Aminoalcohol compounds and acid addition salts thereof, useful in the prevention and treatment of dental caries and periodontitis, are disclosed. Methods of preparing said derivatives, orally acceptable compositions containing said compounds, and a method of treatment therewith are also disclosed.

The present invention relates to aminoalcohols, the process for their 
preparation and the use of the compounds. 
The aminoalcohols provided by the invention are compounds of the general 
formula 
##STR1## 
wherein R.sub.1 is H or an alkyl group, straight-chain or branched, 
R.sub.2 is H or an alkyl group, straight-chain or branched, or a 
cycloalkyl group substituted by CH.sub.3 - to C.sub.5 H.sub.11 groups or 
unsubstituted, or an alkyl group containing a cycloalkyl group substituted 
by CH.sub.3 -C.sub.5 H.sub.11 groups or unsubstituted, and R.sub.1 and 
R.sub.2 contain 10-26 C-atoms together and R.sub.3 is an alkyl group, 
straight-chain or branched, having 2-10 C-atoms and substituted by a 
hydroxy group. The sum of the C-atoms in R.sub.1, R.sub.2 and R.sub.3 
preferably between 12 and 32, inclusive. 
The compounds according to the invention have valuable novel properties and 
can be used in the treatment of oral diseases such as periodontitis and 
dental caries. Said aminoalkanols are prepared as follows: 
Reaction (a) 
BY ALKYLATION OF A SECONDARY AMINE OF THE FORMULA 
##STR2## 
with an alkylating agent of the formula 
EQU R.sub.3 X III 
(wherein R.sub.3 is as hereinbefore defined and X is a reactive group, for 
example a halogen atom or a sulphonate ester or oxide group) or with an 
appropriate alkylene oxide. 
Reaction (b) 
FROM A TERTIARY AMINE OF THE FORMULA 
##STR3## 
(wherein R.sub.4 is alkyl, straight-chain or branched, and has a group 
convertible to or replaceable by OH or CH.sub.2 OH). 
Reaction (b1) 
R.sub.4 contains halogen, NH.sub.2, OAc, O--CH.sub.2 C.sub.6 H.sub.5. 
Reaction (b2) 
R.sub.4 contains COOEt, CN, CHO or is CO(CH.sub.2).sub.n COOEt wherein n is 
an integer from 0 to 8. 
Reaction (c) 
BY ALKYLATING THE SECONDARY AMINE 
##STR4## 
with an alkylating agent of the formula 
EQU R.sub.2 X VI 
(wherein X is halogen or an organic sulphonic ester group). 
Reaction (d) 
FROM A TERTIARY AMINE OF THE FORMULA 
##STR5## 
wherein R.sub.5 contains such a group that R.sub.5 is easily convertible 
to R.sub.1. 
Reaction (d1) 
R.sub.5 contains halogen or a double bond. 
Reaction (d2) 
R.sub.5 contains a carbonyl group or is CO(CH.sub.2).sub.m H wherein m is 
an integer from 0 to 25. 
Reaction (e) 
from a tertiary amine of the formula 
##STR6## 
wherein R.sub.6 contains such a group that R.sub.6 is easily convertible 
to R.sub.2. 
Reaction (e1) 
R.sub.6 contains halogen or a double bond. 
Reaction (e2) 
R.sub.6 contains a carbonyl group or is 
##STR7## 
wherein the sum of x and y is from 0 to 20. Reaction (a) 
The secondary amine is reacted with a haloalkanol or an organic sulphonate 
ester of formula III or an alkylene oxide in an organic solvent, such as 
benzene or xylene. Where a haloalkanol or organic sulphonate ester of 
formula III is used as alkylating agent it is preferable to effect the 
reaction in the presence of an acid binding agent, e.g. triethylamine or 
potassium carbonate. Alternatively an excess of the compound of formula II 
may serve as acid binding agent. The reaction is preferably effected at 
elevated temperature, e.g., 75.degree. to 200.degree. C., in an autoclave. 
The above described synthesis can be performed for all substituted 
aminoalcohols of the general formula I. 
Reaction (b) 
The compound 
##STR8## 
is synthesized as described in (a) (NH.sub.2 -groups in the side chain 
R.sub.4 is protected by Ac). The halogen is replaced by OAc by treatment 
with AgOAc in HAc at 100.degree. C. OAc may be hydrolyzed by alkali. The 
NHAc is hydrolyzed to NH.sub.2 and the NH.sub.2 -group is converted to OH 
by treatment with NaNO.sub.2 in acid solution. 
CH.sub.2 C.sub.6 H.sub.5 is removed by reduction in a conventional manner. 
COOEt, CHO and CO(CH.sub.2).sub.n COOEt are reduced with LiAlH.sub.4 in a 
conventional manner. 
Reaction (c) 
is performed under the same conditions as reaction (a). 
