Patent Application
20080207659
The present invention relates to inhibitors of phosphodiesterase (PDE) type 4.
Compounds disclosed herein can be useful for treating, preventing, inhibiting or suppressing asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), AIDS, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases, especially in humans.
Processes for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds and their use as phosphodiesterase (PDE) type 4 inhibitors are provided.
It is known that cyclic adenosine-3′,5′-monophosphate (cAMP) exhibits an important role of acting as an intracellular secondary messenger (Sutherland et al., Pharmacol. Rev., (1960) 12, 265). Its intracellular hydrolysis to adenosine 5′-monophosphate (AMP) causes number of inflammatory conditions which are not limited to psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis or ulcerative colitis. The most important role in the control of cAMP (as well as of cGMP) levels is played by cyclic nucleotide phosphodiesterases (PDE) which represent a biochemically and functionally, highly variable superfamily of enzymes. Eleven distinct families with more than 25 gene products are currently recognized. Although PDE 1, PDE 2, PDE 3, PDE 4, and PDE 7 all use cAMP as a substrate, only the PDE 4 and PDE 7 types are highly selective for hydrolysis of cAMP. Inhibitors of PDE, particularly the PDE 4 inhibitors, such as rolipram or Ro-1724 are therefore known as cAMP-enhancers. Immune cells contain type 4 and type 3 PDE, the PDE 4 type being prevalent in human mononuclear cells. Thus the inhibition of phosphodiesterase type 4 has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes.
The initial observation that xanthine derivatives, theophylline and caffeine inhibit the hydrolysis of cAMP led to the discovery of the required hydrolytic activity in the cyclic nucleotide phosphodiesterase (PDE) enzymes. Distinct classes of PDEs have been recognized (Beavo et al., TIPS, (1990) 11, 150), and their selective inhibition has led to improved drug therapy (Nicholus, et al. TIPS, (1991) 12, 19). Thus it was recognized that inhibition of PDE 4 could lead to inhibition of inflammatory mediator release (Verghese et. al, J. Mol. Cell. Cardiol, (1989) 12 (Suppl.II), S 61) and airway smooth muscle relaxation.
WO 01/19798 discloses inhibitors of Factor Xa. WO 2005/016862 discloses substituted arylalkanoic acid derivatives, having superior suppressing action on prostaglandin production and leukotriene production. WO 02/76946 discloses pyridine derivatives, described as functional blockers of human vanilloid receptor 1 (hVR1). WO 2004/064835 discloses use of substituted benzimidazolones, benzoxazolones and benzothiazolones, described as ion channel modulating agents. WO 00/34248 discloses benzimidazolone, benzoxazolone or benzothiazolone derivatives, described as ion channel modulating agents. WO 00/66564 discloses benzimidazolones and analogues as progesterone receptor ligands. WO 93/08180 discloses benzoxazole, benzothiazole and benzimidazole derivatives, described as fungicides. WO 2004/096130 discloses heterocyclic compounds, described as inhibitors of Akt kinase activity. WO 02/14275 discloses heterocyclic sulfonamide derivatives, described as useful for potentiating glutamate receptor function.
The present invention provides inhibitors of phosphodiesterase (PDE) type 4, which can be used for treating, preventing, inhibiting or suppressing asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), AIDS, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases. Processes for the synthesis of these compounds are also provided.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides of these compounds having the same type of activity are also provided.
Pharmaceutical compositions containing the compounds, along with pharmaceutically acceptable carriers, excipients or diluents and optionally containing one or more other compounds, are provided, which can be used for treating, preventing, inhibiting or suppressing asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), AIDS, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases.
The present invention encompasses compounds having the structure of Formula I,
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides, wherein
Y1 and Y2 independently can be hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl or heteroarylalkyl;
X1 and X2 independently can be oxygen or sulphur;
X can be nitrogen or carbon;
R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, —CORx, —NRxRy, carboxy, or —C(═X3)NRxRy; and
Rx and Ry independently can be hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl or heteroarylalkyl; Rx and Ry may also join together to form cycloalkyl or heterocyclyl ring and X3 can be oxygen or sulfur.
The following definitions apply to terms as used herein.
The term “alkyl,” unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or —NRα—, wherein Rα can be hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl, —C(═O)ORλ, SOmRχ or —C(═O)NRλRπ. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, (heterocyclyl)alkyl, cycloalkoxy, —CH═N—O(C1-6alkyl), —CH═N—NH(C1-6alkyl), —CH═N—NH(C1-6alkyl)-C1-6alkyl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, —NHC(═O)Rλ, —NRλRπ, —C(═O)NRλRπ, —NHC(═O)NRλRπ, —C(═O)heteroaryl, C(═O)heterocyclyl, —O—C(═O)NRλRπ, {wherein Rλ and Rπ are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or carboxy}, nitro or —SOmRχ (wherein m is an integer from 0-2 and Rχ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, —NRλRπ, —C(═O)NRλRπ, —OC(═O)NRλRπ, —NHC(═O)NRλRπ, hydroxy, alkoxy, halogen, CF3, cyano, and —SOmRχ; or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or —NRα— (wherein Rα, Rλ, Rπ, m and Rλ, are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, —NRλRπ, —C(═O)NRλRπ, —O—C(═O)NRλRπ, hydroxy, alkoxy, halogen, CF3, cyano, and —SOmRχ (wherein Rλ, Rπ, m and Rχ are the same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term “alkylene,” as used herein, refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms and one or more hydrogen can optionally be substituted with alkyl, hydroxy, halogen or oximes. This term can be exemplified by groups such as methylene, ethylene, propylene isomers (e.g., —CH2CH2CH2 and —CH(CH3)CH2) and the like. Alkylene may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryloxy, heteroaryloxy, aminosulfonyl, —COORχ, —NHC(═O)Rλ, —NRλRπ, —C(═O)NRλRπ, —NHC(═O)NRλRπ, —C(═O)heteroaryl, C(═O)heterocyclyl, —O—C(═O)NRλRπ, nitro, —S(O)mRλ (wherein Rλ, Rπ, and Rχ are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, —COORχ, —NRλRπ, C(═O)NRλRπ, —OC(═O)NRλRπ, —NHC(═O)NRλRπ, hydroxy, alkoxy, halogen, CF3, cyano, and —S(O)mRλ (wherein Rλ, Rπ, m and Rχ are the same as defined earlier). Alkylene can also be optionally interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and —NRα (wherein Rα is the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, acyl, aralkyl, alkoxy, hydroxy, carboxy, —C(═O)ORχ, halogen, CF3, cyano, —NRλRπ, —S(O)mRχ, —C(═O)NRλRπ, —OC(═O)NRλRπ, —CONH—, —C═O or —C═NOH (wherein Rλ, Rπ, m and Rχ are the same as defined earlier).
