DERIVES DE L'INDANAMINE

INDANAMINE DERIVATIVES

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
Indanamine derivatives having specific substituents
are represented by the following formula:
<IMG>
wherein R1 represents a lower alkyl group R2 and
R3 each, which may be the same or different, represents
a hydrogen atom, a lower alky' group or an acyl group
having 1 to 6 carbon atoms: R4 represents a hydrogen
atom or a lower alkyl group and n represents 0, 1 or 2;
and pharmaceutically acceptable non-toxic salts thereof.
The indanamine derivatives represented by the formula (I)
exhibit excellent analgesic activity with minimized
toxicity and are useful for alleviating pains by oral or
parenteral administration thereof.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a substituted indanamine compound
of the formula:
<IMG> (I)
wherein R1 represents a lower alkyl group; R2 and R3 each,
which may be the same or different, represents a hydrogen atom, a
lower alkyl group or an acyl group having 1 to 6 carbon atoms;
R4 represents a hydrogen atom or a lower alkyl group; and n
represents 0, 1 or 2; and pharmaceutically accpetable non-toxic
salts thereof, which process being selected from the group
consisting of:
(a) a process for producing said compound of formula (I)
wherein R1 and n are defined as above, R2 is a
hydrogen atom or an acetyl group, R3 is a hydrogen
atom, and R4 is a hydrogen atom or a lower alkyl group,
which comprises subjecting to catalytic reduction a
compound of formula (II):
<IMG> (II)
wherein R1, R4 and n are defined as above; and X is
halogen atom or a hydrogen atom in an organic solvent;
27

(b) a process for producing the compound of formula (I)
wherein R1 is a lower alkyl group, R2 and R3 each,
is a hydrogen atom, R4 is a hydrogen atom or a lower
alkyl group, and n is 0, 1 or 2, which comprises
subjecting a compound of formula (III):
<IMG> (III)
wherein R1, R4 and n are defined as above, to a
Curtius reaction involving heating the compound of
formula (III) and then hydrolyzing in the presence of an
organic or inorganic acid;
(c) A process for producing the compound of formula (I)
wherein R1 is a lower alkyl group, R2 is a hydrogen
atom or a lower alkyl group, R3 is a lower alkyl group,
R4 is a hydrogen atom or a lower alkyl group, n is 0, 1
or 2, which comprises reacting a compound of formula (IV)
<IMG> (IV)
wherein R1, R2, R4 and n are defined as above with
an alkylating agent selected from the group consisting of
an alkyl halide of formula:
R3-X
(wherein R3 is defined as above and X is a halogen
atom), formic acid and a carbonyl compound;
(d) a process for producing the compound of formula (I)
wherein R1 is a lower alkyl group, R2 is a hydrogen
atom or a lower alkyl group, R3 is a lower alkyl group
28

R4 is a hydrogen atom or a lower alkyl group, and n is
0, 1 or 2, which comprises reducing a compound of formula
(v):
<IMG> (V)
wherein R1, R2, R4 and n are defined as above and
R3' is a lower alkyl group or a lower alkoxy group, in
the presence of a lithium aluminum hydride;
(e) a process for producing the compound of formula (I)
wherein R1 and R3 each is a lower alkyl group, R2
is an acyl group having 1 to 6 carbon atoms; R4 is a
hydrogen atom or a lower alkyl group, and n is 0, 1 or 2,
which comprises reacting a compound of formula (VI):
<IMG> (VI)
wherein R1, R2, R4 and n are defined as above, with
an alkyl halide of formula:
R3-X
wherein R3 is defined as above and X is a halogen atom;
(f) a process for producing the compound of formula (I)
wherein R1 is a lower alkyl group, R2 is an acyl
group having 1 to 6 carbon atoms, R3 is a hydrogen
atom, R4 is a hydrogen atom or a lower alkyl group, and
n is 0, 1 or 2, which comprises reacting a compound of
formula (VII):
29

<IMG> (VII)
wherein R1, R4 and n are defined as above, with an
acid halide or acid anhydride, with an acid halide of
formula:
R3'-COX
wherein R3' is a lower alkyl group and X is a halogen
atom, or an acid anhydride of formula:
R3' - CO-O-CO-R3'
wherein R3' is defined as above; and
(g) a process for producing the compound of formula (I)
wherein R1 is a lower alkyl group, R2 and R3 each,
which may be the same or different, is a hydrogen atom or
a lower alkyl group, R4 is a hydrogen atom and n is 1
or 2, which comprises dealkylating a compound of formula
(VIII):
<IMG> (VIII)
wherein R1, R2, R3 and n are defined as above, and
R4 is a lower alkyl group.
2. A process according to any one of the steps of claim 1,
wherein said lower alkyl group has 1 to 4 carbon atoms.
3. A process according to any one of the steps of claim 1,
wherein n is 1.

4. A process according to either steps (a) or (b) of claim 1
for preparing 1,1-dimethyl-6-methoxy-2-indanamine, wherein R1
is methyl, R2 and R3 are both hydrogen and R4 is methyl and
n is 1.
5. A process according to any one of steps (a), (b), (c) or
(d) of claim 1 for preparing N-ethyl-l,l-dimethyl-6-methoxy-2-
indanamine, wherein R1 is methyl, one of R2, and R3 is ethyl
and the other is hydrogen, R4 is methyl and n is 1.
6. A process according to either of steps (a) or (b) of
claim 1 for preparing 1,1-dimethyl-2-indanamine, wherein R1 is
methyl, R2 and R3 are both hydrogen and n is 0.
7. A process according to any one of steps (a), (b), (c) or
(d) of claim 1 for preparing N-ethyl-l,l-dimethyl-2-indanamine,
wherein R1 is methyl, one of R2 and R3 is ethyl and the
other is hydrogen and n is 0.
8. A process according to either of steps (a) or (b) of
claim 1 for preparing 1,1-dimethyl-5-methoxy-2-indanamine,
wherein R1 is methyl, R2 and R3 are both hydrogen, R4 is
methyl and n is 1.
9. A process according to either of steps (a) or (b) of
claim 1 for preparing 1,1-dimethyl-7-methoxy-2-indanamine,
wherein R1 is methyl, R2 and R3 are both hydrogen, R4 is
methyl and n is 1.
31

10. A process according to either of steps (a) or (b) of
claim 1 for preparing 1,1-dimethyl-5,6-dimethoxy-2-indanamine,
wherein R1 is methyl, R2 and R3 are both hydrogen, R4 is
methyl and n is 2.
11. A process according to either of steps (a) or (b) of
claim 1 for preparing 1,1-diethyl-6-methoxy-2-indanamine, wherein
R1 is ethyl, R2 and R3 are both hydrogen, R4 is methyl
and n is 1.
12. A process according to any one of steps (a), (b), (c) or
(d) of claim 1 for preparing N-ethyl-l,l-diethyl-6-methoxy-2-
indanamine, wherein R1 is ethyl, one of R2 and R3 is ethyl
and the other is hydrogen, R4 is methyl and n is 1.
13. A substituted indanamine compound of the formula:
<IMG>
wherein R1 represents a lower alkyl group; R2 and R3 each,
which may be the same or different, represents a hydrogen atom, a
lower alkyl group or an acyl group having 1 to 6 carbon atoms;
R4 represents a hydrogen atom or a lower alkyl group; and n
represents 0, 1 or 2; and pharmaceutically acceptable non-toxic
salts thereof, when prepared by the process of claim 1.
14. The substituted indanamine compound of claim 13, wherein
said lower alkyl has 1 to 4 carbon atoms, when prepared by the
process of claim 2.
32

15. The substituted indanamine compound of claim 13, wherein
said n has 1, when prepared by the process of claim 3.
16. The compound 1,1-dimethyl-6-methoxy-2-indanamine, when
prepared by the process of claim 4.
17. The compound N-ethyl-l,l-dimethyl-6-methoxy-2-indanamine,
when prepared by the process of claim 5.
18. The compound 1,1-dimethyl-2-indanamine, when prepared by
the process of claim 6.
19. The compound N-ethyl-l,l-dimethyl-2-indanamine, when
prepared by the process of claim 7.
20. The compound 1,1-dimethyl-5-methoxy-2-indanamine, when
prepared by the process of claim 8.
21. The compound 1,1-dimethyl-7-methoxy-2-indanamine, when
prepared by the process of claim 9.
22. The compound 1,1-dimethyl-5,6-dimethoxy-2-indanamine,
when prepared by the process of claim 10.
23. The compound 1,1-diethyl-6-methoxy-2-indanamine, when
prepared by the process of claim 11.
24. The compound N-ethyl-l,l-diethyl-6-methoxy-2-indanamine,
when prepared by the process of claim 12.
33

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
25. A process for the preparation of compounds of the
formula:
<IMG>
wherein R1 represents methyl or ethyl and the pharmaceutically
acceptable non-toxic salts thereof, comprising dealkylating
a compound of the formula:
<IMG>
by heating said compound either in the presence of a Lewis
acid and an inert organic solvent, or in the presence of a
strong mineral acid.
26. A process for the preparation of compounds of the
formula:
<IMG>
wherein R1 represents methyl or ethyl and the pharmaceutically
acceptable non-toxic salts thereof, comprising dealkylating
a compound of the formula;
34

<IMG>
wherein R1 is as defined above and R4 is lower alkyl, by
heating said compound in the presence of a Lewis acid and an
inert organic solvent or in the presence of a strong mineral
acid.
27. A process according to claim 25, wherein the Lewis
acid is selected from the group aluminum chloride or
borotribromide and the inert organic solvent is selected
from the group halogenated hydrocarbons, benzene, toluene or
xylene.
28. A process according to claim 25, wherein the strong
mineral acid is hydrobromic acid or hydroiodic acid.
29. A process according to claim 26 for the preparation
of l,l-dimethyl-6-hydroxy-2-indanamine hydrochloride wherein
R1 is methyl.
30. A process according to claim 26 for the preparation
of l,l-diethyl-6-hydroxy-2-indanamine, wherein R1 is ethyl.
31. Compounds of the formula:
<IMG>
wherein R1 is methyl or ethyl or its pharmaceutically acceptable

non-toxic salts, when prepared by the process of claim 26.
32. A compound according to claim 31, namely l,l-dimethyl-
6-hydroxy-2-indanamine hydrochloride when prepared by the
process of claim 29.
33. A compound according to claim 31, namely, l,l-diethyl-
6-hydroxy-2-indanamine, when prepared by the process of claim
30.
36

Description

i~()9~80
The present invention relates to indanamine compounds repre-
sented by the formula:
6 ~ N\ (I)
(R40n Rl
wherein Rl represents a lower alkyl group; R2 and R3, which may be
the same or different, represent a hydrogen atom, a lower alkyl
group or an acyl group' R4 represents a hydrogen atom or a lower
alkyl group; and n represents 0, 1 or 2; and non-toxic pharmaceu-
tically acceptable salts thereof.
The present invention also relates to pharmaceutical composi-
tions containing the indanamine compound (I) and further to a
method of treating the patient with pains.
It is known that Indanamine or 2-aminoindane of the formula:
~ NH2
possesses analgesic activity in the test of mouse (L.B. Witkin
et al., J. Pharm. Exp. Therapy, vol. 133, page 400 (1961)). The
prior art compound is, however, unsatisfactory because of its
serious toxicity and side effects, and has not yet been commer-
cially available.
An object of the present invention is to provide a satisfac-
tory therapeutic agent having high order of analgesic activity but
minimized toxicity, which is the substituted indanamine compou~ds
of the formula(I) above.

A further object of the present invention is to provide a
therapeutic composition containing the compound of the formula(I)
which exhibit analgesic activity, and a method of treating the
patient with pains.
In more detail, the alkyl group for Rl to R4 represents a
lower alkyl group having 1 to 6 carbon atoms, preferably 1 to 4
carbon atoms; and the acyl group for R2 and R3 represents an acyl
group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
The substituted indanamine compounds of the formula(I) can
be prepared, depending upon the products desired, by alkylation,
acylation, reduction, hydrolysis, a Curtius rearrangement, etc.,
which are illustratively shown below using the compound of the
formula(I) wherein Rl to R4 are all a methyl group. _

~9~80
,~'``~
~ 11 ~ COOH (II-l)
CH30 CH / \CH
socl2
~ ~ -COCl (II-2
CH30 CH3 H3
NaN3
II-3) X
O
CH30 CH3 CH3 (CH30)n CH3 CH3
1. Curtius
Rearrangement ~ / ~ Reduction
2. Hydrolysis ~
~ ~ ~32 ~ 2 ~ COC~3
(OH)n 3 3(CH30)n CH3 CH3 (CH30)n CH3 3
(I-5) (I-l) Acylation (I-2)
Hydrolysis /~
o Hydrolysis
Alkylation
ô~ (mono) ~eduction
~ N ~ 3 ~ ~ NHCH2CH3 ~Alkylation
(3 n 2 3 ( 3 )n 3 3
(I-8) 1 (I-7) ,
`l l
Hydrolysis lAlkylation
(mono) CH
< CH3 ~ N-COCH
~ or-C~ ~ CH. ~
(OH)n 3 CH3 ( (CH 0) 3 3 3 n 3 3
Hydrolysis ~Reductlon
(I-6) ~ (I-3) (I-4)
X= H or 2 halogen atom, e.g.Cl, Br, I
n= O, 1 or 2. 3

~O9¢~E30
The reactions shown above also proceed with compounds of
formula (I) wherein Rl to R4 represent a group other than a methyl
group.
The hydroxyimino compound represented by the formula(II) is
subjected to catalytic hydrogenation in organic solvents in the
presence of Raney-nickel, platinum oxide, palladium-carbon, etc.
preferably using palladium-carbon in acetic acid under pressure and
heating to thereby obtain the compounds represented by the formula
(I-l) and/or (I-2). Typical examples of organic solvents include
acetic acid, ethanol, methanol, etc. The pressure is usually 20
to 50 atoms, preferably 20 to 30 atoms. The heating is performed
generally at temperatures from 50 to 100C., preferably 70 to 80C.
The reaction time is not limitative but generally for 2 to 10 hrs.,
preferably 6 to 7 hrs.
The compound of the formula (I-2) can be converted into the -
compound of the formula (I-l) by hydrolysis. The hydrolysis
generally proceeds by heating to reflux for about to about 48
hours, preferably 15 to 24 hours in the presence of ~aO in organic
solvents such as ethylene glycol.
The compounds of the formulae (I-2(, (I-3) and (I-4) can be
prepared by monoalkylation, dialkylation and acylation of the
Compound of the formula(I-l), respectively. The acylated compounds
of the formulae (I-2) and (I-4) can be converted into the corres-
ponding mono- or dialkylated compound of the formula(I-3) by
reduction.
In more detail, the alkylation is usually performed by reac-
ting the compound of the formula (I-l) or (I-2) with an equimolar
amount to excess of alkyl halides (e.g., methyl halides, ethyl
halides, propyl halides, butyl halides wherein the halides include
chlorides, bromides, iodides, etc.) at a boiling point of the

1 solvent used (i.e., reflux temperature) for about 1 to about 20
hours, preferably 5 to 10 hours under normal pressure, in the
presence of alkali carbonates (e.g., potassium carbonate,
sodium carbonate, etc.). If necessary, reaction accelerators
such as sodium hydride, sodium amide, etc. can be employed.
Alternatively, the alkylation can also be performed by reacting
the compound of the formula (I-l) with an equimolar amount or
somewhat excess of formic acid and carbonyl compounds (e.g.
formaldehyde, acetaldehyde, etc.) in combination, under reaction
conditions similar to the above.
The acylation is ordinarily conducted by reacting the com-
pound of the formula (I-l) with an equimolar amount to excess
of organic carboxylic acids (e.g. formic acid, acetic acid, pro-
pionic acid, butyric acid, etc.) at about 0 degrees C to reflux
temperature for about 30 min. to about 6 hours, preferablyl to
1.5 hours in non-polar solvents (e.g. benzene, toluene, xylene,
etc.) or withour using any solvent, under normal pressure.
~ he acylated compounds of the formulae (I-2) and (I-4)
can be converted into the corresponding alkylated compound (I-3)
by mild reduction using lithium aluminum hydride at reflux
temperature for about 3 to 20 hours, preferably 4 to 6 hours.
This reduction should be performed in the absence of water, as
is well known in the art.
The Curtius rearrangement which occurs in the preparation
of the compound of the formula (I-l) from the compound of the
formula (II-3) in the presence of solvents, e.g., water,
acetone, benzene, etc. to form the corresponding isocyanate.
The isocyanate is successively hydrolyzed to give the compound
of formula (I). The hydrolysis is generally carried out in the
presence of organic or inorganic acids, e.g. hydrochloric acid,

1 sulfuric acid, acetic acid, etc., water, or mixture thereof, at
reflux temperature for 1 to 10 hours, preferably 3 to 5 hours.
The compound of the formula (II-3) is prepared by reaeting
indane carboxylie acid of the formula (II-l) with an exeess of
thionyl ehloride at room temperature for 0.5 to 2 hours and
then reaeting the resulting acid chloride of the formula (II-2)
with an equimolar -to exeess of sodium azide.
The compound of the present invention represented by the
formula (I) can be converted into pharmaceutically acceptable
acid addition salts using inorganic acids (e.g. hydrochlorie
aeid, hydrobromie aeid, sulfurie aeid, ete.) or organie aeids
(e.g. maleie aeid, fumarie aeid, eitrie aeid, tartaric aeid,
oxalie acid, succinic aeid, ete.) in a eonventional manner.
The novel indanamine eompounds of the formula (I) posses
exeellent analgesie aetivity and are valuable as medieine as
well as intermediates for preparing analgesies.
The eompound of the formula (II) is also novel and is
preparea as follows:
1) isoamyl nitrate
eone, HCl in EtOH
50C, 2 - 3 hours
X O 2) in MeOH NaOMeX
O - 5, overnight ~
~ 1 ) or 2) ~ N
; (R40 ) R ~ (R4O)n Rl
; 90 100C ~\ \ O O in AcOH
30 min. or PPA* \ r 3
1 hour \ or 20, 10 hrs.
X \ * PPA: polyphos-
~R4O~ 1 IR4'~ Rl phorie aeid

o
The hydrolysis for converting the R40-substituted compounds
into the OH-substituted compounds can be performed by heating with
diluted hydrohalogenic acids (preferably 4,3O/o hydrobromic acid) at
100-120C. for 2 to 10 hours. (preferably 3-4 hours.)
The raw compound of formula (II-l) can be synthesized in
accordance with the following reaction schemes:
l0~ l ~ B reduction, ~aBB4
OH
~ ~ reflux in benzene in the
CH O ~ 3 3 presence of p-toluenesul-
3 ~ fonic acid
15~ ~ CH phosphorous chloride in
CH30 CH3 3 dimethyl formamide
CHO
~ ~ CH Photo-oxidation
20CH30 lCH3 3
~ ~ Cll 2CH reduction, Pd/C or Pt
CH3O l 3 3
(II-l) -
The compound of the present invention represented by the
formula(I) exhibits strong analgesic activity with minimized side
effects and minimized toxicity. The high order of this activity
of the active agent of the present invention, together with its
reduced side effects, is evidenced by test in lower animals. The
compound of the present invention represented by the formula(I)

~ 9~o
can be administered per os, e.g., in the form of pills or tablets,
in which it may be present together with the usual pharmaceutical
carriers, conventionally by compounding the compound of the present
invention together with a customary carrier or adjuvant, such as
talc, magnesium stearate, starch, lactose, gelatin, any of numerous
gums, and the like. Thus in its most advantageous form, the compo-
sitions of the invention will contain a non-toxic pharmaceutical
carrier in addition to the active ingredient of the present inven-
tion. Exemplary solid carriers are lactose, magnesium stearate,
calcium stearate, starch, terra alba, dicalcium acacia, or the
like. Representative liquid carriers are peanut oil, sesame oil,
olive oil, water, or the like. The active agent of the invention
can be conveniently administered in such compositions containing
active ingredient so as to eventually be within the dosage range
illustrated hereafter. Thus, a wide variety of pharmaceutical
forms suitable for many modes of administration and dosages may be
employed. For oral administration, the active ingredient and
pharmaceutical carrier may, for example, take the form of a granule,
pill, tablet, lozenge, elixir, syrup, or other liquid suspension
or emulsion, whereas, for parenteral administration such as intra-
venous or intramuscular injection, the composition may be in the
form of a sterile solution.
The method of using the compound of the present invention
comprises internally or externally administering the compound of
the invention, preferably orally or parenterally and preferably
admixed with the pharmaceutical carrier, for example, in the form
of any of the above compositions, or filled into a capsule, to
alleviate conditions to be treated and symptoms thereof in a living
animal body. Illustratively, it may be preferably 10 to 100 mg.
for an oral dose, while parenteral dosages are usually less and

ordinarily about one-half of the oral dose. The unit dose is pre-
ferably given a suitable number of times daily, typically three
times. The daily dose may vary depending upon the number of times
given. Naturally, a suitable clinical dose must be adjusted in
accordance with the condition, age, and weight of the patient, and
it goes without saying that the enhanced activity of the compound
of the invention, together with its reduced side effects, also
make it suitable for wide variations, and the invention therefore
should not be limited by the exact ranges stated. The exact
dosage, both unit dosage and daily dosage, will of course have to
be determined according to established medical principles.
Analgesic activity of representative compounds of the present
invention was examined by acetic acid stretching method using
animal.
Using ddY-strain male mice, weighing about 20 g., six(6) as
one grouping, the number of rising was measured after administering
a pain-inducing agent(acetic acid) in aceordance with aeetie aeid
stretehing method.
A test compound was orally administered at a dose of 100 mg.
20 (100 mg. of the eompound was dissolved in 0.2 ml. of water, whieh
was administered per os). A 0.7% aeetie aeid aqueous solution was
then intraperitoneously administered 30 minutes after the adminis-
tration of the test compound. Then, the number of rising was
measured during 4 to 15 minutes after the administration of aeetie
aeid. As control, only water was administered instead of the test
compound, in which the number of rising occurred was made 100. The
results are shown below, wherein percentage indicates inhibition
of rising as compared to the control. Therefore, the higher the
inhibition percentage, the better the analgesic activity.

~9~t~80
Compound Inhibition %
2-Indanamine 77
l,l-Diethyl-6-methoxy-2-indanamine lO0
l,l-Dimethyl-6-methoxy-2-indanamine 79
5 N-Ethyl-6-methoxy-l,l-dimethyl-2-indanamine91
l,l-Dimethyl-2-indanamine 91
l,l-Dimethyl-7-methoxy-2-indanamine 85
N-Ethyl-7-methoxy-1,1-diethyl-2-indanamine 89
It is understood from the results above that the compounds
of the invention possess superior in analgesics to known 2-indan-
amine.
The present invention will be described in detail below with
reference to the examples, in which pressure is normal pressure
and atmosphere is in the air, unless otherwise indicated.
15 Example 1 1,1-Dimethyl-6-methoxy-2-indanamine hydrochloride:
To 0.8 g. of 2,3-dihydro-1,1-dimethyl-6-methoxy-lH-indene-2-
carboxylic acid was added 2.0 ml. of thionyl chloride under ice-
cooling. The mixture was stirred at room temperature. Then,
anhydrous benzene was added to the mixture to thereby remove an
excess of thionyl chloride by ageotropic distillation. The resul-
ting acid chloride was dissolved in 7 ml. of anhydrous benzene and
0.24 g. of sodium azide was added to the solution. The mixture
was heated under refluxing for 22 hrs. After cooling, the mixture
was filtered. To the filtrate, 4 ml. of conc. hydrochloric acid
was added and the mixture was heated under refluxing for 3 hrs.
After completion of the reaction, the aqueous layer was made
alkaline with sodium hydroxide, followed by axtraction with ether.
The ethereal layer was washed with water and dried. The solvent
was removed by distillation. To the residue was added ethereal
hydrochloric acid to convert into the hydrochloride. By recrystal-

lization from ethanol, 0.07 g. of colorless prisms were obtained;
m.p. 238 to 240C. (decomposed).
Elemental Analysis for C12H17NO. H2O . HC1
C _ N
Calcd. 58.65 8.20 5.70
Found 58.13 8.43 5.40
Example 2 1,1-Dimethyl-6-methoxy-2-indanamine hydrochloride:
In 100 ml. of acetic acid was dissolved 10 g. of 3,3-
dimethyl-2-hydroxyimino-5-methoxy-1-indanone. To the solution
was added 4 g. of 5% palladium-carbon. The mixture was subjected
to catalytic reduction for 6.5 hrs. under pressure and heating
( 30 kg/cm , 80C.). The catalyst was removed by filtration
and the filtrate was distilled to dryness under reduced pressure.
After adding a 10% aq. hydrochloric acid to the residue, the
mixture was washed with ether. The aqueous layer was made
alkaline with potassium carbonate, followed by extraction with
ether. The ethereal layer was washed with water and dried.
The solvent was removed by distillation so that 3.94 g. of a
slightly yellow oil was obtained. The oil was converted into
the hydrochloride using ethanolic hydrochloride. By recrystal-
lization from ethanol, colorless prisms having a melting point
of 238 to 240C. (decomposed) were obtained. The hydrochloride
so obtained possessed IR spectrum identical with that of the
compound obtained in Example 1. No reduction in melting point
occurred when mixed with the compound of Example 1.
Example 3 1,1-Dimethyl-6-ethoxy-2-indanamine hydrochloride:
To a solution of 30 g. of 3,3-dimethyl-2-hydroxyimino-5-
ethoxy-1-indanone in 150 ml. of acetic acid was added 12 g.of
10% palladium-carbon. The mixture was treated as in Example 2
to obtain 12.3 g. of the hydrochloride. By recrystallization
from ethanol-ether, colorless needles having a melting point of 270
~, -- 1 1 --

0
to 272C. (decomposed) were obtained.
Elemental Analysis for C13HlgN0. HCl. 1/4 H20
C H N
Calcd. 63.40 8.39 5.69
Found 63.44 8.48 5.58
Example 4 1,1-Diethyl-6~methoxy-2-indanamine hydrochloride:
To a solution of 7.42 g. of 3,3-diethyl-2-hydroxyimino-5-
methoxy-l-indanone in 100 ml. of acetic acid was added 2.6 g of
10 % palladium-carbon. The mixture was treated as in Example 2
to obtain 2.46 g. of the hydrochloride. By recrystallization from
ethanol-isopropyl ether, colorless needles having a melting point
of 218 to 220C. were obtained.
Elemental analysis for C14H21NO. HCl. 1/4 H2O
C H
Calcd. 64.60 8.71 5.38
Found 64.54 8.84 5.46
Example 5 6-Methoxy-l,l,~,N-tetramethyl-2-indanamine hydrochloride
A mixture of 6.0 g. of 6-methoxy-1,1-dimethyl-2-indanamine,
9.3 ml. of a 37% aq. formaldehyde solution and 6.58 ml. of formic
acid was heated at 80 to 100C for 4 hrs. with stirring. After
completion of the reaction, water was poured into the reaction
mixture. After rendering the system alkaline with sodium hydrox-
ide, the system was extracted with ether. The ethereal layer was
washed with water and dried. After removing the solvent by dis-
tillation, the residue was converted into the hydrochloride usingethanolic hydrochloric acid. Colorless crystals were obtained in
an amount of 4.41 g. By recrystallization from ethanol-isopropyl
ether, colorless needles having a melting point of 215 to 216C.
(decomposed) were obtained.
Elemental Analysis for C14 21 2

~9~o
C H N
Calcd. 64.60 8.62 5.38
Found 64.42 8.7L 5.23
Example 6 N-Acetyl-6-methoxy-1,1-dimethyl-2-indanamine:
To a solution of 10 g. of 3,3-dimethyl-2-hydroxyimino-5-
methoxy-l-indanone in 100 ml. of acetic acid was added 4 g. of 5 %
palladium-carbon. The mixture was subjected to catalytic reduc-
tion for 6.5 hrs. under pressure and heating (30 kg/cm , 80C).
After removing the catalyst by distillation, the filtrate was dis-
tilled to dryness. To the residue was added a 10 % aq. hydro-
chloric acid. The mixture was extracted with ether and the
ethereal layer was washed with water and dried. After removing
the solvent by distillation, 4.86 g. of colorless crystals were
obtained. By recrystallization from isopropyl ether, colorless
15 crystals having a melting point of 99 to 100C were obtained.
Elemental Analysis for C14HlgNO2
C H N
Calcd. 72.07 8.21 6.00
Found 71.92 8.39 5.85
This compound can also be obtained by the reaction of 1,1-
dimethyl-6-methoxy-2-indanamine with acetic anhydride. The thus
obtained compound is well consistent with the compound obtained as
above.
Example 7 N-Ethyl-6-methoxy-1.1-dimethyl-2-indanamine hydro-
chloride:
To a suspension of 2.45 g. of lithium aluminum hydride in 10
ml. of anhydrous tetrahydrofuran was added a solution of 5 g. of
N-acetyl-6-methoxy-1,1-dimethyl-2-indanamine in 10 ml. of anhydrous
tetrahydrofuran. The mixture was stirred at room temperature for
20 mins. and then heated under refluxing for 1 hr. After completion
13

3C3 8(1
of the reaction, aqueous ether and water were added in succession
to the reaction mixture under ice cooling. Thereafter, the mix-
ture was filtered by suction and the filtrate was distilled to
dryness under reduced pressure. After adding a 10 % aq. hydro-
chloric acid solution to the residue, the mixture was washed withether. The aqueous layer was made alkaline with sodium hydroxide,
followed by extraction with ether. The ethereal phase was washed
with water and dried. After removing the solvent by distillation,
the residue was converted into the hydrochloride with ethanolic
hydrochloric acid. Thus 4.01 g. of colorless crystals were
obtained. By recrystallization from ethanol-isopropyl ether,
colorless needles having a melting point 217 to 218C. (decomposed)
were obtained.
Elemental Analysis for C14H21NO. HCl
C H N
Calcd. 65.48 8.64 5.45
Found 65.43 8.76 5.42
Example 8 N-Acetyl-6-methoxy-l,l,N-trimethyl-2-indanamine:
A suspension of 5 g. of N-acetyl-6-methoxy-1,1-dimethyl-2-
20 indanamine and 2.1 g. of 50 % sodium hydride in 70 ml. of dimethyl
formamide was heated at 30 to 50C. for 1 hr. with stirring. Then,
7.63 g. of methyl iodide was added to the suspension. The mixture
was stirred for 15 mins. at 30 to 50C. and then for 1 hr. at room
temperature. After completion of the reaction, water was poured
into the reaction mixture, followed by extraction with ether. The
ethereal layer was washed with water and dried. After removing
the solvent by distillation, the residue was crystallized from n-
hexane to obtain 5.2 g. of colorless crystals. By recrystallization
from isopropyl ether, colorless crystals having a melting point of
97 to 98C. were obtained.
14

Elemental Analysis for C15H21N02
C H N
Calcd. 72.84 8.56 5.66
Found 72.68 8.66 5.61
5 ExamPle 9N-Ethyl-6-hvdroxy-1~1-dimethyl-2-indanamine hvdro-
bromide:
To 1.92 g. of N-ethyl-6-methoxy-1,1-dimethyl-2~indanamine
hydrochloride was added 30 ml. of 48 % hydrobromic acid. The mix-
ture was heated at 100 to 120C. for 3.5 hrs. with stirring.
After completion of the reaction, ethanol was added to the reac-
tion mixture. The mixture was filtered by suction to obtain 2.08 g
of light brown powders. By recrystallization from water-containing
ethanol, brown prisms having a melting point of 298 to 299C. were 7
obtained.
Elemental Analysis for C13HlgNO.HBr
C H N
Calcd. 54.55 7.04 4.89
Found 54.33 7.19 4.77
ExamPle 10 6-HYdroxy-1 l,N N-tetramethYl-2-indanamine hydrobro-
.
mide:
In a manner similar to Example 9 but using 2.5 g. of 6-
methoxy-l,l,N,N-tetramethyl-2-indanamine hydrochloride, 2.61 g. of
light green crystals were obtained. By recrystallization from
ethanol, lightly green scales having a melting point of 229 to
230C. were obtained.
Elemental Analysis for C13HlgNO. HBr. H2O
C H N
Calcd. 51.32 7.29 4.60
Found 51.08 7.30 4.49
Example 11 N-AcetYl-6-ethoxy-1 1-dimethyl-2-indanamine:

~9~
To a solution of 30 g. of 3,3-dimethyl-2-hydroxyimino-5-
ethoxy-l-indanone in 150 ml. of acetic acid was added 12 g. of 10 %
palladium-carbon. The mixture was treated in a manner similar to
Example 6 to obtain 10.9 g. of colorless crystals. By recrystal-
lization from ethyl acetate-isopropyl ether, colorless scales
having a melting point of 137 to 138C were obtained.
Elemental Analysis for C15H21NO2
C H N
Calcd. 72.84 8.56 5.66
Found 72.79 8.83 5.60
Example 12 N-Ethyl-6-ethoxy-1,1-dimethvl-2-indanamine hydro-
chloride:
To a suspension of 2.16 g. of lithium aluminum hydride in
20 ml. of anhydrous tetrahydrofuran was added a solution of 4.0 g.
of N-acetyl-6-ethoxy-1,1-dimethyl-2-indanamine in 25 ml. of anhy-
drous tetrahydrofuran. The mixture was heated under refluxing
for 6 hrs. Thereafter, the mixture was treated as in Example 7
to obtain 3.42 g. of the hydrochloride. By recrystallization
from ethanol-isopropyl ether, colorless needles having a melting
point of 207 to 208C. were obtained.
Elemental Analysis for C15H23N0. HCl
C H N
Calcd. 66.77 8.97 5.19
Found 66.54 9.21 4.98
Example 13 6-EthoxY-l,l,N,N-tetramethyl-2-indanamine hydro-
chloride:
In a similar manner to Example 5 but using 4.0 g. of 6-ethoxy-
1,1-dimethyl-2-indanamine, 2.16 g. of the hydrochloride was
obtained. From recrystallization from ethanol-isopropyl ether,
colorless needles having a melting point of 219 to 220C were
16

0
obtained.
Example 14 N-Acetyl-l,l-diethyl-6-methoxy-2-indanamine;
To a solution of 7.42 g. of 3,3-diethyl-2-hydroxyimino-5-
methoxy-l-indanone in 100 ml. of acetic acid was added 2.6 g. of
lOo/o palladium-carbon. Then, the system was treated in a manner
similar to Example 6 to obtain 3.28 g. of colorless crystals.
By recrystallization from benzene, colorless needles having a
melting point of 115 to 116C. were obtained.
Elemental Analysis for C16H23NO2
C H N
Calcd. 73.53 8.87 5.36
Found 73.65 9.08 5.33
Example 15 1 l,N-Triethyl-6-methoxv-2-indanamine hydrochloride:
In a manner similar to Example 7 but using 3.0 g. of N-acetyl-
1,1-diethyl-6-methoxy-2-indanamine, the hydrochloride was obtained.
By recrystallization from ethanol-isopropyl ether, 1.18 g. of
colorless needles having a melting point of 208 to 210C. were
obtained.
Elemental Analysis for C16H25N0. HCl. 1/4H2O
C H N
Calcd. 66.65 9.26 4.86
Found 66.91 9.44 4.98
Example 16 1,1-Diethyl-N,N-dimethyl-6-methoxy-2-indanamine
hydrochloride:
In a manner similar to Example 5 but using 1.0 g. of 6-
methoxy-l,l-diethyl-2-indanamine, the hydrochloride was obtained.
By recrystallization from isopropanol, colorless needles having a
melting point of 176 to 178C. were obtained.
Elemental Analysis for C16H25NO. HCl. 1/4H2O
17
. . .

~9~'~30
Example 17 N-Ethoxycarbonyl-l,l-dimethyl-6-methoxy-2-lndanamine:
To a solution of 4.3 g. of 6-methoxy-1,1-dimethyl-2-indan-
amine hydrochloride in 50 ml. of wate:r were added 30 ml. of ether
and 1.5 g. of sodium hydroxide. Then, 2.64 g. of ethyl chlorocar-
bonate was dropwise added to the mixture. The mixture was stirredat room temperature overnight. After insoluble matters were
removed by filtration, the ethereal layer was separated and washed
with dil. hydrochloric acid and then with water and dried. The
resulting residue was recrystallized from benzene to obtain 3.7 g.
of colorless needles having a melting point of 153 to 154C.
Elemental Analysis for C15H21N03.3/4H20
C H N
Calcd. 65.08 8.19 5.06
Found 64.92 7.89 5.15
ExamPle 18 1,l,N-Trimethyl-6-methoxy-2-indanamine hydrochloride:
To a suspension of 3.3 g. of lithium aluminum hydride in 40
ml. of anhydrous tetrahydrofuran was added a solution of 3.3 g. of
~ 18

~$~ 0
N-ethoxycarbonyl-l,l-dimethyl-6-methoxy-2-indanamine in 40 ml. of
anhydrous tetrahydrofuran. The mixture was heated under refluxing
for 7 hrs. Thereafter, the system was treated as in Example 7 to
obtain 2.46 g. of the hydrochloride. By recrystallization from
ethanol, colorless needles having a melting point 288 to 289C.
were obtained.
Elemental Analysis for C13HlgN0. HCl
C H N
Calcd. 64.59 8.34 5.79
10 Found 64.53 8.62 5.75
Example 19 1,1-Dimethyl-2-indanamine hydrochloride:
To a solution of 22.3 g. of 3,3-dimethyl-2-hydroxyimino-1-
indanone in 100 ml. of acetic acid was added 8 g. of 10 % palladium-
carbon. The mixture was subjected to catalytic hydrogenation for
15 8 hrs. under pressure and heating (30 kg/cm , 80C.). The cata-
lyst was removed by filtration and the filtrate was distilled to
dryness under reduced pressure. After adding 10 % hydrochloric
acid to the residue, the mixture was washed with ether. The
aqueous layer was made alkaline with an aqueous sodium hydroxide
solution and extracted with ether. The ethereal layer was washed
with water and dried. After the solvent was evaporated off, the
residue was converted into the hydrochloride with ethanolic hydro-
chloride. By recrystallization from ethanol-ether, 8.4 g. of
colorless needles having a melting point of 251 to 252C. were
obtained.
Elemental Analysis for CllH14N.HCl. 1/2H20
C H N
Calcd. 63.91 8.29 6.78
Found 64.10 8.10 6.63
0 Example 20 N-AcetYl-l,l-dimethyl-2-indanamine:
19

~39~0
The ether-washed liquid collected after rendering the system
acidic with hydrochloric acid in Example 19 was washed with water
and dried. After the solvent was evaporated off, the resulting
residue was distilled under reduced pressure to obtain 4.32 g. of
a colorless viscous oil having a boiling point of 157 to 161C.
(2 mmHg).
Mass Spectrum as C13H17~0
m/e: 203 (M ), 144 (base peak)
Example 21 1,1-Dimethyl-5-methoxy-2-indanamine hydrochloride:
In a manner similar to Example 19 but using 30 g. of 3,3-
dimethyl-2-hydroxy-6-methoxy-1-indanone, the hydrochloride was
obtained. By recrystallization from ethanol, 5.0 g. of colorless
prisms having a melting point of 279 to 281C. were obtained.
Elemental analysis for C H NO HCl
C H
Calcd. 63.91 8.29 6.78
Found 64.10 8.10 6.63
Example 22 N-Acetyl-l,l-dimethyl-5-methoxy-2-indanamine:
The ether-washed liquid collected after rendering the system
acidic with hydrochloric acid in Example 21 was washed with water
and dried. After the solvent was evaporated off, 4.65 g. of a
slight}y brownish oil was obtained.
Mass Spectrum as C14HlgN02
m/e: 233 (M ), 92 (base peak) -
Example 23 1,1-Dimethyl-5,6-dimethoxy-2-indanamine hydrochloride:
In a manner similar to Example 19 but using 9.5 g. of 3,3-
dimethyl-2-hydroxyimino-5,6-dimethoxy-1-indanone, the hydrochlor-
ide was obtained. By recrystallization from ethanolisopropyl
ether, 0.86 g. of colorless plates having a melting point of 228
to 230C were obtained.

~lr3C~o
Elemental Analysis for C13HlgN02.HCl
C EI N
Calcd. 60.58 7.82 5.43
Found 60.34 8.05 5.62
Example 24 N-Acetyl-l,l-dimethyl-5,6-dimethoxy-2-indanamine:
The ether-washed liquid obtained after rendering the system
acidic with hydrochloric acid in Example 23 was washed with water
and dried. After solvent was removed by distillation, the resul-
ting residue was recrystallized from benzene-hexane to obtain
4.27 g. of colorless needles having a melting point of 145 to 146C.
Elemental Analysis for C15H21N03
C H N
Calcd. 68.42 8.04 5.32
Found 68.29 8.28 5.21
ExamPle 25 1,1-Dimethyl-7-methoxy-2-indanamine hydrochloride: ~ -
In a manner similar to Example 19 but using 6.0 g. of 7-
chloro-3,3-dimethyl-2-hydroxyimino-4-methoxy-1-indanone, the
hydrochloride was obtained. By recrystallization from isopropanol-
isopropyl ether, 0.7 g. of colorless needles having a melting
point of 248 to 249C. were obtained.
Elemental Analysis for C12H17NO. ~Cl
C H N
Calcd. 63.29 7.97 6.15
Found 63.11 8.13 6.04
Example 26 N-Acetyl-l,l-dimethyl-4-methoxy-2-indanamine:
To a solution of 6.0 g. of 3,3-dimethyl-2-hydroxyimino-7-
methoxy-l-indanone in 100 ml. of acetic acid was added 2.5 g. of
10 % palladium-carbon. The mixture was subjected to catalytic
hydrogenation for 7 hrs. under pressure and heating (30 kg/cm ,
70C). The catalyst was removed by filtration and the filtrate
i21

o
was distilled to dryness under reducecl pressure. After adding
10 % hydrochloric acid to the residue, the mixture was extracted
with ether. The ethereal layer was washed with water and dried.
The solvent was removed by distillation. The resulting residue
was crystallized from benzene to obtain 0.85 g. of colorless
plates having a melting point of 140 to 141C.
Elemental Analysis for Cl4HlgNO2
C H N
Calcd. 72.07 8.21 6.00
Found 72.25 8.49 5.83
Example 27 ~-Ethyl-l~l-dimethyl-4-methoxy-2-indanamine hydro-
chloride:
To a suspension of 0.91 g. of lithium aluminum hydride in
10 ml. of anhydrous tetrahydrofuran was dropwise added a solution
of 1.4 g. of N-acetyl-l,l-dimethyl-4-methoxy-2-indanamine in 20
ml of anhydrous tetrahydrofuran. The mixture was heated under
refluxing for 4 hrs. After completion of the reaction, water-
containing ether and water were in succession added to the reac-
tion mixture. Then, the mixture was filtered by suction and the
filtrate was extracted with lO % hydrochloric acid. The aqueous
layer was made alkaline with an aqueous sodium hydroxide solution
and extracted with ether. The ethereal layer was washed with
water and dried. The solvent was removed by distillation and the
resulting residue was converted into the hydrochloride by adding
thereto ethanolic hydrochloric acid. By recrystallization from
ethanol-ether, 0.8 g. of colorless plates having a melting point
of 300C. or higher were obtained.
Elemental Analysis for Cl4H2lNO.HCl
C H N
Calcd. 65.74 8.67 5.48
22

Q
Found 65.39 8.92 5.40
Example 28 N-Ethyl-l,l-dimethyl-2-indanamine hydrochloride:
In a manner similar to Example 27 but using 2.82 g. of N-
acetyl-l,l-dimethyl-2-indanamine, 1.8 g. of the hydrochloride was
obtained, which was recrystallized from ethanol-isopropyl ether
to give colorless needles having a melting point of 203 to 204C.
Elemental Analysis for C13HlgN.HCl
C H N
Calcd. 69.16 8.93 6.20
Found 69.38 9.19 6.12
Example 29 N-Ethyl-l,l-dimethyl-5-methoxy-2-indanamine hydro-
chloride:
In a manner similar to Example 27 but using 4.29 g. of N-
acetyl-l,l-dimethyl-5-methoxy-2-indanamine, the hydrochloride was
obtained, which was recrystallized from ethanol to give 1.28 g. of
colorless prisms having a melting point of 239 to 242C.
Elemental Analysis for C14H21NO.HCl. 1/4H2O ~ -
C H N
Calcd. 64.60 8.71 5.38
Found 64.37 8.79 5.42
Example 30 N-Ethyl-l,l-dimethyl-5,6-dimethoxy-2-indanamine hydro-
chloride:
In a manner similar to Example 27 but using 2.63 g. of N-
acetyl-l,l-dimethyl-5,6-dimethoxy-2-indanamine, 1.59 g. of the
hydrochloride was obtained, which was recrystallized from ethanol
to obtain colorless prisms having a melting point of 289 to 290C.
Elemental Analysis for C15H23NO2. HCl
C H N
Calcd. 63.04 8.46 4.90
Found 62.88 8.57 4.99
23

~9~o
Example 31 1 l,N,N-Tetramethyl-2-indanamine hydrochloride:
A mixture of 3.26 g. of 1,1-dimethyl-2-indanamine, 6 ml. of
37 % an aq. formaldehyde solution and 4.3 ml. of 90 % formic acid
was heated with stirring for 4 hrs. at 100C. After completion of
the reaction, the system was made alkaline with an aqueous sodium
hydroxide solution and extracted with ether. The ethereal layer
was washed with water and dried. The solvent was removed by dis-
tillation and the resulting residue was converted into the hydro-
chloride with ethanolic hydrochloric acid. By recrystallization
from ethanol-isopropyl ether, 3.4 g. of colorless needles having
a melting point of 263 to 264C. were obtained.
Elemental Analysis for C13HlgN.Hcl. 1/2H2O
C H N
Calcd. 66.51 9.02 5.97
Found 66.61 8.92 5.91
While the invention has been described in detail and with
reference to specific embodiments thereof, it will be apparent to
one skilled in the art that various changes and modifications can
be made therein without departing from the spirit and scope
thereof.
24

s~o
SUPPLEMENTARY DISCLOSURE
The conversion of the compounds of the formula (I-l)
into the compounds of the formula (I-5) can also be performed
by dealkylation, i.e,, by heating the system in the presence
of a Lewis acid (aluminum chloride, borotribromide) and inert
organic solvents (halogenated hydrocarbons, benzene, toluene,
zylene, etc.), or in the presence of a strong mineral acid
( e.g., hydrobromic acid, hydroiodic acid).
_EXAMPLE A
1,1-Dimethyl-6- hydroxy-2-indanamine hydrochloride;
To 5.0 g. of 1,1-dimethyl-6-methoxy-2-indanamine hydro-
chloride was added 50 ml. of a 48% hydrobromic acid. The
mixture was heated at 140C for 1.5 hours in,,a nitrogen flow.
After completion of the reaction, the system was rendered
alkaline with an aqueous sodium hydroxide solution, followed
by washing with ether. The ethereal layer was rendered acidic ' -
with hydrochloric acid and then weakly alkaline with ammonia
water. The mixture was extracted with ethyl acetate. The
organic acid was washed with water and dried. After the
solvent was removed by distillation, the residue was converted
into the hydrochloride with ethanolic hydrochloric acid. By
recrystallization from methanol-ethyl acetate, 1.9 g. of cûlor-
less needles having a melting point of 150 to 153C. were
obtained.
Elemental analysis for CllH15NO.HCl. 1/2 H2O
C _ N
Calcd. 59.32 7.69 6.29
Found 59.51 7.92 6.05
--25--

~39~
EXAMPLE B
1,1-Diethyl-6-hydroxy-2-indanamine:
In a manner similar to Example A, 2.5 g. of colorless
plate-like crystals having a melting point of 142 to 144C
were obtained.
Elemental analysis for C13H NO
C _ N
Calcd. 76.06 9.33 6.82
Found 75.97 9.54 6.77
., '~.
-26-