NO160848B - ANALOGY PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE AMINOCYCLOPENTANOL HEPETIC ACID DERIVATE. - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE AMINOCYCLOPENTANOL HEPETIC ACID DERIVATE. Download PDFInfo
- Publication number
- NO160848B NO160848B NO833328A NO833328A NO160848B NO 160848 B NO160848 B NO 160848B NO 833328 A NO833328 A NO 833328A NO 833328 A NO833328 A NO 833328A NO 160848 B NO160848 B NO 160848B
- Authority
- NO
- Norway
- Prior art keywords
- formula
- compound
- acid
- salt
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 13
- 239000002253 acid Substances 0.000 title claims description 11
- 230000001225 therapeutic effect Effects 0.000 title claims 2
- BVJYDVKFDDPCAW-UHFFFAOYSA-N 1-aminocyclopentan-1-ol Chemical compound NC1(O)CCCC1 BVJYDVKFDDPCAW-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 23
- -1 hydrates) thereof Chemical class 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 12
- 230000007062 hydrolysis Effects 0.000 claims description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims description 12
- 235000010290 biphenyl Nutrition 0.000 claims description 9
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000004305 biphenyl Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940126062 Compound A Drugs 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000013067 intermediate product Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclo-pentanone Natural products O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 2
- 230000007885 bronchoconstriction Effects 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 238000005341 cation exchange Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- MIPAPDLHDVYRRT-UHFFFAOYSA-M (2,6-ditert-butyl-4-methylphenoxy)-bis(2-methylpropyl)alumane Chemical compound CC(C)C[Al](CC(C)C)OC1=C(C(C)(C)C)C=C(C)C=C1C(C)(C)C MIPAPDLHDVYRRT-UHFFFAOYSA-M 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YCQANBSROMMIQP-UHFFFAOYSA-N 1-chloropyrrolidine-2,5-dione;methylsulfanylmethane Chemical compound CSC.ClN1C(=O)CCC1=O YCQANBSROMMIQP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 206010050902 Postoperative thrombosis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000004044 bronchoconstricting agent Substances 0.000 description 1
- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- BKBOLLQVQKYWHV-UHFFFAOYSA-N cyclopentyl hept-4-enoate Chemical compound C1(CCCC1)OC(CCC=CCC)=O BKBOLLQVQKYWHV-UHFFFAOYSA-N 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- DOIRQSBPFJWKBE-UHFFFAOYSA-N phthalic acid di-n-butyl ester Natural products CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 239000002396 thromboxane receptor blocking agent Substances 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- MCULRUJILOGHCJ-UHFFFAOYSA-N triisobutylaluminium Chemical compound CC(C)C[Al](CC(C)C)CC(C)C MCULRUJILOGHCJ-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av en aminocyklopentanol-syre med formel (1) This invention relates to a method for the production of an aminocyclopentanol acid with formula (1)
og de fysiologisk godtagbare salter og solvater derav. and the physiologically acceptable salts and solvates thereof.
De her angitte strukturformler skal forstås å omfatte enantiomerene av hver av de aktuelle forbindelser, såvel som blandinger av enantiomerene innbefattet racemater, selv om den nøyaktige sturktur som er angitt, bare gjelder for en enantiomer. The structural formulas given here are to be understood to include the enantiomers of each of the compounds in question, as well as mixtures of the enantiomers including racemates, even if the exact structure given only applies to one enantiomer.
Forbindelsen med formel (1) har vist endoperoksyd og tromboksan antagonist-aktivitet, og er derfor av interesse ved behandling av astma og kardiovaskulære lidelser. The compound of formula (1) has shown endoperoxide and thromboxane antagonist activity, and is therefore of interest in the treatment of asthma and cardiovascular disorders.
Ifølge et trekk ved oppfinnelsen tilveiebringes en fremgangsmåte for fremstilling av en forbindelse med formel (1) eller et salt eller solvat derav, som omfatter reduksjon og samtidig eller påfølgende hydrolyse av en tilsvarende cyklopentanon-ester; og derefter eventuelt dannelse av et salt av forbindelsen med formel (1). Ifølge dette trekk ved oppfinnelsen er cyklopentanon-esteren en forbindelse med formel (3) angitt nedenfor. Reduksjon-og hydrolysetrinnene kan utføres som generelt beskrevet nedenfor for forbindelsene med formel (3) og formel (2). According to a feature of the invention, a method is provided for the preparation of a compound of formula (1) or a salt or solvate thereof, which comprises reduction and simultaneous or subsequent hydrolysis of a corresponding cyclopentanone ester; and then optionally forming a salt of the compound of formula (1). According to this feature of the invention, the cyclopentanone ester is a compound of formula (3) indicated below. The reduction and hydrolysis steps can be carried out as generally described below for the compounds of formula (3) and formula (2).
Ifølge et ytterligere trekk ved oppfinnelsen tilveiebringes en fremgangsmåte for fremstilling av en forbindelse med formel (1) eller et salt eller solvat derav, ved hydrolyse av en tilsvarende ester med formel (2) According to a further feature of the invention, a method is provided for the preparation of a compound of formula (1) or a salt or solvate thereof, by hydrolysis of a corresponding ester of formula (2)
hvor R<1> er: where R<1> is:
-OCR<7>R<8>R<9>, hvor R<7> og R<8> hver er fenyl (eventuelt substituert med C1_4 alkyl, Cj-4 alkoksy, di- ( C-^-^) alkylamino, nitro eller halogen), og R<9> er et hydrogenatom eller en substituert eller usubstituert fenylgruppe som definert for R<7> og R<8>; og derefter eventuelt fremstilling av et salt av forbindelsen med formel (1). R<1> er fortrinnsvis trifenylmetoksy (hvor fenylgruppene eventuelt er substituert med metyl, metoksy eller nitro), eller difenyl-metoksy (hvor fenylgruppene eventuelt er substituert med halogen, metyl, metoksy eller dimetylamino). Spesielt er R<1> trifenylmetoksy. -OCR<7>R<8>R<9>, where R<7> and R<8> are each phenyl (optionally substituted with C1-4 alkyl, C1-4 alkoxy, di-(C-^-^) alkylamino, nitro or halogen), and R<9> is a hydrogen atom or a substituted or unsubstituted phenyl group as defined for R<7> and R<8>; and then optionally producing a salt of the compound of formula (1). R<1> is preferably triphenylmethoxy (where the phenyl groups are optionally substituted with methyl, methoxy or nitro), or diphenyl-methoxy (where the phenyl groups are optionally substituted with halogen, methyl, methoxy or dimethylamino). In particular, R<1> is triphenylmethoxy.
