DK165003B - Chlorsulfat - Google Patents
Chlorsulfat Download PDFInfo
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- DK165003B DK165003B DK198191A DK198191A DK165003B DK 165003 B DK165003 B DK 165003B DK 198191 A DK198191 A DK 198191A DK 198191 A DK198191 A DK 198191A DK 165003 B DK165003 B DK 165003B
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- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000002009 alkene group Chemical group 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-M chlorosulfate Chemical compound [O-]S(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-M 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 18
- 206010015037 epilepsy Diseases 0.000 abstract description 6
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 abstract description 4
- 230000001773 anti-convulsant effect Effects 0.000 abstract description 3
- 229960003965 antiepileptics Drugs 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- -1 methylenedioxy group Chemical group 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000006188 syrup Substances 0.000 description 7
- 235000020357 syrup Nutrition 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- 208000010412 Glaucoma Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960002737 fructose Drugs 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- FZUJWWOKDIGOKH-UHFFFAOYSA-N sulfuric acid hydrochloride Chemical class Cl.OS(O)(=O)=O FZUJWWOKDIGOKH-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- UUBPRIUBEQJUQL-UHFFFAOYSA-N (1-methylcyclohexyl)methanol Chemical compound OCC1(C)CCCCC1 UUBPRIUBEQJUQL-UHFFFAOYSA-N 0.000 description 1
- QWBRAALMTSQLEN-UHFFFAOYSA-N 1,1-dimethylcyclohexane;sulfamic acid Chemical compound NS(O)(=O)=O.CC1(C)CCCCC1 QWBRAALMTSQLEN-UHFFFAOYSA-N 0.000 description 1
- WWPWWAHQDTYCPM-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-2-ylmethanol Chemical compound C1=CC=C2CC(CO)CCC2=C1 WWPWWAHQDTYCPM-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000003846 Carbonic anhydrases Human genes 0.000 description 1
- 108090000209 Carbonic anhydrases Proteins 0.000 description 1
- LKDRXBCSQODPBY-VRPWFDPXSA-N D-fructopyranose Chemical compound OCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-VRPWFDPXSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- CVZHVPDGAGIDDX-UHFFFAOYSA-N oxan-2-yl n-methylsulfamate Chemical compound CNS(=O)(=O)OC1CCCCO1 CVZHVPDGAGIDDX-UHFFFAOYSA-N 0.000 description 1
- ROTONRWJLXYJBD-UHFFFAOYSA-N oxan-2-ylmethanol Chemical compound OCC1CCCCO1 ROTONRWJLXYJBD-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019553 satiation Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
- C07H9/04—Cyclic acetals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D309/06—Radicals substituted by oxygen atoms
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- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Pyrane Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
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Description
DK 165003B
i
Den foreliggende opfindelse angår hidtil ukendte chlorsulfater med formlen RCI^OSi^Cl, hvor R har formlen (III) R, R, hvori R2, R3, R4 og Rg er, uafhængigt af hinanden, hydrogen eller lavere alkyl og, når X er CH2, er R^ og R5 eventuelt alkengrupper, der tilsammen danner en benzenring og, når X er oxygen, danner R2 og R^ og/ 10 eller R4 og Rg eventuelt en methylendioxygruppe med formel (II) R6 o- <n> r7 o— 15 hvori
Rg og Rj, som er ens eller forskellige, er hydrogen, lavere al kyl eller al kyl, som tilsammen danner en cyclopentyl- eller cyclohexylring.
De omhandlede chlorsulfater er nyttige som mellemprodukter til fremstilling af lægemiddelaktive sulfamater som nærmere diskuteret i det 20 følgende.
Sulfamater med forskellige strukturer, inklusive sådanne, der afledes af monosaccharider, er beskrevet i referencer såsom N.K.
Kochetkow, et al., i Zhurnal Obshchei Kimii, bind 41, nr. 8, 1866-1871 (1971), bind 42, nr. 12, 2755-2757 (1972) og bind 44, nr. 4, 871-875 25 (1974), og i Doklady Akademii Nauk SSR, bind 216, nr. 1, 97-100 (1974); T. Tsuchiya et al., i Tetrahedron Letters, nr. 36, 3365-3368 (1978); og A.F. Hirsch i Journal of Medicinal Chemistry, 24, 901-903 (1981), samt US-patentskrift nr. 4.075.351.
Det har nu vist sig, at sulfamater med formel (I) 30 /—X. CH.OSO.NHR, R, Ri hvori X er 0 eller CH2 og Rp R2, R3, R^ og Rg er som defineret i det 35 følgende, besidder anti-konvulsivisk aktivitet i pattedyr og derfor er anvendelige til behandling af sygdomstilstande såsom epilepsi og glaukom.
