CH497389A - Phenylacetonitrile derivs coronary dilators - Google Patents
Phenylacetonitrile derivs coronary dilatorsInfo
- Publication number
- CH497389A CH497389A CH1079566A CH1079566A CH497389A CH 497389 A CH497389 A CH 497389A CH 1079566 A CH1079566 A CH 1079566A CH 1079566 A CH1079566 A CH 1079566A CH 497389 A CH497389 A CH 497389A
- Authority
- CH
- Switzerland
- Prior art keywords
- sep
- molecular weight
- low molecular
- hydrogen
- phenylacetonitrile
- Prior art date
Links
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 239000003218 coronary vasodilator agent Substances 0.000 title abstract 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 150000007962 benzene acetonitriles Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- -1 methylene dioxy group Chemical group 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 abstract description 2
- 208000001953 Hypotension Diseases 0.000 abstract 1
- 125000005055 alkyl alkoxy group Chemical group 0.000 abstract 1
- 125000002619 bicyclic group Chemical group 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 208000021822 hypotensive Diseases 0.000 abstract 1
- 230000001077 hypotensive effect Effects 0.000 abstract 1
- 125000002950 monocyclic group Chemical group 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- HNJWKRMESUMDQE-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-n-methylethanamine Chemical compound CNCCC1=CC=C(OC)C(OC)=C1 HNJWKRMESUMDQE-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- VFXFHWXYUVPJIL-UHFFFAOYSA-N 5-chloro-2-propan-2-yl-2-[3-(trifluoromethyl)phenyl]pentanenitrile Chemical compound ClCCCC(C(C)C)(C#N)C1=CC=CC(C(F)(F)F)=C1 VFXFHWXYUVPJIL-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- YHRUOJUYPBUZOS-UHFFFAOYSA-N 1,3-dichloropropane Chemical compound ClCCCCl YHRUOJUYPBUZOS-UHFFFAOYSA-N 0.000 description 1
- WIOOTMZLCZPTDW-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)ethylazanium;chloride Chemical compound Cl.COC1=CC=C(CCN)C=C1OC WIOOTMZLCZPTDW-UHFFFAOYSA-N 0.000 description 1
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 1
- ILKMEIJZBXEJCL-UHFFFAOYSA-N 3-methyl-2-[3-(trifluoromethyl)phenyl]butanenitrile Chemical compound CC(C)C(C#N)C1=CC=CC(C(F)(F)F)=C1 ILKMEIJZBXEJCL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Jib Cranes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Basic derivs. of phenylacetonitrile of the follg. general formula:- where A, B, C = H, halogen, alkyl/alkoxy or 2 may form CH2O2 R = aliphatic radical R1 = alkyl; hydrocarbyl satd./unsatd., mono/bicyclic; Ph, PhCH2 n = 2-4; m = 1-3 and in which at least 1 substd. phenyl is monotrifluorophenyl. As coronary dilators and hypotensives.
Description
Verfahren zur Herstellung basisch substituierter Phenylacetonitrile
Nach einem nicht zum Stand der Technik gehörenden Verfahren werden basisch substituierte Phenyl- acetonitrile der Formel
EMI1.1
hergestellt, in welche A, B und C Wasserstoff- oder Halogenatome, niedermolekulare Alkyl- bzw. Alkoxygruppen. wobei in letzterem Falle zwei benachbarte Gruppen auch gemeinsam eine Methylendioxydgruppe bilden können, R einen niedermolekularen aliphatischen Rest, R1 einen niedermolekularen Alkylrest, einen gesättigten oder ungesättigten, cyclischen oder bicyclischen Kohlenwasserstoffrest oder die Benzyl- bzw.
Phenylgruppe, n die Zahl 2, 3 oder 4 und m die Zahl 1, 2 und 3 bedeutet.
Die vorliegende Erfindung betrifft nun ein Verfahren zur Herstellung neuer basisch substituierter Phenylacetonitrile der Formel
EMI1.2
worin die Ringe I und/oder II durch Halogenatome, niedermolekulare Alkyl- bzw. Alkoxygruppen substituiert sein können, wobei in letzterem Falle zwei be nachbarte Gruppen auch gemeinsam eine Methylendioxygruppe bilden können, R Wasserstoff oder einen niedermolekularen aliphatischen Rest, R1 einen niedermolekularen Alkylrest, einen cycloaliphatischen Kohlenwasserstoffrest oder eine Benzyl- oder Phenylgruppe; n die Zahl 2, 3 oder 4 und m die Zahl 1, 2 oder 3 bedeutet, wobei mindestens einer der Ringe I und II und/ oder die Benzyl- oder Phenylgruppe R1 mit CF3 substituiert ist.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man ein Phenylacetonitril der Formel
EMI1.3
worin X einen reaktionsfähigen Säurerest bedeutet, mit einer Verbindung der Formel
EMI1.4
umsetzt.
