Pyridyl and quinoline derivatives

The present invention relates to compounds of formula I ##STR1## in which formula I X stands for O, S, ##STR2## R.sub.1 and R.sub.2 which can be the same or different stand for hydrogen, straight or branched, saturated or unsaturated, unsubstituted or substituted C.sub.1 -C.sub.8 -alkyl, or for ar-C.sub.1 -C.sub.4 -alkyl, aryl and ar being unsubstituted or substituted phenyl; R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are the same or different and stand for hydrogen, halogen, pseudo halogen, cyano, nitro, amino, carboxy, hydroxy, alkyl, alkoxy; or R.sub.5 and R.sub.6 form an aromatic ring which is fused to the pyridyl ring, and which aromatic ring may substituted; provided that R.sub.1 and R.sub.2 cannot be hydrogen at the same time, and provided that when R.sub.5 and R.sub.6 both are chlorine and R.sub.1 is hydrogen, then R.sub.2 cannot be n-propyl; and salts and bioreversible derivatives thereof. The compounds of formula I are useful in the human and veterinary therapy, as they exert specific 5-lipoxygenase inhibition.

The present invention relates to hitherto unknown compound useful in the 
human and veterinary therapy, to pharmaceutically acceptable salts 
thereof, to bioreversible derivatives thereof, to methods for producing 
said new compounds, to pharmaceutical compositions containing the new 
compounds, to dosage units of the compositions, and to methods of treating 
patients using said compositions and dosage units. 
It has recently been discovered that leukotrienes, which are formed via the 
5-lipoxygenase pathway of arachidonic acid metabolism, are implicated in a 
variety of pathophysiologic functions such as bronchoconstriction, plasma 
exudation, coronary artery spasm, leukocyte chemotaxis and neutrophilic 
degranulation (for review, see J. L. Marx, Science 215 (1982), 1380-83). 
It is therefore of considerable interest to develop compounds which 
inhibit 5-lipoxygenases and thereby the production of leukotrienes. It has 
surprisingly turned out that the present compounds show a pronounced 
lipoxygenase inhibitory effect, as discussed below. 
The present compounds have the formula I 
##STR3## 
in which formula I X stands for O, S, 
##STR4## 
R.sub.1 and R.sub.2 which can be the same or different stand for hydrogen, 
straight or branched, saturated or unsaturated, unsubstituted or 
substituted C.sub.1 -C.sub.8 -alkyl, aryl or for ar-C.sub.1 -C.sub.4 
-alkyl, aryl and ar being unsubstituted or substituted phenyl, the above 
substitution being with one or more of the following substituents: 
halogen, pseudo halogen, such as trifluoromethyl, cyano, nitro, amino, 
carboxy, hydroxy, alkyl, alkoxy; R.sub.3, R.sub.4, R.sub.5, and R.sub.6 
are the same or different and stand for hydrogen, halogen, pseudo halogen, 
cyano, nitro, amino, carboxy, hydroxy, alkyl, alkoxy; or R.sub.5 and 
R.sub.6 form an aromatic ring which is fused to the pyridyl ring, and 
which aromatic ring may be substituted with one or more of the following: 
halogen, pseudo halogen, such as trifluoromethyl, cyano, nitro, amino, 
carboxy, hydroxy, alkyl, alkoxy; provided that R.sub.1 and R.sub.2 cannot 
be hydrogen at the same time, and provided that when R.sub.5 and R.sub.6 
both are chlorine and R.sub.1 is hydrogen, then R.sub.2 cannot be 
n-propyl. 
Among the preferred compounds of the invention are compounds in which 
R.sub.5 and R.sub.6 in formula I form an aromatic ring fused to the 
pyridine ring, i.e. compounds containing a quinoline ring or an 
isoquinoline ring, these compounds furthermore being preferred by having 
the --NR.sub.1 R.sub.2 and the 
##STR5## 
functions in formula I placed in meta position to each other. Of 
particular value among compounds having these characteristics are 
compounds of the invention in which X in formula I is oxygen, in which 
##STR6## 
in formula I is a 2-quinoly methoxy radical, and in which R.sub.1 in 
formula I is hydrogen, these examples, however, not being considered 
limiting for the invention. 
The present salts of the compounds of formula I may be formed with 
pharmaceutically acceptable inorganic or organic acids, such as 
hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric 
acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic 
acid, acetic acid, propionic acid, citric acid, tartaric acid, and maleic 
acid, without these examples being considered limiting for the invention. 
In some cases it can be advantageous to prepare suitable bioreversible 
derivatives of compounds of the invention, i.e. to prepare so-called 
prodrugs, preferably derivatives, the physicochemical properties of which 
leads to improved solubility at physiological pH and/or absorption of the 
compound in question. 
Such derivatives are for instance esters of N-hydroxymethyl derivatives of 
compounds of the invention, such compounds being prepared by reaction of 
the secondary amine-function of compounds of the invention with 
formaldehyde (1,2,3,4) followed by reaction with a suitable acidic 
compound or activated derivatives of such compounds, for instance with 
bisulfite (5), N,N-dimethylglycine, N,N-diethyl-.beta.-alanine, or 
phosphoric acid (6), but other suitable acids which form bioreversible 
derivatives with desirable physicochemical properties can be used as well. 
FNT (1) R. G. Kallen and W. P. Jencks, J. Biol. Chem., 241, 5864, (1966). 
FNT (2) C. J. Martin and M. A. Marini, J. Biol. Chem., 242, 5736 (1967). 
FNT (3) M. Levy and D. E. Silberman, J. Biol. Chem., 118, 723 (1937). 
FNT (4) S. Lewin and D. A. Humphany, J. Chem. Soc. B, 1966, 210. 
FNT (5) B. C. Jain, B. H. Iyer, and P. C. Guha (Indian Inst. Sci., Bangalore). 
Science and Culture 11, 568-9 (1946). 
FNT (6) S. A. Varia, S. Schuller, K. B. Sloan and V. J. Stella, J. Pharm. Sci., 
73(8), 1068-1073 (1985) and following papers. 
These examples are not to be considered as limiting for the invention, and 
other suitable methods to improve the physicochemical properties and 
solubility of the compounds concerned can be used as well. 
Metabolites of arachidonic acid include prostaglandins and leukotrienes. 
Both of these two groups of metabolites are important in the 
pathophysiology of inflammatory and allergic reactions. Many inhibitors of 
prostaglandin synthesis are known and are being used as anti-inflammatory 
agents (7), but relatively few leukotriene synthesis inhibitors are 
presently known (8), and they are generally not clinically acceptable. The 
first step in the biochemical synthesis of all leukotrienes is the 
peroxidation at the 5-carbon atom of arachidonic acid. This reaction is 
catalyzed by the enzyme 5-lipoxygenase, present mainly in leukocytes. 
Leukotriene B.sub.4 is one of the most potent chemoattractants for 
polymorphonuclear leukocytes, and at the same time causes aggregation and 
degranulation of these inflammatory cells. It is thus a potent 
pro-inflammatory hormone. Leukotriene C.sub.4, D.sub.4, and E.sub.4 
together comprise the agent known previously as "slow-reacting substance 
of anaphylaxis" (SRS-A), which is three orders of magnitude more potent 
than histamine in causing bronchoconstriction, and also regulates 
microvascular smooth muscle contractibility and permeability. It is 
therefore a mediator of asthmatic, allergic and inflammatory reactions. 
FNT (7) R. J. Flower, S. Moncada and J. R. Vane, in The Pharmacological Basis 
of Therapeutics (Ed. A. G. Gilman, L. S. Goodmann and A. Gilman), p. 
682-728, Macmillan, New York (1980). 
FNT (8) M. A. Bray, A. W. Ford-Hutchinson and M. J. H. Smith, in SRS-A and 
Leukotrienes (Ed. P. J. Piper), p. 253, Wiley, New York (1981). 
Inhibition of 5-lipoxygenase thus leads to a decrease in the formation of 
all of these inflammatory and allergic mediators. This has very important 
clinical implications, as specific 5-lipoxygenase inhibitors are of 
potential interest in the therapy of asthma, allergy, rheumatoid 
arthritis, atherosclerosis, psoriasis and other proliferative 
skin-disorders, ulcerative colitis and other chronic inflammatory 
conditions, vasospasm associated with angina pectoris, etc. The 
identification of specific 5-lipoxygenase inhibitors is thus a novel 
approach with very wide implications for the treatment of a diversity of 
clinical disorders. 
As stated above, the present compounds have surprisingly been shown to 
exert such specific 5-lipoxygenase inhibition. 
The biological activity of the present compounds was determined both in 
vitro and in vivo. The following method was used to assay 5-lipoxygenase 
activity in vitro: Rat peritoneal cells were harvested by i.p. injection 
of 10 ml Hank's balanced salt solution (GIBCO), cat. No. 4025, U.S.A.) 
containing 12.5 U/ml sodium heparin (Leo, Denmark) in anaesthesized rats. 
The resulting cell suspension, which mainly contained macrophages, was 
transferred to a test tube and washed twice by centrifugation (200 g, 10 
min.) and resuspended in Hank's balanced salt solution containing 0.5% 
bovine serum albumin (Sigma Chem. Co., U.S.A.). The cells from 6 rats were 
finally resuspended in Hank's balanced salt solution containing 5 .mu.Ci 
(1-.sup.14 C) arachidonic acid (The Radiochemical Centre, Amersham, U.K.) 
and incubated for 90 minutes at 30.degree. C. This caused labelling of 
cell membrane phospholipids as radioactive arachidonic acid was 
incorporated in the 2-position of the glycerol moiety. Excess arachidonic 
acid was then removed by washing the cells twice as described above. The 
cells were finally resuspended in the same solution at 10.sup.7 cells/ml. 
475 .mu.l of the cell suspension was preincubated at 37.degree. C. for 5 
minutes with either 5 .mu.l DMSO (control tube), or 5 .mu.l of a drug 
solution in DMSO. Then 20 .mu.l of a mixture of equal volumes of the 
calcium ionophore A 23187, 10.sup.-4 M in ethanol (Calbiochem, U.S.A.), 
and 0.5M CaCl.sub.2 in water was added. The final concentration of A 23187 
was thus 2.times.10.sup.-6 M, and of Ca.sup.++ 8 mM. After minutes of 
incubation the tubes were transferred to an ice-bath and centrifugated for 
10 minutes at 3,000 g (4.degree. C.). An aliquot of the supernatant was 
counted by liquid scintillation spectrometry in order to calculate the 
total radioactive release induced by A 23187 in presence of drugs. A 
decrease in radioactive release was taken as indication of phospholipase 
A.sub.2 -inhibition. The supernatant was then extracted twice with ethyl 
acetate (2 ml), adjusted to pH 3 with 1N HCl and further extracted with 
2.times.2 ml ethyl acetate. The combined extracts were evaporated to 
dryness in vacuo, the residue was redissolved in a small volume of 
methanol and applied by means of a Desage Autospotter.TM. to a silica-gel 
coated thin-layer plate fitted with a polar concentrating zone (Merck Art. 
