WO1996030381A1 - Agents immunodepresseurs - Google Patents
Agents immunodepresseurs Download PDFInfo
- Publication number
- WO1996030381A1 WO1996030381A1 PCT/DK1996/000124 DK9600124W WO9630381A1 WO 1996030381 A1 WO1996030381 A1 WO 1996030381A1 DK 9600124 W DK9600124 W DK 9600124W WO 9630381 A1 WO9630381 A1 WO 9630381A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxy
- hydrogen
- ethyl
- methyl
- alkyl
- Prior art date
Links
- 239000003018 immunosuppressive agent Substances 0.000 title description 9
- 229940125721 immunosuppressive agent Drugs 0.000 title description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 72
- 239000001257 hydrogen Substances 0.000 claims abstract description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 64
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 54
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 37
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims abstract description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 21
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 21
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 21
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 20
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- -1 hydroxy, methyl Chemical group 0.000 claims abstract description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 210000000987 immune system Anatomy 0.000 claims abstract description 13
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 56
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 29
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 29
- 208000023275 Autoimmune disease Diseases 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 238000002054 transplantation Methods 0.000 claims description 11
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 8
- 208000024908 graft versus host disease Diseases 0.000 claims description 8
- 210000000056 organ Anatomy 0.000 claims description 8
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 8
- 201000004624 Dermatitis Diseases 0.000 claims description 7
- 206010012442 Dermatitis contact Diseases 0.000 claims description 7
- 208000010247 contact dermatitis Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 6
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- 239000002552 dosage form Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
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- 230000008629 immune suppression Effects 0.000 claims description 5
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- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 1
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical class NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 36
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 28
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 28
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 28
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
Definitions
- the present invention relates to ⁇ -amino amide derivatives which are useful for treating ailments related to the immune system.
- the present invention involves suppression of an immune response in a patient in need of such suppression. Immunosuppression is desired for patients having certain diseases or medical procedures, including trans ⁇ plant graft versus host disease, autoimmune disease and inflammatory skin diseases. Methods for preparing such immunosuppressive com- pounds and pharmaceutical compositions containing them are disclosed.
- therapies for autoimmune diseases are comprised of therapies that are more or less general for all autoimmune diseases, aimed at the immunological processes or the following inflammatory cascade, and therapies that are specific for a particular disease. Often a combination of disease-specific and -general treatments are supplementary to each other. Examples of therapies that are disease-specific are bronchodilators for asthma, surgical removal of the synovium in rheumatoid arthritis, and insulin for type I diabetes.
- the therapies for autoimmune diseases in general are nonsteroidal antiinflammatory drugs (NSAID) aimed at the inflammatory cascade (Azathioprine, Methotrexate, Cyclophosphamide) that, among other tissues, inhibits proliferation of cells of the immune system; immune suppressants, including so-called disease-modifying drugs (Chloroquine, Gold, D-Penicillamin); Glucocorticosteroids, and specific immune suppressants (Cyclosporin A, Tacrolimus (FK 506) and Rapamycin).
- NSAIDs have no effect on the cause of the underlying diseases, and often is used only to alleviate pain.
- the cytotoxic therapies are associated with severe side-effects, and are thus not attractive for treating non-malignant diseases.
- the disease modifying drugs often fail to completely control the diseases, and are associated with potentially severe side-effects, such as retinopathy, thrombo- and granulocytopenia. Prolonged use of Glucocorticosteroids may lead to a Cushing-like s ⁇ n- drome.
- Cyclosporin A Unfortunately also has side-effects that make it less attractive for long time treatment of autoimmune diseases.
- side-effects of Cyclosporin A one of the most serious is interstitial fibrosis of the kidneys, which can lead to kidney failure.
- Tacrolimus (FK 506) and Rapamycin have not been used extensively clinically yet, but have the same receptor as Cyclosporin A, and is thus thought also to have the interstitial fibrosis side-effects, too.
- Serine palmitoyl transferase inhibitors can be used therapeutically in any medical condition where systemic or local immune suppression is clinical ⁇ ly warranted.
- autoimmune diseases such as rheumatoid arthritis, systemic sclerosis, Sj ⁇ grens syndrom, inflammatory bowel disease, and inflammatory skin diseases including psoriasis, atopic dermatitis, and contact dermatitis.
