NO904470L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZOTIAZEPINE DERIVATIVES. - Google Patents
PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZOTIAZEPINE DERIVATIVES.Info
- Publication number
- NO904470L NO904470L NO90904470A NO904470A NO904470L NO 904470 L NO904470 L NO 904470L NO 90904470 A NO90904470 A NO 90904470A NO 904470 A NO904470 A NO 904470A NO 904470 L NO904470 L NO 904470L
- Authority
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- Norway
- Prior art keywords
- group
- stands
- general formula
- derivatives
- compounds
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 2
- 230000001225 therapeutic effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 9
- PSYYHKIRDZMRAC-UHFFFAOYSA-N 1$l^{4},2-benzothiazepine 1-oxide Chemical compound O=S1N=CC=CC2=CC=CC=C12 PSYYHKIRDZMRAC-UHFFFAOYSA-N 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- -1 nitro, cyano, carbamoyl Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 claims 1
- 150000007657 benzothiazepines Chemical class 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 230000002253 anti-ischaemic effect Effects 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- NAGQFZCSSPZDGA-UHFFFAOYSA-N 2-[2-[3-hydroxy-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-5-yl]ethyl-methylamino]acetamide Chemical class C1=CC(OC)=CC=C1C1C(O)C(=O)N(CCN(C)CC(N)=O)C2=CC=CC=C2S1 NAGQFZCSSPZDGA-UHFFFAOYSA-N 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører et fremgangsmåte for fremstilling av terapeutisk aktive 5-{2-[[2-amino-2-oksoetyl]-metylamino]etyl}-2,3-dihydro-3-hydroksy-2-(4-metoksy-fenyl)-1,5(5H)benzotiazepin-4-onderivater. The present invention relates to a method for the production of therapeutically active 5-{2-[[2-amino-2-oxoethyl]-methylamino]ethyl}-2,3-dihydro-3-hydroxy-2-(4-methoxy-phenyl) -1,5(5H)benzothiazepin-4-one derivatives.
De ved oppfinnelsen fremstillbare forbindelser svarer til den generelle formel (I) The compounds that can be prepared by the invention correspond to the general formula (I)
hvori RI står for et hydrogenatom eller en C2- C4alkanoylgruppe in which RI stands for a hydrogen atom or a C2-C4 alkanoyl group
R2 står for et hydrogenatom eller en c^- C4alkylgruppeR 2 stands for a hydrogen atom or a C 1 -C 4 alkyl group
n står for et helt tall 0-3, ogn stands for an integer 0-3, and
R3 står for enten en fenylgruppe inneholdende 1-3 substituenter valgt blant halogenatomer og trifluormetyl, metyl, R3 stands for either a phenyl group containing 1-3 substituents selected from halogen atoms and trifluoromethyl, methyl,
cl~~ c4alkoksy eller C^- C4alkyltio, nitro, cyano, karbamoyl, acetamido, metansulfonamido, metoksykarbonyl eller fenylkarbonyl, eller en aromatisk heterosyklisk gruppe som f.eks. en pyridinylgruppe eller imidazolylgruppe. C1-C4 alkoxy or C1-C4 alkylthio, nitro, cyano, carbamoyl, acetamido, methanesulfonamido, methoxycarbonyl or phenylcarbonyl, or an aromatic heterocyclic group such as e.g. a pyridinyl group or imidazolyl group.
Forbindelsene med en generell formel (I) kan foreligge i form av fri baser eller addisjonssalter med syrer. Ved at karbon-atomene i 2-stillingen og 3-stillingen er asymmetriske kan forbindelsen også forekomme i forskjellige diastereoisomere, racemiske eller optisk rene former. Fremstilling av disse former utgjør en del av oppfinnelsen. The compounds with a general formula (I) can exist in the form of free bases or addition salts with acids. As the carbon atoms in the 2-position and 3-position are asymmetric, the compound can also occur in different diastereoisomers, racemic or optically pure forms. Production of these forms forms part of the invention.
