FAVORABLE MODULATION OF HEALTH-RELATED QUALITY OF LIFE AND HEALTH-RELATED QUALITY-ADJUSTED TIME-TO-PROGRESSION OF DISEASE IN PATIENTS WITH PROSTATE CANCER

MODULATION FAVORABLE DE LA QUALITE DE LA VIE EN LIAISON AVEC LA SANTE ET DE LA PROGRESSION DANS LE TEMPS DE LA MALADIE AJUSTEE PAR LA QUALITE DE LA VIE LIEE A LA SANTE CHEZ DES PATIENTS ATTEINTS DU CANCER DE LA PROSTATE

English Abstract

Disclosed herein is a method for favorably modulating the health-related
quality of life and the health-related quality-adjusted time-to-disease
progression in a patient having prostate cancer and a method for measuring of
the health-related quality-adjusted time-to-disease progression.

French Abstract

La présente invention concerne une méthode qui permet de moduler de manière favorable la qualité de la vie en liaison avec la santé et la progression de la maladie dans le temps ajustée par la qualité de la vie liée à la santé chez un patient atteint d'un cancer de la prostate et une méthode de mesure de la progression dans le temps de la maladie ajustée par la qualité de la vie liée à la santé.

Claims

WHAT IS CLAIMED IS:

1. A method for sustaining the health-related quality of life in a patient
with
prostate cancer comprising administering thereto a therapeutically effective
amount of an
endothelin receptor antagonist.

2. A method for improving the health-related quality of life in a patient with
prostate cancer comprising administering thereto a therapeutically effective
amount of an
endothelin receptor antagonist.

3. A method for sustaining the health-related quality-adjusted time-to-
progression of disease in a patient with prostate cancer comprising
administering thereto a
therapeutically effective amount of an endothelin receptor antagonist.

4. A method for improving the quality-adjusted time-to-progression of disease
in a patient with prostate cancer comprising administering thereto a
therapeutically
effective amount of an endothelin receptor antagonist.

5. A method for extending the quality-adjusted time-to-progression of disease
in a patient with prostate cancer comprising administering thereto a
therapeutically
effective amount of an endothelin receptor antagonist.

6. The method of claims 1, 2, 3, 4, or 5 in which the health-related quality
of
life comprises domains of physical functioning, emotional functioning,
social/family
functioning, role functioning, cognitive functioning, self-perception, and
other domains
relating to patients with prostate cancer, the other domains comprising pain,
fatigue,
nausea and vomiting, change in appetite, dyspnea, sleep disturbance, diarrhea,
constipation, urinary function, and change in weight, the domains being
assessed by the
patient.

7. The method of claims 1, 2, 3, 4, or 5 in which the endothelin receptor
antagonist is administered at or near the beginning of prostate cancer
progression.



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The method of claims 1, 2, 3, 4, or 5 in which the endothelin receptor
antagonist is administered toward the end of prostate cancer progression.
9. The method of claims 1, 2, 3, 4, or 5 in which the therapeutically
effective
amount of the endothelin receptor antagonist is between about 1 mg per day to
about 25
mg per day.
10. The method of claim 9 in which the endothelin receptor antagonist is
administered once or twice per day without missing a day.
11. The method of claim 10 in which the endothelin receptor antagonist is an
endothelin A receptor antagonist.
12. The method of claim 11 in which the endothelin A receptor antagonist
is a compound having formula (I)-a
Image
or a compound having formula (I)-a with the relative or absolute
stereochemistry shown in
the compound having formula (I)-b
Image
or a therapeutically acceptable salt, prodrug, or salt of prodrug of either,
in which
R1 and R2 are independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heteroaryl, or
alkyl substituted with one cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, -
OH, or
-O(alkyl) substituent;
R3 is R4SO2R5- or R4C(O)R5-;
R4 is alkyl, -(CH2)alkenyl, -(CH2)alkynyl, -NR6R7, alkyl independently
substituted
with one or two cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -OH, -
O(alkyl), -NH2,
-NH(alkyl), or -N(alkyl)2 substituents, or alkenyl independently substituted
with one or



30


two cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -OH, -O(alkyl), -NH2, -
NH(alkyl), or
-N(alkyl)a substituents;
R5 is a covalent bond, alkylene, -N(H)(alkylene)-, or -N(alkyl)(alkylene)-,
the latter two of which are drawn from left or right, and
R6 and R7 are independently hydrogen, alkyl, -(CH2)alkenyl, -(CH2)alkynyl,
cycloalkyl, aryl, or alkyl independently substituted with one or two
cycloalkyl, aryl,
heteroaryl, heterocyclyl, halo, -OH, -O(alkyl), -OCH2CF3, -OCH2CF2CF3, -NH2,
-NH(alkyl), or -N(alkyl)2 substituents.
13. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 2,2-dimethylpentyl; R2 is 1,3-benzodioxol-5-
yl; and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.
14. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 3-fluoro-4-methoxyphenyl; R2 is 1,3-
benzodioxol-5-yl;
and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.
15. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 4-methoxyphenyl; R2 is 1,3-benzodioxol-5-yl;
and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.



31


16. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 2,2-dimethylpentyl; R2 is
7-methoxy-1,3-benzodioxol-5-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.
17. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 3-fluoro-4-methoxyphenyl; R2 is
7-methoxy-1,3-benzodioxol-5-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.
18. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 4-methoxyphenyl; R2 is 7-methoxy-1,3-
benzodioxol-5-yl;
and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.
19. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 2,2-dimethylpentyl; R2 is 1,3-benzodioxol-5-
yl; and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.



32


20. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 3-fluoro-4-methoxyphenyl; R2 is 1,3-
benzodioxol-5-yl;
and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.
21. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 4-methoxyphenyl; R2 is 1,3-benzodioxol-5-yl;
and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.
22. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 2,2-dimethylpentyl; R2 is
7-methoxy-1,3-benzodioxol-5-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.
23. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 3-fluoro-4-methoxyphenyl; R2 is
7-methoxy-1,3-benzodioxol-5-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.



33


24. The method of claim 12 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 4-methoxyphenyl; R2 is 7-methoxy-1,3-
benzodioxol-5-yl;
and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.
25. The method of claim 12 in which the endothelin A receptor antagonist is
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(aminocarbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-propenyl)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-methyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-2-methylpropyl)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,4-benzodioxol-6-yl)-
1-(((N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,4-benzodioxol-6-yl)-
1-(((N-methyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-methylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-bis(3-methylbutyl)amino)carbonyl)methyl)pyrrolidine-3-carboxylic
acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dipentylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4(1,3-benzodioxol-5-yl)-
1-(((N-methyl-N-pentylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,



34




trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-diisobutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-hexyl-N-methylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-diethylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dipropylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-isobutyl-N-methylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((isopropyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-ethylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-(2,2-dimethylpropyl)-N-methylamino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-methylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-methyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
(2R,3R,4R)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1R)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,
(25,3S,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1R)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,
(25,3S,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1S)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,
(2R,3R,4R)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1S)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,




trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N,N-dibutylamino)carbonyl)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((R,S)-2-(N,N-dibutylamino)carbonyl)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-pentyl-4-(1,3-benzodioxol-5-yl)-
1-((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-pentyl-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-propyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-propyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-butyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-propyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-butyl-N-((butyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-hydroxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-(2-methylpropyl)-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-
carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((ethyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(isopropyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
36




1-(2-((N-(2-methylpropyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-
carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((heptyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((hexyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-ethylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-propyl-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(3-(N-((pentyl)sulfonyl)-N-propylamino)propyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-butyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2-methylbutyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-methylbutyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((hexyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-hexyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-heptyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
37




trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((3-methylbutyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic
acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-(2-methylpropyl)-N-((pentyl)sulfonyl)amino)ethyl)pyrrolidine-3-
carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-((N-(non-5-ylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((2-methylpropyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-
carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dihexylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(hept-4-yl)amino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2-propylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-methylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2-ethylbutyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-(2-methylpropyl)amino)ethyl)pyrrolidine-3-
carboxylic acid,
trans,trans-2-(3-methyl-(E)-pent-3-en-1-yl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2-methylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2,2-dimethylphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2,2,4-trimethyl-3-(E)-pent-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2,2,-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-
yl)-
38




1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-(4-aminobutyl)-N-butylamino)carbonyl)methyl)pyrrolidine-3-carboxylic
acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,
(2R,3R,4S)-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,
(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid, or
(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-

1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof.

