U.S. patent number 3,872,171 [Application Number 05/330,042] was granted by the patent office on 1975-03-18 for polyamines as antiviral agents in animals.
This patent grant is currently assigned to Pfizer Inc.. Invention is credited to Timothy H. Cronin, Hermann Faubl, William W. Hoffman, James J. Korst.
United States Patent |
3,872,171 |
Cronin , et al. |
March 18, 1975 |
POLYAMINES AS ANTIVIRAL AGENTS IN ANIMALS
Abstract
Combating viral infections in vertebrate animals by
administering to the animals an amine selected from those having
the formulae: ##SPC1## And the non-toxic acid addition salts
thereof wherein R.sub.1 is selected from the group consisting of
alkyl of from 1 to 20 carbon atoms, aralkyl, aryloxyalkyl,
hydroxyalkyl of from 2 to 8 carbon atoms and ##SPC2## R.sub.2 is
selected from the group consisting of alkyl of from 12 to 20 carbon
atoms, aralkyl and aryloxyalkyl of from 12 to 24 carbon atoms and
##SPC3## R.sup.o is alkoxy of from 1 to 18 carbon atoms; Each of R'
and R" is selected from the group consisting of hydrogen, alkyl,
alkoxy of from 1 to 18 carbon atoms; R' and R" when taken together
are methylenedioxy; Provided that the total number of carbon atoms
in R.sup.o, R' and R" is from 5 to 48; R.sub.3 is selected from the
group consisting of hydrogen, alkyl of from 1 to 20 carbon atoms,
hydroxyalkyl of from 2 to 8 carbon atoms, phenylcarbamoyloxy(lower
alkyl), .omega.-carboxyalkanoyloxy-(lower alkyl), allyl, alkanoyl
of from 1 to 6 carbon atoms, alkanoyloxy(lower alkyl), carbo(lower
alkoxy)lower alkyl, carboxy(lower alkyl), alkoxy(lower alkyl) and
gem-di(lower alkoxy)-lower alkyl; R.sub.4 is selected from the
group consisting of hydrogen, alkyl of from 1 to 8 carbon atoms,
hydroxyalkyl of from 2 to 8 carbon atoms, carbo(lower alkoxy)lower
alkyl, alkanoyloxy(lower alkyl), carboxy(lower alkyl), alkoxy(lower
alkyl), phenyl-carbamoyloxy(lower alkyl),
.omega.-carboxyalkanoyloxy(lower alkyl), allyl, dihydroxyalkyl of
from 3 to 8 carbon atoms, and morpholinoethyl; with the proviso
that no more than two of the R variables are hydroxyalkyl; R.sub.3
and R.sub.4 when taken together with the nitrogen to which they are
attached are morpholino; X is selected from the group consisting of
straight chain alkylene of from 2 to 6 carbon atoms and ##SPC4## X'
is selected from the group consisting of X, phenylene-dimethylene
and ##SPC5## m is 0 or 1, with the provisos that only one of X and
X' is ##SPC6## And when X' is phenylenedimethylene, m is 0; Y is
selected from the group consisting of straight chain alkylene of
from 2 to 8 carbon atoms and phenylenedimethylene; A is selected
from the group consisting of hydrogen, cyano, hydroxy, alkoxy of
from 1 to 20 carbon atoms, alkanoyloxy of from 2 to 20 carbon
atoms, phenylcarbamoyloxy, chloro, bromo,
.omega.-carboxyalkanoyloxy(lower alkyl), alkanoyloxy of from 1 to 6
carbon atoms, carbo(lower alkoxy) and alkanoylthio of from 2 to 20
carbon atoms and alkylthio of from 1 to 20 carbon atoms; R.sub.5 is
selected from the group consisting of hydrogen, alkyl of from 1 to
20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, (lower
alkoxy)lower alkyl and ##SPC7## R.sub.6 is selected from the group
consisting of hydrogen, alkyl of from 12 to 20 carbon atoms,
hydroxyalkyl of from 2 to 8 carbon atoms, (lower alkoxy)lower alkyl
and ##SPC8## R.sub.7 is selected from the group consisting of alkyl
of from 12 to 20 carbon atoms and ##SPC9## R.sub.8 is selected from
the group consisting of alkyl of from 1 to 20 carbon atoms and
##SPC10## each of p and n is 0 or an integer from 1 to 6, with the
proviso that the sum of p and n is no greater than 6; and Z is
selected from the group consisting of .omega.-carboxy(lower alkyl),
morpholino, piperidino, piperazino, N-(.omega.-hydroxy lower
alkyl)piperazino and N-(lower alkyl)piperazino.
Inventors: |
Cronin; Timothy H. (Niantic,
CT), Faubl; Hermann (Groton, CT), Hoffman; William W.
(Mystic, CT), Korst; James J. (Old Lyme, CT) |
Assignee: |
Pfizer Inc. (New York,
NY)
|
Family
ID: |
26844040 |
Appl.
No.: |
05/330,042 |
Filed: |
February 6, 1973 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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146548 |
May 24, 1971 |
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62192 |
Aug 7, 1970 |
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Current U.S.
Class: |
564/506; 564/60;
549/437; 560/32; 560/33; 560/39; 560/169; 560/251; 560/253;
562/553; 562/565; 564/224; 564/292; 564/354; 564/389; 564/490;
564/503; 564/507; 564/509; 564/511; 549/435; 549/438; 560/34;
560/155; 560/196; 560/252; 562/444; 562/560; 564/59; 564/143;
564/297; 564/388; 564/481; 564/501; 564/504; 564/508; 564/510 |
Current CPC
Class: |
C07C
275/14 (20130101) |
Current International
Class: |
C07C
275/14 (20060101); C07C 275/00 (20060101); C07c
091/12 () |
Field of
Search: |
;260/584R |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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112,366 |
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Dec 1965 |
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NL |
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1,079,597 |
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Aug 1965 |
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GB |
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Other References
Primary Examiner: Gotts; Lewis
Assistant Examiner: Phillips; D. R.
Attorney, Agent or Firm: Connolly and Hutz
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of my copending
application Ser. No. 146,548, filed May 24, 1971, and now abandoned
which in turn is a continuation-in-part of my application Ser. No.
62,192, filed Aug. 7, 1970 and now abandoned.
Claims
1. A compound of the formula ##SPC65##
and the non-toxic acid addition salts therof wherein
R.sub.1 is alkyl of from 1 to 20 carbon atoms;
R.sub.2 is alkyl of from 12 to 20 carbon atoms;
R.sub.3 and R.sub.4 are each hydroxyalkyl of from 2 to 8 carbon
atoms;
X and X' are each straight chain alkylene of from 2 to 6 carbon
atoms; and
2. A compound according to claim 1 wherein
R.sub.1 is alkyl of from 6 to 20 carbon atoms;
R.sub.3 and R.sub.4 are each hydroxyalkyl of from 2 to 4 carbon
atoms;
X and X' are each alkylene of from 2 to 3 carbon atoms; and
4. A compound according to claim 1 wherein R.sub.1 and R.sub.2 are
each alkyl of from 12 to 20 carbon atoms; R.sub.3 and R.sub.4 are
each hydroxyethyl; X' is straight chain alkylene of from 3 to 5
carbon atoms;
5. N,N-Dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine, a
compound according to claim 4 wherein R.sub.1 and R.sub.2 are each
octadecyl and X'
6. A compound according to claim 1 wherein R.sub.1 is alkyl of from
12 to 20 carbon atoms.
Description
BACKGROUND OF THE INVENTION
This invention relates to a novel method for combating viral
infections in vertebrate animals which comprises administering to
the animals a monoamine, a diamine or a triamine. More
particularly, it relates to combating viral infections in
vertebrate animals by parenteral, intranasal or topical
administration of a substituted aliphatic primary amine, a
substituted alkanediamine, a substituted nitrogen-containing
heterocyclic compound or a triamine compound.
The cells of vertebrates produce, in response to virus infection, a
substance which enables cells to resist the multiplication of a
variety of viruses. The viral-resisting or viral-interfering
substances are referred to as "interferons." They are a
heterogeneous group of antiviral proteins which vary quite widely
in their molecular weights. Although such proteins may differ in
their physico-chemical properties, they all exhibit the same
biological properties; namely, they inhibit a wide range of
unrelated viruses, hav no toxic or other deleterious effects on
cells, and are species-specific (Lockart, Frontiers of Biology,
Vol. 2, "Interferons," edited by Fintner, W. B. Saunder Company,
Philadelphia, 1966, pp. 19-20).
This discovery, by Isaacs and Lindenmann, in 1957 (Proc. Roy. Soc.
B. 147, 258-267) gave rise to great optimism that an economic
preparation of exogeneous interferon might be developed for routine
clinical use against viral infections. However, despite great
expenditures of effort and money, no safe, effective, economical
source has yet been developed. An alternate approach to producing
interferon has, therefore, been pursued. This approach comprises
administering to the animal to be protected, or treated, a
non-viral substance which stimulates--or induces--production of
interferon in the cells. The interferon produced in this fashion is
referred to as "endogenous" interferon.
The discovery of antiviral compounds is far more complicated and
difficult than is the discovery of antibacterial and antifungal
agents. This is due, in part, to the close structural similarity of
viruses and the structures of certain essential cellular components
such as ribonucleic and deoxyribonucleic acids, and to the
difficulty of establishing suitable tests for evaluating antiviral
agents. However, despite these difficulties, numerous non-viral
substances have been found capable of stimulating or inducing
interferon formation in animals. Included among such substances are
bacteria, parasites, bacterial endotoxins, pyran copolymers,
helenine, phytohemagglutinin, polyacrylic compounds, nucleic acids
and polynucleotides. Use of these inducers is, however, objected to
for one or more reasons, e.g., toxicity, antigenicity,
infectiousness, and their routine clinical use appears remote
(Zhdanov, et al., Internat'l. Virol. I, 1st Int. Congr. Virol.
Helsinki 1968, S. Karger, New York, pp. 100-1, 1969).
More recently, 2,7-bis[2-(diethylamino)ethyoxy]fluorene-9-one
dihydrochloride, a purely synthetic material of relatively low
molecular weight, has been reported to be an oral inducer of
interferon in mice (Abstracts Federation Proceedings, Vol. 29, No.
2, page 635, 1970; Abstracts 2189 and 2190).
A variety of "antiviral agents" are described in the literature.
These have been summarized by Osdene in "Topics in Medicinal
Chemistry," edited by Rabinowitz and Myerson, Interscience
Publishers, New York, 1968, pages 141-171. For the purposes of this
review, Osdene has made use of Herrmann's definition of "antiviral
agent" (Herrmann, et al., Proc. Soc. Exptl. Biol. Med. 103, 625,
1960); namely, an agent "which can produce either a protective or
therapeutic effect to the clear detectable advantage of the virus
infected host, or any material that can significantly enhance
antibody formation, improve antibody activity, improve non-specific
resistance, speed convalescence or depress symptoms." This
definition is of such breadth as to cover both prophylactic and
therapeutic agents. It includes substances such as interferon, and
a host of synthetic materials, such as 1-adamantanamine,
pyrimidines, biguanides, guanidine, pteridines to mention a few. It
is noted that such synthetic materials are antiviral agents. They
are not interferon inducers but operate by a totally different
mechanism. Interferon inducers may, or course, be referred to an
antiviral agents. The converse, however, is not true.
Virus infections which attack animals, including man, are normally
contagious afflictions which may spread so rapidly that they can
reach explosive proportions in relatively short periods of time. In
the past, many of these epidemics have resulted in large numbers of
deaths and have been responsible for huge economic losses.
Obviously a method of reducing the incidence of these viral
infections, such as the method of this invention, would be welcome
as an addition to the armamentarium of medical technology.
SUMMARY OF THE INVENTION
It has now been found that certain monoamines and diamines,
including heterocyclic amines having one or two nitrogen atoms in
the ring, and triamines are capable of combating viral infections
in vertebrate animals when administered by the parenteral,
intranasal and topical routes. The compounds of this invention,
many of which are novel, have the formulae ##SPC11## ##SPC12##
and the non-toxic acid addition salts thereof wherein R.sub.1 is
selected from the group consisting of alkyl of from 1 to 20 atoms,
aralkyl, aryloxyalkyl, hydroxyalkyl of from 2 to 8 carbon toms and
##SPC13##
R.sub.2 is selected from the group consisting of alkyl of from 12
to 20 carbon atoms, aralkyl and aryloxyalkyl of from 12 to 24
carbon atoms and ##SPC14##
R.sup.o is alkoxy of from 1 to 18 carbon atoms;
each of R' and R" is selected from the group consisting of
hydrogen, alkyl and alkoxy of from 1 to 18 carbon atoms; R' and R"
when taken together are methylenedioxy;
provided that the total number of carbon atoms in R.sup.o, R' and
R" is from 5 to 48;
R.sub.3 is selected from the group consisting of hydrogen, alkyl of
from 1 to 20 carbon atoms, hydroxyalklyl of from 2 to 8 carbon
atoms, phenylcarbamoyloxy(lower alkyl),
.omega.-carboxyalkanoyloxy(lower alkyl), allyl, alkanoyl of from 1
to 6 carbon atoms, alkoxy(lower alkyl), gem-di(lower alkoxy)lower
alkyl, alkanaoyloxy(lower alkyl), carbo(lower alkoxy)lower alkyl,
and carboxy(lower alkyl);
R.sub.4 is selected from the group consisting of hydrogen, alkyl of
from 1 to 8 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms,
carbo(lower alkoxy)lower alkyl, alkanoyloxy(lower alkyl),
carboxy(lower alkyl), alkoxy(lower alkyl), phenylcarbamoyloxy(lower
alkyl), .omega.-carboxyalkanoyloxy(lower alkyl), allyl,
dihydroxyalkyl of from 3 to 8 carbon atoms and morpholinoethyl;
with the proviso that no more than two of the R variables are
hydroxyalkyl;
R.sub.3 and R.sub.4 when taken together with the nitrogen to which
they are attached are morpholino;
X is selected from the group consisting of straight chain alkylene
of from 2 to 6 carbon atoms and ##SPC15## ;
X' is selected from the group consisting of X,
phenylenedimethylene, and ##SPC16## ;
m is 0 or 1, with the provisos that only one of X and X' is
##SPC17##
and when X' is phenylenedimethylene, m is 0;
Y is selected from the group consisting of straight chain alkylene
of from 2 to 8 carbon atoms and phenylenedimethylene;
A is selected from the group consisting of hydrogen, cyano,
hydroxy, alkoxy of from 1 to 20 carbon atoms, alkanoyloxy of from 2
to 20 carbon atoms, phenylcarbamoyloxy, chloro, bromo,
.omega.-carboxyalkanoyloxy(lower alkyl), alkanoyloxy of from 1 to 6
carbon atoms, carbo(lower alkoxy) and alkanoylthio of from 2 to 20
carbon atoms and alkylthio of from 1 to 20 carbon atoms;
R.sub.5 is selected from the group consisting of hydrogen, alkyl of
from 1 to 20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon
atoms, (lower alkoxy)lower alkyl and ##SPC18##
R.sub.6 is selected from the group consisting of hydrogen, alkyl of
from 12 to 20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon
atoms, (lower alkoxy)lower alkyl and ##SPC19## ;
R.sub.7 is selected from the group consisting of alkyl of from 12
to 20 carbon atoms and ##SPC20## ;
R.sub.8 is selected from the group consisting of alkyl of from 1 to
20 carbon atoms and ##SPC21## ;
each of p and n is 0 or an integer from 1 to 6, with the proviso
that the sum of p and n is no greater than 6; and
Z is selected from the group consisting of .omega.-carboxy(lower
alkyl), morpholino, piperidino, piperazino, N-(.omega.-hydroxy
lower alkyl)piperazino and N-(lower alkyl)piperazino.
Of the lower alkoxy, lower alkyl and carbo(lower alkoxy)groups,
those having up to four carbon atoms in the alkoxy and alkyl groups
are preferred since the starting materials are readily available.
The term "phenylenedimethylene" includes, of course, the three
isomeric, that is, the o-, the m- and the p-phenylenedimethylene
groups.
By "non-toxic" acid addition salts is meant those salts which are
non-toxic at the dosages administered. The non-toxic acid addition
salts of the above-mentioned bases which may be employed are the
water-soluble and water-insoluble salts as the hydrochloride,
hydrobromide, phosphate, nitrate, sulfate, acetate,
hexafluorophosphate, citrate, gluconate, benzoate, propionate,
butrate, sulfosalicylate, maleate, laurate, malate, fumarate,
succinate, oxalate, tartrate, amsonate
(4,4'-diaminostilbene-2,2'-disulfonate), pamoate
(1,1'-methylene-bis-2-hydroxy-3-naphthoate), stearate,
3-hydroxy-2-naphthoate, p-tolenesulfonate, picrate, lactate and
suramin salt.
In addition to the above compounds, compounds of formulae I and II
wherein (a) the X, X' and Y variables represent straight chain
alkylene radicals of up to 13 carbon atoms, or branched-chain
alkylene groups of 3 to 13 carbon atoms; (b) X, X' and Y are
arylene, e.g., phenylene, naphthylene, anthrylene, biphenylene or
--(CH.sub.2).sub.x --arylene--(CH.sub.2).sub.y --wherein x and y
are integers from 1 to 4; (c) those wherein one or more of the R
variables represent unsaturated alkyl radicals having from 2 to 20
carbon atoms and from 1 to 3 double bonds; polyhydroxyalkyl; aryl
(phenyl, naphthyl); aralkyl (benzyl, phenethyl, phenylpropyl);
phenoxyalkyl and substituted derivatives of the aforementioned
aryl, aralkyl and phenoxyalkyl wherein the substituent is in the
aryl moiety and is alkyl, chloro, bromo, alkoxy or carbo (lower
alkoxy); (d) compounds of formulae I and II wherein the R groups
together with the nitrogen atoms to which they are attached form a
heterocyclic structure wherein the heterocyclic moiety contains
from 3 to 7 carbon atoms and wherein the hetero atom is at least
one of N, O, or S, such as morpholino, thiomorpholino, piperidino,
piperazino, N-lower alkyl piperazino, N-(hydroxy lower
alkyl)-piperazino, pyrrolo, pyrolidino, 2-(lower
carbalkoxy)pyrrolidino, indolo, benzimidazolo, 1-benzotriazolo,
2,1,3-benzothiazole, pyrazolo, phenoxazino, azetidino; azepino;
tetrazolo; an azacycloalkane such as azacyclooctadecane;
10,11-dihydro-5-H-dibenz[b,f]azepino; a triazepino, e.g.,
1,3,5-triazepino, and 11-dibenzo[1,2,5]triazepino; (e) and
compounds of formula I wherein X or X' represent C=NH or C=S; (f)
N-oxides of the compounds of formulae I through IV; (g) and
compounds of formula III wherein Z is N-substituted piperazino
wherein the substituent is carbalkoxy, acyl or --X'-NR.sub.3
R.sub.4 wherein X', R.sub.3 and R.sub.4 are as defined above; also
combat viral infections when administrated to vertebrate animals by
the parenteral route.
One preferred group of compounds of Formula I includes those
wherein R.sub.1 is selected from the group consisting of alkyl of
from 1-20 carbon atoms, aralkyl, aryloxyalkyl, and ##SPC22##
wherein R.sup.o is alkoxy of from 1 to 18 carbon atoms; each of R'
and R" is hydrogen, alkyl or alkoxy of from 1 to 18 carbon atoms;
R' and R" when taken together are methylenedioxy;
R.sub.2 is selected from the group consisting of alkyl of from 12
to 20 carbon atoms, aralkyl, aryloxyalkyl and ##SPC23##
wherein R.sup.o is alkoxy of from 1 to 18 carbon atoms; each of R'
and R" is hydrogen, alkyl or alkoxy of from 1 to 18 carbon atoms;
R' and R" when taken together are methylenedioxy;
R.sub.3 and R.sub.4 are each hydrogen;
m is O; and
X' is phenylenedimethylene.
