Substituted glutarimides and their use as inhibitors of...

Details Substituted glutarimides and their use as inhibitors of... Substituted glutarimides and their use as inhibitors of...

2002-07-19

2003-12-02

Desai, Rita (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S237200, C514S326000, C514S328000, C546S207000, C546S208000, C546S219000, C544S111000, C544S129000

Reexamination Certificate

active

06656937

ABSTRACT:

FIELD OF THE INVENTION
The invention concerns substituted glutarimides having the general formula I
their production and their use in medicaments.
BACKGROUND OF THE INVENTION
Autoimmune diseases arise as a result of a reactivity of the immune system against structures or components occurring naturally in the body. As part of this process, the normally existing tolerance towards the body's own tissue lapses. In addition to antibodies, T-lymphocytes and monocytes/macrophages in particular play a significant role in the pathogenesis of the various autoimmune diseases. Activated monocytes and/or macrophages secrete a number of different proinflammatory mediators that are directly or indirectly responsible for destroying the tissue affected by the autoimmune disease. The activation of monocytes/macrophages occurs either in the interaction with T-lymphocytes or via bacterial products such as lipopolysaccharide (LPS).
IL-12 is a heterodimeric molecule consisting of a covalently bonded p35 and p40 chain. The molecule is formed by antigen-presenting cells (monocytes/macrophages, dendritic cells, B-lymphocytes). The formation of 1L-12 by monocytes/macrophages is triggered either by various microbial products such as LPS, lipopeptides, bacterial DNA or in the interaction with activated T-lymphocytes (Trinchieri, 1995, Ann. Rev. Immunol. 13: 251). IL-12 has a central immunoregulatory significance and is responsible for the development of proinflammatory TH1 reactivities. The presence of a TH1 immune reaction against self-antigens leads to the occurrence of serious diseases.
The significance of inflammatory cytokines such as IL-12 for the development and course of inflammations and autoimmune diseases has been clearly documented by numerous animal experimental and preliminary clinical trials. The pathophysiological importance of IL-12 has been demonstrated in various animal models for diseases such as rheumatoid arthritis, multiple sclerosis, diabetes mellitus and inflammatory diseases of the intestines, skin and mucous membranes (Trembleau et al., 1995, Immunol. Today 16: 383; Muller et al., 1995, J. Immunol. 155: 4661; Neurath et al., 1995, J. Exp. Med. 182: 1281; Segal et al., 1998, J. Exp. Med. 187: 537; Powrie et al., 1995, Immunity 3: 171; Rudolphi et al., 1996, Eur. J. Immunol. 26: 1156; Bregenholt et al., 1998, Eur. J. Immunol. 28: 379). Application of IL-12 could trigger the relevant disease and neutralisation of endogenous IL-12 led to the course of the disease being moderated, or even the cure of the animals. The use of antibodies against IL-12 in humans is imminent.
It can be said in summary that an excess of IL-12 conditions the pathophysiology of a number of inflammatory diseases. Attempts to normalize the IL-12 level therefore have great therapeutic potential.
IL-12 is also involved in regulating the survival of cells. Uncontrolled cell growth is regulated by apoptosis (programmed cell death) amongst other things. Using T-lymphocytes it has been shown that IL-12 has an anti-apoptotic action and promotes the survival of T-cells (Clerici et al., 1994, Proc. Natl. Acad. Sci. USA 91: 11811; Estaquier et al., 1995, J. Exp. Med. 182: 1759). A local overproduction of IL-12 can therefore contribute to the survival of tumour cells.
Inhibitors of IL-12 formation therefore possess great therapeutic potential.
One potential inhibitor of IL-12 formation is the known active agent thalidomide (Journal of Immunology 159 (10), 5157-5161 (1997)).
U.S. Pat. No. 5,114,937 describes renin-inhibiting peptide derivatives, the carboxamide groups in which are replaced by their isosteres. The compounds are suitable for the treatment of renin-associated hypertension, congestive heart failure, hyperaldosteronism, glaucoma and diseases caused by the retroviruses HTLV-I, -II and -III.
DE 198 43 793 describes substituted benzamides with immunomodulatory properties in which the ring-containing structural parts of the molecule are linked together by an amide bond. The disadvantage of the amide bond is its susceptibility to hydrolysis with an accompanying loss of action for the compound.
The object of the invention was therefore to develop new immunomodulators that are suitable for the treatment and/or prophylaxis of diseases caused by formation of the proinflammatory cytokine IL-12 and that at the same time display an improved hydrolytic stability.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that substituted glutarimides satisfy the above requirements.
The invention accordingly provides substituted glutarimides having the formula I
in which X denotes a group having the formula CH
2
—NH or S—CH
2
,
R
1
stands for a carboxyl group; an ester group having the formula COOR
5
in which R
5
denotes an alkyl group (straight-chain or branched) with 1 to 6 carbon atoms or a benzyl radical; or an amide group having the formula CONR
6
R
7
, in which R
6
and R
7
are the same or different and represent hydrogen, an alkyl group (straight-chain or branched) with 1 to 6 Carbon atems (optionally substituted with the radical COOR
5
and/or a phenyl group), a phenyl radical or taken together with the N atom represent a hydrazide group, a pyrrolidine, piperidine or morpholine ring or stand for an amino group substituted with the radical CH(═O) or COR
5
, in which R
5
is as defined above, and
R
2
stands for hydrogen, an amino or nitro group, and enantiomers, mixtures of enantiomers, racemates, diastereomers or mixtures of diastereomers thereof in the form of their bases or salts with physiologically compatible acids.
The following substituted glutarimides are particularly preferred:
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzoic acid,
2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]benzoic acid,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethylbenzamide,
(3S)-[2-morpholine-4-carbonyl)benzylamino]piperidine-2,6-dione,
{2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzoylamino}methyl acetate,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzamide,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-ethyl benzamide,
(3S)-[2-pyrrolidine-1-carbonyl)benzylamino]piperidine-2,6-dione,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzoic acid hydrazide,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl benzamide,
2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl benzamide,
2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethyl benzamide,
2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]benzamide,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]methyl benzoate,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzyl benzoate,
2-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl benzoate,
N-{2-[2,6-dioxopiperidin-3-ylamino)methyl]phenyl}acetamide,
N-{2-[2,6-dioxopiperidin-3-ylamino)methyl]phenyl}formamide,
3-(2,6-dioxopiperidin-3-yl methyl sulfanyl)-6-nitro methylbenzoate, and
2-amino-5-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl benzoate.
The present invention also provides methods for the production of compounds according to the invention having the general formula I.
Compounds having the general formula I can be obtained by cyclizing glutaric acid derivatives having the general formula II,
in which X, R
1
and R
2
have the same meaning as defined above for formula I, A stands for OH, B for NH
2
or NHOH, or vice versa, in the presence of activating reagents such as carbonyl diimidazole. If X in the compound having the formula I denotes a CH
2
—NH group, cyclization is preferably performed with compounds having the formula II, in which the NH function is present in protected form, for example with a benzyl oxycarbonyl group, which is then removed at a temperature of between 20 and 40 ° C., e.g. with a solution of hydrogen bromide in acetic acid.
Heating a compound of formula II in which A and B both stand for OH in acetic anhydride, first produces a cyclization to the cyclic anhydride, fr

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