ZA200407382B - Microglia inhibitors for interrupting immune reactions induced by interleukin 12 and IFNy. - Google Patents
Microglia inhibitors for interrupting immune reactions induced by interleukin 12 and IFNy. Download PDFInfo
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- ZA200407382B ZA200407382B ZA200407382A ZA200407382A ZA200407382B ZA 200407382 B ZA200407382 B ZA 200407382B ZA 200407382 A ZA200407382 A ZA 200407382A ZA 200407382 A ZA200407382 A ZA 200407382A ZA 200407382 B ZA200407382 B ZA 200407382B
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Description
o
Microglia Inhibitors for Interrupting Immune Reactions
Mediated by Interleukin 12 and IFN,
The invention pertains to the use of microglia inhibitors for the manufacturing of a medication, which inhibits the immune reactions mediated by interleukin 12 (IL 12) and interferon-y, and its use for the treatment of immune diseases mediated by T cells and inflammatory reactions that are not mediated by T cells.
The immune system includes a multitude of cells and tissue complexes, which communicate among themselves mainly through soluble agents. It is known that many immune diseases are triggered by imbalance of the soluble immune agents, as, for instance, the cytokines (Mosmann and Coffmann., Ann. Rev.
Immunol. Z: 145 -173 (1989 Street and Mosmann, FASEB J. 5: 171-177 (1991);
Lucey et al., Clin. Microbiol. Rev. 4: 532 -562 (1 996); Powrie and Coffman,
Trends Pharmacol. Sci 14:164 -168 (1 993); Singh et al., Immunolog. Res.. 20: 164 - 168 (1999)). So there are, for instance, many indications that pointing to a certain role of interferon gamma and interleukin 12 in the pathogenesis of the autoimmune diseases. Particularly, we can mention diseases, which can be characterized by means of T cells mediated inflammatory reactions, as multiple sclerosis, diabetes, chronic inflammatory bowel diseases. The cytokine interleukin 12 (IL 12) is produced by phagocyte cells like monophages/monocytes, dendrites, B-cells, and other antigen-presenting cells (APC) and influences both the function of the natural killer cells (NC cells) and the function of the of the T lymphocytes. The IL 12 can trigger the production of interferon gamma (IFN,) in both types of cells. The T lymphocytes can be divided roughly in two categories, which can be characterized by the expression of certain surface antigens (CD4 and CD8): CD4-positive T cells (helper T cells) and CD8-positive T cells (cytotoxic T cells). The CD4 cells can be divided again in T helper cells 1 (Th1) and T helper cells 2 (Th2). Particularly, the immune responses mediated by the Th1 cells are associated with the pathogenesis of many immune diseases, especially with the autoimmune diseases, as, for
® ® instance: Type 1 insulin-dependent diabetes mellitus (IDDM), multiple sclerosis, allergic contact eczema, psoriasis, rheumatoid arthritis, chronic inflammatory bowel diseases (morbus Crohn, ulcerous colitis), lupus diseases,, and other collagenoses as well as acute rejection reactions in the allotransplantations (“host-versus-graft” — allotransplantation rejection, “graft-versus-host disease). i It is known about the interleukin 12 that it plays a critical role in the regulation of the Th1 response. Interleukin 12 induces in these cells mainly the production of
IL-2, IFN,, TNF, and TNF (Mosmann and Sad, Immunol. Today 17: 138 -146 (1996) ;Gately et al., Annu. Rev. Immunol. B:495 -521-(1 998)). Particularly, the
IFN, is a potential mediator of the IL-12 action. For instance, the overproduction of interferon gamma can be responsible for the autoimmune diseases that are associated with the MHC 1l (Major Histocompatibility Complex). (Additionally, there is also sufficient evidence regarding the pathological role of interferon gamma in allergic diseases as well as in the sarcoidosis and the psoriasis (Billiau
A., Adv. Immunol., 62: 61-130 (1996); Basham et al. J. Immunol. 130:1492 -1494 (1983); Hu et al., Immunology, 98: 379-385 (1999); Seery JP., Arthritis Res., 2: 437-440 (2000)). In addition to that, the IL-12 and IL-12/IL-18 induced IFN, from
NK cells essentially participates in the pathological mechanism of not T cell mediated inflammatory reactions (for example, “toxic shock syndrome”, endotoxinemia, sepsis and sepsic shock, ARDS, “first dose response” in antibody therapy, for instance, OKT3 in allotransplantations) — (Kum et al., Infect Immun. 69: 25 7544-7549 (2001); Arad et al., J Leukoc. Biol. B:921-927 (2001); Hultgren et al., Arthritis Res. 3: 41-47 (2001), Arndt et al., Am. J. Respir. Cell. Mol. Biol. 22: 708-713 (2000); Grohmann et al., J. Immunol. 164:4197-4203 (2000);
Muraille et al., Int. Immunol. 11:1403-1410 (1999)). IL-12 play also certain role in inflammations with pathogenic mechanisms (for instance, eclampsia) that are not clear for now (Hayakawa et al., J. Reprod. Immunol. 47: 121-1 38 (2000); Daniel et al., Am. J. , Reprod. Immunol. 39:376-380 (1998)).
Besides interleukin 12 and IFN,, other cyclokines are also ascribed certain role in the pathogenesis of the immune diseases and the systemic inflammatory
® ® reactions, as, for instance, the TNF. The TNF, plays a significant pathological role in infectious diseases like sepsis, “toxic shock syndrome” (Tracey et al.,
Nature 330:662 -664 (1987); Basger et al., Circ. Shock, 27: 51 -61 (1989);
Hinshaw et al., Circ. Shock, 3: 279 -292 (1990); Waage A., Lancet, 351: 603 (1998); Cohen et al., Lancet, 351: 1731 (1998), but also in many other immune- mediated diseases.
For the treatment of the diseases mediated by IL 12 and for reducing the acute symptoms of these diseases, corticosteroids are often used whose side effects, particularly in the case of long treatment, often lead to interruption of the treatment.
The activation of the microglia represents a central step in the inflammation occurrence in almost all degenerative diseases of the central nervous system.
The microglia can remain in an activated state for a long time, during which they produce and secrete various inflammatory agents, for instance, reactive oxygen/hydrogen intermediate, proteases, cytokines, complement agents, and neurotoxins. On the other hand, these cause neuronal dysfunction and degeneration. The activation of the microglia can take place through various stimuli, as, for instance, AB-peptide (8-amyloid, Araujo, D.M. and Cotman, C.M.,
Brain 25 Res. 569: 141-145 (1992)), prion protein, cytokine, or through cell fragments (Combs, C. K. et al., J. Neurosci. 19:928 -939 (1999), Wood, P. L.,
Neuroinflammation: Mechanisms and Management, Humana Press (1998).
Compounds that inhibit the activation of the microglia after stimulation with the
AB-peptide are described in WO 01151473, DE - reference number101 34 775.8 and DE - reference number 101 35 050.3. It is also known from there that benzimidazoles, which inhibit the activation of the microglia, are used in the treatment of neuro-inflammatory diseases like AIDS dementia, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Down's syndrome, diffuse Lewy body disease, Huntington's disease, leukoencephalopathy, multiple scleroses,
® ®
Parkinson's disease, Pick's disease, Alzheimer disease, apoplectic stroke, temporary lobe-epilepsy, as well as of tumors.
The invention is based on solving the following problem: To provide a medication that is suitable for the treatment of immune diseases, since the immune diseases are caused by the increased production of cytokines, as, for instance, IL 12, IFN, and TNF,, and does not affect other factors of the immune system, whereby the side effect can be reduced or prevented.
Now it has been found out that, surprisingly, the microglia inhibitors inhibit the production of IL 12 and IFN,, and induce the production of interleukin 10 (IL 10), and because of that they are used in the manufacturing of a medication for the treatment of immune diseases mediated by monocyte cells, macrophage cells, or
T cells, and particularly by Th1 cells, as well as of not T cell mediated patho- physiological inflammatory reactions.
As it has been mentioned above, the T lymphocytes can be divided in CD4 positive T cells (helper T celis) and CD8-positive T cells (cytotoxic T cells) depending on the expression of their surface antigen, and the CD4 helper T cells can be divided again in T helper cells 1 (Th1) and T helper cells 2 (Th2), which, among other things, differentiate themselves in their ability to prevent tolerance.
The cyclokines IL 12 and IFN, play an important role in the induction and the maintenance of the Th1 cells differentiation. The differentiated Th1 cells secrete
IFN,, interleukin 2, and TNF. These cytokines activate again the macrophages and the cytotoxic CD8 positive T cells.
The invention regards particularly the use of the microglia inhibitors for the manufacturing of a medication that will cause interruption of the production of the
IL 12 and, respectively, the IFN, in the cells of monocytic origin — T cells and NK cells, respectively. On the basis of their ability to interrupt the production of IL 12 and IFN, in monophages/monocytes/dendrites as well as the production of IFN,
® in the T cells and the NK cells and to enhance the induction of the production of
IL 10, the microglia inhibitors are suitable for the treatment of many diseases, which are caused by the increased production of cytokines, as, for instance,
TNF, IFNy, 11 2, and IL 12, like some inflammatory diseases, which are not based on neuro-inflammation, autoimmune diseases, allergic and infectious ) diseases, toxin-induced inflammations, pharmacologically induced inflammatory reactions as well as patho-physiologically relevant inflammatory reactions with unclear genesis for the time being.
Examples of inflammatory and autoimmune diseases are: chronic inflammatory bowel diseases (inflammatory bowel diseases, Crohn's disease, ulcerative colitis), arthritis, allergic contact eczemas, psoriasis, pemphigus, asthma, multiple scleroses, diabetes, type 4 Insulin-dependent diabetes mellitus, rheumatoid arthritis, Lupus-diseases and other collagenoses, Graves' disease, Hashirnoto's disease, "graft-versus-host disease" and transplant rejection.
Examples of allergic, infectious, and toxin-induced diseases as well as ischemic - induced diseases are: sarcoidosis, asthma, hypersensitive pneumonitis, sepsis, septic shock, endotoxin shock, toxic shock syndrome, toxic liver failure, ARDS (acute shortness of breath syndrome), eclampsia, cachexia, acute virus infections (for example, mononucleosis, fulminant hepatitis), organ damages following reperfusion.
