US2904591A - Alpha-alkyl-propiophenones - Google Patents

Alpha-alkyl-propiophenones Download PDF

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Publication number
US2904591A
US2904591A US566388A US56638856A US2904591A US 2904591 A US2904591 A US 2904591A US 566388 A US566388 A US 566388A US 56638856 A US56638856 A US 56638856A US 2904591 A US2904591 A US 2904591A
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Prior art keywords
alkyl
carbon atoms
compounds
local
propiophenones
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US566388A
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Hanell Erik Sixten
Sundbeck Bertil
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Pharmacia Animal Health Inc
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Ferrosan AB
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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings

Definitions

  • R is an alkyl comprising from 2 to and preferably 2-'3 carbon atoms
  • R is an alkylcomprising from 1 to 5 and preferably l-2 carbon atoms
  • R and R are alkyls comprising from 1 to 4 carbon atoms, the num- 1 her of carbon atoms of R and R together preferably ranging from 2 to 6.
  • the basic ketones themselves but also their salts with e.g. hydrohalic acids have the desired local anesthetic effect and the invention comprises also salts of the basic ketones.
  • the basic ketones according to the present invention are usually employed in the form of diluted aqueous solutions of their salts with hydrohalic acids. As a rule, about 1% solutions of these salts are used, e.g. for administering local anesthesia by injection or by dropping droplets into the eyes.
  • the new compounds are equivalent to the best known local anesthetics such as for instance xylocaine.
  • An important advantage of the new local anesthetics according to the invention consists in that they have a very low toxicity and, in particular, in that they cause extremely little local irritation.
  • a further advantage of the local anesthetics according to the invention consists in their being very stable, also when heated in aqueous solution for a longer period of time. It is common practice to sterilize solutions of local anesthetic compounds by heating them to 100 C. in sealed ampoules. Many of the known local anesthetics, especially also certain basic ketones closely related to the compounds according to the present invention, have been found to be chemically unstable when exposed to a longer period of heating. This appears from changes in their absorption spectrum, particularly with respect to the position of the absorption maximum in the ultraviolet range, and also from a decrease in the extinction by a solution of a given concentration.
  • such basic ketones of this class in which the aliphatic radical attached to the carbonyl group is branched but the substituents .at..the basic nitrogen atom form ,a cyclic .radical together with said nitrogen atom have proved to be far less resistant to prolonged heating than the compounds according to the present invention.
  • R maybe an alkyl radical having from .1 to 5 carbon atoms, but particnlarlygoodresults are obtained with those of :our compoundsin which R comprises only 1 or 2 carbon atoms, it having been found that compounds in which R contains from 3 carbon atoms may still cause a certain degree of local irritation, while this is avoided practically completely with the compoundsin which R comprises only '1 or 2 carbon atoms. When these latter compounds are embe no danger of necrose formations. which may otherwise sometimes occur due to theme at local anesthetics causing local irritation.
  • the compounds according to the present invention are obtained by reacting, preferably in a solution of hydrohalic acid, a ketone having the formula water, and then adjusted to an in which R and R have the same meanings as above.
  • a salt of said amine with an acid e.g. a hydrohalic acid.
  • Example 1 A mixture of 17.9 gms. of p-ethoxypropiophenone, 8.2 gms. of dimethylamino hydrochloride, 5 gms. of paraformaldehyde, 80 cc. of ethanol and 1 cc. of concentratcd hydrochloric acid is boiled for 12 hours, 9 gms. of paraformaldehyde being added in small portions about every three hours.
  • Example 2 19.2 gms. 'of p-propoxypropiophenone, 18.2 gms. of -dipropylamino hydrobromide, 15 cc. of 40% formalin,

