Bicyclic sPLA2 inhibitors

Details Bicyclic sPLA2 inhibitors Bicyclic sPLA2 inhibitors

2000-12-11

2002-05-07

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S280000

Reexamination Certificate

active

06384041

ABSTRACT:

This invention relates to novel pyrrolo[2,3-d]-pyrimidines useful for inflammatory diseases.
The structure and physical properties of human non-pancreatic secretory phospholipase A
2
(hereinafter called, “sPLA
2
”) has been thoroughly described in two articles, namely, “Cloning and Recombinant Expression of Phospholipase A
2
Present in Rheumatoid Arthritic Synovial Fluid” by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.;
The Journal of Biological Chemistry,
Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and “Structure and Properties of a Human Non-pancreatic Phospholipase A
2
” by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake;
The Journal of Biological Chemistry,
Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA
2
is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA
2
mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA
2
; such as sepsis or rheumatoid arthritis.
It is desirable to develop new compounds and treatments for sPLA
2
induced diseases.
This invention is a novel use of the class of compounds known as pyrrolo[2,3-d]pyrimidines to inhibit mammalian sPLA
2
mediated release of fatty acids.
This invention Is also a novel class of pyrrolo[2,3-d]pyrimidines having potent and selective effectiveness as inhibitors of mammalian sPLA
2
.
This invention is also a pyrrolo[2,3-d]pyrimidine compound in the treatment of Inflammatory Disease.
This invention is also pharmaceutical compositions containing the pyrrolo[2,3-d]pyrimidines of the invention.
This invention is also a method of preventing and treating Inflammatory Diseases in mammals by contact with a therapeutically effective amount of the pyrrolo[2,3-d]pyrimidines of the invention.
This invention is also the use, in the manufacture of a medicament of pyrrolo[2,3-d]pyrimidine compound as an active ingredient in an sPLA
2
inhibiting composition in admixture with an inert carrier.
Definitions
The term, “Inflammatory Diseases” refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with “vasculitic syndromes”, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA
2
mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
The term, “pyrrolo[2,3-d]pyrimidine nucleus” refers to a nucleus (having numbered positions)with the structural formula (X):
The pyrrolo[2,3-d]pyrimidine compounds of the invention employ certain defining terms as follows:
The term, “alkyl” by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.
The term, “alkenyl” employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number range of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.
The term, “hydrocarbyl” means an organic group containing only carbon and hydrogen.
The term, “halo” means fluoro, chloro, bromo, or iodo.
The term, “heterocyclic radical”, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl and quinoxalinyl.
The term, “carbocyclic radical” refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, thiophenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluoyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a):
where n is a number from 1 to 8.
The term, “non-interfering substituent”, refers to radicals suitable for substitution at the 2 position of the pyrrolo[2,3-d]pyrimidine nucleus and on other nucleus substituents (as hereinafter described for Formula I), infra. Illustrative non-interfering radicals are C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
7
-C
12
aralkyl, C
7
-C
12
alkaryl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl, phenyl, toluoyl, xylenyl, biphenyl, C
1
-C
8
alkoxy, C
2
-C
8
alkenyloxy, C
2
-C
8
alkynyloxy, C
2
—C
12
alkoxyalkyl, C
2
-C
12
alkoxyalkyloxy, C
2
-C
12
alkylcarbonyl, C
2
-C
12
alkylcarbonylamino, C
1
-C
12
alkoxyamino, C
2
-C
12
alkoxyaminocarbonyl, C
1
-C
12
alkylamino, C
1
-C
8
alkylthio, C
2
-C
12
alkylthiocarbonyl, C
1
-C
8
alkylsulfinyl, C
1
-C
8
alkylsulfonyl, C
1
-C
8
haloalkoxy, C
1
-C
8
haloalkylsulfonyl, C
1
-C
8
haloalkyl, —CF
3
, C
1
-C
8
hydroxyalkyl, —C(O)O(C
1
-C
8
alkyl), —(CH
2
)
n
—O—(C
1
-C
8
alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO
2
R

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