US3828090A - Alkylsulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds - Google Patents
Alkylsulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds Download PDFInfo
- Publication number
- US3828090A US3828090A US00225273A US22527372A US3828090A US 3828090 A US3828090 A US 3828090A US 00225273 A US00225273 A US 00225273A US 22527372 A US22527372 A US 22527372A US 3828090 A US3828090 A US 3828090A
- Authority
- US
- United States
- Prior art keywords
- formula
- compounds
- solution
- ether
- acid esters
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000002253 acid Substances 0.000 title description 4
- 150000002148 esters Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract description 44
- 230000000694 effects Effects 0.000 abstract description 7
- 150000003459 sulfonic acid esters Chemical class 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- -1 alkyl sulfonic acid esters Chemical class 0.000 description 9
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- BQHMRVKGQBPYPQ-UHFFFAOYSA-N 2-[[3-(2-chloroethyl)-2-oxo-1,3,2lambda5-oxazaphosphinan-2-yl]amino]ethanol Chemical compound OCCNP1(OCCCN1CCCl)=O BQHMRVKGQBPYPQ-UHFFFAOYSA-N 0.000 description 1
- NKRLFWXSRKGPOE-UHFFFAOYSA-N 2-hydroxyoxazaphosphinine Chemical compound ON1OC=CC=P1 NKRLFWXSRKGPOE-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000589562 Brucella Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- MRIMWDXKBILRPB-UHFFFAOYSA-N O=P1NCCCO1 Chemical compound O=P1NCCCO1 MRIMWDXKBILRPB-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Chemical group 0.000 description 1
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- PWQOZRPSDQKNPW-UHFFFAOYSA-N pentane-1-sulfonyl chloride Chemical compound CCCCCS(Cl)(=O)=O PWQOZRPSDQKNPW-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 229920001195 polyisoprene Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 1
- DRINJBFRTLBHNF-UHFFFAOYSA-N propane-2-sulfonyl chloride Chemical compound CC(C)S(Cl)(=O)=O DRINJBFRTLBHNF-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65844—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a five-membered ring which may be condensed with another ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
Definitions
- the present invention is related to alkyl sulfonic acid esters of 1,3,2 oxazaphospha-cyclic compounds which produce a high immunsuppressing activity.
- the invention is further related to process for the production thereof and to pharmaceutical preparations containing the same.
- R is a halogen atom, preferably a chlorine atom, or a lower alkyl sulfonic acid group having a straight or branched lower alkyl chain with 1 to 6 carbon atoms
- R and R are hydrogen or a lower alkyl group with 1 to 4 carbon atoms which alkyl group may be substituted with a halogen atom, preferably a chlorine atom, or with a lower alkyl sulfonic ester group having a straight or branched lower alkyl chain with 1 to 6 carbon atoms
- R and R being identical or difierent from each other and there being present in the molecule of formula I at least one such lower alkyl sulfonic acid ester group
- alk represents a straight or branched alkylene group with 2 or 3 carbon atoms in the chain and, if branched, with a total of 3 or 4 carbon atoms
- X represents oxygen or sulphur
- Z represents
- the new compounds of formula I are produced by using methods known as such.
- the process for the production of the compounds according to the present invention comprises (A) Subjecting a compound of formula IV wherein R has the same meaning as R, in formula IV and Z and m have the same meaning as in formula I, or
- the reactions are preferably carried out in the presence of an inert solvent such as acetonitrile or a lower halogenated hydrocarbon such as chloroform or methylene chloride, or in an ether such as diethylether or dioxane, or in an aromatic hydrocarbon such as benzene or toluene.
- an inert solvent such as acetonitrile or a lower halogenated hydrocarbon such as chloroform or methylene chloride
- an ether such as diethylether or dioxane
- aromatic hydrocarbon such as benzene or toluene.
- the reactions are preferably carried out in the presence of an acid binding agent.
- the acid binding agent should be present in an amount ranging from 1 to 2 mole equivalents.
- alkaline compounds which may be used as acid binding agents such as alkali metal and alkaline earth metal carbonates and bicarbonates and particularly tertiary mines such as triethylmine and pyridine.
- Halogenating agents for exchanging aliphatically bound hydroxy groups against halogen atoms are also known.
- Useful for this purpose are for instance the phosphorous halides such as phosphorous trichloride or tribromide, phosphorous pentachloride, phosphorous oxychloride or oxybromide, the sulfurous and sulfonic acid halides such as sulfurylchloride and thionylchloride, or phosgene.
- Thionylchloride is most preferably used in view of the ease to handle it.
- Usual carrier products for pharmaceutical preparations which may contain a compound according to formula I as active agent, are pharmacologically inert products as they are known for the production of tablets, drages, suppositories and injection solutions.
- the following examples further illustrate the present invention without however limiting the same thereto.
