U.S. patent application number 12/454537 was filed with the patent office on 2009-09-24 for pyrido[3,2-e]pyrazines, their use as inhibitors of phospohodiesterase 10, and processes for preparing them.
Invention is credited to Ute Egerland, Norbert Hofgen, Barbara Langen, Thomas Pfeifer, Chris Rundfeldt, Rudolf Schindler, Hans Stange.
Application Number | 20090239874 12/454537 |
Document ID | / |
Family ID | 38441604 |
Filed Date | 2009-09-24 |
United States Patent
Application |
20090239874 |
Kind Code |
A1 |
Hofgen; Norbert ; et
al. |
September 24, 2009 |
Pyrido[3,2-e]pyrazines, their use as inhibitors of
phospohodiesterase 10, and processes for preparing them
Abstract
The invention relates to pyrido[3,2-e]pyrazines, to processes
for preparing them, to pharmaceutical preparations which comprise
these compounds and to the pharmaceutical use of these compounds,
which are inhibitors of phosphodiesterase 10, as active compounds
for treating diseases of mammals including a human which can be
influenced by using the compounds according to the invention to
inhibit phosphodiesterase 10 activity in the central nervous
system. More particularly, the invention relates to the treatment
of neurologic and psychiatric disorders, for example psychosis and
disorders comprising cognitive deficits as symptoms.
Inventors: |
Hofgen; Norbert;
(Ottendorf-Okrilla, DE) ; Stange; Hans; (Riesa,
DE) ; Langen; Barbara; (Radebeul, DE) ;
Egerland; Ute; (Radebeul, DE) ; Schindler;
Rudolf; (Dresden, DE) ; Pfeifer; Thomas;
(Radebeul, DE) ; Rundfeldt; Chris; (Coswig,
DE) |
Correspondence
Address: |
FULBRIGHT & JAWORSKI, LLP
666 FIFTH AVE
NEW YORK
NY
10103-3198
US
|
Family ID: |
38441604 |
Appl. No.: |
12/454537 |
Filed: |
May 19, 2009 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11753207 |
May 24, 2007 |
7550465 |
|
|
12454537 |
|
|
|
|
60809242 |
May 30, 2006 |
|
|
|
Current U.S.
Class: |
514/250 |
Current CPC
Class: |
A61P 25/14 20180101;
A61P 25/30 20180101; A61P 25/32 20180101; A61P 25/22 20180101; A61P
25/16 20180101; A61P 25/24 20180101; A61P 25/18 20180101; C07D
471/14 20130101; A61P 25/28 20180101; A61P 43/00 20180101; A61P
25/00 20180101; A61P 25/36 20180101; A61P 25/34 20180101; A61P
31/18 20180101; A61P 9/10 20180101 |
Class at
Publication: |
514/250 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61P 25/18 20060101 A61P025/18 |
Claims
1-40. (canceled)
41. A method comprising treating or preventing disorders associated
with, accompanied by or caused by phosphodiesterase 10
hyperactivity or a disorder in which inhibiting phosphodiesterase
10 is of value by administering a therapeutically effective amount
of a compound of formula (II) ##STR00037## wherein the bond between
A and N is a single bond or a double bond; A is C when the bond is
a double bond and CH when the bond is a single bond; m is 0 or 1; n
is 0 or 1; R.sup.1 and R.sup.2 are independently selected from H, a
cyclic radical; C.sub.1-8 alkyl, optionally mono- or
polysubstituted with at least one of halo, OH, O--C.sub.1-3 alkyl
or a cyclic radical; C.sub.2-8 alkenyl, optionally mono- or
polysubstituted with at least one of halo, OH, O--C.sub.1-3 alkyl
or a cyclic radical; C.sub.2-8 alkynyl, optionally mono- or
polysubstituted with at least one of halo, OH, O--C.sub.1-3-alkyl
or a cyclic radical; a saturated, monounsaturated or
polyunsaturated carbocycle ring system with 3 to 8 atoms or a
heterocyclic ring with 5 to 15 ring atoms, each optionally mono- or
polysubstituted with at least one of halo, amino, C.sub.1-3
alkylamino, di-C.sub.1-3 alkylamino, nitro, C.sub.1-3 alkyl,
O--C.sub.1-3 alkyl or a cyclic radical; and R.sup.3 is selected
from H, a cyclic radical, N.sub.3, CN, R.sup.6, OR.sup.6, SR.sup.6,
SOR.sup.6, SO.sub.2R.sup.6, NH(CO)OR.sup.6, N((CO)OR.sup.6).sub.2,
NR.sup.6((CO)OR.sup.6), NH--(C.dbd.O)--NH.sub.2,
NR.sup.6--(C.dbd.O)--NH.sub.2, NH--(C.dbd.O)--NHR.sup.6,
NR.sup.6--(C.dbd.O)--NHR.sup.6, NH--SO.sub.2R.sup.6,
N(SO.sub.2R.sup.6).sub.2 and NR.sup.6(SO.sub.2R.sup.6), wherein
R.sup.6 is independently, a cyclic radical, C.sub.1-8 alkyl,
C.sub.3-8 cyclo(hetero)alkyl, C.sub.2-8 alkenyl, C.sub.3-8
cyclo(hetero)alkenyl, or C.sub.2-8 alkynyl each optionally mono or
polysubstituted with at least one of halo, OH, O--C.sub.1-3 alkyl
or a cyclic radical, R.sup.7, OR.sup.7, SR.sup.7,
NHSO.sub.2R.sup.7, N(SO.sub.2R.sup.7), or
N(R.sup.8)SO.sub.2R.sup.7, wherein R.sup.7 is aryl, heteroaryl,
aryl-C.sub.1-5 alkyl, heteroaryl-C.sub.1-5 alkyl, wherein aryl is
phenyl or naphthyl, heteroaryl is an aromatic heterocyclic ring
system of 5 to 15 ring atoms containing at least one atom selected
from N including N-oxide, S, and O and wherein aryl and heteroaryl
are optionally mono- or polysubstituted with at least one of halo,
amino, C.sub.1-3 alkylamino, di-C.sub.1-3 alkylaminio, nitro,
C.sub.1-3 alkyl, O--C.sub.1-3 alkyl or a cyclic radical and R.sup.8
is C.sub.1-5 alkyl, optionally mono or polysubstituted with at last
one of halo, OH, O--C.sub.1-3 alkyl or a cyclic radical, R.sup.4 is
selected from H, halo, a cyclic radical, R.sup.9 OH or OR.sup.9,
NH(C.dbd.O)--C.sub.1-3 alkyl, optionally mono- or polysubstituted
with at least one of halo, OH, O--C.sub.1-3 alkyl or a cyclic
radical, NH.sub.2, NHR.sup.X or NR.sup.9R.sup.10, wherein R.sup.9
and R.sup.10 are independently selected from a cyclic radical,
C.sub.1-6 alkyl or C.sub.3-6 cyclo(hetero)alkyl, optionally mono-
or polysubstituted with at least one of halo, OH, O--C.sub.1-3
alkyl or a cyclic radical, aryl-C.sub.1-5-alkyl wherein aryl is
phenyl, optionally mono- or polysubstituted with at least one of
halo, amino, C.sub.1-3 alkylamino, di-C.sub.1-3 alkylamino, nitro,
C.sub.1-3 alkyl, O--C.sub.1-3 alkyl or a cyclic radical or
NR.sup.9R.sup.10 together form a saturated or unsaturated five-,
six- or seven-membered ring which can contain up to 3 heteroatoms,
preferably N including N-oxide, S or O, optionally mono- or
polysubstituted with at least one of halo, amino, C.sub.1-3
alkylamino, di-C.sub.1-3 alkylamino, nitro, C.sub.1-3 alkyl,
O--C.sub.1-3 alkyl or aryl-C.sub.1-5-alkyl, wherein aryl is phenyl,
optionally mono- or polysubstituted with at least one of halo,
amino, C.sub.1-3 alkylamino, di-C.sub.1-3 alkylamino, nitro,
C.sub.1-3 alkyl, O--C.sub.1-3 alkyl or a cyclic radical, and
R.sup.5 is selected from H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl
or (CO)--C.sub.1-5 alkyl, optionally mono or polysubstituted with
at least one of halo, OH, O--C.sub.1-3 alkyl or a cyclic radical,
or a pharmaceutically acceptable salt or prodrug thereof, wherein
if m and n are 1, A and N are not a double bond; wherein if m is 1
and n is 0, A and N are not double bond; wherein if n is 1 and m is
0, A and N are not a single bond; and wherein if m and n are 0, A
and N are not a single bond. to a subject in need thereof.
42. A method comprising treating or preventing central nervous
system disorder by administering a therapeutically effective amount
of a compound of formula (II) ##STR00038## wherein the bond between
A and N is a single bond or a double bond; A is C when the bond is
a double bond and CH when the bond is a single bond; m is 0 or 1; n
is 0 or 1; R.sup.1 and R.sup.2 are independently selected from H, a
cyclic radical; C.sub.1-8 alkyl, optionally mono- or
polysubstituted with at least one of halo, OH, O--C.sub.1-3 alkyl
or a cyclic radical; C.sub.2-8 alkenyl, optionally mono- or
polysubstituted with at least one of halo, OH, O--C.sub.1-3 alkyl
or a cyclic radical; C.sub.2-8 alkynyl, optionally mono- or
polysubstituted with at least one of halo, OH, O--C.sub.1-3-alkyl
or a cyclic radical; a saturated, monounsaturated or
polyunsaturated carbocycle ring system with 3 to 8 atoms or a
heterocyclic ring with 5 to 15 ring atoms, each optionally mono- or
polysubstituted with at least one of halo, amino, C.sub.1-3
alkylamino, di-C.sub.1-3 alkylamino, nitro, C.sub.1-3 alkyl,
O--C.sub.1-3 alkyl or a cyclic radical; and R.sup.3 is selected
from H, a cyclic radical, N.sub.3, CN, R.sup.6, OR.sup.6, SR.sup.6,
SOR.sup.6, SO.sub.2R.sup.6, NH(CO)OR.sup.6, N((CO)OR.sup.6).sub.2,
NR.sup.6((CO)OR.sup.6), NH--(C.dbd.O)--NH.sub.2,
NR.sup.6--(C.dbd.O)--NH.sub.2, NH--(C.dbd.O)--NHR.sup.6,
NR.sup.6--(C.dbd.O)--NHR.sup.6, NH--SO.sub.2R.sup.6,
N(SO.sub.2R.sup.6).sub.2 and NR.sup.6(SO.sub.2R.sup.6), wherein
R.sup.6 is independently, a cyclic radical, C.sub.1-8 alkyl,
C.sub.3-8 cyclo(hetero)alkyl, C.sub.2-8 alkenyl, C.sub.3-8
cyclo(hetero)alkenyl, or C.sub.2-8 alkynyl each optionally mono or
polysubstituted with at least one of halo, OH, O--C.sub.1-3 alkyl
or a cyclic radical, R.sup.7, OR.sup.7, SR.sup.7,
NHSO.sub.2R.sup.7, N(SO.sub.2R.sup.7), or
N(R.sup.8)SO.sub.2R.sup.7, wherein R.sup.7 is aryl, heteroaryl,
aryl-C.sub.1-5alkyl, heteroaryl-C.sub.1-5 alkyl, wherein aryl is
phenyl or naphthyl, heteroaryl is an aromatic heterocyclic ring
system of 5 to 15 ring atoms containing at least one atom selected
from N including N-oxide, S, and O and wherein aryl and heteroaryl
are optionally mono- or polysubstituted with at least one of halo,
amino, C.sub.1-3 alkylamino, di-C.sub.1-3 alkylamino, nitro,
C.sub.1-3 alkyl, O--C.sub.1-3 alkyl or a cyclic radical and R.sup.8
is C.sub.1-5 alkyl, optionally mono or polysubstituted with at last
one of halo, OH, O--C.sub.1-3 alkyl or a cyclic radical, R.sup.4 is
selected from H, halo, a cyclic radical, R.sup.9, OH or OR.sup.9,
NH(C.dbd.O)--C.sub.1-3 alkyl, optionally mono- or polysubstituted
with at least one of halo, OH, O--C.sub.1-3 alkyl or a cyclic
radical, NH.sub.2, NHR.sup.9 or NR.sup.9R.sup.10, wherein R.sup.9
and R.sup.10 are independently selected from a cyclic radical,
C.sub.1-6 alkyl or C.sub.3-6 cyclo(hetero)alkyl, optionally mono-
or polysubstituted with at least one of halo, OH, O--C.sub.1-3
alkyl or a cyclic radical, aryl-C.sub.1-5-alkyl wherein aryl is
phenyl, optionally mono- or polysubstituted with at least one of
halo, amino, C.sub.1-3 alkylamino, di-C.sub.1-3 alkylamino, nitro,
C.sub.1-3 alkyl, O--C.sub.1-3 alkyl or a cyclic radical or
NR.sup.9R.sup.10 together form a saturated or unsaturated five-,
six- or seven-membered ring which can contain up to 3 heteroatoms,
preferably N including N-oxide, S or O, optionally mono- or
polysubstituted with at least one of halo, amino, C.sub.1-3
alkylamino, di-C.sub.1-3 alkylamino, nitro, C.sub.1-3 alkyl,
O--C.sub.1-3 alkyl or aryl-C.sub.1-5-alkyl, wherein aryl is phenyl,
optionally mono- or polysubstituted with at least one of halo,
amino, C.sub.1-3 alkylamino, di-C.sub.1-3 alkylamino, nitro,
C.sub.1-3 alkyl, O--C.sub.1-3 alkyl or a cyclic radical, and
R.sup.5 is selected from H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl
or (CO)--C.sub.1-5 alkyl, optionally mono or polysubstituted with
at least one of halo, OH, O--C.sub.1-3 alkyl or a cyclic radical,
or a pharmaceutically acceptable salt or prodrug thereof, wherein
if m and n are 1, A and N are not a double bond; wherein if m is 1
and n is O, A and N are not double bond; wherein if n is 1 and m is
O, A and N are not a single bond; and wherein if m and n are O, A
and N are not a single bond. to a subject in need thereof, wherien
the bond between A and N is a double bond.
43. A method according to claim 42, wherein the disorder is
neurological or psychiatric disorder including schizophrenia or
other psychotic disorder; an affective disorder; a neurosis, a
stress-related disorder, a somatofonn disorder, and anxiety
disorder; an eating disorder; a sexual dysfunction; a disorder of
adult personality and behavior; a disorder usually first diagnosed
in infancy, childhood or adolescence, mental retardation; a
disorder of psychological development; a disorder comprising the
symptom of a cognitive deficit in a mammal and a factitious
disorder.
44. A method according to claim 43, wherein the schizophrenia and
other psychotic disorders are continuous or episodic schizophrenia
selected from the group consisting of, paranoid, hebephrenic,
catatonic, undifferentiated, residual, and schizophreniform
disorder; schizotypal disorder; a persistent delusional disorder;
an acute psychotic disorder, a transient psychotic disorder, a
persistent psychotic disorder; an induced delusional disorder; a
schizoaffective disorder; puerperal psychosis and other and
unspecified nonorganic psychosis.
45. A method according to claim 43, wherein the affective disorder
is a manic episode associated to bipolar disorder, a single manic
episode, hypomania, mania with psychotic symptoms; a bipolar
affective disorder; a depressive disorder, a depressive disorder
with postpartum onset, a depressive disorder with psychotic
symptoms; a persistent affective disorder and premenstrual
dysphoric disorder.
46. A method according to claim 43, wherein the disorder is a
phobic anxiety disorder selected from the group consisting of
agoraphobia and social phobia primarily but not exclusively related
to psychosis; a panic disorder, a general anxiety disorder; an
obsessive compulsive disorder; reaction to sever stress and
adjustment disorder, a dissociative disorder and
depersonalisation-derealization syndrome.
47. A method according to claim 43, wherein the disorder is a
specific personality disorder of the paranoid, schizoid,
schizotypal, antisocial, borderline, histrionic, narcissistic,
avoidant, dissocial, emotionally unstable, anankastic, anxious and
dependent type; a mixed personality disorder; a habit and impulse
disorder or disorders of sexual preference.
48. A method according to claim 43, wherein the disorder is a
hyperkinetic disorder, attentional deficit/hyperactivity disorder
(AD/HD), a conduct disorder; a mixed disorder of conduct and
emotional disorder; a nonorganic enuresis, a nonorganic encopresis;
a stereotyped movement disorder; attention deficit disorder without
hyperactivity, excessive masturbation, excessive nail-biting,
excessive nose-picking and excessive thumb-sucking; a schizoid
disorder of childhood and a pervasive development disorder.
