U.S. patent application number 09/772321 was filed with the patent office on 2002-10-10 for methods for the treatment of central nervous system disorders in certain patient groups.
This patent application is currently assigned to R.T. Alamo Ventures I, L.L.C.. Invention is credited to Cutler, Neal R., Sramek, John.
Application Number | 20020147215 09/772321 |
Document ID | / |
Family ID | 25094675 |
Filed Date | 2002-10-10 |
United States Patent
Application |
20020147215 |
Kind Code |
A1 |
Cutler, Neal R. ; et
al. |
October 10, 2002 |
METHODS FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS IN
CERTAIN PATIENT GROUPS
Abstract
Methods and compositions for treating specific patient groups
for Central Nervous System disorders, including but not limited to
Tourette Syndrome, are provided. The methods of the present
invention comprise the utilization of pharmaceutical compositions
comprising quinolinones (and derivatives thereof) in patients with
symptoms of a Central Nervous System Disorder who are otherwise
free of cardiac disease and/or who have not been given organic
nitrates.
Inventors: |
Cutler, Neal R.; (Los
Angeles, CA) ; Sramek, John; (Irvine, CA) |
Correspondence
Address: |
MEDLEN & CARROLL, LLP
101 HOWARD STREET
SUITE 350
SAN FRANCISCO
CA
94105
US
|
Assignee: |
R.T. Alamo Ventures I,
L.L.C.
|
Family ID: |
25094675 |
Appl. No.: |
09/772321 |
Filed: |
January 26, 2001 |
Current U.S.
Class: |
514/312 |
Current CPC
Class: |
A61K 31/47 20130101 |
Class at
Publication: |
514/312 |
International
Class: |
A61K 031/4709 |
Claims
We claim:
1. A method, comprising: a) providing: i) a subject with symptoms
of a Central Nervous System disorder, and ii) a formulation
comprising flosequinan; and b) introducing said formulation to said
subject such that said symptoms are reduced.
2. The method of claim 1, wherein said flosequinan is present as a
racemic mixture.
3. The method of claim 1, wherein said flosequinan is a purified
enantiomer.
4. The method of claim 1, wherein said flosequinan is introduced
into said subject by oral administration.
5. The method of claim 4, wherein said subject is an adult human
and said oral administration comprises up to approximately 200
milligrams of flosequinan.
6. The method of claim 1, wherein said flosequinan is introduced
into said subject cutaneously.
7. The method of claim 1, wherein said flosequinan is introduced
into said subject intravenously.
8. The method of claim 1, wherein said subject is free from cardiac
disease.
9. The method of claim 1, wherein said subject is male.
10. The method of claim 1, wherein said subject is female.
11. The method of claim 1, wherein said subject is an adult.
12. The method of claim 1, wherein said subject is a child.
13. The method of claim 1, wherein said Central Nervous System
disorder is Tourette Syndrome.
14. The method of claim 1, wherein said subject is not being
treated with a drug that causes hypotensive effects.
15. The method of claim 1, wherein said subject has not been
treated in the past with a drug that causes hypotensive
effects.
16. The method of claim 1, wherein said subject is not being
treated with a nitrite or nitrate.
17. The method of claim 16, wherein said nitrate is selected from
the group consisting of glyceryl trinitrate, isosorbide dinitrate,
isosorbide-5-mononitrate and erythrityl tetranitrate.
18. A method, comprising: a) providing: i) a subject with symptoms
of a Central Nervous System disorder, and ii) a formulation
comprising cilostazol; and b) introducing said formulation to said
subject such that said symptoms are reduced.
19. The method of claim 18, wherein said cilostazol is introduced
into said subject by oral administration.
20. The method of claim 19, wherein said subject is an adult human
and said oral administration comprises up to approximately 100
milligrams of cilostazol twice a day.
21. The method of claim 18, wherein said cilostazol is introduced
into said subject cutaneously.
22. The method of claim 18, wherein said subject is male.
23. The method of claim 18, wherein said subject is female.
24. The method of claim 18, wherein said subject is an adult.
25. The method of claim 18, wherein said subject is a child.
26. The method of claim 18, wherein said Central Nervous System
disorder is Tourette Syndrome.
27. The method of claim 18, wherein said subject is free of cardiac
disease.
28. The method of claim 18, wherein said subject is not being
treated with a drug that causes hypotensive effects.
29. The method of claim 18, wherein said patient is not being
treated with nitrates or nitrites.
30. The method of claim 29, wherein said nitrate is selected from
the group consisting of glyceryl trinitrate, isosorbide dinitrate,
isosorbide-5-mononitrate and erythrityl tetranitrate.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to methods and compositions
for the treatment of Central Nervous System (CNS) disorders,
including but not limited to Tourette Syndrome, in adults and
children. The methods of the present invention comprise the
utilization of pharmaceutical compositions to patients who are free
of symptoms of cardiac disease and who have not been treated with
drugs which cause hypotensive effects, such as nitrites and
nitrates.
BACKGROUND
[0002] Tourette Syndrome (TS) is an autosomal dominant
neuropsychiatric disorder affecting up to one person in 2,500 and
is characterized by a range of neurological and behavioral
symptoms. Such symptoms include: (A) the presence of both motor and
vocal tics at some time during the illness, although not
necessarily concurrently; (B) the occurrence of quasi-daily tics
throughout a period of time exceeding one year; (C) variance in the
clinical phenomenology of the tics; and (D) marked distress or
significant impairment in social, occupational, or other important
areas of functioning. Patients with TS also often suffer from
co-morbid disorders such as Obsessive-Compulsive Disorder (OCD),
Attention-Deficit Hyperactivity Disorder (ADHD), anxiety disorders,
mood disorders, and panic disorders.
[0003] Tics experienced by a sufferer of TS can be transient or
acute, and simple or complex. Motor tics generally include eye
blinking, nose twitching, grimacing, muscle tensing, hopping,
touching objects or others, and rapid jerking of any part of the
body. Vocal or phonic tics typically include coughing, spitting,
grunting, barking, hissing, sucking sounds, gurgling, screeching,
whistling, palilalia, echolalia, and coprolalia.
[0004] The etiology and pathophysiology of TS are currently
unknown. However, pharmacological and metabolic evidence suggests
the involvement of several neurochemical systems, such as the
dopaminergic, noradrenergic, GABAergic, and serotonergic mechanisms
for example, and implicates neurotransmission dysfunction with the
disorder.
[0005] Historically, attempts at treating TS by psychotherapeutic
and behavior modification approaches were not encouraging in terms
of dramatic, lasting improvement. Thus, the pursuit of behavioral
strategies for decreasing the occurrence of tics has diminished.
Current treatment of TS includes the administration of medications
which are prescribed for neurotransmitter disorders. For example,
neuroleptic drugs (i.e. those which reduce the amount of dopamine
in the CNS) such as haloperidol, pimozide, fluphenazine, and
chloropromazine have been administered to TS patients with success,
but with side effects such as tardive dyskinesia, akinesia,
increased appetite and weight gain, amenorrhea, Q and T wave
changes, hypotension, and impotence. Other drugs such as clonidine
(an antihypertensive), clonazepam (an anticonvulsant), and various
antidepressants have been used to treat TS symptoms, but also
induce side effects in the patient such as, for example,
impotence.
[0006] Moreover, compounds that modulate activity of various
receptors have been suggested as treatment due to a decreased
number of receptors in the brains of patients suffering CNS
disorders. (Cosford et al., U.S. Pat. No. 5,868,473 and Kerrigan et
al., U.S. Pat. No. 5,767,116). Additionally, nicotine pharmacology
has been suggested in suppressing TS. (Bencherif et al., U.S. Pat.
No. 5,731,314). It has also been suggested that TS is caused by the
supply of tryptophan to the brain, and TS symptoms have been
treated by regulating the supply of tryptophan to the brain.
(Richardson et al., U.S. Pat. No. 5,670,539).
[0007] Stimulants such as methylphenidate, dextroamphetamine, and
pemoline may be prescribed for hyperactivity and ADHD, but often
lead to an increase in the tics in TS. Antidepressants such as
fluoxetine and clomiprimine are often prescribed to treat OCD
symptoms. However, such antidepressants may also induce side
effects such as muscle weakness, seizures, constipation, and
impotence.
[0008] Although other pharmacological methods of treatment of TS
are available, such methods have not proven to be highly
satisfactory and can be accompanied by severe side-effects. What is
needed is an improved method for the treatment of CNS disorders,
including but not limited to Tourette Syndrome, without the
induction of side effects in the patient such as, for example,
impotence.