11798, Darmstadt, FRG). The plates were developed in the organic layer of 
the solvent mixture ethyl acetate/acetic acid/iso-octane/water 
(55:10:25:50). Radioactive spots were detected by autoradiography 
(AGFA-GEVAERT, Osray-RPI X-ray film, Belgium), and changes induced by 
drugs in the metabolic pattern of arachidonic acid were quantified by a 
laser densitometer (LKB, Ultroscan.TM.2202, Bromma, Sweden) in combination 
with an integrating computer (SP 4100, Spectra-Physics, San Jose, Calif., 
U.S.A.). 
These cells produced measurable amounts of radioactive 6-keto-prostaglandin 
F.sub.1.alpha., thromboxane B.sub.2, prostaglandin D.sub.2, 
hydroxyheptadecatrienoic acid (HHT) (all cyclooxygenase products), 
5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B.sub.4 (both 
5-lipoxygenase products). 
When OT 3447 (Example 2C) at final concentrations from 10.sup.-6 M and 
above was added to the reaction mixture described above, a significant and 
specific decrease in the production of leukotriene B.sub.4 and 5-HETE 
occurred. At the same time, the synthesis of the cyclooxygenase products 
HHT, prostaglandin D.sub.2 and thromboxane B.sub.2 and 
6-keto-prostaglandin F.sub.1.alpha. was not affected, and the synthesis of 
6-keto-prostaglandin F.sub.1.alpha., the stable metabolite of 
prostacyclin, was accelerated. This pattern of drug activity is indicative 
of truly specific 5-lipoxygenase inhibition. 
Two in vivo methods were used to assess the effect of either oral or 
parenteral administration of the compounds to experimental animals on the 
release of leukotrienes. In the first method, calcium ionophore A 23187 
was injected into the peritoneal cavity of adrenalectomized and 
anaesthesized rats. 5 minutes later the cavity was washed, and the 
leukotrienes were extracted with ethanol and redissolved in water or 
buffer. The amount of leukotriene D.sub.4 released in response to A 23187 
was determined by bioassay, using the contraction of an isolated 
guinea-pig ileum-strip as indicator. Leukotriene C.sub.4 and B.sub.4 were 
measured by commercially available radioimmunoassays (New England Nuclear, 
Dreieich, West Germany, and The Radiochemical Centre, Amersham, U.K., 
respectively). By all 3 assays a substantial inhibition of leukotriene 
formation was observed following administration of OT 3447 (Example 2C) 
prior to intraperitoneal injection of A 23187. 
The other method was used to measure a physiological consequence of 
leukotriene release in the lungs, an asthmatic attack. Guinea-pigs 
hypersensitive to ovalbumin were anaestesized and mechanically ventilated 
with a constant air-volumen ad modum Konzett-Rossler. The animals were 
pre-treated with mepyramine, indomethacin and propranolol to avoid 
interference with endogenous production of histamine, prostaglandins and 
.beta.-adrenergic mechanisms, respectively. They were then challenged with 
an intravenous injection of ovalbumin, and the increase in airway 
resistance was measured by the respiratory overflow. Pretreatment of the 
animals with OT 3447 (Example 2C) significantly reduced the asthmatic 
reaction, indicating a clinically beneficial effect of inhibiting 
endogenous leukotriene release by the administration of these compounds. 
Antagonism of leukotriene mediated effects at the receptor level, in 
addition to inhibition of leukotriene synthesis, is an additional mode of 
action of some of the present compounds. Obviously, this dual mechanism is 
of potentially great interest in preventing leukotriene mediated 
reactions. 
Leukotriene antagonists may be identified by observing the contractions 
elicited in preparations of guinea-pig ileum strips suspended in 
physiological buffers by addition of pure leukotriene D.sub.4. The ileum 
strips are connected to an isotonic transducer, and the contractions are 
continuously recorded on a multichannel recorder. 
Before addition of leukotriene D.sub.4, atropine and indomethacin are added 
to the buffer in order to block any cholinergic or prostaglandin-mediated 
contractile effects. Test compounds to be studied with respect to 
leukotriene antagonism are dissolved in dimethylsulphoxide (DMSO) and 
added to the organ bath 2 minutes prior to addition of leukotriene D.sub.4 
at 10.sup.-9 M (final concentration), the final concentration of DMSO 
being 0.1%, a concentration which can be shown not to affect the ileum 
response to leukotriene D.sub.4. The test compounds may be added at 
various concentrations, often beginning at 10.sup.-6 M and then decreasing 
the concentration in case of antagonism. 
When the compounds of the present invention were added to the ileum 
preparation before addition of leukotriene D.sub.4 a significant 
inhibition occurred of the specific leukotriene D.sub.4 -induced 
contraction. In several cases this inhibition occurred at concentrations 
in the submicromolar range, e.g. Examples 39, 11 (part A), 11 (part C), 
18, 23, 22, and 78 (part C). 
On the other hand, contractions induced with histamine at 10.sup.-6 M were 
not inhibited by these compounds even at micromolar concentrations. 
Products formed by the enzyme responsible for the first step in leukotriene 
synthesis, 5-lipoxygenase, which is probably the target enzyme of 
compounds of the present invention, play a role as mediators of mast cell 
degranulation. One of the effects of mast cell degranulation is the 
release of histamine. Thus, 5-lipoxygenase inhibitors may suppress 
histamine release from mast cells. 
In order to investigate this possibility, cells obtained from washings of 
the peritoneal cavity of rats, were studied. These peritoneal washings 
contain mainly macrophages and mast cells. The mast cells were passively 
sensitized with IgE-antibodies to ovalbumin, and then challenged with the 
antigen, ovalbumin, to induce histamine release. Alternatively, the 
unsensitized mast cells were exposed to an ionophore, compound 48/80*, 
which induces histamine release independently of immunologic mechanisms. 
Histamine released to the medium after degranulation of the peritoneal 
mast cells was measured by a fluorometric method. 
FNT *(the condensation product of N-methyl-p-methoxyphenethylamine with 
formaldehyde) 
Several of the compounds of the present invention inhibited histamine 
release from mast cells (see Table I below). below). 
TABLE I 
______________________________________ 
Effect of compounds of the invention on rat peri- 
toneal mast cell histamine release 
Inhibition (%) of histamine 
Compound.sup.a release induced by 
according to Antigen Cp. 48/80 
______________________________________ 
Ex. 10, part C 51 19 
Ex. 39 100 95 
Ex. 38 91 85 
Ex. 22 100 75 
Ex. 68 45 17 
Ex. 78, part C 96 95 
Ex. 79, part C 100 95 
Ex. 70 100 45 
Ex. 77 100 92 
Ex. 66 100 65 
______________________________________ 
.sup.a The compounds were studied at 10 .mu.M concentrations 
*(the condensation product of N--methylp-methoxyphenethylamine with 
formaldehyde) 
There was a tendency for stronger inhibition of antigen than cp. 
48/80-induced histamine release, in agreement with the postulated role for 
5-lipoxygenase products in immunologically mediated mast cell 
degranulation. The present observation further demonstrates the efficacy 
of the compounds of the invention in suppressing anaphylactic reactions. 
The present invention also relates to a method for producing the present 
compounds. 
In one embodiment, an amine of the formula II 
##STR7## 
in which R.sub.3, R.sub.4, R.sub.5, R.sub.6 and X have the above meanings, 
is reacted with a compound of the formula III 
EQU R.sub.2 Y (III) 
in which R.sub.2 has the above meanings except hydrogen and Y is capable of 
forming a "good leaving group", Y thus standing for e.g. a halogen atom, 
such as chlorine, bromine or iodine, or an alkyl- or arylsulphonyloxy 
group, but other leaving groups can be used as well, such as an 
alkylsulphate group, a chlorosulphonyloxy group, an alkylsulphite group, a 
mono- or dialkylphosphate group or a nitrate group, to form a compound of 
the formula I in which R.sub.1 stands for hydrogen. 
The reaction is performed in a suitable inert organic solvent, such as 
methanol, ethanol, dimethylformide or hexamethyl phosphoric triamide, but 
other solvents can be used as well; the reaction is performed at a 
temperature about or above room temperature, up to the boiling point of 
the solvent used. In some cases it can, however, be convenient to cool the 
reaction mixture below room temperature, depending on the nature of the 
compound of the formula III used. The reaction is also conveniently 
performed in the presence of an organic base, such as pyridine, 
triethylamine, sodium methanolate or sodium ethanolate or in the presence 
of a suitable inorganic base, such as an alkalimetal hydroxide, an 
alkalimetal carbonate or an alkalimetal hydrogen carbonate, but other 
bases can be used as well. The crude reaction products of the formula I 
are collected by filtration, if convenient after dilution with e.g. water, 
or are extracted from the reaction mixture with a suitable solvent, such 
as diethyl ether, ethyl acetate, dichloromethane or chloroform. The 
products are purified e.g. by recrystallization or by chromatography, if 
convenient after conversion to salts with suitable inorganic or organic 
acids as defined above. 
In another embodiment, an amine of the formula II is converted to a 
compound of the formula I, in which R.sup.1 stands for hydrogen by 
reductive alkylation, e.g. by reaction with a carbonyl compound of the 
formula IV 
##STR8## 
in which R.sub.7, R.sub.8, and the carbonyl function together are capable 
of forming a substituent R.sub.2 with the above meanings, followed by 
hydrogenation in the presence of a suitable catalyst or by reduction e.g. 
with an alkalimetal borohydride. The hydrogenation or reduction can, if 
convenient, be performed simultaneously with the reaction with the 
carbonyl compound, that is, without isolation of the intermediary, so 
called Schiff-base. 
The reaction is performed in a suitable inert organic solvent, such as 
methanol or ethanol, but other solvents can be used as well. The reaction 
is preferably performed at ambient temperature, but in some cases it is 
convenient to cool the reaction mixture below room temperature, or to heat 
the reaction mixture above room temperature, up to the boiling point of 
the solvent used, depending on the nature of the reactants of the formulae 
II and IV used. The isolation and purification of the products can be 
performed as described above. 
If a compound of the formula I, in which R.sub.1 is different from 
hydrogen, is desired, the above compounds of formula I in which R.sub.1 
stands for hydrogen can be further alkylated by reaction with a compound 
of the formula V 
EQU R.sub.1 Y (V) 
in which R.sub.1 and Y have the above meanings, except that R.sub.1 cannot 
be hydrogen. The solvents and reaction conditions used are preferably as 
described above. 
