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| United States Patent |
4,105,695
|
|
Partyka
, et al.
|
August 8, 1978
|
2-Amino-1-(2,5-dimethoxyphenyl)-butanes
Abstract
Compounds of the formula
##STR1##
wherein R.sup.1 is Cl, Br, (lower)alkylthio or
##STR2##
in which R.sup.3 is H or (lower)alkyl including the racemic mixtures and
the dextrorotatory and levorotatory isomers, and the pharmaceutically
acceptable non-toxic salts thereof have been found to enhance the learning
capacity of mammals, including man, and to improve the mental alertness
and attitudes of geriatrics without producing the undesirable stimulant
side effects associated with the use of amphetamines.
| Inventors:
|
Partyka; Richard A. (Liverpool, NY);
Standridge; Robert T. (Cazenovia, NY);
Howell; Henry G. (East Syracuse, NY);
Shulgin; Alexander T. (Lafayette, CA)
|
| Assignee:
|
Bristol-Myers Company (New York, NY)
|
| Appl. No.:
|
795699 |
| Filed:
|
May 11, 1977 |
| Current U.S. Class: |
564/381; 514/878; 548/473; 564/375; 564/377; 568/587 |
| Intern'l Class: |
C07C 087/28 |
| Field of Search: |
260/570.8 R,501.17
|
References Cited [Referenced By]
U.S. Patent Documents
| 3655737 | Apr., 1972 | Carlsson et al. | 260/501.
|
Other References
Barfknecht et al. "Jour. of Med. Chem.", vol. 14, No. 4, pp. 370-372
(1971).
Shulgin, "Chemical Abstracts", vol. 81, p. 481, Section 104988s (1974).
|
Primary Examiner: Hines; Robert V.
Attorney, Agent or Firm: Lloyd; Richard R.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of our co-pending application
Ser. No. 639,676 filed Dec. 11, 1975 and now abandoned.
Claims
We claim:
1. The compound of the formula
##STR21##
or a pharmaceutically acceptable nontoxic acid addition salt thereof.
2. The compound of the formula
##STR22##
or a pharmaceutically acceptable nontoxic acid addition salt thereof.
3. The hydrochloride salt of the compound of claim 1.
4. The hydrochloride salt of the compound of claim 2.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel compounds which are useful for enhancing
the learning capacity 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 stimulant side effects
commonly associated with amphetamines.
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 enhancing the learning capacity of mammals. In a further aspect,
this invention relates to compositions useful in the method of enhancing
the learning 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., Sargent, T. and
Naranjo, C.: Structure-Activity Relationships of One-Ring
Psychotomimetics, Nature, 521-537 (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.
(3) 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.
Belgian Pat. No. 806,990 describes and claims the compounds having the
formula
##STR3##
wherein R.sup.1, R.sup.2 and R.sup.3 are alike or different and each is
(lower)alkyl. The patent describes a method of preparation that is
non-stereospecific.
D. E. Nichols, C. F. Barfkneckt and D. B. Rusterholz describe the
"Asymmetric Synthesis of Psychotomimetic Phenylisopropylamines" in the
Journal of Medicinal Chemistry, 1973, Vol. 16, No. 5, 480-483.
C. F. Barfknecht and D. E. Nichols, in J. Medicinal Chemistry, 14, 370-2
(1971), disclose inter alia the compound of the formula
##STR4##
which is the lower homolog of one of the compounds claimed herein.
However, unlike the compounds of the present invention, that compound was
disclosed as having mescaline-like side-effects which are much more
profound than those produced by DOM.
Chemical Abstracts, 81, 104988s (1974) (corresponding to West German OLS
No. 2,355,350) discloses the compound of the formula
##STR5##
as the racemate and the optically active antipodes. The compound improved
the chronic avoidance aquisition of rats.
U.S. Pat. No. 3,457,354 discloses compounds of the formula
##STR6##
in which X is --OH or --NH.sub.2 and R is H, --CH.sub.3 or --C.sub.2
H.sub.5 as antihypertensive agents.
U.S. Pat. No. 3,655,737 discloses compounds of the formula
##STR7##
in which R.sup.1 is --CH.sub.3, --C.sub.2 H.sub.5 or --C.sub.3 H.sub.7 and
R.sup.2 (in position 2, 4, 5 or 6) is F, Cl, Br, --CH.sub.3, --C.sub.2
H.sub.5 or --C.sub.3 H.sub.7 as antihypertensive and antidepressant
agents.
