A compound having the formula ##STR1## where Ar=naphthyl, biphenyl, or quinolinyl; PA1 X=oxygen or NH; PA1 Y=2 to 8; PA1 R.sub.1 =phenyl, substituted phenyl, hydrogen, lower alkyl; and PA1 R.sub.2 is the same or different from R.sub.3 and is alkyl, cycloalkyl, phenyl, substituted phenyl, thiazolyl; and PA1 the pharmaceutically acceptable salts thereof. Compounds of this general formula are useful as anti-inflammatories, and as anti-psoriatic agents.

BACKGROUND OF THE INVENTION 
This invention relates to a series of guanidine derivatives characterized 
by an (aryloxy or arylamino) alkyl substituent. In particular, this 
invention relates to guanidine derivatives useful as anti-inflammatory 
agents. 
Substituted guanidines are known in the art. U.S. Pat. No. 3,159,676 issued 
to Spickett et al discloses a series of arylamino and aryloxy alkyl 
guanidines. These guanidines have only one of the three guanidine 
nitrogens substituted with other than hydrogen atoms. Other similar 
examples include J Med Chem 9, 22 (1966) in which a variety of substituted 
phenoxy alkyl guanidines were reported to have anti-inflammatory 
properties. The substituents on the benzene ring in that reference are 
lower alkyl or halogen. 
SUMMARY OF THE INVENTION 
This invention provides compounds having the formula 
##STR2## 
where Ar=naphthyl, biphenyl, or quinolinyl; 
X=oxygen or NH; 
Y=2 to 8; 
R.sup.1 =phenyl, substituted phenyl, hydrogen, lower alkyl; and 
R.sub.2 is the same or different from R.sub.3 and is alkyl, cycloalkyl, 
phenyl, substituted phenyl, thiazolyl; and the pharmaceutically acceptable 
salts thereof. 
Preferred compounds are those wherein Ar is naphthyl, especially 
1-naphthyl, Y is 6 to 8, and X is O R.sub.1 is hydrogen, and R.sub.2 is 
the same as R.sub.3 and R.sub.2 and R.sub.3 are selected from the group 
consisting of phenyl and optionally substituted phenyl. Particularly 
preferred compounds include those where R.sub.2 and R.sub.3 are lower 
alkyl phenyl and lower alkoxy phenyl, particularly preferred when R.sub.2 
and R.sub.3 are 2-methylphenyl. 
DETAILED DESCRIPTION OF THE INVENTION 
Definitions 
As used herein: 
"Alkyl" means a branched or unbranched saturated hydrocarbon chain 
containing 1-8 carbon atoms, such as methyl, ethyl, propyl, tert-butyl, 
n-hexyl, n-heptyl or iso-octyl and the like. 
"Alkoxy" means the group --OR wherein R is alkyl as herein defined. 
"Cycloalkyl" means saturated carbocyclic rings containing 5-7 carbon atoms. 
"Alkylene" means (CH.sub.2).sub.n wherein n is an integer from 2-8. 
"Optional" or "optionally" means that the subsequently described event or 
circumstance may or may not occur, and that the description includes 
instances where said event or circumstances occurs and instances in which 
it does not. For example, "optionally substituted phenyl" means that the 
phenyl may or may not be substituted and that the description includes 
both unsubstituted phenyl and phenyl wherein there is substitution; 
"optionally followed by converting the free base to the acid addition 
salt" means that said conversion may or may not be carried out in order 
for the process described to fall within the invention, and the invention 
includes those processes wherein the free base is converted to the acid 
addition salt and those processes in which it is not. "Optionally 
substituted phenyl" means a phenyl moiety, which may or may not be 
substituted as indicated in the previous paragraph, with 1-3 substituents 
selected from the group consisting of halo, lower alkyl, lower alkoxy, 
where lower refers to fewer than four carbon atoms, and hydroxy. 
"Substituted phenyl" means a phenyl moiety that is so-substituted. 
The guanidines of this invention contain basic nitrogens that can be 
reacted with mineral or organic acids to form pharmaceutically acceptable 
acid addition salts. 
"Pharmaceutically acceptable acid addition salt" refers to those salts 
which retain the biological effectiveness and properties of the free bases 
and which are not biologically or otherwise undesirable, formed with 
inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric 
acid, nitric acid, phosphoric acid and the like, and organic acids such as 
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, 
malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, 
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, 
menthanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 
salicylic acid and the like. 
METHODS OF PREATION 
Substituted guanidines can be synthesized by several methods well known to 
the art. For example, "Methoden Der Organishe Chemie (Houben-Weyl)" Vol. 
VIII, p. 180-188 describes methods for preparing guanidines. 
In equations 1 through 7, R.sup.4, R.sup.5, and R.sup.6 can be any 
substituent to give a guanidine of Formula 1, although it should be 
realized that the reactions that are represented are general for all 
guanidines. 
Guanidines can be synthesized by reacting a primary amine with a 
cyanoamine. The particular guanidine produced depends on the substituents 
present on the amine and cyanoamine starting materials (Equation 1). 
Approximately equimolar amounts of the starting materials are heated 
together at from about 50.degree. C. to about 250.degree. C., preferably, 
at about 170.degree. C. A polar organic solvent such as ethanol or 
dimethylformamide (DMF) may be optionally used. 
