| US3830824A | 1974-08-20 | |||
| US3979382A | 1976-09-07 | |||
| US4177199A | 1979-12-04 | |||
| US3911115A | 1975-10-07 |
| 1. | Nitrogen and silver containing derivative in which a substituted or not substituted aliphatic or aromatic group is attached via a carbonyl group, possibly followed by at least one carbon atom and/or aromatic or aliphatic ring, to an amino group or a heterocyclic nitrogen containing ring structure, with at least one silver atom being attached directly to at least one nitrogen atom, as well as the complexes of this derivative formed via the silver atom. |
| 2. | Derivative according to claim 1, characterized in that the aromatic group is attached via an amide or ester bond and possibly followed by one or two successive carbon atoms to a secondary or tertiary amino group or a heterocyclic nitrogen containing structure, with at least one silver atom being attached directly to at least one nitrogen atom, as well as the complexes of this derivative formed via the silver atom. |
| 3. | Derivative according to claim 1 or 2, characterized in that it corresponds to the following general structure: 0 R3 II / Ar N C CH N (I) or i I Λ \ 2 Ag R1 R^ (ID wherein Ar represents an aromatic group, such as a substituted or 1 not substituted phenyl or naphtyl group, R represents hydrogen or 2 3 a (C..C alkyl, alkenyl or alkynyl group and R and R represent hydrogen or a (C1C ) alkyl, alkenyl, alkynyl, hexyl or tetra 1 2 3 methylene group, the total amount of carbon atoms in R , R and R being at lesit 4, as well as the complexes, in particular dimer, of this derivative formed via the silver atom. |
| 4. | Derivative according to claim 1 or 2, characterized in that it corresponds to the following general structure: S Ar C 0 C. H,Rm N (III) or K X Ml \ Λ Rd 0 Ag Ar _ o c CkHlRm l( (IV) RJ wherein Ar represents an aromatic group, such as a substituted or 3 not substituted phenyl or naphtyl group, R represents a (C..C.) alkyl, alkenyl, alkynylhexyl or tetramethylene group, and k being 2 or 3, 1 varies from 2 to 6 and m varies from 0 to 4, as well as the complexes, in particular dimer, of this derivative formed via the silver atom. |
| 5. | Derivative according to claim 1 or 2, characterized in that it is formed by an NAg acylxylide with the following general structure: CnH2n+l N wherein R represents an v_J or CH N^] group, in which n varies from 1 to 4, as well as the complexes, in particular dimer, of the derivative formed via the silver atom. |
| 6. | Derivative according to claim 1 or 2, characterized in that it is formed by the NAg cinchocaine with following structure: ,0C4H9 (C2H5)2NCH2 CH2 N CO θ) (VI) Ag £> as well as the complexes, particularly dimer, of this derivative formed via the silver atom. |
| 7. | Derivative according to claim 1, characterized in that it corresponds to the following general structure: (VII) 5 wherein R represents a (CpC.) alkyl group substituted or not substituted by N(CpH[)p, as well as the complexes of this derivative formed via the silver atom, particularly dimer. |
| 8. | Pharmaceutical product with as active compound a nitrogen and silver containing derivative as defined in any one of the preceeding claims. |
| 9. | Use of the nitrogen and silver containing derivative according to any one of the preceeding claims for obtaining a micro organism killing and analgesic medicine. |
| 10. | Method for preparing the nitrogen and silver containing derivative according to any one of the preceeding claims, characterized in that a compound with general formula NN'NH is caused to react with AgNO, and NaOH to form a complex with following structure RR'NAgAgNR'R, which precipitates and is separated from the remaining reaction products in dissolved state, the meaning of R and R' being determined by the desired structure of the nitrogen and silver containing derivative to be prepared according to any one of the claims 1 to 8. |
The invention relates to a new nitrogen and silver containing derivative with very specific pharmacological properties, such that this derivative thus in an advantageous manner can be applied as a medicine.
