U.S. patent application number 11/615396 was filed with the patent office on 2007-12-27 for use of etodolac to treat hyperplasia.
Invention is credited to Dennis A. Carson, Mary Patricia Corr, Lorenzo M. Leoni.
Application Number | 20070299042 11/615396 |
Document ID | / |
Family ID | 32030827 |
Filed Date | 2007-12-27 |
United States Patent
Application |
20070299042 |
Kind Code |
A1 |
Carson; Dennis A. ; et
al. |
December 27, 2007 |
USE OF ETODOLAC TO TREAT HYPERPLASIA
Abstract
The present invention provides a therapeutic method to treat
non-malignant diseases characterized by the excessive tissue
growth, e.g., hyperplastic diseases, comprising administering to a
mammal (e.g., human) afflicted with excessive tissue growth, an
effective amount of a derivative of an indole compound of formula
(I):formula (I): ##STR1## wherein R.sup.1 is lower alkyl,
(hydroxy)lower alkyl, lower alkenyl, lower alkynyl, lower
cycloalkyl, phenyl, benzyl or 2-thienyl; R.sup.2, R.sup.3, R.sup.4
and R.sup.5 are the same or different and are each hydrogen or
lower alkyl; each R.sup.6 is individually hydrogen, lower alkyl,
hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower
alkanoyloxy, nitro or halo, R.sup.7 is hydrogen, lower alkyl or
lower alkenyl, X is oxy and thio, Y is carbonyl,
--(CH.sub.2).sub.1-3--, --(C.sub.1-C.sub.3)alkyl(CO)--, or
--(CH.sub.2).sub.1-3SO.sub.2--; Z is hydroxy, lower alkoxy,
(C.sub.2-C.sub.4)acyloxy, --N(R.sup.8)(R.sup.9), phenylamino,
(.omega.-(4-pyridyl)(C.sub.2-C.sub.4 alkoxy),
(.omega.-((R.sup.8)(R.sup.9) amino)(C.sub.2-C.sub.4 alkoxy), an
amino acid ester of (.omega.-(HO)(C.sub.2-C.sub.4))alkoxy,
--N(R.sup.8)CH(R.sup.8)CO.sub.2H, 1'-D-glucuronyloxy, --SO.sub.3H,
--PO.sub.4H.sub.2, --N(NO)(OH), --SO.sub.2NH.sub.2,
--PO(OH)(NH.sub.2), --OCH.sub.2CH.sub.2N(CH.sub.3).sub.3.sup.+, or
tetrazolyl; wherein R.sup.8 and R.sup.9 are each H,
(C.sub.1-C.sub.3)alkyl or together with N are a 5- or 6-membered
heterocyclic ring comprising 1-3 N(R.sup.8), S or nonperoxide O; n
is 0, 1, 2, or 3; wherein R.sup.8 and R.sup.9 are each H,
(C.sub.1-C.sub.3)alkyl or together with N are a 5- or 6-membered
heterocyclic ring comprising 1-3 N(R.sup.8), S or nonperoxide O;
each alkyl or phenyl group of R.sup.1, R.sup.2, R.sup.3,
R.sup.4,R.sup.5, R.sup.6, R.sup.7 and Z is optionally substituted
with 1, 2, or 3 (C.sub.1-C.sub.4)alkyl groups; or a
pharmaceutically acceptable salt thereof.
Inventors: |
Carson; Dennis A.; (La
Jolla, CA) ; Leoni; Lorenzo M.; (San Diego, CA)
; Corr; Mary Patricia; (San Diego, CA) |
Correspondence
Address: |
SCHWEGMAN, LUNDBERG & WOESSNER, P.A.
P.O. BOX 2938
MINNEAPOLIS
MN
55402
US
|
Family ID: |
32030827 |
Appl. No.: |
11/615396 |
Filed: |
December 22, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10667208 |
Sep 19, 2003 |
7211599 |
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11615396 |
Dec 22, 2006 |
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60412193 |
Sep 19, 2002 |
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Current U.S.
Class: |
514/171 ;
514/252.16; 514/411 |
Current CPC
Class: |
A61K 31/18 20130101;
A61K 31/675 20130101; A61K 31/4745 20130101; A61K 31/407 20130101;
A61K 31/496 20130101; A61K 31/12 20130101; A61P 35/00 20180101;
A61P 43/00 20180101; A61K 31/56 20130101; A61K 31/40 20130101; A61K
31/7052 20130101; A61K 31/50 20130101 |
Class at
Publication: |
514/171 ;
514/252.16; 514/411 |
International
Class: |
A61K 31/407 20060101
A61K031/407; A61K 31/496 20060101 A61K031/496; A61K 31/56 20060101
A61K031/56; A61P 35/00 20060101 A61P035/00 |
Goverment Interests
GOVERNMENT FUNDING
[0002] This invention was made with the assistance of the National
Institutes of Health under Grant Nos. AR47360 and GM23200. The U.S.
Government has certain rights in this invention.
Claims
1. A therapeutic method for treatment of non-malignant diseases
characterized by the excessive growth of tissue comprising
administering to a patient in need of said therapy, an effective
amount of a compound of formula (I): ##STR5## wherein R.sup.1 is
lower alkyl, (hydroxy)lower alkyl, lower alkenyl, lower alkynyl,
lower cycloalkyl, phenyl, benzyl or 2-thienyl; R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are the same or different and are each hydrogen
or lower alkyl; each R.sup.6 is independently hydrogen, lower
alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy,
lower alkanoyloxy, nitro or halo; R.sup.7 is hydrogen, lower alkyl
or lower alkenyl, X is oxy and thio, Y is carbonyl,
--(C.sub.1-C.sub.3)alkyl(CO)--, --(CH.sub.2).sub.1-3--, or
--(CH.sub.2).sub.1-3SO.sub.2--; Z is hydroxy, lower alkoxy,
(C.sub.2-C.sub.4)acyloxy, --N(R.sup.8)(R.sup.9), phenylamino,
(.omega.-(4-pyridyl)(C.sub.2-C.sub.4 alkoxy),
(.omega.-((R.sup.8)(R.sup.9) amino)(C.sub.2-C.sub.4 alkoxy), an
amino acid ester of (.omega.-(HO)(C.sub.2-C.sub.4))alkoxy,
--N(R.sup.8)CH(R.sup.8)CO.sub.2H, 1'-D-glucuronyloxy, --SO.sub.3H,
--PO.sub.4H.sub.2, --N(NO)(OH), --SO.sub.2NH.sub.2,
--PO(OH)(NH.sub.2), --OCH.sub.2CH.sub.2N(CH.sub.3).sub.3.sup.+, or
tetrazolyl; wherein R.sup.8 and R.sup.9 are each H,
(C.sub.1-C.sub.3)alkyl or together with N are a 5- or 6-membered
heterocyclic ring comprising 1-3 N(R.sup.8), S or nonperoxide O; n
is 0, 1, 2, or 3; and each alkyl or phenyl group of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and Z is
optionally substituted with 1, 2, or 3 (C.sub.1-C.sub.4)alkyl
groups; or a pharmaceutically acceptable salt thereof; wherein the
disease comprises fibroplastic dysplasia of the breast or
fibroplastic growth in the uterus or cervix or gastric hyperplastic
polyposis.
2. A therapeutic method for treatment of mammalian hyperplastic
cells comprising administering to a patient in need of said therapy
a chemotherapeutic agent in combination with an effective amount of
a compound of formula (I): ##STR6## wherein R.sup.1 is lower alkyl,
(hydroxy)lower alkyl, lower alkenyl, lower alkynyl, lower
cycloalkyl, phenyl, benzyl or 2-thienyl; R.sup.2, R.sup.3, R.sup.4
and R.sup.5 are the same or different and are each hydrogen or
lower alkyl; each R.sup.6 is independently hydrogen, lower alkyl,
hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower
alkanoyloxy, nitro or halo; and n is 1-3; R.sup.7 is hydrogen,
lower alkyl or lower alkenyl, X is oxy and thio, Y is carbonyl,
--(C.sub.1-C.sub.3)alkyl(CO)--, --(CH.sub.2).sub.1-3--, or
--(CH.sub.2).sub.1-3SO.sub.2--; Z is hydroxy, lower alkoxy,
(C.sub.2-C.sub.4)acyloxy, --N(R.sup.8)(R.sup.9), phenylamino,
(.omega.-(4-pyridyl)(C.sub.2-C.sub.4 alkoxy),
(.omega.-((R.sup.8)(R.sup.9) amino)(C.sub.2-C.sub.4 alkoxy), an
amino acid ester of (.omega.-(HO)(C.sub.2-C.sub.4))alkoxy,
--N(R.sup.8)CH(R.sup.8)CO.sub.2H, 1'-D-glucuronyloxy, --SO.sub.3H,
--PO.sub.4H.sub.2, --N(NO)(OH), --SO.sub.2NH.sub.2,
--PO(OH)(NH.sub.2), --OCH.sub.2CH.sub.2N(CH.sub.3).sup.3+, or
tetrazolyl; wherein R.sup.8 and R.sup.9 are each H,
(C.sub.1-C.sub.3)alkyl or together with N are a 5- or 6-membered
heterocyclic ring comprising 1-3 N(R.sup.8), S or nonperoxide O;
wherein each alkyl or phenyl group of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and Z is optionally substituted
with 1, 2, or 3 (C.sub.1-C.sub.4)alkyl groups; or a
pharmaceutically acceptable salt thereof; wherein the hyperplastic
cells are associated with fibroplastic dysplasia of the breast or
fibroplastic growth in the uterus or cervix or gastric hyperplastic
polyposis.
3. (canceled)
4. (canceled)
5. (canceled)
6. The method of claim 1 or 2, wherein the compound of formula (I)
is administered orally.
7. The method of claims 1 or 2, wherein the compound of formula (I)
is administered in combination with an androgen inhibitor, or an
.alpha.-1 adrenergic receptor blocker.
8. The method of claim 7, wherein the androgen inhibitor is
finasteride.
9. The method of claim 7, wherein the .alpha.-1 adrenergic receptor
blocker is phenoxybenzamine, prozosin, terazin, doxazosin, or
tamsulosin.
10. The method of claim 1 or 2, wherein Z is the L-valine or
L-glycine ester of 2-hydroxyethoxy.
11. The method of claim 1 or 2, wherein Z is
N-morpholinoethoxy.
