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| United States Patent |
4,034,113
|
|
Shulgin
|
July 5, 1977
|
Treatment of senile geriatric patients to restore performance
Abstract
Compounds of the formula
##STR1##
wherein R.sup.1, R.sup.2 and R.sup.3 are alike or different and each is
(lower)alkyl, including the racemic mixtures and the dextrorotatory and
levorotatory isomers, and the pharmaceutically acceptable nontoxic salt
thereof have been found to restore the performance of mammals, including
man, and upon use in clinical studies in human geriatric patients have had
a profound effect upon their mental alertness and attitudes without
producing the undesirable stimulant side effects associated with the use
of amphetamines.
| Inventors:
|
Shulgin; Alexander T. (1483 Shulgin Road, Lafayette, CA 94549)
|
| Appl. No.:
|
677348 |
| Filed:
|
April 15, 1976 |
| Current U.S. Class: |
514/654 |
| Intern'l Class: |
A61K 031/135 |
| Field of Search: |
424/330
|
References Cited [Referenced By]
U.S. Patent Documents
Primary Examiner: Friedman; Stanley J.
Attorney, Agent or Firm: Lloyd; Richard R.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of co-pending Ser. No. 566,458
now abandoned, filed Apr. 9, 1975, which is a continuation-in-part of Ser.
No. 304,069 filed Nov. 6, 1972 now abandoned.
Claims
I claim:
1. A method of treating senile geriatric humans to restore performance
which comprises administering to said human an effective amount of a
compound of the formula
##STR9##
wherein R.sup.1, R.sup.2 and R.sup.3 are alike or different and each is
(lower)alkyl; or a pharmaceutically acceptable nontoxic salt thereof.
2. The method of claim 1 wherein the compound administered has the formula
##STR10##
3. The method of claim 1 wherein the compound administered is a
pharmaceutically acceptable nontoxic salt of the compound of the formula
##STR11##
4. The method of claim 1 wherein the compound administered is the
hydrochloride salt of the compound of the formula
##STR12##
5. The method of claim 1 wherein the compound administered is
(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane.
6. The method of claim 1 wherein the compound administered is a
pharmaceutically acceptable nontoxic salt of
(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane.
7. The method of claim 1 wherein the compound administered is
(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride.
8. The method of claim 1 wherein the compound administered is
(+)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane.
9. The method of claim 1 wherein the compound administered is a
pharmaceutically acceptable nontoxic salt of
(+)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane.
10. The method of claim 1 wherein the compound administered is
(+)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride.
11. The method of claim 1 which comprises administering about 25 to about
100 milligrams per dose, one to four times a day.
Description
BACKGROUND OF THE INVENTION
(1) Field of the Invention
This invention relates to novel compounds which are useful for restoring
the performance of mammals, including man, and they have been found to
have a profound beneficial effect in human geriatric patients by
increasing their mental alertness and improving their mental attitude and
physical appearance without the undesirable side effects commonly
associated with amphetamines, e.g., hypertension, tachycardia, anorexia,
insomnia and post drug dysphoria.
In another aspect, this invention relates to a method of preparing the
novel compounds. In still another aspect, this invention relates to a
method of restoring the performance of mammals. In a further aspect, this
invention relates to compositions useful in the method of restoring the
performance capacity of mammals.
(2) Description of the Prior Art
Numerous compounds structurally related to amphetamine
(.alpha.-methylphenethylamine) have been prepared and reported in the
literature and are the subject matter of various patents. Of particular
interest with respect to the compounds disclosed herein are U.S. Pat. No.
3,547,999, Shulgin, A. T.: Chemistry and Structure-Activity Relationships
of the Psychotomimetics which appeared in the book, Psychotomimetic Drugs,
Ed. D. H. Efron, Raven Press 1970 and Shulgin, A. T., Sargen, T. and
Naranjo, C.: Structure-Activity Relationships of One-Ring
Psychotomimetics, Nature, 221:537 (1969). The foregoing patent and
references disclose compounds closely related to the compounds of this
invention. However, none of the compounds is disclosed as having the
activity of the compounds of this invention. The Shulgin article in
Psychotomimetic Drugs at pages 35-36 indicates that a "four chain
compound" had been synthesized; however, the particular compound
synthesized is not named, the structure is not disclosed, the method of
preparation is not disclosed and no utility is disclosed in the article.