Sul famaterne har den følgende formel (I) 2 DK 165003 B i } i / \-CHjOSOjNHR, ! ‘Λ-Λ. (I) !
R«, R3 I
hvori i 5 X er CH2 eller oxygen. !
Rj er hydrogen eller al kyl, og R2, R3, R4 og Rg, uafhængigt af hinanden, er hydrogen eller lavere al kyl og, når X er CH2, er R^ og Rg eventuelt alkengrupper, der tilsammen danner en benzenring og, når X er oxygen, danner R2 og R3 og/ 10 eller R4 og Rg eventuelt en methyl endioxygruppe med formel (II) \ /°_ (II)
Pi'S- hvori 15 Rg og R7, som er ens eller forskellige, er hydrogen, lavere al kyl eller al kyl, som tilsammen danner en cyclopentyl- eller cyclohexylring.
Rj er især hydrogen eller al kyl med 1 til 4 carbonatomer såsom methyl, ethyl og isopropyl. I hele beskrivelsen betyder "alkyl" ligekædede og forgrenede alkylgrupper. Specifikke alkylgrupper for R2, 20 Rj, R4, Rg, Rg og Ry omfatter methyl, ethyl, isopropyl og n-propyl. Når X er CH2, kan R^ og Rg kombineres til dannelse af en benzenring, der er fusioneret til den 6-leddede, X-holdige ring, dvs. at R^ og Rg definerer al katrienylgruppen =CH-CH=CH-CH=.
En speciel gruppe forbindelser med formel (I) er sådanne, hvori X 25 er oxygen og både R2 og Rg og R^ og Rg tilsammen danner methylendioxy-grupper med formel (II), hvori Rg og Ry begge er hydrogen og al kyl eller tilsammen danner en spiro-cyclopentyl- eller cyclohexylring, især, når Rg og Ry begge er al kyl såsom methyl. En anden gruppe forbindelser er sådanne, hvori X er CH2 og R^ og Rg danner en benzenring. En tredje 30 gruppe forbindelser med formel (I) er sådanne, hvori både R2 og Rg er hydrogen.
Forbindelserne med formel (I) kan syntetiseres ved hjælp af følgende fremgangsmåde:
Omsætning af en alkohol med formlen RCHgOH, hvor R har formlen 35 (III) -O. (III) R, Rj
DK 165003 B
3 med sulfurylchlorid med formlen SOgCl^ i nærværelse af en base såsom triethylamin eller pyridin ved en temperatur på ca. -40 til 25°C i et opløsningsmiddel såsom diethylether eller methylenchlorid til dannelse af et chlorsulfat med formlen RCHgOSi^Cl.
5 Chlorsulfatet med formlen RCH20S02C1 kan dernæst omsættes med en amin med formlen RjNH2 ved en temperatur på ca. -40 til 25°C i et opløsningsmiddel såsom methylenchlorid eller acetonitril til dannelse af en forbindelse med formel (I). Omsætningsbetingelserne er også beskrevet af T. Tsuchiya, et al., i Tet. Letters, nr. 36, side 3365-3368 10 (1978).
Udgangsforbindelserne med formlen RCH20H kan fås kommercielt eller som kendt i teknikken. Eksempelvis kan udgangsforbindelser med formlen RCHgOH, hvori både R2 og Rg og R^ og Rg er identiske og har formlen (II), opnås ved fremgangsmåderne ifølge R.F. Brady i Carbohydrate 15 Research, bind 15, side 35-40 (1970), eller ved omsætning af trimethyl-silylenoletheren af en RgCORj-keton eller -aldehyd med fruktose ved en temperatur på ca. 25°C i et opløsningsmiddel såsom et halogencarbon, fx. methylenchlorid, i nærværelse af en protisk syre såsom saltsyre eller en Lewis-syre såsom zinkchlorid. Trimethylsilylenoletherreaktionen er be-20 skrevet af G. L. Larson et al i J. Org. Chem., bind 38, nr. 22, side 3935 (1973).
Desuden kan carboxylsyrer og aldehyder med formlen RCOOH og RCHO reduceres til forbindelser med formel RCHgOH ved standard-reduktionsteknikker, fx. omsætning med lithiumaluminiumhydrid, natriumborhydrid 25 eller boran-THF-kompleks i et inert opløsningsmiddel såsom dig!yme, THF eller toluen ved en temperatur fra ca. 0 til 100°C, fx. som beskrevet af H.O. House i "Modern Synthetic Reactions", 2. oplag, side 45-144 (1972).