The introduction of the substituents R.sub.1 and R.sub.2 can be performed 
simultaneously, e.g. when R.sub.1 =R.sub.2, but also when R.sub.1 and 
R.sub.2 are different, the reaction can be performed without isolation of 
the monoalkylated intermediate. 
In still another embodiment a compound of the formula VII 
##STR9## 
in which R.sub.1, R.sub.2, R.sub.3, and R.sub.4 have the above meanings, 
and X stands for oxygen or sulfur, is reacted with a compound of the 
formula VIII 
##STR10## 
in which R.sub.5, R.sub.6 and Y have the above meanings, to form the 
desired compound of formula I. 
The solvent and reaction conditions used are conveniently as described 
above for the alkylation of amines of the formula II, but other solvents 
and/or reaction conditions can be used as well, depending on the nature of 
the compounds of the formulae VII and VIII which are reacted. 
Another embodiment is described in the following reaction scheme: 
##STR11## 
in which n stands for 1 or 2, and R.sub.1, R.sub.2, R.sub.3, R.sub.4, 
R.sub.5, and R.sub.6 have the above meanings. 
If R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, or R.sub.6 are or contain 
substituents, which can react under the above mentioned conditions, such 
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, or R.sub.6 are protected in 
usual manner before the reaction, and deprotected afterwards. 
The present compounds are intended for use in pharmaceutical compositions 
which are useful in the treatment of asthma, allergy, rheumatoid 
arthritis, atherosclerosis, psoriasis and other proliferative 
skin-disorders, ulcerative colitis and other inflammatory conditions, 
vasospasms, etc. 
The amount required of a compound of formula (I) (hereinafter referred to 
as the active ingredient) for therapeutic effect will, of course, vary 
both with the particular compound, the route of administration and the 
mammal under treatment. A suitable dose of a compound of formula (I) for a 
mammal suffering from e.g. an inflammatory condition as defined 
hereinbefore is 0.5 to 100 mg per kilogram bodyweight, the most preferred 
dosage being 0.5 to 50 mg/kg of mammal bodyweight, for example 5 to 25 
mg/kg; administered once or more times daily. 
In the case of the treatment or prophylaxis of inflammatory airway 
conditions, a suitable anti-asthmatic dose of a compound of formula (I) is 
1 .mu.g to 50 mg of compounds per kilogram bodyweight, the most preferred 
dosage being 1 .mu.g to 10 mg/kg of mammal bodyweight, for example from 1 
.mu.g to 5 mg/kg. 
While it is possible for an active ingredient to be administered alone as 
the raw chemical, it is preferable to present it as a pharmaceutical 
formulation. Conveniently, the active ingredient comprises from 0.1% to 
100% by weight of the formulation. Conveniently, dosage units of a 
formulation contain between 0.1 mg and 1 g of the active ingredient. For 
topical administration, the active ingredient preferably comprises from 1% 
to 2% by weight of the formulation but the active ingredient may comprise 
as much as 10% w/w. Formulations suitable for nasal or buccal 
administration, (such self-propelling powder-dispensing formulations 
described hereinafter), may comprise 0.1 to 20% w/w, for example about 2% 
w/w of active ingredient. 
By the term "dosage unit" is meant a unitary, i.e. a single dose which is 
capable of being administered to a patient, and which may be readily 
handled and packed, remaining as a physically and chemically stable unit 
dose comprising either the active material as such or a mixture of it with 
solid or liquid pharmaceutical diluents or carriers. 
The formulations, both for veterinary and for human medical use, of the 
present invention comprise an active ingredient in association with a 
pharmaceutically acceptable carrier therefor and optionally other 
therapeutic ingredient(s). The carrier(s) must be "acceptable" in the 
sense of being compatible with the other ingredients of the formulations 
and not deleterious to the recipient thereof. 
The formulations include those in a form suitable for oral, opthalmic, 
rectal, parenteral (including subcutaneous, intramuscular and 
intravenous), intra-articular, topical, nasal or buccal administration. 
The formulations may conveniently be presented in dosage unit form and may 
be prepared by any of the methods well known in the art of pharmacy. All 
methods include the step of bringing the active ingredient into 
association with the carrier which constitutes one or more accessory 
ingredients. In general, the formulations are prepared by uniformly and 
intimately bringing the active ingredient into association with a liquid 
carrier or a finely divided solid carrier or both, and then, if necessary, 
shaping the product into the desired formulation. 
Formulations of the present invention suitable for oral administration may 
be in the form of discrete units as capsules, sachets, tablets or 
lozenges, each containing a predetermined amount of the active ingredient; 
in the form of a powder or granules; in the form of a solution or a 
suspension in an aqueous liquid or non-aqueous liquid; or in the form of 
an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient 
may also be administered in the form of a bolus, electuary or paste. 
A tablet may be made by compressing or moulding the active ingredient 
optionally with one or more accessory ingredient. Compressed tablets may 
be prepared by compressing, in a suitable machine, the active ingredient 
in a free-flowing form such as a powder or granules, optionally mixed with 
a binder, lubricant, inert diluent, surface active or dispersing agent. 
Moulded tablets may be made by moulding, in a suitable machine, a mixture 
of the powdered active ingredient and a suitable carrier moistened with an 
inert liquid diluent. 
Formulations for rectal administration may be in the form of a suppository 
incorporating the active ingredient and a carrier such as cocoa butter, or 
in the form of an enema. 
Formulations suitable for parenteral administration conveniently comprise a 
sterile oily or aqueous preparation of the active ingredient which is 
preferably isotonic with the blood of the recipient. 
Formulations suitable for intra-articular administration may be in the form 
of a sterile aqueous preparation of the active ingredient which may be in 
microcrystalline form, for example, in the form of an aqueous 
microcrystalline suspension. Liposomal formulations or biodegradable 
polymer systems may also be used to prevent the active ingredient for both 
intra-articular and ophthalmic administration. 
Formulations suitable for topical administration include liquid or 
semi-liquid preparations such as liniments, lotions, applications; 
oil-in-water or water-in-oil emulsions such as creams, ointments or 
pastes; or solutions or suspensions such as drops. For example, for 
ophthalmic administration, the active ingredient may be presented in the 
form of aqueous eye drops as, for example, a 0.1-1.0% solution. 
Formulations suitable for administration to the nose or buccal cavity 
include powder, self-propelling and spray formulations such as aerosols 
and atomizers. The formulations, when dispersed, preferably have a 
particle size in the range of 10 to 100.mu.. 
Such formulations are most preferably in the form of a finely comminuted 
powder for pulmonary administration from a powder inhalation device or 
self-propelling powder-dispensing formulations, where the active 
ingredient, as a finely comminuted powder, may comprise up to 99.9% w/w of 
the formulation. In the case of self-propelling solution and spray 
formulations, the effect may be achieved either by choice of a value 
having the desired spray characteristics (i.e. being capable of producing 
a spray having the desired particle size) or by incorporating the active 
ingredient as a suspended power in controlled particle size. These 
self-propelling formulations may be either powder-dispensing formulations 
or formulations dispensing the active ingredient as droplets of a solution 
or suspension. 
Self-propelling powder-dispensing formulations preferably comprise 
dispersed particles of solid active ingredients, and a liquid propellant 
having a boiling point below 18.degree. C. at atmospheric pressure. The 
liquid propellant may be any propellant known to be suitable for medicinal 
administration and may comprise one or more lower alkyl hydrocarbons or 
halogenated lower alkyl hydrocarbons or mixtures thereof; chlorinated and 
fluorinated lower alkyl hydrocarbons are especially preferred. Generally, 
the propellant constitutes 50 to 99.9% w/w of the formulation whilst the 
active ingredient constitutes 0.1 to 20% w/w, for example about 2% w/w, of 
the formulation. 
The pharmaceutically acceptable carrier in such self-propelling 
formulations may include other constituents in addition to the propellant, 
in particular a surfactant or a solid diluent or both. Surfactants are 
desirable since they present agglomeration of the particles of active 
ingredient and maintain the active ingredient in suspension. Especially 
valuable are liquid non-ionic surfactants and solid anionic surfactants or 
mixtures thereof. Suitable liquid non-ionic surfactants are esters and 
partial esters of fatty acids with aliphatic polyhydric alcohols, for 
instance, sorbitan monooleate and sorbitan trioleate, known commercially 
as "Span 80" (Trade Name) and "Span 85" (Trade Name), respectively. The 
liquid non-ionic surfactant may constitute from 0.01 up to 20% w/w of the 
formulation, though preferably it constitutes below 1% w/w of the 
formulation. Suitable solid anionic surfactants include alkali metal, 
ammonium and amine salts of dialkyl sulphosuccinate (where the alkyl 
groups have 4 to 12 carbon atoms). The solid anionic surfactants may 
constitute from 0.01 up to 20% w/w of the formulation, though preferably 
below 1% w/w of the composition solid diluents may be advantageously 
incorporated in such self-propelling formulation where the density of the 
active ingredient differs substantially from the density of the 
propellant; also, they help to maintain the active ingredient in 
suspension. The solid diluent is in the form of a fine powder, preferably 
having a particle size of the same order as that of the particles of the 
active ingredient. Suitable solid diluents include sodium chloride, sodium 
sulphate and sugars. 
Formulations of the present invention may also be in the form of a 
self-propelling formulation wherein the active ingredient is present in 
solution. Such self-propelling formulations may comprise the active 
ingredient, propellant and co-solvent, and advantageously an antioxidant 
stabiliser. The propellant is one or more of these already cited above. 
Co-solvents are chosen for their solubility in propellant, their ability 
to dissolve the active ingredient, and for their having the lowest boiling 
point consistent with these above-mentioned properties. Suitable 
co-solvents are lower alkyl alcohols and ethers and mixtures thereof. The 
co-solvent may constitute 5 to 40% w/w of the formulation, though 
preferably less than 20% w/w of the formulation. Antioxidant stabilisers 
may be incorporated in such solutions-formulations to inhibit 
deterioration of the active ingredient and are conveniently alkali metal 
ascorbates or bisulphites. They are preferably present in an amount of up 
to 0.25% w/w of the formulation. 
Such self-propelling formulations may be prepared by any method known in 
the art. For example, the active ingredient (either as particles as 
defined hereinbefore in suspension in a suitable liquid or in up to 20% 
w/v solution in an acceptable co-solvent, as appropriate) is mixed with 
any other constituents of a pharmaceutically acceptable carrier. The 
resulting mixture is cooled, introduced in a suitable cooled container and 
propellant is added thereto in liquid form; and the container is sealed. 
Alternatively, such self-propelling formulations may be prepared by mixing 
the active ingredient either in particles as hereinbefore defined in 2 to 
20% w/v alcohol or aqueous solution as appropriate, together with the 
remaining constituents of the pharmaceutically acceptable carrier other 
than the propellant; introducing the resulting mixture; optionally with 
some propellant, into a suitable container; and injecting the propellant, 
under pressure, into the container at ambient temperature through a valve 
which comprises a part of the container and is used to control release of 
the formulation from it. Desirably, the container is purged by removing 
air from it at a convenient stage in the preparation of the 
self-propelling formulation. 
