Claims for Patent: 6,740,655

Summary for Patent: 6,740,655

Title:	Pyrimidine carboxamides useful as inhibitors of PDE4 isozymes
Abstract:	This invention is directed to compounds of the formula: ##STR1## wherein j is 0 or 1; k is 0 or 1; m is 0 or 1; n is 0 or 1; W is --O--; --S(.dbd.O).sub.t --, where t is 0, 1, or 2; or --N(R.sup.3)--; where R.sup.3 is --H, --(C.sub.1 -C.sub.3) alkyl, --OR.sup.12, phenyl, or benzyl; R.sup.C and R.sup.D have the same meaning as R.sup.A and R.sup.B, except that at least one of R.sup.C and R.sup.D must be --H; and the other variables are defined as set forth in the specification. The invention is also directed to pharmaceutical compositions comprising the above compounds and to methods of treating a subject suffering from a disease, disorder or condition mediated by the PDE4 isozyme, the method comprising administering a therapeutically effective amount of a compound as described above. The invention is particularly directed to methods of treating inflammatory, respiratory and allergic diseases and conditions, especially asthma; chronic obstructive pulmonary disease (COPD) including chronic bronchitis, emphysema, and bronchiectasis; chronic rhinitis; and chronic sinusitis.
Inventor(s):	Magee; Thomas Victor (Mystic, CT), Marfat; Anthony (Mystic, CT), Chambers; Robert James (Mystic, CT)
Assignee:	Pfizer Inc (New York, NY)
Application Number:	10/181,417
Patent Claims:	1. A compound of Formula (1.0.0): ##STR156## or a pharmaceutically acceptable salt thereof; wherein where R.sup.3 is --H; --(C.sub.1 -C.sub.3) alkyl; --OR.sup.12 ; phenyl; or benzyl; R.sup.A and R.sup.B are each a member independently selected from the group consisting of --H; --F; --CF.sub.3 ; --(C.sub.1 -C.sub.4) alkyl; --(C.sub.3 -C.sub.7) cycloalkyl; phenyl; or benzyl; wherein said alkyl, cycloalkyl, phenyl, or benzyl moiety is each independently substituted with 0 to 3 substituents R.sup.10 ; provided that for the above and all other applicable meanings of R.sup.A and R.sup.B, when R.sup.10 as a substituent of R.sup.A or R.sup.B has the meaning of --OR.sup.12, --OC(.dbd.O)R.sup.12, or --OC(.dbd.O)NR.sup.12 R.sup.13, the positional relationship of said --OR.sup.12, --OC(.dbd.O)R.sup.12, or --OC(.dbd.O)NR.sup.12 R.sup.13 to --OR.sup.12 as a meaning of E, is other than a vicinal one; where R.sup.10 is a member selected from the group consisting of --F; --Cl; --CF.sub.3 ; --CN; --OR.sup.12 ; (C.sub.1 -C.sub.2) alkyl; hydroxy(C.sub.1 -C.sub.2) alkyl; --O--C(.dbd.O)R.sup.13 ; --O--C(.dbd.O)NR.sup.12 R.sup.13 ; --NR.sup.12 R.sup.13 ; --NR.sup.12 C(.dbd.O)R.sup.13 ; --NR.sup.12 C(.dbd.O)OR.sup.13 ; --NR.sup.12 C(.dbd.O).sub.2 R.sup.13 ; and --S(.dbd.O).sub.2 NR.sup.12 R.sup.13 ; where R.sup.12 and R.sup.13 are each a member independently selected from the group consisting of --H; --(C.sub.1 -C.sub.4) alkyl; phenyl; or benzyl; wherein said alkyl, phenyl, or benzyl is substituted by 0 to 3 substituents selected from the group consisting of F and Cl; or R.sup.A and R.sup.B are taken together, provided that m is 1, to form a spiro moiety of Formula (1.1.0): ##STR157## where r and s are independently 0 to 4 provided that the sum of r+s is at least 1 but not greater than 5; and Q.sup.A is selected from the group consisting of --CH.sub.2 --, --CHF, --CF.sub.2, --N(R.sup.3)--, --O--; and --S(.dbd.O).sub.t --, where t is 0, 1, or 2; and said spiro moiety is substituted as to any one or A more carbon atoms thereof, including the carbon atom of the group --CH.sub.2 -- defining Q.sup.A, by 0 to 3 substituents R.sup.10, where R.sup.3 and R.sup.10 have the same meanings as defined above; provided that for the above and all other applicable meanings of R.sup.A and R.sup.B, when R.sup.10 as a substituent of R.sup.A or R.sup.B has the meaning of --OR.sup.12, --OC(.dbd.O)R.sup.12, or --OC(.dbd.O)NR.sup.12 R.sup.13, the positional relationship of said --OR.sup.12, --OC(.dbd.O)R.sup.12, or --OC(.dbd.O)NR.sup.12 R.sup.13 to --OR.sup.12 as a meaning of E, is other than a vicinal one; R.sup.C and R.sup.D have the same meaning as defined above for R.sup.A and R.sup.B, except that at least one of R.sup.C and R.sup.D must be --H, and they are selected independently of each other and of R.sup.A and R.sup.B ; A.sup.A is a member independently selected from the group consisting of the following (a) a saturated or unsaturated cyclic or bicyclic (C.sup.3 -C.sup.9) heterocyclic group which is a member selected from the group consisting of furanyl; thienyl; pyrrolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrazolyl; oxadiazolyl; thiadiazolyl; imidazolyl; pyrazinyl; pyrimidinyl; pyridazinyl; triazolyl; tetrazolyl; 2,3-benzofuranyl; 2,3-dihydrobenzo-furanyl; 1,3-dihydroiso-benzofuranyl; benzo[b]thienyl; indolyl; indolinyl; isoindolinyl; 2H-1-benzopyranyl; 4H-1-benzopyranyl; 1H-2-benzopyranyl; chromanyl; isochromanyl; quinolinyl; isoquinolinyl; 1,2,3,4-tetrahydro-quinolinyl; 1,2,3,4-tetrahydro-isoquinolinyl; 1,3-benzodioxolyl; 3H-2, 1-benzoxathiolyl; benzoxazolyl; 1,2-benzisoxazolyl; 2,1-benzisoxazolyl; 1,2-benzodithiolyl; 1,3-benzodithiolyl; benzothiazolyl; 1,2-benzisothiazolyl; benzimidazolyl; indazolyl; 1,4-benzodioxanyl; 4H-3,1-benzoxazinyl; 2H-1,4-benzoxazinyl; 1,4-benzothiazinyl; 1,2-benzothiazinyl; quinazolinyl; quinoxalinyl; phthalazinyl; cinnolinyl; 1,2,3-benzothiadiazolyl; 2H-1,2,4-benzo-thiadiazinyl; 2H-1,2,4-benzo-oxadiazinyl; benzoxtriazinyl; 1,2,3-benzotriazinyl; 1,2,4-benzotriazinyl; and benzotetrazinyl; wherein said heterocyclic group is substituted as to any one or more nitrogen atoms thereof by 0 or 1 R.sup.9 substitutent, where R.sup.9 is independently selected from the group consisting of --H; and --(C.sub.1 -C.sub.4) alkyl; further wherein said heterocyclic group is substituted as to any one or more carbon atoms thereof by 0-3 R.sup.16 substitutents, where R.sup.16 is independently selected from the group consisting of --F; --Cl; --CN; --OR.sup.12 ; (C.sub.1 -C.sub.4) alkyl; (C.sub.3 -C.sub.7) cycloalkyl; --CF.sub.3 ; --C(.dbd.O)OR.sup.12 ; --NO.sub.2 ; --NR.sup.12 R.sup.13 ; hydroxy(C.sub.1 -C.sub.4) alkylamino; phenyl; and benzyl; where R.sup.12 and R.sup.13 have the same meaning as defined above; and where said alkyl, alkoxy or cycloalkyl is each independently substituted by 0-3 R.sup.18 substituents, where R.sup.18 is independently selected from the group consisting of --F; --Cl; --CN; --OR.sup.12 ; --CF.sub.3 ; --NR.sup.12 R.sup.13 and phenyl; where R.sup.12 and R.sup.13 have the same meanings as defined above; and further Z.sup.A (b) is (C.sub.3 -C.sub.7) cycloalkyl independently substituted by 0-3 R.sup.16 substituents where R.sup.16 has the same meaning as defined above; and still