US2006014780A1PendingUtilityA1
Nicotinamide derivatives useful as PDE4 inhibitors
Est. expiryFeb 11, 2022(expired)· nominal 20-yr term from priority
Inventors:Simon BaileyElisabeth Colette Louise GautierAlan John HendersonThomas Victor MageeAnthony MarfatJohn Paul MathiasDale G. McleodSandra Marina MonaghanBlanda Luzia Christa Stammen
A61P 7/06A61P 43/00A61P 37/00A61P 3/10A61P 31/16A61P 37/02A61P 31/22A61P 9/12A61P 35/00A61P 25/28A61P 25/00A61P 25/30A61P 25/24A61P 29/00A61P 27/02A61P 25/14A61P 25/16A61P 19/00A61P 17/06A61P 19/02A61P 17/04A61P 19/10A61P 11/00A61P 1/04A61P 13/12A61P 1/16A61P 11/08A61P 1/18A61P 17/02A61P 1/00A61P 11/06C07D 451/10C07D 405/12A61K 45/06C07D 401/12A61K 31/46A61K 31/537C07D 451/04C07D 213/82A61K 31/455A61K 31/4433Y02A50/30
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Claims
Abstract
The invention relates to nicotinamide derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The nicotinamide derivatives according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic, respiratory diseases, disorders and conditions, as well as wounds.
Claims
exact text as granted — not AI-modified1 . A compound of the formula (1):
in which:
R 1 and R 2 are each independently hydrogen, halo, cyano, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy;
X is —O—, —S— or —NH—;
R 3 is:
(a) phenyl, naphthyl, heteroaryl or (C 3 -C 8 )cycloalkyl, each optionally substituted independently with 1 to 3 halo, cyano, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethyloxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )thioalkyl, —C(═O)NH 2 , —C(═O)NH((C 1 -C 4 )alkyl), hydroxy, —O—C(═O)(C 1 -C 4 )alkyl, —C(═O)—O—(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy; or
(b) a bicyclic group of the formula:
where the symbol “*” in the definition of R 3 indicates the point of attachment of each partial formula (1.1) through (1.4) to the remaining portion of formula (1);
Y is:
where the symbol “*” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions —NH— of formula (1) and “**” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions Z of formula (1);
R 5 is (C 1 -C 4 )alkyl or phenyl-(C 1 -C 4 )alkyl, where said phenyl in the definition of R 5 is optionally substituted independently with 1 to 3 halo, cyano, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy, hydroxy(C 1 -C 4 )alkyl, carboxylic acid (—COOH), —C(═O)—O—(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl or —C(═O)NH 2 ;
Z is:
where the symbol “*” in the definition of Z indicates the point of attachment of each partial formula (1.9) through (1.15) to the remaining portions Y of formula (1) and “**” in the definition of Z indicates the point of attachment of each partial formula (1.9) through (1.15) to the remaining portions R 4 of formula (1);
or Y and Z are taken together to form a group of formula (1.16):
where the symbol “*” in the definition of Y and Z taken together indicates the point of attachment of the partial formula (1.16) to the remaining portions —NH— of formula (1) and “**” in the definition of Y and Z taken together indicates the point of attachment of the partial formula (1.16) to the remaining portions —R 4 of formula (1); and
R 4 is:
(a) phenyl, naphthyl, heteroaryl or (C 3 -C 8 )cycloalkyl, each optionally substituted independently with 1 to 3 carboxy, —C(═O)—O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-COOH, —(C 1 -C 4 )alkyl-C(═O)—O—(C 1 -C 4 )alkyl, halo, cyano, —C(═O)NH 2 , —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )haloalkyl, hydroxy or hydroxy(C 1 -C 4 )alkyl; or
(b) (C 1 -C 6 )alkyl optionally substituted independently with 1 or 2 hydroxy, carboxy, —C(═O)—O—(C 1 -C 4 )alkyl, phenyl, naphthyl, heteroaryl or (C 3 -C 8 )cycloalkyl, where said phenyl, naphthyl, heteroaryl and (C 3 -C 8 )cycloalkyl are each optionally substituted independently with 1 to 3 carboxy, C(═O)O(C 1 -C 4 )alkyl, halo, cyano, —C(═O)NH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, hydroxy or hydroxy(C 1 -C 4 )alkyl,
