DE4028678A1 - TRICYCLIC COMPOUNDS CONTAINING HETEROATOMES, METHOD FOR THEIR PRODUCTION AND THEIR USE - Google Patents
TRICYCLIC COMPOUNDS CONTAINING HETEROATOMES, METHOD FOR THEIR PRODUCTION AND THEIR USEInfo
- Publication number
- DE4028678A1 DE4028678A1 DE19904028678 DE4028678A DE4028678A1 DE 4028678 A1 DE4028678 A1 DE 4028678A1 DE 19904028678 DE19904028678 DE 19904028678 DE 4028678 A DE4028678 A DE 4028678A DE 4028678 A1 DE4028678 A1 DE 4028678A1
- Authority
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- Germany
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- formula
- compounds
- tricyclic compounds
- heteroatomes
- production
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- 150000001875 compounds Chemical class 0.000 title claims description 31
- 238000000034 method Methods 0.000 title claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 4
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 4
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 3
- 210000001185 bone marrow Anatomy 0.000 abstract description 3
- 238000011282 treatment Methods 0.000 abstract description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
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- 229910052720 vanadium Inorganic materials 0.000 description 3
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- 241000699670 Mus sp. Species 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- -1 dichloromethane Chemical class 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000028996 humoral immune response Effects 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
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- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die Erfindung betrifft Heteroatome enthaltende tricyclische Verbindungen der FormelThe invention relates to tricyclic compounds of the formula containing heteroatoms
worin R₁ für eine gegebenenfalls geschützte Hydroxygruppe, R₂ für Methyl, Ethyl, n-Propyl oder Allyl und R₃ für Methoxy oder Hydroxy stehen, Verfahren zu ihrer Herstellung und ihre Verwendung.wherein R₁ for an optionally protected hydroxy group, R₂ for methyl, ethyl, n-propyl or allyl and R₃ are methoxy or hydroxy, processes for their preparation and their Use.
Erfindungsgemäß gelangt man zu den Verbindungen der Formel I, indem manAccording to the invention, the compounds of the formula I are obtained by
- a) Verbindungen der Formel worin R₁, R₂ und R₃ obige Bedeutung besitzen, oxidiert odera) Compounds of the formula wherein R₁, R₂ and R₃ have the above meaning, oxidized or
- b) zur Herstellung von Verbindungen der Formel worin R₂ und R₃ obige Bedeutung besitzen, Verbindungen der Formel worin R₂ und R₃ obige Bedeutung besitzen und R für eine Schutzgruppe steht, nach an sich bekannten Methoden entschützt.b) for the preparation of compounds of the formula wherein R₂ and R₃ have the above meaning, compounds of the formula wherein R₂ and R₃ have the above meaning and R represents a protective group, deprotected by methods known per se.
Die erfindungsgemäße Verfahrensvariante a) kann beispielsweise ausgeführt werden, indem man eine Verbindung der Formel II mit N-Methylmorpholin in einem unter den Reaktionsbedingungen inerten Lösungsmittel, z. B. in einem chlorierten Kohlenwasserstoff wie Dichlormethan, unter einer Inertgasatmosphäre, z. B. unter Argon, mit Molekularsieb rührt und dann Tetrapropylammoniumperruthenat zusetzt. Nach Beendigung der Reaktion, die vorteilhafterweise bei Raumtemperatur durchgeführt wird, kann das Reaktionsgemisch nach an sich bekannten Methoden aufgearbeitet werden.Process variant a) according to the invention can be carried out, for example, by a compound of formula II with N-methylmorpholine in one under the reaction conditions inert solvents, e.g. B. in a chlorinated hydrocarbon such as dichloromethane, under an inert gas atmosphere, e.g. B. under argon, stirred with molecular sieve and then tetrapropylammonium perruthenate adds. After completion of the reaction, which advantageously at Is carried out at room temperature, the reaction mixture according to methods known per se be worked up.