Hydrolysen av estrene med formel (2) kan generelt utføres under sure eller basiske betingelser, f.eks. i et organisk eller vandig organisk oppløsningsmiddel, og ved enhver egnet temperatur opp til tilbakeløpstemperatur, f.eks. -5 til 25°C, og fortrinnsvis ved romtemperatur. The hydrolysis of the esters of formula (2) can generally be carried out under acidic or basic conditions, e.g. in an organic or aqueous organic solvent, and at any suitable temperature up to reflux temperature, e.g. -5 to 25°C, and preferably at room temperature.
Egnede baser omfatter uorganiske baser så som NaOH og KOH. Egnede syrer omfatter uorganiske syrer så som saltsyre, og organiske syrer så som trifluoreddiksyre eller eddiksyre. Suitable bases include inorganic bases such as NaOH and KOH. Suitable acids include inorganic acids such as hydrochloric acid, and organic acids such as trifluoroacetic acid or acetic acid.
Egnede oppløsningsmidler for slike hydrolyser omfatter tetrahydrofuran, dioksan, eter, vandig eter, CH2C12, toluen, CH3CN og vandige alkoholer. Suitable solvents for such hydrolyses include tetrahydrofuran, dioxane, ether, aqueous ether, CH 2 Cl 2 , toluene, CH 3 CN and aqueous alcohols.
Den fremstilte syre med formel (1) isoleres hensiktsmessig i form av et salt, f.eks. et salt med en uorganisk syre så som saltsyre. Eventuelt kan den frie syre frigjøres fra saltet og/eller omdannes til et annet salt hvis dette ønskes. Det først isolerte salt kan også omdannes direkte til et annet salt uten frigjøring av syren, f.eks. ved kationebytting. The produced acid with formula (1) is conveniently isolated in the form of a salt, e.g. a salt with an inorganic acid such as hydrochloric acid. Optionally, the free acid can be released from the salt and/or converted into another salt if this is desired. The first isolated salt can also be converted directly into another salt without releasing the acid, e.g. by cation exchange.
Salter av uorganiske baser kan fremstilles ved at basen Salts of inorganic bases can be prepared by making the base
settes til en oppløsning av syren med formel (1) i et vandig, organisk oppløsningsmiddel. Visse salter kan også fremstilles ved kationebytting, f.eks. kan kalsiumsaltet fremstilles ved at et kalsiumsalt (f.eks. kloridet eller acetatet) settes til en oppløsning av et salt av en forbindelse med formel (1), f.eks. et amin- eller alkalimetallsalt. is added to a solution of the acid with formula (1) in an aqueous organic solvent. Certain salts can also be prepared by cation exchange, e.g. the calcium salt can be prepared by adding a calcium salt (e.g. the chloride or the acetate) to a solution of a salt of a compound of formula (1), e.g. an amine or alkali metal salt.
Oppfinnelsen tilveiebringer en fremgangsmåte for fremstilling av hydrokloridsaltet av en forbindelse med formel (1) ved at forbindelsen med formel (1) behandles med hydrogenklorid eller saltsyre. The invention provides a method for producing the hydrochloride salt of a compound of formula (1) by treating the compound of formula (1) with hydrogen chloride or hydrochloric acid.
Oppfinnelsen tilveiebringer også en fremgangsmåte for fremstilling av et salt av en forbindelse med formel (1) som ( omfatter behandling av en ester med formel (2) med en syre eller base. Oppfinnelsen tilveiebringer også en ytterligere fremgangsmåte for fremstilling av hydrokloridsaltet av en forbindelse med formel (1) som omfatter hydrolyse av en tilsvarende ester med formel (2) hvor R<1> er C^g alkoksy og derefter behandling av den dannede syre med formel (1) med hydrogenklorid eller saltsyre. Hydrolysetrinnet kan foretas som generelt beskrevet ovenfor med hensyn til forbindelser med formel (2). Saltdannelse kan utføres i et egnet organisk oppløsningsmiddel, så som eter, etylacetat, CH2Cl2 eller dimetoksyetan, ved temperaturer på f.eks. 0°C til romtemperatur. The invention also provides a method for the preparation of a salt of a compound of formula (1) which comprises treating an ester of formula (2) with an acid or base. The invention also provides a further method for the preparation of the hydrochloride salt of a compound of formula (1) which comprises hydrolysis of a corresponding ester of formula (2) where R<1> is C 1-6 alkoxy and then treatment of the formed acid of formula (1) with hydrogen chloride or hydrochloric acid. The hydrolysis step can be carried out as generally described above with respect to compounds of formula (2) Salt formation can be carried out in a suitable organic solvent, such as ether, ethyl acetate, CH 2 Cl 2 or dimethoxyethane, at temperatures of, for example, 0°C to room temperature.
Estrene med formel (2) kan fremstilles ved reduksjon av det tilsvarende cyklopentanon med formel (3) The esters with formula (2) can be prepared by reduction of the corresponding cyclopentanone with formula (3)
I noen tilfeller, særlig når R<1> f.eks. er trityl, vil hydrolyse av den dannede ester med formel (2) finne sted enten under reduksjonen eller under isolering av produktet, med den fordel at intet separat hydrolysetrinn er nødvendig. Forbindelsen med formel (1) kan således fremstilles ved reduksjon og samtidig eller påfølgende hydrolyse av den tilsvarende forbindelse med formel (3). In some cases, especially when R<1> e.g. is trityl, hydrolysis of the formed ester of formula (2) will take place either during the reduction or during isolation of the product, with the advantage that no separate hydrolysis step is necessary. The compound with formula (1) can thus be prepared by reduction and simultaneous or subsequent hydrolysis of the corresponding compound with formula (3).