12. The method of claim 1 or 2, wherein each R.sup.8 is H, CH.sub.3
or i-Pr.
13. The method of claim 1 or 2, wherein Z is
OCH.sub.2CH.sub.2N(CH.sub.3).sub.3.
14. The method of claim 1 or 2, wherein the compound of formula (I)
is etodolac.
15. The method of claim 1 or 2, wherein the compound of formula (I)
is the R(-)isomer.
16. The method of claim 1 or 2 wherein at least one R.sup.6 is
halo.
17. The method of claim 16 wherein at least one R.sup.6 is
bromo.
18. The method of claim 17 wherein n is 1.
19. The method of claim 1 or 2 wherein the compound of formula (I)
is ##STR7##
20. The method of claim 19 wherein X is O, R.sup.1 is ethyl and Y-Z
is --CH.sub.2CH.sub.2OH.
21. The method of claim 19 wherein R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 are hydrogen.
22. The method of claim 19 wherein the compound of formula (I) is
the R-isomer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority of U.S. provisional patent
application Ser. No. 60/412,193, filed Sep. 19, 2002, which is
incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0003] Hyperplastic diseases are non-malignant conditions that
represent an unmet medical need. Typically, these diseases are
characterized by the uncontrolled growth of cells. In many patients
these cells are not malignant and the hyperplastic cells do not
lead to the development of cancer. Thus, the hyperplastic cells are
not treated with the conventional chemotherapeutic agents useful
against malignant diseases.
[0004] One example of a hyperplastic disease is benign prostatic
hypertrophy (BPH). This disease is characterized by the abnormal
growth of the prostate. Substantial data currently exist showing
that prostate volume increases with age in a measurable group of
middle-aged and older men, following a post-pubertal plateau. In
addition, the incidence and prevalence of prostate disease increase
with age, and are very high in elderly men (>40%). Other
non-malignant hyperplastic diseases include, but are not limited to
fibroplastic dysplasia of the breast, fibroplastic growths in the
uterus or cervix, and gastric hyperplastic polyposis. In many
patients, hyperplastic diseases do not lead to the development of
cancer, and are not treated with the conventional chemotherapeutic
agents used against malignant diseases.
[0005] Therefore, a continuing need exists for new, potent, and
selective agents useful to prevent detrimental effects or control
the growth of hyperplastic cells.
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides a therapeutic
method to treat non-malignant diseases characterized by the
excessive tissue growth, e.g., hyperplastic diseases, comprising
administering to a mammal (e.g., human) afflicted with excessive
tissue growth, an effective amount of a derivative of an indole
compound of formula (I): ##STR2##
[0007] wherein R.sup.1 is lower alkyl, (hydroxy)lower alkyl, lower
alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyl or
2-thienyl;
[0008] R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or
different and are each hydrogen or lower alkyl;
[0009] each R.sup.6 is independently hydrogen, lower alkyl,
hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower
alkanoyloxy, nitro or halo;
[0010] R.sup.7 is hydrogen, lower alkyl or lower alkenyl, X is oxy
and thio, Y is carbonyl, --(C.sub.1-C.sub.3)alkyl(CO)--,
--(CH.sub.2).sub.1-3--, or --(CH.sub.2).sub.1-3SO.sub.2--;
[0011] Z is hydroxy, lower alkoxy, (C.sub.2-C.sub.4)acyloxy,
--N(R.sup.8)(R.sup.9), phenylamino,
(.omega.-(4-pyridyl)(C.sub.2-C.sub.4 alkoxy),
(.omega.-((R.sup.8)(R.sup.9) amino)(C.sub.2-C.sub.4 alkoxy), an
amino acid ester of (.omega.-(HO)(C.sub.2-C.sub.4))alkoxy,
--N(R.sup.8)CH(R.sup.8)CO.sub.2H, 1'-D-glucuronyloxy, --SO.sub.3H,
--PO.sub.4H.sub.2, --N(NO)(OH), --SO.sub.2NH.sub.2,
--PO(OH)(NH.sub.2), --OCH.sub.2CH.sub.2N(CH.sub.3).sub.3.sup.+, or
tetrazolyl;
[0012] wherein R.sup.8 and R.sup.9 are each H,
(C.sub.1-C.sub.3)alkyl or together with N are a 5- or 6-membered
heterocyclic ring comprising 1-3 -N(R.sup.8)-, S or nonperoxide O;
n is 1-3; and
[0013] each alkyl or phenyl group of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and Z is optionally substituted
with 1, 2, or 3 (C.sub.1-C.sub.4)alkyl groups; or a
pharmaceutically acceptable salt thereof.
[0014] In addition, the invention includes a therapeutic method for
treatment of mammalian hyperplastic cells comprising administering
to a patient in need of said therapy a chemotherapeutic agent in
combination with an effective amount of a compound of formula
(I).
[0015] In another embodiment, the compound of formula (I) is
etodolac, R(-)-etodolac, or an analog thereof, effective to inhibit
or control the growth of the hyperplastic cells of said mammal. The
viability of the hyperplastic cells is reduced selectively, while
maintaining the viability of normal cells.
