 130.6, 130.5, 127.8, 125.6, 120.4, 120.3, 116.9, 115.4, 110.8, 110.4, 102.2, 55.3, 21.0 Example 12 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-ethoxy-2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 112) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-chloro-4'-ethoxy-2'-methyl-benzophenone 13C NMR (CDC13): 8 195.6, 161.8, 155.1, 147.2, 142.5, 134.2, 134.0, 132.1, 132.1, 132.0, 131.0, 130.5, 130.0, 127.4, 125.5, 119.8, 117.8, 116.5, 115.5, 113.3, 110.9, 63.6, 21.7, 14.7 Example 13 2,2,2-Trifluoro-N-[5-bromo-2-[3-ethoxy-4-(2-methylbenzoyl)-phenylamino]phenyl]-acetamide (Compound 113) General procedure: 1 Starting compound II: 4-(2-Amino-4-bromophenylamino)-2-ethoxy-2'-methyl-benzophenone Purification: Crystallization from a mixture of ethanol and water 13C NMR (CDC13): 8 197.3, 160.6, 155.1, 149.6, 141.9, 136.0, 133.4, 132.1, 131.1, 130.5, 130.3, 129.6, 127.7, 127.5, 125.5, 125.1, 121.8, 119.7, 115.5, 107.5, 98.9, 63.9, 19.9, 13.8 Example 14 Tablet containing compound Compound 101 (active substance) 50 mg Lactose 125 mg Starch 12 mg Methyl cellulose 2 mg Sodium carboxymethyl cellulose 10 mg Magnesium stearate 1 mg The active substance, lactose and starch are mixed to a homogeneous state in a suitable mixer and moistened with a 5 per cent aqueous solution of methyl cellulose 15 cps. The mixing is continued until granules are formed. If necessary, the wet granulation is passed SUBSTITUTE SHEET (RULE 26) through a suitable screen and dried to a water content of less than 1% in a suitable drier, e.g. fluid bed or drying oven. The dried granules are passed through a 1 mm screen and mixed to a homogeneous state with sodium carboxymethyl cellulose. Magnesium stearate is added, and the mixing is continued for a short period of time. Tablets with a weight of 200 mg are produced from the granulation by means of a suitable tabletting machine.
Example 15: Formulation for injection containing compound 101.
Compound 101 (active substance) 1%
Sodium chloride q.s.
Ethanol 10%
Water for injection to make 100%
The active substance is dissolved in ethanol (10%) then water for injection made isotonic with sodium chloride is added to make 100%. The mixture is filled into ampoules and sterilized.
Example 16 Cream formulation containing compound 101.
Compound 101 (10 g) was dissolved in Octyldodecyl myristate (250g) to form Part A.
Methyl paraben (1 g) and propylparaben (0.2 g) were dissolved in phenoxyethanol (6 g) and mixed with a 0.025 M Phosphate buffer pH = 7.5 (632,8 g) to form Part B.
Cetostearyl alcohol (50 g) and ARLACEL 165~ (50 g) was melted in a vessel at 70° to 80 °C. Part A
was added and heated to 60-70°C. The aqueous phase was likewise heated to 60-70 °C
and slowly added to the melted oil phase under high speed stirring. The homogenized components were cooled to room temperature.
SUBSTITUTE SHEET (RULE 26)
Claims (10)
1. A compound of the general formula I
wherein R1 independently represents one or more, same or different substituents selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyi, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, carbamoyl, phenyl, or nitro, provided that when R1 represents one substituent, it is in the ortho position, and when R1 represents more than one substituent, at least one R1 substituent is in the ortho position; and R2 represents one substituent in the ortho position, said substituent being selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, carbamoyl, phenyl, or nitro;
R3 represents hydrogen, halogen, hydroxy, mercapto, trifiuoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, phenyl, cyano, carboxy, or carbamoyl;
R4 represents hydrogen, (C1-C3)alkyl, or allyl; X represents oxygen or sulphur;
with the proviso that formula I does not comprise the compound 2,2,2-trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide wherein R1 is 2-methyl, R2 is 2-chloro, R3 and R4 is hydrogen, and X is oxygen;
and a salt thereof with a pharmaceutically acceptable acid, a hydrate or a solvate thereof.
