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WO2008085008A1 - Composés inhibant les lymphocytes t et leur utilisation pour le traitement de maladies à médiation par les lymphocytes t - Google Patents

Composés inhibant les lymphocytes t et leur utilisation pour le traitement de maladies à médiation par les lymphocytes t Download PDF

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Publication number
WO2008085008A1
WO2008085008A1 PCT/KR2008/000195 KR2008000195W WO2008085008A1 WO 2008085008 A1 WO2008085008 A1 WO 2008085008A1 KR 2008000195 W KR2008000195 W KR 2008000195W WO 2008085008 A1 WO2008085008 A1 WO 2008085008A1
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phenyl
dihydro
thione
imidazole
imidazol
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Jonghwa Won
Eun Joo Jung
Minkyu Hur
Sungjoo Kim
Young Lim Kim
Doo-Hong Park
Ge Hyeong Lee
Ikyon Kim
Sung-Eun Yoo
Ji Young Kim
Hye Kyoung Won
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Mogam Biotechnology Research Institute
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Mogam Biotechnology Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the compounds of formula IA or IB with T-cell inhibiting activities, a method of treating immunologic diseases or pathological conditions in association with T-cell activity by administering the compounds of formula IA or IB to a human being or an animal, a pharmaceutical composition comprising the compounds of formula IA or IB, and a use of said compounds for the manufacture of a pharmaceutical composition for the treatment of immunologic diseases or pathological conditions.
  • T cells play cardinal roles in protective immune responses against neoplasia and microbial infection by actively participating in cell-mediated killing as well as by triggering activation of other immune cells. Uncontrolled T cell responses or recognition of auto- or allo-antigens as foreign antigens, however, provoke undesirable immune responses such as allergy, autoimmune disease and transplantation rejection.
  • SUBSTITUTE SHEET (RULE 26) glomerulonephritis and lung fibrosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, allergic asthma, multiple sclerosis and type 1 diabetes (Hanke J H et al. (1995) Inflamm. Res. 357).
  • MS Multiple sclerosis
  • CNS central nervous system
  • MS has been considered as a CD4 T cell-dependent disease (Hohlfeld. (2001) Curr. Opin. Neurol. 14:299-304). This notion is based on observation of the genetic linkage of MS susceptibility with MHC II genes (Zamvil SS et al.
  • EAE experimental autoimmune encephalomyelitis
  • T-cell-targeted drugs would provide a strong therapeutic tool for
  • SUBSTITUTE SHEET (RULE 26) the treatment of said immunologic diseases or pathological conditions.
  • T-cell-specific inhibitor would fulfill unmet needs of current drugs and be effective for the treatment of those said immunologic diseases or pathological conditions, which include inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis and lung fibrosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, multiple sclerosis and type 1 diabetes, allergic asthma, atopic disease, transplantation rejections and GvHD after allogeneic bone marrow and stem cell transplantation.
  • immunologic diseases or pathological conditions which include inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis and lung fibrosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, multiple sclerosis and type 1 diabetes, allergic asthma, atopic disease, transplantation rejections and GvHD after allogeneic bone marrow and stem cell transplantation.
  • R 1 is H or C 1 -C 4 alkyl
  • SUBSTITUTE SHEET (RULE 26) substituents selected from the group consisting of halo, hydroxy, cyano and C 1 -C 4 alkoxy, -CH 2 -pyridine,
  • R a and R b is independently H, C 1 -C 4 alkyl or benzyl substituted with halo, or R a and R b together with N atom to which they are attached may form a five or six-membered ring selected from the group consisting of morpholine, pyrrolidine, piperidine and piperazine, that optionally substituted with C 1 -C 4 alkyl or CpC 4 alkoxycarbonyl,
  • R e and R f is independently H, C 1 -C 4 alkyl or phenyl optionally substituted with C 1 -C 4 alkoxy, or R e and R f together with
  • Ci-C 4 alkyl optionally substituted with hydroxy, or Ci-C 4 alkoxycarbonyl;
  • R g is hydrogen or Cj-C 4 alkyl;
  • n is 1 or 2;
  • m is 0 or 1 ;
  • R is Ci-C 6 alkyl, CpC 6 alkenyl, C 3 -C 8 cycloalkyl, pyridyl, thienyl optionally substituted with halo,
  • Y is N or CR 7 , wherein R 7 is H or CpC 4 alkyl; each of R 5 and R 8 is independently H or CpC 4 alkyl; and R 6 is H, halo or CpC 4 alkyl; or R 5 and R 6 together with the atoms to which they are attached may form a six membered aromatic ring, or tautomers, stereoisomers or pharmaceutically acceptable salts thereof.