##STR3## 
The cyanoamine starting materials can be conveniently synthesized by 
heating a mixture of an appropriately substituted amine and an equimolar 
amount of cyanogen bromide in the presence of an inert organic solvent 
such as benzene (Equation 2) 
##STR4## 
The reactants are heated at from about 50.degree. to reflux temperature, 
for from 1 to 24 hours. 
Guanidines can be synthesized by reacting together an amine and either an 
appropriately substituted urea or, more preferably, an appropriately 
substituted thiourea (Equation 3). A mixture of equimolar amounts of each 
of the reactions, dissolved in a polar organic solvent such as methanol or 
ethanol, is heated. The reaction proceeds at a temperature in the range of 
about 50.degree. to reflux temperature, preferably at reflux temperature. 
The reaction is continued from 6 to 48 hours. Synthetic Organic Chemistry 
by R. B. Wagner and H. B. Zook. p. 645-652 and 827-831 describes methods 
to synthesize the urea and thiourea starting materials. 
##STR5## 
where X=O or S. 
Guanidines can be synthesized by reacting a primary amine and either an 
appropriately substituted alkyl isourea or an appropriately substituted 
alkyl isothiourea (Equation 4). Equimolar amounts of the reactants are 
heated together at a temperature of from about 50.degree. C. to about 
150.degree. C., preferably about 100.degree. C. The reaction may 
optionally be conducted in a polar solvent such as methanol, ethanol or 
DMF. 
##STR6## 
where X=O or S, R.sup.7 =alkyl. 
The alkyl isourea and alkyl isothiourea starting materials can be prepared 
by any standard methods. For example, they may be prepared by the 
alkylation reaction of, for example, methyl iodide, and a thiourea, or by 
the reaction between a chloroimine compound R.sub.2 N.dbd.C(Cl)--NHR.sub.3 
and an alcohol or mercaptan (Equation 5). 
##STR7## 
X=O or S, R.sub.7 =alkyl. 
Guanidines can be synthesized by reacting an amine and a substituted 
carbodiimide (Equation 6). Equimolar amounts of the reactants are heated 
together at a temperature of between 50.degree. C. and 150.degree. C., 
preferably about 100.degree. C., for about 1/2 to 12 hours. The reaction 
proceeds well in an optional inert organic solvent such as tetrahydrofuran 
or DMF. 
##STR8## 
The carbodiimide starting material is conveniently synthesized by, for 
example, the treatment of a urea with a dehydrating agent such as 
toluenesulfonyl chloride and pyridine (Equation 7) 
##STR9## 
or by the oxidation of a thiourea using, for example, mercuric oxide. 
The compounds of Formula 1 in free base form may be converted to the acid 
addition salts by treating with a stoichiometric excess of the appropriate 
organic or inorganic acid, for example, hydrochloric acid, nitric acid, 
sulfuric acid, malic acid, and the like. Typically, the free base is 
dissolved in a polar organic solvent such as ethanol or methanol, and the 
acid added thereto. The temperature is maintained between about 0.degree. 
C. and 100.degree. C. The resulting acid addition salt precipitates 
spontaneously or may be brought out of solution with a less polar solvent. 
The acid addition salts of the compounds of Formula 1 may be decomposed to 
the corresponding free base by treating with a stoichiometric excess of a 
suitable base, such as potassium carbonate or sodium hydroxide, typically 
in the presence of aqueous solvent, and at a temperature of between about 
0.degree. C. and 100.degree. C. The free base form is isolated by 
conventional means, such as extraction with an organic solvent. 
Salts of the compounds of Formula 1 may be interchanged by taking advantage 
of differential solubilities of the salts, volatilities or acidities of 
the acids, or by treating with the appropriately loaded ion exchange 
resin. For example, the interchange is effected by the reaction of a salt 
of the compounds of Formula 1 with a slight stoichiometric excess of an 
acid of a lower pK than the acid component of the starting salt. This 
conversion is carried out at a temperature between about 0.degree. C. and 
the boiling point of the solvent being used as the medium for the 
procedure. 
The compounds of Formula 1 have been shown in standard laboratory tests to 
inhibit inflammation. Thus, the antiinflammatory activity of compounds of 
Formula 1 can be demonstrated by standard in vitro laboratory tests, such 
as by their ability to inhibit the enzymes phospholipase and lipoxygenase, 
or to inhibit the chemotaxis of leukocytes, or to inhibit the generation 
of superoxide. The antiinflammatory activity of compounds of Formula 1 can 
also be demonstrated by standard in vivo laboratory tests, such as by 
their ability to inhibit carageenan-induced pleural inflammation in rats, 
or to inhibit adjuvant arthritis in rats, or to inhibit topical 
inflammation induced by croton oil, oxazolone or arachidonic acid in rats 
or mice. Accordingly, the compounds of Formula 1 or their salts or 
pharmaceutical compositions containing them, may be used in inhibiting, 
preventing, or controlling inflammation in mammals. In addition, the 
compounds of Formula 1 have been shown to be effective as anti-psoriatic 
agents. 
The antipsoriatic activity of compounds of Formula I can be demonstrated by 
the ability of the compounds to inhibit psoriasis in humans. One skilled 
in the art will recognize that other tests may be applicable for verifying 
anti-inflammatory or anti-psoriatic activity. 