wherein R1 independently represents one or more, same or different substituents selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyi, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, carbamoyl, phenyl, or nitro, provided that when R1 represents one substituent, it is in the ortho position, and when R1 represents more than one substituent, at least one R1 substituent is in the ortho position; and R2 represents one substituent in the ortho position, said substituent being selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, carbamoyl, phenyl, or nitro;
R3 represents hydrogen, halogen, hydroxy, mercapto, trifiuoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, phenyl, cyano, carboxy, or carbamoyl;
R4 represents hydrogen, (C1-C3)alkyl, or allyl; X represents oxygen or sulphur;
with the proviso that formula I does not comprise the compound 2,2,2-trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide wherein R1 is 2-methyl, R2 is 2-chloro, R3 and R4 is hydrogen, and X is oxygen;
and a salt thereof with a pharmaceutically acceptable acid, a hydrate or a solvate thereof.
2. A compound according to the preceding claim wherein independently ~ R1 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C2)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, or -CONH2.
~ R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy.
~ R3 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, carboxy, or -CONH2.
~ R4 represents hydrogen, (C1-C2)alkyl, or allyl.
~ X represents oxygen.
~ R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy.
~ R3 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, carboxy, or -CONH2.
~ R4 represents hydrogen, (C1-C2)alkyl, or allyl.
~ X represents oxygen.
3. A compound according to any one of the preceding claims wherein independently ~ R1 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, or methoxy.
~ R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, or methoxy.
~ R3 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, or methoxy.
~ R4 represents hydrogen or (C1-C2)alkyl.
~ R2 represents one or more, same or different substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, or methoxy.
~ R3 represents one or more, same or different substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, or methoxy.
~ R4 represents hydrogen or (C1-C2)alkyl.
4. A compound according to any one of the preceding claims wherein R1 is 2-methyl.
5. A compound according to any one of the preceding claims wherein R2 is 2-Cl.
6. A compound according to claim 1 selected from the group consisting of 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-phenyl]acetamide (Compound 101), 2,2,2-Trifluoro-N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]-5-fluoro-phenyl]acetamide (Compound 102), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)-phenylamino]phenyl]acetamide (Compound 105), 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(2-methylbenzoyl)-phenylamino]phenyl]acetamide (Compound 106), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)-phenylamino]phenyl]acetamide (Compound 107), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)-phenylamino]phenyl]acetamide (Compound 108), 2,2,2-Trifluoro-N-[5-bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)-phenylamino]phenyl]acetamide (Compound 109), 2,2,2-Trifluoro-N-[5-bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)-phenylamino]phenyl]acetamide (Compound 111), and salts thereof with pharmaceutically acceptable acids, hydrates and solvates.
7. A method of preparing a compound of formula I according to the reaction scheme said scheme describing a process comprising coupling of an amine of the formula II with an acid of the formula III or an activated derivative thereof, especially trifluoroacetic anhydride, to obtain a compound of formula I, where R1, R2, R3, R4, and X are as defined above and where any substituents or functional group which are potentially reactive in the coupling reaction are, if necessary, protected before the coupling reaction is performed and subsequently deprotected.
8. A pharmaceutical composition containing as an active ingredient a compound according to any one of claims 1 to 6 together with a pharmaceutically acceptable carrier and optionally together with a second active ingredient optionally selected from the group consisting of glucocorticoids, vitamin D's, anti-histamines, platelet activating factor (PAF) antagonists, anticolinergic agents, methyl xanthines, .beta.-adrenergic agents, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, and salicylazosulfapyridin (Salazopyrin).
9. Use of a compound according to any one of claim 1 to 6 for the preparation of a medicament for the treatment and/or prophylaxis of asthma, allergy, arthritis, including rheumatoid arthritis and spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin disorders, such as psoriasis, atopic dermatitis, uveitis, septic shock, AIDS, osteoporosis and acne.