  • SUBSTITUTE SHEET (RULE 26) It is a further object of the invention to provide a method of treating T cell-mediated diseases such as graft/tissue rejection and Graft versus Host Diseases.
  • FIG. IA shows the dose-dependent inhibitory effect of 1,4-diphenyl -l,3-dihydro-imidazole-2-thione (IA-I l)) and l-(3-hydroxy-benzyl)-2H-imidazo [l,5-a]pyridine-3-thione (IB-29) on anti-CD3 antibody-induced NFAT activation.
  • FIG. IB illustrates the dose-dependent inhibitory effect of 1, 4-diphenyl
  • FIG. 1C depicts the dose-dependent inhibitory effect of 1, 4-diphenyl- 1, 3 -dihydro-imidazole-2-thione (IA-I l) and [l,5-a]pyridine-3-thione (IB-29) of the subject invention on phorbol 12-myristate 13 -acetate (PMA) and ionomycin (IM)-induced NFAT activation.
  • IA-I l 1, 4-diphenyl- 1, 3 -dihydro-imidazole-2-thione
  • IB-29 [l,5-a]pyridine-3-thione
  • FIG. 2A shows the dose-dependent inhibitory effect of 1, 4-diphenyl
  • FIG. 2B illustrates the dose-dependent inhibitory effect of 1,4-diphenyl- 1,3 -dihydro-imidazole-2-thione (IA-I l) on mixed lymphocyte reaction.
  • FIG. 3 depicts a series of graphs depicting in vivo efficacy of l,4-diphenyl-l,3-dihydro-imidazole-2-thione (IA-I l) and l-(3-hydroxy-benzyl)- 2H-imidazo[l,5-a]pyridine-3-thione (IB-29) of the subject invention on anti-CD3 antibody-induced T cell activation and subsequent secretion of IL-2.
  • FIG. 4 shows in vivo inhibitory effect of 1, 4-diphenyl-l,3-dihydro
  • FIG. 5 illustrates the dose-dependent inhibitory effect of 1, 4-diphenyl-l,3 -dihydro-imidazole-2-thione (IA-I l) and l-(3-Hydroxy-benzyl)-2H-imidazo[l,5-a] pyridine-3-thione (IB-29) on EAE.
  • FIG. 6 depicts in vitro proliferation of splenocytes taken from mice after 10 days from the immunization with MOG emulsified with CFA in 1 : 1 ratio and given l,4-diphenyl-l,3-dihydro-imidazole-2-thione (IA-11) or vehicle .
  • R 1 is H or C 1 -C 4 alkyl
  • SUBSTITUTE SHEET (RULE 26) they are attached may form morpholine or piperazine optionally substituted with CpC 4 alkoxycarbonyl,
  • phenyl being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano and C 1 -C 4 alkoxy,
  • R 8 is hydrogen or C 1 -C 4 alkyl; n is 1 or 2; m is 0 or 1 ; R is CpC 6 alkyl,
  • Y is N or CR 7 , wherein R 7 is H or Cj-C 4 alkyl; each of R 5 and R 8 is independently H or C]-C 4 alkyl; and R 6 is H, halo or CpC 4 alkyl; or
  • R 5 and R 6 together with the atoms to which they are attached may form a six membered aromatic ring, or the tautomers, stereoisomers or physiologically acceptable salts thereof.
  • the object of the subject invention is to provide the compounds of formula IA or IB with T-cell inhibiting activities. These compounds suppress T-cell antigen
  • T-cell proliferation Intraperitoneal or oral administration of these compounds also inhibit T-cell activation in vivo as exemplified by IL-2 level measured after anti-CD3 antibody inoculation and this implicates that their T-cell inhibitory activities are functional in vivo. Further, disease models indicate that these compounds exhibit prophylactic and therapeutic effects in delayed type hypersensitivity (DTH), experimental autoimmune encephalomyelitis (EAE) and rheumatoid arthritis (RA).