The compounds described herein exhibit broad spectrum activity
against a variety of viruses in vivo when administered parenterally
(subcutaneously, intramuscularly, intraperitoneally), intranasally
(e.g., by inhalation or spray) or topically to vertebrate animals.
This usefulness is primarily one of prophylactic rather than of
therapeutic control of virus infections. Although the present
invention is not to be construed as limited by such a theory, it is
possible that the compounds of this invention function in combating
viral infections by virtue of their ability to induce the
production of endogenous interferon. They do not produce interferon
in tissue culture but only in vivo and can, therefore, be
considered as stimulators of host defense mechanisms.
Further, these compounds stimulate the animal body to produce
interferon when administered alone and/or in combination with an
otherwise inactive, single-stranded ribonucleic acid, such as
highly polymerized ribonucleic acid from yeast, yeast nucleic acid
(Calbiochem 55712, Calbiochem, Los Angeles, Calif.). Those
compounds which induce interferon when administered alone are given
at considerably lower doses when given in combination with the
single-stranded ribonucleic acid. Particularly useful as inducers
of interferon when used alone are compounds of formula I wherein
R.sub.1 is alkyl of from 1 to 20 carbon atoms; R.sub.2 is alkyl of
from 12 to 20 carbon atoms; R.sub.3 is hydrogen, formyl, alkyl or
from 1 to 20 carbon atoms or hydroxyalkyl of from 2 to 4 carbon
atoms; R.sub.4 is hydrogen or hydroxyalkyl of from 2 to 4 carbon
atoms; X' is alkylene of from 3 to 6 carbon atoms or
phenylenedimethylene; and m is O, with the proviso that at least
one and not more than two hydroxyalkyl groups are present;
compounds of formula I wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are as defined immediately above, X is C=O, m is O and X'
is alkylene of from 2 to 6 carbon atoms; compounds of formula II
wherein A is hydroxy; Y is straight chain alkylene of 2 to 4 carbon
atoms; and R.sub.5 and R.sub.6 are alkyl of from 12 to 20 carbon
atoms; and compounds of formula III wherein Z is N-substituted
piperazino and R.sub.7 and R.sub.8 are each alkyl. An especially
preferred group of compounds of formula I includes those in which
R.sub.1 and R.sub.2 are each alkyl of 12 to 20 carbon atoms,
R.sub.3 and R.sub.4 are each hydroxyethyl, X' is straight chain
alkylene of from 3 to 5 carbon atoms, and m is O. Particularly
valuable are the following compounds:
N,n-dioctadecyl-N'-formyl-1,3-propanediamine,
N,n-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine,
1-dioctadecylaminomethyl-3-aminomethylbenzene,
N,n-dihexadecyl-N',N'-bis(2-hydroxyethyl)-1,4-butanediamine,
N,n-dioctadecyl-N',N'-bis(2-hydroxypropyl)-1,3-propanediamine,
N-(2-hydroxyethyl)dioctadecylamine,
N-(3-hydroxypropyl)dioctadecylamine,
1,1-dioctadecyl-3-(2-[bis(2-hydroxyethyl)amino]ethyl)urea,
1-(N,N-dioctadecylcarbamoyl)-4-methylpiperazine,
1(N,N-dioctadecylcarbamoyl)-4-(2-hydroxyethyl)piperazine.
The compounds of this invention, many of which are known, are
prepared by methods familiar to those skilled in the art.
U.S. Pat. No. 3,235,501, for example, discloses, in theory at least
when all combinations and permutations of the several variables are
considered, thousands upon thousands of polyoxyalkylated aliphatic
amines derived from primary and secondary mono- and diamines. The
compounds are produced by alkoxylation (etnoxylation or
propoxylation) of primary and secondary mono- and diamines. In such
cases, the alkoxylation reaction occurs in a random manner to
produce a mixture of alkoxylated compounds in which from 1 to 25
alkylene oxide moieties may be present. Many of the compounds of
formula I above fall within the theoretical list of compounds
encompassed by this patent. However, despite the extremely broad,
indeed infinite, disclosure to polyoxylated aliphatic amines, the
patent is completely devoid of reference to specific compounds
embraced by formula I above. The innumerable possibilities of the
patent disclosure coupled with the ambiguous and vague nature of
the method of preparation disclosed, render it unlikely that any
specific compound would be suggested to one skilled in the art.
Also disclosed in the literature are compounds of formula III
wherein each of R.sub.7 and R.sub.8 is hydrogen or lower alkyl
(Kushner, et al., J. Org. Chem. 13, 133-53, 1948; Pressman, et al.,
J. Am. Chem. Soc. 70, 1352-8, 1948). Such compounds do not induce
interferon when administered to animals as described herein. Quite
unexpectedly, however, it has been found that when at least one of
R.sub.7 and R.sub.8 is alkyl of twelve or more carbon atoms, the
compounds do function to comat viral infections.
The basic reaction is the alkylation of an amine, primary or
secondary with, for example, an alkyl halide or hydroxyalkyl
halide, usually chloride or bromide in an organic solvent in the
presence of a base or acid acceptor. Other methods of alkylation
can, of course, be employed such as the use of aluminum alkoxides,
esters of sulfuric and p-toluenesulfonic acid. Appropriate methods
for preparing compounds of the above formulae are described by Zook
and Wagner, "Synthetic Organic Chemistry," John Wiley and Sons,
Inc., New York, 1953, pages 666-670.
Derivatives of 1,3-propanediamine are conveniently made by
cyanoethylation of the appropriate primary or secondary amines by
conventional methods. The propionitrile compound (R.sub.1 R.sub.2
NCH.sub.2 CH.sub.2 CN) thus obtained is then hydrogenated to the
corresponding 1,3-propanediamine (R.sub.1 R.sub.2 NCH.sub.2
CH.sub.2 CH.sub.2 NH.sub.2) by well-known methods, e.g.,
hydrogenation over Raney nickel.
Acylated amines are readily prepared by treating the appropriate
amine with an acyl halide or anhydride in the presence of a base
according to procedures well known to those skilled in the art.
An alternative method for preparing compounds of formulae I and II
having N-hydroxyalkyl groups comprises treating a hydroxyalkyl
reactant, e.g., an N,N-dialkylamino alkanol, with methane sulfonyl
chloride and then reacting the reaction mixture with the
appropriate hydroxyalkylamine or di(hydroxyalkyl) amine.
Urea derivatives of formulae I and III are also prepared by
conventional methods as by reaction of a carbamyl chloride (R.sub.1
R.sub.2 NCOCl) with an amino reactant H.sub.2 N--X'--NR.sub.3
R.sub.4 or N-substituted piperazine in an organic solvent in the
presence of an acid acceptor which can, of course, be an excess of
the amine reactant.
Compounds of formula I wherein the x' variable is
phenylenedimethylene are prepared by Standard procedures from
cyanobenzylbromides or chlorides. The appropriate amine, e.g.,
R.sub.1 R.sub.2 NH, is benzylated with a cyanobenzylbromide or
chloride and the cyanobenzylamine compound produced reduced to the
corresponding aminomethylbenzylamine derivative. The aminomethyl
group (--CH.sub.2 NH.sub.2) is then treated, e.g., alkylated, with
appropriate reactants to convert it to --CH.sub.2 NR.sub.3 R.sub.4.
Compounds of formula II wherein Y is phenylenedimethylene are also
prepared by benzylation of the appropriate amine R.sub.5 R.sub.6 NH
with a cyanobenzylbromide (or chloride). The cyanobenzylamine thus
produced is converted to an ortho ester which is reduced to an
acetal and subsequently hydrolyzed to the aldehyde. Reduction of
the aldehyde affords a hydroxymethyl benzylamine. The hydroxymethyl
serves as convenient route via known procedures to formula II
compounds, and also to formula I compounds, e.g., by halogenation
and amination.
The herein-described compounds of formulae I, II and III wherein
the R.sub.1, R.sub.2, R.sub.5, R.sub.6, R.sub.7 or R.sub.8 groups
are substituted benzyl ##SPC24##
are conveniently produced from appropriate benzaldehydes via
reduction to a benzyl alcohol followed by conversion to a benzyl
chloride and then amination. Alternatively, the benzaldehyde is
reductively aminated to produce, depending upon the conditions, a
mono- or dibenzylamine. Utilization of the benzylamine derivatives
in conventional reactions as described above affords compounds of
formulae I-III.
Acid addition salts of the compounds described herein are prepared
by conventional procedures as by mixing the amine compound in a
suitable solvent with the required acid and recovering the salt by
evaporation or by precipitation by addition of a non-solvent for
the salt. Hydrochloride salts are readily prepared by passing dry
hydrogen chloride through a solution of the amine compound in an
organic solvent such as ether.
The antiviral activity of the above-described materials is
determined by the following procedures. In the first procedure, the
test compound is administered to mice by the intraperitoneal route
18 to 24 hours prior to challenging the mice with a lethal dose of
encephalomyocarditis virus and determining the survival rate 10
days after challenge. The procedure in which the drug is given
eighteen to 24 hours before and at a distinctly different site from
virus injection is designed to eliminate local effects between drug
and virus and select only compounds which produce a systemic
interferon response.
The second general procedure discriminates between compounds which
exhibit antiviral activity in the first procedure for their ability
to produce an antiviral state in mice as indicated by their ability
to stimulate circulating interferon after parenteral
administration. In both procedures, the test compounds are
administered alone and in combination with from about 2 to about 20
times by weight of an otherwise inactive (nor-inducer of interferon
and nonantiviral), single-stranded, highly-polymerized ribonucleic
acid from yeast, yeast nucleic acid.
DETAILED DESCRIPTION OF THE INVENTION
Parenteral, topical and intranasal administration of the
above-described amines to an animal, including man, before exposure
of the animal to an infectious virus provide rapid resistance to
the virus. The resistance engendered is non-specific and is
effective against a great number of viruses. Such administration is
effective when given as much as seven days prior to exposure to the
virus. Preferably, however, administration should take place from
about three days to about one day before exposure to the virus,
although this will vary somewhat with the particular animal species
and the particular infectious virus.
When administered parenterally the materials of this invention are
used at a level of from about 1 mg./kg. of body weight to about 250
mg./kg. of body weight. The favored range is from about 5 mg./kg.
to about 100 mg./kg. of body weight, and the preferred range from
about 5 mg. to about 50 mg./kg. of body weight. The dosage, of
course, is dependent upon the animal being treated and the
particular amine compound involved and is to be determined by the
individual responsible for its administration. Generally, small
doses will be administered initially with gradual increase in
dosage until the optimal dosage level is determined for the
particular subject under treatment.
Intraperitoneal injections are the preferred method of parenteral
injection for several reasons: simplicity, convenience and the
compounds appear less toxic. Vehicles suitable for parenteral
injection may be either aqueous such as water, isotonic saline,
isotonic dextrose, Ringer's solution, or non-aqueous such as fatty
oils of vegetable origin (cottonseed, peanut oil, corn, sesame) and
other non-aqueous vehicles which will not interfere with the
efficacy of the preparation and are non-toxic in the volume or
proportion used (glycerol, ethanol, propylene glycol, sorbitol).
Additionally, compositions suitable for extemporaneous preparation
of solutions prior to administration may advantageously be made.
Such compositions may include liquid dilvents, for example,
propylene glycol, diethyl carbonate, glycerol, sorbitol.
When the materials of this invention are administered, they are
most easily and economically used in a dispersed form in an
acceptable carrier. When it is said that this material is
dispersed, it means that the particles may be molecular in size and
held in true solution in a suitable solvent or that the particles
may be colloidal in size and dispersed through a liquid phase in
the form of a suspension or an emulsion. The term "dispersed" also
means that the particles may be mixed with and spread throughout a
solid carrier so that the mixture is in the form of a powder or
dust. This term is also meant to encompass mixtures which are
suitable for use as sprays, including solutions, suspensions or
emulsions of the agents of this invention.
In practicing the intranasal route of administration of this
invention any practical method can be used to contact the inducer
with the respiratory tract of the animal. Effective methods include
administration of the inducer by intranasal or nasopharyngeal drops
and by inhalation as delivered by a nebulizer or an aerosol. Such
methods of administration are of practical importance because they
provide an easy, safe and efficient method of practicing this
invention. For intranasal administration of the inducer, usually in
an acceptable carrier, a concentration of inducer between 1.0
mg./ml. and 100 mg./ml. is satisfactory. Concentrations in the
range of about 30 to 50 mg./ml. allow administration of a
convenient volume of material.
For topical application the inducers are most conveniently used in
an acceptable carrier to permit ease and control of application and
better absorption. Here also concentrations in the range of from
about 1.0 mg./ml. to about 250 mg./ml. are satisfactory. In
general, in the above two methods of administration a dose within
the range of about 1.0 mg./kg. to about 250 mg./kg. of body weight
and, preferably, from about 5.0 mg./kg. to about 50 mlg./kg. of
body weight will be administered.
The compounds employed in this invention may be employed alone,
i.e., without other medicinals, as mixtures of more than one of the
herein-described compounds or in combination with other medicinal
agents, such as analgesics, anesthetics, antiseptics,
decongestants, antibiotics, vaccines, buffering agents and
inorganic salts, to afford desirable pharmacological properties.
Further, they may be administered in combination with hyaluronidase
to avoid or, at least, to minimize local irritation and to increase
the rate of absorption of the compound. Hyaluronidase levels of at
least about 150 (U.S.P.) units are effective in this respect
although higher or lower levels can, of course, be used.
Those materials of this invention which are water-insoluble,
including those which are of low and/or difficult solubility in
water, are, for optimum results, administered in formulations,
e.g., suspensions, emulsions, which permit formation of particle
sizes of less than about 20.mu.. The particle sizes of the
formulations influence their biological activity apparently through
better absorption of the active materials. In formulating these
materials various suface active agents and protective colloids are
used. Suitable surface active agents are the partial esters of
common fatty acids, such as lauric, oleic, stearic, with hexitol
anhydrides derived from sorbitol, and the polyoxyethylene
derivatives of such ester products. Such products are sold under
the trademarks "Spans" and "Tweens," respectively, and are
available from the Atlas Powder Co., Wilmington, Del. Cellulose
ethers, especially cellulose methyl ether (Methocel, available from
the Dow Chemical Co., Midland, Mich.) are highly efficient as
protective colloids for use in emulsions containing the materials
of this invention.
The water-soluble materials described herein are administered for
optimum results in aqueous solution.
The production of interferon by the administration of compounds
described herein is demonstrated by the protection of animals,
generally mice as the initial test animal, against viral
infections. Encephalomyocarditis virus is a convenient test
organism. The challenge virus is prepared by inoculating mice for
at least five passages with a neurotropic strain of
encephalomyocarditis virus (infected mouse brain). A 10 percent
suspension of infected brain tissues is prepared from infected mice
and stored at -70.degree. C. until needed (Takano, et al., J. Bact.
90, 1542, 1965). It is titrated to a dose which will cause death in
5 to 7 days after challenge to unprotected animals. It is given
subcutaneously into the neck scruff. The appropriate dose is
contained in 0.1 ml. In general, the dose administered to the
animals is from 10 to 25 times the LD.sub.50 (the dose which causes
the death of 50 percent of the animals).
For determination of antiviral activity, mice are parenterally
(intraperitoneally) injected with the test compound at levels of 5
or 10 mg./kg. and 50 mg./kg. of body weight 18 to 20 hours prior to
virus challenge and the number of survivors determined 10 days
after challenge. Interferon production is monitored following
injection of the test compound according to the procedure described
by Wheelock, Proc. Soc. Exptl. Biol. Med. 124, 855-85 (1967).
Once interferon induction by a given compound is observed, the
compound is administered to the test animal at various time
intervals prior to challenge, e.g., 6, 36, 48 and 72 hours, and by
other parenteral routes, e.g., intramuscular and subcutaneous.
The induction of interferon is demonstrated in the following
manner. A representative formulation containing N,N-dioctadecyl-N',
N'-bis(2-hydroxyethyl)-1,3-propanediamine as the inducer is
exemplified.
A mixture of the inducer (100 mg.) and polysorbate 80 (Tween 80;
0.1 ml.) is heated in a boiling water bath. The amine melts and is
completely miscible with the polysorbate 80. To this mixture is
then added with vigorous vortexing 2.5 ml. of the following
composition previously warmed to about 55.degree. C:
Methocel-15 (Dow Chemical Co.) 0.50 g. Tween 80 1.00 g. CMC-70*
10.00 g. Sodium chloride 9.00 g. Distilled water 984.80 g. *Sodium
carboxymethyl cellulose available from Hercules Powder Co.,
Wilmington, Delaware.
Then 7.28 ml. of a 0.14M sodium chloride-0.01M sodium phosphate
solution of pH 7.0 warmed at 55.degree. C. is added with continued
vigorous vortexing. The formulation thus produced contains 10 mg.
of inducer per ml. of suspension.
The hydrochloride salt of
N,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine is
readily formulated by vigorous vortexing of the salt in hot 0.14M
sodium chloride-0.01M sodium phosphate of pH 7.0.
Interferon induction is determined using female albino Swiss mice
(Charles-River) as the test animal. Mice weighing 20 to 25 grams
are housed in groups of five and are given food and water ad
libitum. The test material is evaluated at 5 mg./kg. and 50 mg./kg.
of body weight and given in a single intraperitoneal injection (0.5
ml.) 18 to 20 hours prior to bleeding. The mice are bled under
ether anesthesia from the bracheal artery, the blood collected in
heparinized pipettes and tubes, and the pooled plasma from the five
mice prepared by centrifugation of the blood for 30 minutes at
2,000 RPM. Dilutions of the plasma are pipetted into plastic tubes
containing sheets of L-929 mouse fibroblasts (available from Flow
Laboratories, Rockville, Md.). These latter are 24 hour cultures in
L-15 media containing 10 percent fetal calf serum and antibiotics
(available from Grand Island Biological Company, Grand Island,
N.Y.). The cultures are grown from initial plantings of 1 ml. of
100,000 cells/ml. After 24 hours of incubation with the plasma, the
cultures are washed with media and challenged with 0.2 ml of a
dilution of vesicular stomatitis virus titrated to produce a
complete destruction of the cell sheets in 24 to 48 hours. The
cultures are in contact with the virus dilution in protein-free
media for one hour to allow the virus to adsorb to the cells and
then the tubes receive 1 ml. of complete media. After 24 to 48
hours of incubation at 37.degree. C., the tubes are scored for
cytopathogenic effect of the virus and compared with standard
interferon samples. Interferon units are recorded as the reciprocal
of the plasma concentration which affords 50 percent protection to
the cell sheets.
The antiviral activity of
N,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine is
determined using female albino Swiss mice (Charles-River) as the
test animal. Mice weighing 20 to 25 grams are housed in groups of
five and are given food and water ad libitum. The test material is
evaluated at two dose levels (5 mg./kg. and 50 mg./kg of body
weight) and administered in a single 0.5 ml. intraperitoneal
injection 18 to 20 hours prior to virus challenge. On the following
day 18 to 20 hours post injection the mice are challenged
subcutaneously with an 0.2 ml. injection of encephalomyocarditis
virus at a dilution titrated to give a 5- to 6-day death endpoint
in unprotected animals. Survival data is recorded for the
subsequent 10 days and the 10-day survival is used as an index of
efficacy. Validity of each test is established by the inclusion of
unprotected groups and groups receiving pyran co-polymer, 100
mg./kg., for positive control.
The water-soluble compounds of the invention are conveniently
administered in phosphate buffered saline. The water-insoluble
compounds are administered in formulations of the type described
above or in various other formulations as previously noted.
Dimethysulfoxide serves as a suitable vehicle for water-insoluble
compounds. A representative formulation for such compounds
comprises 25 to 100 mg. of the chosen drug, dimethylsulfoxide (1
ml.), polysorbate 80 (1 ml.) and 8 ml. of a composition
comprising
Methocel-15 0.50 g./l. Polysorbate 80 1.00 g./l. CMC-70 10.00 g./l.
Sodium chloride 9.00 g./l. Methyl p-hydroxybenzoate 1.80 g./l.
Propyl p-hydroxybenzoate 0.20 g./l. Distilled water 984.00
g./l.