It concerns more particularly compounds which at the same time combine an unusually long-lasting or strong local analgesic or local anaesthetic action with an extraordinary micro-organism killing activity, having few irritating or sensitizing properties and a small toxicity.
Therefore, these compounds, according to the invention, are useful as local analgesic and anaesthetic agent, on the one hand, and as a disinfectant, on the other hand.
When attending to open wounds a micro-organism killing property is important. On the other hand, many open wounds are very painful, in particular at the time of bandage renewal.
The aim of the above mentioned invention is to develop a simple molecule, with little solubility in water, which slowly dissociates simultaneously to, on the one hand an active micro¬ organism killing ion (Ag+) and, on the other hand, an active local analgesic product.
The nitrogen and silver containing derivative, according to the invention, is characterized in that it is formed by a compound in which a substituted or not substituted aliphatic or aromatic group is attached via a carbonyl group possibly followed by at least one carbon atom and/or aromatic or aliphatic ring, to an amino group or a heterocyclic nitrogen containing ring structure, with at least one silver atom being attached directly to at least one nitrogen atom, as well as the complexes of this derivative
formed via the silver atom.
Efficiently, the aromatic radical is attached via an amide or ester bond and possibly followed by one or two successive carbon atoms to a secondary or tertiary amino group or a hetero¬ cyclic nitrogen containing ring structure, with at least one silver atom being attached directly to at least one nitrogen atom, as well as the complexes of this derivative formed via the silver atom.
In a particular embodiment of the invention the concerned derivative corresponds to the following general structure:
0 R 3 II / Ar - N - C - CH - N (I) or
I H \ 2 Ag R 1 R
wherein Ar represents an aromatic group, such as a substituted or
1 not substituted pheπyl or naphtyl group, R represents hydrogen or X. 3 a (C..-C.) alkyl, alkenyl or alkynyl group and R and R represent a (C.-C4) alkyl, alkenyl, alkynyl, hexyl or tetra ethylene group,
1 2 3 the total number of carbon atoms in R , R and R being at least , as well as the complexes, more particularly di er, of this derivative formed via the silver atom.
The invention relates also to a pharmaceutical product with as an active component a nitrogen and silver containing derivative, such as defined hereabove.
Further the invention relates also to the use of this derivative for obtaining a micro-organism killing and analgesic medicine.
Finally protection is claimed for a particular method for preparing the hereabove defined nitrogen and silver containing derivative, which is characterized in that a compound with general formula RR'HN is caused to react with AgNOg and NaOH to form a complex with following structure RR'N-Ag-Ag-NR'R, which precipitates and is separated from the remaining reaction products in dissolved state, with the meaning of R and R' being determined by the desired
structure of the nitrogen and silver containing derivative to be prepared.
Other details and advantages of the invention will become apparent in the description following hereafter in which a.o. examples are given of the preparation of some specific compounds according to the invention. This description is only provided as an illustration or clarification of the invention and hence does by no means limit the scope of it.
In general the invention relates to a new nitrogen and silver containing derivative, which comprises complexes formed via the silver atom, as well as racemic mixtures, and in which a substituted or not substituted aliphatic or aromatic group is attached via a carbonyl group, possibly followed by at least one carbon atom and/or aromatic or aliphatic ring, to an amino group or a hetero¬ cyclic nitrogen containing ring structure, with at least one silver atom being attached directly to at least one nitrogen atom.
It was found that compounds with such a structure usually show at the same time long-lasting and/or strong local anaesthetic action and an extraordinary micro-organism killing activity, having few irritating or sensitizing properties and a small acute toxicity.
As mentioned already hereabove compounds are concerned here which are little soluble in water and dissociate slowly to at the same time, on the one hand, an active micro-organism killing Ag-ion and, on the other hand, an active local analgesic agent.
