Novel compounds for use as antidepressants, aphrodisiacs and adjunctive therapies in humans

16 Pages·2013·1.11 MB·English

US 20010053789A1
(19) United States
(12) Patent Application Publication (10) Pub. N0.2 US 2001/0053789 A1
Rosenfeld et al. (43) Pub. Date: Dec. 20, 2001
(54) NOVEL COMPOUNDS FOR USE AS Publication Classi?cation
ANTIDEPRESSANTS, APHRODISIACS AND
ADJ UNCTIVE THERAPIES IN HUMANS (51) Int. c1.7 ................... .. A61K 31/423, C07D 263/58;
c07c 217/76; c07c 43/20
(76) Inventors: Mark J. Rosenfeld, Salt Lake City, UT (52) US. Cl. ....................... .. 514/375, 548/221; 564/443;
(US); Patricia J. Berger, Cora, WY 568/650
(US); Norman C. Negus, Cora, WY
(Us) (57) ABSTRACT
Correspondence Address: Phenolic compounds With a phenolic molecule to Which are
covalently linked an oxygen-containing group, a nitrogen
MALLINCKRODT & MALLINCKRODT
or another oxygen containing group, and a Cl-C4 alkoxy
10 EXCHANGE PLACE, SUITE 510
group, obtainable from monocotyledonous plants, animals
SALT LAKE CITY, UT 84111 (US)
that eat such plants, or chemical synthesis, have been found
(21) Appl. No.: 09/834,592 to act as an antidepressant or otherWise a treatment for
bettering mood, a therapy for improving sexual desire or
(22) Filed: Apr. 13, 2001 performance, an adjunctive therapy for achieving Weight
loss, and an adjunctive therapy for substance abuse and
Related US. Application Data addiction. These compounds, at concentrations suitable for
human therapeutic use, may be obtained from plants such as
(63) Non-provisional of provisional application No. corn in their early groWth stages and from parts of animals
60/196,829, ?led On Apr. 13, 2000. such as the velvet antler tips of deer and elk.
Patent Application Publication Dec. 20, 2001 Sheet 1 of 8 US 2001/0053789 A1
FIG. 1. Generalized chemical structures and parameters de?ning the compounds of
invention.
Formula 1 -- A compound according to the formula
Wherein "R" represents CI-C4 alkoxy, With the proviso that R is in the 4 or 5 ring
position;
Wherein "n" represents one ofthe integers 0,1 or 2;
Wherein "A" represents -OH, -NH2, or NHCR', Where R' represents C1-C4 alkyl;
Or a pharmaeeutieally acceptable salt thereof.
Formula II ~— A compound according to the formula
' O
1\
Rn yzo
3
N
l
H
Wherein "R“ represents C1—C4 alkoxy, with the proviso that R is in the 5 or 6 ring
position;
Wherein "n" represents one ofthe integer O, l or 2;
Or a pharmaeeutically acceptable salt thereof.
Patent Application Publication Dec. 20, 2001 Sheet 2 0f 8 US 2001/0053789 A1
FIG. 1. Continued
Formula III -- A compound according to the formula
1 2GB
R l
3'c
4 \
N/ \
O
OH
Wherein "R" represents C1-C4 alkoxy, with the proviso that R is in the 6 or 7 ring
position;
Wherein “n" represents one of the integer 0, l or 2;
Or a pharmaceutically acceptable salt thereof.
Patent Application Publication Dec. 20, 2001 Sheet 3 0f 8 US 2001/0053789 A1
FIG. 2. Chemical structures for representative members of Formulas I, II and III. That
members of Formulas I, II and Ill have similar effects on vertebrates is evidenced by
Example 1. Such forms a foundation for members of Formulas I, II and III to be
collectively uni?ed as compounds of invention.
1. 2-amino—5-meth0xyphenol [Member of Formula I]
CH3O OH
‘NH2
2. 6-mcth0xy-2-benzoxazolinone [Member of Formula II]
CH0 0
3. 2,4-dihydroxy-7-methoxy-l,4-(2H)-benzoxazin-3-one [Member of Formula
III]
CHBO O OH
Patent Application Publication Dec. 20, 2001 Sheet 4 0f 8 US 2001/0053789 A1
FIG. 2. Continued,
4. 2-hydr0xy-4-meth0xyacetanili(1e [Member of Formula I]
CH3O :: :NOHH- C—CH
H 3
o
54 2-hydr0xy-4—eth0xyacetanilide [Member of Formula I]
CZHSOM OH
NH CH3
6. 5—methoxy-2~benzoxazolinone [Member of Formula lll]
O\c=o
N/
CHBO
7. 2~hydr0Xy-5-meth0xyacetanilide [Member of Formula I]
OH
’ : - —CH
CH3O NH S 3
O
Patent Application Publication Dec. 20, 2001 Sheet 5 of 8 US 2001/0053789 A1
FIG. 3. Effect of injecting compounds of invention, members of Formulas I, II and III as
de?ned in FIG. 1 and FIG. 2, intraperitoneally for 3 consecutive days and sacri?cing 24
hours after the last injection on uterine Weight in the montane vole, Microtus montanus.