Die Erfindung betrifft auch die Verwendung dieser Phenylacetonitrile, in denen R Wasserstoff ist, zur Herstellung entsprechender Phenylacetonitrile, in denen R ein niedermolekularer aliphatischer Rest ist, indem der Wasserstoff mit Hilfe eines entsprechenden Aldehydes durch den niedermolekularen aliphatischen Rest ersetzt wird.
Die neuen Verbindungen besitzen bei niedriger Toxizität signifikante coronardilatatorische Wirksamkeit und sollen als Arzneimittel Verwendung finden. Von den Verbindungen der deutschen Patente Nrn. 1154 810 und 1158 083 unterscheiden sie sich auch hinsichtlich der blutdrucksenkenden Eigenschaften. Versuche haben gezeigt, dass die neuen Verbindungen den Durchfluss durch die Coronargefässe und den Sauerstoffgehalt des venösen Herzblutes erhöhen, ohne praktisch auf den Blutdruck zu wirken. Die Erweiterung der Coronargefässe setzt bei einer intravenösen Injektion von 0,03 mg/ kg Körpergewicht ein und wird bei 0,125 mg/kg ausgesprochen kräftig. Die Wirkung übertrifft diejenige von Papaverin, Theophyllin nd anderer coronarerweiternden Wirkstoffe um das Mehrfache. Dosierungen von 0,06 bis 0,125 mg/kg erhöhen die Durchflussmenge um 100 bis 300 %.
Es zeigen sich keine schädlichen Wirkungen auf den Herz-Metabolismus und auch keine toxischen Nebenwirkungen.
Beispiel 1 a-Isopropyl-a-[(N-methyl-N-homoveratryl) -y aminopropyl]-3-trifluormethylphenylacetonitril
30 g (0,1 Mol) a-Isopropyl-a-(3'-chlorpropyl)-3-tri- fluonmethylphenylacetonitril und 39 g (0,2 Mol) N-Methylhomoveratrylamin werden im Ölbad 7 Stunden auf 130-1500 C erhitzt. Die glasig erstarrte Schmelze wird in der Wärme mit 1 Liter Benzol behandelt, worauf das Hydrochlorid des N-Methylhomoveratrylamins ausfällt und abgesaugt wird. Das Filtrat wird mit 10 zeiger Natronlauge gewaschen, mit wasserfreiem Magnesiumsulfat getrocknet, das Benzol abdestilliert und der Rückstand fraktioniert.
Man erhält 36,5 g a-Isopropyl-a-[(N-methyl-Nhomoveratryl) -y- aminopropylj -3 - trifluormethylphenylacetonitril als gelbes zähes Ö1. Ausbeute: 79 % der Theorie. Kp. 0,1 = 195-200 C. Saures Oxalat F = 1580 C.
a-Isopropyl-a-(3'-chlorpropyl)-3-trifluormethylphenyl- acetonitril wird hergestellt durch Kondensation von l-Chlor-3-brompropan oder 1 ,3-Dichlorpropan mit a-Isopropyl-3-trifluormethylphenylacetonitril in Gegenwart von Natriumamid.
Beispiel 2 a-Isopropyl-a-[(N-methyl-N-homoveratryl) -y- aminopropyl]-3 -trifluormethylphenylacetonitril
45 g (0,15 Mol) a-Isopropyl-a-(3'-chlorpropyl)-3- trifluormethylphenylacetonitril und 55 g (0,3 Mol) Homoveratrylamin werden 7 Stunden auf 130-150 C erhitzt. Die abgekühlte, glasig erstarrte Schmelze wird in der Wärme mit 1 1 Benzol behandelt, worauf das Hydrochlorid des Homoveratrylamins ausfällt und abgesaugt wird.
Das Filtrat wird mit 10 einer Natronlauge gewaschen, mit wasserfreiem Magnesiumsulfat getrocknet, das Lösungsmittel abdestilliert und der Rückstand fraktioniert.
