DE1288587B - N- (3-Carbamoyloxyalkyl) -carbamidsaeureaethylester and process for their preparation - Google Patents
N- (3-Carbamoyloxyalkyl) -carbamidsaeureaethylester and process for their preparationInfo
- Publication number
- DE1288587B DE1288587B DEK64627A DEK0064627A DE1288587B DE 1288587 B DE1288587 B DE 1288587B DE K64627 A DEK64627 A DE K64627A DE K0064627 A DEK0064627 A DE K0064627A DE 1288587 B DE1288587 B DE 1288587B
- Authority
- DE
- Germany
- Prior art keywords
- carbamic acid
- diethyl
- carbamoyloxyalkyl
- preparation
- ethyl ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 4
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- -1 2,2-diethyl-3-hydroxypropyl Chemical group 0.000 description 3
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 206010002091 Anaesthesia Diseases 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
- 230000002908 adrenolytic effect Effects 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960002456 hexobarbital Drugs 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000004651 carbonic acid esters Chemical class 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229940112021 centrally acting muscle relaxants carbamic acid ester Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical class OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 230000004622 sleep time Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- SQMCFUSVGSBKFK-UHFFFAOYSA-M sodium;5-(cyclohexen-1-yl)-1,5-dimethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].O=C1N(C)C(=O)[N-]C(=O)C1(C)C1=CCCCC1 SQMCFUSVGSBKFK-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Die Carbamate bzw. Kohlensäureester verschiedener 1,3-Propandiole sind seit einigen Jahren bekannt und von therapeutischer Bedeutung. Strukturell verwandt sind mit ihnen auch N-substituierte N-(3-Oxyalkyl)-carbamidsäureäthylester, wie sie z. B. in der deutschen Patentschrift 1 150 973 und in der belgischen Patentschrift 606 096 beschrieben werden.The carbamates or carbonic acid esters of various 1,3-propanediols have been known for some years and of therapeutic importance. Structurally related to them are also N-substituted N- (3-oxyalkyl) -carbamic acid ethyl esters, how they z. B. in the German patent specification 1 150 973 and in the Belgian patent specification 606 096 are described.
Es wurde nun gefunden, daß N-(3-Carbamoyloxyalkyl) - carbamidsäureäthylester der allgemeinen FormelIt has now been found that N- (3-carbamoyloxyalkyl) - ethyl carbamate of the general formula
C2H5 C 2 H 5
C2H5 C 2 H 5
CH3 CH 3
CH — O — CO — NCH - O - CO - N
CH2 — N — CO — OC2H5
RCH 2 - N - CO - OC 2 H 5
R.
in der R ein Wasserstoffatom oder die Äthylgruppe bedeutet, starke pharmakologische Wirkungen, besonders auf das Nervensystem, ausüben und als Arzneimittel Verwendung finden können.in which R is a hydrogen atom or the ethyl group, strong pharmacological effects, especially on the nervous system, and can be used as medicinal products.
Die Verbindungen werden erhalten, indem man in an sich bekannter Weise N-(3-Oxyalkyl)-carbamidsäureäthylester der allgemeinen FormelThe compounds are obtained by adding N- (3-oxyalkyl) -carbamic acid ethyl ester in a manner known per se the general formula
CH3 CH 3
CH-OH
:CCH-OH
: C
CH2 — N — CO — OC2H5 RCH 2 - N - CO - OC 2 H 5 R
C2H5^
C2H5/C 2 H 5 ^
C 2 H 5 /
in der R die oben angegebene Bedeutung hat, mit Phosgen umsetzt und das gebildete Chlorcarbonat mit Diäthylamin zur Reaktion bringt. Die beanspruchten Verbindungen weisen gegenüber den konstitutionell vergleichbaren und ähnlich wirkenden Stoffen, z. B. den N-(3-Oxyalkyl)-carbamidsäureestern, wesentliche Vorteile bezüglich Intensität der Sedierung und der adrenolytischen Wirksamkeit auf, wie aus der nachstehenden Tabelle ersichtlich ist.in which R has the meaning given above, reacts with phosgene and the chlorocarbonate formed with diethylamine to react. The claimed compounds have constitutionally opposite the comparable and similar substances, e.g. B. the N- (3-oxyalkyl) carbamic acid esters, essential Advantages in terms of intensity of sedation and adrenolytic effectiveness on how from the can be seen in the table below.