Administration of the active compounds and salts described herein can be 
via any of the accepted modes of administration for agents that control 
inflammation. These methods include oral, parenteral and otherwise 
systemic or topical. 
Depending on the intended mode of administration, the compositions used may 
be in the form of solid, semi-solid or liquid dosage forms, such as, for 
example, tablets, suppositories, pills, capsules, powders, liquids, 
suspensions, or the like, preferably in unit dosage forms suitable for 
single adminstration of precise dosages. The compositions will include a 
conventional pharmaceutical carrier or excipient and an active compound of 
Formula 1 or the pharmaceutically acceptable salts thereof and, in 
addition, may include other medicinal agents, pharmaceutical agents, 
carriers, adjuvants, etc. 
For solid compositions, conventional non-toxic solid carriers include, for 
example, pharmaceutical grades of mannitol, lactose, starch, magnesium 
stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium 
carbonate, and the like may be used. The active compound as defined above 
may be formulated as suppositories using, for example, polyalkylene 
glycols, for example, propylene glycol, as the carrier. Liquid 
pharmaceutically administerable compositions can, for example, be prepared 
by dissolving, dispersing, etc. an active compound as defined above and 
optional pharmaceutical adjuvants in a carrier, such as, for example, 
water, saline, aqueous dextrose, glycerol, ethanol, and the like, to 
thereby form a solution or suspension. If desired, the pharmaceutical 
composition to be administered may also contain minor amounts of nontoxic 
auxiliary substances such as wetting or emulsifying agents, pH buffering 
agents and the like, for example, sodium acetate, sorbitan monolaurate, 
triethanolamine sodium acetate, triethanolamine oleate, etc. Actual 
methods of preparing such dosage forms are known, or will be apparent, to 
those skilled in this art; for example, see Remington's Pharmaceutical 
Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. The 
composition or formulation to be administered will, in any event, contain 
a quantity of the active compound(s) in an amount effective to alleviate 
the symptoms of the subject being treated. 
For the compounds of formula 1, either oral or topical administration is 
preferred depending on the nature of the disorder being treated. 
For oral administration, a pharmaceutically acceptable non-toxic 
composition is formed by the incorporation of any of the normally employed 
excipients, such as, for example pharmaceutical grades of mannitol, 
lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, 
glucose, sucrose, magnesium, carbonate, and the like. Such compositions 
take the form of solutions, suspensions, tablets, pills, capsules, 
powders, sustained release formulations and the like. Such compositions 
may contain 1%-95% active ingredient, preferably 25-70%. 
For topical administration, these compositions comprise an effective amount 
of a compound of this class in admixture with a pharmaceutically 
acceptable non-toxic carrier. A suitable range of composition would be 
0.1%-10% active ingredient, and the balance carrier, preferably 1-2% 
active ingredient. The concentration of active ingredient in 
pharmaceutical compositions suitable for topical application will vary 
depending upon the particular activity of the compound used in conjunction 
with the condition and subject to be treated. Suitable carriers or 
medicament vehicles for topical application of these compounds include 
creams, ointments, lotions, emulsions, solutions and the like. 
For example, a suitable ointment for topical application of compounds of 
the instant invention contains 15 to 45 percent of a saturated fatty 
alcohol having 16 to 24 carbon atoms such as cetyl alcohol, stearyl 
alcohol, behenyl alcohol, and the like and 45 to 85 wt. percent of a 
glycol solvent such as propylene glycol, polyethylene glycol, dipropylene 
glycol, and mixtures thereof. The ointment can also contain 0 to 15 wt. 
percent of a plasticizer such as polyethylene glycol, 1,2,6-hexanetriol, 
sorbitol, glycerol, and the like; 0 to 15 wt. percent of a coupling agent 
such as a saturated fatty acid having from 16 to 24 carbon atoms, e.g., 
stearic acid, palmitic acid, behenic acid, a fatty acid amide e.g., 
oleamide, palmitamide, stearamide, behenamide and an ester of a fatty acid 
having from 16 to 24 carbon atoms such as sorbitol monostearate, 
polyethylene glycol monostearate, polypropylene glycol or the 
corresponding mono-ester of other fatty acids such as oleic acid and 
palmitic acid; and 0 to 20 wt. percent of a penetrant such as dimethyl 
sulfoxide, or dimethylacetamide. 
The amount of active compound administered will of course, be dependent on 
the subject being treated, the severity of the affliction, the manner of 
administration and the judgment of the prescribing physician. However, an 
effective dosage is in the range of 1-100 mg/kg/day, preferably about 25 
mg/kg/day. For an average 70 kg human, this would amount to 70 mg-7 g per 
day, or preferably about 1.5 g/day. 
The compositions of the present invention may be formulated for 
administration in any convenient way by analogy with other topical 
compositions adapted for use in mammals. These compositions may be 
presented for use in any conventional manner with the aid of any of a wide 
variety of pharmaceutical carriers or vehicles. 
The compounds of Formula 1 may be formulated with suitable pharmaceutical 
vehicles known in the art to form particularly effective topical 
compositions. An effective amount of the guanidine compound is about 
0.001% w/w to about 10% w/w of the total formulated composition. The rest 
of the formulated composition will be about 90% w/w to about99.999% w/w of 
a suitable excipient which may include a pharmaceutically acceptable 
solvent and other pharmaceutically acceptable additives to form a 
topically effective pharmaceutical formulation. 