The term “alkenyl,” unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans or geminal geometry. Alkenyl groups can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and —NRα— (wherein Rα is the same as defined earlier). In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, —NHC(═O)Rλ, —NRλRπ, —C(═O)NRλxRπ, —NHC(═O)NRλRπ, —O—C(═O)NRλRπ, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, keto, carboxyalkyl, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, hydroxyamino, alkoxyamino, nitro or SOmRχ (wherein Rλ, Rπ, m and Rχ are as defined earlier). Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkoxy, halogen, —CF3, cyano, —NRλRπ, —C(═O)NRλRπ, —O—C(═O)NRλRπ, and —SOmRχ (wherein Rλ, Rπ, m and Rχ are as defined earlier). Groups, such as ethenyl or vinyl (CH═CH2), 1-propylene or allyl (—CH2CH═CH2), iso-propylene (—C(CH3)═CH2), bicyclo[2.2.1]heptene, and the like, exemplify this term.
The term “alkenylene” unless otherwise specified, refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 6 carbon atoms with cis, trans or geminal geometry. In the event that alkenylene is attached to the heteroatom, the double bond cannot be alpha to the heteroatom. The alkenylene group can be connected by two bonds to the rest of the structure of compound of Formula I. Alkenylene may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, —NHC(═O)Rλ, —NRλRπ, —C(═O)NRλRπ, —NHC(═O)NRλRπ, —OC(═O)NRλRπ, (wherein Rλ and Rπ are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, —COORχ (wherein Rχ is the same as defined earlier), arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, alkoxyamino, nitro, —S(O)mRχ (wherein Rχ and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, —COORχ (wherein Rχ is the same as defined earlier), hydroxy, alkoxy, halogen, —CF3, cyano, —NRλRπ, —C(═O)NRλRπ, —OC(═O)NRxRπ (wherein Rλ and Rπ are the same as defined earlier) and —S(O)mRχ (wherein Rχ and m are the same as defined earlier).
The term “alkynyl,” unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. Alkynyl groups can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and —NRα (wherein Rα is the same as defined earlier). In the event that alkynyl groups are attached to a heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, —NHC(═O)Rλ, —NRλRπ, —NHC(═O)NRλRπ, —C(═O)NRλRπ, —O—C(═O)NRλRπ or SOmRχ (wherein Rλ, Rπ, m and Rχ are the same as defined earlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF3, —NRλRπ, —C(═O)NRλRπ, —NHC(═O)NRλRπ, —C(═O)NRλRπ, cyano or —SOmRχ (wherein Rλ, Rπ, m and Rχ are the same as defined earlier).
The term “alkynylene” unless otherwise specified, refers to a diradical of a triply-unsaturated hydrocarbon, preferably having from 2 to 6 carbon atoms. In the event that alkynylene is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom. The alkenylene group can be connected by two bonds to the rest of the structure of compound of Formula I. Alkynylene may further be substituted with one or more substituents such as alkyl, alkenyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, nitro, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroarylalkyl, —NHC(═O)Rλ, —NRλRπ, —NHC(═O)NRλRπ, —C(═O)NRλxRπ, —OC(═O)NRλRπ, (wherein Rλ and Rπ are the same as defined earlier), —S(O)mRχ (wherein Rχ and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, —COORχ (wherein Rχ is the same as defined earlier), hydroxy, alkoxy, halogen, CF3, —NRλRπ, —C(═O)NRλRπ, —NHC(═O)NRλRπ, —C(═O)NRλRπ, (wherein Rλ and Rπ are the same as defined earlier), cyano, and —S(O)mR9χ (wherein Rχ and m are the same as defined earlier).
The term “cycloalkyl,” unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like or multiple ring structures, including adamantanyl, and bicyclo[2.2.1]heptane or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, —NRλRπ, —NHC(═O)NRλRπ, —NHC(═O)Rλ, —C(═O)NRλRπ, —O—C(═O)NRλRπ, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or SOmRχ (wherein Rχ, Rπ, m and Rχ are the same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkoxy, halogen, CF3, —NRλRπ, —C(═O)NRλRπ, —NHC(═O)NRλRπ, —OC(═O)NRλRπ, cyano or —SOmRχ (wherein Rχ, Rπ, m and Rχ are the same as defined earlier). “Cycloalkylalkyl” refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier
The term “alkoxy” denotes the group O-alkyl, wherein alkyl is the same as defined above.
