5-arylsulfonyl-imidazo[1′,2′:1,6]pyrid...

Details 5-arylsulfonyl-imidazo[1′,2′:1,6]pyrid... 5-arylsulfonyl-imidazo[1′,2′:1,6]pyrid...

2002-03-11

2003-04-29

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S343000, C544S346000

Reexamination Certificate

active

06555538

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to 5-arylsulfonyl-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazine-6-amines and related compounds. The compounds are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosins factor (TNF), and as such are useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia, and AIDS.
This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Since the recognition that cyclic adenosine tri-phosphate (cAMP) is an intracellular second messenger, inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized and their selective inhibition has led to improved drug therapy. More particularly, it has been recognized that inhibition of PDE4 can lead to inhibition of inflammatory mediator release and airway smooth muscle relaxation. Thus, compounds that inhibit PDE4, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
Recent molecular cloning has revealed a complexity and diversity of PDE4 enzymes. It is now known that there are four distinct PDE4 isozymes (A, B, C and D), each encoded for by a separate gene. Kinetic studies of human recombinant materials suggest that these four isozymes may differ in their Km's and Vmax's for hydrolysis of cAMP. Analysis of tissue distribution of PDE4 mRNAs suggests that each isozyme may be localized in a cell-specific pattern.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula
and the pharmaceutically acceptable salts thereof; wherein
a is 1, 2, 3 or 4;
X is CH or N;
R
1
and R
2
are each independently selected from hydrogen, (C
1
-C
6
)alkyl, cyano, amino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
3
-C
7
)cycloalkyl, (C
6
-C
10
)aryl and a saturated or unsaturated, cyclic or bicyclic (C
2
-C
9
)heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen or NR
6
wherein R
6
is hydrogen or (C
1
-C
6
)alkyl;
R
3
and R
4
are each independently selected from hydrogen, halo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, cyano, hydroxy, amino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
3
-C
7
)cycloalkyl, (C
3
-C
7
)cycloalkoxy, (C
6
-C
10
)aryl or a saturated or unsaturated, cyclic or bicyclic (C
2
-C
9
)heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen or NR
6
wherein R
6
is defined as above;
or R
1
and R
2
may be taken together with the carbons to which they are attached to form a compound of formula II
wherein
a, X, R
3
and R
4
are as defined above;
b is 1,2,3 or 4; and
R
5
is hydrogen, halo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, cyano, hydroxy, amino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
3
-C
7
)cycloalkyl, (C
3
-C
7
)cycloalkoxy, (C
6
-C
10
)aryl or a saturated or unsaturated, cyclic or bicyclic (C
2
-C
9
)heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen or NR
6
wherein R
6
is defined as above.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term “a saturated or unsaturated, cyclic or bicyclic (C
2
-C
9
) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen or NR
6
wherein R
6
is as defined above”, as used herein, unless otherwise indicated, includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyi, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl.
The term “halo”, as defined herein, includes fluoro, chloro, bromo or iodo.
Preferred compounds of formula I include those wherein X is nitrogen.
Other preferred compounds of formula I include those wherein R
1
is hydrogen, (C
1
-C
6
)alkyl, amino, cycloalkyl or (C
6
-C
10
)aryl.
Other preferred compounds of formula I include those wherein R
2
is hydrogen, (C
1
-C
6
)alkyl, amino, cycloalkyl or (C
6
-C
10
)aryl.
Other preferred compounds of formula I include those wherein R
3
is hydrogen, halo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, cyano, amino, hydroxy, cycloalkyl or (C
6
-C
10
)aryl.
Other preferred compounds of formula I include those wherein R
4
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, amino, hydroxy, cycloalkyl or (C
6
-C
10
)aryl.
Other preferred compounds of formula II include those wherein R
5
is hydrogen, halo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, cyano, amino, hydroxy, cycloalkyl or (C
6
-C
10
)aryl.
More preferred compounds of formula I include those wherein X is nitrogen; R
1
is hydrogen, (C
1
-C
6
)alkyl, amino, cycloalkyl or (C
6
-C
10
)aryl; R
2
is hydrogen, (C-C
6
)alkyl, amino, cycloalkyl or (C
6
-C
10
)aryl; R
3
is hydrogen, halo, (C
1
-C
6
)alkyl, cyano, amino, hydroxy, cycloalkyl or (C
6
-C
10
)aryl; and R
4
is hydrogen, (C
1
-C
6
)alkyl, amino, hydroxy, cycloalkyl or (C
6
-C
10
)aryl.
More preferred compounds of formula II include those wherein X is nitrogen; R
3
is hydrogen, halo, (C
1
-C
6
)alkyl, cyano, amino, hydroxy, cycloalkyl or (C
6
-C
10
)aryl; R
4
is hydrogen, (C
1
-C
6
)alkyl, amino, hydroxy, cycloalkyl or (C
6
-C
10
)aryl and R
5
is hydrogen, (C
1
-C
6
)alkyl, cyano, amino, hydroxy, cycloalkyl or (C
6
-C
10
)aryl.
Specific preferred compounds of formula I include the following:
5-[(4-methylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-methylphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-ethylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-isopropylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-propylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-methoxyphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]

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