Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION THERAPY FOR TREATMENT OF PSYCHOSES
The present invention belongs to the fields of
pharmacology, medicine, and medicinal chemistry, and
provides methods and compositions for the treatment of a
disorders, including psychoses.
BACKGROUND OF THE INVENTION
Psychoses are serious mental illnesses characterized by
defective reality or lost contact with reality. Psychotic
patients may suffer hallucinations, delusions, and grossly
disorganized behavior as part of their disease. Psychoses
exact a tremendous emotional and economic toll on the
patients, their families, and society as a whole. For
example, it has been estimated that as many as 50% of the
homeless people living in the United States are psychotic.
(Bachrach, Treating the Homeless Mentally Ill, Washington;
D.C., American Psychiatric Press, 1340, Lamb et al. ed.
(1992)). In addition, approximately 2.50 of the total
dollars spent for health care in the United States is spent
in the treatment of psychoses (Rupp et al., Psychiatric
Clin. North Am., 16:413-423 (1993)).
Several classes of compounds are useful for treating
psychotic disorders. The drugs available for such conditions
are often associated with undesirable side effects.
Furthermore, many patients do not respond or only partially ,;
respond to present drug treatment, and estimates of such
partial-responders and non-responders vary between 40% and
800 of those treated. Thus, further methods of treating
psychoses are highly desirable.
The present invention addresses these needs by
providing a method of treating psychosis, and other
disorders as described herein, by the synergistic effect of
combination therapy of a typical or atypical antipsychotic
and a muscarinic agonist.
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SZTMMARY OF THE INVENTION
The invention provides a method for treating a patient
suffering from or susceptible to psychosis, comprising
administering to the patient an effective amount a first
component which is a typical antipsychotic or an atypical
antipsychotic and an effective amount of a second component
which is a muscarinic agonist.
The invention also provides a pharmaceutical
composition which comprises a first component which is a
typical antipsychotic or an atypical antipsychotic, and a
second component which is a muscarinic agonist.
That is, the present invention provides the use of a
pharmaceutical composition comprising an effective amount of
a first component which is a typical antipsychotic or an
atypical antipsychotic, in combination with an effective
amount of a second component which is a muscarinic agonist
for treating psychosis.
DETAILED DESCRIPTION OF THE INVENTION
20~ The present invention provides for treatment for
patients suffering from psychosis comprising the
administration of a typical antipsychotic or an atypical
antipsychotic and a muscarinic agonist. It has been
discovered that the administration of a typical
antipsychotic or an atypical antipsychotic and a muscarinic
agonist unexpectedly enhances the therapeutic effect of the
combination. That is, the combined administration of a
typical antipsychotic or an atypical antipsychotic and a
muscarinic agonist provides a synergistic effect. Thus, the
combination therapy of the present invention provides an
effective treatment of psychoses with lessened side effects
and of broader applicability than each of the individual
components alone.
Within the context of the present invention, the term
"psychosis" includes schizophrenia, schizophreniform
diseases, mania, schizoaffective disorders, and depression
with psychotic features. The above mentioned conditions
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represent multiple disease states. For example,
schizophrenia is referred to in various forms as catatonic,
disorganized, paranoid, undifferential, residual, among
others. All the various forms of the disorders mentioned
herein are contemplated as part of the present invention.
The following list further illustrates a number of
these disease states, many of which are classified in the
Diagnostic and Statistical Manual of Mental Disorders, 4th
Edition, published by the American Psychiatric Association
(DSM IV): Paranoid Type Schizophrenia, Disorganized Type
Schizophrenia, Catatonic Type Schizophrenia,
Undifferentiated Type Schizophrenia, Residual Type
Schizophrenia, Schizophreniform Disorder, Schizoaffective
Disorder, Delusional Disorder, Brief Psychotic Disorder,
Shared Psychotic Disorder, Psychotic Disorder Due to a
General Medical Condition, Substance-Induced Psychotic
Disorder, Psychotic Disorder Not Otherwise Specified, Major
Depressive Disorder with Psychotic Features, Bipolar
Disorder I, Bipolar Disorder II, Bipolar Disorder Not
Otherwise Specified, Schizoid Personality Disorder, and
Schitzotypal Personality. Disorder.
In addition, other disorders that are treated by the
present combination include, dementia, including Alzheimer's
disease, mood disorders, including depression, anxiety
disorders, including general anxiety disorder and panic
disorder, adjustment disorders, decreased cognition.
All of these disorders are readily diagnosed by the
skilled clinician using well established criteria, including
those in the DSM IV. In particular, a patient suffering
from or susceptible to psychosis can be readily diagnosed
using the methods described in the DSM-IV and other criteria
known in the art.
As will be appreciated by the skilled person, there are
alternative nomenclatures, nosologies, and classification
systems for the psychoses described herein and that these
systems evolve with medical scientific progress. Applicants
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do not intend that the present invention be limited to any
disorders literally mentioned in the DSM-IV.
The term "patient" refers to a mammal and includes,
mice, rats, dogs, sheep, cattle, pigs, guinea pigs, cats,
chimpanzees, monkeys, apes, and humans, etc. In particular
the term includes a human suffering from psychosis.
The term "effective amount of a first component" and
"an effective amount a second component" refers to the
amounts of typical antipsychotic or an atypical
antipsychotic and amounts of a muscarinic agonist,
respectively, which, upon single or multiple administration
to the patient, is synergistically effective in alleviating
or controlling the disorders described herein, and in
particular psychosis.
An effective amount of a first component and an
effective amount of a second component can be readily
determined by the attending diagnostician, as one skilled in
the art, by the use of conventional techniques and by
observing results.. In determining an effective amount of
the first and second components a number of factors are
considered by the attending diagnostician, including, but
not limited to: the properties of the individual components,
the properties of the components in combination as
determined in preclinical and clinical trials, the dose of
each component, the species of mammal; its size, age, and
general health; the specific disorders) involved; the
degree of involvement or the severity of the disorder(s);
the response of the individual patient; the mode of
administration; the bioavailability of the formulation
administered; the dose regimen selected; and other factors
known in the art.
Some preferred dosages are provided here for dosing of
the combination of xanomeline and olanzapine: xanomeline,
from about 1 to 225 mg per day, preferred; and most
preferably about 25 to 125 mg per day; and for olanzapine
from about 0.25 to 50 mg, once/day; preferred, from 1 to 30
mg, once/day;.and most preferably 1 to 25 mg once/day.
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The class of compounds referred to a "typical
antipsychotic" are effective in improving symptoms of
psychoses, and in particular schizophrenia, by acting as
dopamine receptor antagonists, more particularly D2 dopamine
receptor antagonists, which also are known as D~ dopamine
receptor blockading agents. As used herein, the term
"typical antipsychotic" include those drugs known as typical
neuroleptics.