A pharmaceutically acceptable solvent is one which is substantially 
non-toxic and non-irritating under the conditions used and may be readily 
formulated into any standard drug formulations such as powders, creams, 
ointments, lotions, gels, foams, aerosols, solutions and the like. 
Particularly suitable solvents include water, ethanol, acetone, glycerine, 
propylene carbonate, dimethylsulfoxide (DMSO), and glycols such as 
1,2-propylene diol, i.e., propylene glycol, 1,3-propylene diol, 
polyethylene glycol having a molecular weight of from 100 to 10,000, 
dipropylene glycol, etc. and mixtures of the aforementioned solvents with 
each other. 
A topical cream may be prepared as a semi-solid emulsion of oil in water or 
water in oil. A cream base formulation by definition is an emulsion, which 
is a two-phase system with one liquid (for example fats or oils) being 
dispersed as small globules in another substance (e.g., a glycol-water 
solvent phase) which may be employed as the primary solvent for the 
quanidine compounds therein. The cream formulation may contain fatty 
alcohols, surfactants, mineral oil or petrolatum and other typical 
pharmaceutical adjuvants such as anti-oxidants, antiseptics, or compatible 
adjuvants. A typical cream base formulation is as follows: 
______________________________________ 
Water/glycol mixture 
50-99 parts by weight 
(15% or more glycol) 
Fatty Alcohol 1-20 
Non-ionic Surfactant 
0-10 
Mineral Oil 0-10 
Typical pharmaceutical 
0-5 
Adjuvants 
Active Ingredients 
0.001-10 
______________________________________ 
The fatty alcohol, non-ionic surfactant, and other adjuvants are discussed 
in U.S. Pat. No. 3,934,013 to Poulsen which is incorporated herein by 
reference. 
The compounds of Formula 1 may also be formulated as topical ointments. The 
standard ointment is a semisolid anhydrous composition which may contain 
mineral oil, white petrolatum, a suitable solvent such as a glycol and may 
include propylene carbonate and other pharmaceutically suitable additives 
such as surfactants, for example Span and Tween, or wool fat (lanolin), 
along with stabilizers such as antioxidants and other adjuvants as 
mentioned before. Following is an example of a typical standard ointment 
base: 
______________________________________ 
White Petrolatum 
40-94 parts by weight 
Mineral Oil 5-20 
Glycol Solvent 
1-15 
Surfactant 0-10 
Stabilizer 0-10 
Active Ingredients 
0.001-10.0 
______________________________________ 
Other suitable ointment base formulations which employ propylene carbonate 
are described in U.S. Pat. No. 4,017,615 issued Apr. 12, 1977 by Shastri 
et al entitled "Propylene Carbonate Ointment Vehicle" and U.S. Pat. No. 
3,924,004 issued Dec. 2, 1975 by Chang et al entitled "Fatty 
Alcohol-Propylene Carbonate-Glycol Solvent Cream Vehicle". As much of 
those applications as is pertinent is incorporated herein by reference. 
Following is a typical ointment base formulation containing propylene 
carbonate: 
______________________________________ 
Active Ingredients 
0.001-10.0 parts by weight 
Propylene Carbonate 
1-10 
Solvent 1-10 
Surfactant 0-10 
White Petrolatum 
70-97 
______________________________________ 
Suitable solvents, surfactants, stabilizers, etc. are discussed in U.S. 
Pat. No. 3,934,013 and such as incorporated herein by reference. 
A suitable topical anhydrous, water washable, ointment type, base is 
described in U.S. Pat. No. 3,592,930 to Katz and Neiman, and that patent 
is incorporated herein by reference. A representative composition of this 
invention utilizing such base is as follows: 
______________________________________ 
Glycol Solvent 40-35 parts by weight 
Fatty Alcohol 15-45 
Compatible Plasticizer 
0-15 
Compatible Coupling 
0-15 
Agent 
Penetrant 0-20 
Active Ingredients 
0.001-10.0 
______________________________________ 
Another aspect of the invention is a method for relieving the condition of 
psoriasis in a mammal by topically administering a composition containing 
a compound of Formula 1. Generally, the anti-psoriatic manifestation in 
mammals, particularly humans, is combatted by contacting the inflamed 
areas with a therapeutically effective amount of the guanindine-containing 
compositions of this invention, that is, an amount which results in a 
lessening of the epidermal cell proliferation (an anti-psoriatic effect). 
Preferably the guanidines are first formulated to prepare a suitable 
pharmaceutical formulation, as discussed hereinabove, which is then placed 
in contact with the afflicted area(s). An effective amount of the 
guanidine compound will depend upon the particular condition and the 
mammal receiving the treatment and will vary between 0.001% to 10% by 
weight of the pharmaceutical composition and preferably will be between 
0.01% and 1% by weight of the formulation. Using these levels in the 
formulation, a therapeutically effective and non-side effect producing 
amount, i.e. enough to effect an anti-psoriatic response, but not enough 
to adversely effect the recipient, is applied to the afflicted area(s).

EXAMPLES 
Preparation 1 
1-Amino-6-(7-chloro-4-quinolinyl)hexane 
17.1 Grams of hexane-1,6-diamine and 4.3 g of 4,7-dichloroquinoline were 
mixed together and heated to 150.degree. C. for four hours. The reaction 
was cooled and water and methylene chloride were then added. The organic 
phase was washed, dried with anhydrous magnesium sulfate and evaporated 
thereby affording 1-amino-6-(7-chloro-4-quinolinyl)hexane having a melting 
point of 133.degree.-134.degree.. 