An example of a pharmacologically induced inflammation with patho- physiological relevance is the "first dose response” after the administration of anti-T-cell antibodies like OKT3.
An example of systemic inflammatory reactions, which for now are with unclear genesis, is the eclampsia.
According to the invention, compounds, which after stimulation with the Ap peptide achieve an inhibition of the microglia activity of at least 20 per cent and an inhibition of the cytokine activity of at least 30 per cent, are suitable to be used as microglia inhibitors. The biological properties of the microglia inhibitors can be shown by means of the methods that are known to the specialists, for example ) with the help of the research methods described below as well as those described in WO 01151473.
Particularly suitable microglia inhibitors with the properties described above are the benzimidazoles in formula | and their tautomeric and isomeric forms and salts.
Formula (1)
R® N
Be,
N
B-A-Y \
R!
Among them there are:
R' An aryl group or a five or six-member hetero-aryl group with one or two hetero-atoms, selected from the group and containing N, S, and O, whereby the aryl or the hetero-aryl group can be substituted with up to three rests that are independent of each other and selected from the group containing:
® ®
GINFINF, CINHINHR', C(NHNR*R*, C(NR*)NH,, C(NR*)NHR*,
C(NR’)N R'R™,
X-OH, X-OR*, X-OCOR*, X-OCONHR*,
X-COR*, X-C(NOH)R?,
X-CN, X-COOH, X-COOR?, X-CONH,, X-CONR*R*, X-CONHR*,
X-CONHOH,
B X-SR*, X-S0,, X-SO;R?,
SO,NH,, SO,NHR?, SONR*R*,
NO, X-NH,, X-NHR*, X-NR*R*, X-NHSO,R*, X-NR*SO,R*,
X-NHCOR*, X-NHCOOR*, X-NHCONHR* and
RY,
Whereby X is a compound CH, (CHa) 2, or CH(CHa) 2, whereby further under the given conditions the rests R* and R*, are selected independently from each other and whereby two substitutions of R'- when they are orthogonally standing — can be connected to each other, so that they form together a methan-diyl-bisoxy-, ethan-1,2-diyl-bisoxy propan-1,3-diyl- or butan-1,4-diyl group, or a rest selected from the group containing C1.6Alkyl, (Co-3-Alkandiyl-C3.7-
Cycloalkyl), and C;.6Alkenyl, where one H-atom can be exchanged in such a way with one heterocyclic rest selected from the group containing piperazin, morpholine, piperidin, and pyrrolidin, so that a bond to one first
N-atom of the heterocyclic rest can be built, whereby the above mentioned alkyl, cycloalkyl, and alkenyl! rests and the heterocyclic rest can be substituted with up to two rests selected from the group containing Co.2-
Alkandiyl-OH, Cy.,-Alkandiyl-OR’,
Co-2-Alkandiyl-NH2, Co.2-Alkandiyl-NHR’, Cq_o-Alkandiyl-NR'R",
Co-2-Alkandiyl-NHCOR’, Cq.o-Alkandiyl-NR’ COR’, Cy.o-Alkandiyl-
NHSO3R’, Co.2-Alkandiyl-NR’SO,R”, Cy.o-Alkandiyl-CO,H,
Co-2-Alkandiyl-COzR’,
Co.2-Alkandiyl-CONH;, Cq.>-Alkandiyl-CONHR’, Cy.-Alkandiyl-CONR’ R”, phenyl, and one five or six-member heteroaryl rest, whereby the
® _ heteroaryl rest contains one or two hetero-atoms selected from the group containing N, S, and O, whereby further the phenyl and the heteroaryl rests can be substituted with up to two rests selected from the group that contains F, Cl, Br, CH3, C2Hs, OH, OCH3;, OC,Hs, NO2, N(CHa) 2, CF3,
C,Fs, and CO,NH,;, and/or also can carry an anellated methandiyl-bisoxy ” or ethan-1,2-diyl- bisoxy group, whereby the piperazin rest can be substituted at a second oxygen atom also with R’, COR’, or SOR, whereby R” and R” can be selected independently of each other in accordance with the meanings given further below,
R? -Z-R?- an aryl group or a five or six-member heteroaryl group with one or two hetero-atoms selected from the group containing N, S, and O, a benzothienyl group or an indolyl group, whereby the above mentioned aryl or heteroaryl group can be substituted with up to three rests independently of each other selected from the group containing
F, CI, Br,
C(NH)NH,, C(NH)NHR?, C(NH)NR*R*, C(NR*)NH,, C(NR*)NHR*,
C(NRY)N R*R*,
X-OH, X-OR*, X-OCOR?*, X-OCONHR*,
X-COR?*, X-C(NOH)R?,
X-CN, X-COOH, X-COOR?, X-CONH,, X-CONR*R*, X-CONHR?,
X-CONHOH,
X-SR*, X-80,, X-SO;R?,
SO;NH,, SO;NHR?, SO,NR*R*,
NO,, X-NHa, X-NHR*, X-NR*R*, X-NHSO,R*, X-NR*SO,R*,
X-NHCOR*, X-NHCOOR*, X-NHCONHR* and
RY,
Whereby X is a compound CH, (CH) 2, or CH(CH3) 2, whereby further under the given conditions the rests R* and R*, are selected independently from each other and whereby two rests of R' — when they are orthogonally standing — can be connected to each other, so that they
® ® form together a methan-diyl-bisoxy-, ethan-1,2-diyl-bisoxy propan-1,3-diyl- or butan-1,4-diyl group,
V4 NH, NR?*, O, S, SO or SO,, whereby R” has the meaning that is given below,
R? and R* each one is a rest independent of the other and selected from the group that contains:
C14-Perfluoralkyl, C1.6-Alkyl, (Co-3-Alkandiyl-Cs.7- Cycloalkyl), (Co-3Alkandiyl-Aryl), and (Cy.sAlkandiyl-Heteroaryl), where the heteroaryl group is a five or six-member one and contains one or two hetero-atoms selected from the group containing N, S, and O, and whereby the aryl and the heteroaryl groups can be each one substituted with up to two rests selected from the group containing F, Cl, Br, CH3, CoHs, OH, OCH3,
OC,Hs, NO2, N(CHj3),, CF3, CoFs, and SO,NHSs, and/or also can carry an anellated methandiyl-bisoxy or ethan-1,2-diyl-bisoxy group, and further a ring link can be in a five-member cycloakryl ring N or ring O and one or two ring links in a six- or seven-member cycloakryl ring N and/or ring O atoms, whereby the ring N atoms can eventually be substituted with Cy.3-
Alkyl or C1.3-Alkanoyl, or R* and R? together with Z can build one six- or seven-member hetero-cyclic, where Z is an atom, whereby Z has the meaning that has been mentioned above, whereby further the hetero- cyclic ring contains another N, O, or S atom and can optionally be substituted with a rest selected from the group containing C1.4-Alkyl, (Co.3-
Alkandiyl-C4.3- Alcoxy), Ci4-Alkanoyl, C44-Alkoxycarbonoyl,
Aminocarbonyl, and Aryl,
R® one or two rests that are independent of each other and are selected from the group that contains:
Hydrogen,
F, Cl, Br,
®
OH, OR*, OCOR*, OCONHR?,
COR’,
CN, COOH, COOR*, CONH,, CONHR*, CONHOH,
CONHOR®,
SR*, SOR*, SO,R*, SO;NH;, SO,NHR?, SO.NR*R?, - NO,, NH,, NHR*, NR*R,
NHSO,R*, NR*SO,R*, NHSO,R®, NR*SO,R®,
NHCOR®*, NHCOOR*, NHCONHR®, and R?, whereby the rests R*, R*, and R®, can be selected independently of each other and according to the meanings that are given further below,
A a group selected from the group containing Ci.1o-Alkandiyl, Ca.1o-Alkendiyl,
C..10-Alkindiyl, and (C,.3-Alkandiyl-C3.7-Cycloalkandiyl- Co.3-Alkandiyl), whereby in one five-member cycloacryl ring there can be one ring-link ring
N or ring O and in one six- or seven-member cycloacryl ring there can be one or two ring links - ring N and/or ring O atoms, respectively, whereby the ring N atoms can be eventually replaced with C4.3-Alkyl or C.3-
Alkanoyl, whereby in the above mentioned aliphatic chains one C atom can be exchanged with O, OH, N-C,.3-Alkyl, or C.3-Alkanoyl and whereby the alkyl or the cycloalkyl groups can be substituted optionally with a rest selected from the group containing = O, OH, O-C1.3-Alkyl, NH2, NH-C1.3-
Alkyl, NH-C4_3-Alkanoyl, N(C1.3-Alkyl)z, and N(C1.3-Alkyl)( C1.3-Alkanoyl),
B a rest selected from the group containing COOH, COOR?®, CONH,
CONHNH,, CONHR®, CONR®’R®, CONHOH, CONHOR?, and tetrazolyl,
With each one linked to a C atom of the group A, whereby the rests R® and R® can be selected independently of each other under the meanings specified below,
Y a group selected from the group containing O, NH, NR*, NCOR* NSO,R*, and NSO,R®, whereby the rests R* and R® have the meanings given
@® further below and where among the aforementioned rests the rests R*, R*,
R® R%, and R® have the following meanings; Among them there are:
R* and R* each of them is a rest independent of the other and selected from the group containing CF3, C,Fs, C14-Alkyl, Ca4-Alkenyl, Co_3-Alkinyl, and } (Co-3-Alkandiyl-C3.7- Cycloalkyl), whereby in one five-member cycloacryl ring there can be one ring-link ring N or ring O and in one six- or seven- member cycloacryl ring there can be one or two ring links - ring N and/or ring O atoms, respectively, whereby the ring N atoms can be eventually replaced with C4.3-Alkyl or C1.3-Alkanoyl,
R®and R® each of them is a rest independent of the other and selected from the group containing C1.s-Alkyl, C,s-Alkenyl, and C,.s-Alkinyl, whereby one C atom can be exchanged with O, S, SO, SO2, NH, N-C1.3-Alkyl, or N-
Ci.3-Alkanoyl, and further in one five-member cycloacryl ring there can be one ring-link ring N or ring O and in one six- or seven-member cycloacryl ring there can be one or two ring links - ring N and/or ring O atoms, respectively, whereby the ring N atoms can be eventually replaced with
C1-3-Alkyl or Cq.3-Alkanoyl and further with (Co.3-Alkandiyl-Aryl) and (Co-3-
Alkandiyl-Heteroaryl), whereby the heteroaryl group is five or six member one and contains one or two hetero-atoms selected from the group containing N, S, and O, whereby all aforementioned alkyl and cycloalkyl rests can be substituted with up to two rests selected from the group containing SF3, SoFs, OH, O-C16-Alkyl, NHz, NH-C1.3-Alkyl, NH-C4_3-
Alkanoyl, N(C1.3-Alkyl),, N(C1-3-Alkyl)(C1-3-Alkanoyl), COOH, CONH,, and
COO-C4.3-Alkyl, and all aforementioned aryl and heteroaryl groups can be substituted with up to two rests selected from the group containing F, Cl,
Br, CH3, C,Hs, OH, OCHj3, OC;Hs, NO,, N(CHj3),, CF3, CoFs, and SO,NH,, and/or can also carry one anellated methandiyl-bisoxy or ethan-1,2-diyl- bisoxy group, or R® and R* together with the amid N atom of B can build a five to seven-member saturated or unsaturated heterocyclic ring, which
® ® can contain another N or O atom and which can be replaced with Cy.4-
Alkyl, (C1.4-Alkandiyl-C14-Alkoxy), C.4-Alkoxycarbonyl, aminocarbonyl, or aryl,
R® a rest selected from the group containing (Co.3-Alkandiyl-Aryl) and (Co.3- ) Alkandiyi-Heteroaryl), whereby the heteroaryl group is a five-member or a six-member one and contain one or two hetero-atoms selected from the group containing N, S, and O, and whereby the aryl and heteroaryl groups can be substituted with up to two rests selected from the group containing
F, Cl, Br, CHj;, C;Hs, OH, OCH3, OC,Hs, NO,, N(CHs)2, CF3, CoFs, and
SO2NH,, and/or can carry also one anellated methandiyl-bisoxy or ethan- 1,2-diyl-bisoxy group,
R” and R" independent of each other R* or R®.
