U.S. patent application number 13/919454 was filed with the patent office on 2013-11-28 for pde-10 inhibitors.
The applicant listed for this patent is EnVivo Pharmaceuticals, Inc.. Invention is credited to Richard CHESWORTH, Amy RIPKA, Gideon SHAPIRO.
Application Number | 20130317025 13/919454 |
Document ID | / |
Family ID | 41507725 |
Filed Date | 2013-11-28 |
United States Patent
Application |
20130317025 |
Kind Code |
A1 |
RIPKA; Amy ; et al. |
November 28, 2013 |
PDE-10 INHIBITORS
Abstract
Vicinal substituted cyclopropyl compounds which are inhibitors
of phosphodiesterase 10 are described as are processes,
pharmaceutical compositions, pharmaceutical preparations and
pharmaceutical use of the compounds in the treatment of mammals,
including human(s) for central nervous system (CNS) disorders and
other disorders which may affect CNS function, for example
neurological, neurodegenerative and psychiatric disorders
including, but not limited to, those comprising cognitive deficits
or schizophrenic symptoms.
Inventors: |
RIPKA; Amy; (Reading,
MA) ; SHAPIRO; Gideon; (Gainesville, FL) ;
CHESWORTH; Richard; (Boston, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EnVivo Pharmaceuticals, Inc. |
Watertown |
MA |
US |
|
|
Family ID: |
41507725 |
Appl. No.: |
13/919454 |
Filed: |
June 17, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13002922 |
Apr 4, 2011 |
8481532 |
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PCT/US2009/050055 |
Jul 9, 2009 |
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13919454 |
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61079179 |
Jul 9, 2008 |
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Current U.S.
Class: |
514/234.5 ;
514/233.8; 514/307; 514/311; 514/367; 514/375; 514/394;
514/406 |
Current CPC
Class: |
A61K 31/5377 20130101;
C07D 401/12 20130101; C07D 471/04 20130101; C07D 215/12 20130101;
C07D 217/02 20130101; A61K 31/416 20130101; A61K 31/423 20130101;
A61K 31/519 20130101; A61P 3/04 20180101; A61P 25/00 20180101; A61P
25/14 20180101; C07D 405/04 20130101; A61P 15/00 20180101; C07D
277/62 20130101; A61K 31/472 20130101; A61K 31/428 20130101; A61P
25/18 20180101; A61P 25/20 20180101; A61P 3/10 20180101; C07D
217/04 20130101; A61K 31/4184 20130101; A61K 31/47 20130101; A61P
25/30 20180101; C07D 215/02 20130101; C07D 263/54 20130101; C07D
235/06 20130101; A61P 3/00 20180101 |
Class at
Publication: |
514/234.5 ;
514/307; 514/311; 514/375; 514/367; 514/406; 514/394;
514/233.8 |
International
Class: |
A61K 31/472 20060101
A61K031/472; A61K 31/423 20060101 A61K031/423; A61K 31/5377
20060101 A61K031/5377; A61K 31/416 20060101 A61K031/416; A61K
31/4184 20060101 A61K031/4184; A61K 31/47 20060101 A61K031/47; A61K
31/428 20060101 A61K031/428 |
Claims
1-78. (canceled)
79. A pharmaceutical composition comprising: (a) a compound of
Formula (I) or (II) ##STR00313## or a pharmaceutically acceptable
salt thereof, wherein: X is hydrogen, halogen, C.sub.3-C.sub.8
alkyl, C.sub.1-C.sub.4 alkoxy, optionally substituted cycloalkyl,
optionally substituted cycloalkyloxy, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkoxy,
optionally substituted heterocycloalkyl, optionally substituted
heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy,
optionally substituted phenyl, optionally substituted heteroaryl,
optionally substituted heteroaryloxy or optionally substituted
heteroarylalkyl; Y is hydrogen, C.sub.3-C.sub.8 alkyl,
C.sub.1-C.sub.4 alkoxy, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocycloalkyl, optionally substituted heterocycloalkylalkyl,
optionally substituted phenyl or optionally substituted heteroaryl;
T.sub.1 is C; T.sub.2 is C; Z.sub.1 is CR.sub.1 or N; Z.sub.2 is
CR.sub.2 or N; Z.sub.3 is CR.sub.3 or N; Z.sub.4 is CR.sub.4 or N;
HET is (i) an optionally substituted monocyclic heteroaryl having 5
ring atoms selected from the group consisting of C, O, S and N
provided the total number of ring heteroatoms is less than or equal
to three and wherein no more than one of the total number of
heteroatoms is oxygen or sulfur, (ii) an optionally substituted
monocyclic heteroaryl having 6 atoms selected from the group
consisting of C and N provided that not more than 2 ring atoms are
N, or (iii) an optionally substituted monocyclic heterocycloalkyl;
R.sub.1 is hydrogen, halogen, C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4 alkoxy,
optionally substituted C.sub.3-C.sub.6 cycloalkyloxy, cyano, amino,
alkylamino, dialkylamino, alkylsulfonyl, carboxy, nitro amido,
alkylamido or dialkylamido; R.sub.2 is hydrogen, halogen,
C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.3-C.sub.6
cycloalkyl, C.sub.1-C.sub.4 alkoxy, optionally substituted
C.sub.3-C.sub.6 cycloalkyloxy, cyano, amino, alkylamino,
dialkylamino, alkylsulfonyl, carboxy, nitro amido, alkylamido or
dialkylamido; R.sub.3 is hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
optionally substituted C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4
alkoxy, optionally substituted C.sub.3-C.sub.6 cycloalkyloxy,
cyano, amino, alkylamino, dialkylamino, alkylsulfonyl, carboxy,
nitro amido, alkylamido or dialkylamido; R.sub.4 is hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4 alkoxy, optionally
substituted C.sub.3-C.sub.6 cycloalkyloxy, cyano, amino,
alkylamino, dialkylamino, alkylsulfonyl, carboxy, nitro amido,
alkylamido or dialkylamido; R.sub.5 is hydrogen, halogen,
C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.3-C.sub.6
cycloalkyl, C.sub.1-C.sub.4 alkoxy, optionally substituted
C.sub.3-C.sub.6 cycloalkyloxy, cyano, amino, alkylamino,
dialkylamino, alkylsulfonyl, carboxy, nitro amido, alkylamido or
dialkylamido; R.sub.6 is hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
optionally substituted C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4
alkoxy, optionally substituted C.sub.3-C.sub.6 cycloalkyloxy,
cyano, amino, alkylamino, dialkylamino, alkylsulfonyl, carboxy,
nitro amido, alkylamido or dialkylamido; R.sub.7 is hydrogen,
C.sub.1-C.sub.4 alkyl or optionally substituted C.sub.3-C.sub.6
cycloalkyl; and R.sub.5 is hydrogen, C.sub.1-C.sub.4 alkyl or
optionally substituted C.sub.3-C.sub.6 cycloalkyl; and (b) and a
pharmaceutically acceptable carrier or excipient.
80. The pharmaceutical composition of claim 79, wherein R.sub.7 is
hydrogen or C.sub.1-C.sub.4.
81. The pharmaceutical composition of claim 79, wherein R.sub.8 is
hydrogen or C.sub.1-C.sub.4 alkyl.
82. The pharmaceutical composition of claim 79, wherein R.sub.5 is
hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6
cycloalykl, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyloxy,
cyano or alkylsulfonyl.
83. The pharmaceutical composition of claim 79, wherein R.sub.6 is
hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6
cycloalykl, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyloxy,
cyano or alkylsulfonyl.
84. The pharmaceutical composition of claim 79, wherein Y is
C.sub.3-C.sub.6 cycloalykl, C.sub.4-C.sub.7 cycloalkylalkyl,
C.sub.4-C.sub.7 cycloalkylalkoxy, heterocycloalkyl, or
heterocycloalkyloxy.
85. The pharmaceutical composition of claim 79, wherein X is alkyl,
phenyl or heteroaryl.
86. The pharmaceutical composition of claim 79, wherein HET is a
monocyclic heterocycloalkyl.
87. The pharmaceutical composition of claim 86, wherein HET is a
monocyclic heterocycloalkyl having only 6 ring atoms.
88. The pharmaceutical composition of claim 86, wherein HET is a
monocyclic heterocycloalkyl having only 5 ring atoms.
89. The pharmaceutical composition of claim 79, wherein HET is
imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrmidinyl, pyrazinyl,
triazolyl, pyrazolyl, cinnolinyl, piperidinyl, pyrrolidinyl,
tetrahydrofuranyl, or pyranyl.
Description
DESCRIPTION OF THE DISCLOSURE
[0001] The disclosure relates to vicinal substituted cyclopropyl
compounds which are inhibitors of phosphodiesterase 10. The
disclosure further relates to processes, pharmaceutical
compositions, pharmaceutical preparations and pharmaceutical use of
the compounds in the treatment of mammals, including human(s) for
central nervous system (CNS) disorders and other disorders which
may affect CNS function. The disclosure also relates to methods for
treating neurological, neurodegenerative and psychiatric disorders
including, but not limited to, those comprising cognitive deficits
or schizophrenic symptoms.
BACKGROUND
[0002] Cyclic phosphodiesterases are intracellular enzymes which,
through the hydrolysis of cyclic nucleotides cAMP and cGMP,
regulate the levels of these mono phosphate nucleotides which serve
as second messengers in the signaling cascade of G-protein coupled
receptors. In neurons, PDEs also play a role in the regulation of
downstream cGMP and cAMP dependent kinases which phosphorylate
proteins involved in the regulation of synaptic transmission and
homeostasis. To date, eleven different PDE families have been
identified which are encoded by 21 genes. The PDEs contain a
variable N-terminal regulatory domain and a highly conserved
C-terminal catalytic domain and differ in their substrate
specificity, expression and localization in cellular and tissue
compartments, including the CNS.
[0003] The discovery of a new PDE family, PDE10, was reported
simultaneously by three groups in 1999 (Soderling et al. "Isolation
and characterization of a dual-substrate phosphodiesterase gene
family: PDE10A" Proc. Natl Sci. 1999, 96, 7071-7076; Loughncy et
al. "Isolation and characterization of PDE10A, a novel human
3',5'-cyclic nucleotide phosphodiesterase" Gene 1999, 234, 109-117;
Fujishige et al. "Cloning and characterization of a novel human
phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)"J.
Biol. Chem. 1999, 274, 18438-18445). The human PDE10 sequence is
highly homologous to both the rat and mouse variants with 95% amino
acid identity overall, and 98% identity conserved in the catalytic
region.
[0004] PDE10 is primarily expressed in the brain (caudate nucleus
and putamen) and is highly localized in the medium spiny neurons of
the striatum, which is one of the principal inputs to the basal
ganglia. This localization of PDE10 has led to speculation that it
may influence the dopaminergic and glutamatergic pathways both
which play roles in the pathology of various psychotic and
neurodegenerative disorders.
[0005] PDE10 hydrolyzes both cAMP (K.sub.m=0.05 uM) and cGMP
(K.sub.m=3 uM) (Soderling et al. "Isolation and Characterization of
a dual-substrate phosphodiesterase gene family: PDE10" Proc, Natl
Sci. USA 1999, 96(12), 7071-7076). In addition, PDE10 has a
five-fold greater V.sub.max for cGMP than for cAMP and these
in-vitro kinetic data have lead to the speculation that PDE10 may
act as a cAMP-inhibited cGMP phosphodiesterase in vivo (Soderling
and Beavo "Regulation of cAMP and cGMP signaling: New
phosphodiesterases and new functions," Curr. Opin. Biol., 2000, 12,
174-179).
