DE10303669A1 - New quaternary ammonioalkyl carbonate esters useful for treating bacterial and fungal infections and potentially useful for regulating cholesterol biosynthesis - Google Patents
New quaternary ammonioalkyl carbonate esters useful for treating bacterial and fungal infections and potentially useful for regulating cholesterol biosynthesis Download PDFInfo
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- DE10303669A1 DE10303669A1 DE2003103669 DE10303669A DE10303669A1 DE 10303669 A1 DE10303669 A1 DE 10303669A1 DE 2003103669 DE2003103669 DE 2003103669 DE 10303669 A DE10303669 A DE 10303669A DE 10303669 A1 DE10303669 A1 DE 10303669A1
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- Prior art keywords
- methyleneoxycarbonyloxy
- iodide
- androsten
- triethylammonium
- atoms
- Prior art date
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- 150000004649 carbonic acid derivatives Chemical class 0.000 title abstract 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title description 4
- 208000031888 Mycoses Diseases 0.000 title description 2
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 235000012000 cholesterol Nutrition 0.000 title description 2
- 208000035143 Bacterial infection Diseases 0.000 title 1
- 206010017533 Fungal infection Diseases 0.000 title 1
- 230000001580 bacterial effect Effects 0.000 title 1
- 208000022362 bacterial infectious disease Diseases 0.000 title 1
- 230000001105 regulatory effect Effects 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- -1 3-12C alkynyl Chemical group 0.000 claims abstract description 15
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims abstract description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims abstract description 3
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- INLFWQCRAJUDCR-LYLBMTSKSA-N spirostane Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CCCCC4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 INLFWQCRAJUDCR-LYLBMTSKSA-N 0.000 claims abstract description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- XEWVCDMEDQYCHX-UHFFFAOYSA-N n,n-diethylethanamine;hydron;iodide Chemical compound [I-].CC[NH+](CC)CC XEWVCDMEDQYCHX-UHFFFAOYSA-N 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 9
- 150000005621 tetraalkylammonium salts Chemical class 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 150000004651 carbonic acid esters Chemical class 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 claims description 4
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 229920002866 paraformaldehyde Polymers 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- KXZTYEDTIVFJMB-UHFFFAOYSA-N [I-].C(#CC)[NH3+] Chemical compound [I-].C(#CC)[NH3+] KXZTYEDTIVFJMB-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 150000001649 bromium compounds Chemical group 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- HUKPSOLHZPASDU-UHFFFAOYSA-N n,n-dipropylpropan-1-amine;hydroiodide Chemical compound [I-].CCC[NH+](CCC)CCC HUKPSOLHZPASDU-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- AUQMPMUASLJUGD-UHFFFAOYSA-N prop-1-enylazanium iodide Chemical compound [I-].CC=C[NH3+] AUQMPMUASLJUGD-UHFFFAOYSA-N 0.000 claims description 2
- JIHRCSHIQCFSPM-UHFFFAOYSA-N prop-2-ynylazanium;iodide Chemical compound [I-].[NH3+]CC#C JIHRCSHIQCFSPM-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 2
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 claims description 2
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract 2
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 150000003863 ammonium salts Chemical class 0.000 description 3
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229940107816 ammonium iodide Drugs 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 229940127226 anticholesterol agent Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 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 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Die Erfindung betrifft Tetraalkylammoniumsalze
vom Kohlensäureestertyp
der allgemeinen Formel I, 
A= ein Trägermolekül bestehend
aus anellierten Ringen, das aus zwei und mehr Ringen, auch Spirostanen