Such benzimidazole derivatives are preferred, in which the substituent B-A-Y is linked to the 6™ position of the benzimidazole.
The present invention includes also physiologically digestible salts as well as esters of the aforementioned compounds, particularly acid salts of nitrogen base of the benzimidazole derivatives in accordance with the present invention, further the salts of the carbon acids of the derivatives in accordance with the present invention with bases, and the esters of the carbon acids of the derivatives as well as the carbon acids, which are derived from carbon acid derivatives, eventually from carbon acid amides.
The benzimidazole derivatives can show one chorale center or many chorale centers, so that the compounds can appear in many isomeric forms. The compounds of Formula | can also appear as tautomers, stereo-isomers, or geometrical isomers. The invention comprises also all possible isomers as E- and Z-isomers, S- and R-enantiomers, diastereomers, razemates, and mixtures
® of those, including the tautomer compounds. All these isomer compounds are — also when this has not been explicitly stated — a constituent part of the present invention. The isomer mixtures can be undone into enantiomers or E/Z isomers using the traditional methods, as, for instance, crystallization, chromatography, or salt formation.
The heteroaryl groups that are contained in the benzimidazole derivatives are built of five or six structural atoms and can contain one or two hetero-atoms. The hetero-atoms are oxygen (O), nitrogen (N), and sulfur (S). Some examples of heteroaryl groups are pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
When the heteroaryl groups are part of R' or R?, the group is linked through a C atom to the particular N atom of the benzimidazole structure or to the substituent
Z, respectively.
As aryl rests can be considered above all the phenyl rests, but also the naphtyl rests. The aryl rests and the hetero-rests can be connected in an arbitrary way to the benzimidazole base structure or to another group, fro example as 1- or 2- naphthyl or as 2-, 3-, or 4-pyridinyl.
The alkyl groups can be in strait chains or in branched chains. Examples of alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n- pentyl, sec-pentyl, tert-pentyl, neo-pentyl, n-hexyl, sec-hexyl, heptyl, octyl, nonyl, decyl. Also the higher-level homologues include both the linear as well as the branched alkyl groups, as, for example, 2-ethylhexyl for octyl and 3-propyl-hexyl for nonyl.
Perfluorated alkyls are preferably CF3 and C;Fs.
The alkenyl groups can be in strait chains or in branched chains. Examples for that in the sense of the present invention are: vinyl, 2-Propenyl, I-Propenyl, 2-
® ® butenyl, I-Butenyl, I-Methyl-I -propenyl, 2- Methyl-2-propenyl, and 3-Methyl-2- propenyl Akenyl rests.
The alkinyl groups can be in strait chains or in branched chains. Examples for that are: ethinyl, 1-Propinyl, 2- Propinyl, 1-Butinyl, and 2-Butinyl.
Preferentially, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl (corresponds to Cj 7-cycloalkyl), respectively, are to be understood under the cycloalkyl groups.
The following compounds can be mentioned as an example of a saturated heterocyclic ring with one or many hetero-atoms: Piperidin, Pyrrolidin,
Tetrahydrofuran, Morpholin, Piperazin, Hexahydroazepin as well as 2,6-
Dimethyl- morpholin, N-Phenyl-piperazin, and Methoxymethyl-pyrrolidin, whereby the linking with one of the C atoms close to the ring can take place through the eventually available N atoms of the ring.
The Alkandiyl-, Alkendiyl, Alkindiyl, and Cyloalkandiyl rests, which are mentioned in the invention description, have the same meaning as the Alkylen, Alkenylen,
Alkinylen, and Cycloalkylen. As far as the number of the contained C atoms in the general formulas of the alkandiyl rests is given and when this number is assigned the value of 0 as the bottom range limit, this alkandiyl rest is in any case not contained.
As an example, the following compounds are named as alkane, alkene, and alkine for A: alkandiyl in a straight chain or in branched chain with one and up to eight atoms, for example, Methandiyl, Ethandiyl, Propandiyl, Butandiyl,
Pentandiyl, Hexandiyl, and further 1-Methylethandiyl, 1-Ethylethandiyl, 1-
Methylpropandiyl, 2-Methylpropandiyl, 1-Methylbutandiyl, 2-Methylbutandiyl, 1-
Ethylbutandiyl, 2-Ethylbutandiyl, 1-Methylpentandiyl, 2-Methylpentandiyl, 3-
Methylpentandiyl as well as analogous compounds.
® ®
The alkendiyl and alkindiyl in a straight chain or in branched chain with two up to eight C atoms are alkendiyl, respectively, alkindiyl groups with double and triple links in all possible positions as well as with all possible methyl or ethyl substitutions. In these rests, one or two C atoms can be exchanged with O, NH,
N-C,.3-alkyl, or N-C,_s3-alkanoyl, whereby the exchanged group is separated from
Y by at least two C atoms.
When two rests stand orthogonally, they can build a common ring with the neighboring aromatics. The connections, in which the V, O, or S atoms are linked to olefinic or acetylenic manifold formations or in which several N, O, S, or halogen atoms are linked to the same aliphatic C atom or in which the N, O, or S atoms are immediately connected to each other, are excluded so long as these connections are not explicitly defined in the particularly mentioned functional groups or in the hetero-aromatics.
The physiologically compatible acid salts on nitrogen bases of the benzimidazole derivatives corresponding to the present invention can be built with inorganic and organic acids, for example with oxal acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulphuric acid, p-toluol-sulfonic acid, and methane-sulfonic acid.
For the generation of salts of acid groups, and particularly of carbon acid groups, also the inorganic or organic bases are suitable, which are known for the generation of physiologically compatible salts, as, for example, alkali hydroxide, and particularly sodium and potassium hydroxide, alkaline-earth hydroxide, as well as calcium hydroxide, and further ammonia, as well as amines, as ethanol amine, di-ethanol amine, tri-ethanol amine, N-methyl-glucamine, and tris- (hydroxymethy1)- 4 —methyl amine.
®
All univalent, bivalent, and trivalent alcohols are suitable for the formation of esters, and particularly the methanol, ethanol, iso-propanol and tert-butanol as well as the ethylene-glycol and glycerin.
Particularly preferred are the benzimidazoles with the general formula |, in which — the following given below rests and groups have independently of each other the following meaning:
R' a phenyl group, which can be substituted with up to two rests that are independent of each other and are selected from the group containing:
F, Cl, Br,
C(NH)NH,, C(NH)NHR?, C(NH)NR*R*, C(NR*)NH,, C(NR*)NHR*,
C(NR*)NR'R?,
OH, OR*, OCOR*, OCONHR®,
COR?®, C(NOH)R?,
CN, COOH, COOR?*, CONH,, CONR*R*, CONHR*, CONHOH,
SR*, SOR?, SOR",
SO,NH,, SO.NHR*, SO,NR* R?,
NO,, NH,, NHR*, NR*R*, NHCONHR®, and
RY, whereby the rests R* and R*, according to the below meaning, can be selected independently of each other and whereby two substituents of R’ can be linked with each other in such a way that they form together one methandiylbisoxy, ethan-1,2- diylbisoxy, propan-1,3-diyl, or butan-1,4-diyl group when they are standing orthogonally to one another.