In certain instances, as where clumping of the drug particles
occurs, sonication is employed to provide a homogeneous system.
EXAMPLE I
N,n-dioctadecyl-N',N'-Bis (2-Hydroxyethyl)-1,3-Propanediamine
A mixture of octadecylbromide (666 g., 2.0 moles),
N-(3-aminopropyl)-diethanolamine (162 g., 1.0 mole) and potassium
carbonate (276 g., 2.0 moles) is stirred vigorously and heated
slowly to 120.degree.C. and held at this temperature for one-half
hour. The mixture is allowed to cool to 70.degree.C. then 500 ml.
of a 1:1 methylene chloride-water mixture added. The mixture is
then slowly poured into a stirred mixture of methylene chloride
(9.75 liters)-water (9.75 liters). The methylene chloride phase is
separated after 15 minutes and the remaining aqueous phase
extracted with methylene chloride (4 liters). The combined
methylene chloride extracts are dried over anhydrous magnesium
sulfate then stripped to one-half volume under reduced pressure.
The concentrate is then stirred with silicic acid (300 g.) for
one-half hour, the silicic acid removed and the clear solution
slowing poured into acetone (16 liters) containing succinic acid
(300 g.). The mixture is cooled slowly to 10.degree.C. and the
succinate salt filtered off; 615 g. (68 percent of theory); m.p.
78.degree.-90.degree.C.
It is purified by recrystallization from acetone-methylene chloride
(2-1).
The free base is obtained by dissolving the succinate salt (420 g.)
in methylene chloride (4 liters) and aqueous sodium hydroxide (2.5
liters of 5 percent solution). The mixture is stirred for 15
minutes, the methylene chloride phase separated and washed
successively with aqueous sodium hydroxide (1 .times. 18 liters of
5 percent solution), water (3 .times. 6 liters) and saturated
aqueous sodium chloride (1 .times. 6 liters). It is then dried
(MgSO.sub.4), filtered and evaporated in vacuo to the oil. The oil
is dissolved in acetone (5 liters) at 50.degree.C. and the solution
allowed to cool slowly to give a white precipitate (267 g.) m.p.
39.degree.-41.degree.C. Another preparation yielded a somewhat
lower melting point of 36-36.8.degree.C.
Additional product (20 g.) is obtained by cooling the filtrate to
0.degree.C. Total yield is 287 g.; 43 percent of theory.
______________________________________ Elemental analysis Theory
for C.sub.43 H.sub.90 N.sub.2 O.sub.2 Found: C 77.41 C 77.42 H
13.60 H 13.84 N 4.20 N 4.16 Potentiometric Titration Solvent:
acetic acid Titrant: 0.5 N perchloric acid in acetic acid Theory =
333.6 Found = 342.0 Infra-red (1% in KBr) Major absorption maxima
(in microns) at: 3.05, 3.43 3.52, 6.80, 7.15, 7.25, 7.65, 8.32,
8.39, 8.68, 9.15, 9.24, 9.30, 9.62, 9.70, 11.04, 13.96.
______________________________________
The dilactate salt is prepared by adding two equivalents of lactic
acid dissolved in ether to an ether solution of the base, followed
by evaporation of the ether; m.p. 50.degree.-52.degree. C. becomes
tacky and melts at 60.degree.-62.degree. C.
The diphosphate salt is prepared by adding excess phosphoric acid
to a solution of the base in hexane. It is recrystallized from a
large volume of methanol; m.p. becomes a gel at 140.degree. C.;
brown at 175.degree.-190.degree.C. and melts at
245.degree.-247.degree. C.
The dihydrochloride salt is prepared by bubbling dry hydrogen
caloride into an ether solution of the base. The residue obtained
by removal of the ether is slurried in acetone, filtered, and
recrystallized from ether containing some methanol; m.p. gels at
180.degree.-182.degree. C. and melts completely at
238.degree.-240.degree.C.
EXAMPLE II
N,N-Dioctadecyl ,N'-Bis(2-Hydroxyethyl)Ethanediamine
A mixture of octadecylbromide (6.66 g., 0.02 mole),
N-(2-aminoethyl)-diethanolamine (1.48 g., 0.01mole) and potassium
carbonate (2.76 g., 0.02 mole) is heated at reflux under an
atmosphere of nitrogen for 2 hours. The reaction mixture is then
cooled and treated with aqueous sodium hydroxide (50 ml. of 10
percent solution). Ethyl acetate (50 ml.) is added, the mixture
thoroughly agitated and the ethylacetace separated, washed with
water, and dried over anhydrous magnesium sulfate. Removal of the
solvent by evaporation affords the crude product which is
recrystallized from ethylacetate or acetone; m.p.
33.degree.-34.degree. C.
The hydrochloride, phosphate, succinate and picrate salts are made
by adding the above base to ethylacetate containing stochiometric
amounts of the respective acids. The salts are recovered by
filtration,, washed with cold ethylacetate, and dried.
______________________________________ Salt M.P. (.degree.C.)
______________________________________ dihydrochloride 228-30
diphosphate 102-3 disuccinate 155-6 dipicrate 84-6
______________________________________
Repetition of the above procedure but using the appropriate
(2-hydroxyalkyl)alkanediamine derivative and the appropriate alkyl
bromide produces the following compounds: ##SPC25##
R.sub.1 R.sub.2 R.sub.3 R.sub.4 n Salt M.P. (.degree.C.)
__________________________________________________________________________
C.sub.16 H.sub.33 C.sub.16 H.sub.33 CH.sub.2 CH.sub.2 OH CH.sub.2
CH.sub.2 OH 2 2H.sub.3 PO.sub.4 133-5 CH.sub.2 CH.sub.2 OH C.sub.18
H.sub.37 C.sub.18 H.sub.37 CH.sub.2 CH.sub.2 OH 2 2HBr 236-8
C.sub.20 H.sub.41 C.sub.20 H.sub.41 CH.sub.2 CH.sub.2 OH CH.sub.2
CH.sub.2 OH 3 -- 38-45 C.sub.20 H.sub.41 C.sub.20 H.sub.41 CH.sub.2
CH.sub.2 OH CH.sub.2 CH.sub.2 OH 2 2HCl 188-9 C.sub.20 H.sub.41
C.sub.20 H.sub.41 CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH 2
2H.sub.3 PO.sub.4 220-3 C.sub.18 H.sub.37 C.sub.18 H.sub.37
CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH 4 -- 51--2 C.sub.16
H.sub.33 C.sub.16 H.sub.33 CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2
OH 4 -- 44-5 C.sub.14 H.sub.29 C.sub.14 H.sub.29 CH.sub.2 CH.sub.2
OH CH.sub.2 CH.sub.2 OH 4 -- 39 C.sub.16 H.sub.33 C.sub.16 H.sub.33
--CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 -- 3 2HCl 167-170
C.sub.14 H.sub.29 C.sub.14 H.sub.29 --CH.sub.2 CH.sub.2
--O--CH.sub.2 CH.sub.2 -- 3 2HCl 174-7 C.sub.18 H.sub.37 C.sub.18
H.sub.37 --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 -- 3 2HCl
170--1 C.sub.18 H.sub.37 C.sub.18 H.sub.37 CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH 5 -- 32-3 C.sub.18 H.sub.37 C.sub.18 H.sub.37
CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH 6 -- 49-50
__________________________________________________________________________
EXAMPLE III
N,N-Dioctadecyl-1,3-Propanediamine
A. A 2-gallon autoclave is charged with
3-(dioctadecylamino)propionitrile (100 g.), ethanol (3750 ml.)
containing anhydrous ammonia (100 g.) and Raney nickel (20 g. dry
basis) and purged with nitrogen, then with hydrogen. It is then
sealed and the hydrogen pressure raised to 250 psi. The autoclave
is agitated, the temperature raised to 70.degree. C. and the
mixture held at this temperature for 1.5 hours at which time
hydrogen absorption has ceased. The autoclave is cooled to
20.degree. C., vented, and the contents removed. The catalyst is
filtered off, washed with ethanol, and the combined washings and
reaction mixture concentrated in vacuo to a viscous green-yellow
oil (82 g.) which solidified upon standing; m.p.
39.degree.-41.degree. C.
______________________________________ Analysis Calc'd. for
C.sub.39 H.sub.82 N.sub.2 : C, 80.97; H, 14.17; N, 4.44 percent
Found: C, 80.60; H, 14.17; N, 4.79 percent.
______________________________________
3-(Dioctadecylamino)propionitrile is prepared by refluxing a
mixture of dioctadecylamine (200 g.) and acrylonitrile (1903.8 ml.)
for 18 hours. The mixture is then concentrated to a waxy semi-solid
which is slurried in acetone, filtered, and air dried
overnight.
B. The monacyl derivatives of N,N-dioctadecyl-1,3-propanediamine
are prepared as follows:
To a solution of methylene chloride (500 ml. per 0.1 mole of
reactants) containing equimolar amounts of
N,N-dioctadecyl-1,3-propanediame and triethylamine and cooled in an
ice-bath is added an equimolar amount of the appropriate acyl
chloride in methylene chloride (25 ml. per 0.1 mole of acyl
chloride) over a period of 15 minutes. The mixture is stirred for
10 minutes then brought to room temperature and stirred for 1 hour.
The methylene chloride phase is separated and extracted with water
(3 .times. 25 ml.). The water extract is in turn extracted with
methylene chloride (2 .times. 25 ml.) and the combined methylene
chloride phases dried (Na.sub.2 SO.sub.4) then evaporated under
reduced pressure. The residue is taken up in benzene and the
solution passed through a silica gel column. The column is eluted
with benzene, then with benzene containing increasing amounts of
ethyl acetate; e.g., 5, 10, 25, and 50 percent. The eluate is
subjected to thin layer chromatography (ethyl acetate) and those
fractions which show only one spot, combined and evaporated.
The following are thus prepared:
N-acetyl derivative M.P. 50.degree.-52.degree.C.
N-propionyl derivative M.P. 48 .5.degree.-49.degree.C.
In like manner, the following compounds are prepared from
appropriate reactants: ##SPC26##
R.sub.1 R.sub.2 R.sub.3.sub.'
______________________________________ C.sub.18 H.sub.37 C.sub.18
H.sub.37 C.sub.3 H.sub.7 C.sub.18 H.sub.37 C.sub.18 H.sub.37
C.sub.5 H.sub.11 C.sub.16 H.sub.33 C.sub.16 H.sub.33 H C.sub.16
H.sub.33 C.sub.16 H.sub.33 CH.sub.3 CH.sub.3 C.sub.12 H.sub.25
C.sub.2 H.sub.5 CH.sub.3 C.sub.12 H.sub.25 H
______________________________________
C. Formyl derivatives are prepared as follows:
N,N-dioctadecyl-N'-formyl-1,3-propanediamine
A mixture of N,N-dioctadecyl-1,3-propanediamine (4.88 g.), ethanol
(15ml.) and methyl formate (35 ml.) is heated at reflux for
one-half hour. By-product methanol is distilled off and additional
methyl formate (20 ml.) added. The mixture is refluxed for a half
hour and allowed to stand overnight. It is taken to dryness under
reduced pressure and the white solid residue recrystallized from
ethyl acetate. Yield = quantitative: m.p. 42.degree.-46.degree.
C.
EXAMPLE IV
N-(2-Hydroxyethyl)-N',N'-Dioctadecyl-1,3-Propanediamine
To a stirred solution of N,N-dioctadecyl-3-aminopropanol (1.16 g.,
2 mM.) in chloroform (30 ml.) is added methanesulfonyl chloride
(0.285 g., 2.5 mM.) and the mixture stirred for 75 minutes.
Ethanolamine (1.22 g., 20 mM.) is added and the mixture refluxed
for 45 minutes, then cooled and diluted with chloroform (200 ml.).
The chloroform solution is washed successively with aqueous sodium
hydroxide (5 percent), water and saturated aqueous sodium chloride.
It is then dried (Na.sub.2 SO.sub.4) and concentrated to a waxy
solid.
Picrate Salt: The free base is dissolved in ethanol (100 ml.) and a
solution of picric acid (2 g.) in ethanol (20 ml.) added. The salt
precipitates upon chilling the solution. It is filtered off, washed
with cold ethanol and dried, 1.2 g., m.p. 149.degree.-151.degree.
C. Recrystallization from hot ethanol raises the melting point to
150.degree.-152.degree. C.
In like manner, the following compounds are prepared using
appropriate reactants (HNR.sub.3 R.sub.4) in place of ethanolamine.
The hydrochloride salts are prepared by bubbling excess dry
hydrogen chloride gas into a chloroform solution of the free base
and the salt recovered by evaporation of the solvent. ##SPC27##
R.sub.3 R.sub.4 Salt M.P. (.degree.C.)
______________________________________ H CH.sub.2 CH.sub.2 CH.sub.2
OH picrate 121-2 H CH.sub.2 CH(OH)CH.sub.2 OH picrate 39-41 H
n--C.sub.3 H.sub.7 picrate 64-6 H n--C.sub.6 H.sub.13 HCl 119-22 H
n--C.sub.7 H.sub.15 HCl 53-7 H CH.sub.2 CH.sub.2 OCH.sub.3 HCl 96-9
H CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5 HCl 90-4 H CH.sub.2
CH(OCH.sub.3).sub.2 HCl 83-8 H (CH.sub.2).sub.3 N(CH.sub.2 CH.sub.2
OH).sub.2 picrate 116-8 H (CH.sub.2).sub.3 NH(CH.sub.2
CHOHCH.sub.3) picrate 105-10 H CH.sub.2 CHOHCH.sub.2 N(C.sub.2
H.sub.5).sub.2 HCl 115-7 C.sub.2 H.sub.5 C.sub.2 H.sub.5 picrate
108-10 n--C.sub.4 H.sub.9 n--C.sub.4 H.sub.9 picrate 66-7 CH.sub.3
CH.sub.2 CH.sub.2 OH picrate 80-2 n--C.sub.4 H.sub.9 CH.sub.2
CH.sub.2 OH picrate 48-52 CH.sub.2 CHOHCH.sub.3 CH.sub.2
CHOHCH.sub.3 -- (an oil) CH.sub.2 CHOHCH.sub. 3 HCl 52-4; 98-101 H
CH.sub.2 CH.sub.2 --morpholino -- 55-67, 90 H CH.sub.2 CH.sub.2
--morpholino HCl 137 H CH(CH.sub.3)CH.sub.2 COOC.sub.2 H.sub.5 HCl
56-79 H (CH.sub.2).sub.4 --OH -- 34-34.5 H (CH.sub.2).sub.4 --OH
picrate 84-6; 94 H (CH.sub.2).sub.5 --OH -- 35-6 H (CH.sub.2).sub.5
--OH picrate 65-70; 85-90 C.sub.2 H.sub.5 CH.sub.2 CH.sub.2 OH
picrate 80-6 CH.sub.3 (CH.sub.2).sub.4 --OH -- 91-4 CH.sub.2 COOH
CH.sub.2 COOH -- 75-90 CH.sub.2 COOCH.sub.3 CH.sub.2 COOCH.sub.3 --
75-7 (CH.sub.2).sub.3 OH (CH.sub.2).sub.3 OH -- 41-3
(CH.sub.2).sub.3 OH (CH.sub.2).sub.3 OH picrate 91-5; 100-5
______________________________________
EXAMPLE V
N,n-dioctadecyl-N',N'-Diallyl-1,3-propanediamine
A slurry of N,N-dioctadecyl-1,3-propanediamine (2.895 g., 5 mM.),
allyl bromide (4.3 ml., 50 mM), potassium carbonate (2.0 g.) and
methylene chloride (10 ml.) is stirred at room temperature for 3
hours. The mixture is then cooled in an ice-bath, filtered, and the
filtrate chromatographed on acid-washed silica gel. The product is
eluted with 5 percent methanol-95 percent ethylacetate and the free
base recovered by evaporation of the solvent.
The picrate salt, prepared according to the procedure of Example
IV, melts at 86.degree.-88.degree. C.
Repetition of this procedure but substituting methyl bromoacetate
for allyl bromide produces
N,N-dioctadecyl-N',N'-bis(carbomethoxymethyl)-1,3-propanediamine.
Its hydrochloride, prepared by the procedure of Example IV, melts
at 75.degree.-77.degree. C.
The following compounds are similarly prepared from appropriate
reactants: ##SPC28##
R.sub.1 R.sub.2 R.sub.3 n ______________________________________
C.sub.16 H.sub.33 C.sub.16 H.sub.33 --CH.sub.2 --CH=CH.sub.2 2
C.sub.20 H.sub.41 C.sub.20 H.sub.41 --CH.sub.2 --CH=CH.sub.2 3
CH.sub.3 C.sub.16 H.sub.33 --CH.sub.2 --CH=CH.sub.2 2 C.sub.18
H.sub.37 C.sub.18 H.sub.37 --CH.sub.2 --CH=CH.sub.2 6 C.sub.18
H.sub.37 C.sub.18 H.sub.37 n--C.sub.3 H.sub.7 3 C.sub.18 H.sub.37
C.sub.18 H.sub.37 --CH.sub.2 CH.sub.2 OCH.sub.3 3 C.sub.18 H.sub.37
C.sub.18 H.sub.37 --CH.sub.2 CH.sub.2 --morpholino 3 C.sub.18
H.sub.37 C.sub.18 H.sub.37 --CH.sub.2 CH(OCH.sub.3).sub.2 3
C.sub.18 H.sub.37 C.sub.18 H.sub.37 --CH.sub.2 CH.sub.2 OCOCH.sub.3
3 C.sub.18 H.sub.37 C.sub.18 H.sub.37 --CH.sub.2 CH.sub.2
OCONHC.sub.6 H.sub.5 3 ______________________________________
EXAMPLE VI
N,N-Bis(2-Hydroxyethyl)-N'-Octadecyl-1,3-Propanediamine
A solution of octadecyl bromide (26.65 g., 80 mM.),
N-(3-aminopropyl)diethanolamine (105 g., 640 mM.) and benzyl
alcohol (120 ml.) is heated at 130.degree.C. for 23 hours. The
benzyl alcohol is removed in vacuo (0.1 mm. Hg, and 75.degree.C.)
and the residue taken up in methylene chloride (250 ml.). The
methylene chloride solution is washed with aqueous sodium hydroxide
(1N) then with brine. It is dried (Na.sub.2 SO.sub.4),
concentrated, and distilled; b.p. 242.degree.-246.degree.C. at 0.1
mm Hg. The product is a waxy solid.
EXAMPLE VII
N,n-bis(2-Hydroxyethyl)-N'-(n-Butyl)-N'-Octadecyl-1,3-Propanediamine
A mixture of
N,N-bis(2-hydroxyethyl)-N'-octadecyl-1,3-propanediamine (500 mg.,
1.2 mM.), n-butyl bromide (164 mg., 1.2 mM.) and potassium
carbonate (160 mg., 1.2 mM.) is heated at 100.degree.C. for 2 hours
then at 130.degree.C. for 2 more hours. The mixture is cooled,
taken up in chloroform (100 ml.) and the chloroform solution washed
successively with 5 percent aqueous sodium hydroxide (100 ml.),
water and brine, then dried (Na.sub.2 SO.sub.4). Removal of the
chloroform provides the free base (540 mg.).
The picrate salt, prepared by the procedure of Example IV, melts at
85.degree.-87.degree.C.
In like manner,
N,N-bis(2-hydroxyethyl)-N'-n-propyl)-N'-octadecyl-1,3-propanediamine
is prepared from n-propylbromide. Its picrate salt melts at
105.degree.-106.degree.C. The following compounds and their picrate
salts are prepared in like manner by alkylation of the products of
Examples IV and VI with the appropriate reactant: ##SPC29##
##SPC30##
EXAMPLE VIII
N,n-dioctadecyl-N',
N'-Bis[2-(3'-Carboxypropionyloxy)-ethyl]-1,3-Propanediamine
N,N-Dioctadecyl-N', N'-bis(2-hydroxyethyl)-1,3-propanediamine
(3.335 g., 5 mM.) is added to a solution of succinic anhydride (9.0
g., 90 mM.) in a mixture of ethylacetate (60 ml.) and acetone (60
ml.) at room temperature. After stirring for three hours, the
reaction mixture is cooled in an ice-bath and the precipitate which
forms filtered off, washed with cold acetone and dried.