A. T. Shulgin, in Experientia, 19, 127-8 (1963), reports the testing of a
series of mescaline homologs of the formula
##STR8##
in which R varied from H through C.sub.7 H.sub.15. He reports that
toxicity and behavioral studies with mice could not distinguish between
the first three members of this series (i.e. the ethylamino, propylamino
and butylamino compounds). In humans it is established that the compound
in which R is CH.sub.3 (the propylamino compound) is more than twice as
potent as mescaline (R = H; the ethylamino compound), but Shulgin found
that the compound in which R = C.sub.2 H.sub.5 (the butylamino compound)
produced neither central nervous system activity nor psychtotomimetic
(hallucinogenic) disturbance. Surprisingly, the compounds of the present
invention have been found to possess the desirable central nervous system
activity (e.g. enhancement of learning capacity and improvement of mental
alertness) without the undesirable psychotomimetic side-effects.
SUMMARY OF THE INVENTION
The compounds having the formula
##STR9##
wherein R.sup.1 is Cl, Br, (lower)alkylthio or
##STR10##
in which R.sup.3 is H or (lower)alkyl; or a pharmaceutically acceptable
non-toxic salt thereof have been found to enhance the learning capacity of
mammals, including man, and to improve the mental alertness and attitudes
of geriatrics without producing the undesirable stimulant side effects
associated with the use of amphetamines.
COMPLETE DISCLOSURE
There is provided according to the present invention a pharmaceutical
composition useful for enhancing the learning capacity of mammals which
comprises an effective amount of a compound of the formula
##STR11##
wherein R.sup.1 is Cl, Br, (lower)alkylthio or
##STR12##
in which R.sup.3 is H or (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 enhancing
the learning capacity 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, psychotic, schizophrenic, manic depressive and senile
geriatric humans, 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 atom and thus
normally occur as a racemic mixture of the dextro- and levorotatory
optical isomers. Both and 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, sulfonic, 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
##STR13##
wherein R.sup.1 is Cl, Br, --SCH.sub.3 or --CH.sub.2 OH; or a
pharmaceutically acceptable nontoxic salt thereof.
A more preferred embodiment is the compound of formula I wherein R.sup.1 is
Cl.
Another more preferred embodiment is the compound of formula I wherein
R.sup.1 is Br.
Another more preferred embodiment is the compound of formula I wherein
R.sup.1 is --SCH.sub.3.
Another more preferred embodiment is the compound of formula I wherein
R.sup.1 is --CH.sub.2 OH.
A more preferred embodiment is the essentially pure dextrorotatory or
levorotatory isomer of the compound having formula I supra.
The most preferred embodiment is the levorotatory isomer of compound I
supra.
When the process illustrated in Scheme II is employed, the compounds I are
stereoselectively prepared as either the R or S isomer. When the synthesis
employed is non-stereospecific, the compounds I are obtained as racemic
mixture which must then be resolved if one desires to obtain the
essentially pure R and S optical isomers.
The racemic compounds of formula I may be resolved by forming a mixture of
the two diastereoisomeric salts of said compounds with a dextrorotatory or
levorotatory ring-substituted tartranilic acid, e.g., nitro, chloro or
bromo substituted, separating said 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 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 learning enhancement
activity making them useful for enhancing the learning capacity of
mammals. The compounds while structurally related to amphetamine do not
produce amphetamine-like central nervous system stimulant activity in
mammals.
The compounds of the invention were tested in a primary mouse screen.sup.1
as illustrated in Table I. Most of the compounds exhibited some degree of
stimulation which were characterized by clonic convulsions, tremors,
irritability and ataxia when given orally at the indicated doses (mg/kg).
.sup.1 S. Irwin, Psychopharmacol. 13, 222 (1968).
These agents were also compared to R-2,5-dimethoxy-4-methylamphetamine
(R-DOM) in terms of affecting cat behavior.sup.2. DOM-like activity was
described as depression, dissassociation from the enviroment, catatonia,
diarrhea, miosis, salivation, piloerection, arched back, and muscle
rigidity. Reference compound
(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane hydrochloride
(BL-3912A) had no effect on the behavior of the cat at 5-10 mg. mg./kg.
s.c., while resulting in alertness, piloerection, mydriasis and some
arching at 20 mg./kg. The results are found in Table I.
.sup.2 M. B. Wallack et al, J. Pharm. Exp. Thera. 182, 145 (1972).
