DK169817B1 - Analogifremgangsmåde til fremstilling af benzo(5,6)cyclohepta(1,2-b)pyridiner - Google Patents
Analogifremgangsmåde til fremstilling af benzo(5,6)cyclohepta(1,2-b)pyridiner Download PDFInfo
- Publication number
- DK169817B1 DK169817B1 DK263481A DK263481A DK169817B1 DK 169817 B1 DK169817 B1 DK 169817B1 DK 263481 A DK263481 A DK 263481A DK 263481 A DK263481 A DK 263481A DK 169817 B1 DK169817 B1 DK 169817B1
- Authority
- DK
- Denmark
- Prior art keywords
- compound
- formula
- cyclohepta
- benzo
- reacted
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 26
- 230000008569 process Effects 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title claims description 7
- VVJQGUSMDLABEG-UHFFFAOYSA-N 11h-benzo[1,2]cyclohepta[3,4-b]pyridine Chemical class C1=CC2=CC=CN=C2CC2=CC=CC=C21 VVJQGUSMDLABEG-UHFFFAOYSA-N 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 229910052736 halogen Chemical group 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 238000005809 transesterification reaction Methods 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000000739 antihistaminic agent Substances 0.000 abstract description 4
- 230000001624 sedative effect Effects 0.000 abstract description 3
- 229940125715 antihistaminic agent Drugs 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 26
- -1 N-Carboethoxy-4-piperidylidene-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine Chemical compound 0.000 description 18
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- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 3
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- ACGXYICMMNRYMS-UHFFFAOYSA-N 1-methylsulfonyl-5-piperidin-4-ylidene-6,11-dihydro-2h-benzo[1,2]cyclohepta[6,7-b]pyridine Chemical compound CS(=O)(=O)N1CC=CC2=C1CC1=CC=CC=C1CC2=C1CCNCC1 ACGXYICMMNRYMS-UHFFFAOYSA-N 0.000 description 2
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- 239000000463 material Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- PTHGDVCPCZKZKR-UHFFFAOYSA-N (4-chlorophenyl)methanol Chemical compound OCC1=CC=C(Cl)C=C1 PTHGDVCPCZKZKR-UHFFFAOYSA-N 0.000 description 1
- BAUWRHPMUVYFOD-UHFFFAOYSA-N 1-methylpiperidin-4-ol Chemical compound CN1CCC(O)CC1 BAUWRHPMUVYFOD-UHFFFAOYSA-N 0.000 description 1
- TYDPEPRGSQPCKB-UHFFFAOYSA-N 10-(1-methylpiperidin-2-ylidene)-5h-benzo[1,2]cyclohepta[3,4-b]thiophen-4-one Chemical compound CN1CCCCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 TYDPEPRGSQPCKB-UHFFFAOYSA-N 0.000 description 1
- VEHMROQZMLRPSA-UHFFFAOYSA-N 11-piperidin-4-ylidene-5,6-dihydrobenzo[1,2]cyclohepta[3,4-b]pyridine Chemical compound C1CNCCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 VEHMROQZMLRPSA-UHFFFAOYSA-N 0.000 description 1
- HCLXLZGAYCTHQJ-UHFFFAOYSA-N 1h-cyclohepta[b]pyridine Chemical compound C1=CC=CC=C2NC=CC=C21 HCLXLZGAYCTHQJ-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- SYHCARCAUJVIDU-UHFFFAOYSA-N 9-ethylidene-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3(8),4,6,11,13-hexaene Chemical compound C(C)=C1CC2=C(CC3=NC=CC=C31)C=CC=C2 SYHCARCAUJVIDU-UHFFFAOYSA-N 0.000 description 1
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- 206010030113 Oedema Diseases 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- 240000001890 Ribes hudsonianum Species 0.000 description 1
- 235000016954 Ribes hudsonianum Nutrition 0.000 description 1
- 235000001466 Ribes nigrum Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 230000002567 autonomic effect Effects 0.000 description 1
- SEBMTIQKRHYNIT-UHFFFAOYSA-N azatadine Chemical compound C1CN(C)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 SEBMTIQKRHYNIT-UHFFFAOYSA-N 0.000 description 1
- 229960000383 azatadine Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
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- MTDZGBSATVLDRM-UHFFFAOYSA-N ethyl 2-(4-oxo-5h-benzo[1,2]cyclohepta[3,4-b]thiophen-10-ylidene)piperidine-1-carboxylate Chemical compound CCOC(=O)N1CCCCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 MTDZGBSATVLDRM-UHFFFAOYSA-N 0.000 description 1
- YVMQUVFVYIFGLY-UHFFFAOYSA-N ethyl 4-(5,6-dihydrobenzo[1,2]cyclohepta[3,4-b]pyridin-11-ylidene)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 YVMQUVFVYIFGLY-UHFFFAOYSA-N 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
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- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- AGNOKNMESONMLJ-UHFFFAOYSA-N methyl 4-(5,6-dihydrobenzo[1,2]cyclohepta[3,4-b]pyridin-11-ylidene)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 AGNOKNMESONMLJ-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
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- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
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- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
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Description
DK 169817 B1
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte benzo[5,6]-cyclohepta[1,2-b]pyridiner med den almene formel I
10 Ϋ hvori X betegner hydrogen eller halogen, og Y betegner en af grupperne -COOR^ og -SC^Rg, hvori R7 betegner alkyl, C3_7-cycloalkyl eller halogenphenyl-C^_4alkyl, og ^ Rg betegner alkyl, Cg_7-cycloalkyl eller phenyl-C^_4alkyl.