The term “aryl,” unless otherwise specified, refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups. For example, aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COORχ, NHC(═O)Rλ, —NRλRπ, —C(═O)NRλRπ, —NHC(═O)NRλRπ, —O—C(═O)NRλRπ, —SOmRχ, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino, mercapto, haloalkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, thioalkyl, —CONHRπ, —OCORπ, —CORπ, —NHSO2Rπ or —SO2NHRπ (wherein Rλ, Rπ, m and Rχ are the same as defined earlier). Aryl groups optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S. Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
The term “aralkyl,” unless otherwise specified, refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined below. Examples of aralkyl groups include benzyl, ethylphenyl, propylphenyl, naphthylmethyl and the like.
The term “carboxy,” unless otherwise specified, refers to —C(═O)OR2 (wherein R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heteroarylalkyl or heterocyclylalkyl).
The term “heteroaryl,” unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms or a bicyclic or tricyclic aromatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S optionally substituted with 1 to 4 substituent(s) selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, —NRλRπ, CH═NOH, —(CH2)wC(═O)Rη {wherein w is an integer from 0-4 and Rη is hydrogen, hydroxy, ORλ, NRλRπ, —NHORω or —NHOH}, —C(═O)NRλRπ, —NHC(═O)NRλRπ, —SOmRχ, —O—C(═O)NRλRπ, —O—C(═O)Rλ, or —O—C(═O)ORλ (wherein m, Rχ, Rλ and Rπ are as defined earlier and Rω is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl, benzothiazolyl, benzoxazolyl, 3H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl and the like.
The term “heterocyclyl,” unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, optionally substituted aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, —O—C(═O)Rλ, —O—C(═O)ORλ, —C(═O)NRλRπ, SOmRχ, —O—C(═O)NRλRπ, —NHC(═O)NRλRπ, NRλRπ, mercapto, haloalkyl, thioalkyl, —COORχ, —COONHRλ, —CORλ, —NHSO2Rλ or SO2NHRλ (wherein m, Rχ, Rλ and Rπ are as defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more double bonds. Such ring systems can be mono-, bi- or tricyclic. Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, carbaxolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl, isoquinolinyl, or piperazinyl and the like.
“Heteroarylalkyl,” unless otherwise specified, refers to an alkyl-heteroaryl group, wherein the alkyl and heteroaryl portions are the same as defined earlier.
“Heterocyclylalkyl,” unless otherwise specified, refers to an alkyl-heterocyclyl group, wherein the alkyl and heterocyclyl portions of the group are the same as defined earlier.
The term “acyl” as defined herein refers to —C(═O)R1 wherein R1 is the same as defined earlier.
The term “haloalkyl” refers to a branched or straight chain alkyl group in which at least one hydrogen atom is replaced with a halogen. Examples of haloalkyl include, but are not limited to, chloromethyl, difluoromethyl, trifluoromethyl, 1-fluoro-2-chloro-ethyl, 5-fluoro-hexyl, 3-difluoro-isopropyl, 3-chloro-isobutyl, chlorodifluoromethyl and the like.
The term “substituted amino” unless otherwise specified, refers to a group —N(Rk)2 wherein each Rk is independently selected from the group hydrogen provided that both Rk groups are not hydrogen (defined as “amino”), alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, S(O)mRχ (wherein m and Rχ are the same as defined above), —C(═Rv)NRλRy (wherein Rv is O or S & Rλ and Ry are the same as defined earlier) or NHC(═Rv)NRyRλ (wherein Rv, Ry and Rλ are the same as defined earlier). Unless otherwise constrained by the definition, all amino substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, carboxy, —COORχ (wherein Rχ is the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, —C(═Rv)NRλRy (wherein Rv is the same as defined earlier), —O(C═O)NRλRy, —OC(═Rv)NRλRy (wherein Rλ, Ry and Rv are the same as defined earlier), —S(O)mRχ (wherein Rχ and m are the same as defined above).
The compounds of the present invention can be used for treating, preventing, inhibiting or suppressing asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), AIDS, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases. Accordingly, the present invention encompasses a method for treating, preventing, inhibiting or suppressing asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), AIDS, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases, which comprises administering to a mammal, a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
The compounds of the present invention may be prepared by the process described herein. Further, the various synthetic steps described herein may be performed in an alternate sequence in order to give the desired compounds.
The compounds of Formulae V, VI, VIII, IX, XI and XII can be prepared by following reaction procedure as depicted in Scheme I, which comprises coupling of a compound of Formula II (wherein X1, X2, Y1, Y2 and X are the same as defined earlier) with a compound of Formula IIa (wherein hal is fluorine, chlorine, bromine or iodine) to give a compound of Formula III, which can undergo reduction to give a compound of Formula IV, which can undergo cyclization by reacting with a compound of Formula K [wherein Formula K is (CO2CH2C6H5)2O, (CO2C(CH3)3)2O, (CO2C(CH3)2CHBr2)2O or (CO2C(CH3)2CCl3)2O] to give a compound of Formula V [wherein K′ is —CH2C6H5, —C(CH3)3, —C(CH3)2CHBr2 or —C(CH3)2CCl3, respectively], which can be deprotected to give a compound of Formula VI, which can be reacted with
The coupling of a compound of Formula II with a compound of Formula IIa to give a compound of Formula III can be carried out in the presence of a base, for example, sodium hydride, potassium hydride or lithium hydride in a solvent, for example, tetrahydrofuran, dioxane, toluene or iso-propyl alcohol.
The reduction of a compound of Formula III to give a compound of Formula IV can be carried out with reducing agents, for example, palladium on carbon in presence of hydrogen gas or source of hydrogen (for example, ammonium formate solution, formic acid or cyclohexene) in a solvent, for example, methanol, ethanol, iso-propyl alcohol, ethyl acetate, dimethylformamide, tetrahydrofuran, diethylether or dioxane.
