DK145906B - Analogifremgangsmaade til fremstilling af n,n-dimethyl-trans-2-(m-halogenphenyl)bicyclo(2,2,2)oct-3-yl-methylamin og syreadditionssalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af n,n-dimethyl-trans-2-(m-halogenphenyl)bicyclo(2,2,2)oct-3-yl-methylamin og syreadditionssalte deraf Download PDFInfo
- Publication number
- DK145906B DK145906B DK335776AA DK335776A DK145906B DK 145906 B DK145906 B DK 145906B DK 335776A A DK335776A A DK 335776AA DK 335776 A DK335776 A DK 335776A DK 145906 B DK145906 B DK 145906B
- Authority
- DK
- Denmark
- Prior art keywords
- trans
- acid
- bicyclo
- oct
- methylamine
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 9
- 150000003839 salts Chemical class 0.000 title description 8
- 239000002253 acid Substances 0.000 title description 7
- 238000002360 preparation method Methods 0.000 title description 4
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- 150000001875 compounds Chemical class 0.000 description 20
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- 229910052736 halogen Inorganic materials 0.000 description 3
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- 239000001257 hydrogen Substances 0.000 description 2
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- OTYWCOYIHJPZKE-UHFFFAOYSA-N 4-phenylbicyclo[2.2.2]octane Chemical class C1CC(CC2)CCC21C1=CC=CC=C1 OTYWCOYIHJPZKE-UHFFFAOYSA-N 0.000 description 1
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- 125000001475 halogen functional group Chemical group 0.000 description 1
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- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 1
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- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical class CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
- C07C211/19—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing condensed ring systems
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- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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Description
i ir\ (19) DANMARK {Wj
^ (12) FREMLÆGGELSESSKRIFT (11) 145906B
DIREKTORATET FOR
PATENT- OG VAREMÆRKEVÆSENET
(21) Ansøgning nr. 5557/76 (51> |ntCL3 g 07 C 87/457 (22) Indleveringsdag 25- jul. 1976 (24) Løbedag 25- jul. 1976 (41) Aim. tilgængelig 25· jan. 1977 (44) Fremlagt 11 . apr. 19^5 (86) International ansøgning nr.
(86) International indleveringsdag (85) Videreførelsesdag - (62) Stamansøgning nr. -
(30) Prioritet 24. jul. 1975* 51064/75, GB
(71) Ansøger LILLY INDUSTRIES LIMITED, London W1R OPA, GB.
(72) Opfinder Eric Wildsmith, GB.
(74) Fuldmægtig Th. Ostenfeld Patenfrbureau A/S.
(54) Analogifremgangs måde til fremstil® ling af N, N-dimethyl-trans-2-(m-ha= logenphenyl )bicyclo (2,2,2) oct-3-yl-methylamin og syreadditionssalte deraf.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte meta-halogenphenylbicyclo[2,2,2]octan-derivater, der er yderst aktive på det centrale nervesystem.
® I belgisk patentskrift nr. 806.808 redegøres der for en klasse ^ af phenylbicyclo[2,2,2]octaner af den samme almene type som de ved T> fremgangsmåden ifølge den foreliggende opfindelse fremstillede for- ^ bindeiser, hvilke forbindelser deri beskrives som havende aktivitet på det centrale nervesystem.
^ Det har nu overraskende vist sig, at en lille hidtil ukendt 3 2 145906 klasse af forbindelser, som ligger inden for rammerne af redegørelsen i det førnævnte belgiske patentskrift, har effektfuld og uventet bedre virkning på det centrale nervesystem, idet forbindelserne især besidder bemærkelsesværdig forbedret anti-depressions- og anti-psykotisk aktivitet, i sammenligning med de kendte bicyclo[2,2,2]octaner af den samme type, som der omtales i dette patentskrift. Forbindelserne, som fremstilles ifølge den foreliggende opfindelse, besidder også gode terapeutiske indices.
De ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede forbindelser er trans-forbindelser med den almene formel (Il ch2n(ch3)2 (I)
kJ
hvor X er halogen, eller syreadditionssalte deraf.
Med udtrykket "halogen" menes fluor, brom, chlor eller iod.
Grupperne -CH2N (CH^og m-halogenphenyl er trans-stillede i forhold til hinanden.