A suitable container for a self-propelling formulation is one provided with 
a manually-operable valve and constructed of aluminium, stainless steel or 
reinforced glass. The valve should, of course, be one having the desired 
spray characteristics of particle size as hereinbefore defined. 
Advantageously, the valve is of the type which delivers a fixed amount of 
the formulation on the occasion of each operation of the value, for 
example, about 50 to 100 microliters of formulation in each delivery. 
Formulations of the present invention may also be in the form of an aqueous 
or dilute alcoholic solution, optionally a sterile solution, of the active 
ingredient for use in a nebuliser or atomizer, wherein an accelerated air 
stream is used to produce a fine mist consisting of small droplets of the 
solution. A buffering agent and a surface active agent mmay also be 
included in such a formulation which should also contain a preservative 
such as methylhydroxybenzoate. 
Other formulations suitable for nasal administration include a fine powder 
having a particle size of 10 to 100 microns which is administered in the 
manner in which snuff is taken, i.e. by rapid inhalation through the nasal 
passage from a container of the powder held close up to the nose. 
In addition to the aforementioned ingredients, the formulations of this 
invention may include one or more additional ingredients such as diluents, 
buffers, flavouring agents, binders, surface active agents, thickeners, 
lubricants, preservatives, e.g. methylhydroxybenzoate (including 
anti-oxidants), emulsifying agents and the like. 
The compositions may further contain other therapeutically active compounds 
usually applied in the treatment of the above mentioned pathological 
conditions, for instance glucocorticoids, anti-histamines, anticholinergic 
agents, methyl xanthines, .beta.-adrenergic agents, salicylates, 
indomethacin, flufenamate, naproxen, timegadine, gold salts, 
penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, 
and salicylazosulfapyridin (Salazopryin). 
According to the invention, the present compounds are administered to a 
patient suffering from one of the above mentioned pathological conditions 
in a daily dose (for adults) from 0.1 mg to 7000 mg, preferably from 
35-3500 mg, and in the veterinary practice correspondingly in daily doses 
from 0.5 to 100 mg/kg bodyweight.

The invention will now be further described in the following non-limiting 
Examples: 
EXAMPLE 1 
4-(4'-Pyridylmethoxy)-N-methylaniline 
A. 4-(4'-Pyridylmethoxy)acetanilide 
A mixture of 4-acetaminophenol (30.5 g), 4-chloromethylpyridine 
hydrochloride (40 g), potassium carbonate (85 g) and dimethylformamide 
(400 m l) is stirred at ambient temperature for about 20 hours and is 
finely stirred at 60.degree.-80.degree. for a further 3-4 hours. The 
resulting mixture is diluted with water to precipitate the product, which 
is filtered off, washed with water and dried in air. An analytically pure 
sample has a melting point of 165.degree.-67.degree. C. 
B. 4-(4'-Pyridylmethoxy)aniline 
A mixture of 4-(4'-pyridylmethoxy)acetanilide (40 g), 4N hydrochloric acid 
(400 ml) and ethanol (100 ml) is refluxed for 3 hours. After cooling, the 
resulting solution is neutralized to pH 8 with a solution of sodium 
hydroxide to precipitate the product, which is filtered off, washed with 
water and dried in air. It is obtained as a hydrate with a melting point 
of 130.degree.-131.degree. C. 
C. 4-(4'-Pyridylmethoxy)-N-methylaniline 
To a solution of sodium methoxide (prepared from 2.3 g of sodium) in 
methanol (30 ml) is added 4-(4'-pyridylmethoxy)aniline (4.0 g) followed by 
paraformaldehyde (0.85 g), and the mixture if stirred at ambient 
temperature for 5 hours. Sodium borohydride (0.7 g) is then added, and the 
mixture is stirred at ambient temperature for a further 12 hours and is 
finally refluxed for 1 hour. 2N Sodium hydroxide (30 ml) is added, and the 
mixture is refluxed for 2 hours, and is then cooled and extracted twice 
with ethylacetate. The extract is evaporated and the resulting product 
recrystallized from acetone/water to give the title compound with a 
melting point of 129.degree.-131.degree. C. 
EXAMPLE 2 
4-(3'-Pyridylmethoxy)-N-methylaniline 
A. 4-(3'-Pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-chloromethylpyridine hydrochloride with 3-chloromethylpyridine 
hydrochloride, the title compound is obtained. 
B. 4-(3'-Pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 4-(3'-pyridylmethoxy)acetanilide, 
the title compound is obtained as a hydrate with a melting point of 
72.degree.-75.degree. C. 
C. 4-(3'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 4-(3'-pyridyl-methoxy)aniline, the title 
compound is obtained. It is conveniently isolated as the dihydrochloride, 
having a melting point of 212.degree. C. 
EXAMPLE 3 
4-(2'-Pyridylmethoxy)-N-methylaniline 
A. 4-(2'-Pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-chloromethylpyridine hydrochloride with 2-chloromethylpyridine 
hydrochloride, the title compound is obtained. 
B. 4-(2'-Pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 4-(2'-pyridylmethoxy)acetanilide, 
the title compound is obtained as an oil. 
C. 4-(2'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 4-(2'-pyridylmethoxy)aniline, the title 
compound is obtained with a melting point of 135.degree.-137.degree. C. It 
can further be isolated as the dihydrochloride having a melting point of 
187.degree.-189.degree. C. 
EXAMPLE 4 
3-(4'-Pyridylmethoxy)-N-methylaniline 
A. 3(4'-Pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 3-acetaminophenol, the title compound is obtained. 
B. 3-(4'-Pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 3-(4'-pyridylmethoxy)acetanilide, 
the title compound is obtained with a melting point of 
114.degree.-116.degree. C. 
C. 3-(4'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(4'-pyridylmethoxy)aniline, the title 
compound is obtained. It is isolated as a hemihydrate of the 
dihydrochloride having a melting point of 211.degree.-214.degree. C. 
EXAMPLE 5 
3-(3'-Pyridylmethoxy)-N-methyaniline 
A. 3-(3'-Pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 3-acetaminophenol, and 4-chloromethylpyridine 
hydrochloride with 3-chloromethylpyridine hydrochloride, the title 
compound is obtained. 
B. 3-(3'-Pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 3-(3'-pyridylmethoxy)acetanilide, 
the title compound is obtained with a melting point of 
99.degree.-100.degree. C. 
C. 3-(3'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Exampel 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(3'-pyridylmethoxy)aniline, the title 
compound is obtained. It is isolated as the dihydrochloride with a melting 
point of 179.degree.-182.degree. C. 
EXAMPLE 6 
3-(2'-Pyridylmethoxy)-N-methylaniline 
A. 3-(2'-Pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 3-acetaminophenol, and 4-chloromethylpyridine 
hydrochloride with 2-chloromethylpyridine hydrochloride, the title 
compound is obtained with a melting point of 160.degree.-163.degree. C. 
B. 3-(2'-Pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 3-(2'-pyridylmethoxy)acetanilide, 
the title compound is obtained as a dihydrate with a melting point of 
96.degree. C. 
C. 3-(2'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(2'-pyridylmethoxy)aniline, the title 
compound is obtained It is isolated as the dihydrochloride with a melting 
point of 195.degree.-198.degree. C. 
EXAMPLE 7 
2-(4'-Pyridylmethoxy)-N-methylaniline 
A. 2-(4'-Pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 2-acetaminophenol, the title compound is obtained. 
B. 2-(4'-Pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 2-(4'-pyridylmethoxy)acetanilide, 
the title compound is obtained. 
C. 2-(4'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 2-(4'-pyridylmethoxy)aniline, the title 
compound is obtained. 
EXAMPLE 8 
2-(3'-Pyridylmethoxy)-N-methylaniline 
A. 2-(3'-Pyridylmethoxy)acetanilide 
By following the procedure of Example 1, Part A, but replacing 
4-acetaminophenol with 2-acetaminophenol, and 4-chloromethylpyridine 
hydrochloride with 3-chloromethylpyridine hydrochloride, the title 
compound is obtained. 
B. 2-(3'-Pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 2-(3'-pyridylmethoxy)acetanilide, 
the title compound is obtained. 
C. 2-(3'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 2-(3'-pyridylmethoxy)aniline, the title 
compound is obtained. 
EXAMPLE 9 
2-(2'-Pyridylmethoxy)-N-methylaniline 
A. 2-(2'-Pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 2-acetaminophenol, and 4-chloromethylpyridine 
hydrochloride with 2-chloromethylpyridine hydrochloride, the title 
compound is obtained. 
B. 2-(2'-Pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 2-(2'-pyridylmethoxy)acetanilide, 
the title compound is obtained. 
C. 2-(2'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 2-(2'-pyridylmethoxy)aniline, the title 
compound is obtained. 
EXAMPLE 10 
4-(2'-Quinolylmethoxy)-N-methylaniline 
A. 4-(2'-Quinolylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-chloromethylpyridine hydrochloride with 2-chloromethylquinoline 
hydrochloride, the title compound is oibtained with a melting point of 
178.degree.-180.degree. C. 
B. 4-(2'-Quinolylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 4-(2'-quinolylmethoxy)acetanilide, 
the title compound is obtained with a melting point of 
132.degree.-133.degree. C. 
C. 4-(2'-Quinolylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 4-(2'-quinolylmethoxy)aniline, the title 
compound is obtained. It is isolated as a hemihydrate of the 
dihydrochloride having a melting point of 225.degree. C. 
EXAMPLE 11 
3-(2'-Quinolylmethoxy)-N-methylaniline 
A. 3-(2'-Quinolylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 3-acetaminophenol, and 4-chloromethylpyridine 
hydrochloride with 2-chloromethylquinoline hydrochloride, the title 
compound is obtained as a trihydrate with a melting point of 
160.degree.-162.degree. C. 
B. 3-(2'-Quinolylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 3-(2'-quinolylmethoxy)acetanilide 
the title compound is obtained as a dihydrate with a melting point of 
98.degree. C. 
C. 3-(2'-Quinolylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(2'-quinolylmethoxy)aniline, the title 
compound is obtained. It is isolated as a hemihydrate of the 
dihydrochloride with a melting point of 227.degree. C. 
EXAMPLE 12 
2-Chloro-4-(4'-pyridylmethoxy)-N-methylaniline 
A. 2-Chloro-4-(4'-pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 3-chloro-4-acetaminophenol, the title compound is 
obtained as a hydrate with a melting point of 126.degree.-128.degree. C. 
B. 2-Chloro-4-(4'-pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 
2-chloro-4-(4'-pyridylmethoxy)acetanilide, the title compound is obtained 
with a melting point of 120.degree.-121.degree. C. 
C. 2-Chloro-4-(4'-pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 2-chloro-4-(4'-pyridylmethoxy)aniline, 
the title compound is obtained. 
EXAMPLE 13 
3-Chloro-4-(4'-pyridylmethoxy)-N-methylaniline 
A. 3-Chloro-4-(4'-pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 2-chloro-4-acetaminophenol, the title compound is 
obtained. 
B. 3-Chloro-4-(4'-pyridylmethoxy)aniline 
By following the procedure of Example 1, part A, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 
3-chloro-4-(4'-pyridylmethoxy)acetanilide, the title compound is obtained 
as a dihydrate with a melting point of 94.degree.-96.degree. C. 
C. 3-Chloro-4-(4'-pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-chloro-4-(4'-pyridylmethoxy)aniline, 
the title compound is obtained. 
EXAMPLE 14 
2,3-Dichloro-4-(4'-pyridylmethoxy)-N-methylaniline 
A. 2,3-Dichloro-4-(4'-pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 2,3-dichloro-4-acetaminophenol, the title compound 
is obtained as a hydrate with a melting point of 159.degree.-161.degree. 
C. 
B. 2,3-Dichloro-4-(4'-pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 
2,3-dichloro-4-(4'-pyridylmethoxy)acetanilide, the title compound is 
obtained with a melting point of 123.degree.-124.degree. C. 
C. 2,3-Dichloro-4-(4'-pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 
2,3-dichloro-4-(4'-pyridylmethoxy)aniline, the title compound is obtained 
with a melting point of 160.degree.-162.degree. C. 
EXAMPLE 15 
4-(4'-Pyridylmethoxy)-N,N-dimethylaniline 
To a solution of 4-(4'-pyridylmethoxy)aniline (10.0 g; prepared as 
described in Example 1, part B) in hexamethyl phosphoric triamide (50 ml) 
is added sodium hydrogen carbonate (12.5 g) followed by methyl iodide 
(14.2 g), and the mixture is stirred at ambient temperature for 12 hours. 
The product is precipitated by dilution with water (about 500 ml) and is 
collected by filtration, washed with water and dried in air. After 
recrystallization from ethanol/water the title compound is obtained with a 
melting point of 123.degree.-125.degree. C. 
EXAMPLE 16 
4-(3'-Pyridylmethoxy)-N,N-dimethylaniline 
By following the procedure of Example 15, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(4'-pyridylmethoxy)aniline (prepared 
as described in Example 4, part B), the title compound is obtained. It is 
isolated as the dihydrochloride with a melting point of 
211.degree.-213.degree. C. 
EXAMPLE 17 
2,3-Dichloro-4-(4'-pyridylmethoxy)-N,N-dimethylaniline 
By following the procedure of Example 15, but replacing 
4-(4'-pyridylmethoxy)aniline with 
2,3-dichloro-4-(4'-pyridylmethoxy)aniline (prepared as described in 
Example 14, part B), the title compound is obtained with a melting point 
of 95.degree.-96.degree. C. 
EXAMPLE 18 
3-(2'-Quinolylmethoxy)-N,N-dimethylaniline 
By following the procedure of Example 15, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(2'-quinolylmethoxy)aniline (prepared 
as described in Example 11, part B), the title compound is obtained. It is 
isolated as a dihydrate of the dihydrochloride with a melting point of 
155.degree. C. 
EXAMPLE 19 
3-(4'-Pyridylmethoxy)-N-methylaniline 
To a cooled solution of 3-(4'-pyridylmethoxy)aniline (2.0 g, 10 mmole; 
prepared as described in Example 4, part B) in hexamethyl phosphoric 
triamide (10 ml) is added sodium hydrogen carbonate (2.5 g) followed by 
methyl iodide (1.42 g, 10 mmole), and the mixture is stirred at -5.degree. 
to -10.degree. C. for about 6 hours. The product is precipitated by 
dilution with water (about 50 ml) and is collected by filtration, washed 
with water and dried in air. After recrystallization from ethanol-water, 
the title compound, identical (IR, analysis, TLC) with the compound 
prepared as in Example 4, part C, is obtained. 
EXAMPLE 20 
4-(2'-Quinolylmethoxy)-N-methylaniline 
By following the procedure of Example 19, but replacing 
3-(4'-pyridylmethoxy)aniline with 4-(2'-quinolylmethoxy)aniline (prepared 
as described in Example 10, part B), the title compound, identical (IR, 
analysis, TLC) with the compound prepared as described in Example 10, part 
C, is obtained. 
EXAMPLE 21 
3-(2'-Quinolylmethoxy)-N-methylaniline 
By following the procedure of Example 19, but replacing 
3-(4'-pyridylmethoxy)aniline with 3-(2'-quinolylmethoxy)aniline (prepared 
as described in Example 11, part B), the title compound, identical (IR, 
analysis, TLC) with the compound prepared as described in Example 11, part 
C, is obtained. 
EXAMPLE 22 
4-(2'-Quinolylmethoxy)-N-n-butylaniline 
To a solution of 4-(2'-quinolylmethoxy)aniline (2.5 g, 10 mmole; prepared 
as described in Example 10, part B) in hexamethyl phosphoric triamide 
(12.5 ml) is added sodium hydrogen carbonate (3.5 g) followed by n-butyl 
iodide (2.0 g, 11 mmole), and the mixture is stirred at ambient 
temperature for about 24 hours. The product is precipitated by dilution 
with water (about 150 ml) and is collected by filtration, washed with 
water and dried in air. The product is dissolved in ethanol (25 ml) and an 
excess of 6N ethanolic hydrochloric acid is added to precipitate the 
dihydrochloride of the title compound which is obtained as a hydrate 
having a melting point of 225.degree. C. 
EXAMPLE 23 
3-(2'-Quinolylmethoxy)-N-n-butylaniline 
By following the procedure of Example 22, but replacing 
4-(2'-quinolylmethoxy)aniline with 3-(2'-quinolylmethoxy)aniline (prepared 
as described in Example 11, part B), the title compound is obtained as the 
dihydrochloride with a melting point of 218.degree. C. 
EXAMPLE 24 
4-(4'-Pyridylmethoxy)-N-n-butylaniline 
A mixture of 4-(4'-pyridylmethoxy)aniline hydrate (3.3 g; prepared as 
described in Example 1, part B), n-butanal (1.1 g), sodium acetate (1.5 g) 
and ethanol (40 ml) is hydrogenated in the presence of PtO.sub.2 (50 mg). 
After about 3-5 hours, the theoretical amount of hydrogen has been 
absorbed and the uptake becomes negligible. The catalyst is removed by 
filtration, and the filtrate is evaporated in vacuo. The remaining 
material is partitioned between water and ethyl acetate, and the organic 
layer is separated, dried and evaporated in vacuo. The resulting product 
is purified by chromatography (SiO.sub.2, diethyl ether), and the title 
compound is, after treatment with ethanolic hydrochloric acid by analogy 
to the method of Example 22, obtained as the dihydrochloride with a 
melting point of 234.degree. C. 
EXAMPLE 25 
4-(3'-Pyridylmethoxy)-N-n-butylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 4-(3'-pyridylmethoxy)aniline (prepared 
as described in Example 2, part B), the title compound is obtained with a 
melting point of 81.degree.-82.degree. C. 
EXAMPLE 26 
4-(2'-Pyridylmethoxy)-N-n-butylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 4-(2'-pyridylmethoxy)aniline (prepared 
as described in Example 3, part B), the title compound is obtained. It is 
isolated as the dihydrochloride with a melting point of 
209.degree.-210.degree. C. 
EXAMPLE 27 
3-(4'-Pyridylmethoxy)-N-n-butylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(4'-pyridylmethoxy)aniline (prepared 
as described in Example 4, part B), the title compound is obtained. It is 
isolated as a dihydrate of the dihydrochloride with a melting point of 
165.degree. C. 
EXAMPLE 28 
3-(3'-Pyridylmethoxy)-N-n-butylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(3'-pyridylmethoxy)aniline (prepared 
as described in Example 5, part B), the title compound is obtained with a 
melting point of 46.degree.-48.degree. C. 
EXAMPLE 29 
2,3-Dichloro-4-(4'-pyridylmethoxy)-N-n-butylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 
2,3-dichloro-4-(4'-pyridylmethoxy)aniline (prepared as described in 
Example 14, part B), the title compound is obtained with a melting point 
of 80.degree.-82.degree. C. 
EXMAPLE 30 
4-(2'-Quinolylmethoxy)-N-n-butylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 4-(2'-quinolylmethoxy)aniline (prepared 
as described in Example 10, part B, the title compound is obtained 
identical (IR, analysis, TLC) with the compound prepared as described in 
Example 22. 
EXAMPLE 31 
3-(2'-quinolylmethoxy)-N-n-butylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(2'-quinolylmethoxy)aniline (prepared 
as described in Example 11, part B), the title compound is obtained 
identical (IR, analysis, TLC) with the compound prepared as described in 
Example 23. 
EXAMPLE 32 
4-(4'-Pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 24, but replacing n-butanal with 
benzaldehyde, the title compound is obtained with a melting point of 
97.degree.-98.degree. C. 
EXAMPLE 33 
4-(3'-Pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 4-(3'-pyridylmethoxy)aniline (prepared 
as described in Example 2, part B) and n-butanal with benzaldehyde, the 
title compound is obtained with a melting point of 88.degree.-90.degree. 
C. 
EXAMPLE 34 
4-(2'-Pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 4-(2'-pyridylmethoxy)aniline (prepared 
as described in Example 3, part B) and n-butanal with benzaldehyde, the 
title compound is obtained with a melting point of 109.degree.-110.degree. 
C. 
EXAMPLE 35 
3-(4'-Pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(4'-pyridylmethoxy)aniline (prepared 
as described in Example 4, part B) and n-butanal with benzaldehyde, the 
title compound is obtained with a melting point of 85.degree.-87.degree. 
C. 
EXAMPLE 36 
3-(3'-Pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(3'-pyridylmethoxy)aniline (prepared 
as described in Example 5, part B) and n-butanal with benzaldehyde, the 
title compound is obtained. It is isolated as the dihydrochloride with a 
melting point of 200.degree. C. 
EXAMPLE 37 
2,3-Dichloro-4-(4'-pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 
2,3-dichloro-4-(4'-pyridylmethoxy)aniline (prepared as described in 
Example 14, part B) and n-butanal with benzaldehyde, the title compound is 
obtained with a melting point of 119.degree.-120.degree. C. 
EXAMPLE 38 
4-(2'-Quinolylmethoxy)-N-benzylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 4-(2'-quinolylmethoxy)aniline (prepared 
as described in Example 10, part B) and n-butanal with benzaldehyde, the 
title compound is obtained with a melting point of 96.degree.-98.degree. 
C. 
EXAMPLE 39 
3-(2'-Quinolylmethoxy)-N-benzylaniline 
By following the procedure of Example 24, but replacing 
4-(4'-pyridylmethoxy)aniline with 3-(2'-quinolylmethoxy)aniline (prepared 
as described in Example 11, part B) and n-butanal with benzaldehyde, the 
title compound is obtained. It is isolated as a hemihydrate of the 
dihydrochloride with a melting point of 212.degree. C. 
EXAMPLE 40 
3-(4'-Pyridylmethoxy)-N-benzylaniline 
A mixture of 3-(4'-pyridylmethoxy)aniline (2.0 g; prepared as described in 
Example 4, part B), benzaldehyde (1.6 g) and methanol (25 ml) is stirred 
at ambient temperature for 20 hours and is then refluxed for a further 1 
hour. After cooling, sodium borohydride (2.0 g) is added in portions 
during about 1 hour, keeping the temperature of the reaction mixture 
between 15.degree. and 20.degree. C. by external cooling. The mixture is 
stirred at ambient temperature for further 5 hours, whereafter the excess 
of 4N hydrochloric acid is added carefully, and the acidified mixture is 
stirred at ambient temperature for a further 16-20 hours. The resulting 
mixture is extracted twice with ethylacetate, and the combined extracts 
are dried and evaporated in vacuo. The resulting product is recrystallized 
(ethanol-water) to yield the title compound, identical (IR, analysis, TLC) 
with the compound prepared as described in Example 35. 
EXAMPLE 41 
3-(2'-Quinolylmethoxy)-N-benzylaniline 
By following the procedure of Example 40, but replacing 
3-(4'-pyridylmethoxy)aniline with 3-(2'-quinolylmethoxy)aniline (prepared 
as described in Example 11, part B), the title compound is obtained. It is 
isolated as a hemihydrate of the dihydrochloride, identical (IR, analysis, 
TLC) with the compound prepared as described in Example 39. 
EXAMPLE 42 
4-(2'-Pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 40, but replacing 
3-(4'-pyridylmethoxy)aniline with 4-(2'-pyridylmethoxy)aniline (prepared 
as described in Example 3, part B), the title compound is obtained, 
identical (IR, analysis, TLC) with the compound as prepared as in Example 
34. 
EXAMPLE 43 
3-(4'-Pyridylmethoxy)-N-(3"-chlorobenzyl)aniline 
By following the procedure of Example 40, but replacing benzaldehyde with 
3-chlorobenzaldehyde, the title compound is obtained. 
EXAMPLE 44 
4-(4'-Pyridylmethoxy)-N-(4"-methoxybenzyl)aniline 
By following the procedure of Example 40, but replacing 
3-(4'-pyridylmethoxy)aniline with 4-(4'-pyridylmethoxy)aniline (prepared 
as described in Example 1, part B), and benzaldehyde with 
4-methoxybenzaldehyde, the title compound is obtained. 
EXAMPLE 45 
2,5-Dichloro-4-(2'-pyridylmethylthio)-N-methylaniline 
A. 2,5-Dichloro-4-(2'-pyridylmethylthio)aniline 
To a stirred and cooled solution of 2,5-dichloro-4-mercaptoaniline (2.5 g) 
in 2N sodium hydroxide (100 ml) is at 15.degree.-20.degree. C. added 
2-chloromethylpyridine hydrochloride (2.1 g) in portions during about 30 
minutes. The mixture is then stirred at ambient temperature for a further 
1 hour, whereafter the precipitated product is collected by filtration, 
washed with water and dried in air. After recrystallization from 
ethanol-water, the title compound is obtained with a melting point of 
105.degree.-106.degree. C. 
B. 2,5-Dichloro-4-(2'-pyridylmethylthio)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 
2,5-dichloro-4-(2'-pyridylmethylthio)aniline, the title compound is 
obtained with a melting point of 94.degree.-96.degree. C. 
EXAMPLE 46 
2,5-Dichloro-4-(3'-pyridylmethylthio)-N-methylaniline 
A. 2,5-Dichloro-4-(3'-pyridylmethylthio)aniline 
By following the procedure of Example 45, part A, but replacing 
2-chloromethylpyridine hydrochloride with 3-chloromethylpyridine 
hydrochloride, the title compound is obtained with a melting point of 
136.degree.-138.degree. C. 
B. 2,5-Dichloro-4-(3'-pyridylmethylthio)N-methylaniline 
By following the procedure of Example 19, but replacing 
3-(4'-pyridylmethoxy)aniline with 
2,5-dichloro-4-(3'-pyridylmethylthio)aniline, the title compound is 
obtained. 
EXAMPLE 47 
2,5-Dichloro-4-(4'-pyridylmethylthio)-N-ethylaniline 
A. 2,5-Dichloro-4-(4'-pyridylmethylthio)aniline 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 2,5-dichloro-4-mercaptoaniline, the title compound 
is obtained with a melting point of 133.degree.-135.degree. C. 
B. 2,5-Dichloro-4-(4'-pyridylmethylthio)-N-ethylaniline 
By following the procedure of Example 22, but replacing 
4-(2'-quinolylmethoxy)aniline with 
2,5-dichloro-4-(4'-pyridylmethylthio)aniline, and n-butyl iodide with 
ethyl iodide, the title compound is obtained. 
EXAMPLE 48 
2,6-Dichloro-4-(4'-pyridylmethylthio)-N-isopropylaniline 
A. 2,6-Dichloro-4-(4'-pyridylmethylthio)aniline 
By following the procedure of Example 1, part C, but replacing 
4-acetaminophenol with 2,6-dichloro-4-mercaptoaniline, the title compound 
is obtained with a melting point of 88.degree.-89.degree. C. 
B. 2,6-Dichloro-4-(4'-pyridylmethylthio)-N-isopropylaniline 
By following the procedure of Example 22, but replacing 
4-(2'-quinolylmethoxy)aniline with 
2,6-dichloro-4-(4'-pyridylmethylthio)aniline, and n-butyl iodide with 
isopropylbromide, the title compound is obtained. 
EXAMPLE 49 
2,6-Dichloro-4-(3'-pyridylmethylthio)-N-benzylaniline 
A. 2,6-Dichloro-4-(3'-pyridylmethylthio)aniline 
By following the procedure of Example 45, part A, but replacing 
2,5-dichloro-4-mercaptoaniline with 2,6-dichloro-4-mercaptoaniline, and 
2-chloromethylpyridine hydrochloride with 3-chloromethylpyridine 
hyrochloride, the title compound is obtained with a melting point of 
97.degree. C. 
B. 2,6-Dichloro-4-(3'-pyridylmethylthio)-N-benzylaniline 
By following the procedure of Example 40, but replacing 
3-(4'-pyridylmethoxy)aniline with 
2,6-dichloro-4-(3'-pyridylmethylthio)aniline, the title compound is 
obtained. 
EXAMPLE 50 
2,6-Dichloro-4-(2'-quinolylmethylthio)-N-(2"-methylbenzyl)aniline 
A. 2,6-Dichloro-4-(2'-quinolylmethylthio)aniline 
By following the procedure of Example 1, part C, but replacing 
4-acetaminophenol with 2,6-dichloro-4-mercaptoaniline, and 
4-chloromethylpyridine hydrochloride with 2-chloromethylquinoline 
hydrochloride, the title compound is obtained with a melting point of 
115.degree.-117.degree. C. 
B. 2,6-Dichloro-4-(2'-quinolylmethylthio)-N-(2"-methylbenzyl)aniline 
By following the procedure of Example 40, but replacing 
3-(4'-pyridylmethoxy)aniline with 
2,6-dichloro-4-(2'-quinolylmethylthio)aniline, and benzaldehyde with 
2-methylbenzaldehyde, the title compound is obtained. 
EXAMPLE 51 
3-Chloro-4-(3'-pyridylmethylthio)-N-methylaniline 
A. 3-Chloro-4-(3'-pyridylmethylthio)aniline 
To a solution of 4,4'-diamino-2,2'-dichlorodiphenyldisulphide (3.2 g) in 
dimethylformamide (20 ml) is added sodium dithionite (4.0 g), and the 
mixture is stirred at ambient temperature for 5-10 minutes. Potassium 
carbonate (8.4 g) is then added, followed by 3-chloromethylpyridine 
hydrochloride (3.3 g), and the mixture is stirred at ambient temperature 
for about 20 hours. The reaction mixture is then diluted with water (about 
100 ml), and the precipitated material is extracted twice with ethyl 
acetate. The combined extracts are dried and evaporated in vacuo, and the 
resulting product purified by chromatography (SiO.sub.2, ethyl acetate) to 
give the title compound with a melting point of 101.degree.-103.degree. C. 
B. 3-Chloro-4-(3'-pyridylmethylthio)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 
3-chloro-4-(3'-pyridylmethylthio)aniline, the title compound is obtained. 
EXAMPLE 52 
3-Chloro-4-(3'-pyridylmethylsulfinyl)-N-methylaniline 
A. 3-Chloro-4-(3'-pyridylmethylsulfinyl)aniline 
To a stirred mixture of 3-chloro-4-(3'-pyridylmethylthio)aniline (3.8 g, 15 
mmole; prepared as described in Example 51, part A) in chloroform (60 ml) 
is set at 5.degree.-10.degree. C. added 3-chloroperbenzoic acid (2.7 g) in 
portions during 15-30 minutes. After stirring for a further 1 hour, the 
resulting solution is washed twice with sodium hydrogen carbonate solution 
and twice with water, and is then dried and evaporated in vacuo. The 
resulting product is recrystallized from ethanol-water to give the title 
compound. 
B. 3-Chloro-4-(3'-pyridylmethylsulfinyl)-N-methylaniline 
By following the procedure of Example 1, part C, but replacing 
4-(4'-pyridylmethoxy)aniline with 
3-chloro-4-(3'-pyridylmethylsulfinyl)aniline, the title compound is 
obtained. 
EXAMPLE 53 
3-Chloro-4-(3'-pyridylmethylsulfonyl)-N-benzylaniline 
A. 2-Chloro-4-(3'-pyridylmethylsulfonyl)aniline 
To a stirred solution of 3-chloro-4-(3'-pyridylmethylthio)aniline (3.8 g, 
15 mmole; prepared as described in Example 51, part A) in glacial acetic 
acid (75 ml) is at ambient temperature dropwise added hydrogen peroxide 
(4.0 ml; 30% in water) during about 1 hour. The mixture is stirred at 
ambient temperature for a further 20 hours and is then diluted water 
(about 300 ml) to precipitate the reaction product. It is collected by 
filtration, washed with water, and recrystallized from ethanol-water to 
give the title compound. 
B. 3-Chloro-4-(3'-pyridylmethylsulfonyl)-N-benzylaniline 
By following the procedure of Example 40, but replacing 
3-(4'-pyridylmethoxy)aniline with 
3-chloro-4-(3'-pyridylmethylsulfonyl)aniline, the title compound is 
obtained. 
EXAMPLE 54 
4-(2'-Quinolylmethoxy)-N-methylaniline 
A mixture of 4-hydroxy-N-methylaniline (3.5 g), 2-chloromethylquinoline 
hydrochloride (4.3 g), potassium carbonate (4.2 g) and dimethylformamide 
(100 ml) is stirred at 80.degree.-100.degree. C. for 20 hours and is then 
poured into ice-water (about 400 ml). The precipitated reaction product is 
dissolved in ethyl acetate, and the solution is stirred for about 2 hours 
with a mixture of active carbon and SiO.sub.2, filtered, dried and 
evaporated in vacuo. The resulting material is dissolved in ethanol (30 
ml), and an excess of 6N ethanolic hydrochloric acid is added to 
precipitate of dihydrochloride of the title compound. The compound is 
obtained as a hemihydrate, identical (IR, analysis, TLC) with the compound 
prepared as described in Example 10, part C. 
EXAMPLE 55 
4-(4'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 54, but replacing 
2-chloromethylquinoline hydrochloride with 4-chloromethylpyridine 
hydrochloride, the title compound is obtained, identical (IR, analysis, 
TLC) with the compound prepared as described in Example 1, part C. 
EXAMPLE 56 
4-(3'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 54, but replacing 
2-chloromethylquinoline hydrochloride with 3-chloromethylpyridine 
hydrochloride, the title compound is obtained, identical (IR, analysis, 
TLC) with the compound prepared as described in Example 2, part C. 
EXAMPLE 57 
4-(2'-Pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 54, but replacing 
2-chloromethylquinoline hydrochloride with 2-chloromethylpyridine 
hydrochloride, the title compound is obtained, identical (IR, analysis, 
TLC) with the compound prepared as described in Example 3, part C. 
EXAMPLE 58 
2,3-Dichloro-4-(4'-pyridylmethoxy)-N-n-butylaniline 
A. 2,3-Dichloro-4-methoxy-N-n-butylaniline 
A mixture of 2,3-dichloro-4-methoxyaniline (19.2 g), n-butylbromide (22.0 
g), sodium hydrogen carbonate (40 g) and methylcellosolve (350 ml) is 
stirred at 95.degree.-100.degree. C. for about 48 hours. The cooled 
mixture is filtered, and the filtrate is evaporated in vacuo. The 
remaining material is washed with water and is thereafter recrystallized 
from ethanol to give the title compound with a melting point of 
47.degree.-49.degree. C. 
B. 2,3-Dichloro-4-hydroxy-N-n-butylaniline 
To a stirred solution of 2,3-dichloro-4-methoxy-N-n-butylaniline (8.5 g) in 
1,1,2,2-tetrachloroethane (80 ml) is added anhydrous aluminium chloride 
(8.5 g), and the mixture is refluxed for about 40 hours. The resulting 
mixture is poured into ice/water (about 500 ml), and the precipitated 
material is extracted twice with methylene chloride. The combined extracts 
are dried and evaporated in vacuo to give the title compound as a heavy 
oil. 
C. 2,3-Dichloro-4-(4'-pyridylmethoxy)-N-n-butylaniline 
By following the procedure of Example 54, but replacing 
4-hydroxy-N-methylaniline with 2,3-dichloro-4-hydroxy-N-n-butylaniline, 
and 2-chloromethylquinoline hydrochloride with 4-chloromethylpyridine 
hydrochloride, the title compound is obtained, identical (IR, analysis, 
TLC) with the compound prepared as described in Example 29. 
EXAMPLES 59-65 
By following the procedure of Example 22 and using the appropriate 
substituted alkyl halogenide, compounds of Table II are obtained. 
TABLE II 
______________________________________ 
##STR12## 
Ex. Melting 
No. R.sub.1 point Remarks 
______________________________________ 
59 CH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2 
217.degree. C. 
3HCl, H.sub.2 O 
60 CH.sub.2 (CH.sub.2).sub.5N(CO).sub.2C.sub.6 H.sub.4 
112-114.degree. C. 
61 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 
272.degree. C. 
3HCl, 2H.sub.2 O 
62 CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 
210.degree. C. 
3HCl, H.sub.2 O 
63 CH.sub.2 CH.sub.2 OH 
221.degree. C. 
2HCl 
64 CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5 
193-195.degree. C. 
2HCl, 0.5H.sub.2 O 
65 CH.sub.2 CH.sub.2 COOH 
159-161.degree. C. 
______________________________________ 
EXAMPLE 66 
4-(2'-Quinolylmethoxy)-N-1"-(6"-amino-n-hexyl)aniline 
To a stirred solution of 
4-(2'-quinolylmethoxy)-N-1"-(6"-phthaloyl-n-hexyl)aniline (1.05 g, 
prepared as described in Example 60) in a mixture of isopropanol (25 ml) 
and water (4 ml), sodium borohydride (0.44 g) is added, and the resulting 
solution is stirred at ambient temperature for about 16 hours. Acetic acid 
(2.3 ml) is then carefully added, and the mixture refluxed for 2 hours. 
After addition of 4N hydrochloric acid (5 ml) the solution is evaporated, 
and the resulting precipitate is crystallized from ethanol. After 
recrystallization from ethanol, the title compound is obtained as a 
hydrate of the trihydrochloride with a melting point of 224.degree. C. 
EXAMPLE 67 
2-(2'-Quinolylmethoxy)-N-benzylaniline 
By following the procedure of Example 22, but replacing 
4-(2'-quinolylmethoxy)aniline with 2-(2'-quinolylmethoxy)aniline and 
n-butyliodide with benzylbromide, the title compound is obtained with a 
melting point of 84.degree.-85.degree. C. 
EXAMPLE 68 
3-(2'-Pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 22, but replacing 
4-(2'-quinolylmethoxy)aniline with 3-2'-(pyridylmethoxy)aniline and 
n-butyliodide with benzylbromide, the title compound is obtained as a 
dihydrate of the dihydrochloride with a melting point of 
161.degree.-163.degree. C. 
EXAMPLES 69-76 
By following the procedure of Example 22, and using the appropriate 
starting materials, compounds of Table III are obtained. 
TABLE III 
______________________________________ 
##STR13## 
Melting 
Ex. No. 
R.sub.1 point Remarks 
______________________________________ 
69 CH.sub.2 CH.sub.3 
245.degree. C. 
2HCl 
70 CH.sub.2 CH.sub.2 CH.sub.3 
240.degree. C. 
2HCl 
71 CH(CH.sub.3).sub.2 
240.degree. C. 
2HCl 
72 (CH.sub.2).sub.4 CH.sub.3 
200-202.degree. C. 
2HCl H.sub.2 O 
73 (CH.sub.2).sub.5 CH.sub.3 
198-200.degree. C. 
2HCl 
74 cyclohexyl 208.degree. C. 
2HCl 
75 CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5 
130.degree. C. 
2HCl H.sub.2 O 
76 CH.sub.2 CH.sub.2 COOH 
210.degree. C. 
2HCl 1.5H.sub.2 O 
______________________________________ 
EXAMPLE 77 
4-(2'-Quinolylmethoxy)-N,N-di-n-propylaniline 
By following the procedure of Example 22, but replacing n-butyl iodide with 
n-propyl iodide, and performing the reaction at 60.degree. C. for about 48 
hours using an excess of n-propyl iodide, the title compound is obtained 
as a hemihydrate of the dihydrochloride with a melting point of 
216.degree. C. 
EXAMPLE 78 
2-Chloro-4-(4'-pyridylmethoxy)-N-benzylaniline 
A. 2-Chloro-4-(4'-pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 2-chloro-4-hydroxyacetanilide, the title compound 
is obtained as a hydrate with a melting point of 126.degree.-128.degree. 
C. 
B. 2-Chloro-4-(4'-pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 
2-chloro-4-(4'-pyridylmethoxy)acetanilide, the title compound is obtained 
with a melting point of 120.degree.-121.degree. C. 
C. 2-Chloro-4-(4'-pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 40, but replacing 
3-(4'-pyridylmethoxy)aniline with 2-chloro-4-(4'-pyridylmethoxy)aniline, 
the title compound is obtained as a hydrate of the dihydrochloride with a 
melting point of 234.degree. C. 
EXAMPLE 79 
3-Chloro-4-(4'-pyridylmethoxy)-N-benzylaniline 
A. 3-Chloro-4-(4'-pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 3-chloro-4-hydroxyacetanilide, the title compound 
is obtained as a hydrate with a melting point of 153.degree.-154.5.degree. 
C. 
B. 3-Chloro-4-(4'-pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 
3-chloro-4-(4'-pyridylmethoxy)acetanilide, the title compound is obtained 
with a melting point of 94.degree.-96.degree. C. 
C. 3-Chloro-4-(4'-pyridylmethoxy)-N-benzylaniline 
By following the procedure of Example 40, but replacing 
3-(4'-pyridylmethoxy)aniline with 3-chloro-4-(4'-pyridylmethoxy)aniline, 
the title compound is obtained as a hemihydrate of the dihydrochloride 
with a melting point of 238.degree. C. 
EXAMPLE 80 
2-Methyl-4-(4'-pyridylmethoxy)-N-methylaniline 
A. 2-Methyl-4-(4'-pyridylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 2-methyl-4-hydroxyacetanilide, the title compound 
is obtained. 
B. 2-Methyl-4-(4'-pyridylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 
2-methyl-4-(4'-pyridylmethoxy)acetanilide, the title compound is obtained 
with a melting point of 140.degree.-141.degree. C. 
C. 2-Methyl-4-(4'-pyridylmethoxy)-N-methylaniline 
By following the procedure of Example 19, but replacing 
3-(4'-pyridylmethoxy)aniline with 2-methyl-4-(4'-pyridylmethoxy)aniline, 
the title compound is obtained as a hydrate with a melting point of 
103.degree. C. 
EXAMPLE 81 
2-Methyl-4-(2'-quinolylmethoxy)-N-methylaniline 
A. 2-Methyl-4-(2'-quinolylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 2-methyl-4-hydroxyacetanilide, and 
4-chloromethylpyridine hydrochloride with 2-chloromethylquinoline 
hydrochloride, the title compound is obtained. 
B. 2-Methyl-4-(2'-quinolylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 
2-methyl-4-(2'-quinolylmethoxy)acetanilide, the title compound is obtained 
with a melting point of 103.degree.-105.degree. C. 
C. 2-Methyl-4-(2'-quinolylmethoxy)-N-methylaniline 
By following the procedure of Example 19, but replacing 
3-(4'-pyridylmethoxy)aniline with 2-methyl-4-(2'-quinolylmethoxy)aniline, 
the title compound is obtained as a hydrate of the dihydrochloride with a 
melting point of 218.degree. C. 
EXAMPLE 82 
4-Carbethoxy-3-(2'-quinolylmethoxy)-N-methylaniline 
A. 4-Carbethoxy-3-(2'-quinolylmethoxy)acetanilide 
By following the procedure of Example 1, part A, but replacing 
4-acetaminophenol with 4-carbethoxy-3-hydroxyacetanilide, and 
4-chloromethylpyridine hydrochloride with 2-chloromethylquinoline 
hydrochloride, the title compound is obtained as a hydrate with a melting 
point of 68.degree.-70.degree. C. 
B. 4-Carbethoxy-3-(2'-quinolylmethoxy)aniline 
By following the procedure of Example 1, part B, but replacing 
4-(4'-pyridylmethoxy)acetanilide with 
4-carbethoxy-3-(2'-quinolylmethoxy)acetanilide, the title compound is 
obtained with a melting point of 178.degree.-181.degree. C. 
C. 4-Carbethoxy-3-(2'-quinolylmethoxy)-N-methylaniline 
By following the procedure of Example 19, but replacing 
3-(4'-pyridylmethoxy)aniline with 
4-carbethoxy-3-2'-quinolylmethoxy)aniline, the title compound is obtained. 
EXAMPLE 83 
3-(2'-Quinolylmethoxy)-N-(2"-carboxyphenyl)aniline 
By following the procedure of Example 54, but replacing 
4-hydroxy-N-methylaniline with 3-hydroxy-N-(2"-carboxyphenyl)aniline, the 
title compound is obtained with a melting point of 218.degree.-220.degree. 
C. 
EXAMPLES 84-92 
By following the procedures mentioned in Table IV, and using the 
appropriate starting materials, compounds of Table IV are obtained. 
TABLE IV 
______________________________________ 
##STR14## 
Procedure 
Ex. Position described Melting 
No. of bond in R.sub.1 point Remarks 
______________________________________ 
84 4 19 CH.sub.3 
220.degree. C. 
2HCl 
85 4 22 (CH.sub.2).sub.3 CH.sub.3 
239.degree. C. 
2HCl 
86 4 40 CH.sub.2 C.sub.6 H.sub.5 
117-119.degree. C. 
87 6 54 CH.sub.3 
145-147.degree. C. 
88 6 22 (CH.sub.2).sub.3 CH.sub.3 
200.degree. C. 
2HCl 
0.5H.sub.2 O 
89 6 40 CH.sub.2 C.sub.6 H.sub.5 
114-116.degree. C. 
90 8 54 CH.sub.3 
101-103.degree. C. 
H.sub.2 O 
91 8 22 (CH.sub.2).sub.3 CH.sub.3 
212.degree. C. 
2HCl 
92 8 40 CH.sub.2 C.sub.6 H.sub.5 
200.degree. C. 
2HCl 
1.5H.sub.2 O 
______________________________________ 
EXAMPLE 93 
3-(2'-Quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline ester with 
N,N-dimethylglycine 
A. 3-(2'-Quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline 
A mixture of 3-(2'-quinolylmethoxy)-N-benzylaniline (4.2 g, prepared as 
described in Example 39), 37% aqueous formalin (10 ml), potassium 
carbonate (6.0 g) and water (50 ml) is stirred at 60.degree. C. for about 
20 hours. After cooling, the resulting precipitate is collected by 
filtration and washed with water to give the title compound. 
B. 3-(2'-Quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline ester with 
N,N-dimethylglycine 
A suspension of 3-(2'-quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline (3.4 
g), dicyclohexylcarbodiimide (2.1 g) and N,N-dimethylglycine (1.1 g) in 
dry pyridine (25 ml) is stirred at ambient temperature for about 24 hours. 
The resulting mixture is evaporated in vacuo, and the remaining oil is 
extracted with dichloromethane (150 ml). After filtration and drying over 
magnesium sulphate, the dichloromethane is evaporated in vacuo, and the 
residue triturated with diethyl ether to give the title compound. 
EXAMPLE 94 
3-(2'-Quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline disodium phosphate 
ester 
A. 3-(2'-Quinolylmethoxy)-N-benzyl-N-chloromethylaniline 
A solution of 3-(2'-quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline (8.4 
g, prepared as described in Example 93, part A) and phosphorous 
trichloride (2.5 ml) in dichloromethane (100 ml) is stirred at ambient 
temperature for 24 hours and is then washed once with water (100 ml) and 
twice with 5% aqueous sodium carbonate solution (200 ml). The organic 
layer is separated, dried over magnesium sulphate and evaporated in vacuo 
to give the crude title compound, which is used in the following step 
without further purification. 
B. 3-(2'-Quinolylmethoxy)-N-benzyl-N-hydroxymethyl aniline dibenzyl 
phosphate ester 
A mixture of 3-(2'-quinolylmethoxy)-N-benzyl-N-chloromethylaniline (20 
mmole, prepared as described in Part A) and silver dibenzylphosphate (15 
g) in benzene (350 ml) is refluxed for 2 hours, and is filtered while 
still hot. The mixture is then extracted with 5% aqueous potassium 
carbonate solution (300 ml), and the organic layer is separated dried over 
magnesium sulphate and evaporated in vacuo. The remaining material is 
triturated with diethyl ether to give the title compound. 
C. 3-(2'-Quinolylmethyl)-N-benzyl-N-hydroxymethylaniline disodium phosphate 
ester 
A solution of 3-(2'-quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline 
dibenzylphosphate ester (6.0 g) in ethyl acetate (150 ml) is hydrogenated 
at ambient temperature in the presence of palladium on activated carbon 
(2.0 g). After 30-60 minutes, the theoretical amount of hydrogen has been 
absorbed, and the uptake becomes negligible. The catalyst is removed by 
filtration, and the filtrate is evaporated in vacuo to give crude 
3-(2'-quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline phosphate ester. 
This material is dissolved in methanol (50 ml), and the solution is 
neutralized with 1N sodium hydroxide solution. The solvent is removed in 
vacuo, and the residue is triturated with acetone to crystallize the title 
compound. 
EXAMPLE 95 
Aerosol 
3-(2'-Quinolylmethoxy)-N-benzylaniline (active substance): 1000 mg 
Sorbitan trioleate: 700 mg 
Monofluorotrichloromethane: 595 g 
Difluorodichloromethane: 798 g 
The active substance is micronized in a jet-mill. The majority of the 
particles should be less than 5 .mu.m in diameter. 
A drug concentrate is prepared by dissolving sorbitan trioleate in a small 
amount of monofluorotrichloromethane and adding the active substance. The 
concentrate is homogenized carefully. The concentrate is transferred to a 
sealed tank provided with a refrigeration system. The remaining 
propellants are added under stirring and cooling to -50.degree. C. 
Suitable aerosol containers are filled with the calculated amount of 
formulation and sealed immediately with metering valves with suitable 
actuators. Each puff delivers 50 .mu.g of the active substance. 
EXAMPLE 96 
Capsule 
3-(2'-Quinolylmethoxy)-N-benzylaniline (active substance): 100 mg 
Lactose fine crystalline: 197 mg 
Magnesium stearate: 3 mg 
The active substance is mixed in a suitable mixer with lactose until a 
homogeneous state is reached. The magnesium stearate is added and the 
blending procedure is continued for a few minutes. By means of a suitable 
capsule-filling machine hard gelatine capsules size 0 are filled, each 
with 300 mg of the mixture. 
EXAMPLE 97 
Tablet 
3-(2'-Quinolylmethoxy)-N-benzylaniline (active substance): 100 mg 
Lactose: 75 mg 
Starch: 12 mg 
Methylcellulose: 2 mg 
Sodium carboxymethylcellulose (CMC-Na): 10 mg 
Magnesium stearate: 1 mg 
The active substance, lactose and starch are mixed to a homogeneous state 
in a suitable mixer and moistened with a 5 percent aqueous solution of 
methylcellulose 15 cps. The mixing is continued until granules are formed. 
If necessary, the wet granulation is passed through a suitable screen and 
dried to a water content of less than 1% in a suitable dryer, e.g. fluid 
bed or drying oven. The dried granulation is passed through a 1 mm screen 
and mixed to a homogeneous state with CMC-Na. Magnesium stearate is added 
and the mixing is continued for a short period of time. 
Tablets with a weight of 200 mg are produced from the granulation by means 
of a suitable tabletting machine. 
EXAMPLE 98 
Suppository 
3-(2'-Quinolylmethoxy)-N-n-butylaniline (active substance): 100 mg 
Cocoa butter: 1900 mg 
Cocoa butter is slowly heated to form a melt not exceeding 40.degree. C. 
The active substance is incorporated in the melt, and suppositories with a 
weight of 2 grams are prepared by moulding. 
EXAMPLE 99 
Topical formulation 
3-(2'-Quinolylmethoxy)-N-benzylaniline (active substance): 2% w/w 
II 
Cetostearyl alcohol: 10% w/w 
Liquid paraffin: 10% w/w 
White soft paraffin: 5% w/w 
Polyoxyethylene sorbitane monostearate: 5% w/w 
III 
Methylparaben: 0.2% w/w 
Glycerol: 10% w/w 
Water to make: 100% w/w 
The ingredients stated under II are melted together and heated to 
70.degree. C. in a vessel fitted with stirrer and homogenizer. In another 
vessel, the water phase (III) is prepared by heating to 70.degree. C. The 
water phase is slowly added to the oil phase with continuous stirring and 
homogenization. 
The active substance is added and the temperature is kept for 15 minutes at 
70.degree. C. The vessel is cooled to 40.degree. C. under continuous 
stirring and homogenization. The cooling is continued to a temperature 
below 25.degree. C. under slow stirring. 
EXAMPLE 100 
Formulation for injection 
3-(2'-Pyridylmethoxy)-N-benzylaniline, 2 HCl (active substance): 1% 
Sodium chloride: q.s. 
Water for injection to make: 100% 
The active substance is dissolved in water for injection. The solution is 
made isotonic with sodium chloride. The solution is filled into ampoules 
and sterilized. 
EXAMPLE 101 
Ophthalmic solution 
3-(2'-Quinolylmethoxy)-N-benzylaniline, HCl (active substance): 0.2% 
Mannitol: 5% 
Hydroxyethylcellulose: 0.5% 
Phenyl ethyl alcohol: 0.5% 
Water for injection to make: 100% 
A 2 percent concentrate of hydroxyethylcellulose in water for injection 
including phenyl ethyl alcohol is prepared by slowly spreading the 
cellulose on the water surface. The concentrate is allowed to stand for 
complete swelling of the cellulose. 
The active substance and mannitol are dissolved in the remaining amount of 
water for injection. 
The solutions are carefully mixed together and sterilized. Under aseptic 
conditions the solution is filled into suitable sterile containers.