further Z.sup.A (c) is phenyl or pyridyl substituted by 0 to 3 substituents R.sup.4, where R.sup.4 is a member independently selected from the group consisting of the following (1) --F; --Cl; --CN; --OR.sup.12 ; --S(.dbd.O).sub.p R.sup.12 ; --C(.dbd.O)OR.sup.12 ; --OC(.dbd.O)R.sup.12 ; --NO.sub.2 ; --C(.dbd.O)NR.sup.12 R.sup.13 ; --OC(.dbd.O)NR.sup.12 R.sup.13 ; --NR.sup.12 R.sup.13 ; --NR.sup.14 C(.dbd.O)R.sup.12 ; --NR.sup.14 C(O)OR.sup.12 ; --NR.sup.14 S(.dbd.O).sub.p R.sup.12 ; and --S(.dbd.O).sub.p NR.sup.12 R.sup.13 ; where p is 0, 1, or 2; and R.sup.12 and R.sup.13 have the same meaning as defined above; where R.sup.14 is selected from the group consisting of --H; --CH.sub.3 ; and --CH.sub.2 CH.sub.3 ; and further R.sup.4 (2) is independently --(C.sub.1 -C.sub.4) alkyl; or --(C.sub.1 -C.sub.4) alkoxy where R.sup.12 of --OR.sup.12 in the above definition of R.sup.4 has the meaning of --(C.sub.1 -C.sub.4) alkyl; wherein said alkyl or alkoxy are each independently substituted with 0 to 3 substituents --F or --Cl; or 0 or 1 substituent (C.sub.1 -C.sub.2) alkoxycarbonyl-; (C.sub.1 -C.sub.2) alkylcarbonyl-; or (C.sub.1 -C.sub.2) alkylcarbonyloxy-; and still further R.sup.4 (3) is independently phenyl; benzyl; or a heterocyclyl moiety selected from the group consisting of furanyl; tetrahydrofuranyl; oxetanyl; thienyl; tetrahydrothienyl; pyrrolyl; pyrrolidinyl; oxazolyl; oxazolidinyl; isoxazolyl; isoxazolidinyl; thiazolyl; thiazolidinyl; isothiazolyl; isothiazolidinyl; pyrazolyl; pyrazolidinyl; oxadiazolyl; thiadiazolyl; imidazolyl; imidazolidinyl; pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; piperidinyl; piperazinyl; triazolyl; triazinyl; tetrazolyl; pyranyl; azetidinyl; morpholinyl, parathiazinyl; indolyl; indolinyl; benzo[b]furanyl; 2,3-dihydrobenzofuranyl; 2-H-chromenyl; chromanyl; benzothienyl; 1-H-indazolyl; benzimidazolyl; benzoxazolyl; benzisoxazolyl; benzthiazolyl; quinolinyl; isoquinolinyl; phthalazinyl; quinazolinyl; quinoxalinyl; and purinyl; wherein said phenyl, benzyl, or heterocyclyl moiety is each independently substituted with 0 to 2 substituents R.sup.10 where R.sup.10 has the same meaning as defined above; or on adjacent carbon atoms, where Z.sup.A is selected as phenyl, are taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form a benzofused heterocyclyl moiety comprising a member selected from the group consisting of 2,3-benzofuranyl; 2,3-dihydrobenzofuranyl; 1,3-dihydroisobenzofuranyl; benzo[b]thienyl; indolyl; indolinyl; isoindolinyl; 2H-1-benzopyranyl; 4H-1-benzopyranyl; 1H-benzopyranyl; chromanyl; isochromanyl; quinolinyl; isoquinolinyl; 1,2,3,4-tetrahydroquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl; 1,3-benzodioxolyl; 3H-2,1-benzoxathiolyl; benzoxazolyl; 1,2-benzisoxazolyl; 2,1-benzisoxazolyl; 1,2-benzodithiolyl; 1,3-benzodithiolyl; benzothiazolyl; 1,2-benzisothiazolyl; benzimidazolyl; indazolyl; 1,4-benzodioxanyl; 4H-3,1-benzoxazinyl; 2H-1,4-benzoxazinyl; 1,4-benzothiazinyl; 1,2-benzothiazinyl; quinazolinyl; quinoxalinyl; phthalazinyl; cinnolinyl; 1,2,3-benzothiadiazolyl; 2H-1,2,4-benzothiadiazinyl; 2H-1,2,4-benzoxadiazinyl; benzoxtriazinyl; 1,2,3-benzotriazinyl; 1,2,4-benzotriazinyl; and benzotetrazinyl; Z.sup.B is