Alle de i ovenstående definitioner nævnte alkyl-grupper har lige eller forgrenede kæder.
De ved fremgangsmåden ifølge opfindelsen fremstille lede forbindelser har udmærkede antihistaminegenskaber med ikke-sedativ virkning.
De i US-patentskrift nr. 3.264.342 omhandlede forbindelser har en struktur, der minder om ovenstående formel I, men deres antihistaminvirkning er ubetydelig.
25 De i US-patentskrift nr. 3.419.565 beskrevne antihistaminer har en struktur, der minder om ovenstående formel I, men de har en beroligende indvirkning i modsætning til de ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede forbindelser.
3® Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at en forbindelse med den almene formel 1' (X^-* τ' t Y’ DK 169817 B1 2
hvori X har den ovenfor anførte betydning, og Y' betegner en udskiftelig gruppe, omsættes med en forbindelse med formlen II
TY II
5 hvori Y har den ovenfor anførte betydning, og T betegner en gruppe, der kan elimineres sammen med Y', og at en således opnået forbindelse med formlen I om nødvendigt overføres i en anden forbindelse med formlen I ved trans-esterifikation af gruppen Y.
10 Til fremstilling af forbindelser med den almene formel I, hvori Y betegner COORy, hvor Ry har den ovennævnte betydning, kan man således omsætte en forbindelse med formlen I', hvori Y' betegner methyl, med en forbindelse med formlen TCOORy, hvori T betegner 15 halogen, fortrinsvis chlor. Omsætningen udføres bekvemt ved opvarmning af udgangsmaterialerne i et indifferent opløsningsmiddel, fortrinsvis ved tilbagesvalingstempe-ratur. Typiske eksempler på indifferente opløsningsmidler er benzen, toluen, tetrahydrofuran, chloroform osv.
20 Ved en yderligere udførelsesform for den ovenfor skitserede generelle fremgangsmåde omsættes en forbindelse med formlen I ’, hvori Y' betegner H, med en forbindelse med formlen TCOORy, hvori T betegner ORy, hvor Ry har den ovennævnte betydning, men dog fortrinsvis er t-25 butyl.
De forbindelser med formlen I, hvori Y betegner SC^Rg, fremstilles fortrinsvis ved omsætning af en forbindelse med formlen I', hvori Y' betegner H, med en forbindelse med formlen II, hvori T betegner halogen, 30 fortrinsvis chlor, og Y betegner S02Rg. Omsætningen udføres fortrinsvis ved stuetemperatur i et indifferent opløsningsmiddel, såsom benzen eller toluen, i nærværelse af en base, såsom K2C03, Na2C03, NaH, NaOH, triethylamin eller andre stærke organiske baser. De uorganiske baser 3 5 foretrækkes.
Som det tydeligt fremgår af arten af gruppen Y i forbindelserne med formlen I, kan visse estergrupper opnået efter de ovenfor skitserede procedurer omdannes til 3 DK 169817 B1 DK 169817 B1 andre estergrupper ved transesterifikation.Således kan f.eks. en forbindelse, hvori Y betegner -C00, , omsættes med NaOR7 til opnåelse af en forbindelse, hvori I Y betegner COOR^ (hvor R^ er forskellig fra phenyl).