49. A method according to claim 43, wherein the disorder is a
disorder of speech and language or a developmental disorder of
scholastic skill.
50. A method according to claim 63, wherein the disorder is a
cognitive deficit primarily but not exclusively related to
psychosis; age-associated memory impairment, Parkinson's disease,
Alzheimer's disease, multi infarct dementia, Lewis body dementia,
stroke, frontotemporal dementia, progressive supranuclear palsy
Huntington's disease, HIV disease, cerebral trauma, drug abuse and
mild cognitive disorder.
51. A method according to claim 63, wherein the disorder is
associated with a malfunction of basal ganglia is a focal dystonia,
a multiple-focal or segmental dystonia, torsion dystonia,
hemispheric, generalized and tardive dyskinesia, akathisias, or a
dyskinesia.
52. A method according to claim 63, wherein the disorder is a
symptomatic mental disorder, an organic delusional disorder, a
presenil or senile psychosis associated to dementia, to psychosis
in epilepsy and Parkinson's disease and other organic and
symptomatic psychosis; delirium; infective psychosis; personality
and a behavioral disorder due to brain disease, damage and
dysfunction.
53. A method according to claim 63, wherein the disorder is a
mental and behavioural disorder due to a psychoactive compound.
54. A method according to claim 63, wherein the learning and memory
capacities are enhanced in a mammal.
55. A method according to claim 63, wherein the active agent is
administered to a human or an animal.
Description
[0001] This application is a divisional application of U.S. Ser.
No. 11/753,207 filed May 24, 2009, which claims priority from
provisional U.S. Ser. No. 60/809,242 filed May 30, 2006, each of
which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates to pyrido[3,2-e]pyrazines, to
processes for preparing them, to pharmaceutical preparations which
comprise these compounds and to the pharmaceutical use of these
compounds, which are inhibitors of phosphodiesterase 10, as active
compounds for treating diseases of mammals including a human which
can be influenced by using the compounds according to the invention
to inhibit phosphodiesterase 10 activity in the central nervous
system. More particularly, the invention relates to the treatment
of neurologic and psychiatric disorders, for example psychosis and
disorders comprising cognitive deficits as symptoms.
BACKGROUND
[0003] Psychotic disorders, especially schizophrenia, are severe
mental disorders which extremely impair daily life. The symptoms of
psychosis may be divided into two fractions. In the acute phase, it
is predominated by hallucinations and delusions being called the
positive symptoms. When the agitated phase abates the so called
negative symptoms become obvious. They include cognitive deficits,
social phobia, reduced vigilance, indifference and deficits in
verbal learning and memory, verbal fluency and motor function.
[0004] Although several antipsychotics are available since, the
present therapy of psychosis is not satisfactory. The classic
antipsychotics, such as haloperidol, with a high affinity to
dopamine D2 receptor show extreme side effects, such extrapyramidal
symptoms (=EPS) and do not improve the negative symptoms of
schizophrenia so that they do not enable the patient to return to
everyday life.
[0005] Clozapine which has emerged as a benchmark therapeutic
ameliorating positive, negative and cognitive symptoms of
schizophrenia and devoid of EPS shows agranulocytosis as a major,
potential lethal side-effect (Capuano et al., 2002). Besides, there
is still a high amount of therapy resistant cases (Lindenmayer et
al., 2002).
[0006] In conclusion, there is still a need for developing new
antipsychotics which ameliorate positive, negative and cognitive
symptoms of psychosis and have a better side effect profile.
[0007] The exact pathomechanism of psychosis is not yet known. A
dysfunction of several neurotransmitter systems has been shown. The
two major neurotransmitter systems that are involved are the
dopaminergic and the glutamatergic system:
[0008] Thus, acute psychotic symptoms may be stimulated by
dopaminergic drugs (Capuano et al., 2002) and classical
antipsychotics, like haloperidol, have a high affinity to the
dopamine D2 receptor (Nyberg et al., 2002). Animal models based on
a hyperactivity of the dopaminergic neurotransmitter system
(amphetamine hyperactivity, apomorphine climbing) are used to mimic
the positive symptoms of schizophrenia.
[0009] Additional there is growing evidence that the glutamatergic
neurotransmitter system plays an important role in the development
of schizophrenia (Millan, 2005). Thus, NMDA antagonists like
phencyclidine and ketamine are able to stimulate schizophrenic
symptoms in humans and rodents (Abi-Saab et al., 1998; Lahti et
al., 2001). Acute administration of phencyclidine and MK-801 induce
hyperactivity, stereotypies and ataxia in rats mimicking psychotic
symptoms. Moreover, in contrast to the dopaminergic models the
animal models of psychosis based on NMDA antagonists do not only
mimic the positive symptoms but also the negative and cognitive
symptoms of psychosis (Abi-Saab et al., 1998; Jentsch and Roth,
1999). Thus, NMDA antagonists, additionally induce cognitive
deficits and social interaction deficits.
[0010] Eleven families of phosphodiesterases have been identified
in mammals so far (Essayan, 2001). The role of PDEs in the cell
signal cascade is to inactivate the cyclic nucleotides cAMP and/or
cGMP (Soderling and Beavo, 2000). Since cAMP and cGMP are important
second messenger in the signal cascade of G-protein-coupled
receptors PDEs are involved in a broad range of physiological
mechanisms playing a role in the homeostasis of the organism.
[0011] The PDE families differ in their substrate specificity for
the cyclic nucleotides, their mechanism of regulation and their
sensitivity to inhibitors. Moreover, they are differentially
localized in the organism, among the cells of an organ and even
within the cells. These differences lead to a differentiated
involvement of the PDE families in the various physiological
functions.
[0012] PDE10A is primarily expressed in the brain and here in the
nucleus accumbens and the caudate putamen. Areas with moderate
expression are the thalamus, hippocampus, frontal cortex and
olfactory tubercle (Menniti et al., 2001). All these brain areas
are described to participate in the pathomechanism of schizophrenia
(Lapiz et al. 2003) so that the location of the enzyme indicates a
predominate role in the pathomechanism of psychosis.
[0013] In the striatum PDE10A is predominately found in the medium
spiny neurons and there are primarily associated to the
postsynaptic membranes of these neurons (Xie et al., 2006). By this
location PDE10A may have an important influence on the signal
cascade induced by dopaminergic and glutamatergic input on the
medium spiny neurons two neurotransmitter systems playing a
predominate role in the pathomechanism of psychosis.
[0014] Phosphodiesterase (PDE) 10A, in particular, hydrolyses both
cAMP and cGMP having a higher affinity for cAMP (K.sub.m=0.05
.mu.M) than for cGMP (K.sub.M=3 .mu.M) (Sonderling et al.,
1999).
[0015] Psychotic patients have been shown to have a dysfunction of
cGMP and cAMP levels and its downstream substrates (Kaiya, 1992;
Muly, 2002; Garver et al., 1982). Additionally, haloperidol
treatment has been associated with increased cAMP and cGMP levels
in rats and patients, respectively (Leveque et al., 2000; Gattaz et
al., 1984). As PDE10 hydrolyses both cAMP and cGMP (Kotera et al.,
1999) an inhibition of PDE10A would also induce an increase of cAMP
and cGMP and thereby having a similar effect on cyclic nucleotide
levels as haloperidol.
[0016] The antipsychotic potential of PDE10A inhibitors is further
supported by studies of Kostowski et al. (1976) who showed that
papaverine, a moderate selective PDE10A inhibitor, reduces
apomorphine-induced stereotypies in rats, an animal model of
psychosis, and increases haloperidol-induced catalepsy in rats
while concurrently reducing dopamine concentration in rat brain.
Activities that are also seen with classical antipsychotics. This
is further supported by a patent application establishing
papaverine as a PDE10A inhibitor for the treatment of psychosis (US
Patent Application No. 2003/0032579).
[0017] In addition to classical antipsychotics which mainly
ameliorate the positive symptoms of psychosis PDE10A also bears the
potential to improve the negative and cognitive symptoms of
psychosis.
[0018] Focusing on the dopaminergic input on the medium spiny
neurons PDE10A inhibitors by up-regulating cAMP and cGMP levels act
as D1 agonists and D2 antagonists because the activation of
Gs-protein coupled dopamine D1 receptor increases intracellular
cAMP, whereas the activation of the Gi-protein coupled dopamine D2
receptor decreases intracellular cAMP levels through inhibition of
adenylyl cyclase activity (Mutschler et al., 2001).
[0019] Elevated intracellular cAMP levels mediated by D1 receptor
signalling seems to modulate a series of neuronal processes
responsible for working memory in the prefrontal cortex (Sawaguchi,
2000), and it is reported that D1 receptor activation may improve
working memory deficits in schizophrenic patients (Castner et al.,
2000). Thus, it seems likely that a further enhancement of this
pathway might also improve the cognitive symptoms of
schizophrenia.
[0020] Further indication of an effect of PDE10A inhibition on
negative symptoms of psychosis are given by Rodefer et al. (2005)
who could show that papaverine reverses attentional set-shifting
deficits induced by subchronic administration of phencyclidine, an
NMDA antagonist, in rats. Attentional deficits including an
impairment of shifting attention to novel stimuli belongs to the
negative symptoms of schizophrenia. In the study the attentional
deficits were induced by administering phencyclidine for 7 days
followed by a washout period. The PDE10A inhibitor papaverine was
able to reverse the enduring deficits induced by the subchronic
treatment.
[0021] Imidazo[1,5-a]pyrido[3,2-e]pyrazinones its synthesis and
some medical uses are well described in patents and the
literature.
[0022] The applications EP 0 400 583 and U.S. Pat. No. 5,055,465
from Berlex Laboratories, Inc. disclose a group of
imidazoquinoxalinones, their aza analogs and a process for their
preparation. These compounds have been found to have inodilatory,
vasodilatory and venodilatory effects. The therapeutic activity is
based on the inhibition of phosphodiesterase 3 (PDE3).
[0023] EP 0 736 532 discloses pyrido[3,2-e]pyrazinones and a
process for their preparation. These compounds are described to
have anti-asthmatic and anti-allergic properties. Examples of this
invention are inhibitors of PDE4 and PDE5.
[0024] WO 00/43392 discloses the use of
imidazo[1,5-a]pyrido[3,2-e]pyrazinones which are inhibitors of PDE3
and PDE5 for the therapy of erectile dysfunction, heart failure,
pulmonic hypertonia and vascular diseases which are accompanied by
insufficient blood supply.
[0025] An other group of pyrido[3,2-e]pyrazinones, disclosed in WO
01/68097 are inhibitors of PDE5 and can be used for the treatment
of erectile dysfunction.
[0026] Further methods for the preparation of
imidazo[1,5-a]pyrido[3,2-e]pyrazinones are described also by D.
Norris et al. (Tetrahedron Letters 42 (2001), 4297-4299).
[0027] WO 92/22552 refers to imidazo[1,5-a]quinoxalines which are
generally substituted at position 3 with a carboxylic acid group
and derivatives thereof. These compounds are described to be useful
as anxiolytic and sedative/hypnotic agents.
[0028] In contrast only a limited number of
imidazo[1,5-a]pyrido[3,2-e]pyrazines and their medical use are
already published.
[0029] WO 99/45009 describes a group of imidazopyrazines of formula
(I)
##STR00001##
[0030] Part of the definition of Q is to form a 6-membered
heterocyclic ring including pyridin. While R.sub.1, R.sub.2 and
R.sub.3 are representing a large variety of substituents the
definition of the group --NR.sub.4R.sub.5 is of special
importance.
[0031] R.sub.4 and R.sub.5 are each independently hydrogen, R.sub.6
or --C(O)R.sub.6 or the whole group NR.sub.4R.sub.5 forms a 3- to
8-membered saturated or unsaturated ring.
[0032] R.sub.6 is alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl,
heterocyclo or heterocycloalkyl, each of which is unsubstituted or
substituted.
[0033] These compounds are described to be inhibitors of protein
tyrosine kinases used in the treatment of protein tyrosine
kinase-associated disorders such as immunologic disorders.
[0034] Interestingly, for all examples listed in claim 9 the
structure of the group NR.sub.4R.sub.5 is limited in a way that one
of R.sub.4 and R.sub.5 is hydrogen and for the other one R.sub.6 is
phenyl (unsubstituted or substituted).
[0035] This structural selection of the group NR.sub.4R.sub.5 is
inline with published SAR data from the same company (P. Chen et
al., Bioorg. Med. Chem. Lett. 12 (2002), 1361-1364 and P. Chen et
al., Bioorg. Med. Chem. Lett. 12 (2002), 3153-3156).
SUMMARY OF THE INVENTION
[0036] This invention relates to compounds of formula (II) and to
pharmaceutically acceptable salts, solvates and prodrugs
thereof.
##STR00002##
[0037] wherein the bond between A and N is a single bond or a
double bond,
[0038] A is C when the bond is a double bond and CH when the bond
is a single bond,
[0039] m is 0 or 1,
[0040] n is 0 or 1,
[0041] wherein R.sup.1 and R.sup.2 are independently selected
from
[0042] H,
[0043] a cyclic radical,
[0044] C.sub.1-8 alkyl, optionally mono- or polysubstituted with
halo, OH, O--C.sub.1-3 alkyl and/or a cyclic radical,
[0045] C.sub.2-8 alkenyl, optionally mono- or polysubstituted with
halo, OH, O--C.sub.1-3 alkyl and/or a cyclic radical,
[0046] C.sub.2-8 alkynyl, optionally mono- or polysubstituted with
halo, OH, O--C.sub.1-3-alkyl and/or a cyclic radical,
[0047] a saturated, monounsaturated or polyunsaturated carboxylic
ring system with 3 to 8 atoms, e.g. phenyl, or a heterocyclic ring
system with 5 to 15 ring atoms containing at least one heteroatom
selected from N including N-oxide, O and S, each optionally mono-
or polysubstituted with halo, amino, C.sub.1-3 alkylamino,
di-C.sub.1-3 alkylamino, nitro, C.sub.1-3 alkyl, O--C.sub.1-3
alkyl, and/or a cyclic radical, and
[0048] R.sup.3 is selected from
[0049] H,
[0050] a cyclic radical,
[0051] N.sub.3,
[0052] CN,
[0053] R.sup.6, OR.sup.6, SR.sup.6, SOR.sup.6, SO.sub.2R.sup.6,
[0054] NH(CO)OR.sup.6, N((CO)OR.sup.6).sub.2,
NR.sup.6((CO)OR.sup.6),
[0055] NH--(C.dbd.O)--NH.sub.2, NR.sup.6--(C.dbd.O)--NH.sub.2,
[0056] NH--(C.dbd.O)--NHR.sup.6,
NR.sup.6--(C.dbd.O)--NHR.sup.6,
[0057] NH--SO.sub.2R.sup.6, N(SO.sub.2R.sup.6).sub.2, and
NR.sup.6(SO.sub.2R.sup.6),
[0058] wherein R.sup.6 is in each case independently,
[0059] a cyclic radical,
[0060] C.sub.1-8 alkyl, C.sub.3-8 cyclo(hetero)alkyl,
[0061] C.sub.2-8 alkenyl, C.sub.3-8 cyclo(hetero)alkenyl,
[0062] or C.sub.2-8 alkynyl each optionally mono or polysubstituted
with halo, OH and/or O--C.sub.1-3 alkyl, and/or a cyclic
radical,
[0063] R.sup.7, OR.sup.7, SR.sup.7, NHSO.sub.2R.sup.7,
N(SO.sub.2R.sup.7).sub.2, or N(R.sup.8)SO.sub.2R.sup.7,
[0064] wherein R.sup.7 is aryl, heteroaryl, aryl-C.sub.1-5 alkyl,
heteroaryl-C.sub.1-5 alkyl,
[0065] wherein aryl is phenyl or naphthyl, heteroaryl is an
aromatic heterocyclic ring system of 5 to 15 ring atoms containing
at least one atom selected from N including N-oxide, S, and O and
wherein aryl and heteroaryl are optionally mono- or polysubstituted
with halo, amino, C.sub.1-3 alkylamino, di-C.sub.1-3 alkylamino,
nitro, C.sub.1-3 alkyl, O--C.sub.1-3 alkyl and/or a cyclic
radical,
[0066] R.sup.8 is C.sub.1-5 alkyl, optionally mono or
polysubstituted with halo, OH, O--C.sub.1-3 alkyl and/or a cyclic
radical,
[0067] R.sup.4 is selected from
[0068] H,
[0069] halo,
[0070] a cyclic radical,
[0071] R.sup.9,
[0072] OH or OR.sup.9,
[0073] NH(C.dbd.O)--C.sub.1-3 alkyl, optionally mono- or
polysubstituted with halo, OH, O--C.sub.1-3 alkyl and/or a cyclic
radical or
[0074] NH.sub.2, NHR.sup.9 or NR.sup.9R.sup.10,
[0075] wherein R.sup.9 and R.sup.10 are independently selected from
[0076] a cyclic radical, [0077] C.sub.1-6 alkyl or C.sub.3-6
cyclo(hetero)alkyl, optionally mono- or polysubstituted with halo,
OH, O--C.sub.1-3 alkyl and/or a cyclic radical, [0078]
aryl-C.sub.1-5-alkyl wherein aryl is phenyl, optionally mono- or
polysubstituted with halo, amino, C.sub.1-3 alkylamino,
di-C.sub.1-3 alkylamino, nitro, C.sub.1-3 alkyl, OH, O--C.sub.1-3
alkyl and/or a cyclic radical, or [0079] NR.sup.9R.sup.10 together
form a saturated or unsaturated five-, six- or seven-membered ring
which can contain up to 3 heteroatoms, preferably N including
N-oxide, S and/or O, optionally mono- or polysubstituted with halo,
amino, C.sub.1-3 alkylamino, di-C.sub.1-3 alkylamino, C.sub.1-3
alkyl, O--C.sub.1-3 alkyl and/or aryl-C.sub.1-5-alkyl, wherein aryl
is phenyl, optionally mono- or polysubstituted with halo, amino,
C.sub.1-3 alkylamino, di-C.sub.1-3 alkylamino, nitro, C.sub.1-3
alkyl, O--C.sub.1-3 alkyl and/or a cyclic radical,
[0080] and R.sup.5 is selected from
[0081] H,
[0082] C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl or (CO)--C.sub.1-5
alkyl, optionally mono or polysubstituted with halo, OH,
O--C.sub.1-3 alkyl and/or a cyclic radical,
[0083] or pharmaceutically acceptable salts and derivatives
thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0084] FIG. 1 shows PDE10 detection with specific antibodies by
Western blot.