Man erhält 45 g a-Isopropyl-a-[(N-homoveratryl) y-aminopropyl]-3-trifluormethylphenylacetonitril als gelbes zähes Ö1. Ausbeute: 68 % der Theorie. Kp. 0,1 = 203-208 C.
45 g der erhaltenen sekundären Base werden in 100 ml Methanol und 40 ml 35 %iger wässriger Formaldehydlösung gelöst und durch portionsweise Zugabe von 7,5 g (0,2 Mol) Natriumborhydrid in der Wärme methyliert. Während der Reaktion erhitzt sich die Lösung zum Sieden. Danach wird der Ansatz 2 Stunden ohne Wärmezufuhr weiter gerührt. Die Methanollösung wird zur Trockne eingedampft, der Rückstand mit 200 ml Wasser versetzt und ausgeäthert. Die getrocknete Ätherlösung wird wiederum eingedampft und der Rückstand destilliert. Man erhält 30,5 g a-Isopropyl-a (N-methyl - N - homoveratryl)-y-aminopropyl)-3 -trifluor- methylphenylacetonitril als zähes gelbes Öl. Ausbeute 66 Wj der Theorie. Kp. 0,1 = 195-200 C. Saures Oxalat F. 1580 C.
Das Salze ist mit dem in Beispiel 1 beschriebenen identisch.
Die Methylierung kann auch mit Formaldehyd/ Ameisensäure oder durch Einwirkung von Wasserstoff in Gegenwart von Palladium- oder Nickelkatalysator oder amalgamiertem Aluminium durchgeführt werden.
Auf die gleiche Weise wurden die in der Tabelle beschriebenen Verbindungen hergestellt.
EMI2.1
<tb>
<SEP> Kp. <SEP> 0 <SEP> (saures <SEP> Oxalat <SEP> Ausbeute <SEP> in <SEP> %
<tb> <SEP> C) <SEP> der <SEP> Theorie
<tb> <SEP> CF3 <SEP> CN <SEP> CM <SEP> OCH3
<tb> <SEP> oC <SEP> (CHs)3-N-(CH2)2ÓS)CH3 <SEP> I <SEP> CIH2) <SEP> CHs <SEP> 195-200/0,1 <SEP> mm <SEP> 158 <SEP> 70
<tb> <SEP> C3117
<tb> <SEP> OCH3 <SEP> CN <SEP> CH3 <SEP> CF3
<tb> CHaO--C-(CHI)3--(CHe)r <SEP> 6 <SEP> ) <SEP> 195-200/0,1 <SEP> mm <SEP> 147 <SEP> 62
<tb> <SEP> C3H7
<tb> <SEP> CF3 <SEP> CN <SEP> CH3 <SEP> OCH3
<tb> <SEP> --C-(CH.)3-N-(CH2) <SEP> 77-OCM3 <SEP> 232-235/0X3 <SEP> mm <SEP> 79 <SEP> 51
<tb> <SEP> CH2
<tb> <SEP> i$K1C <SEP> F3
<tb>
EMI3.1
<tb> <SEP> Kp. <SEP> Q <SEP> C <SEP> (saures <SEP> Oxalat <SEP> Ausbeute <SEP> in <SEP> %
<tb> <SEP> p.
<SEP> oc) <SEP> der <SEP> Theorie
<tb> <SEP> OCH3 <SEP> CN <SEP> CH3 <SEP> <SEP> CH3
<tb> <SEP> ii <SEP> 0
<tb> CHSOA <SEP> C-(CH2)3-N-(CH2) <SEP> OCH3 <SEP> 235-240/0,05 <SEP> mm <SEP> 105 <SEP> 66
<tb> (Zers.)