Furthermore because of the low solubility a deposit of undissolved product is formed. This will dissolve gradually because of the fact that the dissolved and dissociated products are carried off. Dissolving and dissociating occur slowly. In such a way, in function of time and the product used, during a longer period a constant and continuous supply of micro-organims killing and analgesic agent is available (so-called "deposit" or "retard" effect) .
This is of the utmost importance for the patient. It guarantees a safe and comfortable healing of an inflamed or not inflamed wound.
An additional advantage of silver compounds in general and more particularly of the ones according to the invention is their limited stability in the presence of light and/or of other ions. Because of this the dissociation will go on more efficiently. Particularly in combination with Ce(N0--,) dissociation would be influenced positively without any disadvantageous effect on the toxicity.
Amide compounds corresponding to this general formulation appeared to have interesting properties. In this respect it was e.g. found that they have very low sensitizing properties. Thus amide compounds corresponding to the following general structure are of importance:
0 R 3 n /
Ar - N - C - CH - N (I) or
I t \ 2 Ag R 1 R
0 Ag II / a Ar - N - C - CH - N (II)
I '1 ^ 2
H R 1 R wherein Ar represents an aromatic group, such as a substituted or
1 not substituted phenyl or naphtyl group, R represents hydrogen or
2 3 a (C j - C.) alkyl, alkenyl or alkynyl group and R and R represent a (C..-C,) alkyl, alkenyl, alkynyl, hexyl or tetramethylene group
1 2 3 with the total number of carbon atoms in R , R and R being at least 4, as well as the complexes more particularly dinner, of this derivative formed via the silver atom.
This concerns here a.o. following specific amide compounds: N-Ag articaine, N-Ag butaπilicaine, N-Ag tolicaine, N-Ag etidocaine and N-Ag lidocaine.
Furthermore cyclic N-N-Ag acylxylidides appear also of importance for the application described hereabove. These correspond to the following general structure: 0 . CH- li j t-. 3
R4 _ C - N -/0) (V)
Ag CH 3
c n H 2n+l N
wherein R represents a or -CH -N group, in which n varies from 1 to 4, as well as the complexes of this derivative, particular¬ ly dimer, formed via the silver atom. The N-Ag bupivacaine is a.o. concerned here, the N-Ag-pyrrocaine and the N-Ag mepivacaine. Also N-Ag-ciπchocaine with the structure mentioned below has, for the application intended, interesting properties:
0C 4 H g (C 2 H 5 ) 2 NCH 2 - CH 2 - N - CO - GY
Ag <£/ as well as the complexes, more particularly dimer, of this derivative formed via the silver atom.
Another important group contains the ester compounds which correspond a.o. to one of the following basic structures:
(III) or
(IV) wherein Ar represents an aromatic group, such as a substituted or
3 not substituted phenyl or naphtyl group, R represents a (C..-C.) alkyl, alkenyl, alkynyl, hexyl or tetramethylene radical and k is
2 or 3, 1 varies from 2 to 6 and m varies between 0 and 4, as well as the complexes of the derivative, particularly dimer, formed via the silver atom.
Examples of such compounds are N-Ag-hexylcaine, N-Ag benzocaine, N-Ag-butylamino-benzoate, N-Ag-butacaine, N-Ag oxy- buprocaine and N-Ag-procaine.
The amide compounds can be prepared according to the following reaction plan:
2 RR'NH + 2 AgN0 3 + 2 NaOH → RR'N-Ag-Ag-NR'R + 2 Na 0 3 + 2 H 2 0 The silver compound precipitates, can be removed by filtration and
purified if necessary. The racemic compounds can be separated in a well-known manner (with use of optically active tartaric acid) .
The nitrogen and silver containing derivative, according to the invention, can be administered in several different ways. Parenteral solutions can be administered peridurally by infiltrat¬ ion, subarachπoidally, intra-arterially or intravenously. Gels, ointments, sprays or dusting powders which can be composed of the base or a pharmaceutically tolerable salt thereof, can be applied locally on the mucosa or on an injured or not injured open or grazed skin.
