NO865177L - Analogifremgangsmaate for fremstilling av terapeutisk virksomme piperazinderivater av theofyllin og theobromin. - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk virksomme piperazinderivater av theofyllin og theobromin.Info
- Publication number
- NO865177L NO865177L NO865177A NO865177A NO865177L NO 865177 L NO865177 L NO 865177L NO 865177 A NO865177 A NO 865177A NO 865177 A NO865177 A NO 865177A NO 865177 L NO865177 L NO 865177L
- Authority
- NO
- Norway
- Prior art keywords
- piperazine
- hydroxypropyl
- formula
- hydrogen
- dihydro
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 28
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 title description 8
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Natural products O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 title description 5
- 229960004559 theobromine Drugs 0.000 title description 4
- 229960000278 theophylline Drugs 0.000 title description 4
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 112
- 150000003839 salts Chemical class 0.000 claims description 38
- 239000002253 acid Substances 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 150000002431 hydrogen Chemical group 0.000 claims description 15
- -1 1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 239000012458 free base Substances 0.000 claims description 10
- 230000003287 optical effect Effects 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 230000000172 allergic effect Effects 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 208000010668 atopic eczema Diseases 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 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
- 208000023504 respiratory system disease Diseases 0.000 claims description 5
- 208000024891 symptom Diseases 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- ZLFQPZNQYGVCOQ-UHFFFAOYSA-N 7-[3-[4-[3-(benzenesulfonyl)propyl]piperazin-1-yl]-2-hydroxypropyl]-1,3-dimethylpurine-2,6-dione Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CC(O)CN(CC1)CCN1CCCS(=O)(=O)C1=CC=CC=C1 ZLFQPZNQYGVCOQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
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- 125000004432 carbon atom Chemical group C* 0.000 description 6
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- YRFGJZXFUZOMGX-UHFFFAOYSA-N 3-chloropropylsulfonylbenzene Chemical compound ClCCCS(=O)(=O)C1=CC=CC=C1 YRFGJZXFUZOMGX-UHFFFAOYSA-N 0.000 description 5
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- 239000000969 carrier Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- QAGJABVPPQBKQB-UHFFFAOYSA-N hydron;7-[2-hydroxy-3-[4-(3-phenylsulfanylpropyl)piperazin-1-yl]propyl]-1,3-dimethylpurine-2,6-dione;chloride Chemical compound Cl.C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CC(O)CN(CC1)CCN1CCCSC1=CC=CC=C1 QAGJABVPPQBKQB-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 230000026536 negative regulation of muscle contraction Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000050 smooth muscle relaxant Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- DCQXTYAFFMSNNH-UHFFFAOYSA-M sodium;2-[bis(2-hydroxyethyl)amino]ethanol;acetate Chemical compound [Na+].CC([O-])=O.OCCN(CCO)CCO DCQXTYAFFMSNNH-UHFFFAOYSA-M 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/10—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 3 and 7, e.g. theobromine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Denne oppfinnelse angår piperazinderivater av theofyllin og theobromin og deres anvendelse for behandling av åndedrettssykdommer og allergisyksommer.
Theofyllin og theobromin er velkjente som diuretika, hjertestimulerende midler og relaksasjonsmidler for glatte muskler. Adde ring av denpiperazinholdige substituent tilfører en rekke farmakologiske aktiviteter som gjør de resulterende forbindelser anvendelige ved symptomatisk behandling av astma, høyfeber og andre åndedrettssykdommer, som f.eks. vanlig forkjølelse.
Piperazinderivater av theofyllin og theobromin er beskrevet i US patentskrifter nr. 4 374 835, 4 374 837 og 4 400 381.
Det har vist seg at de nye forbindelser som tilveiebringes i henhold til oppfinnelsen, oppviser en uventet høy grad av antihistaminisk aktivitet og lang tids varighet av virkningen.
I henhold til oppfinnelsen tilveiebringes nye forbindelser med formler I og II:
og de i farmasøytisk henseende aksepterbare syreaddisjonssalte: og optiske isomerer derav, i hvilke formler: M er valgt blant hydrogen, morfolin, benzylamino, di-n-lavere-alkylamino, n-lavere-alkylamino og hvor Ar er eventuelt substituert fenyl,
Z-| og 7>2 uavhengig av hverandre er valgt blant CH2, CHOB og C=0, hvor B er hydrogen eller alkanoyl,
Y er oxygen eller ingenting,
n er et helt tall fra 0 til 4, men ikke kan være 0 når Z-| er CHOB,
m er et helt tall fra 0 til 4, men ikke kan være 0 når Z2er CHOB,
R-| , R2og R3uavhengig av hverandre er hydrogen, halogen, hydroxy, trifluormethyl, alkyl eller alkoxy,
R4er lavere-alkyl, og
R5er hydrogen eller lavere-alkyl.
Oppfinnelsen angår videre farmasøytiske preparater som inneholder en effektiv mengde av en forbindelse med formel I eller II i kombinasjon med minst én i farmasøytisk henseende aksepterbar eksipient.
Oppfinnelsen angår videre en metode til å behandle eller lindre symptomene av åndedrettsforstyrrelser og allergiske forstyrrelser under anvendelse av de ovenfor beskrevne forbindelser eller farmasøytiske preparater som inneholder disse.
Videre angår oppfinnelsen fremgangsmåter for fremstilling av forbindelsene med formler I og II.
Nedenfor defineres noen betegnelser og uttrykk som benyttes i denne beskrivelse.
Med "alkyl'! menes en forgrenet eller uforgrenet mettet hydrocarbonkjede som inneholder 1-6 carbonatomer, såsom methyl, ethyl, propyl, tert-butyl, n-hexyl o.l.
Med "lavere-alkyl" menes en forgrenet eller uforgrenet, mettet hydrocarbonkjede som inneholder 1-4 carbonatomer, såsom methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, tert-butyl o.l.
Med "n-lavere-alkylamino" menes en aminogruppe som er monosubstituert med en uforgrenet, mettet hydrocarbonkjede med 1-4 carbonatomer, såsom methyl, ethyl, n-propyl og n-butyl.
Med di-n-lavere-alkylamino" menes en aminogruppe som er disubstituert med to uforgrenede, mettede hydrocarbon-kjeder med 1-4 carbonatomer som uavhengig av hverandre er valgt blant methyl, ethyl, n-propyl og n-butyl.
Med "alkoxy" menes -OR, hvor R er alkyl som ovenfor definert.
Med "alkanoyl" menes gruppen
hvor R er alkyl som ovenfor definert.
Med "halogen" menes klor, brom eller jod. Med "arylpiperazino" menes et radikal av formelen
hvor Ar er eventuelt substituert fenyl.
Med "substituert fenyl" menes at ett eller flere av hydrogenatomene på fenylringen er erstattet med grupper valgt blant lavere-alkyl, lavere-alkoxy, halogen og trifluormethyl. Substitueringen kan finne sted i en hvilken som helst av vinylringens stillinger, og høyst tre hydrogenatomer kan erstattes på denne måte.
