U.S. patent application number 10/653188 was filed with the patent office on 2004-03-11 for substituted glutarimides and their use as inhibitors of il-12 production.
This patent application is currently assigned to Gruenenthal GmbH. Invention is credited to Buschmann, Helmut, Frosch, Stefanie, Germann, Tieno, Wade, Erik, Zimmer, Oswald.
Application Number | 20040048859 10/653188 |
Document ID | / |
Family ID | 7628270 |
Filed Date | 2004-03-11 |
United States Patent
Application |
20040048859 |
Kind Code |
A1 |
Germann, Tieno ; et
al. |
March 11, 2004 |
Substituted glutarimides and their use as inhibitors of IL-12
production
Abstract
Substituted glutarimides of formula I 1 and their method of
making. Also disclosed are pharmaceutical compositions comprising
the glutarimidie, particularly as immunomodulators and as
inhibitors of angiopathies, or haematological or oncological
diseases, as well as a method for treating various diseases using
the glutarimides.
Inventors: |
Germann, Tieno;
(Herzogenrath, DE) ; Frosch, Stefanie; (Aachen,
DE) ; Wade, Erik; (Aachen, DE) ; Buschmann,
Helmut; (Aachen, DE) ; Zimmer, Oswald;
(Wuerselen, DE) |
Correspondence
Address: |
CROWELL & MORING LLP
INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
Gruenenthal GmbH
Aachen
DE
|
Family ID: |
7628270 |
Appl. No.: |
10/653188 |
Filed: |
September 3, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10653188 |
Sep 3, 2003 |
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10198073 |
Jul 19, 2002 |
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6656937 |
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10198073 |
Jul 19, 2002 |
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PCT/EP01/00155 |
Jan 9, 2001 |
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Current U.S.
Class: |
514/235.5 ;
514/316; 514/317; 514/326; 544/130; 546/188; 546/208; 546/219 |
Current CPC
Class: |
A61P 1/04 20180101; C07D
211/88 20130101; A61P 31/04 20180101; A61P 43/00 20180101; A61P
7/00 20180101; C07D 211/92 20130101; A61P 17/06 20180101; A61P
37/00 20180101; A61P 19/02 20180101; A61P 1/16 20180101; A61P 35/00
20180101; A61P 9/10 20180101; A61P 37/06 20180101; A61P 1/18
20180101; A61P 3/10 20180101; A61P 9/00 20180101; A61P 13/12
20180101; A61P 29/00 20180101; A61P 37/02 20180101; A61P 17/00
20180101; A61P 11/02 20180101; A61P 27/02 20180101; A61P 11/06
20180101; A61P 25/00 20180101; A61P 11/00 20180101 |
Class at
Publication: |
514/235.5 ;
514/316; 514/317; 514/326; 544/130; 546/188; 546/208; 546/219 |
International
Class: |
A61K 031/5377; A61K
031/4545; A61K 031/454; C07D 413/02; C07D 41/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 21, 2000 |
DE |
100 02 509.9 |
Claims
We claim:
1. A substituted glutarimide compound of formula I 13wherein X is
CH.sub.2--NH or S--CH.sub.2, R.sup.1 is a carboxyl group; an ester
group having the formula COOR.sup.5 in which R.sup.5 is a
C.sub.1-C.sub.6 straight-chain or branched alkyl group or a benzyl
group; or an amide group having the formula CONR.sup.6R.sup.7, in
which R.sup.6 and R.sup.7 are the same or different and represent a
hydrogen; a C.sub.1-C.sub.6 straight-chain or branched alkyl group
optionally substituted with a COOR.sup.5 group or a phenyl group or
both; or a phenyl group; or R.sup.6 and R.sup.7 taken together with
the N atom represent a hydrazide group; a pyrrolidine; a piperidine
or a morpholine ring; or an amino group substituted with a
CH(.dbd.O) or COR.sup.5; and R.sup.2 is a hydrogen, an amino or a
nitro group, or a salt thereof with a physiologically compatible
acid.
2. An enantiomer, or a salt thereof with a physiologically
compatible acid, of a compound according to claim 1.
3. A mixture of enantiomers, or salts thereof with a
physiologically compatible acid, of at least a compound according
to claim 1.
4. A racemate, or a salt thereof with a physiologically compatible
acid, of a compound according to claim 1.
5. A diastereomer, or mixture of diastereomers thereof, or a salt
thereof with a physiologically compatible acid, of a compound
according to claim 1.
6. A compound according to claim 1, selected from the group
consisting of: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] bezoic
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.
7. A pharmaceutical composition comprising as an active agent at
least one compound according to claim 1, and a pharmaceutically
acceptable excipient.
8. A method for modulating immune action in a mammal in need
thereof, comprising administering to the mammal an effective
immunomodulatory amount of a compound of claim 1.
9. A method according to claim 8, wherein the mammal is a
human.
10. A method for the treatment of angiopathies, or hematological or
oncological diseases, comprising administering to a patient in need
thereof an effective amount of a compound according to claim 1.
11. A method for the production of a substituted glutarimide
compound according to claim 1, the method comprising cyclizing a
glutaric acid derivative of formula II, 14wherein X, R.sup.1 and
R.sup.2 are as defined in formula I; and A is OH, and B is NH.sub.2
or NHOH; or A is NH.sub.2 or NHOH, and B is OH, in the presence of
an activating reagent.
12. A method according to claim 11, wherein the activating agent is
carbonyl diimidazole.
13. A method according to claim 11, wherein X is CH.sub.2--NH, and
wherein cyclization is performed with the --NH group of X protected
by a protective group, which protective group is removed after
cyclization.
14. A method according to claim 13, wherein the protective group is
a benzyloxycarbonyl group.
15. A method for the production of a substituted glutarimide
compound according to claim 1, the method comprising heating a
glutaric acid derivative of formula II, 15wherein X, R.sup.1 and
R.sup.2 are as defined in formula I, and A and B are both OH, in
acetic anhydride to obtain an anhydride by cyclization, and heating
the anhydride with a nitrogen source to obtain a compound of
formula I.
16. A method according to claim 15, wherein the nitrogen source is
urea.
17. A method for producing a substituted glutarimide of formula I
according to claim 1, the method comprising oxidizing a lactam of
formula 16in which R.sup.1, R.sup.2 and X are as defined for
formula I, thereby converting the lactam to a corresponding
imide.
18. A method according to claim 17, wherein the lactam is oxidized
with at least one oxidizer selected from the group consistin of
m-chloroperbenzoic acid, ruthenium(IV) oxide and sodium
periodate.
19. A method for producing a substituted glutarimide of formula I
according to claim 1 wherein X stands for a CH.sub.2--NH group, the
method comprising alkylating an .alpha.-aminoglutarimide compound
of formula IV, 17with a compound of formula V, 18in which R.sup.1
and R.sup.2 are as defined for formula I, and Y is selected from
the group consisting of chlorine, bromine, iodine, and a
toluene-4-sulfonate group.