- diseases of obscure pathogenesis with involvement of the immune system such as Sarcoidosis and Wegener's gramelomatosis.
- lymphomas and leukemias may be inhibited by serine palmitoyl transferase inhibitors, inasmuch as the proliferating cells in these diseases usually are lymphocytes.
- R 1 is hydrogen or C*,. 3 -alkyl, optionally substituted with hydroxy
- R 2 is hydrogen, straight or branched C*,. ⁇ -alkyl, or straight or branched
- R 1 and R 2 forms a optionally mono-, di or tri- substituted in any position with hydroxy
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl,
- R 8 is methano or ethano
- R 4 is C,. 20 -alkyl, optionally substituted in any position with oxo, hydroxy, methyl or ethyl,
- R 5 and R ⁇ are hydrogen or hydroxy
- R 7 is hydrogen or hydroxy
- R 2 is methano or ethano
- R 10 is C,. 20 -alkyl, optionally substituted in any position with oxo, hydroxy, methyl or ethyl,
- R 11 and R 12 are hydrogen or hydroxy, or pharmaceutically acceptable salts thereof.
- Physiologically and pharmaceutically acceptable salts of the compounds of the invention include acid addition salts formed with inorganic or organic acids, for example acetates, hydrochlorides, hydrobromides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maleates, succinates, and sulphonates, e.g., mesylates. If desirable, selected salts may be subjected to further purification by recrystallization.
- the invention includes within its scope all optical isomers of compounds of the general formula I and their mixtures including racemic mixtures thereof. 381 PCIYDK96/00124
- Preferred compounds of the invention are compounds of the following formulas:
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl or either
- R 8 is methano or ethano and R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl, octadecyl, nonadecyl or icosyl or R 3 is -R 8 -(CR 5 R 6 )-R 4 wherein R 8 is methano or ethano, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentade
- R 5 is hydrogen or hydroxy
- R ⁇ is hydrogen or hydroxy
- R 5 is hydrogen or hydroxy and R 6 is hydrogen or hydroxy
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl or either
- R 8 is methano or ethano and R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl, octadecyl, nonadecyl or icosyl or R 3 is -R 8 -(CR 5 R 6 )-R 4 wherein R 8 is methano or ethano, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentade
- R s is hydrogen or hydroxy and R ⁇ is hydrogen or hydroxy
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl or either
- R 8 is methano or ethano and R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl, octadecyl, nonadecyl or icosyl or R 3 is -R 8 -(CR 5 R ⁇ )-R 4 wherein R 8 is methano or ethano, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, oct ⁇ l, nonyl, decyl, undecyl, dodecyl,
- R 5 is hydrogen or hydroxy
- R ⁇ is hydrogen or hydroxy
- R ⁇ is hydrogen or hydroxy
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl or either
- R 8 is methano or ethano and R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl, octadecyl, nonadecyl or icosyl or R 3 is -R 8 - ⁇ CR 5 R ⁇ )-R 4 wherein R 8 is methano or ethano, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, penta
- R 5 is hydrogen or hydroxy
- R ⁇ is hydrogen or hydroxy
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl or either
- R 8 is methano or ethano and R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl, octadecyl, nonadecyl or icosyl or R 3 is -R 8 -(CR 5 R ⁇ )-R 4 wherein R 8 is methano or ethano, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,
- R 5 is hydrogen or hydroxy
- R ⁇ is hydrogen or hydroxy
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl or either
- R 8 is methano or ethano and R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl, octadecyl, nonadecyl or icosyl or R 3 is -R 8 -(CR 5 R ⁇ )-R 4 wherein R 8 is methano or ethano, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,
- R 5 is hydrogen or hydroxy
- R ⁇ is hydrogen or hydroxy
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl or either
- R 8 is methano or ethano and R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl, octadecyl, nonadecyl or icosyl or R 3 is -R 8 -(CR 5 R ⁇ )-R 4 wherein R 8 is methano or ethano, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, penta
- R 5 is hydrogen or hydroxy
- R ⁇ is hydrogen or hydroxy
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl or either
- R 8 is methano or ethano and R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl, octadecyl, nonadecyl or icosyl or R 3 is -R 8 -(CR 5 R ⁇ )-R 4 wherein R 8 is methano or ethano, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,
- R 5 is hydrogen or hydroxy
- R ⁇ is hydrogen or hydroxy
- R 3 is hydrogen, methyl, ethyl, vinyl, iso-propyl, allyl or either
- R 8 is methano or ethano and R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl, octadecyl, nonadecyl or icosyl or R 3 is -R 8 -(CR R ⁇ )-R 4 wherein R 8 is methano or ethano, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentade
- R 5 is hydrogen or hydroxy and R ⁇ is hydrogen or hydroxy, or pharmaceutically acceptable salts thereof.