SUMMARY OF THE INVENTION
[0009] The present invention relates to methods and compositions
for the treatment of Tourette Syndrome and other central nervous
system disorders in adults and children. The methods of the present
invention comprise the utilization of pharmaceutical compositions
to patients who have symptoms of TS, but who are otherwise free of
symptoms of cardiac disease and who have not been treated with
drugs which cause hypotensive effects, such as nitrites and
nitrates. The compositions comprise quinolinones, including
derivatives and purified enantiomers thereof. Quinolinones are also
known as quinolones and oxo-quinolines.
[0010] It is not intended that the present invention be limited by
the nature of the derivative. In one embodiment, the quinolinone
derivative is cilostazol
(6-[4-(1-cyclohexyl-1-H-tetrazol-5-yl)butoxyl]-3,4-dihydro--
2(1H)-quinolinone;
6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-
carbostyril;
6-[4-(1-cyclohexyl-5-tetrazoyl)butoxy]-1,2,3,4-tetrahydro-2-o-
xoquinoline).
[0011] In yet other embodiments, metabolites of cilostazol are
contemplated for use in the methods of the presently claimed
invention. Metabolites of cilostazol include, but are not limited
to monohydroxycilostazol, monohydroxydehydrocilostazol,
3,4-dihydro-6-hydroxy-2(1H)-quinolinone, their conjugates and
dehydrocilostazol.
[0012] In one embodiment, the present invention contemplates
halogenated quinolinones (e.g., fluoroquinolinone). In a preferred
embodiment, the quinolinone is a thioquinolinone or a sulphinyl or
suphonyl derivatives thereof. In one embodiment, the halogenated
quinolinone is flosequinan
(7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone). In a preferred
embodiment, an enantiomer of flosequinan is used.
[0013] In one embodiment, the present invention contemplates a
method, comprising: a) providing: i) an adult or child with
symptoms of a Central Nervous System (CNS) disorder, and ii)
flosequinan; and b) administering said flosequinan to said adult or
child. It is not intended that the present invention be limited to
symptoms of Tourette Syndrome (TS). A variety of such symptoms are
contemplated, including but not limited to, motor and vocal tics.
In one embodiment, the present invention contemplates administering
said flosequinan to said adult or child under conditions such that
frequency and/or severity of tics of said adult or child is
diminished.
[0014] In another embodiment, the method comprises providing: i) an
adult or child with Tourette Syndrome, and ii) flosequinan; and
introducing said flosequinan to adult or child (e.g. such that the
symptoms of Tourette Syndrome of said adult or child are
reduced).
[0015] In another embodiment, the present invention contemplates a
method, comprising: a) providing: i) a male or female with symptoms
of Tourette Syndrome, and ii) a composition comprising a
quinolinone selected from the group consisting of a racemic mixture
of flosequinan and an enantiomer of flosequinan; and b)
administering said composition to said male or female (e.g. such
that said symptoms are reduced). A variety of such symptoms are
contemplated, including but not limited to, motor and vocal tics.
In one embodiment, the present invention contemplates administering
said composition to said adult or child under conditions such that
frequency and/or severity of tics of said adult or child is
diminished.
[0016] In a preferred embodiment, the male or female is an adult
human and the oral dosage of flosequinan is in a single dose per
day of up to approximately two hundred milligrams, and more
preferably, between approximately ten to approximately seventy-five
milligrams. In another preferred embodiment, flosequinan is
administered in a single oral dose per day of between approximately
one hundred and ten and approximately two hundred milligrams. In
another preferred embodiment, the male or female is an adult human
and the oral dosage of flosequinan is in three daily doses, before
meals, each dose of up to approximately two hundred milligrams, and
more preferably, between approximately ten to approximately
seventy-five milligrams. In another preferred embodiment,
flosequinan is administered in three oral doses per day, before
meals, of between approximately one hundred and ten and
approximately two hundred milligrams. In other embodiments said
flosequinan is introduced cutaneously, by standard injection (e.g
intravenously or intramuscularly), or intranasally.
[0017] In one embodiment, the method comprises a) providing: i) a
subject (whether adult or child) suffering from symptoms of a CNS
disorder who is free from cardiac disease; and ii) flosequinan; and
b) introducing said flosequinan to said subject (e.g. such that
said symptoms are reduced). A variety of such symptoms are
contemplated, including but not limited to, motor and vocal tics.
In one embodiment, the present invention contemplates administering
said composition to said adult or child under conditions such that
frequency and/or severity of tics of said adult or child is
diminished. In another embodiment, said subject suffering from
symptoms of a CNS disorder is not free from cardiac disease.
[0018] In another embodiment, the method comprises a) providing: i)
a subject (whether adult or child) suffering from symptoms of a CNS
disorder who is not being treated (and/or has not been treated in
the past) with a drug that causes hypotensive effects, and ii)
flosequinan; and b) introducing said flosequinan to said subject
such that said symptoms are reduced. In another embodiment, said
subject suffering from symptoms of a CNS disorder is being, or has
been, treated with a drug that causes hypotensive effects.
[0019] In another embodiment, the method comprises a) providing: i)
a subject (whether adult or child) suffering from symptoms of a CNS
disorder who is not being treated (and/or has not been treated in
the past) with a nitrite or nitrate, and ii) flosequinan; and b)
introducing said flosequinan to said subject such that said
symptoms are reduced. In another embodiment, said subject suffering
from symptoms of a CNS disorder is being, or has been, treated with
a nitrate or nitrite.
[0020] In yet other preferred embodiments, metabolites of
cilostazol are contemplated for use in the methods of the presently
claimed invention. Metabolites of cilostazol include, but are not
limited to monohydroxycilostazol, monohydroxydehydrocilostazol,
3,4-dihydro-6-hydroxy-2(1H)-quinolinone, their conjugates and
dehydrocilostazol.
[0021] In one embodiment, the method comprises a) providing: i) a
subject (whether adult or child) suffering from symptoms of a CNS
disorder; and ii) cilostazol; and b) administering cilostazol to
the subject (e.g. such that said symptoms are reduced). A variety
of such symptoms are contemplated, including but not limited to,
motor and vocal tics. In one embodiment, the present invention
contemplates administering said composition to said adult or child
under conditions such that frequency and/or severity of tics of
said adult or child is diminished.
[0022] In one embodiment, the method comprises a) providing: i) a
subject (whether adult or child) suffering from symptoms of a CNS
disorder who is not being treated (and/or has not been treated in
the past) with a drug that causes hypotensive effects, and ii)
cilostazol; and b) introducing said cilostazol to said subject such
that said symptoms are reduced. In another embodiment, said subject
suffering from symptoms of a CNS disorder is being, or has been,
treated with a drug that causes hypotensive effects.
[0023] In another embodiment, the method comprises a) providing: i)
a subject (whether adult or child) suffering from symptoms of a CNS
disorder who is not being treated (and/or has not been treated in
the past) with a nitrite or nitrate, and ii) cilostazol; and b)
introducing said cilostazol to said subject such that said symptoms
are reduced. In another embodiment, said subject suffering from
symptoms of a CNS disorder is being, or has been, treated with a
nitrate or nitrite.
[0024] It is not intended that the present invention be limited to
the mode of administration. In one embodiment, cilostazol is
administered orally. In another embodiment, cilostazol is
administered cutaneously. In yet another embodiment, cilostazol is
administered intranasally. In an alternative embodiment, cilostazol
is administered through respiratory inhalation. In yet another
alternative embodiment, cilostazol is administered by standard
injection (e.g intravenously or intramuscularly).
[0025] In a preferred embodiment, the male or female is an adult
human and the oral dosage of cilostazol is in a single dose per day
of up to approximately two hundred milligrams, and more preferably,
between approximately ten to approximately one hundred milligrams.
In an even more preferred embodiment, cilostazol is administered in
two oral doses per day of between approximately fifty and
approximately one hundred milligrams. In another preferred
embodiment, the male or female is an adult human and the oral
dosage of cilostazol is in three daily doses, before meals, each
dose of up to approximately two hundred milligrams, and more
preferably, between approximately ten to approximately seventy-five
milligrams, and even more preferably, between approximately fifty
to approximately one hundred milligrams.
[0026] It is not intended that the present invention be limited to
the treatment of certain patient groups. In one embodiment, the
patient is an adult. In another embodiment, the patient is a child.
In one embodiment, the patient is free from cardiac diseases
including, but not limited to, congestive heart failure. In another
embodiment, the patient has not been treated with a drug that
causes hypotensive effects. In yet another embodiment, the patient
has not been treated with nitrates or nitrites.
[0027] In another embodiment, the method comprises providing: i) an
adult or child with Tourette Syndrome, and ii) a pharmaceutical
composition comprising cilostazol; and introducing the
pharmaceutical composition to the adult or child (e.g. such that
the symptoms of Tourette Syndrome of said adult or child are
reduced).