5 ' Udgangsforbindelserne med formlen I' er for en dels vedkommende kendte forbindelser, der fås på markedet, f.eks. azatadin:
15 i CjD
I I
“3
Andre udgangsforbindelser med formlen I1 kan fremstilles efter metoder, der er beskrevet i litteraturen, f.
20 eks. i US-patentskrift nr. 3.326.924 og belgisk patentskrift nr. 647.043, eller efter analoge fremgangsmåder.
Som det fremgår klart af den kemiske struktur, har omhandlede forbindelser asymmetriske centrer (f. eks. stilling 11 i formel I ).
25 Ved fremstillingen opnås der en blanding af de optiske isomere (d og 1), der kan adskilles ved velkendte fremgangsmåder.
De ovenfor beskrevne procesvariationer belyses nærmere ved hjælp af de efterfølgende eksempler.
30
Eksempel 1 A. 11- (N-Carboethoxy-4-piperidylideii-6,ll-dihydro-5H-ben-zo[5,6]cyclohepta[l,2-b]pyridin.
Til en opløsning af 10,9 g (0,1 mol) ethylchlor-35 formiat i 300 ml vandfrit benzen sættes der dråbevis under omrøring ved stuetemperatur en opløsning af 14,5 g (0,05 mol) 11-(N-methyl-4-piperidyliden)-6,11-dihy- DK 169817 B1 4 dro-5H-benzo[5,6]cyclohepta[l,2-b]pyridin (i det følgende betegnet som forbindelse IIA) i 200 ml benzen. Opløsningen omrøres og opvarmes under tilbagesvaling natten over (16-20 timer). Blandingen afkøles og hældes ud i isvand, 5 og det organiske lag fraskilles, vaskes med vand, tørres og koncentreres derefter til tørhed. Remanensen triture-res med petroleumsether, og et hvidt fast stof med et smeltepunkt på 106-107°C omkrystalliseres af isopropyl-ether efter affarvning med affarvende kul.
10 B. 11-(N-Carboethoxy-4-piperidyliden)-8-chlor-6,ll-di-hydro-5H-benzo [5,6]cyclohepta[l,2-b]pyridin.
Under anvendelse af proceduren ifølge eksempel 1A omsættes 16,2 g af 8-chlorderivatet af forbindelse Ila og 10,9 g (0,1 mol) ethylchlorformiat til fremstil-15 ling af den i overskriften anførte forbindelse, der har et smeltepunkt på 128-130°C. 7-, 9- og 10-Chloranaloge-ne fremstilles på tilsvarende måde.
C. 11-(N-(Carbomethoxy-4-piperidyliden)-6,ll-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin.
20 Under anvendelse af proceduren ifølge eksempel 1A omsættes 14,5 g af forbindelse IIA og 9,4 g methyl-chlorformiat til fremstilling af den i overskriften anførte forbindelse, der har et smeltepunkt på 116-118°C.
D. 11- ((3-N-Methyl-N-carboethoxy) ethyl-8-chlor-6,11-di-25 hydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin.
Under anvendelse af proceduren ifølge eksempel 1A omsættes en opløsning af 15,1 g (0,05 mol) ll-(3-di-methylaminoethyl)-8-chlor-6,ll-dihydro-5H-benzo[5,6]cyclohepta [1,2 -b] pyridin i 300 ml vandfrit benzen med 10,9 30 g ethylchlorformiat ved stuetemperatur til fremstilling af den i overskriften anførte forbindelse.
E. 11-(3-N-Methyl-N-carboethoxy)ethyliden-6,11-dihydro-[5H]-benzo[5,6]cyclohepta[1,2-b]pyridin.
35 Den i overskriften anførte forbindelse fremstilles ved proceduren ifølge eksempel 1A under anvendelse af 14,9 g dimethylaminoethyliden-6,11-dihydro-[5H]-benzole] cyclohepta [1, 2-b] pyridin og 10,9 g ethylchlorformi- DK 169817 B1 5 at ved stuetemperatur i benzen.