Reduksjonen kan f.eks. utføres med et selektivt reduksjons-middel, så som diisobutylaluminium-2,6-di-t-butyl-4-metylfenoksyd, litium, trisamylborhydrid, 2,6-di-tert-butyl-4-metylfenoksy-magnesiumhydrid eller kaliumtriisopropoksyborhydrid eller triisobutylaluminium. Reaksjonstemperaturen kan være fra -10 til The reduction can e.g. is carried out with a selective reducing agent, such as diisobutylaluminum-2,6-di-t-butyl-4-methylphenoxide, lithium, trisamylborohydride, 2,6-di-tert-butyl-4-methylphenoxy-magnesium hydride or potassium triisopropoxyborohydride or triisobutylaluminium. The reaction temperature can be from -10 to
-78°C. Tetrahydrofuran og toluen er egnede oppløsningsmidler. Estrene med formel (3) fremstilles fortrinnsvis ved oksydasjon av en tilsvarende a-hydroksy-forbindelse med formel (4) -78°C. Tetrahydrofuran and toluene are suitable solvents. The esters of formula (3) are preferably produced by oxidation of a corresponding α-hydroxy compound of formula (4)
Egnede oksydasjonsmetoder omfatter anvendelse av et Cr<VI >oksydasjonsmiddel i et egnet oppløsningsmiddel, f.eks. kromsyre i aceton (f.eks. Jones reagens, fortrinnsvis anvendt i nærvær av en diatoméjord så som "Celite") eller Cr03 i pyridin. Disse reagenser anvendes f.eks. ved temperaturer fra -20°C til romtemperatur . Suitable oxidation methods include the use of a Cr<VI>oxidizing agent in a suitable solvent, e.g. chromic acid in acetone (eg Jones reagent, preferably used in the presence of a diatomaceous earth such as "Celite") or Cr0 3 in pyridine. These reagents are used e.g. at temperatures from -20°C to room temperature.
Andre viktige metoder omfatter anvendelse av et aktivert svovelreagens, f.eks. (i) N-klorsuccinimid-dimetylsulfid-kompleks i et egnet oppløsningsmiddel (f.eks. toluen eller diklormetan) ved temperaturer på f.eks. -25 til 25°C, fortrinnsvis ved 0 til 5°C, (ii) et dialkylsulfoksyd (f.eks. dimetylsulfoksyd) aktivert med et egnet elektrofilt reagens (så som oksalylklorid, acetyl-bromid eller tionylklorid) i et egnet oppløsningsmiddel (f.eks. toluen eller diklormetan). f.eks. ved -70 til -20°C; og dicyklo-heksylkarbodiimid kan også anvendes som elektrofilt reagens (fortrinnsvis i nærvær av CF3C00H eller dens pyridiniumsalt) ved f.eks. -10°C til romtemperatur, under anvendelse av de samme oppløsningsmidler, eller (iii) pyridin-S03-kompleks i dimetylsulfoksyd, fortrinnsvis ved 0°C til romtemperatur. Other important methods include the use of an activated sulfur reagent, e.g. (i) N-chlorosuccinimide-dimethylsulphide complex in a suitable solvent (e.g. toluene or dichloromethane) at temperatures of e.g. -25 to 25°C, preferably at 0 to 5°C, (ii) a dialkyl sulfoxide (eg dimethyl sulfoxide) activated with a suitable electrophilic reagent (such as oxalyl chloride, acetyl bromide or thionyl chloride) in a suitable solvent (f .eg toluene or dichloromethane). e.g. at -70 to -20°C; and dicyclohexylcarbodiimide can also be used as electrophilic reagent (preferably in the presence of CF3CO0H or its pyridinium salt) by e.g. -10°C to room temperature, using the same solvents, or (iii) pyridine-SO 3 complex in dimethylsulfoxide, preferably at 0°C to room temperature.
Valg av oksydasjonsmetode vil være avhengig av hva R<1> er. The choice of oxidation method will depend on what R<1> is.
Når piperidinogruppen er i a-konfigurasjon, bør betingelsene velges slik at man får epimerisering efter oksydasjon, f.eks. under anvendelse av et Cr<VI> oksydasjonsmiddel. When the piperidino group is in a-configuration, the conditions should be chosen so that epimerization is obtained after oxidation, e.g. using a Cr<VI> oxidizing agent.
Forbindelsene med formel (4) kan fremstilles ved forestring av den tilsvarende karboksylsyre, dvs. en forbindelse med formel (4) hvor R<1> betyr en hydroksylgruppe. Vanlige forestringsmetoder kan anvendes. The compounds of formula (4) can be prepared by esterification of the corresponding carboxylic acid, i.e. a compound of formula (4) where R<1> means a hydroxyl group. Usual esterification methods can be used.
Således kan f.eks. forbindelser med formel (4) fremstilles ved at den tilsvarende karboksylsyre omsettes med et passende halogenid R^-Hal, hvor Hal betyr halogen. Omsetningen utføres i nærvær av en egnet base, f.eks. kalium-t-butoksyd eller et sterisk hindret amin så som N,N-diisopropyletylamin eller trietylamin, i et egnet oppløsningsmiddel (så som CH3CN, CH2C12 eller dimetylsulfoksyd), f.eks. ved en temperatur fra 0°C til romtemperatur. Thus, e.g. compounds of formula (4) are prepared by reacting the corresponding carboxylic acid with a suitable halide R^-Hal, where Hal means halogen. The turnover is carried out in the presence of a suitable base, e.g. potassium t-butoxide or a sterically hindered amine such as N,N-diisopropylethylamine or triethylamine, in a suitable solvent (such as CH 3 CN, CH 2 Cl 2 or dimethylsulfoxide), e.g. at a temperature from 0°C to room temperature.
Utgangs-karboksylsyren som er nødvendig for fremstilling av estrene med formel (4), kan fremstilles ved metoder beskrevet i britisk patentskrift 2075503A. The starting carboxylic acid which is necessary for the preparation of the esters of formula (4) can be prepared by methods described in British patent document 2075503A.
Når en spesifikk enantiomer med formel (1) ønskes, bør utgangsmaterialer med den ønskede stereokjemiske konfigurasjon anvendes ved de ovenfor beskrevne fremgangsmåter. Slike mellom-produkter kan f.eks. fremstilles fra et enantiomert bromhydrin som generelt beskrevet i britisk patentskrift 2075503A. When a specific enantiomer of formula (1) is desired, starting materials with the desired stereochemical configuration should be used in the above-described methods. Such intermediate products can e.g. is prepared from an enantiomeric bromohydrin as generally described in British patent document 2075503A.
Piperidinogruppen gjør det mulig for forbindelsen med formel (1) å danne salter med uorganiske eller organiske syrer, f.eks. hydroklorider eller maleater. Salter kan også dannes med baser, og eksempler på slike salter er alklaimetall- (f.eks. natrium eller kalium), jordalkalimetall- (f.eks. kalsium eller magnesium), The piperidino group enables the compound of formula (1) to form salts with inorganic or organic acids, e.g. hydrochlorides or maleates. Salts can also be formed with bases, and examples of such salts are alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium),
i in
ammonium-, substituert ammonium- (f.eks. trometamin eller dimetylaminoetanol), piperazin-, N,N-dimetylpiperazin-, ammonium-, substituted ammonium- (e.g. tromethamine or dimethylaminoethanol), piperazine-, N,N-dimethylpiperazine-,
morfolin-, piperidin- og tertiære amino- (f.eks. trimetylamin) salter. Hydrokloridsaltet foretrekkes. morpholine, piperidine and tertiary amino (eg trimethylamine) salts. The hydrochloride salt is preferred.
Generelt foretrekkes forbindelsen med formel (1), hvor karbonatomet som bærer -(CH2)2CH=CH(CH2)COOH-gruppen, er i R-konfigurasjon (og blandinger inneholdende denne isomer). In general, the compound of formula (1) is preferred, where the carbon atom carrying the -(CH 2 ) 2 CH=CH(CH 2 )COOH group is in the R configuration (and mixtures containing this isomer).
[lR-[loc(Z), 2P,3e,5a]]-(+)-7-[5-[[l,l'-bifenyl)-4-yl]metoksy]-3-hydroksy-2-(1-piperidinyl)-cyklopentyl]-4-heptensyre-hydroklorid (referert til nedenfor som forbindelse A) er særlig foretrukket. [1R-[loc(Z), 2P,3e,5a]]-(+)-7-[5-[[1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-( 1-piperidinyl)-cyclopentyl]-4-heptenoic acid hydrochloride (referred to below as compound A) is particularly preferred.
Utgangs-aminosyren for forbindelse A er beskrevet i vårt britiske patentskrift 2097397A, sammen med andre aminocyklo-pentanolsyrer og -estere. Forbindelse A er fordelaktig i en rekke henseender sammenlignet med disse forbindelser i sin alminnelighet og særlig sammenlignet med dens utgangs-aminosyre og andre salter eller solvater derav, både med hensyn til fremstilling og anvendelse i medisinen. Således kan f.eks. forbindelse A lett isoleres fra reaksjonsblandinger hvor den fremstilles, og den oppnås i krystallinsk form med høy renhet som har de ønskede egenskaper for farmasøytisk anvendelse. The starting amino acid for compound A is described in our UK patent document 2097397A, together with other aminocyclopentanol acids and esters. Compound A is advantageous in a number of respects compared to these compounds in general and especially compared to its starting amino acid and other salts or solvates thereof, both with regard to production and use in medicine. Thus, e.g. compound A is easily isolated from reaction mixtures in which it is prepared, and it is obtained in crystalline form with high purity that has the desired properties for pharmaceutical use.
Forbindelsen med formel (1) hemmer blodplateaggregasjon og bronkokonstriksjon. For å bestemme hemmingen av blodplate-aggregasjon, administreres utsultede marsvin oralt med forbindelsen i et egnet bæremiddel. Blodplaterik plasma fremstilles fra hvert dyr, og aggregasjon overfor et område av kollagenkonsentrasjoner måles ved metode ifølge Born (Nature 194. 927-929, (1962)). Kollagenkonsentrasjon-effektkurver for hver plasmaprøve beregnes, og resultatene uttrykkes som forskyvning av kurvene efter behandling med prøveforbindelsen. The compound of formula (1) inhibits platelet aggregation and bronchoconstriction. To determine the inhibition of platelet aggregation, starved guinea pigs are administered orally with the compound in a suitable vehicle. Platelet-rich plasma is prepared from each animal, and aggregation over a range of collagen concentrations is measured by the method of Born (Nature 194. 927-929, (1962)). Collagen concentration-effect curves for each plasma sample are calculated, and the results are expressed as displacement of the curves after treatment with the test compound.
Forbindelsens evne til å hemme bronkokonstriksjon bestemmes hos bedøvede marsvin ved å måle virkningen av forbindelsen på dose-reaksjonskurven for bronkokonstriktoren [lR-[loc,4a,5P(Z),6a-(1E,3S<*>)]]-7-[6-(3-hydroksy-l-oktenyl)-2-oksabicyklo[2,2,l]hept-5-yl]-5-heptensyre (U-46619). The ability of the compound to inhibit bronchoconstriction is determined in anesthetized guinea pigs by measuring the effect of the compound on the dose-response curve of the bronchoconstrictor [lR-[loc,4a,5P(Z),6a-(1E,3S<*>)]]-7- [6-(3-hydroxy-1-octenyl)-2-oxabicyclo[2,2,1]hept-5-yl]-5-heptenoic acid (U-46619).
Forbindelsen med formel (1), særlig forbindelse A, er The compound with formula (1), especially compound A, is
således av interesse for behandling av astma, og som en inhibitor for blodplate-aggregasjon og trombose for anvendelse ved nyre-dialyse og behandling eller forhindring av tilstoppende karsykdommer så som arteriosclerose, atherosclerose, perifere karsykdommer, cerebrale karsykdommer innbefattet forbigående thus of interest for the treatment of asthma, and as an inhibitor of platelet aggregation and thrombosis for use in renal dialysis and the treatment or prevention of occlusive vascular diseases such as arteriosclerosis, atherosclerosis, peripheral vascular diseases, cerebral vascular diseases including transient
lokal blodmangel, slag, pulmonar emboli, diabetisk retinopati, postoperativ trombose, angina og myokardialt infarkt. Forbindelsene kan tilberedes på vanlig måte for bruk, med et eller flere farmasøytiske bæremidler. local anemia, stroke, pulmonary embolism, diabetic retinopathy, postoperative thrombosis, angina and myocardial infarction. The compounds can be prepared in the usual way for use, with one or more pharmaceutical carriers.
For oral administrering kan det farmasøytiske preparat være For oral administration, the pharmaceutical preparation may be
i form av f.eks. tabletter, kapsler, pulvere, oppløsninger eller siruper fremstilt på vanlig måte med godtatte hjelpestoffer. in the form of e.g. tablets, capsules, powders, solutions or syrups prepared in the usual way with accepted excipients.