[0085] FIG. 2 shows that the main part of the protein PDE10 was
found in the membrane fraction.
[0086] FIG. 3 shows the gene alignment of rat, guinea pig and pig
PDE10 catalytic domains.
[0087] FIG. 4 is a protein alignment showing difference in the
protein sequences without the catalytic domain of PDE10 for rat,
guinea pig and pig.
[0088] FIG. 5 shows the effect of the compounds of Examples 91, 35,
95 and 55 on MK-801-induced psychosis.
[0089] FIG. 6 shows the effect of the compounds of Example 38 and
47 on MK-801-induced psychosis.
[0090] FIG. 7 shows the effect of the compounds of Example 62 and
69 on MK-801 induced psychosis.
[0091] FIG. 8 shows the effect of the compounds of Example 24 and
30 on MK-801 induced psychosis.
DETAILED DESCRIPTION
[0092] The term "halo" refers to fluoro, chloro, bromo or iodo.
[0093] The terms "alkyl", "alkenyl" and "alkynyl" refer to straight
or branched radicals with up to 8 carbon atoms preferably up to 6
carbon atoms and more preferably up to 5 carbon atoms such as
methyl, ethyl, vinyl, ethynyl, propyl, allyl, propynyl, butyl,
butenyl, butynyl etcl. which may optionally be substituted as
indicated above.
[0094] The terms "cyclo(hetero)alkyl" and "cyclo(hetero)alkyenyl"
refer to cyclic radicals, which may optionally contain one or more
heteroatoms selected from N including N-oxide, O and S, which may
optionally be substituted as indicated above.
[0095] The term "cyclic radical" refers to saturated, unsaturated
or aromatic carbocyles or carboheterocycles, optionally mono- or
polysubstituted with halo, amino, C.sub.1-3 alkylamino,
di-C.sub.1-3 alkylamino, nitro, C.sub.1-3 alkyl, OH, O--C.sub.1-3
alkyl and/or a cyclic radical. The cyclic radical preferably
contains 3 to 20, in particular 4 to 10 C-atoms. Carboheterocyles
may contain 1 to 6, in particular 1 to 3 heteroatoms, preferably
selected from O, N, S and/or P. The cyclic radical can be bound via
a C-atom or optionally via a N, O, S, SO or SO.sub.2-group. An
example for a cyclic radical is phenyl.
[0096] A preferred embodiment of this invention relates to
compounds of formula (II) wherein the bond between A and N is a
double bond.
[0097] An other preferred embodiment of this invention relates to
compounds of formula (II) wherein m and n are both 0.
[0098] A further preferred embodiment of this invention relates to
compounds of formula (II) wherein R.sup.1 is selected from
[0099] H,
[0100] C.sub.1-4 alkyl, particularly C.sub.2-4 alkyl optionally
mono- or polysubstituted with halo, OH, O--C.sub.1-3 alkyl and/or a
cyclic radical or
[0101] phenyl, optionally mono- or polysubstituted with halo,
amino, C.sub.1-3 alkylamino, di-C.sub.1-3 alkylamino, nitro,
C.sub.1-3 alkyl, O--C.sub.1-3 alkyl and/or a cyclic radical.
[0102] Especially preferred are C.sub.2-4-alkyl, e.g. propyl such
as n-propyl or i-propyl, or phenyl, optionally substituted.
[0103] A further preferred embodiment of this invention relates to
compounds of formula (II) wherein R.sup.2 is
[0104] H or
[0105] C.sub.1-4 alkyl, particularly methyl, optionally
substituted, e.g. halo substituted.
[0106] Especially preferred are hydrogen, a methyl group or a
trifluoromethyl group.
[0107] A further preferred embodiment of this invention relates to
compounds of formula (II) wherein R.sup.3 is H, CN or C.sub.1-3
alkyl, e.g. methyl.
[0108] A further preferred embodiment of this invention relates to
compounds of formula (II) wherein R.sup.3 is NH--(C.dbd.O)OR.sup.6,
particularly NH--(C.dbd.O)--OC.sub.1-5 alkyl, optionally mono- or
polysubstituted as indicated above.
[0109] A further preferred embodiment of this invention relates to
compounds of formula (II) wherein R.sup.3 is NH--SO.sub.2R.sup.6,
particularly NH--SO.sub.2--C.sub.1-5 alkyl, optionally mono- or
polysubstituted as indicated above.
[0110] A further preferred embodiment of this invention relates to
compounds of formula (II) wherein R.sup.4 is selected from
[0111] H, C.sub.1-3 alkyl, O--C.sub.1-3 alkyl, NH.sub.2,
NHC.sub.1-3 alkyl, wherein alkyl is optionally mono- or
polysubstituted with halo, OH, O--C.sub.1-3 alkyl and/or a cyclic
radical or
[0112] NH(C.dbd.O)--C.sub.1-3 alkyl, optionally mono- or
polysubstituted with halo, OH, O--C.sub.1-3 alkyl and/or a cyclic
radical or
[0113] cyclopropyl, cyclobutyl, tetrahydropyrrolyl, pyrrolyl,
pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
piperidinyl, morpholinyl, piperazinyl, optionally mono- or
polysubstituted with halo, OH, C.sub.1-5 alkyl and/or O--C.sub.1-3
alkyl, or aryl-C.sub.1-5-alkyl, wherein aryl is phenyl, optionally
mono- or polysubstituted with halo, amino, C.sub.1-3 alkylamino,
di-C.sub.1-3 alkylamino, nitro, C.sub.1-3 alkyl, O--C.sub.1-3 alkyl
and/or a cyclic radical, for example
##STR00003##
[0114] A further especially preferred embodiment of this invention
relates to compounds of formula (II), wherein R.sup.4 is H,
C.sub.1-3 alkyl or O--C.sub.1-3 alkyl, particularly H or
OCH.sub.3.
[0115] Examples of specific compounds of the formula (II) are the
following: [0116]
4,8-dimethoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0117] 4,8-dimethoxy-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0118]
4,8-dimethoxy-1-ethyl-3-methyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0119]
4,8-dimethoxy-1,3-dimethyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0120] 4,8-dimethoxy-3-methyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0121]
1-ethyl-4-isopropyloxy-8-methoxy-3-methyl-imidazo[1,5-a]pyrido[3,2-e]pyra-
zine [0122]
1-ethyl-8-methoxy-3-methyl-4-propyloxy-imidazo[1,5-a]pyrido[3,2-e]pyrazin-
e [0123]
4-cyclopentyloxy-1-ethyl-8-methoxy-3-methyl-imidazo[1,5-a]pyrido[-
3,2-e]pyrazine [0124]
4-isopropyloxy-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyr-
azine [0125]
8-methoxy-1,3-dimethyl-4-(2,3,6-trifluorobenzyloxy)-imidazo[1,5-a]pyrido[-
3,2-e]pyrazine [0126]
4-(2,4-dichlorobenzyloxy)-1-ethyl-8-methoxy-3-methyl-imidazo[1,5-a]pyrido-
[3,2-e]pyrazine [0127]
4-(2-chloro-6-fluorobenzyloxy)-1-ethyl-8-methoxy-3-methyl-imidazo[1,5-a]p-
yrido[3,2-e]pyrazine [0128]
1-ethyl-8-methoxy-3-methyl-4-(2,3,6-trifluorobenzyloxy)-imidazo[1,5-a]pyr-
ido[3,2-e]pyrazine [0129]
1-ethyl-8-methoxy-3-methyl-4-(2,4,6-trimethylbenzyloxy)-imidazo[1,5-a]pyr-
ido[3,2-e]pyrazine [0130]
4-(2-chloro-6-fluorobenzyloxy)-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]-
pyrido[3,2-e]pyrazine [0131]
4-(2,6-difluorobenzyloxy)-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrid-
o[3,2-e]pyrazine [0132]
1-ethyl-8-methoxy-3-methyl-4-(2-phenylethyloxy)-imidazo[1,5-a]pyrido[3,2--
e]pyrazine [0133]
8-methoxy-3-methyl-4-(2-phenylethyloxy)-1-propyl-imidazo[1,5-a]pyrido[3,2-
-e]pyrazine [0134]
8-methoxy-1,3-dimethyl-4-(2-phenylethyloxy)-imidazo[1,5-a]pyrido[3,2-e]py-
razine [0135]
8-methoxy-3-methyl-4-(2-phenylethyloxy)-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
ne [0136]
8-methoxy-3-methyl-4-(3-phenylpropyloxy)-1-propyl-imidazo[1,5-a]-
pyrido[3,2-e]pyrazine [0137]
1-ethyl-8-methoxy-3-methyl-4-(3-phenylpropyloxy)-imidazo[1,5-a]pyrido[3,2-
-e]pyrazine [0138]
1,3-dimethyl-8-methoxy-4-(3-phenylpropyloxy)-imidazo[1,5-a]pyrido[3,2-e]p-
yrazine [0139]
4-[(3,5-dimethylisoxazol-4-yl)methyloxy]-1-ethyl-8-methoxy-3-methyl-imida-
zo[1,5-a]pyrido[3,2-e]pyrazine [0140]
1-ethyl-8-methoxy-3-methyl-4-methylthio-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
ne [0141]
8-methoxy-3-methyl-4-methylthio-1-propyl-imidazo[1,5-a]pyrido[3,-
2-e]pyrazine [0142]
1,3-dimethyl-8-methoxy-4-methylthio-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0143]
8-methoxy-3-methyl-4-methylthio-imidazo[1,5-a]pyrido[3,2-e]pyrazin-
e [0144]
4-cyano-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]py-
razine [0145]
4-cyano-8-methoxy-3-methyl-1-ethyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0146]
4-azido-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyr-
azine [0147]
8-methoxy-3-methyl-4-methylsulfinyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]p-
yrazine [0148]
8-methoxy-3-methyl-4-methylsulfonyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]p-
yrazine [0149]
1-ethyl-8-methoxy-3-methyl-4-methylsulfinyl-imidazo[1,5-a]pyrido[3,2-e]py-
razine [0150]
8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0151]
1-ethyl-8-methoxy-3-methyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0152]
4-ethyl-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0153]
3,4-dimethyl-8-methoxy-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-
e [0154]
3,4-dimethyl-8-methoxy-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
ne hydrochloride [0155]
1-ethyl-3,4-dimethyl-8-methoxy-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0156]
1,3,4-trimethyl-8-methoxy-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0157]
3,4-dimethyl-8-methoxy-1-(3,3,3-trifluoropropyl)-imidazo[1,5-a]pyrido[3,2-
-e]pyrazine [0158]
3,4-dimethyl-8-methoxy-1-pentyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0159]
1-cyclohexyl-3,4-dimethyl-8-methoxy-imidazo[1,5-a]pyrido[3,2-e]pyr-
azine [0160]
3,4-dimethyl-1-hexyl-8-methoxy-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0161]
3,4-dimethyl-8-methoxy-1-phenethyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0162]
3,4-dimethyl-8-methoxy-1-phenyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-
e [0163]
3,4-dimethyl-8-methoxy-1-phenyl-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
ne dihydrochloride [0164]
3,4-dimethyl-8-methoxy-1-(2-chlorophenyl)-imidazo[1,5-a]pyrido[3,2-e]pyra-
zine [0165]
3,4-dimethyl-8-methoxy-1-(4-fluorophenyl)-imidazo[1,5-a]pyrido[3,2-e]pyra-
zine [0166]
1-propyl-3,4,8-trimethyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine [0167]
1-propyl-3,4-dimethyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine [0168]
1-propyl-4,8-dimethyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine [0169]
8-difluoromethoxy-3,4-dimethyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
ne [0170]
3,4-dimethyl-8-(piperidin-1-yl)-methoxy-1-propyl-imidazo[1,5-a]p-
yrido[3,2-e]pyrazine [0171]
3,4-dimethyl-8-(4-methyl-piperazin-1-yl)-methoxy-1-propyl-imidazo[1,5-a]p-
yrido[3,2-e]pyrazine [0172]
3,4-dimethyl-8-(2-ethyl-4-methyl-imidazol-1-yl)-methoxy-1-propyl-imidazo[-
1,5-a]pyrido[3,2-e]pyrazine [0173]
3,4-dimethyl-8-(2-propyl-4-methyl-imidazol-1-yl)-methoxy-1-propyl-imidazo-
[1,5-a]pyrido[3,2-e]pyrazine [0174]
4-difluoromethoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine-8-
-ol [0175]
8-methoxy-3-methyl-5-oxo-1-propyl-imidazo[1,5-a]pyrido[3,2-e]py-
razine [0176]
3,4-dimethyl-8-methoxy-5-oxo-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0177]
8-methoxy-4-methoxycarbonylamino-3-methyl-1-propyl-imidazo[1,5-a]p-
yrido[3,2-e]pyrazine [0178]
4-ethoxycarbonylamino-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,-
2-e]pyrazine [0179]
4-(N,N-bis-methoxycarbonyl)-amino-8-methoxy-3-methyl-1-propyl-imidazo[1,5-
-a]pyrido[3,2-e]pyrazine [0180]
8-methoxy-4-(methoxycarbonyl-methyl-amino)-3-methyl-1-propyl-imidazo[1,5--
a]pyrido[3,2-e]pyrazine [0181]
8-methoxy-3-methyl-4-(3-methyl-ureido)-1-propyl-imidazo[1,5-a]pyrido[3,2--
e]pyrazine [0182]
8-methoxy-3-methyl-1-propyl-4-ureido-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0183]
8-methoxy-3-methyl-4-(3-isopropyl-ureido)-1-propyl-imidazo[1,5-a]p-
yrido[3,2-e]pyrazine [0184]
8-methoxy-3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,-
2-e]pyrazine [0185]
4-(N,N-bis-methylsulfonyl)-amino-8-methoxy-3-methyl-1-propyl-imidazo[1,5--
a]pyrido[3,2-e]pyrazine [0186]
4-ethylsulfonylamino-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-
-e]pyrazine [0187] 1-ethyl-8-methoxy-3-methyl-4-methyl
sulfonylamino-imidazo[1,5-a]pyrido[3,2-e]pyrazine [0188]
8-methoxy-3-methyl-1-propyl-4-trifluoromethylsulfonylamino-imidazo[1,5-a]-
pyrido[3,2-e]pyrazine [0189]
8-methoxy-3-methyl-1-propyl-4-propylsulfonylamino-imidazo[1,5-a]pyrido[3,-
2-e]pyrazine [0190]
4-isopropylsulfonylamino-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido-
[3,2-e]pyrazine [0191]
8-methoxy-3-methyl-4-(4-methylphenylsulfonylamino)-1-propyl-imidazo[1,5-a-
]pyrido[3,2-e]pyrazine [0192]
4-[N,N-bis-(4-methylphenylsulfonyl)-amino]-8-methoxy-3-methyl-1-propyl-im-
idazo[1,5-a]pyrido[3,2-e]pyrazine [0193]
8-methoxy-3-methyl-1-(3,3,3-trifluoropropyl)-4-methylsulfonylamino-imidaz-
o[1,5-a]pyrido[3,2-e]pyrazine [0194]
1-hexyl-8-methoxy-3-methyl-4-methylsulfonylamino-imidazo[1,5-a]pyrido[3,2-
-e]pyrazine [0195]
8-methoxy-3-methyl-1-phenethyl-4-methylsulfonylamino-imidazo[1,5-a]pyrido-
[3,2-e]pyrazine [0196]
8-methoxy-3-methyl-1-phenyl-4-methylsulfonylamino-imidazo[1,5-a]pyrido[3,-
2-e]pyrazine [0197]
1-(2-chlorophenyl)-8-methoxy-3-methyl-4-methylsulfonylamino-imidazo[1,5-a-
]pyrido[3,2-e]pyrazine [0198]
1-(4-fluorophenyl)-8-methoxy-3-methyl-4-methylsulfonylamino-imidazo[1,5-a-
]pyrido[3,2-e]pyrazine [0199]
3-methyl-8-(4-methyl-2-propyl-imidazol-1-yl)-1-propyl-4-methylsulfonylami-
no-imidazo[1,5-a]pyrido[3,2-e]pyrazine [0200]
3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
n-8-ol hydrobromide [0201]
3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
n-8-ol [0202]
8-difluoromethoxy-3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]p-
yrido[3,2-e]pyrazine [0203]
8-cyclopropylmethoxy-3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5--
a]pyrido[3,2-e]pyrazine [0204]
3-methyl-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0205]
8-methoxy-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0206]
8-methoxy-3-methyl-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
ne [0207]
8-methoxy-3-methyl-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,2-
-e]pyrazine hydrochloride [0208]
1-ethyl-8-methoxy-3-methyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,2-e]pyrazin-
e [0209]
3,5-dimethyl-8-methoxy-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[-
3,2-e]pyrazine [0210]
5-acetyl-8-methoxy-3-methyl-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,2-
-e]pyrazine
[0211] and their pharmaceutically acceptable salts and derivatives
thereof.