The cyclization of a compound of Formula IV with a compound of Formula K to give a compound of Formula V can be carried out in a solvent, for example, acetonitrile, dichloromethane, dichloroethane, chloroform or carbon tetrachloride in the presence of a base, for example, 4-dimethylaminopyridine, N,N-diisopropylethylamine, N-methylmorpholine or pyridine.
The deprotection of a compound of Formula V [wherein K′ is —C(CH3)3], to give a compound of Formula VI can be carried out in the presence of an alkali metal carbonate, for example, potassium carbonate, sodium carbonate or lithium carbonate or an alkali metal bicarbonate, for example, potassium bicarbonate, lithium bicarbonate or sodium bicarbonate in an alcohol, for example, methanol, ethanol, propanol or isopropylalcohol.
Alternatively, the deprotection of a compound of Formula V [wherein K′ is —C(CH3)3] can be carried out in the presence of trifluoro acetic anhydride in dichloromethane.
The deprotection of a compound of Formula V (wherein K′ is —CH2C6H5) to give a compound of Formula VI can be carried out in the presence of an alkali metal hydroxide, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide in an alcohol, for example, methanol, ethanol, propanol or isopropylalcohol.
Alternatively, the deprotection of a compound of Formula V (wherein K′ is —CH2C6H5) can be carried out in the presence of a deprotecting agent, for example, palladium on carbon in presence of hydrogen gas or palladium on carbon with a source of hydrogen gas (for example, ammonium formate solution, cyclohexene or formic acid) in a solvent, for example, methanol, ethanol, propanol or isopropylalcohol.
The deprotection of a compound of Formula V (wherein K′ is —C(CH3)2CHBr2) to give a compound of Formula VI can be carried out in an acidic solution of an alcohol (for example, hydrochloric acid solution of methanol, ethanol, propanol or isopropylalcohol) or trifluoroacetic acid in dichloromethane.
The deprotection of a compound of Formula V (wherein K′ is —C(CH3)2CCl3) to give a compound of Formula VI can be carried out by a supernucleophile, for example, lithium cobalt (I) phthalocyanine, zinc and acetic acid or cobalt phthalocyanine.
Alternatively, the compound of Formula VI can be prepared by reacting compound of Formula IV with a carbonylating agent (for example, carbonyldiimidazole) in the presence of a base, for example, 4-dimethylaminopyridine, N,N-diisopropylethylamine, N-methylmorpholine or pyridine.
The reaction of a compound of Formula VI with a compound of Formula VII to give a compound of Formula VIII can be carried out in the presence of a base, for example, 4-dimethylaminopyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or pyridine in a solvent, for example, dichloromethane, dichloroethane, carbon tetrachloride or chloroform.
The reaction of a compound of Formula VI with a compound of Formula VIa to give a compound of Formula IX can be carried out in the presence of a base, for example, potassium tert-butoxide, sodium hydride, lithium hydride or potassium hydride in a solvent, for example, dimethylformamide, acetonitrile or tetrahydrofuran.
The reaction of a compound of Formula VI with a compound of Formula X to give a compound of Formula XI can be carried out in the presence of a base, for example, potassium tert-butoxide, sodium hydride, lithium hydride, dimethylaminopyridine or potassium hydride in a solvent, for example, tert-butanol, dichloromethane, tetrahydrofuran, acetonitrile or dimethylformamide.
The reaction of a compound of Formula VI with a compound of Formula XIIa to give a compound of Formula XII can be carried out in the presence of a base, for example, cesium carbonate, sodium hydride, lithium hydride or potassium hydride in a solvent, for example, dichloromethane, tetrahydrofuran or dimethylformamide.
Particular illustrative compounds which may be prepared by following, for example, the scheme disclosed herein include:
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides thereof.
The term “pharmaceutically acceptable” means approved by regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.
The term “pharmaceutically acceptable salts” refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as carboxylic acids), and the like.
The term “pharmaceutically acceptable solvates” refers to solvates with water (i.e. hydrates, hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents, for example, solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
All stereoisomers of the compounds of the invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at particular carbon atoms, or their substituents. Consequently, compounds of present invention can exist in enantiomeric or diastereomeric forms or in mixture(s) thereof. The processes for the preparation can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods, for example, chromatographic or fractional crystallization.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.
In another aspect, the present invention includes pharmaceutical compositions comprising, as an active ingredient, at least one of the disclosed compound or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, an enantiomer, a diastereomer or N-oxide, together with a pharmaceutically acceptable carrier, excipient or diluent. Compounds disclosed herein may be administered to a mammal for treatment, prevention, inhibition or suppression of asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), AIDS, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases, by any route, which effectively transports the active compound to the appropriate or desired site of action such as oral, nasal, pulmonary, transdermal or parenteral (rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal). The choice of pharmaceutical carrier, excipient or diluent can be made with regard to the intended route of administration and standard pharmaceutical practice.
Where desired, the compounds of Formula I or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides may be advantageously used in combination with one or more other compounds. Examples of other compounds, which may be used in combination with compounds of Formula I of this invention or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides include corticosteroids, B2-agonists, leukotriene antagonists, 5-lipoxygenase inhibitors, chemokine inhibitors, muscarinic receptor antagonists, p38 MAP kinase inhibitors, anticholinergics, antiallergics, PAF (platelet activating factor) antagonists, EGFR (epidermal growth factor receptor) kinase inhibitors, additional PDE 4 inhibitors, or combinations thereof.