Recrystallization from hot acetone-ethylacetate (1:1) gives the
ester as a fine white powder (1.783 g.), m.p.
64.degree.-67.degree.C.
The following compounds are prepared from appropriate reactants in
like manner. ##SPC31##
R.sub.1 R.sub.2 n s R ______________________________________
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 2 CH.sub.2 CH.sub.2 COOH
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 3 CH.sub.2 CH.sub.2 COOH
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 2 (CH.sub.2).sub.3 COOH
C.sub.16 H.sub.33 C.sub.16 H.sub.33 3 2 CH.sub.2 CH.sub.2 COOH
C.sub.20 H.sub.41 C.sub.20 H.sub.41 3 2 CH.sub.2 CH.sub.2 COOH
C.sub.14 H.sub.29 C.sub.14 H.sub.29 3 2 CH.sub.2 CH.sub.2 COOH
C.sub.14 H.sub.29 C.sub.14 H.sub.29 3 2 (CH.sub.2).sub.3 COOH
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 3 CH.sub.2 CH.sub.2 COOH
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 8 CH.sub.2 Ch.sub.2 COOH
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 6 CH.sub.2 CH.sub.2 COOH
CH.sub.3 C.sub.18 H.sub.37 3 3 CH.sub.2 CH.sub.2 COOH CH.sub.3
C.sub.18 H.sub.37 3 6 CH.sub.2 CH.sub.2 COOH CH.sub.3 C.sub.18
H.sub.37 3 4 CH.sub.2 CH.sub.2 COOH CH.sub.3 C.sub.18 H.sub.37 3 4
(CH.sub.2).sub.3 COOH C.sub.18 H.sub.37 C.sub.18 H.sub.37 4 2
CH.sub.2 CH.sub.2 COOH C.sub.20 H.sub.41 C.sub.20 H.sub.41 2 2
CH.sub.2 CH.sub.2 COOH C.sub.18 H.sub.37 C.sub.18 H.sub.37 6 2
CH.sub.2 CH.sub.2 COOH ______________________________________
EXAMPLE IX
N,n-dioctadecyl-N',
N'-bis(2-Phenylcarbamoyloxyethyl)-1,3-Propanediamine
Phenyl isocyanate (3.85 g.) is added to a warm solution of
N,N-dioctadecyl-N', N'-bis(2-hydroxyethyl)-1,3-propanediamine (5.0
g.) in ethylacetate (20 ml.) and the mixture heated to reflux for
one hour. The mixture is cooled, then taken to dryness under
reduced pressure. The residue is triturated with carbon
tetrachloride, filtered, and the filtrate evaporated to dryness.
Ethyl acetate (25 ml.) is then added, the mixture cooled, filtered,
washed with ethylacetate and dried in vacuo; m.p.
54.degree.-6.degree.C.
The following compounds are prepared from appropriate reactants by
this procedure: ##SPC32##
R.sub.1 R.sub.2 n s ______________________________________ C.sub.18
H.sub.37 C.sub.18 H.sub.37 3 3 C.sub.16 H.sub.33 C.sub.16 H.sub.33
3 2 C.sub.20 H.sub.41 C.sub.20 H.sub.41 3 2 C.sub.14 H.sub.29
C.sub.14 H.sub.29 3 2 C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 3
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 8 C.sub.18 H.sub.37 C.sub.18
H.sub.37 3 6 CH.sub.3 C.sub.18 H.sub.37 3 3 CH.sub.3 C.sub.18
H.sub.37 3 6 CH.sub.3 C.sub.18 H.sub.37 3 4 C.sub.18 H.sub.37
C.sub.18 H.sub.37 4 2 C.sub.18 H.sub.25 C.sub.12 H.sub.25 2 2
C.sub.18 H.sub.37 C.sub.18 H.sub.37 6 2
______________________________________
EXAMPLE X
N,n-dioctadecyl-N',
N'-bis(2-Palmitoyloxyethyl)-1,3-Propanediamine
Palmitoyl chloride (2.75 g.) is added all at once to a solution of
N,N-dioctadecyl-N', N'-bis(2-hydroxyethyl)-1,3-propanediamine
(1,334 g.) in ethylacetate (50 ml.) and chloroform (5 ml.) at room
temperature. The mixture is stirred for 1 hour then dry hydrogen
chloride gas bubbled in for 2 minutes. The temperature rose to
42.degree.C. and the initial precipitate (of the amine salt) which
formed dissolved. The mixture is chilled to 5.degree.C. then
filtered. The product is washed with ethylacetate and air dried. It
is recrystallized from ethylacetate-hexane; m.p.
122.degree.-4.degree.C.
Replacement of palmitoyl chloride by acetyl chloride produces
N,N-dioctadecyl-N', N'-bis(2-acetyloxyethyl)-1,3-propanediamine.
Its hydrochloride salt prepared by standard methods melts at
103.degree.-7.degree.C.
Repetition of this procedure but using the appropriate acid
chloride in place of palmitoyl chloride produces the following
compounds: ##SPC33##
R.sub.1 R.sub.2 n s R ______________________________________
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 2 C.sub.5 H.sub.11 C.sub.18
H.sub.37 C.sub.18 H.sub.37 3 2 C.sub.2 H.sub.5 C.sub.18 H.sub.37
C.sub.18 H.sub.37 2 2 C.sub.15 H.sub.31 C.sub.18 H.sub.37 C.sub.18
H.sub.37 2 2 CH.sub.3 C.sub.6 H.sub.13 C.sub.16 H.sub.3 3 2
C.sub.15 H.sub.31 C.sub.6 H.sub.13 C.sub.15 H.sub.3 3 2 C.sub.3
H.sub.7 C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 3 C.sub.2 H.sub.5
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 3 C.sub.15 H.sub.31 C.sub.18
H.sub.37 C.sub.18 H.sub.37 4 2 C.sub.17 H.sub.35 C.sub.18 H.sub.37
C.sub.18 H.sub.37 6 2 C.sub.15 H.sub.31 C.sub.18 H.sub.37 C.sub.18
H.sub.37 3 8 CH.sub.3 C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 8
C.sub.17 H.sub. 35 ______________________________________
EXAMPLE XI
1,1-dioctadecyl-3-{2-[Bis(2-Hydroxyethyl)Amino]Ethyl}Urea
A mixture of N,N-dioctadecylcarbamyl chloride (2.9 g.),
N,N-bis-(2-hydroxyethyl)-1,2-ethanediamine (4.0 g.) and benzene (50
ml.) is refluxed and stirred for 3 hours. The mixture is then
cooled, concentrated in vacuo and the residue taken up on
chloroform (100 ml.). The chloroform solution is washed
successively with water (2 .times. 50 ml.), aqueous sodium
hydroxide (1 .times. 50 ml. of 1N) and water (2 .times. 50 ml.),
then dried (Na.sub.2 SO.sub.4). Removal of the chloroform in vacuo
leaves the crude product as an oil (3.3 g.).
It is purified by chromatography on silica gel and elution with
ethylacetate.
The hydrochloride salt is obtained by dissolving the purified
product (0.75 g.) in ether (30 ml.) and bubbling in dry hydrogen
chloride gas. Concentration of the ether provides the salt; 0.55
g., m.p. 152.degree.-153.degree.C.
The N,N-dioctadecylcarbamyl chloride is prepared by bubbling
phosgene into a solution of N,N-dioctadecylamine (100 g.) in
chloroform (1.2 liters) at room temperature for 3 hours. The
mixture is stirred for 2 hours, then filtered. The filtrate is
evaporated to provide the product (48 g.).
The following urea derivatives are similarly prepared but
substituting N,N-bis(2-hydroxyethyl)-1,2-ethanediamine by the
appropriate reactant: ##SPC34##
R.sub.3 R.sub.4 m m Salt M.P. (.degree.C.)
______________________________________ CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH 1 3 -- 53-5 CH.sub.3 CH.sub.3 1 2 HCl 71-4
CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH 1 5 HCl 120-3 H CH.sub.2
CH.sub.2 OH 0 -- -- 60-1 CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH
0 -- -- 46-7 H CH.sub.2 CH.sub.2 OCH.sub.3 0 -- -- 44-5 CH.sub.2
CH.sub.2 OH CH.sub.2 CH.sub.2 OH 1 2 HCl 152-3 H CH.sub.2 CH.sub.2
COOH 0 -- -- 77-81 H H 0 -- -- 61-2 --CH.sub.2 --CH.sub.2
--O--CH.sub.2 --CH.sub.2 -- 0 -- -- 42- 4
______________________________________
The compounds listed below are prepared in like manner from the
appropriate reactants. ##SPC35##
R.sub.1 R.sub.2 R.sub.3 R.sub.4 m n
__________________________________________________________________________
C.sub.6 H.sub.5 OCH.sub.2 C.sub.18 H.sub.37 C.sub.2 H.sub.5
C.sub.18 H.sub.37 1 3 C.sub.6 H.sub.5 OCH.sub.2 C.sub.12 H.sub.25
C.sub.16 H.sub.33 C.sub.16 H.sub.33 1 3 C.sub.6 H.sub.5 OCH.sub.2
C.sub.12 H.sub.25 C.sub.16 H.sub.33 C.sub.16 H.sub.33 1 5 C.sub.18
H.sub.37 C.sub.18 H.sub.37 (CH.sub.2).sub.8 OH (CH.sub.2).sub.8 OH
0 -- C.sub.18 H.sub.37 C.sub.18 H.sub.37 (CH.sub.2).sub.8 OH
(CH.sub.2).sub.8 OH 1 3 C.sub.18 H.sub.37 C.sub.18 H.sub.37
(CH.sub.2).sub.8 OH (CH.sub.2).sub.8 OH 1 6 C.sub.14 H.sub.29
C.sub.14 H.sub.29 H CH.sub.2 CH.sub.2 Ch.sub.2 OH 0 -- C.sub.18
H.sub.37 C.sub.18 H.sub.37 CH.sub.2 COOCH.sub.3 CH.sub.2
COOCH.sub.3 1 3 C.sub.18 H.sub.37 C.sub.18 H.sub.37 CH.sub.2
COOCH.sub.3 CH.sub.2 COOCH.sub.3 0 -- C.sub.18 H.sub.37 C.sub.18
H.sub.37 CH.sub.2 --CH=CH.sub.2 CH.sub.2 --CH=CH.sub.3 0 --
C.sub.18 H.sub.37 C.sub.18 H.sub.37 CH.sub.2 --CH=CH.sub.2 CH.sub.2
--CH=CH.sub.2 1 3 C.sub.18 H.sub.37 C.sub.18 H.sub.37 CH.sub.2
CH.sub.2 OCOCH.sub.3 CH.sub.2 CH.sub.2 OCOCH.sub.3 1 3* C.sub.18
H.sub.37 C.sub.18 H.sub.37 CH.sub.2 CH.sub.2 OCOCH.sub.3 CH.sub.2
CH.sub.2 OCOCH.sub.3 1 5* C.sub.18 H.sub.37 C.sub.18 H.sub.37
CH.sub.2 CH.sub.2 OCOC.sub.15 H.sub.31 CH.sub.2 CH.sub.2 OOC.sub.15
H.sub.31 1 3* C.sub.18 H.sub.37 C.sub.18 H.sub.37 CH.sub.2 CH.sub.2
OCOC.sub.15 H.sub.31 CH.sub.2 CH.sub.2 OCOC.sub.15 H.sub.31 1 5*
C.sub.18 H.sub.37 C.sub.18 H.sub.37 CH.sub.2 CH.sub.2 OCOC.sub.15
H.sub.31 CH.sub.2 CH.sub.2 OCOC.sub. 15 H.sub.31 0 --* C.sub.18
H.sub.37 C.sub.18 H.sub.37 CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5
CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5 0 --* C.sub.18 H.sub.37
C.sub.18 H.sub.37 CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5 CH.sub. 2
CH.sub.2 OCONHC.sub.6 H.sub.5 1 2* C.sub.18 H.sub.37 C.sub.18
H.sub.37 CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5 CH.sub.2 CH.sub.2
OCONHC.sub.6 H.sub.5 1 5* C.sub.18 H.sub.37 C.sub.18 H.sub.37
CH.sub.2 CH.sub.2 OCOCH.sub.2 CH.sub.2 COOH CH.sub.2 CH.sub.2
OCOCH.sub.2 CH.sub.2 COOH 0 --* C.sub.18 H.sub.37 C.sub.18 H.sub.37
CH.sub.2 CH.sub.2 OCOCH.sub.2 CH.sub.2 COOH CH.sub.2 CH.sub.2
OCOCH.sub.2 CH.sub.2 COOH 1 3*
__________________________________________________________________________
*Prepared from the corresponding hydroxyalkyl compounds of this
example b the reactions of Examples VIII - X.
EXAMPLE XII
N-(2-hydroxyethyl)Octadecylamine
A mixture of octadecyl bromide (6.66 g., 0.02 mole), ethanolamine
(0.61 g., 0.01 mole), potassium carbonate (4.14 g., 0.03 mole) and
benzyl alcohol (4 ml.) is heated overnight at
135.degree.-145.degree.C. The mixture is cooled, treated with
ethylacetate (50 ml.) and 10 percent aqueous sodium hydroxide (10
ml.) The ethylacetate layer is separated, washed with water, and
dried (Na.sub.2 SO.sub.4). Removal of the organic solvents under
reduced pressure gives an oily residue which solidifies upon
cooling. It is purified by chromatography on alumina with
chloroform as eluant. Its hydrobromide salt is prepared by adding
hydrogen bromide to an ethanol solution of the base. It melts at
172.degree.-173.degree.C.
The compounds tabulated below are prepared from the appropriate
reactants A-Y-Br and H-NR.sub.5 R.sub.6 by the above procedure:
##SPC36##
Y A R.sub.5 R.sub.6 Salt M.P. (.degree.C.)
__________________________________________________________________________
--(CH.sub.2).sub.3 -- OH C.sub.18 H.sub.37 C.sub.18 H.sub.37 HBr
78-82 --(CH.sub.2).sub.3 -- OH C.sub.18 H.sub.37 C.sub.18 H.sub.37
-- 37-40 --(CH.sub.2).sub.3 -- OH C.sub.18 H.sub.37 C.sub.18
H.sub.37 -- 38-42 --(CH.sub.2).sub.6 -- OH C.sub.18 H.sub.37
C.sub.18 H.sub.37 -- (a wax) --(CH.sub.2).sub.2 -- CN.sup.(a)
C.sub.18 H.sub.37 C.sub.18 H.sub.37 -- 57-58 --(CH.sub.2).sub.2 --
CN C.sub.18 H.sub.37 C.sub.18 H.sub.37 HCl 73-74 --(CH.sub.2).sub.2
-- OH C.sub.18 H.sub.37 C.sub.18 H.sub.37 -- 35-37
--(CH.sub.2).sub.2 -- OH C.sub.18 H.sub.37 C.sub.18 H.sub.37 HBr
74-78 --(CH.sub.2).sub.2 -- OCOCH.sub.3.sup.(b) C.sub.18 H.sub.37
C.sub.18 H.sub.37 -- 32-35 --(CH.sub.2).sub.2 -- OC.sub.2 H.sub.5
C.sub.18 H.sub.37 C.sub.18 H.sub.37 -- <30 --(CH.sub.2).sub.3 --
OCONHC.sub.6 H.sub.5.sup.(b) C.sub.18 H.sub.37 C.sub.18 H.sub.37 --
197-198 --(CH.sub.2).sub.3 -- Br C.sub.18 H.sub.37 C.sub.18
H.sub.37 -- 116-119 --(CH.sub.2).sub.3 -- CHO C.sub.18 H.sub.37
C.sub.18 H.sub.37 -- 52-52.5 --(CH.sub.2).sub.3 --
OCOCH.sub.3.sup.(b) C.sub.18 H.sub.37 C.sub.18 H.sub.37 -- (a wax)
--(CH.sub.2).sub.2 -- CN.sup.(a) C.sub.18 H.sub.37 H -- 84-85
__________________________________________________________________________
.sup.(a) Prepared by cyanoethylation procedure of Vogel et al.,
J.C.S. 514-49 (1952). .sup.(b) The acyl and carbamyl derivatives
are prepared by the standard methods described by Shriner et al.,
"The Systematic Identification of Organic Compounds," John Wiley
& Sons, Inc., New York, 1956, pp. 212 and 211,
respectively.