20. A method for producing a substituted glutarimide of formula I
according to claim 1 wherein X stands for a CH.sub.2--NH group, the
method comprising reacting by reductive amination a compound of
formula VI with a compound of formula IV, 19in which R.sup.1 and
R.sup.2 are as defined for formula I, to obtain the substituted
glutarimide.
21. A method according to claim 20, wherein the compound of formula
VI and the compound of formula IV are reduced by a member selected
from the group consisting of sodium borohydride, sodium
triacetoxyborohydride, sodium cyanoborohydride, a borane-pyridine
complex, and a catalytically excited hydrogen.
22. A method for producing a substituted glutarimide of formula I
according to claim 1 wherein X is a CH.sub.2--NH group, the method
comprising: alkylating a compound of formula VII, 20in which
R.sup.1 and R.sup.2 are as defined for formula I, with an
.alpha.-bromoglutarimide of formula VIII 21
23. A method for producing a substituted glutarimide of formula I
according to claim 1 wherein X is an S--CH.sub.2 group, the method
comprising adding in a solvent a mercaptan of formula X 22in which
R.sup.1 and R.sup.2 are as defined for formula I, to a 3-methylene
glutarimide of formula IX, 23
24. A method according to claim 23, wherein the solvent is
acetonitrile or toluene.
25. A method according to claim 24 wherein the solvent further
comprises a tertiary amine.
26. A method according to claim 25, wherein the tertiary amine is
triethylamine or diisopropyl ethylamine.
27. A method according to claim 24, wherein the mercaptan is added
to the 3-methylene glutarimide at a temperature between about
80.degree. C. and about 110.degree. C.
28. A method for producing a substituted glutarimide of formula I
according to claim 1 wherein R.sup.2 is an amino group, the method
comprising reducing a compound of formula I wherein
R.sup.2.dbd.NO.sub.2 by catalytically excited hydrogen in an
acid-containing organic solvent.
29. A method according to claim 28, wherein the organic solvent is
ethyl acetate.
30. A method according to claim 28, wherein the reduction is
performed using a palladium catalyst or with a metal in an acid
solution.
31. A method according to claim 30, wherein the metal is tin or
iron.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation-in-part of
international patent application no. PCT/EP01/00155, filed Jan. 9,
2001, designating the United States of America, the entire
disclosure of which is incorporated herein by reference. Priority
is claimed based on Federal Republic of Germany patent application
no. 100 02 509.9, filed Jan. 21, 2000.
FIELD OF THE INVENTION
[0002] The invention concerns substituted glutarimides having the
general formula I 2
[0003] their production and their use in medicaments.
BACKGROUND OF THE INVENTION
[0004] 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).
[0005] 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 IL-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.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] Inhibitors of IL-12 formation therefore possess great
therapeutic potential.
[0010] One potential inhibitor of IL-12 formation is the known
active agent thalidomide (Journal of Immunology 159 (10), 5157-5161
(1997)).
[0011] 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.
[0012] 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.
[0013] 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
[0014] It has now been discovered that substituted glutarimides
satisfy the above requirements.
[0015] The invention accordingly provides substituted glutarimides
having the formula I 3
[0016] in which X denotes a group having the formula CH.sub.2--NH
or S--CH.sub.2,
[0017] R.sup.1 stands for a carboxyl group; an ester group having
the formula COOR.sup.5 in which R.sup.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.sup.6R.sup.7, in
which R.sup.6 and R.sup.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.sup.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(.dbd.O) or COR.sup.5, in which R.sup.5 is as defined
above, and
[0018] R.sup.2 stands for hydrogen, an amino or nitro group,
[0019] and enantiomers, mixtures of enantiomers, racemates,
diastereomers or mixtures of diastereomers thereof in the form of
their bases or salts with physiologically compatible acids.
[0020] The following substituted glutarimides are particularly
preferred:
[0021] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic
acid,
[0022] 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic
acid,
[0023]
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethylbenzamide,
[0024]
(3S)-[2-morpholine-4-carbonyl)benzylamino]piperidine-2,6-dione,
[0025] {2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoylamino}
methyl acetate,
[0026] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide,
[0027] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-ethyl
benzamide,
[0028] (3S)-[2-pyrrolidine-1-carbonyl)benzylamino]
piperidine-2,6-dione,
[0029] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid
hydrazide,
[0030] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl
benzamide,
[0031] 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl
benzamide,
[0032] 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethyl
benzamide,
[0033] 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide,
[0034] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] methyl
benzoate,
[0035] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzyl
benzoate,
[0036] 2-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl
benzoate,
[0037] N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] phenyl}
acetamide,
[0038] N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] phenyl}
formamide,
[0039] 3-(2,6-dioxopiperidin-3-yl methyl sulfanyl)-6-nitro
methylbenzoate, and
[0040] 2-amino-5-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl
benzoate.
[0041] The present invention also provides methods for the
production of compounds according to the invention having the
general formula I.
[0042] Compounds having the general formula I can be obtained by
cyclizing glutaric acid derivatives having the general formula II,
4
[0043] in which X, R.sup.1 and R.sup.2 have the same meaning as
defined above for formula I, A stands for OH, B for NH.sub.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.sub.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.degree. C., e.g. with a solution of hydrogen bromide in acetic
acid.
[0044] 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, from which the compound having formula I is
obtained by heating with urea or another nitrogen source.
[0045] Compounds having the general formula I can also be produced
from lactams having the general formula III, 5
[0046] in which R.sup.1, R.sup.2 and X have the same meanings as
defined above for formula I, by oxidizing compound III to an imide,
preferably with m-chloroperbenzoic acid or ruthenium(IV)
oxide/sodium periodate.
[0047] Compounds having the formula I, in which X stands for the
CH.sub.2--NH group, can also be obtained by alkylating
.alpha.-aminoglutarimides having the general formula IV, 6
[0048] with compounds having the general formula V, 7
[0049] in which R.sup.1 and R.sup.2 have the same meanings as above
and Y stands for a chlorine, bromine or iodine atom or a
toluene-4-sulfonate radical.
[0050] Compounds in which X stands for the CH.sub.2--NH group can
also be obtained by reductive amination from compounds having the
general formulae VI and IV, in which R.sup.1 and R.sup.2 have the
same meanings as above. 8
[0051] Sodium borohydride, sodium triacetoxyborohydride, sodium
cyanoborohydride, the borane-pyridine complex or catalytically
excited hydrogen is preferably used as the reducing agent.
[0052] Compounds having the formula I where X is CH.sub.2--NH can
also be obtained by alkylating a compound having the general
formula VII, 9
[0053] in which R.sup.1 and R.sup.2 have the same meanings as
above, with .alpha.-bromoglutarimide having the general formula
VIII 10
[0054] Compounds having the general formula I, in which X stands
for an S--CH.sub.2 group, can be obtained by adding a mercaptan
having the general formula X 11
[0055] to 3-methylene glutarimide having the general formula IX
12
[0056] The reaction is preferably performed in solvents such as
acetonitrile or toluene with addition of tertiary amines such as
triethylamine or diisopropyl ethylamine at temperatures of 80 to
110.degree. C.