[0028] It is not intended that the present invention be limited by
the nature of the formulation. In one embodiment, the present
invention contemplates a formulation comprising a quinolinone or
derivative thereof in a mixture comprising lactose.
[0029] The present invention is not limited by the degree of
response by the subject. It is expected that the administration of
quinolinones will reduce symptoms of CNS disorders, including but
not limited to, motor and vocal tics associated with Tourette
Syndrome.
DESCRIPTION OF FIGURES
[0030] FIG. 1 depicts the chemical structure of a quinolinone (top)
and 16 C-7 substituents (bottom).
[0031] FIG. 2 depicts the respective HPLC column retention times
and optical rotations of the enantiomers of flosequinan separated
by the method provided in Example 1.
[0032] Definitions
[0033] As used herein, the term "quinolinone" refers to chemical
compositions comprising quinoline as set forth in the following
structure (2-quinolone): 1
[0034] as well as other forms of quinolinone, (e.g., isoquinolone):
2
[0035] As used herein, the phrase "derivatives of quinolinone"
refers to chemical compositions comprising quinolinone with a
chemical group attached, including (but not limited to) halogenated
quinolinone.
[0036] As used herein, the phrase "methylsulphinyl derivatives of
quinolinone" refers to chemical compositions comprising quinolinone
with a methylsulphinyl group attached. Examples include flosequinan
(7-fluoro-1-methyl-3-(methylsulphinyl)-4(1H)-quinolone;
7-fluoro-1-methyl-3-(methylsufinyl)-4(1H)-quinolinone): 3
[0037] and sulfone metabolites of flosequinan: 4
[0038] Other examples of quinolinone derivatives include cilostazol
(6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinon-
e;
6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril;
[3,4-Dihydro-6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-2(1
H)-quinolinone)]: 5
[0039] and metabolites of cilostazol. Examples include
monohydroxycilostazol, monohydroxydehydrocilostazol,
3,4-dihydro-6-hydroxy-2(1H)-quinolinone, their conjugates and
dehydrocilostazol.
[0040] As used herein, "Central Nervous System disorder (CNS)"
refers to any neurological disorder that affects the brain or
spinal column, including, but not limited to Tourette Syndrome
(TS), Parkinson's Disease, Huntington's Corea, Attention Deficit
Hyperactivity Disorder (ADHD), Obsessive-Compulsive Disorder (OCD),
Alzheimer's Disease, Tardive Dyskinesia (TD), Multiple Sclerosis
(MS), depression, mania, and psychosis.
[0041] As used herein, the terms "lower alkyl", "lower alkoxy",
"lower alkanoyl", and "lower alkythio" denote such groups
containing 1-8 carbon atoms, especially 2-4 carbon atoms for lower
alkanoyl and 1-4 carbon atoms for the other groups. Examples of
such groups include methyl, ethyl, propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, n-heptyl, n-octyl, methoxy, ethoxy, propoxy,
n-butoxy, isobutoxy, acetyl, propionyl, butyryl, methylthio,
ethylthio, propylthio and n-butylthio.
[0042] As used herein, the term "active compound" denotes a
pyridinone compound of general formula I (See "Other Compounds
Useful in the Treatment of Central Nervous System Disorders"
below), or a quinolinone or quinolinone derivative as illustrated
and described above.
[0043] As used herein, "Tourette Syndrome" refers to an autosomal
dominant neuropsychiatric disorder which affects the CNS and is
characterized by a range of neurological and behavioral symptoms
including, but not limited to, motor and vocal tics.
[0044] As used herein, "symptoms of Tourette Syndrome" refers to
any two of the following symptoms: (A) the presence of both motor
and vocal tics at some time during the illness, although not
necessarily concurrently; (B) the occurrence of quasi-daily tics
throughout a period of time exceeding one year; (C) variance in the
clinical phenomenology of the tics; (D) marked distress or
significant impairment in social, occupational, or other important
areas of functioning; and (E) co-morbid symptoms such as
Obsessive-Compulsive Disorder (OCD), Attention-Deficit
Hyperactivity Disorder (ADHD), anxiety disorders, mood disorders,
and panic disorders. Symptoms are "reduced" when the magnitude
(e.g. intensity) or frequency of symptoms is reduced. It is not
intended that the present invention be limited only to cases where
the symptoms are eliminated. The present invention specifically
contemplates treatment such that symptoms are reduced (and the
condition of the patient is thereby "improved"), albeit not
completely eliminated.
[0045] As used herein, a patient who is "free from cardiac disease"
and a patient who is "free from symptoms of cardiac disease"
indicate that the patient has not been diagnosed with angina,
myocardial infarction, congestive heart failure and that symptoms
of angina, ischemia, myocardial infarction, and/or congestive heart
failure have not been detected.
[0046] As used herein, "drugs that have hypotensive effects" are
those drugs which, when administered, cause the patient's
end-diastolic blood pressure to be reduced. Nitrates are commonly
used drugs which have hypotensive effects.
[0047] As used herein, "nitrates" are compounds that contain the
--NO.sub.3-- moiety. Nitrates typically used in the clinic are
shown in Table 1.
[0048] As used herein, "nitrites" are compounds that contain the
--NO.sub.2-- moiety. Nitrites typically used in the clinic are
shown in Table 1. As used herein "standard injection" refers to the
placement of a pharmaceutical composition into a subject (e.g.,
with a hypodermic needle). For example, such injection can be made
subcutaneously, intravenously, intramuscularly, intrathecally,
etc.
[0049] As used herein, "by oral administration" refers to the
introduction of a pharmaceutical composition into a subject by way
of the oral cavity (e.g., in aqueous liquid or solid form).
[0050] As used herein, "cutaneously" refers to the introduction of
a pharmaceutical composition into a subject by application to the
surface of the skin such that the composition is absorbed into the
subject.
[0051] As used herein, "intranasally" refers to the introduction of
a pharmaceutical composition within the nasal cavity.
[0052] As used herein, "respiratory inhalation" refers to the
introduction of a pharmaceutical composition within the respiratory
tract.
[0053] As used herein "single dosage" refers to a pharmaceutical
composition of a formulation that is capable of achieving its
intended effect in a single administration or application.
[0054] As used herein, the term "subject" refers to both humans and
animals.
[0055] As used herein, the term "enantiomer" refers to
stereoisomers of molecules that are non-superimposable mirror
images of each other. Enantiomers have identical physical
properties, such as melting points and boiling points, and also
have identical spectroscopic properties. Enantiomers differ from
each other with respect to their interaction with plane-polarized
light, and with respect to biological activity.
[0056] As used herein, the term "stereoisomer" refers to compounds
that have their atoms connected in the same order but differ in the
arrangement of their atoms in space. (e.g. cis-2-butane and
trans-2-butane).
1TABLE 1 NONPROPRIETARY NAMES AND TRADE CHEMICAL PREPARATIONS,
USUAL DOSES, AND NAMES STRUCTURE ROUTES OF ADMINISTRATION* Amyl
nitrite (isoamyl nitrite) 6 Inh: 0.18 or 0.3 ml, inhalation
Nitroglycerin (glyceryl trinitrate; NITRO-BID, NITROSTAT, NITROL,
NITRO-DUR, others) 7 T: 0.15 to 0.6 mg as needed S: 0.4 mg per
spray as needed C: 2.5 to 9 mg two to four times daily B: 1 mg
every 3 to 5 h O: 1.25 to 5 cm (1/2 to 2 in.), topically to skin
every 4 to 8 h D: 1 disc (2.5 to 15 mg) every 24 h # IV: 5
.mu.g/min; increments of 5 .mu.g/min Isosorbide dinitrate (ISORDIL,
SORBITRATE, DILATRATE, others) 8 T: 2.5 to 10 mg every 2 to 3 h
T(C): 5 to 10 mg every 2 to 3 h T(O): 10 to 40 mg every 6 h C: 40
to 80 mg every 8 to 12 h Isosorbide-5-mononitrate (IMDUR, ISMO,
others) 9 T: 10 to 40 mg twice daily C: 60 mg daily Erythrityl
tetranitrate (CARDILATE) 10 T: 5 to 10 mg as needed T(O): 10 mg
three times daily B, buccal (transmucosal) tablet; C,
sustained-release capsule or tablet; D, transdermal disc; Inh,
inhalant; IV, intravenous injection; O, ointment; S, lingual spray;
T, tablet for sublingual use; T(C), chewable tablet; T(O), oral
tablet or capsule.
[0057] As used herein, the term "diastereoisomers" refers to
stereoisomers that are not mirror images of each other.
[0058] As used herein, the terms "purified enantiomer" and
"purified enantiomer preparation" are meant to indicate a
preparation (e.g. derived from the racemic mixture) wherein one
enantiomer represents less than 10%, and more preferably less than
5%, and still more preferably, less than 2% of the preparation.