- the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of ailments related to the immune system.
- the invention also relates to the use of the inventive com ⁇ pounds of formula (I) as medicaments useful for treating ailments related to the immune system such as transplantation of bone marrow or other organs and graft versus host disease, autoimmune diseases such as rheumatoid arthritis, systemic sclerosis, Sj ⁇ grens syndrom, inflammatory bowel disease, and inflammatory skin diseases including psoriasis, atopic dermatitis, and contact dermatitis.
- autoimmune diseases such as rheumatoid arthritis, systemic sclerosis, Sj ⁇ grens syndrom, inflammatory bowel disease, and inflammatory skin diseases including psoriasis, atopic dermatitis, and contact dermatitis.
- the invention relates to l-cycloserine, in particular (R)- 4-amino-3-isoxazolidinone, and to enactin-derivatives and neoenactin- derivatives as described in Yamamoto et al; J. of Antibiotics, vol. 43, 1012, 1990, in particular the structures EN-la, EN-lb*,, EN-lb 2 , EN-IVa, EN-IVb, EN-Va, EN-Vb, EN-VIa, NE-NL-,, NE-NL 2 and EN-Vlb of Fig. 1 , p.
- the invention also relates to the use of l-cycloserine , neoenactin-derivatives and enactin-derivatives as medicaments useful for treating ailments related to the immune system such as transplantation of bone marrow or other organs and graft versus host disease, auto ⁇ immune diseases such as rheumatoid arthritis, systemic sclerosis, Sj ⁇ grens syndrom, inflammatory bowel disease, and inflammatory skin diseases including psoriasis, atopic dermatitis, and contact dermatitis.
- auto ⁇ immune diseases such as rheumatoid arthritis, systemic sclerosis, Sj ⁇ grens syndrom, inflammatory bowel disease, and inflammatory skin diseases including psoriasis, atopic dermatitis, and contact dermatitis.
- the invention relates to a method of preparing compounds of formula I.
- the procedure involves the following 3 steps:
- An ⁇ -amino acid having proper protecting groups is coupled to an O-protected hydroxylamine.
- the ⁇ -amino acid is preferably purchased from a commercial source, having proper protecting groups and an activated carbonyl group.
- the ⁇ -amino acid is synthesized by standard procedures or minor modifica ⁇ tions thereof.
- the carboxylic acid is activated with standard reagents used in peptide synthesis.
- the coupling is carried out directly using reagents such as DCC (1 ,3 dicyclohexylcarbodiimide) or other standard procedures normally applied in peptide synthesis.
- reagents such as DCC (1 ,3 dicyclohexylcarbodiimide) or other standard procedures normally applied in peptide synthesis.
- the O-protected hydroxylamine should preferably be O-Benzyl- hydroxylamine.
- the resultant hydroxamate is alkylated using a reactive electrophilic reagent of the desired composition.
- the reactive electrophilic group can be a monohalogenated alkyl such as Br-CH 2 -R.
- the reaction can be carried out in acetone ⁇ K 2 CO 3 using Kl as catalyst.
- R can be a broad defined composition with suitable protection of possible functional groups.
- the reaction could be carried out in eg. refluxing benzene or dioxane using eg. Potassium ferf-butoxide as catalyst.
- R can be a broad defined composition with suitable protection of possible functional groups.
- the introduced alkyl moiety can be of the type: -CH 2 -CH 2 -CO-R.
- the ketone functionality could subsequently be reduced using eg. NaBH 4 to generate a mixture of the corresponding R and S hydroxy functionality.
- the preferred O-benzyl group from the hydroxamic acid is removed eg. by stirring in an ethanol solution containing a pal ⁇ ladium on activated charcoal catalyst under an atmosphere of hydrogen.