Other patents and publications reported from a search are U.S. Pat. No.
2,246,529; Journal of the American Chemical Society, Vol. 78, pages
4419-22 (1956); Journal of Medicinal Chemistry, Vol. 9, No. 4, pages
469-70 (1966); Arch. int. Pharmacodyn Vol. 154; No. 1, pages 26, 31-32
(1965); Chemical Abstracts, Vol. 61, page 6954a; Chemical Abstracts, Vol.
71, page 12786q; Chemical Abstracts, Vol. 67, pages 10215w; Chemical
Abstracts, Vol. 72, page 12364w; and Chemical Abstracts, Vol. 59, page
3797d.
SUMMARY OF THE INVENTION
There is provided according to the present invention a pharmaceutical
composition useful for restoring the performance of mammals which
comprises an effective amount of a compound of the formula
##STR2##
wherein R.sup.1, R.sup.2 and R.sup.3 are alike or different and each is
(lower)alkyl; or a pharmaceutically acceptable nontoxic salt thereof and a
pharmaceutically acceptable carrier.
Another aspect of this invention is the provision of a method of restoring
the performance of mammals, including man, which comprises administering
to said mammal an effective amount, of a compound of formula I or a
pharmaceutically acceptable nontoxic salt thereof.
A further aspect of this invention is the provision of a method of treating
despondent, asocial, depressed, anxious and senile geriatric humans
suffering from chronic organic brain disease and parkinsonism, which
comprises administering to said humans an effective amount of a compound
of formula I, or a pharmaceutically acceptable nontoxic salt thereof. The
treatment of patients suffering the above-described symptoms results in
the patients exhibiting near-normal behavior patterns.
The compounds of formula I contain an asymmetric carbon atoms and thus
normally occur as a racemic mixture of the dextro- and levorotatory
optical isomers. Both the dextro- and levorotatory isomers of these
compounds, as well as the racemic mixtures are useful in the composition
and method described above and are considered to be an integral part of
the invention.
A further aspect of this invention is the provision of the dextro- and
levorotatory isomers of the compounds of formula I; and the
pharmaceutically acceptable nontoxic salts thereof.
The pharmaceutically acceptable nontoxic salts include the organic and
inorganic acid addition salts, e.g., those prepared from acids such as
hydrochloric, sulfuric, tartaric, fumaric, hydrobromic, hydriodic,
glycolic, citric, maleic, phosphoric, succinic, acetic and the like. Such
salts are prepared by conventional methods by reacting the free base with
the desired acid on about an equivalent basis.
The term "(lower)alkyl" as used herein includes both straight chain and
branched chain alkyl radicals containing from 1 to 4 carbon atoms, e.g.,
methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and t-butyl.
A preferred embodiment of the instant invention is the compound having the
formula
##STR3##
or a pharmaceutically acceptable nontoxic salt thereof.
A more preferred embodiment is the essentially pure dextrorotatory and
levorotatory isomer of the compound having formula II supra.
The most preferred embodiment is the levorotatory isomer of compound II
supra.
The compounds of formula I are prepared as exemplified below by reducing a
2-nitro-1-(2,5-(lower)alkoxy- 4-(lower)alkylphenyl)butene-1 of the formula
##STR4##
wherein R.sup.1, R.sup.2 and R.sup.3 are as described above, with, for
example, lithium aluminum hydride in the presence of a nonreactive solvent
medium. Suitable solvents include diethyl ether, tetrahydrofuran,
diethylene glycol dimethyl ether and the like. The reaction proceeds at
temperatures from about 0.degree. C. to 150.degree. C. Preferably the
reaction is carried out at the boiling temperature of the reaction mixture
and under reflux and about 2 moles of lithium aluminum hydride per mole of
butene are used. The preferred solvent is ether.
The general procedures for the preparation of the compounds of this
invention and the starting materials are described in U.S. Pat. No.
3,547,999.