Reaction (d) 
The compound 
##STR9## 
is synthesized as described in (a) (NH.sub.2 -groups in the R.sub.5 chain 
are protected by Ac). The halogen is removed by treatment with LiAlH.sub.4 
in a conventional manner. The double bonds are removed by catalytic 
reduction in a conventional manner. 
The carbonyl groups are removed according to Huang-Minions method and the 
CO-group in CO(CH.sub.2).sub.m H is reduced to a CH.sub.2 -group with 
LiAlH.sub.4 in a conventional manner. 
Reaction (e). 
The reactions are performed under the same conditions as described for 
reaction (d). 
The compounds according to the present invention may be incorporated into 
preparations for dental and/or oral hygiene together with conventional 
carriers and excipients. Such preparations constitute a further feature of 
the present invention. 
The oral diseases, periodontitis and dental caries, in man appear to be the 
result of complex biological interactions of various organisms of which 
the dental plaque is composed. Chronic periodontitis, perhaps the most 
common cause of tooth loss, is an inflammatory process of the supporting 
tissues of the teeth and about as prevalent as dental caries. 
The development of tooth diseases has a common cause, viz, the dental 
plaque. The dental plaque is a deposit upon the surface of a tooth which 
contains for example food debris which act as a medium for a variable 
bacterial flora. It leads to a special structure of a harder 
water-insoluble plaque followed by an onset of both caries and 
inflammatory periodontal diseases in this region. 
In the field of oral and dental hygiene there is a large variety of 
preparations employed as cleansing and hygienic agents for the oral 
activity. They may be used in tooth pastes, tablets, etc. A wide variety 
of chemical and biological agents have been suggested in order to retard 
dental plaque after it is formed or to protect the teeth against the 
resulting diseases. However, the mechanical removal of the dental plaque 
is up to now the most effective method. The chemical approach to plaque 
inhibition involved different groups of compounds, antibiotics, 
chemotherapeutics and desinfectants, fluoro compounds, organic 
phosphatases, chelate-forming compounds, emulsifiers, etc. Some examples 
are penicillin (antibiotics), chlorohexidine and 8-hydroxyquinoline 
(desinfectants). ethylenediamine tetraacetate (chelate-forming), NaF 
(strenghtening of the tooth enamel). 
Some of them have too insignificant effects. Others, such as antiseptics 
and antibiotics, are likely to produce side effects worse than the 
diseases as such and still others show a certain toxicity, e.g., the 
fluorine compounds. (NaF may not be used as an antiplaque compound, but 
under strong supervision as an enamel reinforcing compound.) 
It seems clear that the plaque formation is of a very complicated nature 
and for its chemical removal it is necessary to use compounds having a 
special chemical structure without pronounced antibacterial effect and 
having a very low toxicity. 
The compounds according to the present invention have been submitted to 
intensive in vitro and in vivo tests and compared with 
reference-substances which are clinically used. 
The plaque inhibiting effect has been studied in a so-called 
Artificial-mouth originally described by Pigman et al. (J. dent. Res. 31, 
627, 1952), but later on modified (Naylor et al., "Dental Plaque," 1969); 
see also the Belgian patent specification No. 841,001. 
Such tests with our substances have shown that they exert a clear plaque 
inhibiting effect, much better than chlorohexidine. Chlorohexidine has, 
besides its antiseptic activity, unwanted side effects, such as colouring 
of the teeth and development of resistance by continuous use. The test 
results have shown that even after 14 days no plaque has been formed. 
For tests in vivo of a plaque inhibiting effect, dogs have turned out to be 
suitable experimental animals (Egelberg: Odont. Revy 16, 31-41, 1965). 
The tests have been performed by giving the dogs hard food and several 
tooth-cleanings during a period of 14 days, after which the dogs have 
obtained a very good tooth status, i.e., clean teeth without caries; 
gingival pockets and other membranes of the oral cavity are clinically 
without objections. 
After these weeks of treatment, the real test was started. The dogs were 
now given soft food and the tooth-cleaning was discontinued thereby 
creating favourable conditions for plaque forming and, later on, tooth 
decay. 
By painting the teeth with the compounds of the invention it is possible to 
estimate the extent of the plaque inhibition. 
Another way to register the plaque forming is to estimate, quantitatively, 
the increase of gingival fluid in the gingival pockets, which means that 
the secretion of gingival fluid increases. (Attstrom et al.: J. periodont. 
Res., Preprint 1971). 
According to these criteria we have studied the effect of our compounds 
which have been painted on the tooth surface twice a day during a 
4-week-period. As a control on the same dogs we have used physiological 
saline. 
The visual as well as the quantitative estimations of the status of the 
teeth after treatment show that teeth treated with, e.g., the compound 
N-n-butyl-N-cetyl-6-amino-1-hexanol (Compound A) gives very low formation 
of plaque. It has also appeared that said compound shows very low toxicity 
as compared to similar compounds. 