Fagmanden vil indse, at forbindelserne med den almene formel (I) kan eksistere i to enantiomere former, og opfindelsen omfatter fremstilling af (+)- og (-)- formerne hver for sig og ikke-race-miske blandinger deraf såvel som den racemiske blanding af de enantiomere former.
Som eksempler på syreadditionssalte kan nævnes de farmaceutisk acceptable ikke-toksiske additionssalte med egnede syrer, såsom saltene med uorganiske syrer, f.eks. saltsyre, hydrogenbromid-syre, salpetersyre, svovlsyre eller phosphorsyre, eller med organiske 3 165906 syrer, såsom organiske carboxylsyrer, f.eks. glycolsyre, malein-syre, hydroxymaleinsyre, æblesyre, vinsyre, citronsyre, salicylsyre, o-acetoxybenzoesyre, nicotinsyre eller isonicotinsyre, eller organiske sulphonsyrer, f.eks. methansulphonsyre, ethansulphonsyre, 2-hydroxyethansulphonsyre, toluen-p-sulphonsyre eller naphthalen-2-sulphonsyre;
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man methvlerer aminogruppen i en trans-forbindelse, som har den almene formel (II) rTYCH2<“ \ (II) I i hvor X er halogen, og R er hydrogen eller methyl, hvorefter man om ønsket opspalter en fremstillet racemisk forbindelse i de individuelle enantiomere, eller om ønsket omdanner en fremstillet forbindelse til et syreadditionssalt deraf.
En særligt foretrukken forbindelse, som fremstilles ifølge opfindelsen, er N,N-dimethyl-trans-2-(m-chlorphenyl)bicyclo[2,2,2] oct-3-yl-methylamin, fx. i form af forbindelsens hydrochlorid.
Den overraskende forøgede virkning af de hidtil ukendte forbindelser med formel (I) og deres syreadditionssalte kan vises ved velkendte testforsøg, såsom antagonisme af reserpin-hypoter-mia og reserpin-katalepsi i mus og rotter.
Til påvisning af antagonisme af reserpin-induceret hypotermia i rotter anvendtes grupper af 4 Wister-rotter af hunkøn. Dyrene injiceredes subkutant med 5 mg/kg reserpin og efter 17 timer måltes rektaltemperaturen. Umiddelbart herefter blev testforbindelserne indgivet oralt og yderligere temperaturbestemmelser foretoges efter 30 minutter og hver time derefter i indtil 6 1/2 time. For at forenkle bestemmelsen af reverseringen af reserpin-induceret hypotermia anvendtes den såkaldte "temperatur-indeks"-metode. Idet man gik ud fra den gennemsnitlige for-dos is temperatur for hver gruppe, opsummeredes de gennemsnitlige temperaturforandringer fra dette tal efter 0,5, 1,5, 2,5, 3,5, 4,5, 5,5 og 6,5 timer og ϊ· ' - 4 145906 kaldtes "temperatur-indeks" (TI). Testforbindelserne betragtedes som aktive såfremt TI-værdien var mere end 5 enheder hypertermisk fra kontrolresultaterne. I den efterfølgende tabel viser 0 ingen virkning (TI mindre end 5), + angiver en TI i intervallet 5-10, .++ angiver en TI i intervallet 10-15 og +++ angiver en TI på mere end 15. Denne procedure er en god test for afprøvning af forbindelser, der antages at være værdifulde som antidepressive midler.
Testresultaterne og de testede forbindelser fremgår af den følgende tabel: /p^.cVNtclV2 S /; 'Ar
Porbindelse Ar Reversering af reserpin- 1 induceret hypotermia(dosis) 1· 3-chlorphenyl +++(25) 2. phenyl (usubst.) 0(40) 3. 2-chlorphenyl ++(20) 4. 4-chlorphenyl 0(20) +(40) 5. 4-fluorphenyl +(40) 6. 4-bromphenyl ++(40) 7. 3,4-dichlorphenyl +(20) +(40) , _____ [___
Forbindelse 1. er en ved fremgangsmåden ifølge opfindelsen fremstillet forbindelse og det ses, at den er væsentlig mere aktiv end de tilsvarende usubstituerede, 2- og 4-halogen-, samt 3,4-dihalogensubstituerede forbindelser, jvf. belgisk patentskrift nr. 806.808.