  • DTH delayed type hypersensitivity
  • EAE experimental autoimmune encephalomyelitis
  • RA rheumatoid arthritis
  • Examples of preferred compounds of formula IA are the following:
  • SUBSTITUTE SHEET (RULE 26) 2-methylsulfanyl- 1 ,4-diphenyl- lH-imidazole, 4-(4-methoxy-phenyl)- 1 -phenyl- 1 ,3-dihydro-imidazole-2-thione, 4-(4-nitro-phenyl)- 1 -phenyl- 1 ,3-dihydro-imidazole-2-thione, 4-(4-amino-phenyl)- 1 -phenyl- 1 ,3-dihydro-imidazole-2-thione, 4-(4-hydroxy-phenyl)- 1 -phenyl- 1 ,3-dihydro-imidazole-2-thione, 1 -(4-hydroxy-phenyl)-4-phenyl- 1 ,3-dihydro-imidazole-2-thione, 4-(l-phenyl-2-thioxo-2,3-dihydro-lH-imi
  • SUBSTITUTE SHEET (RULE 26) 1 -(2-hydroxy- 1 -methyl-ethyl)-4-phenyl- 1 ,3-dihydro-imidazole-2-thione, l-mo ⁇ holin-4-yl-2-(4-phenyl-2-thioxo-2,3-dihydro-imidazol-l-yl)-ethanone, 2-(4-phenyl-2-thioxo-2,3-dihydro-imidazol- 1 -yl)- 1 -piperidin- 1 -yl-ethanone, 1 -(4-methyl-piperazin- 1 -yl)-2-(4-phenyl-2-thioxo-2,3-dihydro-imidazol- 1 -yl)-etha none,
  • Preferred compounds of formula IB of the present invention are compounds of formula IB wherein Y is CH and R is phenyl optionally substituted with halo,
  • Compounds of formulae IA and IB may form acid addition salts.
  • the acids may be hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, salicylate, sulphate, pyruvate, citrate, lactate, mandelate, tartarate and methansulphonate.
  • Compounds of formula IA or IB can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the optically active forms can be obtained, e.g., by resolution of the racemates, asymmetric synthesis or asymmetric chromatograph (chromatography with a chiral adsorbents or eluants). All of these forms are included in the scope of the subject invention.
  • the compound of formula IA can be prepared according to schemes 1 to 3 as follows:
  • inventive compounds are effective inhibitors of T-cell activation demonstrated by in vitro cell-based assays, and therefore, the subject invention provides a method of treating immunologic diseases or pathological conditions associated with T-cell activity.
  • the compounds of formula IA or IB of the present invention can be used as medicaments for the prophylactic and/or therapeutic treatment of T-cell mediated disease including graft rejection, Graft versus Host Disease, asthma, atopic diseases and autoimmune diseases such as multiple sclerosis, psoriasis, inflammatory bowl disease, rheumatoid arthritis, lupus and type I diabetes.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula IA or IB and a pharmaceutically acceptable carrier.
  • the compounds of formula IA or IB and their pharmaceutically acceptable salts possess valuable pharmacological properties. Specifically, these compounds exhibit inhibitory activity on T-cell antigen receptor induced NFAT (one of major transcription factors important for the activation and expression of interleukin-2) activation, IL-2 production and subsequent T-cell proliferation.
  • T-cell antigen receptor induced NFAT one of major transcription factors important for the activation and expression of interleukin-2
  • the pharmacological activities of the subject compounds have been tested by measuring the level of TCR- or PMA/IM-induced NFAT activation (Example 10) and by the mixed lymphocyte reaction (MLR) (Example 11), which is a known method for determining the transplantation
  • SUBSTITUTE SHEET (RULE 26) compatibility between the donor (graft) and the recipient (Park “ and Good, p71, in Tissue typing and organ transplantation, 1973, Academic Press Inc., N. Y.).
  • T cell activation status in vivo was monitored, after T cell activation by administering anti-CD3 antibody to mice (Example 12).
