Compounds for use in weight loss and appetite suppression in

33 Pages·2013·2.07 MB·English

US007507731B2
(12) Ulllted States Patent (10) Patent N0.: US 7,507,731 B2
Rosenfeld et a]. (45) Date of Patent: *Mar. 24, 2009
(54) COMPOUNDS FOR USE IN WEIGHT LOSS 5,322,849 A 6/1994 Yous et al.
AND APPETITE SUPPRESSION IN HUMANS 5,326,775 A 7/1994 Yous et al.
5,386,034 A 1/1995 Yous et al.
(75) Inventors: Mark J. Rosenfeld, Draper, UT (US); i gfusg e1'M_ kal d tal
Scott R‘ Forsberg’ Layton’ UT (Us) 5,,78,6, 367 A 7/1998 Osh0iuro1 ety aSl. -1cae.
(73) Assignee: Seroctin Research & Technology, Inc., $1 geilleutiettagl'
lt Lake Cit UT (US) ’ ’ e 1° ‘e I
Se 3’, RE37,478 E 12/2001 StrupcZeWskl et al.
* _ _ _ _ _ 6,331,660 B1 * 12/2001 Chomet et al. ............ .. 800/278
( ) Nome? 31111160110 any dlsclalmer, the term Ofthls 6,667,308 B2 * 12/2003 Rosenfeld et al. ...... .. 514/2305
patent is extended or adjusted under 35 2004/003g909 A1 2/2004 Chawan
U.S.C. 154(b) by 0 days.
FOREIGN PATENT DOCUMENTS
This patent is subject to a terminal dis- CH 683593 M1994
Clalmer- DE 670 584 1/1939
EP 0070016 A1 1/1983
(21) APP1- NO-I 11/393,312 EP 0478446 4/1992
_ EP 0 506 539 9/1992
(22) F1led: Mar. 30, 2006 EP 0506539 9/1992
(65) Prior Publication Data OTHER PUBLICATIONS
US 2006/0173001 A1 Aug. 3, 2006 Ortego et al., “Effect of DIMBOA on Growth and Digestive Physi
ology of Sesamia nonagrioides (Lepidoptera: Noctuidae) Larvae”,
Related US. Application Data Journal of Insect Physiology, vol. 44, No. 2, pp. 95-101 (1998).*
(62) D1_v 1_ s1_ on of appl1_ cat1_ 0n No. 10/718,232, ?led on Nov. &Hotbtjpe:c/t/:WpWwWy._b4i o16c y1 c(.20o0r6g)/,*M ETA/NEW-IMAGE?type:PATHWAY
20, 2003 Klun et al., “Concentration of Two 1,4-BenZoXaZinones in Dent Corn
at Various Stages of Development of the Plant and Its Relation to
(51) Int. Cl. Resistance of the Host Plant to the European Corn Borer”, Journal of
A61K 31/535 (2006.01) Economic Entomology, vol. 62, No. 1, pp. 214-222- (1969).*
A61K 36/899 (2006.01) (Continued)
(52) US. Cl. ............... .. 514/230.5; 514/230.8; 514/909;
424/750 Primary ExamineriKevin E Weddington
(58) Field of Classi?cation Search ............ .. 514/2305, (74) Attorney, Agent, or Firmiworkman Nydegger
514/2308, 909
See application ?le for complete search history. (57) ABSTRACT
(56) References Cited Phenolic compounds With a phenolic molecule to Which are
covalently linked an oxygen-containing group, a nitrogen or
US. PATENT DOCUMENTS
another oxygen containing group, and a C1 -C4 alkoxy group,
3,862,180 A * 1/1975 Jernow et a1. ............... .. 544/64 obtainable from monocotyledonous plants, or by chemical
3,882,107 A * 5/1975 Tipton et a1. ................ .. 544/64 synthesis, have been found to act as Weight loss agents, appe
4,457,872 A 7/1984 Beriger et al. tite suppressants, mood enhancers and adj unctive therapy for
4,558,060 A 12/1985 Caignard et a1. arthritis, sleep apnea, ?bromyalgia, diabetes and hyperglyce
4,778,792 A 10/1988 Lesieur et al.
mia. Additional chemical compounds of the present invention
4,960,778 A 10/1990 Lesieur et al.
may include benZoXaZinoids-cyclic hydroxyamic acids, lac
5,071,863 A 12/1991 Ito et a1.
5,112,843 A 5/1992 Bjostad, III et a1. tams, and corresponding glucosides, Which may serve as
5,147,883 A 9/1992 Aichaioui et al. precursors to phenolic compounds. The phenolic compounds
5,179,091 A 1/1993 Lesieur et al. and precursors of phenolic compounds of the present inven
5,182,278 A 1/1993 Lesieur et al. tion, at concentrations suitable for human therapeutic use,
5,196,434 A 3/1993 Tavernet et al. may be obtained from monocotyledonous plants such as corn
5,240,919 A 8/1993 Yous et a1. in their early groWth states Which are timely harvested for
5,292,735 A 3/1994 Sugimoto et al. optimum yield.
5,296,477 A 3/1994 Taverne et al.
5,300,507 A 4/1994 Yous et a1.
5,322,843 A 6/1994 Yous et a1. 29 Claims, 17 Drawing Sheets
US 7,507,731 B2
Page 2
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US. Patent Mar. 24, 2009 Sheet 1 0f 17 US 7,507,731 B2
Generalized Chemical structures and parameters de?ning the compounds of the
invention.
Formula I — A chemical composition according to the formula
OH
A
Wherein "R" represents C1-C4 alkoxy, with the proviso that R is in the 4 or 5 ring position;
Wherein "n“ represents one of the integers 0,1 or 2;
Wherein "A" represents -OH, -NH,, or NHCR', where R‘ represents C1-C4 alkyl;
or pharrnaceutically acceptable salts thereof.
Formula II - A chemical composition according to the formula
Wherein "R" represents Cl-C4 alkoxy, with the proviso that R is in the 5 or 6 ring position;
Wherein "n" represents one of the integers 0, l or 2;
or pharmaceutically acceptable salts thereof.
FIG. 1
US. Patent Mar. 24, 2009 Sheet 2 of 17 US 7,507,731 B2
Formula lII -- A chemical composition according to the formula
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 integers 0, 1 or 2;
or phannaceutically acceptable salts thereof.
H
o\ P
CH
R |
[Pl/cs0
OH
FIG. 1 (continued)
US. Patent Mar. 24, 2009 Sheet 3 0f 17 US 7,507,731 B2
Formula IV -- A chemical composition according to the formula
/
‘a’,
A _
Wherein "R" represents CFC4 alkoxy, with the proviso that R is in the 4 or 5 ring position;
Wherein "n“ represents one of the integers 0, 1 or 2;
Wherein “B” represents H and “A” represents -OH, -NH2, or NHCR’, Where R’ denotes C1-C4
alkyl; and “B A” represents
0 H
II |
C|)H O OH
H I
('3 C N
H
or pharmaceutically acceptable salts thereof.
FIG. 1 (continued)
US. Patent Mar. 24, 2009 Sheet 4 of 17 US 7,507,731 B2
Chemical structures for representative members of Formulas I, II and III. That members
of Formulas I, II and III 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 under Formula
IV as compounds of the invention.
1. Z-amino-S-methoxyphenol [Member of Formula I]
CH3O\ OH
NH2
2. 6-meth0xy-2-benzoxazo1in0ne [Member of Formula II]
CH3O 0\ :0
@I ,N/
H
3. 2,4-dihydroxy-7-methoxy-1,4-(2H)-benzoxazin-3-one [Member of Formula III]
H
CH0 0 P
3
C
OH
FIG. 2
US. Patent Mar. 24, 2009 Sheet 5 0f 17 US 7,507,731 B2
4. 2-hydroxy-4-methoxyacetani1ide [Member of Formula I]
CHSQK OH
5. 2-hydroxy-4-eth0xyacetanilide [Member of Formula I]
6. 5-methoxy-2-benzoxazolinone [Member of Formula III]
0
@I \ ‘0
CH3O/ [1/
H
FIG. 2 (continued)
US. Patent Mar. 24, 2009 Sheet 6 0f 17 US 7,507,731 B2
7. 2-hydroxy-5-methoxyacetanilide [Member of Formula I]
OH
CH3O NH—CH;_CH3
0
FIG. 2 (continued)
US. Patent
Mar. 24, 2009 Sheet 7 0f 17 US 7,507,731 B2
Effect of injecting compounds of the 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 a?er
the last injection on uterine weight in the montane vole, Microtus montanus. The results indicated
similar physiological responses for compounds belonging to the compounds of the invention.
“Formula Numeral” refers to the formula categories speci?ed in FIG. 1. Average uterine weight
is in milligrams.
Compound Injected Formula Number of Average
Numeral Animals Uterine Weight
Control (Propylene Glycol) --- 8 15.2:t2.4
6-methoxy-2-benzoxazolinone II 1 l 27.7:t5.6*
S-methoxy-Z-benzoxazolinone III 8 20.0i4.7**
2-hydroxy-4-methoxyacetanilide I 8 23 . 11:2 . 7 *
2-hydroxy-4-ethoxyacetanilide I 8 22.2:l:3.9*
2- amino-S-methoxyphenol I 8 21 . 8:l:3 .5 *
2-hydroxy-S-methoxyacetanilide I 8 21 . 1:l:4.4***
2- aInino-4-methoxyphenol I 8 22.2:l: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
FIG. 3