Depending on the product used concentrations of 0,05 to 100% (i.e. as dusting powder) can be used. Limitations will occur depending on the product used. Thus N-Ag lidocaine can safely be administered to adults locally up to 2.5 g a time. For N-Ag tetracaine this limit is 1 g.
Finally, hereafter some specific examples are given of the preparation of some nitrogen and silver containing derivatives, according to the invention. Example 1 N-Argentum-l-butyl-piperdine-2-(2.6-dimethyl-carboxanilide) 28.84 g l-butyl-piperdine-2-(2.6-dimethylcarboxanilide) and 16.98 g Ag O are dissolved in 200 ml 50% ethanol. It is heated to boiling and then an equimolar quantity of 1 to 5 M NaOH is added in drops. The precipitate created is removed by filtration and washed with 95% ethanol and afterwards with ether. The precipitate is dried in the dark over PpO ς in a vacuumexicator. A greyish solid substance is obtained which decomposes at 320°C. Yield 85% (0.085 mol) . Calculated for AgC lg H 7 N 2 0:
C 54.8; H 6.8; N 7.1; 0 4.0; Ag 27.4 Found: C 54.4; H 6.9; N 6.9; 0 3.9; Ag 27.2
Example 2 N-Argentum-2butoxy-N-(2-diethylamiπo-ethyl) chinoline-4-carboxamide To 50.15 g 2-butoxy-N-(diethylamino-ethyl) -chinoline-4-carboxiamide dissolved in 600 ml pure ethanol a solution of 24, 80 g AgN0 3 in
100 ml DMSO is added. Next, hereto is added in drops 365 ml of a 0.4 N ethanolic NaOH solution with intense stirring over a period of 2 hours. The pale grey precipitate is removed by filtration and thoroughly washed with pure ethanol, afterwards with acetone. The powder is dried in a vacuu dessicator (20 mm) for 48 hours. Yield 91% (0.133 mol). The product decomposes at 208°C. Calculated for AgC gH gH^:
C 53.3; H 6.4; N 9.3; 0 7.1; Ag 24 Found: C 53.6; H 5.9; N 8.9; 0 7.0; Ag 24.2
Example 3 N-Argeπtum-2-(ethyl-propyl-a ino)-2* .6'-butyro-xylidine To 62.19 g 2-(ethyl-propyl-amino)-2' .6'-butyroxylidine-xylidine dissolved in 800 ml pure ethanol, a solution of 38.22 g AgNO- in 250 ml DMSO is added. Next hereto with intense stirring, 560 ml of a solution of 0.4 N ethanolic NaOH solution is added in drops over a period of 4 hours. The grey precipitate is removed by filtration and thoroughly washed with pure ethanol, afterwards with acetone. The powder is dried in a vacuumdessicator (20 mm) for 48 hours. Yield 89% (0.200 mol). The product decomposes above 278°C. Calculated for AgC 17 H 2R N 2 0:
C 53.1; H 7.3; N 7.30; 0 4.2; Ag 28.1 Found: C 53.4; H 6.9; N 7.10; 0 3.9; Ag 27.8
Example 4 N-Argentum-(rf-propylamino-propio-o-toluidine) 38.55 g x-propylamino-propio-o-toluidine and 29.73 g AgN0 3 are dissolved in 500 ml 50% ethanol. It is heated to boiling and then an equi olar quiantity 1 to 5 M NaOH is added slowly in drops. The precipitate obtained is removed by filtration and washed with 95% ethanol and afterwards with ether. The precipitate is dried in the dark 3ver P„0 5 in a vacuumexicator. A greyish solid substance is obtained which decomposes at 278°C. Yield 81% (0.142 mol). Calculated for AgC 13 H 2 pN 2 0:
C 47.6; G 6.1; N 8.5; 0 4.8; Ag 32.9 Found: C 47.2; H 6.5; N 8.8; 04.6; Ag 32.7
