US3872171A - Polyamines as antiviral agents in animals - Google Patents

Abstract

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; R5 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

R6 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

R7 is selected from the group consisting of alkyl of from 12 to 20 carbon atoms and

R8 is selected from the group consisting of alkyl of from 1 to 20 carbon atoms and

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.

M IS 0 OR 1, WITH THE PROVISOS THAT ONLY ONE OF X and X'' is

X'' is selected from the group consisting of X, phenylenedimethylene and

Ro 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 Ro, R'' and R'''' is from 5 to 48; R3 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; R4 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; R3 and R4 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

R2 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

AND THE NON-TOXIC ACID ADDITION SALTS THEREOF WHEREIN R1 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

Combating viral infections in vertebrate animals by administering to the animals an amine selected from those having the formulae:

Description

baited States Patent 1191 Cronin et a1.

11] 3,872,171 1 1Mar. is, 1975 Related 1.1.5. Application Data [63] Continuation-in-part of Ser. No. 146,548, May 24, 1971, abandoned, which is a continuation-in-part of Ser No. 62,192, Aug. 7, 1970, abandoned.

[52] US. Cl .1 260/584 R, 424/250, 424/298, 424/304, 424/311, 260/583 P, 260/570.5 P, 260/570.7, 260/340.5, 260/584 R, 260/471 C, 260/518 R, 260/584 A [51] Int. Cl. C070 91/12 [58] Field of Search 260/584 R [56] References Cited UNITED STATES PATENTS 2,368,521 1/1945 Clifford et a] 260/584 R 2,393,825 l/1946 Senkus 260/584 R 2,541,089 2/1951 Nikawitz 260/584 R 2,759,021 3/1956 Gaar et a1. 260/584 R 3,200,153 8/1965 Kirkpatrick 260/584 R 3,494,870 2/1970 Kersnar 260/584 R FOREIGN PATENTS OR APPLICATIONS 112,366 12/1965 Netherlands 260/584 R 1,079,597 8/1965 United Kingdom.,........,. 260/584 R OTHER PUBLICATIONS Chem. Abstracts 2151 Primary Examiner-Lewis Gotts Assistant Errmu'ncw-D, R. Phillips Attorney, Agent, or Firm-Connolly and Hutz {57] ABSTRACT Combating viral infections in vertebrate animals by administering to the animals an amine selected from and the non-toxic acid addition salts thereof wherein R is selected from the group consisting of alkyl of from 1 to 20 carbon atoms, aralkyl, aryloxyalkyl, hydroxyaikyl of from 2 to 8 carbon atoms and CH2"; n

R 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 R RI R" CH -3 R" 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". R and R is from 5 to 48;

R isselectecl from the group consisting of hydrogen, alkyl of from 1 to 20 carbon atoms, hydroxyaikyl of from 2 to 8 carbon atoms, phenylcarbamoyloxy( lower alkyl), w-carboxyalkanoyloxy-(lower alkyl), allyl, alkanoyl of from 1 to 6 carbon atoms, alkanoyloxy(lower alkyl), carbo(lower alkoxy)lower alkyl, carboxy(1ower alkyl), a1koxy(lower alkyl) and gem-di(1ower alkoxy)-lower alkyl;

R, 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)1ower alkyl, a1kanoy1oxy(1ower alkyl), carboxy(1ower alkyl), alkoxy(lower alkyl), phenyl-carbamoyloxy(lower alkyl), w-carboxya1kanoy1oxy(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 and R 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 and United States Patent [191 Cronin et al.

[ Mar. 18. 1975 [54] POLYAMINES AS ANTIVIRAL AGENTS IN ANIMALS X is selected from the group consisting of X, phenylene-dimethylene and m is O or I, with the provisos that only one of X and X is O at and when X is phenylenedi methylene, m is 0;

Y is selected from the group consisting of straight chain alkylene of from 2 to 8 carbon atoms and phenylenedimethylene;

R! R CH -5 R is selected from the group consistingof hydrogen, alkyl of from 12 to 20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, (lower alkoxy)lower alkyl and R is selected from the group consisting of alkyl of from 12 to 20 carbon atoms and R" R is selected from the group consisting of alkyl of from 1 to 20 carbon atoms and each ofp and n is 0655518 from I :66, withthe proviso that the sum of p and n is no greater than 6; and

Z is selected from the group consisting of arcarboxyflower alkyl), morpholino, piperidino, piperazino, N-(w-hydroxy lower alkyl)piperazino and N-( lower alkyl)piperazino.

6 Claims, No Drawings POLYAMINES AS ANTIVIRAL AGENTS IN ANIMALS CROSS RFERENCE 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-inpart of my application Ser. No. 62.192. filed Aug. 7, 1970 and now abandoned.

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. l9-20).

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 dif ficulty 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., Internatl. Virol. 1, 1st Int. Congr. Virol. Helsinki 1968, S. Karger, New York, pp. -1, 1969).