26. The method of claim 25 in which the endothelin A receptor antagonist is
(2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2R,3R,4S)-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,
39




(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid, or
(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-

1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof.

27. The method of claim 26 in which the endothelin A receptor antagonist is
(2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof.

28. A method for determining modulation of the health-related quality-adjusted
time-to-progression of disease in a patient undergoing endothelia antagonist
chemotherapy
for prostate cancer,
the method comprising the steps of:
(a) providing a patient population;
(b) administering to each member of the patient population either a
therapeutically effective amount of an ET receptor antagonist or placebo;
(c) measuring the health-related QoL domains of each patient over a period of
time to provide a health-related QATTP of disease for each patient in the
patient
population;
and
(d) determining the health-related QATTP for each health-related QoL domain
and
the sum of the mean or median health-related QATTP's of disease for the
patient
population.

29. The method of claim 28 in which the patient population comprises about
280 patients with prostate cancer.

30. The method of claim 28 in which the endothelia receptor antagonist
sustains the health-related quality-adjusted time-to-progression of disease in
the patient
with prostate cancer.


31. The method of claim 28 in which the endothelin receptor antagonist
extends the health-related quality-adjusted time-to-progression of disease the
a patient
with prostate cancer.

32. The method of claim 28 in which the endothelin receptor antagonist
improves the health-related quality-adjusted time-to-progression of disease in
a patient
with prostate cancer.

33. The method of claim 28 in which the endothelin receptor antagonist is
administered at or near the beginning of prostate cancer progression.

34. The method of claim 28 in which the endothelin receptor antagonist is
administered toward the end of prostate cancer progression.

35. The method of claim 28 in which the health-related quality of life domains
comprise physical functioning, emotional functioning, social/family
functioning, role
functioning, cognitive functioning, self-perception, and other domains
relating to patients
with prostate cancer, the other domains comprising pain, fatigue, nausea and
vomiting,
change in appetite, dyspnea, sleep disturbance, diarrhea, constipation,
urinary function,
and change in weight, the domains being assessed by the patient.

36. The method of claim 28 in which the period of time is about six weeks
after
the beginning of the treatment.

37. The method of claim 28 in which the therapeutically effective amount of
the endothelin receptor antagonist is between about 1 mg per day to about 25
mg per day.

38. The method of claim 37 in which the endothelin receptor antagonist is
administered once or twice per day without missing a day.

39. The method of claim 28 in which the endothelin receptor antagonist is an
endothelin A receptor antagonist.
41




40. The method of claim 28 in which the endothelin A receptor antagonist
is a compound having formula (I)-a
Image
or a compound having formula (I)-a with the relative or absolute
stereochemistry shown in
the compound having formula (I)-b
Image
or a therapeutically acceptable salt, prodrug, or salt of prodrug of either,
in which
R1 and R2 are independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heteroaryl, or
alkyl substituted with one cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, -
OH, or
-O(alkyl) substituent;
R3 is R4SO2R5- or R4C(O)R5-;
R4 is alkyl, -(CH2)alkenyl, -(CH2)alkynyl, -NR6R7, alkyl independently
substituted
with one or two cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -OH, -
O(alkyl), -NH2,
-NH(alkyl), or -N(alkyl)2 substituents, or alkenyl independently substituted
with one or
two cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -OH, -O(alkyl), -NH2, -
NH(alkyl), or
-N(alkyl)2 substituents;
R5 is a covalent bond, alkylene, -N(H)(alkylene)-, or -N(alkyl)(alkylene)-,
the latter two of which are drawn from left or right, and
R6 and R7 are independently hydrogen, alkyl, -(CH2)alkenyl, -(CH2)alkynyl,
cycloalkyl, aryl, or alkyl independently substituted with one or two
cycloalkyl, aryl,
heteroaryl, heterocyclyl, halo, -OH, -O(alkyl), -OCH2CF3, -OCH2CF2CF3, -NH2,
-NH(alkyl), or -N(alkyl)2 substituents.

41. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
42




prodrug thereof, in which R1 is 2,2-dimethylpentyl; R2 is 1,3-benzodioxol-5-
yl; and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

42. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 3-fluoro-4-methoxyphenyl; R2 is 1,3-
benzodioxol-5-yl;
and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

43. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 4-methoxyphenyl; R2 is 1,3-benzodioxol-5-yl;
and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

44. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 2,2-dimethylpentyl; R2 is
7-methoxy-1,3-benzodioxol-5-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

45. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a



43




prodrug thereof, in which R1 is 3-fluoro-4-methoxyphenyl; R2 is
7-methoxy-1,3-benzodioxol-5-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

46. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 4-methoxyphenyl; R2 is 7-methoxy-1,3-
benzodioxol-5-yl;
and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

47. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 2,2,-dimethylpentyl; R2 is 1,3-benzodioxol-5-
yl; and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

48. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 3-fluoro-4-methoxyphenyl; R2 is 1,3-
benzodioxol-5-yl;
and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

49. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
44


prodrug thereof, in which R1 is 4-methoxyphenyl; R2 is 1,3-benzodioxol-5-yl;
and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

50. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 2,2-dimethylpentyl; R2 is
7-methoxy-1,3-benzodioxol-5-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,

(N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or

2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

51. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 3-fluoro-4-methoxyphenyl; R2 is
7-methoxy-1,3-benzodioxol-5-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,

((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or

2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

52. The method of claim 40 in which the endothelin A receptor antagonist is a
compound having formula (I)-a with the relative or absolute stereochemistry
shown in the
compound having formula (I)-b, or a therapeutically acceptable salt, prodrug,
or salt of a
prodrug thereof, in which R1 is 4-methoxyphenyl; R2 is 7-methoxy-1,3-
benzodioxol-5-yl;
and R3 is ((N,N-dibutylamino)carbonyl)methyl,

((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or

2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl.

53. The method of claim 40 in which the endothelin A receptor antagonist is
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-

45



1-(aminocarbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-propenyl)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-methyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-2-methylpropyl)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,4-benzodioxol-6-yl)-
1-(((N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,4-benzodioxol-6-yl)-
1-(((N-methyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-methylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-bis(3-methylbutyl)amino)carbonyl)methyl)pyrrolidine-3-carboxylic
acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dipentylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-methyl-N-pentylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)
1-(((N,N-diisobutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-hexyl-N-methylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-diethylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dipropylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-isobutyl-N-methylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

46



trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)
1-(2-(N-((isopropyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)
1-(((N-butyl-N-ethylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)
1-(((N-(2,2-dimethylpropyl)-N-methylamino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-methylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-methyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,

(2R,3R,4R)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1R)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,

(25,3S,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1R)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,

(2S,3S,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1S)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,

(2R,3R,4R)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1S)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N,N-dibutylamino)carbonyl)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((R,S)-2-(N,N-dibutylamino)carbonyl)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-pentyl-4-(1,3-benzodioxol-5-yl)-
1-((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-pentyl-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-propyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-propyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

(2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

47



trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-butyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2,-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-propyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-butyl-N-((butyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-hydroxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-(2-methylpropyl)-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-
carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((ethyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(isopropyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-((N-(2-methylpropyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-
carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((heptyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((hexyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-ethylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-propyl-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-