<tb> <SEP> CH2
<tb> <SEP> CF3
<tb> <SEP> CF3 <SEP> CN <SEP> CH3 <SEP> CF3
<tb> <SEP> 1 <SEP> 1 <SEP> .¯I$ <SEP> 207-210,01 <SEP> <SEP> < \ <SEP> vC-(CHo)l-N-(CH2)4 <SEP> 207-210/001 <SEP> mm <SEP> 142 <SEP> 59
<tb> <SEP> CH2
<tb> <SEP> I
<tb> <SEP> ,#CF3
<tb> <SEP> OCH3 <SEP> CN <SEP> CH3 <SEP> LOCHS
<tb> CH <SEP> Ow <SEP> C-(CHX <SEP> -N-(CH2) > l3 <SEP> 2l215/0,01 <SEP> mm <SEP> 111 <SEP> 39
<tb> <SEP> O <SEP> CH3 <SEP> CM2
<tb> <SEP> ; <SEP> )LCF3
<tb> <SEP> OCH3 <SEP> CN <SEP> CM5 <SEP> CF3
<tb> CH:O <SEP> > -\C(Cff.NI(Cff). <SEP> 202-204/0,1 <SEP> mm <SEP> CH3 <SEP> 56
<tb> CH::O-G <SEP> C-(CH-)J-N-(CHi)
<tb> <SEP> OCH3 <SEP> C3H7
<tb>
Process for the preparation of basic substituted phenylacetonitriles
In a process not belonging to the prior art, basic substituted phenyl acetonitriles of the formula
EMI1.1
produced, in which A, B and C are hydrogen or halogen atoms, low molecular weight alkyl or alkoxy groups. in the latter case, two adjacent groups can also jointly form a methylenedioxide group, R a low molecular weight aliphatic radical, R1 a low molecular weight alkyl radical, a saturated or unsaturated, cyclic or bicyclic hydrocarbon radical or the benzyl or
Phenyl group, n is the number 2, 3 or 4 and m is the number 1, 2 and 3.
The present invention now relates to a process for the preparation of new basic substituted phenylacetonitriles of the formula
EMI1.2
wherein the rings I and / or II can be substituted by halogen atoms, low molecular weight alkyl or alkoxy groups, in the latter case two neighboring groups can also jointly form a methylenedioxy group, R is hydrogen or a low molecular weight aliphatic radical, R1 is a low molecular weight alkyl radical cycloaliphatic hydrocarbon radical or a benzyl or phenyl group; n is the number 2, 3 or 4 and m is the number 1, 2 or 3, at least one of rings I and II and / or the benzyl or phenyl group R1 being substituted by CF3.
The process according to the invention is characterized in that a phenylacetonitrile of the formula
EMI1.3
wherein X is a reactive acid residue, with a compound of the formula
EMI1.4
implements.
The invention also relates to the use of these phenylacetonitriles, in which R is hydrogen, for the production of corresponding phenylacetonitriles in which R is a low molecular weight aliphatic radical, in that the hydrogen is replaced by the low molecular weight aliphatic radical with the aid of a corresponding aldehyde.
The new compounds have a significant coronary dilatory activity with low toxicity and are intended to be used as medicaments. They also differ from the compounds of German Patents Nos. 1154 810 and 1158 083 with regard to their antihypertensive properties. Tests have shown that the new compounds increase the flow through the coronary vessels and the oxygen content of the venous heart blood without having any practical effect on the blood pressure. The expansion of the coronary vessels begins with an intravenous injection of 0.03 mg / kg body weight and becomes extremely strong at 0.125 mg / kg. The effect exceeds that of papaverine, theophylline and other coronary-widening agents several times over. Dosages of 0.06 to 0.125 mg / kg increase the flow rate by 100 to 300%.
There are no harmful effects on the cardiac metabolism and also no toxic side effects.
Example 1 α-Isopropyl-α - [(N-methyl-N-homoveratryl) -y aminopropyl] -3-trifluoromethylphenylacetonitrile
30 g (0.1 mol) of α-isopropyl-α- (3'-chloropropyl) -3-trifluonmethylphenylacetonitrile and 39 g (0.2 mol) of N-methylhomoveratrylamine are heated to 130-1500 ° C. in an oil bath for 7 hours. The glassy, solidified melt is treated with 1 liter of benzene while warm, whereupon the hydrochloride of N-methylhomoveratrylamine precipitates and is filtered off with suction. The filtrate is washed with 10% sodium hydroxide solution, dried with anhydrous magnesium sulfate, the benzene is distilled off and the residue is fractionated.
36.5 g of α-isopropyl-α - [(N-methyl-Nhomoveratryl) -y-aminopropylj -3 - trifluoromethylphenylacetonitrile are obtained as a yellow, viscous oil. Yield: 79% of theory. Bp 0.1 = 195-200 C. Acid oxalate F = 1580 C.
α-Isopropyl-α- (3'-chloropropyl) -3-trifluoromethylphenyl acetonitrile is prepared by condensation of 1-chloro-3-bromopropane or 1,3-dichloropropane with α-isopropyl-3-trifluoromethylphenylacetonitrile in the presence of sodium amide.