I samsvar med oppfinnelsen kan man fremstille forbindelsene med den generelle formel (I) i henhold til det etterfølgende reaksj onsskj erna. In accordance with the invention, the compounds of the general formula (I) can be prepared according to the following reaction sequence.
En første metode består i å omsette et benzotiazepinon med formel (V) (hvori RI er som angitt i det foregående) med et halogenert amin med generelle formel (IV) (hvori R2 og R3 har den ovennevnte betydning og Y er et halogenatom som klor eller brom). A first method consists in reacting a benzothiazepinone of formula (V) (where RI is as indicated above) with a halogenated amine of general formula (IV) (where R 2 and R 3 have the above meaning and Y is a halogen atom such as chlorine or bromine).
Den annen metode består i å omsette et benzotiazepinon med generell formel (VI) (hvori RI har den ovennevnte betydning) med et halogenert derivat med generell formel (II) (hvori R2 og R3 har den ovennevnte betydning og Y er et halogenatom som klor eller brom). The second method consists in reacting a benzothiazepinone of general formula (VI) (where RI has the above meaning) with a halogenated derivative of general formula (II) (where R 2 and R 3 have the above meaning and Y is a halogen atom such as chlorine or bromine).
Disse to reaksjoner, enten mellom et benzotiazepinon (V) eller et amin (VI) (i form av fri base eller syreaddisjonssalt) og et halogenert derivat er av klassisk type og foregår følgelig under betingelser velkjente for den fagkyndige, det vil si for eksempel i et aprotisk løsningsmiddel, som aceton, butanon-2 eller etylacetat, ved tilbakeløpstemperaturen, i nærvær av en base for å binde den frigitte syre (og i det enkelte tilfelle å frigi basen i utgangsforbindelsen), for eksempel kaliumkarbonat, og eventuelt i nærvær av en faseoverføringskataly-sator som tetra-n-butylammoniumjodid eller benzyltrietyl-ammoniumklorid. These two reactions, either between a benzothiazepinone (V) or an amine (VI) (in the form of a free base or acid addition salt) and a halogenated derivative are of the classical type and consequently take place under conditions well known to the person skilled in the art, i.e. for example in an aprotic solvent, such as acetone, butanone-2 or ethyl acetate, at the reflux temperature, in the presence of a base to bind the released acid (and in the individual case to release the base in the starting compound), for example potassium carbonate, and optionally in the presence of a phase transfer catalyst such as tetra-n-butylammonium iodide or benzyltriethylammonium chloride.
Det følger at man kan omdanne en forbindelse med formel (I) hvori RI står for et hydrogenatom til en forbindelse med formel (I) hvori RI står for en alkanoylgruppe ved hjelp av en acylering av kjent type, idet også den omvendte omdannelse er mulig ved hydrolyse. Benzotiaazepinonene med formel (V) er beskrevet i US patent-skrift 3.562.257. Forbindelsene med formel (VI) er beskrevet i europeiske patentansøkninger 158.339 og 158.340. It follows that one can convert a compound of formula (I) in which RI stands for a hydrogen atom into a compound of formula (I) in which RI stands for an alkanoyl group by means of an acylation of a known type, as the reverse conversion is also possible by hydrolysis. The benzothiazepinones of formula (V) are described in US patent document 3,562,257. The compounds of formula (VI) are described in European patent applications 158,339 and 158,340.