[0006] PDE10 is also one of five phosphodiesterase members to
contain a tandem GAF domain at their N-terminus. It is
differentiated by the fact that the other GAF containing PDEs
(PDE2, 5, 6, and 11) bind cGMP while recent data points to the
tight binding of cAMP to the GAF domain of PDE10 (Handa et al.
"Crystal structure of the GAF-B domain from human phosphodiesterase
10A complexed with its ligand, cAMP" J. Biol. Chem. 2008, May 13,
ePub).
[0007] PDE10 inhibitors have been disclosed for the treatment of a
variety of neurological and psychiatric disorders including
Parkinson's disease, schizophrenia, Huntington's disease,
delusional disorders, drug-induced psychoses, obsessive compulsive
and panic disorders (US Patent Application 2003/0032579). Studies
in rats (Kostowski et. al "Papaverine drug induced stereotypy and
catalepsy and biogenic amines in the brain of the rat" Pharmacol.
Biochem. Behav. 1976, 5, 15-17) have showed that papaverine, a
selective PDE 10 inhibitor reduces apomorphine induced stereotypes
and rat brain dopamine levels and increases haloperidol induced
catalepsy. This experiment lends support to the use of a PDE10
inhibitor as an antipsychotic since similar trends are seen with
known, marketed antipsychotics.
[0008] Antipsychotic medications are the mainstay of current
treatment for schizophrenia. Conventional or classic
antipsychotics, typified by haloperidol, were introduced in the
mid-1950s and have a proven track record over the last half century
in the treatment of schizophrenia. While these drugs are effective
against the positive, psychotic symptoms of schizophrenia, they
show little benefit in alleviating negative symptoms or the
cognitive impairment associated with the disease. In addition,
drugs such as haloperidol have extreme side effects such as
extrapyramidal symptoms (EPS) due to their specific dopamine D2
receptor interaction. An even more severe condition characterized
by significant, prolonged, abnormal motor movements known as
tardive dyskinesia also may emerge with prolonged classic
antipsychotic treatment.
[0009] The 1990s saw the development of several new drugs for
schizophrenia, referred to as atypical antipsychotics, typified by
risperidone and olanzapine and most effectively, clozapine. These
atypical antipsychotics are generally characterized by
effectiveness against both the positive and negative symptoms
associated with schizophrenia, but have little effectiveness
against cognitive deficiencies and persisting cognitive impairment
remain a serious public health concern (Davis, J. M et al. "Dose
response and dose equivalence of antipsychotics." Journal of
Clinical Psychopharmacology, 2004, 24 (2), 192-208; Friedman, J. H.
et al "Treatment of psychosis in Parkinson's disease: Safety
considerations." Drug Safety, 2003, 26 (9), 643-659). In addition,
the atypical antipsychotic agents, while effective in treating the
positive and, to some degree, negative symptoms of schizophrenia,
have significant side effects. For example, clozapine which is one
of the most clinically effective antipsychotic drugs shows
agranulocytosis in approximately 1.5% of patients with fatalities
due to this side effect being observed. Other atypical
antipsychotic drugs have significant side effects including
metabolic side effects (type 2 diabetes, significant weight gain,
and dyslipidemia), sexual dysfunction, sedation, and potential
cardiovascular side effects that compromise their clinically
effectiveness. In the large, recently published NIH sponsored CATIE
study, (Lieberman et al "The Clinical Antipsychotic Trials Of
Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical
comparison of subgroups with and without the metabolic syndrome."
Schizophrenia Research, 2005, 80 (1), 9-43) 74% of patients
discontinued use of their antipsychotic medication within 18 months
due to a number of factors including poor tolerability or
incomplete efficacy. Therefore, a substantial clinical need still
exists for more effective and better tolerated antipsychotic
mediations possibly through the use of PDE10 inhibitors.
BRIEF SUMMARY
[0010] Described herein are vicinal substituted cyclopropyl
compounds of Formula (I) or (II) and pharmaceutically acceptable
salts thereof, which are inhibitors of at least one
phosphodiesterase 10
##STR00001##
[0011] Wherein:
[0012] X is selected from hydrogen, halogen, C.sub.3-C.sub.8 alkyl,
C.sub.1-C.sub.4 alkoxy, optionally substituted cycloalkyl,
optionally substituted cycloalkyloxy, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkoxy,
optionally substituted heterocycloalkyl, optionally substituted
heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy,
optionally substituted phenyl, optionally substituted heteroaryl,
optionally substituted heteroaryloxy and optionaly substituted
heteroarylalkyl
[0013] Y is selected from hydrogen, C.sub.3-C.sub.8 alkyl,
C.sub.1-C.sub.4 alkoxy, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocycloalkyl, optionally substituted heterocycloalkylalkyl,
optionally substituted phenyl or optionally substituted
heteroaryl
[0014] T.sub.1 is C
[0015] T.sub.2 is C
[0016] Z.sub.1 is selected from CR.sub.1 and N
[0017] Z.sub.2 is selected from CR.sub.2 and N
[0018] Z.sub.3 is selected from CR.sub.3 and N
[0019] Z.sub.4 is selected from CR.sub.4 and N
[0020] HET is selected from an optionally substituted monocyclic
heteroaryl having 5 ring atoms selected from C, O, S and N provided
the total number of ring heteroatoms is less than or equal to three
and where no more than one of the total number of heteroatoms is
oxygen or sulfur, an optionally substituted monocyclic heteroaryl
having 6 atoms selected from C and N provided that not more than 2
ring atoms are N, and an optionally substituted monocyclic
heterocycloalkyl.
[0021] R.sub.1 is selected from hydrogen, halogen, C.sub.1-C.sub.4
alkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, optionally substituted C.sub.3-C.sub.6
cycloalkyloxy, cyano, amino, alkylamino, dialkylamino,
alkylsulfonyl, carboxy, nitro amido, alkylamido or
dialkylamido.
[0022] R.sub.2 is selected from hydrogen, halogen, C.sub.1-C.sub.4
alkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, optionally substituted C.sub.3-C.sub.6,
cycloalkyloxy, cyano, amino, alkylamino, dialkylamino,
alkylsulfonyl, carboxy, nitro amido, alkylamido or
dialkylamido.
[0023] R.sub.3 is selected from hydrogen, halogen, C.sub.1-C.sub.4
alkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, optionally substituted C.sub.3-C.sub.6
cycloalkyloxy, cyano, amino, alkylamino, dialkylamino,
alkylsulfonyl, carboxy, nitro amido, alkylamido or
dialkylamido.
[0024] R.sub.4 is selected from hydrogen, halogen, C.sub.1-C.sub.4
alkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, optionally substituted C.sub.3-C.sub.6
cycloalkyloxy, cyano, amino, alkylamino, dialkylamino,
alkylsulfonyl, carboxy, nitro amido, alkylamido or
dialkylamido.
[0025] R.sub.5 is selected from hydrogen, halogen, C.sub.1-C.sub.4
alkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, optionally substituted C.sub.3-C.sub.6
cycloalkyloxy, cyano, amino, alkylamino, dialkylamino,
alkylsulfonyl, carboxy, nitro amido, alkylamido or
dialkylamido.
[0026] R.sub.6 is selected from hydrogen, halogen, C.sub.1-C.sub.4
alkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, optionally substituted C.sub.3-C.sub.6
cycloalkyloxy, cyano, amino, alkylamino, dialkylamino,
alkylsulfonyl, carboxy, nitro amido, alkylamido or
dialkylamido.
[0027] R.sub.7 is selected from hydrogen, C.sub.1-C.sub.4 alkyl and
C.sub.3-C.sub.6 cycloalkyl.
[0028] R.sub.8 is selected from hydrogen, C.sub.1-C.sub.4 alkyl and
C.sub.3-C.sub.6 cycloalkyl.
[0029] In some embodiments, alkyl groups are fully saturated
whether present on their own or as part of another group (e.g.,
alkylamino and alkylamido).
[0030] In certain embodiments, substituent groups are not further
substituted.
[0031] In various embodiments, any group that is defined as being
optionally substituted is independently singly or multiply
substituted.
[0032] In various embodiments, any group that is defined as being
optionally substituted is not substituted.
[0033] In one embodiment, X is selected from cycloalkyl,
cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl,
heterocycloalkylalkyl, heterocycloalkyloxy, phenyl, heteroaryl,
heteroaryloxy and heteroarylalkyl.
[0034] In another embodiment, X is selected from alkyl, cycloalkyl,
cycloalkyloxy, cycloalkylalkyl and cycloalkylalkoxy.
[0035] In another embodiment, X is selected from halogen,
C.sub.1-C.sub.4 alkoxy, alkyl, cycloalkyl, cycloalkyloxy,
cycloalkylalkyl and cycloalkylalkoxy.
[0036] In another embodiment, X is selected from cycloalkyl,
cycloalkyloxy, cycloalkylalkyl and cycloalkylalkoxy.
[0037] In an additional embodiment, X is selected from alkyl,
heterocycloalkyl, heterocycloalkylalkyl and
heterocycloalkyloxy.
[0038] In an additional embodiment, X is selected from alkyl,
heterocycloalkyl, heterocycloalkylalkyl and
heterocycloalkyloxy.
[0039] In a further embodiment, X is heterocycloalkyl.
[0040] In another embodiment, X is selected from heteroaryl,
heteroaryloxy and heteroarylalkyl.
[0041] In another embodiment, X is selected from alkyl, phenyl and
heteroaryl.
[0042] In another embodiment, X is selected from phenyl and
heteroaryl.
[0043] In an additional embodiment, X is heteroaryl.
[0044] In an additional embodiment, X is phenyl.
[0045] In an additional embodiment, X is restricted phenyl.
[0046] In another embodiment, X is selected from a monocyclic
heteroaryl having 5 ring atoms selected from C, O, S and N provided
the total number of ring heteroatoms is less than or equal to four
and where no more than one of the total number of heteroatoms is
oxygen or sulfur, and a monocyclic heteroaryl having 6 atoms
selected from C and N provided that not more than 3 ring atoms are
N, and where said ring may be optionally and independently
substituted with up to two groups selected from C.sub.1-C.sub.4
alkyl, cycloalkyl, cycloalkyloxy, C.sub.1-C.sub.4 alkoxy, CF.sub.3,
carboxy, alkoxyalkyl, C.sub.1-C.sub.4 cycloalkylalkoxy, amino,
alkylamino, dialkylamino, amido, alkylamido, dialkylamido,
thioalkyl, alkylsulfonyl, halogen, cyano, and nitro. Examples
include but are not limited to 1H-pyrroyl, furanyl, thiophenyl,
imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl,
thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,
1,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl,
1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl,
pyrazinyl, pyridazinyl and pyrimidinyl.
[0047] In one embodiment. Y is hydrogen.
[0048] In another embodiment, Y is selected from alkyl and
alkoxy.
[0049] In another embodiment, Y is selected from cycloalkyl,
cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl,
heterocycloalkyloxy.
[0050] In another embodiment, Y is selected from cycloalkyl,
cycloalkylalkyl and cycloalkylalkoxy.