TABLE 1
__________________________________________________________________________
Compound
No. Mouse CNS Screen, mg/kg po
Cat Behavior, mg/kg sc
__________________________________________________________________________
1 300 - toxic, 10 - no DOM-like effects
50, 150 - stimulation
2 300, 150 - stimulation
10 - no DOM-like effects
3 300 - toxic, 10 - no DOM like effects
100 - stimulation
4 300 - toxic; 150 - stimulation
10 - weak DOM-like effects
5 300, 150 - weak stimulation
10 - questionable Dom-like
effects
6 300 - toxic, convulsant;
10 - questionable or weak
150, 50 - stimulation
DOM-like effects
7 300 - tremors, stimulation;
10 - questionable DOM-like
150, 50 - stimulation
effects
8 300 - no effects 10 - no DOM-like effects
9 300 - no effects 10 - no DOM like effects
10 300 - no effects 10 - no DOM-like effects
12 300 - initial (10-30 min) ataxia,
10 - no DOM-like effects
jumping motions tremors and shaking; -
no significant effects for next 3
hours
150 - no significant effects
__________________________________________________________________________
Remarks:
A. In general, most the compounds exhibited predominantly stimulant
effects in the mouse CNS screen.
B. Some of the compounds exhibited signs of DOM-like effects in the cat.
However, they were weak and incomplete as compared to those seen with DOM
One of the preferred compounds of the present invention (the 4-methylthio
compound; BL-5485A) was compared with R-DOM for the facilitation of
avoidance acquisition. The test animals were retired breeder rats of the
Long-Evans strain (Blue Spruce Farms, Altamont, N.Y.). Experiments were
conducted in automated shuttle cages (BRS/LVE, Model No. 146-04) contained
within a light and sound-attenuated chamber equipped with a ventilation
fan. Control of the shuttle box and recording of responses were
accomplished by means of standard electromechanical modules. Injection of
drugs i.p. and placement of the subjects into the shuttle cage were
followed by a 1-minute pre-session acclimation period. The first avoidance
trail was then initiated by activating a white light on the side of the
shuttle cage occupied by the subject. If the animal did not cross to the
other side of the chamber within 5 seconds (avoid), the grid floor under
the animal was electrified with 0.8 mA of scrambled shock (BRS/LVE, Model
No. 1531 shocker). Each subject received 120 avoidance trials during a 1
hour session. The results of the test are shown in Table II.
TABLE II
______________________________________
Dose, i.p. Avoidance Response
Compound (mg./kg.) N (Mean .+-. S.E.)
______________________________________
Saline -- 15 57.7 .+-. 4.1
BL-5485A 5 8 70.5 .+-. 10.4
BL-5485A 10 7 89.0 .+-. 3.3
BL-5485A 20 8 77.5 .+-. 6.7
Vehicle -- 24 46.0 .+-. 6.5
R-DOM 0.5 8 70.9 .+-. 4.8
R-DOM 1 8 36.1 .+-. 4.5
R-DOM 5 8 13.8 .+-. 7.3
______________________________________
Table II shows that BL-5485A increased avoidance response at all doses
tested while R-DOM increased avoidance response at one dosage and reduced
it at all other doses tested.
More specific tests also were employed to determine the presence or absence
of undesirable psychotomimetic activity in the compounds of this
invention. The test procedure is a modification of that described by
Wallach et al. in J. Pharmacol. Exp. Ther. 182, 145-154 (1972).
Various compounds are known to produce sensory distortions in man and
characteristic responses in the act. These psychotomimetic effects
(so-called hallucinogenic effects) in a compound under test are often
compared with the effects produced by
R-2-amino-1-(2,5-dimethoxy-4-methylphenyl)propane (usually referred to as
R-DOM). R-DOM is Compound 1 in the Table below, and was used as a
comparison standard in the test.
Adult female cats are housed in a large communal cage. On test day the
animals are transferred to the observation room and placed into separate
cages approximately 12-15 sq. feet in floor area with front wired door
allowing observation of the cats. The animals can see the experimenter and
each other across the room, and may have auditory and olfactory contact
among themselves in adjacent cages. The experimental subjects are
accustomed to this environment and settle down rapidly (< 30 min.) after
being brought in.