[0057] Compounds having the formula I, in which R.sup.2 stands for
an amino group, can generally be obtained by reduction of compounds
having the formula I where R.sup.2.dbd.NO.sub.2. The reduction is
performed, for example, by catalytically excited hydrogen in
acid-containing organic solvents such as ethyl acetate, whereby
palladium catalysts are preferably used. Alternatively, the
reduction can be performed with metals such as tin or iron in acid
solution.
[0058] The compounds according to the invention possess
immunomodulatory activity which is demonstrated by an inhibition of
the production of IL-12 by LPS-activated monocytes. In comparison
to compounds that have already been proposed, they also demonstrate
an improved hydrolytic stability. They are suitable for the
treatment and/or prophylaxis of inflammation and autoimmune
diseases and also of haematological/oncologic- al diseases.
[0059] Accordingly, the present invention also includes methods and
pharmaceutical compositions for the treatment of these diseases.
The method according to the invention comprises administering to a
mammal, such as a human, in need thereof, an effective amount of a
suitable pharmaceutical composition comprising a substituted
glutarimide of the invention.
[0060] The above groups of diseases include, amongst others,
inflammations of the skin (e.g. atopic dermatitis, psoriasis,
eczema), inflammations of the respiratory tracts (e.g. bronchitis,
pneumonia, bronchial asthma, ARDS (adult respiratory distress
syndrome), sarcoidosis, silicosis/fibrosis), inflammations of the
gastrointestinal tract (e.g. gastroduodenal ulcers, Crohn's
disease, ulcerative colitis), and diseases such as hepatitis,
pancreatitis, appendicitis, peritonitis, nephritis, aphthosis,
conjunctivitis, keratitis, uveitis, and rhinitis.
[0061] The autoimmune diseases include, for example, arthritic
diseases (e.g. rheumatoid arthritis, HLA-B27-associated diseases),
Behcet's disease, and multiple sclerosis, juvenile diabetes or
lupus erythematosus.
[0062] Further indications are sepsis, bacterial meningitis,
cachexia, transplant rejection reactions, graft-versus-host
reactions as well as reperfusion syndrome and atherosclerosis along
with angiopathies (such as macula degeneration, diabetic
retinopathies).
[0063] The symptoms that can be inhibited by a reduction in IL-12
also include haematological diseases such as multiple myeloma and
leukaemias, along with other oncological diseases such as
glioblastoma, prostate cancer and mammary cancer.
[0064] Medicaments according to the invention contain, in addition
to at least one compound having the general formula I, carriers,
fillers, solvents, diluents, dyestuffs and/or binders. The choice
of auxiliaries and the quantities to be used depend on whether the
medicament is to be administered by oral, rectal, ophthalmic
(intravitreal, intracameral), nasal, topical (including buccal and
sublingual), vaginal or parenteral (including subcutaneous,
intramuscular, intravenous, intradermal, intratracheal and
epidural) means.
[0065] Preparations in the form of tablets, chewable tablets,
sugar-coated tablets, capsules granules, drops, liquids or syrups
are suitable for oral administration, while solutions, suspensions,
easily reconstituted dry preparations and sprays are suitable for
administration by parenteral or topical means or by inhalation.
Cutaneous administration forms are salves, gels, creams and pastes.
Ophthalmic administration forms include drops, salves and gels.
Compounds according to the invention contained in a reservoir in
dissolved form, a carrier film or a plaster, optionally with the
addition of skin-penetrating agents, are examples of suitable
percutaneous administration forms. The compounds according to the
invention can be released on a delayed basis from oral or
percutaneous forms of preparation.
[0066] The amount of active agent to be administered to patients
varies according to the weight of the patient, the type of
administration, the indication and the severity of the disease. 1
to 150 mg/kg of at least one compound according to the invention
having the formula I are conventionally administered.
EXAMPLES
[0067] The following examples serve to describe the present
invention in greater detail, and should not be construed to limit
the invention in any way.
[0068] Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt, was
used as stationary phase for the chromatographic separations. The
mixing ratios of the eluents are always given as percentages by
volume.
[0069] The substances were characterised by their melting point
and/or the .sup.1H-NMR spectrum. The spectra were recorded at 300
MHz using a Gemini 300 device from Varian. The chemical shifts are
given in ppm (.delta.-scale). Tetramethyl silane (TMS) was used as
internal standard.
Example 1
3-(2-chlorobenzylamino) Piperidine-2,6-dione; Hydrochloride
[0070] Step 1:
[0071] 3-bromopiperidine-2,6-dione
[0072] 4.5 ml bromine were added to 10.2 g glutarimide suspended in
20 ml chloroform and the mixture was stirred in a closed vessel for
90 minutes at a bath temperature of 110.degree. C. After cooling,
the vessel was opened and stirring was continued until no more
hydrogen bromide escaped. The reaction mixture was evaporated in
vacuo, the residue dissolved in ethanol and evaporated again. 17.1
g (99% of theoretical) of the title compound remained in the form
of practically white crystals, which melted at 76 to 83.degree.
C.
[0073] Step 2:
[0074] 3-(2-chlorobenzylamino) Piperidine-2,6-dione;
Hydrochloride
[0075] A solution of 0.39 g of the product from step 1 and 0.71 g
2-chlorobenzylamine in 8 ml N,N-dimethylformamide was stirred for
36 hours at 20.degree. C. After evaporation in vacuo the oily
residue was dissolved in 25 ml methanol and the solution stirred
for two hours with 1 g Amberlyst A-21. It was filtered, 2 g silica
gel were added to the filtrate and it was evaporated until dry. The
adsorbed substance was placed in a chromatography column and the
product was eluted with a mixture of ethyl acetate/cyclohexane
(1/2->1/1) containing 1% triethylamine. The residue remaining
after evaporation of the product fractions was dissolved in 10 ml
methanol and 25 ml each of diethyl ether saturated with hydrogen
chloride and diethyl ether were added to the solution. The
precipitated hydrochloride was separated off and recrystallised
from methanol/diethyl ether. 0.24 g (41% of theoretical) of the
title compound were obtained in the form of crystals, which melted
at 217.degree. C. with decomposition.
[0076] .sup.1H-NMR (DMSO-d.sub.6): 2.15-2.34 (1H, m); 2.40-2.56
(1H, m); 2.60-2.80 (2H, m); 4.35 (1H, t, J=13.5 Hz); 4.45 (2H, d,
J=13.8 Hz); 7.40-7.94 (4H, m).