- a solution of 121.3 g. (0.5 mole) of the above compound and 50.6 g. (0.5 mole) of triethylamine in 320 cc. of dioxane is prepared. This solution is added to a solution of 57.3 g. (0.5 mole) of methane sulfonic acid chloride in 340 cc. of dioxane dropwise within 30 minutes at 26-28 C. Thereafter, 150 cc. of ether are added and stirring at 10 C. is continued for another 30 minutes. The precipitated triethylamine hydrochloride is filtered off with suction and the filtrate is evaporated at 30-35 C. in a water jet vacuum.
- Ether is added to the oily residue which crystallizes while standing in an ice box after seeding.
- the product is purified by dissolving it in etha nol and adding ether to the ethanolic solution and allowing to stand in the ice box.
- the product is obtained in nice colorous crystals upon extraction in a soxhlet appa ratus with a mixture of methylene chloride and ether.
- a solution of 38.6 g. of the above compound and 15.5 g. of triethylamine in cc. of anhydrous dioxane is added to a solution of 17.2 g. of methane sulfonylchloride in 120 cc. of anhydrous dioxane dropwise with stirring Within 30 minutes at a temperature ranging from 28-30 C.
- the separated triethylamine hydrochloride is filtered ofi with suction and the filtrate is evaporated in a water jet vacuum.
- the oily residue is dissolved in water and purified by means of the ion exchanger Duolit (A 102).
- Anhydrous ether is added to the colorless oil and the mixture is cooled in an ice-bath and scratched from time to time. Thus, the product crystallizes. The crystals are recrystallized from ethyl acetate.
- EXAMPLE 7 The following recipe is used for the production of 100,000 drages containing each 50 mg. of the active compound according to the present invention:
- the crystalline active compound is passed together with 3 kg. of corn starch through a sieve having a mesh size of 1 mm.
- the products are thoroughly mixed and a paste is formed with a 10% solution of the olyvinylpyrrolidon in isopropanol.
- the moist product is granulated by passing it through a sieve having a mesh size of 3 mm. It is then dried and ground to a particle size of 1 mm.
- the remaining auxiliary products of the above recipe are sieved and thoroughly admixed and 100,000 drages are pressed each weighing mg., having a diameter of 7 mm. and a camber diameter of 6 mm.
- the resulting kernels are coated in manner known per se by first applying a lager resistant to the gastric juices giving each kernel a weight of mg., then applying a cover until a kernel weight of 205 mg., smoothing the surfaces of the kernels until a kernel weight of 215 mg. and thereafter applying color layers up to a kernel weight of 240 mg. Finally, the coated kernels are rendered glossy by applying a layer of hard wax.
- EXAMPLE 8 A dry mix of active compound and sodium chloride is filled into glass to be for the production of injection solution.
- the solution thereof is passed through a filter holding back germs.
- the further processing is effected under aseptic conditions.
- the crystallized compound is separated by centrifugation and dried and held in an atmosphere of ethylene oxide.
- a sample is taken and checked for purity and sterility.
- the compound is mixed with sterile sodium chloride pa. in a weight proportion of 100 to 45 under aseptic conditions,
- the compounds according to the present invention are useful in the treatment of autoimmune diseases (autoaggressive diseases), such as autoimmunehaemolytic anemia, lupus erythematodes and polyarteritis nodosa.
- autoimmune diseases autoaggressive diseases
- the compounds are preferably applied in a daily dose ranging from 2 to 4 mg./ kg.
- a particularly useful and therefore most preferred compound is that of Example 1.
- alk is 3.