Forbindelserne ifølge opfindelsen omfatter forskellige individuelle isomere samt racematerne deraf, fx. de forskellige forbindelser, hvori 30 R2, Rg> R^ og Rg er bundet i alfa- eller beta-stilling i forhold til den 6-leddede ring, dvs. under og over tegningens plan. Fortrinsvis er methylendioxygruppens (II) oxygener bundet på samme side af den 6-leddede ring.
Forbindelserne med formel (I) er nyttige som antikonvulsiviske 35 midler. Den antikonvulsiviske aktivitet af forbindelserne bestemtes under anvendelse af en standard "maksimal elektrochock-test" (MES). I denne test indikeres aktivitet ved en blokering af den toniske ekstensor-spasme, der frembringes ved påføring af et elektrisk chock til
DK 165003 B
4 mus via hornhindeelektroder som beskrevet af Swinyard, et al., i J.
Pharmacol. Exptl. Therap. 106, 319 (1952), og anføres som % blokering.
En nyere beskrivelse af nutidig antikonvulsivisk lægemiddel-screening kan findes i Swinyard, et al., Epilepsia 19, 409 (1978).
5 Den antikonvulsiviske aktivitet af forbindelser med formel (I), der testes iht. Swinyard-metoden (1952), vises i den følgende tabel (I):
Tabel (I) 10 Eksempel Forbindelse MES-test EDgg *(mg/kg, i.p.) 1 /-—o 195 / \-CH,OSO,NH, 15 CH, 2 ^ ^t-C8,0S0,NH, 270 O CH,OSO,NH, 20 3 ch‘^/^Vch* 26 cC° CH‘ _0 ch^so.hhch, 70% blok ved 200 mg/kg} i p 4 ch^*>^Vch‘ 25 CHj CH, - CH,OSO,NH, 5 O 55 30 ♦Medmindre andet er anført.
Til behandling af epilepsi kan der i et voksent gennemsnitsmenneske anvendes en forbindelse med formel (I) i en daglig dosering i området fra ca. 30 til 2000 mg, sædvanligvis i 2 til 4 doser.
35 En enhedsdosis indeholder ca. 10 til 500 mg aktiv bestanddel.
Almindeligvis kan forbindelser med formel (I) anvendes til behandling af epilepsi på en måde, der ligner den, der anvendes med phenytoin. Medicinske aspekter af behandlingen af epilepsi er 5 beskrevet af L.S. Goodman, et al., i "The Pharmacological Basis of Therapeutics", 5. oplag, s. 201-226, Macmillan (1975).
Desuden inhiberer forbindelser med formel (I) carbonsyreanhy-drase, som vist ved de af S.J. Dodgson. et al., i The Proc. Natl.
5 Acad. Sci., USA, 77, s. 5562-5566 (1980) eller af N. Itada, et al., i The Journal Biol. Chem., 252, s. 3881-3890 (1977) beskrevne fremgangsmåder og er som sådanne anvendelige til behandling af glaukom. Sammenhængen mellem behandling af glaukom og carbon-syreanhydrase-inhi bering er beskrevet af A. Stein, et al., i The 10 American Journal of Opthalmology, 95:222-228 (1983). Til behandling af glaukom kan en forbindelse med formel (I) administreres systemisk, fx. ad oral eller parenteral vej som beskrevet nedenfor, eller topisk i øjet som en mineralolieopløsning eller -suspension, eller vandig suspension. Når forbindelsen anvendes systemisk, administre-15 res den i en mængde fra ca. 50 til 500 mg per dag for et voksent gennemsnits-menneske, mens den topiske dosering er ca. 1 til 3 dråber (per øje) af en opløsning eller suspension, der indeholder ca. 1 til 5 vægt-% af en forbindelse med formel (I), idet dosen administreres ca. 1 til 4 gange daglig.
20 Den foreliggende opfindelse omfatter mellemprodukter med formlen rch2oso2ci.
I de følgende eksempler og i hele beskrivelsen anvendes følgende forkortelser: g (gram), ml (milliliter), cm (centimeter), v/v (volumen til volumen), smp. (smeltepunkt), TLC (tyndtlagskromatografi), NMR 25 (kernemagnetisk resonans), IR (infrarød), DMF (dimethylformamid), THF (tetrahydrofuran) og C, Η, N, etc. (de kemiske symboler for grundstofferne) .