EXAMPLE XIII
The procedure of Example XI is followed using the appropriate
reactants A--Y--NHR.sub.6 and R.sub.5 --Br to give the compounds
listed below: ##SPC37##
Y A R.sub.5 R.sub.6 ______________________________________
--(CH.sub.2).sub.3 -- CN CH.sub.3 C.sub.18 H.sub.37
--(CH.sub.2).sub.3 -- CN C.sub.6 H.sub.13 C.sub.16 H.sub.33
--(CH.sub.2).sub.2 -- OH C.sub.2 H.sub.5 C.sub.12 H.sub.25
--(CH.sub.2).sub.6 -- OH C.sub.2 H.sub.5 C.sub.12 H.sub.25
--(CH.sub.2).sub.6 -- Br C.sub.12 H.sub.25 C.sub.12 H.sub.25
--(CH.sub.2).sub.5 -- Br C.sub.14 H.sub.29 C.sub.14 H.sub.29
--(CH.sub.2).sub.5 -- OCOCH.sub.3 C.sub.12 H.sub.25 C.sub.12
H.sub.25 --(CH.sub.2).sub.5 -- OCOC.sub.3 H.sub.7 C.sub.18 H.sub.37
C.sub.18 H.sub.37 --(CH.sub.2).sub.3 -- OCH.sub.3 C.sub.16 H.sub.33
C.sub.16 H.sub.33 --(CH.sub.2).sub.3 -- OCH.sub.3 C.sub.12 H.sub.25
C.sub.12 H.sub.25 --(CH.sub.2).sub.4 -- OC.sub.4 H.sub.9 C.sub.10
H.sub.21 C.sub.10 H.sub.21 --(CH.sub. 2).sub.5 -- OCONHC.sub.6
H.sub.5 H C.sub.16 H.sub.33 --(CH.sub.2).sub.2 -- OCOCH.sub.2
CH.sub.2 COOH C.sub.14 H.sub.29 C.sub.14 H.sub.29
--(CH.sub.2).sub.2 -- OCOCH.sub.2 CH.sub.2 COOH C.sub.18 H.sub.37
C.sub.18 H.sub.37 --(CH.sub.2).sub.6 -- OCOCH.sub.2 CH.sub.2 COOH
C.sub.18 H.sub.37 C.sub.18 H.sub.37 --(CH.sub.2).sub.3 --
OCOC.sub.2 H.sub.5 C.sub.18 H.sub.37 C.sub.18 H.sub.37
--(CH.sub.2).sub.4 --OCOC.sub.2 H.sub.5 C.sub.18 H.sub.37 C.sub.18
H.sub.37 --(CH.sub.2).sub.2 -- OCOC.sub.2 H.sub.5 C.sub.18 H.sub.37
C.sub.18 H.sub.37 --(CH.sub.2).sub.3 -- OCOC.sub.15 H.sub.31
C.sub.18 H.sub.37 C.sub.18 H.sub.37 --(CH.sub.2).sub.3 --
OCOC.sub.15 H.sub.31 C.sub.12 H.sub.25 C.sub.12 H.sub.25
--(CH.sub.2).sub.2 -- COOCH.sub.3 C.sub.18 H.sub.37 C.sub.18
H.sub.37 --(CH.sub.2).sub.3 -- COOC.sub.15 H.sub.31 C.sub.18
H.sub.37 C.sub.18 H.sub.37 --(CH.sub.2).sub.3 -- COOC.sub.15
H.sub.31 C.sub.16 H.sub.33 C.sub.16 H.sub.33 --(CH.sub.2).sub.5 --
Cl C.sub.2 H.sub.5 C.sub.12 H.sub.25 --(CH.sub.2).sub.5 -- CN
C.sub.2 H.sub.5 C.sub.12 H.sub.25 --(CH.sub.2).sub.5 -- COOC.sub.2
H.sub.5 C.sub.12 H.sub.25 C.sub.12 H.sub.25 --(CH.sub.2).sub.4 --
COOC.sub.2 H.sub.5 C.sub.16 H.sub.33 C.sub.16 H.sub.33
--(CH.sub.2).sub.4 -- COOC.sub.9 H.sub.19 C.sub.16 H.sub.33
C.sub.16 H.sub.33 --(CH.sub.2).sub.8 -- OH C.sub.18 H.sub.37
C.sub.18 H.sub.37 -- (CH.sub.2).sub.8 -- Cl C.sub.18 H.sub.37
C.sub.18 H.sub.37 --(CH.sub.2).sub.8 -- CN C.sub.18 H.sub.37
C.sub.18 H.sub.37 --(CH.sub.2).sub.8 -- OC.sub.2 H.sub.5 C.sub.18
H.sub.37 C.sub.18 H.sub.37 ______________________________________
##SPC38##
A Y R.degree. R' R" ______________________________________ HO
--(CH.sub.2).sub.2 -- 4--OC.sub.18 H.sub.37 H H HO
--(CH.sub.2).sub.3 -- 4--OC.sub.18 H.sub.37 H H HO
--(CH.sub.2).sub.3 -- 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H
HO --(CH.sub.3).sub.6 -- 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13
H HO --(CH.sub.2).sub.3 -- 2--OCH.sub.3 4--OC.sub.12 H.sub.25
5--OCH.sub.3 HO --(CH.sub.2).sub.4 -- 2--OC.sub.6 H.sub.13
3--OC.sub.2 H.sub.5 H HO --(CH.sub.2).sub.3 -- 3--OC.sub.12
H.sub.25 4--OC.sub.2 H.sub.5 H HO --(CH.sub.2).sub.2 --
4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 HO --(CH.sub.2).sub.8
-- 4--OC.sub.8 H.sub.17 H H CN --(CH.sub.2).sub.2 -- 4--OC.sub.18
H.sub.37 H H CN --(CH.sub.2).sub. 2 -- 2--OCH.sub.3 4--OC.sub.12
H.sub.25 5--OCH.sub.3 CN --(CH.sub.2).sub.2 -- 2--OC.sub.6 H.sub.13
3--OC.sub.2 H.sub.5 H CN --(CH.sub.2).sub.5 -- 4--OC.sub.8 H.sub.17
H H Cl --(CH.sub.2).sub.3 -- 3--OC.sub.6 H.sub.13 4--OC.sub.6
H.sub.13 H Cl --(CH.sub.2).sub.6 -- 3--OC.sub.6 H.sub.13
4--OC.sub.6 H.sub.13 H Cl --(CH.sub.2).sub.3 -- 4--OC.sub.14
H.sub.29 H H Br --(CH.sub.2).sub.3 -- 4--OC.sub.14 H.sub.29 H H Br
--(CH.sub.2).sub.3 -- 2--OCH.sub.3 4-- OC.sub.12 H.sub.25
5--OCH.sub.2 Cl --(CH.sub.2).sub.3 -- 4--OC.sub.18 H.sub.37
2--CH.sub.3 6--CH.sub.3 OCOCH.sub.3 --(CH.sub.2).sub.2 --
4--OC.sub.18 H.sub.37 H H OCOC.sub.3 H.sub.7 --(CH.sub.2).sub.3 --
4--OC.sub.18 H.sub.37 H H OCOC.sub.15 H.sub.31 --(CH.sub.2).sub.3
-- 4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 OCO.sub.10
H.sub.21 --(CH.sub.2 H.sub.3 -- 2--OCH.sub.3 4--OC.sub.12 H.sub.25
5--OCH.sub.3 OCOC.sub.3 H.sub.7 --(CH.sub.2).sub.4 -- 2--OC.sub.6
H.sub.13 3--OC.sub.2 H.sub.5 H OCOC.sub.4 H.sub.9
--(CH.sub.2).sub.3 -- 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H
OCOC.sub.4 H.sub.9 --(CH.sub.2).sub.6 -- 3--OC.sub.6 H.sub.13
4--OC.sub.6 H.sub.13 H OCOC.sub.17 H.sub.35 --(CH.sub.2).sub.8 --
4--OC.sub.8 H.sub.17 H H COOC.sub.2 H.sub.5 --(CH.sub.2).sub.2 --
4--OC.sub.18 H.sub.37 H H COOCH.sub.3 --(CH.sub.2).sub.3
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H COOCH.sub.3
--(CH.sub.2).sub.6 -- 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H
COOH.sub.2 H.sub.5 --(CH.sub.2).sub.4 -- 2--OCH.sub.3 4--OC.sub.12
H.sub.25 5--OCH.sub.3 COOH.sub.2 H.sub.5 --(CH.sub.2).sub.13 --
4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 OCH.sub.3
--(CH.sub.2).sub.3 -- 4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3
OCH.sub.3 --(CH.sub.2).sub.3 -- 4--OC.sub.18 H.sub.37 H H OCH.sub.3
--(CH.sub.2).sub.3 -- 4--OC.sub.18 H.sub.37 H H OC.sub.6 H.sub.13
--(CH.sub.2).sub.3 -- 4--OC.sub.18 H.sub.37 H H OCH.sub.3
--(CH.sub.2).sub.3 -- 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H
OC.sub.10 H.sub.21 --(CH.sub.2).sub.3 -- 3--OC.sub.6 H.sub.13
4--OC.sub.6 H.sub.13 H OC.sub.17 H.sub.35 --(CH.sub.2).sub.3 --
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H O-- n--C.sub.4 H.sub.9
--(CH.sub.2).sub.3 -- 2--OCH.sub.3 4--OC.sub.12 H.sub.25
5--OCH.sub.3 OCONHC.sub.6 H.sub.5 --(CH.sub.2).sub.2 --
4--OC.sub.18 H.sub.37 H H OCONHC.sub.6 H.sub.5 --(CH.sub.2).sub.3
-- 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H OCONHC.sub.6 H.sub.5
--(CH.sub.2).sub.6 -- 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H
OCONHC.sub.6 H.sub.5 --(CH.sub.2).sub.4 -- 2--OCH.sub.2
4--OC.sub.12 H.sub.25 5--OCH.sub.3
______________________________________
EXAMPLE XIV
N,N-Dioctadecylsuccinamate
Dioctadecylamine (5.21 g., 0.01 mole) and succinic anhydride (0.50
g., 0.005 mole) are heated overnight at 105.degree.C. on an oil
bath. The mixture is poured over ice and the solid which forms
separated by filtration: 4.9 g.; m.p. 57.degree.-62.degree.C. It is
dissolved in chloroform (50 ml.) and the solution extracted with 6N
hydrochloric acid (3 .times. 50 ml.). (The solid which formed at
the interface is removed by filtration).
The chloroform phase is separated, washed with saturated aqueous
solution carbonate (3 .times. 50 ml.) and the emulsion which forms
allowed to separate overnight. The chloroform layer is separated,
dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to an oil.
Trituration of the oil with acetone produces a brown solid; 2.03
g.; m.p. 52.degree.-58.degree.C. Recrystallization from ethyl
acetate raises the melting point to 77.degree.-81.degree.C.
The following compounds are made from appropriate reactants
(anhydrides and amines) by this procedure: ##SPC39##
Y' R.sub.5 R.sub.6 ______________________________________ CH.sub.2
CH.sub.2 C.sub.16 H.sub.33 C.sub.16 H.sub.33 CH.sub.2 CH.sub.2
C.sub.16 H.sub.33 C.sub.16 H.sub.33 CH.sub.2 Ch.sub.2 CH.sub.3
C.sub.18 H.sub.37 (CH.sub.2).sub.3 C.sub.18 H.sub.37 C.sub.18
H.sub.37 (CH.sub.2).sub.3 C.sub.12 H.sub.25 C.sub.12 H.sub.25
(CH.sub.2).sub.3 C.sub.18 H.sub.37 H (CH.sub.2).sub.3 C.sub.12
H.sub.25 C.sub.12 H.sub.25 CH.sub.2 CH.sub.2 H C.sub.12 H.sub.25
CH.sub.2 CH.sub.2 H C.sub.16 H.sub.33 (CH.sub.2).sub.3 H C.sub.20
H.sub.41 ______________________________________ ##SPC40##
Y' R.degree. R" ______________________________________ CH.sub.2
CH.sub.2 4--OC.sub.18 H.sub.37 H H (CH.sub.2).sub.3 4--OC.sub.18
H.sub.37 H H (CH.sub.2).sub.3 3--OC.sub.6 H.sub.13 4--OC.sub.6
H.sub.13 H CH.sub.2 CH.sub.2 3--OC.sub.6 H.sub.13 4--OC.sub.6
H.sub.13 H CH.sub.2 CH.sub.2 3,4 -- O -- CH.sub.2 --O -- H CH.sub.2
CH.sub.2 4,5 -- O -- CH.sub.2 -- -- 2--C.sub.3 H.sub.7 CH.sub.2
CH.sub.2 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3
(CH.sub.2).sub.3 3,4 -- O -- CH.sub.2 -- O -- H (CH.sub.2).sub.3
4--OC.sub.8 H.sub.17 H H (CH.sub.2).sub.3 4--OC.sub.18 H.sub.37
2--CH.sub.3 6--CH.sub.3 CH.sub.2 CH.sub.2 4--OC.sub.18 H.sub.37
2--CH.sub.3 6--CH.sub.3 ______________________________________
EXAMPLE XV
N-(3-dodecyloxypropyl)diethanolamine and
N-(3-Dodecyloxypropyl)Monoethanolamine
A mixture of bromoethanol (2.50 g., 0.05 mole),
3-dodecyloxy-1-propylamine (2.43 g., 0.01 mole) and ethanol (20
ml.) is heated at reflux overnight. The solvent is removed by
evaporation, the residue slurried in hot water (20 ml.) and made
strongly alkaline with potassium hydroxide. The basic mixture is
extracted with ether (3 .times. 50 ml.), the ethereal extracts
dried (MgSO.sub.4) and evaporated. The crude product mixture is
purified by chromatography on alumina. Using ether as eluant
removes the least polar impurity; elution with methanol removes the
diethanolamine first, then the monoethanolamine derivative.
These two products appear as blue and yellow spots, respectively,
when subjected to thin layer chromatography on a silica plate with
methanol as eluant and iodoplatinic spray as developer.
The monoethanolamine derivatives boils at 160.degree.-166.degree.
C. at 0.3 mm. mercury.
The following compounds are prepared in like manner from approprite
reactants: A'--O--(CH.sub.2).sub.n --NH.sub.2 and Br--R.sub.5
##SPC41##
A' n R.sub.5 R.sub.6 Salt M.P. (.degree.C.)
______________________________________ C.sub.12 H.sub.25 2 CH.sub.3
CH.sub.3 CH.sub.3 I 165-7 C.sub.18 H.sub.37 3 CH.sub.2 H HI 210-I
C.sub.18 H.sub.37 3 CH.sub.2 CH.sub.2 OH H HBr
______________________________________
EXAMPLE XVI
N-(3-Dodecylthiopropyl)Diethanolamine
A mixture of 3-octadecylthiopropyl chloride (3.35 g., 0.01 mole),
diethanolamine (2.1 g., 0.02 mole) and benzyl alcohol (5 ml.) is
heated under reflux for one-half hour, then treated with an
ethanolic solution of sodium hydroxide (0.4 g., 0.01 mole) and
refluxed for 5 more minutes. The mixture is cooled, filtered and
the ehtanol removed by evaporation. The benzyl alcohol is then
removed by distillation in vacuo and the residue chromatographed on
silica using first ether then methanol as eluants. The desired
product is contained in the methanol eluate. It is isolated by
evaporation of the solvent, m.p. 53.degree.-54.degree. C. Its
hydrochloride salt melts at 65.degree.-66.degree. C.
In like manner, the following compounds are prepared from the
appropriate reactants: A'--S--(CH.sub.2).sub.n --Cl and H--NR.sub.5
R.sub.6 ##SPC42##
A' n R.sub.5 R.sub.6 Salt M.P. (.degree.C.)
__________________________________________________________________________
C.sub.18 H.sub.37 3 CH.sub.2 CH.sub.2 OH H -- C.sub.18 H.sub.37 3
CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5 H -- 155-7 C.sub.16 H.sub.33 3
CH.sub.2 CH.sub.2 OH H -- C.sub.16 H.sub.33 3 CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH HCl 129-30 C.sub.14 H.sub.29 3 CH.sub.2
CH.sub.2 OH CH.sub.2 CH.sub.2 OH -- 30-1 C.sub.14 H.sub.29 3
CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH HCl 72 (dec.) C.sub.16
H.sub.33 3 C.sub.2 H.sub.5 C.sub.2 H.sub.5 -- 175-8 (0.3 mm.)
C.sub.18 H.sub.37 3 C.sub.2 H.sub.5 C.sub.2 H.sub.5 -- 170-4 (0.2
mm.) C.sub.18 H.sub.37 2 C.sub.2 H.sub.5 C.sub.2 H.sub.5 -- 170-4
(0.2 mm.) C.sub.18 H.sub.37 2 C.sub.2 H.sub.5 C.sub.2 H.sub.5 HCl
102- 4 C.sub.18 H.sub.37 2 (Ch.sub.2).sub.3 N(C.sub.2
H.sub.5).sub.2 H 2HCl
__________________________________________________________________________
EXAMPLE XVII
Following the procedures of Examples XV and XVI the compounds
listed below are prepared from appropriate reactants: ##SPC43##
A n R.sub.5 R.sub.6 A n R.sub.5 R.sub.6
__________________________________________________________________________
CH.sub.3 O 2 C.sub.18 H.sub.37 C.sub.18 H.sub.37 C.sub.13 H.sub.25
O 3 C.sub.18 H.sub.37 H C.sub.12 H.sub.25 O 3 C.sub.18 H.sub.37
C.sub.18 H.sub.37 C.sub.6 H.sub.5 S 3 C.sub.10 H.sub.21 C.sub.10
H.sub.21 C.sub.2 H.sub.5 O 6 C.sub.18 H.sub.37 C.sub.18 H.sub.37
C.sub.18 H.sub.37 S 3 C.sub.18 H.sub.37 H C.sub.18 H.sub.37 O 3
C.sub.18 H.sub.37 C.sub.18 H.sub.37 C.sub.18 H.sub.37 S 3 C.sub.18
H.sub.37 C.sub.18 H.sub.37 C.sub.6 H.sub.13 O 3 C.sub.16 H.sub.33
C.sub.16 H.sub.33 C.sub.16 H.sub.33 S 2 C.sub.12 H.sub.25 C.sub.12
H.sub.25 C.sub.16 H.sub.33 S 2 H C.sub.12 H.sub.25 CH.sub.3 S 6
C.sub.18 H.sub.37 C.sub.18 H.sub.37
__________________________________________________________________________
##SPC44##
A n R.degree. R' R" ______________________________________ C.sub.18
H.sub.37 O 3 4--OC.sub.18 H.sub.37 H H C.sub.18 H.sub.37 O 3
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.18 H.sub.37 O 3
2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.18 H.sub.37 O
3 4,5 -- O -- CH.sub.2 -- O -- 2-- C.sub.3 H.sub.7 C.sub.18
H.sub.37 O 3 4--OCH.sub.18 H.sub.17 H H C.sub.18 H.sub.37 O 2
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.16 H.sub.33 O 2
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.16 H.sub.33 O 3
4--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.16 H.sub.33 O 3
4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 CH.sub.3 O 3
4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 C.sub.6 H.sub.13 O 3
4--OC.sub.18 H.sub. 37 2--CH.sub.3 6--CH.sub.3 C.sub.2 H.sub.5 O 3
3,4 -- O -- CH.sub.2 -- O -- H CH.sub.3 O 2 3,4 -- O -- CH.sub.2 --
O -- H C.sub.10 H.sub.21 O 3 2--OC.sub.6 H.sub.13 3--OC.sub.2
H.sub.5 H CH.sub.3 O 6 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H
C.sub.10 H.sub.21 O 5 4--OC.sub.18 H.sub.37 H H CH.sub.3 O 6
4--OC.sub.14 H.sub.29 H H C.sub.4 H.sub.9 S 6 4--OC.sub.14 H.sub.29
H H C.sub.12 H.sub.25 S 4 3--OC.sub.18 H.sub.37 H H C.sub.12
H.sub.25 S 4 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.10
H.sub.21 S 5 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H CH.sub.3 S
6 4--OC.sub.18 H.sub.37 H H C.sub.18 H.sub.37 S 3 4--OC.sub.18
H.sub.37 H H C.sub.18 H.sub.33 S 2 3,4 -- O -- CH.sub.2 --O -- H
C.sub.10 H.sub.21 S 4 4--OC.sub.8 H.sub.17 H H
______________________________________
EXAMPLE XVIII
N-(2-Dodecanoylthioethyl)Diethylamine
Decanoyl chloride (1.90 g., 0.01 mole) in ether (250 ml.) is added
to a mixture of diethylaminoethanoethiol (1.33 g., 0.01 mole) and
triethylamine (1.01 g., 0.01 mole) in ether (250 ml.) and the
reaction mixture stirred overnight at room temperature. The white
precipitate is filtered off and the filtrate evaporated in vacuo to
provide the product.
In like manner, N-(2-dodecanoyloxyethyl)diethylamine is prepared
from decanoyl chloride and diethylaminoethanol. It boils at
103.degree.-106.degree.C. at 0.05 mm. mercury.
The following compounds are likewise prepared from appropriate
reactants by this procedure: ##SPC45##
A" R.sub.5 R.sub.6 t ______________________________________
C.sub.17 H.sub.35 CO n--C.sub.4 H.sub.9 CH.sub.2 CH.sub.2 OH 3
C.sub.9 H.sub.19 CO C.sub.16 H.sub.33 C.sub.16 H.sub.33 5 C.sub.13
H.sub.27 CO CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH 2 C.sub.11
H.sub.23 CO C.sub.18 H.sub.37 C.sub.18 H.sub.37 2 C.sub.2 H.sub.5
CO C.sub.20 H.sub.41 C.sub.20 H.sub.41 2 C.sub.11 H.sub.23 CO
C.sub.20 H.sub.41 C.sub.20 H.sub.41 2 C.sub.11 H.sub.23 CO
(CH.sub.2).sub.4 OH (CH.sub.2).sub.4 OH 3 C.sub.11 H.sub.23 CO
C.sub.18 H.sub.37 C.sub.18 H.sub.37 6
______________________________________ ##SPC46##
A" R.degree. R' R" t ______________________________________
CH.sub.3 CO 4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 2
CH.sub.3 CO 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H 3 CH.sub.3
CO 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 3 CH.sub.3 CO
4,5 -- O -- CH.sub.2 -- O -- 2--C.sub.3 H.sub.7 6 C.sub.3 H.sub.7
CO 4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 2 C.sub.3 H.sub.7
CO 4--OC.sub.14 H.sub.29 H H 3 C.sub.3 H.sub.7 CO 3--OC.sub.6
H.sub.13 4--OC.sub.6 H.sub.13 H 6 C.sub.17 H.sub.35 CO 3--OC.sub.6
H.sub.13 4--OC.sub.6 H.sub.13 H 6 C.sub.17 H.sub.35 CO 3--OC.sub.6
H.sub.13 4--OC.sub.6 H.sub.13 H 3 C.sub.17 H.sub.35 CO 4--OC.sub.14
H.sub.29 H H 3 C.sub.17 H.sub.35 CO 4,5 -- O -- CH.sub.2 -- O --
2--C.sub.3 H.sub.7 3 C.sub.12 H.sub.25 CO 4--OC.sub.18 H.sub.37 H H
3 C.sub.7 H.sub.15 CO 4--OC.sub.18 H.sub.37 H H 3 CH.sub.3 CO
4--OC.sub.18 H.sub.37 H H 3 C.sub.12 H.sub.25 CO 4--OC.sub.18
H.sub.37 H H 6 C.sub.2 H.sub.5 CO 4--OC.sub.18 H.sub.37 H H 6
C.sub.5 H.sub.11 CO 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H 6
C.sub.11 H.sub.23 CO 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H 6
CH.sub.3 CO 3,4 -- O -- CH.sub.2 -- O -- H 6 C.sub.9 H.sub.19 CO
3,4 -- O -- CH.sub.2 -- O -- H 6 C.sub.7 H.sub.15 CO 4--OC.sub.18
H.sub.37 2--CH.sub.3 6--CH.sub.3 6 C.sub.13 H.sub.27 CO
4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 3
______________________________________
EXAMPLE XIX
Ethyl 4-Dioctadecylaminobutyrate
A solution of dioctadecylamine (5.2 g., 0.01 mole), ethyl
4-bromobutyrate (1.95 g., 0.01 mole) and toluene (50 ml.) is heated
at reflux for sixteen hours, then cooled and concentrated in vacuo
to a semi-solid oil. The oil is triturated with ethylacetate,
filtered, and the filtrate washed with water, then dried (Na.sub.2
SO.sub.4). Removal of the solvent gives the product as an oil (3.7
g.).