R2 means a mono- or bi-cyclic Cg.1g-argyl group or a mono- or bi-cyclic 5 — 10-member heteroaryl group with 1 — 2 hetero-atoms selected from the group consisting of N, S, or O, whereby the aforementioned aryl or heteroaryl group can be substituted independently of one another with up to three of the following substituents:
® ®
F, Cl, Br,
XOH, XOR*, XOCOR*, XOCONHR?*, XOCOOR?,
XCOR*, XC(NOH)R*, XC(NOR*)R*, XC(NO(COR*)R?,
XCOOH, XCOOR*, XCONH,, XCONHR*, XCONR‘R*, XCONHOH,
XCONHOR*, XCOSR?,
XSR*, XSOR*, XSO,R*, SO,NH;, SO.NHR*,,SONR‘R,
NO,, XNHR?, XNR*R*, XNHSO,R*, XN(SO;R*) SO;R*, XNR*SO,R",
RY, whereby two substituents of R?, when they are orthogonally standing to one another, can be linked one to the other in such a way that they build together methandiylbisoxy, ethan-1 ,2-diylbisoxy, propan-1,3-diyl, butan- 1,4- diyl,
R® a rest selected from the group containing hydrogen, F, Cl, Br, CHs, CzHs,
CF3, C,F5, OH, OR* NHSO,R®, and NHCOR?, whereby R* and R® have the meaning given below,
A Ci-10-Alkandiyl, Cz.10-Alkendiyl, Cz-10-Alkindiyl, (COq.s-Alkandiyl-Ca.7-
Cycloalkandiyl-Cg.s-Alkandiyl), whereby in one five-member cycloacryl ring there can be one ring link, one N, or one O, and in one six- or seven- member cycloacryl ring there can be one or two ring links N, and/or one O, whereby the ring hydrogen can be eventually replaced with C4.3-Alkyl or
Ci.3-Alkanoyl, whereby in the above mentioned aliphatic chains one carbon atom or two carbon atoms can be exchanged with O, NH, NC.3-
Alkyl, NC4_3-Alkanoyl,
B a rest selected from the group containing COOH, COOR®, CONH,,
CONHR®, and CONR®R® where every one is linked to a C atom in the A group, whereby the rests R® and R® can be selected independently of one another in accordance with the meanings given below,
_ ®
Y 6) whereby in the above rests the rests R*, R*, R®, R®, and R® have the following meanings; there they mean: - R*and R* the same as it was given further above,
R5 and RY both are rests independent of each other and selected from the group containing C4.6-Alkyl, C,.s-Alkenyl, Cos-Alkinyl, whereby one C atom can be exchanged with O, S, SO, SO,, NH, N-C.3-Alkyl, or N-C,_3-Alkanoyl, and further (Co.3-Alkandiyl-Cs.7-Cycloalkyl), whereby in one five-member cycloalkyl! ring there can be one ring link ring N or ring O, and in one six- or seven-member cycloacryl ring there can be one or two ring links each one ring N and/or ring O atoms, whereby the ring N atoms can be substituted where applicable with C4_3-Alkyl or C.3-Alkanoyl, and further with (C1.3-Alkandiyl-Phenyl) and (C1-3-Alkandiyl-Heteroaryl), whereby the heteroaryl group is a five- or six-member group and contains one or two hetero atoms selected from the group containing N, S, and O, whereby all above mentioned alkyl and cycloalkyl rests can be replaced with one rest selected from the group containing CFs, CFs, OH, O- Cq.3-Alkyl, NH, NH-
C1-3-Alkyl, NH-C4.3-Alkanoyl, N(C1.3-Alkyl)z, N(C1.3- Alkyl)(C1.3-Alkanoyt),
COOH, CONH,, and COO-C1.3-Alkyl, and all above mentioned phenyl and heteroaryl groups can be replaced with up to two rests selected from the group containing F, Cl, Br, CH3, CoHs, OH, OCH3, OC2Hs, NO2, N(CHa) 2,
CF3, CFs, and SO,NH; and/or can carry an anellated methandiyl-bisoxy or ethan-1,2-diyl-bisoxy group, or R® and R® can build together with the amid N atom of B one five- to seven-member saturated or unsaturated heterocyclic ring, which can contain a further N or O or S atom and which can be substituted with C14-Alkyl, (Co-2-Alkandiyl-C14-Alkoxy), C14-Alkoxy- carbonyl, amino-carbonyl, or phenyl,
R® a phenyl or heteroaryl group, whereby the heteroaryl group is a five- or six-member one and contains one or two hetero atoms selected from the group containing N, S, and U, and whereby the phenyl and heteroaryl groups can be replaced with up to two rests selected from the group containing F, Cl, Br, CH3, CoHs, OH, OCH3;, OC,Hs, NO2, N(CH) 2, CF,
Bh C.Fs, and SO,NH,, or they can also carry an anellated ethandiyl-bisoxy or ethan-1,2-diyl-bisoxy group.
R3 is preferably hydrogen. The grouping Y — A is reproduced in a preferable implementation form by means of a C4.s-Alkylenoxy group, which is linked to the benzimidazole structure by means of an O atom.
The invention pertains further to the pharmaceutical means, which contain one or more compounds of the general formula | as well as one or more carrier substances. The pharmaceutical means, and respectively the compositions of the invention, are manufactured in the known ways with the customary solid or liquid carrier substances or diluting means as well with the customary pharmaceutical and technological auxiliary materials according to the desired method of administration as well as with a suitable dosage. The preferred preparations consist in an administrable form, which is suitable for oral, enteral or parenteral, for example i. p. (intraperitoneal), i. v. (intravenous), i. m. (intramuscular), or percutaneous application. Such administrable forms are for example tablets, film tablets, dragees, pills, capsules, powders, creams, ointments, lotions, liquids like syrups, gels, injectable liquids, for instance i. p., i. v., i. m., or percutaneous shots, etc. Further, there are also suitable depot forms like implantable formulations as well as suppositories. Moreover, the separate formulations of the derivatives according to the present invention in accordance with their way of administration deliver the whole amount to the body gradually or in a short time.
_
For oral administration, capsules, pills, tablets, dragees, and liquids or other forms of administration like pharmaceutical preparations can be used. In these cases, the medications can be formulated in such a way that they could release the active substances and deliver them to the body either in a short period of time or to effect a depot action so that a longer lasting and slower delivery of the active substance could be achieved. The dosage units can contain along with at least one benzimidazole derivative one or more pharmaceutically compatible carriers, for instance substances for regulation of the rheology of the medication, surface-active substances, solving agents, micro capsules, micro particles, granulates, diluters, binding substances like starch, sugar, sorbit, and gelatin, and further filling substances like silicic acid and talc, lubricants, pigments, scents, and other substances.
The corresponding tablets can be offered for instance by means of mixing the active substance with known auxiliary substances, for example inert diluting agents like dextrose, sugar, sorbit, mannit, polyvinylpyrrolidon, exploders like corn starch or alginic acid, binding substances as, for instance, starches or gelatin, lubricants like carboxypolymethylen, carboxymethylcellulose, celluloseacetatphthalat, or polyvinylacetat. The tablets can consist also of many layers.
Correspondingly, the dragees can be manufactured with coatings using materials similar to those normally used in the manufacturing of the tablets with kernels, for example polyvinylpyrrolidon or schellack, Arabic gum, talc, titan oxide, or sugar.
Thereby the shell of the dragee can also consist of several layers, whereby the tablet auxiliary materials mentioned above can be used.
Capsules containing the active substances can be manufactured for instance in a way where the active substance is mixed with an inert carrier like milk sugar or sorbit and encapsulated in gelatin capsules.
®
The active substances can also be prepared in the form of a solution, which is intended for oral administration and which contains as composition components along with the active benzimidazole derivatives also pharmaceutically compatible oil and/or pharmaceutically compatible lipophile, a surface active substance and/or a pharmaceutically compatible hydrophile, a surface active substance and/or a pharmaceutically compatible solvent that can be mixed with water.
In order to achieve better biological availability of the active substances, the compounds can be formulated also as cyclodextrin chlathrates. Here the compounds are transformed with a-, 8-, or y-cyclodextrin or their derivatives.
In the case when crémes, ointments, lotions, or other externally applicable liquids have to be used, they have to be conditioned in such a way that the compounds could be supplied to the body in sufficient amount. In these forms of preparation, auxiliary substances are contained, for example substances for regulating the rheology of the medication, surface-active agents, preservation substances, solution facilitators, dilutors, substances for increasing the permeation capability for the active substances through the skin, pigments, scents, and skin protection agents such as conditioners and humidity regulators. Along with the compounds, the medication can contain also other active substances (Ullimanns Enzyklopé&die der technischen Chemie, Band 4 (1953), Seiten 1-39; J. Pharm. Sci., 52, 918 ff. (1963); H. v.Czetsch-Lindenwald, Hilfsstoffe fiir Pharmazie und angrenzende
Gebiete; Pharm. Ind., 2,72 ff (1 961); Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fur
Pharmazie, Kosmetik und angrenzende Gebiete, Cantor AG, Aulendorf/Wrtt., 1971).
The substances can be applied also in suitable solutions as, for instance, physiological table salt solution, infusion solution, or injection solution. For parenteral application, the active substances can be solved or put in a suspension in physiologically compatible dilution agent. The oily solutions such as for instance solutions in sesame seed oil, castor oil, and cotton seed oil are particularly suitable as dilution agents. Solving facilitators such as for instance benzyl benzoate or benzyl alcohol can be added for increasing the solvability.
For the formulation of an injectable preparation, an arbitrary liquid carrier can be used, into which the compounds prepared in accordance with the present invention can be solved or emulsified. These liquids often contain also substances for the regulation of the viscosity, surface-active agents, preservation agents, solving agent, diluters, and other additional substances, through which the solution can be isotonically regulated. Along with the benzimidazole derivatives, other active substances can also be administered.
It is also possible the substances to be incorporated into a transdermal system and in this way to be applied transdermally. For this purpose, the benzimidazole derivatives can be applied in the form of a depot shot or as an implantation preparation, for example in a subcutane manner. Such preparations can be formulated in such a way that a delayed release of the active substance to become possible. For this purpose, some known techniques can be used, for example self-terminating depots or depots functioning with a membrane. The implantates can contain as inert materials biologically degradable polymers or synthetic silicones, for instance silicone rubber. The benzimidazole derivatives can further be incorporated for percutane administration, for instance into a plaster.
The dosage of the substances is determined by the attending physician and depends among other things on the administered substance, the way of administration, the ailment to be treated, and the gravity of the ailment. The daily dose amounts to no more than 1000 mg, preferably no more than 100 mg, whereby the dose can be administered as a single dose that is to be administered once or it can be divided into two or more daily doses.