145906 5
Fremgangsmåden ifølge opfindelsen belyses nærmere under henvisning til det følgende eksempel.
Eksempel trans-m-chlorcinnamonitril.
m-chlorbenzaldehyd (210,75 g, 1,5 m) cyanoeddikesyre (127,5 g, 1,5 m) og pyridin (150 ml) opvarmedes under tilbagesvaling i 2 dage. Opløsningen inddampedes til dannelse af en olie, som destilleredes til dannelse af en blanding af isomere (72% trans/23% cis, 5% aldehyd) . Udbytte (129 g, 53%), kogepunkt 70-85 °C ved 0,8 mm. Stoffet opløstes i isopropanol og henstod til fraktioneret krystallisation ved 0 °C. Faststoffet frafiltreredes og frysetørredes. Udbytte af ren trans-isomer var 15 g(6,l%), kogepunkt 104-106 °C ved 1 mm, smeltepunkt 26-28 °C.
trans-6-(m-chlorphenyl)-bicyclo[2,2,2]oct-2-en-5- carbonitril._ trans-m-chlorcinnamonitril, der var fremstillet som ovenfor (9,2 g, 0,056 m) og 1,3-cyclohexadien (8,03 ml, 0,084 m) sattes til et forseglet rør med et spor af hydroquinon og 1,2-dichlor-benzen og opvarmedes ved 150-160 °C i 2 uger. Opløsningen inddampedes til dannelse af en gylden olie (12 g), som udvaskedes adskillige gange med kold 40-60 °C benzin og derpå gentagne gange med 60-80 °C benzin. Disse sidste udvaskningsfraktioner samledes og reduceredes til en viskos olie (10,2 g, 75%).
trans-2-(m-chlorphenyl)bicyclo[2,2,2]octan-3-carbonitril.
trans-6-(m-chlorphenyl)bicyclo[2,2,2]oct-2-en-5-carbonitril, der var fremstillet som ovenfor (9,4 g, 0,038 m) hydrogeneredes i ethanol ved atmosfæretryk i nærværelse af 5% Palladium-på-trækul (1,0 g). Efter optagelse af den teoretiske mængde hydrogen frafiltreredes katalysatoren, og opløsningen reduceredes til en olie (9,1 g, 97%). Denne udkrystalliseredes ved opløsning i ethanol, smeltepunkt 112-113 °C.
Analyse: beregnet: C 73,32; H 6,56; N 5,7; Cl 14,43; fundet : C 73,43; H 6,41; N 5,82; Cl 14,38.
6 145906 trans-2-(m-chlorphenyl)bicyclo[2,2,2]oct-3-yl-methylamin, hydrochloric!. __ trans-2-(m-chlorphenyl)bicyclo[2,2,2]-octan-3-carbonitril, som var fremstillet som ovenfor (8,0 g, 0,032 m) i tør tetrahydro-furan (20 ml) sattes dråbevis til en afkølet og omrørt opløsning af lithiumaluminiumhydrid (1,61 g, 0,042 m) i tør tetrahydrofuran (20 ml). Efter tilsætningen henstod opløsningen til antagelse af stuetemperatur og omrørtes natten over. 5N natriumhydroxid (1,6 ml) og derpå vand (7 ml) tilsattes forsigtigt til dannelse af et fint hvidt bundfald, som frafiltreredes. Filtratet tørredes over mag-nesiumsulphat og inddampedes efter filtrering til en olie, som ved opløsning i ethanol-saltsyre og langsom tilsætning af ether gav hydrochloridsaltet (6,8 g, 74%) smeltepunkt 220-222 °C.
N,N-dimethyl-trans-2-(m-chlorphenyl)bicyclo[2,2,2]oct-3- yl-methylamin,hydrochlorid._
Til trans-2-(m-chlorphenyl)bicyclo[2,2,21oct-3-yl-methyl-amin,hydrochloridet, som var fremstillet ovenfor (3,0 g, 0,011 m) sattes natriumhydrogencarbonat (0,92 g, 0,011 m) og dimethyl-formamid (30 ml). Kolben afkøledes til 0 °C, og en blanding af myresyre 90% (2,29 ml, 0,055 m) og formaldehyd 37-40% (3,78 ml, 0,055 m) tilsattes langsomt. Efter tilsætning opvarmedes opløsningen langsomt til tilbagesvaling. Efter 5 timers forløb afkøledes opløsningen, sattes til vand (80 ml), gjordes alkalisk med fast kaliumhydroxid (pH=8) og ekstraheredes med ethylacetat (3 x 30 ml). Den kombinerede organiske fase udvaskedes med vand (2 x 30 ml), tørredes over magnesiumsulphat, filtreredes, og opløsningsmidlet fjernedes i vakuum til dannelse af en olie (2,10 g, 61%). Hydrochloridsaltet, som dannedes under anvendelse af ethanol-saltsyre og titelforbindelsen, omkrystalliseredes fra ethanol-ether (2,1 g) smeltepunkt 217-219 °C.