F. 4- (N-Carboethoxy-piperidyliden)-4H-benzo [4,5] cyclohep-ta[l,2-b]thiophen-10(9H)-on.
Under anvendelse af proceduren ifølge eksempel 5 1A omsættes 21,3 g N-methylpiperidyliden-4H-benzo[4,5]-cyclohepta[l,2-b]thiophen-10(9H)-on i 300 ml benzen med en opløsning af 10,9 g ethylchlorformiat i 300 ml benzen til fremstilling af den i overskriften anførte forbindelse .
10 Eksempel 2 11- (N-Carbophenoxy-4-piperidyliden) -6, ll-dihydr<3-5H-ben-zo[5,6]cyclohepta[l,2-b]pyridin (forbindelse IIB).
Til en opløsning af 29,1 g (0,1 mol) af forbindelse IIA i 150 ml vandfrit carbontetrachlorid sættes 15 17 g phenylchlorformiat i et lige så stort rumfang vandfrit carbontetrachlorid. Blandingen opvarmes under tilbagesvaling i 15 minutter under omrøring og hældes ud i vand.Dét organiske lag fraskilles og vaskes med vand, og opløsningsmidlet fjernes. Remanensen ekstraheres med 20 ether, det uopløselige materiale frafiltreres, og ethe-ren fjernes. Remanensen omkrystalliseres af isopropyl-ether til opnåelse af den i overskriften anførte forbindelse med et smeltepunkt på 127-130°C. På tilsvarende måde fremstilles 7-, 8-, 9- eller 10-chlorderivatet af 25 den i overskriften anførte forbindelse under anvendelse af denne procedure.
Eksempel 3 11-(N-Carboisopropoxy-4-piperidyliden-6,ll-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin.
30 0,5 g natriummetal opløses i 50 ml isopropanol, og der tilsættes 7,9 g af forbindelse IIB fra eksempel 2. Blandingen opvarmes under omrøring i 5 timer på et dampbad til 90-95°C, og man lader den afkøle natten over. .
Der tilsættes isvand til udfældning af produktet 35 og ekstraheres 3 gange med ether og 1 gang med chloroform. Man vasker med vand, afdestillerer opløsningsmid DK 169817 B1 6 lerne, triturerer med hexan og omkrystalliserer af iso-propylether. Smeltepunktet er 147-148°C.
Under anvendelse af denne procedure og ved erstatning af i s opr o'p anale t med n-butanol, cyclopentanol, 5 allylalkohol, cyclopropylmethanol, benzylalkohol, p-chlorbenzylalkohol, phenethylalkohol, dimethylamino-ethylalkohol eller N-methyl-4-hydroxy-piperidin fremstilles de tilsvarende estere. På tilsvarende måde under anvendelse af 7-, 8-, 9- og 10-chlorderivaterne af for-10 bindelse IIB og natriumsaltene af de ovennævnte alkoholer fremstilles de tilsvarende 7-, 8-, 9- og 10-chlor-forbindelser.
Eksempel 4 11-(N-Carbo-t-butoxy-4-piperidyliden-6,ll-dihydro-5H-15 benzo[5,6]cyclohepta[l,2-b]pyridin.
13,8 g 11-(4-piperidyliden)-6,ll-dihydro-5H-ben-zo[5,6]cyclohepta[l,2-b]pyridin (forbindelse IIC), fremstillet efter den fremgangsmåde, der er angivet af Villa-ni et al., J. Med. Chem. 15, 750 (1972), opløses i 250 20 ml tørt tetrahydrofuran. Der tilsættes 12 g dibutylcar-bonat under omrøring og omrøres ved stuetemperatur natten over. Blandingen hældes ud i vand, ekstraheres med ether og vaskes med vand, og opløsningsmidlet fjernes. Remanensen omkrystalliseres af isopropylether. Smelte-25 punktet er 144-145°C.
Eksempel 5 N-Methansulfonyl-4-piperidyliden-6,ll-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridin.
Til 10 g af forbindelse IIC i 200 ml tørt toluen 30 sættes 13 g vandfrit kaliumcarbonat. Efter flere minutters omrøring ved stuetemperatur tilsættes der dråbevis en opløsning af 6 g methansulfonylchlorid i 20 ml toluen. Omrøringen fortsættes i 16-20 timer, hvorefter der filtreres. Det faste materiale omkrystalliseres af ethanol.