Die Abspaltung der Schutzgruppe nach Verfahrensvariante b) kann nach einer der verwendeten Schutzgruppe entsprechenden bekannten Methode durchgeführt werden. Beispielsweise kann sie im Falle der t.Butyldimethylsilylgruppe durch Behandeln mit HF in einem Lösungsmittel, z. B. in Acetonitril erfolgen.The protective group can be split off according to process variant b) according to one of the methods used Protecting group according to known method. For example in the case of the t.butyldimethylsilyl group, it can be treated with HF in a solvent, e.g. B. in acetonitrile.
Die als Ausgangsprodukte benötigten Verbindungen der Formel II können erhalten werden, indem manThe compounds of the formula II required as starting products can be obtained by one
- a) Verbindungen der Formel worin R₁, R₂ und R₃ obige Bedeutung besitzen, mit Vanadiumoxyacetylacetonat und anschließend mit t.Butylhydroperoxid behandelt odera) Compounds of the formula wherein R₁, R₂ and R₃ have the above meaning, treated with vanadium oxyacetylacetonate and then with t-butyl hydroperoxide or
- b) zur Herstellung von Verbindungen der Formel worin R₂ und R₃ obige Bedeutung besitzen, Verbindungen der Formel worin R für eine Schutzgruppe steht und R₂ und R₃ obige Bedeutung besitzen, nach an sich bekannten Methoden entschützt.b) for the preparation of compounds of the formula wherein R₂ and R₃ have the above meaning, compounds of the formula wherein R stands for a protective group and R₂ and R₃ have the above meaning, deprotected by methods known per se.
Die Verfahrensvariante a) kann beispielsweise ausgeführt werden, indem man eine Verbindung der Formel III in einem unter den Reaktionsbedingungen inerten Lösungsmittel, z. B. in einem chlorierten Kohlenwasserstoff wie Dichlormethan, mit Vanadiumoxyacetylacetonat und anschließend bei vorzugsweise tiefer Temperatur, z. B. bei etwa 0°C, mit t.Butylhydroperoxid behandelt. Nach üblicher Aufarbeitung erhält man ein Diastereomerengemisch, das nach an sich bekannten Methoden, z. B. chromatographisch, aufgetrennt werden kann.Process variant a) can be carried out, for example, by making a connection of formula III in an inert solvent under the reaction conditions, for. B. in one chlorinated hydrocarbon such as dichloromethane, with vanadium oxyacetylacetonate and then at preferably low temperature, e.g. B. at about 0 ° C, with t.Butylhydroperoxid treated. After the usual work-up, a mixture of diastereomers is obtained, which after known methods, e.g. B. can be separated chromatographically.
Die Abspaltung der Schutzgruppe kann wie bei der erfindungsgemäßen Verfahrensvariante b) beschrieben durchgeführt werden.The protective group can be split off, as in the process variant b) according to the invention described.
Die übrigen als Ausgangsprodukte benötigten Verbindungen sind bekannt oder können nach bekannten Methoden bzw. analog wie in den Beispielen beschrieben hergestellt werden.The other compounds required as starting products are known or can be based on known methods or analogously as described in the examples.
Die Verbindungen der Formel I besitzen interessante pharmakologische Eigenschaften und können daher als Heilmittel verwendet werden. Insbesondere zeigen sie immunosuppressive und antiinflammatorische Wirkung. Die immunosuppressive Wirkung zeigt sich z. B. in vitro durch die Hemmung der Allogen-stimulierten Hyperproliferation von Lymphozyten (MLR = mixed lymphocyte reaction) sowie in der Unterdrückung der primären humoralen Immunantwort gegen Schaferythrozyten. In vitro konnte auch eine Hemmung des Keratinozytenwachstums festgestellt werden, was die Verbindungen der Formel I als antiproliferative Substanzen ausweist. Die immunosuppressive Wirkung zeigt sich in vivo in den Modellen Graft versus host- Reaktion und der Hypersensitivität der Maus gegen Schaferythrozyten. Die antiinflammatorische Wirkung läßt sich an Modellen einer allergischen Dermatitis an Maus und Schwein zeigen.The compounds of formula I have interesting pharmacological properties and can therefore be used as a remedy. In particular, they show immunosuppressive and anti-inflammatory effect. The immunosuppressive effect shows z. B. in vitro by inhibiting the allogen-stimulated hyperproliferation of lymphocytes (MLR = mixed lymphocyte reaction) and in suppressing the primary humoral immune response against sheep erythrocytes. Inhibition of keratinocyte growth was also possible in vitro be determined what identifies the compounds of formula I as antiproliferative substances. The immunosuppressive effect is shown in vivo in the models graft versus host Response and hypersensitivity of the mouse to sheep erythrocytes. The anti-inflammatory Effect can be shown in models of allergic dermatitis in mice and pigs.