As used herein the term "typical antipsychotic"
includes, but is not limited to, thiopropazate,
chlorpromazine, triflupromazine, mesoridazine,
piperacetazine, thioridazine, acetophenazine, fluphenazine,
perphenazine, trifluoperazine, chlorprathixene, thiothixene,
haloperidol, bromperidol, loxapine, molindone, loxapine,
molindone, and pimozide. These compound are well known in
the art.
The class of compounds referred to a "atypical
antipsychotic" are effective in improving symptoms of
psychoses, and in particular schizophrenia. These compounds
act be a variety of mechanisms, including antagonism of D2,
D3 and D4 dopamine neurons, 5-HTZ receptors, and an alpha2-
adrenergic receptors. As used herein, the term "atypical
antipsychotic" include those drugs known as atypical
neuroleptics.
As used herein the term "atypical antipsychotic"
includes, but is not limited to, clozapine, 8-chloro-11-(4-
methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine (U. S.
Patent No. 3,539,573); olanzapine, 2-methyl-4-(4-methyl-1-
piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (U. S.
Patent No. 5,229,382); zotepine, iloperidone, amisulpiride
perospirone, risperidone, 3-[2-[4-(6-fluoro-1,2-
benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-
tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (U.S. Patent No.
4, 804, 663) ; and sertindole, 1- [2- [4- [5-chloro-1- (4-
fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]
imidazolidin-2-one (U. S. Patent Nos. 4,710,500; 5,112,838;
5, 238, 945) ; quetiapine, 5- [2- (4-dibenzo [b, f] [1, 4] thiazepin-
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12-yl-1-piperazinyl)ethoxy]ethanol (U.S. Patent No.
4,879,288); and ziprasidone, 5-[2-[4-(1,2-benzoisothiazol-3-
yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one
(U. S. Patent Nos. 4,831,031 and 5,312,925). These compound
are also well known in the art.
The class of compounds referred to as "muscarinic
agonists" are effective in improving symptoms of psychoses,
and in particular schizophrenia. As used herein the term
"muscarinic agonist " includes, but is not limited to,
pilocarpine, oxotremorine, bethanechol, carachol,
sabcomeline, milameline, talsaclidine, and the compounds of
the formula I, II, and III below:
G-(CH2)r-W R
N N
formula I
15.
wherein
W is oxygen or sulfur;
R is selected from the group consisting of -OR4, -SR4,
-Z-C3_lo-cycloalkyl and -Z-C4-12-(cYcloalkylalkyl);
R4 is selected from the group consisting of CZ_15-alkyl,
C2-15-alkenyl and C~_15-alkynyl, each of which is
optionally substituted with one or more independently
selected from the group consisting of halogen(s), -CF3,
-CN, C1_4-alkoxy, phenyl, and phenoxy wherein the phenyl
or phenoxy is optionally substituted with one or more
independently selected from the group consisting of
halogen, -CN, C1_g-alkyl, C1_4-alkoxy, -OCF3, -CF3, -CONHZ
and -CSNH2;
Z is oxygen or sulphur;
Z2 is oxygen or sulphur
G is selected from the group consisting of:
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R1 R1 R2 R2 R1
Cp
R2 N /N~Cm
R ~3
13
R3
R1 , R1
I
R2 R2 p
N Cn~N,Cm
R3
R1 and R2 independently are selected from the group
consisting of hydrogen, C1_15-alkyl, C2-5-alkenyl, C2-5-
alkynyl, C1_lo-alko~y, and Cl_5-alkyl substituted with one
or more independently selected from the group consisting
of -OH, -CORE, CH2-OH, halogen, -NH2, carboxy, and phenyl;
R6 is hydrogen, Cl_~-alkyl;
R3 is selected from the group consisting of hydrogen,
C1_5-alkyl, C2_5-alkenyl and C2_5-alkynyl;
n is 1 or 2;
m is 1 or 2;
p is 1 or 2;
q is 1 or 2;
r is 0, 1 or 2; or
a pharmaceutically acceptable salt thereof;
V
.f
N
iula II
R7
R5 is selected from the group consisting of -OR's, -SR4,
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_g_
R4 is selected from the group consisting Of Cl-15-alkyl,
C2-15-alkenyl and C2_15-alkynyl, each of which is
optionally substituted with one or more independently
selected from the group consisting of halogen(s), -CF3,
-CN, Cl_4-alkoxy, phenyl, and phenoxy wherein the phenyl
or phenoxy is optionally substituted with one or more
independently selected from the group consisting of
halogen, -CN, C~_4-alkyl, C1_4-alkoxy, -OCF3, -CF3, -CONH2
and -CSNH2;
Z1 is oxygen or sulphur,
R7 is selected from the group consisting of hydrogen,
C1-15-alkyl, C2_5-alkenyl, C2-5-alkynyl;
R8 is selected from the group consisting of hydrogen, and
C~,_4-alkyl; or
a pharmaceutically acceptable salt thereof;
G-(CH2)r-W N
R N
formula III
W is oxygen or sulfur;
R is selected from the group consisting of -OR4, -SR4,
-Z-C3_1o-cycloalkyl and -Z-C4_12-(cycloalkylalkyl);
R~ is selected from the group consisting Of C1-15-alkyl,
C2_15-alkenyl and C2-15-alkynyl, each of which is
optionally substituted with one or more independently
selected from the group consisting of halogen(s), -CF3,
-CN, Cl_4-alkoxy, phenyl, and phenoxy wherein the phenyl
or phenoxy is optionally substituted with one or more
independently selected from the group Consisting of
halogen, -CN, C1_4-alkyl, C1_4-alkoxy, -OCF3, -CF3, -CONH2
and -CSNH2;
Z is oxygen or sulphur,
G is selected from the group consisting of:
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R1 R1 R2 R2 R1
. Cp
R2 N N\ ' /Cm
N R3 ~~
R3
R3
R1 R1
R2 R~
'' ~ 1
N Cn~N/Cm
4
R3
R1 and R2 independently are selected from the group
consisting of hydrogen, C1_15-alkyl, C2-5-alkenyl, C2-5-
alkynyl, Cx_1p-alkoxy, and C1-5-alkyl substituted with one
or more independently selected from the group consisting
of -OH, -CORE, CH2-OH, halogen, -NH2, carboxy, and phenyl;
R6 is hydrogen, C1_6-alkyl;
R3 is selected from the group consisting of hydrogen,
C1_5-alkyl, C2_5-alkenyl and C2_5-alkynyl;
n is 1 or 2;
m is 1 or 2;
p is 1 or 2;
q is 1 or 2;
r is 0, 1 or 2; or
a pharmaceutically acceptable salt thereof.
The compounds of formula I, II, and III are readily
prepare according to the methods described in U.S. Patent
Nos. 5,043,345; 5,968,926; 5, 744,489; and 5,998,404.
Preferred compounds of formula I are
(~) 3-{3- [4- (trifluoromethyl)phenyl]propylthio~-4- [-3- (1-
azabicyclo[2.2.2]octyloxy)]-1,2,5-thiadiazole, (~)-3-
Methoxy-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-
thiadiazo1e, (~)-3-Ethoxy-4-(1-azabicyclo[2.2.2]octyl-3-
oxy)-1,2,5-thiadiazole, (~)-3-Propyloxy-4-(1-
azabicyclo [2 .2 .2] octyl-3-oxy) -1, 2, 5-thiadiazole, (~) -3-
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Butyloxy-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-
thiadiazole, (~)-3-Pentyloxy-4-(1-azabicyclo[2.2.2]octyl-
3-oxy)-1,2,5-thiadiazole, (~)-3-Hexyloxy-4-(1-
azabicyclo [2 .2 .2] octyl-3-oxy) -1, 2, 5-thiadiazole, (~) -3-
(4-Methylpentyloxy) -4- (1-azabicyclo [2 .2 .2] octyl-3-oxy) -
1,2,5-thiadiazole, (~)-3-Propylthio-4-(1-
azabicyclo [2 .2 .2] octyl-3-oxy) -1, 2, 5-thiadiazole, (~) -3-
Butylthio-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-
thiadiazole,(~)-3-Pentylthio-4-(1-azabicyclo[2.2.2]octyl-
3-oxy)-1,2,5-thiadiazole, (S)-3-Pentylthio-4-(1-
azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-oxadiazole,
(~)-3-Hexylthio-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-
1,2,5-thiadiazole, (~)-3-(2,2,3,3,3-Pentafluoropropylthio)-
4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole, (~)-3-
Butylthio-4-((1-azabicyclo[2.2.2]octan-3-yl)methoxy)-1,2,5-
thiadiazole, (~)-Exo-3-pentylthio-4-(1-
azabicyclo[3.2.1]octyl-6-oxy)-1,2,5-thiadiazole, (~)-Endo-3-
pentylthio-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5-
thiadiazole, (~)-Endo-3-butyloxy-4-,(1-
azabicyclo[2.2.1]heptyl-3-oxy)-1,25-thiadiazole, (~)-Exo-3-
butyloxy-4-(1-azabicyclo[2.2.1]heptyl-3-oxy)-1,2,5-
thiadiazole, (~)-3-Butyloxy-4-(3-pyrrolidinyloxy)-1,2,5-
thiadiazole, (~)-3-Butyloxy-4-(1-methyl-3-pyrrolidinyloxy)-
1,2,5-thiadiazole, (~)-3-Butylthio-4-(1-methyl-3-
piperidyloxy)-1,2,5-thiadiazole, 3-Butylthio-4-(1-methyl-4-
piperidyloxy)-1,2,5-thiadiazole, (S)-3-Butyloxy-4-(1-methyl-
2-pyrrolidinylmethoxy)-1,2,5-thiadiazole, (S)-3-Butyloxy-4-
(2-pyrrolidinylmethoxy)-1,2,5-thiadiazole, (R)-3-Pentylthio-
4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole, (~)-3-
(4-Methylpentylthio)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-
1, 2, 5-thiadiazole, (~) -3- (3-Phenylpropylthio) -4- (1-
azabicyclo [2 .2 .2] octyl-3-oxy) -1, 2, 5-thiadiazole, (~) -3- (4-
Cyanobenzylthio)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-
thiadiazole, (~)-3-(4-Fluorobenzylthio)-4-(1-
azabicyclo [2 . 2 . 2] octyl-3-oxy) -1, 2., 5-thiadiazole, (~) -3- (2-
Phenylethylthio)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-
thiadiazole, (~)-3-(2-Phenyloxyethylthio)-4-(1-
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azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole, (~)-Endo-3-
(4-cyanobenzylthio)-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-
1,2,5-thiadiazole, 3-Butyloxy-4-(3-azetidinyloxy)-1,2,5-
thiadiazole, 3-Butylthio-4-(3-azetidinyloxy)-1,2,5-
thiadiazole, (~)-3-Butylthio-4-(3-pyrrolidinyloxy)-1,2,5-
thiadiazole, (+/-)-3-butylthio-4-(azabicyclo[2.2.2]octyl-3-
oxy) -1, 2, 5-oxadiazole, (+/-) -3- (2-butyloxy) -4- [ (+/-) -3-
azabicyclo[2.2.2]octyloxy)-1,2,5-oxadiazole, 3-
(2,2,3,3,4,4,4-heptaflurorobutyloxy)-4-[(+/-)-3-(1-
azabicyclo[2.2.2]octyloxy)].-1,2,5-oxadiazole, 3-methoxy-4-
(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-oxadiazole, 3-
pentylthio-4-(1-azabicyclo[2.2.2]ocytl-3-oxy)-1,2,5-
oxadiazole, trans-3,-butyloxy-4-(2-
dimethylaminocyclopentyloxy)-1,2,5-oxadiazole, 3-butylthio-
4-(3-azetidinyloxy)-1,2,5-oxadiazole, 3-(3-N-(2-
thiazolidonyl)propylthio)-4-(1-azabicyclo[2.2.2]octyl-3-
oxy)-1,2,5-oxadiazole, 3-chloro-4-.(1-azabicyclo[3.2.1]octyl-
6-oxy) -1, 2, 5-oxadiazole and (+/-) -3-butyloxy-4- [endo- (+/-) -
6- [1-azabicyclo [3 .2 . 1] octyloxy) ] -'1, 2, 5-oxadiazole.