The test compounds (initially 10 mg./kg.) are administered subcutaneously
into the back of the neck. Following the dosing animals (N=2-4) are
observed for 3 hrs. but the scoring is usually done at 1 hr. which usually
corresponds to the time of peak effects induced by a compound. The effects
are scored utilizing a check list containing 12 categories, each of which
contains 2 sub-categories. Each sub-category is worth 1 point, giving a
maximum numerical score of 24. The categories and sub-categories are as
follows:
1. Body Posture: Arched Back/Stiff Tail
2. Extension of Limbs: Legs/Legs and Toes
3. Muscle Rigidity: Legs/Abdomen
4. Abnormal Leg Position/Immobility
5. Motor Coordination: Ataxia/Loss of Righting Reflex
6. Open Mouth/Protruding Tongue
7. Claws Out/Attempts To Bite or Claw
8. Teeth Baring/Hissing or Growling
9. Contact with Environment: Reduced/Absent
10. Piloerection: Tail/Back
11. Pupillary Constriction: Moderate/Extreme
12. Salivation/Emesis
In addition to the above-described tests in cats, a hyperthermia test in
rabbits was run with certain of the compounds. The ability of
hallucinogenic phenylalkylamines to increase the rectal temperature of
rabbits at low doses is well established (Aldous et al., 1974). The
hyperthermia test is not absolutely predictive of the presence of
psychotomimetic activity in a given compound, because this test detects
some compounds which prove to be lacking psychotomimetic activity upon
further evaluation. Nevertheless, this method provides a reliable
quantitative measure of relative psychotomimetic potencies of compounds in
a given series or once a given compound has been shown by other tests (as
is here the case) to have such activity.
The results of the foregoing test procedures are summarized in the
following Table III. It should be noted that the test compounds were
administered at 10 mg/kg while the comparison compounds, because of their
high psychotomimetic activity were administered at 1 mg/kg.
TABLE III
__________________________________________________________________________
##STR14##
Hyperthermia In
Test Dose In Cats
Effect In Cats
Rabbits (i.v. dose
Compound
R.sup.1
X Isomer
(mg./g.; s.c.)
(Score).sup.a
for 1.degree. C rise;
__________________________________________________________________________
mg./kg.)
A (R-DOM)
CH.sub.3
CH.sub.3
R 1 13.3 .+-. 1.8 (N = 4)
0.04 (0.04).sup.c
B (BL-3912A)
CH.sub.3
C.sub.2 H.sub.5
R 10 1.3 .+-. 0.5 (N = 4)
1.00
C Cl CH.sub.3
R, S
1 11.5 (N = 2; 10, 13).sup.b
0.01.sup.c
D Cl C.sub.2 H.sub.5
R 10 6.5 (N = 2; 6, 7)
not done
E Br CH.sub.3
R 1 17.5 (N = 2; 17, 18)
0.01.sup.c
F Br C.sub.2 H.sub.5
R 10 3.5 .+-. 0.9 (N = 4)
0.80
G CH.sub.3 S
CH.sub.3
R, S
1 11 (N = 2; 9, 13)
not done
H CH.sub.3 S
C.sub.2 H.sub.5
R 10 0 (N = 2; 0, 0)
not done
I CH.sub.2 OH
C.sub.2 H.sub.5
R 10 0.5 (N = 2; 0, 1)
not done
__________________________________________________________________________
.sup.a Total score in test described in text (mean .+-. S.E.M.).
.sup.b Any mean with less than three subjects have the individual values
in parentheses.
.sup.c Aldous, et al., J. Med. Chem., 17, 1100 - 1111 (1974).
The results obtained in these tests show that:
1. R-DOM produced marked psychotomimetic effects in the cat at 1 mg./kg..
2. Test Compounds C, E and G, having .alpha.-methyl substitution on the
aliphatic side-chain like R-DOM, have psychotomimetic effects in the cat
which are very similar (in terms of potency and quality) to that of R-DOM.
3. test Compounds B, D, F, H and I, having .alpha.-ethyl substitution on
the aliphatic side-chain, exhibit practically no psychotomimetic effects
(in the case of Compounds B, F, H and I) or a psychotomimetic effect which
is approximately 18 times weaker than R-DOM (in the case of Compound D).
4. the hyperthermia tests indicate that the psychotomimetic activity of
Compound F (.alpha.-ethyl substitution on the aliphatic side-chain) is 80
times weaker than its lower homolog (Compound E) and 20 times weaker than
R-DOM.
Thus, highly significant decreases in psychotomimetic properties (or the
virtual absence thereof) were demonstrated in the 4-chloro-, 4-bromo-,
4-methylthio- and 4-hydroxymethyl-compounds containing .alpha.-ethyl
substitution on the aliphatic side-chain, when compared with their
correspondingly 4-substituted lower homologs containing .alpha.-methyl
substitution on the aliphatic side-chain and/or with R-DOM.