Diese Wirksamkeit können mit den folgenden Testmethoden nachgewiesen werden:This effectiveness can be demonstrated using the following test methods:
Der Test wird wie in der Literatur beschrieben durchgeführt: T. Meo (1979): The MLR in the mouse. In "Immunological Methods", L. Lefkovits and B. Pernis, Eds., Acad. Press, N.Y., S. 227-239. Die Verbindungen der Formel I zeigen in diesem Test eine Suppression (IC50) bei einer Dosis von etwa 0,09 bis etwa <0,0008 µg/ml.The test is carried out as described in the literature: T. Meo (1979): The MLR in the mouse. In "Immunological Methods", L. Lefkovits and B. Pernis, Eds., Acad. Press, N.Y., S. 227-239. The compounds of formula I show suppression (IC50) in this test a dose of about 0.09 to about <0.0008 µg / ml.
Der Test wird wie in der Literatur beschrieben durchgeführt: R. I. Mishell, R. W. Dutton: Immunization of normal mouse spleen cell suspensions in vitro, Science 153/1004-1006 (1966); R. I. Mishell, R. W. Dutton: Immunization of dissociated spleen cell cultures from normal mice, J. Exp. Med. 126/423-442 (1967). Die Verbindungen der Formel I sind in diesem Test in einer Konzentration von etwa 0,32 bis etwa 0,0024 µg/ml aktiv (IC50).The test is carried out as described in the literature: R.I. Mishell, R.W. Dutton: Immunization of normal mouse spleen cell suspensions in vitro, Science 153 / 1004-1006 (1966); R.I. Mishell, R. W. Dutton: Immunization of dissociated spleen cell cultures from normal mice, J. Exp. Med. 126 / 423-442 (1967). The compounds of formula I are in one in this test Concentration from about 0.32 to about 0.0024 µg / ml active (IC50).
Dieser Test wird analog wie in der EP 3 15 978 beschrieben ausgeführt. Die Verbindungen der Formel I hemmten in Konzentrationen von 1 bis 10 µg/ml das Keratinozytenwachstum von etwa 30 bis etwa 90%.This test is carried out analogously to that described in EP 3 15 978. The connections of the Formula I inhibited keratinocyte growth by about 1 to 10 µg / ml 30 to about 90%.
Dieser Test wird analog, wie bei F. M. Dietrich und R. Hess in Int. Arch. Allergy 38/246-259 (1970) beschrieben, durchgeführt. Die Verbindungen der Formel I zeigen in diesem Test eine Hemmung der entzündlich bedingten Schwellung von etwa 15% bis etwa 68% bei topischer Verabreichung in einer Konzentration von 0,01%.This test is analogous to that of F. M. Dietrich and R. Hess in Int. Arch. Allergy 38 / 246-259 (1970). The compounds of formula I show one in this test Inhibition of inflammatory swelling from about 15% to about 68% in topical Administration at a concentration of 0.01%.
Dieser Test wird analog wie in der EP 3 15 978 beschrieben ausgeführt. Zweimalige topische Applikation von 1,2%igen Bereitungen der Verbindungen der Formel I führten zu einer Hemmung der entzündlichen Reaktion von 36 bis 40%.This test is carried out analogously to that described in EP 3 15 978. Twice topical Application of 1.2% preparations of the compounds of formula I led to an inhibition the inflammatory response of 36 to 40%.