Particularly preferred-compounds of formula II are
Z,2,5,6-Tetrahydro-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-
methylpyridine; 3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 1,2,5,6-Tetrahydro-1-methyl-3-
(3-propoxy-1,2,5-thiadiazol-4-yl)pyridine; 3-(3-Butoxy-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
1,2,5,6-Tetrahydro-3-(3-isopropoxy-1,2,5-thiadiazol-4-yl)-1-
methylpyridine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-pentyloxy-
1,2,5-thiadiazol-4-yl)pyridine; 1,2,5,6-Tetrahydro-3-(3-
isobutoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridine; 1,2,5,6-
Tetrahydro-3-(3-isopentyloxy-1,2,5-thiadiazol-4-yl)-1-
methylpyridin e; 3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(3-Butenyloxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-(2-Butynyloxy)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 1,2,5,6-Tetrahydro-1-
methyl-3-(3-propargyloxy-1,2,5-thiadiazol-4-yl)pyridine; 3-
(3-Butoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-
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tetrahydropyridine; 3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1-
ethyl-1,2,5,6-tetrahydropyridine; 3-(3-Heptyloxy-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(3-Pentynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyri dine; 3-(3-(4-Pentenyloxy)-1,2,5-thiadiazol-4-
yl)-1,2,5,6-tetrahydro-1-methylpyri dine; 3-(3-(2-
Propenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyri dine; 3-(3-OCtyloxy-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(3-Hexynyloxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-(3-Methyl-2-butenyloxy)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(3-Butenyl-2-oxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-
1-methylpyridine; 3-(3-(4-Hexenyloxy)-1,2,5-thiadiazol-4-
yl)-1,2,5,6-tetrahydro-1-methylpyridine; trans-3-(3-(3-
Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methy-1-pyridine; cis-3-(3-(2-Pentenyloxy)-1,2,5-thiadiazol-
4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; cis-3-(3-(2-
Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-(5-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; cis-3-(3-(3-
Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; trans-3-(3-(2-Hexenyloxy)-1,2,5-thiadiazol-
4-yl)-1,2,5,6-tetrahydro-1-methy-1-pyridine; ,2,5,6-
Tetrahydro-3-(3-hexyloxy-1,2,5-thiadiazol-4-
yl)pyridine; 1,2,5,6-Tetrahydro-3-(3-methoxy-1,2,5-
thiadiazol-4-yl)-1,4-dimethylpyridine; 3-(3-Hexyloxy-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,4-dimethylpyridine; 3-
(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-
dimethylpyridine; 3-(3-Pentyloxy-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1,6-dimethylpyridine; 3-(3-Butoxy-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine; 3-
(3-(4-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1,6-dimethylpyridine; 3-(3-(3-Hexynyloxy)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine; 3-
(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-
dimethylpyridine; 3-(3-(1-Ethylpentyloxy)-1,2.,5-thiadiazol-
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4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(1-
Ethylbutoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyri dine; 3-(3-(1-Methylpentyloxy)-1,2,5-thiadiazol-
4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(5-
Hexynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-(3-Methyl-4-pentenyloxy)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(2,3-Dimethylpentyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(4-Methylhexyloxy)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(1-Methylhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(3-Methylpentyloxy)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
Isoheptyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-Isohexyloxy-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-Hexyloxy-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-l-ethylpyridine; 3-(3-
Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;
3-(3-CyClopropylmethoxy-1.,2.,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 1,2,5,6-Tetrahydro-3-(3-
methoxyethoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridine;
3-(3-(2-(2-Methoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(3-Ethoxy-1-
propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methy
1-pyridine; 3-(3-(2-Ethoxyethoxy)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(2-Butoxyethoxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3- (3- (2- (2-Butoxyethoxy) ethoxy) -1, 2, 5-thiadiazol-4-yl) -
1,2,5,6-tetrahydro-1-methylpyridine; 1,2,5,6-Tetrahydro-1-
methyl-3-(3-(6,6,6-trifluorohexyloxy)-1,2,5-thiadiazol -4-
yl)pyridine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(4-
methoxyphenyl)-1-propoxy)-1,2,5-thia diazol-4-yl)pyridine;
1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(4-methoxyphenyl)-1-
ethoxy)-1,2,5-thiad iazol-4-yl)pyridine; 1,2,5,6-Tetrahydro-
1-methyl-3-(3-(3-hydroxy-1-propoxy)-1,2,5-thiadiazol-4-
yl)pyridine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-phenyl-1-
ethoxy)-1,2,5-thiadiazol-4-yl)pyridine; 1,2,5,6-Tetrahydro-
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1-methyl-3-(3-(3-hydroxy-1-hexyloxy)-1,2,5-thiadiazol-4-
yl)pyridine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-phenyl-1-
propoxy)-1,2,5-thiadiazol-4-yl )pyridine; 1,2,5,6-
Tetrahydro-1-methyl-3-(3-(6-acetamido-1-hexyloxy)-1,2,5-
thiadiazol- 4-yl)pyridine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-
(2-acetamido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;
1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-propionamido-1-ethoxy)-
1,2,5-thiadiazol -4-yl)pyridine; 1,2,5,6-Tetrahydro-1-
methyl-3-(3-(2-benzylthio-1-ethoxy)-1,2,5-thiadiazol-4 -
yl)pyridine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-ureido-1-
ethoxy)-1,2,5-thiadiazol-4-yl) pyridine; 3-(3-(4-
Fluorophenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(4-Chlorophenylpropoxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(3-Meth.ylphenylpropoxy)-1,2.,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(4-Methylphenylpropoxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-Phenylbutoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-
1-methylpyridine; 3-(3-(2-Methylphenylpropoxy)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(2,5-Dimethylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(3,4-
Dichlorophenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(4-Methylphenylpropoxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(4-Cyclohexylbutoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methy-1-pyridine; 3-(3-(5-Hydroxyhexyloxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(5-Oxyhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(3-Cyclohexenylmethoxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-Isobutylthioethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-Cyclopropylpropoxy-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(2-Methylcyclopropylmethoxy)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
Cyclopentylpropyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-
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tetrahydro-1-methylpyridine; 3-(3-(4,4,4-Trifluorobutoxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(6,6,6-Trifluorohexyloxy)-1,2,5-thiadiazol-4-y1)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(3-
Cyclobutylpropoxy)-1,2,5-thiadiazol-4-y1)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-Isopropoxyethoxy-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(2,2,2-Trifluoroethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(2-Chlorophenylpropoxy-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(3-Cyclohexylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(2-Cyclohexylethoxy)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(2,2,2-Trifluoroethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydropyridine; 3-(3-(3-Carboxypropoxy)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-Benzyloxy-1,2,5-thiadiazoh-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-(4-Ethylbenzyloxy)-1,2,5-thiadiazol-4-
yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(4-
Butylbenzyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-Propylthio-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-Butylthio-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
Methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-Octylthio-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-Ethylthio-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
Pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-Hexylthio-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;
3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-
1,6-dimethylpyridine; 3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1,6-dimethylpyridine; 3-(3-Ethylthio-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-
dimethylpyridine; 3-(3-(4-Pentynylthio)-1,2,5-thiadiazol-4-
yl)-1,2,5,6-tetrahydro-1,6-dimethy-1-pyridine; 3-(3-
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Hexylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
ethylpyridine; 3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-ethylpyridine; 3-(3-Ethylthio-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine; 3-(3-
Propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydropyridine; 3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydropyridine; 3-(3-Pentylthio-1,2,5-
thiadiazol-4-yl)-1,2,5, 6-tetrahydropyridine; 3-(3-Hexylthio-
1,2,5-thiadiazol-4-yl-1,2,5,6-tetrahydropyridine; 3-(3-(4-
Pentynylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydropyridine; 3-(3-Isohexylthio-1,2,5-thiadiazol-4-
yl)-1,2,5,6-tetrahydro-1-methylpyridin e; cis-3-(3-(3-
Hexenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-(5-Hexenylthio.)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-Cyclopentylthio-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(4-Pentynylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine;. 3-(3-Heptylthio-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(7-OCtenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-(3-Butenylthio)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(4-Pentenylthio)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(5-Cyanopentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(3-Chloropropylthio)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(3-Cyanopropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(3-Phenylpropylthio)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(2-Phenoxyethylthio)-1,2,5-thiadiazol-4-y1)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(4-Cyanobutylthio)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(8-Hydroxyoctylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(4-Chlorobutylthio)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(4,4-Bis-(4-fluorophenyl)-butylthio)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(2-
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Phenylethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-
1-methylpyridine; 3-(3-(2-Benzoylethylthio)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methy-1-pyridine;
3-(3-(4,4,4-Trifluorobutylthio)-1,2,5-thiadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(5,5,5-
Trifluoropentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-.(6,6,6-
Trifluorohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-Ethoxycarbonylpentylthio
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(4-Cyanobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6
tetrahydro-1,6-dimethylpyridine; 3-(3-(3-Phenylpropylthio)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-
dimethylpyridine; 3-(3-(2,2,2-Trifluoroethylthio)-1,2,5-
-15 thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine; 3-(3-(2-
Phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydropyridine; 3-(3-(2,2,2-Trifluoroethylthio)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
Ethoxycarbonylpropylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(6-Hydroxyhexylthio)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methy-1-
pyridine; 3-(3-(1-Cyclopropylmethylthio)-1,2,5-thiadiazol-4-
yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(2-
Methoxyethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-
l-methy-1-pyridine; 3-(3-(2-(2-Ethoxymethoxy)-ethylthio)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahy dro-1-methylpyridine;
3-(3-(2-Ethylbutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-Cyclohexylmethylthio-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methy-1-
pyridine; 3-(3-(3,3,3-Trifluoropropylthio)-1,2,5-thiadiazol-
4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(1-Oxo-1-
phenylpropylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-
1-methylpyridine; 3-(3-(4-Phenylthiobutylthio)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
Cyanomethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; 3-(3-(6-Chlorohexylthio)-1,2,5-thiadiazol-4-
yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(5-
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Chloropentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-
1-methy-1-pyridine; 3-(3-(3-Carboxypropylthio)-1,2,5-
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(5-Carboxypentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(5-Mercaptopentylthio)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(6-Mercaptohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(4-Mercaptobutylthio)-
1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-(4-Cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methylpyridine; 3-(3-(4-Bromobenzylthio)-1,2,5-
thiadiazol-4-yl)-1~2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(4-Methylbenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1-methy-1-pyridine; 3-(3-Benzylthio-1,2,5- .
thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
(4-Cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-
tetrahydro-1,6-dimethylpyridine; 3-.(3-Hexyloxy-1,2,5-
oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-
Butyloxy-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-
20. methylpyridine; 3-(3-(3-Hexynyloxy)-1,2,5-oxadiazol-4-yl)-
1,2,5,6-tetrahydro-1-methylpyridine;.3-(3-(3-
Phenylpropylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-
1-methylpyridine; 3-(3-(2-Phenoxyethylthio)-1,2,5-oxadiazol-
4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-Pentylthio-
1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(3-Hexylthio-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-
methylpyridine; and 3-(3-(4-Pentynylthio)-1,2,5-oxadiazol-4-
yl)-1,2,5,6-tetrahydro-1-methylpyridine.
A more particularly preferred compound of formula II is
xanomeline, 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-
tetrahydro-1-methylpyridine.
Preferred compounds of formula III are 2-[exo-(+/-)-3-
[1-azabicyclo[3.2.1]octyloxy)]pyrazine, 3-butylthio-2-(1-
azabicyclo[2.2.2]ocytl-3-oxy)]pyrazine, 3-butyloxy-2-[3-~-
endo-(1-azabicyclo[2.2.1] heptyloxy)]pyrazine, 3-(2-
butynyloxy) -2- [6-~-endo- (1-
azabicyclo[3.2.1]octyloxy)pyrazine, 3-hexylthio-2-[6-~-exo-
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(2-azabicyclo[2.2.1]heptyloxy)]pyrazine, 3-(3-
phenylpropynylthio)-2-[2-~-exo-(7-azabicyclo[2.2.1]
heptyloxy)]pyrazine, 3-(2-methylthioethoxy)-2-[3-~-exo-(1-
azabicyclo [3 .2 . 11 octyloxy) ] pyrazine, 3-propargyl-2- [4- (1-
azabicyclo [2 . 2 .1] heptyloxy) ] pyrazine, and 3-
cyclopropylmethylthio-2-[2-~-exo-(8-azabicyclo[3.2.1]
octyloxy)]pyrazine
When the present invention is regarded in its broadest
sense, the first component is either a typical or an
atypical antipsychotic. Similarly, when the invention is
regarded in its broadest sense, the second component
compound is a compound which functions as a muscarinic
agonist. It will be understood that while the use of a
single typical antipsychotic or a single atypical
antipsychotic as a first component compound is preferred,
combinations of two or more antipsychotic may be used as a
first component if necessary or desired. Similarly, while,
the use of a single muscarinic agonist as a second component
compound is preferred, combinations of two or more
muscarinic agonists~may be used as a second component if
necessary or desired.
While all combinations of first and second component
compounds are useful and valuable, certain combinations are
particularly valued and are preferred. In general,
combinations and methods of treatment using an atypical
antipsychotic as the first component are preferred.
Particularly preferred combinations and methods of treatment
using olanzapine as the first component are preferred.
Furthermore, combinations and methods of treatment using
xanomeline as the second component are preferred. Especially
preferred are combinations and methods use olanzapine as the
first component and xanomeline as the second component. It
is especially preferred that when the first component is
olanzapine, it will be the Form II olanzapine polymorph.as
described in U.S. Patent No. 5,229,382. Form II olanzapine
is characterized by x-ray powder diffraction pattern, of a
well prepared sample, having an interplanar spacing at
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10.2689. The x-ray diffraction pattern of Form II
olanzapine can be obtained using a Siemens D5000 x-ray
powder diffractometer having a copper Ka radiation source of
wavelength, ~,=1-541A.
It is further preferred that the Form II olanzapine
polymorph will be administered as the substantially pure
Form II olanzapine polymorph. As used herein "substantially
pure" refers to Form II associated with less than about 50
Form I, preferably less than about 2% Form I, and more
preferably less than about 1% Form I. Further,
"substantially pure" Form II will contain less than about
0.5o related substances, wherein "related substances" refers
to undesired chemical impurities or residual solvent or
water. In particular, "substantially pure" Form II should
contain less than about 0.05% content of acetonitrile, more
preferably, less than about 0.005% content of acetonitrile.
Additionally, the polymorph of the invention should contain
less than 0.50 of associated water.
Though Form II olanzapine is preferred it will be
understood that as.used herein, the term "olanzapine"
embraces all solvate and polymorphic forms except where
specifically indicated.
As used in this application the following terms have
the meanings indicated:
The term "halogen" means a fluoro, chloro, bromo, or
iodo atom.