The racemic compounds of formula I may be resolved by forming a mixture of
the two diastereoisomeric salts of said compounds with a dextrorotatory
ring-substituted tartranilic acid, e.g., nitro, chloro or bromo
substituted, separating and diastereoisomeric salts by fractional
crystallization and converting the separated diastereoisomeric salts to
the respective optical isomers of the compound preferably by treatment
with a strong base, e.g. sodium carbonate, potassium carbonate and the
like. (+)-2'-Nitrotartranilic acid and (+)-2'-chlorotartranilic acid are
particularly useful in the resolution of the racemic compounds of Formula
I. The general resolution procedure using tartranilic acids is described
in U.S. Pat. No. 3,452,086 and by T. A. Montzka et al, J. Org. Chem. 33,
3993 (1968).
The compounds of formula I in the form of racemic mixtures or their
dextrorotatory or levorotatory isomers possess performance restoring
activity making them useful for enhancing the performance ability of
mammals. The compounds while structurally related to amphetamine do not
produce hypertension, tachycardia, anorexia, insomnia and post drug
dysphoria which are common with amphetamine.
The performance restoration activity of the compounds of this invention was
determined by the shuttle box acute acquisition, pole climb acute
acquisition and pole climb chronic avoidance acquisition tests.
Shuttle Box-- Acute Acquisition
Male hooded rats (500-700 gm.) were used as experimental subjects. The
compounds are administered either subcutaneously or orally 30 minutes
prior to shuttle box test. (shuttle box-- manufactured by Lehigh Valley
Electronics Co.). Each trial is 60 seconds long consisting of a 5 second
avoidance period, during which the animal is required to move to the other
side of shuttle box to avoid shock, and a 5 second shock period, if the
animal fails to move during the avoidance period. During these 10 seconds,
the cue light is lit on the other side of the test box but turned off if
the animal moves to the other side of the box. The rat is given a maximum
of 100 trials or until it acquires the ability to avoid 8 shocks out of 10
consecutive trials. Its score is the number of the trial which is the last
trial prior to avoiding 8 shocks out of 10.
Pole Climb--Acute Acquisition
Male hooded rats (200- 300 gms.) were used as experimental subjects. The
compounds are administered subcutaneously 30 minutes prior to placement of
the animal into the pole climb chamber (Cook, L., and Weidly, E. (1957),
Ann. N.Y. Acad. Sci., 66, p. 740). Each trial is 60 seconds long
consisting of a 5 second avoidance period, during which a sound is sounded
and the animal has to jump up onto the pole and a 5 second shock period if
the animal fails to jump. During the avoidance and shock periods the tone
and electric shock are turned off if the animal jumps onto the pole. The
animal is given a maximum of 100 trials or until it acquires the ability
to avoid 8 shocks out of 10 consecutive trials. Its score is the number of
the trial which is the last trial prior to attaining avoidance of 8 of 10
consecutive trials.
Pole Climb--Chronic Avoidance Acquisition
A similar procedure was used as in the pole climb-acute acquisition
procedure described above but each animal was given 20 trials every day
and the number of avoidances was determined. With each day there was an
improvement in the performance; the number of avoidance responses
increased.
When (.+-.)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride
and the dextrorotatory and levorotatory isomers were tested according to
the foregoing procedures, the following results were obtained.
Table 1
______________________________________
Acute Avoidance Acquisiton by Breeder Rats in the Shuttle Box
No. Trials
required
Dose No. of to reach 80%
Compound (mg/kg) Animals Avoidance
______________________________________
(+)-2-amino-1-(2,5-
1 sc 8 57
dimethoxy-4-methyl-
5 sc 10 58
phenyl)butane hydro-
10 sc 10 47
chloride 10 po 9 58
(-)-2-amino-1-(2,5-
1 sc 9 65
dimethoxy-4-methyl-
5 sc 10 43
phenyl)butane hydro-
10 sc 9 39
chloride 10 po 7 66
(.+-.)-2-amino-1-(2,5-
1 sc 6 67
dimethoxy-4-methyl-
10 sc 8 37
phenyl)butane hydro-
chloride
Saline -- 20 85
______________________________________
Table 2
______________________________________
Acute Avoidance Acquisition by Adult Rat in the Pole Climb
No. Trials Re-
Dose No. of quired to Reach
Compound (mg/kg sc)
Animals 80% Avoidance
______________________________________
(+)-2-amino-1-(2,5-
10 10 85
dimethoxy-4-methyl-
phenyl)butane hydro-
chloride
(-)-2-amino-1-(2,5-
10 10 65
dimethoxy-4-methyl-
phenyl)butane hydro-
chloride
Saline -- 10 100
______________________________________
Table 3
______________________________________
Chronic Avoidance Acquisiton by Adult Rats in the Pole Climb
(12 Rats Used) No. Avoidances/240 Trials.