(mit 3 bis 7-C-Atomen), oder ein Kohlenwasserstoffrest 
mit m= 5 bis 24,
n= 1 bis 3,
R1=
H oder Methyl,
R2, R3 und R4 = Alkyl (mit 1 bis 12 C-Atomen),
Cycloalkyl (mit 2 bis 8 C-Atomen),
Alkenyl (mit 3 bis 12 C-Atomen), Cycloalkenyl (mit 4 bis 8 C-Atomen),
Alkinyl (mit 3 bis 12 C-Atomen), Aralkyl (mit Alkyl von 1 bis 4
C-Atomen), Alkyloxymethyl (mit Alkyl von 1 bis 4) Hydroxyethyl,
Hydroxypropyl und/oder Propargyl,
wobei R3 und R4 auch Bestandteil
eines stickstoffhaltigen Heterocyclus wie Urotropin, Morpholin,
Imidazolyl, Oxazol, Pyrazol, Tamoxifen, Pyrrolidin sein kann und – ohne den
Substituenten R2 – auch
Bestandteil eines stickstoffhaltigen aromatischen Immoniumsalzes
wie Pyridin, Dimethylaminopyridin oder Dipyridyl sein kann,
Y=
Bromid, Iodid, Chlorid oder Tosyloxy bedeutet.The invention relates to tetraalkylammonium salts of the carbonic acid ester type of the general formula I,
A = a carrier molecule consisting of fused rings, consisting of two or more rings, also spirostanes (with 3 to 7 C atoms), or a hydrocarbon residue
with m = 5 to 24,
n = 1 to 3,
R1 = H or methyl,
R2, R3 and R4 = alkyl (with 1 to 12 C atoms), cycloalkyl (with 2 to 8 C atoms), alkenyl (with 3 to 12 C atoms), cycloalkenyl (with 4 to 8 C atoms), Alkynyl (with 3 to 12 C atoms), aralkyl (with alkyl from 1 to 4 C atoms), alkyloxymethyl (with alkyl from 1 to 4) hydroxyethyl, hydroxypropyl and / or propargyl,
where R3 and R4 can also be part of a nitrogen-containing heterocycle such as urotropin, morpholine, imidazolyl, oxazole, pyrazole, tamoxifen, pyrrolidine and - without the substituent R2 - can also be part of a nitrogen-containing aromatic immonium salt such as pyridine, dimethylaminopyridine or dipyridyl,
Y = bromide, iodide, chloride or tosyloxy.
AryI in Resten wie Aralkyl und dergleichen bedeutet insbesondere Phenyl oder Alkylphenyl (Alkyl mit 1 bis 4 C-Atomen).AryI means in residues such as aralkyl and the like in particular phenyl or alkylphenyl (alkyl with 1 to 4 carbon atoms).
Aus der Literatur bekannt sind Verbindungen in Kombination mit einem Lokalanästhetikum (N. Kasch, C. Goldschmidt WO 2001, 01/45678 A3) oder aber von Mono- und Bis-Tetraalkylammoniumsaizen langkettiger aliphatischer Ether, die aufgrund antibakterieller Wirksamkeit, aber Oberflächenaktivität, nur für Desinfektionszwecke und nicht für topische und systemische Anwendungen genutzt werden können.Compounds in are known from the literature Combination with a local anesthetic (N. Kasch, C. Goldschmidt WO 2001, 01/45678 A3) or from mono- and bis-tetraalkylammonium seeds long-chain aliphatic ether, which due to antibacterial effectiveness, but surface activity, only for disinfection purposes and not for topical and systemic applications can be used.
Der Erfindung liegt die Aufgabe zugrunde, neue Tetraalkylammoniumsalze vom Kohlensäureestertyp zur Verfügung zu stellen, sowie Verfahren zu ihrer Herstellung aufzuzeigen, deren biologische Aktivität durch das Trägermolekül und die charakteristische Ammoniumstruktur geprägt ist, bei denen die an und für sich zu erwartende Tensidwirkung stark zurückgedrängt ist und damit der Weg zur pharmakologischen Nutzung dieser Verbindungsklasse geebnet wird.The invention is based, new task Carbonic ester type tetraalkylammonium salts are available , as well as to show processes for their production, their biological activity through the carrier molecule and the characteristic ammonium structure, in which the and for themselves expected surfactant effect is strongly suppressed and thus the way to pharmacological use of this class of compounds is leveled.
Aus der Literatur sind die Ausgangsmaterialien für die Herstellung bekannt. Die erfindungsgemäßen Verbindungen sind neu, ihre biologische Wirksamkeit wurde bisher nicht beschrieben.The starting materials are from the literature for the Manufacturing known. The compounds according to the invention are new, their biological effectiveness has not yet been described.
Die Aufgabe wird erfindungsgemäß dadurch gelöst, dass neue Tetraalkylammoniumsalze vom Kohlensäureestertyp zur Verfügung gestellt werden.The object is achieved in that new tetraalkylammonium salts of the carbonic acid ester type provided become.