The one or more β2-agonists as described herein may be chosen, for example, from those described in the art. The 132-agonists may include, for example, one or more compounds described in U.S. Pat. No. 3,705,233; 3,644,353; 3,642,896; 3,700,681; 4,579,985; 3,994,974; 3,937,838; 4,419,364; 5,126,375; 5,243,076; 4,992,474; or 4,011,258.
β2-agonists include, for example, one or more of albuterol, salbutamol, biltolterol, pirbuterol, levosalbutamol, tulobuterol, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol, carmoterol, arformoterol, formoterol, and their pharmaceutically acceptable salts or solvates thereof.
Corticosteroids as described herein may be chosen, for example, from those described in the art. Corticosteroids may include, for example, one or more compounds described in U.S. Pat. No. 3,312,590; 3,983,233; 3,929,768; 3,721,687; 3,436,389; 3,506,694; 3,639,434; 3,992,534; 3,928,326; 3,980,778; 3,780,177; 3,652,554; 3,947,478; 4,076,708; 4,124,707; 4,158,055; 4,298,604; 4,335,121; 4,081,541; 4,226,862; 4,290,962; 4,587,236; 4,472,392; 4,472,393; 4,242,334; 4,014,909; 4,098,803; 4,619,921; 5,482,934; 5,837,699; 5,889,015; 5,278,156; 5,015,746; 5,976,573; 6,337,324; 6,057,307; 6,723,713; 6,127,353; or 6,180,781.
Corticosteroids may include, for example, one or more of alelometasone, amcinonide, amelometasone, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, cloticasone, cyclomethasone, deflazacort, deprodone, dexbudesonide, diflorasone, difluprednate, fluticasone, flunisolide, halometasone, halopredone, hydrocortisone, hydrocortisone, methylprednisolone, mometasone, prednicarbate, prednisolone, rimexolone, tixocortol, triamcinolone, tolterodine, oxybutynin, ulobetasol, rofleponide, GW 215864, KSR 592, ST-126, dexametbasone and pharmaceutically acceptable salts, solvates thereof. Preferred corticosteroids include, for example, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, and dexamethasone, while budesonide, fluticasone, mometasone, ciclesonide. Examples of possible salts or derivatives include: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates, or furoates. In some cases, the corticosteroids may also occur in the form of their hydrates.
Muscarinic receptor antagonists include substances that directly or indirectly block activation of muscarinic cholinergic receptors. Examples include, but are not limited to, quaternary amines (e.g., methantheline, ipratropium, propantheline), tertiary amines (e.g., dicyclomine, scopolamine) and tricyclic amines (e.g., telenzepine). Other muscarinic receptor antagonists include benztropine, hexahydro-sila-difenidol hydrochloride (HHSID hydrochloride), (+/−)-3-quinuclidinyl xanthene-9-carboxylate hemioxalate (QNX-hemioxalate), telenzepine dihydrochloride and atropine.
Anticholinergics include, for example, tiotropium salts, ipratropium salts, oxitropium salts, salts of the compounds known from WO 02/32899: tropenol N-methyl-2,2-diphenylpropionate, scopine N-methyl-2,2-diphenylpropionate, scopine N-methyl-2-fluoro-2,2-diphenylacetate and tropenol N-methyl-2-fluoro-2,2-diphenylacetate; as well as salts of the compounds known from WO 02/32898: tropenol N-methyl-3,3′,4,4′-tetrafluorobenzilate, scopine N-methyl-3,3′,4,4′-tetrafluorobenzilate, scopine N-methyl-4,4′-dichlorobenzilate, scopine N-methyl-4,4′-difluorobenzilate, tropenol N-methyl-3,3′-difluorobenzilate, scopine N-methyl-3,3′-difluorobenzilate, and tropenol N-ethyl-4,4′-difluorobenzilate, optionally in the form of their hydrates and solvates. By salts are meant those compounds which contain, in addition to the above mentioned cations, as counter-ion, an anion with a single negative charge selected from among the chloride, bromide, and methanesulfonate.
Antiallergic agents include, for example, epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifene, emedastine, dimetindene, clemastine, bamipine, hexachloropheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratadine, and meclizine. Preferred antiallergic agents include, for example, epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratadine, and mizolastine, epinastine. Any reference to the above-mentioned antiallergic agents also includes any pharmacologically acceptable salts thereof, which may exist.
PAF antagonists include, for example, 4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-α][1,4]diazepine and 6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta[4.5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.
EGFR kinase inhibitors include, for example, 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{4-[(S)-(2-oxotetrahydrofuran-5-yl)carbonyl]piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((S)-6-methyl-2-oxomorpholin-4-yl)butyloxy]-6-[(vinylcarbonyl)amino]quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((R)-6-methyl-2-oxomorpholin-4-yl)butyloxy]-6-[(vinylcarbonyl)amino]quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-((S)-6-methyl-2-oxomorpholin-4-yl)ethoxy]-6-[(vinylcarbonyl)amino]quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)ethyl]-N-[(ethoxycarbonyl)methyl]-amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline, 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-methoxyquinazoline, and 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)propyloxy]-7-methoxyquinazoline. Any reference to the above-mentioned EGFR kinase inhibitors also includes any pharmacologically acceptable salts thereof which may exist.