phenyl; pyridyl; pyrimidinyl; imidazolyl; oxazolyl; furanyl; thienyl; thiazolyl; indonin-2-onyl; pyrazinyl; cyclopentyl; cyclohexyl; cyclopentenyl, cyclohexenyl, norbornanyl, norbornenyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]oct-5-enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo[3.3.1]nonanyl, or adamantanyl; R1 and R2 are each a member independently selected from the group consisting of --H; --F; --Cl; --OR.sup.12 ; --S(.dbd.O).sub.p R.sup.12 ; --C(.dbd.O)OR.sup.12 ; --OC(.dbd.O)R.sup.12 ; --CN; --NO.sub.2 ; --C(.dbd.O)NR.sup.12 R.sup.13 ; --NR.sup.12 R.sup.13 ; and --S(.dbd.O).sub.p NR12R.sup.13 ; where p is 0, 1, or 2; and R.sup.12 and R.sup.13 have the same meanings as defined above; E is selected from the group consisting of --H; --F; --Cl; --CN; --OR.sup.12 ; (C.sub.1 -C.sub.4) alkyl; hydroxy(C.sub.1 -C.sub.4) alkyl; --CF.sub.3 ; --NO.sub.2 ; --NR.sup.12 R.sup.13 ; --NR.sup.12 S(.dbd.O).sub.2 R.sup.13 ; and --S(.dbd.O).sub.2 NR.sup.12 R.sup.13 ; where R.sup.12 and R.sup.13 have the same meanings as defined above; and R.sup.7 and R.sup.8 are each independently selected from the group consisting of --H; --F; --Cl; --OR.sup.12 ; (C.sub.1 -C.sub.4) alkyl; hydroxy(C.sub.1 -C.sub.4) alkyl; --CF.sub.3 ; --C(.dbd.O)OR.sup.12 ; --NR.sup.12 R.sup.13 ; hydroxy(C.sub.1 -C.sub.4) alkylamino; phenyl; benzyl; or a heterocyclyl moiety selected from the group consisting of pyrrolyl; oxazolyl; thiazolyl; oxadiazolyl; thiadiazolyl; imidazolyl; pyridinyl; tetrazolyl; indolyl; and benzimidazolyl; wherein said phenyl, benzyl, or heterocyclyl moiety is each independently substituted with 0 to 2 substituents R.sup.10 where R.sup.10 has the same meaning as defined above; in the event that j or k is 1, or both j and k are 1 at the same time, a compound of Formula (1.0.0) is in the form of a N-oxide. 2. A compound according to claim 1, wherein m is 0 or 1; n is 1; j and k are 0 or 1; R is --H, --F, or --Cl; R.sup.2 is --H, --F, or --Cl; R.sup.3 is --H; one of R.sup.A and R.sup.6 is --OH.sub.3 and the other is --H or --CH.sub.3 ; one of R.sup.C or R.sup.D is --H, and the other is --H or --CH.sub.3 ; Z.sup.B is phenyl, pyridyl, cyclopentyl, cyclohexyl, furanyl, thienyl, thiazolyl, indolin-2-onyl, or pyrazinyl; E is --H, --OR.sup.12, --NR.sup.12 R.sup.13, --NHS(.dbd.O).sub.2 CH.sub.3, or --S(.dbd.O).sub.2 NH.sub.2 ; Z.sup.A is unsubstituted pyridyl, or phenyl substituted by R.sup.4 where R.sup.4 is taken twice and is --F or --Cl, or else R.sup.4 is a single substituent consisting of --F, --Cl, --ON, --NO.sub.2, --NH.sub.2, --CF.sub.3, --SCH.sub.3, --OCH.sub.3, --OCH.sub.2 CH.sub.3, --C(.dbd.O)CH.sub.3, or --C(.dbd.O)OCH.sub.3 ; or Z.sup.A is phenyl where two R.sup.4 are taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl, indolinyl, chromanyl, 1,3-benzodithiolyl, or 1,4-benzodioxanyl. 3. A compound according to claim 1, wherein m is 0; n is 1; j is 0; k is 0; R.sup.1 is --H, --F, or --Cl; R.sup.2 is --H, --F, Cl, or --CH.sub.3 ; R.sup.3 is --H; R.sup.C is --H; R.sup.D is --H or --CH.sub.3 ; Z.sup.B is phenyl, cyclopentyl, cyclohexyl, furanyl, thienyl, thiazolyl, oxazolyl, indolin-2-onyl, pyridyl, or pyrazinyl, E is --H, --OCH.sub.3, --OH, --CH(OH)CH.sub.3, --C(OH)(CH.sub.3).sub.2, --OC(.dbd.O)R.sup.12, --NHS(.dbd.O).sub.2 CH.sub.3, --S(.dbd.O).sub.2 NH.sub.2, or --N(CH.sub.3).sub.2 ; Z.sup.A is phenyl or pyridyl where R.sup.4 is taken twice and is --F or --Cl, or else R.sup.4 is a single substituent consisting of --F, --Cl, --CN, --NO.sub.2, --NH.sub.2, --CF.sub.3, --SCH.sub.3, --OCH.sub.3, --OCH.sub.2 CH.sub.3, --C(.dbd.O)CH.sub.3, or --C(.dbd.O)OCH.sub.3 ; or Z.sup.A is phenyl where two R.sup.4 are taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form 1,3-benzodioxolyl. 