Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-08
2003-09-02
Rotman, Alan L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S263200
Reexamination Certificate
active
06613786
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to novel 2phenyl-5thiophenyl-2,4-dihydro-[1,2,4]-triazol-3-one derivatives which are smooth muscle relaxants and therefore are useful in treating disorders responsive to relaxation of smooth muscle such as asthma, irritable bowel syndrome, male erectile dysfunction and particularly urinary incontinence. The present invention is also directed to a method of treatment with the novel compounds and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Urinary incontinence is a common condition that is the frequent cause of confinement to nursing homes among the elderly. It afflicts significant numbers among both men and women and all ages. In addition studies show some degree of daily incontinence reported among as many as 17% of young apparently healthy women. Safe and reliable methods for treating incontinence are clearly needed. Urinary incontinence is a manifestation of the failure to control the muscles of the bladder or urinary sphincter. Incontinence results when the pressure within the bladder is too great as a result of excessive force exerted by the bladder muscles, or when the sphincter muscles are too weak. Urinary incontinence can be a manifestation of other diseases such as Parkinsonism, multiple sclerosis, lesions of the central nervous system, or bladder infections. Interstitial cysts can result in instability of the bladder detusor muscles and a particularly unpleasant form of urge incontinence. Urinary incontinence is believed to currently affect over 12 million people in the United States alone, and to occur in between 15 and 30% of the population over 60. The current standard of care is quite unsatisfactory. All of the current drugs now utilized to treat urinary incontinence suffer from polypharmacology and unwanted side effects.
Relaxation of the smooth muscle tissue of the bladder results in a decrease in the pressure within the bladder. Relaxation of the smooth muscle tissue of the bladder would therefore be desirable to treat urinary incontinence which results when the pressure within the bladder is too great as a result of excessive force exerted by the bladder muscles. Relaxation of other smooth muscle tissues may also result in alleviation of diseases or disorders in which excessive smooth muscle contraction has been implicated such as asthma, irritable bowel syndrome, male erectile dysfunction.
The present invention provides novel 2phenyl-5thiophenyl-2,4-dihydro-[1,2,4]-triazol-3-one derivatives which have been found to be smooth muscle relaxants. The present invention also provides compositions containing the novel 2phenyl-5thiophenyl-2,4-dihydro-[1,2,4]-triazol-3-one derivatives and a method of treating diseases or disorders responsive to the relaxation of smooth muscle tissue such as asthma, irritable bowel syndrome, male erectile dysfunction and particularly urinary incontinence.
U.S. Pat. No. 5,869,509, issued Feb. 9, 1999, provides novel diphenyl heterocyclic derivatives having the general formula
wherein “Het” is a moiety selected from the group consisting of (A) through (H):
wherein Z is independently for each occurrence selected from O or S; R
a
, R
b
and R
c
each are independently selected from hydrogen, halogen, OH, CF
3
, NO
2
, or
provided R
c
is not hydrogen; and when R
a
and R
b
are hydrogen, R
c
may be a heterocyclic moiety selected from the group consisting of imidazol-1-yl, morpholinomethyl, N-methylimidazol-2-yl, and pyridin-2-yl; R
d
and R
e
each are independently selected from hydrogen, halogen, CF
3
, NO
2
or imidazol-1-yl; m, n and p each are independently selected from 0 or 1; and R
f
and R
g
each are independently hydrogen; C
1-4
alkyl; or R
f
and R
g
, taken together with the nitrogen atom to which they are attached, is a heterocyclic moiety selected from the group consisting of N-methylpiperazine, morpholine, thiomorpholine, N-benzylpiperazine and imidazolinone.
A method for preparing [1,2,4]-2,4-dihydrotriazolones was disclosed in
J. Org. Chem.
1976, 41, 3233-3237, including a single thiophen-2-yl derivative, 2phenyl-5thiophen-2-yl-2,4-dihydro-[1,2,4]triazol-3-one, shown below.
Nippon Kagaku Zasshi
1968, 89, 69-74 also discloses 2phenyl-5thiophen-2-yl-2,4-dihydro-[1,2,4]triazol-3-one, prepared by the ring closure reaction of the corresponding 1-aryl-4-acyl semicarbazide.
A method to oxidize oxadiazoles to provide [1,2,4]-2,4-dihydrotriazolones was reported in
J. Heterocyclic Chem.
1985, 22, 1383-1388. The four 5-(5-nitrothiophen-2-yl)-2,4-diphenyl-2,4-dihydro-[1,2,4]triazol-3-one derivatives shown below were disclosed in this publication.
International Application WO9954315, published Oct. 28,1999, discloses triazolones of the general formula shown below, which act as neuroprotectants. In the general structure
R
2
may be a carbon linked 5 or 6-membered saturated or unsaturated heterocycle, such that 1, 2, 3, or 4 atoms can be chosen from oxygen, nitrogen or sulfur and the substituents can be C
1-6
alkyl or benzyl. R
1
may be phenyl or substituted phenyl.
SUMMARY OF THE INVENTION
Novel compounds of formula I are useful to treat disorders responsive to relaxation of smooth muscle:
wherein:
Q is
R
1
and R
2
are each independently selected from the group consisting of hydrogen, halogen, C
1-6
alkyl and C
2-6
alkenyl;
R
3
is halogen or trifluoromethyl; and
R
4
, R
5
and R
6
are each independently selected from the group consisting of hydrogen, halogen and C
1-6
alkyl;
or a nontoxic pharmaceutically acceptable salt or solvate thereof. The present invention also provides pharmaceutical compositions thereof and methods which employ them.
DETAILED DESCRIPTION OF THE INVENTION
The term “C
1-6
alkyl” as used herein and in the claims (unless the context indicates otherwise) means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, 3-methylbutyl, hexyl and the like. The term “C
2-6
alkenyl” as used herein and in the claims (unless the context indicates otherwise) means straight or branched chain alkenyl groups such as ethenyl (i.e. vinyl), propenyl, allyl, butenyl, 3-methylbutenyl, pentenyl, hexenyl and the like. Unless otherwise specified, the term “halogen” as used herein and in the claims is intended to include bromine, chlorine, iodine and fluorine while the term “halide” is intended to include bromide, chloride and iodide anion.
The term “nontoxic pharmaceutically acceptable salt” as used herein and in the claims is intended to include nontoxic acid and base addition salts. Suitable acids include sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, cinnamic, fumaric, mandelic, phosphoric, nitric, mucic, isethionic, palmitic, heptanoic, and the like. Suitable inorganic bases, such as alkali and alkaline earth metal bases, include metallic cations such as sodium, potassium, magnesium, calcium and the like.
Generally, pharmaceutically acceptable salts of the invention are those in which the counter-ion does not contribute significantly to the toxicity or pharmacological activity of the salt. In some instances, they have physical properties which make them more desirable for pharmaceutical formulations, such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation and compatibility with other ingredients with which the substance may be used for pharmaceutical purposes. The salts are routinely made by admixture of a Formula I compound with the selected acid or base, preferably by contact in solution employing an excess of commonly used inert solvents such as water, ether, benzene, methanol, ethanol, ethyl acetate and acetonitrile. They may also be made by metathesis or treatment with an ion exchange resin under conditions in which the appropriate ion of a salt of the substance of the Formula I is replaced by another ion under conditions which allow for separation of the desired species such as by precipitation from solut
Hewawasam Piyasena
King Dalton
Lodge Nicholas J.
Starrett John E.
Sun Li-Quang
Algieri Aldo A.
Bristol--Myers Squibb Company
Rotman Alan L.
Wright Sonya
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