p38 MAP kinase inhibitors include, for example, 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-ylethoxy)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea; and 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea disclosed in WO06021848; 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester; Hydrochloride salt of 2-(Piperidin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 2-(1-Methanesulfonyl-piperidin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 2-(1-Benzyl-piperidin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 2-(1-Methyl-piperidin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 2-(4-Methyl-piperazin-1-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 4-[6-(2-Chloro-phenyl)-7-oxo-8-(tetrahydro-pyran-4-yl)-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester; 2-(Piperidin-1-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 2-Cyclobutylamino-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 2-(1-Acetyl-piperidin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 2-(1-Benzoyl-piperidin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 2-(1-Benzoyl-piperidin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperidine-1-carboxylic acid (4-fluoro-phenyl)-amide; 2-(1-Ethanesulfonyl-piperidin-4-ylamino)-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-O— tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperidine-1-carbothioic acid (4-fluoro-phenyl)-amide; 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperidine-1-carboxylic acid (4-trifluoromethyl-phenyl)-amide; 2-[4-(Propane-2-sulfonyl)-piperazin-1-ylamino]-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one; 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperazine-1-carboxylic acid propylamide; 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperazine-1-carboxylic acid ((R)-1,2-dimethyl-propyl)-amide; 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperazine-1-carboxylic acid cyclohexylamide; 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperazine-1-carboxylic acid (4-fluoro-phenyl)-amide; 4-[7-Oxo-8-(tetrahydro-pyran-4-yl)-6-o-tolyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-piperazine-1-carboxylic acid cyclopentyl methyl-amide; and the compounds; which are disclosed in WO 2006/016237, WO 2006/056863, WO 2006/117657 and WO 2006/082492. Any reference to the above mentioned p38 kinase inhibitors also includes any pharmacologically acceptable salts thereof which may exist.
Additional PDE 4 inhibitors include, for example, enprofylline, roflumilast, oglemilast, ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A, Z-15370, and AWD-12-281. Preferred PDE 4 inhibitors are selected from enprofylline, roflumilast, ariflo, Z15370, and AWD-12-281. Any reference to the above mentioned PDE 4 inhibitors also includes any pharmacologically acceptable salts thereof which may exist.
The leukotriene antagonist can be selected, for example, from compounds not limited to those described in U.S. Pat. No. 5,565,473; 5,583,152; 4,859,692; or 4,780,469.
Examples of leukotriene antagonist include, but are not limited to, montelukast, zafirlukast, pranlukast and pharmaceutically acceptable salts thereof.
5-Lipoxygenase inhibitors can be selected, for example, from the compounds disclosed in U.S. Pat. Nos. 4,826,868 and 4,873,259, or European Patent Nos. 0 419 049, 0 542 356 or 0 542 355. Examples may include but are not limited to atreleuton, zyflo (zileuton), ABT-761, fenleuton or tepoxalin.
Chemokine inhibitors can be selected from, for example, the compounds disclosed in European Patent Nos. 0 287 436, 0 389 359, 0 988 292, or WO 02/26723 or WO 01/90106.
Examples of chemokine inhibitors include, but are not limited to AMD3 100, AZD 8309, BX-471, GW-766994, 11K-427857, CP-481715, UK-107543, UK-382055 or UK-395859.
Examples set forth below demonstrate the synthetic procedures for the preparation of the representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not constrain the scope of the present invention as defined by the claims.
Sodium hydride (2 eq.) was added to a solution of 4-[3-(cyclopentyloxy)-4-methoxyphenyl]pyrimidin-2-amine (3.5 mmol), cooled at 0-5° C., in dry tetrahydrofuran and the mixture was stirred at same temperature for 30 minutes. o-Fluoronitrobenzene (1.5 eq.) was added and the resulting mixture was allowed to come to room temperature. The reaction mixture was heated at reflux for 12 hours. The organic solvent was distilled off and crude mass was dissolved in water and extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue thus obtained was purified by column chromatography to furnish the title compound.
Palladium on carbon (10% w/w) was added to a solution of the compound obtained from step a above (3.72 mmol) in ethanol (25 mL). The reaction mixture was stirred for 12 hours under H2 gas atmosphere. It was filtered through celite bed and the crude product thus obtained was purified by column chromatography to furnish title compound.
Di-tert-butyl-di-carbonate (4 eq.) and 4-dimethylaminopyridine (10% w/w) were added to a solution of the compound obtained from step b above (2.12 mmol) in acetonitrile and the reaction mixture was stirred for 2 hours. It was concentrated under reduced pressure and the residue was purified by column chromatography to furnish the title compound. Yield=61%.
IR (neat): 2962, 1772, 1736, 1577, 1484, 1323, 1273, 1152 cm−1.
1H NMR (300 MHz, CDCl3): δ 8.84 (d, J=5.26 Hz, 1H), 7.85-8.00 (m, 3H), 7.59-7.76 (m, 2H), 7.11-7.33 (m, 3H), 6.96-7.02 (m, 1H), 4.89-4.90 (m, 1H), 3.94 (s, 3H), 1.86-2.04 (m, 8H), 1.69 (s, 9H).
Mass (m/z): 502 (M)+.
Following compounds were prepared similarly
Mass (m/z): 503.1 (M+1)+.
Mass (m/z): 502.9 (M+1)+.
Mass (m/z): 449.3 (M+1)+.
Mass (m/z): 449.6 (M+1)+.
Mass (m/z): 448.7 (M+1)+.
Mass (m/z): 501.7 (M+1)+.
Anhydrous potassium carbonate (10 mol %) was added to a solution of tert-butyl 3-{4-[3-(cyclopentyloxy)-4-methoxyphenyl]pyrimidin-2-yl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Compound No. 24) (1.29 mmol) in methanol and reaction mixture was refluxed for 2 hours. The resulting mixture was filtered and the residue thus obtained was purified by column chromatography to furnish the title compound. Yield=66%.
IR (KBr): 2960, 1751, 1710, 1633, 1578, 1518, 1409, 1273, 1180 cm−1.