More recently, 2,7-bis[ Z-(diethyIaniino )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 Rabinowit z and Myerson, lnterscience Publishers, New York, 1968, pages 141-171. For the purposes of this review, Osdene has made use of Herrmanns 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 nonspecific 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 l-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 55615 e nonioii fifacidaddifiofi salts thereof wherein; is selected from the group consisting of alkyl of from 1 to 20 atoms, aralkyl, aryloxyalkyl, hydroxyalkyl of from 2 to 8 carbon atoms and R 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 R 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", R and R is from 5 to 48;

R is selected from the group consisting of hydrogen, alkyl of from 1 to carbon atoms, hydroxyalklyl of from 2 to 8 carbon atoms, phenylcarbamoyloxyflower alkyl), w-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, 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), w-carboxyalkanoyloxy(lower alkyl), allyl, dihydroxyalkyl of from 3 to 8 carbon atoms and morpholinoethyl;

with the' proviso that no ma'r'etfiatrtws of tlie R vari ables are hydroxyalkyl;

R and R 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 X is selected from the group consisting of X, phenylenedimethylene, and

m is 0 or 1, with the provisos that only one of X and X is 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, w-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 l to 20 carbon atoms;

R is selected from the group consisting of hydrogen, alkyl of from I to 20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, (lower alkoxy)lower alkyl and R is selected from the group consisting of alkyl of from 12 to 20 carbon atoms and R,; is selected from the group consisting of alkyl of from 1 to 20 carbon atoms and each of p and n is or an integer from 1 to 6, with the proviso that the sum ofp and n is no greater than 6', and

Z is selected from the group consisting of w-carboxy(lower alkyl), morpholino, piperidino, piperazino, N- (w 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 0-, the mand the pphenylenedimethylene 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 abovementioned bases which may be employed are the water-soluble and water-insoluble salts as the hydrochloride, hydrobromide, phosphate, nitrate, sulfate, ac etate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate (4,4'-diaminostilbene-2,2-disulfonate), pamoate (l,l '-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 Il 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 l3 carbon atoms; (b) X, X and Y are arylene, e.g., phenylene, naphthylene, anthrylene, biphenylene or -(CH ),arylene-(CH ),,wherein x and y are integers from i to 4; (0) those wherein one or more ofthe R variables represent unsaturated alkyl radicals having from 2 to 20 carbon atoms and from l 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 l and Il 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, l-benzotriazolo, 2,1,3-benzothiazole, pyrazolo, phenoxazino, azetidino; azepino; tetrazolo; an azacycloalkane such as azacyclooctadecane; 10,11- dihydro--H-dibenz[b,f]a2epino; a triazepino, e.g., 1,3,5-triazepino, and ll-dibenzo[l,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 N; (g) and compounds of formula III wherein Z is N-substituted piperazino wherein the substituent is carbalkoxy, acyl or --X-NR R wherein X, R, and R, are as defined above; also combat viral infections when administrated t0 vertebrate animals by the parenteral route.

One preferred group of compounds of Formula I includes those wherein R is selected from the group consisting of alkyl of from l-20 carbon atoms, aralkyl, aryloxyalkyl, and

R is selected from the group consisting of alkyl of from 12 to 20 carbon atoms, aralkyl, aryloxyalkyl and WE CH2 wherein R" 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 and R are each hydrogen;

in 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, singlestranded 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 is alkyl of from 1 to 20 carbon atoms; R is alkyl of from 12 to 20 carbon atoms; R is hydrogen, forrnyl, alkyl or from 1 to 20 carbon atoms or hydroxyalkyl of from 2 to 4 carbon atoms; R, 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,, R R and R. 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 ll wherein A is hydroxy; Y is straight chain alkylene of 2 to 4 carbon atoms; and R and R are alkyl of from 12 to 20 carbon atoms; and compounds of formula Ill wherein Z is N-substituted piperazino and R and R are each alkyl. An especially preferred group of compounds of formula I includes those in which R, and R are each alkyl of 12 to 20 carbon atoms, R; and R 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 -formyll ,3-propanediamine,

N,N-dioctadecyl-N,N-bis(2-hydroxyethyl)-1 ,3-

propanediamine, 1-dioctadecylaminomethyl-3-aminomethylbenzene,

butanediamine,

N,N-dioctadecyl-N,N-bis(2-hydroxypropyl)-l,3-

propanediamine,

N-(2-hydroxyethyl)dioctadecylamine,

N-(3-hydroxypropyl)dioctadecylamine,

l,l-dioctadecyl-3-(2-[bis(2-hydroxyethyl)amino]ethyl)urea, l-(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.

vU.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 monoand diamines. The compounds are produced by alkoxylation (etnoxylation or propoxylation) of primary and secondary monoand 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 1 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 Ill wherein each of R and R 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 and R is alkyl of twelve or more carbon atoms, the compounds do function to comat viral infectrons.

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,R NCH CH CN) thus obtained is then hydrogenated to the corresponding 1,3- propanediamine (R,R NCH CH' CH NH by I wellknown methods, e.g., hydrogenation over Raney nickel.

I 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 1 and 11 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 1 and III are also prepared by conventional methods as by reaction of a'carbamyl chloride (R,R NCOCl) with an amino reactant H NX-NR R, 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 R NH, is benzylated with a cyanobenzylbromide or chloride and the cyanobenzylamine compound produced reduced to the corresponding aminomethylbenzylamine derivative. The a'minomethyl group (-CH NH is then treated, e.g., alkylated, with appropriate reactants to convert it to CH NR R Compounds of. formula 11 wherein Y is phenylenedimethylene are also prepared by benzylation of the appropriate amine R R 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 hydroxymethylserves as convenient route viaknown procedures to formula 11 compounds, and also to formula 1 compounds, e.g., by halogenation and amination.

