Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-08
2003-02-18
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S364000
Reexamination Certificate
active
06521611
ABSTRACT:
Vasopressin, a neurohypophyseal neuropeptide produced in the hypothalamus, is involved in water metabolism homeostasis, renal function, mediation of cardiovascular function, non-opioid mediation of tolerance for pain, and regulation of temperature in mammals. In addition to being released into the circulation via the posterior pituitary, vasopressin acts as a neurotransmitter in the brain. Three vasopressin receptor subtypes, designated V
1a
, V
1b
, and V
2
have been identified. The human V
1a
receptor has been cloned (Thibonnier et al.,
The Journal of Biological Chemistry,
269(5), 3304-3310 (1994)), and has been shown by radioligand binding techniques to be present in vascular smooth muscle cells, hepatocytes, blood platelets, lymphocytes and monocytes, type II pneumocytes, adrenal cortex, brain, reproductive organs, retinal epithelium, renal mesangial cells and the A10, A7r5, 3T3 and WRK-1 cell lines (Thibonnier,
Neuroendocrinology of the Concepts in Neurosurgery Series
5, (Selman, W., ed), 19-30, Williams and Wilkins, Baltimore, (1993)).
Structural modification of vasopressin has provided a number of vasopressin agonists (Sawyer,
Pharmacol. Reviews,
13, 255 (1961)). In the past decade, several potent and selective vasopressin peptide antagonists have been designed (Lazslo, et al.,
Pharmacological Reviews,
43, 73-108 (1991); Mah and Hofbauer,
Drugs of the Future,
12, 1055-1070 (1987); Manning and Sawyer,
Trends in Neuroscience,
7, 8-9 (1984)) Their lack of oral bioavailability and short half-life, however, have severely limited their therapeutic potential. While novel structural classes of non-peptidyl vasopressin V
1A
antagonists have been discovered (Yamamura, et al.,
Science,
275, 572-574 (1991); Serradiel-Le Gal, et al.,
Journal of Clinical Investigation,
92, 224-231 (1993); Serradiel-Le Gal, et al.,
Biochemical Pharmacology,
47(4), 633-641 (1994)), a clinically useful agent is yet to be identified.
The general structural class of substituted 2-(azetidin-2-on-1-yl)acetic acid esters and amides are well known in the art as synthetic intermediates for the preparation of &bgr;-lactam antibiotics (U.S. Pat. No. 4,751,299). While certain compounds within this structural class have been reported as possessing antibiotic activity, their activity at the vasopressin V
1a
receptor has heretofore not been appreciated.
This invention provides a method for the antagonism of the vasopressin V
1a
receptor comprising administering to a mammal in need of such antagonism a pharmaceutically effective amount of a 2-(azetidin-2-on-1-yl)acetic acid derivative of Formula I
where
R
1
is hydrogen, C
1
-C
5
alkyl, —C(O)NR
5
X′, (C
1
-C
4
alkylene)C(O)NR
5
X′, hydroxy substituted C
1
-C
5
alkyl, C
1
-C
5
acyl optionally substituted as the ethylene glycol ketal, C
3
-C
6
cycloalkylcarbonyl, benzoyl, phenyl, phenyl(C1-C4 alkylene), phenoxyacetyl, phenylacetyl where the phenyl is optionally substituted with halo, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, or trifluoromethyl, or &agr;-hydroxy-&agr;-benzoylbenzyl;
R
2
is hydrogen, or hydroxy substituted C
1
-C
5
alkyl;
R
3
is phthalimido, azido, phenoxyacetamido, 4,5-diphenyloxazol-2-on-3-yl, or a structure selected from the group consisting of
R
4
is:
phenethyl, or 2-arylethen-1-yl where aryl is selected from the group consisting of furyl, pyrrolyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrimidinyl, thiadiazolyl, oxadiazolyl, quinolyl, isoquinolyl, naphthyl, and phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, nitro, halo, carboxy, and amido;
Q is —O—, —S—, or —NR
5
—;
R
5
is hydrogen, hydroxy, C
1
-C
4
alkoxycarbonyl, benzyl, or C
1
-C
4
alkyl;
R
6
is C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, phenyl, or phenyl(C1-C4 alkylene) optionally substituted on the alkylene chain with C
1
-C
4
alkoxycarbonyl;