Med "i farmasøytisk henseende aksepterbare syreaddisjonssalter" menes de salter som bibeholder de frie basers biologiske virkning og egenskaper, som ikke i biologisk henseende eller på annen måte er uønskede, og som dannes med uorganiske syrer, såsom saltsyre, hydrobromsyre, svovelsyre, salpetersyre, fosforsyre o.l., og med organiske syrer, såsom eddiksyre, propionsyre, glycolsyre, pyrovinsyre, oxalsyre, eplesyre, malonsyre, ravsyre, maleinsyre, fumarsyre, vinsyre, citronsyre, benzoesyre, kanelsyre, mandelsyre, methansulfon-syre, ethansulfonsyre, p-toluensulfonsyre, salicylsyre, o.l.
Forbindelsene med formler I og II kan fremstilles ved oxydasjon av en forbindelse av formelen: eller
hvor M, m, n, Z-| , Z2, R-| , R2 < R31 R4og R5er som angitt for forbindelsene med formler I og II, eller ved omsetning av et piperazin som bærer én av sidekjedene i forbindelsen med formel I eller II med en kilde for den andre sidekjede i forbindelsen med formel I eller II, eller ved overføring av den frie base av en forbindelse med formel I eller II til et i farmasøytisk henseende aksepterbart syreaddisjonssalt, eller ved overføring av et salt av forbindelsen med formel I eller II til en fri base, eller ved overføring av et salt av forbindelsen med formel I eller II til et annet salt, eller ved spalting av den racemiske form av forbindelsen med formel I eller II til de enkelte optiske isomerer.
Reaksjonsskjemaer 1, 2 og 3 illustrerer fremgangsmåter for fremstilling av forbindelsene med formler I og II.
I reaksjonsskjemaene betegner "R" den del av forbindelsene med formler 1, 2, I og II som har formelen:
hvor M, m, n, Z-| , Z2, R4og R5er som ovenfor angitt.
Forbindelsene angitt ved formler "1" og " 2" er de ikke-oxyderte forløpere for de tilsvarende nye forbindelser med henholdsvis formel I og formel II, og de har de følgende formler:
hvor M, m, n, Z-| , Z2, R-| , R2 / R3»R4og R5er som ovenfor angitt.
I. Forbindelser i hvilke Y er intet
Sulfinylforbindelsene bland de nye forbindelser (de hvor Y er intet) fremstilles som vist nedenfor i Reak-sj onsskj erna 1:
Reaksjonsskjema 1
Som vist i Reaksjonsskjerna 1 fremstilles sulfinylforbindelsene blant de nye forbindelser ved oxydasjon av de tilsvarende forbindelser med formel 1 eller 2. Oxydasjonen finner sted ved omsetning med ca. 1,1 ekvivalenter hydrogen-peroxyd i vann, og utføres ved en temperatur på fra 0 til 40°C, fortrinnsvis ved ca. 20°C. Reaksjonsblandingen omrøres deretter ved romtemperatur i 1-8 timer, fortrinnsvis i ca. 4 timer, og den resulterende forbindelse med formel I eller II isoleres på konvensjonell måte. Metoder for fremstilling av utgangsmaterialene med formler 1 og 2 er beskrevet i detalj i US patentskrifter nr. 4 374 835, 4 374 837 og 4 400 381. I US patentskrift nr. 4 374 835 beskrives fremstillingen av forbindelser med formel 1 hvor R4, R5hver er methyl og M er hydrogen. I US patentskrift nr. 4 400 381 beskrives fremstillingen av forbindelser med formel 1 hvor hver av gruppene R4, R5og M kan være hydrogen eller diverse substituenter
som ikke er hydrogen. I US patentskrift nr. 4 374 837 beskrives fremstillingen av forbindelser med formel 2.
II. Forbindelser hvor Y er oxygen
Sulfonylforbindelsene blant de nye forbindelser (de hvor Y er et oxygenmolekyl) fremstilles som vist i Reaksjonsskjemaer 2 og 3. I disse reaksjonssekvenser betegner X
en uttredende gruppe, såsom f.eks. en halogengruppe.
Som vist i Reaksjonsskjemaer 2 og 3 fremstilles sulfonylforbindelsene med formler I og II ved kondensasjon av en forbindelse med formel 4 med en forbindelse med formel 5 eller 6 (Reaksjonsskjerna 2) eller ved kondensasjon av en forbindelse med formel 8 med en forbindelse med formel 9 eller 10 (Reaksjonsskjema 3). Reaksjonen utføres med omtrent ekvimolare mengder reaktanter i nærvær av et polart oppløs-ningsmiddel, såsom f.eks. en vandig alkanol, en ren, polar alkohol, et kloralkan, et polart keton, vann eller, fortrinnsvis dimethylformamid. Det benyttes en basisk katalysator, såsom natrium- eller kaliumhydroxyd eller -carbonat, fortrinnsvis kaliumcarbonat, og reaksjonen utføres ved forhøyede temperaturer på 50-120°C, mest hensiktsmessig ved oppløs-ningsmidlets tilbakeløpstemperatur. Reaksjonen tillates å pågå i 12-36 timer, fortrinnsvis i 20-25 timer, og den resulterende forbindelse med formel I eller II isoleres så etter konvensjonelle metoder som vil være velkjente for en fagmann på området.
Forbindelser med formler 3, 5, 6, 7, 9 og 10 fremstilles som beskrevet i US patentskrifter nr. 4 374 835,
4 374 837 og 4 400 381.Forbindelser med formel 3 og 7 over-føres til de tilsvarende sulfoner med henholdsvis formel 4
og formel 8, ved oxydasjon med et egnet oxydasjonsmiddel, f.eks. med ca. 2 molekvivalenter metaklorperboenzoesyre (MCPBA). Reaksjonen utføres i et polart oppløsningsmiddel, såsom en vandig alkanol, en ren, polar alkohol, et kloralkan eller et klorketon, fortrinnsvis kloroform, i et tidsrom på 1-5 timer, fortrinnsvis i ca. 2 timer, i romtemperatur. Det resulterende sulfonmellomprodukt med formel 4 eller 8 isoleres så på i og for seg konvensjonell måte og omsettes med en egnet forbindelse med formel 5, henholdsvis 6 eller med formel 9, henholdsvis 10, for dannelse av den tilsvarende sulfonylforbindelse med formel I eller II.
Isolasjon og rensning av de sluttforbindelser og mellomprodukter som er vist i reaksjonsskjemaene eller som er beskrevet i den generelle del av beskrivelsen eller i eksemplene, kan foretas ved hjelp av en hvilken som helst egnet separasjons- eller renseprosedyre, såsom f.eks. ved filtrering, ekstraksjon, krystallisasjon, søylekromatografe-ring, tynnskiktkromatografering eller tykkskiktkromatografering eller gjennom en kombinasjon av disse prosedyrer. Spesifikke eksempler på egnede separerings- og isoleringsprosedyrer vil finnes i de nedenstående eksempler. Imidlertid kan selvfølgelig også andre effektive separerings- eller isoleringsprosedyrer benyttes.
Også saltene isoleres etter konvensjonelle metoder. Eksempelvis kan reaksjonsblandingene inndampes til tørrhet
og saltene renses ytterligere ved hjelp av konvensjonelle metoder.
De av de nye forbindelser hvor Z-| og/eller Z2er CHOB, inneholder minst ett chiralsenter. Disse forbindelser kan fremstilles enten i optisk aktiv form eller som racemiske blandinger. Med mindre annet er spesifikt angitt, foreligger de her beskrevne forbindelser alle i den racemiske form. Imidlertid omfattes både de enkelte optiske isomerer og de racemiske former av forbindelsene med formler I og II innenfor rammen av oppfinnelsen.