The herein-described compounds of formulae I, II and 111 wherein the R R R R R or R groups are substituted benzyl 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 monoor dibenzylamine. Utilization of the benzylamine derivatives in conventional reactions as described above affords compounds of formulae l-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 ofa 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 encephalo myocarditis virus and determining the survival rate 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 times by weight of an otherwise inactive (norinducer of interferon and nonantiviral), singlestranded, 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, administra tion 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 dex trose, Ringers 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 ofinducer between 1.0 mg./ml. and 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 (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 waterinsoluble, including those which are of low and/or difficult solubility in water, are, for optimum results, administered in formulations, e.g., suspensions, emulsions, whichpermit formationof particle sizes of less than about 20p. The particle sizes of the formulations influence their biological activity apparently through better absorption of the active materials. In formulating these materials various surface 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 1 l are sold under the trademarks Spans and "Tweensf 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 ad ministered 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 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 (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. ofthe following composition previously warmed to about 55 C:

Q-P DOOM COCO 984.80 g. available from Hercules Powder C0,,

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-l5 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 C., the tubesv are scoredfor cytopathogenie 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)-l,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 l0- 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 compoundsof 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 waterinsoluble compounds. A representative formulation for such compounds comprises 25 to 100 mg. of the chosen drug, dime'thylsulfoxide (1 ml.), polysorbate 80 (1 ml.) and 8 ml. of a composition comprising Methocel-lS 0.50 g./l Polysorbate 80 1.00 g./l CMC- 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)-l,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 120C. and held at this temperature for one-half hour. The mixture is allowed to cool to 70C. then 500 ml. ofa 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-halthour. 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 C. and the succinate salt filtered off; 615 g. (68 percent of theory); m.p. 7890C.

It is purified by recrystallization from acetonemethylene chloride (21 The free baseis obtained by dissolving the succinate salt (420 g.) in methylene chloride (4 liters) and aqueous sodium hydroxide (2.5 liters ofS percent solution). The mixture is stirred for minutes, the methylene chloride phase separated and washed successively with aqueous sodium hydroxide (1 X 18 liters of 5 percent solution), water (3 X 6 liters) and saturated aqueous sodium chloride (1 X 6 liters). It is then dried (MgSO,), filtered and evaporated in vacuo to the oil. The oil is dissolved in acetone (5 liters) at 50C. and the solution allowed to cool slowly to give a white precipitate (267 g.) m.p. 394lC. Another preparation yielded a somewhat lower melting point of 36-36.8C.

Additional product (20 g.) is obtained by cooling the filtrate to 0C. Total yield is 287 g.; 43 percent of theory.

Elemental analysis infra-red (1% in KBr) Major absorption maxima (in microns) at: 3.05, 3.43 3.52, 6.80, 7.15, 7.25,

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. 50-52 C. becomes tacky and melts at 62 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 C.; brown at 190C. and melts at 245247 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 180-182 C. and melts completely at 238-240C.

EXAMPLE ll N.N-Dioctadecyl-N'.N'-Bis(2-Hydroxyethyl)E thanediamine A mixture of octadecylbromide (6.66 g., 0.02 mole), N-(Z-aminoethyl)-diethano1amine (1.48 g., 0.0lmo1e) 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. 33-34 C.

The hydrochloride, phosphate, succinate and pierate 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. (C.)

dihydrochloride 228-30 diphosphate 102-3 disuccinatc 155-6 dipicrate 84-6 7 Repetition of the above procedure but usingthe appropriate (Z-hydroxyalkyl)alkanediamine derivative 7.65, 8.32, 8.39, 8.68, 9.15, 9.24, and the appropriate alkyl bromide produces the follow- 9.30. 9.62, 9.70, 11.04. 13.96. ing compounds:

R 11 l N (caw m 11 R, R. R, R, 11 Salt M.P. (C.;

(3.11.... C,,-,H,,, CH2CH2OH CH CH OH 2 2H,,P0, 1 33-5 CH. .CH.,OH C,,H,, C nt-, CH CH OH 2 2HBr 236-8 C,,,H.,. CH CH OH CH CH OH 3 3&45 (3,11,, CH CH OH CH CH OH 2 2HC1 188-9 -Continued 1 R2 RH R. n slur M.P'fr c') .11., c rt cni cn on CH2CH2O'H "'2 ZHHPO. 221m m c cn cn on cmcmon 4 51-2 irart m aa 2 CHCH2OH 4 44 5 c u c rt... cn cn on CHQCHZOH 4 39 o n... cn.r:it. o cn.c- 3 2HCI 167-170 C H c t-1 g CH CH -O-CH C- 3 ZHCI 174-7 c n. c n 2CTH2CH2OCH2C- 3 2HC1 l70l C,,.H:,T c n cincmoH CH CH Ol-l 5 32-3 CWHM c,.,n, cn cn on cH cnpn 6 49-50 I EXAMPTQE Ill 5 In like nian n erft he following compounds are pre- N,N-Dioctadecyl-1,3-Propanediamine A. A Z-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 C. and the mixture held at this temperature for 1.5 hours at which timehydrogen absorption has ceased. The autoclave is cooled to 20 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. 3941 C.