Example 2
[0077] Using the procedure described in Example 1, step 2 and the
corresponding benzylamines, the following compounds were obtained
in the same way:
[0078] 2.1: 3-(2-trifluoromethyl Benzylamino) Piperidine-2,6-dione;
Hydrochloride
[0079] Melting point: >250.degree. C. (decomposition)
[0080] 2.2: 3-(2,4-dimethoxybenzylamino) Piperidine-2,6-dione;
Hydrochloride
[0081] Melting point: 214.degree. C. (decomposition)
[0082] 2.3: 3-(2,6-difluorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0083] Melting point: 208-215.degree. C. (decomposition)
[0084] 2.4: 3-(2,5-difluorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0085] Melting point: 208.degree. C. (decomposition)
[0086] 2.5: 3-(3,5-difluorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0087] Melting point: 230-236.degree. C. (decomposition)
[0088] 2.6: 3-[(naphth-1-ylmethyl)amino] piperidine-2,6-dione;
Hydrochloride
[0089] Melting point: 188.degree. C. (decomposition)
[0090] 2.7: 3-(2,3-difluorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0091] Melting point: 206-212.degree. C. (decomposition)
[0092] 2.8: 3-(4-dimethylaminobenzylamino) Piperdine-2,6-dione;
Base
[0093] 2.9: 3-(4-nitrobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0094] 2.10: 3-(3-trifluoromethylbenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0095] 2.11: 3-(3-trifluoromethoxybenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0096] Melting point: 199-201.degree. C.
[0097] 2.12: 3-[(naphth-2-ylmethyl)amino] piperidine-2,6-dione,
Base
[0098] Melting point: 120-125.degree. C. (decomposition)
[0099] 2.13: 3-(2-chloro-4-fluorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0100] Melting point: 241-242.degree. C.
[0101] 2.14: 3-(3-nitrobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0102] Melting point: from 240.degree. C. with decomposition
[0103] 2.15: 3-(2-chloro-6-methylbenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0104] Melting point: 238-240.degree. C.
[0105] 2.16: 3-(2-methylbenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0106] Melting point: 235-240.degree. C.
[0107] 2.17: 3-(3,5-dichlorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0108] Melting point: 234-238.degree. C.
[0109] 2.18: 3-[3-fluoro-5-(trifluoromethyl) Benzylamino]
piperidine-2,6-dione; Hydrochloride
[0110] Melting point: 241-243.degree. C.
[0111] 2.19: 3-(3-fluorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0112] Melting point: 231-235.degree. C.
[0113] 2.20: 3-(3-methylbenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0114] Melting point: 240-242.degree. C.
[0115] 2.21: 3-(4-trifluoromethylbenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0116] Melting point: 252-255.degree. C.
[0117] 2.22: 3-[4-fluoro-2-(trifluoro Methyl) Benzylamino]
Piperidine-2,6-dione; Hydrochloride
[0118] Melting point: from 241.degree. C. with decomposition
[0119] 2.23: 3-(4-fluorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0120] Melting point: 241-242.degree. C.
[0121] 2.24: 3-(4-tert-butylbenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0122] Melting point: from 239.degree. C. with decomposition
[0123] 2.25: 3-(3,5-dimethylbenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0124] Melting point: from 226.degree. C. with decomposition
[0125] 2.26: 3-(3-chlorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0126] Melting point: 237-238.degree. C.
[0127] 2.27: 3-(4-methoxybenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0128] Melting point: from 227.degree. C. with decomposition
[0129] 2.28: 3-(2,4-dichlorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0130] Melting point: 240-242.degree. C.
[0131] 2.29: 3-(2-fluorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0132] Melting point: 245-247.degree. C.
[0133] 2.30: 3-(2-bromobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0134] Melting point: 244-246.degree. C.
[0135] 2.31: 3-[2-fluoro-5-(trifluoromethyl) Benzylamino]
Piperidine-2,6-dione; Hydrochloride
[0136] Melting point: from 251.degree. C. with decomposition
[0137] 2.32: 3-(2,3-dichlorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0138] Melting point: 246-248.degree. C.
[0139] 2.33: 3-(3,4-dichlorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0140] Melting point: 252-254.degree. C.
[0141] 2.34: 3-[3,5-bis(trifluoromethyl) Benzylamino]
Piperidine-2,6-dione; Hydrochloride
[0142] Melting point: 263-265.degree. C.
[0143] 2.35: 3-(3-bromobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0144] Melting point: 229-232.degree. C.
[0145] 2.36: 3-(4-trifluoromethoxybenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0146] Melting point: 253-255.degree. C.
[0147] 2.37: 3-(4-chlorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0148] Melting point: 262-265.degree. C.
[0149] 2.38: 3-(4-methylbenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0150] Melting point: 256.degree. C. with decomposition
[0151] 2.39: 3-(2-ethoxybenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0152] Melting point: 208-212.degree. C.
[0153] 2.40: 3-(2,5-dichlorobenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0154] Melting point: 242-246.degree. C.
[0155] 2.41: 3-(3-methoxybenzylamino) Piperdine-2,6-dione;
Hydrochloride
[0156] Melting point: 217-219.degree. C.
[0157] All compounds listed under 2.1 to 2.41 are in the form of
the racemate.
Example 3
3-(3-aminobenzylamino) Piperdine-2,6-dione; Hydrochloride
[0158] 0.56 g of the product from example 2.14 in a mixture
consisting of 17 ml ethyl acetate and 0.85 ml 6N hydrochloric acid
were hydrogenated at 20.degree. C. under a pressure of 4 bar over
0.17 g palladium on activated carbon (10% Pd). After consumption of
the theoretical amount of hydrogen, the mixture was filtered off
from the catalyst and the filtrate evaporated in vacuo. After
recrystallisation of the residue from methanol, 0.25 g (50% of
theoretical) of the racemic title compound were obtained in the
form of slightly colored crystals, which melted at 236-239.degree.
C.
[0159] .sup.1H-NMR (DMSO-d.sub.6): 2.05-2.20 (m, 1H); 2.28-2.39 (m,
1H); 2.55-2.74 (m, 2H); 3.97-4.12 (q, 2H); 4.18-4.28 (m, 1H);
6.58-6.70 (m, 3H); 7.02-7.11 (m, 1H).
Example 4
[0160] Using the procedure described in Example 1, step 2 and the
corresponding arylalkylamines, the following compounds were
obtained in the same way:
[0161] 4.1: 3-phenethylaminopiperidine-2,6-dione; Hydrochloride
[0162] Melting point: from 220.degree. C. with decomposition
[0163] 4.2: 3-[2-(2-chlorophenyl) Ethylaminopiperidine-2,6-dione;
Hydrochloride
[0164] Melting point: 230.degree. C. (decomposition)
[0165] 4.3: 3-(4-phenylbutylamino) Piperdine-2,6-dione;
Hydrochloride
[0166] Melting point: from 231.degree. C. with decomposition
[0167] 4.4: 3-(N-benzyl-N-methylamino) Piperdine-2,6-dione;
Base
[0168] Melting point: 95-115.degree. C.
[0169] 4.5: 3-(methylnaphth-1-yl Methylamino) Piperdine-2,6-dione;
Base
[0170] Melting point: 157-162.degree. C.
[0171] All compounds listed under 4.1 to 4.5 are in racemic
form.
[0172] 4.6: (2S)-[(3S) or (3R)-(2,6-dioxopiperidin-3-ylamino)]
Methyl Phenylacetate; Hydrochloride
[0173] Melting point: 200-207.degree. C.