It is purified by chromatography on silica gel and elution of the
column first with benzene, then with benzene containing 20 percent
ethylacetate. The residue obtained by evaporation of the benzene-20
percent ethylacetate solvent is taken up in ethylacetate and
converted to the hydrochloride salt by bubbling dry hydrogen
chloride through the solution. Concentration of the mixture in
vacuo provides a crystalline material; m.p.
98.degree.-101.degree.C.
Substitution of ethyl 4-bromobutyrate by the appropriate lower
alkyl .omega.-bromoalkanoate in the above procedure produces the
following compounds: ##SPC47##
A Y R.sub.5 R.sub.6 Salt M.P.(.degree.C.)
______________________________________ COOC.sub.2 H.sub.5
--CH.sub.2 -- C.sub.18 H.sub.37 C.sub.18 H.sub.37 -- 40 COOC.sub.2
H.sub.5 --(CH.sub.2).sub.4 -- C.sub.18 H.sub.37 C.sub.18 H.sub.37
HCl 46-48 COOC.sub.2 H.sub.5 --(CH.sub.2).sub.2 -- C.sub.18
H.sub.37 C.sub.18 H.sub.37 HCl 52-53
______________________________________
EXAMPLE XX
1-(N,N-Dioctadecylcarbamyl)-4-Methylpiperazine
A mixture of 1-methylpiperazine (5 ml.),
N,N-dioctadecylcarbamylchloride (5.0 g.) and benzene (50 ml.) is
refluxed and stirred for 3 hours. The white precipitate of
1-methylpiperazine hydrochloride is removed by filtration and the
filtrate concentrated in vacuo to a yellow oil (4.5 g.). The oil is
then charged on a silica gel pad and eluted with benzene in 50 ml.
fractions. Fractions 10-15 are combined, a large volume of methanol
added and the white crystalline material which separates filtered
and dried, m.p. 46.degree.-47.degree. C. (1.45 g.).
The following compounds are prepared from the appropriate reactants
(R.sub.7 R.sub.8 NCOCl and H-Z): ##SPC48##
R.sub.7 R.sub.8 Z ______________________________________ C.sub.12
H.sub.25 C.sub.12 H.sub.25 butylpiperazino C.sub.12 H.sub.25
C.sub.12 H.sub.25 piperidino C.sub.12 H.sub.25 C.sub.12 H.sub.25
morpholino C.sub.18 H.sub.37 CH.sub.3 methylpiperazino C.sub.18
H.sub.37 CH.sub.3 morpholino C.sub.18 H.sub.37 C.sub.18 H.sub.37
hydroxyethylpiperazino C.sub.12 H.sub.25 C.sub.12 H.sub.25
hydroxyethylpiperazino C.sub.18 H.sub.37 CH.sub.3
hydroxyethylpiperazino C.sub.18 H.sub.37 C.sub.18 H.sub.37
piperazino C.sub.12 H.sub.25 C.sub.12 H.sub.25 piperazino C.sub.18
H.sub.37 CH.sub.3 piperazino ______________________________________
##SPC49##
R.degree. R' R" Z ______________________________________
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H piperidino 3--OC.sub.6
H.sub.13 4--OC.sub.6 H.sub.13 H morpholino 3--OC.sub.6 H.sub.13
4--OC.sub.6 H.sub.13 H piperazino 4--OC.sub.18 H.sub.37 H H
piperazino 4--OC.sub.18 H.sub.37 H H morpholino 4--OC.sub.18
H.sub.37 H H N-methylpiperazino 4--OC.sub.18 H.sub.37 2--CH.sub.3
6--CH.sub.3 N-methylpiperazino 4--OC.sub.18 H.sub.37 2--CH.sub.3
6--CH.sub.3 N-butylpiperazino 3,4 -- O -- CH.sub.2 -- O -- H
morpholino 3,4 -- O-- CH.sub.2 -- O -- H
N-(2-hydroxyethyl)piperazino 4--OC.sub.8 H.sub.17 H H
N-(2-hydroxyethyl)piperazino 2--OCH.sub.3 4--OC.sub.12 H.sub.25
5--OCH.sub.3 N-(2-hydroxyethyl)piperazino 2--OCH.sub.3 4--OC.sub.12
H.sub.25 5--OCH.sub.3 piperidino 2--OCh.sub.3 4--OC.sub.12 H.sub.25
5--OCH.sub.3 N-isopropylpiperazino
______________________________________
EXAMPLE XXI
N,N-Dioctadecyl-N',N'
-bis(2Hydroxyethyl)-1,3-Propanediamine-N,N'-Dioxide
To a solution of N,N-dioctadecyl-N',N' -bis(
2-hydroxyethyl)-1,3-propanediamine (3.34 g., 5 mM.) in chloroform
(20 ml.) is added m-chloroperbenzoic acid (2.76 g., 12 mM. of 86
percent material) in chloroform (20 ml.) dropwise. The temperature
is maintained at 28.degree. C. throughout the addition and for 1.5
hours thereafter. The mixture is then diluted with chloroform (20
ml.) and the solution washed first with 1N aqueous sodium hydroxide
then with brine. It is then dried (Na.sub.2 SO.sub.4) and
concentrated to an oil (2.5 g.).
The hydrochloride salt is prepared by the procedure of Example V;
m.p. 89.degree.-94.degree. C., 114.degree. c. (1.65 g. from 2.5 g.
of oil).
Dissolution of the hydrochloride salt in chloroform and
neutralization with aqueous sodium hydroxide regenerates the free
base. It is recovered by drying the chloroform layer (Na.sub.2
SO.sub.4) and evaporation of the solvent. Recrystallization from
chloroform-ethylacetate provides the pure base; m.p.
95.degree.-99.degree. C.
The products of the preceding examples are converted to their
N-oxide derivatives in like manner.
EXAMPLE XXII
N,N-Dioctadecyl-N',N' -bis(2-Hydroxyethyl)-1,3-Propanediamine
N-Methonium Iodide
Methyl iodide (568 mg., 4.0 mM.) is added all at once to a solution
of N,N-dioctadecyl-N',N' -bis(2-hydroxyethyl)-1,3-propanediamine
(1.334 g., 2.0 mM.) in methylene chloride (10 ml.) which is cooled
in an ice-bath. The mixture is stirred and allowed over a 4-hour
period to warm to room temperature, then stirred at room
temperature overnight. The solid residue obtained by removal of the
chloroform is recrystallized from ethylacetate; 1.35 g., m.p.
120.degree.-122.degree. C.
EXAMPLE XXIII
Repetition of the procedures of Example III-B and C, but using the
appropriate alkanediamine and acid chloride reactants provides the
following compounds: ##SPC50##
R.sub.1 R.sub.2 n R.sub.3 R.sub.4
______________________________________ C.sub.18 H.sub.37 C.sub.18
H.sub.37 2 H H C.sub.18 H.sub.37 C.sub.38 H.sub.37 2 C.sub.4
H.sub.9 H C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 H (CH.sub.2).sub.4
OH C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 CH.sub.3 (CH.sub.2).sub.4
OH C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 H (CH.sub.2).sub.5 OH
C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 C.sub.2 H.sub.5
(CH.sub.2).sub.5 OH C.sub.18 H.sub.37 C.sub.18 H.sub.37 2 H
(CH.sub.2).sub.3 OH C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 H
n--C.sub.3 H.sub.7 C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 H
n--C.sub.9 H.sub.19 C.sub.18 H.sub.37 C.sub.18 H.sub.37 3 C.sub.2
H.sub.5 n--C.sub.9 H.sub.19
______________________________________
EXAMPLE XXIV
1-Dodecyl-4-(2-Hydroxyethyl)Piperazine
A solution of dodecylbromide (12.45 g., 0.05 mole) in ethanol (100
ml.) is added to a solution of 1-(2-hydroxyethyl)piperazine (6.5
g., 0.05 mole) in ethanol (100 ml.) and the mixture stirred and
refluxed overnight. Evaporation of the solvent gives the
hydrobromide salt which is recrystallized from acetone containing a
small amount of ethanol. The white crystalline salt melts at
99.degree.-103.degree. C.
The free base is obtained by making an aqueous solution of the
hydrobromide salt strongly alkaline with sodium hydroxide and
extracting the base with chloroform. The chloroform solution is
washed with water, dried (Na.sub.2 SO.sub.4) and evaporated. The
white solid which remains melts at 65.degree.-67.degree. C.
By means of the above procedure, the following compounds are
prepared but using the appropriate alkyl bromide and
1-(hydroxyalkyl)piperazine reactants: ##SPC51##
R.sub.8 p + 1 n M.P. (degrees C.)
______________________________________ C.sub.12 H.sub.25 3 0 55-7
C.sub.12 H.sub.25 3 0 95-8 (HBr salt) -C.sub.18 H.sub.37 2 0 108-1
0 (HBr salt) C.sub.18 H.sub.37 3 0 111-12 (HBr salt) C.sub.12
H.sub.25 6 0 C.sub.20 H.sub.41 3 0 C.sub.18 H.sub.37 5 0 C.sub.18
H.sub.37 2 1 C.sub.12 H.sub.25 3 2
______________________________________ ##SPC52##
EXAMPLE XXV
N,N-Bis(3,4-Dihexoxybenzyl)-N',N'-Bis(2-Hydroxyethyl)-1,3-Propanediamine
A mixture of 3,4-dihexoxybenzaldehyde (15.3 g., 0.05 M), sodium
borohydride (1.85 g., 0.05 M) and ethanol (350 ml.) is stirred at
room temperature for 1 hour and then concentrated in vacuo. The
residue is dissolved in chloroform (500 ml.), the solution washed
with water (4 .times.100 ml.), dried (Na.sub.2 SO.sub.4) and
evaporated under reduced pressure to give 3,4-dihexoxybenzyl
alcohol (15.0 g.) as a pale yellow oil.
Thionyl chloride (140 ml.) and 3,4-dihexoxybenzyl alcohol (14.0 g.)
are combined and stirred at room temperature for one-half hour, at
which time gas evolution ceases. The mixture is refluxed for
one-half hour and then distilled to remove thionyl chloride (about
100 ml.). The residue is poured into ice-water (250 g. of each) and
the aqueous solution extracted with chloroform (3 .times.100 ml.).
The chloroform extracts are combined, washed successively with
saturated sodium bicarbonate solution (2 .times.100 ml.) and water
(3 .times.100 ml.). It is then dried (Na.sub.2 SO.sub.4) and
concentrated to give 3,4-dihexoxybenzyl chloride as a brown oil
(11.7 g.).
A mixture of N-(3-aminopropyl)diethanolamine (11.3 g., 7 mM),
3,4-dihexoxybenzyl chloride (4.8 g., 15 mM) and potassium carbonate
(2.07 g., 15 mM) is stirred at room temperature for 16 hours and
then at 130.degree. C. for 2 hours. It is cooled, benzene (50 ml.)
added and the mixture filtered. The benzene filtrate is charged
onto a column and the column eluted with benzene (75 ml.
fractions). The first 11 fractions collected are discarded. The
column is then eluted with benzene containing 10% ethanol. The
second and third fractions are collected, evaporated and the
residue dissolved in methanol. The dihydrochloride salt is prepared
by bubbling hydrogen chloride into the solution and then
evaporating to a waxy solid (400 mg.).
In like manner, the following
N,N-bis(alkoxybenzyl)-N',N'-bis(2-hydroxyethyl)-1,3-propanediamines
are prepared from appropriate reactants. ##SPC53##
Di--HCl R' R.degree. Base M.P. (.degree.C.)
______________________________________ H 4--C.sub.18 H.sub.37 O --
>200 H 4--C.sub.12 H.sub.25 O oil -- H 4--C.sub.6 H.sub.13 O oil
-- 3--C.sub.12 H.sub.25 O 4--C.sub.12 H.sub.25 O -- 202-4
______________________________________
EXAMPLE XXVI
N,N-Bis(3,4-Dihexoxybenzyl)-1,3-Propanediamine
Raney nickel (500 mg.), 3,4-dihexoxybenzaldehyde (6.12 g., 0.02 M)
and ammonia (3.0 g., 0.177 M) in ethanol (100 ml.) are charged into
a Paar shaker and hydrogenated at 40.degree. C. and an initial
pressure of 51 psi. When approximately 20 psi drop in hydrogen
pressure is observed, about 24 hours, the contents are removed and
filtered. The filtrate is concentrated in vacuo to an amber oil
which is dissolved in ethyl acetate (50 ml.). The solution is
treated with ethyl acetate saturated with hydrogen chloride (100
ml.) and the resulting white hydrochloride salt collected; 3.7 g.,
m.p. 205.degree.-206.degree. C. The salt is then partitioned
between chloroform (100 ml.) and saturated sodium bicarbonate
solution (50 ml.). The chloroform phase is separated, washed with
water (50 ml.), dried (Na.sub.2 SO.sub.4) and concentrated to give
3,4-dihexoxybenzylamine as an oil; 3.2 g., 52.1% yield.
A solution of 3,4-dihexoxybenzylamine (2.0 g., 6.52 mM),
3,4-dihexoxybenzaldehyde (2.0 g., 6.52 mM), benzene (75 ml.) and
p-toluenesulfonic acid (200 mg.) is refluxed with stirring in
apparatus equipped with a Dean-Stark collector for 16 hours. It is
then cooled and concentrated in vacuo to an oil which crystallizes
upon standing: 4.0 g. of the Schiff base.
The Schiff base is reduced by treatment with sodium borohydride
(0.378 g.) in ethanol (50 ml. per 2.0 g. of Schiff base) at room
temperature for 20 hours. The mixture is concentrated under reduced
pressure to a solid which is taken up in methanol. Hydrogen
chloride gas is bubbled into the solution, water (50 ml.) added and
the salt filtered, washed with water and air dried. The dry salt is
dissolved in warm methanol (75 ml.), saturated aqueous sodium
bicarbonate (50 ml.) and water (50 ml.) added. The solid is
filtered off, washed with water and air dried. It is then dissolved
in chloroform (75 ml.), the solution washed with water (50 ml.),
dried (Na.sub.2 SO.sub.4) and concentrated to give
bis(3,4-dihexoxybenzyl)amine as an oil; 1.4 g., 69.8 % yield.
Acrylonitrile (15 ml.) and bis (3,4-dihexoxybenzyl)amine are
refluxed together for 18 hours. The mixture is then cooled and
concentrated in vacuo to an oil: 1.2 g.
The cyanoethyl derivative (1.2 g.), Raney nickel (500 mg.), ammonia
(1.0 g.) and ethanol (75 ml.) are charged into a Paar shaker and
hydrogenated at room temperature and an initial pressure of 50 psi.
When uptake of hydrogen is complete, the contents are removed
filtered and concentrated to give the title produce as an oil (1.02
g.).
The dihydrochloride salt is formed by dissolving the product in
ether and bubbling hydrogen chloride into the solution. Removal of
the ether under reduced pressure gives the salt.
Similarly, N,N-bis(3,4-diisopropoxybenzyl)-1,3-propanediamine is
prepared by substituting 3,4-diisopropoxybenzaldehyde for
3,4-dihexoxybenzaldehyde. Its dihydrochloride salt metls at
65.degree.-68.degree. C.