[0051] In another embodiment, Y is selected from cycloalkyl,
heterocycloalkyl and heterocycloalkyloxy.
[0052] In a further embodiment, Y is selected from phenyl and
heteroaryl.
[0053] In an additional embodiment, Y is heteroaryl.
[0054] In another embodiment, Y is selected from phenyl, a
monocyclic heteroaryl having 5 ring atoms selected from C, O, S and
N provided the total number of ring heteroatoms is less than or
equal to four and where no more than one of the total number of
heteroatoms is oxygen or sulfur, and a monocyclic heteroaryl having
6 atoms selected from C and N provided that not more than 3 ring
atoms are N, and where said ring may be optionally and
independently substituted with up to two groups selected from
C.sub.1-C.sub.4 alkyl, cycloalkyl, cycloalkyloxy, C.sub.1-C.sub.4
alkoxy, CF.sub.3, carboxy, alkoxyalkyl, C.sub.1-C.sub.4
cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido,
alkylamido, dialkylamido, thioalkyl, alkylsulfonyl, halogen, cyano,
and nitro. Examples include but are not limited to 1H-pyrrolyl,
furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl,
isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazoyl, 1,3,4-thiadiazolyl, tetrazolyl,
1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl,
1,2,3,5-thiatriazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl,
1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and
pyrimidinyl.
[0055] In another embodiment, Y is selected from a monocyclic
aromatic ring having 5 ring atoms selected from C, O, S and N
provided the total number of ring heteroatoms is less than or equal
to four and where no more than one of the total number of
heteroatoms is oxygen or sulfur, and a monocyclic aromatic ring
having 6 atoms selected from C and N provided that not more than 3
ring atoms are N, and where said ring may be optionally and
independently substituted with up to two groups selected from
C.sub.1-C.sub.4 alkyl, cycloalkyl, cycloalkyloxy, C.sub.1-C.sub.4
alkoxy, CF.sub.3, carboxy, alkoxyalkyl, C.sub.1-C.sub.4
cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido,
alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro.
Examples include but are not limited to 1H-pyrrolyl, furanyl,
thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,
oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,
1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl,
1,2,3,5-thiatriazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl,
1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and
pyrimidinyl.
[0056] In a further embodiment, Y is phenyl
[0057] In another embodiment, Y is restricted phenyl.
[0058] In one embodiment Z.sub.1 is CR.sub.1.
[0059] In another embodiment Z.sub.1 is N.
[0060] In one embodiment Z.sub.2 is CR.sub.2.
[0061] In another embodiment Z.sub.2 is N.
[0062] In one embodiment Z.sub.3 is CR.sub.3.
[0063] In another embodiment Z.sub.3 is N.
[0064] In one embodiment Z.sub.4 is CR.sub.4.
[0065] In another embodiment Z.sub.4 is N.
[0066] In one embodiment, HET is selected from a monocyclic
heteroaryl having 5 ring atoms selected from C, O, S and N provided
the total number of ring heteroatoms is less than or equal to three
and where no more than one of the total number of heteroatoms is
oxygen or sulfur, and a monocyclic heteroaryl having 6 atoms
selected from C and N provided that not more than 2 ring atoms are
N, and where said ring may be optionally and independently
substituted with up to two groups selected from C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.6 cycloalkyl, alkoxy, C.sub.3-C.sub.6
cycloalkyloxy, carboxy, halogen, nitro, alkylsulfonyl, amino,
alkylamino, dialkylamino, amido, alkylamido, dialkylamido and
cyano. Examples include but are not limited to 1H-pyrrolyl,
furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl,
isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl,
1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,3-triazinyl,
1,2,4-triazinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and
pyridin-2(1H)-onyl.
[0067] In another embodiment, HET is a monocyclic heteroaryl having
5 ring atoms selected from C, O, S and N provided the total number
of ring heteroatom-s is less than or equal to three and where no
more than one of the total number of heteroatoms is oxygen or
sulfur where said ring may be optionally and independently
substituted with up to two groups selected from C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.6 cycloalkyl, alkoxy, C.sub.3-C.sub.6
cycloalkyloxy, carboxy, halogen, nitro, alkylsulfonyl, amino,
alkylamino, dialkylamino, amido, alkylamido, dialkylamido and
cyano. Examples include but are not limited to 1H-pyrrolyl,
furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl,
isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl,
1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,3-triazinyl and
1,2,4-triazinyl.
[0068] In another embodiment, HET is a monocyclic aromatic ring
having 6 atoms selected from C and N provided that not more than 2
ring atoms are N, where said ring may be optionally and
independently substituted with up to two groups selected from
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, alkoxy,
C.sub.3-C.sub.6 cycloalkyloxy, carboxy, halogen, nitro,
alkylsulfonyl, amino, alkylamino, dialkylamino, amido, alkylamido,
dialkylamido and cyano. Examples include but are not limited to
pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and
pyridin-2(1H)-onyl.
[0069] In an additional embodiment, HET is a monocyclic
heterocycloalkyl.
[0070] In a further embodiment HET is a monocyclic heterocycloalkyl
having only 6 ring atoms. Examples include, but are not limited to,
morpholinyl, piperidinyl, piperazinyl N-Me-piperazinyl and
pyranyl.
[0071] In another embodiment HET is a monocyclic heterocycloalkyl
having only 5 ring atoms. Examples include, but are not limited to,
tetrahydrofuranyl and pyrrolidinyl.
[0072] In another embodiment, HET is selected from, imidazolyl,
thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazolyl,
pyrazolyl, cinnolinyl, piperidinyl, pyrrolidinyl,
tetrahydrofuranyl, and pyranyl.
[0073] In another embodiment, R.sub.1 is selected from hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and
alkylsulfonyl.
[0074] In another embodiment, R.sub.1 is selected from halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and alkylsulfonyl.
[0075] In another embodiment, R.sub.1 is selected from hydrogen,
alkoxy, halogen, cyano, alkylsulfonyl and nitro.
[0076] In one embodiment, R.sub.1 is hydrogen.
[0077] In another embodiment, R.sub.2 is selected from hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and
alkylsulfonyl.
[0078] In another embodiment, R.sub.2 is selected from halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and alkylsulfonyl.
[0079] In another embodiment, R.sub.2 is selected from hydrogen,
alkoxy, halogen, cyano, alkylsulfonyl and nitro.
[0080] In one embodiment, R.sub.2 is hydrogen.
[0081] In another embodiment, R.sub.3 is selected from hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and
alkylsulfonyl.
[0082] In another embodiment, R.sub.3 is selected from halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and alkylsulfonyl.
[0083] In another embodiment, R.sub.3 is selected from hydrogen,
alkoxy, halogen, cyano, alkylsulfonyl and nitro.
[0084] In one embodiment, R.sub.3 is hydrogen.
[0085] In another embodiment, R.sub.4 is selected from hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and
alkylsulfonyl.
[0086] In another embodiment, R.sub.4 is selected from halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.6 cycloalkyloxy, cyano and alkylsulfonyl.
[0087] In another embodiment, R.sub.4 is selected from hydrogen,
alkoxy, halogen, cyano, alkylsulfonyl and nitro.
[0088] In one embodiment, R.sub.4 is hydrogen.
[0089] In another embodiment, R.sub.5 is selected from hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and
alkylsulfonyl.
[0090] In another embodiment, R.sub.5 is selected from halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and alkylsulfonyl.
[0091] In another embodiment, R.sub.5 is selected from hydrogen,
alkoxy, halogen, cyano, alkylsufonyl and nitro.
[0092] In one embodiment, R.sub.5 is hydrogen.
[0093] In another embodiment, R.sub.6 is selected from hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and
alkylsulfonyl.
[0094] In another embodiment, R.sub.6 is selected from halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.3-C.sub.6 cycloalkyloxy, cyano and alkylsulfonyl.
[0095] In another embodiment, R.sub.6 is selected from hydrogen,
alkoxy, halogen, cyano, alkylsulfonyl and nitro.
[0096] In one embodiment, R.sub.6 is hydrogen.
[0097] In one embodiment, R.sub.7 is selected from hydrogen and
C.sub.1-C.sub.4 alkyl.
[0098] In another embodiment, R.sub.7 is C.sub.1-C.sub.4 alkyl.
[0099] In another embodiment, R.sub.7 is hydrogen.
[0100] In one embodiment, R.sub.8 is selected from hydrogen and
C.sub.1-C.sub.4 alkyl.
[0101] In another embodiment, R.sub.8 is C.sub.1-C.sub.4 alkyl.
[0102] In another embodiment, R.sub.8 is hydrogen.
[0103] Compounds of the disclosure may contain asymmetric centers
and exist as different enantiomers or diastereomers or a
combination of these therein. All enantiomeric, diastereomeric
forms of Formulas (I) and (II) are embodied herein.
[0104] Compound of the disclosure may exist as geometric isomers
and tautomeric forms or a combination of these therein. When a
compound of Formulas (I) or (II) contains an alkenyl or an imino
group, geometric cis/trans (E/Z) isomers are possible. All
cis/trans isomeric forms and tautomeric forms of Formulas (I) and
(II) are embodied herein and are represented by the formula.
[0105] Compounds in the disclosure may be in the form of
pharmaceutically acceptable salts. The phrase "pharmaceutically
acceptable" refers to salts prepared from pharmaceutically
acceptable non-toxic bases and acids, including inorganic and
organic bases and inorganic and organic acids. Salts derived from
inorganic bases include lithium, sodium, potassium, magnesium,
calcium and zinc. Salts derived from organic bases include ammonia,
primary, secondary and tertiary amines, and amino acids. Salts
derived from inorganic acids include sulfuric, hydrochloric,
phosphoric, hydrobromic. Salts derived from organic acids include
C.sub.1-6 alkyl carboxylic acids, di-carboxylic acids and
tricarboxylic acids such as acetic acid, proprionic acid, fumaric
acid, maleic acid, succinic acid, tartaric acid, adipic acid and
citric acid, and alkylsulfonic acids such as methanesulphonic, and
aryl sulfonic acids such as para-tolouene sulfonic acid and benzene
sulfonic acid.
[0106] Compounds in the disclosure may be in the form of a solvate.
This occurs when a compound of Formulas (I) or (II) has an
energetically favorable interaction with a solvent, crystallizes in
a manner that it incorporates solvent molecules into the crystal
lattice or a complex is formed with solvent molecules in the solid
or liquid state. Examples of solvents forming solvates are water
(hydrates), MeOH, EtOH, iPrOH, and acetone.
[0107] Compounds in the disclosure may exist in different crystal
forms known as polymorphs. Polymorphism is the ability of a
substance to exist in two or more crystalline phases that have
different arrangements and/or conformations of the molecule in the
crystal lattice.
[0108] Compounds in the disclosure may exist as isotopically
labeled compounds of Formulas (I) or (II) where one or more atoms
are replaced by atoms having the same atomic number but a different
atomic mass from the atomic mass which is predominantly seen in
nature. Examples of isotopes include, but are not limited to
hydrogen isotopes (deuterium, tritium), carbon isotopes (.sup.11C,
.sup.13C, .sup.14C) and nitrogen isotopes (.sup.13N, .sup.15N). For
example, substitution with heavier isotopes such as deuterium
(.sup.2H) may offer certain therapeutic advantages resulting from
greater metabolic stability which could be preferable and lead to
longer in vivo half-life or dose reduction in a mammal or
human.