14.17; N, 4.44 percent 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-l.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) overa period of 15 minutes. The mixture is stirred for 10 min-' utes then brought to room temperature and stirred for 1 hour. The methylene chloride phase is separated and extracted with water (3 X 25 ml.). The water extract is in turn extracted with methylene chloride (2 X 25 ml.) and the combined methylene chloride phases dried (Na SO.,) 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. 5052C.

N-propionyl derivative M.P. 48 .5-49C.

pared from appropriate reactants:

C. Formyl derivatives are prepared as follows:

N,N-dioctadecyl-N -formyl-l ,3-propanediamine A mixture of N,N-dioctadecyl-1,3-propanediamine (4.88 g.), ethanol (l5ml.) 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. 4246 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 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 SO and concentrated to a waxy solid. Picrate Salt: The free base is dissolved in ethanol m1.) and a solution of picric acid (2 g.) in ethanol (20 ml.) added. The salt precipitates upon chilling the solution. lt is filtered off, washed with cold ethanol and dried, 1.2 g., m.p. 149-151 C. Recrystallization from hot ethanol raises the melting point to 150l52 C.

In like manner, the following compounds are prepared using appropriate reactants (HNR R 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.

N CH CH CH N l8 37 u R R Salt M.P. (C.)

H C H CH CH OH picrate 121-2 H CH CH(OH)CH OH picrate 39-41 H 11-C H H icrate 64-6 H 11 C31 HCI 119-22 H n-C H, HCI 53-7 H C H CH OCH HCI 96-9 H C H CH OC H HCI 90-4 H CH CH(OCH3)-.- HCI 83-8 H (CH N(CH CH OH picrate 1 16-8 H (CH NH(CH CHOHCH;iDiCratc 105-10 H CHgCHOHCH2 (C2 5)2 HCI 1 -7 C H,-, C- H picrate 108-10 |1C ,H,, n-C H,, pier-ate 66-7 CH CH CH OH picrate 80-2 n-C H,, CH CH OH picratc 48-52 CH CHOHCH, CH CHOHCH (an oil) CH CHOHCH HCI 52-4; 3 98-101 H CHgCHz-HlUFPhUllHQ 55-67, 90 H CH CH morpholino HCI 137 H CH(CH=;)CH COOC H HCI 56-79 H (CH -OH 34-345 H (CH -OH picratc 84-6; 94 H (CH2l5 OH 35-6 H (CH =,OH picrate 65-70; 85-90 C H CH CH OH picrate 80-6 CH (CH OH 91-4 CH COOH CH COOH 75-90 CH COOCH', CH COOCH 75-7 (CHmOl-l (CHM- OH 41-3 (CH MOH (CHmOH picrate 91-5; 100-5 EXAMPLE V N.N-Dioctadecyl-N,N'-Diallyl-1,3-propanediamine A slurry of N,N-dioctadecyl-l,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 per- E2 CH CH OH (CH M OH (CH OH (CH MOH I A solution of octadecyl bromide (26.65 g., mM. N-(3-aminopropyl)diethanolamine g., 640 mM.) and benzyl alcohol ml.) is heated at C. for 23 hours. The benzyl alcohol is removed in vacuo (0.1 mm. Hg, and 75C.) 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 SO concentrated, and distilled; b.p. 242-246C. at 0.1 mm Hg. The product is a waxy solid.

EXAMPLE VII cyl-l ,3-Propanediamine A mixture of N,N-bis(2-hydroxyethyI)-N-octadecyl- 1,3-propanediamine (500 mg., 1.2 mM.), n-butyl bromide (164 mg., 1.2 mM.) and potassium carbonate mg.. 1.2 mM.) is heated at 100C. for 2 hours then at 130C. 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 SO Removal of the chloroform provides the free base (540 mg.).

The picrate salt, prepared by the procedure of Example IV, melts at 8587C.

In like manner, N,N-bis(2hydroxyethyl)-N-npropyl)-N-octadecyl-l,3-propanediamine is prepared from n-propylbromide. Its picrate salt melts at 105-106C. The following compounds and their picrate salts are prepared in like manner by alkylation of the products of Examples 1V and V1 with the appropriate reactant:

l N (CH )n N 3 Ba R2 E 11 (cu moa 018E137 CH3 3 (ca moa c a 0 a 3 (ca hoa 0 CH3 '3 Replacement of palmitoyl chloride by acetyl chloride produces N,N-dioctadecyl-N, N-bis(2-acetyloxyethyl)-l,3-propanediamine. its hydrochloride salt prepared by standard methods melts at l03-7C.

Repetition of this procedure but using the appropriate acid chloride in place of palmitoyl chloride produces the following compounds:

:" 4 co R N (CH N (CH)-O-CO-R R'. n s R IH ZW Ht -Tl 3 2 S H m nr m a 3 Z C2H5 IN TIT IH IH 2 2 IS UI m nr ur a 2 2 CH1 G III IIi II 3 2 I 3I li l-i IS K 3 2 II 7 m ar is m 3 3 z s m m w u 3 3 m m IR IU IH K 4 2 IT QG IN IKT lfl -3 6 2 IS IH m ar lR fl 3 8 CH3 m ur rs a 3 8 H fB andthe mixture heated to reflux for one hour. The mix EXAMPLE XI ture is cooled, then taken to dryness under reduced pressure. The residue is triturated with carbon tetral,l Dioctadecyl-3-{2-[Bis(2-Hydroxyethyl) chloride, filtered, and the filtrate evaporated to dry- Amino]Ethyl}Urea ness. Ethyl acetate (25 ml.) is then added, the mixture cooled, filtered, washed with ethylacetate and dried in vacuo; m.p. 54-6C.