10. A method for the treatment and/or prophylaxis of asthma, allergy, arthritis, including rheumatoid arthritis and spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin disorders, such as psoriasis, atopic dermatitis, uveitis, septic shock, AIDS, osteoporosis and acne, characterised in administering to a patient suffering from at least one of said diseases an effective amount of one or more compounds according to any one of claims 1 to 6 as an active ingredient alone, or if necessary together with a pharmaceutically acceptable carrier, and, optionally, a second active ingredient optionally selected from the group consisting of glucocorticoids, vitamin D's, anti-histamines, platelet activating factor (PAF) antagonists, anticolinergic agents, methyl xanthines, .beta.-adrenergic agents, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, and salicylazosulfapyridin (Salazopyrin).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14416999P | 1999-07-16 | 1999-07-16 | |
| US60/144,169 | 1999-07-16 | ||
| PCT/DK2000/000388 WO2001005745A1 (en) | 1999-07-16 | 2000-07-11 | AMINOBENZOPHENONES AS INHIBITORS OF IL-1β AND TNF-$g(a) |
Publications (1)
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|---|---|
| CA2379319A1 true CA2379319A1 (en) | 2001-01-25 |
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| CA002379319A Abandoned CA2379319A1 (en) | 1999-07-16 | 2000-07-11 | Aminobenzophenones as inhibitors of il-1.beta. and tnf-.alpha. |
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|---|---|
| US (1) | US6555710B1 (en) |
| EP (1) | EP1202957B1 (en) |
| JP (1) | JP2003505360A (en) |
| KR (1) | KR20020013960A (en) |
| CN (1) | CN1174956C (en) |
| AT (1) | ATE277889T1 (en) |
| AU (1) | AU768816B2 (en) |
| CA (1) | CA2379319A1 (en) |
| CZ (1) | CZ2002158A3 (en) |
| DE (1) | DE60014393T2 (en) |
| DK (1) | DK1202957T3 (en) |
| ES (1) | ES2228557T3 (en) |
| HK (1) | HK1048465B (en) |
| HU (1) | HUP0201909A3 (en) |
| PL (1) | PL353639A1 (en) |
| PT (1) | PT1202957E (en) |
| RU (1) | RU2238933C2 (en) |
| WO (1) | WO2001005745A1 (en) |
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| US5763429A (en) * | 1993-09-10 | 1998-06-09 | Bone Care International, Inc. | Method of treating prostatic diseases using active vitamin D analogues |
| US6242434B1 (en) * | 1997-08-08 | 2001-06-05 | Bone Care International, Inc. | 24-hydroxyvitamin D, analogs and uses thereof |
| US6566353B2 (en) * | 1996-12-30 | 2003-05-20 | Bone Care International, Inc. | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
| US20020128240A1 (en) * | 1996-12-30 | 2002-09-12 | Bone Care International, Inc. | Treatment of hyperproliferative diseases using active vitamin D analogues |
| US6087350A (en) * | 1997-08-29 | 2000-07-11 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Use of pretreatment chemicals to enhance efficacy of cytotoxic agents |
| EP2340840B1 (en) * | 1998-03-27 | 2012-08-29 | Oregon Health Sciences University | Pulse dose Vitamin D drug for the treatment of hyperproliferative skin diseases |
| JP2003534327A (en) | 2000-05-22 | 2003-11-18 | レオ・ファーマ・アクティーゼルスカブ | Benzophenone as inhibitor of IL-1β and TNF-α |
| AU2001278956B2 (en) * | 2000-07-18 | 2007-04-05 | Genzyme Corporation | Stabilized 1alpha-hydroxy vitamin d |
| IL160442A0 (en) | 2001-08-28 | 2004-07-25 | Leo Pharma As | Novel aminobenzophenones |
| JP2005515996A (en) * | 2001-12-03 | 2005-06-02 | ノバセア インコーポレイティッド | Pharmaceutical composition comprising active vitamin D compound |
| US20030225089A1 (en) * | 2002-04-10 | 2003-12-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors |
| ES2278170T3 (en) | 2002-07-09 | 2007-08-01 | BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG | PHARMACEUTICAL COMPOSITIONS OF ANTICOLINERGIC AND INHIBITORS OF QUINASE P38 IN THE TREATMENT OF RESPIRATORY DISEASES. |
| US20050026877A1 (en) * | 2002-12-03 | 2005-02-03 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