- a desired hydroxylamine derivative is prepared (NH 2 -O-R).
- a derivative of hydroxylamine having suitable protection of the aminogroup (Prot-NH-OH) is purchased from a commercial source or prepared by standard procedures.
- the free hydroxy group is subsequently alkylated using a reactive electrophilic reagent of the desired composition.
- the reactive electrophilic group could be monohalogenated alkyl such as Br-CH 2 -R.
- reaction could be carried out in acetone ⁇ K 2 CO 3 using Kl as catalyst.
- R could be a broad defined composition with suitable protection of possible functional groups.
- reaction could be carried out in eg. refluxing benzene or dioxane using eg. Potassium ferf-butoxide as catalyst.
- R could be a broad defined composition with suitable protection of possible functional groups.
- H 2 C CH-CO-R could be prepared from eg. HOOC-R through 2 steps:
- the introduced alkyl moiety would be of the type: -CH 2 -CH 2 -
- the ketone functionality could subsequently be reduced using eg. NaBH 4 to generate a mixture of the corresponding R and S hydroxy functionality.
- the ⁇ -amino acid is preferably purchased from an commercial source carrying proper protecting groups and an activated carbo- nylgroup.
- the ⁇ -amino acid is synthesized by standard procedures or minor modifica ⁇ tions thereof.
- the carboxylic acid is activated with standard reagents used in peptide synthesis. Eg. forming N-Hydroxysuccinimide or O-Nitro-phenyl esters, which eventually will enable coupling of the carbonyl function to a hydroxylamin derivative (NH 2 -O-R).
- the coupling is carried out directly using reagents such as DCC (1 ,3 dicyclohexylcarbodiimide) or other standard procedures normally applied in peptide synthesis.
- reagents such as DCC (1 ,3 dicyclohexylcarbodiimide) or other standard procedures normally applied in peptide synthesis.
- MNC mononuclear cells
- Peripheral venous blood was drawn (using 1 U/ml heparin as an anticoagulant) from normal healthy adult volunteers tested negative for HIV and Hepatitis B. After dilution 1 : 1 with Phosphate buffered isotonic saline (PBS) pH 7.4 the blood was layered on Ficoll-Hypaque ® (Pharma ⁇ cia, Discataway, NJ) and centrifuged at 300xg for 35 minutes. The interphase containing the MNC was removed, and the cells washed three times in PBS supplemented by 2% (v/v) fetal bovine serum (FBS) (GIBCO, Grand Island, NY). The MNC were resuspended in Dulbecco's
- Modified Eagle's Medium DMEM supplemented with 10% (v/v) FBS, antibiotics, and 2 mM l-Glutamine, which was then used as medium for the described experiments.
- Test substance stocks were dissolved in methanol as follows: Myriocin (1 mg/ml), Compound FWR6107 (100 g/ml), Dihydrosphingosine (Calbiochem, La Jolla, CA); (10 mg/ml) and stored at -20°C. I-Cyclose- rine (SIGMA, St. Louis, MO) was prepared at 0.1 M in PBS.
- PHA Phytohemagglutinin
- SEB Staphy- lococcal Enterotoxin B
- PMA Phorbol 12 Myristate 13 Acetate
- MNC One hundred thousand MNC were seeded per well in 96-well U-botto- med microtiter wells.
- the test substances were added to the wells at varying concentrations.
- the dilutions of the test substances were made in medium containing corresponding amounts of stock solvent to ensure that the final methanol concentration was the same in all wells, including the control wells without test substance.
- the mitogen PHA or SEB was added to a final concentration of 1 ⁇ g/ml; lonomycin to 100nM; and PMA to 3 g/ml. Final volume was 200 ⁇ in all wells.
- the plates were incubated at 37°C, 5% CO2, 100% relative humidity for four days. Sixteen hours before harvest 0.5 ⁇ C ⁇ 3H-thymidine, specific activity 25 Ci/mmol (Amersham, Arlington Heights, ILL), was added to each well. The cells were harvested onto filter mats using a
- Myriocin inhibited proliferation of mononuclear cells in response to PHA, and this inhibitory effect was attenuated by Dihydrosphingosine.