- alk is CH CH and R is methyl or ethyl, or alk is -(i ⁇ HCH2- and R is methyl.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2107936A DE2107936C3 (de) | 1971-02-19 | 1971-02-19 | Alkylsulfonsäureester von 2-Oxo-13,2-oxazaphosphorinanen und diese enthaltende pharmazeutische Präparate |
| DE19722201675 DE2201675A1 (de) | 1972-01-14 | 1972-01-14 | Alkylsulfonsaeureester 1,3,2-oxazaphospha-cyclischer verbindungen, verfahren zu ihrer herstellung und pharmazeutische praeparate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3828090A true US3828090A (en) | 1974-08-06 |
Family
ID=25760687
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00225273A Expired - Lifetime US3828090A (en) | 1971-02-19 | 1972-02-10 | Alkylsulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US3828090A (nl) |
| JP (1) | JPS5620317B1 (nl) |
| AR (1) | AR195863A1 (nl) |
| BE (1) | BE779516A (nl) |
| CA (1) | CA957696A (nl) |
| CH (3) | CH596231A5 (nl) |
| DD (1) | DD94812A5 (nl) |
| DK (1) | DK137013C (nl) |
| ES (1) | ES399910A1 (nl) |
| FI (1) | FI56387C (nl) |
| FR (1) | FR2125595B1 (nl) |
| HK (1) | HK11477A (nl) |
| HU (1) | HU169427B (nl) |
| IE (1) | IE36065B1 (nl) |
| LU (1) | LU64702A1 (nl) |
| MY (1) | MY7700155A (nl) |
| NL (1) | NL170287C (nl) |
| SE (1) | SE381464B (nl) |
| YU (3) | YU38772A (nl) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4085128A (en) * | 1974-11-20 | 1978-04-18 | Shionogi & Co., Ltd. | Cyclic phosphamide derivatives |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3910982A (en) * | 1971-02-19 | 1975-10-07 | Asta Werke Ag Chem Fab | Alkylsulfonic acid esters of 1,3,2-oxazaphospha-cyclic compounds |
| CN114965770B (zh) * | 2022-05-24 | 2023-03-28 | 江苏海洋大学 | 一种异环磷酰胺原料药中起始物料、杂质d、杂质f的检测方法 |
-
1972
- 1972-01-31 CH CH1183575A patent/CH596231A5/xx not_active IP Right Cessation
- 1972-01-31 CH CH1183675A patent/CH586230A5/xx not_active IP Right Cessation
- 1972-01-31 CH CH134972A patent/CH581145A5/xx not_active IP Right Cessation
- 1972-02-01 LU LU64702D patent/LU64702A1/xx unknown
- 1972-02-07 IE IE147/72A patent/IE36065B1/xx unknown
- 1972-02-10 US US00225273A patent/US3828090A/en not_active Expired - Lifetime
- 1972-02-16 YU YU00387/72A patent/YU38772A/xx unknown
- 1972-02-17 SE SE7201916A patent/SE381464B/xx unknown
- 1972-02-17 DD DD160930A patent/DD94812A5/xx unknown
- 1972-02-18 HU HUAA698A patent/HU169427B/hu unknown
- 1972-02-18 AR AR240595A patent/AR195863A1/es active
- 1972-02-18 BE BE779516A patent/BE779516A/xx not_active IP Right Cessation
- 1972-02-18 FI FI445/72A patent/FI56387C/fi active
- 1972-02-18 DK DK76172A patent/DK137013C/da not_active IP Right Cessation
- 1972-02-18 JP JP1655672A patent/JPS5620317B1/ja active Pending
- 1972-02-18 CA CA135,044A patent/CA957696A/en not_active Expired
- 1972-02-18 NL NLAANVRAGE7202177,A patent/NL170287C/nl not_active IP Right Cessation
- 1972-02-18 FR FR7205549A patent/FR2125595B1/fr not_active Expired
- 1972-02-18 ES ES399910A patent/ES399910A1/es not_active Expired
-
1977
- 1977-03-03 HK HK114/77A patent/HK11477A/xx unknown
- 1977-12-30 MY MY155/77A patent/MY7700155A/xx unknown
-
1978
- 1978-10-12 YU YU2387/78A patent/YU35031B/xx unknown
- 1978-10-12 YU YU2388/78A patent/YU35030B/xx unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4085128A (en) * | 1974-11-20 | 1978-04-18 | Shionogi & Co., Ltd. | Cyclic phosphamide derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| BE779516A (fr) | 1972-06-16 |
| NL7202177A (nl) | 1972-08-22 |
| YU35030B (en) | 1980-06-30 |
| DK137013C (da) | 1978-06-05 |
| CH581145A5 (nl) | 1976-10-29 |
| MY7700155A (en) | 1977-12-31 |
| JPS5620317B1 (nl) | 1981-05-13 |
| ES399910A1 (es) | 1975-06-16 |
| FI56387B (fi) | 1979-09-28 |
| CH586230A5 (nl) | 1977-03-31 |
| IE36065B1 (en) | 1976-08-04 |
| HK11477A (en) | 1977-03-11 |
| YU38772A (en) | 1982-02-28 |
| YU238778A (en) | 1979-12-31 |
| DK137013B (da) | 1978-01-02 |
| NL170287C (nl) | 1982-10-18 |
| CH596231A5 (nl) | 1978-03-15 |
| LU64702A1 (nl) | 1972-06-29 |
| YU238878A (en) | 1979-12-31 |
| NL170287B (nl) | 1982-05-17 |
| FR2125595B1 (nl) | 1975-03-14 |
| FR2125595A1 (nl) | 1972-09-29 |
| DD94812A5 (nl) | 1973-01-05 |
| AU3891472A (en) | 1973-08-16 |
| HU169427B (nl) | 1976-11-28 |
| CA957696A (en) | 1974-11-12 |
| SE381464B (sv) | 1975-12-08 |
| YU35031B (en) | 1980-06-30 |
| IE36065L (en) | 1972-08-19 |
| AR195863A1 (es) | 1973-11-15 |
| FI56387C (fi) | 1980-01-10 |
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