5-lipoxygenase inhibitors: (2-azinylamino) quinone derivatives

Details 5-lipoxygenase inhibitors: (2-azinylamino) quinone derivatives 5-lipoxygenase inhibitors: (2-azinylamino) quinone derivatives

2002-06-25

2003-11-25

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S275000, C514S352000, C514S242000, C514S243000, C544S316000, C544S336000, C544S182000, C544S183000, C546S312000

Reexamination Certificate

active

06653311

ABSTRACT:

This invention pertains to a series of new derivatives of (2-azinylamino) quinone, their synthesis, and the use of these derivatives as 5-lipoxygnease inhibitors.
Leukotrienes, identified as 5-lipoxygenase (5-LO) metabolites of arachidonic acid (AA), have been implicated as mediators in a diversity of diseases, including asthma and a number of other inflammatory pathologies, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and glomerulonephritis. See S. W. Crooks et al., “Molecules in focus: Leukotriene B4,” The Internat. J. Biochem. and Cell Biol., vol. 30, pp. 173-178 (1998). Although leukotrienes may not be involved in the initial stages of a disease, they appear to play an important role in the propagation of the disease, by exacerbating the initial, primarily local events and eventually leading to tissue damage.
Through the action of 5-LO, AA is initially oxygenated to give 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is then transformed by the same enzyme to leukotriene A
4
(LTA
4
). LTA
4
is then converted by LTA
4
-hydrolase to leukotriene B
4
(“LTB
4
”), a potent chemotactic agent that enhances infiltration of leukocytes and their subsequent degranulation. See Crooks et al., 1998. Alternatively, LTA
4
can couple to glutathione to produce peptidoleukotrienes (PLTs) LTC
4
, LTD
4
and LTE
4
that have profound effects on bronchial and vascular smooth muscle contractility, and promote extensive plasma extravascularization by increasing the permeability of the postcapillary venules. See, e.g., S. P. O'Hickey et al., “Leukotrienes C
4
, D
4
, and E
4
enhance histamine responsiveness in asthmatic airways,” Am. Rev. Resp. Dis., vol. 144, pp. 1053-1057 (1991).
Since the elucidation of the 5-LO biosynthetic pathway, an ongoing debate in drug development has been whether inhibition of the 5-LO enzyme is more efficacious than antagonization of the peptido- or non-peptido-leukotriene receptors. However, evidence suggests that 5-LO inhibitors may be superior to LT-receptor antagonists, since 5-LO inhibitors block the action of the full spectrum of 5-LO products, whereas LT-antagonists produce narrower effects. See D. G. Redkar-Brown et al., “Inhibition of antigen-induced contraction of guinea pig trachea by ICI 198,615,” Eur. J. Pharmacol. vol. 165, pp. 113-121 (1989); and T. R. Jones et al., “Antigen-induced contraction of guinea-pig isolated trachea: Studies with novel inhibitors and antagonists of arachidonic acid metabolites,” Br. J. Pharmacol., vol. 95, pp. 309-321 (1988). In addition, LT-receptor antagonists appear to prolong the half-lives of LTs by hindering their metabolism. See C. Denzlinger et al., “Effect of leukotriene receptor antagonists on leukotriene elimination in the rat,” Allergy Clin. Immunol., vol. 85, pp. 218 (1990).
Numerous attempts have been made in the last decade to identify and develop 5-lipoxygenase (5-LO) inhibitors as therapeutic agents. Among the compounds include several having a 1,4(or 1,2)-quinone moiety. The p-benzoquinone derivative 1 and the o-naphthoquinone 2, with structures as shown below, have been revealed as potent inhibitors of 5-LO. See S. Terao et al., “Quinones. Part 2. General Synthetic Routes to Quinone Derivatives with Modified Polyprenyl Side Chains and the Inhibitory Effects of these Quinones on the Generation of the Slow Reacting Substance of Anaphylaxis (SRS-A),”
J. Chem. Soc. Perkin Trans
., vol. 1, pp. 2909-2920 (1982); A. Rakhit et al., “Pharmacokinetic Screening of o-Naphtoquinone 5-Lipoxygenase Inhibitors,”
Pharm. Res
., vol. 7, pp. 1071-1076 (1990); S. Ohkawa et al., “Dual Inhibition of Thromboxane A
2