_
Research Regarding the Biological Properties
Example 1:
Activation of the Macrophages
For testing the substances on the macrophages/monocytes, LPS-activated THP- 1 cells have been used. For this purpose, 2.5 x 106 cells/ml were sown in RPMi medium (RPMI 1640 + 10 % FCS). The compounds prepared in accordance with the present invention were added in concentration of 5 uM and were pre- incubated for 30 minutes. The stimulation of the cells took place during the night at 37° C with 0.1 ug/ml LPS. Afterwards, the medium was reaped and the TNFa amount was quantitatively determined. The treatment of the cells with the substances prepared in accordance with the present invention led to a reduction of the TNFa amount of at least 30 per cent.
Example 2:
Inhibition of the TNFa and IL 12 Production in THP-1 Cells
The inhibition of the cytokin production can be represented for instance by means of measurement of the TNFa and the interleukin 12 in the lipopolysaccharid (LPS) stimulated THP-1 cells.
For this purpose, 2.5 x 10° THP-1 cells (American Type Culture Company,
Rockville, Md) / ml RPMI 1640 Medium (Life Technologies) /10 % FCS (Life
Technologies, Cat.-No. 10270-1 06) were sown (100 ul/hole) on 96-holes flat- bottom cell-culture plate (TPP, Product-No. 9296). The compounds prepared in accordance with the present invention were adder in different concentrations and were pre-incubated for 30 minutes. The preliminary dilution of the test substances was performed in the incubation medium. The addition of the test substances was performed as twice concentrated substance solution (100 ul/hole). The stimulation of the cells was performed during the night at 37° C with 0.1 pg/ml LPS (Sigma L2630 of E. Coli serotype 0111.B4). Afterwards, the medium was reaped and the TNFa amount and, respectively, the interleukin 12
® amount were quantitatively determined. For the measurement of the TNFa, a commercially available TNFa kit of the company CIS bio international (product
No. 62TNFPEB) was used. The interleukin 12 amount was determined by using the ORIGEN technology (IGEN International, Inc., Gaithersburg, Maryland). The obtained IC50 value corresponds to the concentration of the test substance that is necessary in order to achieve a 50 % inhibition of the maximum TNFa and, respectively, interleukin 12 production.
In this experiment, the substances show an IC50 below 10 uM. By means of similar methods, the inhibition of IL 12 and TNFa with the substances can be represented also in the case of using peripheral blood leucocytes and other comparable stimuli.
Example 3
Inhibition of the Production of IFNy by Peripherial Mononuclear Blood Cells
In order to represent the effect of the substances on the T-cell activation, for instance the measurement of the IFNy secretion can be used.
Human full blood was used for isolation of the peripherial mononuclear cells (blood taking via Na-Zitrat S-Monovettes, “coagulation 9 NC/10 ml"/Sarstedt).
The enrichment of the blood cells was performed by means of thickness gradient centrifugation: for this purpose, 15 ml Histopaque 1077 (Sigma, Cat. No. H8880) in LEUCOSEP tubule (Greiner, Cat. No. 227290) were used and were centrifuged for 30 seconds at 1000 g. Thereafter, 15 ml of full blood were added and were centrifuged for 10 minutes at 1000 g. Subsequently, the upper plasma layer was removed with a pipette and the cell layer lying below (peripherial mononuclear blood cells) was transferred in 15 ml test tube (Falcon) and was subsequently washed many times with 10 ml HBSS (HANKS balanced 25
Solution (without Mg2+ and Ca2+), Cat. No. 14175-53). Finally, the cell pellet was re-suspended (1 X 10° cells/ml) in culture medium RPMI 1640 + 25 mM
Hepes (Life Technologies Cat. No. 52400-041 10 % FCS (Life Technologies,
Cat. No. 10270-1 O06), 0,4 % Penicillin-Streptomycin-solution (Life Technologies,
_
Cat. No. 151 40-1 06). Every 100 pl cell suspension solution were spread on 96- holes flat- bottom cell-culture plate (TPP, Product-No. 9296) and were stimulated by means of 5 ng/ml phytohaemaglutinin. The substance prepared in accordance with the present invention were added in different concentrations and were pre-incubated for 30 minutes. The stimulation of the cells took place during a period of 48 hours. Afterwards, the medium was reaped and the IFNy amount was quantitatively determined. The IFNy amount was determined by using the
ORIGEN technology (IGEN International, Inc., Gaithersburg, Maryland). The calculated IC50 value corresponds to the concentration of the test substance, which is necessary in order to achieve a 50m per cent inhibition of the maximum
IFNy production.
The treatment of the cells with the test substances has led to a reduction of the
IFNy amount of at least 30 per cent at concentration of 10 uM. By using similar methods, the inhibition of IFNy with the substances can be represented also in the case of using specific T-cell activators as, for instance, monoclonal anti-CD3 antibodies.
Table 1
Substance Inhibition of the | Inhibition of the | Inhibition of the | Inhibition of the
IL 12 Secretion | TNFa Secretion | IFNy Secretion Microglia
Substance 1: 6-[[1-(4-Methylpheny1)-2-phenyl-1H-benzimidazol-6-ylJoxy]hexan-acid- isopropylester
Substance 2: 6-[[1-(4-Methylphenyl)-2-phenyl-1H-benzimidazol-6-ylJoxy]hexan-acid.
_ ®
Example 4:
Induction of the IL 10 Production by Peripherial Mononuclear Blood Cells
The induction of the IL 12 production is represented for example through measurement of IL 10 in phytohaemaglutinin (PHA) or lipoplysaccharid (LPS) simulated peripherial mononuclear blood cells.
For isolation of the peripherial mononuclear blood cells, human full blood has been used (blood taking via Na-Zitrat S-Monovettes, “coagulation 9 NC/10 ml"/Sarstedt). The enrichment of the lymphocytes and the monocytes has been performed by means of thickness gradient centrifugation. For this purpose, 15 mi
Histopaque 1077 (Sigma, Cat. No. H8880) in 50 ml LEUCOSEP tubule (Greiner,
Cat. No. 227290) were used and were pressed down through the frit in the tubules by means of centrifugation for 30 seconds at 250 g. Subsequently, 20 mi full blood were added and centrifuged for 15 minutes at 800 g and at room temperature. After the centrifugation, the residue (plasma and thrombocytes) was removed with a pipette and thrown out while the cell layer lying below (lymphocytes and monocytes) was transferred to a 50 ml centrifuge tubule (Falcon) and was subsequently washed (centrifugation every time for 10 minutes at 250 g and at room temperature) three times in culture medium VLE RPMI 1640 (Seromed, No. FG1415). Finally, the cell pellet was re-suspended in culture medium VLE RPMI 1640 (Seromed, No. FG1415), 10 % FCS (Life Technologies,
Cat. No. 16000-044, low endotoxin, heat activated 1 hour, 56° C), 50 pg/ml penicillin/streptomycin solution (Life Technologies, Cat. No. 15140-106) and after cell counting by means of trypan blue coloring was set to 3 x 10° cells. Every 100 ul of cell suspension solution were spread on 96-holes flat- bottom celi-culture plate (Costar, Product No. 3599). Added to every one of them were 100 pl triply concentrated stimulation solution (3 ug/ml LPS of E. coli Serotype 0127:B8;
Sigma, Cat. No. L-4516, respectively 300 ng/ml PHA-L, Biochrom KG, Cat No.
M5030). The substances prepared in accordance with the present invention were added in different concentrations as a triply concentrated substance solution (100
® ® pliwell). The stimulation of the cells took place at 37° C and 5 % CO. during a period of 24 hours. Afterwards, the cell culture residue was reaped and the IL 10 was quantitatively determined. The IL 10 concentration was determined by means of a commercially available ELISA kit of the company BioSource
International (Human IL-10, Cat.No. KHCOIOIC). The calculated value of ECs corresponds to the concentration of the test substance that is necessary in order to increase the IL 10 secretion with 50 % of the maximum increase.
The substances prepared in accordance with the present invention increase the
IL 10 production of peripherial mononuclear blood cells.
Example 5:
Inhibition of the TNFa and IL 12 HD Production of Peripherial Mononuclear Blood
Cells
The inhibition of the TNFa and IL. 12 HD p70 production is represented for instance through the measurement of the TNFa and IL 12 HD p70 in the . peripherial mononuclear blood cells stimulated with lipopolysaccharid (LPS) and interferon gamma (IFNy).
For isolation of the peripherial mononuclear blood cells, human full blood has been used (blood taking via Na-Zitrat S-Monovettes, “coagulation 9 NC/10 mi"/Sarstedt). The enrichment of the lymphocytes and the monocytes has been performed by means of thickness gradient centrifugation. For this purpose, 15 ml
Histopaque 1077 (Sigma, Cat. No. H8880) in 50 ml LEUCOSEP tubule (Greiner,
Cat. No. 227290) were used and were pressed down through the frit in the tubules by means of centrifugation for 30 seconds at 250 g. Subsequently, 20 mi full blood were added and centrifuged for 15 minutes at 800 g and at room temperature. After the centrifugation, the residue (plasma and thrombocytes) was removed with a pipette and thrown out and the cell layer lying below (lymphocytes and monocytes) was transferred to a 50 ml centrifuge tubule (Falcon) and was subsequently washed (centrifugation every time for 10 minutes at 250 g and at room temperature) three times in culture medium VLE RPMI
® 1640 (Seromed, No. FG1415). Finally, the cell pellet was re-suspended in culture medium VLE RPMI 1640 (Seromed, No. FG1415), 10 % FCS (Life Technologies,
Cat. No. 16000-044, low endotoxin, heat activated 1 hour, 56° C), 50 pg/ml penicillin/streptomycin solution (Life Technologies, Cat. No. 15140-106) and after cell counting by means of trypan blue coloring was set to 3 x 10° cells. Every 100 ul of cell suspension solution were spread on 96-holes flat- bottom cell-culture plate (Costar, Product No. 3599). Added to every one of them were 100 pl triply concentrated stimulation solution (3 ug/ml LPS of E. coli Serotype 0127:B8;
Sigma, Cat.No. L-4516 and 30 ng/ml INF, 1b, imukin, Boehringer, Ingelheim).
The substances prepared in accordance with the present invention were added in different concentrations as a triply concentrated substance solution (100 pl/well). The stimulation of the cells took place at 37° C and 5 % CO, during a period of 24 hours. Afterwards, the cell culture residue was reaped and the concentrations of the TNFa and the IL 12 were determined by means of the commercially available ELISA kit of the companies BioSource International (TNF- a EASIA, Cat. No. KAC1752) and R&D Systems (Quantikine™ HS IL 12, Cat.