[0059] As used herein, the term "racemic mixture" refers to a
mixture of the two enantiomers of one compound. An ideal racemic
mixture is one wherein there is a 50:50 mixture of both enantiomers
of a compound such that the optical rotation of the (+) enantiomer
cancels out the optical rotation of the (-) enantiomer.
DETAILED DESCRIPTION OF THE INVENTION
[0060] The present invention provides relates to methods and
compositions for the treatment of Central Nervous System disorders
in adults and children (including but not limited to Tourette
Syndrome) in particular treatment groups. The methods of the
present invention comprise the utilization of pharmaceutical
compositions to patients who are free of symptoms of cardiac
disease and who have not been treated with drugs which cause
hypotensive effects, such as nitrites and nitrates. The
compositions comprise quinolinones, including derivatives and
enantiomers thereof. A variety of quinolinone derivatives are shown
in FIG. 1. Methods for producing antibiotic derivatives of a
particular quinolone carboxylic acid skeleton are provided in U.S.
Pat. No. 4,623,650 to Gilligan et al., hereby incorporated by
reference.
[0061] In one embodiment, racemic flosequinan or an enantiomer of
flosequinan is administered. Importantly, flosequinan may
potentiate the hypotensive effects of nitrates, and its
administration to patients who are concurrently using organic
nitrates in any form may be contraindicated.
[0062] In one embodiment, the present invention contemplates the
use of compositions that are effective to control the symptomatic
motor and vocal tics suffered by adults and children with Tourette
Syndrome. The compositions comprise a quinolinone, including
derivatives and enantiomers thereof.
[0063] While the present invention is not limited by the nature of
the derivatives, in one embodiment, the present invention
encompasses the use of a variety of quinolinone derivatives (e.g.,
5-bromoquinoline, 5-nitroisoquinoline, 8-nitroisoquinoline and
1-methylisoquinoline). One skilled in the art can readily produce
such derivatives as set forth in McMurry, Organic Chemistry, 2nd
Ed., Brooks/Cole Publishing, Belmont, Calif. (1988), pages
1044-1045 and 1076.
[0064] In another embodiment, the present invention contemplates
the use of methylthio and methylsulphinyl derivatives of
quinolinone. In a preferred embodiment, the methylsulphinyl
derivative is flosequinan (whether as a racemic mixture or as a
purified enantiomer).
[0065] Flosequinan
[0066] Methods of producing methylsuphinyl and methylthio
derivatives of quinolinone, including flosequinan, are set forth in
U.S. Pat. Nos. 5,079,264 and 5,011,931 to MacLean et al., hereby
incorporated by reference. While it is not necessary to understand
any particular mechanism to carry out the present invention, it is
believed that in some circumstances flosequinan can act to diminish
the symptoms of CNS disorders, including but not limited to, the
symptoms associated with Tourette's Syndrome.
[0067] The action of flosequinan in the body is not precisely
understood. Its activity in the body is attributed to flosequinan
itself, as well as its sulfone metabolite. It has been reported to
be useful to some degree in the treatment of heart failure. (See
Kelso et al., J. Cardiovasc. Pharmacol. 25: 376 (1995)). However,
its action appears to have little effect in patients with end-stage
failure [Perreault et al., Br. J. Pharmacol. 106: 511 (1992)] and
does not affect mortality or arrhythmias following coronary artery
ligation. (See Jones et al, Br. J. Pharmacol. 108: 1111
(1993)).
[0068] Likewise, flosequinan has been reported to be a selective
inhibitor of phosphodiesterase III. (See Gristwood et al., Br. J.
Pharmacol. 105: 985 (1992) and Frodsham et al., Eur. J. Pharmacol.
211: 383 (1992); See also, Examples 2 & 3). However, report
that the phosphodiesterase inhibition of flosequinan, as relevant
to its efficacy in heart failure, is questionable. Thus, the
application of flosequinan to particular purposes in the body is
not well-characterized and must be determined empirically.
[0069] In another embodiment, the present invention contemplates
the use of purified enantiomers of flosequinan. Although the
present invention is not limited by a specific means of producing
enantiomers of flosequinan, methods of producing a racemic mixture
of flosequinan, are set forth in U.S. Pat. Nos. 5,079,264 and
5,011,931 to MacLean et al., hereby incorporated by reference.
Moreover, a means of resolving the enantiomers of flosequinan is
set forth in Morita et al., "Synthesis and Absolute Configuration
of the Enantiomers of 7-Fluoro-1-methyl-3-(methylsulfinyl)--
4(1H)-quinolinone (Flosequinan)," Chem. Pharm. Bull., 42(10):
2157-2160 (1994), hereby incorporated by reference.
[0070] Resolution of the (+) and (-) Enantiomers of Flosequinan
[0071] The present invention contemplates the resolution of the (+)
and (-) enantiomers of flosequinan. Many organic compounds,
including flosequinan, exist in optically active forms (i.e., they
have the ability to rotate the plane of plane-polarized light). In
describing an optically active compound, the prefixes D and L or R
and S are used to denote the absolute configuration of the molecule
about its chiral center(s). The prefixes d and 1 or (+) and (-) are
employed to designate the sign of rotation of plane-polarized light
by the compound, with (-) or 1 meaning that the compound is
levorotatory (rotates to the left). A compound prefixed with (+) or
d is dextrorotatory (rotates to the right). For a given chemical
structure, these compounds, called "stereoisomers," are identical
except that they are mirror images of one another.
[0072] Stereochemical purity is of importance in the field of
pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit
chirality. A case in point is provided by the L-form of the
beta-adrenergic blocking agent, propranolol, which is known to be
100 times more potent than the D-enantiomer. Furthermore, optical
purity is important since certain isomers may actually be
deleterious rather than simply inert. For example, it has been
suggested that the D-enantiomer of thalidomide was a safe and
effective sedative when prescribed for the control of morning
sickness during pregnancy, while the corresponding L-enantiomer has
been believed to be a potent teratogen.
[0073] The present invention is not limited by any specific means
of resolving the (+) and (-) enantiomers of flosequinan to obtain a
purified enantiomer of flosequinan. In one embodiment, said
enantiomers are resolved as follows. A racemic mixture of
flosequinan is subjected to high-performance liquid chromatography
(HPLC) over a Chiracel OD column (Chiral Technologies, Exton, Pa.)
at a flow rate of 1.0 ml/minute. A mobile phase comprising methanol
is utilized, resulting in the resolution of a distinct peak for
each enantiomer. The resolved (+) and (-) enantiomers of
flosequinan are eluted with methanol with an optical purity greater
than 99%.
[0074] Cilostazol
[0075] In another embodiment, the compositions utilized in the
methods of the present invention comprise cilostazol, including
derivatives thereof. Cilostazol is a phosphodiesterase inhibitor
(type III) that suppresses platelet aggregation and also acts as a
direct arterial vasodilator. In addition to its reported
vasodilator and antiplatelet effects, cilostazol has been proposed
to have beneficial effects on plasma lipoproteins, increasing
plasma high density lipoprotein cholesterol and apoliproprotein
(See e.g., Dawson et al., Circulation 98: 678-686 (1998); Elam et
al, Arterioscler Thromb. Vasc. Biol. 18: 1942-1947 (1998); Drug
Evaluation Monographs, vol. 99, Micromedex Inc.).
[0076] Method of preparation of cilostazol are set forth by Nishi
et al, Chem. Pharm. Bull. 31: 1151 (1983), and U.S. Pat. No.
4,277,479, hereby incorporated by reference), and its pharmacology,
metabolism, mechanism of action and clinical evaluations are
described in Arzneimittel-Forsch. 35: 1117-1208 (1985), hereby
incorporated by reference. While it is not necessary to understand
any particular mechanism to carry out the present invention, it is
believed that in some circumstances cilostazol can act to diminish
the symptoms of CNS disorders, including but not limited to, the
symptoms associated with Tourette's Syndrome.
[0077] In one embodiment cilostazol is administered. It is
contemplated that cilostazol be administered cutaneously, by
standard injection, intranasally, or through respiratory
inhalation, although it is not intended that the methods of the
present invention be limited to the mode of administration of
cilostazol. In one embodiment, cilostazol is administered as a
tablet. In another embodiment, cilostazol is administered as a
pharmaceutical composition.
[0078] While the present invention is not limited to the treatment
of a particular patient group, it is contemplated that the methods
of the present invention comprise the utilization of pharmaceutical
compounds and compositions to patients who are free of symptoms of
cardiac disease and who have not been treated with drugs which
cause hypotensive effects, such as nitrites and nitrates.