Om ønsket, kan de nye forbindelser spaltes i deres optiske antipoder ved hjelp av konvensjonelle spaltningsme-toder, f.eks. ved separasjon (f.eks. fraksjonert krystallisasjon) av de diastereomere salter som dannes ved omsetning av disse forbindelser med optisk aktive syrer. Eksempler på
slike optisk aktive syrer er de optisk aktive former av kamfer-10-sulfonsyre, 2-brom-kamfer-sulfonsyre, kamfersyre, methoxyeddiksyre, vinsyre, eplesyre, diacetylvinsyre, pyrro-lidin-5-carboxylsyre o.l. De utseparerte rene diastereomere
salter kan så spaltes ved hjelp av standardmetoder for å tilveiebringe de respektive optiske isomerer av forbindelsene med formel I og formel II.
De viste reaksjonsskjemaer angir fremgangsmåter for fremstilling av samtlige av de nye forbindelser. Dessuten kan forbindelser med formler I og II hvor Z-| og/eller Z2er C=0, reduseres til de tilsvarende alkoholer med formel I under anvendelse av et metallhydrid, såsom KBH4eller NaBH4i et polart oppløsningsmiddel, såsom vandig methanol. Reaksjonen utføres ved at carbonylforbindelsen oppløses i det valgte oppløsningsmiddel og at det tilsettes et overskudd (størrelen av overskuddet avhenger av bireaksjonen med opp-løsningsmidlet) av hydridet i små porsjoner under omrøring, inntil reaksjonen er fullført. Temperaturen holdes ved 0-25°C, fortrinnsvis ved 4-15°C.
Omvendt kan forbindelser med formler I og II hvor Z-j og/eller Z2er CHOH oxyderes til de tilsvarende carbonylfor-bindelser under egnede milde betingelser. Egnede oxydasjons-midler er f.eks. fortynnet nøytralt permanganat eller kromsyre, fortrinnsvis permanganat. Alkoholforbindelsen oppløses i et polart oppløsningsmiddel, såsom vann, aceton, methylethylketon eller eddiksyre, og en oppløsning av oxydasjonsmidlet tilsettes inntil reaksjonen er fullført. I enkelte tilfeller kan reaksjonen alternativt utføres med et aprotisk oppløsningsmid-del, såsom diklormethan. Det kreves omtrent støkiometriske mengder oxydasjonsmiddel. Temperaturen holdes ved 5-30°C, fortrinnsvis ved 15-20°C.
Forbindelser med formler I og II hvor Z-| og/eller
Z2er CHOH, kan forestres til de tilsvarende alkanoylderivater. Dette utføres ved oppvarmning av forbindelsen med formel I eller II med et molart overskudd av det egnede carboxylsyre-anhydrid eller -klorid i et tertiært amin som oppløsnings-middel, f.eks. pyridin. Temperaturen holdes ved 20-90°C, fortrinnsvis ved 15-30°C.
Omvendt kan forbindelsene med formler I og II hvor
Z-| og/eller Z2er CHOOCR, hydrolyseres til de tilsvarende alkoholer under anvendelse av konvensjonelle metoder som vil være velkjente for en fagmann på området. Esteren oppvarmes i en vannoppløsning med en sur eller basisk katalysator inntil hydrolysen er fullført.
Forbindelser med formel I eller II hvor Z-| er CH2
og Y er oxygen, kan fåes direkte ved behandling av en forbindelse med formel (1) eller (2) med et egnet oxydasjonsmiddel, f.eks. med ca. 2 ekvivalenter metaklorperbenzoesyre (MCPBA) i et polart oppløsningsmiddel, såsom en vandig alkanol, en ren, polar alkohol, et kloralkan eller et klorketon, fortrinnsvis kloroform, i et tidsrom på 1-5 timer, fortrinnsvis i ca. 2 timer, ved romtemperatur. Den resulterende sulfonylforbindelse med formel I eller II isoleres deretter på i og for seg konvensjonell måte.
Salter av forbindelsene med formel I og II fremstilles ved omsetning av de tilsvarende frie baser med egnede syrer eller sure salter ved en temperatur mellom 0°C og 100°C. Omvendt kan de frie baser fremstilles ved omsetning av tilsvarende syreaddisjonssalter med egnede alkaliske midler, såsom natrium- eller kaliumhydroxyd, ved 0-100°C.
Forbindelsene med formel I, som kan være fremstilt på en hvilken som helst av de ovenfor beskrevne måter, over-føres eventuelt til den frie base eller til et hvilket som helst salt, som kan innbefatte, men som ikke er begrenset til, de i farmasøytisk henseende aksepterbare syreaddisjonssalter, eller til en optisk isomer.
Foretrukne forbindelser blant de nye forbindelser er de i hvilke n og m er 1 , Z-j og Z2er CHOH eller CH2, R5er lavere-alkyl, og minst én av substituentene R-) , R2og R3er hydrogen, og de i farmasøytisk henseende aksepterbare syreaddisjonssalter derav.
Mer foretrukne er de forbindelser hvor Z-| og Z2uavhengig av hverandre betegner CH2eller CHOH, M er hydrogen, minst én av substituentene R4og R5er methyl og minst to av substituentene R-| , R2og R3er hydrogen.
Blant disse er de mest foretrukne forbindelser de forbindelser med formel I hvor n og m begge er 1 , Z-| og Z2
er CHOH eller CH2, R-] , R2og R3hver er hydrogen og R4og R5begge er methyl, og de i farmasøytisk henseende aksepterbare syreaddisjonssalter derav.
Mest foretrukne er: 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfinylpropyl)-piperazin
og
1 - [ 3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropylJ-4-(3-fenylsulfonylpropyl)-piperazin. Virkning og administrering
De nye forbindelser er særlig effektive antihista-miner. De har vist seg å motvirke virkningene av histamin ved en rekke forskjellige tester som benyttes for påvisning av slik aktivitet, deriblant ved tester på forhindring av anafylaktiske sjokk hos rotter, bronkieutvidelse hos marsvin, inhibiering av muskelkontraksjonen i respons til stress hos rotter og brachycardiale virkninger hos marsvin. I tillegg har de nye forbindelser langvarig virkning in vivo, vanligvis i 16-24 timer. Derfor er forbindelsene særlig anvendelige ved behandling av åndedrettssykdommer og allergiske reaksjoner hos pattedyr, deriblant astma, høyfeber og vanlig forkjølelse. Forbindelsene med formler I og II kan også påføres topisk og er således anvendelige for behandling av allergiske dermatose-tilstander, såsom pruritis og andre allergiske hudlidelser.
Administreringen av de aktive forbindelser, salter og optiske isomerer derav som her er beskrevet, kan foretas på en hvilken som helst måte som benyttes for administrering av antihistaminiske midler som lindrer congestio eller på annen måte lindrer allergiske symptomer eller andre åndedretts-symptomer. Disse metoder innkluderer oral, parenteral og annen systemisk administrering og administrering i aerosol-former. Avhengig av administreringsmåten kan preparatene foreligge i form av faste, halvfaste eller væskeformige preparater, såsom f.eks. tabletter, stikkpiller, piller, kapsler, pulvere, væsker, suspensjoner og lignende, idet de fortrinnsvis foreligger i enhetsdoseformer som egner seg for administrering av nøyaktige doser.