48



1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(3-(N-((pentyl)sulfonyl)-N-propylamino)propyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-butyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(2-methylbutyl)-4-(1,3-benzodioxol-5-yl)
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-methylbutyl)-4-(1,3-benzodioxol-5-yl)
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((hexyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-hexyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-heptyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((3-methylbutyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic
acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-(2-methylpropyl)-N-((pentyl)sulfonyl)amino)ethyl)pyrrolidine-3-
carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-((N-(non-5-ylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((2-methylpropyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-
carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dihexylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

49



trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(hept-4-yl)amino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(2-propylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-methylpentyl)-4-(1,3-benzodioxol-5-yl)
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(2-ethylbutyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-(2-methylpropyl)amino)ethyl)pyrrolidine-3-
carboxylic acid,

trans,trans-2-(3-methyl-(E)-pent-3-en-1-yl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(2-methylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(2,2-dimethylphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(2,2,4-trimethyl-3-(E)-pent-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(2,2,-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-
yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-(4-aminobutyl)-N-butylamino)carbonyl)methyl)pyrrolidine-3-carboxylic
acid,

trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,

(2R,3R,4S)-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

50



(2S,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,

(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid, or

(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-

1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof.

54. The method of claim 53 in which the endothelin A receptor antagonist is
(2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

(2R,3R,4S)-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,

(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

(2S,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,

(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid, or

(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-

1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof.

55. The method of claim 54 in which the endothelin A receptor antagonist is
(2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,

or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof.

51

Description

CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
FAVORABLE MODULATION OF HEALTH-RELATED QUALITY OF LIFE AND
HEALTH-RELATED QUALITY-ADJCTSTED TIME-TO-PROGRESSION OF
DISEASE IN PATIENTS WITH PROSTATE CANCER
TECHNICAL FIELD
This invention is directed to a method for favorably modulating the health-
related
quality of life and the health-related quality-adjusted time-to-disease
progression in a
patient with prostate cancer and a method for measuring of the health-related
quality-adjusted time-to-disease progression in a patient with prostate
cancer.
BACKGROUND OF THE INVENTION
Prostate cancer patients often face poor prognosis, limited treatment options,
and a
decline in their health-related quality of life (QoL) with disease
progression. Because
conventional analyses of responses in prostate cancer trials fail to account
for the effect of
treatment on a patient's self perception of their health status and general
well-being,
qualitative and quantitative evaluation of the multidimensional health-related
QoL
responses of the patient over time could potentially provide a more
comprehensive
assessment and understanding of the benefit of a given therapeutic
intervention.
Thus, there is a long-standing need in the art for a method of favorably
modulating
the health-related QoL and the health-related quality-adjusted time-to-
progression . -
(QATTP) of disease in patients with prostate cancer and a method for measuring
the
health-related QATTP of disease in patients undergoing treatment for prostate
cancer.
DISCLOSURE OF THE INVENTION
A first embodiment of this invention, therefore, is directed to a method for
favorably modulating the health-related QoL of a patient with prostate cancer
comprising
administering thereto a therapeutically effective amount of an endothelin (ET)
receptor
antagonist.
A second embodiment of this invention is directed to a method for favorably
modulating the health-related QATTP of disease of a patient with prostate
cancer


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
comprising administering thereto a therapeutically effective amount of an ET
receptor
antagonist.
As used herein, the following terms have the meanings ascribed.
The term "endothelin receptor antagonist" means a compound which binds to the
endothelin receptor, which binding may be evaluated by the ability of the
compound to
inhibit endothelin from binding to its receptor, which inhibition is
preferably between
about 50%-100% at 1 Nxn inhibitor concentration, more preferably about 80%-
100% at
1 ~.m inhibitor concentration, most preferably about 95%-100% at 1 ~,m
inhibitor
concentration.
The term "favorably modulating" means sustaining and/or improving the
health-related QoL and/or sustaining and/or improving and/or extending the
health-related
QATTP of disease in a patient with prostate cancer.
The term "quality-adjusted time-to-progression of disease" or "QATTP of
disease"
means the interval between the initiation of chemotherapy in a patient with
prostate cancer
to the time of disease progression adjusted by the patient's health-related
QoL score.
The term "health-related quality of life" or "health-related QoL" means
domains
comprising physical functioning, emotional functioning, social/family
functioning, role
functioning, cognitive functioning, self perception, and other domains for
patients with
prostate cancer, the other domains comprising pain, fatigue, nausea and
vomiting, change
in appetite, dyspnea, sleep disturbance, diarrhea, constipation, urinary
function, and
change in weight.
A third embodiment of this invention is directed to a method for determining
modulation of the health-related QATTP of disease in a patient undergoing
endothelin
antagonist chemotherapy for prostate cancer,
the method comprising the steps of:
(a) providing a patient population,
in which the patient population comprises at least one patient with
prostate cancer, preferably about 100 patients with prostate
cancer, more preferably about 150 patients with prostate
cancer, most preferably about 280 patients with prostate
cancer;
(b) administering to each member of the patient population either a
therapeutically effective amount of an ET receptor antagonist or placebo,


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
in which ET receptor antagonist favorably modulates, preferably
sustains and/or extends, more preferably improves and/or
extends, the health-related QATTP of disease of a patient
with prostate cancer;
(c) measuring the health-related QoL domains of each patient over a period of
time to provide a health-related QATTP of disease for each patient in the
patient population,
in which the period of time is at least one interval time
period between the beginning and end of the treatment,
preferably about five to about seven weeks after the
beginning of treatment, more preferably about six weeks
after the beginning of the treatment;
and
(d) determining the health-related QATTP for each health-related QoL domain
and
the sum of the mean or median health-related QATTP's of disease for the
patient
population.
A fourth embodiment of this invention is directed to a method for increasing
the
survival time of a patient with prostate cancer comprising administering
thereto a
therapeutically effective amount of an ET receptor antagonist.
In one part of the first, second, third, and fourth embodiments of this
invention, the
ET receptor antagonist may be administered at any time during disease
progression, such
as, for example, at or near beginning of disease (such as, for example,
progression
indicated by elevation of prostate-specific antigen levels) or toward the end
of disease
(such as progression indicated by signs and symptoms consistent with the
progression of
prostate cancer or progression indicated by hormone refractoriness).
In another part of the first, second, third, and fourth embodiments of this
invention,
the therapeutically effective amount of the ET receptor antagonist is between
about 0.01
mg per day to about 100 mg per day, more preferably between about 1 mg per day
to
about 25 mg per day, most preferably about 2.5 mg or about 10 mg per day.
In still another part of the ftrst, second, third, and fourth embodiments of
this
invention, the foregoing therapeutically effective amount of the ET receptor
antagonist, or
combinations of submultiples thereof, may be administered once or twice per
day,
preferably without missing a day, more preferably once per day without missing
a day.


