Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-30
2003-04-29
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06555548
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of neuromuscular agents, and the pharmacologically acceptable salts thereof, for the treatment of nervous system disorders, and more particularly to the use of compounds of U.S. Pat. Nos. 5,273,975, 5,436,240, 5,594,024, 5,462,947, and 4,526,892 for the treatment of symptoms of fibromyalgia syndrome and chronic fatigue syndrome.
BACKGROUND OF THE INVENTION
Chronic fatigue syndrome (CFS), also referred to as chronic fatigue immune disorders syndrome, yuppie flu; fatigue—chronic, and chronic fatigue and immune dysfunction syndrome, is a clinically defined condition characterized by profound tiredness or fatigue. In addition, patients with CFS generally report various nonspecific symptoms, including weakness, muscle aches and pains, excessive sleep, malaise, fever, sore throat, tender lymph nodes, impaired memory and/or mental concentration, insomnia, and depression. The exact cause of CFS is unknown and, to date, there are no specific tests to confirm the diagnosis of CFS, though a variety of tests are usually done to exclude other possible causes of the symptoms.
Fibromyalgia syndrome (FMS), also referred to as fibromyalgia, fibromyositis, fibrositis, or myofasical pain syndrome, is a rheumatic condition generally characterized by widespread pain in fibrous tissues, muscles, tendons, and other connective tissues, fatigue, headaches, lack of restorative sleep, and numbness. Thus, FMS shares many clinical features with CFS. Similar to CFS, there are no specific diagnostic tests for FMS.
Many medications are commonly used to treat CFS and FMS. Examples of the more common medications include hypnotics, immune suppressants, various other prescribed medications, and an array of non-prescription medications. Examples of other prescription drugs include opioid antagonists, sodium retention agents/beta blockers, calcium channel blockers/histamine blockers, anti-depressants, allergy medications, and acute anxiety medications. However, there are no known medications that permanently resolve the symptoms of either CFS or FMS. In addition, many of the currently used medications produce side effects ranging from mild side effects, e.g., drowsiness, dizziness, and nausea to serious side effects, e.g., addiction and liver damage
Accordingly, there is clearly a need for better treatments for chronic fatigue syndrome and fibromyalgia. Now, the present invention reveals several compounds that can be formulated into useful therapeutic treatments for these conditions.
SUMMARY OF THE INVENTION
Disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a heterocyclic amine-type compound of formula (A),
or a pharmaceutically acceptable salt thereof, wherein:
R
1
, R
2
, and R
3
are independently hydrogen, C
1-6
alkyl, C
3-5
alkenyl, C
3-5
alkynyl, C
3-7
cycloalkyl, C
4-10
cycloalkyl or phenyl-substituted C
1-6
alkyl, or R
1
and R
2
are joined to form a C
3-7
cyclic amine which can contain additional heteroatoms and/or unsaturation;
X is hydrogen, C
1-6
alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;
A is CH, CH
2
, CH-halogen, CHCH
3
, C═O, C═S, C—SCH
3
, C═NH, C—NH
2
, C—NHCH
3
, C—NHCOOCH
3
, C—NHCN, SO
2
, or N;
B is CH
2
, CH, CH-halogen, C═O, N, NH or N—CH
3
, or O;
n is 0 or 1; and
D is CH, CH
2
, CH-halogen, C═O, O, N, NH, or N—CH
3
.
