Compounds and their use as PDE inhibitors

Details Compounds and their use as PDE inhibitors Compounds and their use as PDE inhibitors

2002-02-28

2003-09-09

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S084000

Reexamination Certificate

active

06617357

ABSTRACT:

BACKGROUND OF INVENTION
This invention relates to certain benzenesulfonamides and their use as PDE7 inhibitors.
Cyclic nucleotide phosphodiesterases (PDEs) represent a family of enzymes that hydrolyze the ubiquitous intracellular second messengers, adenosine 3′,5′-monophosphate (cAMP) and guanosine 3′,5′-monophosphate (cGMP) to their corresponding inactive 5′-monophosphate metabolites. At least 14 distinct classes of PDE isozymes are believed to exist, each possessing unique physical and kinetic characteristics and each representing a product of a different gene family. These are distinguished using Arabic numerals 1-14. And within each distinct class; there may be two or more distinct sub-types. See reviews by Crocker, I et al, Drugs Today, 35(7), 519-535 (1999), Fawcett, L. et al, PNAS, 97(7), 3702-3703 (2000) and Yuasa, K et al, J Biol Chem., 275(40), 31496-31479 (2000).
The present invention relates to the PDE isozyme which is currently identified as PDE7 or HCP1-PDE. This type 7 isozyme is found in various tissues and in particularly high concentrations in skeletal muscle. Two sub-types have been identified, PDE7A Michaeli, T, et al, J Biol Chem., 268 (17) 12925-12932 (1993); Han, P et al, J Biol Chem. 272(26), 16152-16157 (1997) and PDE7B; U.S. Pat. No. 6,146,876; Gardner, C. et al, Biochem Biophys Res. Commun. 272 (1) 186-192 (2000); and Saski, T. et al, Biochem Biophys Res Commun. 271 (3), 575-583 (2000). Herein these will be referred to collectively as PDE7 unless otherwise stated.
PDE7 inactivates secondary messenger cAMP by hydrolysis and inhibition of PDE7 results in increased levels of cAMP. Inhibition of PDE7 may be useful in the treatment of asthma, rheumatoid arthritis, psoriasis, atopic dermatitis and chronic bronchitis. While assessment of PDE7 message expression indicates a broad cellular distribution, PDE7 protein expression and activity is localized mostly to T-lymphocytes and lymphoid tissue. Consequently, PDE7 inhibitors may be useful in the treatment of T-cell-mediated disorders. Morerover, selective PDE7 inhibitors may have reduced adverse events sometimes encountered with other PDE inhibitors, events such as CNS, GI and cardiovascular side effects.
SUMMARY OF INVENTION
This invention relates to compounds of Formula 1 for use in the mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE7 in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula 1:
wherein,
R
1
is NR
a
R
b
where R
a
and R
b
are independently H or C
1-6
alkyl, or —NR
a
R
b
represents a 5 to 7 member ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
R
2
is H, C
1-8
alkyl, C
1-3
alkyl-Ar, C
1-3
alkyl-C
3-6
cycloalkyl, C
2-8
alkenyl, C
2-4
alkenyl-Ar, or C
2-4
alkenyl-C
3-6
cycloalkyl;
Ar is substituted or unsubstituted phenyl;
R
3
is NO
2
, halo, CN, C(O)OR
7
, COR
1
, or NR
a
R
b
where R
a
and R
b
are independently H or C
1-6
alkyl;
R
4
is H, —OC
1-6
alkyl, halo, C(O)NR
a
R
b
, C(O)OR
7
, C
1-8
alkyl, —OCHF
2
, —CH
2
OR
8
, —OC
1-3
alkylAr, or CH
2
NHC(O)CH
3
;
R
5
is H, halo, or alkyl;
R
6
is C
1-8
alkyl, OC
1-4
alkyl or halo;
R
7
is hydrogen or an ester or amide-forming group;
R
8
is hydrogen or C
1-6
alkyl;
or a pharmaceutically acceptable salt or solvate thereof.
Included in this invention are the novel compounds of Formula 1 and pharmaceutically acceptable formulations thereof.
DETAILED DESCRIPTION
These PDE7 inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, and chronic glomerulonephritis.