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
In still yet another hart=o; ~he first, second, third, and fourth embodiments
of this
invention, the ET receptor antagonist is an endothelin A (E,TA) receptor
antagonist,
preferably an ETA receptor antagonist having formula (I)-a
R1
R3~N COZH
R2
(I)-a
or an ETA receptor antagonist having formula (I)-a with the relative or
absolute
stereochemistry shown in a compound having formula (I)-b
R1
R3~N .,vC02H
R2
(I)_b~
or a therapeutically acceptable salt, prodrug, or salt of prodrug of either,
in which
Rl and R2 are independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heteroaryl, or
alkyl substituted with one cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, -
OH, or
-O(alkyl) substituent;
R3 is R4SOaR5- or R4C(O)RS-;
R4 is alkyl, -(CHa)alkenyl, -(CHa)alkynyl, -NR6R~, alkyl independently
substituted
with one or two cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -OH, -
O(alkyl), -NH2,
-NH(alkyl), or -N(alkyl)2 substituents, or alkenyl independently substituted
with one or
two cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -OH, -O(alkyl), -NH2, -
NH(alkyl), or
-N(alkyl)a substituents;
RS is a covalent bond, alkylene, -N(H)(alkylene)-, or -N(alkyl)(alkylene)-,
the latter two of which are drawn from left or right, and
R6 and R~ are independently hydrogen, alkyl, -(CH2)alkenyl, -(CH2)alkynyl,
cycloalkyl, aryl, or alkyl independently substituted with one or two
cycloallcyl, aryl,
heteroaryl, heterocyclyl, halo, -OH, -O(alkyl), -OCHZCF3, -OCH2CFZCF3, -NH2,
-NH(alkyl), or -N(alkyl)Z substituents;
in which, for the foregoing,
the term "alkenyl" means a monovalent, straight or branched hydrocarbon having
two to ten carbon atoms and at least one carbon-carbon double bond, attached
through a
carbon atom;


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
the term "alkynyl" means a monovalent, straight or branched hydrocarbon,
having
two to ten carbon atoms and at least one carbon-carbon triple bond, attached
through a
carbon atom;
the term "alkyl" means a monovalent, saturated, straight or branched
hydrocarbon,
having one to ten carbon atoms, attached through a carbon atom;
the term "aryl" means phenyl, unfused or fused with phenyl (naphthyl),
cyclopentyl (indanyl), cyclopentenyl (indenyl) 1,3-dioxolanyl (1,3-
benzodioxolyl), or
1,4-dioxanyl (1,4-benzodioxolyl) and unsubstituted or independently
substituted with one,
two, or three alkyl, halo, -CN, -OH, -CF3, -CH2CF3, -CF2CF3, -OCF3, -OCH2CF3,
-OCH2CF2CF3, -O(alkyl), -N02, -NH2, -NH(alkyl), -N(alkyl)2, -C(O)NH2,
-C(O)NH(alkyl), or -C(O)N(alkyl)2 substituents;
the term "cycloalkyl" means a monovalent, saturated cyclic hydrocarbon, having
three to six carbon atoms, attached through a carbon atom and unsubstituted or
independently substituted with one or two alkyl, halo, -O(alkyl), =O, -NH2, -
NH(alkyl), or
1 S -N(alkyl)2 substituents;
the term "heteroaryl" means furanyl, oxazolyl, pyridyl, pyridazinyl,
pyrimidinyl,
pyrrolyl, pyrazinyl, thiazolyl, and thiophenyl, each of which is connected
through a carbon
atom and unsubstituted or independently substituted with one, two, or three
alkyl, halo,
-CN, -OH, -CF3, -CH2CF3, -CFaCF3, -OCF3, -OCH2CF3, -OCHaCFZCF3, -O(alkyl),
-N02, -NH2, -NH(alkyl), -N(alkyl)2, -C(O)NH~, -C(O)NH(alkyl), or -
C(O)N(alkyl)a
substituents; and
the term "heterocyclyl" means 1,4-dioxanyl, 1,3-dioxolanyl, piperidinyl,
pyrrolidinyl, morpholinyl, and thiomorpholinyl, each of which is connected
through a
carbon atom or nitrogen atom and unsubstituted or independently substituted
with one or
two alkyl, halo, -O(alkyl), =O, -NH2, -NH(alkyl), or -N(alkyl)2 substituents;
and
in which preferred Rl moieties are butyl, 4-methoxyphenyl,
2,2-dimethyl-(E)-pent-3-enyl, 2,2-dimethylpentyl, 2-ethylbutyl,
3-fluoro-4-methoxyphenyl, heptyl, hexyl, 4-hydroxyphenyl, isopropyl, 2-
methylbutyl,
3-methylbutyl, pentyl, propyl, 3-methyl-(E)-pent-3-enyl, 3-methylpentyl, 2-
propylpentyl,
and 2,2,4-trimethyl-(E)-pent-3-enyl;
preferred Ra moieties are 1,3-benzodioxol-5-yl and
7-methoxy-1,3-benzodioxol-5-yl; and


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
preferred R3 moieties are ((N-(4-aminobutyl)-N-butylamino)carbonyl)methyl,
(aminocarbonyl)methyl, ((N,N-bis(3-methylbutyl)amino)carbonyl)methyl,
((N-butylamino)carbonyl)methyl, 2-(N-butyl-N-((butyl)sulfonyl)amino)ethyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl,
((N-butyl-N-ethylamino)carbonyl)methyl, ((N-butyl-N-
methylarnino)carbonyl)methyl,
((N-butyl-N-propylamino)carbonyl)methyl, 2-(N-butyl-N-
((propyl)sulfonyl)amino)ethyl,
2-(N-((butyl)sulfonyl)-N-methylamino)ethyl,
2-(N-((butyl)sulfonyl)-N-(2-methylpropyl)amino)ethyl,
2-(N-((butyl)sulfonyl)-N-propylamino)ethyl,
((N-butyl-N-(3-trimethylaminopropyl)amino)carbonyl)methyl,
(2-(N,N-dibutylamino)carbonyl)ethyl, ((N,N-dibutylamino)carbonyl)methyl,
((N,N-diethylamino)carbonyl)methyl, ((N,N-dihexylamino)carbonyl)methyl,
((N,N-diisobutylamino)carbonyl)methyl,
((N-(2,2-dimethylpropyl)-N-methylamino)carbonyl)methyl,
((N,N-dipentylamino)carbonyl)methyl, ((N,N-dipropylamino)carbonyl)methyl,
((1R)-1-(N,N-dipropylamino)carbonyl)but-1-yl,
((1 S)-1-(N,N-dipropylamino)carbonyl)but-1-yl,
2-(N-((ethyl)sulfonyl)-N-propylamino)ethyl,
2-(N-((heptyl)sulfonyl)-N-propylamino)ethyl,
((N-hexyl-N-methylamino)carbonyl)methyl, 2-(N-((hexyl)sulfonyl)-N-
propylamino)ethyl,
((N-isobutyl-N-methylamino)carbonyl)methyl, 2-(N-
((isopropyl)sulfonyl)amino)ethyl,
2-(N-((3-methylbutyl)sulfonyl)-N-propylamino)ethyl,
((N-methyl-N-pentylamino)carbonyl)methyl, ((N-2-methylpropyl)carbonyl)methyl,
((N-methyl-N-propylamino)carbonyl)methyl, 2-(N-(2-methylpropyl)-N-
((pentyl)sulfonyl)amino)ethyl, 2-(N-methyl-N-((propyl)sulfonyl)amino)ethyl,
2-((N-(2-methylpropyl)sulfonyl)-N-propylamino)ethyl,
2-(N-(2-methylpropyl)-N-((propyl)sulfonyl)amino)ethyl,
(N-(non-5-ylamino)carbonyl)methyl, 2-(N-((pentyl)sulfonyl)-N-ethylamino)ethyl,
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl,
3-(N-((pentyl)sulfonyl)-N-propylamino)propyl, ((N-propenyl)carbonyl)methyl,
((N-propylamino)carbonyl)methyl,
(2-(N-propyl-N-(((2-N,N-dimethylamino)ethyl)sulfonyl))amino)ethyl, and
2-(N-propyl-N-((propyl)sulfonyl)amino)ethyl;