No. HS 120).
The calculated value of ICsy corresponds to the concentration of the test substance that is necessary in order to achieve a 50 % inhibition of the maximum
TNFa production and, respectively, of the interleukin 12 HD p70 production.
The substances prepared in accordance with the present invention inhibit the
TNFa and the IL 12 HD p70 production of peripherial mononuclear blood cells.
_
Table 2
Substance | Inhibition of the IL 12 Inhibition of the TNF- Induction of the IL 10
HD Secretion after alpha Secretion after Secretion after PHA e mi
B IC50 Efficiency IC50 Efficiency IC50 Efficiency ew | ew Tw ee | we
Substance 1: 6-[[I-(4-Methylphenyl)-2-phenyl- 1H-benzimidazol-6-yljoxyjhexan acid- isopropylester.
Substance 2: 6-[[1-(4-Methylphenyl)-2-phenyl-1 H-benzimidazol-6-yl]Joxylhexan acid.
Claims (19)
1. Use of Microglia inhibitors in the manufacture of a medicament for the treatment of monocyte mediated, macrophage mediated, or T cell mediated immune reactions.
2. Use in accordance with Claim 1 for treatment of interleukin 12 (IL 12) and interferon y (IFNy) mediated immune reactions.
3. Use in accordance with Claim 1 for treatment of not T cell mediated inflammatory reactions.
4. Use in accordance with Claim 1 for treatment of autoimmune diseases, inflammatory diseases, which are not based on neuro- inflammation, allergic, and infectious diseases.
5. Use in accordance with Claim 4 for treatment of chronic inflammatory intestinal diseases, for example the inflammatory bowel disease, Crohn's disease, or ulcerous colitis, arthritis, allergic contact eczema, psoriasis, pemphigus, asthma, diabetes, type | insulin-dependent diabetes mellitus, rheumatoid arthritis, lupus diseases, and other" collagenoses, Graves’ disease, Hashimoto's disease, graft versus host disease and transplant rejection, sarcoidose, asthma, hypersensitive pneumonitis, sepsis, septic shock, endotoxin shock, toxic shock syndrome, toxic lever failure, ARDS (acute shortness of breath syndrome), eclampsia, cachexia, acute virus infections, organ damage after re-perfusion, “first dose response” after administration of anti-T- cell antibodies.
6. Use of the benzimidazole of Formula I, its tautomer or isomer form or salt AMENDED SHEET
PCT/EP03/00467 R® N PrN R? (1 | / N B-A-Y \ R’ Among them there are: R’ An aryl group or a five or six-member hetero-aryl group with one or two hetero-atoms, selected from the group and containing N, S, and O, whereby the aryl or the hetero-aryl group can be substituted with up to three rests that are independent of each other and selected from the group containing: F, Cl, Br, C(NH)NH,, C(NH)NHR*, C(NH)NR*R*', C(NR*)NH,, C(NR*)NHR*', C(NR*)N R*R*, X-OH, X-OR*, X-OCOR*, X-OCONHR*, X-COR*, X-C(NOH)R?, X-CN, X-COOH, X-COOR?*, X-CONH,, X-CONR*R*, X-CONHR*, X-CONHOH, X-SR*, X-S0,, X-SO,R%, SO,NH,, SO,NHR*, SO,NR*R*', NO,, X-NH,, X-NHR*, X-NR*R*, X-NHSO,R*, X-NR*SO,R*, X-NHCOR?®, X-NHCOOR?*, X-NHCONHR* and R* Whereby X is a compound CH,, (CH,) ,, or CH(CH;) ,, whereby further under the given conditions the rests R*and R*', are selected 31 AMENDED SHEET
PCT/EP03/00467 ® independently from each other and whereby two substitutions of R' - when they are orthogonally standing — can be connected to each other, so that they form together a methan-diyl-bisoxy-, ethan-1,2- diyl-bisoxy propan-1,3-diyl- or butan-1,4-diyl group, or : a rest selected from the group containing C, (Alkyl, (C, ;-Alkandiyl-C, ,- Cycloalkyl), and C5; Alkenyl, where one H-atom can be exchanged in such a way with one heterocyclic rest selected from the group containing piperazin, morpholine, piperidin, and pyrrolidin, so that a bond to one first N-atom of the heterocyclic rest can be built, whereby the above mentioned alkyl, cycloalkyl, and alkenyl rests and the heterocyclic rest can be substituted with up to two rests selected from the group containing C,,-Alkandiyl-OH, C,,-Alkandiyl-OR’,
C,.,-Alkandiyl-NH,, C, ,-Alkandiy!l-NHR’, C,,-Alkandiyl-NR’R"",
Co.o-Alkandiyl-NHCOR’, C,,-Alkandiyl-NR’ COR”, C,,-Alkandiyl- NHSO,R’, C, ,-Alkandiyl-NR’SO,R”, C,,-Alkandiyl-CO,H,
C,.,-Alkandiyl-CO,R’,
C,.,-Alkandiyl-CONH,, C,.,-Alkandiyl-CONHR’, C, ,-Alkandiyl-CONR’ R’', phenyl, and one five or six-member heteroaryl rest, whereby the heteroaryl rest contains one or two hetero-atoms selected from the group containing N, S, and O, whereby further the phenyl and the heteroaryl rests can be substituted with up to two rests selected from the group that contains F, Cl, Br, CH;, C,H;, OH, OCH;, OC,H;, NO, N(CH,) ,, CF;, C,F;, and CO,NH,, and/or also can carry an anellated methandiyl-bisoxy or ethan-1,2-diyl- bisoxy group, whereby the piperazin rest can be substituted at a second oxygen atom also with R’, COR’, or SO,R’, whereby R’ and R” can be selected independently of each other in accordance with the meanings given further below, R? -Z-R? — an aryl group or a five or six-member heteroaryl group with one or two hetero-atoms selected from the group containing N, S, and O, a 32 AMENDED SHEET
PCT/EP03/00467 ® benzothienyl group or an indolyl group, whereby the above mentioned aryl or heteroaryl! group can be substituted with up to three rests independently of each other selected from the group containing F, Ci, Br, C(NH)NH,, C(NH)NHR*, C(NH)NR*R*', C(NR*)NH,, C(NR*)NHR*", C(NR*)N R*R™, X-OH, X-OR*, X-OCOR?*, X-OCONHR*, X-COR*, X-C(NOH)R?, X-CN, X-COOH, X-COOR*, X-CONH,, X-CONR‘R?, X-CONHR?, X-CONHOH, X-SR*, X-S0,, X-SO,R?, SO,NH,, SO,NHR*, SO,NR*R*, NO,, X-NH,, X-NHR*, X-NR*R*, X-NHSO,R*, X-NR*SO,R*, X-NHCOR?*, X-NHCOOR*, X-NHCONHR* and R*, Whereby X is a compound CH,, (CH,),, or CH(CH,) ,, whereby further under the given conditions the rests R*and R*', are selected independently from each other and whereby two rests of R' — when they are orthogonally standing — can be connected to each other, so that they form together a methan-diyl-bisoxy-, ethan-1,2-diyl-bisoxy propan-1,3-diyl- or butan-1,4-diyl group, Z NH, NR“, O, S, SO or SO,, whereby R” has the meaning that is given below, R?' and R?” each one is a rest independent of the other and selected from the group that contains:
C,.,-Perfluoralkyl, C,sAlkyl, (Cy ;-Alkandiyl-C,,- Cycloalkyl),
(Co.sAlkandiyl-Aryl), and (Cy, ;Alkandiyl-Heteroaryl), where the heteroaryl group is a five or six-member one and contains one or two hetero-atoms selected from the group containing N, S, and O, and whereby the aryl and 33 AMENDED SHEET
PCT/EP03/00467 ® the heteroaryl groups can be each one substituted with up to two rests selected from the group containing F, Cl, Br, CH;, C,H, OH, OCH,, OC,H,, NO,, N(CH,),, CF;, C,F5, and SO,NHg, and/or also can carry an anellated methandiyl-bisoxy or ethan-1,2-diyl-bisoxy group, and further a ring link can be in a five-member cycloakryl ring N or ring O and one or two ring links in a six- or seven-member cycloakryl ring N and/or ring O atoms, whereby the ring N atoms can eventually be substituted with C,,-Alkyl or C, ,-Alkanoyl, or R* and R?“ together with Z can build one six- or seven-member hetero-cyclic, where Z is an atom, whereby Z has the meaning that has been mentioned above, whereby further the hetero-cyclic ring contains another N, O, or S atom and can optionally be substituted with a rest selected from the group containing C, ,-Alkyl, (C, ;-Alkandiyl-C, ;- Alcoxy), C,,-Alkanoyl, C, ,-Alkoxycarbonoyl, Aminocarbonyl, and Aryl, R® one or two rests that are independent of each other and are selected from the group that contains: Hydrogen, F, Cl, Br, OH, OR*, OCOR?*, OCONHR?, COR*, CN, COOH, COOR?*, CONH,, CONHR*, CONHOH, CONHOR®, SR*, SOR“, SO,R*, SO,NH,, SO,NHR*, SO,NR*R?, NO,, NH,, NHR? NR*R?, NHSO.R*, NR*SO,R*, NHSO,R®, NR*SO,R®, NHCOR®*, NHCOOR*, NHCONHR*, and R*, whereby the rests R*, R*, and R®, can be selected independently of each other and according to the meanings that are given further below, 34 AMENDED SHEET
PCT/EP03/00467 ® A a group selected from the group containing C,_;,-Alkandiyl, C,.;¢-
Alkendiyl, C,,,-Alkindiyl, and (C, ;-Alkandiyl-C, ,-Cycloalkandiyl- C,_;- Alkandiyl), whereby in one five-member cycloacryl ring there can be one ring-link ring N or ring O and in one six- or seven-member cycloacryl ring there can be one or two ring links - ring N and/or ring O atoms, respectively, whereby the ring N atoms can be eventually replaced with C, ;-Alkyl or C, ;-Alkanoyl, whereby in the above mentioned aliphatic chains one C atom can be exchanged with O, OH, N-C, ;-Alkyl, or C, ;-Alkanoyl and whereby the alky! or the cycloalkyl groups can be substituted optionally with a rest selected from the group containing = 0, OH, O-C, ;-Alkyl, NH,, NH-C, ;-Alkyl, NH-C, ;- Alkanoyl, N(C, ;-Alkyl),, and N(C, ;-Alkyl){ C,;-Alkanoyl),