Die Verbindungen der Formel I sind daher für die Behandlung und Vorbeugung der Resistenz bei Transplantationen von Organen und Geweben wie Herz, Niere, Leber, Knochenmark, Haut usw., von Graft-versus-Host Erkrankungen bei Knochenmarktransplantationen, Autoimmunerkrankungen wie Rheumatoider Arthritis, Systemischer Lupus erythematodes, Hashomotos Thyroiditis, Multiple Sklerose, Myasthenia gravis, Typ I Diabetes, Uveitis usw., sowie für die Therapie von entzündlichen und hyperproliferativen Hauterkrankungen, wie Psoriasis, atopischer Dermatitis, Kontakt-Dermatitis und anderen ekzematösen Dermatitiden, seborrhoeischer Dermatitis, Lichen planus, Pemphigus, bullosem Pemphigoid, Epidermolysis bullosa, Urticaria, Angioödemen, Vaskulitiden, Erythemen, kutanen Eosinophilien, Lupus erythermatodes, Akne, sowie von Alopecia areata geeignet. Die Verbindungen können topisch oder systemisch verabreicht werden.The compounds of formula I are therefore for the treatment and prevention of resistance for transplants of organs and tissues such as heart, kidney, liver, bone marrow, skin etc., from graft versus host diseases in bone marrow transplants, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, hashomotos Thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis etc., as well as for the Therapy of inflammatory and hyperproliferative skin diseases, such as psoriasis, atopic Dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoeic Dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, Urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythermatodes, Acne and alopecia areata. The compounds can be topical or systemic be administered.
Für die oben angeführten Verwendungsmöglichkeiten hängt die zu verabreichende Dosis von der verwendeten Verbindung, der Verabreichungsart sowie der Behandlungsart ab. Man erhält bei größeren Säugetieren zufriedenstellende Ergebnisse bei mehrmals täglicher lokaler Verabreichung einer 1- bis 3%igen Wirkstoffkonzentration, z. B. 2- bis 5mal täglich. Beispiele von geeigneten galenischen Formen sind Lotionen, Gele oder Cremen. Für systemische Anwendung kann die Tagesdosis etwa 0,15 mg/kg bis etwa 1,5 mg/kg Körpergewicht betragen. Für größere Säuretiere, z. B. für den Menschen, liegt die tägliche Dosis im Bereich von etwa 0,01 mg bis etwa 100 mg und kann gewünschtenfalls in bis zu vier Teildosen täglich oder in Retardform verabreicht werden.For the uses listed above, the dose to be administered depends on the compound used, the mode of administration and the type of treatment. You get in larger mammals, satisfactory results with local administration several times a day a 1 to 3% concentration of active ingredient, e.g. B. 2 to 5 times a day. Examples of suitable galenic forms are lotions, gels or creams. For systemic use the daily dose can be about 0.15 mg / kg to about 1.5 mg / kg body weight. For larger acidic animals, e.g. B. for humans, the daily dose is in the range of about 0.01 mg up to about 100 mg and can, if desired, be taken in up to four divided doses daily or in sustained release form be administered.
Die Verbindungen der Formel I besitzen auch die Wirksamkeit, die Wirkung und/oder Sensitivität anderer chemotherapeutischer Mittel zu erhöhen bzw. zu verstärken. Sie können daher dazu eingesetzt werden, um die regulären Dosishöhen zu vermindern, beispielsweise bei der antineoplastischen und cytostatischen Therapie, wodurch auch die allgemeine Toxizität gesenkt werden kann. Diese Wirkung wurde in Tests nachgewiesen, die in der EP 3 60 760 beschrieben sind.The compounds of the formula I also have the activity, the activity and / or sensitivity increase or increase other chemotherapeutic agents. So you can can be used to reduce the regular dose levels, for example at the antineoplastic and cytostatic therapy, which also lowers overall toxicity can be. This effect has been demonstrated in tests described in EP 3 60 760 are.