[0109] Prodrugs of compounds embodied by Formulas (I) or (II) are
also within the scope of this disclosure. Particular derivatives of
compounds of Formulas (I) or (II) which may have little to
negligible pharmacological activity themselves, can, when
administered to a mammal or human, be converted into compounds of
Formulas (I) or (II) having the desired biological activity.
[0110] Compounds in the disclosure and their pharmaceutically
acceptable salts, prodrugs, as well as metabolites of the
compounds, may also be used to treat certain eating disorders,
obesity, compulsive gambling, sexual disorders, narcolepsy, sleep
disorders, diabetes, metabolic syndrome, neurodegenerative
disorders and CNS disorders/conditions as well as in smoking
cessation treatment.
[0111] In one embodiment the treatment of CNS disorders and
conditions by the compounds of the disclosure can include
Huntington's disease, schizophrenia and schizo-affective
conditions, delusional disorders, drug-induced psychoses, panic and
obsessive compulsive disorders, post-traumatic stress disorders,
age-related cognitive decline, attention deficit/hyperactivity
disorder, bipolar disorders, personality disorders of the paranoid
type, personality disorders of the schizoid type, psychosis induced
by alcohol, amphetamines, phencyclidine, opioids hallucinogens or
other drug-induced psychosis, dyskinesia or choreiform conditions
including dyskinesia induced by dopamine agonists, dopaminergic
therapies, psychosis associated with Parkinson's disease, psychotic
symptoms associated with other neurodegenerative disorders
including Alzheimer's disease, dystonic conditions such as
idiopathic dystonia, drug-induced dystonia, torsion dystonia, and
tardive dyskinesia, mood disorders including major depressive
episodes, post-stroke depression, minor depressive disorder,
premenstrual dysphoric disorder, dementia including but not limited
to multi-infarct dementia, AIDS-related dementia, and
neurodegenerative dementia.
[0112] In another embodiment, compounds of the disclosure may be
used for the treatment of eating disorders, obesity, compulsive
gambling, sexual disorders, narcolepsy, sleep disorders as well as
in smoking cessation treatment.
[0113] In a further embodiment, compounds of the disclosure may be
used for the treatment of obesity, schizophrenia, schizo-affective
conditions, Huntington's disease, dystonic conditions and tardive
dyskinesia.
[0114] In another embodiment, compounds of the disclosure may be
used for the treatment of schizophrenia, schizo-affective
conditions, Huntington's disease and obesity.
[0115] In a further embodiment, compounds of the disclosure may be
used for the treatment of schizophrenia and schizo-affective
conditions.
[0116] In an additional embodiment, compounds of the disclosure may
be used for the treatment of Huntington's disease.
[0117] In another embodiment, compounds of the disclosure may be
used for the treatment of obesity and metabolic syndrome.
[0118] Compounds of the disclosure may also be used in mammals and
humans in conjunction with conventional antipsychotic medications
including but not limited to Clozapine, Olanzapine, Risperidone,
Ziprasidone, Haloperidol, Aripiprazole, Sertindole and Quetiapine.
The combination of a compound of Formula (I) or (II) with a
subtherapeutic dose of an aforementioned conventional antipsychotic
medication may afford certain treatment advantages including
improved side effect profiles and lower dosing requirements.
DEFINITIONS
[0119] Alkyl is meant to denote a linear or branched saturated or
unsaturated aliphatic C.sub.1-C.sub.8 hydrocarbon which can be
optionally substituted with up to 3 fluorine atoms. Unsaturation in
the form of a double or triple carbon-carbon bond may be internal
or terminally located and in the case of a double bond both cis and
trans isomers are included. Examples of alkyl groups include but
are not limited to methyl, trifluoromethyl, ethyl, trifluoroethyl,
isobutyl, neopentyl, cis- and trans-2-butenyl, isobutenyl,
propargyl. C.sub.1-C.sub.4 alkyl is the subset of alkyl limited to
a total of up to 4 carbon atoms.
[0120] In each case in which a size range for the number of atoms
in a ring or chain is disclosed, all subsets are disclosed. Thus,
C.sub.x-C.sub.y includes all subsets, e.g., C.sub.1-C.sub.4
includes C.sub.1-C.sub.2, C.sub.2-C.sub.4, C.sub.1-C.sub.3 etc.
[0121] Acyl is an alkyl-C(O)-- group wherein alkyl is as defined
above. Examples of acyl groups include acetyl and propionyl.
[0122] Alkoxy is an alkyl-O-- group wherein alkyl is as defined
above. C.sub.1-C.sub.4 alkoxy is the subset of alkyl-O-- where the
subset of alkyl is limited to a total of up to 4 carbon atoms.
Examples of alkoxy groups include methoxy, trifluoromethoxy,
ethoxy, trifluoroethoxy, and propoxy.
[0123] Alkoxyalkyl is an alkyl-O--(C.sub.1-C.sub.4 alkyl)-group
wherein alkyl is as defined above. Examples of alkoxyalkyl groups
include methoxymethyl and ethoxymethyl.
[0124] Alkoxyalkyloxy is an alkoxy-alkyl-O-- group wherein alkoxy
and alkyl are as defined above. Examples of alkoxyalkyloxy groups
include methoxymethyloxy (CH.sub.3OCH.sub.2O--) and methoxyethyloxy
(CH.sub.3OCH.sub.2CH.sub.2O--) groups.
[0125] Alkylthio is alkyl-S-- group wherein alkyl is as defined
above.
[0126] Alkylsulfonyl is alkyl-SO.sub.2-- wherein alkyl is as
defined above.
[0127] Alkylamino is alkyl-NH-- wherein alkyl is as defined
above.
[0128] Dialkylamino is (alkyl).sub.2-N-- wherein alkyl is as
defined above.
[0129] Amido is H.sub.2NC(O)--
[0130] Alkylamido is alkyl-NHC(O)-- wherein alkyl is as defined
above.
[0131] Dialkylamido is (alkyl).sub.2-NC(O)-- wherein alkyl is as
defined above.
[0132] Aromatic is heteroaryl or aryl wherein heteroaryl and aryl
are as defined below.
[0133] Aryl is a phenyl or napthyl group. Aryl groups may be
optionally and independently substituted with up to three groups
selected from halogen, CF.sub.3, CN, NO.sub.2, OH, alkyl,
cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy,
alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl,
heterocycloalkyloxy, heteroaryl, heteroaryloxy,
--OCH.sub.2CH.sub.2OCH.sub.3, --OC(O)R.sub.a, --OC(O)OR.sub.a,
--OC(O)NHR.sub.a, --OC(O)N(R.sub.a), --SR.sub.a, --S(O)R.sub.a,
--NH.sub.2, --NHR.sub.a, --N(R.sub.a)(R.sub.b), --NHC(O)R.sub.a,
--N(R.sub.a)C(O)R.sub.b, --NHC(O)OR.sub.a,
--N(R.sub.a)C(O)OR.sub.b, --N(R.sub.a)C(O)NH(R.sub.b),
--N(R.sub.a)C(O)NH(R.sub.b).sub.2, --C(O)NH.sub.2, --C(O)NHR.sub.a,
--C(O)N(R.sub.a)(R.sub.b), --CO.sub.2H, --CO.sub.2R.sub.a,
--COR.sub.a, wherein R.sub.a and R.sub.b are independently chosen
from alkyl, alkoxyalkyl, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OMe, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
heterocycloalkylalkyl, each of which is optionally and
independently substituted with up to three groups selected from
only halogen, Me, Et, .sup.iPr, .sup.tBu, unsubstituted
cyclopropyl, unsubstituted cyclobutyl, CN, NO.sub.2, NH.sub.2,
CF.sub.3, NHMe, NMe.sub.2, OMe, OCF.sub.3, each of which are
attached via, carbon-carbon or carbon-nitrogen or carbon-oxygen
single bonds; or R.sub.a, and R.sub.b taken together with the
atom(s) to which they are attached form a 5-6 membered ring.
[0134] Arylalkyl is an aryl-alkyl-group wherein aryl and alkyl are
as defined above.
[0135] Aryloxy is an aryl-O-- group wherein aryl is as defined
above.
[0136] Arylalkoxy is an aryl-(C.sub.1-C.sub.4 alkyl)-O-- group
wherein aryl is as defined above.
[0137] Carboxy is a CO.sub.2H or CO.sub.2R.sub.c group wherein
R.sub.c is independently chosen from, alkyl, C.sub.1-C.sub.4 alkyl,
cycloalkyl, arylalkyl, cycloalkylalkyl, CF.sub.3, and alkoxyalkyl,
wherein alkyl is as defined above and cycloalkyl is as defined
below.
[0138] Cycloalkyl is a C.sub.3-C.sub.7 cyclic non-aromatic
hydrocarbon which may contain a single double bond and is
optionally and independently substituted with up to three groups
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
hydroxyl and oxo. Examples of cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and
cyclohexanonyl.
[0139] Cycloalkyloxy is a cycloalkyl-O-- group wherein cycloalkyl
is as defined above. Examples include cyclopropyloxy, cyclobutyloxy
and cyclopentyloxy. C.sub.3-C.sub.6 cycloalkyloxy is the subset of
cycloalkyl-O-- where cycloalkyl contains 3-6 carbon atoms.
[0140] Cycloalkylalkyl is a cycloalkyl-(C.sub.1-C.sub.4
alkyl)-group. Examples include cyclopropylmethyl, cyclopropylethyl,
cyclohexylmethyl and cyclohexylethyl.
[0141] Cycloalkylalkoxy is a cycloalkyl-(C.sub.1-C.sub.4 alkyl)-O--
group wherein cycloalkyl and alkyl are as defined above. Examples
of cycloalkylalkoxy groups include cyclopropylmethoxy,
cyclopentylmethoxy and cyclohexylmethoxy.
[0142] Halogen is F, Cl, Br or I.
[0143] Heteroaryl is a tetrazole, 1,2,3,4-oxatriazole,
1,2,3,5-oxatriazole, a mono or bicyclic aromatic ring system, or a
heterobicyclic ring system with one aromatic ring having 5 to 10
ring atoms independently selected from C, N, O and S, provided that
not more than 3 ring atoms in any single ring are other than C.
Examples of heteroaryl groups include but are not limited to
thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl, imidazolyl,
1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl, indolyl,
quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl,
indazolyl, benzthiadiazololyl, benzoxadiazolyl and benzimidazolyl.
Heteroaryl groups may be optionally and independently substituted
with up to 3 substituents independently selected from halogen,
CF.sub.3, CN, NO.sub.2, OH, alkyl, cycloalkyl, cycloalkylalkyl,
alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl,
heterocycloalkylyalkyl, heterocycloalkyloxy, heteroaryl,
heteroaryloxy, --OCH.sub.2CH.sub.2OCH.sub.3, --OC(O)R.sub.a,
--OC(O)OR.sub.a, --OC(O)NHR.sub.a, --OC(O)N(R.sub.a), --SR.sub.a,
--S(O)R.sub.a, --NH.sub.2, --NHR.sub.a, --N(R.sub.a)(R.sub.b),
--NHC(O)R.sub.a, --N(R.sub.a)C(O)R.sub.b, --NHC(O)OR.sub.a,
--N(R.sub.a)C(O)OR.sub.b, --N(R.sub.a)C(O)NH(R.sub.b),
--N(R.sub.a)C(O)NH(R.sub.b).sub.2, --C(O)NH.sub.2, --C(O)NHR.sub.a,
--C(O)N(R.sub.a)(R.sub.b), --CO.sub.2H, --CO.sub.2R.sub.a,
--COR.sub.a wherein R.sub.a and R.sub.b, are independently chosen
from alkyl, alkoxyalkyl, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OMe, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
heterocycloalkylalkyl, each of which is optionally and
independently substituted with up to three groups selected from
only halogen, Me, Et, .sup.iPr, .sup.tBu, unsubstituted
cyclopropyl, unsubstituted cyclobutyl, CN, NO.sub.2, NH.sub.2,
CF.sub.3, NHMe, NMe.sub.2, OMe, OCF.sub.3, each of which are
attached via carbon-carbon or carbon or carbon-nitrogen or
carbon-oxygen single bonds; or R.sub.a and R.sub.b taken together
with the atom(s) to which they are attached form a 5-6 membered
ring.
[0144] Heteroarylalkyl is a heteroaryl-(C.sub.1-C.sub.4
alkyl)-group wherein heteroaryl and alkyl are as defined above.
Examples of heteroarylalkyl groups include 4-pyridinylmethyl and
4-pyridinylethyl.
[0145] Heteroaryloxy is a heteroaryl-O group wherein heteroaryl is
as defined above.
[0146] Heteroarylalkoxy is a heteroaryl-(C.sub.1-C.sub.4 alkyl)-O--
group wherein heteroaryl and alkoxy are as defined above. Examples
of heteroarylalkyl groups include 4-pyridinylmethoxy and
4-pyridinylethoxy.
[0147] Heterobicyclic ring system is a ring system having 8-10
atoms independently selected from C, N, O and S, provided that not
more than 3 ring atoms in any single ring are other than carbon and
provided that at least one of the rings is aromatic; said bicyclic
ring may be optionally and independently substituted with up to 3
substituents independently selected from alkyl, alkoxy, cycloalkyl,
C.sub.3-C.sub.6 cycloalkyloxy, cycloalkylalkyl, halogen, nitro,
alkylsulfonyl and cyano. Examples of 8-10 membered heterobicyclic
ring systems include but are not limited to 1,5-naphthyridyl,
1,2,3,4-tetrahydro-1,5-naphthyridyl, 1,6-naphthyridyl,
1,2,3,4-tetrahydro-1,6-naphthyridyl, 1,7-naphthyridyl,
1,2,3,4-tetrahydro-1,7-naphthyridinyl, 1,8-naphthyridyl,
1,2,3,4-tetrahydro-1,8-naphthyridyl, 2,6-naphthyridyl,
2,7-naphthyridyl, cinnolyl, isoquinolyl, tetrahydroisoquinolinyl,
phthalazyl, quinazolyl, 1,2,3,4-tetrahydroquinazolinyl, quinolyl,
tetrahydroquinolinyl, quinoxalyl, tetrahydroquinoxalinyl,
benzo[d][1,2,3]triazyl, benzo[e][1,2,4]triazyl,
pyrido[2,3-b]pyrazyl, pyrido[2,3-c]pyridazyl,
pyrido[2,3-d]pyrimidyl, pyrido[3,2-b]pyrazyl,
pyrido[3,2-c]pyridazyl, pyrido[3,2-d]pyrimidyl,
pyrido[3,4-b]pyrazyl, pyrido[3,4-c]pyridazyl,
pyrido[3,4-d]pyrimidyl, pyrido[4,3-b]pyrazyl,
pyrido[4,3-c]pyridazyl, pyrido[4,3-d]pyrimidyl, quinazolyl,
1H-benzo[d][1,2,3]triazoyl, 1H-benzo[d]imidazoyl, 1H-indazoyl,
1H-indoyl, 2H-benzo[d][1,2,3]triazoyl, 2H-pyrazolo[3,4-b]pyridinyl,
2H-pyrazolo[4,3-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl,
[1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl,
benzo[b]thienyl, benzo[c][1,2,5]oxadiazyl,
benzo[c][1,2,5]thiadiazolyl, benzo[d]isothiazoyl,
benzo[d]isoxazoyl, benzo[d]oxazoyl, benzo[d]thiazoyl, benzofuryl,
imidazo[1,2-a]pyrazyl, imidazo[1,2-a]pyridinyl,
imidazo[1,2-a]pyrimidyl, imidazo[1,2-b]pyridazyl,
imidazo[1,2-c]pyrimidyl, imidazo[1,5-a]pyrazyl,
imidazo[1,5-a]pyrimidyl, imidazo[1,5-a]pyrimidyl,
imidazo[1,5-b]pyridazyl, imidazo[1,5-c]pyrimidyl, indolizyl,
pyrazolo[1,5-a]pyrazyl, pyrazolo[1,5-a]pyridinyl,
pyrazolo[1,5-a]pyrimidyl, pyrazolo[1,5-b]pyridazine,
pyrazolo[1,5-c]pyrimidine, pyrrolo[1,2-a]pyrazine,
pyrrolo[1,2-a]pyrimidyl, pyrrolo[1,2-b]pyridazyl,
pyrrolo[1,2-c]pyrimidyl, 1H-imidazo[4,5-b]pyridinyl,
1H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl,
1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl,
1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,
1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl,
1H-pyrrolo[3,2-c]pyridinyl, 2H-indazoyl,
3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-c]pyridinyl,
benzo[c]isothiazyl, benzo[c]isoxazyl, furo[2,3-b]pyridinyl,
furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridiyl,
isothiazolo[4,5-b]pyridinyl, isothiazolo[4,5-c]pyridinyl,
isothiazolo[5,4-b]pyridinyl, isothiazolo[5,4-c]pyridinyl,
isoxazolo[4,5-b]pyridinyl, isoxazolo[4,5-c]pyridinyl,
isoxazolo[5,4-b]pyridinyl, isoxazolo[5,4-c]pyridinyl,
oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl,
oxazolo[5,4-b]pyridinyl, oxazolo[5,4-c]pyridinyl,
thiazolo[4,5-b]pyridiyl, thiazolo[4,5-c]pyridinyl,
thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl,
thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl,
thieno[3,2-b]pyridinyl and thieno[3,2-c]pyridinyl.
[0148] Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic
saturated or partially unsaturated ring system comprising 5-10 ring
atoms selected from C, N, O and S, provided that not more than 2
ring atoms in any single ring are other than C. In the case where
the heterocycloalkyl group contains a nitrogen atom the nitrogen
may be substituted with an alkyl, acyl, --C(O)O-alkyl,
--C(O)NH(alkyl) or a --C(O)N(alkyl).sub.2 group. Heterocycloalkyl
groups may be optionally and independently substituted with
hydroxy, alkyl and alkoxy groups and may contain up to two oxo
groups where said oxo groups are attached via a carbon atom.
Heterocycloalkyl groups may be linked to the rest of the molecule
via either carbon or nitrogen ring atoms. Examples of
heterocycloalkyl groups include tetrahydrofuranyl,
tetrahydrothienyl, tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl,
pyrrolidinyl, pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl,
N-methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl,
thiomorpholin-3-one, 2,5-diazabicyclo[2.2.2]octanyl,
2,5-diazabicyclo[2.2.1]heptanyl,
octahydro-1H-pyrido[1,2-a]pyrazine,
3-thia-6-azabicyclo[3.1.1]heptane and
3-oxa-6-azabicyclo[3.1.1]heptanyl.
[0149] Heterocycloalkylalkyl is a heterocycloalkyl-(C.sub.1-C.sub.4
alkyl)-group wherein heterocycloalkyl is as defined above.
[0150] Heterocycloalkyloxy is a heterocycloalkyl-O-- group wherein
heterocycloalkyl is as defined above.
[0151] Heterocycloalkylalkoxy is a
heterocycloalkyl-(C.sub.1-C.sub.4 alkyl)-O-- group wherein
heterocycloalkyl is as defined above.
[0152] Imino is a --N.dbd.C-- group.
[0153] Oxo is a --C(O)-- group.
[0154] Phenyl is a benzene ring which may be optionally and
independently substituted with up to three groups selected from
halogen, CF.sub.3, CN, NO.sub.2, OH, alkyl, cycloalkyl,
cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy,
heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy,
heteroaryl, heteroaryloxy, --OCH.sub.2CH.sub.2OCH.sub.3,
--OC(O)R.sub.a, --OC(O)OR.sub.a, --OC(O)NHR.sub.a,
--OC(O)N(R.sub.a), --SR.sub.a, --S(O)R.sub.a, --NH.sub.2,
--NHR.sub.a, --N(R.sub.a)(R.sub.b), --NHC(O)R.sub.a,
--N(R.sub.a)C(O)R.sub.b, --NHC(O)OR.sub.a,
--N(R.sub.a)C(O)OR.sub.b, --N(R.sub.a)C(O)NH(R.sub.b),
--N(R.sub.a)C(O)NH(R.sub.b).sub.2, --C(O)NH.sub.2, --C(O)NHR.sub.a,
--C(O)N(R.sub.a)(R.sub.b), --CO.sub.2H, --CO.sub.2R.sub.a,
--COR.sub.a, wherein R.sub.a and R.sub.b are independently chosen
from alkyl, alkoxyalkyl, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OMe, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
heterocycloalkylalkyl, each of which is optionally and
independently substituted with up to three groups selected from
only halogen, Me, Et, .sup.iPr, .sup.tBu, unsubstituted
cyclopropyl, unsubstituted cyclobutyl, CN, NO.sub.2, NH.sub.2,
CF.sub.3, NHMe, NMe.sub.2, OMe, OCF.sub.3, each of which are
attached via carbon-carbon or carbon-nitrogen or carbon-oxygen
single bonds; or R.sub.a and R.sub.b taken together with the
atom(s) to which they are attached form a 5-6 membered ring.
[0155] Restricted phenyl is a benzene ring which may be optionally
and independently substituted with up to three groups selected from
halogen, CF.sub.3, CN, alkoxy, alkoxyalkyl, aryloxy,
alkoxyalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl,
heteroaryloxy, --OCH.sub.2CH.sub.2OCH.sub.3, --OC(O)R.sub.a,
--OC(O)OR.sub.a, --OC(O)N(R.sub.a), --N(R.sub.a)(R.sub.b),
--NHC(O)R.sub.a, --N(R.sub.a)C(O)R.sub.b, --NHC(O)OR.sub.a,
--N(R.sub.a)C(O)OR.sub.b, --C(O)N(R.sub.a)(R.sub.b), --COR.sub.a
wherein R.sub.a and R.sub.b are independently chosen from alkyl,
alkoxyalkyl, --CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2OMe,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each
of which is optionally and independently substituted with up to
three groups selected from only halogen, Me, Et, .sup.iPr,
.sup.tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN,
NO.sub.2, NH.sub.2, CF, NHMe, NMe.sub.2, OMe, OCF.sub.3, each of
which are attached via carbon-carbon or carbon-nitrogen or
carbon-oxygen single bonds; or R.sub.a and R.sub.b, taken together
with the atom(s) to which they are attached form a 5-6 rembered
ring.
[0156] Abbreviations used in the following examples and
preparations include: [0157] Ac Acyl (Me-C(O)--) [0158] AcN
Acetonitrile [0159] BINAP
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [0160] Bn Benzyl [0161]
Celite.RTM. Diatomaceous earth [0162] DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene [0163] DCC N,N',
Dicyclohexylcarbodiimide [0164] DCM Dichloromethane [0165] DIEA
Di-isopropylethyl amine [0166] DIPEA Di-isopropylethyl amine [0167]
DMAP 4-Dimethylaminopyridine [0168] DMF Dimethylformamide [0169]
DMP Dess Martin Periodinane [0170] DMSO Dimethyl sulfoxide [0171]
Dppf 1,4-Bis(diphenylphosphino) ferrocene [0172] EDC
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride [0173]
Et.sub.3N Triethylamine [0174] g gram(s) [0175] h Hour(s) [0176] hr
Hour(s) [0177] HATU
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0178] HMDS Hexamethyldisilazide [0179] HOBt
1-Hydroxybenzotriazole [0180] HPLC High Pressure Liquid
Chromatography [0181] HRMS High resolution mass spectrometry [0182]
i.v. Intravenous [0183] KHMDS Potassium Hexamethyldisilazide [0184]
LDA Lithium Di-isopropylamide [0185] m Multiplet [0186] m- meta
[0187] MEM Methoxyethoxymethyl [0188] MeOH Methyl Alcohol or
Methanol [0189] min Minute(s) [0190] mmol millimoles [0191] mmole
millimoles [0192] Ms Mesylate [0193] MS Mass Spectrometry [0194] MW
Molecular Weight [0195] NBS N-Bromosuccinamide [0196] NIS
N-Iodosuccinamide [0197] NMR Nuclear Magnetic Resonance [0198] NMM
N-Methyl Morpholine [0199] NMP N-Methyl-2-pyrrolidone [0200] o
ortho [0201] o/n overnight [0202] p para [0203] PCC Pyridiniurn
Chlorochromate [0204] PEPPSI
1,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridinyl)palladium(-
II) dichloride [0205] PhNTf.sub.2
1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
[0206] POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp)
palladate (2-) [0207] p.s.i. Pounds per square inch [0208] PPA
Polyphosphoric acid [0209] PPAA 1-Propanephosphonic Acid Cyclic
Anhydride [0210] PTSA p-Toluenesulfonic acid [0211] PyBOP.RTM.
Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
[0212] RT (or rt) room temperature (about 20-25.degree. C.) [0213]
s Singlet [0214] sat. Saturated [0215] t Triplet [0216] TBAF
Tetra-butyl ammonium fluoride [0217] TEA Triethylamine [0218] TFA
Trifluoroacetic Acid [0219] THF Tetrahydrofuran [0220] TLC Thin
layer chromatography [0221] TMS Trimethylsilyl [0222] Tf Triflate
[0223] Tof-MS Time of Flight Mass Spectrometry [0224] Ts Tosylate
[0225] v/v volume/volume [0226] wt/v weight/volume
DETAILED DESCRIPTION OF THE DISCLOSURE
[0227] The cyclopropyl compounds of Formulas (I) and (II) may be
prepared from multi-step organic synthesis routes from aryl or
heteroaryl aldehydes by one skilled in the art of organic synthesis
using established organic synthesis procedures. The starting aryl
aldehydes may be prepared from halobenzenes via. treatment with a
lithium base and dimethylformamide. Alternatively, the aryl
aldehydes may be prepared by oxidation of the corresponding
methylpyridine or substituted toluene to the corresponding
aldehyde.
[0228] Compounds of the disclosure of Formula (I) in which Y.dbd.H
are as described previously and thus having general Formula XXVI
may be prepared generally as depicted in Scheme 1.
##STR00002##
[0229] Compounds of the disclosure of Formula (II) in which Y.dbd.H
are as described previously and thus having general Formula XXVIII
may be prepared generally as depicted in Scheme 2.
##STR00003##
[0230] Reactive groups not involved in the above processes can be
protected with standard protecting groups during the reactions and
removed by standard procedures (T. W. Greene & P. G. M. Wuts,
Protecting Groups in Organic Synthesis, Third Edition,
Wiley-Interscience) known to those of ordinary skill in the art.
Presently preferred protecting groups include methyl, benzyl, MEM,
acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC,
Cbz, trifluoroacetamide and benzyl for the amino moiety, methyl,
ethyl, tert-butyl and benzyl esters for the carboxylic acid
moiety.
Experimental Procedures
HPLC Conditions
Condition-A:
Column: Hypersil BDS (C8 250.times.4.6 mm, 5 um (SHCL06E001)
Mobile Phase AcN (A): 0.1% TFA in Water. (B).
[0231] Flow rate: 1.5 ml/min (Gradient)
Condition-B:
Column: Zobrax SB-C18 250.times.4.6 mm, 5 um
Mobile Phase AcN (A): 0.1% TFA in Water. (B).
[0232] Flow rate: 1.5 ml/min (Gradient)
Condition-C:
Column: Targa C-18 250.times.4.6 mm, 5 um
Mobile Phase AcN (A): 0.1% TFA in Water. (B).
[0233] Flow rate: 1.5 ml/min (Gradient)
Condition-D:
Column: Targa C18 250.times.4.6 mm, 5 um (SHCL-12)
Mobile Phase AcN (A): 5M Ammonium Acetate in Water. (B).
[0234] Flow rate: 1.0 ml/min (Gradient
Condition-E:
Column: Higgins-C18 250.times.4.6 mm, 5 um
Mobile Phase AcN (A): 0.1% TFA in Water. (B).
[0235] Flow rate: 1.5 ml/min (Gradient)
Condition-F:
Column: Chiralpak AD
[0236] Mobile Phase: n-Hexane:Ethanol (50:50) Flow rate: 0.6 ml/min
(Gradient)
Condition-G:
Column: Venusil C8, 250.times.4.6 mm, 5 um.
Mobile Phase: AcN (A): 0.1% TFA in Water. (B).
[0237] Flow rate: 1.5 ml/min (Gradient)
Condition-H:
Column: Eclipse XDB-C18, 150.times.4.6 mm, 5 um.
Mobile Phase: 0.1% TFA in Water. (A).ACN (B)
[0238] Flow rate: 1.5 ml/min (Gradient)
Condition-I:
Column: Acquity BEH-C18, (50.times.2.1 mm, 1.7 um.)
Mobile Phase AcN (B)
[0239] Flow rate: 0.5 ml/min (Gradient)
Condition-J:
Column: Zobrax C18, (150.times.4.6 mm, 5 um.)
Mobile Phase AcN (A): 0.1% TFA in Water. (B).
[0240] Flow rate: 1.0 ml/min (Gradient)
Synthesis of
(E)-2-(4-tert-butylphenyl)-N'-(isoquinolin-5-ylmethylene)cyclopropanecarb-
ohydrazide (Example 122)
##STR00004##
[0242] To a solution of 4-tert-butylbenzaldehyde (5 g, 0.03 mot) in
xylenes (120 mL) was added the phosphine ylide (12.8 g, 0.036 mol)
and the reaction mixture was then heated at 110.degree. C. for 16
h. The reaction was concentrated in vacuo, and the residue diluted
with water and extracted with ethyl acetate (2.times.100 mL). The
combined organic layers were dried over magnesium sulfate, filtered
and then concentrated in vacuo. The crude material was purified via
silica gel column chromatography eluting with 5% ethyl acetate in
hexanes to afford (E)-ethyl 3-(4-tert-butylphenyl)acrylate (5.5 g,
77%) as an oil.
[0243] To a -40.degree. C. solution of (E)-ethyl
3-(4-tert-butylphenyl)acrylate (1.0 g, 4.3 mol) in ether (20 mL),
freshly prepared diazomethane was added dropwise over 10 minutes.
Pd(OAc).sub.2 (30 mg, 0.133 mol) was then added. The reaction
mixture was stirred for another 10 min at -40.degree. C., and then
filtered through a pad of Celite.RTM. and precipitate washed with
ether. The filtrate was concentrated in vacuo and the crude
material was then purified via silica gel column chromatography to
afford ethyl 2-(4-tert-butylphenyl)cyclopropanecarboxylate (0.9 g,
84%) as an oil.
[0244] To a room temperature solution of ethyl
2-(4-tert-butylphenyl)cyclopropanecarboxylate (1.0 g, 0.004 mol) in
ethanol (10 mL) was added hydrazine hydrate (2 g, 0.04 mol) and the
reaction mixture was then heated at 95.degree. C. for 16 h. The
mixture was then concentrated in vacuo and the solid that was
obtained was washed with hexanes to afford
2-(4-ter-butylphenyl)cyclopropanecarbohydrazide (0.78 g, 82%) as a
white solid.
[0245] To a room temperature solution of
2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (200 mg, 0.86
mmol) in ethanol (10 mL) were added isoquinoline-5-carbaldehyde
(162 mg, 1.0 mmol) and a catalytic amount of glacial AcOH (0.4 mL)
under an inert atmosphere. The reaction mixture was then stirred at
90.degree. C. for 4 h, concentrated in vacuo, and the residue was
then dissolved in DCM (50 mL). The organic layer was washed with
saturated NaHCO.sub.3 solution (15 mL) and brine (15 mL). The
organic layer was then separated, dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated in vacuo to obtain the
crude product. The crude material was purified via silica gel
column chromatography eluting with 1% MeOH in dichloromethane to
afford
(E)-2-(4-tert-butylphenyl)-N-(isoquinolin-5-ylmethylene)cyclopropanecarbo-
hydrazide (160 mg, 50%) as a white solid. .sup.1H NMR (500 MHz,
d.sub.6-DMSO): .delta. 11.60 (s, 1H), 9.38 (s, 1H), 8.71-8.56 (m,
2H), 8.25-8.12 (m, 2H), 8.11-7.99 (m, 2H), 7.39-7.29 (m, 2H),
7.19-7.06 (m, 2H), 2.41-2.33 (m, 1H), 1.95-1.90 (m, 1H), 1.42-1.34
(m, 2H), 1.25 (s, 9H). MS: M.sup.+H: m/z=372.2 HPLC: 96%,
(Condition-A).
Synthesis of
(E)-2-(4-tert-butylphenyl)-N'-(isoquinolin-5-ylmethylene)cyclopropanecarb-
ohydrazide (Example 195)
##STR00005##
[0247] To a solution of 1-bromo-4-cyclohexylbenzene (850 mg, 3.55
mmol) in THF (4.0 mL) was added n-BuLi (3.1 mL, 4.62 mmol) at
-78.degree. C. under an inert atmosphere. The reaction mixture was
stirred for 60 min at -78.degree. C., and then DMF (2.8 mL) was
added. The reaction mixture was then stirred for an additional hour
at -78.degree. C., warmed to 0.degree. C. and quenched with a
saturated NH.sub.4Cl solution. The mixture was then extracted with
ethyl acetate (2.times.30 mL). The combined organic layers were
then dried over magnesium sulfate, filtered and concentrated in
vacuo to obtain the crude product. The crude material was purified
via silica gel column chromatography to afford
4-cyclohexylbenzaldehyde (250 mg, 38%) as a solid.