[0212] Especially preferred, the compound of formula (II) is
selected from
3,4-dimethyl-8-methoxy-1-propyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazine
and pharmaceutically acceptable salts and derivatives thereof.
[0213] The invention furthermore relates to the physiologically
acceptable salts, solvates and derivatives of the compounds
according to formula (II). Derivatives of the compounds according
to formula (II) are, for example, amides, esters and ethers.
Further, the term "derivative" also encompasses prodrugs and
metabolites of compounds of formula (II).
[0214] The physiologically acceptable salts may be obtained by
neutralizing the bases with inorganic or organic acids or by
neutralizing the acids with inorganic or organic bases. Examples of
suitable inorganic acids are hydrochloric acid, sulphuric acid,
phosphoric acid or hydrobromic acid, while examples of suitable
organic acids are carboxylic acid, sulpho acid or sulphonic acid,
such as acetic acid, tartaric acid, lactic acid, propionic acid,
glycolic acid, malonic acid, maleic acid, fumaric acid, tannic
acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic
acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric
acid, maleic acid, salicylic acid, 3-aminosalicylic acid, ascorbic
acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid,
gluconic acid, amino acids, methanesulphonic acid, ethanesulphonic
acid, 2-hydroxyethanesulphonic acid, ethane-1,2-disulphonic acid,
benzenesulphonic acid, 4-methylbenzenesulphonic acid or
naphthalene-2-sulphonic acid. Examples of suitable inorganic bases
are sodium hydroxide, potassium hydroxide and ammonia, while
examples of suitable organic bases are amines, preferably, however,
tertiary amines, such as trimethylamine, triethylamine, pyridine,
N,N-dimethylaniline, quinoline, isoquinoline, .alpha.-picoline,
.beta.-picoline, .gamma.-picoline, quinaldine and pyrimidine.
[0215] In addition, physiologically acceptable salts of the
compounds according to formula (II) can be obtained by converting
derivatives which possess tertiary amino groups into the
corresponding quaternary ammonium salts in a manner known per se
using quaternizing agents. Examples of suitable quaternizing agents
are alkyl halides, such as methyl iodide, ethyl bromide and
n-propyl chloride, and also arylalkyl halides, such as benzyl
chloride or 2-phenylethyl bromide.
[0216] Furthermore, in the case of the compounds of the formula
(II) which contain an asymmetric carbon atom, the invention relates
to the D form, the L form and D,L mixtures and also, where more
than one asymmetric carbon atom is present, to the diastereomeric
forms. Those compounds of the formula (II) which contain asymmetric
carbon atoms, and which as a rule accrue as racemates, can be
separated into the optically active isomers in a known manner, for
example using an optically active acid. However, it is also
possible to use an optically active starting substance from the
outset, with a corresponding optically active or diastereomeric
compound then being obtained as the end product.
[0217] The compounds according to the invention have been found to
have pharmacologically important properties which can be used
therapeutically. The compounds according to formula (II) can be
used alone, in combination with each other or in combination with
other active compounds. The compounds according to the invention
are inhibitors of phosphodiesterase 10. It is therefore a part of
the subject-matter of this invention that the compounds according
to formula (II), and their salts and also pharmaceutical
preparations which comprise these compounds or their salts, can be
used for treating or preventing discorders associated with,
accompanied by and/or covered by phosphodiesterase hyperactivity
and/or disorders in which inhibiting phosphodiesterase 10 is of
value.
[0218] Surprisingly, the compounds of formula (II) are potent
inhibitors of the enzyme PDE10.
[0219] It is an embodiment of this invention, that compounds of
formula (II) including their salts, solvates and prodrugs and also
pharmaceutical compositions comprising an amount of a compound of
formula (II) or one of its salts, solvates or prodrugs effective in
inhibiting PDE10 can be used for the treatment of central nervous
system disorders of mammals including a human.
[0220] More particularly, the invention relates to the treatment of
neurological and psychiatric disorders including, but not limited
to, (1) schizophrenia and other psychotic disorders; (2) mood
[affective] disorders; (3) neurotic, stress-related and somatoform
disorders including anxiety disorders; (4) eating disorders; sexual
dysfunction comprising excessive sexual drive; (5) disorders of
adult personality and behaviour; (6) disorders usually first
diagnosed in infancy, childhood and adolescence; (7) mental
retardation and (8) disorders of psychological development; (9)
disorders comprising the symptom of cognitive deficiency in a
mammal, including a human; (10) factitious disorders.
[0221] (1) Examples of schizophrenia and other psychotic disorders
disorders that can be treated according to the present invention
include, but are not limited to, continuous or episodic
schizophrenia of different types (for instance paranoid,
hebephrenic, catatonic, undifferentiated, residual, and
schizophreniform disorders); schizotypal disorders (such as
borderline, latent, prepsychotic, prodromal, pseudoneurotic
pseudopsychopathic schizophrenia and schizotypal personality
disorder); persistent delusional disorders; acute, transient and
persistent psychotic disorders; induced delusional disorders;
schizoaffective disorders of different type (for instance manic
depressive or mixed type); puerperal psychosis and other and
unspecified nonorganic psychosis.
[0222] (2) Examples of mood [affective] disorders that can be
treated according to the present invention include, but are not
limited to, manic episodes associated to bipolar disorder and
single manic episodes, hypomania, mania with psychotic symptoms;
bipolar affective disorders (including for instance bipolar
affective disorders with current hypomanic and manic episodes with
or without psychotic symptoms); depressive disorders, such as
single episode or recurrent major depressive disorder, depressive
disorder with postpartum onset, depressive disorders with psychotic
symptoms; persistent mood [affective] disorders, such as
cyclothymia, dysthymia; premenstrual dysphoric disorder.
[0223] (3) Examples of disorders belonging to the neurotic,
stress-related and somatoform disorders that can be treated
according to the present invention include, but are not limited to,
phobic anxiety disorders, for instance agoraphobia and social
phobia primarily but not exclusively related to psychosis; other
anxiety disorders such as panic disorders and general anxiety
disorders; obsessive compulsive disorder; reaction to sever stress
and adjustment disorders, such as post traumatic stress disorder;
dissociative disorders and other neurotic disorders such as
depersonalisation-derealisation syndrome.
[0224] (5) Examples of disorders of adult personality and behaviour
that can be treated according to the present invention include, but
are not limited to, specific personality disorders of the paranoid,
schizoid, schizotypal, antisocial, borderline, histrionic,
narcissistic, avoidant, dissocial, emotionally unstable,
anankastic, anxious and dependent type; mixed personality
disorders; habit and impulse disorders (such as trichotillomania,
pyromania, maladaptive aggression); disorders of sexual
preference.
[0225] (6) Examples of disorders usually first diagnosed in
infancy, childhood and adolescence that can be treated according to
the present invention include, but are not limited to, hyperkinetic
disorders, attentional deficit/hyperactivity disorder (AD/HD),
conduct disorders; mixed disorders of conduct and emotional
disorders; nonorganic enuresis, nonorganic encopresis; stereotyped
movement disorder; and other specified behavioural emotional
disorders, such as attention deficit disorder without
hyperactivity, excessive masturbation nail-biting, nose-picking and
thumb-sucking; disorders of psychological development particularly
schizoid disorder of childhood and pervasive development disorders
such as psychotic episodes associated to Asperger's syndrome.
[0226] (8) Examples of disorders of psychological development
include but are not limited to developmental disorders of speech
and language, developmental disorders of scholastic skills, such as
specific disorder of arithmetical skills, reading disorders and
spelling disorders and other learning disorders. These disorders
are predominantly diagnosed in infancy, childhood and
adolescence.
[0227] (9) The phrase "cognitive deficiency" as used here in
"disorder comprising as a symptom cognitive deficiency" refers to a
subnormal functioning or a suboptimal functioning in one or more
cognitive aspects such as memory, intellect, learning and logic
ability, or attention in a particular individual comparative to
other individuals within the same general age population.
[0228] (10) Examples of disorders comprising as a symptom cognitive
deficiency that can be treated according to the present invention
include, but are not limited to, cognitive deficits primarily but
not exclusively related to psychosis; age-associated memory
impairment, Parkinson's disease, Alzheimer's disease, multi infarct
dementia, Lewis body dementia, stroke, frontotemporal dementia,
progressive supranuclear palsy Huntington's disease and in HIV
disease, cerebral trauma, drug abuse and mild cognitive
disorder.
[0229] (11) Additionally, the invention relates to movement
disorders with malfunction of basal ganglia. Examples of movement
disorders with malfunction of basal ganglia that can be treated
according to the present invention include, but are not limited to,
different subtypes of dystonia, such as focal dystonias,
multiple-focal or segmental dystonias, torsion dystonia,
hemispheric, generalised and tardive dyskinesias (induced by
psychopharmacological drugs), akathisias, dyskinesias such as
Huntington's disease, Parkinson's disease, Lewis body disease,
restless leg syndrome, PLMS.
[0230] (12) Furthermore the invention relates to the treatment of
organic, including symptomatic mental disorders, especially to
organic delusional (schizophrenia-like) disorders, presenil or
senile psychosis associated to dementia, to psychosis in epilepsy
and Parkinson's disease and other organic and symptomatic
psychosis; delirium; infective psychosis; personality and
behavioural disorders due to brain disease, damage and
dysfunction.
[0231] (13) The invention relates to the treatment of mental and
behavioural disorders due to psychoactive compounds, more
particular to the treatment of psychotic disorders and residual and
late-onset psychotic disorders induced by alcohol, opioids,
cannabinoids, cocaine, hallucinogens, other stimulants, including
caffeine, volatile solvents and other psychoactive compounds.
[0232] (14) The invention further relates to a general improvement
of learning and memory capacities in a mammal, including a
human.
[0233] An effective dose of the compounds according to the
invention, or their salts, is used, in addition to physiologically
acceptable carriers, diluents and/or adjuvants for producing a
pharmaceutical composition. The dose of the active compounds can
vary depending on the route of administration, the age and weight
of the patient, the nature and severity of the diseases to be
treated, and similar factors. The daily dose can be given as a
single dose, which is to be administered once, or be subdivided
into two or more daily doses, and is as a rule 0.001-2000 mg.
Particular preference is given to administering daily doses of
0.1-500 mg, e.g. 0.1-100 mg.
[0234] Suitable administration forms are oral, parenteral,
intravenous, transdermal, topical, inhalative, intranasal and
sublingual preparations. Particular preference is given to using
oral, parenteral, e.g. intravenous or intramuscular, intranasal
preparations, e.g. dry powder or sublingual, of the compounds
according to the invention. The customary galenic preparation
forms, such as tablets, sugar-coated tablets, capsules, dispersible
powders, granulates, aqueous solutions, alcohol-containing aqueous
solutions, aqueous or oily suspensions, syrups, juices or drops,
are used.
[0235] Solid medicinal forms can comprise inert components and
carrier substances, such as calcium carbonate, calcium phosphate,
sodium phosphate, lactose, starch, mannitol, alginates, gelatine,
guar gum, magnesium stearate, aluminium stearate, methyl cellulose,
talc, highly dispersed silicic acids, silicone oil, higher
molecular weight fatty acids, (such as stearic acid), gelatine,
agar agar or vegetable or animal fats and oils, or solid high
molecular weight polymers (such as polyethylene glycol);
preparations which are suitable for oral administration can
comprise additional flavourings and/or sweetening agents, if
desired.
[0236] Liquid medicinal forms can be sterilized and/or, where
appropriate, comprise auxiliary substances, such as preservatives,
stabilizers, wetting agents, penetrating agents, emulsifiers,
spreading agents, solubilizers, salts, sugars or sugar alcohols for
regulating the osmotic pressure or for buffering, and/or viscosity
regulators.
[0237] Examples of such additives are tartrate and citrate buffers,
ethanol and sequestering agents (such as ethylenediaminetetraacetic
acid and its non-toxic salts). High molecular weight polymers, such
as liquid polyethylene oxides, microcrystalline celluloses,
carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or
gelatine, are suitable for regulating the viscosity. Examples of
solid carrier substances are starch, lactose, mannitol, methyl
cellulose, talc, highly dispersed silicic acids, high molecular
weight fatty acids (such as stearic acid), gelatine, agar agar,
calcium phosphate, magnesium stearate, animal and vegetable fats,
and solid high molecular weight polymers, such as polyethylene
glycol.
[0238] Oily suspensions for parenteral or topical applications can
be vegetable synthetic or semisynthetic oils, such as liquid fatty
acid esters having in each case from 8 to 22 C atoms in the fatty
acid chains, for example palmitic acid, lauric acid, tridecanoic
acid, margaric acid, stearic acid, arachidic acid, myristic acid,
behenic acid, pentadecanoic acid, linoleic acid, elaidic acid,
brasidic acid, erucic acid or oleic acid, which are esterified with
monohydric to trihydric alcohols having from 1 to 6 C atoms, such
as methanol, ethanol, propanol, butanol, pentanol or their isomers,
glycol or glycerol. Examples of such fatty acid esters are
commercially available miglyols, isopropyl myristate, isopropyl
palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric
acid esters of saturated fatty alcohols, polyoxyethylene glycerol
trioleates, ethyl oleate, waxy fatty acid esters, such as
artificial ducktail gland fat, coconut fatty acid isopropyl ester,
oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate,
diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone
oils of differing viscosity, or fatty alcohols, such as isotridecyl
alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol,
or fatty acids, such as oleic acid, are also suitable. It is
furthermore possible to use vegetable oils, such as castor oil,
almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil
or soybean oil.