[0174] 4.7: (2R)-[(3S) or (3R)-(2,6-dioxopiperidin-3-ylamino)]
Methyl Phenylacetate; Hydrochloride
[0175] Melting point: 171-177.degree. C. (decomposition)
[0176] 4.8: (2S)-[(3R,S)-(2,6-dioxopiperidin-3-ylamino)] -3-methyl
Phenylpropionate; Hydrochloride
[0177] (Mixture of Diastereomers)
[0178] Melting point: 146-150.degree. C. (decomposition)
Example 5
[0179] 3-benzylaminopiperidine-2,6-dione
[0180] A) A solution of 0.50 g 3-aminopiperidine-2,6-dione (K.
Fickentscher, Arch. Pharm. 1974, 307, 840-844), 1.5 ml
triethylamine and 0.4 ml benzyl bromide was stirred for 20 h at
20.degree. C. It was then evaporated, the residue taken up in 50 ml
aqueous potassium carbonate solution (10% K.sub.2CO.sub.3) and the
solution extracted twice with 40 ml ethyl acetate each. The organic
phases were washed with 50 ml each of distilled water and saturated
sodium chloride solution, dried over sodium sulfate and evaporated
in vacuo. The residue was purified by flash chromatography on
silica gel with a mixture of ethyl acetate/ cyclohexane (2/1)
containing 1% triethylamine as eluent, whereby 0.21 g (26% of
theoretical) of the title compound was obtained as viscous oil.
[0181] The title compound could also be obtained in the form of the
hydrobromide as pure S enantiomer in the following way:
[0182] B) Step 1:
[0183] (2S)-(N-benzyl-N-benzyloxycarbonylamino)-4-carbamoyl
Butanoic Acid
[0184] 0.6 ml benzyl chloroformate were added dropwise to 0.95 g
(2S)-benzylamino-4-carbamoyl butanoic acid (E. Davidov et al., Isr.
J. Chem. 1969, 7, 487-489) dissolved in 4 ml 2 M aqueous sodium
hydroxide and 8 ml 1 M sodium hydrogen carbonate solution, over 2.5
h at 20.degree. C. whilst being stirred. The mixture was then
extracted twice with 20 ml diethyl ether each. The aqueous phase
was acidified with conc. hydrochloric acid to pH 2-3 and extracted
twice with 30 ml ethyl acetate each. The extracts were washed with
distilled water, dried over sodium sulfate and evaporated in vacuo.
After adding diethyl ether to the oily residue, 0.55 g (37% of
theoretical) of the title compound were obtained in the form of
colorless crystals, which melted at 98-99.degree. C.
[0185] Step 2:
[0186] (3S)-(N-butyl-N-benzyloxycarbonylamino)
Piperdine-2,6-dione
[0187] A solution of 0.162 g N,N-carbonyl diimidazole in 3 ml dry
tetrahydrofuran was dripped into a solution of 0.37 g of the
product from step 1 in 2.5 ml dry tetrahydrofuran. It was refluxed
for 3.5 h then stirred for a further 3 h at 20.degree. C. The oil
remaining after evaporation of the solvent in vacuo was dissolved
in ethyl acetate and the solution washed successively with 20 ml
each of 1 M aqueous sodium hydrogen carbonate solution, saturated
sodium chloride solution and distilled water. It was then dried
over sodium sulfate and evaporated in vacuo. 0.23 g (65% of
theoretical) of the title compound remained in the form of
crystals, which melted at 51-52.degree. C.
[0188] Step 3:
[0189] (3S)-benzylaminopiperidine-2,6-dione; Hydrobromide
[0190] The solution of 0.15 g of the product from step 2 in 3 ml of
a solution of hydrogen bromide in acetic acid (33% HBr) was stirred
for 1 h at 20.degree. C. The reaction mixture was then poured onto
50 ml diethyl ether. The precipitate that was formed was separated
off, washed with diethyl ether and dried in vacuo. 0.08 g (63% of
theoretical) of the title compound remained in the form of
crystals, which melted at 228-230.degree. C. with
decomposition.
[0191] 1H-NMR (DMSO-d.sub.6): 2.01-2.43 (m, 2H); 2.60-2.80 (m, 2H);
4.20-4.45 (m, 3H); 7.40-7.60 (m, 5H).
Example 6
[0192] 6.1 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] Benzoic
Acid, Hydrobromide
[0193] Step 1:
[0194] 2-[(1S)-(3-carbamoyl-1-carboxypropylamino)methyl] Benzoic
Acid
[0195] A suspension of 1.65 g 2-formylbenzoic acid in 5 ml ethanol
and 5 ml 2 M sodium hydroxide solution was added to a solution of
1.46 g L-glutamine in 5 ml of a 2 M aqueous sodium hydroxide
solution. After stirring for 1 h at 20.degree. C., the mixture was
cooled to 0.degree. C. and 0.25 g sodium borohydride were added in
portions over 15 min with vigorous stirring. After 90 min a further
0.33 g 2-formyl benzoic acid and 0.05 g sodium borohydride were
added. After stirring for 16 h at 20.degree. C., the reaction
mixture was acidified with conc. hydrochloric acid to pH 2 and
cooled to 0.degree. C. The precipitate formed was separated off,
washed with acetone and dried in vacuo. 0.87 g (31% of theoretical)
of the title compound remained in the form of crystals, which
melted at 132-133.degree. C.
[0196] Step 2:
[0197]
2-{(1S)-[N-benzyloxycarbonyl-N-(3-carbamoyl-1-carboxypropyl)amino]
Methyl} Benzoic Acid
[0198] Using the procedure described in Example 5 B, step 1, the
title compound was obtained in the same way from the product from
step 1 in the form of crystals, which melted with decomposition at
103-104.degree. C.
[0199] Step 3:
[0200]
2-{(3S)-[N-benzyloxycarbonyl-N-(2,6-dioxopiperidin-3-yl)amino]
Methyl} Benzoic Acid
[0201] Using the procedure described in Example 5 B, step 2, the
title compound was obtained in the same way from the product from
step 2 in the form of crystals, which melted at 71-73.degree.
C.
[0202] Step 4:
[0203] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] Benzoic Acid,
Hydrobromide
[0204] Using the procedure described in Example 5B, step 3, the
title compound was obtained in the same way from the product from
step 3 in the form of colorless crystals, which melted at
158-161.degree. C.
[0205] .sup.1H-NMR (DMSO-d.sub.6): 2.00-2.25 (m, 1H); 2.35-2.95 (m,
1H); 2.60-2.80 (m, 2H); 4.35-4.50 (m, 1H); 4.50-4.70 (m, 2H);
7.50-7.75 (m, 3H); 8.00-8.10 (m, 1H).
[0206] 6.2 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] Benzoic
Acid; Hydrobromide
[0207] Replacing L- by D-glutamine in Example 6.1, step 1, and
using the procedure described in Example 6.1, the title compound
was obtained in the same way in the form of crystals, which melted
at 148-152.degree. C.