Erfindungsgemäß bevorzugte Verbindungen sind
beispielsweise:
N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on), N,N,N-triethylammonium-iodid,
N-(3β-Ethylidenoxycarbonyloxy-5-androsten-l7-on), N,N,N-triethylammonium-iodid,
N-(3β-Methylenoxycarbonyloxy-5-cholesten), N,N,N-triethylammonium-bromid,
N-(3β-Methylenoxycarbonyloxy-24-ethyl-5-cholesten),
N,N,N-triethylammonium-bromid,
N-(3β-Methylenoxycarbonyloxy-24-ethyl-5,22-cholestadien),
N,N,N-triethylammonium-iodid,
N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on), N,N,N-trimethylammonium-chlorid,
N,N-Dimethyl,
N-hexyl, N-(3β-methylenoxycarbonyloxy-5-androsten-l7-on)-ammonium-iodid,
N,N-Diethyl,
N-methyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-ammonium-iodid,
N,N-Dimethyl,
N-butyl, N-(3β-methylenoxycarbonyloxy-5-androsten-l7-on)-ammonium-iodid,
N,N-Dimethyl,
N-(3β-methylenoxycarbonyloxy-5-androsten-17-on),
N-propargyl-ammonium-iodid,
N,N-Dimethyl,
N-(3β-methylenoxycarbonyloxy-5-androsten-17-on),
N-propinyl-ammonium-iodid,
N,N-Dimethyl,
N-dodecyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-ammonium-iodid,
N,N-Dimethyl,
N-(3β-methylenoxycarbonyloxy-5-androsten-17-on),
N-propenyl-ammonium-iodid,
N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on), N,N,N-tripropyl-ammonium-iodid,
N-Methyl,
N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-imidazolonium-iodid,
N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-pyrrolidinium-hydrochlorid,
N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-pyridinium-iodid,
N-Methyl,
N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-pyrrolidinium-iodid,
N-(3β-Methylenoxycarbonyloxy-5-androsten-17β-ol), N,N,N-triethyl-ammonium-iodid,
N-(17β-Methylenoxycarbonyloxy-5-androsten-3-on), N,N,N-triethyl-ammonium-iodid,
N-(17β-Methylenoxycarbonyloxy-5-androsten-3β-ol), N,N,N-triethyl-ammonium-iodid,
N,N'-[3β,17β-(Di-methylenoxycarbonyloxy)-5-androsten]-(N,N,N)-,(N',N',N')-bis-triethyl-ammonium-diodid
N-[3-Methoxy-17β-methylenoxycarbonyloxy-estra-1,3,5(10)-trien],
N,N,N-triethyl-ammonium-iodid,
N-[17β-methylenoxycarbonyloxy-3-sulfamoyloxy-estra-1,3,5(10)-trien],
N,N,N-triethyl-ammonium-iodid
N-[17β-methylenoxycarbonyloxy-3-oxysulfonyloxy-estra-1,3,5(10)-trien],
N,N,N-triethyl-ammonium-iodid
N-[17β-methylenoxycarbonyloxy-3-oxysulfonylpropyl-estra-1,3,5(10)-trien],
N,N, N-triethyl-ammonium-iodid
N-[3-Methoxy-17β-methylenoxycarbonyloxy-estra-1,3,5(10),9(11)-tetraen],
N,N N-triethyl-ammonium-iodid,
N-(1-Methylenoxycarbonyloxy-dodecyl),
N,N,N-triethyl-ammonium-iodid
N,N'-[1,12-(Di-methylenoxycarbonyloxy)-dodecyl]-(N,N,N)-,(N',N',N')-bis-triethyl-ammonium-diodidCompounds preferred according to the invention are, for example:
N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-triethylammonium iodide,
N- (3β-ethylidenoxycarbonyloxy-5-androsten-l7-one), N, N, N-triethylammonium iodide,
N- (3β-methyleneoxycarbonyloxy-5-cholestene), N, N, N-triethylammonium bromide,
N- (3β-methyleneoxycarbonyloxy-24-ethyl-5-cholestene), N, N, N-triethylammonium bromide,
N- (3β-methyleneoxycarbonyloxy-24-ethyl-5,22-cholestadiene), N, N, N-triethylammonium iodide,
N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-trimethylammonium chloride,
N, N-dimethyl, N-hexyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-l7-one) ammonium iodide,
N, N-diethyl, N-methyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) ammonium iodide,
N, N-dimethyl, N-butyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-l7-one) ammonium iodide,
N, N-dimethyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N-propargylammonium iodide,
N, N-dimethyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N-propynylammonium iodide,