35 Smeltepunktet er 223-224°C.
Under anvendelse af denne procedure og ved af- DK 169817 B1 7 pasning af vægten af det nødvendige sulfonylchlorid, således at der anvendes 0,04 mol af nævnte alkansulfonyl-chlorid, opnås der ethansulfonyl-, n-propylsulfonyl-, n-butylsulfonyl-, cyclopropylsulfonyl-, heptylsulfonyl-, 5 dodecylsulfonyl-, phenylsulfonyl-, p-methylphenylsulfo-nyl-, p-fluorphenylsulfonyl-/ p-chlorphenylsulfonyl-, benzylsulfonyl-, p-chlorbenzylsulfonyl-, p-tert-butyl“ phenylsulfonyl- og cyclopentylsulfonylforbindelser med formlen I, hvori Y er SC^R. På tilsvarende måde frem-10 stilles de tricycliske ringsubstituerede chlorderivater.
Ved i stedet at anvende et passende udgangsmateriale med en dobbeltbinding mellem 5- og 6-stillingerne i ringsystemet og ved at anvende de i ovenstående eksempler 1-5 anførte procedurer (der viser fremstillingen af 15 6,11-dihydroforbindelseme) fremstilles de tilsvarende 6,11-dehydroforbindelser.
Ved at anvende en passende brom- eller anden halogen-analog i stedet for det ovenfor nævnte 7-, 8-, 9-eller 10-chlorsubstituerede udgangsmateriale kan der des-20 uden fremstilles andre ønskede halogenforbindelser med formlen I.
Typiske repræsentanter for forbindelser fra den foretrukne gruppe med den almene formel I
*4—χ 30 Γ
Y
er anført i nedenstående tabel: 8· DK 169817 B1
Forbindelse nr. X Y_Smp._
1 H COOC2H5 106-107°C
2 H COOCH2CCl3 147°C
3 H COO-<Q 127-130°C
54 H COOCH(CH3)2 147-148°C
5 H COO(CH2)2.N(CH3)2 84-87°C
6 H COOCH3 116-118°C
7 H COO(CH2)3CH3 86-89°C
8 H COOC(CH3)3 144-145°C
10 9 H COO-^ N-CH3 158-160°C
10 H COOCH2-^r~^ 106-108°C
11 8-Cl COOC2H5 128-130°C
12 H COOCH2CH=CH2 88-91°C
13 H COQCH2-^Cl 131-134°C
15 14 H COO(CH2)2- O 101-104°C
15 H COOCH2-^J 126-127°C
16 H COO- <a 162-164°C
17 H S02-^-CH3 197-199°C
18 8-C1 S02- O -CH3 185-187°C
20 19 H S02-^-F 186-187°C
20 H S02CH3 223-224°C
21 H S02(CH2)2CH3 183-184°C
22 H S02CH2CH3 173-174°C
23 H S02(CH2)3CH3 185-186°C
35 24 H SQ2-CH2-^ 185-186°C
DK 169817 B1 9
Forbindelse nr. X Y_Sitip._
25 H S02^[ 157-158°C
De omhandlede forbindelser er nyttige som ikke-sederende antihistaminer. Disse forbindelser virker som 5 antiallergiske midler ved behandling af sådanne lidelser som stadig tilbagevendende og sæsonbestemt allergisk rhinitis og kronisk urticaria.
De omhandlede forbindelser administreres i farmaceutiske formuleringer, der omfatter forbindelsen i blan-10 ding med en farmaceutisk bærer, som er egnet til enteral eller parenteral administrering. Formuleringerne kan være i fast form, som f.eks. tabletter og kapsler, eller i flydende form, som f.eks. syrupi, eliksirer, emulsioner og injektionspræparater. Ved formuleringen af farmaceuti-15 ske doseringsformer anvendes der almindeligvis hjælpestoffer, f.eks. vand, gelatine, lactose, stivelsesarter, magnesiumstearat, talkum, vegetabilske olier, benzylal-koholer, gummier, polyalkylenglycoler og vaseline. Foretrukne formuleringer er belyst nærmere i eksempel 6.
20 Selv om den nødvendige dosering bestemmes af så danne faktorer som patientens alder, køn og vægt og alvorligheden af den allergiske reaktion, der skal behandles, er det foretrukne dosisområde for mennesker passende 4 til 50 mg af den virksomme forbindelse 1 til 3 gange 25 pr. dag. De foretrukne doseringsområder for andre dyr kan let bestemmes ved anvendelse af sædvanlige prøvemetoder.