| US20050020546A1 (en) * | 2003-06-11 | 2005-01-27 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
| US20060189586A1 (en) * | 2003-06-11 | 2006-08-24 | Cleland Jeffrey L | Pharmaceutical compositions comprising active vitamin D compounds |
| PT1658263E (en) * | 2003-07-24 | 2010-09-06 | Leo Pharma As | Novel aminobenzophenone compounds |
| US20060003950A1 (en) * | 2004-06-30 | 2006-01-05 | Bone Care International, Inc. | Method of treating prostatic diseases using a combination of vitamin D analogues and other agents |
| US7094775B2 (en) * | 2004-06-30 | 2006-08-22 | Bone Care International, Llc | Method of treating breast cancer using a combination of vitamin D analogues and other agents |
| US20060035893A1 (en) | 2004-08-07 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders |
| PL1828148T3 (en) | 2004-12-13 | 2010-08-31 | Leo Pharma As | Triazole substituted aminobenzophenone compounds |
| PE20060777A1 (en) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | INDOLINONE DERIVATIVES FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES |
| EP1992344A1 (en) | 2007-05-18 | 2008-11-19 | Institut Curie | P38 alpha as a therapeutic target in pathologies linked to FGFR3 mutation |
| DK2266557T3 (en) * | 2008-04-22 | 2013-09-23 | Toyama Chemical Co Ltd | Combination of benzophenone derivative or salt thereof and immunosuppressant, as well as pharmaceutical composition, comprised these components |
| EP2206534A1 (en) | 2008-10-09 | 2010-07-14 | c-a-i-r biosciences GmbH | Dibenzocycloheptanone derivatives und pharmaceutical agents containing these compounds |
| HUE029018T2 (en) | 2011-10-12 | 2017-02-28 | Novartis Ag | Method for making uv-absorbing ophthalmic lenses by coating |
| MY172901A (en) | 2012-12-17 | 2019-12-13 | Alcon Inc | Method for making improved uv-absorbing ophthalmic lenses |
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- 2000-07-11 US US10/031,071 patent/US6555710B1/en not_active Expired - Fee Related
- 2000-07-11 CA CA002379319A patent/CA2379319A1/en not_active Abandoned
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- 2000-07-11 AT AT00943702T patent/ATE277889T1/en not_active IP Right Cessation
- 2000-07-11 ES ES00943702T patent/ES2228557T3/en not_active Expired - Lifetime
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- 2000-07-11 CZ CZ2002158A patent/CZ2002158A3/en unknown
- 2000-07-11 EP EP00943702A patent/EP1202957B1/en not_active Expired - Lifetime
- 2000-07-11 KR KR1020027000614A patent/KR20020013960A/en not_active Application Discontinuation
- 2000-07-11 PL PL00353639A patent/PL353639A1/en not_active Application Discontinuation
- 2000-07-11 WO PCT/DK2000/000388 patent/WO2001005745A1/en active IP Right Grant
- 2000-07-11 AU AU58071/00A patent/AU768816B2/en not_active Ceased
- 2000-07-11 JP JP2001511406A patent/JP2003505360A/en active Pending
- 2000-07-11 DK DK00943702T patent/DK1202957T3/en active
- 2000-07-11 RU RU2002103867A patent/RU2238933C2/en not_active IP Right Cessation
-
2003
- 2003-01-23 HK HK03100589.4A patent/HK1048465B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001005745A1 (en) | 2001-01-25 |
| HK1048465B (en) | 2005-04-08 |
| CZ2002158A3 (en) | 2002-08-14 |
| US6555710B1 (en) | 2003-04-29 |
| PL353639A1 (en) | 2003-12-01 |
| ES2228557T3 (en) | 2005-04-16 |
| EP1202957A1 (en) | 2002-05-08 |
| DE60014393D1 (en) | 2004-11-04 |
| AU768816B2 (en) | 2004-01-08 |
| HUP0201909A3 (en) | 2002-11-28 |
| HUP0201909A2 (en) | 2002-10-28 |
| AU5807100A (en) | 2001-02-05 |
| DK1202957T3 (en) | 2005-01-31 |
| CN1368953A (en) | 2002-09-11 |
| JP2003505360A (en) | 2003-02-12 |
| KR20020013960A (en) | 2002-02-21 |
| RU2238933C2 (en) | 2004-10-27 |
| ATE277889T1 (en) | 2004-10-15 |
| PT1202957E (en) | 2005-01-31 |
| EP1202957B1 (en) | 2004-09-29 |
| DE60014393T2 (en) | 2006-02-16 |
| HK1048465A1 (en) | 2003-04-04 |
| CN1174956C (en) | 2004-11-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |