Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-07
2004-02-24
Wang, Shengjun (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06696466
ABSTRACT:
TECHNICAL FIELD
This invention relates to methods of treating neuronal inflammatory disorders.
THE INVENTION
Certain hydroxyalkyiquinoline acids and ether acids, as well as their corresponding salts, are known to be leukotriene antagonists. See, e.g., U.S. Pat. Nos. 5,266,568, 5,270,324, 5,428,033, 5,565,473 and 5,856,322. As noted in the foregoing patents, these compounds are known to be useful in the treatment of pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases, allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like, inflammation such as arthritis or inflammatory bowel disease, pain, skin disorders such as psoriasis, a topic eczema, and the like, cardiovascular disorders such as angina, myocardial ischemia, hypertension, platelet aggregation and the like, renal insufficiency arising from ischemia induced by immunological or chemical (cyclosporin) etiology, migraine or cluster headache, ocular conditions such as uveitis, hepatitis resulting from chemical, immunological or infectious stimuli, trauma or shock states such as burn injuries, endotoxemia and the like, allograft rejection, prevention of side effects associated with therapeutic administration of cytokines such as Interleukin II and tumor necrosis factor, chronic lung diseases such as cystic fibrosis, bronchitis and other small and large-airway diseases, cholecystitis; erosive gastritis; erosive esophagitis; diarrhea; cerebral spasm; premature labor; spontaneous abortion; dysmenorrhea; ischemia; noxious agent-induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CCl
4
and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma-or stress-induced cell damage; glycerol-induced renal failure; and cytoprotective activity in gastrointestinal mucosa and prevention of gastric lesions.
However, it has now been found that select hydroxyalkylquinoline acids (and the pharmaceutically acceptable salts thereof) are useful in the treatment of conditions which are believed to be caused by neuronal inflammation. Neuronal inflammatory disorders share a particular pathophysiology in relation to the select hydroxyalkylquinoline compounds. In particular, compounds which have the biological property in mammals of acting as “leukotriene antagonists” are particularly effective in the treatment of neuronal inflammatory disorders.
Furthermore, it has been discovered that certain hydroxyalkylquinoline acids and their salts can be utilized to treat some disorders which have not been conclusively shown to originate with inflamed neurons. One particularly painful and debilitating group of disorders, members of which have responded remarkably well to treatment with hydroxyalkylquinolines, are those commonly referred to as repetitive motion disorders. In the case of such disorders, hydroxyalkylquinolines not only effectively relieve the symptoms, but often effect a complete cure, allowing return to the same repetitive motion-type activity which caused the disorder without incidence of relapse. Regardless of any previous association with repetitive motion, the disorders referred to hereinafter are considered to be neuronal inflammatory disorders for the purposes of this description, even if it has not been conclusively established that the symptoms of the particular disorder are caused or mediated by inflamed neuronal elements.
Disorders which are known to be neural inflammatory in nature include viral infections, such as Herpes simplexes I and II. The present invention has demonstrated success in the treatment of symptoms of viral infections. Thus a method is provided for the treatment and/or the long term suppression of symptoms of viral infection such as skin lesions and postherpetic neuralgia, as well as other symptoms of viral infection which are neuronal inflammatory in origin.
The present invention has also been successful in halting the course of a condition which has long been suspected by the present inventor to be neuronal inflammatory in origin: the progressive graying of the scalp hair. Thus the present invention provides a method for the treatment and/or long-term suppression of symptoms of scalp hair conditions which are neuronal inflammatory in nature, such as progressive graying.
In addition, the present invention provides a method for treating and/or suppression of symptoms of neuronal inflammatory conditions whose etiology is often partially or fully unknown, some of which are Multiple sclerosis, Guillian-Barre syndrome and Bell's palsy.
Furthermore, the present invention provides a method for the treatment of neuronal inflammatory conditions which originate with external factors, such conditions including traumatic spinal injury.
Moreover, the present invention provides a method for treatment and long term suppression of symptoms associated with disorders previously considered repetitive motion disorders.
The above-described methods comprise administering, to a mammal in need of such treatment, a therapeutically effective amount of a compound having a chemical structural formula as follows:
wherein:
R
1
is H, halogen, —CF
3
, —CN, —NO
2
, or N
3
;
R
2
is lower alkyl, lower alkenyl, lower alkynyl, —CF
3
, —CH
2
F, —CHF
2
, CH
2
CF
3
, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or two R
2
groups joined to the same carbon to form a carbocyclic ring of up to 8 members;
R
3
is H or R
2
;
R
4
is halogen, —NO
2
, —CN, —OR
3
, —SR
3
, NR
3
R
3
, NR
3
C(O)R
7
or R
3
;
R
5
is H, halogen, —NO
2
, —N
3
, —CN, —SR
2
, NR
3
R
3
, —OR
3
, lower alkyl, or —C(O)R
3
;
R
6
is —(CH
2
)
5
—C(R
7
R
7
)—(CH
2
), —R
8
or —CH
2
C(O)NR
12
R
12
;
R
7
is H or C
1
-C
4
alkyl;
R
8
is the radical W—R
9;
R
9
contains up to 20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclic or monocyclic carboxylic acid;
R
11
is lower alkyl, —C(O)R
14
, unsubstituted phenyl, or unsubstituted benzyl;
R
12
is H, or R
11
;
R
13
is lower alkyl, lower alkenyl, lower alkynyl, —CF
3
or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R
14
is H or R
13
;
R
16
is H, C
1
-C
4
alkyl, or OH;
R
17
is lower alkyl, lower alkenyl, lower alkynyl, or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R
18
is lower alkyl, lower alkenyl, lower alkynyl, —CF
3
or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R
19
is lower alkyl, lower alkenyl, lower alkynyl, —CF
3
or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R
21
is H or R
17
;
R
22
is R
4
, CHR
7
OR
3
, or CHR
7
SR
2
;
m is 0-8;
m′ is 2 or 3;
n and n′ are independently 0 or 1,
p and p′ are independently 0-8;
m+n+p is 1-10 when r is 1 and X
2
is O, S, S(O), or S(O)
2
;
m+n+p is 0-10 when r is 1 and X
2
is CR
3
R
16
;
m+n+p is 0-10 when r is 0;
m′+n′+p′ is 2-10;
r and r′ are independently 0 or 1;
s is 0-3;
Q
1
is —C(O)OR
3
, 1H (or 2H)-tetfazol-5-yl, —C(O)OR
6
, —C(O)NHS(O)
2
R
13
, —CN, —C(O)NR
12
R
12
, NR
21
S(O)
2
R
13
, —NR
12
C(O)NR
12
R
12
, —NR
21
C(O)R
18
, —OC(O)NR
12
R
12
, —C(O)R
19
, —S(O)R
18
, —S(O)
2
R
18
, —S(O)
2
NR
12
R
12
, —NO
2
, —NR
21
C(O)OR
17
, —C(NR
12
R
12
)═NR
12
, —C(R
13
)═NOH;
Q
2
is OH;
W is O, S, or NR
3
;
X
2
and X
3
are independently O, S, S(O), S(O)
2
, or CR
3
R
16
; with the proviso that at least on is S or SO
2
;
Y is —CR
3
═CR
3
—
Z
1
and Z
2
are independently —HET(—R
3
—R
5
)—;
HET is the diradical of a benzene, a pyridine, a furan, or a thiophene;
or a pharmaceutically acceptable salt thereof. The term “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects, e.g., an acid or base addition salt.
Prefer
Sieberth & Patty, L.L.P.
Wang Shengjun
LandOfFree
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