[0016] Thus, the invention provides a therapeutic method for the
treatment of a human or other mammal afflicted with a hyperplastic
disease such as, for example, benign prostate hyperplasia (BPH),
fibroplastic dysplasia of the breast, fibroplastic growth in the
uterus or fibroplastic growth in the cervix wherein an effective
amount of etodolac or an analog thereof is administered to an
afflicted subject undergoing treatment with one or more
chemotherapeutic agents, wherein the hyperplastic cells are
rendered more susceptible to the chemotherapeutic agent(s).
[0017] The present invention also provides a method of increasing
the susceptibility of human hyperplastic cells to a
chemotherapeutic agent comprising contacting the cells with an
effective sensitizing amount of a compound of formula (I), e.g.,
etodolac, or an analog thereof.
[0018] Further it is applicants' belief that the present invention
can provide a synergistic effect when an effective amount of a
compound of formula (I), e.g., etodolac, or an analog thereof is
administered in combination with a chemotherapeutic agent.
[0019] In one aspect, the compounds of formula (I) are administered
in conjunction with one or more chemotherapeutic agents effective
against BPH, fibroplastic dysplasia of the breast, fibroplastic
growths in the uterus or cervix, and gastric hyperplastic
polyposis. Examples of chemotherapeutic agents include androgen
inhibitors, such as, for example, finasteride, and the like;
.alpha.-1 adrenergic receptor blockers such as, for example,
phenoxybenzamine, prozosin, terazin, doxazosin, tamsulosin, and the
like. Thus, the compound of formula (I) can be used alone, or
preferably, in combination with a chemotherapeutic agent.
[0020] The invention also provides a compound of formula I for use
in medical therapy (preferably for use in treating hyperplastic
diseases as well as the use of a compound of formula I for the
manufacture of a medicament for the treatment of a pathological
condition or symptom in a mammal, such as a human, which is
associated with hyperplastic diseases.
[0021] The present invention is based on the discovery by the
inventors that a compound of formula (I), such as, for example,
R-etodolac reduces the overall size of the prostates of mice
treated with these compounds. The treated mice were found to have
prostates that had a reduction of the overall size of the prostates
when compared to untreated mice.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The compounds useful in the methods of the invention include
a compound of formula (I): ##STR3## [0023] wherein R.sup.1 is lower
alkyl, (hydroxy)lower alkyl, lower alkenyl, lower alkynyl, lower
cycloalkyl, phenyl, benzyl or 2-thienyl; R.sup.2, R.sup.3, R.sup.4
and R.sup.5 are the same or different and are each hydrogen or
lower alkyl; each R.sup.6 is individually hydrogen, lower alkyl,
hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower
alkanoyloxy, nitro or halo, R.sup.7 is hydrogen, lower alkyl or
lower alkenyl, X is oxy and thio, Y is carbonyl,
--(CH.sub.2).sub.1-3--, --(C.sub.1-C.sub.3)alkyl(CO)--, or
--(CH.sub.2).sub.1-3SO.sub.2--; Z is hydroxy, lower alkoxy,
(C.sub.2-C.sub.4)acyloxy, --N(R.sup.8)(R.sup.9), phenylamino,
(.omega.-(4-pyridyl)(C.sub.2-C.sub.4 alkoxy),
(.omega.-((R.sup.8)(R.sup.9) amino)(C.sub.2-C.sub.4 alkoxy), an
amino acid ester of (.omega.-(HO)(C.sub.2-C.sub.4))alkoxy,
--N(R.sup.8)CH(R.sup.8)CO.sub.2H, 1'-D-glucuronyloxy, --SO.sub.3H,
--PO.sub.4H.sub.2, --N(NO)(OH), --SO.sub.2NH.sub.2,
--PO(OH)(NH.sub.2), --OCH.sub.2CH.sub.2N(CH.sub.3).sub.3.sup.+, or
tetrazolyl; wherein R.sup.8 and R.sup.9 are each H,
(C.sub.1-C.sub.3)alkyl or together with N are a 5- or 6-membered
heterocyclic ring comprising 1-3 N(R.sup.8), S or nonperoxide O; n
is 0, 1, 2, or 3; wherein R.sup.8 and R.sup.9 are each H,
(C.sub.1-C.sub.3)alkyl or together with N are a 5- or 6-membered
heterocyclic ring comprising 1-3 N(R.sup.8), S or nonperoxide O;
each alkyl or phenyl group of R.sup.1, R.sup.2, R.sup.3,
R.sup.4,R.sup.5, R.sup.6, R.sup.7 and Z is optionally substituted
with 1, 2, or 3 (C.sub.1-C.sub.4)alkyl groups; or a
pharmaceutically acceptable salt thereof.
[0024] The following definitions are used, unless otherwise
described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy,
alkenyl, alkynyl, etc. denote both straight and branched groups;
but reference to an individual radical such as "propyl" embraces
only the straight chain radical, a branched chain isomer such as
"isopropyl" being specifically referred to.
[0025] As used herein, with respect to hyperplasia, the term
"inhibition" or "inhibit" includes both the reduction in cellular
proliferation, blockage of cellular proliferation, or killing some
or all of the hyperplastic cells. Thus, the term can be used in
both the context of a prophylactic treatment to prevent development
of hyperplasia or as a treatment that will block, or slow the
growth of hyperplastic cells.
[0026] As used herein "treating" includes (i) preventing a
pathologic condition from occurring (e.g., prophylaxis) or symptoms
related to the same; (ii) inhibiting the pathologic condition or
arresting its development or symptoms related to the same; and
(iii) relieving the pathologic condition or symptoms related to the
same.