Preparatene vil inneholde en konvensjonel farmasøy-tisk bærer eller eksipient og en aktiv forbindelse med formel I eller et i farmasøytisk henseende aksepterbart salt derav, samt eventuelt andre medisinske stoffer, farmasøytiske midler, bærere, hjelpestoffer osv.
Mengden av aktiv forbindelse som administreres,
vil selvfølgelig være avhengig av pasienten som skal behandles, graden av tilstanden, administreringsmetoden og legens bedøm-melse av situasjonen. Imidlertid vil en effektiv dose være i området fra 1 jig til 1 mg pr. kg pr. dag, fortrinnsvis 5-500 ng/kg/dag. For et menneske av gjennomsnittsvekt 70 kg vil dette svare til fra 70 \ iq til 70 mg pr. dag eller fortrinnsvis fra 350 ug til 70 mg pr. dag.
Typiske preparater inneholder 0,01-95 vekt% aktiv bestanddel, idet resten utgjøres av én eller flere akseptable, ikke toksiske bærere. Den prosentvise mengde aktiv bestanddel vil selvfølgelig avhenge av preparatformen og administreringsmåten.
For faste preparater innbefatter konvensjonelle ikke-toksiske, faste bærere f.eks. farmasøytiske kvaliteter av mannitol, lactose, stivelse, magnesiumstearat, natriumsaccharin, talkum, cellulose, glucose, sucrose, magnesiumcarbonat o.l. Den ovenfor definerte aktive forbindelse kan benyttes i stikkpiller utblandet med f.eks. av polyalkylen-glycoler, f.eks. propylenglycol som bærer. Væskeformige farmasøytisk administrerbare preparater kan for eksempel fremstilles ved oppløsning, dispergering, osv. av en aktiv forbindelse som ovenfor definert og eventuelle farmasøytiske hjelpestoffer i en bærer, såsom f.eks. vann, saltoppløsning, vandig dextrose, glycerol, ethanol o.l., slik at det dannes en oppløsning eller suspensjon. Om ønsket, kan det farmasøy-tiske preparat som skal administreres, også inneholde mindre mengder ikke-toksiske hjelpestoffer, såsom fuktemidler eller emulgeringsmidler, pH-buffere o.l., f.eks. natriumacetat, sorbitanmonolaurat, triethanolaminnatriumacetat, triethanolaminoleat, osv. Anvendelige metoder for fremstilling av slike preparater vil være kjent for en fagmann på området, eller vil kunne finnes beskrevet i f.eks. Remington's Pharma-ceutical Sciences, Mack Publishing Company, Easton, Pennsyl-vania, 15de utgave, 1975. Preparatet som skal administreres, vil i ethvert tilfelle inneholde en mengde av den eller de aktive forbindelser som er effektiv med hensyn til å lindre symptomene hos pasienten som behandles.
For oral administrering dannes et i farmasøytisk henseende aksepterbart ikke-toksisk preparat gjennom innlem-melse av en hvilken som helst av de vanligvis benyttede eksipienter, såsom f.eks. farmasøytiske kvaliteter av mannitol, lactose, stivelse, magnesiumstearat, natriumsaccharin, talkum, cellulose, glucose, sucrose, magnesiumcarbonat o.l. Slike preparater har form av oppløsninger, suspensjoner, tabletter, piller, kapsler, pulvere, preparater for frigjøring av den aktive bestanddel over lengre tid, o.l. Preparatene kan inneholde 2-95% aktiv bestanddel, fortrinnsvis 5-25%.
Parenteral administrering foretas vanligvis ved injeksjon, enten subkutant, intramuskulært eller intravenøst. Injiserbare preparater kan fremstilles i konvensjonelle former, enten som væskeoppløsninger eller som suspensjoner,
i faste former som egner seg for oppløsning eller oppslemning i væske før injeksjonen foretas, eller som emulsjoner. Egnede eksipienter er f.eks. vann, saltoppløsning, dextrose, glycerol, ethanol o.l. dessuten kan de farmasøytiske preparater som administreres, om ønskes også inneholde mindre mengder ikke-toksiske hjelpestoffer, såsom fuktemidler eller emulgeringsmidler, pH-buffere o.l., såsom f.eks. natriumacetat, sorbitanmonolaurat, triethanolaminoleat, osv.
Ved en mer nylig utviklet metode for parenteral administrering benyttes et legemiddelavgivelsessystem som gir regulert frigjørelse eller langvarig frigjørelse av den aktive bestanddel, slik at en konstant dosering opprettholdes. Eksempler på slike systemer er implantede systemer for vedvarende frigjørelse av den aktive bestanddel, væskeinfusjons-pumper, orale doseringsformer for vedvarende frigjøring av den aktive bestanddel o.l.
For systemisk administrering ved hjelp av stikkpiller innbefatter tradisjonelle bindemidler og bærere f.eks. poly-alkylenglycoler og triglycerider. Slike stikkpiller kan dannes ut fra blandinger som inneholder den aktive bestanddel i en mengde av fra 0,1 til 10%, fortrinnsvis fra 0,5 til 2%.
For administrering med en aerosol vil den aktive bestanddel fortrinnsvis foreligge i findelt form sammen med et overflateaktivt middel og et drivmiddel. Typiske prosent-andeler for de aktive bestanddeler er 0,01-20 vekt%, fortrinnsvis 0,04-1,0%.
De overflateaktive midler må selvfølgelig være ikke-toksiske, og de bør fortrinnsvis være oppløselige i drivmidlet. Representative slike midler er esterne eller de partielle estere av fettsyrer inneholdende 6-22 carbonatomer, såsom capronsyre, octansyre, laurinsyre, palmitinsyre, stea-rinsyre, linolsyre, linolensyre, oleostearinsyre og oljesyre, med en alifatisk flerverdig alkohol eller et syklisk anhydrid av en slik, såsom f.eks. ethylenglycol, glycerol, erythritol, arabitol, mannitol, sorbitol, hexitolanhydridene avleded fra sorbitol (sorbitanesterne som føres i handelen under varemerket "Spans") og polyoxyethylen- og polyoxypropylenderivatene av disse estere. Også blandede estere, såsom blandede eller naturlig forekommende glycerider, kan benyttes. De foretrukne overflateaktive midler er oleatene av sorbitan, f.eks. de som selges under varemerkene "Arlacel C" (Sorbitanseskvioleat), "Span 80" (sorbitanmonooleat) og "Span 85" (sorbitantrioleat). Det overflateaktive middel kan utgjøre 0,1-20 vekt% av preparatet, fortrinnsvis 0,25-5 vekt%.
Resten av preparatet utgjøres vanligvis av drivmidlet. Forvæskede drivmidler er vanligvis gasser ved omgivel-senes temperatur, og de kondenseres under trykk. Blant egnede forvæskede drivmidler kan nevnes de lavere alkaner inneholdende inntil 5 carbonatomer, såsom butan og propan, og fortrinnsvis de fluorerte eller fluorklorerte alkaner, såsom de som selges under varemerket "Freon". Også blandinger av de ovennevnte drivmidler kan benyttes.
For fremstilling av aerosolen blir en beholder som er utstyrt med en egnet ventil, fylt med det passende drivmiddel inneholdende den findelte aktive bestanddel og overflateaktivt middel. Bestanddelene holdes således ved et forhøyet trykk inntil de frigjøres ved aktivering av ventilen. De følgende Fremstillinger og Eksempler illustrerer henholdsvis fremstillingen av utgangsmaterialer og fremstillingen av de nye terapeutisk virksomme forbindelser.