The results indicate similar physiological responses for compounds belonging to the
compounds of invention. "Formula Numeral" refers to the formula categories speci?ed
in FIG. 1. Average uterine weight is in milligrams.
Formula Number of Average
Compound Injected Numeral Animals Uterine Weight
Control (Propylene Glycol) --- 8 15.2 d: 2.4
6-methoxy-2-benzoazolinone I1 11 27.7 :1: 5.6 *
5-methoxy-Z-benzoxazolinone III 8 20.0 d: 4.7 **
2-hydroxy-4-mcthoxyacetanilide I 8 23.1 i 2.7 *
2-hydroxy-4—ethoxyacetanilide I 8 22.2 i 3.9 *
2-amino-5-methoxyphenol I 8 21.8 d: 3.5 *
2-hydroxy-S-methoxyacetanilide l 8 21.1 i 4.4 ***
2-amino-4-methoxyphenol I 8 22.2 :1: 3.2 *
* Signi?cantly different from control at P < 0.001
** Signi?cantly different from control at P = 0.015
*** Signi?cantly different from control at P = 0.004

Patent Application Publication Dec. 20, 2001 Sheet 8 0f 8 US 2001/0053789 A1
FIG. 6. 6-MBOA in Dried Velvet Antler from Elk, Cervus elaphus.
Drying
Animal Origin Tip or Other Method 6-MBOA
' (mg/g dry Wight)
Wapiti Canada Tip Air 2.5
Wapiti Canada Tip Air 2.8
Wapiti Canada Other Air 0.3
Red Deer New
Zealand Tip Freeze 1.9
Red Deer New
Zealand Other Freeze 0.5
US 2001/0053789 A1 Dec. 20, 2001
NOVEL COMPOUNDS FOR USE AS rodents. In 1981, 6-MBOA became the ?rst naturally occur
ANTIDEPRESSANTS, APHRODISIACS AND ring compound in a plant veri?ed as impacting seasonal
ADJ UNCTIVE THERAPIES IN HUMANS reproductive cycling. Since then, a substantial body of Work
has accumulated on 6-MBOA as an initiator of seasonal
BACKGROUND OF THE INVENTION breeding and an effector of population siZe for many rodents
[0001] 1. Field and a feW birds. Compounds related to and possibly co
occurring With 6-MBOA remain unexplored in this regard.
[0002] The invention is in the ?eld of treating depression,
[0009] 6-MBOA is passed from adult females to offspring
sexual dysfunction, substance abuse or addiction, and in
inducing Weight loss, compounds used in such treatments, during gestation and lactation, With increased groWth and
and the making of such compounds. greater gonadal siZe in the recipient young. Juveniles rely on
the interaction of maternal photoperiod history and
[0003] 2. State of the Art 6-MBOA to time the onset of groWth and puberty. Adults fed
[0004] An estimated 35-40 million living Americans Will a diet containing 6-MBOA produce more female progeny.
suffer major depressive episodes, and many more Will expe When 6-MBOA is fed to pregnant females, gonadal devel
opment in the male offspring is enhanced.