[0027] As used herein "in combination with" or "administered in
conjunction with" includes simultaneous administration, separate
administration or sequential administration of the active agents in
a manner that allows the beneficial effect desired to occur.
[0028] As used herein, an "analog of etodolac" includes the
compounds of formula (I) and pharmaceutically acceptable salts
thereof.
[0029] Specific and preferred values listed below for radicals,
substituents, and ranges, are for illustration only; they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents. The compounds of the invention
include compounds of formula I having any combination of the
values, specific values, more specific values, and preferred values
described herein.
[0030] Specifically, lower alkyl refers to (C.sub.1-C.sub.6)alkyl
and includes methyl, ethyl, propyl, isopropyl, butyl, iso-butyl,
sec-butyl, pentyl, 3-pentyl, or hexyl; (C.sub.3-C.sub.6)cycloalkyl
includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; lower
alkoxy refers to (C.sub.1-C.sub.6)alkoxy and includes methoxy,
ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy,
pentoxy, 3-pentoxy, or hexyloxy; lower alkenyl refers to
(C.sub.1-C.sub.6)alkenyl and includes vinyl, allyl, 1-propenyl,
2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl,
2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, or 5-hexenyl; lower alkynyl refers to
(C.sub.1-C.sub.6)alkynyl and includes ethynyl, 1-propynyl,
2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,
2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl,
3-hexynyl, 4-hexynyl, or 5-hexynyl; (hydroxy)lower alkyl refers to
(hydroxy)(C.sub.1-C.sub.6)alkyl and includes hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl,
3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl,
5-hydroxypentyl, 1-hydroxyhexyl, or 6-hydroxyhexyl; lower
alkanoyloxy refers to (C.sub.2-C.sub.6)alkanoyloxy and includes
acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy,
or hexanoyloxy.
[0031] The term "amino acid," comprises the residues of the natural
amino acids (e.g., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His,
Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and
Val) in D or L form, as well as unnatural amino acids (e.g.,
phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline,
gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic
acid, statine, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid,
penicillamine, ornithine, citruline, -methyl-alanine,
para-benzoylphenylalanine, phenylglycine, propargylglycine,
sarcosine, and tert-butylglycine). The term also comprises natural
and unnatural amino acids bearing a conventional amino protecting
group (e.g., acetyl or benzyloxycarbonyl), as well as natural and
unnatural amino acids protected at the carboxy terminus (e.g., as a
(C.sub.1-C.sub.6)alkyl, phenyl or benzyl ester or amide; or as an
-methylbenzyl amide). Other suitable amino and carboxy protecting
groups are known to those skilled in the art (See for example, T.
W. Greene, Protecting Groups In Organic Synthesis; Wiley: New York,
1981, and references cited therein). An amino acid can be linked to
the remainder of a compound of formula I through the carboxy
terminus, the amino terminus, or through any other convenient point
of attachment, such as, for example, through the sulfur of
cysteine. [0032] A specific value for R.sup.1 is hydrogen or lower
alkyl. [0033] A more specific value for R.sup.1 is ethyl. [0034] A
specific value for R.sup.2 is hydrogen. [0035] A specific value for
R.sup.3 is hydrogen. [0036] A specific value for R.sup.4 is
hydrogen. [0037] A specific value for R.sup.5 is hydrogen. [0038] A
specific value for R.sup.6 is hydrogen or alkyl. [0039] A more
specific value for R.sup.6 is hydrogen. [0040] A more specific
value for R.sup.6 is ethyl. [0041] A specific value for n is 1.
[0042] A specific value for R.sup.7 is hydrogen. [0043] A specific
value for Y is --(CH.sub.2).sub.1-3C(O). [0044] A more specific
value for Y is --(CH.sub.2)C(O). [0045] A specific value for Z is
OH., OCH.sub.2CH.sub.2N(CH.sub.3).sub.3.sup.+, N-morpholinoethoxy,
L-valine ester of 2-hydroxyethoxy or L-glycine ester of
2-hydroxyethoxy. [0046] A more specific value for Z is OH [0047] A
more specific value for Z is
OCH.sub.2CH.sub.2N(CH.sub.3).sub.3.sup.+. [0048] A more specific
value for Z is N-morpholinoethoxy. [0049] A more specific value for
Z is the L-valine ester of 2-hydroxyethoxy or L-glycine ester of
2-hydroxyethoxy. [0050] A specific value for X is oxy. [0051]
Specific compounds of the invention are the R(-) isomer of the
compounds having formula (I).
[0052] A specific compound of the invention, Etodolac
(1,8-diethyl-1,3,4,9-tetrahydro[3,4-6]indole-1-acetic acid) is a
NSAID of the pyranocarboxylic acid class that was developed in the
early 1970s. See, C. A. Demerson et al., Ger. Pat. No. 2,226,340
(Am. Home Products); C. A. Demerson, et al. U.S. Pat. No.
3,843,681; R. R. Martel et al., Can. J. Pharmacol., 54, 245 (1976).