(+)-2-amino-1-(2,5-
(-)-2-amino-1-(2,5-
dimethoxy-4-methyl-
dimethoxy-4-methyl-
Treat- phenyl)butane hydro-
phenyl)butane hydro-
ment chloride chloride
Day 5 mg/kg sc 5 mg/kg sc Saline
______________________________________
-1 17/240 18/240 20/240
1 56/240 63/240 51/240
2 76/240 85/240 63/240
3 91/240 108/240 77/240
4 103/240 101/240 94/240
______________________________________
The above test results disclose that the racemic mixture,
(.+-.)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride, and
the dextrorotatory and levorotatory isomers exhibit learning enhancing
activity, the levorotatory isomer appeared to exhibit greater activity
than the dextrorotatory isomer. No increase in locomotion activity was
observed after administration of the racemic mixture or either of the
isomers.
The ability of (-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane
hydrochloride (BL-3912A) to restore performance in humans have been
confirmed in the initial clinical trials.
(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride has
demonstrated remarkable and profound effects in initial clinical studies
in senile geriatric patients. For example, in geriatric nursing home
patients that were dull and presented varying degrees of inactivity and
withdrawal, a dose of 100-300 mg. per day produced remarkable results.
Mood and behavior improved and patients became more alert, active and less
disabled.
At similar doses a reduction in rigidity and tremor occurred in patients
suffering from moderate to severe Parkinsonism. During BL-3912A therapy,
handwriting, speech and feeding habits dramatically improved.
In one study involving 14 nursing home patients, improvement progressed to
the point where the investigator felt some patients were well enough to
return home.
The response to a particular dose level of the compound is variable and
peculiar to each patient. In general, the patient should be titrated to
his own needs.
In clinical trials BL-3912A did not produce hypertension, tachycardia,
anorexia, insomnia and post drug dysphoria which are commonly seen
following administration of amphetamine and other stimulants commonly used
to restore performance, e.g., Ritalin.RTM. and pemoline.
BL-3912A is devoid of hallucinogenic activity in mammals, including man and
has been found to antagonize the effects of
2,5-dimethoxy-4-methyl-amphetamine (DOM) in rodents and cats. DOM is a
hallucinogenic agent widely subjected to abuse by thrill-seeking youth and
others.
The compounds of formula I may be administered as the free bases or in the
form of their nontoxic addition salts. They may be compounded and
formulated into pharmaceutical preparations in unit dosage form for oral
or parenteral administration with organic or inorganic solid materials or
liquids which are pharmaceutically acceptable carriers. Some examples of
the carriers which can be used are gelatin capsules, sugars, cellulose
derivatives such as carboxymethyl-cellulose, gelatin, talc, magnesium
stearate, vegetable oil such as peanut oil, etc., liquid petroleum,
glycerin, sorbitol, ethanol, agar, elixirs, syrups and water including
sterile water. The composition may take the form of tablets, powders,
granules, capsules, suspensions, solutions and the like.
The compounds of formula I when administered orally or parenterally in an
effective amount restore performance in mammals. An oral dosage range of
about 1 to about 5 milligrams per kilogram of body weight is a convenient
dosage for producing these effects in mammals. However, in general, the
particular dosage most suitable for a particular application, as might be
expected, will vary with the age, weight and general health of the mammal
under treatment and the degree of performance improvment present. After
taking into consideration these factors and any other factors to be
considered, one skilled in the art of treating diseases of mammals can
readily determine the appropriate dosage.
The compounds of formula I are administered orally or parenterally in the
treatment of geriatric patients suffering from senility or parkinsonism in
dosages of 25 to 100 mg. one to four times a day depending upon the effect
desired. However, in general, the particular dosage most suitable for a
particular application, as might be expected, will vary with the age,
weight and general health of the human under treatment. One skilled in the
art of treating human diseases can readily determine the appropriate dose
for the respective patient.