Det halogenerte amin med formel (IV) kan fremstilles for eksempel fra alkoholen med formel (III) ved innvirkning av et halogenerende middel som for eksempel tionylklorid. Amino-alkoholen med formel (III) kan selv fremstilles ved hjelp av en hvilken som helst kjent metode, for eksempel fra et halogenert derivat med forme (II) og 2-metylaminoetanol. Forbindelsene med formel (II) kan fås fra kloroacetylklorid og aminer med generell formel R2-HN-(CH2)-R3 (hvori R2, n og R3 er som angitt i det foregående) som er beskrevet i lit-teraturen. The halogenated amine of formula (IV) can be prepared, for example, from the alcohol of formula (III) by the action of a halogenating agent such as thionyl chloride. The amino alcohol of formula (III) can itself be prepared using any known method, for example from a halogenated derivative of formula (II) and 2-methylaminoethanol. The compounds of formula (II) can be obtained from chloroacetyl chloride and amines of general formula R 2 -HN-(CH 2 )-R 3 (in which R 2 , n and R 3 are as indicated above) which are described in the literature.
De etterfølgende eksempler illustrerer detaljert fremstilling-en av noen forbindelser i samsvar med oppfinnelsen. Elementær-mikroanalyser og spektra IR og NMR bekrefter strukturene av de oppnådde produkter. Tallangivelsene i paranteser for hvert eksempel tilsvarer tallangivelsen i den etterfølgende tabell som illustrerer strukturer og fysiske egenskaper av noen av de ved oppfinnelsen fremstilte forbindelser. The following examples illustrate in detail the preparation of some compounds in accordance with the invention. Elemental microanalyses and IR and NMR spectra confirm the structures of the products obtained. The figures in parentheses for each example correspond to the figures in the following table which illustrate the structures and physical properties of some of the compounds produced by the invention.
Eksempel 1 ( forbindelse nr 1) Example 1 (compound no. 1)
(+)-cis-(2S,3S)-3-acetyloksy-2,3-dihydro-5-{2-[[2-(3,4-di-metoksyfenyl)amino-2-oksoetyl]metylamino]etyl}-2-(4-metoksy-fenyl)-1,5(5H)-benzotiazepin-4-on. (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-5-{2-[[2-(3,4-dimethoxyphenyl)amino-2-oxoethyl]methylamino]ethyl} -2-(4-methoxy-phenyl)-1,5(5H)-benzothiazepin-4-one.
Under tilbakeløp oppvarmes i 9 timer en blanding av 4 g (9,15 mmol) (+)-cis-(2S,3S)-3-acetyloksy-2,3-dihydro-2-(4-metoksy-fenyl)-5-(2-metylaminoetyl)-1,5(5H)-benzotiazepin-4-on-hydro-klorid, 2,4 g (10 mmol) 1-kloro-N-(3,4-dimetoksyfenyl)acetamid og 9,9 g kaliumkarbonat i 50 ml butanon-2. Blandingen filtreres og filtratet inndampes og resten renses ved kromatografering på silikakolonne. Man oppnår på denne måte 5,3 g olje som opptas i 60 ml etanol og som behandles med 0,81 g oksalsyre. Bunnfallet oppnådd ved tilsetning av eter frafUtreres og omkrystalliseres fra etanol. Man isolerer 4 g oksalat. Under reflux, a mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxy-phenyl)-5 is heated for 9 hours -(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 2.4 g (10 mmol) 1-chloro-N-(3,4-dimethoxyphenyl)acetamide and 9.9 g potassium carbonate in 50 ml butanone-2. The mixture is filtered and the filtrate is evaporated and the residue is purified by chromatography on a silica column. In this way, 5.3 g of oil is obtained, which is taken up in 60 ml of ethanol and which is treated with 0.81 g of oxalic acid. The precipitate obtained by adding ether is filtered off and recrystallized from ethanol. 4 g of oxalate is isolated.
Smp: 144°C [a]D<20>=+59,5° (c=0,5; MeOH).M.p.: 144°C [α]D<20>=+59.5° (c=0.5; MeOH).
Eksempel 2 ( forbindelse nr 11) Example 2 (compound no. 11)
(+)-cis-(2S,3S)-3-acetyloksy-2,3-dihydro-5-{2-[[2-(4-metyl-fenyl)metyl]metylamino-2-oksoetyl]metylamino]etyl}-2-(4-metoksy-fenyl)-1,5(5H)-benzotiazepin-4-on. (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-5-{2-[[2-(4-methyl-phenyl)methyl]methylamino-2-oxoethyl]methylamino]ethyl} -2-(4-methoxy-phenyl)-1,5(5H)-benzothiazepin-4-one.