4. A compound according to claim 1, wherein m is 0; n is 1; j is 0; k is 0; R.sup.1 is --H; R.sup.2 is --H, --F, --Cl, or --CH.sub.3 ; R.sup.3 is --H; R.sup.C is --H; R.sup.D is --H or --CH.sub.3 ; Z.sup.B is phenyl, furanyl, or thienyl; E is --OCH.sub.3, --OH, --CH(OH)CH.sub.3, or --C(OH)(CH.sub.3).sub.2 ; Z.sup.A is phenyl or pyridyl where R.sup.4 is taken twice and is --F or --Cl, or else R.sup.4 is a single substituent consisting of --F, --Cl, --CN, --OCH.sub.3, or --NO.sub.2 ; or Z.sup.A is phenyl where two R.sup.4 are taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form 1,3-benzodioxolyl. 5. A compound according to claim 1, selected from the group consisting of: 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-(1-hydroxy-1-methyl-ethyl)-benzylamide; 2-N-(2-Chloro-benzyl)-1-[6-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-carboxami de; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(methoxy)benzyl]-carboxamide ; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[(thiophene-2-yl)methyl]-carbox amide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (thiophen-2-ylmethyl)-amide; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[(furan-2-yl)methyl]-carboxamid e; 2-N-(2-Chloro-benzyl)-1-[6-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-carboxami de; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[1-methyl-1-(4-methoxy)benzyl]- carboxamide; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[1-methyl-1-(thiophene-2-yl)met hyl]-carboxamide; 2-N-[1-Methyl-1-(thiophene-2-yl)methyl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5 -yl]-carboxamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (1-thiophen-2-yl-ethyl)-amide; 1-[6-(5-Chloro-pyridin-3-yl)-oxy-pyrimidin-5-yl]-2-N-[(3-methyl)thiophene-2 -yl)methyl]-carboxamide; 2-N-[(4-Methoxy)phenyl)methyl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carb oxamide; 2-N-[(4-Chloro-thiophene-2-yl)methyl]-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-y l]-carboxamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (4-chloro-thiophen-2-ylmethyl)-amide; 2-N-[(5-Chloro-furan-2-yl)methyl]-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-c arboxamide; 1-[6-(5-Chloro-pyridin-3-yl)-oxy-pyrimidin-5-yl]-2-N-[thiazol-2-yl)methyl]- carboxamide; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)benzyl ]-carboxamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-(1-hydroxy-ethyl)-benzylamide; 2-N-(2,3-Difluoro-benzyl)-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxami de; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(4-hydroxy-benzyl)-carboxamide; 2-N-(2-Chloro-benzyl)-1-{6-[3-(N,N-dimethylamino)-phenoxy]-pyrimidin-5-yl}- carboxamide; 2-N-(2-Chloro-benzyl)-1-[6-(4-cyano-phenoxy)-pyrimidin-5-yl]-carboxamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 2-chloro-benzylamide; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(4-methylsulfoamino-benzyl)-car boxamide; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[1-methyl-1-(5-chloro-2-thiophe neyl)methyl]-carboxamide; 