N, N-dimethyl, N-dodecyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) ammonium iodide,
N, N-dimethyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N-propenyl-ammonium iodide,
N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-tripropyl-ammonium iodide,
N-methyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) -imidazolonium iodide,
N- (3β-methylenoxycarbonyloxy-5-androsten-17-one) -pyrrolidinium hydrochloride,
N- (3β-methylenoxycarbonyloxy-5-androsten-17-one) pyridinium iodide,
N-methyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) pyrrolidinium iodide,
N- (3β-methyleneoxycarbonyloxy-5-androsten-17β-ol), N, N, N-triethylammonium iodide,
N- (17β-methyleneoxycarbonyloxy-5-androsten-3-one), N, N, N-triethylammonium iodide,
N- (17β-methyleneoxycarbonyloxy-5-androsten-3β-ol), N, N, N-triethylammonium iodide,
N, N '- [3β, 17β- (di-methylenoxycarbonyloxy) -5-androsten] - (N, N, N) - (N', N ', N') - bis-triethyl-Ammoni to-diodid
N- [3-methoxy-17β-methyleneoxycarbonyloxy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide,
N- [17β-methyleneoxycarbonyloxy-3-sulfamoyloxy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide
N- [17β-methyleneoxycarbonyloxy-3-oxysulfonyloxy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide
N- [17β-methyleneoxycarbonyloxy-3-oxysulfonylpropyl-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide
N- [3-methoxy-17β-methyleneoxycarbonyloxy-estra-1,3,5 (10), 9 (11) -tetraen], N, N N-triethylammonium iodide,
N- (1-methyleneoxycarbonyloxy dodecyl), N, N, N-triethylammonium iodide
N, N '- [1,12- (di-methylenoxycarbonyloxy) dodecyl] - (N, N, N) - (N', N ', N') - bis-triethyl-ammonium-diodid
Gegenstand der vorliegenden Erfindung sind ferner pharmazeutische Zusammensetzungen, die als Wirkstoff mindestens ein Tetraalkylammoniumsalz vom Kohlensäureestertyp der allgemeinen Formel I enthalten, wobei diesen Zusammensetzungen gegebenenfalls geeignete Hilfs-, Träger- und Zusatzstoffe und/oder Stabilisatoren beigefügt sind.Object of the present invention are also pharmaceutical compositions that act as an active ingredient at least one carbonic ester type tetraalkylammonium salt of general formula I, these compositions optionally suitable auxiliary, carrier and additives and / or stabilizers are added.
Die erfindungsgemäßen Verbindungen besitzen neben einer antibakteriellen eine bevorzugte antimykotische Wirkung, wobei die spezifische Antcandida-Wirkung hervorzuheben ist. Darüber hinaus sind die erfindungsgemäßen Verbindungen als potentielle HMG-Co-A-Reduktasehemmer einzustufen, die die Cholesterinbiosynthese zu regulieren vermögen. Überraschend ist die verminderte bzw. bei einigen Verbindungen nicht vorhandene Tensidwirkung, die sehr durch das verwendete Trägermolekül und die Aminkomponente beeinflusst wird.The compounds of the invention also have an antibacterial a preferred antifungal activity, wherein the specific Antcandida effect is to be emphasized. About that in addition, the compounds of the invention classified as a potential HMG-Co-A reductase inhibitor, the cholesterol biosynthesis able to regulate. Surprised is the reduced or not available for some connections Surfactant effect, which is very influenced by the carrier molecule and the amine component becomes.
Aufgrund ihrer spezifischen Partialwirkungen können die Wirkstoffkomponenten für den Einsatz bei Mykosen und als Cholesterinsenker eingesetzt werden, auch nicht zuletzt deshalb, weil keine hormonellen Nebenwirkungen auftreten.Due to their specific partial effects, the Active ingredient components for used for mycoses and as a cholesterol-lowering agent, not least because there are no hormonal side effects occur.