I 9 timer oppvarmes under tilbakeløp en blanding av 4 g (9,15 mmol) (+)-cis-(2S,3S)-3-acetyloksy-2,3-dihydro-2-(4-metoksy-fenyl)-5-(2-metylaminoetyl)-1,5(5H)-benzotiazepin-4-on-hydro-klorid, 1,85 g (8,73 mmol) 1-kloro-N-metyl-N-(4-metylfenyl)-metyl]acetamid og 6,05 g kaliumkarbonat i 50 ml butanon-2. Blandingen filtreres, filtratet inndampes og resten renses ved kromatografering på silikakolonne. Man oppnår på denne måte 3,5 g olje som opptas i etanol og som behandles med 1 ekvivalent oksalsyre. Bunnfallet oppnådd ved tilsetning av eter frafUtreres og omkrystalliseres fra etanol. Man isolerer 2,5 g oksalat. For 9 hours, a mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxy-phenyl)-5 is heated under reflux -(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 1.85 g (8.73 mmol) 1-chloro-N-methyl-N-(4-methylphenyl)- methyl]acetamide and 6.05 g of potassium carbonate in 50 ml of butanone-2. The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on a silica column. In this way, 3.5 g of oil is obtained, which is taken up in ethanol and which is treated with 1 equivalent of oxalic acid. The precipitate obtained by adding ether is filtered off and recrystallized from ethanol. 2.5 g of oxalate is isolated.
Smp: 108,3 - 109,2°C [a]D<20>=+71,4° (c=0,3; MeOH). Mp: 108.3 - 109.2°C [α]D<20>=+71.4° (c=0.3; MeOH).
Eksempel 3 ( forbindelse nr 18) Example 3 (compound no. 18)
(_+) -cis- (2S, 3S) -3-acetyloksy-2, 3-dihydro-5-{2- [ [2- (2- (3 , 4-di-metoksyfenyl)etyl]metylamino-2-oksoetyl]metylamino]etyl}-2-(4-metoksyfenyl)-1,5(5H)-benzotiazepin-4-on. (_+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-5-{2- [[2-(2-(3,4-dimethoxyphenyl)ethyl]methylamino-2- oxoethyl]methylamino]ethyl}-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.
Under tilbakeløp oppvarmes i 8 timer en blanding av 3 g (6,7 mmol) (+)-cis-(2S,3S)-3-acetyloksy-2,3-dihydro-2-(4-metoksy-fenyl)-5-(2-metylaminoetyl)-1,5(5H)-benzotiazepin-4-on-hydro-klorid, 2,4 g (8,9 mmol) 1-kloro-N-metyl-N-[2-(3,4-dimetoksy-fenyl)etylacetamis og 7 g kaliumkarbonat i 50 ml butanon-2. Blandingen filtreres, filtratet inndampes og resten renses ved hjelp av kromatografering på silikakolonne. Man oppnår en olje som opptas i etanol og som behandles med 1 ekvivalent oksalsyre. Bunnfallet oppnådd ved tilsetning av eter fra filtreres og omkrystalliseres fra etanol. Man isolerer 2 g oksalat. Under reflux, a mixture of 3 g (6.7 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxy-phenyl)-5 is heated for 8 hours -(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 2.4 g (8.9 mmol) 1-chloro-N-methyl-N-[2-(3, 4-dimethoxy-phenyl)ethylacetamis and 7 g of potassium carbonate in 50 ml of butanone-2. The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on a silica column. An oil is obtained which is taken up in ethanol and which is treated with 1 equivalent of oxalic acid. The precipitate obtained by adding ether from is filtered and recrystallized from ethanol. 2 g of oxalate is isolated.