Ein weiterer Teil der Erfindung sind pharmazeutische Zusammensetzungen für obige topische Verwendung, enthaltend eine Verbindung der Formel I in freier Form oder in Form eines pharmazeutisch verträglichen Salzes, zusammen mit pharmazeutisch verträglichen Träger- oder Verdünnungsmitteln.Another part of the invention are pharmaceutical compositions for the above topical Use containing a compound of formula I in free form or in the form of a pharmaceutical compatible salt, together with pharmaceutically acceptable carrier or Thinners.
In den nachfolgenden Beispielen, die die Erfindung näher erläutern, ihren Umfang jedoch in keiner Weise einschränken sollen, erfolgen alle Temperaturangaben in Celsiusgraden.In the following examples, which explain the invention in more detail, however, its scope in should not restrict in any way, all temperatures are given in degrees Celsius.
In den Beispielen werden die folgenden Verbindungen durch Kurzbezeichnungen dargestellt:In the examples, the following connections are represented by short names:
Eine Lösung von 300 mg 33-t.Butyldimethylsilyloxy-22(S)-dihydro-19,20-oxiran-FR 520 (Diastereomeres A) und 57 mg N-Methylmorpholinoxid in 20 ml Dichlormethan wird unter Argon bei Raumtemperatur mit 100 mg 4A Molekularsieb gerührt. Dann werden 15 mg Tetrapropylammoniumperruthenat zugesetzt. Die grün/schwarze Reaktionsmischung wird bei Raumtemperatur 1 Stunde gerührt und anschließend im Vakuum konzentriert. Der Rückstand wird in Ethylacetat aufgenommen, durch ein Silicagelbett filtriert, mit weiteren 500 ml Ethylacetat eluiert, im Vakuum eingedampft und mittels Silicagelchromatographie (Toluol/Ethylacetat: Gradient 5/1→4/1) gereinigt. Man erhält die Titelverbindung als farblosen amorphen Feststoff.A solution of 300 mg of 33-t-butyldimethylsilyloxy-22 (S) -dihydro-19.20-oxirane-FR 520 (Diastereomer A) and 57 mg of N-methylmorpholine oxide in 20 ml of dichloromethane is made under argon stirred at room temperature with 100 mg 4A molecular sieve. Then 15 mg of tetrapropylammonium perruthenate added. The green / black reaction mixture is at room temperature Stirred for 1 hour and then concentrated in vacuo. The backlog will taken up in ethyl acetate, filtered through a bed of silica gel, with a further 500 ml of ethyl acetate eluted, evaporated in vacuo and by means of silica gel chromatography (toluene / ethyl acetate: Gradient 5/1 → 4/1) cleaned. The title compound is obtained as a colorless amorphous solid.
Ausgehend vom Diastereomeren B verfährt man analog wie in Beispiel 1 beschrieben und erhält die Titelverbindung als farblosen amorphen Feststoff.Starting from diastereomer B, the procedure is analogous to that described in Example 1 and receives the title compound as a colorless amorphous solid.
65 mg 33-t.Butyldimethylsilyloxy-22(S)-dihydro-24-oxo-19,20-oxiran-FR 520 (Diastereomeres A) werden mit 1 ml eines Gemisches von Acetonitril/HF (95/5) bei Raumtemperatur behandelt. Nach 15 Minuten wird das Reaktionsgemisch mit Diethylether verdünnt, nacheinander mit gesättigter wäßriger NaHCO₃-Lösung und gesättigter wäßriger NaCl-Lösung gewaschen, die Etherphase über Na₂SO₄ getrocknet, im Vakuum konzentriert und der Rückstand chromatographisch (Toluol/Aceton = 1,5/1) gereinigt. Man erhält so die Titelverbindung als farblosen amorphen Feststoff.65 mg 33-t-butyldimethylsilyloxy-22 (S) -dihydro-24-oxo-19.20-oxirane-FR 520 (diastereomer A) with 1 ml of a mixture of acetonitrile / HF (95/5) at room temperature treated. After 15 minutes, the reaction mixture is diluted with diethyl ether, one after the other washed with saturated aqueous NaHCO₃ solution and saturated aqueous NaCl solution, the ether phase dried over Na₂SO₄, concentrated in vacuo and the residue purified chromatographically (toluene / acetone = 1.5 / 1). The title compound is thus obtained as colorless amorphous solid.