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
which preferred variable moieties combine with the fixed moieties to form an
ETA
receptor antagonist of the first, second, third, and fourth embodiments having
formula (I)-
a with the relative or absolute stereochemistry shown in the compound having
formula (I)-
b
Ri
.,,vCO2H
R2
(I)-b,
or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof,
in which
Rl is alkyl, alkenyl, or phenyl, in which the phenyl is independently
substituted
with one or two halo, -OH, or -O(alkyl) substituents;
R~ is phenyl fused with 1,3-dioxolane and unsubstituted or substituted with
one
-O(alkyl) substituent;
R3 is (alkyl)S02N(alkyl)(alkylene)-, (alkyl)SOaN(H)(alkylene)-, or
(R~)(R8)NC(O)(alkylerie)-; and
R7 and Rg are independently hydrogen, alkyl, or alkyl substituted with one -
NH2
and -N(alkyl)a substituent;
an ETA receptor antagonist having formula (I)-a with the relative or absolute
stereochemistry shown in the compound having formula (I)-b
Ri
.,vC02H
Ra
(I)-b,
or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof,
in which
Rl is C3-C8-alkyl, C6-C8-alkenyl, or phenyl, in which the phenyl is
independently
substituted with one or two halo, -OH, or -O(C1-alkyl) substituents;
Ra is phenyl fused with 1,3-dioxolane and unsubstituted or substituted with
one
-O(Cl-alkyl) substituent;
R3 is (Ca-C7-alkyl)S02N(C1-C4-alkyl)(C2-C3-alkylene)-,
(C2-C7-alkyl)SOaN(H)(C1-C2-alkylene)-, or (R~)(R8)NC(O)(C1-C4-alkylene)-; and
R7 and R8 are independently hydrogen, C1-C9-alkyl, or Ca-G4-alkyl substituted
with one -NHa or -N(C1-alkyl)a substituent; and


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
an ETA receptor antagonist having formula (I)-a with the relative or absolute
stereochemistry shown in the compound having formula (I)-b, or a
therapeutically
acceptable salt, prodrug, or salt of a prodrug thereof, in which Rl is 2,2-
dimethylpentyl;
R2 is 1,3-benzodioxol-5-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl;
an ETA receptor antagonist having formula (I)-a with the relative or absolute
stereochemistry shown in the compound having formula (1'-b, or a
therapeutically
acceptable salt, prodrug, or salt of a prodrug thereof, in which Rl is
3-fluoro-4-methoxyphenyl; R2 is 1,3-benzodioxol-S-yl; and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl;
an ETA receptor antagonist having formula (I)-a with the relative or absolute
I S stereochemistry shown in the compound having formula (I)-b, or a
therapeutically
acceptable salt, prodrug, or salt of a prodrug thereof, in which Rl is 4-
methoxyphenyl; R2
is 1,3-benzodioxol-S-yl; and R3 is ((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl;
an ETA receptor antagonist having formula (I)-a with the relative or absolute
stereochemistry shown in the compound having formula (I)-b, or a
therapeutically
acceptable salt, prodrug, or salt of a prodrug thereof, in which Rl is 2,2-
dimethylpentyl;
Ra is 7-methoxy-1,3-benzodioxol-S-yl; and R3 is ((N,N-
dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl;
an ETA receptor antagonist having formula (I)-a with the relative or absolute
stereochemistry shown in the compound having formula (I)-b, or a
therapeutically
acceptable salt, prodrug, or salt of a prodrug thereof, in which Rl is
3-fluoro-4-methoxyphenyl; Ra is 7-methoxy-1,3-benzodioxol-5-yl; and R3 is
((N,N-dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl; and °


CA 02442591 2003-09-26
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an ETA receptor antagonist having formula (I)-a with the relative or absolute
stereochemistry shown in the compound having formula (I)-b, or a
therapeutically
acceptable salt, prodrug, or salt of a prodrug thereof, in which Rl is 4-
methoxyphenyl; RZ
is 7-methoxy-1,3-benzodioxol-5-yl; and R3 is ((N,N-
dibutylamino)carbonyl)methyl,
((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl; and
a compound, or a therapeutically acceptable salt, prodrug, or salt of a
prodrug
thereof, which is
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(((N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(aminocarbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-propenyl)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-methyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-2-methylpropyl)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1,4-benzodioxol-6-yl)-
I-(((N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,4-benzodioxol-6-yl)-
1-(((N-methyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-methylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(((N,N-bis(3-methylbutyl)amino)carbonyl)methyl)pyrrolidine-3-carboxylic
acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(((N,N-dipentylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-methyl-N-pentylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
1-(((N,N-diisobutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)
1-(((N-hexyl-N-methylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(((N,N-diethylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dipropylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-isobutyl-N-methylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)
1-(2-(N-((isopropyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)
1-(((N-butyl-N-ethylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(((N-(2,2-dimethylpropyl)-N-methylamino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,
trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-methylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(2-(N-methyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
(2R,3R,4R)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1R)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,
(2S,3S,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1R)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,
(2S,3S,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1S)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,
(2R,3R,4R)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((1S)-1-(N,N-dipropylamino)carbonyl)but-1-yl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-propylamino)carbonyl)rnethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
to


CA 02442591 2003-09-26
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1-(2-(N,N-dibutylamino)carbonyl)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((R,S)-2-(N,N-dibutylamino)carbonyl)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-pentyl-4-(I,3-benzodioxol-5-yl)-
1-((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-pentyl-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-propyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-propyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-.dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(2-(N-butyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(2-(N-propyl-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(2-(N-butyl-N-((butyl)sulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-hydroxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(2-(N-(2-methylpropyl)-N-((propyl)sulfonyl)amino)ethyl)pyrrolidine-3-
carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(2-(N-((ethyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(isopropyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)earbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-((N-(2-methylpropyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-
carboxylic acid,
11


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trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((heptyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((hexyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-ethylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-propyl-4-( 1, 3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(I,3-benzodioxol-5-yI)-
1-(3-(N-((pentyl)sulfonyl)-N-propylamino)propyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-butyl-4-( 1, 3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2-methylbutyl)-4-(1,3-benzodioxol-5-yl)
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-methylbutyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((hexyl)sulfonyl)-N-propylamino)ethyl)pynrolidine-3-carboxylic acid,
trans,trans-2-hexyl-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-propylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-heptyl-4-( 1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
12


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1-(2-(N-((3-methylbutyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic
acid,
traps,traps-2-(3-fluoro-4-methoxyphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(3-fluoro-4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(2-(N-(2-methylpropyl)-N-((pentyl)sulfonyl)amino)ethyl)pyrrolidine-3-
carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-
1-((N-(non-5-ylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((2-methylpropyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-
carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dihexylarnino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(hept-4-yl)amino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(2-propylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(3-methylpentyl)-4-( 1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(2-ethylbutyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((butyl)sulfonyl)-N-(2-methylpropyl)amino)ethyl)pyrrolidine-3-
carboxylic acid,
traps,traps-2-(3-methyl-(E)-pent-3-en-1-yl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(2-methylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(2,2-dimethylphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(2,2,4-trimethyl-3-(E)-pent-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(2,2,-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
traps,traps-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-
yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
13


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trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
I-(((N-(4-aminobutyl)-N-butylamino)carbonyl)methyl)pyrrolidine-3-carboxylic
acid,
trans,trans-2-(4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,
(2R,3R,4S)-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(I,3-benzodioxol-5-y1)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,
IS (2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)rnethyl)pyrrolidine-3-carboxylic acid, and
(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-

1-(((N,N-dibutylarnino)carbonyl)methyl)pyrrolidine-3-carboxylic acid;
preferred compounds of which are
trans,trans-2-(4-methoxyphenyl)-4-(I,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2,2-dimethylpentyl)-4-(7-methoxy-I,3-benzodioxol-5-y1)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(2,2-dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid, and
trans,trans-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-rnethoxy-1,3-benzodioxol-5-
yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid;
more preferred compounds of which include
14


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(2R,3R,4S)-2-(4-rnethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2R,3R,4S)-2-(3-fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(2,2-dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid,
(2S,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl)pyrrolidine-3-
carboxylic
acid,
(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid, and
(2S,3R,4S)-2-(2,2-dimethyl-(E)-pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-