In der Tabelle bedeutet:In the table means:
I = N-[2,2-Diäthyl-3-(N',N'-diäthyl-carbamoyloxy)-butyö-carbamidsäureäthylester, I = N- [2,2-diethyl-3- (N ', N'-diethyl-carbamoyloxy) -butyö-carbamic acid ethyl ester,
II = N-Äthyl-N-[2,2-Diäthyl-3-(N',N'-diäthylcarbamoyloxy)
- butyl] - carbamidsäureäthylester,
IH = N-(2,2-Diäthyl-3-hydroxy-propyl)-carbamid-II = N-ethyl-N- [2,2-diethyl-3- (N ', N'-diethylcarbamoyloxy) - butyl] - carbamic acid ethyl ester,
IH = N- (2,2-diethyl-3-hydroxypropyl) -carbamide-
säureäthylester*),
IV = N-Methyl-N-(2,2-Diäthyl-3-hydroxy-propyI)-carbamidsäureäthylester*), ethyl acid ester *),
IV = N-methyl-N- (2,2-diethyl-3-hydroxy-propyI) -carbamic acid ethyl ester *),
V = N-(2,2-Diäthyl-3-hydroxy-butyl)-carbamidsäureäthylester*). V = N- (2,2-diethyl-3-hydroxy-butyl) -carbamic acid ethyl ester *).
Im einzelnen wurden folgende pharmokologische Prüfungen vorgenommen:The following pharmocological tests were carried out in detail:
1. Akute Toxizität (bestimmt an weißen Mäusen nach subkutaner Injektion der Substanz; angegeben ist der 24-Stunden-Wert als DL50 in mg/kg).1. Acute toxicity (determined on white mice after subcutaneous injection of the substance; the 24-hour value is given as DL 50 in mg / kg).
2. Sedierende Wirkung. Zur Feststellung der sedierenden Wirkung wurde die prozentuale Verlängerung des Hexobarbitalschlafes in der Weise bestimmt, wie sie von Holten und L a r s e η in Acta pharmacol. et toxicol., 12 (1956), S. 346 ff; angegeben worden ist (»Hexobarbital« = nicht schutzfähige internationale Kurzbezeichnung für 5-(Cyclohexen-1 -yl)-5-methyl-N-methylbarbitursäure). 2. Sedative effect. The percentage elongation was used to determine the sedative effect of the hexobarbital sleep is determined in the way as it is determined by Holten and L a r s e η in Acta pharmacol. et toxicol., 12 (1956), p. 346 ff; has been specified ("hexobarbital" = non-protectable international abbreviation for 5- (Cyclohexen-1 -yl) -5-methyl-N-methylbarbituric acid).
*) Vergleichsverbindung, bekannt aus der deutschen
Patentschrift 1 150973.*) Comparison compound, known from the German
U.S. Patent 1,150,973.
In der Tabelle bedeutet: Die Angabe »SW l7o V2«. daß die Schlafzeit durch die Einwirkung von einer Gewichtsmenge Prüfsubstanz, die l7o der toxischen Dosis = DL50 entspricht, V2 Stunde vor der Hexobarbital-Natrium-Gabe appliziert, die angegebene prozentuale Verlängerung erfahren hat; die Angabe »SW 2% l/2« die Verlängerung der Narkose bei Anwendung von 27o der DL50 und die Angabe »SW 57o V2« die Verlängerung der Narkose bei Anwendung von 57o der DL50 unter sonst gleichen Bedingungen.In the table means: The specification "SW 17o V2". that the sleep time has experienced the stated percentage increase due to the action of an amount by weight of test substance which corresponds to 17o of the toxic dose = DL 50 , V applied 2 hours before the hexobarbital sodium administration; the indication "SW 2% l / 2" extension of the anesthesia with the use of 27o the DL 50 and the indication "SW 57o V2" the extension of the anesthesia with the use of 57o the DL 50 under otherwise identical conditions.
3. Adrenolytische Wirksamkeit (gemessen wird die Konzentration in mg/cm3, die in der Lage ist, die durch l,5y/cm3 Adrenalin hervorgerufene Kontraktion der Meerschweinchensamenblase im Bad 50% zu senken; diese Werte sind in der Tabelle unter der Bezeichnung WED50 (mg/cm3)« angegeben). Literatur: R ο t h 1 i η und B r ü g g e r, HeIv. physiologica acta 3, 519 (1945).3. Adrenolytic activity (the concentration is measured in mg / cm 3 , which is able to reduce the contraction of the guinea pig seminal vesicle in the bath caused by 1.5 y / cm 3 of adrenaline by 50%; these values are in the table under the designation WED 50 (mg / cm 3 ) «specified). Literature: R ο th 1 i η and B r ü gger, HeIv. physiologica acta 3, 519 (1945).