The term "C1-is-alkyl" represents a branched or linear
alkyl group having from one to fifteen carbon atoms.
Typical Cl-is alkyl groups include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-
butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl,
decyl, and the like.
°The term "C1-4-alkyl" represents a branched or linear
alkyl group having from one to four carbon atoms. Typical
C1-C4 alkyl groups include, but are not limited to, methyl,
ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl,
and tert-butyl.
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The term " C1_6-alkyl" represents a branched or
linear alkyl group having from one to six carbon atoms.
Typical C1-is alkyl groups include, but are not limited
to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-
butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the
like.
The term "C2-is-alkenyl" represents an branched or
linear group having from two to fifteen carbon atoms and at
least one double bond. Examples of such groups include, but
are not limited to, 1-propenyl, 2-propenyl, 1-butenyl,
hexenyl, pentenyl, hexenyl, heptenyl, octenyl, and the like.
The term "C2_5-alkenyl" represents an branched or
linear group having from two to five carbon atoms and at
least one double bond. Examples of such groups include,
but are not limited to, l-propenyl, 2-propenyl, 1
butenyl, pentenyl, 2,2-dimethylpropenyl, and the like.
The term "C~-C1s alkynyl" refers to an unsaturated
branched or linear group having from two to fifteen carbon
atoms and at least one triple bond'. Examples of such groups
include, but are not limited to, ~.-propynyl, 2-propynyl, 1-
butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, 1-
heptynyl, and the like.
The term "C2-s-alkynyl" refers to an unsaturated
branched or linear group having from two to five carbon
atoms and at least one triple bond. Examples of such
groups include, but are not limited to, 1-propynyl, 2-
propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and the like.
The term "C3-C1o cycloalkyl" represents cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl, and cyclodecyl.
The term "C4-22- (cycloalkylalkyl) " refers to a C3-Cin
cycloalkyl linked to a "C1-4-alkyl group in such a manner
that the total number of carbon atoms in the group is
between 4 and 12. Typical C4_12-(cycloalkylalkyl) groups
include cyclopropylmethyl, cyclopropylethyl,
cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl,
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cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl,
cyclohexylmethyl, 3-cyclopentylpropyl, and the like.
The term "Cz-4-alkoxy" represents a branched or linear
alkyl group having from one to four carbon atoms attached
through and oxygen atom. Typical C1-4-alkoxy groups
include, but are not limited to, methoxy, ethoxy, n-propoxy,
iso-propoxy, butoxy, and the like.
The term "pharmaceutically acceptable salts" include
the physiologically acceptable salts which are often used in
pharmaceutical chemistry. Many such salts are described in
Journal of Pharmaceutical Science, 66, 2 (1977?. It will be
understood by the skilled reader that some of the compounds
used in the present invention are capable of forming salts,
and that the salt forms of pharmaceuticals are commonly
used, often because they are more readily crystallized and
purified than are the free bases. In all cases, the use of
the pharmaceuticals described above as salts is contemplated
in the description herein, and often is preferred, and the
pharmaceutically~acceptable salts of all of the compounds
are included in the names of ahem. It is. also understood
that the term "pharmaceutically acceptable salts" refers to
acid addition and base addition salts. Thus, a
pharmaceutically acceptable salt is formed from a
pharmaceutically acceptable acid or a pharmaceutically-
acceptable base as is well known in the art. Typical
inorganic acids used to form acid addition salts include
hydrochloric, hydrobromic, hydriodic, nitric, sulfuric,
phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric,
and the like. Acid addition salts derived from organic
acids, such as aliphatic mono and dicarboxylic acids, phenyl
substituted alkanoic acids, hydroxyalkanoic and
hydroxyalkandioic acids, aromatic acids, aliphatic and
aromatic sulfonic acids, may also be used. Such
pharmaceutically acceptable salts thus include acetate,
phenylacetate, trifluoroacetate, acrylate, ascorbate,
benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate,
methoxybenzoate, methylbenzoate, o-acetoxybenzoate,
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naphthalene-2-benzoate, isobutyrate, phenylbutyrate, -
hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-
dicarboxylate, caprate, caprylate, cinnamate, citrate,
formats, fumarate, glycollate, heptanoate, hippurate,
lactate, malate, maleate, hydroxymaleate, malonate,
mandelate, mesylate, nicotinate, isonicotinate, nitrate,
oxalate, phthalate, teraphthalate, propiolate, propionate,
phenylpropionate, salicylate, sebacate, succinate, suberate,
benzene-sulfonate, p-bromobenzenesulfonate,
chlorobenzenesulfonate, ethanesulfonate, 2-
hydroxyethanesulfonate, methanesulfonate, naphthalene-1-
sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate,
xylenesulfonate, tartarate, and the like. Typical base
addition salts include lithium, sodium, potassium, calcium,
magnesium, aluminum, and the like.
The following examples are included to more
specifically describe the preparation of the compounds used
in the method of this invention. These.examples are not
intended to limit the present invention in any way.
The terms used in the following examples and
preparations have their normal meanings unless otherwise
designated. For example "°C" refers to degrees Celsius;;
"mmol" refers to millimole or millimoles; "kg" refers to
kilogram or kilograms; "g" refers to gram or grams; "mg"
refers to milligram or milligrams; "mL" refers milliliter or
milliliters; ."L" refers to liter or liters; "brine" refers
to a saturated aqueous sodium chloride solution; "min"
refers to minute; "h" refers to hours, etc.
EXAMPLE 1
Synthesis of xanomeline
To a solution of sulfurmonochloride (2.4 ml, 30 mmol)
in N,N-dimethylformamide (5 ml) was slowly added alpha-
aminoalpha(3-pyridyl)acetonitrile (Archive der Pharmazie 289
(4) (1956)) (1.70 g, 10 mmol). The reaction mixture was
stirred at room temperature for 18 h. Water (20 ml) was
added and the aqueous phase was extracted with ether and the
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ether phase discharged. A 50o potassium hydroxide solution
was added to the aqueous phase to pH>9. The aqueous phase
was extracted several times with ether and the ether phases
were dried and evaporated. The residue was purified by
column'Chromatography (SiO2, eluent: ethyl
acetate/methylene chloride (1:1)). 3-(3-Chloro-1,2,5-
thiadiazol-4-yl)pyridine was collected in 45% (880 mg)
yield. M+: 197.
To a solution of sodium (230 mg, 10 mmol) in 1-hexanol
(15 ml) was added 3-(3-Chloro-1,2,5-thiadiazol-4-yl)pyridine
(490 mg, 2.5 mmol). The mixture was stirred at 50°C. for 2 h
and evaporated. The residue was dissolved in water and
extracted with ether. The combined organic phases were dried
and evaporated to give 3-(3-Hexyloxy-1,2,5-thiadiazol-4-
yl)pyridine.