Other compounds that can be made by the same general synthetic method by 
appropriate substitution of starting materials include: 
1-amino-6(4-quinolinyl)hexane 
1-amino-2(4-quinolinyl)ethane 
1-amino-4(4-quinolinyl)butane 
1-amino-8(4-quinolinyl)octane 
Preparation 2 
1-AMINO-8-(1-NAPHTHYLOXY)OCTANE 
2(A) Preparation of 1-chloro-8-(p-toluenesulphonyloxy)octane 
20.5 Grams of p-toluenesulphonyl chloride were added to a mixture of 17.7 g 
8-chloro-1-octanol and 50 ml of pyridine at 0.degree.. After an hour the 
solution was added to ice and the mixture was extracted with ether. The 
ethereal solution was washed with dilute hydrochloric acid, dried with 
magnesium sulfate, and evaporated to yield the title compound as an oil. 
In a similar manner, using the appropriate .omega.-chloroalkanols, the 
following compounds were prepared: 
1-chloro-2-(p-toluenesulphonyloxy)ethane 
1-chloro-3-(p-toluenesulphonyloxy)propane 
1-chloro-4-(p-toluenesulphonyloxy)butane 
1-chloro-5-(p-toluenesulphonyloxy)pentane 
1-chloro-6-(p-toluenesulphonyloxy)hexane 
1-chloro-7-(p-toluenesulphonyloxy)heptane 
2(B) 1-Chloro-8-(1-naphthyloxy)octane 
A mixture of 1-naphthol (12.9 g), potassium carbonate (23.5 g), 
1-chloro-8-(p-toluenesulphonyloxy)octane (23.5 g) and dimethylformamide 
(200 ml) was stirred at 55.degree. for 2-1/2 days. The solution was then 
cooled and added to water, and extracted with ether. The extract was dried 
and evaporated and the residue was chromatographed on silica gel (750 g), 
eluting with 3:1 hexane: methylene chloride, so as to afford the title 
compound as an oil. 
Similarly, using the procedure in paragraph A and B but substituting a 
different 1-chloro-.omega.-(p-toluenesulphonyloxy)alkane, the 
corresponding 1-chloro-.omega.-(1-naphthyloxy) alkanes are obtained. 
2(C) 1-Amino-8-(1-naphthyloxy)octane 
9.5 g of 1-chloro-8-(1-naphthyloxy)octane and 8.4 g of potassium 
phthalimide were taken up in 50 ml DMF and the resulting solution was 
heated at 140.degree. for 3 hours. The reaction solution was then poured 
into water and extracted with dichloromethane. The extract was washed, 
dried and evaporated and the residue was crystallized from acetone/hexane 
to afford the intermediate N-[8-(1-naphthyloxy)octyl]phthalimide mp 
63.degree.-64.degree.. 
A solution of 10.0 g N-[8-(1-naphthyloxy)octyl]phthalimide, prepared as 
above, and 200 ml of ethanol and 3.2 ml of hydrazine hydrate was refluxed 
for 18 hours. The solution was evaporated to about 100 ml, and diluted 
with 200 ml of water, then basified with aqueous potassium hydroxide and 
extracted with hexane. The extract was washed, dried and evaporated to 
give the title compound as an oil which was converted to the 
hydrochloride, mp 90.5.degree.-92.degree.. 
Similarly, using the procedures of (B) and (C) above, but employing the 
appropriate 1-chloro-.omega.-(p-toluenesulphonyloxy)alkanes instead of 
1-chloro-8-(p-toluenesulphonyloxy)octane, the following compounds were 
prepared: 
1-amino-4-(1-naphthyloxy)butane mp 99.degree.-102.degree. (maleate); 
1-amino-5-(1-naphthyloxy)pentane mp 169.degree.-172.degree. (hemimaleate); 
1-amino-6-(1-naphthyloxy)hexane mp 112.degree.-114.degree. (hemimaleate). 
Similarly, using the procedures of (B) and (C) above, but employing 
1-chloro-2-(p-toluenesulphonyloxy)ethane instead of 
1-chloro-8-(p-toluenesulphonyloxy)octane, the following compound is 
prepared 1-amino-2-(1-naphthyloxy)ethane. 
Preparation 3 
1-AMINO-8-(2-NAPHTHYLYLOXY)OCTANE 
3(A) Preparation of 1-(2-Naphthyloxy)-8-chlorooctane 
A mixture of 17.5 g 2-naphthol, 32.0 g of 
1-chloro-8-(p-toluenesulphonyloxy)octane, 32.0 g of anhydrous potassium 
carbonate and 200 ml of DMF was stirred at 60.degree. for 4 hours. Water 
and ether were then added, the ethereal solution was separated, and washed 
with water and dilute aqueous potassium hydroxide, then dried and 
evaporated. The residue was chromatographed on silica gel, eluting with 
3:2 hexane: dichloromethane, to afford the title compound as a solid, mp 
35.degree.. 