Forbindelsene kan tilberedes for parenteral administrering for enkeltinjeksjon eller kontinuerlig infusjon. Preparater for injeksjon kan tilberedes i enhetsdoseform i ampuller eller i flerdosebeholdere med tilsatt konserveringsmiddel. The compounds may be prepared for parenteral administration by single injection or continuous infusion. Preparations for injection can be prepared in unit-dose form in ampoules or in multi-dose containers with an added preservative.
For administrering ved inhalering leveres forbindelsen hensiktsmessig i form av en aerosol-spray fra trykkpakninger eller en forstøvningsanordning, eller som en patron fra hvilken det pulveriserte preparat kan inhaleres ved hj elp av en egnet anordning. Når det gjelder en aerosol under trykk, kan enhetsdosen bestemmes ved å anvende en ventil som leverer en tilmålt mengde. For administration by inhalation, the compound is conveniently supplied in the form of an aerosol spray from pressure packs or an atomizing device, or as a cartridge from which the powdered preparation can be inhaled by means of a suitable device. In the case of a pressurized aerosol, the unit dose can be determined by using a valve that delivers a metered amount.
For anvendelse som antitrombotisk middel administreres forbindelsen fortrinnsvis oralt, f.eks. i mengder på 0,05 til 5 For use as an antithrombotic agent, the compound is preferably administered orally, e.g. in quantities of 0.05 to 5
mg pr. kg kroppsvekt, 1 til 4 ganger daglig. mg per kg body weight, 1 to 4 times daily.
For anvendelse ved behandling av astma, kan forbindelsen For use in the treatment of asthma, the compound can
også administreres oralt i mengder på 0,05 til 5 mg pr. kg kroppsvekt, 1 til 4 ganger daglig; fortrinnsvis administreres den imidlertid ved inhalering i doser som varierer fra 0,3 til 30 mg, 1 til 4 ganger daglig. Forbindelsen kan anvendes i kombinasjon med andre anti-astmatiske midler. also administered orally in amounts of 0.05 to 5 mg per kg body weight, 1 to 4 times daily; preferably, however, it is administered by inhalation in doses ranging from 0.3 to 30 mg, 1 to 4 times daily. The compound can be used in combination with other anti-asthmatic agents.
Enhetsdose-preparater inneholder således vanligvis 3,5 til 350 mg av forbindelsen. Den nøyaktige dose som administreres, Thus, unit dose preparations usually contain 3.5 to 350 mg of the compound. The exact dose administered,
vil selvsagt avhenge av pasientens alder og tilstand. will of course depend on the patient's age and condition.
De følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Temperaturer er i °C. Temperatures are in °C.
De følgende forkortelser anvendes: The following abbreviations are used:
TLC - tynnskiktkromatografi under anvendelse av Si02 hvis ikke annet er angitt. TLC - thin layer chromatography using SiO2 unless otherwise stated.
ER - eter; ER - ether;
EA - etylacetat; EA - ethyl acetate;
THF - tetrahydrofuran; THF - tetrahydrofuran;
DIBAL - diisobutylaluminium-hydrid. DIBAL - diisobutylaluminum hydride.
Kromatografi ble anvendt under anvendelse av silikagel. Chromatography was performed using silica gel.
"tørket" refererer til tørking med MgS04. "dried" refers to drying with MgSO 4 .
"Hyflor" er et filtreringshjelpemiddel. "Hyflor" is a filtration aid.
Fremstilling av mellomprodukt 1 er beskrevet i britisk patentskrift 2075503A; Preparation of intermediate 1 is described in British patent document 2075503A;
Mellomprodukt 1 Intermediate 1
r IR- fekso. endo)1-C-1- 2- brom- 3- hydroksybicvklor3. 2. 01heptan- 6- on r IR-fekso. endo)1-C-1- 2- bromo- 3- hydroxybicvchlor3. 2. 01heptan-6-one
Fremstilling av mellomproduktene 2 og 3 er beskrevet i britisk patentskrift 2097397A. Preparation of intermediate products 2 and 3 is described in British patent document 2097397A.
Mellomprodukt 2 Intermediate product 2
riR- notm. 2B. 30. 5a1-(+)- metyl- 7- r5r f 1. 1'- bif enyl)- 4- vl") - metoksy 1- 3- hydroksv- 2- ( 1- piperidinvl) cyklopentvl) ~) - 4- heptenoat Mellomprodukt 3 riR- notm. 2B. 30. 5α1-(+)- methyl- 7- r5r f 1. 1'- biphenyl)- 4- vl") - methoxy 1- 3- hydroxyv- 2-( 1- piperidinvl) cyclopentvl) ~) - 4- heptenoate Intermediate 3
riR- fla. 2P. 3a. 5all- 5- r\( 1. 1'- bifenvl)- 4- vlImetoksVI- 3- hydroksy-2-( 1- piperidinyl) cyklopentan- acetaldehyd riR- fla. 2P. 3a. 5-all-5- r\(1.1'- biphenyl)-4- vlImethoxyVI- 3- hydroxy-2-(1-piperidinyl)cyclopentane- acetaldehyde
Mellomprodukt 4 Intermediate product 4
riR-( la. 2P. 3a. 5a) l- m - 5- r r ( 1 . l'- bifenyl) - 4- yl 1 metoksy")- 3-hydroksy- 2- f1- piperidinvl)- cyklopentan- propanal riR-( la. 2P. 3a. 5a ) l- m - 5- r r ( 1 . 1'- biphenyl)- 4- yl 1 methoxy")- 3-hydroxy- 2- f1-piperidinevl)- cyclopentane- propanal
En oppløsning av mellomprodukt 3 (13,0 g) i toluen (39 ml) ble satt dråpevis til en suspensjon av kalium-tert-butoksyd (5,96 g) i toluen (52 ml). Metoksymetyltrifenylfosfoniumklorid (15,93 g) ble tilsatt, og blandingen ble omrørt natten over (18 timer). 2N saltsyre (52 ml) ble tilsatt, og blandingen ble oppvarmet under omrøring ved 40°C i 30 minutter. Fast K2C03A solution of intermediate 3 (13.0 g) in toluene (39 ml) was added dropwise to a suspension of potassium tert-butoxide (5.96 g) in toluene (52 ml). Methoxymethyltriphenylphosphonium chloride (15.93 g) was added and the mixture was stirred overnight (18 hours). 2N hydrochloric acid (52 mL) was added and the mixture was heated with stirring at 40°C for 30 minutes. Fixed K2C03
(13 g) ble tilsatt, den organiske fase ble fraskilt, vasket med vann (52 ml) og tørket azeotropisk for å gi en oppløsning av mellomprodukt 4 i toluen (115 ml). En del av oppløsningen (8,8 ml) ble renset ved kromatografi ved eluering med 9:1 EA-metanol for å gi tittelforbindelsen som et skum (0,53 g). (13 g) was added, the organic phase was separated, washed with water (52 mL) and azeotropically dried to give a solution of intermediate 4 in toluene (115 mL). A portion of the solution (8.8 mL) was purified by chromatography eluting with 9:1 EA-methanol to give the title compound as a foam (0.53 g).