or a pharmaceutically acceptable salt, isomer, tautomer, solvate, polymorph, isotopic variation or metabolite thereof;
with the proviso that:
1) when:
R 1 is hydrogen, halo or methyl;
R 2 is hydrogen;
X is —O—;
R 3 is phenyl substituted by a (C 1 -C 4 )thioalkyl in the −3 or −4 position of said phenyl and is also optionally substituted with halo, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy;
Y is:
R 5 is (C 1 -C 4 )alkyl or phenyl-(C 1 -C 4 )alkyl, wherein said phenyl group is optionally substituted by halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or hydroxy; and
Z is —C(═O)—,
then R 4 is not:
a) (C 3 -C 8 )cycloalkyl optionally substituted by (C 1 -C 3 )alkyl;
b) phenyl or a 5- or 6-membered heterocyclic ring independently incorporating 1 to 3 nitrogen, oxygen or sulfur; wherein said phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy; or
c) (C 1 -C 6 )alkyl optionally substituted with hydroxy, phenyl or a 5- or 6-membered heterocyclic ring independently incorporating 1 to 3 nitrogen, oxygen or sulfur, wherein said phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy; and
2) when:
R 1 is hydrogen, halo or methyl;
R 2 is hydrogen;
X is —O—;
R 3 is phenyl substituted by (C 1 -C 4 )thioalkyl in the −3 or −4 position of said phenyl and is also optionally substituted by 1 halo, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy; and
Y-Z is:
then R 4 is not:
a) (C 3 -C 8 )cycloalkyl or
b) (C 1 -C 6 )alkyl optionally substituted by phenyl or a 5- or 6-membered heterocyclic ring independently incorporating 1 to 3 nitrogen, oxygen or sulfur, wherein said phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy; and
3) when:
R 1 is hydrogen, halo or methyl;
R 2 is hydrogen;
X is —O—;
R 3 is phenyl substituted by (C 1 -C 4 )thioalkyl in the −3 or −4 position of said phenyl and is also optionally substituted independently by 1 or 2 halo, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy;
Y is a partial formula (1.6):
and
Z is a radical —C(═O)—,
then R 4 is not (C 1 -C 6 )alkyl optionally substituted by hydroxy or by a 5- or 6-membered heterocyclic ring independently incorporating 1 to 3 nitrogen, oxygen or sulfur.
2 . A compound of claim 1 wherein:
X is —O—, R 3 is: (a) phenyl optionally substituted independently with 1 to 3 halo, cyano, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )alkyl, (C 11 -C 4 )alkoxy, (C 1 -C 4 )thioalkyl, —C(═O)NH 2 , —C(═O)NH((C 1 -C 4 )alkyl), hydroxy, —O—C(═O)(C 1 -C 4 )alkyl, —C(═O)—O—(C 1 -C 4 )alkyl, hydroxy (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy; or (b) a bicyclic group of the formula: where the symbol “*” in the definition of R 3 indicates the point of attachment of each partial formula (1.1) through (1.4) to the remaining portion of formula (1); and Y is: where the symbol “*” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions —NH— of formula (1) and “**” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions Z of formula (1); Z is: where the symbol “*” in the definition of Z indicates the points of attachment of each partial formula (1.9) through (1.11) and (1.15) to the remaining portions Y of formula (1) and “**” in the definition of Z indicates the point of attachment of each partial formula (1.9) through (1.11) and (1.15) to the remaining portions R 4 of formula (1); or Y and Z are taken together to form a group of formula (1.16): where the symbol “*” in the definition of Y and Z taken together indicates the point of attachment of the partial formula (1.16) to the remaining portions —NH— of formula (1) and “**” in the definition of Y and Z taken together indicates the point of attachment of the partial formula (1.16) to the remaining portions —R 4 of formula (1); or a pharmaceutically acceptable salt, isomer, tautomer, solvate, polymorph, isotopic variation or metabolites thereof.