A mixture of methyl iodide (0..5 ml, 7.5 mmol) and 3-(3-
hexyloxy-1,2,5-thiadiazol-4-yl)pyridine (658 mg, 2.5 mmol)
in acetone (5 ml) was stirred at room temperature for 18 h.
3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium
'20 iodide precipitated from the solution and was collected by
filtration to yield 0.81 g (80%).
Sodium borohydride (230 mg, 6 mmol) was added to a
solution of 3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1-
methylpyridinium iodide (810 mg, 2 mmol) in ethanol (99.9%,
20 ml) and the reaction mixture was stirred at room
temperature for 1 h. After evaporation the residue was
dissolved in water and extracted with ethyl acetate. The
a dried organic phases were evaporated and the residue
purified by column chromatography (Si02, eluent: ethyl
acetate/methanol (4:1)), 3-(3-Hexyloxy-1,2,5-thiadiazol-4-
yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate was
crystallized as the oxalate salt from acetone to yield 350
mg. (M.p. 148°C.; M+ . 281; ) .
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'G~YTT/fDT.L~ '~
Technical grade olanzapine
,N
NH2 N
N HCI ~ ~ N
S S
N N
H, H.
Intermediate .1
In a suitable three neck flask the following was added:
Dimethylsulfoxide (analytical): 6 volumes
Intermediate 1 . . 75 g
N-Methylpiperazine (reagent) . 6 equivalents
Intermediate 1 can be prepared using methods known to
the skilled artisan. For example, the preparation of the
Intermediate 1 is taught in US Patent No. 5,229,382.
A sub-surface nitrogen sparge line was added to remove
the ammonia formed during the reaction. The reaction was
heated to 120°C and maintained at that temperature
throughout the duration of the reaction. The reactions were
followed by HPLC until 50 of the intermediate 1 was left
unreacted. After the reaction was complete, the mixture was
allowed to cool slowly to 20°C (about 2 hours). The
reaction mixture was then transferred to an appropriate
three neck round bottom flask and water bath. To this
solution with agitation was added 10 volumes reagent grade
methanol and the reaction was stirred at 20°C for 30
minutes. Three volumes of water was added slowly over about
minutes. The reaction slurry was cooled to zero to 5°C
and stirred for 30 minutes. The product was filtered and
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the wet cake was washed with chilled methanol. The wet cake
was dried in vacuo at 45°C overnight. The product was
identified as technical olanzapine. Yield: 76.70; Potency:
98.1%
EXAMPLE 3
Form II olanzapine polymorph
A 270 g sample of technical grade 2-methyl-4-(4-methyl-
1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was
suspended in anhydrous ethyl acetate (2.7 L) . The mixture
was heated to 76oC and maintained at 76oC for 30 minutes.
The mixture was allowed to cool to 25oC. The resulting
product was isolated using vacuum filtration. The product
was identified as Form II using x-ray powder analysis.
Yield: 197 g.
The process described above for preparing Form II
provides a pharmaceutically elegant product having potency >
97%, total related substances < 0.5o and an isolated yield
of > 73 % .
According to the present invention the combination is
usually administered in the form of pharmaceutical
compositions. The adjunctive therapy of the present
invention is carried out by administering a first component
together with the second component in any manner which
provides effective levels of the compounds in the body at
the same time. Oral administration of the adjunctive
combination is preferred. They may be administered
together, in a single dosage form, or may be administered
separately.
Oral administration is not the only route or even the
only preferred route. For example, transdermal
administration may be very desirable for patients who are
forgetful or petulant about taking oral medicine. One of
the drugs may be administered by one route, such as oral,
and the others may be administered by the transdermal,
percutaneous, intravenous, intramuscular, intranasal or
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intrarectal route, in particular circumstances. The route
of administration may be varied in any way, limited by the
physical properties of the drugs and the convenience of the
patient and the caregiver.
The adjunctive combination may be administered as a
single pharmaceutical composition, and so pharmaceutical
compositions incorporating both compounds are important
embodiments of the present invention. Such compositions may
take any physical form which is pharmaceutically acceptable,
but orally usable pharmaceutical compositions are
particularly preferred. Such adjunctive pharmaceutical
compositions contain an effective amount of each of the
compounds, which effective amount is related to the daily
dose of the compounds to be administered. Each adjunctive
dosage unit may contain the daily doses of all compounds, or
may contain a fraction of the daily doses, such as one-third
or one-half of the doses. Alternatively, each dosage unit
may contain the entire dose of one of the compounds, and a
fraction of the dose of the other compounds. In such case,
the patient would daily take one of the combination dosage
units, and one or more units containing only the other
compounds. The amounts of each drug to be contained in each
dosage unit depends on the identity of the drugs chosen for
the therapy, and other factors such as the indication for
which the adjunctive therapy is being given.
The inert ingredients and manner of formulation of the
adjunctive pharmaceutical compositions are conventional,
except for the presence of the combination of the present
invention. The usual methods of formulation used in
pharmaceutical science may be used here. All of the usual
types of compositions may be used, including tablets,
chewable tablets, capsules, solutions, parenteral solutions,
intranasal sprays or powders, troches, suppositories,
transdermal patches and suspensions. In general,
compositions contain from about 0.5% to about 500 of the
compounds in total, depending on the desired doses and the
type of composition to be used. The amount of the
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compounds, however, is best defined as the effective amount,
that is, the amount of each compound which provides the
desired dose to the patient in need of such treatment. The
activity of the adjunctive combinations do not depend on the
nature of the composition, so the compositions are chosen
and formulated solely for convenience and economy. Any of
the combinations may be formulated in any desired form of
composition. Some discussion of different compositions will
be provided, followed by some typical formulations.
Capsules are prepared by mixing the compound with a
suitable diluent and filling the proper amount of the
mixture in capsules. The usual diluents include inert
powdered substances such as starch of many different kinds,
powdered cellulose, especially crystalline and
microcrystalline cellulose, sugars such as fructose,
mannitol and sucrose, grain flours and similar edible
powders.
Tablets are prepared by direct compression, by wet
granulation, or by dry granulation. Their formulations
usually incorporate diluents, binders, lubricants and
disintegrators as well as the compound. Typical diluents
include, for example, various types of starch, lactose,
mannitol, kaolin, calcium phosphate or sulfate, inorganic
salts such as sodium chloride and powdered sugar. Powdered
cellulose derivatives are also useful. Typical tablet
binders are substances such as starch, gelatin and sugars
such as lactose, fructose, glucose and the like. Natural
and synthetic gums are also convenient, including acacia,
alginates, methylcellulose, polyvinylpyrrolidone and the
like. Polyethylene glycol, ethylcellulose and waxes can
also serve as binders.
A lubricant is necessary in a tablet formulation to
prevent the tablet and punches from sticking in the die.