[0239] Suitable solvents, gelatinizing agents and solubilizers are
water or water-miscible solvents. Examples of suitable substances
are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol,
2-octyldodecanol, polyethylene glycols, phthalates, adipates,
propylene glycol, glycerol, di- or tripropylene glycol, waxes,
methyl cellosolve, cellosolve, esters, morpholines, dioxane,
dimethyl sulphoxide, dimethylformamide, tetrahydrofuran,
cyclohexanone, etc.
[0240] Cellulose ethers which can dissolve or swell both in water
or in organic solvents, such as hydroxypropylmethyl cellulose,
methyl cellulose or ethyl cellulose, or soluble starches, can be
used as film-forming agents.
[0241] Mixtures of gelatinizing agents and film-forming agents are
also perfectly possible. In this case, use is made, in particular,
of ionic macromolecules such as sodium carboxymethyl cellulose,
polyacrylic acid, polymethacrylic acid and their salts, sodium
amylopectin semiglycolate, alginic acid or propylene glycol
alginate as the sodium salt, gum arabic, xanthan gum, guar gum or
carrageenan. The following can be used as additional formulation
aids: glycerol, paraffin of differing viscosity, triethanolamine,
collagen, allantoin and novantisolic acid. Use of surfactants,
emulsifiers or wetting agents, for example of Na lauryl sulphate,
fatty alcohol ether sulphates, di-Na-N-lauryl-p-iminodipropionate,
polyethoxylated castor oil or sorbitan monooleate, sorbitan
monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin,
glycerol monostearate, polyoxyethylene stearate, alkylphenol
polyglycol ethers, cetyltrimethylammonium chloride or
mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine
salts can also be required for the formulation. Stabilizers, such
as montmorillonites or colloidal silicic acids, for stabilizing
emulsions or preventing the breakdown of active substances such as
antioxidants, for example tocopherols or butylhydroxyanisole, or
preservatives, such as p-hydroxybenzoic acid esters, can likewise
be used for preparing the desired formulations.
[0242] Preparations for parenteral administration can be present in
separate dose unit forms, such as ampoules or vials. Use is
preferably made of solutions of the active compound, preferably
aqueous solution and, in particular, isotonic solutions and also
suspensions. These injection forms can be made available as
ready-to-use preparations or only be prepared directly before use,
by mixing the active compound, for example the lyophilisate, where
appropriate containing other solid carrier substances, with the
desired solvent or suspending agent.
[0243] Intranasal preparations can be present as aqueous or oily
solutions or as aqueous or oily suspensions. They can also be
present as lyophilisates which are prepared before use using the
suitable solvent or suspending agent.
[0244] Inhalable preparations can present as powders, solutions or
suspensions. Preferably, inhalable preparations are in the form of
powders, e.g. as a mixture of the active ingredient with a suitable
formulation aid such as lactose.
[0245] The preparations are produced, aliquoted and sealed under
the customary antimicrobial and aseptic conditions.
[0246] As indicated above, the compounds of the invention may be
administered as a combination therapy with further active agents,
e.g. therapeutically active compounds useful in the treatment of
central nervous system disorders. These further compounds may be
PDE10 inhibitors or compounds which have an activity which is not
based on PDE10 inhibition such as dopamine D2 receptor modulating
agents or NMDA modulating agents.
[0247] For a combination therapy, the active ingredients may be
formulated as compositions containing several active ingredients in
a single dose form and/or as kits containing individual active
ingredients in separate dose forms. The active ingredients used in
combination therapy may be co-administered or administered
separately.
[0248] The synthesis of compounds of formula (II) preferably starts
from imidazo[1,5-a]pyrido[3,2-e]pyrazinones of formula (III):
##STR00004##
[0249] wherein R.sup.1, R.sup.2 and R.sup.4 are as described
above.
[0250] The preparation of compounds of formula (III) is well
described e.g. in WO 00/43392, WO 01/68097 and also by D. Norris et
al. (Tetrahedron Letters 42 (2001), 4297-4299).
[0251] According to standard procedures known from the literature
and already used in WO 99/45009 compounds of formula (III) are
halogenated by treatment with halogenating reagents like
POCl.sub.3, PCl.sub.3, PCl.sub.5 SOCl.sub.2, POBr.sub.3, PBr.sub.3
or PBr.sub.5, yielding e.g. 4-chloro or
4-bromo-imidazo[1,5-a]pyrido[3,2-e]pyrazines of formula (IV),
##STR00005##
[0252] wherein X is Cl or Br and R.sup.1, R.sup.2 and R.sup.4 are
as defined above.
[0253] Compounds of formula (II) where m and n are 0, the bond
between A and N is a double bond and R.sup.3 is selected from
OR.sup.6, SR.sup.6, OR.sup.7 or SR.sup.7 as described above, are
preferably prepared by the treatment of an intermediate of formula
(IV) with the corresponding alcohols or mercaptanes HOR.sup.6,
HOR.sup.7, HSR.sup.6 or HSR.sup.7.
EXAMPLES
Intermediate A1
4-chloro-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0254] 16 g of
8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine-4-one
and 120 ml POCl.sub.3 are mixed and heated up to reflux for 8
hours. After cooling to room temperature the reaction mixture is
treated with 1200 ml crushed ice/water and stirred for 1 hour. The
product is extracted with 2.times.300 ml dichloromethane. The
collected organic layer is washed with 2.times.300 ml water and
dried with Na.sub.2SO.sub.4. The solvent is removed under reduced
pressure.
[0255] Yield: 14.5 g
[0256] m.p.: 121-123.degree. C.
[0257] Many other intermediates A of formula (IV) can be prepared
according to this procedure. Some examples are the following:
TABLE-US-00001 (IV) ##STR00006## Intermediate X R.sup.1 R.sup.2
R.sup.4 m.p.[.degree. C.] A1 --Cl --C.sub.3H.sub.7 --CH.sub.3
--OCH.sub.3 121-123 A2 --Cl --C.sub.2H.sub.5 --CH.sub.3 --OCH.sub.3
148-150 A3 --Cl --CH.sub.3 --CH.sub.3 --OCH.sub.3 176-178 A4 --Cl
--C.sub.6H.sub.11 --CH.sub.3 --OCH.sub.3 211-213 A5 --Cl
--C.sub.6H.sub.13 --CH.sub.3 --OCH.sub.3 115-117 A6 --Cl
--C.sub.5H.sub.11 --CH.sub.3 --OCH.sub.3 110.5-113 A7 --Cl
--CH.sub.2CH.sub.2CF.sub.3 --CH.sub.3 --OCH.sub.3 149-153 A8 --Cl
--(CH.sub.2).sub.2C.sub.6H.sub.5 --CH.sub.3 --OCH.sub.3 130 A9 --Cl
--C.sub.6H.sub.5 --CH.sub.3 --OCH.sub.3 240-242 A10 --Cl
--C.sub.6H.sub.4(4-F) --CH.sub.3 --OCH.sub.3 256-258 A11 --Cl
--C.sub.2H.sub.5 --CH.sub.3 --H 117-120 A12 --Cl --C.sub.3H.sub.7
--CH.sub.3 --H 138-140 A13 --Cl --C.sub.3H.sub.7 --H --OCH.sub.3
153-155 A14 --Cl --CH(CH.sub.3).sub.2 --H --OCH.sub.3 162-164 A15
--Cl --CH.sub.3 --H --OCH.sub.3 225-228 A16 --Cl --H --H --H
222-225 A17 --Cl --H --C.sub.6H.sub.5 --OCH.sub.3 168-171 A18 --Cl
--H --CH.sub.3 --OCH.sub.3 185-187 A19 --Cl --C.sub.3H.sub.7
--CH.sub.3 --CH.sub.3 99-101 A20 --Cl --C.sub.2H.sub.5 --CH.sub.3
--N(C.sub.2H.sub.5).sub.2 145-150 A21 --Cl --C.sub.3H.sub.7
--CH.sub.3 ##STR00007## A22 --Cl --C.sub.2H.sub.5 --CH.sub.3
##STR00008## 283-285 A23 --Cl --C.sub.2H.sub.5 --CH.sub.3
##STR00009## 138-141 A24 --Cl --C.sub.3H.sub.7 --CH.sub.3
##STR00010## 134-136
Intermediate A 25
4-chloro-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-8-ol
[0258] 2 g
4-chloro-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e-
]pyrazine (Intermediate A1) was suspended in 50 ml dichloromethane.
At 0-5.degree. C. 3 ml bortribromide was added dropwise, followed
by 1 h stirring at 0-5.degree. C., 4 h stirring at room
temperature, and standing over night. The reaction mixture was
added slowly to a solution of 10 g potassium carbonate in 100 ml
water. After stirring and constant pH>7 (adding 10% potassium
carbonate solution) the precipitate was filtered off, and washed
with water.
[0259] Yield: 1.87 g
[0260] m.p.: 227-234.degree. C. (EtOH)
[0261] Other intermediates A of formula (IV) can be prepared
according to this procedure. Examples with X=Br were obtained with
a period of 6 h heating to reflux. Some examples are the
following:
TABLE-US-00002 Intermediate X R.sup.1 R.sup.2 R.sup.4 m.p.
[.degree. C.] A25 --Cl --C.sub.3H.sub.7 --CH.sub.3 --OH 227-234 A26
--Br --C.sub.2H.sub.5 --CH.sub.3 --OH >360.degree. C. (x HBr)
A27 --Br --C.sub.6H.sub.11 --CH.sub.3 --OH 212-216
Intermediate A28
4-chloro-8-difluoromethoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]py-
razine
[0262] 5.51 g (0.02 mol)
4-chloro-3-methyl-1-propyl-9H-imidazo[1,5-a]pyrido[3,2-e]pyrazin-8-ol
(Intermediate A25) and 2 g (0.05 mol) sodium hydroxide were
dissolved in 20 ml dimethylformamide. After 10 min stirring 2.53 ml
(0.03 mol) chlorodifluoroacetic acid was added dropwise. The
mixture was heated 5 h at 150.degree. C. bath temperature with
stirring. After cooling the product was extracted with ethyl
acetate (200 ml, 300 ml), the combined organic phases were washed
with water (2.times.100 ml), the organic phase was dried over
sodium sulfate, filtered off, and evaporated to dryness.
[0263] The obtained residue with 3 alkylated products was separated
by preparative chromatography (silica gel,
dichloromethane/methanol=9/1, v/v).
[0264] Yield: 1.21 g
[0265] m.p.: 95-98.degree. C.
Example 1
4,8-dimethoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0266] 1.5 g of intermediate A1 are dissolved in a mixture of 15 ml
methanol and 15 ml dichloromethane. 1 g of solid KOH is added. The
mixture is heated up to reflux for 7 hours. At room temperature 30
ml water are added. The organic layer is separated. The aqueous
layer is extracted with 20 ml dichloromethane. The unified organic
layers are washed with 2.times.20 ml water. The solvent is removed
completely. The residue is purified by LC.
[0267] Yield: 1.2 g
[0268] m.p.: 112-115.degree. C.
[0269] The following examples are prepared using the same route of
synthesis and reaction conditions like described above for example
1:
TABLE-US-00003 ##STR00011## Example R.sup.1 R.sup.2 R.sup.3 R.sup.4
m.p. [.degree. C.] 1 --C.sub.3H.sub.7 --CH.sub.3 --OCH.sub.3
--OCH.sub.3 112-115 2 --C.sub.3H.sub.7 --H --OCH.sub.3 --OCH.sub.3
113-116 3 --C.sub.2H.sub.5 --CH.sub.3 --OCH.sub.3 --OCH.sub.3
155-157 4 --CH.sub.3 --CH.sub.3 --OCH.sub.3 --OCH.sub.3 184-186 5
--H --CH.sub.3 --OCH.sub.3 --OCH.sub.3 152-154 6 --C.sub.2H.sub.5
--CH.sub.3 --OCH(CH.sub.3).sub.2 --OCH.sub.3 80-81 7
--C.sub.2H.sub.5 --CH.sub.3 --OC.sub.3H.sub.7 --OCH.sub.3 78-81 8
--C.sub.2H.sub.5 --CH.sub.3 ##STR00012## --OCH.sub.3 76-78 9
--C.sub.3H.sub.7 --CH.sub.3 --OCH(CH.sub.3).sub.2 --OCH.sub.3 78-80
10 --CH.sub.3 --CH.sub.3 ##STR00013## --OCH.sub.3 227-229 11
--C.sub.2H.sub.5 --CH.sub.3 ##STR00014## --OCH.sub.3 193-195 12
--C.sub.2H.sub.5 --CH.sub.3 ##STR00015## --OCH.sub.3 149-151 13
--C.sub.2H.sub.5 --CH.sub.3 ##STR00016## --OCH.sub.3 158-160 14
--C.sub.2H.sub.5 --CH.sub.3 ##STR00017## --OCH.sub.3 157-160 15
--C.sub.3H.sub.7 --CH.sub.3 ##STR00018## --OCH.sub.3 163-165 16
--C.sub.3H.sub.7 --CH.sub.3 ##STR00019## --OCH.sub.3 147-149 17
--C.sub.2H.sub.5 --CH.sub.3 ##STR00020## --OCH.sub.3 133-135 18
--C.sub.3H.sub.7 --CH.sub.3 ##STR00021## --OCH.sub.3 129-132 19
--CH.sub.3 --CH.sub.3 ##STR00022## --OCH.sub.3 115-118 20 --H
--CH.sub.3 ##STR00023## --OCH.sub.3 111-114 21 --C.sub.3H.sub.7
--CH.sub.3 ##STR00024## --OCH.sub.3 87-89 22 --C.sub.2H.sub.5
--CH.sub.3 ##STR00025## --OCH.sub.3 75-78 23 --CH.sub.3 --CH.sub.3
##STR00026## --OCH.sub.3 83-85 24 --C.sub.2H.sub.5 --CH.sub.3
##STR00027## --OCH.sub.3 173-175 25 --C.sub.2H.sub.5 --CH.sub.3
--SCH.sub.3 --OCH.sub.3 156-159 26 --C.sub.3H.sub.7 --CH.sub.3
--SCH.sub.3 --OCH.sub.3 112-115 27 --CH.sub.3 --CH.sub.3
--SCH.sub.3 --OCH.sub.3 140-144 28 --H --CH.sub.3 --SCH.sub.3
--OCH.sub.3 185-187
[0270] Compounds of formula (II) where m and n are 0, the bond
between A and N is a double bond and R.sup.3 is --CN are preferably
prepared by the treatment of an intermediate of formula (IV) with
the Grignard reagent ethoxycarbonyl-difluoromethyl magnesium
chloride followed by the substitution with a cyanide salt, e.g.
KCN.
Example 29
4-cyano-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0271] 3 g of intermediate A1 are added into a solution of 32 g
ethoxycarbonyl-difluoromethyl magnesia chloride in 100 ml
tetrahydrofurane (THF). The mixture is stirred and heated up to
reflux for 10 hours. Then the solvent is removed and 15 ml
N,N-dimethylformamide and 2 g KCN are added. This reaction mixture
is heated up to reflux for 5 hours. After this time 100 ml toluol
are added. The organic layer is washed with 3.times.50 ml water.
The solvent is removed and purified by preparative HPLC.
[0272] Yield: 0.2 g
[0273] m.p.: 178-180.degree. C.
[0274] Using the same procedure and reaction conditions like
described above for Example 29 also Example 30 was synthesized.
Example 30
4-cyano-8-methoxy-3-methyl-1-ethyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0275] Yield: 0.14 g
[0276] m.p.: 171-178.degree. C.
[0277] Compounds of formula (II) where m and n are 0, the bond
between A and N is a double bond and R.sup.3 is --N.sub.3 are
prepared by the treatment of an intermediate of formula (IV) with
and an azide salt, e.g. NaN.sub.3.
Example 31
4-azido-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0278] 1.5 g of intermediate A1 are stirred into 10 ml
N,N-dimethylformamide. 1 g NaN.sub.3 is added at room temperature.
The mixture is heated up to 60.degree. C. and stirred for 5 hours.
100 ml toluol are added. The organic layer is separated and washed
with 3.times.30 ml water. 90 ml of the solvent are removed. The
reaction product precipitates. The crude product is purified by
crystallisation from toluol.
[0279] Yield: 1.2 g
[0280] m.p.: >205.degree. C. (decomp.)
[0281] Compounds of formula (II) where m and n are 0, the bond
between A and N is a double bond and R.sup.3 is (SO)R.sup.6 or
(SO.sub.2)R.sup.6, wherein R.sup.6 is as defined above, are
prepared by oxidation of the corresponding compounds of formula
(II) where R.sup.3 means --SR.sup.6.
Example 32
8-methoxy-3-methyl-4-methylsulfinyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]py-
razine and
Example 33
8-methoxy-3-methyl-4-methylsulfonyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]py-
razine
[0282] 0.7 g of
8-methoxy-3-methyl-4-methylthio-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyraz-
ine (Example 26) are dissolved in 40 ml dichloromethane. 0.8 g of
3-chloroperoxybenzoic acid are added at 0 to 5.degree. C. in small
portions. The mixture is stirred for 2 hours at room temperature.
The solution is washed with 2.times.30 ml saturated NaHCO.sub.3
solution and than with 2.times.30 ml water. The solvent is removed
from the isolated organic layer. The crude mixture of Example 32
and Example 33 is separated by preparative HPLC.
Example 32
[0283] Yield: 0.2 g
[0284] m.p.: 144-147.degree. C.
Example 33
[0285] Yield: 0.25 g
[0286] m.p.: 42-46.degree. C.
[0287] Example 34 is prepared using the same route of synthesis and
reaction conditions like described above for example 31:
Example 34
1-ethyl-8-methoxy-3-methyl-4-methylsulfinyl-imidazo[1,5-a]pyrido[3,2-e]pyr-
azine
[0288] Yield: 0.23 g
[0289] m.p.: 189-192.degree. C.
[0290] Compounds of formula (II) where m and n are 0, the bond
between A and N is a double bond and R.sup.3 is hydrogen are
preferably prepared by the hydrogenation of an intermediate of
formula (IV), e.g. with hydrogen in the presence of a catalyst such
as palladium.
Example 35
8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0291] 2 g of intermediate A1 are suspended in 50 ml ethanol. 1 ml
triethylamine and 1 g palladium catalyst are added. An autoclave is
used as reaction vessel. Hydrogen is pressed in up to 20 bar
pressure. Now, the mixture is stirred at 30.degree. C. for 4 hours.
After filtration the solvent is removed. The crude product is
dissolved in 100 ml dichloromethane. This solution is washed with
50 ml water. The solvent is removed to isolate pure product.
[0292] Yield: 1.3 g
[0293] m.p.: 134-135.degree. C.
[0294] Using the same procedure and reaction conditions like
described above for Example 35 also Example 36 was synthesized.
Example 36
1-ethyl-8-methoxy-3-methyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0295] Yield: 1.0 g
[0296] m.p.: 159-162.degree. C.
[0297] Compounds of formula (II) where m and n are 0, the bond
between A and N is a double bond and R.sup.3 is R.sup.6 as
described above, are preferably prepared by treatment of an
intermediate of formula (IV) with the corresponding alkyl-,
alkenyl- or alkynyl organometal reagent, e.g. ethyl magnesium
bromide.
Example 37
4-ethyl-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0298] 7 g of intermediate A1 are suspended in 150 ml
tetrahydrofurane. 30 ml of a solution of ethyl magnesium bromide in
tetrahydrofurane (3 M) are added. The mixture is stirred for 4
hours at room temperature. After filtration the solvent is removed.
The crude product is purified by preparative HPLC.
[0299] Yield: 5.1 g
[0300] m.p.: 78-81.degree. C.
[0301] The following compounds are prepared using the same route of
synthesis and reaction conditions like described above for Example
37:
TABLE-US-00004 ##STR00028## Example R.sup.1 R.sup.2 R.sup.3 R.sup.4
m.p. [.degree. C.] 37 --C.sub.3H.sub.7 --CH.sub.3 --C.sub.2H.sub.5
--OCH.sub.3 78-81 38 --C.sub.3H.sub.7 --CH.sub.3 --CH.sub.3
--OCH.sub.3 91-93 39 --C.sub.3H.sub.7 --CH.sub.3 --CH.sub.3
--OCH.sub.3 171-175 (.times. HCl) 40 --C.sub.2H.sub.5 --CH.sub.3
--CH.sub.3 --OCH.sub.3 106-109 41 --CH.sub.3 --CH.sub.3 --CH.sub.3
--OCH.sub.3 157-161 42 --CH.sub.2CH.sub.2CF.sub.3 --CH.sub.3
--CH.sub.3 --OCH.sub.3 145-147 43 --C.sub.5H.sub.11 --CH.sub.3
--CH.sub.3 --OCH.sub.3 70-71 44 --C.sub.6H.sub.11 --CH.sub.3
--CH.sub.3 --OCH.sub.3 149-152 45 --C.sub.6H.sub.13 --CH.sub.3
--CH.sub.3 --OCH.sub.3 73-75 46 --(CH.sub.2).sub.2C.sub.6H.sub.5
--CH.sub.3 --CH.sub.3 --OCH.sub.3 121.5-123 47 --C.sub.6H.sub.5
--CH.sub.3 --CH.sub.3 --OCH.sub.3 189-192 48 --C.sub.6H.sub.5
--CH.sub.3 --CH.sub.3 --OCH.sub.3 210-218 (.times.2 HCl) 49
--C.sub.6H.sub.4(2-Cl) --CH.sub.3 --CH.sub.3 --CH.sub.3 220-222 50
--C.sub.6H.sub.4(4-F) --CH.sub.3 --CH.sub.3 --OCH.sub.3 235-238 51
--C.sub.3H.sub.7 --CH.sub.3 --CH.sub.3 --CH.sub.3 104-107 52
--C.sub.3H.sub.7 --CH.sub.3 --CH.sub.3 --H 92-95 53
--C.sub.3H.sub.7 H --CH.sub.3 --OCH.sub.3 124-126 54
--C.sub.3H.sub.7 --CH.sub.3 --CH.sub.3 --OCHF.sub.2 126-130 55
--C.sub.3H.sub.7 --CH.sub.3 --CH.sub.3 ##STR00029## 98-101 56
--C.sub.2H.sub.5 --CH.sub.3 --CH.sub.3 ##STR00030## 146-149 57
--C.sub.2H.sub.5 --CH.sub.3 --CH.sub.3 ##STR00031## 73-75 58
--C.sub.3H.sub.7 --CH.sub.3 --CH.sub.3 ##STR00032## 105-107
[0302] An analogous compound with R.sup.3.dbd.CH.sub.3 was obtained
during the synthesis of the above described of intermediate A28.
Separation of the obtained 3 alkylated products by preparative
chromatography resulted in Example 59.
Example 59
4-difluoromethoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine-8--
ol
[0303] Yield: 0.81 g
[0304] m.p.: 292-297.degree. C.
[0305] Compounds of formula (II) where m is 0, n=1 and the bond
between A and N is a double bond are synthesized from compounds of
formula (II) where m and n are 0, the bond between A and N is a
double bond by oxidation, e.g. with 3-chloroperoxybenzoic acid.
Example 60
8-methoxy-3-methyl-5-oxo-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0306] 6 g of
8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
(Example 35) are dissolved in 300 ml dichloromethane. A solution of
12 g 3-chloroperoxybenzoic acid in 40 ml acetic acid is added in
small portions during 30 minutes. The reaction mixture is stirred
for 16 hours at room temperature. Than the solution is washed with
2.times.50 ml saturated NaHCO.sub.3 solution and with 50 ml water.
The solvent is removed. The crude product is purified by
preparative HPLC.
[0307] Yield: 1.5 g
[0308] m.p.: 228-232.degree. C.
[0309] The same route of synthesis and reaction conditions like
described above for Example 37 were used for the synthesis of
Example 42.
Example 61
3,4-dimethyl-8-methoxy-5-oxo-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0310] Yield: 1.4 g
[0311] m.p.: 154-157.degree. C.
[0312] Compounds of formula (II) where m and n are 0, the bond
between A and N is a double bond and R.sup.3 is NH(CO)OR.sup.6,
N((CO)OR.sup.6).sub.2, N(R.sup.6)((CO)OR.sup.6), NH(CO)NH.sub.2,
NH(CO)NHR.sup.6, NR.sup.6(CO)NH.sub.2 and NR.sup.6(CO)NHR.sup.6
[0313] are preferably prepared by treatment of an intermediate of
formula (IV) with NH.sub.3 or an alkyl amine, e.g. a C.sub.1-5
alkyl amine to form the corresponding 4-amino derivatives
(according to the method from WO 99/45009). These 4-amino
derivatives (intermediates B) are treated with suitable reagents
such as chloro formic acid esters or amides to prepare the final
products.
##STR00033##
Intermediate B
Intermediate B1
4-amino-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0314] 10 g of intermediate A1 and 200 ml of an aqueous solution of
NH.sub.3 (32%) are mixed in an autoclave and heated up to
130.degree. C. for 8 hours. The reaction mixture is diluted with
200 ml water. The precipitated reaction product is separated washed
with water and dichloro methane and dried at reduced pressure.
[0315] Yield: 8.5 g
[0316] m.p.: 219-221.degree. C.
Example 62
8-methoxy-4-methoxycarbonylamino-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,-
2-e]pyrazine
[0317] 1.4 g of the intermediate B1 are stirred with 20 ml
dichloromethane 5 ml methanol and 1 ml triethylamine. At 0.degree.
C. a solution of 0.6 g chloro formic acid methylester in 10 ml
dichloromethane is added slowly. The mixture is stirred for 2 hours
at 0.degree. C. Than the solution is heated up to reflux 10 hours.
The solution is washed with 30 ml saturated NaHCO.sub.3 solution
and with 30 ml water. The solvent is removed. The crude product is
purified by preparative HPLC.
[0318] Yield: 0.22 g
[0319] m.p.: 137-138.degree. C.
[0320] Further Examples prepared using the same route of synthesis
and reaction conditions like described above for Example 62 are the
following:
Example 63
4-ethoxycarbonylamino-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-
-e]pyrazine
[0321] Yield: 0.3 g
[0322] m.p.: 122-124.degree. C.
Example 64
4-(N,N-bis-methoxycarbonyl-)amino-8-methoxy-3-methyl-1-propyl-imidazo[1,5--
a]pyrido[3,2-e]pyrazine
[0323] Yield: 0.45 g
[0324] m.p.: 137-138.degree. C.
Example 65
8-methoxy-4-(methoxycarbonyl-methyl-amino)-3-methyl-1-propyl-imidazo[1,5-a-
]pyrido[3,2-e]pyrazine
[0325] Yield: 0.04 g
[0326] m.p.: 105-109.degree. C.
Example 66
8-methoxy-3-methyl-4-(3-methyl-ureido)-1-propyl-imidazo[1,5-a]pyrido[3,2-e-
]pyrazine
[0327] 543 mg of Intermediate B1 and 960 mg
N,N'-carbonyldiimidazole were stirred with 20 ml tetrahydrofurane
for 3 hours under reflux. At room temperature 3 ml 40% methylamine
solution was added slowly. The solution was heated up to reflux 30
minutes. After removing the solvent under reduced pressure the
residue was extracted with 50 ml dichloromethane and 2.times.25 ml
water. The organic layer is removed. The crude product was purified
by preparative HPLC.
[0328] Yield: 0.4 g
[0329] m.p.: 178-181.degree. C.
[0330] Further Examples prepared using the same route of synthesis
and reaction conditions like described above for Example 66 are the
following:
Example 67
8-methoxy-3-methyl-1-propyl-4-ureido-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0331] Yield: 0.5 g
[0332] m.p.: 185-187.degree. C.
Example 68
8-methoxy-3-methyl-4-(3-isopropyl-ureido)-1-propyl-imidazo[1,5-a]pyrido[3,-
2-e]pyrazine
[0333] Yield: 0.3 g
[0334] m.p.: 165-166.degree. C.
[0335] Compounds of formula (II) where m and n are 0, the bond
between A and N is a double bond and R.sup.3 is
NH--SO.sub.2R.sup.6, N(SO.sub.2R.sup.6).sub.2,
N(R.sup.6)(SO.sub.2R.sup.6), NHSO.sub.2R.sup.6,
N(SO.sub.2R.sup.7).sub.2 and N(R.sup.8)SO.sub.2R.sup.7, wherein
R.sup.6, R.sup.7 and R.sup.8 are as defined above,
[0336] are preferably prepared by treatment of an intermediate of
formula (IV) with NH.sub.3 or an alkyl amine, e.g. a C.sub.1-5
alkyl amine to form the corresponding 4-amino derivatives according
to the method from WO 99/45009. These 4-amino derivatives
(intermediates B) are treated with sulfonic acid chlorides or
anhydrides forming the final sulfonamides.
Example 69
8-methoxy-3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,2-
-e]pyrazine
[0337] 10 g of the intermediate B1 are mixed with 350 ml toluol and
14 g methylsulfonic acid anhydride. The mixture is heated up to
reflux for 1 hour. After this time 16 ml triethylamine are added at
70.degree. C. The mixture is stirred then for 1 hour. 100 ml water
are added. The product precipitates. After filtration it is washed
with 3.times.80 ml water and 3.times.80 ml toluol. The product is
crystallized from toluol.
[0338] Yield: 9 g
[0339] m.p.: 243-246.degree. C.
[0340] Further Examples prepared using the same route of synthesis
and reaction conditions like described above for Example 46 are the
following:
TABLE-US-00005 ##STR00034## Example R.sup.1 R.sup.2 R.sup.3 R.sup.4
m.p. [.degree. C.] 69 --C.sub.3H.sub.7 --CH.sub.3
--NHSO.sub.2CH.sub.3 --OCH.sub.3 243-246 70 --C.sub.3H.sub.7
--CH.sub.3 --N(SO.sub.2CH.sub.3).sub.2 --OCH.sub.3 198-200 71
--C.sub.3H.sub.7 --CH.sub.3 --NHSO.sub.2C.sub.2H.sub.5 --OCH.sub.3
189-190 72 --C.sub.2H.sub.5 --CH.sub.3 --NHSO.sub.2CH.sub.3
--OCH.sub.3 270-271 73 --C.sub.3H.sub.7 --CH.sub.3
--NHSO.sub.2CF.sub.3 --OCH.sub.3 213-216 74 --C.sub.3H.sub.7
--CH.sub.3 --NHSO.sub.2C.sub.3H.sub.7 --OCH.sub.3 203-206 75
--C.sub.3H.sub.7 --CH.sub.3 --NHSO.sub.2CH(CH.sub.3).sub.2
--OCH.sub.3 235-238 76 --C.sub.3H.sub.7 --CH.sub.3
--NHSO.sub.2(C.sub.6H.sub.4-4-CH.sub.3) --OCH.sub.3 229-232 77
--C.sub.3H.sub.7 --CH.sub.3
--N[SO.sub.2(C.sub.6H.sub.4-4-CH.sub.3)].sub.2 --OCH.sub.3 206-209
78 --(CH.sub.2).sub.2CF.sub.3 --CH.sub.3 --NHSO.sub.2CH.sub.3
--OCH.sub.3 250-253 79 --C.sub.6H.sub.13 --CH.sub.3
--NHSO.sub.2CH.sub.3 --OCH.sub.3 134-136 80
--(CH.sub.2).sub.2C.sub.6H.sub.5 --CH.sub.3 --NHSO.sub.2CH.sub.3
--OCH.sub.3 199-202 81 --C.sub.6H.sub.5 --CH.sub.3
--NHSO.sub.2CH.sub.3 --OCH.sub.3 217-220 82 --C.sub.6H.sub.4(2-Cl)
--CH.sub.3 --NHSO.sub.2CH.sub.3 --OCH.sub.3 246-251 83
--C.sub.6H.sub.4(4-F) --CH.sub.3 --NHSO.sub.2CH.sub.3 --OCH.sub.3
250-256 84 --C.sub.3H.sub.7 --CH.sub.3 --NHSO.sub.2CH.sub.3
##STR00035## 224-225
Example 85
3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-
-8-ol hydrobromide
[0341] 3 g
8-methoxy-3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a-
]pyrido[3,2-e]pyrazine (Example 69) was suspended in 150 ml
dichloromethane. At 0-5.degree. C. 3.3 g bortribromide was added
dropwise, followed by 30 min stirring at 0-5.degree. C., 30 min
stirring at room temperature, and 2 h at 30.degree. C. The reaction
mixture was added slowly to a solution of 10 g sodium carbonate in
100 ml water. After stirring and constant pH>7 (adding 10%
potassium carbonate solution) the precipitate was filtered off,
washed with water, dried, and recrystallized with ethanol.