Smp: 90°C [a]D<20>=+52,8° (c=0,5; MeOH).Mp: 90°C [α]D<20>=+52.8° (c=0.5; MeOH).
Eksempel 4 ( forbindelse nr 20) Example 4 (compound no. 20)
(+)-cis-(2S,3S)-3-acetyloksy-2,3-dihydro-5-{2-[[2-[3-(1-imi-dazolyl)propyl]amino-2-oksoetyl]metylamino]etyl}-2-(4metoksy-fenyl)-1,5(5H)-benzotiazepin-4-on. (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-5-{2-[[2-[3-(1-imidazolyl)propyl]amino-2-oxoethyl]methylamino ]ethyl}-2-(4-methoxy-phenyl)-1,5(5H)-benzothiazepin-4-one.
Under tilbakeløp oppvarmes i 10 timer en blanding av 4 g (9,15 mmol) (+)-cis-(2S,3S)-3-acetyloksy-2,3-dihydro-2-(4-metoksy-fenyl)-5-(2-metylaminoetyl)-1,5(5H)-benzotiazepin-4-on-hydro-klorid, 4 g (19,8 mmol) 1-kloro-N-[3-(1-imidazolyl)propyl]-acetamid og 3,6 g kaliumkarbonat i 60 ml butanon-2. Blandingen filtreres, filtratet inndampes og resten renses ved hjelp av kromatografering på silikakolonne. Man oppnår på denne måte 2 g olje som opptas i 12 ml etanol og som behandles med 0,32 g oksalsyre. Bunnfallet oppnådd ved tilsetning av eter frafiltreres og omkrystalliseres fra etanol. Man isolerer 1,1 g oksalat. Under reflux, a mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxy-phenyl)-5 is heated for 10 hours -(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 4 g (19.8 mmol) 1-chloro-N-[3-(1-imidazolyl)propyl]-acetamide and 3.6 g of potassium carbonate in 60 ml of butanone-2. The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on a silica column. In this way, 2 g of oil is obtained, which is taken up in 12 ml of ethanol and which is treated with 0.32 g of oxalic acid. The precipitate obtained by adding ether is filtered off and recrystallized from ethanol. 1.1 g of oxalate is isolated.
Smp: 55°C [a]D20=+51, 3° (c=0,5; MeOH).Mp: 55°C [α]D 2 O=+51.3° (c=0.5; MeOH).
De ved oppfinnelsen fremstillbare forbindelser ble underkastet en rekke farmakologiske forsøk som viser deres interesse som terapeutiske substanser i det ka.rdiovaskulære system. The compounds that can be prepared by the invention were subjected to a number of pharmacological tests which show their interest as therapeutic substances in the cardiovascular system.
Deres aktivitet som kalsiumantagonister påvises ved hjelp av en prøve med isolert kaninaorta. Førsøksprotokollen som anvendes er en variant av den som ble anvendt av Godfraind og Kaba (1969), (Blockade or reversal of the contraction induced by calsium and adrenaline in depolarized arterial smooth muscle, Br. J. Pharmac; 36, 549-560). Man beregner den molare konsentrasjon som frembringer 50 % dekontraksjon av responsen overfor kalsium (CE50) eller bedre dens antilogaritme (pCE50). Their activity as calcium antagonists is demonstrated using a sample of isolated rabbit aorta. The trial protocol used is a variant of that used by Godfraind and Kaba (1969), (Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle, Br. J. Pharmac; 36, 549-560). One calculates the molar concentration which produces 50% decontraction of the response to calcium (CE50) or better its antilogarithm (pCE50).
pCE50av de ved oppfinnelsen fremstillbare forbindelser er fra 4,5 til 6,6. The pCE50 of the compounds that can be prepared by the invention is from 4.5 to 6.6.
Bemerk: I kolonnen for "salt" betegner oks. et oksalat og fum. betegner et fumarat. Note: In the column for "salt" denotes ox. an oxalate and fum. denotes a fumarate.