Description

United States Patent 2,904,591 ALPHA-ALKYL-PROPIOPHENONES Erik Sixten Hanell and 'Bertil Sundbeck, Malmo, Sweden, assignors to AB'Ferrosan, Malmo, Sweden No Drawing. Application February 20,1956 Serial No. 566,388
Claims priority, application Sweden February 25, 1955 6 Claims. 01. zen-570.5
ing general formula:
in which R is an alkyl comprising from 2 to and preferably 2-'3 carbon atoms, R is an alkylcomprising from 1 to 5 and preferably l-2 carbon atoms, and R and R are alkyls comprising from 1 to 4 carbon atoms, the num- 1 her of carbon atoms of R and R together preferably ranging from 2 to 6. Not only the basic ketones themselves but also their salts with e.g. hydrohalic acids have the desired local anesthetic effect and the invention comprises also salts of the basic ketones.
The basic ketones according to the present invention are usually employed in the form of diluted aqueous solutions of their salts with hydrohalic acids. As a rule, about 1% solutions of these salts are used, e.g. for administering local anesthesia by injection or by dropping droplets into the eyes.
In respect of their local anesthetic effect, the new compounds are equivalent to the best known local anesthetics such as for instance xylocaine. An important advantage of the new local anesthetics according to the invention consists in that they have a very low toxicity and, in particular, in that they cause extremely little local irritation.
A further advantage of the local anesthetics according to the invention consists in their being very stable, also when heated in aqueous solution for a longer period of time. It is common practice to sterilize solutions of local anesthetic compounds by heating them to 100 C. in sealed ampoules. Many of the known local anesthetics, especially also certain basic ketones closely related to the compounds according to the present invention, have been found to be chemically unstable when exposed to a longer period of heating. This appears from changes in their absorption spectrum, particularly with respect to the position of the absorption maximum in the ultraviolet range, and also from a decrease in the extinction by a solution of a given concentration. While closely related compounds already after having been heated for 15 minutes show a substantial change, both as regards the position of their absorption maximum in the ultraviolet range and as regards the extinction-and this change is then greatly increased on still further prolonged heating-the compounds according to the present invention have been found to be unaifected by 15 minutes heating, in respect of their absorption maximum in the ultraviolet range as well as in respect of the extinction. Even after having been heated for 60 minutes the position of their absorption maximum remains completely unchanged, and only a small decrease in extinction can be observed. These desirable properties are found only ployed there will ,2 in the compounds according to the present invention, in which the aliphatic radical attachedtothe carbonyl group is branched while the alkyl radicals attached .tothernitrogen atom do not form a ring together with the nitrogen .atom. Basieketones .of this class in which'thealiphatic radical .attached .to the carbonyl .group "is not branched have been found to be particularly unstable whensubjected to heating for a longerpen'oibut also .such basic ketones of this class in which the aliphatic radical attached to the carbonyl group is branched but the substituents .at..the basic nitrogen atom form ,a cyclic .radical together with said nitrogen atom have proved to be far less resistant to prolonged heating than the compounds according to the present invention. I
In the above formula, R maybe an alkyl radical having from .1 to 5 carbon atoms, but particnlarlygoodresults are obtained with those of :our compoundsin which R comprises only 1 or 2 carbon atoms, it having been found that compounds in which R contains from 3 carbon atoms may still cause a certain degree of local irritation, while this is avoided practically completely with the compoundsin which R comprises only '1 or 2 carbon atoms. When these latter compounds are embe no danger of necrose formations. which may otherwise sometimes occur due to theme at local anesthetics causing local irritation.
"The below table contains physical 'data of some o f our compounds which have proved to be particularly valuable in practical use.
Halogen Melting Point, 0.
Calculated Found As regards the above-mentioned low toxicity of the compounds according to the present invention, it may be mentioned that when e.g. the second compound in the table is administered to mice by subcutaneous injection the 'amount of this compound which will cause death of 50% of the mice treated is 35 times greater than the corresponding DL amount of xylocaine with which said compound of the table is equivalent in its local anesthetic efi ect. Furthermore, the local irritation caused by this compound is 4 times weaker than that caused by a similar compound in which the substituents at the nitrogen atom form a piperidine ring together with the nitrogen.
The compounds according to the present invention are obtained by reacting, preferably in a solution of hydrohalic acid, a ketone having the formula water, and then adjusted to an in which R and R have the same meanings as above. Instead of said amine one may use if desired a salt of said amine with an acid, e.g. a hydrohalic acid.
The preparation of the compounds according to the present invention is further illustrated by the following examples. i
' Example 1 A mixture of 17.9 gms. of p-ethoxypropiophenone, 8.2 gms. of dimethylamino hydrochloride, 5 gms. of paraformaldehyde, 80 cc. of ethanol and 1 cc. of concentratcd hydrochloric acid is boiled for 12 hours, 9 gms. of paraformaldehyde being added in small portions about every three hours.
When the reaction is complete the mixture is evaporated on a water bath, Washed with ether, dissolved in alkaline pH. The base precipitated in this manner is taken up in ether, the ether layer is washed with water, dried, and then admixed with alcoholic hydrochloric acid. This results in the precipitation of a-methyl-fi-dimethylamino-p-ethoxypropiophenone hydrochloride in the form of white crystals melting at ISO-152 C.
Example 2 19.2 gms. 'of p-propoxypropiophenone, 18.2 gms. of -dipropylamino hydrobromide, 15 cc. of 40% formalin,
1 cc. of concentrated hydrobromic acid and 5 0 cc. of ethanol are boiled for 15 hours. The solution is evaporated on a water bath and then treated as in Example 1. On re-crystallization from a mixture of ethanol and ether,
there will be obtained a-methyl-fi-dipropylamino-p-propoxypropiophenone hydrochloride having a melting point of 134l35 C.
We claim:
1. A member of the group of basic ketones having the general formula in which R is an alkyl with 2 to 5 carbon atoms, R is an alkyl with 1 to 5 carbon atoms, and R and R are inter se uncombined alkyls with 1 to 4 carbon atoms and the hydrohalic salts thereof.
2. a methyl B dimethylamino p ethoxypropiophenone hydrochloride.
3. oz methyl 8 diethylamino p propoxypropiophenone hydrobromide. I
4. a methyl 8 diethylamino p ethoxypropiophenone hydrochloride.
5. oz methyl e dirnethylamino p propoxypropiophenone hydrochloride.
6. a methyl 3 dipropylamino p ethoxypropiophenone hydrochloride.
References Cited in the file of this patent Mannich et al.: Ber. (Deutsche Chem. Gesell.), vol. 55, p. 3512 (1922).