Fremstilling I
3- fenylsulfonyl- 1- klorpropan og beslektede forbindelser med formel 4
A. 3-fenylsulfonyl-1-klorpropan
18,6 g (0,1 mol) 3-fenylthio-1-klorpropan oppløses i kloroform og omsettes med 2 molekvivalenter metaklorperbenzoesyre ved romtemperatur i to timer. Benzoesyren som dannes ved reaksjonen, fraskilles ved filtrering. Kloroform-oppløsningen vaskes med natriumcarbonat i vann, tørres og inndampes under vakuum, hvorved det fåes 3-fenylsulfonyl-1-klorpropan i form av en olje og med de følgende karakteristika:
RMN 60 MHZ i CCL4(referanse:tetramethylsilan):
8 ppm mult. 2 H aromater 3,5;
7,6 ppm mult. 3H aromater 2,4,6;
3,5 ppm tripl. 2H CH2CI;
3,2 ppm tripl. 2H Ph-S02CH2-CH2
B. På tilsvarende måte,idet man i stedet starter med andre passende forbindelser med Formel 3, fremstilles de følgende forbindelser med Formel 4: 3-fenylsulfonyl-1-klor-2-hydroxypropan, 3-(4-klorfenyl)-sulfonyl-1-klorpropan, 3-(4-klorfenyl)-sulfonyl-1-klor-2-hydroxypropan, 3-(3-methylfenyl)-sulfonyl-1 -klorpropan, 3-(3-methylfenyl)-sulfonyl-1-klor-2-hydroxypropan, 3-(4-methoxyfenyl)-sulfonyl-1 - klorpropan, 3-(4-methoxyfenyl)-sulfonyl-1-klor-2-hydroxypropan, 3-(4-methylfenyl)-sulfonyl-1 - klorpropan, 3-(4-methylfenyl)-sulfonyl-1-klor-2-hydroxypropan, 3-(4-klor-3,5-dimethylfenyl)-sulfonyl-1-klorpropan,
3-(4-klor-3,5-dimethylfenyl)-sulfonyl-1-klor-2-hydroxypropan,
3-(2,6-dimethylfenyl)-sulfonyl-1-klorpropan,
3-(2,6-dimethylfenyl)-sulfonyl-1-klor-2-hydroxy-propan, 3-(3,4,5-trimethoxyfenyl)-sulfonyl-1 -klorpropan, 3-(3,4,5-trimethoxyfenyl)-sulfonyl-1-klor-2-hydroxy-propan, 3-(4-trifluormethylfenyl)-sulfonyl-1-klorpropan, 3-(4-trifluormethylfenyl)-sulfonyl-1-klor-2-hydroxy-propan, 3-(4-ethylfenyl)-sulfonyl-1-klorpropan, 3-(4-ethylfenyl)-sulfonyl-1-klor-2-hydroxypropan, 3-(4-bromfenyl)-sulfonyl-1-klorpropan, 3-(4-bromfenyl)-sulfonyl-1-klor-2-hydroxypropan, 3- (4-klorfenyl)-sulfonyl-1-klorbutan, 4- (. 4-klor f enyl) - sulfonyl-1 -klor-2-hydroxybutan, 2-(3-methylfenyl)-sulfonyl-1-klorethan, 5- (3-methylfenyl)-sulfonyl-1-klor-2-hydroxypentan, 6- (4-methoxyfenyl)-sulfonyl-1-klorhexan og 6-(4-methoxyfenyl)-sulfonyl-1-klor-2-hydroxyhexan.
Eksempel 1
1 -[3-(1 ,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl1-4-(fenylsulfinylpropyl)-piperazin og beslektede forbindelser med Formler I og II
A. 0,1 mol 1-[3-(1 ,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylthiopropyl)-piperazin-hydroklorid i 200 ml avionisert vann holdt ved 20°C. 120 ml hydro-genperoxyd i 250 ml vann ble tilsatt dråpevis. Blandingen ble omrørt i 4 timer ved romtemperatur. Reaksjonens fullførelse ble sjekket ved tynnskiktkromatografering (TLC) under anvendelse av en blanding av CH2Cl2/methanol/NH40H i mengdeforholdet 80/20/1 som elueringsmiddel. Etter fullført reaksjon ble reaksjonsblandingen gjort alkalisk, ekstrahert med methylen-klorid, vasket med vann og tørret, hvoretter oppløsningsmid-let ble avdampet under vakuum. Derved fikk man 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfinylpropyl)-piperazin i form av den frie base. Hydrokloridsaltet ble fremstilt etter den metode som er beskrevet i Eksempel 3. Smeltepunkt 260-265°C. B. På tilsvarende måte, idet man i stedet starter med andre passende forbindelser med Formel 1 , fremstilles de følgende forbindelser med formel I: 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfinyl-2-hydroxypropyl)-piperazin, 1 - [3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-klorfenyl)-sulfinylpropyl)-piperazin, 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-klorfenyl)-sulfinyl-2-hydroxy-propyl )-piperazin, 1 - [3-(1 ,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(3-methylfenyl)-sulfinylpropyl)-piperazin, 1 - f 3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(3-methylfenyl)-sulfinyl-2-hydroxy-propyl )-piperazin, 1 -t 3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methoxyfenyl)-sulfinylpropyl)-piperazin, 1 - [ 3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methoxyfenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 - [3-(3-i-propyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methylfenyl)-sulfinyl-propyl )-piperazin, 1 - [3-(3-i-propyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3 -(4-methylfenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -[3-(3-i-butyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-klor-3,5-dimethyl-fenyl)-sulfinylpropyl)-piperazin, 1 -[3-(3-i-butyl-1-methyl-3,7-dihydro-1 H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-klor-3,5-dimethyl-fenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -[3-(3-n-propyl-1-methyl-3,7-dihydro-1 H-purin- 2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(2,6-dimethylfenyl)-sulfinylpropyl)-piperazin, 1 -13-(3-n-propyl-1-methyl-3,7-dihydro-1 H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(2,6-dimethylfenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -[3-(3-n-butyl-1-methyl-3,7-dihydro-1 H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(3,4,5-trimethoxyfenyl)-sulfinylpropyl)-piperazin, 1 -[3-(3-n-butyl-1-methyl-3,7-dihydro-1 H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(3,4,5-trimethoxyfenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -[3-(1 ,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-trifluormethylfenyl)-sulfinyl-propyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(3-(4-trifluormethylfenyl)-sulfinyl-2-hydroxy-propyl )-piperazin, 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-ethylfenyl)-sulfinylpropyl)-piperazin, 1 — [3 — (1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(3-(4-ethylfenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-bromfenyl)-sulfinylpropyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(3-(4-bromfenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(4-(4-klorfenyl)-sulfinylbutyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(4-(4-klorfenyl)-sulfinyl-2-hydroxybutyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(2-(3-methylfenyl)-sulfinylethyl)-piperazin, 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(5-(3-methylfenyl)-sulfinyl-2-hydroxypentyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(6-(4-methoxyfenyl)-sulfinylhexyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(6-(4-methoxyfenyl)-sulfinyl-2-hydroxyhexyl)-piperazin, 1 -[3-(8-morfolin-3-i-butyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfinyl-propyl )-piperazin, 1 -[3-(8-morfolin-1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl] - 4-(3-(4-fenylsulfinylpropyl)-piperazin, 1 -[3-(8-morfolin-1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methylfenyl)-sulfinyl-propyl )-piperazin, 1 -[3-(8-morfolin-3-n-butyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfinyl-propyl )-piperazin, 1 -[3-(8-di-n-butylamin-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methylfenyl)-sulfinyl-propyl )-piperazin, 1 -[3-(8-di-n-butylamin-1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfinyl-2-hydroxypropyl)-piperazin, 1 -[3-(8-benzylamino-1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]- 4-(6-fenylsulfiny1-2-hydroxy-hexyl)-piperazin og 1 -[3-(8-(1 -(2-methoxyfenyl)-piperazin-4-yl)-1 ,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropylJ-4-(3-fenylsulfinylpropyl)-piperazin. C. På tilsvarende måte, idet man i stedet starter med andre passende forbindelser med Formel 2, fremstilles de følgende forbindelser med Formel II: 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-fenyl-sulf inylpropyl )-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-fenylsulfinyl-propyl )-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-klorfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(4-klorfenyl)-sulfinylpropyl)-piperazin,