Its structure is depicted as formula (II), below, wherein (*)
denotes the chiral center. See also, The Merck Index, (11th ed.),
at page 608. ##STR4##
[0053] The pharmacokinetics of etodolac have been extensively
reviewed by D. R. Brocks et al., Clin. Pharmacokinet., 26, 259
(1994). Etodolac is marketed as the racemate. The absolute
configurations of the enantiomers were found to be S-(+) and R-(-),
which is similar to that for most other NSAIDs. However, Demerson
et al., J. Med. Chem., 26, 1778 (1983) found that the
S(+)-enantiomer of etodolac possessed almost all of the
anti-inflammatory activity of the racemate, as measured by
reduction in paw volume of rats with adjuvant polyarthritis, and
prostaglandin synthetase inhibitory activity of the drug. No
anti-inflammatory activity was discernible with the
R(-)-enantiomer, and it is not converted significantly to the S(+)
enantiomer in vivo. Hence, R(-) etodolac is not a NSAID. However,
as disclosed below, R(-) etodolac paradoxically was found to have
potent activity against hyperplastic cells that is at least
equivalent to that of the S(+) enantiomer.
[0054] Etodolac possesses several unique disposition features due
to their stereoselective pharmacokinetics. In plasma, after the
administration of RS-etodolac, the concentrations of the "inactive"
R-enantiomer of etodolac are about 10-fold higher than those of the
active S-enantiomer, an observation that is novel among the chiral
NSAIDs. See, D. R. Brocks et al., Clin. Pharmacokinet., 26, 259
(1994). After a 200 mg dose in six elderly patients, the maximum
plasma concentration of the R-enantiomer was about 33 .mu.M. In
contrast, the maximum concentration of the S-enantiomer was 5-fold
lower. The typical dosage of the racemic mixture of etodolac is 400
mg BID, and the drug has an elimination half-life between 6-8
hours. Moreover, it is believed that the administration of the
R-enantiomer alone will not display the side effects associated
with cyclooxygenase (COX) inhibitors, such as ulcers and renal
insufficiency, and thus can be given at considerably higher
dosages. In addition, the compounds of formula (I) can be dissolved
in water and other aqueous carriers at substantially high
concentrations.
[0055] Compounds of the invention can be prepared as disclosed in
U.S. Pat. No. 3,843,681, U.S. patent application Ser. No.
09/313,048, Ger. Pat. No. 2,226,340 (Amer. Home Products), R. R.
Martel et al., Can. J. Pharmacol., 54, 245 (1976); Demerson et al.,
J. Med. Chem., 19, 391 (1976); PCT application Ser. No.
US/01/24978, and Rubin (U.S. Pat. No. 4,337,760).
[0056] The resolution of racemic compounds of formula (I) can be
accomplished using conventional means, such as the formation of a
diastereomeric salt with a optically active resolving amine; see,
for example, "Stereochemistry of Carbon Compounds," by E. L. Eliel
(McGraw Hill, 1962); C. H. Lochmuller et al., J Chromatog., 113,
283 (1975); "Enantiomers, Racemates and Resolutions," by J.
Jacques, A. Collet, and S. H. Wilen, (Wiley-Interscience, New York,
1981); and S. H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 33,
2725 (1977). For example, the racemates of etodolac has been
resolved by fractional crystallization of RS-etodolac using
optically active 1 -phenylethylamine. HPLC has been used to
determine racemic etodolac and enantiomeric ratios of etodolac and
two hydroxylated metabolites in urine (U. Becker-Scharfenkamp et
al., J. Chromatog., 621, 199 (1993)). B. M. Adger et al. (U.S. Pat.
No. 5,811,558), disclosed the resolution of etodolac using
glutamine and N(C.sub.1-C.sub.4 alkyl)-glutamine salts.
[0057] The magnitude of a prophylactic or therapeutic dose of
racemic or R-etodolac in the treatment of a hyperplastic disease,
i.e., BPH, will vary with the progression of the disease, such as
the location of the growth to be treated, the chemotherapeutic
agent(s) or other therapy used, and the route of administration.
The dose, and perhaps the dose frequency, will also vary according
to the age, body weight, and response of the individual patient. In
general, the total daily dose range for racemic or R-etodolac, for
the conditions described herein, is from about 50 mg to about 5000
mg, in single or divided doses. Preferably, a daily dose range
should be about 100 mg to about 4000 mg, most preferably about
1000-3000 mg, in single or divided doses, e.g., 750 mg every 6 hr
of orally administered R(-)-etodolac. This can achieve plasma
levels of about 500-750 .mu.M, which was shown to reduce the size
of the prostate in the animal models. In managing the patient, the
therapy should be initiated at a lower dose and increased depending
on the patient's global response. It is further recommended that
infants, children, patients over 65 years, and those with impaired
renal or hepatic function initially receive lower doses, and that
they be titrated based on global response and blood level. It may
be necessary to use dosages outside these ranges in some cases.
Further, it is noted that the clinician or treating physician will
know how and when to interrupt, adjust or terminate therapy in
conjunction with individual patient response. The terms "an
effective amount" or "an effective sensitizing amount" are
encompassed by the above-described dosage amounts and dose
frequency schedule.
[0058] The compounds of formula (I) can also be prepared in the
form of their pharmaceutically acceptable salts or their
non-pharmaceutically acceptable salts. The non-pharmaceutically
acceptable salts are useful as intermediates for the preparation of
pharmaceutically acceptable salts. Pharmaceutically acceptable
salts are salts that retain the desired biological activity of the
parent compound and do not impart undesired toxicological effects.