Example 7
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]
-N,N-diethylbenzamide; Hydrobromide
[0208] Step 1:
[0209] (3S)-[N-(2-diethylcarbamoylbenzyl)-N-benzyloxycarbonyl]
Aminopiperidine-2,6-dione
[0210] A solution of 1.00 g of the product from Example 6.1, step
3, 0.27 g N-methyl morpholine and 0.46 g
2-chloro-4,6-dimethoxy-1,3,5-triazine in 7 ml dry tetrahydrofuran
was stirred for 1 h at 20.degree. C. After adding 0.19 g
diethylamine, stirring was continued for a further 7 h. The
solution was then diluted with chloroform to a volume of 50 ml and
washed successively with 25 ml 0.05 N hydrochloric acid, 25 ml 1 M
aqueous sodium hydrogen carbonate solution and saturated sodium
chloride solution. The organic phase was dried over sodium sulfate
and evaporated in vacuo. After purifying the residue by flash
chromatography on silica gel with ethyl acetate/cyclohexane (9/1)
as eluent, 0.36 g (32% of theoretical) of the title compound were
obtained in the form of crystals, which melted at 65-66.degree.
C.
[0211] Step 2:
[0212] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]
-N,N-diethylbenzamide; Hydrobromide
[0213] 0.30 g of the product from step 1 were reacted as described
in Example 5B, step 3 with 3 ml of a solution of hydrogen bromide
in acetic acid (33% HBr). After working up and purification by
recrystallisation from methanol/diethyl ether, 0.175 g (66% of
theoretical) of the title compound were obtained in the form of
crystals, which melted at 119-120.degree. C.
[0214] .sup.1H-NMR (DMSO-d.sub.6): 1.06 (t, J=7.5 Hz, 3H); 1.21 (t,
J=6.9 Hz, 3H); 2.04-2.24 (m, 1H); 2.28-2.46 (m, 2H); 2.58-2.80 (m,
2H); 3.19 (dd, 2H); 3.51 (dd, 2H); 4.24 (s, 2H); 4.25-4.40 (m, 1H);
7.44 (d, 1H); 7.48-7.66 (m, 2H); 7.72 (d, 1H).
Example 8
[0215] By replacing diethylamine in Example 7, step 1, by other
amines, ammonia or hydrazine and using the additional procedure
described in Example 7, the following were obtained in the same
way:
[0216] 8.1: (3S)-[2-morpholine-4-carbonyl)benzylamino]
Piperidine-2,6-dione; Hydrobromide
[0217] Melting point: 133-135.degree. C.
[0218] 8.2: {2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]
Benzoylamino} Methyl Acetate; Hydrobromide
[0219] Melting point: 121-123.degree. C.
[0220] 8.3: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]
Benzamide; Hydrobromide
[0221] Melting point: 155-156.degree. C. (decomposition)
[0222] 8.4: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] -N-ethyl
Benzamide; Hydrobromide
[0223] Melting point: 144-146.degree. C.
[0224] 8.5: (3S)-[2-pyrrolidine-1-carbonyl)benzylamino]
Piperidin-2,6-dione; Hydrobromide
[0225] Melting point: 136-138.degree. C.
[0226] 8.6: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] Benzoic
Acid Hydrazide; Hydrobromide
[0227] Melting point: 241-242.degree. C.
[0228] 8.7: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]
-N-phenylbenzamide; Hydrobromide
[0229] Melting point: 136-138.degree. C.
[0230] 8.8: (2R)-{(3S)-2-[(2,6-dioxopiperidin-3-ylamino)methyl]
Benzoylamino} Methyl Phenylacetate; Hydrobromide
[0231] Melting point: 149-151.degree. C.
[0232] 8.9: (2S)-{(3S)-2-[(2,6-dioxopiperidin-3-ylamino)methyl]
Benzoylamino} Methyl Phenylacetate; Hydrobromide
[0233] Melting point: 181-182.degree. C.
[0234] 8.10: 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl
Benzamide; Hydrobromide
[0235] Melting point: 168-171.degree. C.,
[0236] 8.11: 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]
-N,N-diethyl Benzamide; Hydrobromide
[0237] Melting point: 128-132.degree. C.
[0238] 8.12: 2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]
Benzamide; Hydrobromide
[0239] Melting point: 232-233.degree. C.
Example 9
[0240] 9.1: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] Methyl
Benzoate; Hydrobromide
[0241] Step 1:
[0242]
2-{(3S)-[N-benzyloxycarbonyl-N-(2,6-dioxopiperidin-3-yl)amino]-meth-
yl} Methyl Benzoate
[0243] A mixture consisting of 0.60 g of the product from Example
6.1, step 3, and 0.25 g N,N'-carbonyl diimidazole in 5 ml dry
tetrahydrofuran was stirred for 1.5 h at 20.degree. C. 64 .mu.l
methanol were then added and stirring was continued for a further
40 h at 20.degree. C. After evaporating off the solvent in vacuo
the residue was taken up in 80 ml chloroform and the solution
washed with 1 M sodium hydrogen carbonate solution and distilled
water. It was dried over sodium sulfate and evaporated in vacuo.
After purification of the residue by column chromatography on
silica gel with chloroform/acetone (94/6) as eluent, 0.32 g (51% of
theoretical) of the title compound were obtained as a viscous
oil.
[0244] Step 2:
[0245] 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] Methyl
Benzoate; Hydrobromide
[0246] By removing the benzyloxycarbonyl protective group in the
product from step 1 using the procedure described in Example 5B,
step 3, the title compound was obtained in the same way in the form
of crystals, which melted at 187.degree. C.
[0247] 1H-NMR (DMSO-d.sub.6): 2.07-2.30 (m, 1H); 2.30-2.48 (m, 1H);
2.60-2.85 (m, 2H); 3.90 (s, 3H); 4.40-4.70 (m, 3H); 7.58-7.78 (m,
3H); 8.05 (d, J=8 Hz, 1H).
[0248] 9.2: 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] Benzyl
Benzoate; Hydrobromide
[0249] By replacing methanol with benzyl alcohol in Example 9.1 and
using the procedure described therein, the title compound was
obtained in the same way in the form of white crystals, which
melted at 175-177.degree. C.
Example 10
3-phenylaminomethyl Piperidine-2,6-dione
[0250] 30 ml absolute triethylamine and 2.75 ml freshly distilled
aniline were added to a solution of 1.25 g 3-methylene
piperidine-2,6-dione (M. J. Wanner and G.-J. Koomen, Tetrahedron
Lett. 1992, 33, 1513-1516) in 100 ml acetonitrile and the mixture
was stirred for 16 h at 80.degree. C.
[0251] After cooling, 10 g silica gel were added and the mixture
was evaporated in vacuo. The residue was purified by flash
chromatography on silica gel with tert-butyl methyl
ether/cyclohexane (2/1) as eluent. 1.87 g (86% of theoretical) of
the title compound were obtained in the form of crystals, which
melted at 137.degree. C.
[0252] .sup.1H-NMR (CDCl.sub.3): 1.84-1.99 (m, 1H); 2.08-2.17 (m,
1H); 2.49-2.64 (m, 1H); 2.73-2.83 (m, 2H); 3.41-3.50 (m, 1H);
3.60-3.70 (m, 1H); 6.64-6.80 (m, 3H); 7.17-7.29 (m, 2H).