The large decrease in psychotomimetic activity of the compounds of this
invention as compared with their corresponding lower homologs is
particularly surprising in view of Shulgin et al., Nature, 221, 537-541
(1969), cited above. Those authors compared the psychotomimetic activity
of a large number of substituted phenylalkylamines and found significant
changes in psychotomimetic activity with changes of substituents and
position of substitution on the phenyl ring, and also when increasing the
side chain from ethylamino to propylamino. Only two of their compounds
contained the same substitution in the phenyl ring, but with propylamino
and butylamino side chains, respectively, namely compounds of the formula
##STR15##
in which R was CH.sub.3 (their compound VIII) and C.sub.2 H.sub.5 (their
compound XLIII). The activities of these compounds (reported as Mescaline
Units; number of times as active as mescaline) were 2.2 M.U. for the
propylamino compound and <2 M.U. for the butylamino compound. The authors
stated that "there seems to be a decrease" in psychotomimetic activity in
going from propylamino to butylamino, but cautioned that the M.U. values
should not be considered accurate to closer than .+-. 25%.
The compound BL-3912A, a reference compound used in assaying the compounds
of this invention, has demonstrated remarkable and profound effects in
initial clinical studies in psychotics and normal senile geriatric
patients. For example, in psychotics demonstrating schizophrenia and manic
depression, a dose of 50 to 100 mg per day produced remarkable results in
that virtually all the patients so treated behaved in a near normal
manner. The catatonics relaxed, the withdrawn and fearful became sociable,
etc.
In the non-psychotic geriatric patient, at a dose of 25 to 50 mg/day,
BL-3912A had the effect of producing increased mental alertness and a
renewed interest in life characterized by increased sociability, mobility,
concern about appearance, dress and general well-being.
In two instances where the patient had Parkinson's disease, substantially
complete remission of the symptoms of the disease was observed at a dose
of 100 mg/day.
The ability of BL-3912A to increase the learning capacity of humans has
been confirmed in the initial clinical trials.
In view of all the above and in projecting the activity found in rodents to
humans, it is anticipated the compounds of the instant invention will
possess activity in man that is essentially identical to that seen for
BL-3912A.
The compounds I of the instant invention can be prepared by several
alternative methods as illustrated by the following diagramatic schemes:
##STR16##
wherein R.sup.1 is as defined above; followed by resolution into the D and
L isomers.
##STR17##
The isomer obtained has the same absolute configuration as the
.alpha.-methylbenzylamine employed.
##STR18##
EXAMPLE 1
(.+-.)-2-Amino-1-(2,5-dimethoxyphenyl)butane hydrochloride (1).
A suspension of 22.8 g (0.60 mole) of powdered LaH (lithium aluminum
hydride) in 400 ml of anhydrous THF (tetrahydrofuran) was stirred and
refluxed for 30 mins. A solution of 23.73 g (0.10 mole) of
1-(2,5-dimethoxyphenyl)-2-nitro-1-butane in 100 ml of anhydrous THF was
then added dropwise at reflux. After addition was complete, the mixture
was stirred and refluxed for 24 hrs. The reaction mixture was cooled to
0.degree. and then was decomposed by the cautious dropwise addition, with
rapid stirring, of 25 ml of H.sub.2 O and 100 ml of THF. The cooling bath
was removed and 25 ml of 10% NaOH solution, followed by 25 ml. of H.sub.2
O was added dropwise; the mixture was stirred until a granular white solid
was obtained. The inorganic salts were filtered and washed well with THF.
The filtrate was evaporated and the oil thus obtained was partitioned
between very dilute NaOH solution and Et.sub.2 O. The layers were
separated and the aqueous was extracted well with Et.sub.2 O. The combined
organic extracts were washed with H.sub.2 O and with saturated brine and
dried over anhydrous Na.sub.2 SO.sub.4. The desiccant was filtered, the
filtrate was evaporated to ca. 100 ml., and the salt was precipitated with
HCl (g). The solvent and excess HCl were removed under reduced pressure
and the residue was flashed down twice with EtOAc. The solid was
recrystallized from CH.sub.3 CN to give 9.71 of title product as colorless
crystals; mp 175.degree.-177.degree.. The filtrate was cooled and
saturated with HCl (g) to give an additional 4.0 g of product. The total
yield was 13.71 g (56%).
Anal. Calc'd. for C.sub.12 H.sub.19 NO.sub.2.HCl: C, 58.65; H, 8.20; N,
5.70; Cl, 14.42. Found: C, 58.65; H, 8.14; N, 5.91; Cl, 13.96.
EXAMPLE 2
1-(2,5-Dimethoxy-4-formylphenyl)-2-(N-phthalimido)butane.
a. R-isomer
A stirred solution, under N.sub.2, of 9.2 g (27 mmoles) of
R-1-(2,5-dimethoxyphenyl)-2-(N-phthalimido)butane in 75 ml of anhydrous
CH.sub.2 Cl.sub.2 was maintained at 0.degree. while 5 ml (8.63 g., 45
mmoles) of TiCl.sub.4 was added dropwise.
