Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-01-19
2003-03-18
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S171000, C544S277000, C544S310000, C544S312000, C544S373000, C544S171000, C544S146000, C544S165000, C544S200000, C544S277000, C544S171000, C544S305000, C544S312000, C544S253000, C544S403000, C544S403000
Reexamination Certificate
active
06534651
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to inhibitors of inflammation and reperfusion injury. In particular, the invention relates to 2,3-dihydro-isoindol-1-one derivatives and nucleoside analogs, and more particularly to nucleoside-isoindolinone conjugates.
BACKGROUND OF THE INVENTION
Inflammation disorders, such as arthritis, colitis, and autoimmune diabetes typically manifest themselves as disorders distinct form those associated with reperfusion injury, e.g., stroke and heart attack, and can present clinically as different entities. However, there can be common underlying mechanisms between these two types of disorders. In particular, inflammation and reperfusion injury can induce proinflammatory cytokine and chemokine synthesis. Induction of pro-inflammatory cytokines can, in turn, result in production of cytotoxic free radicals such as nitric oxide (NO) and superoxide. Nitric oxide and superoxide can react to form peroxynitrite (ONOO
−
). Szabó et al, Shock 6:79-88, 1996.
Peroxynitrite-induced cell necrosis observed in inflammation and reperfusion injury involves, in significant part, the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Activation of PARS is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion injury. Szabó et al., Trends Pharmacol. Sci. 19: 287-98, 1998.
A number of PARS inhibitors have been described in the art. See, e.g., Banasik et al., J. Biol. Chem., 267:1569-75, 1992, and Banasik et al., Mol. Cell. Biochem., 138:185-97, 1994. Additionally, some potent PARS inhibitors are reported in, for example, WO 00/39104, WO 00/39070, WO 99/59975, WO 99/5973, WO 99/11649, WO 99/11645, WO 99/11644, WO 99/11628, WO 99/11628, WO 99/11623, WO 99/11311, WO 00/42040; Zhang et al., Biochem. Biophys. Res. Commun., 278:590-98, 2000, White et al., J.Med. Chem., 43:4084-4097, 2000; Griffin et al., J. Med. Chem., 41:5247-5256, 1998; Shinkwin et al., Bioorg. Med. Chem., 7:297-308, 1999. Furthermore, side effects of some of the best known-PARP inhibitors have been discussed in Milan et al, Science, 223:589-591, 1984.
Certain isolindolinone derivatives are known in the art. For example, inhibitors of platelet aggregation are reported in Egbertson et al., J. Med. Chem., 42:2409-21, 1999; dopamine D4 receptor isoindolinones are reported in Belliotti et al., Bioorg. Med. Chem. Lett., 8:1499-502, 1998; antipsychotic agents are disclosed in Norman et al., J. Med. Chem., 37: 2552-63, 1994 and in Normal et al., J. Med. Chem., 36: 3417-23, 1993. The antiarrhythmic activity of isoindolione is shown in Dugger et al. Drug Metab. Dispos. 4:262-268, 1976, and substituted 2,3-dihydro-1H-isoindol-1-one derivatives for treating hyperlipemia remedy are disclosed in WO 98/54135.
Syntheses of substituted 2,3-dihydroisoindolinones, other than the compounds of the invention, are reported in, for example, Duckworth et al., J. Chem. Soc., Perkin Trans. 1:815-21, 1996; Kamochi et al., Daiichi Yakka Daigaku Kenkyu Nenpo 20:1-10, 1989; McAlees et al., J. Chem. Soc. Perkin Trans 1, 1:2038-2040, 1977; Tomita et al., J. Chem. Soc. C, 2:183-8, 1969; Do Minh et al., J. Org. Chem., 42:4217-4221, 1977; and O'Sullivan et al., J. Chem. Soc. Chem. Commun., 17:1165-1166, 1984.
Various nucleoside peptides and amide derivatives are shown in, for example, Kawana et al. , J. Org. Chem., 37:288-91 (1972); U.S. Pat. Nos. 3,864,483; 3,914,414; 3,914,415; 3,966,917; 4,029,884; and in German patents DE 2417465 and DE 2213180.