Example 11
[0253] By replacing aniline in Example 10 by other amines and using
the procedure therein described, whereby optionally the mixture of
toluene/diisopropyl ethylamine was also used instead of the solvent
system acetonitrile/triethylamine at a reaction temperature of
110.degree. C., the following compounds could be obtained in the
same way:
[0254] 11.1: 3-[(4-bromophenylamino)methyl]
Piperidine-2,6-dione
[0255] Melting point: 149-150.degree. C.
[0256] 11.2: 3-[(3-trifluoromethyl Phenylamino)methyl]
Piperidine-2,6-dione
[0257] Melting point: 135-138.degree. C.
[0258] 11.3: 3-(naphth-1-ylaminomethyl) Piperidine-2,6-dione
[0259] Melting point: 145-148.degree. C.
[0260] 11.4: 3-(biphenyl-4-ylaminomethyl) Piperidine-2,6-dione
[0261] Melting point: 135-138.degree. C.
[0262] 11.5: 3-[(3-methoxyphenylamino)methyl]
Piperidine-2,6-dione
[0263] Viscous
[0264] 11.6: 3-[(4-trityl Phenylamino)methyl]
Piperidine-2,6-dione
[0265] Melting point: 221-225.degree. C.
[0266] 11.7: 3-[(2,6-dioxopiperidin-3-ylmethyl)amino] Ethyl
Benzoate
[0267] Viscous
[0268] 11.8: 3-(benzylaminomethyl) Piperidine-2,6-dione
[0269] Viscous
[0270] 11.9: 3-[(3-acetyl Phenylamino)methyl]
Piperidine-2,6-dione
[0271] Melting point: 129-132.degree. C.
[0272] 11.10: 3-[(N-methyl-N-phenylamino)methyl]
Piperidine-2,6-dione
[0273] Melting point: 132-134.degree. C.
[0274] 11.11: 3-{[(naphth-1-ylmethyl)amino]methyl}
Piperidine-2,6-dione
[0275] Viscous
[0276] 11.12: 3-[(2-methoxyphenylamino)methyl]
Piperidine-2,6-dione
[0277] Viscous
[0278] 11.13: 3-[(4-methoxyphenylamino)methyl]
Piperidine-2,6-dione
[0279] Melting point: 131-134.degree. C.
[0280] 11.14: (2S)-[(2,6-dioxopiperidin-3-ylmethyl)amino] -3-methyl
Phenylpropionate
[0281] Viscous
[0282] 11.15: 2-[(2,6-dioxopiperidin-3-ylmethyl)amino]
Benzamide
[0283] Melting point: 203-206.degree. C.
[0284] 11.16: 3-[(4-acetylphenylamino)methyl]
Piperidine-2,6-dione
[0285] Melting point: 160.degree. C.
[0286] 11.17: 3-[(3-benzoyl phenylamino)methyl]
Piperidine-2,6-dione
[0287] Melting point: 152-158.degree. C.
[0288] 11.18: 4-[(2,6-dioxopiperidin-3-ylmethyl)amino] Methyl
Benzoate
[0289] Melting point: 142-144.degree. C.
Example 12
3-[(2-hydroxymethyl Phenylamino)methyl] Piperidine-2,6-dione
[0290] Step 1:
[0291] 3-{[2-tert-butyl Dimethyl Silanyloxymethyl)phenylamino]
Methyl} Piperidine-2,6-dione
[0292] By replacing aniline in Example 10 by 2-(tert-butyl dimethyl
silanyloxymethyl) phenylamine and using the procedure therein
described, the title compound was obtained in the form of white
crystals, which melted at 85-87.degree. C.
[0293] Step 2:
[0294] 3-[(2-hydroxymethyl Phenylamino)methyl]
Piperidine-2,6-dione
[0295] 5 ml of a 1 M solution of tetrabutyl ammonium fluoride
trihydrate in tetrahydrofuran were added to a solution of 0.20 g of
the product from step 1 in 5 ml tetrahydrofuran. It was stirred for
3 h at 20.degree. C., evaporated in vacuo and the residue was
purified by flash chromatography on silica gel with ethyl acetate
as eluent. 0.12 g (85% of theoretical) of the title compound were
obtained in the form of a yellowish oil.
Example 13
[0296] By replacing aniline in Example 10 by thiophenols or
mercaptans and using the procedure therein described, the following
were obtained in the same way:
[0297] 13.1: 3-phenylsulfanylmethyl Piperidine-2,6-dione
[0298] Melting point: 98.degree. C.
[0299] 13.2: 3-phenethylsulfanylmethyl Piperidine-2,6-dione
[0300] Melting point: 78.degree. C.
[0301] 13.3: 2-(2,6-dioxopiperidin-3-ylmethyl)sulfanyl) Methyl
Benzoate
[0302] Melting point: 142-144.degree. C.
[0303] 13.4: 3-benzylsulfanylmethyl Piperidine-2,6-dione
[0304] Melting point: 105-107.degree. C.
[0305] 13.5: 3-(3-aminophenylsulfanylmethyl)
Piperidine-2,6-dione
[0306] Melting point: 133-135.degree. C.
[0307] 13.6: 5-(2,6-dioxopiperidin-3-ylmethylsulfanyl)-6-nitro
Methylbenzoate
[0308] Melting point: 147-150.degree. C.
Example 14
2-amino-5-(2,6-dioxopiperidin-3-ylmethylsulfanyl) Methyl
Benzoate
[0309] The title compound was obtained in the same way by catalytic
hydrogenation of the product from Example 13.6 over palladium on
activated carbon (10% Pd) under the conditions described in Example
3.
[0310] Melting point: 164-167.degree. C.
Example 15
3-phenylsulfanylmethyl-1-piperidin-1-ylmethyl
Piperidine-2,6-dione
[0311] 0.52 ml aqueous formaldehyde solution (35%) and 0.43 ml
piperidine were added to a solution of 1.20 g of the product from
Example 13.1 in 30 ml ethanol. After being refluxed for 1 hour, the
mixture was evaporated in vacuo. The residue was taken up in ethyl
acetate and n-hexane was added to the solution until precipitation.
The crystals were separated off and dried in vacuo. 1.23 g (74% of
theoretical) of the title compound were obtained, which displayed a
melting point of 63-66.degree. C.
[0312] .sup.1H-NMR (DMSO-d.sub.6): 1.37-1.47 (m, 6H), 1.72-1.88 (m,
1H), 2.08-2.16 (m, 1H), 2.21-2.33 (m, 4H), 2.49-2.57 (m, 1H),
2.70-2.82 (m, 1H), 3.07-3.18 (m, 1H), 3.28-3.33 (m, 1H), 3.47-3.56
(m, 1H), 4.56-4.69 (m, 2H), 7.17-7.25 (m, 1H), 7.28-7.39 (m,
4H).