Die Arzneimittel der Erfindung werden mit den üblichen festen oder flüssigen Verdünnungsmitteln und den üblicherweise verwendeten pharmazeutisch technischen Hilfsstoffen entsprechend der gewünschten Applikationsroute mit einer geeigneten Dosierung in an sich bekannter Weise hergestellt. Die bevorzugten Zubereitungen bestehen in Darreichungsformen, die zur topischen Anwendung in Form transdermaler Systeme bestehen. Orale Applikationen in Form von Tabletten, Dragees, Pillen, Pulver und Depotformen sind ebenfalls geeignet.The drugs of the invention will with the usual solid or liquid diluents and usually used pharmaceutical technical auxiliaries accordingly the desired one Application route with a suitable dosage in a known manner Manufactured way. The preferred preparations consist of dosage forms, which exist for topical application in the form of transdermal systems. Oral applications in the form of tablets, coated tablets, pills, powder and deposit forms are also suitable.
Zur Herstellung der erfindungsgemäßen Verbindungen
werden Verbindungen der allgemeinen Formeln II, 
A und n die oben
angegebene Bedeutungen haben,
n= 1 bis 3 ist, in an sich bekannter
Weise mit Chlorameisensäurechlormethylester
oder durch Umsetzung mit Phosgen und anschließender Reaktion mit Paraformaldehyd
(Acetaldehyd) nach der Henry-Methode mit ZnCl2 in
Carbonsäure-α-chloralkylester
(mit Alkyl = Methyl oder Ethyl) umgewandelt und diese mit einem
Amin, NR2R3R4, worin R2, R3 und R4 die oben angegebenen
Bedeutungen haben, in einem geeigneten Lösungsmittel, wie Aceton, DMF,
Methylenchlorid oder einer entsprechenden Lösungsmittelkombi-nation, in
Gegenwart von Iodid, Bromid, Tosylat oder Chlorid in Form von Salzen
umgesetzt, isoliert und diese gegebenenfalls in an sich bekannter Weise
oxidiert, verethert, acyliert, wozu unter anderem ein Säurederivat
für Veresterungen,
wie ein Carbonsäureanhydrid,
Carbonsäurehalogenid,
wie Carbosäurechlorid
oder ein Sulfamoylhalogenid wie Sulfamoylchlorid in Gegenwart eines
geeigneten Lösungsmittels
und einer protonenabstrahierenden Base genutzt werden.To prepare the compounds according to the invention, compounds of the general formulas II,
A and n have the meanings given above,
n = 1 to 3, in a manner known per se with chloromethyl chloromate or by reaction with phosgene and subsequent reaction with paraformaldehyde (acetaldehyde) according to the Henry method with ZnCl 2 in carboxylic acid α-chloroalkyl ester (with alkyl = methyl or ethyl) and this with an amine, NR 2 R 3 R 4 , in which R 2 , R 3 and R 4 have the meanings given above, in a suitable solvent, such as acetone, DMF, methylene chloride or a corresponding solvent combination, in the presence of iodide , Bromide, tosylate or chloride in the form of salts, isolated and optionally oxidized, etherified, acylated in a manner known per se, including an acid derivative for esterifications such as a carboxylic acid anhydride, carboxylic acid halide such as carboxylic acid chloride or a sulfamoyl halide such as sulfamoyl chloride in the presence a suitable solvent and a proton-emitting base.
Die pharmazeutischen Zubereitungen, die mindestens ein erfindungsgemäßes Tetraalkylammoniumsalz vom Kohlensäureestertyp enthalten, umfassen pharmazeutisch verträgliche Hilfs-, Träger- und Zusatzstoff und/oder Stabilisatoren.The pharmaceutical preparations the at least one tetraalkylammonium salt according to the invention of the carbonic acid ester type included, include pharmaceutically acceptable auxiliary, carrier and Additive and / or stabilizers.
Die nachfolgenden Beispiele dienen dazu, die Erfindung näher zu erläutern, ohne sie in irgendeiner Weise einzuschränken.The following examples serve to the invention in more detail to explain without restricting them in any way.