1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid; and
a most preferred compound of which is
(2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
1-(((N,N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid, also
known as
atrasentan.
The ET receptor antagonists of this invention comprise asymmetrically
substituted
carbon atoms in the R or S configuration, in which the terms "R" and "S" are
as defined by
the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry,
Pus°e
Appl. Chem. (1976) 45, 13-10. ET receptor antagonists having asymmetrically
substituted
carbon atoms with equal amounts of R and S configurations are racemic at those
carbon
atoms. Atoms with an excess of one configuration over the other are assigned
the
configuration in the higher amount, preferably an excess of about 85%-90%,
more
preferably an excess of about 95%-99%, and: still more preferably an excess
greater than
about 99%. Accordingly, this invention is meant to embrace racemic mixtures,
relative
and absolute stereoisomers, and mixtures of relative and absolute
stereoisomers of the ET
receptor antagonists therein.
The term "relative stereochemistry," as used herein, refers to the direction
of the
variable Rl and R2 moieties in relation to the direction of the fixed carboxyl
moiety to
which each is adjacent. In a preferred'embodiment, Rl and Ra are in the
opposite


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
direction of the carboxyl moiety and form the "trans,trans-" stereochemistry
shown in the
compound having formula (I)-b.
The term "absolute stereochemistry," as used herein, refers to the fixed
direction of
each fixed or variable moiety regardless of the orientation of the other
substituents.
The compounds having formula (I)-a and formula (I)-b may also contain
carbon-carbon double bonds in the Z or E configuration, in which the term "Z"
represents
the larger two of the four substituents on same side of a carbon-carbon double
bond and
the term "E" represents the larger two of the four substituents on opposite
sides of a
carbon-carbon double bond. The compounds having formula (I)-a and formula (I)-
b may
also exist as an equilibrium mixture of Z and E configurations.
Compounds having formula (I)-a and formula (I)-b containing hydroxyl, amino,
or
carboxylic acids may have attached thereto prodrug-forming moieties. The
prodrug-forming moieties are removed by metabolic processes and release the
compounds
having the freed hydroxyl, amino, or carboxylic acid in vivo. Prodrugs are
useful for
adjusting such pharmacokinetic properties of the compounds, or their
metabolites, as
solubility and/or hydrophobicity, absorption in the gastrointestinal tract,
bioavailability,
tissue penetration, and rate of clearance. Examples of prodrugs of the
compounds include
ones in which the carboxyl moiety of the compounds have attached thereto a
methyl,
ethyl, isopropyl, or tert-butyl moiety.
The compounds having formula (I)-a and formula (I)-b may be prepared by
synthetic processes or metabolic processes. Metabolic processes include those
processes
occurnng in vitro or in vivo. An example of a metabolite of the compounds is
one in
which Rl is 4-methoxyphenyl; Ra is 1,3-benzodioxol-5-yl; and R3 is
((N-butylamino)carbonyl)methyl.
The compounds having formula (I)-a and formula (I)-b may exist as acid
addition
salts, basic addition salts, or zwitterions. Salts of the compounds are
prepared during their
isolation or following their purification. Acid addition salts of the
compounds are those
derived from the reaction of the same with an acid. For example, the acetate,
adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
camphorate,
camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate,
hexanoate,
formate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate,
mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate,
oxalate,
pectinate, persulfate, picrate, propionate, succinate, tartrate, thiocyanate,
trichloroacetic,
16


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
trifluoroacetic, phosphate, glutamate, bicarbonate, para-toluenesulfonate,
lactobionate, and
undecanoate salts of the compounds and prodrugs thereof are contemplated as
being
within the scope of this invention. Because the compounds contain carboxylic
acids, basic
addition salts may be prepared therefrom by reaction with a base such as the
hydroxide,
carbonate, or bicarbonate of cations such as lithium, sodium, potassium,
calcium, and
magnesium. A preferred salt of the compounds is the hydrochloride salt.
The compounds having formula (I)-a and formula (I)-b may be administered with
or without an excipient and with or without another chemotherapeutic agent.
Excipients
include encapsulating materials or formulation additives such as absorption
accelerators,
antioxidants, binders, buffers, coating agents, coloring agents, diluents,
disintegrating
agents, emulsifiers, extenders, fillers, flavoring agents, humectants,
lubricants, perfumes,
preservatives, propellants, releasing agents, sterilizing agents, sweeteners,
solubilizers,
wetting agents, and mixtures thereof. Excipients for orally administered
compounds in
solid dosage forms include agar, alginic acid, cocoa butter, gelatin, isotonic
saline, malt,
1 S powdered tragacanth, Ringer's solution, talc, water, aluminum hydroxide,
magnesium
hydroxide, sodium and potassium phosphate salts, cellulose, cellulose acetate,
ethyl
cellulose, sodium carboxymethyl cellulose, ethyl laureate, ethyl oleate,
magnesium
stearate, sodium lauryl sulfate, castor oil, corn oil, cottonseed oil, germ
oil, groundnut oil,
olive oil, peanut oil, safflower oil, sesame oil, soybean oil, benzyl alcohol,
benzyl
benzoate, 1,3-butylene glycol, ethanol, ethyl acetate, ethyl carbonate,
glycerol,
isopropanol, propylene glycol, tetrahydrofurfuryl alcohol, corn starch, potato
starch,
lactose, glucose sucrose, and mixtures thereof. Excipients for ophthalmically
and orally
administered compounds in liquid dosage forms include water, ethanol,
isopropanol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,
1,3-butylene
glycol, cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor
oil, sesame oil,
glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters
of sorbitan, and
mixtures thereof. Excipients for osmotically administered compounds include
water,
ethanol, isopropanol, chlorofluorohydrocarbons, and mixtures thereof.
Excipients for
parenterally administered compounds include water, 1,3-butanediol, Ringer's
solution,
LJ.S.P. or isotonic sodium chloride solution, oleic acid, castor oil, corn
oil, cottonseed oil,
germ oil, groundnut oil, olive oil, peanut oil, safflower oil, sesame oil,
soybean oil,
liposomes, and mixtures thereof. Excipients for rectally administered
compounds include
cocoa butter, polyethylene glycol, wax, and mixtures thereof.
17


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WO 02/085351 PCT/US02/11397
The compounds having formula (I)-a and formula (I)-b may be administered as
the
sole active agent, or they may also be used co-therapeutically with one or
more anticancer
drugs or methods including hormonal agents such as leuprolide (Lupron~);
gonadorelin
antagonists such as goserelin (Zoladex~) and abarelix; bicalutamide;
nilutamide;
flutamide; vitamin D; vitamin D analogues; estrogen and estrogen analogues
such as
diethylstibestrol; prednisone; hydrocortisone; ketoconazole; cyproterone
acetate;
progesterone; 5-alpha reductase inhibitors such as finasteride; bone-seeking
radionuclides
such as samarium (Quadramet~), strontium (Metastron~), and 186rhenium;
external beam
radiation such as three dimensional conformal radiation; brachytherapy (the
implantation
of radioactive seeds in the prostate); monoclonal antibodies such as
trastuzumab
(Herceptin~); anti-angiogenic drugs such as thrombospondin peptide or kringle
5; matrix
rnetalloproteinase inhibitors; farnesyl transferase inhibitors; lycopenes;
urokinase;
plasminogen activator inhibitors; plasminogen activator receptor blockers;
apoptosis
inducers; selective and non-selective alpha blockers; platinum agents such as
cis-platinum
and carbo-platinum; taxane- class drugs such as docetaxil and paclitaxil;
estramustine;
gemcytabine; adriamycin; doxorubicin; daunorubicin; mitoxantrone; vinblastine;
vincristine; capecitabine; irinotecan; topotecan; 5-fluorouracil; interferons;
cytoxan;
methotrexate; cytokines such as IL-2; PPAR agonists such as thiazolidine
diones;
retinoid-type agents; 5-lipooxygenase inhibitors such as zyflo (Zilueton~);
COX-2
inhibitors; gene-therapy based therapeutics, including sense and anti-sense
polynucleotides; cholesterol lowering drugs such as lovastatin, pravastatin,
and
simvistatin; bisphosphonates such as etidronate, ibandronate, pamidronate, and
risendronate; osteoprotegrin; antibodies, both monoclonal and polyclonal;
antibody-coupled radionucleotides; antibody-coupled cytotoxic agents; antibody-
coupled
radionucleotides; viral-vector delivered agents; vaccines directed at protein,
carbohydrate,
or nucleic acid targets; aminoglutethimide; and suramin.
These combinations may be administered separately or singly in dosage forms
containing both or all drugs. When administered as a combination, the drugs
may be
formulated as separate compositions, given at the same time or different
times, or the
therapeutic agents may be given as a single composition.
The compounds having formula (I)-a and formula (I)-b may be administered
parenterally (subcutaneously, intravenously, intramuscularly, and
intrasternally), orally,
osmotically, ophthalmically, rectally, topically, and transdermally. Orally
administered
18