The following compounds are prepared from appropriate reactants by this procedure:

-0 CO-NHQCH A mixture ofN,N-dioctadecylcarbamyl chloride (2.9 g), N,N-bis-(Z-hydroxyethyh-1,2-ethanediamine (4.0 g.) and benzene ml.) is refluxed and stirred for 3 hours. The mixture is then cooled, concentrated in vacuo and the residue taken up on chloroform (100 R (CH N (CH N R (Cl-.1 O CO NH 0 H R R 'n" S'" CIRHIIT CIRHK'F 3 3 lli lL'l lfi llil 3 2 'zo 4i 2n -u 3 2 CHHQED HHZH 3 2 CIHHIW CINHHT 3 3 emu... om... 8 CIRHIIT CINHZU 3 6 CH C 37 3 3 CH C 3 6 CH C H 3 4 CIHHM CIR 3T 4 2 Cali... cum. 2 2

KH37 H1 3? 6 2 EXAMPLE x ml.). The chloroform solution is washed successively with water (2 X 50 ml.), aqueous sodium hydroxide (l X Q.t-.1 l)...and.watertlkiiQ. hen dri (Na SO4). 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. l52-153C.

The N,N-dioctadecylcarbamyl chloride is prepared by bubbling phosgene into a solution of N,N- dioctadecylamine 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 but substituting EXAMPLE xn N-(2-Hydroxyethyl)Octadecylamine A mixture ofoctadecyl 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-l45C. The mixture is cooled,

C H treated with eth lacetate (50 ml.) and 10 percenta ue- 18 37 0 3, y q

n y ous sodium hydroxide (10 ml.) The ethylacetate layer N c NH (Cl-I -1 N 1 is separated, washed with water, and dried (Na SO 4 0 Removal of the organic solvents under reduced pres- C H R sure gives an oil residue which solidifies u on coolin 1837 h 1' 'fdb h h l 'hhl V I V I t1s purl 1e y c romatograp y on a umma wit 0 o- R4 m m M (ac) roform as eluant. Its hydrobromide salt is prepared by CHZCHZOH CHzCHzOH I 3 1 5 gddin hydrogen lb7rggnilcl7e3 t)3 an ethanol solution of the CH3 C l 2 HCl 71-4 2156. t me is at CH CH OH CH-CH OH 1 5 HC] l20-3 I H 2 2 Z Z O 604 The compounds tabulated below are prepared from CHzCHgOH CH CH OH 0 4 the appropriate reactants A-Y-Br and H-NR R by the H CH CH oci-r 0 44-5 CH CH OH CHZCHZOH 1 2 HC] 152-3 above procedure H CH2CH2COOH O 77-81 20 I H H 0 6l-2 R q CH d CH -O-CH- o 42-4 A Y N 5 Y A" R}, R. Salt MP. (C.)

(CH2) 1 OH C H C H HBr 78-82 (gg2)3 0: gmfim gmgar 3 2 2)Zl O I l 17 l .17 1 12;.- g 93H; 5.33.1 .1 6 -(CH:): CN cling; CEIIHZ; Y HCl 73-74 (CH2)2 OH C H C H 35-37 (CH2)2 OH R .1 ix ar H 74-78 -(CH2)2 OCOCHH C H C H 32-35 2)2 2 5 H .7 M BT --(CH2) OCONHC H -I' C H C H 197-198 -25??? 2L0 I a m mg!" 5 -CHZ Z- 0c0cH.-."" QZHZ; KHZ; (a 650 -(CHz)-1 CNW C H H 84-85 Prepared by cyanoclhylation procedure of Vogel ct J.(.S. 5 I449 (i952).

The compounds listed b elo w are prepaied'"'i'i1"m manner from the appropriate reactants.

*Prepared from the corre sp amples Vlll-X.

ending hydroxyalkyl compounds of this example the reactions of the compounds listed below:

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 105C. on an oil bath. The mixture is poured over ice and the solid which forms separated by filtration: 4.9 g.; m.p. 5762C. It is dissolved in chloroform (50 ml.) and the solution extracted with 6N hydrochloricacid (3 X 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 X 50 ml.) and the emulsion which forms allowed to separate overnight. The chloroform layer is separated, dried (Na SO and concentrated in vacuo to an oil. Trituration of the oil with acetone produces a brown solid; 2.03 g.; mp. 52- 58C. Recrystallization from ethyl acetate raises the melting point to 77-8lC.