  • these compounds have prophylactic and therapeutic effects on delayed type hypersensitivity and autoimmune encephalomyelitis in disease models (Examples 13 to 15).
  • the compounds of the present invention have IC 50 values within the range of about 0.4 ⁇ M to 50 ⁇ M, preferably less than 20 ⁇ M, more preferably less than 5 ⁇ M. Tables 1 and 2 show measured IC 50 value ranges for the preferred compounds of the present invention.
  • the compounds of formula IA or IB and their pharmaceutically acceptable salts can be used as medicaments, e.g., in the form of pharmaceutical preparation for enteral, parenteral or topical administration.
  • compositions can be administered, for example, orally, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions; rectally, in the form of suppositories; parenterally, in the form of injection solutions or infusion solutions; or topically, in the form of ointments, creams or oils.
  • the production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula IA or IB and their pharmaceutically acceptable, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets,
  • Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules).
  • Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
  • Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • Suitable carrier materials for topical preparations are glycerides, semi- synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Usual stabilizers preservatives, wetting and emulsifying agents, consistency- improving agents, flavor-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • the dosage of the compounds of formula IA or IB can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case.
  • the pharmaceutical preparations conveniently contain about 500 mg, preferably 50 mg, of the compound of formula IA or IB.
  • the reaction mixture was cooled to room temperature, extracted with ethyl acetate/H 2 O, dried over MgSO 4 and evaporated under reduced pressure.
  • the resulting concentrates were purified by the column chromatography (hexane:ethyl acetate: 3: 1, v/v) to yield 3.19g (11.46mmol) of the desired compounds as brown solid.
  • the obtained solid was charged to 100ml round bottomed flask and a solution of NaOH (1.5g) in MeOHZH 2 O (5/1, v/v) was added. On completion of the reaction, the solution was evaporated under reduced pressure to remove MeOH. Light greenish yellow
  • SUBSTITUTE SHEET (RULE 26) solids were formed in the aqueous solution. 2N HCl was added to acidify the solution to pH 3 and a light yellow solid was formed. The solid was filtered, washed with water and dried to yield 1.77g (7.07mmol, 94%) of the desired yellow solid.
  • ketone (1.27 g, 91%).
  • Activities are based on IC 50 values in cell-based assay, i.e., NFAT-promoter assays: +, >20uM; ++, 5 ⁇ 20uM; +++, ⁇ 5uM.
  • Activities are based on IC 50 values in cell-based assay, i.e., NFAT-promoter assays: +, >20uM; ++, 5 ⁇ 20uM; +++, ⁇ 5uM.
  • Example 10 Measurement of inhibitory effect of 1,4-diphenyl -1,3-dihydro -imidazole-2-thione (IA-I l) and derivatives thereof on TCR- or PMA/ionomycin-induced NFAT activation
  • Jurkat T-cells (5x10 5 cells/ml) transfected with reporter plasmids (NFAT-luciferase-pcDNA3.1) were pre-incubated with various concentrations of compounds (0.5-50 ⁇ M) for 3hrs, and activated with pre-coated anti-CD3 antibody (1-5 ⁇ g/ml) (UCHTl, Pharmingen) or phorbol 12-myristate 13-acetate (PMA) (Sigma, USA) (5 ng/ml) plus ionomycin (Sigma, USA) (500 ng/ml).
  • Jurkat cells were further incubated for 24 hrs, harvested, lysed and centrifuged. The supernatant was assayed for luciferase activity.
  • NFAT reporter plasmid consists of 5 repeats of NFAT binding sites and minimal promoter regions from IL-2 promoter and was inserted in front of the luciferase gene cloned in pcDNA3.1 (Invitrogen Corp., California, USA).
  • SUBSTITUTE SHEET (RULE 26) -l-yl]-benzoic acid ethyl ester (IA-114) also showed inhibitory effects on TCR-induced NFAT activation (Fig. IB) and relative inhibitory effects of compounds are marked as from + to +++ in Tables 1 and 2 above.