4-(Benzo(1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid [1-(5-chloro-thiophen-2-yl)-ethyl]-amide; 2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-nitro-phenoxy)-pyrimidin-5-yl ]-carboxamide; 1-[6-(3-Cyano-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)-benzyl ]-carboxamide; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)-benzy l]-carboxamide; 2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-trifluoromethyl-phenoxy)-pyri midin-5-yl]-carboxamide; 1-[6-(3-Chloro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)-benzy l]-carboxamide; 2-N-(2-Fluoro-benzyl)-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(4-imino-benzyl)-carboxamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-amino-benzylamide; 2-N-[5-(1-Hydroxyethyl)-thiophene-2-yl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5 -yl]-carboxamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid [5-(1-hydroxy-ethyl)-thiophen-2-ylmethyl]-amide; 2-N-[5-(1-Hydroxy-iso-propyl)-thiophene-2-yl]-1-[6-(pyridin-3-yl)-oxy-pyrim idin-5-yl]-carboxamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid [5-(1-hydroxy-1-methyl-ethyl)-thiophen-2-ylmethyl]-amide; 2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-methylthio-phenoxy)-pyrimidin -5-yl]-carboxamide; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-{4-[(1-hydroxy-iso-propyl)-cylc ohexyl]methyl}-carboxamide; 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[(5-methyl-pyrazin-2-yl)methyl] -carboxamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide; 2-N-(4-N,N-Dimethyl-benzyl)-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxa mide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-dimethylamino-benzylamide; 2-N-[(4-Aminosulfonyl)-benzyl]-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carb oxamide; 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide; 2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-methylcarbonyl-phenoxy)-pyrim idin-5-yl]-carboxamide; 1-[6-(3-Cyano-phenoxy)-pyrimidin-5-yl]-2-N-{4-[(1-hydroxy-iso-propyl)-cylco hexyl]methyl}-carboxamide; 2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]1-[6-(3-methoxycarbonyl-phenoxy)-pyrim idin-5-yl]-carboxamide; and 2-N-(2-Chloro-benzyl)1-[6-(3-methylcarbonyl-phenoxy)-pyrimidin-5-yl]-carbox amide. 6. A combination of a compound of claim 1 together with one or more members selected from the group consisting of the following: (a) Leukotriene biosynthesis inhibitors, 5-lipoxygenase (5-LO) inhibitors, and 5-lipoxygenase activating protein (FLAP) antagonists selected from the group consisting of zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides of Formula (5.2.8); 2,6-di-tert-butylphenol hydrazones of Formula (5.2.10); Zeneca ZD-2138 of Formula (5.2.11); SB-210661 of Formula (5.2.12); pyridinyl-substituted 2-cyanonaphthalene compound L-739,010; 2-cyanoquinoline compound L-746,530; indole and quinoline compounds MK-591, MK-886, and BAY x 1005; (b) Receptor antagonists for leukotrienes LTB.sub.4, LTC.sub.4, LTD.sub.4, and LTE.sub.4 selected from the group consisting of phenothiazin-3-one compound L-651,392; amidino compound CGS-25019c; benzoxazolamine compound ontazolast; benzenecarboximidamide compound BIIL 284/260; compounds zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195; (c) PDE4 inhibitors; (d) 5-Lipoxygenase (5-LO) inhibitors; and 5-lipoxygenase