The compounds are preferably obtained and tested as hydrochlorides or 
hydrofluorides. They are also used in the oral preparations, although the 
bases or other pharmacologically acceptable salts may be used. These salts 
can be prepared from the bases according to conventional methods, e.g., 
with maleic, fumaric, succinic acids. 
The preferred clinically used formulations are dentifrices, paste or 
powder, mouth rinses, mouthspray, chewing gum, tablets, etc. In the 
preparations the compounds may be used in concentrations from 0.1 to 5% 
and they may also be used together with other pharmacologically active 
substances, e.g., NaF, 6-n-amyl-m-cresol, 2,4-dichlorobenzyl alcohol.

The invention will be further clarified by the following examples. 
EXAMPLE 1 
N-n-butyl-hexadecanamide 
An amount of 137.4 g of palmitoyl chloride in 100 ml of ethyl ether was 
added, under stirring at room temperature, to 80.5 g of n-butylamine in 
700 ml of ethyl ether. Stirring was continued under gentle reflux for one 
hour. The precipitate was filtered off and thoroughly washed with water. 
The reaction product was recrystallized from ethanol giving 148.4 g of the 
title compound, melting point 74.degree.-76.degree. C. 
EXAMPLE 2 
N-n-butyl-cetylamine-hydrochloride 
An amount of 101.7 g N-n-butyl-hexdecanamide was added under stirring to 
25.8 g of LiAlH.sub.4 suspension in 2.5 l of tetrahydrofuran. The reaction 
mixture was refluxed for 48 hours and then decomposed by slow addition of 
water and sodium hydroxide. The precipitate was filtered off. The 
tetrahydrofuran solution was dried and evaporated. The residue was 
distilled, b.p. 131.degree.-140.degree. C./0.06 mm Hg. Yield 86.2 g. The 
base was dissolved in ethyl ether and the hydrochloride precipitated with 
hydrochloric acid in ethyl acetate. The crude hydrochloride was 
recrystallized from water giving the title compound, melting point 
240.degree.-241.degree. C. 
EXAMPLE 3 
N-n-butyl-N-cetyl-adipamide monomethylester 
A solution of 44.5 g of adipoyl chloride monomethylester in 120 ml of 
toluene was added dropwise, at 20.degree.-25.degree. C., to a mixture of 
80 g of N-n-butyl-cetylamine and 27.7 g of triethylamine in 500 ml of 
toluene. The reaction mixture was stirred at room temperature for 18 
hours. The toluene solution was washed with water, dried over Na.sub.2 
SO.sub.4 was evaporated. Removal of the toluene gave the crude titel 
compound. Yield 109.8 g. 
EXAMPLE 4 
N-n-butyl-N-cetyl-6-amino-1-hexanol (Compound A) 
An amount of 88.2 g of crude N-n-butyl-N-cetyl-adipamide monomethylester in 
600 ml of ethyl ether was added under stirring to 53.9 g of LiAlH.sub.4 
suspension in 2 l of ethyl ether. The reaction mixture was refluxed for 65 
hours and then decomposed by slow addition of water and sodium hydroxide. 
The precipitate was filtered off. The ether solution was dried and 
evaporated. The residual oil was distilled giving 62.6 g of the title 
compound, boiling point 155.degree.-157.degree. C./0.03 mm Hg. The base 
was dissolved in ether and the hydrochloride precipitated with 
hydrochloric acid in ethyl acetate. After recrystallization from ethyl 
acetate the melting point is 58.degree.-59.degree. C. 
EXAMPLE 5 
N-Ethyl-N-n-octyl-ethanolamine 
A mixture of 15.7 g of ethyl-n-octylamine, 5 g of ethyleneoxide and 100 ml 
of 96% ethanol was held at 100.degree. C. for one hour in a steel 
autoclave. The reaction mixture was distilled and gave 16.2 g of 
N-ethyl-N-n-octyl-ethanolamine, b.p. 85.degree.-87.degree. C./0.2 mm Hg, 
n.sub.D.sup.22 = 1.4490. 
The hydrochloride is not crystalline. 
EXAMPLE 6 
N,N-Di-n-octyl-3-amino-1-propanol 
A mixture of 24 g of di-n-octylamine, 10 g of 3-chloro-1-propanol and 11 g 
of triethylamine in 200 ml of toluene was refluxed for 24 hours. The 
toluene solution was washed twice with water to remove the triethylamine 
hydrochloride formed and then evaporated. The residue was distilled and 
gave 19.9 g of N,N-di-n-octyl-3-amino-1-propanol, b.p. 
125.degree.-130.degree. C./0.01 mm Hg, n.sub.D.sup.22 = 1.4613. 
The hydrochloride is not crystalline. 