.alpha.,.alpha.-Dichloromethylmethyl ether (3.1 g., 27 mmoles) was then
added, dropwise, at 0.degree.. The reddish-brown solution was stirred at
0.degree. for 30 mins.; the temperature was raised to 25.degree. over a
period of 15 mins. The solution was then stirred at 35.degree. for 15
mins. and then refluxed for 15 mins. The reaction mixture was then poured
into 200 ml of ice H.sub.2 O. The layers were separated and the aqueous
was extracted with 3 portions of CH.sub.2 Cl.sub.2. The combined organic
solutions were washed with H.sub.2 O and saturated brine and dried over
anhydrous Na.sub.2 SO.sub.4. Removal of the solvent gave 9.6 g of greenish
oil. Upon seeding, the oil crystallized. Recrystallization from MeOH
H.sub.2 O gave 6.36 g. of title product as colorless crystals; mp
111.degree.-113.degree., [.alpha.].sub.D.sup.24.8 -258.6.degree. (c=1.0,
95% EtOH).
The product was initially obtained crystalline by chromatography of 2.0 g
of the crude oil on 150 g of neutral silica gel packed into a 4 cm column.
The column was eluted with Skellysolve B containing increasing proportions
of CH.sub.2 Cl.sub.2 and finally with pure CH.sub.2 Cl.sub.2. Evaporation
of the combined fractions containing the compound first eluted gave 1.35
g. (67%) of an oil which crystallized upon standing.
b. Racemic Mixture
Substitution in the procedure of step a for the
R-1-(2,5-dimethoxyphenyl)-2-(N-phthalamido)butane used therein of an
equimolar quantity of the racemic
1-(2,5-dimethoxyphenyl)-2-(N-phthalimido)butane produced the racemic title
compound.
The crude oily product was chromatographed on 1 kg of Woelm Activity III
neutral alumina packed into a 9 cm column. The column was eluted with
Skellysolve B containing progressively greater proportions of CH.sub.2
Cl.sub.2 (5, 10, 15, 25 and finally 50%). The product began to appear in
fractions containing 25% CH.sub.2 Cl.sub.2. The fractions were combined
and solvents evaporated to give 21.61 g of an oil. This was dissolved in
150 ml of hot 95% EtOH and the solution was incubated at room temperature
for 24 hrs. and then at -15.degree. for 48 hrs. Large, slightly greenish
crystals were obtained; 15.97 g (43%), mp 92.degree.-96.degree..
Anal. Calc'd. for C.sub.21 H.sub.21 NO.sub.5 : C, 68.65; H, 5.76; N, 3.81.
Found, R-isomer: C, 68,84; H, 5.77; N, 3.79. Found, racemic: C, 68.35; H,
5.80; N, 3.73.
EXAMPLE 3
1-(2,5-Dimethoxy-4-hydroxymethylphenyl)-2-(N-phthalimido)butane.
a. R-isomer
To a stirred solution of 3.75 g (10.2 mmoles) of
R-1-(2,5-dimethoxy-4-formylphenyl)-2-(N-phthalimido) butane in 100 ml of
anhydrous diglyme was added 3.57 g (17.3 mmoles) of lithium
tri-t-butoxyalumino hydride. The solution was stirred at room temperature
for 64 hrs. The mixture was poured onto ice and 5% HCl and the product was
extracted out with Et.sub.2 O. The organic solution was dried (anhydrous
Na.sub.2 SO.sub.4) and evaporated. The residue was stripped under high
vacuum to give 4.75 g of a light green oil.
The product was crystallized from EtOAc-Skellysolve B to give 2.13 g (57%
yield) of title product; mp 111-113.degree.; [.alpha.].sub.D.sup.24
-178.0.degree. (c=0.5, 95% EtOH).
b. Racemic Mixture
Substitution in the procedure of step a for the
R-1-(2,5-dimethoxy-4-formylphenyl)-2-(N-phthalimido) butane used therein
of an equimolar quantity of the racemic
1-(2,5-dimethoxy-4-formylphenyl)-2-(N-phthalimido)butane produced the
racemic title compound as colorless crystals from EtOAc-Skelly B; mp
89.degree.-91.degree..
Anal. Calc'd. for C.sub.21 H.sub.23 NO.sub.5 : C, 68.28; H, 6.28; N, 3.79.