The following compounds are made from appropriate reactants (anhydrides and amines) by this procedure:

27 28 EXAMPLE XV half hour, then treated with an ethanolic solution of sodium hydroxide (0.4 g., 0.01 mole) and refluxed for 5 N-3-Dd l ldth l dN-3- g g Egg 3:55 :33;g gi ggg xfii an more mmutes. The mixture is cooled, filtered and the A mixture of bmmoethanol (250 Q05 mole) ehtanol removed by evaporation. The benzyl alcohol is dodecyloxy l pmpylamine (243 g 6 mole) a 5 then removed by distillation in vacuo and the residue ethancl (20 m1) is heated at reflux Overnight. The SOL chromatographed on silica using first ether then methavent is removed by evaporation, the residue slurried in Q as eluams Thehhsired product is cohtained in the hot water (20 mm and made Strongly alkaline with methanol eluate. It 1s isolated by evaporation of the soltassium hydroxide. The basic mixture is extracted with vent -P- 530440 Its hydrochloride Salt melts at ether (3 X 50 ml.), the ethereal extracts dried (MgSO and evaporated. The crude product mixture is purified Ih hke manner, the following compohrfds are P by chromatography on alumina. Using ether as eluant pared from the approphate reactants: A 2- removes the least polar impurity; elution with methanol Cl and removes the diethanolamine first, then the monoethal5 nolamme derivative. H Wm,

These two products appear as blue and yellow spots, respectively, when subjected to thin layer chromatog- 3 N raphy on a silica plate with methanol as eluant and 2 n R iodoplatinic spray as developer. v 6

A v n "R, i R Sult "MIPICCU" IN IIT 3 CHgCH OH H C,,.H;,1 3' CH2CH2OC2H5 H 155-7 m mi 3 CHZCHQOH H "H33 3 CH2CH2OH CHZCHQOH HCl l29-30 4H2 3 CHgCHzOH CHgCHgOH 30-] 4H2 3 CH2CH2OH CHQCHQOH HCl 72 (dcc.) C "H33 2 2 5 C2H5 175-8 (0.3 mm.) m nr 2 2 5 2 s l (0.2 mm.) C H 2 (,H C2H5 (0.2 mm.) m nr 2 CZH5 HC] 102- 4 m :i7 2 (C 2)3 (C' |H5)- g H ZHCl The monoethanolamine derivatives boils at I 7 EXAMPLE XVIl l60-l66 C. at 0.3 mm. mercury. v V V g H h g The following compounds are prepared in like man- Following the procedures of Examples XV and XVI her from approprite reactants: AO-(CH ),,NH 40 the compounds listed below are prepared from approand BrR priate reactants:

I A o (on R h A'-'(CH) ---N 2 n (R a or R )v R n s ma a 2 IN RT lX 37 IH ZS 3 IN IW H |2 25 3 IM KT I8 37 B S 3 IO ZI IO 2I 2 5 6 IH HT I IB 31 lH -TF 3 IH TT H IX IH 3 lH -17 IB -TI' IX JT 3 IH R'I l8 -3T G L'R 3 lli iL'l IG IL'I IE IIH 2 IZ ZS IZ Z') 6 3. 2 H 2 25 II 6 IH BT IX IIT A n R, R, Salt MP. 00) v 32 2 2 2 CH; CH; CHJ l65-7 R chm: 3 CH; H Hi 210-1 3 9 m m 3 CHQCHQOH H HE! R V A if R" "'"R" M R" EXAMPLE XVI W M 3 m 11 H H C H O 3 3 oc,H 4-oc,,H H N-(3-Dodecylth1opropyl)Diethanolamme CINHMO 3 1 iz .1 c u o 3 4,5 0 CH, o 243 a, A mixture of 3-octadecylthiopropyl chloride (3.35 g., W W 3 4OCH8H" H 0.01 mole), diethanolamine (2.1 g., 0.02 mole) and 2 5 443cm H CHHMO 2 3-OCHH 4OC H H benzyl alcohol (5 ml.) is heated under reflux for one- C H O 3 4- 0C,H,, 4 0C 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-l06C. at 0.05 mm. mercury.

The following compounds are likewise prepared from appropriate reactants by this procedure:

EXAMPLE XIX Ethyl 4-Dioctadecylaminobutyrute A solution of dioctadccylamine (5.2 g., 0.01 mole), 5 ethyl 4-bromobutyrate (1.95 g., 0.01 mole) andtoluene (50 ml.) is heated at reflux for sixteen hours, then cooled and concentrated in vacuo to a semisolid oil. The oil is triturated with ethylacetate, filtered, and the filtrate washed with water, then dried (Na SO 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. 98-101C.

Substitution of ethyl 4-bromobutyrate by the appropriate lower alkyl w-bromoalkanoate in the above procedure produces the following compounds:

5 A Y N A Y R R. Salt M.P.(C.)

cooc n CH2 WHM iu rn 40 Z S H2). can, C H HCl 46-48 2 5 H.).- cam, c i-i HCl 52-53 EXAMPLE XX l-(N,N-Dioctadecylcarbamyl )-4-Methylpiperazine A mixture of l-methylpiperazine (5 ml.), N,N-

dioctadecylcarbamylchloride (5.0 g.) and benzene (50 ml.) is refluxed and stirred for 3 hours. The white precipitate of l-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 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. 46-47 C.

Thefollowing compounds are prepared from the appropriate reactants (R R NCOCI and H-Z):

R 7 O n N C Z 8 R R Z C12H25 c H- butylpiperazino iz -zs C H piperidino C|2H25 C H morpholino w m CH methylpiperazino m rn CH morpholino l8 31 C H hydroxycthylpiperazino C H C|2H25 hydroxyethylpiperazino m n: CH hydroxyethylpiperazino ia sr C H, piperazino CI2H25 |2H25 piperazino 3H3: CH piperazino EXAMPLE XXl N,N-Dioctadecyl-N',N'-bis(2Hydroxyethy1)-1,3- Propanediamine-N,N'-Dioxide To a solution of N,N-dioctadecy1-N,N-bis(2- hydroxyethy1)-l,3-propanediamine (3.34 g., 5 mM.) in chloroform m1.) 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 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;. sQ landconcentrated to an oil (2.5 g.).