1-(3-theobromin-1-yl-2-hydroxypropyl) -4-(3-(4-methoxyfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(4-methoxyfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-methylfenyl)-sulfinylpropyl)-piperazin,
1—(3-theobromin-1-yl-propyl-4)-(3-(4-methylfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-y1-2-hydroxypropyl)-4-(3-(4-klor-3,5-dimethylfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(4-klor-3,5-dimethylfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(2,6-dimethy1-fenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(2,6-dimethyl-fenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hyrdoxypropyl)-4-(3-(3,4,5-trimethoxyfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl) -4-(3-(3,4,5-trimethoxyfenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-trifluormethylfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-trifluormethylfenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropy1)-4-(3-(4-ethylfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-ethylfenyl)-sulfiny1-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-bromfenyl)-sulfinylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl) - 4-(3-(4-bromfenyl)-sulfinyl-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(4-(4-klorfenyl)-sulfinylbutyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(4-(4-klorfenyl)-sulfinyl-2-hydroxybutylpiperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(2-(3-methylfenyl)-sulfinylethyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(5-(3-methylfenyl)-sulfinyl-2-hydroxypentyl)-piperazin og 1 -(3-theobromin-1-yl-2-hydroxypropyl) - 4-(6-(4-methoxyfenyl)-sulfinylhexyl)-piperazin.
Eksempel 2
1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfonylpropyl)-piperazin og beslektede forbindelser med Formler I og II
A. 0,13 mol 3-fenylsulfonyl-1-klorpropan fra Fremstilling I ble slått sammen med 0,14 mol 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-piperazin-dihydroklorid og 0,3 mol kaliumcarbonat i 600 g dimethylformamid. Blandingen ble omrørt natten over ved 60°C. Etter avkjøling ble reaksjonsblandingen hellet over i vann, ekstrahert med CH2CI2, vasket med vann, tørret og inndampet under forsiktig oppvarmning. Residuet ble omkrystallisert fra ethanol, hvorved men fikk 1 -13-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfonylpropyl)-piperazin i form av den frie base. Smeltepunkt 168°C. Dihydrokloridet ble dannet ved bruk av en 12N hydrogenkloridoppløsning på tilsvarende måte som beskrevet i Eksempel 3. Smeltepunkt 190°C.
B. På tilsvarende måte, idet man erstatter 3-fenylsulfonyl-1-klorpropan etter behov med andre passende forbindelser med Formel 4, hvis fremstilling er beskrevet under Fremstilling
1, og eventuelt benytter andre passende forbindelser med Formel 5 istedenfor 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-piperazin, fåes de følgende forbindelser med Formel I:
1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfonyl-2-hydroxypropyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl1-4-(3-(4-klorfenyl)-sulfonylpropyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-klorfenyl)-sulfonyl-2-hydroxy-propyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(3-methylfenyl)-sulfonylpropyl)-piperazin, 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(3-methylfenyl)-sulfonyl-2-hydroxy-propyl )-piperazin, 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methoxyfenyl)-sulfonylpropyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methoxyfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -[3-(3-i-propyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methylfenyl)-sulfonyl-propyl )-piperazin, 1 -[3-(3-i-propyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methylfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -[3-(3-i-buty1-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-klor-3,5-dimethy1-fenyl)-sulfonylpropyl)-piperazin, 1 -[3-(3-i-butyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-klor-3,5-dimethyl-fenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -[3-(3-n-propyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(2,6-dimethylfenyl)-sulfonylpropyl)-piperazin, 1 -13-(3-n-propyl-1-methyl-3,7-dihydro-1H-purin- 2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(2,6-dimethylfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -[3-(3-n-butyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(3,4,5-trimethoxyfenyl)-sulfonylpropyl)-piperazin, 1 -13-(3-n-butyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(3,4,5-trimethoxyfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-trifluormethylfenyl)-sulfonyl-propyl )-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(3-(4-trifluormethylfenyl)-sulfonyl-2-hydroxy-propyl )-piperazin, 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-ethylfenyl)-sulfonylpropyl)-piperazin, 1 -[3 -(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(3-(4-ethylfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -[3 - (1 , 3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-bromfenyl)-sulfonylpropyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(3-(4-bromfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(4-(4-klorfenyl)-sulfonylbutyl)-piperazin, 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl1-4-(4-(4-klorfenyl)-sulfonyl-2-hydroxybutyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(2-(3-methylfenyl)-sulfonylethyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(5-(3-methylfenyl)-sulfonyl-2-hydroxypentyl)-piperazin, 1 -[3-(1,3-dimethy1-3,7-dihydro-1H-purin-2, 6-dion-7-yl)-2-hydroxypropyl]-4-(6-(4-methoxyfenyl)-sulfonylhexyl)-piperazin, 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(6-(4-methoxyfenyl)-sulfonyl-2-hydroxyhexyl)-piperazin, 1 -[3-(8-morfolin-3-i-butyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfonyl-propyl )-piperazin, 1 -[3-(8-morfolin-1 ,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfonylpropyl)-piperazin, 1 -[3-(8-morfolin-1 ,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropylJ-4-(3-(4-methylfenyl)-sulfonyl-propyl )-piperazin, 1 -[3-(8-morfolin-3-n-butyl-1-methyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfonyl-propyl )-piperazin, 1 -[3-(8-di-n-butylamin-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-(4-methylfenyl)-sulfonyl-propyl )-piperazin, 1 -[3-(8-di-n-butylamin-1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfonyl-2-hydroxypropyl)-piperazin, 1 -[3-(8-benzylamin-1,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-propyl]-4-(6-fenylsulfonyl-2-hydroxy-hexyl)-piperazin og
1-[3-(8-(1—(2-methoxyfenyl)-piperazin-4-yl)-1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfonylpropyl)-piperazin.
