Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-11
2001-01-16
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S122000, C546S123000
Reexamination Certificate
active
06174895
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to 1-aryl-3-arylmethyl-1,8-naphthyridn4(1H)-ones that are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosis 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, toxic 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 adenosine 3′,-5′-cyclic 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. For example, unlike human skeletal muscle, human peripheral blood leukocytes do not express PDE4C message, and guinea pig eosinophils express predominantly PDE4D message. The structural and distribution diversity of PDE4 isozymes offers an opportunity to discover an isozyme selective inhibitor that blocks the function of inflammatory cells only. Using PDE4D isozyme selective inhibitors, we have demonstrated that the PDE4D isozyme plays a key role in regulating the activation and degranulation of human eosinophils. In a primate model of asthma, PDE4D isozyme selective compounds inhibit antigen-induced pulmonary eosinophilia. Therefore, by selectively blocking the D isozyme, PDE4D inhibitors exhibit reduced side effects and retain anti-asthmatic (anti-inflammatory) efficacy.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula
or the pharmaceutically acceptable salt thereof; wherein
R
1
and R
2
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
7
)cycloalkyl, (C
6
-C
10
)aryl, (C
5
-C
9
)heteroaryl and (C
2
-C
9
)heterocycloalkyl wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl groups are optionally substituted by halo, hydroxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, amino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, thio, (C
1
-C
6
)alkylthio, cyano, carboxy, carboxy(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)acyl, aminosulfonyl, (C
1
-C
6
)alkylaminosulfonyl or ((C
1
-C
6
)alkyl)
2
aminosulfonyl; and
R
3
is hydrogen, halo, hydroxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, amino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, thio, (C
1
-C
6
)alkylthio, carboxy, carboxy(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)acyl, aminosulfonyl, (C
1
-C
6
)alkylaminosulfonyl or ((C
1
-C
6
)alkyl)
2
aminosulfonyl.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g.., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine.
(C
3
-C
10
)Cycloalkyl when used herein refers to cycloalkyl groups containing zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane, norbornanyl etc.
(C
2
-C
9
)Heterocycloalkyl when used herein refers to azetidinyl, 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, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skill in the art will understand that the connection of said (C
2
-C
9
)heterocycloalkyl rings is through a carbon or a sp
3
hybridized nitrogen heteroatom.
(C
2
-C
9
)Heteroaryl when used herein refers to 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, benzothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill in the art will understand that the connection of said (C
2
-C
9
)heterocycloalkyl rings is through a carbon atom or a sp
3
hybridized nitrogen heteroatom.
(C
6
-C
10
)aryl when used herein refers to phenyl or naphthyl.
Preferred compounds of formula I include those wherein R
1
is (C
6
-C
10
)aryl o
Benson Gregg C.
Creagan B. Timothy
Dentz Bernard
Pfizer Inc.
Richardson Peter C.
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