Ausgehend vom Diastereomeren B verfährt man analog wie in Beispiel 3 beschrieben und erhält die Titelverbindung als farblosen amorphen Feststoff.Starting from diastereomer B, the procedure is analogous to that described in Example 3 and receives the title compound as a colorless amorphous solid.
Das als Ausgangsprodukt benötigte 33-t.Butyldimethylsilyloxy-22(S)-dihydro-19,20-oxiran- FR 520 kann folgendermaßen erhalten werden.The 33-t-butyldimethylsilyloxy-22 (S) -dihydro-19,20-oxirane required as the starting product FR 520 can be obtained as follows.
12,04 g 33-t.Butyldimethylsilyloxy-22(S)-dihydro-FR 520 in 500 ml trockenem Dichlormethan werden mit 240 mg Vanadiumoxyacetylacetonat versetzt. Die grüne Lösung wird auf 0° gekühlt und dann mit 7,8 ml einer 3 M Lösung von t.Butylhydroperoxid in Toluol behandelt. Die nun rote Lösung wird auf Raumtemperatur erwärmen gelassen; nach 3 Stunden wird mit Wasser gewaschen, die organische Phase mit Na₂SO₄ getrocknet, filtriert und unter Vakuum konzentriert. Der Rückstand wird in ca. 50 ml Ethylacetat gelöst, durch ein Silicagelbett filtriert und mit ca. 500 ml Ethylacetat eluiert. Nach Konzentration unter Vakuum wird der Rückstand mittels Silicagelchromatographie (Toluol/Aceton: Gradient 6/1→3/1) gereinigt. Man erhält einen Hauptanteil an Diastereomeren A, als Nebenprodukt das Diastereomere B als farblose amorphe Feststoffe.12.04 g 33-t-butyldimethylsilyloxy-22 (S) -dihydro-FR 520 in 500 ml dry dichloromethane 240 mg of vanadium oxyacetylacetonate are added. The green solution is cooled to 0 ° and then treated with 7.8 ml of a 3 M solution of t-butyl hydroperoxide in toluene. The red one now Solution is allowed to warm to room temperature; after 3 hours it is washed with water, the organic phase dried with Na₂SO₄, filtered and concentrated under vacuum. The residue is dissolved in about 50 ml of ethyl acetate, filtered through a bed of silica gel and washed with about 500 ml of ethyl acetate eluted. After concentration under vacuum, the residue is purified by silica gel chromatography (Toluene / acetone: gradient 6/1 → 3/1). You get a major part on diastereomers A, as a by-product, diastereomers B as colorless amorphous solids.
Spektrum
Beispiel
1 Rotamerengemisch ca. 6 : 1
(CDCl₃) Hauptrotameres: 5.32 (d, J = 4 Hz, H-26); 5.18 (d, J = 9 Hz, H-29); 4.42 (d, br,
J- 13 Hz, H-6e); 4.39 (d, J = 4 Hz, H-2); 4.31 (d, J = 10 Hz, H-22); 3.21 (dd,
J₁ = 10 Hz, J₂ = 18 Hz, H-23); 2.58 (dd, J₁ = 1 Hz, J₂ = 18 Hz, H-23′); 2.77 (d, J = 9 Hz,
H-20); 0.08 und 0.07 (s, Si.CH₃).spectrum
example
1 mixture of rotamers approx. 6: 1
(CDCl₃) major rotamer: 5.32 (d, J = 4 Hz, H-26); 5.18 (d, J = 9 Hz, H-29); 4.42 (d, br, J- 13 Hz, H-6e); 4.39 (d, J = 4 Hz, H-2); 4.31 (d, J = 10 Hz, H-22); 3.21 (dd, J₁ = 10 Hz, J₂ = 18 Hz, H-23); 2.58 (dd, J₁ = 1 Hz, J₂ = 18 Hz, H-23 ′); 2.77 (d, J = 9 Hz, H-20); 0.08 and 0.07 (s, Si.CH₃).