  • 1,4-Diphenyl -l,3-dihydro-imidazole-2-thione (IA-I l) and l-(3-Hydroxy-benzyl)-2H-imidazo [l,5-a]pyridine-3-thione (IB-29) also inhibited PMA/ionomycin- induced NFAT reporter activity with a similar range of IC 50 , suggesting that the target of l,4-diphenyl-l,3-dihydro-imidazole-2-thione (IA-I l) and l-(3-Hydroxy-benzyl) -2H-imidazo[l,5-a]pyridine -3-thione (IB-29) is located in downstream of PMA/ionomycin-acting points or in other signaling pathway affecting on PMA/IA-induced signaling (Fig. 1C).
  • Example 11 Measurement of inhibitory effect of l,4-diphenyl-l,3-dihydro -imidazole-2-thione (IA-11) and derivatives thereof on T cell proliferation.
  • splenocytes from C57BL/6 mice were pre-incubated with l,4-diphenyl-l,3-dihydro-imidazole-2 -thione (IA-I l) and stimulated by anti-CD3 antibody.
  • Splenocytes from C57BL/6 mice were pre-incubated with various concentrations of compounds (0.5-50 ⁇ M) for 3hrs and then transferred to the 96-well plates (2x10 5 cells/well) coated with anti-CD3 antibodies (0.2 g/ml, UCHTl, Pharmingen). Splenocytes were further incubated for 96hrs. [3H]thymidine (Amersham Pharmacia Biotech) (0.5 ⁇ Ci) was added to each well, and plates were harvested after an additional 18hrs of culture. Incorporation of [3H] thymidine into DNA was measured by luminometer counter (PerkinElmer).
  • 1,4-Diphenyl- l,3-dihydro-imidazole-2-thione (IA-I l) and derivatives thereof , i.e., [ 1 -(4-Methoxy-phenyl)-2-thioxo-2,3-dihydro- 1 H-imidazol-4-yl]-pyrrolidin- 1 -yl-met hanone (IA-83) and 4-(4- Amino-phenyl)- 1 -phenyl- l,3-dihydro-imidazole-2-thione
  • C57BL/6 (H-2b) splenocytes IxIO 5 cells/100 ⁇ £/well were cultured with ⁇ -irradiated (800 rads) (Gammacell 3000 Elan, MDS Nordion, Canata, Ontario, Canada) Balb/C (H-2d) splenocytes (1x10 5 cells/ 100 ⁇ -C/well) in 96-well microplates.
  • Example 12 Measurement of in vivo inhibitory effect of 1,4-diphenyl -l,3-dihydro-imidazole-2-thione (IA-I l) and derivatives thereof on T cell activation
  • SUBSTITUTE SHEET (RULE 26) Vehicle group was administered orally with 0.2% carboxymethylcellulose only. T cells were activated by intravenous inoculation of anti-CD3 antibody (125ng/100 ⁇ £/mouse). After two hours from anti-CD3 injection, mice were bled via cardiac puncture, and the serum was collected and assayed for IL-2 by ELISA (BD biosciences, San Diego).
  • IA-I l 1, 4-diphenyl-l,3-dihydro-imidazole-2-thione
  • vehicle-treated group showed IL-2 level of 600-900 pg/ml
  • mice treated with l,4-diphenyl-l,3-dihydro-imidazole-2-thione (IA-I l) showed much reduced IL-2 level in a dose-dependent manner.
  • the ED 50 of IA-I l and IA29 for inhibition of anti-CD3-induced IL-2 production was 10 mg/kg and IL-2 production was suppressed 98% at 90 mg/kg (Fig. 3).
  • cyclosporine A As a positive control, cyclosporine A, a currently used immunosuppressant, was used and cyclosporine A showed ED 50 of less than 10 mg/kg.
  • Example 13 Measurement of in vivo inhibitory effect of l,4-diphenyl-l,3-dihydro-imidazole-2-thione (IA-I l) and derivatives thereof on DTH response
  • mice were immunized intradermally with 400 ⁇ g of methylated bovine serum albumin (mBSA, Sigma) in a 1 : 1 emulsion with complete Freund's adjuvant (Difco, Detroit, MI).
  • Mice were administered orally with l,4-diphenyl-l,3-dihydro-imidazole-2-thione (IA-I l) or cyclosporine A from day -1 to day 8 on a daily basis.