Found, R-isomer: C, 67,98; H, 6.32; N, 3.80. Found, racemic: C, 67.86; H,
6.28; N, 3.78.
EXAMPLE 4
R-2-Amino-1-(2,5-dimethoxy-4-hydroxymethylphenyl)-butane (17).
A solution of 2.09 g (5.67 mmoles of
R-1-(2,5-dimethoxy-4-hydroxymethylphenyl)-2-(N-phthalimido)-butane and 2.1
ml (2.12 g., 66.2 mmoles) of 95% hydrazine in 75 ml of absolute EtOH was
refluxed for 2.5 hrs. The mixture was evaporated to dryness and the
residue was flashed down with 2 portions of toluene. The solid was
triturated with dil HCl and filtered. The filtrate was made basic with
NaOH solution and extracted with Et.sub.2 O. The combined extracts were
washed with H.sub.2 O and with saturated brine and dried (anhydrous
Na.sub.2 SO.sub.4). Evaporation of the solvent gave 1.12 g (82%) of a
colorless solid, the title compound, which was pure by glc. An analytical
sample was recrystallized from EtOAc-Skellysolve B; mp
85.degree.-86.degree..
Anal. Calc'd. for C.sub.13 H.sub.21 NO.sub.3 : C, 65.24; H, 8.85; N, 5.85.
Found: C, 65.21; H, 8.68; N, 5.55.
EXAMPLE 5
R-2-Amino-1-(4-bromo-2,5-dimethoxyphenyl)butane hydrochloride (11).
To a stirred solution of R-2-amino-1-(2,5-dimethoxyphenyl)butane (obtained
from 20.0 g (81.6 mmoles) of the corresponding hydrochloride in 150 ml of
glacial HOAc was added dropwise at -10.degree. C., a solution of 13.1 g.
(82 mmole) of Br.sub.2 in 50 ml. of glacial acetic acid. After addition
was complete, the solution was stirred at -10.degree. for 1 hr.; the
reaction mixture solidified. The cooling bath was removed and the reaction
mixture stood at room temperature for 40 hrs.
The mixture was diluted with 150 ml. of Et.sub.2 O and allowed to stand for
2 hrs. The white solid was filtered, washed with Et.sub.2 O, and dried to
give 22.65 g. of the hydrobromide salt of the product. The hydrobromide
was converted to the free base and the salt was formed with HCl (g) in
anhydrous Et.sub.2 O. The crude material was recrystallized from 1PA to
give 18.8 g (71%) of the title compound as colorless crystals; mp
240.degree.-242.degree.; [.alpha.].sub.365.sup.24 -58.0.degree. (c=1.0,
95% EtOH).
Anal. Calc'd. for C.sub.12 H.sub.18 BrNO.sub.2.HCl: C, 44.39; H, 5.90; N,
4.32. Found: C, 44.04; H, 5.63; N, 4.40.
EXAMPLE 6
2-Amino-1-(2,5-Dimethoxy-4-methylthiophenyl)butane hydrochloride.
A) 2,5-Dimethoxy-4-methylthiobenzaldehyde
A solution of 6.07 g (0.33 mole) of 1,4-dimethoxy-3-methylthiobenzene in 40
ml of dry CH.sub.2 Cl.sub.2 under N.sub.2 was cooled in an ice bath. To
the solution was added 13.02 g (0.05 mole) of SnCl.sub.4 over 2 mins.
Dichloromethyl methyl ether, 3.45 g (0.03 mole), was then added, dropwise,
over 5 mins., and stirring was continued with ice bath cooling for 15
mins. The reaction was allowed to warm to room temperature over 30 mins.
and was stirred for an additional 1 hr., at which time HCl evolution has
ceased. The mixture was slowly poured onto 15 g of ice in a separatory
funnel and the aqueous layer was separated and discarded. The organic
phase was washed with 3 .times. 25 ml of 3N HCl, 3 .times. 25 ml of
saturated NaCl solution, dried (Na.sub.2 SO.sub.4) and the solvent removed
in vacuo. The solid residue was dissolved in CH.sub.3 OH, and the solvent
removed in vacuo. The solid residue was dissolved in CH.sub.3 OH,
filtered, and recrystallized from CH.sub.3 OH-H.sub.2 O to give 5.86 g
(92% ) of yellow needles. TLC (thin layer chromatography) (silica
gel-CHCl.sub.3) showed only one product. An analytical sample, further
purified via the NaHSO.sub.3 adduct and recrystallized from CH.sub.3
OH-H.sub.2 O, had a mp of 99.degree.-100.degree. C. Nmr (Nuclear magnetic
resonance) (CDCl.sub.3) .delta.2.48 (s, 3H, SCH.sub.3), 3.92, 3.97, (2s,
6H, OCH.sub.3), 6.74, 7.29 (2s, 2H, ArH), 10.45 ppm (s, 1H, CHO).
