Pyridazines as interleukin-1&bgr; converting enzyme inhibitors

Details Pyridazines as interleukin-1&bgr; converting enzyme inhibitors Pyridazines as interleukin-1&bgr; converting enzyme inhibitors

1996-04-03

2003-09-23

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S247000, C514S252010, C514S252020, C514S252030, C514S252040, C544S238000, C544S215000, C544S224000

Reexamination Certificate

active

06624166

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a series of novel pyridazine analogs which exhibit selective inhibition of interleukin-1&bgr; converting enzyme, to compositions containing the novel pyridazine analogs and methods for therapeutic utility. More particularly, the interleukin-1&bgr; converting enzyme inhibitors described in this invention comprise novel pyridazine analogs which possess particular utility in the treatment of inflammatory, immune-based diseases and cancer.
2. Reported Developments
Interleukin-1&bgr; protease (also known as interleukin-1&bgr; converting enzyme or ICE) is the enzyme responsible for processing of the biologically inactive 31 kD precursor IL-1&bgr; to the biologically active 17 kD form (Kostura, M. J.; Tocci, M. J.; Limjuco, G.; Chin, J.; Cameron, P.; Hillman, A. G.; Chartrain, N. A.; Schmidt, J. A.
Proc. Nat. Acad. Sci
., 1989, 86, 5227-5231 and Black, R. A.; Kronheim, S. R.; Sleath, P. R.
FEBS Let
., 1989, 247, 386-391). In addition to acting as one of the body's early responses to injury and infection, IL-1&bgr; has also been proposed to act as a mediator of a wide variety of diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, and acute and chronic myelogenous leukemia (Dinarello, C. A.; Wolff, S. M.,
New Engl. J. Med
., 1993, 328, 106). The naturally occurring IL-1&bgr; receptor antagonist has been used to demonstrate the intermediacy of IL-1&bgr; in a number of human diseases and animal models (Hannum, C. H.; Wilcox, C. J.; Arend, W. P.; Joslin G. G.; Dripps, D. J.; Heimdal, P. L.; Armes, L. G.; Sommer, A.; Eisenberg, S. P.; Thompson, R. C.,
Nature
, 1990, 343, 336-340; Eisenberg, S. P.; Evans, R. J.; Arend, W. P.; Verderber, E.; Brewer, M. T.; Hannum, C. H.; Thompson, R. C.,
Nature
1990, 343, 341-346; Ohlsson, K.; Bjork, P.; Bergenfeldt, M.; Hageman, R.; Thompson, R. C.,
Nature
, 1990, 348, 550-552; and Wakabayashi, G.,
FASEB
, 1991, 338-343). The specific role of IL-1&bgr; in inflammation and immunomodulation is supported by the recent observation that the cowpox virus employs an inhibitor of ICE to suppress the inflammatory response of its host (Ray, C. A. et al,
Cell
, 1992, 69, 597-604).
The present invention also relates to the modulation of processing of IL-1&bgr; for the treatment of rheumatoid arthritis. Levels of IL-1&bgr; are known to be elevated in the synovial fluid of patients with the disease. Additionally, IL-1&bgr; stimulates the synthesis of enzymes believed to be involved in inflammation, such as collagenase and PLA
2
, and produces joint destruction which is very similar to rheumatoid arthritis following intraarticular injection in animals.
ICE is believed to be a cysteine protease (Thornbury, N.A. et al,
Nature
, 1992, 356-768). Peptidyl methyl ketone analogs constitute a wellknown class of compounds having cysteine protease inhibitory activity. (D. Rich in Chapter 4 of “Proteinase Inhibitors”, Barrett, A. J. and Salvensen, G., eds., Elsevier, 1986). However, there has never been a reported example of a non-peptide heterocyclic inhibitor of a cysteine protease. Hence, the inhibitory activity displayed by the pyridazine analogs described herein against ICE is unique.
An effective therapy has yet to be developed for the treatment of IL-1&bgr; mediated inflammatory diseases. Consequently, there is a need for therapeutic agents effective in the treatment and prevention of these diseases.
SUMMARY OF THE INVENTION
In accordance with the present invention, novel non-peptidic pyridazines are provided having the formula (I) and a pharmaceutically acceptable salt thereof
wherein
R
1
is a halogen, or an oxygen linked leaving group including an aromatic ether, an aromatic ester, an alkyl sulfonate, an aryl sulfonate, an alkyl phosphonate, an aryl phosphonate, an alkyl phosphate or aryl phosphate;
R
2
is OR
5
, NH(CHR
5
)
m
—COOR
5
, NH(CHR
5
)
m
CON(R
5
)R
6
, N(R
5
)R
6
or NH(CHR
5
)
n
OH;
R
3
is H or alkyl;
R
4
is H, substituted or unsubstituted aryl, heteroaryl or alkyl;
R
5
and R
6
are independently H, lower alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or lower cycloalkyl;
m=1-6; and
n=2-6.
As used herein, the term pharmaceutically acceptable salts includes the acid and base addition salts.
The term acid addition salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
The term base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaines, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine.
“Alkyl” is defined as a saturated or unsaturated aliphatic hydrocarbon which may be either straight- or branched-chain. Preferred groups have no more than about 12 carbon atoms and may be methyl, ethyl and structural isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
“Lower alkyl” is defined as an alkyl group as above, having 1 to 4 carbon atoms. Suitable lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and n-heptyl.
“Lower cycloalkyl” is defined as a carbocyclic ring of 3-8 carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
“Aryl” is defined as phenyl, naphthyl and substituted phenyl.
“Substituted phenyl” is defined as a phenyl group in which one or more of the hydrogens has been replaced by the the same or different substituents including halo, lower alkyl, nitro, amino, acylamino, hydroxyl, lower alkoxy, aryl, heteroaryl, alkyl sulfonyl, arylfulsonamido, trifluoromethyl, morpholinoethoxy and morpholino-sulfonyl, and carbobenzoxy-methyl sulfamoyl.
“Halogen” is defined as chloride, fluoride, bromide or iodide.
“Heteroaryl” is defined as pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, triazinyl, quinolyl and isoquinolyl.
“Substituted heteroaryl” means a heteroaryl group in which one or more of the hydrogens has been replaced by the the same or different substituents including halo, lower alkyl, nitro, amino, acylamino, hydroxyl, lower alkoxy, aryl, heteroaryl, lower alkoxy, alkylsulfonyl, trifluoromethyl, morpholinoethoxy, morpholino-sulfonyl, carbobenzoxy-methylsulfamoyl.
“Aralkyl” is defined as an alkyl group susbstituted by an aryl ring. For example, benzyl, phenethyl and 4-chlorobenzyl.
The present invention concerns a method for inhibiting ICE in a mammal by administering a therapeutically effective amount of a compound of the Formula (I) or a pharmaceutical composition containing a compound of the Formula (I) in a pharmaceutically acceptable carrier. The method of inhibition is directed for the treatment

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