Example 16
N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] Phenyl} Acetamide;
Hydrobromide
[0313] Step 1:
[0314] 2[(2-acetyl Aminobenzyl) Benzyloxycarbonylamino]-4-carbamoyl
Butanoic Acid
[0315] 1.20 g N-(2-formyl phenyl) acetamide, dissolved in 10 ml
methanol and 3.7 ml 1 N sodium hydroxide solution, were added to a
solution of 0.98 g L-glutamine in 3.4 ml 2N sodium hydroxide
solution, stirred for 30 minutes at 20.degree. C. and cooled to
0.degree. C. 0.31 g sodium borohydride were then added in portions
with stirring over 30 minutes. Stirring was continued for 16 hours
at 0 to 5.degree. C. and 14.2 ml of a 1 N aqueous sodium hydrogen
carbonate solution were then added. A solution of 1.4 ml benzyl
oxycarbonyl chloride in 1.1 ml tetrahydrofuran and 2.5 ml 4N sodium
hydroxide solution were then simultaneously added dropwise over one
hour. Stirring was continued for 2 hours at 20.degree. C. The
neutral reaction solution was extracted three times with diethyl
ether and the aqueous phase then adjusted to pH 1 to 2 with 1 N
hydrochloric acid. It was then extracted three times with 20 ml
ethyl acetate. The combined organic phases were washed with 20 ml
saturated sodium chloride solution, dried over sodium sulfate and
evaporated in vacuo. 0.93 g of the unpurified title compound were
obtained, which were then reacted further.
[0316] Step 2:
[0317] (2-acetylaminobenzyl)-(2,6-dioxopiperidin-3-yl) Benzyl
Carbamate
[0318] A solution of 0.36 g carbonyl diimidazole in 3 ml absolute
tetrahydrofuran was added to a solution of 0.90 g of the product
from step 1 in 6 ml anhydrous tetrahydrofuran. The mixture was
refluxed for 4 hours. After evaporation of the solvent in vacuo,
the residue was taken up in 50 ml distilled water and extracted
three times with 50 ml ethyl acetate. The extracts were first
washed three times with 50 ml water, then with saturated sodium
chloride solution, dried over sodium sulfate and evaporated in
vacuo. 0.25 g (11% of theoretical, relative to the L-glutamine used
in step 1) of the title compound were obtained by flash
chromatography on silica gel with ethyl acetate/cyclohexane
(2/1).
[0319] Step 3:
[0320] N-{2-[(2,6-dioxopiperidin-3-ylamino)methyl] Phenyl}
Acetamide; Hydrobromide
[0321] 1 ml of a solution of hydrogen bromide in glacial acetic
acid (33% HBr) was added to a suspension of 0.20 g of the product
from step 2 in 1 ml glacial acetic acid. The mixture was stirred
for 1 hour at 20.degree. C. and then poured into 100 ml diethyl
ether. After cooling to 0 to 5.degree. C. the solid that had formed
was separated off, washed with diethyl ether and dried in vacuo.
After reprecipitation from methanol/diethyl ether, 0.09 g (50% of
theoretical) of the title compound were obtained.
[0322] Melting point: 152-156.degree. C.
[0323] .sup.1H-NMR (DMSO-d.sub.6): 2.05-2.22 (m, 1H); 2.13 (s, 3H);
2.35-2.74 (m, 1H); 2.69-2.74 (m, 2H); 4.26 (s, 2H); 4.43 (d, 1H);
7.33-7.60 (m, 4H); 9.88 (s, 1H); 11.41 (s, 1H).
Example 17
N-{2-[(2,6-dioxopiperidin-3-ylamino)methyl] Phenyl} Formamide;
Hydrobromide
[0324] By replacing the acetamide derivative used in Example 16,
step 1, with N-(2-formyl phenyl) formamide and using the procedure
described in steps 1 to 3, the title compound was obtained in the
same way.
[0325] Melting point: 169-174.degree. C.
Example 18
3-(2,6-dioxopiperidin-3-yl Methyl Sulfanyl)-6-nitro
Methylbenzoate
[0326] The title compound was produced using the procedure
described in Example 10, by replacing the aniline with the
corresponding mercaptan (formula X with R.sup.1.dbd.COOCH.sub.3 in
the 3 position and R.sup.2.dbd.NO.sub.2 in the 4 position).
[0327] Melting point: 147-150.degree. C.
Example 19
2-amino-5-(2,6-dioxopiperidin-3-yl Methyl Sulfanyl) Methyl
Benzoate
[0328] The title compound was obtained in the same way by catalytic
hydrogenation of the product from Example 18 over palladium on
activated carbon (10% Pd) under the conditions described in Example
3.
[0329] Melting point: 164-167.degree. C.
[0330] Stimulation of Human Monocytes with Lipopolysaccharide for
Secretion of IL-12
[0331] Human monocytes were isolated from peripheral blood
mononuclear cells (PBMC) obtained by means of a Ficoll
density-gradient centrifugation of heparinized whole blood. To this
end, the PBMC were incubated with a monoclonal antibody directed
against the monocyte-specific surface molecule CD14 and to which
superparamagnetic microbeads (Miltenyi Biotech, Bergisch Gladbach)
are coupled. In order for the marked monocytes to be positively
selected from the mixture of cells in the PBMC, the total cell
suspension was transferred to a column with a ferromagnetic carrier
matrix and the column placed in a magnetic field. This caused the
cells loaded with microbeads to be bonded to the carrier matrix,
whilst unmarked cells passed through the column and were discarded.
After removing the matrix from the magnetic field, the
antibody-loaded cells were eluted by rinsing the now demagnetised
column with buffer. The purity of this CD14-positive monocyte
population thus obtained was around 95 to 98%. These monocytes were
incubated in a density of 10.sup.6 cells/ml culture medium (RPMI,
supplemented with 10% fetal calf serum) with the test substances
dissolved in DMSO for one hour at 37.degree. C. and 5% CO.sub.2. 20
.mu.g/ml LPS from E. coli were then added. After 24 hours,
cell-free culture supernatants were taken and tested for their
IL-12 content.
[0332] The concentration of IL-12 in the cell culture supernatants
was determined by means of sandwich ELISA using two anti-IL-12
monoclonal antibodies (Biosource Europe, Fleurus, Belgium). A
reference standard curve with human IL-12 was included. The
detection limit of the IL-12 ELISA was 10 pg/ml.
1TABLE 1 Influence of the test substances on IL-12 production by
LPS-activated monocytes. Inhibition of IL-12 production Example no.
Maximum (%) IC50 (.mu.g/ml) 6.1 85 1.0 6.2 75 1.0 9.1 90 0.1 9.2 82
1.5 8.3 90 0.15 8.12 84 1.0 7 90 1.5 8.11 90 0.2 8.1 90 1.8 8.5 80
2.0 8.4 80 0.9 8.7 55 0.7 8.10 50 -- 8.6 90 0.04 8.2 70 1.8 13.3 50
6.0 16 95 3.0 17 98 0.02 18 57 3.0 19 66 5.0
[0333] The results set out in Table 1 show that the substituted
glutarimides have an immunomodulatory action. They exert a potent
inhibitory effect on the synthesis of IL-12 by LPS-activated
monocytes.
[0334] The foregoing description and examples have been set forth
merely to illustrate invention and are not intended to be limiting.
Since modifications of the described embodiments incorporating the
spirit and substance of the invention may occur to persons skilled
in the art, the invention should be construed broadly to include
all variations falling within the scope of the appended claims and
equivalents thereof.
* * * * *