B a rest selected from the group containing COOH, COOR®, CONH,, CONHNH,, CONHR®, CONR°R, CONHOH, CONHOR?®, and tetrazolyl, With each one linked to a C atom of the group A, whereby the rests R® and R® can be selected independently of each other under the meanings specified below,
Y a group selected from the group containing O, NH, NR*, NCOR®, NSO,R*, and NSO,R®?, whereby the rests R* and R® have the meanings given further below and where among the aforementioned rests the rests R*, R*, R®, R®, and R® have the following meanings; Among them there are:
R* and R* each of them is a rest independent of the other and selected from the group containing CF;, C,F;, C,,-Alkyl, C,,-Alkenyl, C,,- Alkinyl, and (C,,-Alkandiyl-C,,- Cycloalkyl), whereby in one five- member cycloacryl ring there can be one ring-link ring N or ring O and in one six- or seven-member cycloacryl ring there can be one or two ring links - ring N and/or ring O atoms, respectively, whereby the ring N atoms can be eventually replaced with C, ;-Alkyl or C, ,-Alkanoyl,
AMENDED SHEET
PCT/EP03/00467 ® R® and R®'" each of them is a rest independent of the other and selected from the group containing C, g-Alkyl, C,4-Alkenyl, and C,s-Alkinyl, whereby one C atom can be exchanged with O, S, SO, SO,, NH, N-C,. s-Alkyl, or N-C, ;-Alkanoyl, and further in one five-member cycloacryl ring there can be one ring-link ring N or ring O and in one six- or seven-member cycloacryl ring there can be one or two ring links - ring N and/or ring O atoms, respectively, whereby the ring N atoms can be eventually replaced with C, ;-Alkyl or C, ;-Alkanoyl and further with
(Co.3-Alkandiyl-Aryl) and (Cy ,-Alkandiyl-Heteroaryl), whereby the heteroaryl group is five or six member one and contains one or two hetero-atoms selected from the group containing N, S, and O, whereby all aforementioned alkyl and cycloalkyl rests can be substituted with up to two rests selected from the group containing SF;, S,Fs, OH, O-C, -Alkyl, NH,, NH-C, ;-Alkyl, NH-C, ;-Alkanoyl, N(C;. s-Alkyl),, N(C, ;-Alkyl)(C, ;-Alkanoyl), COOH, CONH,, and COO-C, ;- Alkyl, and all aforementioned aryl and heteroaryl groups can be substituted with up to two rests selected from the group containing F, Cl, Br, CH,;, C,H, OH, OCH,, OC,H;, NO,, N(CH,),, CF;, C,F;, and SO,NH,, and/or can also carry one anellated methandiyl-bisoxy or ethan-1,2-diyl-bisoxy group, or R® and R®' together with the amid N atom of B can build a five to seven-member saturated or unsaturated heterocyclic ring, which can contain another N or O atom and which can be replaced with C, ,-Alkyl, (C, ,-Alkandiyl-C, ,-Alkoxy), C,_,- Alkoxycarbonyl, aminocarbonyl, or aryl, R°® a rest selected from the group containing (C, ;-Alkandiyl-Aryl) and (Cg. s-Alkandiyl-Heteroaryl), whereby the heteroaryl group is a five-member or a six-member one and contain one or two hetero-atoms selected from the group containing N, S, and O, and whereby the aryl and heteroaryl groups can be substituted with up to two rests selected from the group containing F, Cl, Br, CH,, C,H;, OH, OCH,, OCH; NO,, N(CH,),, CF;, C,F;, and 36 AMENDED SHEET
PCT/EP03/00467 ® SO,NH,, and/or can carry also one anellated methandiyl-bisoxy or ethan-1,2-diyl-bisoxy group, R’ and R”' independent of each other R* or R® in the manufacture of a medicament for the treatment of a disease in accordance with claims 1 - b.
7. Use of benzimidazole in accordance with Claim 6 and characterized with the following meaning: R'’ a phenyl group, which can be substituted with up to two rests that are independent of each other and are selected from the group containing: F, Cl, Br, C(NH)NH,, C(NH)NHR*, C(NH)NR*R*, C(NR*)NH,, C(NR*)NHR*, C(NR*NR*R*, OH, OR*, OCOR*, OCONHR?, COR*, C(NOH)R*, CN, COOH, COOR?, CONH,, CONR*R*, CONHR*, CONHOH, SR*, SOR*, SO,R*, SO,NH,, SO,NHR*, SO,NR* R*, NO,, NH,, NHR?*, NR*R*, NHCONHR?*, and R*, whereby the rests R* and R*, according to the below meaning, can be selected independently of each other and whereby two substituents of R' can be linked with each other in such a way that they form together one methandiylbisoxy, ethan-1,2- diylbisoxy, propan-1,3-diyl, or butan-1,4-diyl group when they are standing orthogonally to one another. R? means a mono- or bi-cyclic Cg ,,-argyl group or a mono- or bi-cyclic 5 — 10-member heteroaryl group with 1 — 2 hetero-atoms selected from the group consisting of N, S, or O, whereby the aforementioned aryl or 37 AMENDED SHEET
PCT/EP03/00467
® heteroaryl group can be substituted independently of one another with up to three of the following substituents:
F, Cl, Br,
XOH, XOR*, XOCOR*, XOCONHR*, XOCOOR?,
XCOR*, XC(NOH)R*, XC(NOR*)R*, XC(NO(COR*)R*,
XCOOH, XCOOR?*, XCONH,, XCONHR*, XCONR*R*, XCONHOH,
XCONHOR?, XCOSR?,
XSR*, XSOR*, XSO,R* SO,NH,, SO,NHR*,,SO,NR*R*,
NO,, XNHR*, XNR*R*, XNHSO,R*, XN(SO,R*) SO,R*, XNR*SO,R?,
R*,
whereby two substituents of R?, when they are orthogonally standing to one another, can be linked one to the other in such a way that they build together methandiylbisoxy, ethan-1 ,2-diylbisoxy, propan-1,3-
diyl, butan-1,4- diyl,
R® a rest selected from the group containing hydrogen, F, Cl, Br, CH, C,H,, CF, C,F,, OH, OR? NHSO,R®, and NHCOR*, whereby R* and R® have the meaning given below,
A C,..0-Alkandiyl, C,,,-Alkendiyl, C, ,,-Alkindiyl, (CO, s-Alkandiyl-C, ,- Cycloalkandiyl-C, ;-Alkandiyl), whereby in one five-member cycloacryl ring there can be one ring link, one N, or one O, and in one six- or : seven-member cycloacryl ring there can be one or two ring links N, and/or one O, whereby the ring hydrogen can be eventually replaced with C, ;-Alkyl or C, ;-Alkanoyl, whereby in the above mentioned aliphatic chains one carbon atom or two carbon atoms can be exchanged with O, NH, NC, ;-Alkyl, NC, ;-Alkanoyl,
B a rest selected from the group containing COOH, COOR®, CONH,, CONHR?®, and CONR®R®* where every one is linked to a C atom in the A group, whereby the rests R® and R® can be selected independently of one
38 AMENDED SHEET
POTEPOO ® another in accordance with the meanings given below, Y 0 whereby in the above rests the rests R*, R*, R®, R®, and R® have the following meanings; there they mean: R* and R* the same as it was given further above, RS and R® both are rests independent of each other and selected from the group containing C, s-Alkyl, C,¢-Alkenyl, C,4-Alkinyl, whereby one C atom can be exchanged with O, S, SO, SO,, NH, N-C, ;-Alkyl, or N-C,_ s-Alkanoyl, and further (C4 ;-Alkandiyl-C,_,-Cycloalkyl), whereby in one five-member cycloalkyl! ring there can be one ring link ring N or ring O, and in one six- or seven-member cycloacryl ring there can be one or two ring links each one ring N and/or ring O atoms, whereby the ring N atoms can be substituted where applicable with C, ;-Alky! or C, ;- Alkanoyl, and further with (C, ;-Alkandiyl-Phenyl) and (C, ;-Alkandiyl- Heteroaryl), whereby the heteroaryl group is a five- or six-member group and contains one or two hetero atoms selected from the group containing N, S, and O, whereby all above mentioned alkyl and cycloalkyl rests can be replaced with one rest selected from the group containing CF;, C,Fs, OH, O- C, ;-Alkyl, NH,, NH-C, ;-Alkyl, NH-C, ;- Alkanoyl, N(C, ;-Alkyl),, N(C,_;- Alkyl)(C,_s-Alkanoyl), COOH, CONH,, and COO-C, ;-Alkyl, and all above mentioned phenyl and heteroaryl groups can be replaced with up to two rests selected from the group containing F, Cl, Br, CH;, C,Hs, OH, OCH, OC;H;, NO,, N(CH) 5, CFs, C,F;, and SO,NH, and/or can carry an anellated methandiyl-bisoxy or ethan-1,2-diyl-bisoxy group, or R® and R* can build together with the amid N atom of B one five- to seven-member saturated or unsaturated heterocyclic ring, which can contain a further N or O or S atom and which can be substituted with C, -Alkyl, (C,,-Alkandiyl-C, ,-Alkoxy), C,-Alkoxy- 39 AMENDED SHEET
PCT/EP03/00467 ® carbonyl, amino-carbonyl, or phenyl, R® a phenyl or heteroaryl group, whereby the heteroaryl group is a five- or six-member one and contains one or two hetero atoms selected from the group containing N, S, and U, and whereby the phenyl and heteroaryl groups can be replaced with up to two rests selected from the group containing F, Ci, Br, CH;, C,Hs, OH, OCH;, OC,H;, NO, N(CH,) ,, CF;, C,Fg, and SO,NH,, or they can also carry an anellated ethandiyl-bisoxy or ethan-1,2-diyl-bisoxy group.