[0342] Yield: 0.5 g
[0343] m.p.: 302-306.degree. C.
Example 86
3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-
-8-ol
[0344] Example 86 can be prepared according to procedure of Example
85 without 2 h stirring at 30.degree. C.
[0345] Yield: 0.5 g
[0346] m.p.: 295-297.degree. C.
Example 87
8-difluoromethoxy-3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]py-
rido[3,2-e]pyrazine
[0347] 4.98 g
3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
n-8-ol (Example 86) and 1.6 g sodium hydroxide were dissolved in 20
ml dimethylformamide. After 10 min stirring 1.85 ml
chlorodifluoroacetic acid was added dropwise. The mixture was
heated 5 h at 150.degree. C. bath temperature with stirring. After
cooling the product was extracted with ethyl acetate (200 ml, 300
ml), the combined organic phases were washed with water
(2.times.100 ml), the organic phase was dried over sodium sulfate,
filtered off, and evaporated to dryness.
[0348] The obtained residue was separated by preparative
chromatography (silica gel, dichloromethane/methanol=9/1, v/v).
[0349] Yield: 0.66 g
[0350] m.p.: 210-214.degree. C.
Example 88
8-cyclopropylmethoxy-3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a-
]pyrido[3,2-e]pyrazine
[0351] 0.83 g
3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazi-
n-8-ol (Example 86) was dissolved in 20 ml dimethylformamide. 1.14
g cesium carbonate was added followed by 0.44 ml cyclopropyl
bromide dropwise. The mixture was heated 1 h at 60.degree. C. and 3
h at 130.degree. C. bath temperature with stirring. After cooling
the product was extracted with ethyl acetate (2.times.50 ml), and
water (2.times.50 ml), the organic phase was dried over sodium
sulfate, filtered off, and evaporated to dryness.
[0352] The obtained residue was separated by preparative
chromatography (silica gel, dichloromethane/methanol=95/5,
v/v).
[0353] Yield: 0.26 g
[0354] m.p.: 212-216.degree. C.
[0355] Compounds of formula (II) where m=1, n is 0, the bond
between A and N is a single bond and R.sup.5 is hydrogen are
prepared by the reduction of an intermediate of formula (IV) with
hydrogen, e.g. in the presence of a catalyst such as palladium.
Example 89
3-methyl-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,2-e]pyrazine
[0356] 6 g of the intermediate A12 are suspended in 200 ml ethanol.
3 ml triethylamine and 3 g palladium catalyst are added. An
autoclave is used as reaction vessel. Hydrogen is pressed in up to
20 bar pressure. Now, the mixture is stirred at 70.degree. C. for 4
hours. After filtration the solvent is removed. The crude product
is dissolved in 100 ml dichloromethane. This solution is washed
with 50 ml water. The solvent is removed to isolate the pure
product.
[0357] Yield: 4.5 g
[0358] m.p.: 169-172.degree. C.
[0359] Further Examples prepared using the same route of synthesis
and reaction conditions like described above for Example 89 are the
following:
TABLE-US-00006 ##STR00036## Example R.sup.1 R.sup.2 R.sup.4 R.sup.5
m.p. [.degree. C.] 89 --C.sub.3H.sub.7 --CH.sub.3 --H --H 169-172
90 --C.sub.3H.sub.7 --H --OCH.sub.3 --H 45-49 91 --C.sub.3H.sub.7
--CH.sub.3 --OCH.sub.3 --H 157-160 92 --C.sub.3H.sub.7 --CH.sub.3
--OCH.sub.3 --H .times. HCl 228-231 93 --C.sub.2H.sub.5 --CH.sub.3
--OCH.sub.3 --H 139-142
[0360] Compounds of formula (II) where m=1, n is 0, the bond
between A and N is a single bond and R.sup.5 is --C.sub.1-5 alkyl
are prepared by the treatment of compounds of formula (II) where
m=1, n is 0, the bond between A and N is a single bond and R.sup.5
is hydrogen with a C.sub.1-5 alkyl-aldehyde, e.g. in the presence
of Raney-Nickel and hydrogen.
Example 94
3,5-dimethyl-8-methoxy-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,2-e]pyr-
azine
[0361] 1 g
8-methoxy-3-methyl-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,-
2-e]pyrazine (Example 91) is suspended in 70 ml methanol. 1 ml
methanal and 0.5 g Raney-Nickel are added. An autoclave is used as
reaction vessel. Hydrogen is pressed in up to 20 bar pressure. Now,
the mixture is stirred at 45.degree. C. for 8 hours. After
filtration the solvent is distilled off.
[0362] Yield: 0.97 g
[0363] m.p.: 113-116.degree. C.
[0364] Compounds of formula (II) where m=1, n is 0, the bond
between A and N is a single bond and R.sup.5 is
--(C.dbd.O)--C.sub.1-5 alkyl are prepared by treatment of compounds
of formula (II) where m=1, n is 0, the bond between A and N is a
single bond and R.sup.5 is hydrogen with alkyl acid chlorides or
anhydrides.
Example 95
5-acetyl-8-methoxy-3-methyl-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,2--
e]pyrazine
[0365] 1 g
8-methoxy-3-methyl-1-propyl-4,5-dihydro-imidazo[1,5-a]pyrido[3,-
2-e]pyrazine (Example 91) is suspended in 25 ml dichloromethane.
0.8 g triethylamine are added. At 0.degree. C. a solution of 0.4 g
acetyl chloride in 5 ml dichloromethane is added. The mixture is
stirred for 2 hours at room temperature. 25 ml water are added. The
organic layer is separated. The solvent is distilled off.
[0366] Yield: 1 g
[0367] m.p.: 114-116.degree. C.
[0368] The Synthesis of the preferred compound (Example 38/39) is
described in the following scheme over all steps:
[0369] Step 1:
6-methoxy-2-(4-methyl-2-propyl-imidazol-1-yl)-3-nitro-pyridine
[0370] To a suspension prepared of 20.0 g KOH (solid), 25.8 g
4-methyl-2-propyl imidazole and 130 ml dimethyl formamide were
added 38.0 g 2-chloro-6-methoxy-3-nitro pyridine in small amounts
at a reaction temperature of 5.degree. C. The reaction mixture was
stirred for 75 minutes at room temperature. Then the reaction
mixture was poured in 600 ml water. The mixture was further stirred
for 1 hr. The desired product precipitated during this time. The
resulting solid was collected by filtration, washed with 100 ml
water for 3 times and dried in a dry box with vacuum (40.degree.
C.).
[0371] Yield: 40 g
[0372] m.p.: 96-103.degree. C.
[0373] Step 2:
3-amino-6-methoxy-2-(4-methyl-2-propyl-imidazol-1-yl)-pyridine
[0374] To a solution prepared of 138.2 g
6-methoxy-2-(4-methyl-2-propyl-imidazol-1-yl)-3-nitro-pyridine and
900 ml ethyl alcohol 4 g palladium-charcoal were added. The
reaction mixture was heated to 40.degree. C. and then hydrogenated
under pressure (10 to 15 bar). At room temperature the catalyst was
filtrated off and the filtrate was evaporated. To the solid residue
150 ml methyl tert.-butyl ether (MTBE) were added. After stirring
for 30 minutes the product was collected by filtration, washed with
50 ml MTBE for 2 times and dried in a dry box with vacuum
(40.degree. C.).
[0375] Yield: 100 g
[0376] m.p.: 124-128.degree. C.
[0377] Step 3:
8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazinone
[0378] A mixture of 20 g
3-amino-6-methoxy-2-(4-methyl-2-propyl-imidazol-1-yl)-pyridine and
60 g urea were heated up to 160.degree. C. The reaction mixture was
stirred for 2 hrs. Then 10 ml of glacial acetic acid were added.
The stirring was continued for further 6 hrs. The reaction mixture
was allowed to cool. At a temperature of 70.degree. C. 300 ml of
water were added and the mixture was stirred for 1 hr at 50.degree.
C. The warn mixture was filtrated and washed with 50 ml of water
for 2 times and dried in a dry box.
[0379] Yield: 20.5 g
[0380] m.p.: 297-300.degree. C.
[0381] Step 4:
4-chloro-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazin-
e
[0382] A mixture of 27 g
8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazinone
and 225 ml phosphorus oxychloride were heated to reflux for 8 hrs.
To the cooled mixture 250 ml of toluene were added and then 350 ml
of the liquid were distilled off. Subsequently the same procedure
was performed with 150 ml toluene but 250 ml of the liquid were
distilled off. The reaction mixture was allowed to cool at room
temperature and then poured in a mixture of 500 g ice/500 ml water.
After 30 minutes the mixture was extracted with 250 ml of
dichloromethane for two times. The dichloromethane layer was then
washed with 500 ml water then with sodium carbonate (3% in water)
and after that with 500 ml water. The organic layer was dried with
sodium sulfate. After removal of the sodium sulfate and evaporation
of the dichloromethane the crude product was dried in a dry box
with vacuum (40.degree. C.).
[0383] Yield: 26.5 g
[0384] m.p.: 119-123.degree. C.
[0385] Step 5:
3,4-Dimethyl-8-methoxy-1-propyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazine
(Example 38)
[0386] To a solution prepared of 20 g
4-chloro-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazin-
e (Intermediate 3) and 400 ml tetrahydrofuran 80 ml methylmagnesium
bromide (3 M in diethyl ether) were added drop wise (via 2 hrs).
The reaction mixture was stirred at room temperature for 6 hours.
After that the mixture was poured in a mixture of 300 g water,
which contained 100 g of ice and 10 g of ammonium chloride. The
mixture was extracted for 4 times with 300 ml dichloromethane. The
organic layer was separated and then dried with sodium sulfate.
After removal of the sodium sulfate and evaporation of the
dichloromethane a yellowish-orange crude product remained. This
residue was stirred in 150 ml of diethyl ether. After 1 hr. the
product was filtrated off and dried in a dry box.
[0387] The yield was 11.9 g of crude product (content>95%).
[0388] To a solution of 0.05 mol of the crude product and 100 ml of
dichloromethane 2.5 equiv. of hydrochloric acid dissolved in 100 ml
of water were added. The mixture was vigorously stirred. The
dichloromethane layer was then separated and subsequently the water
layer was extracted for 6 times with 100 ml dichloromethane. To the
organic layer 15 g of sodium carbonate were added. After filtration
of the solid precipitate and evaporation of the dichloromethane
yellowish crystals remains.
[0389] Yield: 18.6 g
[0390] m.p.: 91-92.5.degree. C.
[0391] Step 6:
3,4-Dimethyl-8-methoxy-1-propyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazine
hydrochloride (Example 39)
[0392] To a solution of 13.52 g of pure
3,4-dimethyl-8-methoxy-1-propyl-imidazo-[1,5-a]-pyrido[3,2-e]-pyrazine
and 100 ml of dichloromethane 2.5 equivalents of hydrochloric acid
dissolved in 100 ml of water were added. The mixture was vigorously
stirred. The dichloromethane layer was then separated and
subsequently the water layer was extracted for 6 times with 100 ml
dichloromethane. After evaporation of the dichloromethane yellowish
crystals remains. (yield 85%; yellowish crystals; m. p.
171-175.degree. C.).
[0393] Yield: 13.05 g
[0394] m.p.: 171-175.degree. C.
[0395] Surprisingly, the compounds of formula (II) are potent
inhibitors of the enzyme PDE10. A substance is considered to
effectively inhibit PDE10 if it has an IC.sub.50 of less than 10
.mu.M, preferably less than 1 .mu.M.
Preparation and Characterization of PDE10
[0396] Phosphodiesterase isoenzyme 10 (PDE10) activity was
determined in preparations of rat, pig and guinea pig striatum
respectively. Striatum from male Wistar rats (180-200 g), male
hybrid pigs (150 kg) and male guinea pigs (CRL (HA), 500 g)
respectively were collected and frozen at -70.degree. C.
[0397] In the prepared brain areas gene segments containing the
catalytic domain of the PDE10 were amplified and the sequence
determined. Therefore the RNA from the frozen striatum of the
different animals was isolated according to the instructions of the
RNeasy kit (Qiagen; Hilden; Germany) and transcribed into cDNA
using Oligo-Primer provided with the 1.sup.st strand cDNA synthese
kit for RT-PCR (Roche; Mannheim; Germany). These cDNA was used as
template for the PCR-reaction to amplify the catalytic domain of
the PDE10. For the PCR reaction Taq-Polymerase (Promega; Mannheim;
Germany) was used. Therefore it was possible to clone the
amplificates directly by TA-cloning in the pCR2.1 vector
(Invitrogen; Karlsruhe; Germany). The cloning vector was
transformed into E. coli's (XL-2), replicated within the cells,
prepared and the included gene sequence determined for the pig and
the guinea pig.
[0398] The following primers were used for the PCR-reaction:
TABLE-US-00007 P1: tgcatctacagggttaccatggagaa (SEQ ID NO: 1) P2:
tatccctgcaggccttcagcagaggctct (SEQ ID NO: 2) P3:
ttcacatggatatgcgacggtaccttct (SEQ ID NO: 3) P4:
Ctgtgaagaagaactatcggcgggttcctta. (SEQ ID NO: 4)
[0399] For the pig the priming was successful with P1 and P2. The
following sequence (SEQ ID NO 5) was identified:
TABLE-US-00008 tgcatctacagggttaccatggagaagctgtcctaccacagcatttgtac
cgcggaagagtggcaaggcctcatgcgcttcaaccttcccgtccgtcttt
gcaaggagattgaattgttccacttcgacattggtccttttgaaaacatg
tggcctggaatctttgtctatatggttcatcgcttctgtgggacggcctg
ctttgagcttgaaaagctgtgtcgttttatcatgtctgtgaagaagaact
atcgtcgggttccttaccacaactggaagcacgcggtcacggtggcacac
tgcatgtacgccatcctccagaacagccacgggctcttcaccgacctcga
gcgcaaaggactgctaatcgcgtgtctgtgccacgacctggaccacaggg
gcttcagcaacagctacctgcagaaattcgaccaccccctggccgctctc
tactccacgcccaccatggagcagcaccacttctcccagaccgtgtccat
cctccagttggaagggcacaacatcttctccaccctgagctccagtgagt
acgagcaggtgcttgagatcatccgcaaagccatcattgccacagacctc
gctttgtactttggaaacaggaaacagttggaggagatgtaccagaccgg
atcgctaaaccttaataaccagtcacatagagaccgcgtcattggtttga
tgatgactgcctgtgatctctgttccgtgacaaaactgtggccagtaaca
aaactgacggcaaatgatatatatgcggaattctgggccgagggcgatga
ggtgaagaagctgggaatacagcctattcccatgatggacagagacaaga
aggacgaagtcccacaaggccagctcggattctacaacgcggtagctatc
ccctgctacaccaccctcacccagatcttcccgcccacagagcctcttct
gaaggcctgcagggata
[0400] For the guinea pig the priming was successful with P4 and P2
as well as for P2 and P3.
[0401] The following sequence (SEQ ID NO:6) was identified with P4
and P2:
TABLE-US-00009 ctgtgaagaagaactatcggcgggttccttaccacaactggaagcatgca
gtcacggtggcgcactgcatgtacgccatacttcaaaacaacaatggcct
cttcacagaccttgagcgcaaaggcctgctaattgcctgtctgtgccatg
acctggaccacaggggcttcagtaacagctacctgcagaaattcgaccac
cccctggctgcgttgtactccacctccaccatggagcaacaccacttctc
ccagacggtgttcatcctccagctggaaggacacaacatcttctccaccc
tgagctccagcgagtacgagcaggtgctggagatcatccgcaaagccatc
atcgccactgacctcgcactgtactttgggaacaggaagcagttggagga
gatgtaccagacagggtcgctgaacctcaataaccagtcccatcgagacc
gcgtcatcggcttgatgatgactgcctgcgatctttgctctgtgacgaaa
ctatggccagttacaaaattgacagcaaatgatatatatgcagagttctg
ggctgagggggatgagatgaagaagttggggatacagcccatccctatga
tggacagagacaagaaggatgaagtccctcaaggacagcttggattctac
aatgctgtggccatcccctgctataccaccctgacgcagatcctcccacc
cacagagcctctgctgaaggcctgcagggata
[0402] The following sequence (SEQ ID NO:7) was identified with P2
and P3:
TABLE-US-00010 tagagcctctgctgaaggcctgcagggataacctcaatcagtgggagaag
gtaattcgaggggaagagacagcaatgtggatttcaggcccagcaactag
caaaagcacatcagggaagccgaccaggaaggtcgatgactgatcctgag
gtgatgtctgcctagcaactgactcaacctgcttctgtgacttcgttctt
tttatttttatttttttaacggggtgaaaacctctctcagaaggtaccgt
cgcatatccatgtgaa
[0403] An alignment of the sequences showed a nearly complete
accordance between the rat (published gene number NM.sub.--022236
3437 bp; coding sequence: 281-2665; catalytic domain 1634-2665) and
the guinea pig. More differences were detect between rat and pig.