C. På tilsvarende måte, idet man, om ønsket, starter med andre egnede forbindelser med Formel 4 og erstatter 1 — C3—(1,3 — dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl1 - piperazinet med tilsvarende forbindelser med Formel 6, fremstilles de følgende forbindelser med Formel II: 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-fenyl-sulf onylpropyl )-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-fenylsulfonyl-propyl )-piperaz in, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-klorfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(4-klorfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-methoxyfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(4-methoxyfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4 - ( 3 - ( 4-methylfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3 -(4-methylfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-klor-3,5-dimethylfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(4-klor-3,5-dimethylfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(2,6-dimethy1-fenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-propyl)-4-(3-(2,6-dimethy1-fenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hyrdoxypropyl) -4-(3-(3,4,5-trimethoxyfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(3,4,5-trimethoxyfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-trifluormethylfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-trifluormethylfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-ethylfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-ethylfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-bromfenyl)-sulfonylpropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(3-(4-bromfenyl)-sulfonyl-2-hydroxypropyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl) - 4-(4-(4-klorfenyl)-sulfonylbutyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(4-(4-klorfenyl)-sulfonyl-2-hydroxybutylpiperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(2-(3-methylfenyl)-sulfonylethyl)-piperazin, 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(5-(3-methylfenyl)-sulfonyl-2-hydroxypentyl)-piperazin og 1 -(3-theobromin-1-yl-2-hydroxypropyl)-4-(6-(4-methoxyfenyl)-sulfonylhexyl)-piperazin.
Eksempel 3
Overføring av den frie base til et salt
Et overskudd av 3%-ig hydrogenklorid i methanol settes til en oppløsning av 1,0 g 1 -13-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenyl-sulf inylpropyl ] -piperazin i 20 ml methanol. Diethylether tilsettes inntil utfellingen er fullført. Dihydrokloridet som fåes som produkt, frafiltreres, vaskes med ether, tørres i luft og omkrystalliseres. Smeltepunkt 260-265°C.
På tilsvarende måte kan samtlige forbindelser med Formler I og II i fri baseform overføres til syreaddisjons-saltene gjennom behandling med den passende syre, f.eks. saltsyre, hydrobromsyre, svovelsyre, salpetersyre, fosforsyre, eddiksyre, propionsyre, glucolsyre, pyrovinsyre, oxalsyre, malonsyre, ravsyre, eplesyre, maleinsyre, fumarsyre, vinsyre, citronsyre, benzoesyre, kanelsyre, mandelsyre, methansulfon-syre, ethansulfonsyre, p-toluensulfonsyre o.l.
Eksempel 4
Overføring av et salt til den frie syre
1,0 g 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfinylpropyl]-piperazin-dihydroklorid oppslemmet i 50 ml ether omrøres med et overskudd av fortynnet vandig kaliumcarbonatoppløsning inntil saltet er fullstendig oppløst. Det organiske skikt blir så fraskilt, vasket to ganger med vann, tørret over magnesium-sulfat og inndampet, hvorved 1 -[3-(1,3-dimethyl-3,7-dihydro- 1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfinyl-propyl ]-piperazin fåes i form av den frie base.
Eksempel 5
Overføring av en alkohol til en ester
A. 1,0 g 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl)-4-(3-fenylsulfinylpropyl]-piperazin oppløses i 30 ml pyridin. Det tilsettes så 2 ml eddiksyre-anhydrid. Blandingen holdes ved romtemperatur i 20 timer. Oppløsningsmidlet avdampes, og esteren 1 -[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-acetoxypropylJ-4-3-fenyl-sulf inylpropyl ) -piperazin isoleres deretter og omkrystalliseres etter konvensjonelle metoder i form av dihydrokloridet.
B. På tilsvarende måte som beskrevet i del A av dette eksempel fremstilles de tilsvarende n-propionyloxy-, i-butyryl-oxy-, valeryloxy- og n-capryloxy-forbindelser o.l., ut fra 1 -[3-< 1 ,3-dimethy1-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-fenylsulfinylpropyl)-piperazin.
Eksempel 6
Farmasøytiske preparater
Den aktive bestanddel i dette eksempel er 1-(3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxy-propyl ] -4- ( 3-f enylsulf onylpropyl ) -piperazin . De øvrige av de nye forbindelser kan selvfølgelig også benyttes.
A. Kapsler
B. Injiserbart preparat i ampuller
C. Tabletter
D. Drikkbar suspensjon
E. Aerosol I
Aerosol II
Aerosol III
Aerosol IV
Eksempel 7
Bronkieutvidende virkning
Trefarvede hanmarsvin som veiet 300-350 g (COBO-LABO-LAP-France) ble benyttet ved denne test. Dyrene bedøves med ethylcarbamat (1,5 g pr. kg intraperetonealt). En luftrørs-kanyle anbringes på plass og forbindes med en åndedrettspumpe for små dyr. En trykkomformer, koblet til en skriver, ble satt inn i en luftførende shuntledning.
Dyrene ble holdt under tvungent åndedrett på et bestemt mengde- og frekvensnivå.
Bronkiekramper ble frembragt ved intravenøs injeksjon av histamin-hydroklorid (10 ug/kg). Etter at konstante bronkie-innsnevringer var blitt oppnådd, ble testforbindelsene eller bærer injisert intravenøst i mengder av mellom 1,25 og 25 mg/kg. Histamin ble på ny injisert intravenøst 1, 6, 11 og 16 minutter etter injiseringen av testforbindelsen.
Testforbindelsenes antihistaminiske virkning ble uttrykt som ED50(den effektive dose ved hvilken 50% frembragt bronkiekrampe iakttas) for de behandlede dyr sammenlignet med kontrolldyrene.
Testforbindelsene oppviser de følgende virkninger med hensyn til å hindre bronkieutvidelse (målt 11 minutter etter injiseringen av testforbindelsen):
Eksempel 8
Toksisitet
Ved de ovenfor beskrevne tester ble ingen toksiske virkninger iakttatt.
Claims (13)
1. Forbindelser med de generelle formler:
og de i farmasøytisk henseende aksepterbare syreaddisjonssalter og optiske isomerer derav, i hvilke formler:M er valgt blant hydrogen, morfolin, benzylamino, di-n-lavere-alkylamino, n-lavere-alkylamino og
hvor Ar er eventuelt substituert fenyl, Z-| og Z2 uavhengig av hverandre er valgt blant CH2 og C=0, hvor B er hydrogen eller alkanoyl,
Y er oxygen eller ingenting,
n er et helt tall fra 0 til 4, men ikke kan være 0 når Z-| er CHOB,
m er et helt tall fra 0 til 4, men ikke kan være 0 når Z2 er CHOB,
R-| , R2 og R3 uavhengig av hverandre er hydrogen, halogen, hydroxy, trifluormethyl, alkyl eller alkoxy,
R4 er lavere-alkyl, og
R5 er hydrogen eller lavere-alkyl.
2. Forbindelser ifølge krav 1, hvor M er hydrogen, Z-| er CH2 eller CHOH og Z2 er CH2 , og de i farmasøytisk henseende aksepterbare syreaddisjonssalter derav.
3. Forbindelser ifølge krav 1, med formel I hvor Z-] og Z2 uavhengig av hverandre er CH2 eller CHOH, m og n begge er 1 og minst én av substituentene R-| , R2 og R3 er hydrogen,
og de i farmasøytisk henseende aksepterbare syreaddisjonssalter derav.
4. Forbindelser ifølge krav 3, hvor M er hydrogen, minst én av substituentene R4 , R5 er methyl og minst to av substituentene R-] , R2 og R3 er hydrogen, og de i farmasøytisk henseende aksepterbare syreaddisjonssalter derav.
5. Forbindelser ifølge krav 4, hvor R-| , R2 og R3 er hydrogen, og de i farmasøytisk henseende aksepterbare syreaddisjonssalter derav.