- Myriocin inhibited the proliferative response of MNC to PHA (Fig. 1 , dotted line, squares) to about half of the control. At 2.5 pg/ml the inhibition was approximately 50% (Fig.1 ).
- the inhibitory activity of myriocin towards MNC proliferation may therefore be due to inadequate cellular levels of sphingolipids, which are the end product of sphinoglipid de novo synthesis.
- An intermediary of that pathway, Dihydrosphingosine can attenuate the inhibitory activity of myriocin.
- dihydrosphingosine can attenuate the inhibitory activity of myriocin.
- the inhibition was attenuated to approximately 25% (Fig. 1 , line, diamonds).
- Myriocin also inhibited the proliferation of a mixed lymphocyte reaction (data not shown), as well as MNC stimulated by 100 nM lonomycin and 3 g/ml PMA (Fig. 2), demonstrating that the observed inhibition by myriocin is not due to interference of myriocin with the PHA.
- Compound FWR6107 inhibited proliferation of MNC.
- the IC50 of three indepen ⁇ dent experiments was 131 ⁇ 33 nM (Average ⁇ SD).
- SEB Fig. 4
- PMA a combination of lonomycin and PMA
- Compound FWR6107 inhibits the activity of the enzyme Serine Palmitoyl Transferase.
- DHS Dihydrosphingosine
- concentrations of DHS were not increased further due to toxicity of the DHS.
- l-Cycloserine inhibited proliferation of MNC in response to PHA.
- I-Cyclo- serine reported to be an inhibitor of serine palmitoyl transferase, inhibited proliferation of MNC in response to PHA (Fig. 7).
- the compounds of the invention may be placed into the form of pharmaceutical compo ⁇ sitions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
- the compounds of the invention may be formulated in creams or ointments for topical administration on skin and mucous membranes including the mouth.
- the compounds of the invention may also be formulated as liquid for topical application preferably in the conjunctiva.
- Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- Tablets containing one (1 ) milligram of active ingredient or, more broad ⁇ ly, one (1 ) to thirty (30) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
- the compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral, topical and parenteral admini ⁇ stration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
- Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
- Such carriers are water, salt solutions, alcohols, polyethy ⁇ lene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid jesters, hydroxymethylcellu- lose and polyvinylpyrrolidone.
- the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
- auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
- injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
- the compounds described in the present application may also be formu ⁇ lated to be used topically on skin or mucous membranes including the mouth.
- the preferred concentration of the compounds is from 0.00001 % to 1 % (w/w), a particularly preferred concentration range from 0.001 % to 0.5% and a most preferred concentration range of
- a vehicle of ointments, salves, gels, emulsions or the like formulated by a person skilled in the art of pharmaceutical formula ⁇ tion may be applied topically from once to several times daily.
- Optimal dosage regimen may be investigated in a mouse model of contact dermatitis using topical sensitization with haptens such as DNCB and subsequent challenge.
- Ampoules are convenient unit dosage forms.
- tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
- a syrup, elixir or like can be used when a sweetened vehicle can be employed.
- the compound of the inven- tion is dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
- a typical tablet which may be prepared by conventional tabletting tech ⁇ niques contains:
- Cyclosporin A is a compound that inhibits T-lymphocyte activation after binding to immunophilins in cells.
- Immunophylins are present in many cell types, so even though the inhibition of T-cell activation by Cyclosporin A is fairly specific, it is distributed to many other cell types. Cyclosporin A is lipophilic. Serine palmitoyl transferase is present in most cells like the receptor for Cyclosporin A cyclophylin and serine palmitoyl transferase inhibitors are expected to be lipophilic like Cyclosporin A. Therefore, the in vitro - jn vivo correlate may be similar for Cyclosporin A and serine palmitoyl transferase inhibitors. Preferred clinically used doses of the claimed compounds would be from 0.0001 mg/kg/day to 50 mg/kg/day.
- More particularly preferred dose range is 0.001 mg/kg/day to 25 mg/kg/day and most particularly preferred dose range is 0.01 mg/ kg/day to 10 mg/kg/day. Should the in vitro activity of the claimed compounds be more potent than FWR6107, correspondingly lower doses may be required clinically.
- the frequency of compound dosing may be from 3 times a day to once weekly, depending on the pharmacological pro- perties of the specific compound and the formulation used.