activating protein (FLAP) antagonists; (e) Dual inhibitors of 5-lipoxygenase (5-LO) and antagonists of platelet activating factor (PAF); (f) Leukotriene antagonists (LTRAs) of LTB.sub.4, LTC.sub.4, LTD.sub.4, and LTE.sub.4 ; (g) Antihistaminic H.sub.1 receptor antagonists cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine; (h) Gastroprotective H.sub.2 receptor antagonists; (i) .alpha..sub.1 - and .alpha..sub.2 -adrenoceptor agonist vasoconstrictor sympathomimetic agents administered orally or topically for decongestant use, selected from the group consisting of propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride; (j) one or more .alpha..sub.1 - and .alpha..sub.2 -adrenoceptor agonists as recited in (i) above in combination with one or more inhibitors of 5-lipoxygenase (5-LO) as recited in (a) above; (k) Anticholinergic agents ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine; (l) .beta..sub.1 - to .beta..sub.4 -adrenoceptor agonists selected from the group consisting of metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol, and pirbuterol; (m) Theophylline and aminophylline; (n) Sodium cromoglycate; (o) Muscarinic receptor (M1, M2, and M3) antagonists; (p) COX-1 inhibitors (NSAIDs); and nitric oxide NSAIDs; (q) COX-2 selective inhibitor rofecoxib; (r) insulin-like growth factor type I (IGF-1) mimetics; (s) Ciclesonide; (t) Inhaled glucocorticoids with reduced systemic side effects selected from the group consisting of prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate; (u) Tryptase inhibitors; (v) Platelet activating factor (PAF) antagonists; (w) Monoclonal antibodies active against endogenous inflammatory entities; (x) IPL 576; (y) Anti-tumor necrosis factor (TNF.alpha.) agents selected from the group consisting of etanercept, infliximab, and D2E7; (z) DMARDs selected from the group consisting of leflunomide; (aa) TCR peptides; (bb) Interleukin converting enzyme (ICE) inhibitors; (cc) IMPDH inhibitors; (dd) Adhesion molecule inhibitors including VLA-4 antagonists; (ee) Cathepsins; (ff) MAP kinase inhibitors; (gg) Glucose-6 phosphate dehydrogenase inhibitors; (hh) Kinin-B.sub.1 - and B.sub.2 -receptor antagonists; (ii) Gold in the form of an aurothio group in combination with hydrophilic groups; (jj) Immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine, and methotrexate; (kk) Anti-gout agents selected from the group consisting of colchicine; (ll) Xanthine oxidase inhibitors selected from the group consisting of allopurinol; (mm) Uricosuric agents selected from the group consisting of probenecid, sulfinpyrazone, and benzbromarone; (nn) Antineoplastic agents that are antimitotic drugs selected from the group consisting of vinblastine and vincristine; (oo) Growth hormone secretagogues; (pp) Inhibitors of matrix metalloproteases (MMPs) that are selected from the group consisting of the stromelysins, the collagenases, the gelatinases, aggrecanase, collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11); (qq) Transforming growth factor (TGF.beta.); (rr) Platelet-derived growth factor (PDGF); (ss) Fibroblast growth factor selected from the group consisting of basic fibroblast growth factor (bFGF); (tt) Granulocyte macrophage colony stimulating factor (GM-CSF); (uu) Capsaicin; (vv) Tachykinin NK.sub.1 and NK.sub.3 receptor antagonists selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418; (ww) Elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; and (xx) Adenosine A2a receptor agonists. 