Experimenteller Teil Experimental part
Beispiel 1example 1
N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on)-N,N,N-triethyl-ammonium-iodidN- (3β-Methylenoxycarbonyloxy-5-androsten-17-one) -N, N, N-triethyl-ammonium iodide
300 mg 3β-Hydroxy-5-androsten-l7-on werden
mit 1,2 mmol Chlorameisensäurechlormethylester
und 3 mmol Triethylamin in Gegenwart von 3 mmol Natriumiodid in
3 ml Aceton zur Umsetzung gebracht. Das Ammoniumsalz kristallisiert
aus der Acetonlösung
aus und kann durch Umkristallisation aus Methylenchlorid/n-Hexan
aufgereinigt werden.
F: 208 bis 211 °C
IR [cm-1]:
1635 (CO)
MS [m/z]: ES+ 446,6 [M+] 300 mg of 3β-hydroxy-5-androsten-l7-one are reacted with 1.2 mmol of chloromethyl chloroformate and 3 mmol of triethylamine in the presence of 3 mmol of sodium iodide in 3 ml of acetone. The ammonium salt crystallizes out of the acetone solution and can be purified by recrystallization from methylene chloride / n-hexane.
F: 208-211 ° C
IR [cm -1 ]: 1635 (CO)
MS [m / z]: ES + 446.6 [M + ]
Beispiel 2Example 2
N-(3β-Methylenoxycarbonyloxy-5-cholesten)-N,N,N-triethyl-ammonium-chloridN- (3 β -Methylenoxycarbonyloxy-5-cholesten) -N, N, N-triethyl-ammonium chloride
300 mg 3β-Hydroxy-5-cholesten werden
mit 1,2 mmol Triphosgen in Gegenwart von Triethylamin in 3β-Chlorcarbonyloxy-5-cholesten überführt und anschließend mit
2 mmol Paraformaldehyd in DMF in Gegenwart von wasserfreiem ZnCl2 unter kurzem Erhitzen in 3β-Chlormethylenoxycarbonyloxy-5-cholesten
umgewandelt. Der durch chromatographische Reinigung erhältliche
Chlormethylester wird mit 3 mmol Triethylamin in das Ammoniumsalz überführt und
das Salz aus Methylenchlorid/n-Hexan kristallisiert.
MS [m/z]:
ES+ 544,9 [M+]300 mg of 3β-hydroxy-5-choleste are converted into 3β-chlorocarbonyloxy-5-choleste with 1.2 mmol triphosgene in the presence of triethylamine and then with 2 mmol paraformaldehyde in DMF in the presence of anhydrous ZnCl 2 with brief heating in 3β-chloromethyleneoxycarbonyloxy -5-choles ten converted. The chloromethyl ester obtainable by chromatographic purification is converted into the ammonium salt with 3 mmol of triethylamine and the salt is crystallized from methylene chloride / n-hexane.
MS [m / z]: ES + 544.9 [M + ]
Beispiel 3Example 3
N-(17β-Methylenoxycarbonyloxy-5-androsten-3-on)-N,N,N-triethylammonium-iodidN- (17β-Methylenoxycarbonyloxy-5-androsten-3-one) -N, N, N-triethylammonium iodide
200 mg 17β-Iodmethylenoxycarbonyloxy-5-androsten-3-on,
hergestellt aus 17β-chlormethylenoxycarbonyloxy-5-androsten-3-on
durch Umsetzung mit Natriumiodid in Aceton, werden in 2 ml Aceton
gelöst
und bei Raumtemperatur mit 3 mmol Triethylamin versetzt. Das auskristallisierende
Ammoniumsalz wird abgetrennt und aus Methylenchlorid/n-Hexan kristallisiert.
F:
208 bis 311 °C200 mg of 17β-iodomethyleneoxycarbonyloxy-5-androsten-3-one, prepared from 17β-chloromethyleneoxycarbonyloxy-5-androsten-3-one by reaction with sodium iodide in acetone, are dissolved in 2 ml of acetone and mixed with 3 mmol of triethylamine at room temperature. The crystallizing ammonium salt is separated off and crystallized from methylene chloride / n-hexane.