The hydrochloride salt is prepared by the procedure of Example V; m.p. 89-94 C., 114 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 SO and evaporation of the solvent. Recrystallization from chloroform-ethylacetate provides the pure base; m.p. 95-99 C.

EXAMPLE xxm Repetition of the procedures of Example Ill-B and C,

but using the appropriate alkanediamine and acid chloride reactants provides the following compounds:

EXAMPLE XXIV 1 -Dodecy1-4-(Z-Hydroxyethyl)Piperazine salt melts at 99,103 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- 80 and evaporated. The white solid which remains melts at 6567 C.

By means of the above procedure, the following com- The products of the preceding examples are conpounds are prepared but using the appropriate alkyl' verted to their N-oxide derivatives in like manner. bromide and l-(hydroxyalkyl)piperazine reactants:

R N N (ca H H H EXAMPLE XXII R" p+1 n M.P. (degrees C.) v C,2H25 3 0 55-7 N.N-Dioctadecyl N N bis(2-Hydroxyethy1)-1,3- 812325 3 8 ggj figgg zzg l Propanediamine N-Methonium Iodide 3 |H |2(HBrsa1t) Methyl iodide (568 mg., 4.0 mM.) is added all at C H 6 0 once to a solution of N,N-dioctadecy1-N,N'-bis(2- E E g 8 hydroxyethy1)-1,3-propanediamine (1.334, g., 2.0 2 1 mM.) in methylene chloride (10 ml.) which is cooled CIZHZS 3 2 in an ice-bath. The mixture is stirred and allowed over 7 a 4-hour period to warm to room temperature, then stirred at room temperature overnight. The solid resi 5 I due obtained by removal ofthe chloroform is recrysta1-' R fi lized from ethylacetate; 1.35 g, m.p. 122 C. 8 R" 2 33 34 i .3; e B

a-oc n P 11 a 2 o 3-oc a 4-OC6H13 a 3 o 3OC6H13 4-OC6H13 H 6 o a-oc a 2-cii a-ca 3 0 4-0G l1 H a 3 0 POC 11 a H 5 0 3'OCH3 4-OC H33 H 2 0 4,5--0 CH 0 2-0 11 5 o 2-oc a 4-oc n 5-c a 3 o 3-oc a 4-oc n H 2 1 4-oc t1 H H 2 1 2-oca 4OC H 7 5-0011 2 1 2-oc 1i 4-oc 11 5 00 a 2 1 2-OC16H33 4-OC16H33 5 OC l-I33 Z 2 3-OC6Hl3 4-OC6H13 H 2 2 3-oc a 400 11 H 3 2 a-oc a H n 3 2 EXAMPLE XXV N,N-Bis(3,4-Dihexoxybenzyl)-N,N-Bis(2- l-lydroxyethyl l ,3-Propanecliamine 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 X100 ml.), dried (Na SO 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 evolu tion 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 X100 ml.). The chloroform extracts are combined, washed successively with saturated sodium bicarbonate solution (2 X100 ml.) and water (3 X100 ml.). It is then dried (Na SO 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., mM) and potassium carbonate (2.07 g., 15 mM) is stirred at room temperature for 16 hours and then at 130 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 R E ca 2-11-CH2CH2CH2 ntcrr ca om EXAMPLE XXVI N,N-Bis( 3 ,4-Dihexoxybenzyl)-l ,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 ml.) are charged into a Paar shaker and hydrogenated at 40 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 with water and air dried. It is then dissolved in chloroform (75 ml. the solution washed with water (50 ml.

and filtered. The filtrate is concentrated in vacuo to an dried (Na SO and concentrated to give amber oil which is dissolved in ethyl acetate (50 ml.). bis(3,4-dihexoxybenzyl)aminc as an oil; l.4 g.. 69.8 The solution is treated with ethyl acetate saturated with 5 yield. hydrogen chloride 100 ml.) and the resulting white hy- Acrylonitrile (15 ml.) and his 3,4-dihexoxybenzyldrochloride salt collected; 3.7 g., m.p. 205-206 C. )amine are refluxed together for l8 hours. The mixture The salt is then partitioned between chl r f m (100 is then cooled and concentrated in vacuo to an oil: 1.2 ml.) and saturated sodium bicarbonate solution (50 gi ml.). The chloroform phase is separated, washed with The cyanoethyl ldeflvatlve g), hlckel water (50 ml.), dried (Na SO and concentrated to g ammOma 8-) and ethanol are give 3,4-dihexoxybenzylamine as an oil; 3.2 g., 52.1% charged into a Paar shaker and hydrogenated at room ield. tem erature and an initial ressure of 50 si. When u y I P P P P A solution of 3,4-d1hexoxybenzylamine (2.0 g., 6.52 take of hydrogen is complete, the contents are removed mM), 3,4-dihexoxybenzaldehyde (2.0 g., 6.52 mM), filtered and concentrated to give the title produce as an benzene (75 ml.) and p-toluenesulfonic acid (200 mg.) 011 g-)- is refl xed with ti i i apparatus i d ith a The dihydrochloride salt is formed by dissolving the Dean-Stark collector for 16 hours. It is then cooled and ProduCt ether and bubbling hydrogen Chloride into concentrated in vacuo to an oil which crystallizes upon the SOIUUOII' Removal Of h ther nder reduced presstanding: 4.0 g. of the Schiff base. sure g ves the salt. n