The lubricant is chosen from such slippery solids as talc,
magnesium and calcium stearate, stearic acid and
hydrogenated vegetable oils.
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Tablet disintegrators are substances which swell when
wetted to break up the tablet and release the compound.
They include starches, clays, celluloses, algins and gums.
More particularly, corn and potato starches,
methylcellulose, agar, bentonite, wood cellulose, powdered
natural sponge, ration-exchange resins, alginic acid, guar
gum, citrus pulp and carboxymethylcellulose, for example,
may be used, as well as sodium lauryl sulfate.
Tablets are often coated with sugar as a flavor and
sealant. The compounds may also be formulated as chewable
tablets, by using large.amounts of pleasant-tasting
substances such as mannitol in the formulation, as is now
well-established practice. Instantly dissolving tablet-like
formulations are also now frequently used to assure that the
patient consumes the dosage form, and to avoid the
difficulty in swallowing solid objects that bothers some
patients.
When it is desired to administer the combination as a
suppository, the usual bases may be used. Cocoa butter is a
20- traditional suppository base, which may be modified by
addition of waxes to raise its melting point slightly.
Water-miscible suppository bases comprising, particularly,
polyethylene glycols of various molecular weights are in
wide use, also.
Transdermal patches have become popular recently.
Typically they comprise a resinous composition in which the
drugs will dissolve, or partially dissolve, which is held in
contact with the skin by a film which protects the
composition. Many patents have appeared in the field
recently. Other, more complicated patch compositions are
also in use, particularly those having a membrane pierced
with innumerable pores through which the drugs are pumped by
osmotic action. Transdermal formulations for administration
of xanomeline are described in US Patent No. 5,980,933.
The following typical formula are provided for the
interest and information of the pharmaceutical scientist.
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Formulation 1
Hard gelatin capsules are prepared using the following
ingredients:
Quantity
(mg/capsule)
Olanzapine 25 mg
Xanomeline 80
Starch, dried 150
Magnesium stearate 10
Total 265 mg
Formulation 2
A tablet is prepared using the ingredients below:
Quantity -
(mg/tablet)
Olanzapine 10
Fluoxetine, racemic, hydrochloride 80
Cellulose, microcrystalline 275
Silicon dioxide, fumed 10
Stearic acid 5
Total 375 mg
The components are blended and compressed to form
tablets.
Conditioned Avoidance Behavior in Rats:
In a conditioned avoidance test, animals learn to
respond during a conditioned stimulus in order to avoid mild
shock presentation. A response during the conditioned
stimulus is termed an avoidance response, a response during
shock is termed an escape response; a response failure is
when the animal fails to respond during either the
conditioned stimulus or the shock presentation and is
indicative of motor impairment. Animals rapidly learn to
avoid 99% of the time. Antipsychotic drugs decrease the
percentage of avoidance responses without interfering with
the ability of the animal to respond since the animals do
emit escape responses. The percentage of response failures
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is considered a measure of motor impairment.
Procedure:
Rats were required to press a response lever in an
experimental chamber in order to avoid or escape foot-shock.
Each experimental session consisted of 50 trials. During
each trial, the chamber was illuminated and a tone presented
for a maximum of 10 sec. A response during the tone
immediately terminated the tone and the houselight, ending
the trial. In the absence of a response during the tone
alone, tone+foot-shock (2.0 mA) was presented for a maximum
of 10 sec. A response during shock presentation immediately
terminated the shock, the tone and the houselight, ending
the trial.
The synergistic effects of the present combinations
can be demonstrated by administering an inactive or
relatively inactive dose of one component (such as the
selected muscarinic agonist) and various doses of the
other component. If the effects are simply additive the,
results will be additive. If the effects of are
synergistic, then the dose of second component required
to produce full efficacy will be decreased. In
particular, if the dose of both components are inactive
when administered alone, but produce full efficacy when
given in combination, then the combination is
synergistic.
Results for representative combinations of the
present invention are given in the table below.
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First Dose Second Dose oAvoidance oResponse
Component' Component Responses Failures
+SEM +SEM
-- -- Xanomeline 0 98+1 0+0
-- -- 1 99+0 0+0
-- -- 3 93+3 0+0
-- -- 10 63+18 1+0
-- -- 17.5 11+4 2+1
-- -- 30 2+1 21+14
OIanzapine 0 -- -- 100+0 0+0
1 -- -- 98+1 0+0
3 -- -- 59+16 1+1
10 -- . -- 2+1 5+3
Olanzapine 0 Xanomeline 10 87+9 0+0
0.01 10 66+11 1+1
0.03 10 47+12 0+0
0.1 10 56+6 0+0
0.3 10 53+14 17+10
1.0 10 9+6 6+5
Haloperidol 0 -- -- 99.0+1.0 0+0
0.03 -- -- 98.0+1.0 1+0
0.1 -- -- 59.0+13.0 2+1
0.3 -- -- 10.0+2.0 25+12
Haloperidol 0.001 Xanomeline 10 70+12 5+3
0.003 10 45+'13 14+11
O.Ol 10 57+6 1+0
0.03 10 27+8 8+6
Chlorpromazine 0 -- -- 99+1 0+0
1.25 -- -- 99+1 0+0
2.5 -- -- 96+4 0+0
5 -- -- 27+12 7+5
10 -- -- 10+4 16+8
Chlorpromazine 0 Xanomeline 10 56+13 0+0
0.16 10 56+11 1+1
0.32 10 46+22 19+19
0.625 10 30+17 0+0
1.25 10 20+10 8+7
2.5 10 22+7 1+0
Fluphenazine 0 -- -- 99+1 0+0
0.1 -- -- 100+0 0+0
0.3 -- -- 67+9 2+1
1.0 -- -- 33+6 28+9
Fluphenazine 0 Xanomeline 10 87+9 0+0
0.01 10 77+12 1+0
0.03 10 52+12 3+2
0.1 10 66+11 0+0
0.3 10 33+16 6+6
Risperidone 0 -- -- 100+0 0+0
0.03 -- -- 100+0 0+0
0.1 -- -- 91+5 0+0
0.3 -- -- 37+11 2+2
_ _
I 1 . -_ _- 2+1 38+9
I 0
I
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First Dose Second Dose oAvoidance oResponse
Component Component Responses Failures
+SEM +SEM
Risperidone 0 Xanomeline 10 72+13 0+0
0.002 10 48+8 0+0
0.003 10 48+16 2+1
0.01 10 23+14 0+0
0.03 10 8+2 7+4
-- -- Xanomeline 0 100+0 0+0
-- -- 1 98+2 0+0
-- -- 3 93+3 0+0
-- -- 10 44+18 2+1
-- -- 30 9+12 12+10
-- -- Xanomeline 0 100+0 0+0
- - - -
-_ __ 3 99+1 0+0
- -
_. __ 1~ 78+12 Z+0
-- -- 30 43+13 9+7