- mice Several animal models can be used to demonstrate efficacy and to investigate optimal dosage regimens.
- transplantation one of the most commonly used animal models is rejection of skin allotransplants in mice.
- graft-versus-host disease a commonly used model is injection intravenously of allogenic mononuclear cells in mice sublethally irradiated with gamma-rays.
- BB-rat and NOD mice for type I diabetes, Experimental allergicencephalitis for Multiple Sclerosis, Adjuvant Arthritis in Lewis rats, and Collagen induced Arthritis in rats or mice for Rheumatoid Arthritis; NZB mice and MRL-lpr/lpr mice for lupus erythematosus; and the like.
- serine palmitoyl transferase inhibitors may be administered at doses up to 50 mg/kg/day from 1 -2 days prior to the transplantation until 2 weeks after the transplantation, the period in which the initial priming of the host immune system to the transplant antigens is at its peak. Later the doses may be decreased to a chronic use dose level comparable to that used in the autoimmune diseases described below.
- the doses of serine palmitoyl transferase inhibitors given will be up to 50 mg/kg/day, while the dose given for maintenance therapy may be at the lower end of the anticipated dose range 0.001 mg/kg/day - 25 mg/kg/day.
- the particular doses given in the individual patient will depend upon clinical (e.g. neurological, joint swelling) and paraclinical (e.g. acute phase reactants in serum, kidney function tests) parameters and will vary with time in the same patient according to the clinical course of the disease.
- Sphingolipids are one of the major constituents of the central nervous system (CNS).
- CNS related side-effects such as headache, tremor, convulsions may arise from use of serine palmitoyl transferase inhibitors, an in particular with chronic use.
- molecular modifications of the compound claimed in this application, that are aimed at decreasing the availability of the compound to the CNS may diminish these anticipated side-effects.
- reaction mixture is filtered and the solvent removed by evaporation under reduced pressure.
- 13 C (CDCI 3 ): 166.1 (s,CO-N), 136.5 (s), 133.3 (s), 129.4 (d), 128.2 (d,2C), 128.9 (d,2C), 128.5 (d,2C), 128.1 (d), 127.8 (d,2C), 76.9 (t,CH 2 -O), 73.3 (t,CH 2 -O), 66.1 (t,CH 2 -O), 52.5 (d, ⁇ -CH), 45.8 (t,CH 2 -N),
- the catalyst is removed by filtration and the solvent evaporated to give 80 mg of a clear oil.
- the titled compound FWR6107 crystallized as needles from CHCI 3 and was harvested by filtration. This saltform of FWR6107 is still to be determined, but is most likely the zwitter-ion or the triflouracetic acid salt.
- the CHCI 3 extract is filtered (1 1 ml filtrate) and 1 1 ml 0,2 M H 2 SO 4 is added while stirring.
- IR (KBr powder): 3310, 3120, 2920, 2845, 1630, 1480, 1 1 15, 1080 cm '1 .
- IR spectra were recorded using a Perkin Elmer FTIR model 1600.
- PDMS data were recorded using a Bioion 20.