Eksempel 1 30 (Tetrahydro-2H-pyran-2-ylImethansulfamat
Til en kold opløsning (-5°C) af tetrahydropyran-2-methanol (2,33 g, 0,02 mol) i DMF (40 ml) sattes 50% olieagtigt natriumhydrid (1,17 g, 0,024 mol som NaH). Efter omrøring i 45 minutter tilsattes sulfamoylchlorid (3,42 g, 0,03 mol) og omrøringen fortsattes i yder-35 ligere 45 minutter ved -5°C. Reaktionsblandingen hældtes i koldt vand og ekstraheredes med chloroform. Det organiske lag tørredes (Na2S0^) og opløsningsmidlerne fjernedes under vakuum, hvilke gav en sirup, der kromatograferedes på tør kolonne (der elueredes med ethyl acetat:hexan,
DK 165003 B
6 4:1 v/v), hvilket gav rent (tetrahydro-2H-pyran-2-yl)methansul famat som en svagt gul sirup, IR:(CHC13) 1180 cm"1 og 1370 cm"1 (0S02NH2).
Eksempel 2 5 (1-methylcyclohexyl Imethansulfamat
Til en kold opløsning (-4°C) af (1-methylcyclohexyl)methanol (6,2 g, 0,048 mol) i DMF (90 ml) sattes 50% olieagtigt natriumhydrid (82,81 g, 0,059 mol som NaH). Efter omrøring i 1 time tilsattes sulfamoylchlo-rid (7,82 g, 0,062 mol) og omrøringen fortsattes i yderligere 30 minut-10 ter ved -4°C. Reaktionsblandingen hældtes i koldt vand og ekstraheredes med toluen. Det organiske lag tørredes (Na^O^) og opløsningsmidlerne fjernedes under vakuum, hvilket gav en sirup, der krystalliserede efter afkøling. Omkrystallisation fra chloroform/ hexan gav rent (1-methyl-cyclohexyl)methansulfamat, smp. 40-42°C.
15
Eksempel 3 2,3:4,5-bi s-0-(1-methylethyl i den)-fl-D-fruktopyranosesulfamat
Til en kold opløsning (-4°C) af 2,3:4,5-di-0-isopropyliden-/l-fruktopyranose (75 g, 0,29 mol) i DMF (725 ml) sattes 50% olieagtigt 20 natriumhydrid (16,34 g, 0,34 mol som NaH). Efter omrøring i 90 minutter tilsattes sulfamoylchlorid (54,9 g, 0,48 mol) og omrøringen fortsattes i yderligere 3\ time ved denne temperatur. Reaktionsblandingen hældtes i koldt vand og ekstraheredes med toluen. Det organiske lag tørredes (Na2S04) og opløsningsmidlerne fjernedes 25 under vakuum, hvilket gav en sirup, som øjeblikkeligt krystalliserede. Omkrystall i sati on fra ethylacetat/hexan gav rent 2,3:4,5-bis--0-(l-methylethyliden)-j8-D-fruktopyranosesulfamat, smp. 125-126°C.
Eksempel 4 30 2,3:4,5-bi s-0-(1-methylethyl iden)-g-D-fruktopyranosemethylsul famat En opløsning af sulfonylchlorid (93 ml, 1,15 mol) i methylen-chlorid (100 ml) sattes dråbevis til en kold opløsning (-35°C) af 2,3:4,5-di-0-isopropyliden-/J-D-fruktopyranose (150 g, 0,58 mol) i methylenchlorid (400 ml) og pyridin (150 ml). Reaktionsblandingen 35 omrørtes og opvarmedes til stuetemperatur (25°C); den omrørtes i yderligere 2 timer. Opløsningsmidler fjernedes under vakuum. Det resulterende halvfaste stof opløstes i vandfri acetonitril (35 g, 150 ml) og methylamin bobledes igennem. Reaktionsbeholderen lukkedes tæt og
DK 165003 B
7 opløsningsmidler fjernedes under vakuum. Den resulterende sirup underkastedes væskekromatografi (tør kolonne ethyl acetat: hexan, 4:1), hvilket gav en lysegul sirup, 2,3:4,5-bis-0-(l-methylethyliden)-0-D-fruktopyranosemethylsul famat, som var homogent ifølge TLC og *H NHR.
5
Eksempel 5 (1,2,3,4-tetrahydro-2-naphthal enyl )methyl sul f amsyreester
Til en kold opløsning (-5°) af (l,2,3,4-tetrahydro-2-naphtha-lenyl)methanol (7,1 g, 0,044 mol) i DMF. (80 ml) sattes 50% olieagtigt 10 natriumhydrid (2,56 g, 0,054 mol som NaH). Efter omrøring i 45 minutter tilsattes sulfamoylchlorid (6,6 g, 0,057 mol) og omrøring fortsattes i yderligere 95 minutter ved -5°C. Reaktionsblandingen hældtes i koldt vand og ekstraheredes med toluen. Det organiske lag tørredes (NagSO^) og opløsningsmidlerne fjernedes under vakuum til dannelse af en 15 sirup, der øjeblikkeligt krystalliserede. Omkrystallisation fra chloro-form/hexan gav ren (l,2,3,4-tetrahydro-2-naphthalenyl)methylsulfamsyre-ester, smp. 108-109°C, som et hvidt fast stof.