7. A method of treating a disease, disorder or condition mediated by the PDE4 isozyme in a mammal, said method comprising administering to said mammal in need of such mediation, a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 8. A method of claim/wherein said PDE4 isozyme is the PDE4-D subtype isozyme. 9. A method of claim 7 wherein said disease, disorder or condition is atopic asthma; non-atopic asthma; allergic asthma; bronchial asthma; essential asthma; true asthma; intrinsic asthma caused by pathophysiologic disturbances; extrinsic asthma caused by environmental factors; essential asthma of unknown or inapparent cause; bronchitic asthma; emphysematous asthma; exercise-induced asthma; occupational asthma; infective asthma caused by bacterial, fungal, protozoal or viral infection; non-allergic asthma; incipient asthma; or wheezy infant syndrome. 10. A method of claim 7 wherein said disease, disorder or condition is chronic or acute bronchoconstriction; chronic bronchitis; small airways obstruction; emphysema; pneumoconiosis; chronic eosinophilic pneumonia; chronic obstructive pulmonary disease; adult respiratory distress syndrome; or exacerbation of airways hyper-reactivity consequent to other drug therapy. 11. A method of claim 10 wherein said chronic obstructive pulmonary disease is characterized by irreversible, progressive airways obstruction. 12. A method of claim 10 wherein said pneumonconiosis is aluminosis; bauxite workers' disease; anthracosis; miners' disease; asbestosis; steam-fitters asthma; chalicosis; flint disease; ptilosis caused by inhaling the dust from ostrich feathers; siderosis caused by the inhalation of iron particles; silicosis; grinders' disease; byssinosis; cotton-dust asthma; or talc pneumoconiosis. 13. A method of claim 7 wherein said disease, disorder or condition is bronchitis; acute bronchitis; chronic bronchitis; acute laryngotracheal bronchitis; arachidic bronchitis; catarrhal bronchitis; croupus bronchitis; dry bronchitis; infectious asthmatic bronchitis; productive bronchitis; staphylococcus bronchitis; streptococcal bronchitis; or vesicular bronchitis. 14. A method of claim 7 wherein said disease, disorder or condition is bronchiectasis; cylindric bronchiectasis; sacculated bronchiectasis; fusiform brochiectasis; capillary bronchiectasis; cystic bronchiectasis; dry bronchiectasis or follicular bronchiectasis. 15. A method of claim 7 wherein said disease, disorder or condition is seasonal allergic rhinitis; perennial allergic rhinitis; sinusitis; purulent sinusitis; nonpurulent sinusitis; acute sinusitis; chronic sinusitis; ethmoid sinusitis; frontal sinusitis; or sphenoid sinusitis.

Details for Patent 6,740,655

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2017-04-04
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2017-04-04
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2017-04-04
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2017-04-04
Immunex Corporation	ENBREL	etanercept	Injection	103795	09/27/2004		2017-04-04
Immunex Corporation	ENBREL	etanercept	Injection	103795	02/01/2007		2017-04-04
Immunex Corporation	ENBREL MINI	etanercept	Injection	103795	09/14/2017		2017-04-04