EXAMPLE 7 
______________________________________ 
Tooth paste 
Ingredients Amounts 
______________________________________ 
Compound A 2% by weight 
Dicalcium phosphate 50% 
Sorbitol 6% 
Glycerol 18% 
Na-carboxymethylcellulose 
2% 
Na-lauryl sulphate 1% 
Na-saccharin 0.1% 
Peppermint oil 0.9% 
Water up to 100% 
______________________________________ 
EXAMPLE 8 
______________________________________ 
Chewing gum Amounts 
______________________________________ 
Core 
Compound A 2% by weight 
Fructose 50% 
Glycerol 5% 
Mannitol 30% 
Gum base 2% 
Carboxymethylcellulose 10% 
Sodium cyclamate 1% 
Coating 
Carnauba wax containing: 
Fructose 9% by weight 
Gum arabic 5% 
Dextrin 2% 
Flavour 2% 
(The core materials are mixtured at 50.degree. C.) 
______________________________________ 
EXAMPLE 9 
______________________________________ 
A chewable tablet Amounts 
______________________________________ 
Compound A 20 grams 
Sorbitol 800 
Potato starch 150 
5% aq. sol. of gelatin 30 
Peppermint oil -- 
Na-cyclamate 2 
Na-saccharin 1 
are tabletted to 
1000 tablets with 2% of compound A. 
______________________________________ 
EXAMPLE 10 
______________________________________ 
Mouth rinse liquid Amounts 
______________________________________ 
Compound A 1% by weight 
Glycerol 10% 
Ethanol 15% 
Na-cyclamate 1.0% 
Na-saccharin 0.1% 
Menthol-flavour 0.1% 
Water ad 100 
______________________________________ 
Table 1 
______________________________________ 
##STR10## 
Mp.sup.a) 
R.sub.1 
R.sub.2 
n bp, .degree. C 
n.sub.D.sup.22 b) 
PIE.sup.e) 
______________________________________ 
n-C.sub.8 
C.sub.2 
2 85/0.2 mm Hg 1.4490 (+) 
n-C.sub.8 
C.sub.2 
6 78-81 + 
n-C.sub.8 
n-C.sub.4 
3 115-118/0.6 mm Hg 
1.4510 ++ 
n-C.sub.8 
n-C.sub.4 
4 126-128/0.6 mm Hg 
1.4545 (+) 
n-C.sub.8 
n-C.sub.5 
2 100-105/0.05 mm Hg 
1.4502 +++ 
n-C.sub.8 
n-C.sub.5 
5 90-100/0.05 mm Hg 
1.4570 +++ 
n-C.sub.8 
n-C.sub.8 
2 98/0.1 mm Hg 1.4543 +++ 
n-C.sub.8 
n-C.sub.8 
3 125-130/0.1 mm Hg 
1.4613 +++ 
n-C.sub.8 
C.sub.6 .sup.c) 
4 148-150/0.4 mm Hg 
1.4746 (+) 
n-C.sub.10 
n-C.sub.4 
3 114-117/0.2 mm Hg 
1.4542 +++ 
n-C.sub.10 
n-C.sub.4 
4 121-124/0.2 mm Hg 
1.4572 +++ 
n-C.sub.10 
C.sub. 4 .sup.d) 
3 93-95/0.01 mm Hg 
1.452 +++ 
n-C.sub.10 
C.sub.4 .sup.d) 
4 110-112/0.01 mm Hg 
1.454 +++ 
n-C.sub.11 
C.sub.2 
4 90-92 +++ 
n-C.sub.11 
C.sub.2 
5 71-73 ++ 
n-C.sub.11 
C.sub.2 
6 98-100 ++ 
n-C.sub.14 
C.sub.4 .sup.d) 
3 53-54 +++ 
n-C.sub.14 
C.sub.4 .sup.d) 
4 57-58 +++ 
n-C.sub.16 
C.sub.2 
2 76-78 +++ 
n-C.sub.16 
C.sub.2 
4 92-94 +++ 
n-C.sub.16 
n-C.sub.4 
4 59-60 + 
n-C.sub.16 
n-C.sub.4 
6 58-59 +++ 
155-157/0.03 mm Hg 
1.4620 +++ 
n-C.sub.18 
n-C.sub.8 
2 80-82 + 
n-C.sub.18 
n-C.sub.8 
4 60-62 + 
n-C.sub.18 
n-C.sub.8 
6 54-56 (+) 
______________________________________ 
.sup.a) Hydrochloride salt (melting points are uncorrected) 
.sup.b) Base 
.sup.c) Cyclohexyl 
.sup.d) Isobutyl 
.sup.e) +++ = very good activity 
++ = good activity 
+ = fair activity 
(+) = weak activity 
PIE = plaque inhibiting effect 
Compound A = N-n-butyl-N-cetyl-6-amino-1-hexanol