3(B) 1-Amino-8-(2-naphthyloxy)octane 
1-Chloro-8-(2-naphthyloxy)octane (4.75 g) and potassium phthalimide (4.2 g) 
were heated in dimethylformamide (25 ml) at 120.degree. for 4 hours. The 
solution was then cooled, added to water, and extracted with methylene 
chloride. The extracts were then dried and evaporated to afford 
N-[8-(2-naphthyloxy)octyl]phthalimide as a gum. This material was refluxed 
for 16 hours in ethanol (150 ml) containing 85% aqueous hydrazine hydrate 
(3 ml). The solution was cooled and water (450 ml) and 10% aqueous 
potassium hydroxide (50 ml) were added. The resultant solution was 
extracted with hexane; the extract was dried and evaporated to afford the 
title compound as an oil (hydrochloride mp 169.degree.-170.degree.). 
Similarly, using the procedure of (a) and (b) above, but employing the 
appropriate 1-chloro-.omega.-(p-toluenesulphonyloxy)alkane instead of 
1-chloro-8-(p-toluenesulphonyloxy)octane, the following compounds are 
prepared: 
1-amino-2-(2-naphthyloxy)ethane; 
1-amino-4-(2-naphthyloxy)butane; 
1-amino-7-(2-naphthyloxy)heptane. 
Preparation 4 
1-AMINO-6-(2-BIPHENYLOXY)HEXANE 
4(A) 1-(2-Biphenyloxy)-6-chlorohexane 
1-Chloro-6-(p-toluenesulphonyloxy)hexane (100 g), 2-hydroxybiphenyl (59 g) 
and potassium carbonate (60 g) were heated with stirring in 
dimethylformamide at 70.degree. for 16 hours. The solution was cooled and 
added to water, then extracted with ether. The extract was washed with 
water, dried and evaporated, and the residue was chromatographed on silica 
gel (1800 g) eluting with 99:1 hexane; ethyl acetate, so as to afford the 
title compound as an oil. 
4(B) N-[6-(2-biphenyloxy)hexyl]phthalimide 
A solution of 1-(2-biphenyloxy)-6-chlorohexane 8.0 g) and potassium 
phtalimide (5.6 g) in dimethylformamide (100) ml) was heated at reflux 
temperature for 3 hours. The solution was cooled and poured into water, 
and the product was extracted out with ethyl acetate. The extract was 
dried and evaporated to afford N-[6-(biphenyloxy)hexyl]phthalimide. 
Similarly, using the procedures of A and B above, but employing the 
appropriate chloro p-toluenesulphonyloxyalkane instead of 
1-chloro-6-toluenesulphonyloxyhexane, the following compounds were 
prepared: 
N-[4-(2-biphenyloxy)-butyl]phthalimide; and 
N-[8-(2-biphenyloxy)-octyl]phthalmide. 
4(C) 1-Amino-6-(biphenyloxy)hexane 
A mixture of N-[6-(2-biphenyloxy)hexyl]phthalimide (15.1 g), ethanol (400 
ml) and hydrazine hydrate (30 ml) was heated at reflux for 4 hours, cooled 
to room temperature, filtered, and evaporated to dryness. The material 
that remained was stirred with dichloromethane (500 ml), filtered and 
evaporated to yield 1-amino-6-(2-biphenyloxy) as an oil, which was 
converted to the hydrochloride salt, (m.p. 86.degree.-88.degree. CC.) 
according to the method of Example IV. 
Following the procedure described above in paragraph 4(B) of this 
Preparation, but substituting the appropriate 
N-(2-biphenyloxy)alkyl]phthalimide, the following compounds were prepared 
and converted to pharmaceutically acceptable salts: 
1-amino-4-(2-biphenyloxy)-butane, as the hydrochloride, mp 
162.degree.-164.degree. C.; and 
1-amino-8-(2-biphenyloxy)-octane, as the hydrochloride, mp 136.degree. C. 
Similarly, using the procedures 4(A), 4(B) and 4(C) above, but employing 
3-hydroxybiphenyl or 4-hydroxybiphenyl in place of 2-hydroxybiphenyl, and 
the appropriate 1-chloro-.omega.-(p-toluenesulphonyloxy)alkane, the 
following compounds were prepared: 
1-amino-6-(3-biphenyloxy)hexane(hydrochloride), mp 120.degree.-122.degree.; 
1-amino-4-(4-biphenyloxy)butane(hydrochloride), mp 202.degree.-205.degree.; 
1-amino-5-(4-biphenyloxy)pentane(hydrochloride), mp 
244.degree.-246.degree.; 
1-amino-6-(4-biphenyloxy)hexane(hydrochloride), mp 201.degree.-202.degree.; 
1-amino-7-(4-biphenyloxy)heptane(hydrochloride), mp 
228.degree.-230.degree.; and 
1-amino-8-(4-biphenyloxy)octane(hydrochloride), mp 179.degree.-182.degree.. 
Preparation 5 
Diphenylcarbodiimide 
1,3-Diphenylthiourea (22.8 g), triphenylphosphine (10.1 g) triethylamine 
(10.1 g) and carbon tetrachloride (21.6 g) were refluxed for 4 hours in 
methylene chloride (300 ml). The solvent was removed under vacuum. The 
residue was shaken with hexane (300 ml); the hexane solution was 
evaporated and the residue was distilled to afford the title compound as 
an oil bp 115.degree.-120.degree./0.3 mm. Similarly, by using this 
procedure, but employing other 1,3-disubstituted thioureas instead of 
1,3-diphenylthiourea, other carbodiimides can be made. 