De ved oppfinnelsen fremstillbare forbindelser ble også underkastet et forsøk med binding av [<3>H]nitrendipin på total rottecortex. The compounds that can be prepared by the invention were also subjected to an experiment with the binding of [<3>H]nitrendipine on total rat cortex.
Detaljene ved forsøket er beskrevet i europeisk patentan-søkning 0300865. The details of the experiment are described in European patent application 0300865.
De konsentrasjonerPCE50av de ved oppfinnelsen fremstillbare forbindelser (konsentrasjoner som inhiberer den spesifikke binding av [-^H] nitrendipenet med 50 % er mellom 0,001 og 10 um. The concentrations PCE50 of the compounds that can be prepared according to the invention (concentrations that inhibit the specific binding of [-^H] nitrendipene by 50% are between 0.001 and 10 µm.
De ved oppfinnelsen fremstillbare forbindelser ble ytterligere underkastet et forsøk med inhibering av den spesifikke binding av "PAF", aktiveringsfaktor for blodplater, med forsøksproto-koll beskrevet i europeisk patentansøkning 0320362. The compounds that can be produced by the invention were further subjected to an experiment with inhibition of the specific binding of "PAF", platelet activation factor, with the experimental protocol described in European patent application 0320362.
CI50(de konsentrasjoner som inhiberer den spesifikke binding med 50 %) av de ved oppfinnelsen fremstillbare forbindelser ved dette forsøk er mellom 0,5 og 5 um. CI50 (the concentrations that inhibit the specific binding by 50%) of the compounds that can be prepared by the invention in this experiment is between 0.5 and 5 µm.
Endelig ble de ved oppfinnelsen fremstillbare forbindelser underkastet et forsøk med inhibering av aggregasjon av blodplater indusert med "PAF-aceter" (1-0- (c^-Cig-alkyl) _2-acetyl-sn-glyceryl-3-fosforylcholin) med forsøksprotokoll også beskrevet i europeisk patentansøkning 0320362. Finally, the compounds that can be prepared by the invention were subjected to an experiment with the inhibition of aggregation of blood platelets induced with "PAF-aceter" (1-O-(c^-Ci-alkyl)_2-acetyl-sn-glyceryl-3-phosphorylcholine) with experimental protocol also described in European patent application 0320362.
Anti-aggregasjonsvirkningen av forbindelsene uttrykkes som konsentrasjon IC50, som den konsentrasjon som inhiberer aggregasjonen frembragt av PAF-aceter med 5 0 %. The anti-aggregation effect of the compounds is expressed as concentration IC50, as the concentration which inhibits the aggregation produced by PAF-acetate by 50%.
CI50av de ved oppfinnelsen fremstillbare forbindelser er ved dette forsøk mellom 2 og 20 um. CI50 of the compounds that can be prepared by the invention is between 2 and 20 µm in this experiment.
Resultatene fra forsøkene viser at de ved oppfinnelsen fremstillbare forbindelser er kalsiumantagonister og kan for dette anvendes for behandling av forskjellige lidelser som denne type midler er indikert for. De kan derfor spesielt anvendes innenfor den kardiovaskulære medesin for behandling av lidelser som nødvendiggjør modulatorer for transmembrane og intracellulære bevegelser av kalsium, spesielt hypertensjon, hjertesmerte og hjertearytmi. De kan videre fremvise anti-atrogene, hjerte-antiischemi-, hjerne-antiischemi-, anti-migrene-, antiepileptiske-, antiastmatiske- og antiulcer-virkninger. The results of the experiments show that the compounds that can be prepared by the invention are calcium antagonists and can therefore be used for the treatment of various disorders for which this type of agent is indicated. They can therefore be particularly used within cardiovascular medicine for the treatment of disorders that require modulators for transmembrane and intracellular movements of calcium, especially hypertension, heart pain and cardiac arrhythmia. They can also exhibit anti-athrogenic, cardiac anti-ischemic, cerebral anti-ischemic, anti-migraine, anti-epileptic, anti-asthmatic and anti-ulcer effects.