Claims (3)
- 5 DK 165003B 8 Chlorsulfat med formlen RC^OSOgCl, hvor R har formlen (III): (IH)
- 10 R, R, 15 hvori R2, R3, R4 og Rg er, uafhængigt af hinanden, hydrogen eller lavere al kyl og, når X er CH2, er R4 og R5 eventuelt alkengrupper, der tilsammen danner en benzenring og, når X er oxygen, danner R2 og R3 og/eller R4 og Rg eventuelt en methyl endioxygruppe med formel (II)
- 20 Rfi ο χ / c r{ no- (II) hvori Rø og R^, som er ens eller forskellige, er hydrogen, lavere al kyl, 25 eller al kyl, som tilsammen danner en cyclopentyl- eller cyclohexylring. 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53547583 | 1983-09-26 | ||
| US06/535,475 US4513006A (en) | 1983-09-26 | 1983-09-26 | Anticonvulsant sulfamate derivatives |
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| Publication Number | Publication Date |
|---|---|
| DK198191A DK198191A (da) | 1991-12-09 |
| DK198191D0 DK198191D0 (da) | 1991-12-09 |
| DK165003B true DK165003B (da) | 1992-09-28 |
| DK165003C DK165003C (da) | 1993-02-08 |
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ID=24134409
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK457784A DK165004C (da) | 1983-09-26 | 1984-09-25 | Sulfamatderivater og farmaceutiske praeparater indeholdende disse |
| DK198191A DK165003C (da) | 1983-09-26 | 1991-12-09 | Chlorsulfat |
| DK199101982A DK173923B1 (da) | 1983-09-26 | 1991-12-09 | Azidosulfat |
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| Application Number | Title | Priority Date | Filing Date |
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| DK457784A DK165004C (da) | 1983-09-26 | 1984-09-25 | Sulfamatderivater og farmaceutiske praeparater indeholdende disse |
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| Application Number | Title | Priority Date | Filing Date |
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| DK199101982A DK173923B1 (da) | 1983-09-26 | 1991-12-09 | Azidosulfat |
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Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3997585A (en) * | 1974-12-30 | 1976-12-14 | Ortho Pharmaceutical Corporation | Aliphatic sulfamates |
-
1983
- 1983-09-26 US US06/535,475 patent/US4513006A/en not_active Expired - Lifetime
-
1984
- 1984-09-10 NZ NZ209494A patent/NZ209494A/en unknown
- 1984-09-24 CA CA000463864A patent/CA1241951A/en not_active Expired
- 1984-09-25 DK DK457784A patent/DK165004C/da not_active IP Right Cessation
- 1984-09-25 JP JP59198772A patent/JPS60109558A/ja active Granted
- 1984-09-25 AU AU33504/84A patent/AU564842B2/en not_active Expired
- 1984-09-25 NO NO843836A patent/NO170280C/no not_active IP Right Cessation
- 1984-09-25 FI FI843765A patent/FI79095C/fi not_active IP Right Cessation
- 1984-09-25 ZA ZA847550A patent/ZA847550B/xx unknown
- 1984-09-25 HU HU843621A patent/HU194540B/hu unknown
- 1984-09-25 DE DE8484306512T patent/DE3473143D1/de not_active Expired
- 1984-09-25 EP EP84306512A patent/EP0138441B1/en not_active Expired
- 1984-09-25 IE IE2444/84A patent/IE57684B1/en not_active IP Right Cessation
- 1984-09-25 AT AT84306512T patent/ATE36149T1/de active
- 1984-09-25 ES ES536225A patent/ES536225A0/es active Granted
- 1984-09-25 KR KR1019840005883A patent/KR920001775B1/ko not_active Expired
-
1991
- 1991-12-09 DK DK198191A patent/DK165003C/da not_active IP Right Cessation
- 1991-12-09 DK DK199101982A patent/DK173923B1/da not_active IP Right Cessation
-
1992
- 1992-06-02 MX MX9202630A patent/MX9202630A/es unknown
- 1992-07-21 JP JP4214693A patent/JPH05331132A/ja active Pending
-
1997
- 1997-05-09 NO NO1997004C patent/NO1997004I1/no unknown
-
1999
- 1999-08-18 NL NL990025C patent/NL990025I2/nl unknown
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