Analyse: beregnet: C 64,96; H 8,01; N 4,45; Cl 22,56 fundet : C 64,67; H 7,82; N 4,44; Cl 22,64.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB31064/75A GB1551035A (en) | 1975-07-24 | 1975-07-24 | Derivatives of bicyclo (2,2,2)oct-3-ylmethylamine |
| GB3106475 | 1975-07-24 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK335776A DK335776A (da) | 1977-01-25 |
| DK145906B true DK145906B (da) | 1983-04-11 |
| DK145906C DK145906C (da) | 1983-09-19 |
Family
ID=10317427
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK335776A DK145906C (da) | 1975-07-24 | 1976-07-23 | Analogifremgangsmaade til fremstilling af n,n-dimethyl-trans-2-(m-halogenphenyl)bicyclo(2,2,2)oct-3-yl-methylamin og syreadditionssalte deraf |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5949218B2 (da) |
| BE (1) | BE844429A (da) |
| CH (1) | CH605610A5 (da) |
| DE (1) | DE2632952A1 (da) |
| DK (1) | DK145906C (da) |
| FR (1) | FR2318626A1 (da) |
| GB (1) | GB1551035A (da) |
| IE (1) | IE43254B1 (da) |
| IL (1) | IL49981A (da) |
| NL (1) | NL7607755A (da) |
| SE (1) | SE415251B (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57180767U (da) * | 1981-05-12 | 1982-11-16 | ||
| JPS6173676U (da) * | 1984-10-18 | 1986-05-19 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1444717A (en) * | 1972-11-04 | 1976-08-04 | Lilly Industries Ltd | Bicycloalkyl derivatives |
-
1975
- 1975-07-24 GB GB31064/75A patent/GB1551035A/en not_active Expired
-
1976
- 1976-07-02 IE IE1462/76A patent/IE43254B1/en unknown
- 1976-07-06 IL IL49981A patent/IL49981A/xx unknown
- 1976-07-14 NL NL7607755A patent/NL7607755A/xx not_active Application Discontinuation
- 1976-07-20 FR FR7622097A patent/FR2318626A1/fr active Granted
- 1976-07-20 SE SE7608272A patent/SE415251B/xx not_active IP Right Cessation
- 1976-07-22 DE DE19762632952 patent/DE2632952A1/de active Granted
- 1976-07-22 CH CH937276A patent/CH605610A5/xx not_active IP Right Cessation
- 1976-07-22 BE BE6045622A patent/BE844429A/xx not_active IP Right Cessation
- 1976-07-23 DK DK335776A patent/DK145906C/da not_active IP Right Cessation
- 1976-07-23 JP JP51088036A patent/JPS5949218B2/ja not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5214777A (en) | 1977-02-03 |
| DE2632952C2 (da) | 1987-09-17 |
| DE2632952A1 (de) | 1977-02-10 |
| IE43254L (en) | 1977-01-24 |
| CH605610A5 (da) | 1978-09-29 |
| FR2318626B1 (da) | 1979-10-12 |
| IL49981A0 (en) | 1976-09-30 |
| FR2318626A1 (fr) | 1977-02-18 |
| DK145906C (da) | 1983-09-19 |
| DK335776A (da) | 1977-01-25 |
| IL49981A (en) | 1979-07-25 |
| IE43254B1 (en) | 1981-01-14 |
| SE415251B (sv) | 1980-09-22 |
| NL7607755A (nl) | 1977-01-26 |
| BE844429A (fr) | 1977-01-24 |
| JPS5949218B2 (ja) | 1984-12-01 |
| GB1551035A (en) | 1979-08-22 |
| SE7608272L (sv) | 1977-01-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |