CA1088535A - Pharmaceutically active 2-substituted-1-(omega- aminoalkoxy)benzenes - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
2-Substituted-1-(omega-aminoalkoxy)benzenes are prepared and found useful as pharmaceutical agents, particularly as antidepressants. More particularly the invention relates to the process for producing a compound having the formula (I):

(I) and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of amino, C1-C5 alkylamino, C2-C6 dialkylamino, morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl; R2 is selected from the group consisting of benzyl, phenoxy, phenylthio and 1-phenylethyl; and n is an integer of 3, 4 or 5; with the provisos that when R2 is phenoxy and n is 3, R1 is amino or C1-C5 alkylamino;
when R2 is phenoxy and n is 4 or 5, R1 is amino, C1-C5 alkylamino, C2 - C6 dialkylamino morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl; when R2 is benzyl and n is 4 or 5, R1 is C1 - C5 alkylamino or 1-piperidyl; and when R2 is benzyl and n is 3, R1 is C1 - C5 alkylamino, which comprises reacting a 2-substituted-1-(omega-halogenoalkoxy) benzene of the formula (II):

(II) wherein X is a halogen; and R2 and n are as defined above, with an amine of the formula (III):
R1 - H (III) wherein R1 is defined above, and if desired reacting the said compound with a suitable acid to yield said pharmaceutically acceptable acid addition salt.

Description

1~88S35 PHARMACEUTICALLY ACTIVE 2-SUBSTITUTED-l- -~
(OMEGA-AMINOALKOXY)BENZENES
. BACXG~OUND OF THE IN~N~ON

Fleld Or the Inventio~
This invention relates to 2-substituted-1-(omega-aminoalkoxy) benzenes which are pharmacologically active as antidepre~sants.

DescriPtion o~ the Prior ~rt L. C. Cheney et al, J. Am. Chem. Soc., Vol. 71, 60-64 (1949) deocribeo Jeveral diphenylmethanes contalning a sub~tituent at the 2-position, including 2-dimethylaminoethoxy, 2- -diethylaminoethoxy, 2-morpholinoethoxy, 2-(1-piperidyl)ethoxy,

2-ioopropylaminoethoxy, 3-(1-piperidyl) propoxy, 3-dimethyl-aminopropoxy and 3-dibutylaminopropoxy.
That re~erence al~o indica~es that 2-(2-aminoethoxy)diphenyl-; met~ano~ and 2-(3-aminopropoxy)diphenylmethanes have anti-hiotaminic and local ae~thetic activity in animals. ~-- However, it is to be noted that the 2-(4-aminobutoxy)diphenyl-methanes and 2-(5-aminopentyloxy)diphenylmethane~ of this invention are not deocribed in that reference It is al~o to be noted that there i9 no indication in that reference that the 2-omega-aminoalkoxydiphenylmethanes poooess antidepressant activity.
A~ a matter Or fact, the 2-(3-dimethylaminopropoxy)diphenyl-methane which is described in that reference does not pos~ess ,, ~; antidepr-s~ant activity according to ph~rmacological testing.

.

_ 2 -1~88S35 SUMMARY OF THE INVENTION , - .
.
This invention in one aspect relates to the preparation of compounds of the formula (I):

O- ~ CH2 ) nRl ~ R2 (I) ~.

and a pharmaceutically acceptable acid addition salt thereof, ~-wherein Rl is selected from the group consisting of amino, Cl-C5 a-lkylamino, C2-C6 dialkylamino, morpholino, l-piperidyl, 4-methyl-1-piperazinyl and ~ ,~
l-pyrrolidinyl; R2 is selected from the group consisting of benzyl,.phenoxy, phenylthio and l-phenylethyl; and n is an integer of 3, 4 or 5; with the ~;
provisos that when R2 is phenoxy and n is 3, Rl is amino or Cl-C5 alkylamino;
when R2is phenoxy and n is 4 or 5, R1 is amino, Cl-C5 alkylamino, C2 - C6 dialkylamino msrpholino, l-piperidyl, 4-methyl-1-piperazinyl and .....l-pyrrolidinyl; when R2 is benzyl and n is 4 or 5, Rl is C1 - C5 ~.
alkylamino or l-piperidyl; and when R2 is benzyl and n is 3, Rl -.
i9 Cl - C5 alkylamino, which comprises reacting a 2-substituted-i-(omega-halogenoalkoxy) benzene of the formula (II): . .. --0-(CH2)nX .

wherein X is a halogen; and R2 and n are as defined.above, with.an amine of the formula (111): -R1 ~ H (Ill) .:
wherein Rl is defined above, and if desired reacting the ~: compound with a suitable acid to yield the pharmaceutically :.
: aceeptable acid addition salt. .:
~ -,,~ .

~8535 The compound palLiates conditions of depression in warm-blooded animals when administere~ to the animal in an antidepressant effective amount.

, . , DESCRIPTION OF ~HE INVENTION ~-A~ summarized abo~e, this invention relates to a group of compounds uJerul a~ pharmaceutical agentq, which compound~
are represented by Formula I above.
Illu~trative Or the compounds of thi~ invention are the following:
10 . 2--(4-aminobutoxy)diphenyimethane 2-(4-methylaminobutoxy)diphenylmethane 2-(4-ethylaminobutoxy)diphenylmethane 2-~4-dimethylaminobutoxy)diphenylmethane 2-(5-methylaminopentyloxy)diphenylmethane 2-t5-dimethylaminopentyloxy)diphenylmethane 2-(4-morpholinobutoxy)diphenylmethane 2- ~4-(1-piperidyl)butoxy~ diphenylmethane 4- ~4-(4-methy}-1-piperazinyl)butoxy ~diphenylmethane .
2-(3-methylaminopropoxy)diphenyl ether 2-(3-dimethylaminopropoxy)diphenyl ether 2-(4-aminobutoxy)diphenyl ether 2-(4-methylaminobutoxy)diphenyl ether ~' ' ' ....
: .

1(~88S35-2-(4-dimethylaminobutoxy)diphenyl ether 2-(4-morpholinobutoxy)diphenyl ether 2- (4-~4-methyl-1-pipèrazinyl)butoxy ~ diphenyl ether 2-(5-methylaminopentyloxy)diphenyl ether 2-(5-dimethylaminopentyloxy)diphenyl ether 2- ~5-(1-piperidyl)pentyloxy ~diphenyl ether 2-(3-methylaminopropoxy)diphenyl ~ulfide 2-(3-dimethylaminopropoxy)diphenyl sulfide ' 2-(4-aminobutoxy)diphenyl sulride 2-(4-methylaminobutoxy)diphenyi sulfide 2-(4-dimethylaminobutoxy)diphenyl ~ulfide : :
2-(4-morpholinobutoxy)diphenyl sulfide ~ -2- ~(4-methyl-1-piperaziny~)butoxy ) diphenyl sulfide 2-(5-methylaminopentyloxy)diphenyl ~ulfide 2-(5-dimethylaminopentyloxy)diphenyl ~ulfid~
2- ~4-(1-piperidyl)butoxy ) diphenyl sulfide 2-(3-methylaminopropoxy)diphenylmethane 2-(3-ethylaminopropoxy)diphenylmethane 2-(3-methylaminopropoxy)diphenylmethylmethane 2-(3-dimethylaminopropoxy)diphenylmethylmethane 2-(4-aminobutoxy)diphenylmethylmethane 2-(4-methylaminobutoxy)diphenylmethylmethane 2-(4-dimethylaminobutoxy)diphenylmethylmethane 2 (5-methylaminopentyloxy)diphenylmethylmethane 2-(5-di~methylaminopentyloxy)diphenylmethylmethane ~ . , ~(~88S35 The pharmaceutically ac¢eptable acid addition salts Or the above compound~ are, Or cour~e, also included within the ~cope Or this invention.
It will be understood that the term "pharmaceutically acceptable acid addition salt~" a~ used herein i9 intended !
to include non-toxic salts Or the compound~ Or this inven-tion with an anion. Repre~entative Or ~uch salts are hydrochlorides, hydro~romide~, sulrate~, phosphates, nitrates, a¢etates, ~ucdinates J adipates, propionates~ tartrates, maleates, citrates, benzoate8, toluenesulfonates, and m-thanesulronates.
or the compounds of this invention, it will be understood that the following compounds are most preferred due to their high level Or antidepressant activity and their low level of toxicity.
, :, ,"
`~ "~ ' .

. 1088S35 ::

2-(4-methylaminobutoxy)diphenylmethane 2-(4-ethylaminobutoxy)diphenylmethane 2-(5-methylaminopentyloxy)diphenylmethane 2-(4-methylaminobutoxy)diphenyl ether :
2-(~-dimethylaminobutoxy)diphenyl ether ...
2-(5-methylaminopentyloxy)diphenyl ether 2-(3-methylaminopropoxy)diphenyl sulride ;~ :
2-(4-methylaminobutoxy)diphenyl qulfide -2-(4-dimethylaminobutoxy)diphenyl sul~ide 2-(5-methylamdnopentyloxy)diphenyl ~ul~ide :
2-(3-methylamlnopropoxy)diphenylmethane 2-(4-methylamlnobutoxy)diphenylmethylmethane . .
2-(4-dimethylaminobutoxy).diphenylmethylmethane 2-(3-dimethylamlnopropoxy)diphenylmethylmethane pREPARATION
The compounds of thi~ in~ention are prepared by reacting a 2-~ubstituted-1-(omega-halogenoalkoxy)benzene with an amine.
The 2-substituted-1-(omega-halogenoalkoxy)benzene starting materiala which are represented by Formula II above can be prepared by reacting a 2-substituted phenol with a 1,3-.
. . dihalogenopropa~e, 1,4-dihalogenobutane or 1,5-dihalogeno-pentane in the presence o~ an alkali.
~'~'' ' ' , .

., , .i~

1~88535 The amine starting material~ which are represented by Formula m abo~e lnclude ammonia; primary amine~ such as methylamine, ethylamine, lsopropylamine and the like;
secondary amines such a~ dimethylamine, diethylamine~ N-methylethylamine and the like; morpholine; piperidine;
4-methylpiperazine; and pyrrolidine.
The amine reacts with the equimclecular amount of the 2-~ubstituted-l-(omega-halogenoalkoxy)benzene. However, the use of the exce~s am~ne accelerates the reaction. Normally, 10 . the amount of the amine to be employed i9 in the range of 1 to 100 moles per mole of the 2-substituted-1-(omega-halogenoalkoxy)benzene. . ~-.
The reaction can be carri6~d out without an added solvent.
However, the use of a reaction-inert solvent makes a homo-genous reaction poSsible.
Examples o~ such solvents are water, dioxane, tetrahydrofuran, dimethyl 9ulfoxide, lower aliphatic alcohols and the mixture thereof.
The reactlon temperature i8 not critical, but normally ranges from room temperatures to 150C.
The reaction time varie~ widely with the reaction temperature and the reactivity Or the starting materials, but normally is in the range of from 10 minutes to 40 hours.
The pre~ence of bases wkich neutralize a hydrogen halide formed in the course of the reaction accelerates the reaction. ~`

Examples of ~uch bases are inorganic bases such as po- .
tassium hydroxide, sodium hydroxide, potassium carbonate, - -Oodium carbonate and the like; and tertiary anine~ such as pyridine, triethylamine and the like. ~-The amount Or the base to be employed is normally in the range Or I to 5 moles per mole of the 2-substituted-1-(omega-halogenoalkoxy)benzene.
When the baae i~ aboent, the 2-subst~tuted-1-(omega-aminoslkoxy)benzenes react with a hydrogen halide formed during the reaction, and are con~erted to the acid addi- ' -~
tion aalt9 thereof.
Ac~d addition salts Or the 2-substituted-1-(omega-aminoalkoxy) benzeneJ may be ¢onveniently prepared by contacting the oompound~ with a ~uitable acid.
The 2-~ubstituted-1-(omega-aminoalkQxy)benzene# and the acid addition ~alts thereof may be purified by recry~tallization :: employing a ~uitable solvent ~uch a~ al¢ohol-ether.
Pharmacological testing Or the 2-sub~tituted-1-(omega-aminoalkoxy)benzenes has demonstrated that they are u~eful - -as antidepressant agents as evidenced by their ability to rever9e re9erpine hypothermla in mice.
:~ The compound9 have been te~ted in mice for antidepressant, -:

., - ~ .
~ . . .-- .

1~88S35 ~edative, anticonvulsant and anticholinergic activity.
T~e compounds were administered intraperitoneally and the activities of the compound~ were compared with those of Amitriptyline.
Antidepres~ant activity was evaluated by antagonism of reserpine (5 mg/kg i.p.) induced hypothe~mia (P.S.J. Spencer in "Antidepressant DrugY" S. Garattini and M.N.G. Duhes, ed., Excerpta Medica Foundation, Amsterdam, pages 194-204 (1967)) and antireserpine activity was expressed as rela-tive potency (Amitriptyline = 1).
LD50 was calculated by Lltchfield-Wilcoxon method.
CNS depressant activity was defined by the ability of the compounds to cause neurol~gical deficit as measured by traction test (S. Courvoisier, R. Ducrot, L. Julou;
"P~ychotropic Drugs" ed. by S. Garattini, V. Ghetti, page 373, (1957)) and spontaneous motor activity (Spontaneous motoi activity was measured by ANIMEX apparatus).
Anticon w lsant activity was determined by antagonism of electroshock induced tonic extensor (L. S. Goodman, M.
Singh Grewal, W. C. Brown and E. A. Swinyard, J. P~armacol, Exptal. Therap., 108, 168 (1953)).
Central anticholinergic effect was asse~sed by testing the tre rine induced tre r in mice (G. M. E~erett, L. E.
Bloucus and J. M. Sheppard, Science 124 79 (1956)).

.', .~
.

.. -.

Result~ are summarized in Table 1 and Table II, in which EDS i9 de~ined a~ the dose Or the test compounds, which pre~ent 50% of each re~ponse. :;

Table I. Antire~erpine Activity in Mice .
~ .
. _ . ..
Compound Relative LD50 ~
Potency (mg/kg i.p.) ..
.. _ . , . _ . . ... ,., _. ~ ~ ._ 2-(4-methylaminobutoxy)diphenyl- 0 73 .
methane hydrochloride . 73 . . , .
2-(4-ethylaminobutoxy)diphenyl-0 3 2 methane hydrochloride .5 1 0 .. _ . .
2-(5-methylaminopentyloxy)diphenyl- .
Dethane hydrochloride O.5 160 ~., _ . . .
2-(3-dimethylaminopropoxy)- . .
diphenylmethane hydroch}oride 0.00 .~___ . . _ , . ',, 2-(4-methylaninobutoxy)diphenyl ether hydrochloride 1.10 100 . I `:
2-(4-dimethylaminobutoxy)- .
diphenyl ether hydrochloride 0.S8 . 92 2-(5-methylaminopentyloxy)- 0 :
diphenyl ether hydrochloride 57 85 __ . . . ., 2-~4-methylaminobutoxy)diphenyl 0 0 .
~ulfide hydrochloride .9 120 .. . _ 2-(4-di~ethylaminobutoxy)- -~
diphenyl ~ulfide hydrochloride . 0.70 130 2-(3-methylaminopropoxy)- 0 6 diphenyl ~ulfide hydrochloride . 0 13S
... _. .
::~ 2-(3-methylaninopropoxy)diphenyl-methane hydrochloride 0.56 160 . :' , , .
:

1~88S35 . .
Compound Relati~e LD50 . ~ . . Potency (mg/kg i.p.) ~ .
2-(3-dimethylaminopropoxy)diphenyl- 0 00 .
methane hydrochloride . _ ._ 2-(2-dimethylaminoethoxy)diphenyl-0 00 . methane hydrochloride . _ . . ::
2-(2-methylaminoethoxy)diphenyl-methane hydrochloride 0.00 _ . __ 2-(4-methylaminobutoxyjdiphenyl- ~ .
methylmethane hydrochloride . o.66 140 - - . . . __ _ 2-(4-dimethylaminobutoxy)diphenyl-methylmethane hydrochloride 0.36 110 :~ :
. _ _ .
2-(3-dimethylaminopropoxy)-diphenylmethylmethane hydrochloride 0.34 155 . . . .
~ 1.00 65 .. ~. .:
~ ~ .
,,.. ,~ ~ .

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1~8853S

It will be apparent from Table~ I and II that the 2-~ubsti-tuted-l-(omega-aminoalkoxy)benzenes exhibit antireserpine activity comparable to that of Amitriptyltne~ while they exhibit low toxicity, weak CNS depressant and anticholinergic action.
The compounds Or thi~ invention can be admini~tered by any mean~ that effects palliatin~ conditions Or depre~sion in warm-blooded animal~.
For exsmple, administration can be parenterally, sub-cutaneously, intra~enously, intramuscularly~ or ~ntraperitoneally. Alternati~ely or concurrently, adminis-tration can be by the oral route. The dosage administered will be dependent upon th~ age, health and weight of the recipientJ the extent Or depression, kind of concurrent treatment ir any, frequency of treatment, and the nature Or th- effe¢t de~ired. Generally, a daily dosage of the active ingredient compound will be from about 0.5 to 50 mg .~, , .
per kg of body weight. Normally, from 1 to 30 mg per kg per day, in one or more applications per day i~ effecti~é

to obtain the desired re~ult.

The compound of Formula I can be employed in dosage form~

~uch a~ tablets, cap~ule~, powder packets, or liquid solu-.,:.
tions, YuspenSion~ or elixirs, for oral administration, or sterile liquid formulations such a~ ~olution-~ or suspensions ~`
'~,' ^ .

.-.
.... .
:,:
: _ 14 ---. .
, -- .
. .

1~88S35 for parenteral use. In such compositions, the actire in-gredient will ordinarily always be present in an amount of at least 0.5% by weight based on the total weight Or the composition and not re than 90~ by wei~ht.
Beside~ the active ingredient Or this invention, the com-~ .
position will contain a sol1d or liguid non-toxic phar-maceutical carrier for the actire ingredient. In one embodimont Or a composition, the solid carrier can be a capsule of the ordinary gelatin type. In the capsule will be from about 30-60% by weight Or a compound Or Formula I
and 70-40% Or a carrier. In another embodiment, the act~ve ingredient can be tableted with or without ad~uvants, or put into powder packets. ~These capsule~, tablets and ~;
powders will generally constitute from about 5% to about 95%
and preferably from 2S% to 90% by weight Or the a¢tiYe in-gredient. The~e dosage ~orms preferably contain rrom about 5 to about 500 me of actire ingredients, with from about 25 to about 250 mg being st preferred.
The pharmaceutical carrier can bQ a sterile liquid suc~ as ~0 water and oils, including those Or petroleum, animal, Yege-table or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
In general, water saline~ aqueous dextrose and related sugar solutions, and glycols such a~ ethylene glycol, propylene glycol and polyethylene glycol are preferred liquid carriers, .
:

~ - 15 -1~88S3S

particularly for injectible solutions ~uch as saline will ordinarily contain from about 0.5% to 20% and preferably about 1 to 10% by weight of the active inBredient.
As mentioned above, oral admini3tration can be in a suita- ;
ble suspension or syrup, in which the active ingredient normally will constitute from about 0.5 to 10% by weight.
The pharmaceutical carrier in such compo~ition can be a watery vehicle such a~ an aromatic water, a syrup or a pharmaceutical mucilage.
The following exa~ple9 are presented to rurther illu~trate , : ;
the preparation of the compounds of thi~ invention. : -Example 1 ~ -~
~ .
A Aolution o~ 5.0 g Or 2-(4-bromobutoxy)diphenyl ether~30 ml of 40% dimethylamine aqueous solution, and 100 ml Or ethanol ~8 allowed to ~tand at room temperature for 8 hours. Ethanol ahd éxcea9 dimethylamine are distilled in vacuo, 2N-NaOH
aqueous solution i8 added, and the reaction product is extracted with ether. The ether solution is distilled, 2N-HCl solution i8 added and the solution is evaporated to dryness. .
The re~idue is recrystallized from ethanol-ether to give 4.6 g (89~ yield) of 2-(4-dimethylaminobutoxy)diphenyl ether hydrochloride, m.p. 131-135C.

, -.

_ 16 _ 1~88535 : ~

.
Analysi~ - Calcd. for C18H23N02-HCl (percent): C, 67.17;
H, 7.S2; N, 4.35 Found (percent): C, 67.35; H, 7.46; N, 4.25 . . ~
Example 2 A oolution Or 5.0 g of 2-(5-bromopentyloxy)diphenyl ether and 6 g of methylamine in 100 ml o~ ethanol i8 heated at a temperature Or 50& for 2 houro in a ~ealed tube.
Fthanol and exceJs methylamine are distilled in vacuo, 2N-NaOH agueous solution i~ added, and the reaction product 0 i8 extra¢ted with ether. Dry hydrogén chloride gao lo paosed into the ether ~olution, and the precipitate col-l-oted by flltration. Recry~tallization from ethanol-ether gi~eo 4.2 g (88% yield) Or 2-(5-methylaminopentyloxy)-diphenyl ether hydrochloride, m.p. 88 - 90C.
Analyoio - Calcd. for C18H23N02-HCl (percent): C~ 67.17;
H, 7.~2; N, 4.35 Found (percent): C, 67.30; H, 7.64; N, 4.37 ,,` ~ :

~ - 17 -1~88S35 `

`' Examples 3-38 ~ :~
The compounds in the following table were prepared according to the procedure described in Example 1 or 2 using the appropriate starting materials. ~ ~:

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, Having now fully de~cribed the invention, it will be apparent to one Or ordinary skill in the art that many changes and modirications can be made thereto without departing rrOm the spirit or scope Or the invention a~ ~et forth herein.

, - 28 ~

Claims (42)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for producing a compound having the formula (I):

(I) and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of amino, C1-C5 alkylamino, C2-C6 dialkylamino, morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl; R2 is selected from the group consisting of benzyl, phenoxy, phenylthio and 1-phenylethyl; and n is an integer of 3, 4 or 5; with the provisos that when R2 is phenoxy and n is 3, R1 is amino or C1-C5 alkylamino;
when R2 is phenoxy and n is 4 or 5, R1 is amino, C1-C5 alkylamino, C2 - C6 dialkylamino morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl; when R2 is benzyl and n is 4 or 5, R1 is C1 - C5 alkylamino or 1-piperidyl; and when R2 is benzyl and n is 3, R1 is C1 - C5 alkylamino, which comprises reacting a 2-substituted-1-(omega-halogenoalkoxy) benzene of the formula (II):

(II) wherein X is a halogen; and R2 and n are as defined above, with an amine of the formula (III):
R1 - H (III) wherein R1 is defined above, and if desired reacting the said compound with a suitable acid to yield said pharmaceutically acceptable acid addition salt.

2. The compound having the formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of amino, C1-C5 alkylamino, C2-C6dialkylamino, morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl; R2 is selected from the group consisting of benzyl, phenoxy, phenylthio and 1-phenylethyl; and n is an integer of 3, 4, or 5; with the provisos that when R2 is phenoxy and n is 3, R1 is amino or C1-C5 alkylamino;
when R2 is phenoxy and n is 4 or 5, R1 is amino, C1-C5 alkylamino, C2 - C6 dialkylamino morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl; when R2 is benzyl and n is 4 or 5, R1 is C1 - C5 alkylamino or 1-piperidyl; and when R2 is benzyl and n is 3, R1 is C1 - C5 alkylamino whenever produced by the process of Claim 1.

3. A process for producing a compound of formula (I) and the pharmaceutically acceptable acid addition salts thereof, wherein R1 is selected from the group consisting of amino, methylamino, ethylamino, isopropylamino, dimethylamino, morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl; R2 is selected from the group consisting of benzyl, phenoxy, phenylthio and 1-phenylethyl; and n is an integer of 3, 4 or 5; with the proviso that when R2 is phenoxy and n is 3, R1 is amino, methylamino, ethylamino or isopropylamino; when R2 is phenoxy and n is 4 or 5, R1 is amino, methylamino, ethylamino, isopropylamino, morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl and when R2 is benzyl and n is 3, R1 is methylamino, ethylamino or isopropylamino, which comprises:
reacting a 2-substituted-1-(omega-halogenoalkoxy) benzene of the formula (II):

wherein X is halogen; and R2 and n are as defined above, with an amine of formula (III):

wherein R1 is defined above and if desired reacting the said compound with a suitable acid to yield said pharmaceutically acceptable acid addition salt.

4. The compound of formula (1):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of amino, methylamino, ethylamino, isopropylamino, dimethylamino, morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl; R2 is selected from the group consisting of benzyl, phenoxy, phenylthio and 1-phenylethyl; and n is an integer of 3, 4 or 5; with the proviso that when R2 is phenoxy and n is 3, R1 is amino, methylamino, ethylamino isopropylamino; when R2 is phenoxy and n is 4 or 5, R1 is amino, methylamino, ethylamino,isopropylamino, morpholino, 1-piperidyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl and when R2 is benzyl and n is 3, R1 is methylamino, ethylamino or isopropylamino, whenever produced by the process of Claim 3.

5. A process for producing a compound of formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of amino, C1-C5 alkylamino, C2-C6 dialkylamino, morpholino, 1-piperidyl and 4-methyl-1-piperazinyl;
R2 is benzyl; and n is an integer of 4 or 5, which comprises:
reacting a 2-substituted-1-(omega-halogenoalkoxy) benzene of formula (II):

wherein X is halogen, and R2 and n are as defined above, with an amine of formula (III):

wherein R1 is as defined above, and if desired reacting the said compound with a suitable acid to yield said pharmaceutically acceptable acid addition salt.

6. The compound of formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of amino, C1-C5 alkylamino, C2-C6 dialkylamino, morpholino, 1-piperidyl and 4-methyl-1-piperazinyl;
R2 is benzyl; and n is an integer of 4 or 5, whenever produced by the process of Claim 5.

7. A process for producing a compound of formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein when R2 is phenoxy and n is 3, R1 is amino or C1 - C5 alkylamino and when R2 is phenoxy and n is 4 or 5, R1 is amino, C1 - C5 alkylamino, morpholino, 1-piperidyl and 4-methyl-1-piperazinyl, which comprises:
reacting a 2-substituted-1-(omega-halogenoalkoxy) benzene of formula (II):

wherein X is halogen and R2 and n are as defined above, with an amine of the formula (III):

wherein R1 is as defined above, and if desired reacting the said compound with a suitable acid to yield said pharmaceutically acceptable acid addition salt.

8. The compound of formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein when R2 is phenoxy and n is 3, R1 is amino or C1 - C5 alkylamino and when R2 is phenoxy and n is 4 or 5, R1 is amino, C1 - C5 alkylamino, morpholino, 1-piperidyl and 4-methyl-1-piperazinyl, whenever produced by the process of Claim 7.

9. A process for producing a compound of formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of amino, C1 - C5 alkylamino, C2 - C6 dialkylamino, morpholino, 1-piperidyl and 4-methyl-1-piperazinyl; R2 is phenylthio and n is an integer of 3 to 5, which comprises:
reacting a 2-substituted-1-(omega-halogenoalkoxy) benzene of formula (II):

wherein X is halogen and R2 and n are defined as above, with an amine of formula (III):

wherein R1 is as defined above, and if desired reacting the said compound with a suitable acid to yield said pharmaceutically acceptable acid addition salt.

10. The compound of formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of amino, C1 - C5 alkylamino, C2 - C6 dialkylamino, morpholino, 1-piperidyl and 4-methyl-1-piperazinyl; R2 is phenylthio and n is an integer of 3 to 5, whenever produced by the process of Claim 9.

11. A process for producing a compound of the formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is C1-C5 alkylamino, R2 is benzyl and n is an integer of 3, which comprises:
reacting a 2-substituted-1-(omega-halogenoalkoxy) benzene of formula (II):
wherein X is halogen and R2 and n are as defined above, with an amine of formula (III):

wherein R1 is as defined above, and if desired, reacting the said compound with a suitable acid to yield said pharmaceutically acceptable acid addition salt.

12. The compound of formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is C1-C5 alkylamino, R2 is benzyl and n is 3, whenever produced by the process of Claim 11.

13. A process for producing a compound of formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group of amino, C1 - C5 alkylamino and C2 - C6 dialkylamino; R2 is phenylethyl and n is an integer of 3 to 5, which comprises:
reacting a 2-substituted-1-(omega-halogenoalkoxy) benzene of formula (II):

wherein X is halogen and R2 and n are as defined above, with an amine of formula (III):

wherein R1 is as defined above, and if desired, reacting the said compound with a suitable acid to yield said pharmaceutically acceptable acid addition salt.

14. The compound of formula (I):

and a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of amino, C1 - C5 alkylamino and C2 - C6 dialkylamino; R2 is 1-phenylethyl and n is an integer of 3 to 5, whenever produced by the process of Claim 13.

15. A process for producing 2-(4-methylaminobutoxy) diphenylmethane, or a pharmaceutically acceptable acid addition salt thereof in accordance with Claim 1 wherein 2-(4-halobutoxy) diphenylmethane is reacted with methylamine.

16. 2-(4-Methylaminobutoxy)diphenylmethane or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of Claim 15.

17. A process for producing 2-(4-ethylaminobutoxy) diphenylmethane, or a pharmaceutically acceptable acid addition salt thereof, in accordance with claim 1 wherein 2-(4-halobutoxy)diphenylmethane is reacted with ethylamine.

18. 2-(4-Ethylaminobutoxy)diphenylmethane or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of Claim 17.