Examples of such salts are (a) acid addition salts formed with
inorganic acids, for example hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, nitric acid and the like; and salts
formed with organic acids such as, for example, acetic acid, oxalic
acid, tartaric acid, succinic acid, maleic acid, fumaric acid,
gluconic acid, citric acid, malic acid, ascorbic acid, benzoic
acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid,
naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic
acid, naphthalenedisulfonic acid, polygalacturonic acid, and the
like; and (b) salts formed from elemental anions such as chlorine,
bromine, and iodine. Preferred carboxylic acid salts are those of
hydrophilic amines, such as glucamine or
N-(C.sub.1-C.sub.4)alkylglucamine (see, Adger et al. (U.S. Pat. No.
5,811,558)).
[0059] Pharmaceutically acceptable salts may be obtained using
standard procedures well known in the art, for example by reacting
a sufficiently basic compound such as an amine with a suitable acid
affording a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium or lithium) or alkaline earth metal (for
example calcium) salts of carboxylic acids can also be made.
[0060] Any suitable route of administration may be employed for
providing the patient with an effective dosage of etodolac, ie.,
R(-)etodolac. For example, oral, rectal, parenteral (subcutaneous,
intravenous, intramuscular), intrathecal, transdermal, and like
forms of administration may be employed. Dosage forms include
tablets, troches, dispersions, suspensions, solutions, capsules,
patches, and the like. The etodolac may be administered prior to,
concurrently with, or after administration of chemotherapy, or
continuously, ie., in daily doses, during all or part of, a
chemotherapy regimen, such as, for example, treatment with an
androgen, or .alpha.-1 adrenergic receptor blockers. The etodolac,
in some cases, may be combined with the same carrier or vehicle
used to deliver the anti-cancer chemotherapeutic agent.
[0061] Thus, the present compounds may be systemically
administered, e.g., orally, in combination with a pharmaceutically
acceptable vehicle such as an inert diluent or an assimilable
edible carrier. They may be enclosed in hard or soft shell gelatin
capsules, may be compressed into tablets, or may be incorporated
directly with the food of the patient's diet. For oral therapeutic
administration, the active compound may be combined with one or
more excipients and used in the form of ingestible tablets, buccal
tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
and the like. Such compositions and preparations should contain at
least 0.1% of active compound. The percentage of the compositions
and preparations may, of course, be varied and may conveniently be
between about 2 to about 60% of the weight of a given unit dosage
form. The amount of active compound in such therapeutically useful
compositions is such that an effective dosage level will be
obtained.
[0062] The tablets, troches, pills, capsules, and the like may also
contain the following: binders such as gum tragacanth, acacia, corn
starch or gelatin; excipients such as dicalcium phosphate; a
disintegrated agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, fructose, lactose or aspartame or
a flavoring agent such as peppermint oil of wintergreen, or cherry
flavoring may be added. When the unit dosage form is a capsule, it
may contain, in addition to materials of the above type, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify
the physical form of the solid unit dosage form. For instance,
tablets, pills, or capsules may be coated with gelatin, wax,
shellac or sugar and the like. A syrup or elixir may contain the
active compound, sucrose or fructose as a sweetening agent, methyl
and propylparabens as preservatives, a dye and flavoring such as
cherry or orange flavor. Of course, any material used in preparing
any unit dosage form should be pharmaceutically acceptable and
substantially non-toxic in the amounts employed. In addition, the
active compound may be incorporated into sustained-release
preparations and devices.
[0063] The active compound may also be administered intravenously
or intraperitoneally by infusion or injection. Solutions of the
active compound or its salts can be prepared in water, optionally
mixed with a non-toxic surfactant. Dispersions can also be prepared
in glycerol, liquid polyethylene glycols, triacetin, and mixtures
thereof and in oils. Under ordinary conditions of storage and use,
these preparations contain a preservative to prevent the growth of
microorganisms.
[0064] The pharmaceutical dosage forms suitable for injection or
infusion can include sterile aqueous solutions or dispersions or
sterile powders comprising the active ingredient, which are adapted
for the extemporaneous preparation of sterile injectable or
infusible solutions or dispersions, optionally encapsulated in
liposomes. In all cases, the ultimate dosage form must be sterile,
fluid and stable under the conditions of manufacture and storage.
The liquid carrier or vehicle can be a solvent or liquid dispersion
medium comprising, for example, water, ethanol, a polyol (for
example, glycerol, propylene glycol, liquid polyethylene glycols,
and the like), vegetable oils, non-toxic glyceryl esters, and
suitable mixtures thereof. The proper fluidity can be maintained,
such as, for example, by the formation of liposomes, by the
maintenance of the required particle size in the case of
dispersions or by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars, buffers or sodium chloride. Prolonged absorption
of the injectable compositions can be brought about by the use in
the compositions of agents delaying absorption, such as, for
example, aluminum monostearate and gelatin.
[0065] Sterile injectable solutions are prepared by incorporating
the active compound in the required amount in the appropriate
solvent with various other ingredients enumerated above, as
required, followed by filter sterilization. In the case of sterile
powders for the preparation of sterile injectable solutions, the
preferred methods of preparation are vacuum drying and the freeze
drying techniques, which yield a powder of the active ingredient
plus any additional desired ingredient present in the previously
sterile-filtered solutions.