The following examples are intended to illustrate the invention described
herein without unduly restricting it.
EXAMPLE 1
Preparation of 2,5-Dimethoxytoluene
##STR5##
To a solution of 50 g. potassium hydroxide in methanol is added 50 g. of
toluhydroquinone. The resulting solution is heated on a steam bath, and an
excess of methyl iodide (75 ml.) is added through an effective reflux
condenser. The addition is continued over several hours, and the resulting
combination heated at reflux for several additional hours. At this time,
the reaction mixture is brought to room temperature, acidified with
hydrochloric acid, and exhaustively extracted with methylene chloride.
The organic phase of the above-extraction is washed with 5% sodium
hydroxide solution (to remove all phenolic byproducts), then with water.
The solvent remaining is concentrated by evaporation, yielding a residual
neutral oil (36.9 g.). This upon distillation yielded 2,5-dimethoxytoluene
as a pale amber liquid (b.p. 105.degree.-111.degree. C. at 20 mm/Hg. The
base washes yield, after acifification and extraction, 14.1 g. of a
mixture of the two possible monomethylated derivatives which can be
recycled in a subsequent repetition of the methylation step.
EXAMPLE 2
##STR6##
A solution of 40 ml. phosphorous oxychloride (POCl.sub.3) and 45 ml. of
N-methylformanilide is allowed to stand at ambient temperature for 50
minutes. There is then added 15.2 g. of 2,5-dimethoxytoluene and the
resulting solution is heated on the steam bath for 140 minutes. The
extremely dark viscous reaction mixture is added to 2 liters of water, and
allowed to stir for several hours to complete the hydrolysis of the
reaction intermediates. The solid product is removed by filtration, and
after washing with water and air-drying yields 16.6 g of reddish crumbly
crystals. This solid product is extracted with 2.times.125 ml. of boiling
hexane, which on cooling deposits 12.1 g. of pale cream-colored crystals.
Recrystallization from boiling hexane, yields a brilliant white product
2,5-dimethoxy-4-methylbenzaldehyde.
EXAMPLE 3
Preparation of 2-Nitro-1-(2,5-Dimethoxy-4-Methylphenyl)-Butene-1
##STR7##
A mixture of 31.6 g. of 2,5-dimethoxy-4-methylbenzaldehyde 20.2 ml. of
nitropropane, 6 ml. cyclohexylamine, and 50 ml. benzene is kept at reflux
in a Dean Stark apparatus for 24 hours. Cooling results in the spontaneous
crystallization of an orange product, which on filtration and drying
weighs 14.9 g. Recrystallization from methanol yields the product
2-nitro-1-(2,5-dimethoxy-4-methoxyphenyl)-butene-1 as an orange
crystalline material, mp. 115.degree. C.
EXAMPLE 4
Preparation of (.+-.)-2-Amino-1-(2,5-Dimethoxy-4-Methylphenyl)Butane
##STR8##
A suspension of 16 g. lithium aluminum hydride in 750 ml. anhydrous ether
is brought to reflux, and through a Soxhlet thimble, 19.2 g. of
2-nitro-1-(2,5-dimethoxy-4-methylphenyl)butene-1 is added. The reflux is
maintained for 24 hours, then the reaction mixture is cooled externally
with ice, and 500 ml. of a 20% solution of sulfuric acid is added
cautiously. The two phase result is separated, and the aqueous fraction
washed with ether. To this fraction is added 400 g. potassium sodium
tartrate and the pH adjusted with aqueous sodium hydroxide until greater
than 9. The product is extracted with methylene chloride, which when
removed leaves a clear, colorless oil, (.+-.
)-2-amino-1-(2,5-dimethoxy-4-methylphenyl-butane. This is dissolved in
ether, and saturated with anhydrous hydrogen chloride. The crystalline
hydrochloride of (.+-.)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)-butane
thus obtained, after filtration and washing with additional anhydrous
ether, weighed 12.0 g.
EXAMPLE 5
When in the procedure of Example 4,
2-nitro-1-(2,5-dimethoxy-4-methylphenyl)-butene-1is replaced by an equal
molar amount of
2-nitro-1-(2,5-dimethoxy-4-ethylphenyl)-butene-1,
2-nitro-1-(2,5-dimethoxy-4-propylphenyl)-butene-1,
2-nitro-1-(2,5-dimethoxy-4-isopropylphenyl)-butene-1,
2-nitro-1-(2,5-dimethoxy-4-butylphenyl)-butene-1,
2-nitro-1-(2,5-diethoxy-4-methylphenyl)-butene-1,
2-nitro-1-(2,5-dipropoxy-4-methylphenyl)-butene-1,
2-nitro-1-(2,5-diisopropoxy-4-methylphenyl)-butene-1,
2-nitro-1(2,5-dibutoxy-4-methylphenyl)-butene-1,
2-nitro-1-(2-methoxy-5-ethoxy-4-methylphenyl)-butene-1,
2-nitro-1-(2-ethoxy-5-methoxy-4-methylphenyl)-butene-1,
2-nitro-1-(2,5-diethoxy-4-ethylphenyl)-butene-1, and
2-nitro-1(2,5-diethoxy-4-propylphenyl)-butene-1,
there are obtained
(.+-.)-2-amino-1-(2,5-dimethoxy-4-ethylphenyl)-butane,
(.+-.)-2-amino-1-(2,5-dimethoxy-4-propylphenyl)-butane,
(.+-.)-2-amino-1-(2,5-dimethoxy-4-isopropylphenyl)-butane,
(.+-.)-2-amino-1-(2,5-dimethoxy-4-butylphenyl)-butane,
(.+-.)-2-amino-1-(2,5-diethoxy-4-methylphenyl)-butane,
(.+-.)-2-amino-1-(2,5-dipropoxy-4-methylphenyl)-butane,
(.+-.)-2-(2,5-diisopropoxy-4-methylphenyl)-butane,
(.+-.)-2-amino-1-(2,5-dibutoxy-4-methylphenyl)-butane,
(.+-.)-2-amino-1-(2-methoxy-5-ethoxy-4-methylphenyl)-butane,
(.+-.)-2-amino-1-(2-ethoxy-5-methoxy-4-methylphenyl)-butane,
(.+-.-2-amino-1-(2,5-diethoxy-4-ethylphenyl)-butane,
(.+-.)-2-amino-1-(2,5-diethoxy-4-propylphenyl)-butane
Resolution of 2-Amino-1-(2,5-dimethoxy-4-methylphenyl)butane.
EXAMPLE 6
A. (+)-2-Amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride.
(.+-.)-2-Amino-1-(2,5-dimethoxy-4-methylphenyl)butane (17.9 g., 80.2
mmoles) and 10.82 g. (40.1 mmoles) of (+)-2'-nitrotartranilic acid were
dissolved in 85 ml. of hot 95% ethanol. The solution was cooled, seeded
with salt previously obtained on a test tube scale, and allowed to stand
undisturbed at room temperature (20.degree.-25.degree. C.) until
crystallization was complete (at least 18 hours). The solid was filtered,
sucked as free of mother liquid as possible, and washed with 10 ml. of
cold (-15.degree. C.) 95% ethanol in two portions. The mother liquor and
washings were reserved for recovery of the (-)-isomer. The product was
air-dried to give 12.32 g. of the pure (+)-2'-nitrotartranilic salt of
(+)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane, mp.
155.5.degree.-157.degree. C.
Anal. Calc'd. for C.sub.23 H.sub.31 N.sub.3 O.sub.9 : C, 55.97; H, 6.33; N,
8.52. Found: C, 55.63; H, 6.19; N, 8.43.
This salt was dissolved in 100 ml. of hot ethanol. The solution was cooled
and poured into excess dilute potassium carbonate solution. The mixture
was extracted with two portions of ether; the combined ether extracts were
washed with dilute potassium carbonate solution, dilute sodium bicarbonate
solution, and three portions of water. Drying and evaporation of the
solvent gave 3.8 g. of pure
(+)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane as a light yellow oil
which crystallized upon standing, [.alpha.].sub.365.sup.26 + 155.3.degree.