2 Rotamerengemisch ca. 6 : 1
(CDCl₃) Hauptrotameres: 5.32 (d, J = 4 Hz, H-26); 5.18 (d, J = 9 Hz, H-29); 4.42 (d, br,
J = 13 Hz, H-6e); 4,40 (H-2); 4,14 (d, J = 10 Hz, H-22); 3.66 (d, J = 9 Hz, H-14); 3.21
(dd, J₁ = 8 Hz, J₂ = 11 Hz, H-23); 2.63 (dd, J₁ = 1Hz, J₂ = 18 Hz, H-23′); 2.81 (d, J = 9 Hz,
H-20); 1.56 (d, J = 1 Hz, 28-CH₃); 1.32 (s, 19-CH₃); 0.90 (s, t.Butyl); 0.08 und 0.07
(s, Si.CH₃).2 Rotamer mixture approx. 6: 1
(CDCl₃) major rotamer: 5.32 (d, J = 4 Hz, H-26); 5.18 (d, J = 9 Hz, H-29); 4.42 (d, br, J = 13 Hz, H-6e); 4.40 (H-2); 4.14 (d, J = 10 Hz, H-22); 3.66 (d, J = 9 Hz, H-14); 3.21 (dd, J₁ = 8 Hz, J₂ = 11 Hz, H-23); 2.63 (dd, J₁ = 1Hz, J₂ = 18 Hz, H-23 ′); 2.81 (d, J = 9 Hz, H-20); 1.56 (d, J = 1 Hz, 28-CH₃); 1.32 (s, 19-CH₃); 0.90 (s, t.Butyl); 0.08 and 0.07 (s, Si.CH₃).
3 Rotamerengemisch ca. 5 : 1
(CDCl₃/CH₃OD = 8/1) 4.44 (H-2); 5.32 (d, J = 4 Hz, H-26); 5.19 (d, J = 9 Hz, H-29); 4.40 (d, br, J = 13 Hz,
H-6e); 4.32 (d, J = 11 Hz, H-22); 3.25 (dd, J₁ = 11 Hz, J₂ = 18 Hz, H-23); 2.55 (dd,
J₁ = 1 Hz, J₂ = 18 Hz, H-23′); 2.97 (dq, J₁ = 4 Hz, J₂ = 7 Hz, H-25); 2.80 (d, J = 9 Hz, H-20).3 mixture of rotamers approx. 5: 1
(CDCl₃ / CH₃OD = 8/1) 4.44 (H-2); 5.32 (d, J = 4 Hz, H-26); 5.19 (d, J = 9 Hz, H-29); 4.40 (d, br, J = 13 Hz, H-6e); 4.32 (d, J = 11 Hz, H-22); 3.25 (dd, J₁ = 11 Hz, J₂ = 18 Hz, H-23); 2.55 (dd, J₁ = 1 Hz, J₂ = 18 Hz, H-23 ′); 2.97 (dq, J₁ = 4 Hz, J₂ = 7 Hz, H-25); 2.80 (d, J = 9 Hz, H-20).
4. Rotamerengemisch ca. 6 : 1
(CDCl₃/CH₃OD = 8/1) 5.32 (d, J = 4 Hz, H-26); 5.29 (d, J = 9 Hz, H-29); 4.14 (d, J = 10 Hz, H-22); 3.18 (dd, J₁ =
10 Hz, J₂ = 18 Hz, H-23); 2.64 (dd, J₁ = 1 Hz, J₂ = 18 Hz, H-23′); 2.82 (d, J = 9 Hz, H-20).4. Rotamer mixture approx. 6: 1
(CDCl₃ / CH₃OD = 8/1) 5.32 (d, J = 4 Hz, H-26); 5.29 (d, J = 9 Hz, H-29); 4.14 (d, J = 10 Hz, H-22); 3.18 (dd, J₁ = 10 Hz, J₂ = 18 Hz, H-23); 2.64 (dd, J₁ = 1 Hz, J₂ = 18 Hz, H-23 ′); 2.82 (d, J = 9 Hz, H-20).
a) Rotamerengemisch ca. 2 : 1
Diastereomeres A Hauptrotameres: 4.19 (H-2); 5.21 (s, H-26); 5.15 (d, J = 9 Hz, H-29);
4.43 (d, br, J = 13 Hz, H-6e); ca. 4.05 (H-24); ca. 3.85 (m, H-22); 2.55
(d, J = 9 Hz, H-20); 0.09 und 0.08 (s, Si.CH₃).