De følgende data viser den farmaceutiske virkning af de omhandlede forbindelser. (Dataene udarbejdedes med 30 forbindelsen 8-chlor-6;ll-dihydro-ll-(l-carboethoxy-4-pi-peridyliden)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin).
Den orale ED^q til forhindring af histamin-induceret dødelighed hos marsvin er 0,19 mg/kg. Acetattoksiciteten er meget lav (f.eks. >320 mg/kg hos mus; >60 mg/ 35 kg hos hunde osv.). Den orale ED^q til forhindring af histamin-induceret poteødem hos mus er 1,3 mg/kg.
DK 169817 Bl ίο
Forbindelsen viste meget ringe eller ingen CNS-virkning hos mus, rotter, hunde eller aber, f.eks. ingen physostigmin-dødelighed hos mus ved doser op til 320 mg/ kgj ingen åbenlyse adfærdsmæssige eller neurologiske el-5 ler autonomiske virkninger hos mus eller rotter efter doser på 10-300 mg/kg, hos hunde efter doser på 15-60 mg/kg eller hos aber ved doser på 30-90 mg/kg.
De ovennævnte farmaceutiske præparater belyses ved hjælp af de efterfølgende eksempler.
10 Eksempel 6
En syrup indeholdende en af de omhandlede forbindelser (aktiv forbindelse), f.eks. 11-(N-carboethoxy-4-piperidyliden)-8-chlor-6,ll-dihydro-5H-benzo[5,6]cyclo-hepta[l,2-b]pyridin, 11-(N-methansulfonyl-4-piperidyli-15 den)-6,ll-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin, 11-(N-carboethoxy-4-piperidyliden)-6,ll-dihydro-5H-ben-zo[5,6]cyclohepta[1,2-b]pyridin, 11-(N-carbomethoxy-4-piperidyliden)-6,ll-dihydro-5H-benzo[5,6]cyclohepta[1,2- b]pyridin eller 11-(N-carbophenoxy-4-piperidyliden)-6,11-20 dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin, fremstilles ud fra følgende bestanddele: pr. ml
Aktiv forbindelse 0,100 mg
Saccharose 600 mg 25 Sorbitol 140 mg
Propylenglycol 20,0 mg
Methylparaben 1,00 mg
Propylparaben 0,200 mg F.D. & C. Yellow No. 6 0,225 mg 30 Alkohol USP 0,0021 ml
Kunstig solbærsmag 0,001 ml
Renset vand USP g.s._ 1,0 ml
Syruppen fremstilles ved at kombinere de oven-35 stående bestanddele efter sædvanlige metoder.
DK 169817 B1 '11
Eksempel 7
En tablet omfattende en af de omhandlede forbindelser (aktiv forbindelse) fremstilles ved en forstøvningstørringsproces ud fra følgende bestanddele.
5 Tablet I Tablet II
(mg/tablet) (mg/tablet)
Komponent 1
Aktiv forbindelse* 1,00 10,00
Lactose, vandfri USP
(impalpabelt pulver) 212 180,00
Povidone NF 10,0
Majsstivelse (levnedsmiddel- kvalitet) 15,0 6,0 10 Renset vand USP (fordamper) 0,102 ml 0,1
Yderligere komponenter Majsstivelse (levnedsmiddel- kvalitet) 11,5 6,0
Magnesiumstearat USP 0,500 1,2
Gelatine — 2,5 15 Materialerne i komponent 1 hældes sammen og forstøvningstørres. Det opnåede forstøvningstørrede materiale hældes sammen med de ovenfor anførte yderligere komponenter og behandles til dannelse af tabletter.
*) F.eks. 11-(N-carboethoxy-4-piperidyliden)-8-chlor~ 20 6,ll-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin.
Claims (5)
1. Analogifremgangsmåde til fremstilling af benzo[5,6]cyclohepta[1,2-b]pyridiner med den almene formel I 5 fvr>* 1 ό Y hvori X betegner hydrogen eller halogen, og Y betegner en af grupperne -COOR^ og -SC^Rg, hvori 15 Rj betegner alkyl, C3_7-cycloalkyl eller halogenphenyl-C.|_4alkyl, og Rg betegner alkyl, C3_7-cycloalkyl eller phenyl-C^alkyi, kendetegnet ved, at en forbindelse med den almene formel 1' 20 ^ . x «I A A i' Y* hvori X har den ovenfor anførte betydning, og Y' betegner en udskiftelig gruppe, omsættes med en forbindelse med formlen II TY II hvori Y har den ovenfor anførte betydning, og T betegner en gruppe, der kan elimineres sammen med Y', og at en således opnået forbindelse med formlen I om nødvendigt 35 overføres i en anden forbindelse med formlen I ved trans- DK 169817 B1 13 esterifikation af gruppen Y.