Synthetase and 5-Lipoxygenase with Scavenging Activity of Active Oxygen Species. Synthesis of a Novel Series of (3-Pyridylmethyl)benzoquinone Derivatives,”
J. Med. Chem
., vol. 34, pp. 267-276, (1991). See also, U.S. Pat. Nos. 4,393,075; 4,851,415; 4,985,447; and 5,106,858; and of International Application WO 86/04058. The series of(3-pyridylmethyl)benzoquinone derivatives were evaluated for inhibition of thromboxane A
2
(TXA
2
) synthase, inhibition of 5-LO, and scavenging activity of active oxygen species (AOS), and the compound with the structure 3 shown below was the most promising derivative. (Ohkawa et al., 1991).
We have synthesized a series of new derivatives of (2-azinylamino)-quinone, structure 4 as shown above. All (2-azinylamino)quinones are antioxidants. Several compounds of this new series of derivatives have been shown to be inhibitors of 5-lipoxygenase, with minimal or no effect on cycloxygenase-1 and 2-(COX-1 and COX-2) activity.
The series of new compounds have the following General Formula 4:
where:
A is N, CH, or CCl;
B is N, CH, CCH
3
, or CPh;
X is,H, Cl, Br, or I;
Y is H or CH
3
;
R
1
is H, CH
3
, OCH
3
, or Ph; and R
2
is H, CH
3
, OCH
3
, or Ph; or R
1
—R
2
is (CH═CH)
2
; and
R
3
is H or CH
3
.
Note that in the above formula when R
1
—R
2
is (CH═CH)
2
, this forms a naphthoquinone having a structure as exemplified below:
The compounds of General Formula 4 can be used as medication to be administered orally, rectally, topically, parenterally or inhalation, in the form of a pharmaceutical preparation, which contains at least one of the compounds of General Formula 4 in combination with a pharmaceutically acceptable carrier. The pharmaceutical carrier is selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compounds may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally, for example, intravenously, intramuscularly, or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, salts or glucose. The amount of active compound is between 0.1 and 99% by weight of the preparation, preferably between 2 and 50% by weight in oral preparations. The daily dose of the active substance depends on the type of administration and, in general, is between 25 and 100 mg if administered orally and between 0.1 and 50 mg per dose if administered intravenously. In clinical practice, the dosage will be adjusted for the particular patient and may vary with age, weight, and response of the patient. The above dosages are exemplary of an average case but can be increased or lowered if merited.
The preparation of the compounds of General Formula 4 is further illustrated by the following examples. In general the compounds were synthesized as shown below by reaction between the aminides 5 and the corresponding quinones 6 to yield the aminoquinones 4a-y (Table 1). The aminides 5a-e were prepared from the corresponding pyridinium salts as previously described. See R. Carceller et al., “Pyridinium-N-(2-pyridyl)aminides: A Selective Approach to Substituted 2-Aminopyridines,” Tetrahedron Lett., vol. 34, pp. 2019-2020 (1993); R. Carceller et al., “Azinium-N-(2′-azinyl)aminides: Synthesis, Structure and Reactivity,” Tetrahedron, vol. 50, pp. 4995-5012 (1994); and C. Burgos et al., “Halogenation of Pyridinium-N-(2′-pyridyl)aminide. An Easy Synthesis of Halo-2-aminopyridines,” Tetrahedron, vol. 51, pp. 8649-8654 (1995). Reaction of these compounds with the corresponding N-halosuccinimide in the reported conditions yielded the haloaminides 5f-i. See C. Burgos et al., 1995. The reaction between the aminides 5 and the quinones 6 was performed using silica as acid catalyst in acetonitrile. The process was accomplished at room temperature for 25-50 h.
In compounds 4b, 4c and 4f (defined as in Table 1), heating the reaction mixture that was absorbed on silica under reduced pressure (~0.2 atm) at 30° C. improved the yields with a decrease in reaction times (5-10 min). The synthesis of 4n was only possible, even though in low yield, under microwave irradiation. As it can be seen in the propo

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