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Abstract
La présente invention concerne des dérivés d'amino amide représentés par la formule générale (I) ou certains de leurs sels pharmaceutiquement acceptables, lesquels dérivés et sels conviennent au traitement des affections touchant au système immunitaire. Dans cette formule générale (I) qui peut prendre la forme (Ia) ou (Ib), R1 représente hydrogène ou alkyle C¿1?-C3 éventuellement substitué par hydroxy, R?2¿ représente hydrogène, alkyle C¿1?-C6 droit ou ramifié, ou alkyle C1-C6 droit ou ramifié substitué par un, deux ou trois groupes hydroxy en une position quelconque ou R?1 et R2¿ forment un groupe cycloalkyle C¿4?-C6 éventuellement substitué par un, deux ou trois groupes hydroxy en une position quelconque. R?3¿ représente hydrogène, méthyle, éthyle, vinyle, iso-propyle, allyle, -R8-(C=O)-R?4 ou -R8-(CR5R6)-R4, R8¿ représente méthano ou éthano, R4 représente alkyle C¿1?-C20, éventuellement substitué en une position quelconque par oxo, hydroxy, méthyle ou éthyle, R?5 et R6¿ représentent hydrogène ou hydroxy. R7 représente hydrogène ou hydroxy. R9 représente méthyle, éthyle, vinyle, iso-propyle, allyle, -R13-(C=O)-R?10 ou -R13-(CR11R12)-R10, où R13¿ représente méthano ou éthano, R10 représente alkyle C¿1?-C20, éventuellement substitué en une position quelconque par un groupe oxo, hydroxy, méthyle ou éthyle, R?11 et R12¿ représentent hydrogène ou hydroxy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU50021/96A AU5002196A (en) | 1995-03-28 | 1996-03-27 | Immunosuppressive agents |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK0322/95 | 1995-03-28 | ||
| DK32295 | 1995-03-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996030381A1 true WO1996030381A1 (fr) | 1996-10-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/DK1996/000124 WO1996030381A1 (fr) | 1995-03-28 | 1996-03-27 | Agents immunodepresseurs |
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| Country | Link |
|---|---|
| AU (1) | AU5002196A (fr) |
| WO (1) | WO1996030381A1 (fr) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999037298A1 (fr) * | 1998-01-21 | 1999-07-29 | The Regents Of The University Of Michigan | Compositions et methodes pour le traitement de maladies auto-immunes |
| EP1379679A4 (fr) * | 2001-03-20 | 2004-12-08 | Ortho Mcneil Pharm Inc | Procede de mesure de la serine palmitoyltransferase dans un tissu mammalien et son utilisation |
| WO2008084300A1 (fr) * | 2006-12-20 | 2008-07-17 | Pfizer Products Inc. | Inhibiteurs de la sérine palmitoyl-transférase |
| EP2583678A2 (fr) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Immunopotentiateurs de petites molécules et dosages pour leur détection |
| WO2015166094A1 (fr) * | 2014-04-30 | 2015-11-05 | Syngenta Participations Ag | Procédé de préparation de cyclosérines substituées |
| CN109734680A (zh) * | 2018-12-27 | 2019-05-10 | 南京红杉生物科技有限公司 | 一种d-环丝氨酸合成的方法 |
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| DE3907649A1 (de) * | 1988-03-09 | 1989-09-28 | Biorex Kft | Arzneimittel, geeignet bei der bekaempfung von viren und der immunstimulierung |
| DE4114236A1 (de) * | 1991-04-26 | 1992-10-29 | Zentralinstitut Fuer Organisch | Verfahren zur herstellung von substituierten glycinamiden sowie deren salzen und derivaten |
| WO1994002447A1 (fr) * | 1992-07-23 | 1994-02-03 | British Biotech Pharmaceuticals Limited | Derives d'acide hydroxamique en tant qu'inhibiteurs de metalloproteinase |
| US5302609A (en) * | 1992-12-16 | 1994-04-12 | The Regents Of The University Of Michigan | Treatment of diabetic nephropathy |
| WO1994021625A1 (fr) * | 1993-03-16 | 1994-09-29 | British Biotech Pharmaceuticals Limited | Derives d'acide hydroxamique utilises comme inhibiteurs de metalloproteinase |
| WO1995017418A2 (fr) * | 1993-12-22 | 1995-06-29 | The Coca-Cola Company | NOUVEAUX INTERMEDIAIRES POUR LA SYNTHESE D'AMIDES DE L-ASPARTYL-D-α-AMINOALCANOYL-(S)-N-α-ALKYLBENZYLE UTILES EN TANT QU'EDULCORANTS ARTIFICIELS |