3 . A compound of claim 1 wherein:
R 1 and R 2 are each independently hydrogen or halo; X is —O—, R 3 is: (a) phenyl optionally substituted independently with 1 or 2 halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyloxy and (C 1 -C 4 )thioalkyl; or (b) a bicyclic group of the following formula: where the symbol “*” in the definition of R 3 indicates the point of attachment of each partial formula (1.1), (1.3) or (1.4) to the remaining portion of formula (1); Y is: where the symbol “*” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions —NH— of formula (1) and “**” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions Z of formula (1); R 5 is phenyl-(C 1 -C 4 )alkyl where said phenyl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of hydroxy, carboxylic acid, C(═O)O(C 1 -C 4 )alkyl and hydroxy(C 1 -C 4 )alkyl; Z is: where the symbol “*” in the defintion of Z indicates the points of attachment of each partial formula (1.9) through (1.11) and (1.15) to the remaining portions Y of formula (1) and “**” in the definition of Z indicates the point of attachment of each partial formula (1.9) through (1.11) and (1.15) to the remaining portions R 4 of formula (1); or Y and Z are taken together to form a group of formula (1.16): where the symbol “*” in the definition of Y and Z taken together indicates the point of attachment of the partial formula (1.16) to the remaining portions —NH— of formula (1) and “**” in the definition of Y and Z taken together indicates the point of attachment of the partial formula (1.16) to the remaining portions —R 4 of formula (1); and R 4 is: (a) phenyl, naphthyl, heteroaryl or (C 3 -C 8 )cycloalkyl, each optionally substituted independently with 1 to 3 carboxy, —C(═O)—O—(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-COOH, (C 1 -C 4 )alkyl-C(═O)—O—(C 1 -C 4 )alkyl, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 1 -C 4 )alkyl or hydroxy; or (b) (C 1 -C 6 )alkyl optionally substituted independently with 1 or 2 hydroxy, carboxy, —C(═O)—O—(C 1 -C 4 )alkyl, phenyl, naphthyl, heteroaryl or (C 3 -C 8 )cycloalkyl, where said phenyl, naphthyl, heteroaryl and (C 3 -C 8 )cycloalkyl are each optionally substituted independently with 1 to 3 carboxy, C(═O)O(C 1 -C 4 )alkyl, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 1 -C 4 )alkyl or hydroxy, or a pharmaceutically acceptable salt, isomer, tautomer, solvate, polymorph, isotopic variation or metabolite thereof.
4 . A compound of claim 1 wherein:
R 1 is hydrogen or fluoro; R 2 is hydrogen; X is —O—; R 3 is: (a) phenyl optionally substituted independently with 1 or 2 fluoro, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyloxy or methylthio; or (b) a bicyclic group of the formula: where the symbol “*” in the definition of R 3 indicates the point of attachment of each partial formula (1.1), (1.3) or (1.4) to the remaining portion of formula (1); Y is: where the symbol “*” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions —NH— of formula (1) and “**” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions Z of formula (1); R 5 is phenylmethyl substituted by hydroxy on said phenyl; Z is: where the symbol “*” in the definition of Z indicates the points of attachment of each partial formula (1.9) through (1.11) and (1.15) to the remaining portions Y of formula (1) and “**” in the definition of Z indicates the point of attachment of each partial formula (1.9) through (1.11) and (1.15) to the remaining portions R 4 of formula (1); or Y and Z are taken together to form a group of formula (1.16): where the symbol “*” in the definition of Y and Z taken together indicates the point of attachment of the partial formula (1.16) to the remaining portions —NH— of formula (1) and “**” in the definition of Y and Z taken together indicates the point of attachment of the partial formula (1.16) to the remaining portions —R 4 of formula (l); and R 4 is: (a) phenyl optionally substituted independently with 1 to 3 carboxy, —C(═O)—O-methyl, fluoro, chloro, methyl, iso-propyl, methoxy or hydroxy; (b) naphthyl optionally substituted by hydroxy; (c) pyridyl optionally substituted by hydroxy or —C(═O)Omethyl; (d) (C 3 -C 8 )cycloalkyl optionally substituted with hydroxy, —C(═O)—O—(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-C(═O)—O—(C 1 -C 4 )alkyl; or (e) (C 1 -C 6 )alkyl optionally substituted independently with 1 or 2 hydroxy, carboxy, methoxycarbonyl, ethoxycarbonyl, (C 3 -C 8 )cycloalkyl or phenyl, where said phenyl is optionally substituted independently with 1 or 2 fluoro, chloro, methyl, methoxy or hydroxy, or a pharmaceutically acceptable salt, isomer, tautomer, solvate, polymorph, isotopic variation or metabolites thereof.
5 . A compound of claim 1 of the formula
wherein R 1 is hydrogen and R A is
or
R 1 is fluoro and R A is
6 . A compound of claim 1 of the formula
wherein R 1 is hydrogen and R A is
or R 1 is fluoro and R A is
7 . A compound of claim 1 which is: anti-5-fluoro-2-(3,4-difluoro-phenoxy)-N-[4-(2-fluoro-6-hydroxy-benzoylamino)-cyclohexyl]-nicotinamide; anti-5-fluoro-2-(3-chloro-4-fluoro-phenoxy)-N-[4-(2-fluoro-6-hydroxy-benzoylamino)-cyclohexyl]-nicotinamide; syn-N-(4-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-phthalamic acid methyl ester; anti-N-{4-[acetyl-(2-hydroxybenzyl)-amino]-cyclohexyl}-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide; anti-N-{4-[acetyl-(3-hydroxybenzyl)-amino]-cyclohexyl}-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide; anti-N-{4-[Acetyl-(4-hydroxybenzyl)-amino]-cyclohexyl}-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide; exo-2-(3-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-8-azo-bicyclo[3.2.1]-octane-8-carbonyl)-benzoic acid methyl ester; exo-2-(3-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino} 8-aza-bicyclo[3.2.1]octane-8-carbonyl}-benzoic acid; syn-5-fluoro-2-(4-fluoro-phenoxy)-N-[4-(2-hydroxy-acetylamino)cyclohexyl]-nicotinamide; or syn-5-fluoro-2-(4-fluoro-phenoxy)-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-nicotinamide.
8 . A compound of claim 1 of the formula
wherein R 1 is hydrogen and R A is
or R 1 is fluoro and R A is
9 . A compound of claim 1 of the formula
wherein R B is
10 . A compound of claim 1 of the formula
wherein R A is
11 . A compound of claim 1 of the formula
wherein R A is
12 . A compound of claim 1 of the formula
wherein R C is
13 . A compound of claim 1 of the formula
wherein R A is
14 . A compound of claim 1 of the formula
wherein R A is
15 . A compound of claim 1 which is: syn-2-chloro-N-(4-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-terephthalamic acid; syn-N-(4-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-succinamic acid; syn-3-[1-(4-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexylcarbamoyl)-cyclopentyl]-propionic acid; syn-5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[3-(2-hydroxy-ethyl)-ureido]-cyclohexyl}-nicotinamide; syn-5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[3-(3-hydroxy-propyl)-ureido]-cyclohexyl}-nicotinamide; syn-3-[3-(4-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-ureido]-propionic acid methyl ester; syn-7-[3-(4-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-ureido]-heptanoic acid methyl ester; syn-3-[3-(4-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-ureido]-propionic acid; syn-7-[3-(4-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-ureido]-heptanoic acid; anti-5-Fluoro-2-(4-fluoro-phenoxy)-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-nicotinamide; syn-2-(4-fluoro-phenoxy)-N-[4-(2-hydroxy-benzoylamino)-cyclohexyl]-nicotinamide; syn-2-(4-fluoro-phenoxy)-N-[4-(2-hydroxy-4-methyl-benzoyl-amino)-cyclohexyl]-nicotinamide; syn-2-(4-fluoro-phenoxy)-N-{4-[2-(2-hydroxy-phenyl)-acetylamino]-cyclohexyl}-nicotinamide; or syn-2-(4-fluoro-phenoxy)-N-{4-[3-(2-hydroxy-benzyl)-ureido]-cyclohexyl}-nicotinamide.