The ylidinemalononitrile derivative of the title compound in step A was
prepared from equal weights of the benzaldehyde and malononitrile in
ethanol with triethylamine catalysis. After recrystallization from
ethanol, it had a mp 185.degree.-186.degree. C.
Anal. Calc'd. for C.sub.13 H.sub.12 N.sub.2 O.sub.2 S: C, 59.98; H, 4.62;
N, 10.76; S, 12.32. Found: C, 59.78; H, 4.83; N, 10.80, S, 11.96.
B) 1-[2,5-Dimethoxy -4-methylthiophenyl]-2-nitro-1-butene.
2,5-Dimethoxy-4-methylthiobenzaldehyde (2.3 g), 8.0 ml of 3-nitropropane
and 0.45 g of ammonium acetate are mixed in a flask fitted with a
condenser and placed on a steam bath for about 5 hours. The excess
3-nitropropane is removed in vacuo to produce orange crystals. The
crystals were washed with methanol and filtered to produce the crude
product. The crude product is dissolved in 140 ml of boiling ethanol and
cooled to produce brilliant orange crystals identified as the title
product, 1-[2,5-dimethoxy-4-methylthiophenyl]-2-nitro-1-butene.
C) R-2-Amino-1-(2,5-Dimethoxy-4-methylthiophenyl)butane Hydrochloride.
To a refluxing mixture of 1.4 g of lithium aluminum hydride in 10 ml of
anhydrous ether and 40 ml of dry THF is slowly added 1.8 g of
1-[2,5-dimethoxy-4-methylthiophenyl]-2-nitro-1-butene. An additional 20 ml
of THF is added to dissolve and wash all the nitro compound into the THF
mixture. Refluxing is continued for seven hours. The mixture is cooled and
ice water (3.4 ml) slowly added to decompose the excess lithium aluminum
hydride. When the decomposition is complete, the mixture is filtered and
the solid cake washed with THF. The filtrate is evaporated in vacuo to
produce crude 2-amino-1-(2,5-dimethoxy-4-methylthiophenyl)butane. The
crude is purified as the hydrochloride salt by recrystallization from
isopropanol.
Table IV below represents the physical data of the compounds prepared in
the examples, or by substitution in the examples or schemes with the
proper reagents for those equivalent reagents used therein.
TABLE IV
__________________________________________________________________________
##STR19##
Compd. Opt.
(t).sup.b
Calcd.
Anal.
C Found
No. X mp. .degree. C.
% Yield
Isomer
[.alpha.]365
C H N C H N
__________________________________________________________________________
1 H 175 - 177
56 (.+-.)
-- 58.65
8.20
5.70
58.43
8.44
5.80
2 H 140 - 142
83 R -44.2.degree.
58.65
8.20
5.70
58.72
8.42
5.80
(23)
3 H 141 - 144
42 S +44.3.degree.
58.65
8.20
5.70
58.75
8.38
5.61
(24)
4 Cl 215 - 216.5
53 R -60.8.degree.
51.44
6.83
5.00
51.57
6.95
5.12
(24)
5 Br 206 - 209
69 (.+-.)
-- 44.39
5.90
4.32
44.25
5.99
4.28
6 Br 240 - 242
71 R -57.0.degree.
44.39
5.90
4.32
44.04
5.63
4.40
(24)
7 Br 241 - 243
53 S +57.6.degree.
44.39
5.90
4.32
44.51
5.88
4.62
(24)
8 CH.sub.2 OH
87 - 90
74 (.+-.)
-- 65.24
8.84
5.85
65.52
8.68
5.61
9 CH.sub.2 OH
85 - 86
82 R -- 65.24
8.85
5.85
65.21
8.68
5.55
10
##STR20##
107.5 - 111.5
88 (.+-.)
-- 66.37
9.15
5.53
66.40
9.05
5.36
11 SCH.sub.3
220 - 221
65 (.+-.)
-- 53.50
7.60
4.80
53.49
7.61
4.64
12 SCH.sub.3
254 - 256
10.7
R -79.5.degree.
53.50
7.60
4.80
53.24
7.40
4.80
(24)
13 SCH.sub.3
254 - 256
29.4
S +79.9
53.50
7.60
4.80
53.31
7.37
4.73
__________________________________________________________________________
.sup.b. C = 1.0, 95% EtOH
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