Example 5 N-Argeπtum-N-(2.6-dimethylbeπzyl)-l.NN diethylacetamide Method A
57.41 g N-(2.6 dimethylbenzyl)-l.NN diethylacetamide and 41.62 g AgN0 3 are dissolved in 600 ml 50% ethanol. It is heated to boiling and then an equimolar quantity of 1 to 5 M NaOH is added slowly in drops. The obtained precipitate is removed by filtration and washed with 95% ethanol and afterwards with ether. The precipitate is dried in the dark over P 2 0 5 in a vacuumexicator. A greyish solid substance is obtained which decomposes at 315°C. Yield 86% (0.211 mol). Calculated for AgC 14 H 22 N 2 0:
C 49.1; H 6.4; N 8.1; 0 4.7; Ag 31.5 Found: C 49.5; H 6.1; N 8.6; 04.9; Ag 31.5 Method B
To 78.03 g N-(2.6 dimethylbenzyl)-l.NN diethylacetamide, dissolved in 950 ml pure ethanol, a solution of 56.56 g AgNOg in 400 ml DMSO is added. Next, hereto is added in drops, with intense stirring, 832 ml of a 0.4 N ethanol NaOH solution over a period of 8 hours. The grey precipitate is removed by filtration and washed thoroughly with pure ethanol, afterwards with acetone. The powder is dried in a vacuumdessicator (20 mm) for 68 hours. Yield 93% (0.310 mol). The greyish product decomposes at 315°C. Calculated for AgC 14 N 22 N 2 0:
C 49.1; H 6.4; N 8.1; 0 4.7; Ag 31.5 Found: C 49.9; H 9.6; N 7.9; 0 4.6; Ag 30.7
Example 6 (N-Argentum-4-butylaminobenzoic acid)-2-dimethylamino-ethylester 52.88 g (4-butylaminobeπzoic acid)-2-dimethylamiπo-ethylester and 34.0 g AgN0 3 are dissolved in 600 ml 50% ethanol. It is heated to boiling and then an equimolar quantity of 1 to 5 M NaOH is added slowly in drops. The obtained precipitate is removed by filtration and washed with 95% ethanol and afterwards with ether. The precipitate is dried in the dark over PoO c i π a vacuumexicator. A greyish substance is obtained which decomposes at 315°C. Yield 50%
(0.12 mol) .
Calculated for AgC 15 H 2 .N 2 0 2 :
C 48.4; H 6.4; N 7.5; 0 8.6; Ag 29.0 Found: C 48.1; H 6.0; N 7.1; 0 8.9; Ag 28.6
Finally hereafter some possible galenical forms are given under which the derivative can be used as a medicine according to the invention:
1. Sterile suspension N-Argeπtum-l-butyl-piperdiπe-2(2,- dimethylcarboxanilide) 3 g
Aqua pro injectione ad 100 g
2. 0/W cream
N-Argentum-2-butoxy-N-2-diethylamino-ethyl)- chiπoline-4-caroxamide 1 g
White Vaseline 30 g
Tween 20 5 g
Aqua distillata ad 100 g
3. W/0 cream
N-Argentum-2-(ethyl-propyl-amino)-2' .6'- butyro-xylidine
White Vaseline
Sorbitansesquioleate
Aqua distillata ad
4. Powder
N-Argentum-(-propylanino-propio-o-toluidine) Lactose 100 Mesh a) in a sifter. b) by means of a known technology in a freon-free sprayer (so- called "powder-spray") . c) in a plaster or double bandage, in a separate compartment, the powder being released by removing a protecting folio or through contact with the wound or skin. The plaster will protect against external contamination, the product will fight the existing internal contamination.
5. Pasta
N-Argeπtum-N-(2.6-dimethylbenzyl) -
1-NN-disthyl-acetamide 18 %
Lassarpasta Belgian Pharmacopee IV ad loo g