[0079] Diagnosis of Tourette Syndrome (TS)
[0080] Determination whether a human adult or child is suffering
from Tourette Syndrome is readily made by a person skilled in the
art using a number of readily available diagnostic procedures and
is based on the presence of symptoms associated with the disease.
The prevailing diagnostic criteria for TS recommended by the
American Psychiatric Association include both multiple motor and
vocal tics over a period of more than one year, voluntary
suppression of symptoms, a waxing and waning course, and onset
between ages two and twenty-one years. (See also, Robertson M.,
"Tourette Syndrome, associated conditions and the complexities of
treatment," Brain, 123: 425, 427 (2000)).
[0081] As well as tics, there are a variety of behavioral and
psychological difficulties that are experienced by many, though not
all, patients with TS. The most frequently reported behavioral
problems are attention deficits, obsessions, compulsions,
impulsivity, irritability, aggressivity, immaturity, self-injurious
behaviors, and depression. Some of the behaviors (e.g.
obsessive-compulsive behavior) may be an integral part of TS, while
others may be more common in TS patients because of certain
biological vulnerabilities (e.g. ADHD). Still others may represent
responses to the social stresses associated with a multiple tic
disorder or a combination of biological and psychological
reactions.
[0082] A neurological examination of a patient diagnosed with TS
should include documentation of neuromaturational difficulties and
other neurological findings. About half of TS patients have
non-localizing neurological findings suggesting disturbances in the
body scheme and integration of motor control. Such findings are
worth noting as "baseline" data since the use of medications such
as haloperidol may cloud the neurological picture.
[0083] Additional studies that may be considered in the biological
work-up include serum electrolytes, calcium, phosphorous, copper,
ceruloplasmin, and liver function tests--all related to movement
disorders of various types. However, in practice, such tests are
rarely needed for a diagnosis.
[0084] Finally, previous medications taken by the patient must be
reviewed in detail during a clinical assessment of a patient
diagnosed with TS. For example, if a child has received stimulant
medications, it is important to determine for what indications the
medications were administered, whether there were any pre-existing
tics or compulsions, and the temporal relation between the
stimulants and the new symptoms. Catecholaminergic agonists are
contained in other drugs, such as in decongestant combinations used
in treating allergies and in medications used for asthma. If a
patient with TS is taking a stimulant or a drug containing an
ephedrine-like agent, discontinuation should be strongly
considered.
[0085] Treatment of Tourette Syndrome
[0086] It is not intended that the present invention be limited by
the particular nature of the therapeutic preparation. For example,
the quinolinones (e.g. cilostazol) or quinolinone derivatives
(e.g., flosequinan) can be provided together with physiologically
tolerable liquid, gel or solid carriers, diluents, adjuvants and
excipients. In addition, quinolinone analogs may be used together
with other chemotherapeutic agents. On the other hand, formulations
may also contain such normally employed additives as binders,
fillers, carriers, preservatives, stabilizing agents, emulsifiers,
buffers and excipients as, for example, pharmaceutical grades of
mannitol, lactose, starch, magnesium stearate, sodium saccharin,
cellulose, magnesium carbonate, and the like. These compositions
typically contain 1%-95% of active ingredient, preferably
2%-70%.
[0087] The present invention is not limited by the method of
introduction of the therapeutic compound to the body. Among other
methods, the present invention contemplates administering
cutaneously, orally, or by standard injection (e.g.
intravenous).
[0088] The present invention also contemplates administering
flosequinan or cilostazol to the patient intranasally or through
respiratory inhalation. Formulations suitable for intranasal
administration include ointments, creams, lotions, pastes, gels,
sprays, aerosols, oils and other pharmaceutical carriers which
accomplish direct contact between flosequinan, cilostazol, or a
pharmaceutical composition comprising flosequinan or cilostazol and
the nasal cavity. Examples of pharmaceutical compositions
administered intranasally are described in U.S. Pat. Nos. 5,393,773
and 5,554,639 to Craig et al.; and U.S. Pat. No. 5,801,161 to
Merkus, all hereby incorporated by reference. Formulations suitable
for respiratory inhalation include ointments, creams, lotions,
pastes, gels, sprays, aerosols, oils and other pharmaceutical
carriers which accomplish direct contact between flosequinan,
cilostazol, or a pharmaceutical composition comprising flosequinan
or cilostazol and the respiratory tract. Examples of pharmaceutical
compositions administered through respiratory inhalation are
described in U.S. Pat. No. 4,552,891 to Hu et al.; U.S. Pat. No.
5,869,479 to Kreutner et al., and U.S. Pat. No. 5,864,037 to Chasis
et al., all hereby incorporated by reference.
[0089] In some embodiments, intranasal administration and
respiratory inhalation are the preferred modes of administration
due to the ease of administration and faster onset of therapeutic
activity. It is contemplated that intranasal administration and
respiratory inhalation are advantageous as they may allow a smaller
effective dosage to be administered than would be possible with the
oral route of administration. A preferred mode of administration
comprises administration to the lung. Intrapulmonary delivery of
pharmacologic agents to patients can be accomplished via
aerosolization. Alternatively, the agent may be administered to the
lung through a bronchoscope. Of course, the therapeutic agents may
be investigated for their efficacy via other routes of
administration, including parenteral administration.
[0090] Oral administration of flosequinan is an effective mode of
administration, with a mean absolute bioavailability of 72%
following a single does of fifty milligrams. Peak plasma
concentrations of flosequinan are observed 1-2 hours following oral
administration, while peak metabolite plasma levels are observed
about seven hours following oral dosage. While the present
invention is not limited to a specific dosage level, for adult
humans, in one preferred embodiment the dosage is a single dosage
per day of 25 milligrams, while in another preferred embodiment the
dosage is a single dosage per day of 50 milligrams, while in yet
another preferred embodiment the dosage is a single dosage per day
of 75 milligrams. In another preferred embodiment, the dosage is a
single dosage per day of approximately 125 milligrams and in
another preferred embodiment, the dosage is a single dosage per day
of approximately 150 milligrams. In another preferred embodiment,
the per day dosage is a single dosage of approximately 200
milligrams. Multiple dosages are also contemplated by the
invention.
[0091] Flosequinan is water soluble and is soluble in many organic
solvents. Thus, while the present invention is not limited by the
form of oral administration, aqueous and organic solution of
flosequinan for oral administration is contemplated. Likewise,
flosequinan can be associated with a solid pharmaceutical carrier
for solid oral administration (i.e., in pill form). One skilled in
the art is able to readily prepare such solid formulations, and in
one embodiment, the inactive ingredients include croscarmellose
sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate,
methocel E5, microcrystalline cellulose, povidine, propylene glycol
and titanium dioxide.
[0092] The oral administration of cilostazol is possible. While the
present invention is not limited to a specific dosage level, a
single dosage per day of up to approximately 200 milligrams, and
more preferably, between approximately ten to approximately one
hundred milligrams, is contemplated. In another embodiment, a
dosage of less than 100 milligrams of cilostazol per day is
contemplated (i.e., 25-75 milligrams per day). Multiple dosages are
also contemplated. In a preferred embodiment, two dosages per day
of approximately 50 to approximately 100 milligrams of cilostazol
are contemplated. In an even more preferred embodiment, cilostazol
is administered in two oral doses per day of between approximately
fifty and approximately one hundred milligrams. In another
preferred embodiment, the male or female is an adult human and the
oral dosage of cilostazol is in three daily doses, before meals,
each dose of up to approximately two hundred milligrams, and more
preferably, between approximately ten to approximately seventy-five
milligrams, and even more preferably, between approximately fifty
to approximately one hundred milligrams of cilostazol for adult
humans is contemplated. Peak plasma concentrations of cilostazol
are observed 2-4 hours following oral administration (See e.g.,
Suri et al., J. Clin. Pharmacol. 38: 144-150 (1998); Niki and Mori,
Arzneimittelforschung 35: 1173-1185 (1985)).
[0093] While the present invention is not limited by the form of
oral administration, aqueous and organic solutions of cilostazol
for oral administration are contemplated. Likewise, cilostazol can
be associated with a solid pharmaceutical carrier for solid oral
administration. The compositions may be formulated in a manner
known to one skilled in the art, using pharmaceutically acceptable
carriers suitable for use in such compositions that are also well
known in the art. It is contemplated that the compositions of the
present invention comprise 0.1-90% by weight of cilostazol. In one
embodiment, cilostazol can be prepared in tablet form by mixing
cilostazol with an inert diluent such as lactose (See e.g., U.S.
Pat. No. 5,627,191 to Birch et al., hereby incorporated by
reference). In one preferred embodiment, cilostazol is administered
as a tablet.