Example 2 α-Isopropyl-α - [(N-methyl-N-homoveratryl) -y-aminopropyl] -3 -trifluoromethylphenylacetonitrile
45 g (0.15 mol) of α-isopropyl-α- (3'-chloropropyl) -3-trifluoromethylphenylacetonitrile and 55 g (0.3 mol) of homoveratrylamine are heated to 130-150 ° C. for 7 hours. The cooled, glassy, solidified melt is treated with 1 l of benzene while warm, whereupon the homoveratrylamine hydrochloride precipitates and is filtered off with suction.
The filtrate is washed with 10% sodium hydroxide solution, dried with anhydrous magnesium sulfate, the solvent is distilled off and the residue is fractionated.
45 g of α-isopropyl-α - [(N-homoveratryl) γ-aminopropyl] -3-trifluoromethylphenylacetonitrile are obtained as a yellow, viscous oil. Yield: 68% of theory. Bp 0.1 = 203-208 C.
45 g of the secondary base obtained are dissolved in 100 ml of methanol and 40 ml of 35% strength aqueous formaldehyde solution and methylated in the heat by adding 7.5 g (0.2 mol) of sodium borohydride in portions. During the reaction, the solution is heated to the boil. The batch is then stirred for a further 2 hours without supply of heat. The methanol solution is evaporated to dryness, the residue is mixed with 200 ml of water and extracted with ether. The dried ether solution is evaporated again and the residue is distilled. 30.5 g of α-isopropyl-α (N-methyl-N-homoveratryl) -y-aminopropyl) -3-trifluoromethylphenylacetonitrile are obtained as a viscous yellow oil. Yield 66 Wj of theory. Bp 0.1 = 195-200 C. Acid oxalate F. 1580 C.
The salt is identical to that described in Example 1.
The methylation can also be carried out with formaldehyde / formic acid or by the action of hydrogen in the presence of a palladium or nickel catalyst or amalgamated aluminum.
The compounds described in the table were prepared in the same way.
EMI2.1
<tb>
<SEP> Kp. <SEP> 0 <SEP> (acidic <SEP> oxalate <SEP> yield <SEP> in <SEP>%
<tb> <SEP> C) <SEP> of the <SEP> theory
<tb> <SEP> CF3 <SEP> CN <SEP> CM <SEP> OCH3
<tb> <SEP> oC <SEP> (CHs) 3-N- (CH2) 2ÓS) CH3 <SEP> I <SEP> CIH2) <SEP> CHs <SEP> 195-200 / 0.1 <SEP> mm <SEP> 158 <SEP> 70
<tb> <SEP> C3117
<tb> <SEP> OCH3 <SEP> CN <SEP> CH3 <SEP> CF3
<tb> CHaO - C- (CHI) 3 - (CHe) r <SEP> 6 <SEP>) <SEP> 195-200 / 0.1 <SEP> mm <SEP> 147 <SEP> 62
<tb> <SEP> C3H7
<tb> <SEP> CF3 <SEP> CN <SEP> CH3 <SEP> OCH3
<tb> <SEP> --C- (CH.) 3-N- (CH2) <SEP> 77-OCM3 <SEP> 232-235 / 0X3 <SEP> mm <SEP> 79 <SEP> 51
<tb> <SEP> CH2
<tb> <SEP> i $ K1C <SEP> F3
<tb>
EMI3.1
<tb> <SEP> Kp. <SEP> Q <SEP> C <SEP> (acidic <SEP> oxalate <SEP> yield <SEP> in <SEP>%
<tb> <SEP> p.
<SEP> oc) <SEP> of the <SEP> theory
<tb> <SEP> OCH3 <SEP> CN <SEP> CH3 <SEP> <SEP> CH3
<tb> <SEP> ii <SEP> 0
<tb> CHSOA <SEP> C- (CH2) 3-N- (CH2) <SEP> OCH3 <SEP> 235-240 / 0.05 <SEP> mm <SEP> 105 <SEP> 66
<tb> (decomp.)