16 . A compound of claim 1 of the formula
wherein R 3 is
17 . A compound of claim 1 which is: syn-5-fluoro-N-[4-(2-hydroxy-4-methoxy-benzoylamino)-cyclohexyl]-2-m-tolyloxy-nicotinamide; anti-2-(benzo[1,3]dioxol-5-yloxy)-N-[4-(2-fluoro-6-hydroxy-benzoylamino)-cyclohexyl]-nicotinamide; exo-5-fluoro-N-[8-(2-fluoro-6-hydroxy-benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(4-fluoro-phenoxy)-nicotinamide; exo-5-fluoro-2-(4-fluoro-phenoxy)-N-[8-(2-hydroxy-4-methoxy-benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-nicotinamide; exo-5-fluoro-2-(4-fluoro-phenoxy)-N-{8-[2-(4-hydroxy-phenyl)-acetyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-nicotinamide; exo-3-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid 2-hydroxy-benzyl-amide; Exo-3-{[5-Fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid 3-hydroxy-benzyl-amide; Exo-3-{[5-Fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid 4-hydroxy-benzyl-amide; exo-3-{[5-fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid 3-methyl-benzyl-amide; syn-2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-N-[4-(3-hydroxy-benzylcarbamoyl)-cyclohexyl]-nicotinamide; syn-2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-N-[4-(2-fluoro-4-hydroxy-benzylcarbamoyl)-cyclohexyl]-nicotinamide; anti-5-fluoro-2-(4-fluoro-phenoxy)-N-[4-(3-hydroxy-benzyl-carbamoyl)-cyclohexyl]-nicotinamide; syn-2-(4-fluoro-phenoxy)-N-[4-(2-hydroxy-benzyl-carba-moyl)-cyclohexyl]-nicotinamide; syn-N-[4-(2-fluoro-4-hydroxy-benzylcarbamoyl)-cyclohexyl]-2-(4-fluoro-phenoxy)-nicotinamide; or syn-2-(3,4-difluoro-phenoxy)-5-fluoro-N-[4-(2-hydroxy-5-methyl-benzoylamino)-cyclohexyl]-nicotinamide.
18 . A compound of claim 1 of the formula
wherein R A is
19 . A compound of claim 1 of the formula
wherein R A is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
and R 3 is
or R A is
and R 3 is
20 . A compound of claim 1 of the formula
wherein R 3 is 3,4-difluorophenyl, 3,5-difluorophenyl or 3,4-dichlorophenyl.
21 - 22 . (canceled)
23 . A process for preparing a compound of claim 1 wherein Z is:
or a pharmaceutically acceptable salt or derived form thereof, comprising reacting a compound of formula:
wherein R 1 , R 2 , X, R 3 and Y are as defined in claim 1 , with a corresponding R 4 -sulfonyl chloride derivative.
24 . A process for preparing a compound of claim 1 wherein Z is:
or a pharmaceutically acceptable salt or derived form thereof, comprising reacting a compound of formula:
wherein R 1 , R 2 , X, R 3 and Y are as defined in claim 1 , with a corresponding R 4 -carboxylic acid derivative.
25 . A process for preparing a compound of claim 1 wherein Z is:
or a pharmaceutically acceptable salt or derived form thereof, comprising reacting a compound of formula:
wherein R 1 , R 2 , X, R 3 and Y are as defined in claim 1 , with carbonyldiimidazole.
26 . A process for preparing a compound of claim 1 wherein Y and Z are taken together to form:
or a pharmaceutically acceptable salt or derived form thereof, comprising reacting a compound of formula:
wherein R 1 , R 2 , X, and R 3 are as defined in claim 1 , with an amine bearing a R 4 substituent.
27 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and/or additive.
28 . 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 or a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and/or additive.
29 . A method of claim 28 wherein said disease, disorder or condition is asthma.
30 . A method of claim 29 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.
31 . A method of claim 28 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.
32 . A method of claim 31 wherein said chronic obstructive pulmonary disease is characterized by irreversible, progressive airways obstruction.
33 . A method of claim 31 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.
34 . A method of claim 28 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.
35 . A method of claim 28 wherein said disease, disorder or condition is bronchiectasis; cylindric bronchiectasis; sacculated bronchiectasis; fusiform brochiectasis; capillary bronchiectasis; cystic bronchiectasis; dry bronchiectasis or follicular bronchiectasis.
36 . A method of claim 29 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.
37 . A method of claim 28 wherein said disease, disorder or condition is regulated by the activation and degranulation of eosinophils.
38 . (canceled)Cited by (0)
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