EXAMPLE XXVII
The following N,N-bis (alkoxybenzyl)-.alpha.,.omega.-alkanediamine
derivatives are prepared from appropriate reactants by the
procedures of Examples XXV, XXVI and XI. ##SPC54##
R.degree. R' R" X m X' R.sub.3 R.sub.4
__________________________________________________________________________
2--OC.sub.3 H.sub.7 3--OC.sub.2 H.sub.5 H -- O --CH.sub.2 CH.sub.2
-- CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH 3--OCH.sub.3
4--OC.sub.16 H.sub.33 H -- O --(CH.sub.2).sub.3 -- CH.sub.2
CH.sub.2 OH CH.sub.2 CH.sub.2 OH 4--OC.sub.16 H.sub.33 H H -- 0
--(CH.sub.2).sub.4 -- CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH
3--OC.sub.12 H.sub.25 4--OC.sub.12 H.sub.25 H -- O
--(CH.sub.2).sub.3 -- C.sub.6 H.sub.13 C.sub.6 H.sub.13
3--OC.sub.12 H.sub.25 4--OC.sub.12 H.sub.25 H -- O
--(CH.sub.2).sub.3 -- C.sub.18 H.sub.37 C.sub.18 H.sub.37
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H -- O --(CH.sub.2).sub.6
-- CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH 4--OC.sub.18 H.sub.37 H H
-- O --(CH.sub.2).sub.3 -- (CH.sub.2).sub.6 OH (CH.sub.2).sub.6 OH
3--OCH.sub.3 4--OC.sub.16 H.sub.33 H -- O --(CH.sub.2).sub.2 --
C.sub.20 H.sub.41 H 2--OC.sub.2 H.sub.5 4--OC.sub.2 H.sub.5
5--C.sub.6 H.sub.13 -- O --(CH.sub.2).sub.6 -- C.sub.10 H.sub.21
C.sub.10 H.sub.21 4--OC.sub.8 H.sub.17 H H -- O --(CH.sub.2).sub.3
-- CH.sub.2 --CH=CH.sub.2 CH.sub.2 --CH=CH.sub.2 4--OC.sub.8
H.sub.17 H H --CH.sub.2 CH.sub.2 -- 1 --CH.sub.2 CH.sub.2 --
CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH 4--OC.sub.18 H.sub.37 H H
--(CH.sub.2).sub.3 -- 1 --(CH.sub.2).sub.3 -- CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H
--(CH.sub.2).sub.4 -- 1 --(CH.sub.2).sub.4 -- CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH 2--OC.sub.2 H.sub.5 4--OC.sub.2 H.sub.5
5--C.sub.2 H.sub.5 --(CH.sub.2).sub.3 -- 1 --(CH.sub.2).sub.3 --
C.sub.18 H.sub.37 C.sub.18 H.sub.37 2--CH.sub.3 4--OC.sub.18
H.sub.37 6--CH.sub.3 --CH.sub.2 CH.sub.2 -- 1 --CH.sub.2 CH.sub.2
-- (CH.sub.2).sub.4 OH (CH.sub. 2).sub.4 OH 2--OCH.sub.3
4--OC.sub.12 H.sub.25 6--OCH.sub.3 -- 0 --(CH.sub.2).sub.3 --
CH.sub.2 CHOHCH.sub.2 OH CH.sub.2 CHOHCH.sub.2 OH 4--OC.sub.12
H.sub.25 3--OC.sub.12 H.sub.25 H -- 0 --(CH.sub.2).sub.3 --
CH.sub.2 CHOHCH.sub.2 OH CH.sub.2 CHOHCH.sub.2 OH 4--OC.sub.18
H.sub.37 H H -- 0 --(CH.sub.2).sub.3 -- H C.sub.7 H.sub.15
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H --(CH.sub.2).sub.3 -- 1
--(CH.sub.2).sub.3 -- CH.sub.2 CHOHCH.sub.3 CH.sub.2 CHOHCH.sub.3
4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 -- 0
--(CH.sub.2).sub.3 -- CH.sub.2 COOCH.sub.3 CH.sub.2 COOCH.sub.3
4--OC.sub.16 H.sub.33 H H -- 0 --(CH.sub.2).sub.2 -- CH.sub.2
CH.sub.2 OC.sub.12 H.sub.25 H 2--O--i--C.sub.5 H.sub.11 3--OC.sub.2
H.sub.5 H --(CH.sub.2).sub.2 -- 1 --(CH.sub. 2).sub.2 -- C.sub.18
H.sub.37 CH.sub.2 --CH=CH.sub.2 4--OC.sub.18 H.sub.37 H H
--(CH.sub.2).sub.2 -- 1 --(CH.sub.2).sub.2 -- CH.sub.2
--CH=CH.sub.2 CH.sub.2 --CH=CH.sub.2 3--OC.sub.6 H.sub.13
4--OC.sub.6 H.sub.13 H -- 0 --(CH.sub.2).sub.6 -- H H 4--OC.sub.18
H.sub.37 H H --(CH.sub.2).sub.2 -- 1 --(CH.sub.2).sub.2 -- H H
2--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 5--OC.sub.6 H.sub.13 -- 0
--(CH.sub.2).sub.3 -- CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH
2--OCH.sub.3 4--OC.sub.18 H.sub.37 5--OCH.sub.3 -- 0
--(CH.sub.2).sub.4 -- C.sub.8 H.sub.17 C.sub.8 H.sub.17
2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 -- 0
--(CH.sub.2).sub.3 -- H H 4--OC.sub.14 H.sub.29 H H -- 0
--(CH.sub.2).sub.2 -- H H 2--OC.sub.6 H.sub.13 3--OC.sub.2 H.sub.5
H -- 0 --(CH.sub.2).sub.3 -- H H 3--OC.sub.12 H.sub.25 4--OC.sub.2
H.sub.5 H -- 0 --(CH.sub.2).sub.6 -- H H 4--OC.sub.18 H.sub.37 H H
-- 0 --(CH.sub.2).sub.3 -- H H 4--OC.sub.8 H.sub.17 H H -- 0
--(CH.sub.2).sub.3 -- H H 4--OC.sub.8 H.sub.17 H H -- 0
--(CH.sub.2).sub.3 -- CH.sub.2 CH(OCH.sub.3).sub.2 CH.sub.2
--CH=CH.sub.2 4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3 -- 0
--(CH.sub.2).sub.3 -- H H 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13
H --CO-- 1 --(CH.sub.2).sub.3 -- CH.sub.2 CH.sub.2 OH CH.sub.2
CH.sub.2 OH 4--OC.sub.18 H.sub.37 H H --CO-- 1 --(CH.sub.2).sub.3
-- (CH.sub.2).sub.3 OH (CH.sub.2).sub.3 OH 3--OC.sub.6 H.sub.13
4--OC.sub.6 H.sub.13 H --CO-- 1 --(CH.sub.2).sub.5 -- CH.sub.2
CH.sub.2 OH CH.sub.2 CH.sub.2 OH 4,5 -- O -- CH.sub.2 -- P --
2--C.sub.3 H.sub.7 --CO-- 1 --(CH.sub.2).sub.6 -- (CH.sub.2).sub.8
OH (CH.sub.2).sub.8 OH 4--OC.sub.14 H.sub.29 H H --CO-- 1
--(CH.sub.2).sub.3 -- CH.sub.2 CH.sub.2 OC.sub.4 H.sub.9 CH.sub.2
CH.sub.2 OC.sub.4 H.sub.9 2--OC.sub.6 H.sub.13 3--OC.sub.2 H.sub.5
H --CO-- 1 --(CH.sub.2).sub.3 -- CH.sub.2 COOCH.sub.3 CH.sub.2
COOCH.sub.3 4--OC.sub.8 H.sub.17 H H --CO-- 1 --(CH.sub.2).sub.3 --
CH.sub.2 --CH=CH.sub.2 CH.sub.2 --CH=CH.sub.2 3--OCH.sub.3
4--OC.sub.6 H.sub.13 5--OCH.sub.3 --CO-- 1 --(CH.sub.2).sub.3 --
CH.sub.2 COOC.sub.3 H.sub.7 CH.sub.2 COOC.sub.3 H.sub.7 3--
OC.sub.12 H.sub.25 4--OC.sub.12 H.sub.25 H --CO-- 1
--(CH.sub.2).sub.3 -- (CH.sub.2).sub.6 OH (CH.sub.2).sub.6 OH
4--OC.sub.8 H.sub.17 H H --CO-- 1 --(CH.sub.2).sub.3 -- CH.sub.2
CHOHCH.sub.3 CH.sub.2 CHOHCH.sub.3 4--OC.sub.8 H.sub.17 H H --CO--
1 --(CH.sub.2).sub.5 -- (CH.sub.2).sub.3 OH (CH.sub.2).sub.3 OH
4--OC.sub.8 H.sub.17 H H --(CH.sub.2).sub.3 -- 1 --CO-- CH.sub.2
CH.sub.2 OH CH.sub.2 CH.sub.2 OH 4--OC.sub.8 H.sub.17 H H
--(CH.sub.2).sub.3 -- 1 --CO-- C.sub.6 H.sub.13 C.sub.6 H.sub.13
4--OC.sub.14 H.sub.29 H H --(CH.sub.2).sub.2 -- 1 --CO-- CH.sub.2
CH.sub.2 OC.sub.4 H.sub.9 CH.sub.2 CH.sub.2 OC.sub.4 H.sub.9
4--OC.sub.14 H.sub.29 H H --(CH.sub.2).sub.2 -- 1 --CO-- CH.sub.2
--CH=CH.sub.2 CH.sub.2 -- CH=CH.sub.2 4--OC.sub.18 H.sub.37 H H
--(CH.sub.2).sub.3 -- 1 --CO-- CH.sub.2 COOCH.sub.3 CH.sub.2
COOCH.sub.3 3--OC.sub.12 H.sub.25
4--OC.sub.2 H.sub.5 H --(CH.sub.2).sub.6 -- 1 --CO-- CH.sub.2
CHOHCH.sub.3 CH.sub.2 CHOHCH.sub.3 2--OC.sub.6 H.sub.13 4--OC.sub.6
H.sub.13 5--OC.sub.6 H.sub.13 --(CH.sub.2).sub.3 -- 1 --CO--
(CH.sub.2).sub.3 OH (CH.sub.2).sub.3 OH 4--OC.sub.18 H.sub.37 H H
-- 0 --(CH.sub.2).sub.2 -- --CH.sub.2 CH.sub.2 --O-- CH.sub.2
CH.sub.2 -- 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H -- 0
--(CH.sub.2).sub.2 -- --CH.sub.2 CH.sub.2 --O-- CH.sub.2 CH.sub.2
-- 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 -- 0
--(CH.sub.2).sub.2 -- --CH.sub.2 CH.sub.2 --O-- CH.sub.2 CH.sub.2
-- 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H -- 0 3 --CH.sub.2
CH.sub.2 --O-- CH.sub.2 CH.sub.2
__________________________________________________________________________
-- The compounds of the above tabulation wherein R.sub.3 and
R.sub.4 are hydroxyalkyl groups are converted to various
derivatives by the procedure of Examples VIII - X. In this manner,
the hydroxy groups are converted to --OCH.sub.2 CH.sub.2 COOH,
--OCONHC.sub.6 H.sub.5, --OCOCH.sub.3 and --OCOC.sub.15
H.sub.31.
EXAMPLE XXVIII
1-(Dioctadecylamino)methyl-4-[Bis-(2-Hydroxyethyl)Aminomethyl]Benzene
Dioctadecylamine (26.0 g., 0.05 M), .alpha.-bromo-p-tolunitrile
(4.9 g., 0.025 M) and chloroform (500 ml.) are stirred at room
temperature for 24 hours. The precipitate of dioctadecylamine
hydrobromide is filtered off and the filtrate concentrated under
reduced pressure. The residue is slurried in methanol, filtered,
and evaporated to give 1-(dioctadecylamino)methyl-4-cyanobenzene
(15.5 g., 97.5% yield).
The nitrile (15 g.), ethylene dichloride (200 ml. ), methanol (50
ml.) and water (20 ml.) are combined and stirred at room
temperature. Hydrogen chloride gas is bubbled into the mixture for
3 hours after which the yellow solution is refluxed for 3 hours.
Methanol (50 ml.) and water (10 ml.) are added and hydrogen
chloride bubbled into the mixture for 1 hour and refluxing
continued for 14 hours. Methanol (10 ml.) and water (2 ml.) are
added and hydrogen chloride bubbled in for 1 hour. The mixture is
refluxed for 4 hours, cooled to room temperature and made alkaline
by addition of saturated aqueous sodium bicarbonate solution. The
ethylene dichloride phase is separated and the aqueous phase
extracted with chloroform (2 .times. 100 ml.). The combined organic
solutions are washed with water (100 ml.), dried (Na.sub.2
SO.sub.4) and evaporated to give
1-(dioctadecylamino)methyl-4-carbomethoxy benzene (14.0 g., 73.6%
yield).
A mixture of the thus produced ester (12.5 g., 18.7 mM), sodium
dihydro bis-(2-methoxyethoxy)aluminate (11.0 g. of 70% reagent,
37.5 mM) and benzene (300 ml.) is stirred at reflux for 24 hours.
The mixture is cooled, aqueous sodium hydroxide (50 ml. of 10%
solution) added and the mixture thoroughly stirred. The benzene
layer is separated, washed with water (100 ml.), dried (Na.sub.2
SO.sub.4) and concentrated in vacuo to give the corresponding
alcohol as a semi-solid (9.68 g., 80.8%).
Thionyl chloride (90 ml.) and the alcohol produced above (9.6 g.)
are mixed and refluxed for 1 hour. The mixture is poured into
ice-water (150 g. each of ice and water) and the precipitate which
forms filtered off. It is dissolved in chloroform, the solution
washed with saturated aqueous sodium carbonate until the wash had
pH 8.0, and then with water (2 .times. 100 ml.). It is dried
(Na.sub.2 SO.sub.4) and concentrated to give
1-(dioctadecylamino)methyl-4-chloromethyl benzene as an amber oil
(8.3 g.). The residue is taken up in benzene and purified by
chromatography on silica gel using benzene, benzene-10% ethanol,
ethanol, and ethanol-methanol as successive eluents. The ethanol
and ethanol-methanol eluates are combined and concentrated to give
4.58 g. of product.
A solution of the chloromethyl compound (2.1 g., 3.2 mM),
diethanolamine (1.3 g., 12.8 mM), and ethanol (50 ml.) is stirred
at reflux for 18 hours. It is cooled and concentrated in vacuo to
an oil. The oil is taken up to chloroform (50 ml.), the solution
washed with water (2 .times. 50 ml.), dried with anhydrous sodium
sulfate and evaporated to an oil, 2.3 g. It is purified by
adsorption on a dry column of silica gel and elution with ethyl
acetate. Concentration gives the title compound as a solid; 0.44
g., m.p. 49.degree.-50.degree. C.
In like manner, but using 2-amino-2-(hydroxymethyl)-1,3-propanediol
in place of diethanolamine produces
1-(dioctadecylamino)methyl-4-[2-(2-hydroxymethyl)-1,3-dihydroxypropylamino
methyl]benzene.
Repetition of this procedure but using didodecylamine in place of
dioctadecylamine produces
1-(didodecylamino)methyl-4-[bis(2-hydroxyethyl)-amino
methyl]benzene. Its dihydrochloride salt prepared according to the
procedure of Example XXV melts at 199.degree.-204.degree. C.
EXAMPLE XXIX
The following compounds are prepared from appropriate reactants by
the procedure of Example XXVIII. The column headed "Isomer" refers
to the phenyl-enedimethylene moiety substitutents. ##SPC55##
Isomer R.sub.1 R.sub.2 R.sub.3 R.sub.4
__________________________________________________________________________
1,3 C.sub.18 H.sub.37 C.sub.18 H.sub.37 CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH 1,2 C.sub.18 H.sub.37 C.sub.18 H.sub.37
CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH 1,3 C.sub.12 H.sub.25
C.sub.12 H.sub.25 CH.sub.2 CH.sub.2 OH CH.sub.2 CH.sub.2 OH 1,2
C.sub.12 H.sub.25 C.sub.12 H.sub.25 CH.sub.2 CH.sub.2 OH CH.sub.2
CH.sub.2 OH 1,4 C.sub.18 H.sub.37 C.sub.18 H.sub.37
(CH.sub.2).sub.3 OH (CH.sub.2).sub.3 OH 1,4 CH.sub.3 C.sub.12
H.sub.25 C.sub.2 H.sub.5 C.sub.2 H.sub.5 1,3 C.sub.16 H.sub.33
C.sub.16 H.sub.33 C.sub.6 H.sub.13 C.sub.6 H.sub.13 1,2 C.sub.18
H.sub.37 C.sub.18 H.sub.37 CH.sub.2 CHOHCH.sub.3 CH.sub.2
CHOHCH.sub.3 1,4 n-C.sub.4 H.sub.9 C.sub.16 H.sub.33
(CH.sub.2).sub.8 OH (CH.sub.2).sub.8 OH 1,4 C.sub.18 H.sub.37
C.sub.18 H.sub.37 CH.sub.2 --CH=CH.sub.2 CH.sub.2 --CH=CH.sub.2 1,3
C.sub.2 H.sub.5 C.sub.20 H.sub.41 CH.sub.2 --CH=CH.sub.2 CH.sub.2
CH.sub.2 OH 1,3 C.sub.2 H.sub.5 C.sub.14 H.sub.29 C.sub.12 H.sub.25
C.sub.12 H.sub.25 1,4 C.sub.18 H.sub.37 C.sub.18 H.sub.37 CH.sub.2
CH(OCH.sub.3).sub.2 CH.sub.2 --CH=CH.sub.2 1,4 C.sub.18 H.sub.37
C.sub.18 H.sub.37 H CH.sub.2 CHOHCH.sub.2 OH 1,3 C.sub.18 H.sub.37
C.sub.18 H.sub.37 H n--C.sub.7 H.sub.15 1,3 C.sub.16 H.sub.33
C.sub.16 H.sub.33 H CH(CH.sub.3)CH.sub.2 COOC.sub.2 H.sub.5 1,3
C.sub.18 H.sub.37 C.sub.18 H.sub.37 CH.sub.2 COOCH.sub.3 CH.sub.2
COOCH.sub.3 1,3 C.sub.12 H.sub.25 C.sub.12 H.sub.25
(CH.sub.2).sub.2 OCOCH.sub.2 CH.sub.2 COOH (CH.sub.2).sub.2
OCOCH.sub.2 CH.sub.2 COOH * 1,4 C.sub.18 H.sub.37 C.sub.18 H.sub.37
(CH.sub.2).sub.2 OCOCH.sub.2 CH.sub.2 COOH (CH.sub.2).sub.2
OCOCH.sub.2 CH.sub.2 COOH 1,4 n--C.sub.4 H.sub.9 C.sub.16 H.sub.33
(CH.sub.2).sub.8 OCOCH.sub.2 CH.sub.2 COOH (CH.sub.2).sub.8
OCOCH.sub.2 CH.sub.2 COOH 1,4 C.sub.18 H.sub.37 C.sub.18 H.sub.37
(CH.sub.2).sub.2 OCONHC.sub.6 H.sub.5 (CH.sub.2).sub.2 OCONHC.sub.6
H.sub.5 1,3 C.sub.12 H.sub.25 C.sub.12 H.sub.25 (CH.sub.2).sub.2
OCONHC.sub.6 H.sub.5 (CH.sub.2).sub.2 OCONHC.sub.6 H.sub.5 1,4
n--C.sub.4 H.sub.9 C.sub.16 H.sub.33 (CH.sub.2).sub.8 OCONHC.sub.6
H.sub.5 (CH.sub.2).sub.8 OCONHC.sub.6 H.sub.5 1,3 C.sub.12 H.sub.25
C.sub.12 H.sub.25 (CH.sub.2).sub.2 OCOCH.sub.3 (CH.sub.2).sub.2
OCOCH.sub.3 1,4 C.sub.18 H.sub.37 C.sub.18 H.sub.37
(CH.sub.2).sub.2 OCOCH.sub.3 (CH.sub.2).sub.2 OCOCH.sub.3 1,4
C.sub.18 H.sub.37 C.sub.18 H.sub.37 (CH.sub.2).sub.2 OCOC.sub.17
H.sub.35 (CH.sub.2).sub.2 OCOC.sub.17 H.sub.35 1,3 C.sub.12
H.sub.25 C.sub.12 H.sub.25 (CH.sub.2).sub.2 OCOC.sub.5 H.sub.11
(CH.sub.2).sub.2 OCOC.sub.5 H.sub.11 1,4 C.sub.18 H.sub.37 C.sub.18
H.sub.37 --CH.sub.2 CH.sub.2 -- 0 -- CH.sub.2 CH.sub.2 -- 1,3
C.sub.18 H.sub.37 C.sub.18 H.sub.37 --CH.sub.2 CH.sub.2 -- 0 --
CH.sub.2 CH.sub.2 -- 1,4 n--C.sub.4 H.sub.9 C.sub.16 H.sub.33
--CH.sub.2 CH.sub.2 -- 0 -- CH.sub.2 CH.sub.2
__________________________________________________________________________
-- *This compound and the remaining compounds are prepared from the
corresponding hydroxyalkyl compound by the procedures of Examples
VIII - X.
EXAMPLE XXX
1-(Dioctadecyl)Aminomethyl-4-Aminoemthyl Benzene
A mixture of 1-(dioctadecylamino)methyl-4-cyanobenzene (11.9 g.,
18.7 mM, see Example XXIX), sodium dihydro
bis-(2-methoxyethoxy)aluminate (11.0 g. of 70% reagent, 37.5 mM)
and benzene (300 ml.) under an atmosphere of nitrogen is refluxed
for 40 hours. It is cooled and aqueous sodium hydroxide (50 ml. of
10% solution) is continuously added. The benzene phase is
separated, washed with water (2 .times. 50 ml.) and dried (Na.sub.2
SO.sub.4). Concentration of the benzene solution gives the product
as an oil which solidifies on standing (8.0 g.). It is purified by
chromatography on a dry silica gel column and elution with ethyl
acetate.
The dihydrochloride salt is obtained by dissolving the product (500
mg.) in chloroform (20 ml.) and adding ethyl acetate saturated with
HCl (10 ml.). The salt is filtered, washed with ether, and air
dried: 430 mg., m.p. 208.degree.-210.degree. C.
The following compounds are prepared in like manner from
appropriate reactants. ##SPC56##
Di-HCl Isomer* R.sub.1 R.sub.2 Base M.P. (.degree. C.)
______________________________________ 1,3 C.sub.18 H.sub.37
C.sub.18 H.sub.37 -- 117-8 1,2 C.sub.18 H.sub.37 C.sub.18 H.sub.37
-- 90-2 1,4 C.sub.12 H.sub.25 C.sub.12 H.sub.25 -- 218-20 1,4
3,4-dihexoxy- 3,4-dihexoxy- oil -- benzyl benzyl 1,4 3,4-diisopro-
3,4-diisopro- -- 218-20 poxybenzyl poxybenzyl
______________________________________ * Refers to position of the
aminomethyl groups.
EXAMPLE XXXI
The compounds below are prepared by the procedure of Example XXX
from the appropriate 1-(substituted amino)methyl cyanobenzenes
prepared as intermediates in Example XXIX and from appropriate
di(substituted benzyl)-amines prepared for Examples XXVI and XXVII.