Preparation 6 
1,3-di(2-methylphenyl)-S-methylisothiourea 1,3-di(2-methylphenyl)thiourea 
(60.0 g) and methyl iodide (36.5 g) were refluxed for 3 hours in ethanol 
(1200 ml). The solution was cooled and about 600 ml ethanol was removed 
under vacuum. First water (50 ml), and then saturated aqueous sodium 
bicarbonate were added to the ethanol solution until the pH was 7-8. Water 
(1000 ml) was then added to the solution and the solid was filtered off 
and washed with water before being dried under vacuum to afford the title 
compound. 
Similarly, by using this procedure, but employing other 1,3-disubstituted 
thioureas instead of 1,3-di(2-methylphenyl)thioures other 
1,3-disubstituted S-methylisothioureas can be prepared. 
For example, using the method of Preparation 6 the following are prepared 
1,3-di(3-methylphenyl)-S-methylisothiourea; 
1,3-di(4-methylphenyl)-S-methylisothiourea 
1,3-diphenyl-S-methylisothiourea; and 
1,3-di(2-ethylphenyl)-S-methylisothiourea 
EXAMPLE I 
1,2-Dicyclohexyl-3-[8-(1-naphthyloxy)octyl]guanidine 
700 Milligrams (mg) of 1-amino-8-(1-naphthyloxy)octane and 505 mg of 
dicyclohexylcarbodiimide were mixed well and heated to 120.degree. C. for 
1 hour. The crude product was chromatographically separated on a silica 
gel column eluting with a mobile phase of 25 parts 2-propanol to 1 part 
water to 1 part acetic acid affording 
1,2-dicyclohexyl-3-[8-(1-naphthyloxy)octyl]guanidine as a gum. 
EXAMPLE II 
1,2-diphenyl-3(8-(2-naphthyloxy)octyl)guanidine 
4.0 g of 1-amino-8(2-naphthyloxy)octane and 3.6 g of 
1,3-diphenyl-S-methylisothiourea were heated to 110.degree. C. under a 
nitrogen atmosphere for 3 hours. The crude product was chromatographically 
separated from the reaction mixture on a silica gel column with the mobile 
phase being methylene chloride:methanol:ammonium hydroxide 100:12:1.2 
thereby isolating the 1,2-diphenyl-3-[8-(2-naphthyloxy)octyl]guanidine 
which was converted to the hydrochloride (mp 124.degree.-126.degree.) 
using the procedure of Example IV. 
In a similar manner, using the appropriate amines and isothioureas, the 
following compounds were prepared 1,2-Diphenyl 
3-[6-(7-chloro-quinolinyl)-hexyl]guanidine trihydrochloride, mp 
99.degree.; 
1,2-dicyclohexyl-3[6-(7-chloro-4-quinolinyl))hexyl]guanidine, mp 
122.degree.-124.degree.; 
1,2,3-triphenyl-3-[8-(1-naphthyloxy)octyl]guanidine maleate, mp 
43.degree.-45.degree.; 
1,2-di-(2-methylphenyl)-3-[8-(1-naphthyloxy)octyl]guanidine hydrochloride, 
mp 124.degree.-126.degree.; 
1,2-di-(2-methoxyphenyl)-3[8-(1-naphthyloxy)octyl]guanidine, mp 
90.degree.-92.degree.; 
1,2-diphenyl-3-[2-(2-naphthyloxy)ethyl]guanidine mp, 138.degree.-9.degree.; 
1,2-dicyclohexyl-3-[2-(2-naphthyloxy)ethyl]guanidine diphosphate, mp 
96.degree.-98.degree.; 
1,2-di-4-(ethoxyphenyl)-3-[2-(2-naphthyloxy)etyl]guanidine dihydrochloride, 
mp 177.degree.-180.degree.; 
1-cyclohexyl-2-(2-thiazolyl)-3-[2-(2-naphthyloxy)ethyl]guanidine, mp 
129.degree.-131.degree.; 
1,2-di-(4-methylphenyl)-3-[2-(2-naphthyloxy)ethyl]guanidine, mp 
118.degree.-120.degree.; 
1,2-diphenyl-3-ethyl-3-[2-(2-naphthyloxy)ethyl]guanidine, mp 
109.degree.-110.degree.; 
1,2-diphenyl-3-[2-(4-phenylphenoxy)ethyl]guanidine hydrochloride, mp 
185.degree.-188.degree.; and 
1,2-diphenyl-3-[2-(4-phenylphenoxy)ethyl]guanidine, mp 
100.degree.-102.degree.. 
Similarly, using the procedure of Example II above, but employing the 
appropriate amines and isothioureas, the following are obtained: 
1,2-di-(3-methylphenyl)-3-[8-(1-naphthyloxy)octyl]guanidine; 
1,2-di-(4-methylphenyl)-3-[8-(1-naphthyloxy)octyl]guanidine; 
1,2-di-(2-ethylphenyl)-3-[8-(1-naphthyloxy)octyl]guanidine; 
1,2-di-(2-methylphenyl)-3-[7-(1-naphthyloxy)heptyl]guanidine; 
1,2-di-(2-methylphenyl)-3-[6-(1-naphthyloxy)hexyl guanidine; and 
1,2-di-(2-methylphenyl)-3-[8-(2-naphthyloxy)octyl]guanidine. 