[0094] Flosequinan and cilostazol may also be administered
cutaneously in a carrier adapted for topical administration. Such
carriers include creams, ointments, lotions, pastes, jellies,
sprays, aerosols, bath oils, or other pharmaceutical carriers which
accomplish direct contact between flosequinan, or cilostazol, and
the pore of the skin. In general pharmaceutical preparations may
comprise from about 0.001% to about 10%, and preferably from about
0.01 to 5% by w/w of the active compound (e.g., flosequinan) in a
suitable carrier. In some cases it may be necessary to dissolve the
flosequinan in an appropriate solvent such as ethanol or DMSO
(dimethylsulfoxide), and the like, to facilitate incorporation into
a pharmaceutical preparation.
[0095] Flosequinan and cilostazol may also be administered by any
standard injection means (e.g., employing an hypodermic syringe and
needle or a similar device such as the NovolinPen. sold by
Squibb-Novo, Inc., Princeton, N.J., USA). This injection may be
accomplished by a subject injecting him or herself, or by the
injection of the subject by another person. Standard injection may
be administered to the subject, including but not limited to,
intravenously, intramuscularly, or intrathecally.
[0096] Flosequinan and cilostazol can be introduced by injection in
a physiologically acceptable composition. Such compositions are
aqueous solutions that are physiologically acceptable for
administration by any standard injection means. The physiologically
acceptable carrier is selected such that it is not painful or
irritating upon injection. The physiologically acceptable
compositions will preferably be sterile at the time of
administration by injection.
[0097] Among the physiologically acceptable compositions for use in
the methods is physiological saline or phosphate-buffered saline,
in which flosequinan or cilostazol is dissolved or suspended, such
that the resulting composition is suitable for standard injection.
Such a physiologically acceptable composition can also include a
non-irritant preservative, such as, e.g., benzalkonium chloride at
0.05% (w/v) to 0./2% (w/v). As the skilled artisan will understand,
there are numerous non-toxic salts of VIP, PHM and
.alpha.-adrenergic blockers that can be employed in a
physiologically acceptable composition for use in the methods
herein, including, among others, the chloride, bromide, acetate,
sulfate, and mesylate salts.
[0098] While the present invention is not limited to the method of
injecting flosequinan or cilostazol, in the preferred embodiment,
it is injected with a standard syringe. One skilled in the art
would be capable of injecting flosequinan or cilostazol with a
carrier as described for conventional injection.
[0099] The present invention is not limited by the degree of
response by the subject. It is expected that the administration of
quinolinones will reduce symptoms of CNS disorders, including but
not limited to, motor and vocal tics associated with Tourette
syndrome. It is also expected that the administration of
quinolinones for treatment of CNS disorders will not result in the
side effect of impotence as is seen in the administration of
neuroleptics, anti-obsessives, and anti-depressants.
[0100] From the above, it should be clear that the present
invention provides methods of treatment of CNS disorders with
pharmaceutical agents. In particular, quinolinones are administered
therapeutically to patients having such a disorder.
[0101] All publications and patents mentioned in the above
specification are herein incorporated by reference. Various
modifications and variations of the described method and system of
invention will be apparent to those skilled in the art without
departing from the scope and spirit of the invention. Although the
invention has been described in connection with specific preferred
embodiments, it should be understood that the invention as claimed
should not be unduly limited to such specific embodiments. Indeed,
various modifications of the described modes for carrying out the
invention which are obvious to those skilled in the art are
intended to be within the scope of the following claims. Other
Compounds Useful in the Treatment of Central Nervous System
Disorders
[0102] The invention is further directed to pyridinone compounds
with therapeutic activity, and to therapeutic compositions
containing such compounds, wherein the compounds have the general
formula I: 11
[0103] R.sub.1 is hydrogen, lower alkyl optionally substituted by
hydroxy or C.sub.1-4 alkoxycarbonyl, allyl, propynyl or
phenyl-lower alkyl in which the phenyl ring is optionally
substituted by 1 or 2 C.sub.1-4 alkoxy groups;
[0104] R.sub.2 is hydrogen or lower alkyl;
[0105] R.sub.3 is (X).sub.m--S(O).sub.nR.sub.4, COR.sub.5,
SR.sub.6, or S(OH) (O)NR.sub.7, wherein m is 0 or 1, n is 0, 1, or
2,
[0106] X is oxygen or lower alkylene, R.sub.4 is C.sub.1-4 alkyl,
R.sub.5 is hydroxyl, lower alkyl carbonyl, amino, or lower alkyl
amino, and R.sub.6 and R.sub.7 are lower alkyl; and
[0107] ring A represents an optionally substituted phenyl ring of
the formula: 12
[0108] wherein R.sub.8, R.sub.9 and R.sub.10 , which may be the
same or different, are hydrogen, lower alkyl, lower alkoxy, lower
alkanoyl, halo, tri-fluoromethyl, lower alkylthio, lower
alkylsulphinyl, lower alkylsulphonyl, halogenated lower alkyl,
halogenated lower alkoxy, cyano, phenyl, or phenyl substituted by 1
to 3 groups independently selected from lower alkyl, lower alkoxy
and trifluoromethyl; or
[0109] ring A represents an optionally substituted thiophene ring
of the formula: 13
[0110] wherein R.sub.11, is hydrogen, lower alkyl, lower alkoxy,
lower alkanoyl, halo, trifluoromethyl, lower alkylthio, phenyl, or
phenyl substituted by halogen, or a pharmaceutically acceptable
salt thereof.
[0111] The compounds of the general formula I have been found to
have antihypertensive activity and cardiac activity in warm-blooded
animals. The compounds, methods of making the compounds,
antihypertensive and cardiac therapeutic compositions of the
compounds, and methods for treating hypertension and heart failure
using the compounds are described in U.S. Pat. Nos. 4,302,460,
4,522,884, 4,855,291, 4,877,793, 4,710,506, 4,772,614 and
4,997,840, the disclosures of which patents are expressly
incorporated herein, in their entirety, by reference.
[0112] In a preferred embodiment, the invention provides
pharmaceutical compositions comprising compounds of the general
formula I, and methods of using the compositions to treat subjects
with symptoms of a central nervous system disorder, such that said
symptoms are reduced. As described above for flosequinan and
cilostazol, the invention is not limited by the particular nature
of the pharmaceutical composition, or by the method of introduction
of the active or therapeutic compound to the body. All of the
treatment methods and compositions contemplated above are also
contemplated here for compounds of formula I. The active ingredient
in the compositions is preferably administered in unit dosage form.
In one embodiment, tablets and capsules may conveniently contain a
unit dosage of the active compound of 1-500 mg/kg, more preferably
5-100 mg/kg and still more preferably 5-50 mg/kg.
[0113] The compounds of formula I may contain one or more
asymmetric centers and, therefore, can exist as enantiomers or
diastereoisomers. Furthermore, certain compounds of formula I
containing alkenyl groups may exist as cis-isomers or
trans-isomers. In each case, the invention includes both mixtures
and separate individual isomers. The compounds of formula I may
also exist in tautomeric forms and the invention includes both
mixtures and separate individual tautomers.
[0114] Preferred compounds of the general formula I for use in the
pharmaceutical compositions and methods of the invention are
compounds having the general formulas II and III: 14
[0115] wherein R.sub.1, R.sub.3, R.sub.8, R.sub.9, R.sub.10, and
R.sub.11, are defined as above.
[0116] With regard to compounds of formula II, still more preferred
compounds have the formula IIA: 15
[0117] wherein R.sub.3 is (X).sub.m--S(O).sub.nR.sub.4, COR.sub.5,
SR.sub.6, or S(OH) (O)NR.sub.7; and
[0118] (a) R.sub.10 is hydrogen and R.sub.9 is 6-lower alkoxy,
8-lower alkoxy, 5-halo or 6-halo;
[0119] (b) R.sub.9 is hydrogen and R.sub.10 is halo; lower alkyl,
lower alkoxy, trifluoromethyl or lower alkyl-thio;
[0120] (c) R.sub.10 is halo, lower alkoxy or lower alkyl and
R.sub.9 is 6-lower alkyl, 6-lower alkoxy or 6-halo of a different
value from R.sub.10; or
[0121] (d) R.sub.9 and R.sub.10 are hydrogen.
[0122] Preferred embodiments include compounds of formula IIA
wherein R.sub.1 and R.sub.2 are methyl, R.sub.9 is hydrogen and
R.sub.10 is halo, lower alkyl or trifluoromethyl. More preferably,
R.sub.10 is halo or C.sub.1-C.sub.4 alkyl. In yet another preferred
embodiment, R.sub.9 is 6-lower alkoxy and R.sub.10 is halo or lower
alkoxy. In a further preferred embodiment, R.sub.9 is 6-halo and
R.sub.10 is lower alkoxy. In another preferred embodiment, R.sub.10
is C.sub.1-C.sub.4 alkyl. Thus, preferred embodiments include
compounds of formula IIB, IIC, IID, IIE, IIF, IIIA and IIIB as
follows: 16
[0123] Preferred compounds of formula IIB are those in which m is
1, n is 2, and X is oxygen. Preferred compounds of formula IIC
include those in which m is 0, n is 1 or 2, and R.sub.4 is methyl.
Preferred compounds of formula IID include those in which R.sub.7
is amino or lower alkyl amino. Preferred compounds of formula IIE
include those in which R.sub.6 is methyl. Preferred compounds of
formula IIF include those in which R.sub.7 is methyl. Preferred
compounds of formula IIIA include those in which n is 1 and R.sub.4
is methyl. Preferred compounds of formula IIIB include those in
which R.sub.5 is amino or lower alkyl amino.
[0124] Specific preferred compounds of these formulae include:
1-methyl-3-methylsulphinyl-4-quinolone,
7-fluoro-1-methyl-4-oxo-1,4-dihyd- ro-quinolone-3-carboxamide,
4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridin- e-6-carboxamide,
4-methyl-6-methylsulphinyl-7(4H)-thieno[3,2-b]pyridinone,
7-chloro-1-methyl-3-methylsulphamoyl-4-quinolone,
1-methyl-4-oxo-1,4-dihy- droquinol-3-yl methanesulphonate,
7-chloro-1-methyl-4-oxo-1,4-dihydroquino- line-3-carboxamide,
7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, or
7-fluoro-1-methyl-3-methylthio-4-quinolone, or pharmaceutically
acceptable salts thereof.
[0125] Experimental
[0126] The following examples serve to illustrate certain preferred
embodiments and aspects of the present invention and are not to be
construed as limiting the scope thereof.
[0127] In the experimental disclosure which follows, the following
abbreviations apply: eq (equivalents); M (Molar); .mu.M
(micromolar); N (Normal); mol (moles); mmol (millimoles); .mu.mol
(micromoles); nmol (nanomoles); g (grams); mg (milligrams); .mu.g
(micrograms); L (liters); ml (milliliters); .mu.l (microliters); cm
(centimeters); mm (millimeters); .mu.m (micrometers); nm
(nanometers); .degree. C. (degrees Centigrade).
EXAMPLE 1
[0128] Production and Purification of Enantiomers of
Flosequinan
[0129] In this example, the enantiomers of flosequinan were
resolved by high-performance liquid chromatography (HPLC) as
follows. A 5.0 g sample of a racemic mixture of flosequinan was
resolved over a 10 cm ID.times.50 cm L CHIRALCEL OD HPLC column
(Chiral Technologies, Exton, Pa.) at 25.degree. C. and with a flow
rate of 1.0 ml/minute such that the column pressure was 37 bar. The
mobile phase employed was 100% methanol and the detection of the
mixture was performed at 270 nm. The (-) enantiomer had a retention
time of 3.13 minutes, while the (+) enantiomer had a retention time
of 4.40 minutes. A total of 2.1 g of the (-) enantiomer having an
optical purity greater than 99% was produced. A total of 2.3 g of
the (+) enantiomer having an optical purity greater than 99% was
produced. (See, FIG. 2).
EXAMPLE 2
[0130] Sildenafil citrate (Viagra) has been suggested as a
pharmacological treatment for Tourette Syndrome. However, sidenafil
citrate has a lack of specificity for its target, enzyme
phosphodiesterase 5 (PDE5), and exerts a definite inhibition on the
enzyme phosphodiesterase 6 (PDE6), located in the retina. It has
been shown that the inhibition of PDE6 results in color vision
defects as a side effect of treatment with sildenafil citrate.
Furthermore, side effects such as flushing, headache, nasal
congestion, and dyspepsia (heartburn) have also been associated
with sildenafil citrate treatment of impotence. (See, Moreira et
al., "Side-effect profile of sildenafil citrate (Viagra) in
clinical practice," Urology, 56(3): 474-76 (2000)). In this
example, a biochemical assay was performed to test the percentage
of phosphodiesterase 6 (PDE6) inhibition of various molar
concentrations of sildenafil citrate (Viagra) as compared to that
of a 100 .mu.M concentration of a racemic mixture of flosequinan as
follows. (See also Example 3).
[0131] PDE6 partially purified from bovine retinal rod and
activated by trypsin was used. In four separate reactions, Viagra
at molar concentrations of 0.3 .mu.M, 1.0 .mu.M, and 3.0 .mu.M, and
a 100 .mu.M racemic mixture of flosequinan were incubated with 0.2
.mu.g/ml active PDE6 and 100 .mu.M cGMP containing 0.1 .mu.M
[.sup.3H]cGMP in Tris buffer pH 7.5 for 20 minutes at 30.degree. C.
Each reaction was terminated by raising the temperature to
100.degree. C. for 2 minutes. The resulting GMP was converted to
guanosine by addition of 10 mg/ml snake venom nucleotidase and
further incubated at 30.degree. C. for 10 minutes. Unhydrolyzed
cGMP was bound to AGI-X2 resin, and [.sup.3H]guanosine remaining in
the aqueous phase was quantitated by scintillation counting.
[0132] The results of the assays, as noted in the table below,
indicate that although Viagra inhibits PDE6 around 50% at
concentrations as low as 0.3 .mu.M, such levels of inhibition of
PDE6 require greater than 100 .mu.M amounts of flosequinan (i.e.
more than 300 times more compound on a molar basis). These
empirical results could not be predicted.
2 Compound Concentration % Inhibition of PDE6 Viagra 3.0 .mu.M 87
Viagra 1.0 .mu.M 62 Viagra 0.3 .mu.M 57 Flosequinan 100 .mu.M
36
EXAMPLE 3
[0133] In this example, a racemic mixture of flosequinan and the
(+) and (-) enantiomers of flosequinan were subjected to
biochemical enzyme assays to determine their respective percent
inhibition of a variety of phosphodiesterases (PDE1-PDE6). The
reaction conditions for each PDE assay were as follows.
[0134] PDE1:
[0135] PDE1 partially purified from bovine heart was used. A
racemic mixture of flosequinan, and each enantiomer of flosequinan,
all at a molar concentration of 100 .mu.M, were independently
incubated with 13 .mu.g PDE1 enzyme, 1.0 .mu.M [.sup.3H]cAMP and
CaCl.sub.2/calmodulin in Tris buffer pH 7.5 for 20 minutes at
30.degree. C. The reaction was terminated by boiling for 2 minutes,
and the resulting AMP was converted to adenosine by addition of 10
mg/ml snake venom nucleotidase and further incubation at 30.degree.
C. for 10 minutes. Unhydrolyzed cAMP was bound to AGI-X2 resin, and
the remaining [.sup.3H]adenosine in the aqueous phase was
quantitated by scintillation counting.
[0136] PDE2:
[0137] PDE2 partially purified from human platelets was used. A
racemic mixture of flosequinan, and each enantiomer of flosequinan,
all at a molar concentration of 100 .mu.M, were independently
incubated with 23 .mu.g PDE2 enzyme, 25 .mu.M cAMP containing 0.05
.mu.M [.sup.3H]cAMP in Tris buffer pH 7.5 for 20 minutes at
30.degree. C. The reaction was terminated by boiling for 2 minutes,
and the resulting AMP was converted to adenosine by addition of 10
mg/ml snake venom nucleotidase and further incubation at 30.degree.
C. for 10 minutes. Unhydrolyzed cAMP was bound to AGI-X2 resin, and
the remaining [.sup.3H]adenosine in the aqueous phase was
quantitated by scintillation counting.
[0138] PDE3:
[0139] PDE3 partially purified from human platelets was used. A
racemic mixture of flosequinan, and each enantiomer of flosequinan,
all at a molar concentration of 100 .mu.M, were independently
incubated with 13 .mu.g PDE3 enzyme and 1 .mu.M cAMP containing
0.01 .mu.M [.sup.3H]cAMP in Tris buffer pH 7.5 for 20 minutes at
30.degree. C. The reaction was terminated by boiling for 2 minutes,
and the resulting AMP was converted to adenosine by addition of 10
mg/ml snake venom nucleotidase and further incubation at 30.degree.
C. for 10 minutes. Unhydrolyzed cAMP was bound to AGI-X2 resin, and
the remaining [.sup.3H]adenosine in the aqueous phase was
quantitated by scintillation counting.