6. Forbindelse ifølge krav 5, hvor Z-| er CHOH, Z2 er CH2 , Y er intet og R4 og R5 begge er methyl, nemlig 1 — 13 — (1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxy-propyl ] -4- ( 3-f enylsulf inylpropyl ) -piperazin , og de i farma-søytisk henseende aksepterbare syreaddisjonssalter derav.
7. Forbindelse ifølge krav 5, hvor Z-) er CHOH, Z2 er CH2 , Y er oxygen og og R4 og R5 begge er methyl, nemlig 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion-7-yl)-2-hydroxy-propyl ]-4-(3-fenylsulfonylpropyl)-piperazin, og de i farma-søytisk henseende aksepterbare syreaddisjonssalter derav.
8. Forbindelser ifølge krav 1, formel II, hvor Z-| og Z2 uavhengig av hverandre er CH2 eller CHOH, m og n begge er 1 og minst én av substituentene R-| , R2 og R3 er hydrogen, og de i farmasøytisk henseende aksepterbare syreaddisjonssalter derav.
9. Forbindelser ifølge krav 8, hvor M er hydrogen, minst én av substituentene R4 , R5 er methyl og minst to av substituentene R-| , R2 og R3 er hydrogen, og de i farmasøytisk henseende aksepterbare syreaddisjonssalter derav.
10. Forbindelser ifølge krav 9, hvor R4 og R5 begge er methyl og R-| , R2 og R3 er hydrogen, og de i farmasøytisk henseende aksepterbare syreaddisjonssalter derav.
11. Farmasøytisk preparat omfattende en forbindelse ifølge krav 1 sammen med minst én farmasøytisk aksepterbar eksipient.
12. Forbindelse ifølge krav 1-10 for anvendelse ved behandling av eller lindring av symptomene ved åndedrettsforstyrrelser og allergiske forstyrrelser.
13. Analogifremgangsmåte for fremstilling av terapeutisk virksomme forbindelser ifølge krav 1 , karakterisert ved :(a) oxydasjon av en forbindelse av formelen:
hvor M, m, n, Z-\ , Z2 , R-| , R2 , R3 , R4 og R5 er som angitt i krav 1, eller
(b) omsetning av et piperazin som bærer én av sidekjedene i forbindelsen med formel I eller II med en kilde for den andre sidekjede i forbindelsen med formel I eller II, eller
(c) overføring av den frie base av en forbindelse med formel I eller II til et i farmasøytisk henseende aksepterbart syreaddisjonssalt, eller
(d) overføring av et salt av forbindelsen med formel I eller II til en fri base, eller
(e) overføring av et salt av forbindelsen med formel I eller II til et annet salt, eller
(f) spalting av den racemiske form av forbindelsen med formel I eller II til de enkelte optiske isomerer.
Applications Claiming Priority (1)
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US06/811,568 US4810706A (en) | 1985-12-20 | 1985-12-20 | Piperazine derivatives of theophylline and theobromine |
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NO865177D0 NO865177D0 (no) | 1986-12-19 |
NO865177L true NO865177L (no) | 1987-06-22 |
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO865177A NO865177L (no) | 1985-12-20 | 1986-12-19 | Analogifremgangsmaate for fremstilling av terapeutisk virksomme piperazinderivater av theofyllin og theobromin. |
Country Status (14)
Country | Link |
---|---|
US (1) | US4810706A (no) |
EP (1) | EP0227077A1 (no) |
JP (1) | JPS62289580A (no) |
KR (1) | KR870006050A (no) |
AU (1) | AU589724B2 (no) |
CA (1) | CA1274517A (no) |
DK (1) | DK620586A (no) |
FI (1) | FI865225A (no) |
HU (1) | HU197902B (no) |
NO (1) | NO865177L (no) |
NZ (1) | NZ218716A (no) |
PH (1) | PH23910A (no) |
PT (1) | PT83977B (no) |
ZA (1) | ZA869584B (no) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117582353B (zh) * | 2023-12-21 | 2024-05-03 | 湖北工业大学 | 一种主动引导宠物的雾化吸氧一体机 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55118488A (en) * | 1979-03-05 | 1980-09-11 | Eisai Co Ltd | Theobromine derivative and its preparation |
JPS5677278A (en) * | 1979-09-11 | 1981-06-25 | Maruko Seiyaku Kk | Theobromine derivative |
ZA81160B (en) * | 1980-01-31 | 1982-02-24 | Laroche Navarron Sa | Piperazine derivatives of theophylline |
CH648559A5 (de) * | 1981-07-20 | 1985-03-29 | Siegfried Ag | Theophyllinderivate und verfahren zu deren herstellung. |
US4374837A (en) * | 1981-07-31 | 1983-02-22 | Laroche Navarron, S.A. | Piperazine derivatives of theobromine |
US4400381A (en) * | 1981-07-31 | 1983-08-23 | Laroche-Navarron, S.A. | Piperazine derivatives of theophylline |
FR2531085A1 (fr) * | 1982-07-28 | 1984-02-03 | Adir | Nouveaux derives de la xanthine, leur procede de preparation et les compositions pharmaceutiques les renfermant |
-
1985
- 1985-12-20 US US06/811,568 patent/US4810706A/en not_active Expired - Fee Related
-
1986
- 1986-12-19 EP EP86117812A patent/EP0227077A1/en not_active Ceased
- 1986-12-19 JP JP61305140A patent/JPS62289580A/ja active Pending
- 1986-12-19 KR KR860010939A patent/KR870006050A/ko not_active Application Discontinuation
- 1986-12-19 HU HU865346A patent/HU197902B/hu not_active IP Right Cessation
- 1986-12-19 NZ NZ218716A patent/NZ218716A/en unknown
- 1986-12-19 NO NO865177A patent/NO865177L/no unknown
- 1986-12-19 PT PT83977A patent/PT83977B/pt not_active IP Right Cessation
- 1986-12-19 ZA ZA869584A patent/ZA869584B/xx unknown
- 1986-12-19 DK DK620586A patent/DK620586A/da not_active Application Discontinuation
- 1986-12-19 FI FI865225A patent/FI865225A/fi not_active Application Discontinuation
- 1986-12-19 AU AU66764/86A patent/AU589724B2/en not_active Ceased
- 1986-12-19 PH PH34620A patent/PH23910A/en unknown
- 1986-12-19 CA CA000525883A patent/CA1274517A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
HUT44031A (en) | 1988-01-28 |
ZA869584B (en) | 1988-07-27 |
PT83977A (en) | 1987-01-01 |
AU6676486A (en) | 1987-06-25 |
KR870006050A (ko) | 1987-07-08 |
PT83977B (pt) | 1989-01-17 |
FI865225A0 (fi) | 1986-12-19 |
CA1274517A (en) | 1990-09-25 |
FI865225A (fi) | 1987-06-21 |
DK620586A (da) | 1987-06-21 |
US4810706A (en) | 1989-03-07 |
NZ218716A (en) | 1990-01-29 |
JPS62289580A (ja) | 1987-12-16 |
AU589724B2 (en) | 1989-10-19 |
DK620586D0 (da) | 1986-12-19 |
HU197902B (en) | 1989-06-28 |
PH23910A (en) | 1990-01-23 |
EP0227077A1 (en) | 1987-07-01 |
NO865177D0 (no) | 1986-12-19 |
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