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WO 02/085351 PCT/US02/11397
compounds in solid dosage forms may be administered as capsules, dragees,
granules,
pills, powders, and tablets. Ophthalmically and orally administered compounds
in liquid
dosage forms may be administered as elixirs, emulsions, microemulsions,
solutions,
suspensions, and syrups. Osmotically and topically administered compounds may
be
administered as creams, gels, inhalants, lotions, ointments, pastes, powders,
solutions, and
sprays. Parenterally administered compounds may be administered as aqueous or
oleaginous solutions or aqueous or oleaginous suspensions, the latter of which
contains
crystalline, amorphous, or otherwise insoluble forms of the compounds.
Rectally
administered compounds may be administered as creams, gels, lotions,
ointments, and
pastes. A preferred means of administration of the compounds is orally.
The preparation of the compounds having formula (I)-a and formula (I)-b and
their
binding affinity for ET receptors are disclosed in commonly-owned, U.S.
patents
5,731,434, 5,622,971, and 5,767,144 and commonly owned published PCT
applications
WO/06095, published February 29, 1996; WO 97/30045, published August 21, 1997;
and
WO 99/06397, published February 11, 1999.
DETERMINATION OF HEALTH-RELATED QUALITY-ADJUSTED
TIME-TO-DISEASE PROGRESSION
The health-related QATTP of disease model for this invention expresses
progression-free time as an equally preferable amount of time spent in full
health. This is
achieved by using patient-reported health-related QoL, as measured for the
duration of
observation or progression-free interval, to weight progression-free time.
These data were
collected from randomized patients having hormone refractory prostate cancer
(HRPCa)
with the following validated instruments: the European Organization for
Research and
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) and the
Functional
Assessment of Cancer Therapy (FACT-G) and its prostate cancer-specific module
(FACT-P).
Patients received treatment with 10 mg (N=89) or 2.5 mg (N=95) of atrasentan
or
placebo (N=104) until experiencing a clinical event indicative of disease
progression such
as palliative opiate treatment of new bone or visceral pain, palliative
radiation treatment of
new bone pain, or new tumor growth symptoms requiring intervention or
treatment with
chemotherapy.
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Patient-reported health-related QoL data were collected with the EORTC QLQ-.30
and the FACT-G and FACT-P, both of which were administered at baseline, at six
week
intervals and at each patient's final visit. The results from the 10 mg and
2.5 mg treatment
groups are reported relative to the placebo group.
A patient's transformed domain score and total score from both the
EORTC QLQ-30 and FACT were used to weight the time-to-progression outcome
data.
Transformed domain scores ranged between 0 and 1, so the reported health-
related
QATTP of disease outcome was never larger than the actual time-to-progression.
The
methods used for converting domain scores to weight adjustments are shown in
TABLE 1.
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TABLE 1
TRANSFORMATION OF HEALTH-RELATED QUALITY OF LIFE INSTRUMENT
DOMAIN SCORES TO WEIGHTED ADJUSTMENTS
INSTRUMENT AND DOMAIN NAMEDOMAIN SCORE CONVERSION METHOD


RANGE TO UNIT SCALE


EORTC Physical Functioning,


Emotional Functioning,
Role


Functioning, Social Functioning,0-100 Domain Score/100
'


Cognitive Functioning,
and Global


Scorea


EORTC Pain, Fatigue, Nausea
and


Vomiting, Appetite Loss, 0-100 1-(Domain Score/100)
Dyspnea,


Sleep Disturbance, Diarrhea,


Constipationb


FACT Physical, Social/Family.0-Zcg Domain Score-Lowest
Domain Score


Functional Well-bein
s


g Domain Score Range



a
FACT Emotional Well-being 0-20 Domain Score-Lowest
Domain Score


Domain Score Range


FACT -Ga 0-112 Domain Score-Lowest
Domain Score


Domain Score Range


FACT-Pa 0-48 Domain Score-Lowest
Domain Score


Domain Score Range


FACT-Totals 0-160 Domain Score-Lowest
Domain Score


Domain Score Range


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WO 02/085351 PCT/US02/11397
a A higher score means a better health-related QoL. A higher transformed score
means improved
health-related QoL. . ,
b A higher score means a worse health-related QoL. A higher transformed score
means
improved symptoms.
Possible scores for the fourteen EORTC domains each range between 1 and 100.
For six domains (physical, emotional, role, social, and cognitive functioning
and global
score), a higher score means a better health-related QoL. These six scores
were
transformed to weights by dividing the patient-reported scores by 100.
For the remaining eight EORTC domains, a higher score indicates worse
symptoms (a worse health-related QoL). These domains are pain, fatigue, nausea
and
vomiting, appetite loss, dysnepa, sleep disturbance, diarrhea, and
constipation. These
eight scores were converted to weight adjustments by dividing them by 100 and
subtracting the result from the integer 1 to provide consistent directionality
of response.
FACT domain scores were converted to weights using the linear affine
transformation
suggested in SF 36 Health Survey Manual ahd Inte~p~~etatiora Guide.
Each patient's health-related QATTP of disease was computed as the sum of the
health-related QoL weights multiplied by the duration for which that patient
experienced
that health-related QoL.
If a patient experienced a clinical event between two health-related QoL
assessments, the set of health-related QoL domain scores immediately prior to
the event
were carried forward to the time of the clinical event. The mean and median
health-
related QATTP of disease outcomes were then estimated using Kaplan-Meier
product
limit methodology (Jourfzal of the American Statistical Association, vol. 53,
1958, pp 457-
481). The area under a Kaplan-Meier survival curve conveys an estimated mean
health-
related QATTP of disease. This analysis was applied to both intent-to-treat
and per
protocol population data. All health-related QATTP of disease comparisons
between
atrasentan and placebo treatment groups were based on a log-rank test with
statistical
significance at an a of 0.05.
Results of the Kaplan-Meier product limit survival method analysis are
reported in
TABLE 2 (Intent to Treat) and TABLE 3 (Per Protocol Population). Mean and
median
health-related QATTP of disease are shown by treatment group. Log-rank tests
comparing the differences between treatment groups are also reported.
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The Kaplan-Meier product limit method may provide biased results if study data
are obtained under certain conditions such as staggered entry of subjects into
the study
and/or incomplete follow-up (Biometrics. 1989; 5:781-795). Thus, a second
analysis was
implemented to verify that the conclusions derived from the Kaplan-Meier
method would
remain robust to the length of follow-up. The assumption was that all patients
were
followed for one year. Patients who discontinued from the study prior to one
year of
observation had their last observation for all health-related QoL domains
carried forward
through the remainder of the year. Similarly, patients who had not completed
one year of
observation had their health-related QoL data carried forward through one
year. If the
patient experienced a clinical event within the one year period, the last
observation was
not carned forward. The Area under the Curve (AUC) value for each domain was
computed by multiplying the health-related QoL domain score by the respective
duration
of that score. Finally, AUC values were aggregated across all subjects within
each
respective treatment group (atrasentan (10 mg), atrasentan (2.5 mg), and
placebo).
Aggregated AUC values for each domain were compared for differences between
treatment groups using a t-test.
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WO 02/085351 PCT/US02/11397
TABLE 2
QUALITY-ADJUSTED TIME-TO-PROGRESSION OF DISEASE
(INTENT TO TREAT DATAI
QATTP of P-Value
Disease