[0140] PDE4:
[0141] PDE4 partially purified from human U-937 pronocytic cells
was used. A racemic mixture of flosequinan, and each enantiomer of
flosequinan, all at a molar concentration of 100 .mu.M, were
independently incubated with 20 .mu.g PDE4 enzyme and 1 .mu.M cAMP
containing 0.01 .mu.M [.sup.3H]cAMP in Tris buffer pH 7.5 for 20
minutes at 30.degree. C. The reaction was terminated by boiling for
2 minutes, and the resulting AMP was converted to adenosine by
addition of 10 mg/ml snake venom nucleotidase and further
incubation at 30.degree. C. for 10 minutes. Unhydrolyzed cAMP was
bound to AGI-X2 resin, and the remaining [.sup.3H]adenosine in the
aqueous phase was quantitated by scintillation counting.
[0142] PDE5:
[0143] PDE5 partially purified from human platelets was used. A
racemic mixture of flosequinan, and each enantiomer of flosequinan,
all at a molar concentration of 100 .mu.M, were independently
incubated with 120 .mu.g PDE5 enzyme and 1 .mu.M cGMP containing
0.01 .mu.M [.sup.3H]cGMP in Tris buffer pH 7.5 for 20 minutes at
30.degree. C. The reaction was terminated by boiling for 2 minutes,
and the resulting GMP was converted to guanosine by addition of 10
mg/ml snake venom nucleotidase and further incubation at 30.degree.
C. for 10 minutes. Unhydrolyzed cGMP was bound to AGI-X2 resin, and
the remaining [.sup.3H]guanosine in the aqueous phase was
quantitated by scintillation counting.
[0144] PDE6:
[0145] PDE6 partially purified from bovine retinal rod and
activated by trypsin was used. A racemic mixture of flosequinan,
and each enantiomer of flosequinan, all at a molar concentration of
100 .mu.M, were independently incubated with 0.2 .mu.g/ml active
PDE6 and 100 .mu.M cGMP containing 0.1 .mu.M [.sup.3H]cGMP in Tris
buffer pH 7.5 for 20 minutes at 30.degree. C. Each reaction was
terminated by boiling for 2 minutes. The resulting GMP was
converted to guanosine by addition of 10 mg/ml snake venom
nucleotidase, and further incubated at 30.degree. C. for 10
minutes. Unhydrolyzed cGMP was bound to AGI-X2 resin, and
[.sup.3H]guanosine remaining in the aqueous phase was quantitated
by scintillation counting.
[0146] The results of the above PDE assays are presented in the
following table. The assay results indicate that the (+) enantiomer
of flosequinan demonstrated more PDE1 and PDE3 inhibitory activity
when compared with the (-) enantiomer of flosequinan. These
empirical results could not be predicted.
3 % Inhibition w/ 100 .mu.M racemic % Inhibition w/ % Inhibition w/
Target mixture of 100 .mu.M (+)- 100 .mu.M (-)- Phosphodiesterase
flosequinan flosequinan flosequinan PDE1 31 28 11 PDE2 18 18 13
PDE3 26 32 5 PDE4 24 6 1 PDE5 11 17 10 PDE6 21 22 21
EXAMPLE 4
[0147] This example describes how compounds of general formula (I)
can be prepared.
[0148] a.
7-fluoro-1-methyl-4-oxo-1,4-dihydroquinolone-3-carboxamide can be
prepared as described in Example 1 of U.S. Pat. No. 4,855,291.
[0149] (i) A mixture of ethyl
7-fluoro-4-hydroxyquinoline-3-carboxylate (4.7 g), anhydrous
potassium carbonate (3.0 g), dimethyl sulphate (2.52 g) and
butanone (200 ml) can be boiled under reflux for 14 hours. The
solvent can be evaporated and the residue can be triturated with
dichloromethane (150 ml). The mixture can be filtered and the
filtrate evaporated to a small volume. Diethyl ether can be added,
causing a solid to precipitate. The solid can be collected, washed
with ether, dried and recrystallized from industrial methylated
spirit to give the compound ethyl 7-
fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, m.p.
164-166.degree. C.
[0150] (ii) A mixture of 19.0 g of the above carboxylate ester,
aqueous ammonia (specific gravity 0.88, 750 ml) and capryl alcohol
(2 drops) can be stirred on a steam bath for 1.5 hours, then cooled
to room temperature. The solid product can be collected by
filtration and recrystallized from industrial methylated
spirit/water 3:2 to give the compound
7-fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, m.p.
317-318.degree. C.
[0151] b.
4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide can
be prepared as described in Example 1 of U.S. Pat. No.
4,877,793.
[0152] (i) Dimethyl sulphate (3.9 ml) can be added to a stirred
solution of ethyl 7-hydroxythieno[3,2-b]-pyridine-6-carboxylate
(4.63 g) and potassium hydroxide (3.5 g) in water (50 ml) at
0-5.degree. C. More water (20 ml) can be added and the mixture can
be stirred at ambient temperature for 24 hours. The solid product
can be collected by filtration, washed with water and dried to give
the compound ethyl
4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate, m.p.
122-128.degree. C.
[0153] (ii) A mixture of 3.0 g of the product from (i) above and
aqueous ammonia (specific gravity 0.880, 60 ml) can be stirred and
heated on a steam bath. Effervescence will occur and octan-1-ol (2
ml) and more aqueous ammonia (specific gravity 0.880, 20 ml) can be
added and heating on the steam bath can be continued overnight. The
mixture can then be cooled to ambient temperature and the solid
product collected by filtration, dried and crystallized from
industrial methylated spirit to give the compound
4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carbo- xamide,
m.p. 255-258.degree. C.
[0154] C. 4-methyl-6-methylsulphinyl-7(4H)-thieno[3,2-b]pyridinone
can be prepared as described in Example 2 of U.S. Pat. No.
4,710,506.
[0155] A solution of 3-chloroperbenzoic acid (85%; 1.63 g) in
dichloromethane (60 ml) can be added dropwise during 20 minutes to
a stirred solution of
4-methyl-6-methylthio-thieno[3,2-b]pyrid-7(4H)-one (2.0 g) in
dichloromethane (60 ml) at 0-5.degree. C. After 4 hours, more
3-chloroperbenzoic acid (0.15 g) in dichloromethane (10 ml) can be
added and the mixture stirred overnight at ambient temperature.
More 3-chloroperbenzoic acid (0.15 g) in dichloromethane (10 ml)
can be added and the mixture can again be stirred overnight at
ambient temperature. The resulting solution can be extracted with
saturated aqueous sodium bicarbonate solution (5.times.150 ml) and
saturated aqueous sodium chloride solution (1.times.150 ml) a nd
the organic phase can be discarded. The aqueous extracts are
combined and extracted with dichloromethane (5.times.100 ml). The
organic extracts are combined, dried over anhydrous magnesium
sulphate and evaporated to give a solid product. This product can
be crystallized from industrial methylated spirit to give the
compound: 4-methyl-6-methylsulphinyl-thieno[3,2-b]pyri-
d-7(4H)-one, m.p. 174-176.degree. C.
[0156] d. 7-chloro-1-methyl-3-methylsulphamoyl-4-quinolone can be
prepared as described in Example 4 of U.S. Pat. No. 4,772,614.
[0157] (i) 7-Chloro-1-methyl-4-quinolone (6.9 g) and
chlorosulphonic acid (14 ml) can be stirred and heated at
140.degree. C. for 2 hours. The reaction mixture can be cooled to
room temperature and carefully added dropwise to ice water (200
ml). The solid which forms can be collected, washed with water and
dried in air to give the compound
7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride,
m.p. >300.degree. C.
[0158] (ii) 6.5 g of the above sulphonyl chloride and aqueous
methylamine (30% w/v; 220 ml) can be stirred at room temperature
for 3 hours. The resulting solid can be collected, washed with
water and crystallized from dichloromethane/industrial methylated
spirit 1:1. The product can be collected and partitioned between
water (200 ml) and dichloromethane (200 ml). The organic layer can
be separated, dried over anhydrous sodium sulphate and evaporated
to dryness. The residue can be crystallized from industrial
methylated spirit to give the compound 7-chloro-1,N-dimethyl-4-
-oxo-1,4-di-hydroquinoline-3-sulphonamide, m.p. 220-223.degree.
C.
[0159] e.
7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide can be
prepared as described in Example 4 of U.S. Pat. No. 4,855,291.
[0160] A mixture of ethyl
7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-c- arboxylate (5.0
g) and aqueous ammonia (specific gravity 0.88, 100 ml) can be
stirred and heated on a steam bath for 3.5 hours. More aqueous
ammonia (100 ml) can be added and heating continued for a further
21 hours. The mixture can be cooled in ice. The solid product can
be collected by filtration and dried to give the compound
7-chloro-1-methyl-4-oxo-1,4-dih- ydroquinoline-3-carboxamide, m.p.
>240.degree. C.
* * * * *