Die Herstellung der beanspruchten Verbindungen wird in den folgenden Beispielen näher beschrieben:The preparation of the claimed compounds is described in more detail in the following examples:
N-[2,2-Diäthyl-3-(N',N'-diäthyl-carbamoyloxy)-butyl]-carbamidsäureäthylester N- [2,2-diethyl-3- (N ', N'-diethyl-carbamoyloxy) -butyl] -carbamic acid ethyl ester
Zu einer eisgekühlten Lösung von 37 g N-(2,2-Diäthy 1 - 3 - hydroxy butyl)- carbamidsäureäthylester undTo an ice-cold solution of 37 g of N- (2,2-diethy 1 - 3 - hydroxy butyl) - carbamic acid ethyl ester and
50 g Ν,Ν-Dimethylanilin in 15OmI Toluol läßt man unter Rühren 25 g Phosgen, in 100 ml Toluol gelöst, zutropfen. Danach läßt man etwa 3 Stunden bei Raumtemperatur reagieren und kühlt erneut. Das Reaktionsgemisch wird mit 2 η-Salzsäure ausgeschüttelt, die organische Schicht abgetrennt und mit Natriumsulfat getrocknet. Das gebildete Chlorcarbonat wird unter Rühren und Eiskühlung mit einer Lösung von 50 g Diäthylamin und 50 ml Toluol tropfenweise versetzt, 2 Stunden bei Raumtemperatur gerührt und anschließend noch 1 Stunde unter Rückfluß erhitzt. Nach Erkalten wird mit 2n-Salzsäure ausgeschüttelt, die organische Schicht abgetrennt, getrocknet und das Lösungsmittel im Vakuum entfernt. Der Rückstand wird im Feinvakuum destilliert. Kp^ = 148°C; ni5 = 1,4648; Ausbeute 56% der Theorie.50 g of Ν, Ν-dimethylaniline in 150 ml of toluene are allowed to add dropwise 25 g of phosgene, dissolved in 100 ml of toluene, with stirring. Then left to react for about 3 hours at room temperature and cool again. The reaction mixture is extracted by shaking with 2η hydrochloric acid, the organic layer is separated off and dried with sodium sulfate. A solution of 50 g of diethylamine and 50 ml of toluene is added dropwise to the chlorocarbonate formed, while stirring and cooling with ice, and the mixture is stirred at room temperature for 2 hours and then refluxed for a further hour. After cooling, it is extracted by shaking with 2N hydrochloric acid, the organic layer is separated off, dried and the solvent is removed in vacuo. The residue is distilled in a fine vacuum. Bp ^ = 148 ° C; ni 5 = 1.4648; Yield 56% of theory.
B e i s ρ i e 1 2B e i s ρ i e 1 2
N-Äthyl-N-[2,2-Diäthyl-3-(N',N'-diäthylcarbamoyloxy)-butyl]-carbamidsäureäthylester Ethyl N-ethyl-N- [2,2-diethyl-3- (N ', N'-diethylcarbamoyloxy) butyl] carbamic acid
Entsprechend der im Beispiel 1 beschriebenen Verfahrensweise werden 0,2 Mol N-Äthyl-N-(2,2-Diäthyl-3 - hydroxy - butyl) - carbamidsäureäthy!ester mit 0,2 Mol Phosgen unter Zusatz von 0,4 Mol Ν,Ν-Dimethylanilin in Toluol zur Reaktion gebracht und das gebildete Chlorcarbonat mit 50 g Diäthylamin (Überschuß)umgesetzt. KpO-05 = 1200C; η? = 1,4619; Ausbeute 78% der Theorie.According to the procedure described in Example 1, 0.2 mol of N-ethyl-N- (2,2-diethyl-3-hydroxy-butyl) -carbamic acid ethyl ester with 0.2 mol of phosgene with the addition of 0.4 mol of Ν, Ν-Dimethylaniline reacted in toluene and the chlorocarbonate formed reacted with 50 g of diethylamine (excess). KpO -05 = 120 0 C; η? = 1.4619; Yield 78% of theory.
Claims (2)
C2H5-C 2 H 5 *
C 2 H 5 -
RCH 2 - N - CO - OC 2 H 5
R.
CH-OHCH 3
CH-OH
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEK64627A DE1288587B (en) | 1965-06-26 | 1965-06-26 | N- (3-Carbamoyloxyalkyl) -carbamidsaeureaethylester and process for their preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEK64627A DE1288587B (en) | 1965-06-26 | 1965-06-26 | N- (3-Carbamoyloxyalkyl) -carbamidsaeureaethylester and process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1288587B true DE1288587B (en) | 1969-02-06 |
Family
ID=7231714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEK64627A Pending DE1288587B (en) | 1965-06-26 | 1965-06-26 | N- (3-Carbamoyloxyalkyl) -carbamidsaeureaethylester and process for their preparation |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1288587B (en) |
-
1965
- 1965-06-26 DE DEK64627A patent/DE1288587B/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| None * |
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