For the alignment the coding areas are used only. The gene
alignment is shown in FIG. 3.
[0404] This results in the following differences in the protein
sequences within the catalytic domain as shown in a protein
alignment (FIG. 4).
[0405] For the enzymatic testing of PDE10 activity 0.5 g of the
isolated and frozen striatum was homogenised in 10 ml 50 mM
Tris/Mg-buffer at 4.degree. C. and centrifuged for one hour at
100000 g. The supernatant is called the cytosolic fraction and was
removed and stored on ice. The pellet was resuspended in the same
buffer, but containing 1% Triton and incubated for 45 min at
4.degree. C. Both fractions were independently applied onto a 5 ml
Hi Trap.TM. QHP column at the Akta-FPLC. After washing the columns
the bound PDE protein was eluted with an increasing sodium chloride
gradient (0 mM-500 mM sodium chloride) in 50 mM Tris/Mg-buffer at
4.degree. C. for the cytosolic fraction and in the presence of 1%
Triton for the membrane fraction. The eluted and collected
fractions were tested with 100 nM [.sup.3H]-cAMP for PDE10-activity
in the presence and without a specific PDE-Inhibitor at a
concentration, were a 100% inhibition is expected. The fractions
with PDE10-activity were pooled and frozen in aliquots until use at
-20.degree. C.
[0406] The pooled fractions from the FPLC were additional
characterized by Western blot. It was shown, that the PDE10A
containing pooled fractions include a great number of other
cellular proteins. Nevertheless PDE10 was detected with specific
antibodies by Western blot clearly (FIG. 1).
[0407] The protein was proven in the preparation of the striatum of
the rat, the pig and the guinea pig. The main part of protein was
found in the membrane fraction (FIG. 2).
Inhibition of PDE10
[0408] PDE10 activity was determined in a one step procedure in
microtiterplates. The reaction mixture of 100 .mu.l contained 50 mM
Tris-HCl/5 mM MgCl.sub.2 buffer (pH=7.4) (Sigma, Deisenhofen,
Germany; Merck, Darmstadt, Germany) 0.1 .mu.M [.sup.3H]-cAMP
(Amersham, Buckinghamshire, UK) and the enzyme. Nonspecific
activity was tested without the enzyme. The reaction was initiated
by addition of the substrate solution and was carried out at
37.degree. C. for 30 minutes. Enzymatic activity was stopped by
addition of 25 .mu.l YSi-SPA-beads (Amersham-Pharmacia). One hour
later the mixture was measured in a liquid scintillation counter
for microtiterplates (Microbeta Trilux). To pipette the incubation
mixture a robot Biomek (Fa. Beckman) is used. The determined
Km-values for the substrate cAMP is 78 nM for PDE10 from rat
striatum, 88 nM for pig striatum and 66.7 nM for guinea pig
striatum respectively. cGMP is the second substrate for PDE10, the
Km values are 1800 nM, 2200 nM and 1700 nM for PDE10 from these
species. For the test with cGMP 500 nM of this substrate was used.
The optimal amount of enzyme in the assay has been determined and
optimised for each enzyme preparation and substrate separately
before using the enzyme in compound testing. For determination of
IC.sub.50 values the Hill-plot, 2-parameter-model, was used.
Specific inhibitors of other PDE-Subtypes do not inhibit the PDE10
preparation significantly. Papaverine was used as the most common
PDE10 inhibitor and inhibits the PDE10 with IC50 values of 142 nM,
110 nM and 77 nM for PDE10 from striatum of rat, pig and guinea pig
respectively.
TABLE-US-00011 Inhibition of PDE10 from rat Example IC.sub.50
[.mu.M] 35 0.061 38 0.012 62 0.035 63 0.563 69 0.011 70 0.072 91
0.159 95 0.335
TABLE-US-00012 Inhibition of PDE10 from pig Example IC.sub.50
[.mu.M] 1 0.010 29 0.013 30 0.020 31 0.171 35 0.040 38 0.006 39
0.005 40 0.024 41 0.118 42 0.059 43 0.035 44 0.003 45 0.053 46
0.049 47 0.006 48 0.007 49 0.001 52 0.053 53 0.043 54 0.018 55
0.014 57 0.011 58 0.002 59 0.011 60 0.023 62 0.006 63 0.189 65
0.559 66 0.752 67 0.083 68 0.141 69 0.005 71 0.126 72 0.088 73
0.019 75 0.078 79 0.011 80 0.037 84 0.025 85 0.013 86 0.023 87
0.015 91 0.108 95 0.222
TABLE-US-00013 Inhibition of PDE10 from guinea pig Example
IC.sub.50 [.mu.M] 29 0.018 30 0.051 38 0.019 47 0.015 58 0.004 62
0.026 69 0.011
[0409] The compounds of formula II show significant antipsychotic
effects on the MK-801-induced hyperactivity and stereotyped
sniffing, an animal model of psychosis.
Test Procedure:
[0410] Female Wistar rats (Crl: (WI) BR, Charles River, Sulzfeld,
Germany) weighing 150 to 180 g were used for the MK-801-induced
psychosis. Animals were housed under standard conditions in groups
of five on a 12 h light/dark cycle (light on at 0600 h) with ad
libitum access to food (Pellets, ssniff M/R 15, Spezialdiat GmbH,
Soest/Westfalen) and water.
[0411] MK-801 (dizocilpine, MW 337.37) was obtained by Tocris,
distributed by Biotrend Chemikalien GmbH, Koln, Germany.
Drug Administration Schedule/Dosage:
TABLE-US-00014 [0412] number of dosage pre-treatment application
route of Substance [mg/kg] [min] [n] administration MK-801 0.1 10 1
i.p. Example 91 15, 30 30 1 i.p. Example 35 10, 30 30 1 p.o.
Example 95 10, 30 30 1 p.o. Example 62 2.5, 5.0 30 1 p.o. Example
38 1.0, 2.5, 5.0 30 1 p.o. Example 69 1.0, 2.5, 5.0 30 1 p.o.
Example 29 2.5, 5.0, 30 1 p.o. 7.5, 10 Example 47 5.0, 7.5, 10 30 1
p.o. Example 30 5.0, 10, 15, 60 1 p.o. 20 Example 55 10, 30 30 1
p.o.
Preparation of Compounds:
[0413] Compounds were freshly suspended in 0.5%
hydroxyethylcellulose so that an administration volume of 0.5
ml/100 g was reached for each substance and dose.
Hydroxyethylcellulose was solved in distilled water.
[0414] MK-801 was solved in saline so that an administration volume
of 0.5 ml/100 g was reached. The suspensions and solution were
placed on a magnetic stirrer before and during dosing
procedures.
[0415] The behaviour induced by the NMDA antagonist MK-801 is
generally accepted as a rat model of psychosis. MK-801 induces
stereotyped sniffing, hyperactivity and ataxia in rats after
intraperitoneal administration.
[0416] Locomotor activity of the rats was recorded by the MotiTest
Apparatus (TSE, Bad Homburg, Germany). The test area consisted of a
squared arena (45.times.45 cm) with protective plexiglass walls (20
cm of height) where rats could freely move. Horizontal movements
were recorded by 32 infrared photocells arranged along the bottom
of each wall of the arena. The activity [sec] was measured by the
computer program "ActiMot" (TSE, Bad Homburg, Germany).
[0417] Stereotyped sniffing was scored by the experimenter every
five minutes for one hour (12 intervals) according to the method
described by Andine et al. (1999). The scores of the 12 intervals
were summed up at the end of the recording time.
TABLE-US-00015 score stereotyped sniffing 0 no stereotyped sniffing
1 discontinuous sniffing (free interval > 5 s) 2 continuous
sniffing
[0418] The day of experiment the female rats were placed in the
laboratory and received the test compound or vehicle at the
appropriate time prior to test. MK-801 0.1 mg/kg was
intraperitoneally administered 10 minutes prior to test.
[0419] At the beginning of the test the rats were placed in the
centre of the squared arena of the MotiTest apparatus. Behaviour of
the rats was recorded for one hour. After each run animals were
removed and the boxes thoroughly cleaned and dried.
Statistics:
[0420] Results were analysed by one way analysis of variance
(ANOVA). Tukey test was used for individual comparison. P<0.05
was regarded as significant.
Results:
[0421] The results are shown in FIGS. 5, 6, 7 and 8.
[0422] FIG. 5 shows the effect of the compounds of Example 91, 35,
95 and 55 on MK-801-induced psychosis
[0423] MK-801 at 0.1 mg/kg i.p. was administered 10 min before
testing. Compounds at the described doses were administered 30 min
prior to the test. Activity and stereotyped sniffing was recorded
for 1 h. Cs=control with MK-801 stimulation. Significant to MK-801
stimulated control (=Cs): *p<0.05, ***p<0.001.
[0424] FIG. 6 shows the effect of the compounds of Example 38 and
47 on MK-801-induced psychosis
[0425] MK-801 at 0.1 mg/kg i.p. was administered 10 min before
testing. Compounds at the described doses were administered 30 min
prior to the test. Activity and stereotyped sniffing was recorded
for 1 h. Co=control without MK-801 stimulation. Cs=control with
MK-801 stimulation. Significant to non-stimulated control (Co): ##
p<0.01, ### p<0.001. Significant to MK-801 stimulated control
(Cs): *p<0.05, **p<0.01, ***p<0.001.
[0426] FIG. 7 shows the effect of the compounds of Example 62 and
69 on MK-801-induced psychosis
[0427] MK-801 at 0.1 mg/kg i.p. was administered 10 min before
testing. Compounds at the described doses were administered 30 min
prior to the test. Activity and stereotyped sniffing was recorded
for 1 h. Co=control without MK-801 stimulation. Cs=control with
MK-801 stimulation. Significant to non-stimulated control (Co): ##
p<0.01, ### p<0.001. Significant to MK-801 stimulated control
(Cs): *p<0.05, **p<0.01, ***p<0.001.
[0428] FIG. 8 shows the effect of the compounds of Example 29 and
30 on MK-801-induced psychosis
[0429] MK-801 at 0.1 mg/kg i.p. was administered 10 min before
testing. Compounds at the described doses were administered 30 min
prior to the test. Activity and stereotyped sniffing was recorded
for 1 h. Co=control without MK-801 stimulation. Cs=control with
MK-801 stimulation. Significant to non-stimulated control (Co): ##
p<0.01, ### p<0.001. Significant to MK-801 stimulated control
(Cs): *p<0.05, ***p<0.001.
[0430] The compound of Example 91 significantly reduced
MK-801-induced hyperactivity and stereotyped sniffing starting at
15 mg/kg i.p. The compounds of Example 95 and 55 significantly
reversed MK-801-induced hyperactivity and stereotyped sniffing at
30 mg/kg p.o. Example 35 significantly reversed MK-801-induced
hyperactivity at 30 mg/kg and stereotyped sniffing starting at 30
mg/kg p.o. The compound of Example 30 significantly reversed
MK-801-induced hyperactivity and stereotyped sniffing starting at
10 mg/kg p.o. The compound of Example 47 significantly reversed
MK-801-induced hyperactivity and stereotyped sniffing starting at
7.5 mg/kg p.o. Example 29 significantly reversed MK-801-induced
hyperactivity starting at 7.5 mg/kg and stereotyped sniffing
starting at 5 mg/kg p.o. The compound of Example 62 significantly
reversed MK-801-induced hyperactivity and stereotyped sniffing at 5
mg/kg p.o. The compounds of Example 38 and 69 significantly
reversed MK-801-induced hyperactivity starting at 5.0 mg/kg and
stereotyped sniffing starting at 2.5 mg/kg p.o. The results give
evidence for the antipsychotic potential of the compounds.
Sequence CWU 1
1
7126DNAArtificialPrimer P1 1tgcatctaca gggttaccat ggagaa
26229DNAArtificialPrimer P2 2tatccctgca ggccttcagc agaggctct
29328DNAArtificialPrimer P3 3ttcacatgga tatgcgacgg taccttct
28431DNAArtificialPrimer P4 4ctgtgaagaa gaactatcgg cgggttcctt a
315967DNApigmisc_feature(1)..(967)pig priming with P1 and P2
5tgcatctaca gggttaccat ggagaagctg tcctaccaca gcatttgtac cgcggaagag
60tggcaaggcc tcatgcgctt caaccttccc gtccgtcttt gcaaggagat tgaattgttc
120cacttcgaca ttggtccttt tgaaaacatg tggcctggaa tctttgtcta
tatggttcat 180cgcttctgtg ggacggcctg ctttgagctt gaaaagctgt
gtcgttttat catgtctgtg 240aagaagaact atcgtcgggt tccttaccac
aactggaagc acgcggtcac ggtggcacac 300tgcatgtacg ccatcctcca
gaacagccac gggctcttca ccgacctcga gcgcaaagga 360ctgctaatcg
cgtgtctgtg ccacgacctg gaccacaggg gcttcagcaa cagctacctg
420cagaaattcg accaccccct ggccgctctc tactccacgc ccaccatgga
gcagcaccac 480ttctcccaga ccgtgtccat cctccagttg gaagggcaca
acatcttctc caccctgagc 540tccagtgagt acgagcaggt gcttgagatc
atccgcaaag ccatcattgc cacagacctc 600gctttgtact ttggaaacag
gaaacagttg gaggagatgt accagaccgg atcgctaaac 660cttaataacc
agtcacatag agaccgcgtc attggtttga tgatgactgc ctgtgatctc
720tgttccgtga caaaactgtg gccagtaaca aaactgacgg caaatgatat
atatgcggaa 780ttctgggccg agggcgatga ggtgaagaag ctgggaatac
agcctattcc catgatggac 840agagacaaga aggacgaagt cccacaaggc
cagctcggat tctacaacgc ggtagctatc 900ccctgctaca ccaccctcac
ccagatcttc ccgcccacag agcctcttct gaaggcctgc 960agggata
9676732DNAguinea pigmisc_feature(1)..(732)guinea pig priming with
P4 and P2 6ctgtgaagaa gaactatcgg cgggttcctt accacaactg gaagcatgca
gtcacggtgg 60cgcactgcat gtacgccata cttcaaaaca acaatggcct cttcacagac
cttgagcgca 120aaggcctgct aattgcctgt ctgtgccatg acctggacca
caggggcttc agtaacagct 180acctgcagaa attcgaccac cccctggctg
cgttgtactc cacctccacc atggagcaac 240accacttctc ccagacggtg
ttcatcctcc agctggaagg acacaacatc ttctccaccc 300tgagctccag
cgagtacgag caggtgctgg agatcatccg caaagccatc atcgccactg
360acctcgcact gtactttggg aacaggaagc agttggagga gatgtaccag
acagggtcgc 420tgaacctcaa taaccagtcc catcgagacc gcgtcatcgg
cttgatgatg actgcctgcg 480atctttgctc tgtgacgaaa ctatggccag
ttacaaaatt gacagcaaat gatatatatg 540cagagttctg ggctgagggg
gatgagatga agaagttggg gatacagccc atccctatga 600tggacagaga
caagaaggat gaagtccctc aaggacagct tggattctac aatgctgtgg
660ccatcccctg ctataccacc ctgacgcaga tcctcccacc cacagagcct
ctgctgaagg 720cctgcaggga ta 7327266DNAguinea
pigmisc_feature(1)..(266)guinea pig priming with P2 and P3
7tagagcctct gctgaaggcc tgcagggata acctcaatca gtgggagaag gtaattcgag
60gggaagagac agcaatgtgg atttcaggcc cagcaactag caaaagcaca tcagggaagc
120cgaccaggaa ggtcgatgac tgatcctgag gtgatgtctg cctagcaact
gactcaacct 180gcttctgtga cttcgttctt tttattttta tttttttaac
ggggtgaaaa cctctctcag 240aaggtaccgt cgcatatcca tgtgaa 266
* * * * *