SUMMARY OF THE INVENTION
The invention is based in part on the discovery of novel compounds and their unexpected effects in inhibiting inflammation and in treating reperfusion injuries.
Accordingly, one aspect of the invention includes novel substituted isoindolinone derivatives. In another aspect, the invention relates to substituted nucleoside analogs. In yet another aspect, the invention includes a conjugate according to Formula I, as set forth in the Detailed Description of the Invention, below.
Also provided by the invention is a method of treating inflammatory and reperfusion conditions in mammals by administering to a mammal in need of such treatment an effective amount of the compounds of the invention, for example, a conjugate according to Formula I.
In a further aspect, the invention also includes a method for the production of the compounds of the invention.
In one aspect of the invention, a nucleoside or nucleoside analog is conjugated to a compound that is useful for inhibiting inflammation or for treating reperfusion injuries. In some embodiments, the nucleoside moiety increases the anti-inflammatory or anti-reperfusion activity of the conjugated compound. In a particular embodiment, a nucleoside moiety is conjugated to an isoindolinone moiety.
The compounds described in the current invention are potent compounds that can be used to treat a variety of conditions and diseases, typically those known to involve inflammatory mediator production and cell death.
The details of one or more embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel class of substituted nucleoside derivatives according to Formula I:
A—Z
1
—L—Z
2
—G I
or a pharmaceutically acceptable prodrug, hydrated salt, or mixtures thereof, wherein A and G are connected via Z
1
and Z
2
, respectively, to a linker L.
Moiety A is a ribose-substituted mono- or bi-cyclic heterocycle accordind to formula II or III.
Wherein
X
1
and X
2
are, independently, N or CH;
X
3
is CR
7
═CR
8
, CHR
7
—CHR
8
, CR
7
═N, N═CR
7
, N═N, NR
7
—O, CHR
7
—O or CHR
7
—S, where R
7
and R
8
are, independently, H, alkyl, amino, hydroxy, alkoxy;
R
1
and R
2
are, independently, H, alkyl, NH
2
, OH, SH, Cl, NHR
9
, N═R
9
, N═NR
9
, or amide, where R
9
is alkyl, aryl, arylalkyl, alkyl-heterocycle;
R
3
and R
4
are independently H, C1-5 alkyl, hydroxy, amino or halo;
R
5
and R
6
are, independently, alkyl, other acyl, or R
5
and R
6
, taken together, form a 5-or 6-membered, substituted or unsubstituted heterocycle.
In some embodiments, A is a 5′ modified purine or pyrimidine nucleoside, or a derivative thereof (e.g., where X
1
═X
2
═N, X
3
is N═CH, R
1
and R
2
are NH
2
or OH).
Z
1
is —CH
2
O—, —CH
2
NR
10
—, —CH
2
NR
10
C(O)—, —CONR
10
—, —CO
2
—, —CH
2
NHCONH—, —CH
2
—, —CH
2
NHCSNH—, —CO—, —CH
2
CO
2
—, —NHCO
2
, S, SO
2
, CH
2
S, SO;
Z
2
is; —NR
10
CO—, —C(O)NR
10
—, —NHCONH—, —OC(O)—, —C(O)O—, NHCS, —CSNH—, NHCSNH, O, CO, OCO, OCONH, NH, CH
2
, CH-alkyl, NHCO
2
, S, SO
2
, CS, SO.
It is understood that tautomeric forms, where possible, are included in the invention, and that where tautomerisation is possible, the tautomer represented herein as structures II or III may not represent the dominant tautomer.
The linker, L, can be H, O, S, C1-15 alkylene chain, which can be substituted in one or more positions, or a 5, 6 or 7-membered carbocycle or heterocycle (optionally substituted in one or more positions), provided that when Z
1
is O, L is not H, and when L is H, Z
2
and G are absent. In some embodiments, L is substituted with amino, alkyl, halo, hydroxy, thio, or epoxide groups in any combination;
In some embodiments, L may contain:
i) one or more heteroatoms chos
Jagtap Prakash
Ram Siya
Salzman Andrew
Southan Garry
Szabo Csaba
Inotek Pharmaceuticals Corp.
McKenzie Thomas
Pennie & Edmonds LLP
Shah Mukund J.
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