[0248] To a room temperature solution of 4-cyclohexylbenzaldehyde
(250 mg, 1.32 mmol) in toluene (45 mL) was added phosphine ylide
(535 mg, 1.59 mmol) under an inert atmosphere. The reaction mixture
was then heated at 100.degree. C. for 16 h, cooled to RT, diluted
with n-hexane, stirred for 10 minutes and the precipitate was
filtered. The filtrate was concentrated in vacuo, and the crude
material was purified via silica gel column chromatography to
afford (E)-methyl 3-(4-cyclohexylphenyl)acrylate (200 mg, 62%) as a
solid.
[0249] To a solution of (E)-methyl 3-(4-cyclohexylphenyl)acrylate
(200 mg, 0.82 mmol) in DMSO (20 mL) was added freshly prepared
Corey's reagent (92 mg, 0.98 mmol) at RT and stirred for 3 h. The
reaction was quenched with cold water and then extracted with EtOAc
(2.times.20 mL). The combined organic layers were dried over
magnesium sulfate, filtered and then concentrated in vacuo to
obtain crude product. The crude material was purified via silica
gel column chromatography eluting with 5% EtOAc/95% hexanes to
afford methyl 2-(4-cyclohexylphenyl)cyclopropanecarboxylate (150
mg, 47%) as a solid.
[0250] To a room temperature solution of methyl
2-(4-cyclohexylphenyl)cyclopropanecarboxylate (150 mg, 0.58 mmol)
in ethanol (40 mL) was added hydrazine hydrate (293 mg, 5.85 mmol).
The reaction mixture was then heated at 80.degree. C. for 16 h,
concentrated in vacuo and the residue dissolved in DCM (50 mL). The
organic layer was washed with water, dried over magnesium sulfate,
filtered and concentrated in vacuo to afford
2-(4-cyclohexylphenyl)cyclopropanecarbohydrazide (200 mg) which was
taken on to the next step without further purification.
[0251] To a room temperature solution of
2-(4-cyclohexylphenyl)cyclopropanecarbohydrazide (200 mg) in
ethanol (20 mL), was added isoquinoline-5-carbaldehyde (122 mg,
0.77 mmol) and acetic acid (0.5 mL). The reaction mixture was then
heated at 80.degree. C. for 3 h, concentrated in vacuo and the
residue diluted with water and extracted with EtOAc (2.times.20
mL). The layers were separated and then the combined organic layers
were washed with a saturated NaHCO.sub.3 solution, dried over
magnesium sulfate, filtered and concentrated in vacuo to obtain the
crude product. The crude material was purified via column
chromatography eluting with 2% MeOH in dichloromethane to afford
(E)-2-(4-cyclohexylphenyl)-N'-(isoquinolin-5-ylmethylene)cyclopropanecarb-
ohydrazide (100 mg, 33%) as a white solid.
[0252] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 9.30-9.22 (m,
1H), 8.78-8.69 (m, 1H), 8.58-8.49 (m, 1H), 8.36-8.28 (m, 1H),
8.18-8.09 (m, 1H), 7.78-7.69 (m, 2H), 7.18-7.10 (m, 5H), 2.98-2.92
(m, 1H), 2.56-2.48 (m, 2H), 1.86-1.75 (m, 6H), 1.45-1.36 (m,
4H);
[0253] MS: M.sup.+H: m/z=398.3; and HPLC: 99%, (Condition-C).
Synthesis of
(E)-2-(biphenyl-4-yl)-N'-(isoquinolin-5-ylmethylene)cyclopropanecarbohydr-
azide (Example 196)
##STR00006##
[0255] Following the procedure for the preparation of
(E)-2-(4-tert-butylphenyl)-N'-(isoquinolin-5-ylmethylene)cyclopropanecarb-
ohydrazide provided the title compound
(E)-2-(biphenyl-4-yl)-N'-(isoquinolin-5-ylmethylene)cyclopropanecarbohydr-
azide gave the title compound: Yield: 35%. .sup.1H NMR (500 MHz,
CD.sub.3OD): .delta. 9.38-9.20 (m, 1H), 8.81-8.71 (m, 1H),
8.60-8.58 (m, 1H), 8.38-8.19 (m, 2H), 7.82-7.64 (m, 1H), 7.63-7.54
(m, 5H), 7.51-7.48 (m, 2H), 7.39-7.24 (m, 3H), 3.16-3.08 (m, 1H),
2.08-2.04 (m, 1H), 1.59-1.50 (m, 2H). MS: M.sup.+H: m/z=392.1 HPLC:
97%, (Condition-B).
Synthesis of
(E)-2-(4-tert-butylphenyl)-N'-(1-(isoquinolin-5-yl)ethylidene)cyclopropan-
ecarbohydrazide (Example 197)
##STR00007##
[0257] To a mixture of Mg turnings (0.2 g, 7.9 mmol) in ether (10
mL) was added MeI (1.13 g, 7.9 mmol) slowly at RT under an inert
atmosphere. After being stirred for 1 h at RT, the reaction mixture
was cooled to -10.degree. C. and a solution of
isoquinoline-5-carbaldehyde (0.5 g, 3.18 mmol) in ether (10 mL) was
added. The reaction mixture was then stirred for an additional hour
at RT, quenched with saturated NH.sub.4Cl solution and extracted
with EtOAc (3.times.50 mL). The combined organic layers were washed
with water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to obtain the crude product. The crude
material was purified via silica gel column chromatography using
30% ethyl acetate in hexanes to afford 1-(isoquinolin-5-yl)ethanol
(0.53 g, 97%) as an off-white solid.
[0258] To a 10.degree. C. solution of 1-(isoquinolin-5-yl)ethanol
(530 mg, 3.0 mmol) in DCM (10 ml) was added Dess-Martin periodinane
(1.9 g, 4.0 mmol) under a N.sub.2 atmosphere. The reaction mixture
was stirred for 16 h at room temperature and then quenched with
saturated NaHCO.sub.3 solution (5 mL). The organic layer was
separated, washed with water and brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to obtain the
crude product. The crude material was purified via silica gel
column chromatography using 20% ethyl acetate in hexanes to afford
1-(isoquinolin-5-yl)ethanone (500 mg, 95.4%) as an off-white
solid.
[0259] A solution of
2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (200 mg, 0.86
mmol) and 1-(isoquinolin-5-yl)ethanone (147 mg, 0.86 mmol) in
1,2-dichloroethane (10 mL) was stirred at room temperature for 2 h.
The reaction mixture was then diluted with water (5 mL) and the
organic layer was separated, washed brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
material was purified via silica gel column chromatography to
afford
(E)-2-(4-tert-butylphenyl)-N'-(1-(isoquinolin-5-yl)ethylidene)cyclopropan-
ecarbohydrazide (150 mg, 45%) as an off-white solid.
[0260] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 9.23 (s, 1H),
8.78 (s, 1H), 8.26-8.20 (m, 1H), 8.08-7.94 (m, 2H), 7.79-7.72 (m,
1H), 7.63-7.57 (m, 1H), 7.38-7.22 (m, 2H), 7.08 6.98 (m, 2H),
2.98-2.90 (m, 1H), 2.38 (s, 3H), 2.67-2.61 (m, 1H), 1.91-1.86 (m,
2H), 1.25 (s, 9H). MS: M.sup.+H: m/z=386.2 and HPLC: 90%,
(Condition-G).
Synthesis of
(E)-2-(4-tert-butylphenyl)-N'-(isoquinolin-5-ylmethylene)-N-methylcyclopr-
opanecarbohydrazide (Example 198)
##STR00008##
[0262] To a 0.degree. C. suspension of NaH (16 mg, 0.6 mmol) in DMF
(1 mL),
(E)-2-(4-tert-butylphenyl)-N'-(isoquinolin-5-ylmethylene)cyclopropan-
ecarbohydrazide (200 mg, 0.53 mmol) was added portionwise under
nitrogen atmosphere. After being stirred for 1 h at 0.degree. C.,
MeI (0.15 g, 1.0 mmol) was added and the reaction mixture stirred
at RT for 1 h. The reaction mixture was then quenched with ice
water and stirred for an additional 10 minutes. The precipitated
solid was filtered and dried in vacuo to obtain the crude product.
The crude material was purified via silica gel column
chromatography using 20% ethyl acetate in hexanes to afford
(E)-2-(4-tert-butylphenyl)-N'-(isoquinolin-5-ylmethylene)-N-methyl-
cyclopropanecarbohydrazide (30 mg, 50%) as an off-white solid.
.sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 9.24 (bs, 1H), 8.50-8.41
(m, 1H), 8.26-8.20 (m, 1H), 8.02-7.94 (m, 2H), 7.66-7.58 (m, 2H),
7.39 (d, J=7.2 Hz, 2H), 7.14 (d, J=7.2 Hz, 2H), 3.28 (s, 3H),
3.39-3.12 (m, 1H), 2.63-2.56 (m, 1H), 1.84-1.78 (m, 1H), 1.49-1.38
(m, 1H), 1.37 (s, 9H). MS: M.sup.+H H: m/z=386.2 and HPLC: 91%,
(Condition-G).