Claims (1)

1. A MEMBER OF THE GROUP OF BASIC KETONES HAVING THE GENERAL FORMULA
US566388A 1955-02-25 1956-02-20 Alpha-alkyl-propiophenones Expired - Lifetime US2904591A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3000946A (en) * 1958-03-18 1961-09-19 Ciba Pharm Prod Inc beta-amino-alpha-bromo-propiophenones
US3164601A (en) * 1959-08-01 1965-01-05 Merck Ag E Analeptically active n-substituted aminonorcamphane derivatives and their acid addition salts and quaternary ammonium compounds
US3313687A (en) * 1961-09-18 1967-04-11 Andreas J Rottendorf Chem Fab Appetite-suppressing and weight reducing composition
US3465039A (en) * 1962-09-17 1969-09-02 Andreas J Rottendorf Chem Fab Therapeutically active secondary and tertiary 1 - halogenphenyl - 2 - amino-alkanones (1)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3000946A (en) * 1958-03-18 1961-09-19 Ciba Pharm Prod Inc beta-amino-alpha-bromo-propiophenones
US3164601A (en) * 1959-08-01 1965-01-05 Merck Ag E Analeptically active n-substituted aminonorcamphane derivatives and their acid addition salts and quaternary ammonium compounds
US3313687A (en) * 1961-09-18 1967-04-11 Andreas J Rottendorf Chem Fab Appetite-suppressing and weight reducing composition
US3465039A (en) * 1962-09-17 1969-09-02 Andreas J Rottendorf Chem Fab Therapeutically active secondary and tertiary 1 - halogenphenyl - 2 - amino-alkanones (1)

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