Preferred compounds of formula (A) include (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (uninverted CAS name) and (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, and their pharmaceutically acceptable salts. Also disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a substituted phenylazacycloalkane-type compound of formula (B),
or pharmaceutically acceptable salts thereof, wherein:
n is 0-3;
R
1
and R
2
are independently H (provided only one is H at the same time), —OH (provided R
4
is other than hydrogen), CN, CH
2
CN, 2- or 4-CF
3
, CH
2
CF
3
, CH
2
CHF
2
, CH═CF
2 (CH
2
)
2
CF
3
, ethenyl, 2-propenyl, OSO
2
CH
3
, OSO
2
CF
3
, SSO
2
CF
3
, COR
4
, COOR
4
, CON(R
4
)
2
, SO
x
CH
3
(where, x is 0-2), SO
x
CF
3
, O(CH
2
)
x
CF
3
, SO
2
N( COCOOR
4
, COCOON(R
4
)
2
, C
1-8
alkyls, C
3-8
cycloalkyls, CH
2
OR
4
, CH
2
(R
4
)
2
, NR
4
SO
2
CF
3
, NO
2
, halogen, a phenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;
R
3
is hydrogen, CF
3
, CH
2
CF
3
, C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, C
4
-C
9
cycloalkyl-methyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH
2
)
m
—R
5
(where m is 1-8), CH
2
SCH
3
or a C
4
-C
8
alkyl bonded to said nitrogen and one of its adjacent carbon atoms inclusive to form a cyclic structure;
R
4
is independently hydrogen, CF
3
, CH
2
CF
3
, C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, C
4
-C
9
cycloalkyl-methyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH
2
)
m
—R
5
where m is 1-8;
R
5
is phenyl, phenyl (substituted with a CN, CF
3
, CH
2
CF
3
, C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, C
4
-C
9
cycloalkyl-methyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl), 2-thiophenyl, 3-thiophenyl, —NR
6
CONR
6
R
7
, or —CONR
6
R
7
:
R
6
and R
7
are independently hydrogen, C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, C
4
-C
9
cycloalkyl, methyl, C
2
-C
8
alkenyl or C
2
-C
8
alkynyl; and with the proviso that when R
1
is 2-CN or 4-CN, R
2
is H, R
3
is n-Pr and n is 1 or 3 then such compound is a pure enantiomer.
Preferred compounds of formula (B) include (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide, and (3S)-3-[3-Methylsulfonyl)phenyl]-1-propylpiperidine (2E)-2-butenedioate (1:1).
Further disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a cabergoline-type compound, or pharmaceutically acceptable salts thereof, with the preferred compound of this class being cabergoline.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to therapies for fibromyalgia (FMS) and chronic fatigue syndrome (CFS), and more particularly to the use of three broad classes of compounds having dopamine receptor activities for treating the symptoms of FMS and CFS. The useful compounds identified for the method of the present invention are described in two ways, with generic descriptions of completely enabled and disclosed groups of compounds and with detailed individually described compound structures and names. One class of compounds useful for treating symptoms of CFS and FMS in the present invention are those compounds, or pharmaceutically acceptable salts thereof, di-closed generically or specifically in U.S. Pat. Nos. 5,273,975 and 5,436,240. These compounds are generically referred to as heterocyclic amine type compounds and are structurally represented by formula (A),
wherein:
R
1
, R
2
, and R
3
are independently and are hydrogen, C
1-6
alkyl, C
3-5
alkenyl, or C
3-5
alkynyl, C
3-7
cycloalkyl, C
4-10
cycloalkyl- or phenyl-substituted C
1-6
alkyl, or R
1
and R
2
are joined to form a C
3-7
cyclic amine which can contain additional heteroatoms and/or unsaturation;
X is hydrogen, C
1-6
alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;
A is CH, CH
2
, CH-halogen, CHCH
3
, C═O, C═S, C—SCH
3
, C═NH, C—NH
2
, C—NHCH
3
, C—NHCOOCH
3
, or C—NHCN, SO
2
, or N;
B is CH
2
, CH, CH-halogen, C═O, N, NH, N—CH
3
or O;
n is 0 or 1; and
D is CH, CH
2
, CH-halogen, C═O, O, N, NH or N—CH
3
.
The methods oft m
Ashley Thomas M.
Marshall Robert Clyde
McCall Robert B.
Robertson David W.
Pharmacia & Upjohn Company
Spivack Phyllis G.
Zhang Austin W.
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