På det kardiovaskulære område kan de anvendes alene eller assosiert med kjente aktive andre substanser som deuretiske midler, [3-blokkerende midler, inhibitorer for enzymet for omdannelse av angiotensin, og antagonister overfor a-^-reseptorer. In the cardiovascular area, they can be used alone or in association with known active other substances such as diuretics, β-blocking agents, inhibitors of the enzyme for the conversion of angiotensin, and antagonists to α-β-receptors.
De er likeledes indikert for å potensialisere virkningen eller å nedsette giftigheten av midler anvendt ved behandling av cancer eller ved organtransplantasjoner. They are also indicated to potentiate the effect or to reduce the toxicity of agents used in the treatment of cancer or in organ transplants.
De ved oppfinnelsen fremstillbare forbindelser kan foreligge i alle passende former for oral eller parenteral tilførsel, i assosiasjon med kjente hjelpestoffer, for eksempel i form av tabletter, geler, drageer, kapsler, eller drikkbare eller injiserbare oppløsninger eller suspensjoner. The compounds that can be prepared by the invention can be available in all suitable forms for oral or parenteral administration, in association with known excipients, for example in the form of tablets, gels, dragees, capsules, or drinkable or injectable solutions or suspensions.
Daglig dose kan være for eksempel fra 30 ti 300 mg ved oral tilførsel og 25 til 100 mg ved parenteral tilførsel. The daily dose can be, for example, from 30 to 300 mg for oral administration and 25 to 100 mg for parenteral administration.
Claims (2)
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FR8913540A FR2653122B1 (en) | 1989-10-17 | 1989-10-17 | DERIVATIVES OF 5- [2 - [[2-AMINO-2-OXOETHYL] METHYLAMINO] ETHYL] -2,3-DIHYDRO-3-HYDROXY-2- (4-METHOXYPHENYL) -1.5 (5H) -BENZOTHIAZEPINE-4 -ONE, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS. |
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JP (1) | JPH03133970A (en) |
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AU (1) | AU6479690A (en) |
CA (1) | CA2027738A1 (en) |
FI (1) | FI905089A0 (en) |
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HU (1) | HUT57754A (en) |
IE (1) | IE903720A1 (en) |
IL (1) | IL95931A0 (en) |
NO (1) | NO904470L (en) |
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FR2624117B1 (en) * | 1987-12-08 | 1991-02-22 | Synthelabo | HYDROXY-3 (METHOXY-4 PHENYL) -2 (METHYLAMINO-2 ETHYL) -5 DIHYDRO-2,3 5H-BENZOTHIAZEPINE-1,5 ONE-4 DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
FR2630109B1 (en) * | 1988-04-19 | 1991-11-29 | Synthelabo | DERIVATIVES OF ((N- (2-AMINO-2 OXO-2 ETHYL) METHYLAMINO) -2 ETHYL) -5 HYDROXY-3 (METHOXY-4 PHENYL) -2 DIHYDRO-2,3 5H-BENZOTHIAZEPINE-1,5 ONE-4, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS |
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1989
- 1989-10-17 FR FR8913540A patent/FR2653122B1/en not_active Expired - Fee Related
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1990
- 1990-10-10 EP EP90402820A patent/EP0424214A1/en not_active Withdrawn
- 1990-10-16 PT PT95606A patent/PT95606A/en not_active Application Discontinuation
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PT95606A (en) | 1991-09-13 |
IL95931A0 (en) | 1991-07-18 |
KR910007901A (en) | 1991-05-30 |
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CA2027738A1 (en) | 1991-04-18 |
FR2653122B1 (en) | 1994-04-15 |
FI905089A0 (en) | 1990-10-16 |
HUT57754A (en) | 1991-12-30 |
HU906466D0 (en) | 1991-04-29 |
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EP0424214A1 (en) | 1991-04-24 |
JPH03133970A (en) | 1991-06-07 |
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