EXAMPLE III 
1,3-Diphenyl-1-[8-(1-naphthyloxy)octyl]guanidine 
A The preparation of 1-(1-Naphthyloxy)-8-(phenylamino)octane 
7.0 Gm of 1-chloro-8-(1-naphthyloxy)octane was refluxed for 1 hour in 100 
ml of aniline. The excess aniline was then removed under vacuum and the 
residue was distributed between methylene chloride and dilute aqueous 
potassium hydroxide. The organic solution was dried and evaporated, and 
the residue was chromatographed on silica gel, eluting with methylene 
chloride, so as to produce the title compound as an oil. 
B. The preparation of 1-(1-naphthyloxy)-8-(phenylcyanoamino)octane 
4.5 g of 1-(1-naphthyloxy)-8-(phenylamino)octane and 1.4 g of cyanogen 
bromide were heated in 150 ml of benzene at 55.degree. for 2 hours. The 
benzene was then evaporated from the solution, affording 
1-(1-naphthyloxy)-8-(phenylcyanoamino)octane which was employed in Step B 
(below) without further purification. 
C. The preparation of 1,3-diphenyl-1-[8-(1-naphthyloxy)octyl]guanidine 
5.25 Grams of 1-(1-naphthyloxy)-8-(phenylcyanoamino)octane and 15 ml of 
aniline were heated at 170.degree. for 45 min. The excess aniline was 
removed under vacuum and the residue was chromatographed on a silica gel 
column eluting with a mobile phase of methylene chloride: 
methanol:ammonium hydroxide, 50:30:0.3, affording the title compound, (mp 
132.degree.-134.degree. as the paratoluene sulphonate). 
Similarly, using the procedures of A, B and C above, but employing other 
1-chloro-.omega.-(anyloxy)alkanes instead of 
1-chloro-8-(1-naphthyloxy)octane, and other amines instead of aniline, 
other 1,1,3-trisubstituted guanidines can be prepared. 
EXAMPLE IV 
Conversion of a free base to a salt 
1,2-Dicyclohexyl-3-[2-(2-naphthyloxy)ethyl]guanidine phosphate 
10.0 g of 1,3-dicyclohexyl-3-[2-(2-naphthyloxy)ethyl]guanidine was 
dissolved in ethanol (100 ml) and 5.7 g 85% phosphoric acid in 100 ml 
ethanol was added to this solution. After 16 hours 1400 ml ether was added 
to the solution. The resulting precipitate was removed by filtration and 
dried under vacuum to afford the title compound (mp 
132.degree.-134.degree.). 
In a similar manner, all compounds of Formula 1 in free base form may be 
converted to the acid addition salts by treatment with the appropriate 
acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, 
nitric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, 
oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric 
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic 
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 
and the like. 
EXAMPLE V 
Conversion of a salt to a free base 
10.0 g of 1,2-diphenyl-3-[6-(7-chloro-4-quinolinyl)hexyl]guanidine 
hydrochloride is dissolved in 500 ml water. An excess of aqueous sodium 
hydroxide is then added to the solution. The solution is extracted with 
methylene chloride and the extract is dried and evaporated to afford 
1,2-diphenyl-3-[6-(7-chloro-4-quinolinyl)hexyl]guanidine. 
In a similar manner, other salts of compounds of Formula 1 can be converted 
into the free bases. 
EXAMPLE VI 
Direct Interchange of acid addition salts 
1.0 g of 1,2-dicyclohexyl-3-[6-(2-naphthyloxy)hexyl)guanidine acetate is 
dissolved in 50 ml water and a solution of 0.39 g of p-toluenesulphonic 
acid in 10 ml water is then added. The water is then evaporated under 
vacuum to afford 1,2-dicyclohexyl-3-[6-(2-naphthyloxy)hexyl]guanidine 
p-toluenesulphonate. 
In a similar manner interchanges between other acid addition salts of 
compounds of Formula I can be made by treating with an appropriate 
inorganic or organic acid. 
EXAMPLE VII 
Inhibition of Carrageenan-Induced Pleural Inflammation 
Male albino rats, weighing between 220 and 280 g, are administered an 
appropriate dose of a compound of Formula 1 by oral gavage. After 1 hour 
0.3 ml of a 1% viscavin #402 solution is injected intrapleurally. 
Additional doses of the test compound are administered 24 and 48 hours 
after the intrapleural injections. After 72 hours the rats are sacrificed 
and the pleural cavities are exposed. The exudates are harvested and the 
total volume is measured. An aliquot is removed, diluted, and the number 
of cells is determined using a Coulter counter Compounds of Formula 1 
effect a reduction, compared to undosed control animals, of both the 
volume of the exudate and the number of cells therein. 
EXAMPLE VIII 
Inhibition of Croton-oil Induced Ear Edema in the Rat 
Male 21-day old rats are anesthetized and a solution of the test compound 
in 0.05 ml of a mixture of 20% pyridine, 5% water, 74% diethyl ether and 
1% croton oil is applied to the inside and to the outside of the left ear. 
After 6 hours the ears of the anesthetized rats are removed and pieces of 
uniform size are punched out with an 8 mm punch. The ear pieces are then 
weighed. Compounds of Formula 1 effect an inhibition of the increase in 
weight of the treated ear.