  • mice were challenged in one hind footpad with 100 ⁇ g of mBSA in 20 ⁇ Jl of PBS and in the opposite footpad with
  • Example 14 Measurement of in vivo inhibitory effect of 1,4-diphenyl -l,3-dihydro-imidazole-2-thione (IA-11) and derivatives thereof on EAE
  • mice were immunized s.c. at four sites on the flank, with a total of 100 ⁇ g of MOG 35 -. 55 peptide emulsified in an equal volume of CFA (Difco, Detroit, MI) containing 1 mg/ml Mycobacterium tuberculosis H37 RA (Difco, Detroit, MI) on day 0.
  • CFA Disco, Detroit, MI
  • Mycobacterium tuberculosis H37 RA Difco, Detroit, MI
  • Mice also received i.v. injections of 400 ng of pertussis toxin (List Biological Laboratories, Campbell, CA) on days 0 and 2 after immunization.
  • mice were administered orally with 1, 4-diphenyl-l,3-dihydro-imidazole-2-thione (IA-I l) and derivatives thereof in 0.2% CMC from day 0 to day 30 on a daily basis.
  • Clinical signs were daily monitored and scored based on following criteria: 0, no detectable signs of disease; 0.5, distal limp tail; 1, complete limp tail; 1.5, limp tail and hind limb weakness; 2, unilateral partial hind paralysis; 2.5, bilateral hind limb paralysis; 3, complete bilateral hind limb paralysis; 3.5, complete bilateral hind limb paralysis and unilateral forelimb; 4, total paralysis of fore and hind limbs; and
  • Example 15 Measurement of in vivo inhibitory effect of l,4-diphenyl-l,3-dihydro-imidazole-2-thione(IA-l l) on MOG-specific T cell proliferation in EAE
  • SUBSTITUTE SHEET (RULE 26) to determine if l,4-diphenyl-l,3-dihydro-imidazole-2-thione(IA-l l) inhibits MOG-specific T cell response, draining lymph node (DLN) cells were isolated from vehicle or l,4-diphenyl-l,3-dihydro-imidazole-2-thione(IA-l l)-treated mice and determined for MOG-dependent T cell response in the absence of l,4-diphenyl-l,3-dihydro-imidazole-2-thione(IA-l l).
  • DNN draining lymph node
  • DLN cells auxiliary and inguinal were isolated and cultured with 25/ig/ml of MOG 35 _ 55 peptide for 96hrs in 96-well flat-bottom plates at a concentration of 5 x 10 5 cells/well in complete RPMI 1640 medium (Life Technologies) containing 10% heat-inactivated FCS (Fetal Calf Serum), ImM glutamine, 1% penicillin-streptomycin, 1 mM nonessential amino acids, and 5 x 10 "5 M 2-ME ( ⁇ -mercaptoethanol). Cells were pulsed with [ 3 H]thymidine (Amersham Pharmacia Biotech) at 0.5 ⁇ Ci/well for the final 18 hrs before harvest.
  • DLN cells isolated from vehicle-treated mice showed strong MOG-specific T cell proliferation.
  • DLN cells collected from l,4-diphenyl-l,3-dihydro-imidazole-2-thione (IA-l l)-treated mice did not or weakly respond to MOG, suggesting that MOG-specific T cell activation was efficiently inhibited in vivo (FIG. 6).

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Abstract

La présente invention concerne des composés de formule IA ou IB. L'invention concerne également un procédé pour traiter des maladies immunologiques ou des états pathologiques associés aux lymphocytes T présentant une composante immunologique au moyen d'inhibiteurs des lymphocytes T, éventuellement en combinaison avec un ou plusieurs autres médicaments choisis parmi les stéroïdes, les ARMM, les AINS, les immunodépresseurs et les modificateurs biologiques, des compositions pharmaceutiques comprenant lesdits composés de formule IA ou IB en combinaison avec lesdits autres médicaments, ainsi que l'utilisation d'inhibiteurs des lymphocytes T pour fabriquer une composition pharmaceutique pour le traitement de maladies immunologiques ou d'états pathologiques à composante immunologique.