As regards preferred embodiments of the compounds disclosed herein, the following groups are preferred:
“Halo” means fluoro, chloro, bromo or iodo. The preferred halo groups are chloro and bromo.
“Alkenyl” refers to an unsaturated straight or branched hydrocarbon chain, which has 1 or more double bonds. Preferred groups are substituted ethenyl.
In R
1
, Ra or R
b
is preferably hydrogen or lower alkyl, or NR
a
R
b
is a 5-or 6-membered ring with or without a heteroatom. When Ra or R
b
is an alkyl group it is preferred that it be methyl or ethyl. Where R
1
is NR
a
R
b
is a ring, the ring may be, for example: 1-imidazolyl, 2-R(
7
)-1-imidazolyl, 1-pyrazolyl, 3-(R
7
)-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R
7
)-1-triazolyl, 5-(R
7
)-2-triazolyl, 5-(R
7
)-1-tetrazolyl, 5-(R
7
)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, 4-(R
7
)-1-piperazinyl, pyrrolidinyl or pyrrolyl where R
7
is hydrogen or C
1-4
alkyl. The most preferred rings are morpholinyl and pyrrolidinyl.
Preferred R
2
groups are hydrogen, C
1-8
alkyl or C
1-3
alkyl-Ar where Ar is phenyl unsubstituted or substituted by C(O)OR
7
.
Preferred R
3
groups are NO
2
, Cl, Br, or NR
a
R
b
where R
a
and R
b
are independently H or C
1-6
alkyl.
R
4
is preferably hydrogen, —OC
1-6
alkyl, Cl, C(O)NR
a
R
b
, C
1-4
alkyl, —OCHF
2
, —CH
2
OR
8
, or —OC
1-3
alkylAr where Ar is phenyl, unsubstituted or substituted by C(O)OR
7
.
R
5
is preferably hydrogen.
R
6
is preferably Cl, Br or methyl.
Compounds disclosed herein include the following:
2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
2-methyl-5-nitropyrrolidinylbenzenesulfonamide;
2-methyl-5-nitromorpholinobenzenesulfonamide;
2,4-dimethyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
2-ethyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-methoxy-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-(3-carboxybenzyloxy)-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-difluoromethoxy-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-bromo-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-amido-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-methyleneoxy-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
2-methyl-4-(methyl)methyleneoxy-5-nitro(N,N-dimethyl)benzenesulfonamide;
5-chloro-2-methyl(N,N-dimethyl)benzenesulfonamide;
2,5-dichloro-4-methyl(morpholino)benzenesulfonamide;
4,5-dichloro-2-methyl(N,N-dimethyl)benzenesulfonamide;
2,4,5-trichloro(N,N-dimethyl) benzenesulfonamide;
2,5-dichloro-4-methoxy(N, N-dimethyl)benzenesulfonamide;
2,5-dichloro-4-difluoromethoxy(N,N-dimethyl)benzenesulfonamide;
5-bromo-2-methyl(N,N-dimethyl) benzenesulfonamide;
2-bromo-5-cyano(N,N-dimethyl)benzenesulfonamide;
3-N,N-dimethylamino-2-methyl(N,N-dimethyl)benzenesulfonamide;
methyl 2,5-dichloro-4-(N-morpholino)sulfonyl benzoate;
2,5-dichloro-4-methyleneoxy(morpholino)benzenesulfonamide;
2,5-dichloro-4-(methyl) methyleneoxy(morpholino)benzenesulfonamide;
3,6-dichloro-2-methyl-4-methyleneoxy(morpholino)benzenesulfonamide;
3,6-dichloro-2-(3-methoxy)phenethyl-4-methyleneoxy(morpholino)benzenesulfonamide; or
N-(2,5-dichloro-4-morpholinosulfonyl)benzyl acetamide.
Formulations and Methods of Administration
The present compounds and pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, dermally, transdermally, rectally, via inhalation or via buccal administration. A controlled-release preparation can also be utilized. An orally administered preparation is preferred.
The present compounds and pharmaceutically acceptable salts, which are active when given orally, can be formulated as syrups, tablets, capsules, controlled release preparation, or lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, and peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, steari

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