TLC 4:1 EA-metanol: Rf 0,15. TLC 4:1 EA-methanol: Rf 0.15.
Mellomprodukt 5 Intermediate 5
riR- flafZ) . 26. 3a. Sa]]-(+)- 7- f5- r f( 1. l/- bifenvl)- 4- vl]- metoksy1-3- hvdroksv- 2-( 1- piperidinyl) cvklopentyll- 4- heptensvre- hydroklorid riR- flafZ) . 26. 3a. Sa]]-(+)- 7- f5- r f( 1.1/- biphenyl)- 4- vl]- methoxy1-3- hydroxy- 2-( 1- piperidinyl) cyclopentyl- 4- heptenic acid hydrochloride
Til en oppløsning av kalium-tert-butoksyd (21,49 g) i toluen (198 ml) og THF (52 ml) under N2 ble satt 3-(karboksypropyl)-trifenylfosfoniumbromid (41,14 g). Efter 1,5 timer ble en oppløsning av mellomprodukt 4 (24,5 g) i toluen (220 ml) tilsatt, og blandingen ble omrørt i 3 timer. Vann (125 ml) ble tilsatt, blandingen ble kraftig ristet, og fasene ble separert. Den vandige fase ble vasket med toluen (2 x 225 ml) (kastet), derefter surgjort (til pH 7,5) med 2N saltsyre og ekstrahert med CH2C12 (2 x 225 ml). De samlede CH2C12 ekstrakter ble tørket og inndampet for å gi tittelforbindelsen, base (24,47 g) som en gummi. To a solution of potassium tert-butoxide (21.49 g) in toluene (198 ml) and THF (52 ml) under N 2 was added 3-(carboxypropyl)-triphenylphosphonium bromide (41.14 g). After 1.5 h, a solution of intermediate 4 (24.5 g) in toluene (220 mL) was added and the mixture was stirred for 3 h. Water (125 mL) was added, the mixture was vigorously shaken, and the phases were separated. The aqueous phase was washed with toluene (2 x 225 mL) (discarded), then acidified (to pH 7.5) with 2N hydrochloric acid and extracted with CH 2 Cl 2 (2 x 225 mL). The combined CH 2 Cl 2 extracts were dried and evaporated to give the title compound, base (24.47 g) as a gum.
En oppløsning av basen (93 mg) i CH2C12 (1,5 ml) ble behandlet med et overskudd av eterisk hydrogenklorid. Opp-løsningsmidlene ble fjernet, og den gjenværende olje ble utgnidd med ER (5 ml). Det resulterende, faste stoff ble filtrert, vasket med ER og tørket for å gi tittelforbindelsen (82 mg), A solution of the base (93 mg) in CH 2 Cl 2 (1.5 mL) was treated with an excess of ethereal hydrogen chloride. The solvents were removed and the remaining oil triturated with ER (5 mL). The resulting solid was filtered, washed with ER and dried to give the title compound (82 mg),
sm.p. 132,5-136°C (mykner ved 128°). sm.p. 132.5-136°C (softens at 128°).
Mellomprodukt 6 Intermediate 6
riR- riot( Z) . 26. 3a. 5a] - (+) - trifenvlmetyl- 7- f 5- r f ( 1. 1' - bif enyl) - 4- vilmetoksy1- 3- hvdroksy- 2- f1- piperidinyl) cyklopentvl- 4- heptenoat riR- riot( Z) . 26. 3a. 5a] - (+)- triphenylmethyl- 7- f 5- r f ( 1. 1' - biphenyl) - 4- ylmethoxy1- 3- hydroxy- 2- f1- piperidinyl) cyclopentyl- 4- heptenoate
Trietylamin (2,49 ml) ble satt til en kald (5°) oppløsning av mellomprodukt 5, base (5,88 g) og tritylklorid (4,4 g) i CH2C12 (24 ml). Blandingen ble omrørt i 30 minutter, og derefter ble vann (60 ml) og ytterligere CH2C12 (30 ml) tilsatt. Den organiske fase ble fraskilt og derefter inndampet i vakuum. Residuet ble azeotrop-behandlet med CH2C12 (60 ml) for å gi en olje (10,13 g) som ble kromatografert på aluminiumoksyd (500 g), idet eluering ble foretatt med EA for å gi tittelforbindelsen som en olje (5,14 g). Triethylamine (2.49 mL) was added to a cold (5°) solution of intermediate 5, base (5.88 g) and trityl chloride (4.4 g) in CH 2 Cl 2 (24 mL). The mixture was stirred for 30 min, then water (60 mL) and additional CH 2 Cl 2 (30 mL) were added. The organic phase was separated and then evaporated in vacuo. The residue was azeotroped with CH 2 Cl 2 (60 mL) to give an oil (10.13 g) which was chromatographed on alumina (500 g), eluting with EA to give the title compound as an oil (5.14 g ).
TLC (A1203) 49:1 EA-metanol: Rf 0,52. TLC (A1203) 49:1 EA-methanol: Rf 0.52.