The Schiff base is reduced by treatment with sodium Smnlarly. s p p y y )-l borohydride (03 78 ,)-i th l l per 2 f propanediamme 18 prepared by substituting 3,4diiso- Schiff base) at room temperature for 20 hours. The p p y yd for d y nza d hyd mixture is concentrated under reduced pressure to a 78 Its dihydrochloride salt metls at '68 C.- solid which is taken up in methanol. Hydrogen chloride gas is bubbled into the solution. water (50 ml.) added EXAM E and the salt filtered. washed with water and air dried. The fOHOWIh'g N y y|)- The dry salt is dissolved in warm methanol ml.), alkanediamin'c derivatives are prepared from approprisaturated aqueous sodium bicarbonate (50 ml.) and ate reactants by the procedures of ExamplesXXV, water (50 ml.) added. The solid is filtered off, washed 30 XVI and X I l I? 3 I R CH2 N &X N X' N\ R R R X m X R3 V 2OC3H1 3OC2H,, H O CH2CHI CH2CH2OH CHQCHQOH 3 0CH 4-0C...H H 0 -(CHZ)3 CH CH OH CH CH OH ,G 11 H H 0 (CH..).- CH Cl-l OH CH2CH2OH X2 TS l2 25 H 0 2)1 a m m 3OC H 4OC,2H2,, H O -(CH H3 m a1 r: u n m H 0 (CH2) CHZCHZ OH CH2CH2OH is n H H O (CH2)1-- (CHQGOH (CH OH P H, m :n H o -(CH2)2 C .,H H 2 OC2H 4 OC2H5 n m O (CH2)(F m 2| m -n K H H H 0 CH CH -CH=CH CH -CH=CH |1 H H CH CH l -CH CH CH CH OH cH cH oH m 37 H H -(CH2 l -(CH2)3 CH2CH2OH CH CH OH fi l-'l u m H (CH2)4 l (CH2)4- CH2CH2OH CHZCHZOH C2 5 4 OC2H5 z 2)3 1 (C 2)1- iu m m M 1l nt :n 6 CH:1 *CH2CH2 l CH2CH2 (CH2).|OH (CH 2)40H .-l 4 OC|2H2: 60CH=, 0 -(c CH CHOHCH OH CHZCHOHCHZOH n r. .2 2.-, H 0 -(CH2);, CHZCHOHCHZOH CH2CHOHCH2OH 4OC|M (7 H H 0 (CH2) 1 H C1H|5 -QQH... H (CH2)=, 1 (CH CH2CHOHCH3 cH cHoHcH :IH JW 1! 6 CH:1 0 (CH2) r- CH2COOCH3 CHQCOOCHK Ha H H 0 -(CH,) CH2CH2OCHHZ5 H rx ii 3 0( 2H5 H (CH2)2 1 -(CH )g H37 CH2CH=CH2 4-()( .,.H H H (CH2)2- 1 (CH CH2CH=CH2 CH2CH%H2 N IZI u m H 0 (CH2), H i H m :n H H (CH2) 1 -(CH2)2 H H 2 u m m 6 l1l 0 (CHg)3 CHZCHZOH CHZCHZOH :"O( H:| IN IW 5 OCH.1 O (CH2)4- C H 7 CRHH 2 'OEHII 4-OC lJ LS 7-OCH3 0 -(CH2);; H H 4 o( ..H.,,. H H 0 H2)2- H H 2 oc..H, 3-OC2H5 H 0 (CH2)., H H z ;12 's 4 0C2H5 H 0 (CH2),; H H 4 O(- IN I H H 0 -(CH2 1 H H 2 2 a 0 (CH2).1- H H 0 (CH CH-CH OCH- CH CH H. Foetal. 2CH1, 6 cH 0 r jll H 2 =C Qfi I r m H co 1 (CH CH CH OH CH Cl-l OH i' gg ff 0C H S g8 flgfinr t t H l og (CHMOH 1a i. H CHqCH OH 4 s o c H: 2C '.H CO l (CH:),, rci i i 2

Claims (6)

1. A COMPOUND OF THE FORMULA

2. A compound according to claim 1 wherein R1 is alkyl of from 6 to 20 carbon atoms; R3 and R4 are each hydroxyalkyl of from 2 to 4 carbon atoms; X and X'' are each alkylene of from 2 to 3 carbon atoms; and m is 1.

3. A compound according to claim 1 wherein m is 0.

4. A compound according to claim 1 wherein R1 and R2 are each alkyl of from 12 to 20 carbon atoms; R3 and R4 are each hydroxyethyl; X'' is straight chain alkylene of from 3 to 5 carbon atoms; and m is 0.

5. N,N-Dioctadecyl-N'',N''-bis(2-hydroxyethyl)-1,3-propanediamine, a compound according to claim 4 wherein R1 and R2 are each octadecyl and X'' is propylene.

6. A compound according to claim 1 wherein R1 is alkyl of from 12 to 20 carbon atoms.