(c 1.273, 95% ethanol). The salt was formed with HCl gas in anhydrous
ether. The solid was filtered, washed with ether and air-dried to give
4.34 g. of slightly yellowish powder. Recrystallization from 105 ml. of
2-propanol provided 3.70 g. of pure
(+)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride as
colorless, fluffy needles, m.p. 245.degree.-246.degree. C.,
[.alpha.].sub.375.sup.23 + 49.8.degree. (c 1.000, 95% EtOH). The overall
yield was 35% of available (+)-isomer.
Anal. calc'd. for C.sub.13 H.sub.21 NO.sub.2. HCl: C, 60.10; H, 8.54; N,
5.39; Cl, 13.65. Found: C, 59.79; H, 8.57; N, 5.18; Cl, 13.57.
B. (-)-2-Amino-(2,5-dimethoxy-4-methylphenyl)butane-hydrochloride.
The mother liquor from isolation of the (+)-isomer was evaporated and the
residue was converted to the free base as described above. The oil thus
obtained and 9.37 g. (36.1 mmoles, 0.9 molar equiv.) of
(+)-2'-chloro-tartranilic acid were dissolved in 85 ml. of hot 95%
ethanol. The solution was cooled, seeded with salt previously obtained on
a test tube scale, and allowed to stand undisturbed at room temperature
until crystallization was complete (at least 18 hours). The solid was
filtered, washed with 10 ml. of cold (-15.degree.) 95% ethanol, and
air-dried; 13.22 g. of light yellowish, fluffy crystals was obtained
(76%). Two recrystallizations in a like manner from 10 ml./g. of 95%
ethanol gave 7.99 g. (60% recovery) of pure, colorless
(+)-2'-chlorotartranilic acid salt of
(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane, m.p.
182.5.degree.-184.degree. C.
Anal. calc'd. for C.sub.23 H.sub.31 ClN.sub.2 O.sub.7 : C, 57.19; H, 6.47;
N, 5.80; Cl, 7.34. Found: C, 56.91; H, 6.56; N, 5.90; Cl, 7.16.
This salt was converted to the free base as described for the (+)-isomer.
Pure (-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane (3.6 g.) was
recovered as an almost colorless oil which crystallized upon standing,
[.alpha.].sub.365.sup.23.5 - 156.3.degree. (c 1.274, 95% ethanol). The
salt was formed with anhydrous HCl and the colorless powder (4.18 g.) thus
obtained was recrystallized from 110 ml. of 2-propanol to give 3.64 of
pure (-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride as
colorless, fluffy needles, m.p. 245.degree.-246.degree. C.,
[.alpha.].sub.365.sup.24 - 49.9.degree. (c 1.000 95% ethanol). The overall
yield was 35% of available (-)-isomer.
Anal. calc'd. for C.sub.13 H.sub.21 NO.sub.2.HCl: C, 60.10; H, 8.54; N,
5.39; Cl, 13.65. Found: C, 59.93; H, 8.70; N, 5.44; Cl, 13.73.
EXAMPLE 7
When in the procedure of Example 6
(.+-.)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane is replaced by an
equimolar amount of each of the racemic compounds produced in Example 5,
there is obtained the individual dextrorotatory and levorotatory isomers
of each compound.
EXAMPLE 8
Tablets are prepared from the following formulations.
FORMULATION A
______________________________________
Per tablet, mg.
______________________________________
2-amino-1-(2,5-dimethoxy-4-
10
methylphenyl)butane
hydrochloride
Cornstarch 100
Methylcellulose 400 175
Magnesium stearate 3
Total 288
______________________________________
Each tablet contains 10 mg. of active ingredient.
FORMULATION B
______________________________________
Per tablet, mg.
______________________________________
2-amino-1-(2,5-dimethoxy-4-
10
methylphenyl)butane
hydrochloride
Monocalcium phosphate
70
Dicalcium phosphate 70
Lactose 70
Magnesium stearate 3
Total 223
______________________________________
A mixture of monocalcium phosphate, dicalcium phosphate and lactose is
prepared to which is added magnisium stearate and
2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride and then
tabletted by conventional means. Each tablet contains 10 mg. of active
ingredient.
While this invention has been described and exemplified in terms of its
preferred embodiment, those skilled in the art will appreciate that
modifications can be made without departing from the spirit and scope of
the invention.
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