rience lesser bouts. Of the approximately 17.5 million
Americans With ongoing depressions, about 9.2 million are [0010] For rodents, the inhibitory effects of melatonin on
at a clinically debilitating level. Clinical depression is char groWth and reproduction are blocked partially by 6-MBOA
acteriZed by a list of symptoms that last over a long time (GoWer et al., “Reproductive responses of male Microtus
span. It is a serious problem that is usually or initially caused montanus to photoperiod, melatonin, and 6-MBOA”, Jour
by outside stressors. As stresses escalate or persist, a chemi nal of Pineal Research, 8:297-312, 1990). 6-MBOA may
cal imbalance can result. Clinical depression can be very obstruct melatonin at the melatonin receptors or act inde
debilitating both physically and mentally and even lead to pendently to check melatonin action (SWeat et al., “Utero
death by means of suicide. HoWever, lost productivity and tropic 6-methoxybenZoxaZolinone is an adrenergic agonist
relationship problems are also consequences of lesser and melatonin analog, Molecular and Cellular Endocrinol
depressions. At present, antidepressant medications are the ogy, 57:131-138, 1988). The high melatonin levels that
cornerstones of treating depression, especially those that are accumulate in the presence of 6-MBOA may cause desen
at least moderately severe. Although depressed people tend sitiZation of melatonin receptors (Daya et al., “Effect of
to improve When treated With antidepressants, many do not 6-methoxy-2-benZoxaZolinone on the activities of rat pineal
respond to the ?rst one. Such individuals may eventually N-acetyltransferase and hydroxyindole-O-methyltransferase
bene?t from a different antidepressant or a combination of and on melatonin production”, Journal of Pineal Research,
antidepressants. 8157-66, 1990), but not in all rodents (Anderson et al.,
“Effects of melatonin and 6-methoxybenZoxaZolinone on
[0005] Sexual dysfunction is a pervasive disorder. In the
photoperiodic control of testis siZe in adult male golden
overall population, 43 percent of Women and 31 percent of
hamsters”, Journal of Pineal Research, 5:351-65, 1988).
men betWeen the ages of 18 and 59 repeatedly experience it.
This compound stimulates rather than inhibits melatonin
Sexual dysfunction includes lacking interest in sex, prob
biosynthesis and does not prevent stimulation of melatonin
lems With arousal, not enjoying sex, and anxiety about
synthesis by norepinephrine (YuWiler et al., “Effects of
sexual performance. Indeed, feeling good in general has
6-methoxy-2-benZoxaZolinone on the pineal melatonin gen
signi?cant impact on sexual function, With those people
erating system. J. Pharmacol. Exp. Ther 233:45-50, 1985).
unhappy or depressed more likely to experience dif?culties.
6-MBOA acts at both the a- and b-adrenergic receptors
Arousal problems affect over 20 million American males,
(Daya et al., “Effect of 6-methoxy-2-benZoxaZolinone on the
about tWo in 10 adult men, With such dif?culties often
activities of rat pineal N-acetyltransferase and hydroxyin
associated With or accompanied by some sort of depression.
dole-O-methyltransferase and on melatonin production”,
MeanWhile, prescription antidepressants actually exacerbate
Journal of Pineal Research, 8:57-66, 1990), and stimulates
the situation, since a frequent side effect of their use is sexual
adenylcyclase activity in the pineal, hypothalamus and pitu
dysfunction. In fact, sexual response diminishes in up to
itary glands (SWeat et al., “Uterotropic 6-methoxybenZox
75% of prescription antidepressant users.
aZolinone is an adrenergic agonist and melatonin analog,
[0006] There is a need for treatments to reduce depression Molecular and Cellular Endocrinology, 57:131-138, 1988).
or otherWise better mood With an accompanying enhance Certain responses to 6-MBOA, like uterine hypertrophy, can
ment of sexual response or desire, or at least no sexual be duplicated With estrogen, but 6-MBOA is not an estro
dysfunction. genic compound (GoWer, “Endocrine effects of the naturally
occurring reproductive stimulant, 6-methoxybenZoxaZoli
[0007] Prior Work on the compounds of the invention has
none”, Ph.D. Thesis, University of Utah, Salt Lake City,
solely been on 6-methoxy-2,3-benZoxaZolinone (6-MBOA).
Utah, 116p., 1990). Also, 6-MBOA increases the rate of
Its role in strengthening the resistance of monocotyledonous
synthesis of follicle stimulating hormone (Butterstein et al.,
plants against a Wide range of insect pests has been much
“The plant metabolite 6-methoxybenZoxaZolinone interacts
studied. 6-MBOA and its chemical precursors also have
With follicle-stimulating hormone to enhance ovarian
allelopathic properties that inhibit root and shoot groWth in
groWth”, Biology of Reproduction, 39:465-71, 1988) and
competing species. Furthermore, it has antimicrobial prop
pituitary prolactin (Vaughan et al., “Hormonal consequences
erties. 6-MBOA appears constitutively during early stages of
of subcutaneous 6-methoxy-2-benZoxaZolinone pellets or
groWth, localiZed in those tissues most exposed to microbial
injections in prepubertal male and female rats”, Journal of
and insect attack.
Reproduction and Fertility, 83:859-66, 1988). Hypothalamic
[0008] It had been long suspected that compounds in luteiniZing hormone-releasing hormone contents and pitu
plants affect the seasonal reproductive output of Wild itary gland Weights are greater for at least one rodent species