1H NMR (300 MHz, CDCl3+CD3OD): δ 8.79 (bs, 1H), 7.96-7.98 (m, 2H), 7.71-7.77 (m, 3H), 7.09-7.14 (m, 3H), 4.94 (bs, 1H), 3.94 (s, 3H), 1.88-1.99 (m, 6H), 1.67 (bs, 2H).
Mass (m/z): 402 (M)+.
Following compounds were prepared similarly
Mass (m/z): 402.9 (M+1)+.
Mass (m/z): 349.59 (M+1)+.
Mass (m/z): 349.6 (M+1)+.
Mass (m/z): 403.1 (M+1)+.
Mass (m/z): 349.1 (M+1)+.
Mass (m/z): 401.9 (M+1)+.
Sodium hydride (0.574 mmol) was added to the stirred solution of 1-[4-(3,4-dimethoxyphenyl)pyrimidin-2-yl]-1,3-dihydro-2H-benzimidazol-2-one (Compound No. 10) (0.287 mmol) in dimethylformamide (1.5 mL) at 0° C., followed by the addition of cyclopentyl bromide (0.430 mmol) after a few minutes. The reaction was continued at 90° C. for 6 hours. The resulting mixture was poured in ice-cold water and extracted with ethyl acetate. Organic phase was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography to furnish the title compound. Yield=37%.
IR (KBr): 2957, 2927, 1723, 1575, 1517, 1487, 1407, 1275, 1227, 1152, 1024 cm−1
1H NMR (300 MHz; CDCl3): 8.85 (d, J=5.13 Hz, 1H), 8.03 (d, J=7.47 Hz, 1H), 7.85 (s, 1H), 7.76 (d, J=8.28 Hz, 1H), 7.58 (d, J=5.19 Hz, 1H), 6.75-7.20 (m, 4H), 4.94-5.00 (m, 1H), 3.99 (s, 3H) 3.97 (s, 3H), 2.04-2.22 (m, 6H), 1.76 (brs, 2H).
Mass (m/z): 417.1 (M+1)+.
Following compounds were prepared similarly
Mass (m/z): 376.9 (M+1)+.
Mass (m/z): 438.9 (M+1)+.
Mass (m/z): 416.1 (M+1)+.
Mass (m/z): 442.0 (M+1)+.
Mass (m/z): 492.0 (M+1)+.
Mass (m/z): 430.2 (M+1)+.
Mass (m/z): 443.2 (M+1)+.
Mass (m/z): 470.3 (M+1)+.
Mass (m/z): 444.1 (M+1)+.
Mass (m/z): 522.9 (M+1)+.
Mass (m/z): 492 (a fragment peak).
Mass (m/z): 493.2 (M+1)+.
Mass (m/z): 538.2 (M+1)+.
Cesium carbonate (0.577 mmol) was added to a stirred solution of 1-[4-(3,4-dimethoxyphenyl)pyrimidin-2-yl]-1,3-dihydro-2H-benzimidazol-2-one (Compound No. 10) (0.481 mmol) in dry dimethylformamide (1.5 mL) and the reaction mixture was stirred for 30 minutes. Methyl-2-chloro-2,2-difluoroacetate (0.48 mol) was added to reaction mixture and reaction was continued at 80° C. for 4 h. The reaction mixture was poured on ice water and extracted with ethyl acetate. Organic phase was dried over anhydrous sodium sulphate and evaporated under reduced pressure. Crude product was purified by column chromatography to yield titled compound as white solid. Yield=24%.
IR (KBr): 2926, 1769, 1577, 1545, 1488, 1405, 1377, 1309, 1277, 1181, 1156, 1051, 1027 775 cm−1
1H NMR (300 MHz; CDCl3): 8.85 (d, J=5.07 Hz, 1H), 8.03 (d, J=6.36 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J=8.01 Hz, 1H), 7.64 (d, J=5.37 Hz, 2H), 7.46 (s, 2H), 7.01 (d, J=8.16 Hz, 1H), 3.99 (s, 3H), 3.98 (s, 3H)
Mass (m/z): 399.1 [M+1]+
Isopropyl isocyanate (1.2 mmol) was added to a solution 1-{5-[3-(cyclopentyloxy)-4-methoxyphenyl]pyrimidin-2-yl}-1,3-dihydro-2H-benzimidazol-2-one (Compound No. 9) (0.4 mmol) and 4-dimethylaminopyridine (0.1 mmol) in dry dichloromethane. The reaction mixture was refluxed for 12 hours, diluted with dichloromethane and washed with water, brine, dried over sodium sulphate and the solvent was evaporated. The mixture was concentrated under reduced pressure and the residue thus obtained was purified by column chromatography to furnish the title compound. Yield=30%.
IR (CHCl3): 3313, 2963, 2929, 1741, 1702, 1586, 1537, 1478, 1434, 1386, 1318, 1257, 1177, 1144, 1102, 973 cm−1
1H NMR (CDCl3, 300 MHz) δ 9.04 (s, 2H), 8.74 (d, J=7.19 Hz, 1H), 8.35-8.38 (m, 1H), 7.90-7.93 (m, 1H), 7.27-7.31 (m, 1H), 7.15-7.16 (m, 1H), 7.11 (s, 1H), 7.03 (d, J=8.29 Hz, 1H), 4.85-4.88 (m, 1H), 4.14-4.21 (m, 1H), 3.92 (s, 3H), 1.81-1.99 (m, 6H), 1.64-1.68 (m, 2H), 1.30 (d, J=6.57 Hz, 6H).
Mass (m/z): 487.9 (M+1)+.
Following compounds were prepared similarly
Mass (m/z): 488.0 (M+1)+.
Mass (m/z): 513.9 (M+1)+.
Mass (m/z): 507.0 (M+1)+.
Mass (m/z): 520.9 (M+1)+.