X and X′ are independently hydrogen, C
1
-C
6
alkyl, 2-(trimethylsilyl)-ethyl, C
1
-C
4
alkyl &ohgr;-substituted with C
1
-C
4
alkoxy, Y, (optionally substituted C
1
-C
4
alkylene)-Y, or (optionally substituted C
2
-C
4
alkylene)-NR
7
R
8
;
Y is phenyl, optionally substituted phenyl, diphenylmethyl, C
3
-C
6
cycloalkyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl, pyrrolyl, 1-(C
1
-C
4
alkyl)pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, furyl, benzodioxanyl, tetrahydrofuryl, pyrrolidinyl, 1-(C
1
-C
4
alkyl)pyrrolidinyl, 1-benzylpyrrolidinyl, piperidinyl, 1-benzylpiperidin-4-yl, or quinuclidinyl;
R
7
is hydrogen, or C
1
-C
4
alkyl;
R
8
is C
1
-C
4
alkyl, phenyl, or pyridinyl optionally substituted with nitro;
R
7
and R
8
taken together with the nitrogen atom to which they are attached form morpholinyl, optionally substituted piperazinyl, or pyrrolidinyl;
R
5
and X′ taken together with the nitrogen to which they are attached form:
2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl;
piperidinyl optionally substituted at the 4-position with hydroxy, pyrrolidin-1-yl, piperidin-1-yl, benzyl, or piperidin-1-yl (C1-C4 alkylene);
piperidinyl mono- or disubstituted with methyl;
piperazinyl optionally substituted at the 4-position with C
1
-C
4
alkyl, C
3
-C
6
cycloalkyl, phenyl, phenyl (C1-C4 alkylene), &agr;-methylbenzyl, N-(C
1
-C
4
alkyl)acetamid-2-yl, or C
1
-C
4
alkoxycarbonyl;
1,2,3,4-tetrahydroisoquinolin-2-yl; or
homopiperazinyl substituted in the 4-position with C
1
-C
4
alkyl;
R
2
, Q, and X taken together with the bridging carbon atoms to which they are attached form the lactone
R
10
is C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, phenyl(C1-C4 alkylene) where the phenyl is optionally substituted with C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halo, naphthyl, thienyl, furyl, benzothienyl, benzofuryl, or phenyl optionally monosubstituted with C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halo;
R
11
is C
1
-C
4
alkyl, C
3
-C
7
cycloalkyl, phenyl optionally substituted with one or two substituents independently selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C
1
-C
4
alkyl)amino, di(C
1
-C
4
alkyl)amino, C
1
-C
4
alkylsulfonylamino, and nitro, naphthyl optionally substituted with one or two substituents independently selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C
1
-C
4
alkyl)amino, di(C
1
-C
4
alkyl)amino, and nitro, or C
1
-C
4
alkoxycarbonyl;
R
12
is:
C
1
-C
4
alkyl optionally monosubstituted with a substituent selected from the group consisting of hydroxy, protected carboxy, carbamoyl, thiobenzyl and C
1
-C
4
thioalkyl;
phenyl optionally substituted with one or two substituents independently selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C
1
-C
4
alkyl)amino, di(C
1
-C
4
alkyl)amino, C
1
-C
4
alkylsulfonylamino, and nitro;
naphthyl optionally substituted with one or two substituents independently selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C
1
-C
4
alkyl)amino, di(C
1
-C
4
alkyl)amino, and nitro; or
C
1
-C
4
alkoxycarbonyl;
R
13
is:
C
1
-C
4
alkoxycarbonyl;
benzyloxycarbonyl where the phenyl group is optionally substituted with one or two substituents independently selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, cyano, nitro, amino, carbamoyl, hydroxy, mono(C
1
-C
4
alkyl)amino, and di(C
1
-C
4
alkyl)amino;
benzoyl where the phenyl group is optionally substituted with one or two substituents selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C
1
-C
4
alkyl)amino, di(C
1
-C
4
alkyl)amino, C
1
-C
4
alkylsulfonylamino, and nitro; and
R
14
and R
15
are:
C
1
-C
5
alkanoyloxy;
benzoyloxy optionally substituted with one or two substituents independently selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, cyano, nitro, amino and C
1
-C
4
Bruns, Jr. Robert F
Cooper Robin D G
Dressman Bruce A
Hunden David C
Kaldor Stephen W
Eli Lilly and Company
McKane Joseph K.
Small Andrea D.
Titus Robert D.
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