PCT/KR2008/000195 2007-01-11 2008-01-11 Composés inhibant les lymphocytes t et leur utilisation pour le traitement de maladies à médiation par les lymphocytes t Ceased WO2008085008A1 (fr)

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WO2014152115A1 (fr) 2013-03-15 2014-09-25 Monsanto Technology Llc Azoles n,c-disubstitués de lutte contre les nématodes nuisibles
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US9907306B2 (en) 2010-09-02 2018-03-06 Monsanto Technology Llc Compositions and methods for controlling nematode pests
WO2018056855A1 (fr) * 2016-09-23 2018-03-29 BIAL - PORTELA & Cª, S.A. Inhibiteurs de la dopamine-b-hydroxylase
CN108101856A (zh) * 2018-01-10 2018-06-01 河南农业大学 酰基取代吡嗪类化合物的制备方法
WO2019112457A1 (fr) * 2017-12-04 2019-06-13 BIAL - PORTELA & Cª, S.A. Inhibiteurs de dopamine-b-hydroxylase
US10369353B2 (en) 2008-11-11 2019-08-06 Medtronic, Inc. Seizure disorder evaluation based on intracranial pressure and patient motion
CN111662235A (zh) * 2020-06-23 2020-09-15 黄淮学院 一种苯甲酰基哒嗪衍生物及其制备方法

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US10369353B2 (en) 2008-11-11 2019-08-06 Medtronic, Inc. Seizure disorder evaluation based on intracranial pressure and patient motion
US12036401B2 (en) 2008-11-11 2024-07-16 Medtronic, Inc. Seizure detection algorithm adjustment
US10543359B2 (en) 2008-11-11 2020-01-28 Medtronic, Inc. Seizure detection algorithm adjustment
US9717439B2 (en) 2010-03-31 2017-08-01 Medtronic, Inc. Patient data display
US9907306B2 (en) 2010-09-02 2018-03-06 Monsanto Technology Llc Compositions and methods for controlling nematode pests
US9763449B2 (en) 2013-03-15 2017-09-19 Monsanto Technology Llc N-,C-disubstituted azoles and compositions and methods for controlling nematode pests
WO2014152115A1 (fr) 2013-03-15 2014-09-25 Monsanto Technology Llc Azoles n,c-disubstitués de lutte contre les nématodes nuisibles
EP2967065A4 (fr) * 2013-03-15 2016-08-24 Monsanto Technology Llc Azoles n,c-disubstitués de lutte contre les nématodes nuisibles
US10398144B2 (en) 2013-03-15 2019-09-03 Monsanto Technology Llc N-,C-disubstituted azoles and compositions and methods for controlling nematode pests
CN103436254A (zh) * 2013-08-19 2013-12-11 中国科学院合肥物质科学研究院 一种功能化多元氮杂环荧光探针、其制备方法及其用途
CN109715633A (zh) * 2016-09-23 2019-05-03 巴尔-波特拉及康邦亚股份有限公司 多巴胺-β-羟化酶抑制剂
US10975083B2 (en) 2016-09-23 2021-04-13 Bial—Portela & Ca, S.A. Blood-brain barrier-penetrant dopamine-β-hydroxylase inhibitors
US11034695B2 (en) 2016-09-23 2021-06-15 BIAL—Portela & Cᵃ, S.A. Dopamine-β-hydroxylase inhibitors
AU2017330175B2 (en) * 2016-09-23 2022-02-17 BIAL - PORTELA & Cª, S.A. Dopamine-β-hydroxylase inhibitors
WO2018056855A1 (fr) * 2016-09-23 2018-03-29 BIAL - PORTELA & Cª, S.A. Inhibiteurs de la dopamine-b-hydroxylase
WO2019112457A1 (fr) * 2017-12-04 2019-06-13 BIAL - PORTELA & Cª, S.A. Inhibiteurs de dopamine-b-hydroxylase
US11434242B2 (en) 2017-12-04 2022-09-06 Bial—Portela & Ca, S.A. Dopamine-b-hydroxylase inhibitors
CN108101856A (zh) * 2018-01-10 2018-06-01 河南农业大学 酰基取代吡嗪类化合物的制备方法
CN111662235A (zh) * 2020-06-23 2020-09-15 黄淮学院 一种苯甲酰基哒嗪衍生物及其制备方法
CN111662235B (zh) * 2020-06-23 2023-12-22 黄淮学院 一种苯甲酰基哒嗪衍生物及其制备方法

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