[0066] Useful dosages of the compounds of formula I can be
determined by comparing their in vitro activity, and in vivo
activity in animal models. Methods for the extrapolation of
effective dosages in mice, and other animals, to humans are known
in the art; for example, see U.S. Pat. No. 4,938,949.
[0067] The invention will be further described by reference to the
following detailed example.
EXAMPLE 1
TRAMP Animal Model
[0068] The transgenic adenocarcinoma mouse prostate (TRAMP) mouse,
was used to evaluate the effect of R-etodolac on prostate cancer
progression. The etodolac was compounded into the diet at 312 ppm
(low dose) and 1250 ppm (high dose) and the animals were treated
for 18 weeks. At necoscopy, the urogenital system was removed and
weighed. The prostate lobes, seminal vesicles, lungs, liver, and
periaortic lymph nodes were preserved and sectioned for
histological evaluation and graded on a 1-6 scale for degree of
hyperplasia/neoplasia/carcinoma. TABLE-US-00001 TABLE 1 Tabel 1.
Average weight of dissected prostate lobes. Weights are given as
average .+-. standard deviation Average weigh (g) Control Low Dose
High Dose Anterior Prostate 0.095 .+-. .052 0.062 .+-. 0.033 0.076
.+-. 0.012 Ventral prostate 0.023 .+-. .009 0.024 .+-. 0.017 0.014
.+-. 0.001 Lateral Prostate 0.026 .+-. 0.11 0.015 .+-. 0.001 0.016
.+-. 0.003 Dorsal Prostate 0.169 .+-. 0.167 0.062 .+-. 0.027 0.053
.+-. 0.013 Total Weigh average 3.261 .+-. 4.9 1.804 .+-. 2.38 0.160
.+-. 0.022
[0069] TABLE-US-00002 TABLE 2 Table 2. Histopathological evaluation
of the prostate in TRAMP mice treated with R-etodolac. Average
Ante- Dor- Ven- mouse Overall Number Group rior sal Lateral tral
Staging Mean 19 Control 5 5 5 5 5.0 4.7 46 Control 4 6 5 5 5.0 86
Control 6 6 6 6 6.0 88 Control 4 5 4 3 4.0 90 Control 4 6 6 3 4.8
91 Control n.a. 4 4 3 4.3 101 Control 3 5 3 4 3.8 78 Low dose 3 4 3
6 4.0 4.3 79 Low dose 4 6 6 6 5.5 81 Low dose 4 5 4 3 4.0 85 Low
dose 4 4 3.5 3 3.6 95 Low dose 4 5 5 4 4.5 96 Low dose 6 6 6 6 6.0
25 High dose 3 4 4 4 3.8 3.3* 27 High dose 4 4 3 2 3.3 30 High dose
3 4 3 3 3.3 41 High dose 3 4 3 3 3.3 72 High dose 3 4 4 3 3.5 75
High dose 3 3 3 3 3.0 *statistically significant from control
group, p < 0.005, Mann Whitney t test
[0070] TABLE-US-00003 TABLE 3 Tabel 3: Definition of the
histopathological grades for the TRAMP model. Grade Definition
Description 1 Normal Prostate In the normal prostate, epithelial
cells comprising the glands are uniform in size and orientation,
and their nuclei are small and well-defined. 2 Early
intraepithelial Early neoplastic changes are evident as an increase
in epithelial neoplasia nuclear-to-cytoplasmic ratio and "tufting
up" of the epithelial layer or layers into the glandular lumen.
This lesion is analogous to a low grade PIN lesion in humans. 3
Advanced This lesion is analogous to a more-advanced PIN lesion in
humans intraepithelial neoplasia and is associated with extensive
infolding of epithelial cell layers into the lumen and an increase
in both mitotic and/or apoptotic figures. 4 Well-differentiated
This grade of cancer is represented by early invasion/penetration
adenocarcinoma of the glandular basement membrane by tumor cells
that extend into the stromal compartment. 5 Moderately
Moderately-differentiated cancer is represented by tumor
differentiated formation of primitive glands lacking an obvious
lumen. Tumor adenocarcinoma cells comprising these glands have lost
their tall secretory appearance. 6 Poorly differentiated This most
severe grade of prostate cancer is represented by tumors
adenocarcinoma composed of sheets and cords of highly pleiomorphic
anaplastic tumor cells.
[0071] It was found that for the TRAMP mice treated with R-etodolac
at the highest dose there was a reduction of the overall size of
the prostates (Table 1). In addition, histogical analysis
demonstrated that R-etodolac was able to affect the progression of
the disease, maintaining the animals in a pre-cancerous stage
characterized by a low amount of mitotic events and reduced levels
of morphological alterations (Table 2). The inhibition of the
prostate enlargement may be due to the specific inhibition of
proliferation of cells that are not yet neoplastic, but only
hyperplastic. No other effects in any other tissues were observed
in the TRAMP mice treated with R-etodolac.
[0072] All of the publications and patent documents cited
hereinabove are incorporated by reference herein. The invention has
been described with reference to various specific and preferred
embodiments and techniques. However, it should be understood that
many variations and modifications may be made while remaining
within the spirit and scope of the invention.
* * * * *