<tb> <SEP> CH2
<tb> <SEP> CF3
<tb> <SEP> CF3 <SEP> CN <SEP> CH3 <SEP> CF3
<tb> <SEP> 1 <SEP> 1 <SEP> .¯I $ <SEP> 207-210.01 <SEP> <SEP> <\ <SEP> vC- (CHo) lN- (CH2) 4 <SEP > 207-210 / 001 <SEP> mm <SEP> 142 <SEP> 59
<tb> <SEP> CH2
<tb> <SEP> I
<tb> <SEP>, # CF3
<tb> <SEP> OCH3 <SEP> CN <SEP> CH3 <SEP> HOLES
<tb> CH <SEP> Ow <SEP> C- (CHX <SEP> -N- (CH2)> l3 <SEP> 2l215 / 0.01 <SEP> mm <SEP> 111 <SEP> 39
<tb> <SEP> O <SEP> CH3 <SEP> CM2
<tb> <SEP>; <SEP>) LCF3
<tb> <SEP> OCH3 <SEP> CN <SEP> CM5 <SEP> CF3
<tb> CH: O <SEP>> - \ C (Cff.NI (Cff). <SEP> 202-204 / 0.1 <SEP> mm <SEP> CH3 <SEP> 56
<tb> CH :: O-G <SEP> C- (CH-) J-N- (CHi)
<tb> <SEP> OCH3 <SEP> C3H7
<tb>
Claims (1)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH56470A CH487853A (en) | 1965-07-31 | 1966-07-26 | Process for the preparation of basic substituted phenylacetonitriles |
| CH824769A CH486425A (en) | 1965-07-31 | 1966-07-26 | Process for the preparation of basic substituted phenylacetonitriles |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEK0056774 | 1965-07-31 | ||
| US55595566A | 1966-06-08 | 1966-06-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH497389A true CH497389A (en) | 1970-10-15 |
Family
ID=25984100
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1079566A CH497389A (en) | 1965-07-31 | 1966-07-26 | Phenylacetonitrile derivs coronary dilators |
Country Status (11)
| Country | Link |
|---|---|
| BE (1) | BE684868A (en) |
| BR (1) | BR6681685D0 (en) |
| CH (1) | CH497389A (en) |
| DE (1) | DE1493904A1 (en) |
| DK (1) | DK120241B (en) |
| FI (1) | FI45187C (en) |
| FR (3) | FR313F (en) |
| GB (1) | GB1090609A (en) |
| NL (1) | NL146797B (en) |
| NO (1) | NO118111B (en) |
| SE (1) | SE352886B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE32061T1 (en) * | 1984-06-15 | 1988-02-15 | Heumann Ludwig & Co Gmbh | PROCESS FOR THE PRODUCTION OF BASIC SUBSTITUTED PHENYLACETONITRILES. |
| DE3642331A1 (en) * | 1986-12-11 | 1988-06-23 | Basf Ag | BASICLY SUBSTITUTED PHENYL ACETONITRILES, THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| BRPI0812919B8 (en) | 2007-06-20 | 2021-05-25 | Milestone Pharmaceuticals Inc | pharmaceutical composition comprising a compound and kit |
-
1965
- 1965-07-31 DE DE19651493904 patent/DE1493904A1/en not_active Withdrawn
-
1966
- 1966-07-20 GB GB3256866A patent/GB1090609A/en not_active Expired
- 1966-07-26 CH CH1079566A patent/CH497389A/en not_active IP Right Cessation
- 1966-07-29 BR BR18168566A patent/BR6681685D0/en unknown
- 1966-07-29 NL NL666610730A patent/NL146797B/en unknown
- 1966-07-29 FI FI201866A patent/FI45187C/en active
- 1966-07-29 SE SE1037466A patent/SE352886B/xx unknown
- 1966-07-29 FR FR313D patent/FR313F/fr not_active Expired
- 1966-07-29 NO NO16410666A patent/NO118111B/no unknown
- 1966-07-29 BE BE684868D patent/BE684868A/xx unknown
- 1966-07-29 DK DK395466A patent/DK120241B/en unknown
-
1967
- 1967-06-08 FR FR1553708D patent/FR1553708A/fr not_active Expired
- 1967-09-08 FR FR120463A patent/FR7508M/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR1553708A (en) | 1969-01-17 |
| SE352886B (en) | 1973-01-15 |
| FI45187C (en) | 1972-04-10 |
| NL146797B (en) | 1975-08-15 |
| DK120241B (en) | 1971-05-03 |
| FI45187B (en) | 1971-12-31 |
| FR313F (en) | 1970-05-20 |
| FR7508M (en) | 1969-12-15 |
| DE1493904A1 (en) | 1969-06-19 |
| NO118111B (en) | 1969-11-10 |
| NL6610730A (en) | 1967-02-01 |
| DE1593921B2 (en) | 1976-01-15 |
| DE1593921A1 (en) | 1970-10-01 |
| BR6681685D0 (en) | 1973-10-25 |
| GB1090609A (en) | 1967-11-08 |
| BE684868A (en) | 1967-01-30 |
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| PL | Patent ceased |