Mellomprodukt 7 Intermediate product 7
f IR- f la( Z) . 26. 5aT1- f-)- trifenYlmetyl- 7- r5- rrfl. l/- bifenvl)- 4-ylt- metoksy1-3-okso-2-( 1- piperidinyl) cyklopentyl]- 4- heptenoat f IR- f la( Z) . 26. 5aT1- f-)-triphenYlmethyl- 7- r5- rrfl. 1/-biphenyl)-4-yl-methoxy1-3-oxo-2-(1-piperidinyl)cyclopentyl]-4-heptenoate
Trietylamin (9,17 ml) ble ved 2°C satt til en omrørt oppløsning av mellomprodukt 6 (6,47 g) i CH2C12 (65 ml), fulgt av en oppløsning av pyridin/S03 kompleks (5,75 g) i dimetylsulfoksyd (65 ml). Den resulterende oppløsning ble omrørt ved 3-5°C i 2 timer og avkjølt ved dråpevis tilsetning av isvann (65 ml). Reaksjonsblandingen ble ekstrahert med dietyleter (2 x 65 ml), og ekstrakten ble vasket med vann (65 ml), IM sitronsyre (4 x 10 ml) og vann (10 ml). Avdampning av de tørkede (Na2S04) oppløsnings-midler ga tittelforbindelsen som et skum (5,9 g). Triethylamine (9.17 mL) was added at 2°C to a stirred solution of intermediate 6 (6.47 g) in CH 2 Cl 2 (65 mL), followed by a solution of pyridine/SO 3 complex (5.75 g) in dimethyl sulfoxide (65ml). The resulting solution was stirred at 3-5°C for 2 hours and cooled by dropwise addition of ice water (65 mL). The reaction mixture was extracted with diethyl ether (2 x 65 mL) and the extract was washed with water (65 mL), 1M citric acid (4 x 10 mL) and water (10 mL). Evaporation of the dried (Na 2 SO 4 ) solvents gave the title compound as a foam (5.9 g).
IR (CHBr3) 1740 cm"<1.>IR (CHBr3) 1740 cm"<1.>
Eksempel 1 Example 1
F IR- f la ( Z) . 26 . 36 . 5a] ] - (+) - 7- r 5- [" f ( 1. 1' - bif enyl) - 4- yl "| - metoksy! - 3-hydroksy- 2-( 1- piperidinyl) cyklopentyl1- 4- heptensyre- hydroklorid F IR- f la ( Z) . 26 . 36 . 5a] ] - (+) - 7- r 5- [" f ( 1. 1' - biphenyl) - 4- yl "| - methoxy! - 3-hydroxy- 2-( 1- piperidinyl) cyclopentyl 1- 4- heptenoic acid hydrochloride
Mellomprodukt 2 (10,38 g) ble omrørt med 74 OP etanol Intermediate 2 (10.38 g) was stirred with 74 OP ethanol
(60 ml) og 5N NaOH (30 ml) ved 20° i 16 timer. Oppløsningen ble fortynnet med vann (400 ml) og derefter ekstrahert med ER (60 ml) and 5N NaOH (30 ml) at 20° for 16 hours. The solution was diluted with water (400 mL) and then extracted with ER
(2 x 150 ml). Den vandige fase ble regulert til pH 6 med 2N HC1 og ekstrahert med CH2C12 (3 x 200 ml). Inndampning av de samlede ekstrakter ga et skum (9,45 g), hvorav hovedmengden (9,3 g) ble tatt opp i CH2C12 (50 ml) og behandlet med et overskudd av en eterisk oppløsning av hydrogenklorid. Inndampning i vakuum og utgnidning av residuet med ER (4 x 75 ml) ga tittelforbindelsen som et pulver (9,28 g). Krystallisering av en prøve fra EA-metanol ga et materiale med sm.p. 124-126°. (2 x 150 ml). The aqueous phase was adjusted to pH 6 with 2N HCl and extracted with CH 2 Cl 2 (3 x 200 mL). Evaporation of the combined extracts gave a foam (9.45 g), the bulk of which (9.3 g) was taken up in CH 2 Cl 2 (50 ml) and treated with an excess of an ethereal solution of hydrogen chloride. Evaporation in vacuo and trituration of the residue with ER (4 x 75 mL) gave the title compound as a powder (9.28 g). Crystallization of a sample from EA-methanol gave a material with m.p. 124-126°.
[a]g5 = 63,1° (CHC13). [α]g 5 = 63.1° (CHCl 3 ).
Eksempel 2 Example 2
[ IR- flafZ). 26. 36. 5aH-(+)- 7- r5- rr( l. l,- bi f enyl) - 4- yl ] - metoksy ] - 3 - hydroksy- 2-( l- piperidinvl) cvklopentvll- 4- heptensyre- hydroklorid [ IR- flafZ). 26 36 - hydrochloride
DIBAL (IM i heksan, 5,5 ml) ble satt dråpevis ved 0-2° til en omrørt oppløsning av 2,6-di-t-butyl-4-metylfenol (2,9 g) i CH2C12 (13 ml). Oppløsningen ble omrørt ved -5 til 0° i 1 time og derefter avkjølt til -20°. En oppløsning av mellomprodukt 7 DIBAL (1M in hexane, 5.5 mL) was added dropwise at 0-2° to a stirred solution of 2,6-di-t-butyl-4-methylphenol (2.9 g) in CH 2 Cl 2 (13 mL). The solution was stirred at -5 to 0° for 1 hour and then cooled to -20°. A solution of intermediate 7
(1,3 g) i CH2C12 (13 ml) ble tilsatt ved -18 til -20°. Blandingen ble omrørt ved denne temperatur i 2,5 timer, IN saltsyre (20 ml) ble derefter tilsatt dråpevis, og blandingen ble omrørt ved romtemperatur i 0,5 time. Fasene ble separert, og det vandige lag ble ekstrahert med CH2C12 (10 ml). De organiske ekstrakter ble samlet, vasket med saltvann, tørket (Na2S04) og inndampet for å gi en gul gummi. Produktet ble utgnidd med dietyleter for å (1.3 g) in CH 2 Cl 2 (13 mL) was added at -18 to -20°. The mixture was stirred at this temperature for 2.5 hours, 1N hydrochloric acid (20 mL) was then added dropwise, and the mixture was stirred at room temperature for 0.5 hour. The phases were separated and the aqueous layer was extracted with CH 2 Cl 2 (10 mL). The organic extracts were combined, washed with brine, dried (Na 2 SO 4 ) and evaporated to give a yellow gum. The product was triturated with diethyl ether to
gi et lysegult pulver (0,68 g). Omkrystallisering fra EA-metanol ga sm.p. 128-130°; yield a pale yellow powder (0.68 g). Recrystallization from EA-methanol gave m.p. 128-130°;
[a]g3 = + 66,5° (CHC13). [α]g 3 = + 66.5° (CHCl 3 ).
Mellomprodukt 8 Intermediate 8
F IR- f lo( Z) . 23, 33. 5a11- trifenylmetyl- 7- f 5- r\ 1. 1'- bifenyl)- 4- yll-metoksy1- 3- hydroksy- 2-( 1- piperidinvl) cyklopentvl]- 4- heptenoat F IR- f lo( Z) . 33
Tritylklorid (0,56 g) ble satt til en omrørt, isavkjølt oppløsning av produktet fra eksempel 2 (0,376 g) i CH2C12 (5 ml) fulgt av trietylamin (0,45 ml). Trityl chloride (0.56 g) was added to a stirred, ice-cooled solution of the product of Example 2 (0.376 g) in CH 2 Cl 2 (5 mL) followed by triethylamine (0.45 mL).
Efter 1 1/4 time ble blandingen fortynnet med pH 6,5 fosfatbuffer (50 ml), og produktet ble ekstrahert inn i EA After 1 1/4 hours, the mixture was diluted with pH 6.5 phosphate buffer (50 mL) and the product was extracted into EA
(2 x 50 ml). EA-ekstrakten ble tørket og inndampet i vakuum for å gi en brun olje som ble renset ved kromatografi under anvendelse av 100:1 ER-trietylamin som elueringsmiddel for å gi tittelforbindelsen (0,28 g) som en gummi. (2 x 50 ml). The EA extract was dried and evaporated in vacuo to give a brown oil which was purified by chromatography using 100:1 ER-triethylamine as eluent to give the title compound (0.28g) as a gum.
TLC (A1203), Et20: Rf 0,7. TLC (A1203), Et 2 O: Rf 0.7.
Eksempel 3 Example 3
f IR- fla( Z ) . 26 . 36 . 5a1W+)- 7- f5- r r 1. 17- bifenyl)- 4- vl1- metoksy]- 3-hvdroksv- 2-( 1- piperidinyl)- cyklopentvll- 4- heptensyre- hydroklorid f IR-fla( Z ) . 26 . 36 . 5a1W+)- 7- f5- r r 1. 17- biphenyl)- 4- vl1- methoxy]- 3-hydroxyv- 2-( 1- piperidinyl)- cyclopentyl)- 4- heptenoic acid hydrochloride
En oppløsning av mellomprodukt 8 (0,27 g) i aceton (7 ml) og 2N saltsyre ble omrørt ved 20° i 2 timer. Mesteparten av acetonet ble fjernet i vakuum, og residuet ble ekstrahert med ER A solution of intermediate 8 (0.27 g) in acetone (7 mL) and 2N hydrochloric acid was stirred at 20° for 2 hours. Most of the acetone was removed in vacuo and the residue was extracted with ER
(2 x 15 ml) (kastet). Den vandige fase ble ekstrahert med CH2C12(2 x 15 ml) (discarded). The aqueous phase was extracted with CH 2 Cl 2
(2 x 15 ml), tørket, inndampet, og residuet ble utgnidd med ER (2 x 15 mL), dried, evaporated, and the residue triturated with ER
for å gi et fast stoff. Omkrystallisering fra EA-metanol ga tittelforbindelsen (104 mg), sm.p. 125-126°. to give a solid. Recrystallization from EA-methanol gave the title compound (104 mg), m.p. 125-126°.
Claims (2)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08226378A GB2108116B (en) | 1981-09-16 | 1982-09-16 | Aminocyclopentane esters and their preparation and pharmaceutical formulation |
GB8230771 | 1982-10-28 | ||
GB8230770 | 1982-10-28 |
Publications (3)
Publication Number | Publication Date |
---|---|
NO833328L NO833328L (en) | 1984-03-19 |
NO160848B true NO160848B (en) | 1989-02-27 |
NO160848C NO160848C (en) | 1989-06-07 |
Family
ID=27261737
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO833328A NO160848C (en) | 1982-09-16 | 1983-09-15 | ANALOGY PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE AMINOCYCLOPENTANOL HEPETIC ACID DERIVATE. |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO160848C (en) |
-
1983
- 1983-09-15 NO NO833328A patent/NO160848C/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO160848C (en) | 1989-06-07 |
NO833328L (en) | 1984-03-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5610163A (en) | Esters of thienyl carboxylic acids and amino alcohols and their quaternization products | |
US4342756A (en) | Aminocyclopentane alkenoic acids and esters and pharmaceutical compositions | |
USRE39820E1 (en) | Esters of thienyl carboxylic acids and amino alcohols and their quaternization products | |
NO141487B (en) | WIRELESS INFORMATION TRANSMISSION SYSTEM | |
CZ133493A3 (en) | Thiazolylvinylphenyl compounds process of their preparation and medicaments based thereon | |
BG66162B1 (en) | Quinuclidine derivatives and medical compositions containing them | |
NO300972B1 (en) | Analogous Process for Preparing Therapeutically Active Condensed Polycyclic Compounds | |
JPS6333343A (en) | Novel intermediate compound for manufacturing pyridyl compound | |
KR20110044221A (en) | Quinuclidine carbonate derivatives and medicinal composition thereof | |
WO1996031508A1 (en) | Biphenylamide derivatives as 5ht1d antagonists | |
GB2114565A (en) | Amino carboxylic acids and derivatives thereof | |
NO753935L (en) | ||
NO160848B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE AMINOCYCLOPENTANOL HEPETIC ACID DERIVATE. | |
US4371530A (en) | Aminocyclopentanone amides and pharmaceutical formulation | |
IE55377B1 (en) | 1,5-diphenylpyrazolin-3-one compounds,method for preparing them,and pharmaceutical compositions containing these compounds | |
US4530925A (en) | Aminocyclopentane esters and pharmaceutical formulations | |
EP0074861B1 (en) | Aminocyclopentane esters and their preparation and pharmaceutical formulation | |
US4613597A (en) | Aminocyclopentanes and their preparation and pharmaceutical formulation | |
US4438112A (en) | Prostanoid compounds and pharmaceutical formulations | |
US4690933A (en) | Pyridylvinyl-1H tetrazole having antihistamine activity | |
DK153843B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF 5-SUBSTITUTED 10,11-DIHYDRO-5H-DIBENZOOEA, DAACYCLOHEPTEN-5,10-IMINES OR SALTS THEREOF | |
US4977163A (en) | Aminocyclopentanol acids and esters and their preparation and pharmaceutical formulation | |
JPH05117227A (en) | Leukotriene inhibitor | |
EP0133534B1 (en) | Pyridyl compounds | |
EP0297855A1 (en) | Aminocyclopentyl ethers and their preparation and pharmaceutical formulation |