##SPC57##
Isomer R.sub.1 R.sub.2 ______________________________________ 1,3
C.sub.12 H.sub.25 C.sub.12 H.sub.25 1,2 C.sub.12 H.sub.25 C.sub.12
H.sub.25 1,4 CH.sub.3 C.sub.12 H.sub.25 1,3 C.sub.16 H.sub.33
C.sub.16 H.sub.33 1,4 n--C.sub.4 H.sub.9 C.sub.16 H.sub.33 1,3
C.sub.2 H.sub.5 C.sub.20 H.sub.41 1,3 C.sub.2 H.sub.5 C.sub.14
H.sub.29 ______________________________________ ##SPC58##
Isomer R.degree. R' R" ______________________________________ 1,3
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H 1,2 3--OC.sub.6
H.sub.13 4--OC.sub.6 H.sub.13 H 1,4 4--OC.sub.18 H.sub.37 H H 1,3
4--OC.sub.18 H.sub.37 H H 1,2 4--OC.sub.18 H.sub.37 H H 1,3
4--OC.sub.14 H.sub.29 H H 1,4 2--OCH.sub.3 4--OC.sub.12 H.sub.25
5--OCH.sub.3 1,3 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3
1,3 2--OC.sub.6 H.sub.12 3--OC.sub.2 H.sub.5 H 1,4 4--OC.sub.8
H.sub.17 H H 1,3 3--OC.sub.12 H.sub.25 4--OC.sub.12 H.sub.25 H 1,3
4--OC.sub.18 H.sub.37 2--CH.sub.3 6--CH.sub.3
______________________________________
The above products are converted to monoacyl derivatives by the
procedure of Example III. By this procedure, the formyl, acetyl and
propionyl derivatives are obtained.
EXAMPLE XXXII
1-(substituted amino)methyl-4-hydroxymethyl benzene compounds
prepared according to Examples XXV-XXIX are reacted with succinic
anhydride, glutaric anhydride, phenyl isocyanate and acyl chlorides
as described in Examples VIII, IX and X to give the following
compounds: ##SPC59##
Isomer R.sub.1 R.sub.2 A ______________________________________ 1,4
C.sub.18 H.sub.37 C.sub.18 H.sub.37 OCOCH.sub.2 CH.sub.2 COOH 1,3
C.sub.18 H.sub.37 C.sub.18 H.sub.37 OCOCH.sub.2 CH.sub.2 COOH 1,2
C.sub.18 H.sub.37 C.sub.18 H.sub.37 OCOCH.sub.2 CH.sub.2 COOH 1,3
C.sub.18 H.sub.37 C.sub.18 H.sub.37 OCOCH.sub.2 CH.sub.2 CH.sub.2
COOH 1,4 C.sub.12 H.sub.25 C.sub.12 H.sub.25 OCOCH.sub.2 CH.sub.2
CH.sub.2 COOH 1,4 CH.sub.3 C.sub.6 H.sub.5 CH.sub.2 OCOCH.sub.2
CH.sub.2 CH.sub.2 COOH 1,4 n--C.sub.4 H.sub.9 C.sub.16 H.sub.33
OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH 1,3 C.sub.6 H.sub.5 OCH.sub.2
C.sub.6 H.sub.5 OCH.sub.2 OCOCH.sub.2 CH.sub.2 COOH 1,2 C.sub.6
H.sub.13 C.sub.6 H.sub.13 OCOCH.sub.2 CH.sub.2 COOH 1,3 C.sub.2
H.sub.5 C.sub.20 H.sub.41 OCOCH.sub.2 CH.sub.2 COOH 1,4 CH.sub.2
CH.sub.2 OH CH.sub.2 CH.sub.2 OH OCOCH.sub.2 CH.sub.2 COOH 1,4
C.sub.18 H.sub.37 C.sub.18 H.sub.37 OCONHC.sub.6 H.sub.5 1,3 C.sub.
18 H.sub.37 C.sub.18 H.sub.37 OCONHC.sub.6 H.sub.5 1,2 C.sub.18
H.sub.37 C.sub.18 H.sub.37 OCONHC.sub.6 H.sub.5 1,4 CH.sub.3
C.sub.6 H.sub.5 CH.sub.2 OCONHC.sub.6 H.sub.5 1,3 C.sub.6 H.sub.5
OCH.sub.2 C.sub.6 H.sub.5 OCH.sub.2 OCONHC.sub.6 H.sub.5 1,3
C.sub.16 H.sub.33 C.sub.16 H.sub.33 OCONHC.sub.6 H.sub.5 1,4
n--C.sub.4 H.sub.9 C.sub.16 H.sub.33 OCONHC.sub.6 H.sub.5 1,3
C.sub.2 H.sub.5 C.sub.20 H.sub.41 OCONHC.sub.6 H.sub.5 1,3 C.sub.6
H.sub.5 CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 OCONHC.sub.6 H.sub.5 1,4
C.sub.18 H.sub.37 C.sub.18 H.sub.37 OCOCH.sub.3 1,4 C.sub.18
H.sub.37 C.sub.18 H.sub.37 OCOC.sub.7 H.sub.15 1,4 C.sub.18
H.sub.37 C.sub.18 H.sub.37 OCOC.sub.15 H.sub.31 1,3 C.sub.18
H.sub.37 C.sub.18 H.sub.37 OCOC.sub.15 H.sub.31 1,2 C.sub.18
H.sub.37 C.sub.18 H.sub.37 OCOC.sub.3 H.sub.7 1,4 C.sub.6 H.sub.13
C.sub.6 H.sub.13 OCOC.sub.5 H.sub.11 1,3 C.sub.6 H.sub.5 OCH.sub.2
C.sub.6 H.sub.5 OCH.sub.2 OCOC.sub.2 H.sub.5 1,3 C.sub.6 H.sub.5
CH.sub.2 C.sub.6 H.sub.5 CH.sub.2 OCOC.sub.11 H.sub.23 1,3 C.sub.2
H.sub.5 C.sub.20 H.sub.41 OCOCH.sub.3 1,4 CH.sub.3 C.sub.6 H.sub.5
CH.sub.2 OCOC.sub.17 H.sub.35 1,4 C.sub.12 H.sub.25 C.sub.12
H.sub.25 OCOC.sub.7 H.sub.15 1,2 C.sub.12 H.sub.25 C.sub.12
H.sub.25 OCOC.sub.7 H.sub.15
______________________________________
EXAMPLE XXXIII
The compounds tabulated below are prepared by the procedures of
Examples VIII, IX and X from appropriate 1-[bis-(alkoxy benzyl)
amino methyl]-4-hydroxymethyl benzenes. These latter compounds are
prepared via the procedures of Example XXVI ([bis(alkoxy
benzyl)-amines]) and Example XXVIII ([1-bis(alkoxy
benzyl)aminomethyl]-4-hydroxymethylbenzens). ##SPC60##
Isomer R.degree. R' R" A
__________________________________________________________________________
1,4 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H OH 1,4
3--O--i--C.sub.3 H.sub.7 4--O--i--C.sub.3 H.sub.7 H OH 1,3
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H OH 1,4 4--OC.sub.18
H.sub.37 H H OH 1,3 4--OC.sub.18 H.sub.37 H H OH 1,2 4--OC.sub.18
H.sub.37 H H OH 1.4 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3
OH 1,2 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 OH 1,3
4--OC.sub.14 H.sub.29 H H OH 1,2 2--OC.sub.6 H.sub.13 3--OC.sub.2
H.sub.5 H OH 1,3 3--OC.sub.12 H.sub.25 4--OC.sub.2 H.sub.5 H OH 1,3
4--OC.sub.8 H.sub.17 H H OH 1,4 3--OC.sub.6 H.sub.13 4--OC.sub.6
H.sub.13 H OCOCH.sub.2 CH.sub.2 COOH 1,3 3--OC.sub.6 H.sub.13
4--OC.sub.6 H.sub.13 H OCOCH.sub.2 CH.sub.2 COOH 1,4 4--OC.sub.18
H.sub.37 H H OCOCH.sub.2 CH.sub.2 COOH 1,3 4--OC.sub.18 H.sub.37 H
H OCOCH.sub.2 CH.sub.2 COOH 1,2 4--OC.sub.18 H.sub.37 H H
OCOCH.sub.2 CH.sub.2 COOH 1,2 2--OCH.sub.3 4--OC.sub.12 H.sub.25
5--OCH.sub.3 OCOCH.sub.2 CH.sub.2 COOH 1,4 4--OC.sub.18 H.sub.37 H
H OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH 1,3 3--OC.sub.6 H.sub.13
4--OC.sub.6 H.sub.13 H OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH 1,2
4--OC.sub.18 H.sub.37 H H OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH 1,4
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H OCONHC.sub.6 H.sub.5
1,3 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H OCONHC.sub.6
H.sub.5 1,4 4--OC.sub.18 H.sub.37 H H OCONHC.sub.6 H.sub.5 1,2
4--OC.sub.18 H.sub.37 H H OCONHC.sub.6 H.sub.5 1,2 2--OCH.sub.3
4--OC.sub.12 H.sub.25 5--OCH.sub.3 OCONHC.sub.6 H.sub.5 1,3
4--OC.sub.8 H.sub.17 H H OCONHC.sub.6 H.sub.5 1,4 3--O--i--C.sub.3
H.sub.7 4--O--i--C.sub.3 H.sub.7 H OCONHC.sub.6 H.sub.5 1,4
4--OC.sub.18 H.sub.37 H H OCOCH.sub.3 1,3 4--OC.sub.18 H.sub.37 H H
OCOCH.sub.3 1,4 4--OC.sub.18 H.sub.37 H H OCOC.sub.7 H.sub.15 1,3
4--OC.sub.18 H.sub.37 H H OCOC.sub.15 H.sub.31 1,4 4--OC.sub.8
H.sub.17 H H OCOC.sub.7 H.sub.15 1,2 4--OC.sub.18 H.sub.37 H H
OCOC.sub. 3 H.sub.7 1,2 2--OC.sub.6 H.sub.13 3--OC.sub.2 H.sub.5 H
OCOC.sub.9 H.sub.19 1,4 2--OCH.sub.3 4--OC.sub.12 H.sub.25
5--OCH.sub.3 OCOC.sub.17 H.sub.35 1,4 4--OC.sub.18 H.sub.37 H H Cl
1,4 4--OC.sub.8 H.sub.17 H H Cl 1,3 4--OC.sub.18 H.sub.37 H H Cl
1,3 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H Cl 1,4 4--OC.sub.8
H.sub.17 H H Br 1,2 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3
Br 1,2 2--OC.sub.6 H.sub.13 3--OC.sub.2 H.sub.5 H Br 1,4
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H Cl 1,4 3--O--i--C.sub.3
H.sub.7 4--O--i--C.sub.3 H.sub.7 H Cl 1,2 4--OC.sub.18 H.sub.37 H H
Cl 1,4 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 Br 1,3
4--OC.sub.14 H.sub.29 H H Br 1,3 3--OC.sub.12 H.sub.25 4--OC.sub.2
H.sub.5 H Br 1,3 4--OC.sub.8 H.sub.17 H H Cl
__________________________________________________________________________
EXAMPLE XXXIV
[1-Bis(Alkoxybenzyl)Aminomethyl]-Alkylthiomethyl Benzenes
A solution of the appropriate
]1-bis(alkoxybenzyl)aminomethyl]-chloromethyl (or bromomethyl)
benzene (Example XXXIV) in N,N-dimethylformamide and at least one
equivalent of the appropriate sodium alkylsulfide (prepared from
the appropriate mercaptan and sodium hydride) is stirred for 16-20
hours at 40.degree.-60.degree.C. The mixture is diluted with four
volumes of water and extracted with hexane. The extract is dried
(Na.sub.2 SO.sub.4) and evaporated to give the crude product.
Purification is achieved by column chromatography on silica gel.
The charged column is eluted first with benzene to remove unreacted
starting material and then with ethyl acetate or methanol to elute
the product which is recovered by evaporation of the eluate.
The following compounds are thus prepared: ##SPC61##
Isomer R.degree. R' R" alkyl ______________________________________
1,4 4--OC.sub.18 H.sub.37 H H CH.sub.3 1.4 4--OC.sub.18 H.sub.37 H
H C.sub.6 H.sub.13 1,4 4--OC.sub.18 H.sub.37 H H C.sub.18 H.sub.37
1,3 4--OC.sub.18 H.sub.37 H H C.sub.6 H.sub.13 1,3 4--OC.sub.18
H.sub.37 H H C.sub.18 H.sub.37 1,3 4--OC.sub.18 H.sub.37 H H
i--C.sub.3 H.sub.7 1,2 4--OC.sub.18 H.sub.37 H H C.sub.6 H.sub.13
1,4 4--OC.sub.8 H.sub.17 H H C.sub.12 H.sub.25 1,3 3--OC.sub.6
H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.2 H.sub.5 1,3 3--OC.sub.6
H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.12 H.sub.25 1,2 2--OCH.sub.3
4--OC.sub.12 H.sub.25 5--OCH.sub.3 CH.sub.3 1,2 2--OCH.sub.3
4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.4 H.sub.9 1,2 2--OCH.sub.3
4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.16 H.sub.33 1,2
2--OC.sub.6 H.sub.13 3--OC.sub.2 H.sub.5 H C.sub.2 H.sub.5 1,2
2--OC.sub.6 H.sub.13 3--OC.sub.2 H.sub.5 H C.sub.14 H.sub.29 1,4
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.12 H.sub.25 1,4
3--O--i--C.sub.3 H.sub.7 4--O--i--C.sub.3 H.sub.7 H i--C.sub.3
H.sub.7 1,4 3--O--i--C.sub.3 H.sub.7 4--O--i--C.sub.3 H.sub.7 H
C.sub.12 H.sub.25 1,4 3,4-- O -- CH.sub.2 -- O -- H C.sub.2 H.sub.5
1,4 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.3 H.sub.7
1,4 2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.8
H.sub.17 1,3 4--OC.sub.14 H.sub.29 4--OC.sub.12 H.sub.25
5--OCH.sub.3 C.sub.6 H.sub.13 1,3 4--OC.sub.14 H.sub.29
4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.16 H.sub.33 1,3
3--OC.sub.12 H.sub.25 4--OC.sub.2 H.sub.5 H CH.sub.3 1,3
3--OC.sub.12 H.sub.25 4--OC.sub.2 H.sub.5 H C.sub.10 H.sub.21 1,3
4--OC.sub.8 H.sub.17 H H C.sub.6 H.sub.13 1,3 4--OC.sub.8 H.sub.17
H H C.sub.14 H .sub.29 ______________________________________
EXAMPLE XXXV
[1-Bis(Alkoxybenzyl)Aminomethyl]-Akloxymethyl Benzenes
The procedure of Example XXXIV is repeated using the appropriate
sodium alkoxide in place of a sodium alkyl sulfide to give the
following compounds: ##SPC62##
Isomer R.degree. R' R" alkyl ______________________________________
1,4 4--OC.sub.18 H.sub.37 H H CH.sub.3 1,4 4--OC.sub.18 H.sub.37 H
H C.sub.6 H.sub.13 1,4 4--OC.sub.18 H.sub.37 H H C.sub.18 H.sub.37
1,3 4--OC.sub.18 H.sub.37 H H C.sub.6 H.sub.13 1,3 4--OC.sub.18
H.sub.37 H H C.sub.18 H.sub.37 1,2 4--OC.sub.18 H.sub.37 H H
C.sub.6 H.sub.13 1,2 4--OC.sub.18 H.sub.37 H H C.sub.14 H.sub.29
1,4 4--OC.sub.8 H.sub.17 H H C.sub.12 H.sub.25 1,3 3--OC.sub.6
H.sub.13 4--OC.sub.6 H.sub.13 H i--C.sub.3 H.sub.7 1,2 2--OCH.sub.3
4--OC.sub.12 H.sub.25 5--OCH.sub.3 CH.sub.3 1,2 2--OCH.sub.3
4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.6 H.sub.13 1,2
2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.16 H.sub.33
1,4 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.6 H.sub.13
1,4 3--O--i--C.sub.3 H.sub.7 4--0--i--C.sub.3 H.sub.7 H C.sub.2
H.sub.5 1,4 3--O--i--C.sub.3 H.sub.7 4--O--i--C.sub.3 H.sub.7 H
C.sub.14 H.sub.29 1,3 4--OC.sub.14 H.sub.29 H H C.sub.4 H.sub.9 1,4
2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.3 H.sub.7 1,4
2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.10 H.sub.21
1,3 3--OC.sub.12 H.sub.25 4--OC.sub.2 H.sub.5 H CH.sub.3 1,3
3--OC.sub.12 H.sub.25 4--OC.sub.2 H.sub.5 H C.sub.6 H.sub.13 1,3
3--OC.sub.12 H.sub.25 4--OC.sub.2 H.sub.5 H C.sub.16 H.sub.33 1,3
4--OC.sub.8 H.sub.17 H H C.sub.6 H.sub.13
______________________________________
EXAMPLE XXXVI
[1-Bis(Alkoxybenzyl)Aminomethyl]-Cyanomethyl Benzenes
A solution of the appropriate
[1-bis(alkoxybenzyl)aminomethyl]-chloro (or bromo)methyl benzene in
N,N-dimethylformamide and potassium cyanidepotassium iodide (5
equivalents of each) is stirred at 60.degree.-100.degree.C. for 24
hours. The mixture is diluted with water (4-5 volumes) and
extracted with hexane. The extract is dried (Na.sub.2 SO.sub.4) and
evaporated to give the crude product. It is purified by column
chromatography as in Example XXXIV
In this manner the chloro and bromo compounds of Example XXXIII are
converted to the corresponding cyano derivatives of the formula:
##SPC63##
EXAMPLE XXXVII
[1-Bis(Alkoxybenzyl)Aminomethyl]-Alkanoylthiomethyl Benzenes
A solution of equimolar amounts of the appropriate
[1-bis-(alkoxybenzyl)aminomethyl]-chloro(or bromo)methylbenzene
(Example XXXIII) and the sodium salt of the appropriate
thiolcarboxylic acid in N,N-dimethylformamide is stirred for 16-20
hours at 60.degree.C. The reaction mixture is cooled, diluted with
3-4 volumes of water and extracted with hexane. The extract is
dried (Na.sub.2 SO.sub.4) and evaporated to give the crude product.
It is purified by column chromatography according to the procedure
of Example XXXIV.
The following compounds are thus prepared: ##SPC64##
Isomer R.degree. R' R" A" ______________________________________
1,4 4--OC.sub.18 H.sub.37 H H CH.sub.3 CO 1,4 4--OC.sub.8 H.sub.17
H H C.sub.7 H.sub.15 CO 1,3 4--OC.sub.18 H.sub.37 H H C.sub.11
H.sub.23 CO 1,3 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.2
H.sub.5 CO 1,4 4--OC.sub.8 H.sub.17 H H C.sub.9 H.sub.19 CO 1,2
2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.3 H.sub.7 CO
1,2 2--OC.sub.6 H.sub.13 3--OC.sub.3 H.sub.5 H C.sub.7 H.sub.15 CO
1,4 4--OC.sub.18 H.sub.37 H H C.sub.17 H.sub.35 CO 1,3 3--OC.sub.6
H.sub.13 4--OC.sub.6 H.sub.13 H n--C.sub.4 H.sub.9 CO 1,2
2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.11 H.sub.23
CO 1,3 4--OC.sub.8 H.sub.17 H H n--C.sub.4 H.sub.9 CO 1,4
3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.16 H.sub.33 CO
1,4 3--OC.sub.6 H.sub.13 4--OC.sub.6 H.sub.13 H C.sub.3 H.sub.7 CO
1,4 3--O--i--C.sub.3 H.sub.7 4--O--i--C.sub.3 H.sub.7 H C.sub.11
H.sub.23 CO 1,2 4--OC.sub.18 H.sub.37 H H C.sub.7 H.sub.15 CO 1,4
2--OCH.sub.3 4--OC.sub.12 H.sub.25 5--OCH.sub.3 C.sub.9 H.sub.19 CO
1,3 4--OC.sub.14 H.sub.29 H H C.sub.11 H.sub.23 CO 1,3 3--OC.sub.12
H.sub.25 4--OC.sub.2 H.sub.5 H C.sub.13 H.sub.27 CO 1,3 4--OC.sub.8
H.sub.17 H H C.sub.13 H.sub.27 CO
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