2. Fremgangsmåde ifølge krav 1, kendetegne t ved, at en forbindelse med formlen I', hvori Y' er methyl/ omsættes med en forbindelse med formlen 5 T COOR7 hvori T er halogen, fortrinsvis chlor, og har den i krav 1 anførte betydning.
3. Fremgangsmåde ifølge krav 1, kendete g-10 net ved, at en forbindelse med formlen I', hvori Y' er hydrogen, omsættes med en forbindelse med formlen T COOR7 hvori T betegner gruppen OR7, og har den i krav 1 an-15 førte betydning.
4. Fremgangsmåde ifølge krav 1, kendetegne t ved, at en forbindelse med formlen I', hvori Y' betegner hydrogen, omsættes med en forbindelse med formlen II, hvori T betegner halogen, fortrinsvis chlor, og 20. betegner gruppen S02Rg, hvor Rg har den i krav 1 anførte betydning.
5. Fremgangsmåde ifølge krav T, kendetegnet ved, at en forbindelse med formlen I', hvori X betegner hydrogen eller 8-chlor, omsættes med en forbin- 25 delse med formlen tcooc2h5 hvori T har den i krav 1 anførte betydning.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06160795 US4282233B1 (en) | 1980-06-19 | 1980-06-19 | Antihistaminic 11-(4-piperidylidene)-5h-benzoÄ5,6Ü-cyclohepta-Ä1,2Ü-pyridines |
US16079580 | 1980-06-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
DK263481A DK263481A (da) | 1981-12-20 |
DK169817B1 true DK169817B1 (da) | 1995-03-06 |
Family
ID=22578489
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK263481A DK169817B1 (da) | 1980-06-19 | 1981-06-16 | Analogifremgangsmåde til fremstilling af benzo(5,6)cyclohepta(1,2-b)pyridiner |
Country Status (25)
Country | Link |
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US (1) | US4282233B1 (da) |
EP (1) | EP0042544B1 (da) |
JP (1) | JPS5735586A (da) |
KR (1) | KR850000744B1 (da) |
AT (1) | ATE9695T1 (da) |
AU (1) | AU543054B2 (da) |
CA (1) | CA1160230A (da) |
CY (1) | CY1405A (da) |
DE (1) | DE3166441D1 (da) |
DK (1) | DK169817B1 (da) |
ES (1) | ES8300779A1 (da) |
FI (1) | FI70213C (da) |
HK (1) | HK94387A (da) |
HU (1) | HU186774B (da) |
IE (1) | IE51303B1 (da) |
IL (1) | IL63122A (da) |
KE (1) | KE3758A (da) |
LU (1) | LU88359I2 (da) |
MY (1) | MY8700761A (da) |
NL (1) | NL930094I2 (da) |
NZ (1) | NZ197435A (da) |
PH (1) | PH19252A (da) |
PT (1) | PT73200B (da) |
SG (1) | SG70587G (da) |
ZA (1) | ZA814062B (da) |
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- 1981-06-16 PT PT73200A patent/PT73200B/pt unknown
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- 1981-06-16 DK DK263481A patent/DK169817B1/da not_active IP Right Cessation
- 1981-06-16 IE IE1328/81A patent/IE51303B1/en active Protection Beyond IP Right Term
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- 1981-06-17 KR KR1019810002204A patent/KR850000744B1/ko active
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1993
- 1993-06-24 NL NL930094C patent/NL930094I2/nl unknown
- 1993-07-01 LU LU88359C patent/LU88359I2/fr unknown
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
B1 | Patent granted (law 1993) | ||
CTFF | Application for supplementary protection certificate (spc) filed |
Free format text: CA 1995 00009, 950704 |
|
CTFG | Supplementary protection certificate (spc) issued |
Free format text: CA 1995 00009, 950704, EXPIRES: 20021201 |
|
PUP | Patent expired |