QoL Domain Score
Used for Log
Rank
Adjusting Time-to edian ean Comparison
Progression (days) (days)
Health-Related
QATTP
Of
Diseases


At. At. At. At.
(10 (2.5Pl.(10 (2.5Pl. 10 10 2.5
mg) mg) mg) mg) mg mg mg
vs. vs. vs.
2.5 P1." P1.
mg


EORTC Ph sical Functionin119 118 137164 17286 0.7960.0910.118


EORTC Emotional 125 133 147167 177115 0.7700.2390.225
Functionin


EORTC Role Functionin123 128 145180 176106 0.8630.1600.205


EORTC Social Functionin135 142 151190 184112 0.7220.1060.209


EORTC Co nitive 138 151 151163 180106 0.9200.2140.246
Functionin


EORTC Pain 127 133 139172 179106 0.7530.1190.170


EORTC Fati ue 104 109 134153 16597 0.8470.1690.222


EORTC Nausea & Vomitin156 162 169201 195129 0.6550.1650.323


EORTC A etite Loss 146 151 161175 186118 0.6160.1570.309


EORTC D s nea 123 141 153177 173101 0.6280.2000.425


EORTC Slee Disturbance123 127 143158 172102 0.9330.2530.249


EORTC Diarrhea 176 178 169185 198129 0.7330.2010.270


EORTC Consti ation 132 142 153189 180127 0.8410.2140.297


EORTC Global Score 103 104 119141 15993 0.9280.2450.242


FACT Physical Well 127 135 151184 181117 0.7360.1760.283
Bein


FACT Emotional Well127 133 146163 180112 0.8880.2510.260
Bein


FACT Social/Famil 121 126 141i47 160104 0.7710.2770.380
Well Bein


FACT Functional 98 111 134140 16198 0.9430.3820.318
Well Bein


FACT-G 123 129 143160 172112 0.8350.2080.290


FACT-P 107 115 122135 15287 0.7700.2020.273


FACT Total 117 125 137152 166105 0.7960.1910.279


24


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
aP-Values from Kaplan-Meier log-rank test of differences in health-related
QATTP of
disease curves.
At. is atrasentan.
P1. is placebo.


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
TABLE 3
QUALITY-ADJUSTED TIME-TO-PROGRESSION
(PER PROTOCOL DATA)
QATTP f P-Value
o Disease


QoL Domain Score
Used for Log
Rank
Adjusting Time-to-progressionedian ean Comparison
(days) (days)
Health-Related
QATTP
of
Diseases


At. At. At. At.
(10 (2.5PI. (10 (2.5Pl. 10 10 2.5
mg) mg) mg) mg) mg mg mg
vs. vs. vs.
2.5 P1 Pl.a
mga ~


EORTC Ph sical Functionin127 12485 168 181128 0.9320.019*0.014*


EORTC Emotional 134 143110 169 186135 0.8560.038*0.021*
Functionin ~


EORTC Role Functionin128 142100 187 185134 0.9440.030*0.024*


EORTC Social Functionin141 156106 196 192140 0.8110.017*0.025*


EORTC Co nitive 144 156106 159 190142 0.9440.040*0.031
Functionin


I
EORTC Pain 137 142104 178 188130 0.8640.021*0.021*


EORTC Fati ue 111 12797 158 174125 0.9800.042*0.032*


EORTC Nausea & Vomitin168 178127 207 206158 0.7920.029*0.042*


EORTC A etite Loss 146 162118 179 196150 0.7310.027*0.040*


EORTC D s nea 132 14298 182 180145 0.7380.060 0.119


EORTC Slee Disturbance127 137101 162 179131 0.9600.043*0.030*


EORTC Diarrhea 184 184127 188 209159 0.8920.037*0.029*


EORTC Consti ation 141 151120 198 190145 0.9350.049*0.047*


EORTC Global Score 106 12490 145 167113 0.9750.057 0.038*


FACT Physical Well 130 148112 190 191142 0.8350.036*0.039*
Bein


FACT Emotional Well131 147107 168 188137 0.9950.053 0.035*
Bein


FACT Social/Famil 126 143102 151 169131 0.9120.059 0.049*
Well Bein


FACT Functional 113 11196 144 168126 0.9600.119 0.056
Well Bein


FACT-G 130 143105 165 180135 0.9570.047*0.040*


FACT-P 111 11781 139 160115 0.9090.038*0.035*


FACT Total 127 135102 157 174129 922 0.040*0.035*


26


CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
aP-Values from Kaplan-Meier log-rank test of differences in health-related
QATTP of
disease curves.
* Significant at p<0.05.
At. is atrasentan.
Pl. is placebo.
The data in TABLE 2 show significantly longer (p<0.05) mean health-related
QATTP's of disease for all health-related QoL domains except dyspnea, global
score,
emotional well-being, and social well-being in the 10 mg atrasentan treatment
group. In
the dyspnea, global score, emotional well-being, and social well-being
domains, the trend
favored the 10 mg atrasentan treatment group (p<0.10). The 2.5 mg atrasentan
treatment
group also produced longer mean health-related QATTP of disease. Log rank
tests
showed these results to be statistically significant for all health-related
QoL domains
except dyspnea and functional well-being; and there were no statistical
differences noted
between the atrasentan treatment groups for any health-related QoL domain.
The data in TABLE 3 show both delays and improvement in the mean
health-related QATTP's of disease in the both 10 mg and 2.5 mg atrasentan
treatment
groups.
The AUC analysis results were consistent with the health-related QATTP
analyses
in TABLES 2 and 3. For the Intent to Treat population (TABLE 2), atrasentan
treatment
and placebo groups showed no statistical differences. The AUC analysis of the
per-protocol population showed strong trends in favor of the atrasentan
treatment groups
in every health-related QoL domain score when compared to placebo. The
responses in
the 10 mg and 2.5 mg treatment groups were not statistically differentiable.
The AUC for the health-related QoL domain scores for physical functioning,
social
functioning, and pain were significantly longer (p<0.05) for atrasentan.
Similarly, the
2.5 mg atrasentan group showed significantly improved AUC results except for
dyspnea,
social/family, functional well-being, and FACT-P domain scores.
The impact of the 10 mg and 2.5 mg atrasentan treatment on the patients'
perceived
health-related QoL was also addressed. Patient-reported health-related QoL
data has
validity for two reasons: the perception of health is stated by the patient
directly, and
multidimensional health-related QoL instruments provide a more complete and
balanced
assessment of patients' health status. It was found that after adjusting for
health-related
QoL effects, both 10 mg and 2.5 mg atrasentan therapies offered longer health-
related
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CA 02442591 2003-09-26
WO 02/085351 PCT/US02/11397
QATTP over placebo in the per protocol population. ' These gains in the health-
related
QATTP were robust over a wide range of health-related QoL domain weighting and
were
consistently observed using the EORTC and FACT as the two health-related QoL
instruments. For the intent-to-treat population, there were no statistically
significant
differences in the QATTP across treatment groups. This finding is consistent
with the fact
that, for the intent-to-treat population, no statistically significant
differences were
observed in either the time to disease or PSA progression across treatment
groups.
Additional AUC analyses showed that after adjusting for possible bias induced
by
unequal lengths of follow-up and the staggered entry of subjects, the findings
produced by
the Kaplan-Meier methods were confirmed.
Thus, both the health-related QoL and the health-related QATTP of disease in
patients with prostate cancer are favorably modulated by administration of an
ET
antagonist, preferably an ETA antagonist such as atrasentan.
28