19. A process for producing 2-(5-methylaminopentyloxy) diphenylmethane, or a pharmaceutically acceptable acid addition salt thereof, in accordance with claim 1 wherein 2-(5-halopentyloxy)diphenylmethane is reacted with methylamine.

20. 2-(5-Methylaminopentyloxy)diphenylmethane or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of Claim 19.

21. A process for producing 2-(4-methylaminobutoxy) diphenyl ether, or a pharmaceutically acceptable acid addition salt thereof, in accordance with claim 1 wherein 2-(4-halobutoxy)diphenyl ether is reacted with methylamine.

22. 2-(4-Methylaminobutoxy)diphenyl ether or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of Claim 21.

23. A process of preparing 2-(4-dimethylaminobutoxy) diphenyl ether, or a pharmaceutically acceptable acid addition salt thereof, in accordance with c1aim 1 wherein 2-(4-halobutoxy)diphenyl ether is reacted with dimethylamine.

24. 2-(4-Dimethylaminobutoxy)diphenyl ether or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of Claim 23.

25. A process for producing 2-(5-methylaminopentyloxy) diphenyl ether, or a pharmaceutically acceptable acid addition salt thereof, in accordance with Claim 1, wherein 2-(5-halopentyloxy)diphenyl ether is reacted with methylamine.

26. 2-(5-Methylaminopentyloxy)diphenyl ether, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of Claim 25.

27. A process for preparing 2-(3-methylaminopropoxy) diphenyl sulfide, or a pharmaceutically acceptable acid addition salt thereof, in accordance with Claim 1, wherein reacting 2-(3-halopropoxy)diphenyl sulfide is reacted with methylamine.

28. 2-(3-Methylaminopropoxy)diphenyl sulfide, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of Claim 27.

29. A process for preparing 2-(4-methylaminobutoxy) diphenyl sulfide, or a pharmaceutically acceptable acid addition salt thereof, in accordance with Claim 1, wherein 2-(4-halobutoxy)diphenyl sulfide is reacted with methylamine.

30. 2-(4-Methylaminobutoxy)diphenyl sulfide, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of Claim 29.

31. A process for preparing 2-(4-dimethylaminobutoxy) diphenyl sulfide, or a pharmaceutically acceptable acid addition salt thereof, in accordance with Claim 1, wherein 2-(4-halobutoxy)diphenyl sulfide is reacted with dimethylamine.

32. 2-(4-Dimethylaminobutoxy)diphenyl sulfide, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of Claim 31.

33. A process for preparing 2-(5-methylaminopentyloxy) diphenyl sulfide, or a pharmaceutically acceptable acid addition salt thereof, in accordance with Claim 1, wherein 2-(5-halopentyloxy)diphenyl sulfide is reacted with methylamine.

34. 2-(5-Methylaminopentyloxy)diphenyl sulfide, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of Claim 33.

35. A process for preparing 2-(3-methylaminopropoxy) diphenylmethane, or a pharmaceutically acceptable acid addition salt thereof, in accordance with Claim 1, wherein 2-(3-halopropoxy)diphenylmethane is reacted with methylamine.

36. 2-(3-Methylaminopropoxy)diphenylmethane, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of Claim 35.

37. A process for preparing 2-(4-methylaminobutoxy) diphenylmethylmethane, or a pharmaceutically acceptable acid addition salt thereof, in accordance with Claim 1, wherein 2-(4-halobutoxy)diphenylmethylmethane is reacted with methylamine.

38. 2-(4-Methylaminobutoxy)diphenylmethylmethane, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of Claim 37.

39. A process for preparing 2-(4-dimethylaminobutoxy) diphenylmethylmethane, or a pharmaceutically acceptable acid addition salt thereof, in accordance with Claim 1, wherein 2-(4-halobutoxy)diphenylmethylmethane is reacted with dimethylamine.

40. 2-(4-Dimethylaminobutoxy)diphenylmethylmethane, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of Claim 39.

41. A process for preparing 2-(3-dimethylaminopropoxy) diphenylmethylmethane, or a pharmaceutically acceptable acid addition salt thereof, in accordance with Claim 1, wherein 2-(3-halopropoxy)diphenylmethylmethane is reacted with dimethylamine.

42. 2-(3-Dimethylaminopropoxy)diphenylmethylmethane, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of Claim 41.