Nebenrotameres: 5.78 (d, br, J = 5 Hz, H-2); 5.16 (s, H-26); 5.00 (d,
J = 9 Hz, H-29); ca. 4.0 (H-24); ca. 3.85 (m, H-22); 2.60 (d, J = 8 Hz, H-20).a) Rotamer mixture approx. 2: 1
Major diastereomer A: 4.19 (H-2); 5.21 (s, H-26); 5.15 (d, J = 9 Hz, H-29); 4.43 (d, br, J = 13 Hz, H-6e); about 4.05 (H-24); about 3.85 (m, H-22); 2.55 (d, J = 9 Hz, H-20); 0.09 and 0.08 (s, Si.CH₃).
Minor rotamer: 5.78 (d, br, J = 5 Hz, H-2); 5.16 (s, H-26); 5.00 (d, J = 9 Hz, H-29); about 4.0 (H-24); about 3.85 (m, H-22); 2.60 (d, J = 8 Hz, H-20).
Spektrum
Beispiel
2 213.3 (C-24), 198.6 (C-9); 169.5 (C-1); 165.9 (C-8); 134.6 (C-29); 128.5
(C-28); 99.2 (C-10); 69.7 (C-22); 62.4 (C-20); 59.9 (C-19).spectrum
example
2,213.3 (C-24), 198.6 (C-9); 169.5 (C-1); 165.9 (C-8); 134.6 (C-29); 128.5 (C-28); 99.2 (C-10); 69.7 (C-22); 62.4 (C-20); 59.9 (C-19).
3 213.2 (C-24), 198.4 (C-9); 169.5 (C-1); 166.4 (C-8); 134.2 (C-29); 129.3 (C-28); 99.4 (C-10); 66.5 (C-22); 63.4 (C-20); 60.6 (C-19).3,213.2 (C-24), 198.4 (C-9); 169.5 (C-1); 166.4 (C-8); 134.2 (C-29); 129.3 (C-28); 99.4 (C-10); 66.5 (C-22); 63.4 (C-20); 60.6 (C-19).
Claims (2)
- a) Verbindungen der Formel worin R₁, R₂ und R₃ obige Bedeutung besitzen, oxidiert oder
- b) zur Herstellung von Verbindungen der Formel worin R₂ und R₃ obige Bedeutung besitzen, Verbindungen der Formel worin R₂ und R₃ obige Bedeutung besitzen und R für eine Schutzgruppe steht, nach an sich bekannten Methoden entschützt.
- a) Compounds of the formula wherein R₁, R₂ and R₃ have the above meaning, oxidized or
- b) for the preparation of compounds of the formula wherein R₂ and R₃ have the above meaning, compounds of the formula wherein R₂ and R₃ have the above meaning and R represents a protective group, deprotected by methods known per se.
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0777488A4 (en) * | 1994-09-28 | 2000-09-27 | Univ Jefferson | A COMPOSITION AND METHOD FOR ALLOGENEOUS MONONUCLEAR CELL IMMUNOTHERAPY |
| US6472225B1 (en) | 1994-09-28 | 2002-10-29 | Thomas Jefferson University | Composition and method for allogeneic mononuclear cell immunotherapy |
-
1990
- 1990-09-10 DE DE19904028678 patent/DE4028678A1/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0777488A4 (en) * | 1994-09-28 | 2000-09-27 | Univ Jefferson | A COMPOSITION AND METHOD FOR ALLOGENEOUS MONONUCLEAR CELL IMMUNOTHERAPY |
| US6472225B1 (en) | 1994-09-28 | 2002-10-29 | Thomas Jefferson University | Composition and method for allogeneic mononuclear cell immunotherapy |
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