Mass (m/z): 484.53 (M)+.
Mass (m/z): 534.4 (M)+.
Mass (m/z): 514.5 (M)+.
Mass (m/z): 512.4 (M)+.
Mass (m/z): 542.4 (M)+.
Mass (m/z): 534.4 (M)+.
Mass (m/z): 598 (M)+.
Cyclopentyl bromide (1.1 equivalent) was added to a mixture of 1-{5-[3-(cyclopentyloxy)-4-methoxyphenyl]pyrimidin-2-yl}-1,3-dihydro-2H-benzimidazol-2-one (Compound No. 9) (0.4 mmol) and potassium tert-butoxide (0.4 mmol) in acetonitrile. The reaction mixture was stirred at reflux temperature. After 12 hours, reaction mixture was diluted with dichloromethane and washed with water, brine, dried over anhydrous sodium sulphate and evaporated at reduced pressure to give a residue, which was purified by eluting through silica gel column to give white solid compound. Yield=40%
1H NMR (300 MHz; CDCl3): 1.76-2.22 (m, 16H), 3.91 (s, 6H), 4.87-4.98 (m, 2H), 6.99-7.16 (m, 6H), 7.95 (d, J=8.26 Hz, 1H), 9.01 (s, 2H)
Mass (m/z): 471 (M+1)+.
Following compound was prepared similarly
Mass (m/z): 470 (M)+.
Acetic anhydride (1.1 equivalent) was added to a mixture of 1-{5-[3-(cyclopentyloxy)-4-methoxyphenyl]pyrimidin-2-yl}-1,3-dihydro-2H-benzimidazol-2-one (Compound No. 9) (0.4 mmol) and potassium tert-butoxide (0.4 mmol) in tert-butanol. The reaction mixture was stirred at room temperature. After 2 hours, reaction mixture was diluted with dichloromethane and washed with water, brine, dried over anhydrous sodium sulphate and evaporated at reduced pressure to give a residue, which was purified by eluting through silica gel column to give white solid compound. Yield=30%
IR (KBr): 2965, 1769, 1712, 1598, 1516, 1479, 1434, 1418, 1374, 1313, 1260, 1161, 1017 cm−1
1H NMR (CDCl3, 300 MHz) δ: 9.05 (s, 2H), 8.31-8.33 (m, 1H), 7.85-7.87 (m, 2H), 7.19-7.28 (m, 2H), 7.16-7.19 (m, 1H), 7.02-7.11 (m, 2H), 4.88 (m, 1H), 3.93 (s. 3H), 2.86 (s, 3H), 1.89-1.97 (m, 6H), 1.57-1.66 (m, 2H)
Mass (m/z): 445.1 (M+1)+.
Following compounds were prepared similarly
Mass (m/z): 459.0 (M+1)+.
Mass (m/z): 472.9 (M+1)+.
Mass (m/z): 472.9 (M+1)+.
Mass (m/z): 507.1 (M+1)+.
Mass (m/z): 487.1 (M+1)+.
Mass (m/z): 506.1 (M+1)+.
Mass (m/z): 458.1 (M+1)+.
Mass (m/z): 472 (M+1)+.
Mass (m/z): 444.1 (M+1)+.
The efficacy of particular compounds specifically disclosed herein was determined by an enzyme assay using cell lysate of HEK293 cells transfected with PDE4B2 plasmids as PDE4B source. The enzyme reaction was carried out in the presence of cAMP (1 μM) at 30° C. in the presence or absence of test compound for 45-60 min. An aliquot of this reaction mixture was taken further for the ELISA assay and the protocol of the kit followed to determine level of cAMP in the sample. The concentration of the cAMP in the sample directly correlated with the degree of PDE 4 enzyme inhibition. Results were expressed as percent control and the IC50 values of test compounds were reported. IC50 values of test compounds were found to be in the range of μM to nM concentration. Compound Nos. 3-43 and 47-53 displayed IC50 for the PDE 4 enzyme assay ranging from about 140 nM to about 10 μM, for example, from about 140 μM to about 1 μM, or from about 140 nM to about 500 mM.
Human whole blood is collected in vacutainer tubes containing heparin or EDTA as an anti coagulant. The blood is diluted (1:1) in sterile phosphate buffered saline and 10 ml is carefully layered over 5 ml Ficoll Hypaque gradient (density 1.077 g/ml) in a 15 ml conical centrifuge tube. The sample is centrifuged at 3000 rpm for 25 minutes in a swing-out rotor at room temperature. After centrifugation, interface of cells are collected, diluted at least 1:5 with phosphate-buffered saline (PBS) and washed three times by centrifugation at 2500 rpm for 10 minutes at room temperature. The cells are resuspended in serum free RPMI 1640 medium at a concentration of 2 million cells/ml.
PBMN cells (0.1 ml; 2 million/ml) are co-incubated with 20 ml of compound (final DMSO concentration of 0.2%) for 10 min in a flat bottom 96 well microtiter plate. Compounds are dissolved in DMSO initially and diluted in medium for a final concentration of 0.2% DMSO. LPS (1 mg/ml, final concentration) is then added at a volume of 10 μl per well. After 30 min, 20 μl of fetal calf serum (final concentration of 10%) is added to each well. Cultures are incubated overnight at 37° C. in an atmosphere of 5% CO2 and 95% air. Supernatant are then removed and tested by ELISA for TNF-α release using a commercial kit (e.g. BD Biosciences). The level of TNF-α in treated wells is compared with the vehicle treated controls and inhibitory potency of compound is expressed as IC50 values calculated by using Graph pad prism.
| Number | Date | Country | Kind |
|---|---|---|---|
| 320/DEL/2007 | Feb 2007 | IN | national |