| WO1995032944A1 (fr) * | 1994-05-28 | 1995-12-07 | British Biotech Pharmaceuticals Limited | Acide succinyle hydroxamique, acide n-formyl-n-hydroxy amino carboxylique et derives amides de l'acide succinique en tant qu'inhibiteurs des metalloproteases |
| WO1996006074A1 (fr) * | 1994-08-20 | 1996-02-29 | British Biotech Pharmaceuticals Limited | Inhibiteurs de metalloproteinases |
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1996
- 1996-03-27 WO PCT/DK1996/000124 patent/WO1996030381A1/fr active Application Filing
- 1996-03-27 AU AU50021/96A patent/AU5002196A/en not_active Abandoned
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| DE3907649A1 (de) * | 1988-03-09 | 1989-09-28 | Biorex Kft | Arzneimittel, geeignet bei der bekaempfung von viren und der immunstimulierung |
| DE4114236A1 (de) * | 1991-04-26 | 1992-10-29 | Zentralinstitut Fuer Organisch | Verfahren zur herstellung von substituierten glycinamiden sowie deren salzen und derivaten |
| WO1994002447A1 (fr) * | 1992-07-23 | 1994-02-03 | British Biotech Pharmaceuticals Limited | Derives d'acide hydroxamique en tant qu'inhibiteurs de metalloproteinase |
| US5302609A (en) * | 1992-12-16 | 1994-04-12 | The Regents Of The University Of Michigan | Treatment of diabetic nephropathy |
| WO1994021625A1 (fr) * | 1993-03-16 | 1994-09-29 | British Biotech Pharmaceuticals Limited | Derives d'acide hydroxamique utilises comme inhibiteurs de metalloproteinase |
| WO1995017418A2 (fr) * | 1993-12-22 | 1995-06-29 | The Coca-Cola Company | NOUVEAUX INTERMEDIAIRES POUR LA SYNTHESE D'AMIDES DE L-ASPARTYL-D-α-AMINOALCANOYL-(S)-N-α-ALKYLBENZYLE UTILES EN TANT QU'EDULCORANTS ARTIFICIELS |
| WO1995032944A1 (fr) * | 1994-05-28 | 1995-12-07 | British Biotech Pharmaceuticals Limited | Acide succinyle hydroxamique, acide n-formyl-n-hydroxy amino carboxylique et derives amides de l'acide succinique en tant qu'inhibiteurs des metalloproteases |
| WO1996006074A1 (fr) * | 1994-08-20 | 1996-02-29 | British Biotech Pharmaceuticals Limited | Inhibiteurs de metalloproteinases |
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| STN INTERNATIONAL, File CAPLUS, CAPLUS Accession No. 1995:339184, MIYAKE YURIKA et al., "Action Mechanism of Sphingosine-Like Immunosuppressant, ISP-1"; & IGAKU NO AYUMI, (1994), 171(12/13), 921-5. * |
| THE JOURNAL OF ANTIBIOTICS, Volume 47, No. 3, March 1994, SUZANNE M. MANDALA et al., "Inhibition of Serine Palmitoyltransferase Activity by Lipoxamycin", page 376-379. * |
| THE JOURNAL OF ANTIBIOTICS, Volume XLIII, No. 8, August 1990, KATSUMI YAMAMOTO et al., "A New Group of Antibiotics, Hydroxamic Acid Antimycotic Antibiotics, III Isolation and Characterization of Enactin Congeners", pages 1012-1017. * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999037298A1 (fr) * | 1998-01-21 | 1999-07-29 | The Regents Of The University Of Michigan | Compositions et methodes pour le traitement de maladies auto-immunes |
| EP1379679A4 (fr) * | 2001-03-20 | 2004-12-08 | Ortho Mcneil Pharm Inc | Procede de mesure de la serine palmitoyltransferase dans un tissu mammalien et son utilisation |
| EP2583678A2 (fr) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Immunopotentiateurs de petites molécules et dosages pour leur détection |
| WO2008084300A1 (fr) * | 2006-12-20 | 2008-07-17 | Pfizer Products Inc. | Inhibiteurs de la sérine palmitoyl-transférase |
| WO2015166094A1 (fr) * | 2014-04-30 | 2015-11-05 | Syngenta Participations Ag | Procédé de préparation de cyclosérines substituées |
| US9643938B2 (en) | 2014-04-30 | 2017-05-09 | Syngenta Participations Ag | Process for the preparation of substituted cycloserines |
| US9815803B2 (en) | 2014-04-30 | 2017-11-14 | Syngenta Participations Ag | Process for the preparation of substituted cycloserines |
| CN109734680A (zh) * | 2018-12-27 | 2019-05-10 | 南京红杉生物科技有限公司 | 一种d-环丝氨酸合成的方法 |
| CN109734680B (zh) * | 2018-12-27 | 2021-10-29 | 南京红杉生物科技有限公司 | 一种d-环丝氨酸合成的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5002196A (en) | 1996-10-16 |
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