8. Use of benzimidazole in accordance with Claim 6 or Claim 7 characterized by the fact that R® is hydrogen and Y — A is C, ;-Alkylenoxy.
9. A substance or composition for use in a method for the treatment of monocyte mediated, macrophage mediated, or T cell mediated immune reactions, said substance or composition comprising Microglia inhibitors, and said method comprising administering said substance or composition.
10. A substance or composition for use in a method of treatment in accordance with Claim 9 for treatment of interleukin 12 (IL 12) and interferon y (IFNy) mediated immune reactions.
11. A substance or composition for use in a method of treatment in accordance with Claim 9 for treatment of not T cell mediated inflammatory reactions. 40 AMENDED SHEET
PCT/EP03/00467 ® 12. A substance or composition for use in a method of treatment in accordance with Claim 9 for treatment of autoimmune diseases, inflammatory diseases, which are not based on neuro-inflammation, allergic, and infectious diseases.
13. A substance or composition for use in a method of treatment in accordance with Claim 12 for treatment of chronic inflammatory intestinal diseases, for example the inflammatory bowel disease, Crohn's disease, or ulcerous colitis, arthritis, allergic contact eczema, psoriasis, pemphigus, asthma, diabetes, type | insulin-dependent diabetes mellitus, rheumatoid arthritis, lupus diseases, and other collagenoses, Graves’ disease, Hashimoto's disease, graft versus host disease and transplant rejection, sarcoidose, asthma, hypersensitive pneumonotis, sepsis, septic shock, endotoxin shock, toxic shock syndrome, toxic liver failure, ARDS (acute shortness of breath syndrome), eclampsia, cachexia, acute virus infections, organ damage after reperfusion, “first dose response” after administration of anti-T cell antibodies.
14. A substance or composition for use in a method for the treatment of a disease in accordance with Claims 1-5, said substance or composition comprising the benzimidazole of Formula I, its tautomer or isomer form or salt as defined in Claim 6, and said method comprising administering said substance or composition. 41 AMENDED SHEET
: PCT/EP03/00467 »
15. A substance or composition for use in a method of treatment in accordance with Claim 14 wherein the variables are as defined in Claim
7.
16. A substance or composition for use in a method of treatment in accordance with Claim 14 or Claim 15 characterized by the fact that R® is hydrogen and Y — A is C, s-Alkylenoxy.
17. Use according to any one of Claims 1 to 8, substantially as herein described and illustrated.
18. A substance or composition for use in a method of treatment according to any one of Claims 9 to 16, substantially as herein described and illustrated.
19. A new use of microglia inhibitors, or a substance or composition for a new use in a method of treatment, substantially as herein described. 42 AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10207843A DE10207843A1 (en) | 2002-02-15 | 2002-02-15 | Microlia inhibitors for interruption of interleukin 12 and IFN-gamma mediated immune responses |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200407382B true ZA200407382B (en) | 2005-09-14 |
Family
ID=27674912
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200407382A ZA200407382B (en) | 2002-02-15 | 2004-09-14 | Microglia inhibitors for interrupting immune reactions induced by interleukin 12 and IFNy. |
Country Status (21)
| Country | Link |
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| EP (1) | EP1474138A1 (en) |
| JP (1) | JP2005522447A (en) |
| KR (1) | KR20040084909A (en) |
| CN (1) | CN1756546A (en) |
| AR (1) | AR039556A1 (en) |
| AU (1) | AU2003245523A1 (en) |
| BR (1) | BR0307706A (en) |
| CA (1) | CA2475770A1 (en) |
| DE (1) | DE10207843A1 (en) |
| EC (1) | ECSP045297A (en) |
| MX (1) | MXPA04007943A (en) |
| NO (1) | NO20043840L (en) |
| PE (1) | PE20030906A1 (en) |
| PL (1) | PL371327A1 (en) |
| RS (1) | RS71304A (en) |
| RU (1) | RU2004127677A (en) |
| TW (1) | TW200306823A (en) |
| UA (1) | UA81111C2 (en) |
| UY (1) | UY27662A1 (en) |
| WO (1) | WO2003068225A1 (en) |
| ZA (1) | ZA200407382B (en) |
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| DE10207844A1 (en) * | 2002-02-15 | 2003-09-04 | Schering Ag | 1-phenyl-2-heteroaryl-substituted benzimidazole derivatives, their use for the preparation of medicaments and pharmaceutical preparations containing these derivatives |
| CA2601557A1 (en) * | 2005-03-17 | 2006-09-21 | Proyteco De Biomedicina Cima, S.L. | Use of 5'-methylthioadenosine (mta) in the prevention and/or treatment of autoimmune diseases and/or transplant rejection |
| EP2858983B1 (en) * | 2012-06-11 | 2018-04-18 | UCB Biopharma SPRL | Tnf-alpha modulating benzimidazoles |
| US9586949B2 (en) | 2015-02-09 | 2017-03-07 | Incyte Corporation | Aza-heteroaryl compounds as PI3K-gamma inhibitors |
| WO2017079519A1 (en) | 2015-11-06 | 2017-05-11 | Incyte Corporation | Heterocyclic compounds as pi3k-gamma inhibitors |
| EP3741747B1 (en) * | 2015-12-15 | 2024-10-16 | The Board of Trustees of the Leland Stanford Junior University | Method for preventing and/or treating anxiety |
| US20170190689A1 (en) | 2016-01-05 | 2017-07-06 | Incyte Corporation | Pyridine and pyridimine compounds as pi3k-gamma inhibitors |
| TW201803871A (en) | 2016-06-24 | 2018-02-01 | 英塞特公司 | Heterocyclic compounds as PI3K-[gamma] inhibitors |
| CN118063470A (en) | 2017-10-18 | 2024-05-24 | 因赛特公司 | Condensed imidazole derivatives substituted with tertiary hydroxyl groups as PI 3K-gamma inhibitors |
| HRP20240252T1 (en) | 2018-09-05 | 2024-05-24 | Incyte Corporation | Crystalline forms of a phosphoinositide 3-kinase (pi3k) inhibitor |
| PL3860998T3 (en) | 2018-10-05 | 2024-06-17 | Annapurna Bio Inc. | Compounds and compositions for treating conditions associated with apj receptor activity |
| CN112341450B (en) * | 2019-08-09 | 2022-05-17 | 成都先导药物开发股份有限公司 | Immunomodulator |
| CN112341451B (en) * | 2019-08-09 | 2022-06-17 | 成都先导药物开发股份有限公司 | Immunomodulator |
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| DE4330959A1 (en) * | 1993-09-09 | 1995-03-16 | Schering Ag | New benzimidazole derivatives, processes for their preparation and their pharmaceutical use |
| BR0107628A (en) * | 2000-01-14 | 2002-10-08 | Schering Ag | 1,2-diarylbenzimidazoles for treating diseases that are associated with microglial activation |
| DE10134775A1 (en) * | 2001-07-06 | 2003-01-30 | Schering Ag | 1-alkyl-2.aryl-benzimidazole derivatives, their use for the manufacture of medicaments and pharmaceutical preparations containing these derivatives |
| DE10135050A1 (en) * | 2001-07-09 | 2003-02-06 | Schering Ag | 1-Ary1-2-N-, S- or O-substituted benzimidazole derivatives, their use for the preparation of medicaments and pharmaceutical preparations containing them |
-
2002
- 2002-02-15 DE DE10207843A patent/DE10207843A1/en not_active Ceased
-
2003
- 2003-01-17 PL PL03371327A patent/PL371327A1/en not_active Application Discontinuation
- 2003-01-17 WO PCT/EP2003/000467 patent/WO2003068225A1/en active Application Filing
- 2003-01-17 BR BR0307706-3A patent/BR0307706A/en not_active IP Right Cessation
- 2003-01-17 RS YU71304A patent/RS71304A/en unknown
- 2003-01-17 AU AU2003245523A patent/AU2003245523A1/en not_active Abandoned
- 2003-01-17 CN CNA038039923A patent/CN1756546A/en active Pending
- 2003-01-17 RU RU2004127677/15A patent/RU2004127677A/en unknown
- 2003-01-17 UA UA20040907401A patent/UA81111C2/en unknown
- 2003-01-17 CA CA002475770A patent/CA2475770A1/en not_active Abandoned
- 2003-01-17 EP EP03739380A patent/EP1474138A1/en not_active Withdrawn
- 2003-01-17 MX MXPA04007943A patent/MXPA04007943A/en unknown
- 2003-01-17 KR KR10-2004-7012557A patent/KR20040084909A/en not_active Application Discontinuation
- 2003-01-17 JP JP2003567407A patent/JP2005522447A/en active Pending
- 2003-02-03 PE PE2003000119A patent/PE20030906A1/en not_active Application Discontinuation
- 2003-02-11 UY UY27662A patent/UY27662A1/en not_active Application Discontinuation
- 2003-02-12 AR ARP030100436A patent/AR039556A1/en unknown
- 2003-02-14 TW TW092103072A patent/TW200306823A/en unknown
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2004
- 2004-09-14 ZA ZA200407382A patent/ZA200407382B/en unknown
- 2004-09-14 EC EC2004005297A patent/ECSP045297A/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| RS71304A (en) | 2006-10-27 |
| EP1474138A1 (en) | 2004-11-10 |
| RU2004127677A (en) | 2005-06-10 |
| AR039556A1 (en) | 2005-02-23 |
| KR20040084909A (en) | 2004-10-06 |
| ECSP045297A (en) | 2004-10-26 |
| WO2003068225A1 (en) | 2003-08-21 |
| MXPA04007943A (en) | 2004-11-26 |
| CA2475770A1 (en) | 2003-08-21 |
| TW200306823A (en) | 2003-12-01 |
| PL371327A1 (en) | 2005-06-13 |
| JP2005522447A (en) | 2005-07-28 |
| UA81111C2 (en) | 2007-12-10 |
| NO20043840L (en) | 2004-11-12 |
| PE20030906A1 (en) | 2004-01-17 |
| DE10207843A1 (en) | 2003-09-04 |
| AU2003245523A1 (en) | 2003-09-04 |
| CN1756546A (en) | 2006-04-05 |
| UY27662A1 (en) | 2003-09-30 |
| BR0307706A (en) | 2005-01-11 |
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