F: 208 to 311 ° C
Claims (4)
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| DE2003103669 DE10303669A1 (en) | 2003-01-28 | 2003-01-28 | New quaternary ammonioalkyl carbonate esters useful for treating bacterial and fungal infections and potentially useful for regulating cholesterol biosynthesis |
| PCT/DE2004/000151 WO2004067546A1 (en) | 2003-01-28 | 2004-01-28 | Carboxylic-acid-ester-type tetraalkyl ammonium salts, method for the production thereof and pharmaceutical compositions containing said compounds |
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|---|---|---|---|
| DE2003103669 DE10303669A1 (en) | 2003-01-28 | 2003-01-28 | New quaternary ammonioalkyl carbonate esters useful for treating bacterial and fungal infections and potentially useful for regulating cholesterol biosynthesis |
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| HUE033442T2 (en) | 2009-06-25 | 2017-11-28 | Alkermes Pharma Ireland Ltd | Heterocyclic compounds for the treatment of neurological and psychological disorders |
| WO2010151711A1 (en) | 2009-06-25 | 2010-12-29 | Alkermes, Inc. | Prodrugs of nh-acidic compounds |
| NZ604423A (en) | 2010-06-24 | 2015-01-30 | Alkermes Pharma Ireland Ltd | Prodrugs of nh-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
| RS55434B1 (en) | 2011-03-18 | 2017-04-28 | Alkermes Pharma Ireland Ltd | Injectable pharmaceutical compositions comprising a water-insoluble anti-psychotic, sorbitan laurate and polysorbate 20 |
| AU2012351747B2 (en) | 2011-12-15 | 2016-05-12 | Alkermes Pharma Ireland Limited | Prodrugs of secondary amine compounds |
| WO2013142205A1 (en) | 2012-03-19 | 2013-09-26 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising benzyl alcohol |
| AU2013235519C1 (en) | 2012-03-19 | 2018-04-26 | Alkermes Pharma Ireland Limited | Pharmaaceutical compositions comprising fatty acid esters |
| ES2764383T3 (en) | 2012-03-19 | 2020-06-03 | Alkermes Pharma Ireland Ltd | Pharmaceutical compositions comprising glycerol esters |
| ES2792149T3 (en) | 2012-09-19 | 2020-11-10 | Alkermes Pharma Ireland Ltd | Pharmaceutical Compositions Having Improved Storage Stability |
| WO2015143145A1 (en) | 2014-03-20 | 2015-09-24 | Alkermes Pharma Ireland Limited | Aripiprazole formulations having increased injection speeds |
| JP7384812B2 (en) | 2018-03-05 | 2023-11-21 | アルカームス ファーマ アイルランド リミテッド | Aripiprazole dosing strategy |
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| WO1994020508A1 (en) * | 1993-03-08 | 1994-09-15 | Eisai Co., Ltd. | Phosphonic acid derivatives |
| WO2001036575A1 (en) * | 1999-11-15 | 2001-05-25 | The Procter & Gamble Company | Fabric enhancement treatment |
| WO2001045678A2 (en) * | 1999-12-21 | 2001-06-28 | Id Pharma Gmbh | Medicament, a method for its production and the use thereof |
| WO2001055082A2 (en) * | 2000-01-28 | 2001-08-02 | Rohm And Haas Company | Intermediates for biologically active compounds |
| WO2001057064A2 (en) * | 2000-02-07 | 2001-08-09 | Roche Diagnostics Corporation | Cationic amphiphiles for use in nucleic acid transfection |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994020508A1 (en) * | 1993-03-08 | 1994-09-15 | Eisai Co., Ltd. | Phosphonic acid derivatives |
| WO2001036575A1 (en) * | 1999-11-15 | 2001-05-25 | The Procter & Gamble Company | Fabric enhancement treatment |
| WO2001045678A2 (en) * | 1999-12-21 | 2001-06-28 | Id Pharma Gmbh | Medicament, a method for its production and the use thereof |
| WO2001055082A2 (en) * | 2000-01-28 | 2001-08-02 | Rohm And Haas Company | Intermediates for biologically active compounds |
| WO2001057064A2 (en) * | 2000-02-07 | 2001-08-09 | Roche Diagnostics Corporation | Cationic amphiphiles for use in nucleic acid transfection |
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