Tables
[0263] In a further aspect the compounds of the disclosure are
embodied in with distinct examples listed in the table below taken
from Formula (I):
TABLE-US-00001 Ex HET X Y Z.sub.1 Z.sub.2 Z.sub.3 Z.sub.4 R.sub.5
R.sub.6 R.sub.7 R.sub.8 100 ##STR00009## Ph CH CH CH CH CH H H H H
101 ##STR00010## Ph CH CH CH CH CH H H H H 102 ##STR00011## Ph CH
CH CH CH CH H H H H 103 ##STR00012## Ph CH CH CH CH CH H H H H 104
##STR00013## Ph CH CH CH CH CH H H H H 105 ##STR00014## Ph CH CH CH
CH CH H H H H 106 ##STR00015## Ph CH CH CH CH CH H H H H 107
##STR00016## Ph CH CH CH CH CH H H H H 108 ##STR00017## Ph CH CH CH
CH CH H H H H 109 ##STR00018## Ph CH CH CH CH CH H H H H 110
##STR00019## Ph CH CH CH CH CH H H H H 111 ##STR00020## Ph CH CH CH
CH CH H H H H 112 ##STR00021## Ph CH CH CH CH CH H H H H 113
##STR00022## Ph CH CH CH CH CH H H H H 114 ##STR00023## Ph CH CH CH
CH CH H H H H 115 ##STR00024## Ph CH CH CH CH CH H H H H 116
##STR00025## Ph CH CH CH CH CH H H H H 117 ##STR00026## Ph CH CH CH
CH CH H H H H 118 ##STR00027## .sup.tBu CH CH CH CH CH H H H H 119
##STR00028## .sup.tBu CH CH CH CH CH H H H H 120 ##STR00029##
.sup.tBu CH CH CH CH CH H H H H 121 ##STR00030## .sup.tBu CH CH CH
CH CH H H H H 122 ##STR00031## .sup.tBu CH CH CH CH CH H H H H 123
##STR00032## .sup.tBu CH CH CH CH CH H H H H 124 ##STR00033##
.sup.tBu CH CH CH CH CH H H H H 125 ##STR00034## .sup.tBu CH CH CH
CH CH H H H H 126 ##STR00035## .sup.tBu CH CH CH CH CH H H H H 127
##STR00036## .sup.tBu CH CH CH CH CH H H H H 128 ##STR00037##
.sup.tBu CH CH CH CH CH H H H H 129 ##STR00038## .sup.tBu CH CH CH
CH CH H H H H 130 ##STR00039## .sup.tBu CH CH CH CH CH H H H H 131
##STR00040## .sup.tBu CH CH CH CH CH H H H H 132 ##STR00041##
.sup.tBu CH CH CH CH CH H H H H 133 ##STR00042## .sup.tBu CH CH CH
CH CH H H H H 134 ##STR00043## .sup.tBu CH CH CH CH CH H H H H 135
##STR00044## .sup.tBu CH CH CH CH CH H H H H 136 ##STR00045##
##STR00046## CH CH CH CH CH H H H H 137 ##STR00047## ##STR00048##
CH CH CH CH CH H H H H 138 ##STR00049## ##STR00050## CH CH CH CH CH
H H H H 139 ##STR00051## ##STR00052## CH CH CH CH CH H H H H 140
##STR00053## ##STR00054## CH CH CH CH CH H H H H 141 ##STR00055##
##STR00056## CH CH CH CH CH H H H H 142 ##STR00057## ##STR00058##
CH CH CH CH CH H H H H 143 ##STR00059## ##STR00060## CH CH CH CH CH
H H H H 144 ##STR00061## ##STR00062## CH CH CH CH CH H H H H 145
##STR00063## ##STR00064## CH CH CH CH CH H H H H 146 ##STR00065##
##STR00066## CH CH CH CH CH H H H H 147 ##STR00067## ##STR00068##
CH CH CH CH CH H H H H 148 ##STR00069## ##STR00070## CH CH CH CH CH
H H H H 149 ##STR00071## ##STR00072## CH CH CH CH CH H H H H 150
##STR00073## ##STR00074## CH CH CH CH CH H H H H 151 ##STR00075##
##STR00076## CH CH CH CH CH H H H H 152 ##STR00077## ##STR00078##
CH CH CH CH CH H H H H 153 ##STR00079## ##STR00080## CH CH CH CH CH
H H H H 154 ##STR00081## ##STR00082## CH CH CH CH CH H H H H 155
##STR00083## ##STR00084## CH CH CH CH CH H H H H 156 ##STR00085##
##STR00086## CH CH CH CH CH H H H H 157 ##STR00087## ##STR00088##
CH CH CH CH CH H H H H 158 ##STR00089## ##STR00090## CH CH CH CH CH
H H H H 159 ##STR00091## ##STR00092## CH CH CH CH CH H H H H 160
##STR00093## ##STR00094## CH CH CH CH CH H H H H 161 ##STR00095##
##STR00096## CH CH CH CH CH H H H H 162 ##STR00097## ##STR00098## N
CH CH CH CH H H H H 163 ##STR00099## ##STR00100## N CH CH CH CH H H
H H 164 ##STR00101## ##STR00102## N CH CH CH CH H H H H 165
##STR00103## ##STR00104## N CH CH CH CH H H H H 166 ##STR00105##
##STR00106## N CH CH CH CH H H H H 167 ##STR00107## ##STR00108## N
CH CH CH CH H H H H 168 ##STR00109## ##STR00110## N CH CH CH CH H H
H H 169 ##STR00111## ##STR00112## N CH CH CH CH H H H H 170
##STR00113## ##STR00114## N CH CH CH CH H H H H 171 ##STR00115##
.sup.tBu N CH CH CH CH H H H H 172 ##STR00116## Ph N CH CH CH CH H
H H H 173 ##STR00117## ##STR00118## CH CH N CH CH H H H H 174
##STR00119## ##STR00120## CH CH N CH CH H H H H 175 ##STR00121##
##STR00122## CH CH N CH CH H H H H 176 ##STR00123## ##STR00124## CH
CH N CH CH H H H H 177 ##STR00125## ##STR00126## CH CH N CH CH H H
H H 178 ##STR00127## ##STR00128## CH CH N CH CH H H H H 179
##STR00129## ##STR00130## CH CH N CH CH H H H H 180 ##STR00131##
##STR00132## CH CH N CH CH H H H H 181 ##STR00133## ##STR00134## CH
CH N CH CH H H H H 182 ##STR00135## .sup.tBu CH CH N CH CH H H H H
183 ##STR00136## Ph CH CH N CH CH H H H H 184 ##STR00137##
##STR00138## CH CH CH N CH H H H H 185 ##STR00139## ##STR00140## CH
CH CH N CH H H H H 186 ##STR00141## ##STR00142## CH CH CH N CH H H
H H 187 ##STR00143## ##STR00144## CH CH CH N CH H H H H 188
##STR00145## ##STR00146## CH CH CH N CH H H H H 189 ##STR00147##
##STR00148## CH CH CH N CH H H H H 190 ##STR00149## ##STR00150## CH
CH CH N CH H H H H 191 ##STR00151## ##STR00152## CH CH CH N CH H H
H H 192 ##STR00153## ##STR00154## CH CH CH N CH H H H H 193
##STR00155## .sup.tBu CH CH CH N CH H H H H 194 ##STR00156## Ph CH
CH CH N CH H H H H 195 ##STR00157## cyclohexyl CH CH CH CH CH H H H
H 196 ##STR00158## phenyl CH CH CH CH CH H H H H 197 ##STR00159##
.sup.tBu CH CH CH CH CH H H H Me 198 ##STR00160## .sup.tBu CH CH CH
CH CH H H Me H
[0264] In a further aspect the compounds of the disclosure are
embodied it with distinct examples listed in the table below taken
from Formula (II):
TABLE-US-00002 Ex HET X Y Z.sub.1 Z.sub.2 Z.sub.3 Z.sub.4 R.sub.5
R.sub.6 R.sub.7 R.sub.8 199 ##STR00161## Ph CH CH CH CH CH H H H H
200 ##STR00162## Ph CH CH CH CH CH H H H H 201 ##STR00163## Ph CH
CH CH CH CH H H H H 202 ##STR00164## Ph CH CH CH CH CH H H H H 203
##STR00165## Ph CH CH CH CH CH H H H H 204 ##STR00166## Ph CH CH CH
CH CH H H H H 205 ##STR00167## Ph CH CH CH CH CH H H H H 206
##STR00168## Ph CH CH CH CH CH H H H H 207 ##STR00169## Ph CH CH CH
CH CH H H H H 208 ##STR00170## Ph CH CH CH CH CH H H H H 209
##STR00171## Ph CH CH CH CH CH H H H H 210 ##STR00172## Ph CH CH CH
CH CH H H H H 211 ##STR00173## Ph CH CH CH CH CH H H H H 212
##STR00174## Ph CH CH CH CH CH H H H H 213 ##STR00175## Ph CH CH CH
CH CH H H H H 214 ##STR00176## Ph CH CH CH CH CH H H H H 215
##STR00177## Ph CH CH CH CH CH H H H H 216 ##STR00178## Ph CH CH CH
CH CH H H H H 217 ##STR00179## .sup.tBu CH CH CH CH CH H H H H 218
##STR00180## .sup.tBu CH CH CH CH CH H H H H 219 ##STR00181##
.sup.tBu CH CH CH CH CH H H H H 220 ##STR00182## .sup.tBu CH CH CH
CH CH H H H H 221 ##STR00183## .sup.tBu CH CH CH CH CH H H H H 222
##STR00184## .sup.tBu CH CH CH CH CH H H H H 223 ##STR00185##
.sup.tBu CH CH CH CH CH H H H H 224 ##STR00186## .sup.tBu CH CH CH
CH CH H H H H 225 ##STR00187## .sup.tBu CH CH CH CH CH H H H H 226
##STR00188## .sup.tBu CH CH CH CH CH H H H H 227 ##STR00189##
.sup.tBu CH CH CH CH CH H H H H 228 ##STR00190## .sup.tBu CH CH CH
CH CH H H H H 229 ##STR00191## .sup.tBu CH CH CH CH CH H H H H 230
##STR00192## .sup.tBu CH CH CH CH CH H H H H 231 ##STR00193##
.sup.tBu CH CH CH CH CH H H H H 232 ##STR00194## .sup.tBu CH CH CH
CH CH H H H H 233 ##STR00195## .sup.tBu CH CH CH CH CH H H H H 234
##STR00196## .sup.tBu CH CH CH CH CH H H H H 235 ##STR00197##
##STR00198## CH CH CH CH CH H H H H 236 ##STR00199## ##STR00200##
CH CH CH CH CH H H H H 237 ##STR00201## ##STR00202## CH CH CH CH CH
H H H H 238 ##STR00203## ##STR00204## CH CH CH CH CH H H H H 239
##STR00205## ##STR00206## CH CH CH CH CH H H H H 240 ##STR00207##
##STR00208## CH CH CH CH CH H H H H 241 ##STR00209## ##STR00210##
CH CH CH CH CH H H H H 242 ##STR00211## ##STR00212## CH CH CH CH CH
H H H H 243 ##STR00213## ##STR00214## CH CH CH CH CH H H H H 244
##STR00215## ##STR00216## CH CH CH CH CH H H H H 245 ##STR00217##
##STR00218## CH CH CH CH CH H H H H 246 ##STR00219## ##STR00220##
CH CH CH CH CH H H H H 247 ##STR00221## ##STR00222## CH CH CH CH CH
H H H H 248 ##STR00223## ##STR00224## CH CH CH CH CH H H H H 249
##STR00225## ##STR00226## CH CH CH CH CH H H H H 250 ##STR00227##
##STR00228## CH CH CH CH CH H H H H 251 ##STR00229## ##STR00230##
CH CH CH CH CH H H H H 252 ##STR00231## ##STR00232## CH CH CH CH CH
H H H H 253 ##STR00233## ##STR00234## CH CH CH CH CH H H H H 254
##STR00235## ##STR00236## CH CH CH CH CH H H H H 255 ##STR00237##
##STR00238## CH CH CH CH CH H H H H 256 ##STR00239## ##STR00240##
CH CH CH CH CH H H H H 257 ##STR00241## ##STR00242## CH CH CH CH CH
H H H H 258 ##STR00243## ##STR00244## CH CH CH CH CH H H H H 259
##STR00245## ##STR00246## CH CH CH CH CH H H H H 260 ##STR00247##
##STR00248## CH CH CH CH CH H H H H 261 ##STR00249## ##STR00250## N
CH CH CH CH H H H H 262 ##STR00251## ##STR00252## N CH CH CH CH H H
H H 263 ##STR00253## ##STR00254## N CH CH CH CH H H H H 264
##STR00255## ##STR00256## N CH CH CH CH H H H H 265 ##STR00257##
##STR00258## N CH CH CH CH H H H H 266 ##STR00259## ##STR00260## N
CH CH CH CH H H H H 267 ##STR00261## ##STR00262## N CH CH CH CH H H
H H 268 ##STR00263## ##STR00264## N CH CH CH CH H H H H 269
##STR00265## ##STR00266## N CH CH CH CH H H H H 270 ##STR00267##
.sup.tBu N CH CH CH CH H H H H 271 ##STR00268## Ph N CH CH CH CH H
H H H 272 ##STR00269## ##STR00270## CH CH N CH CH H H H H 273
##STR00271## ##STR00272## CH CH N CH CH H H H H 274 ##STR00273##
##STR00274## CH CH N CH CH H H H H 275 ##STR00275## ##STR00276## CH
CH N CH CH H H H H 276 ##STR00277## ##STR00278## CH CH N CH CH H H
H H 277 ##STR00279## ##STR00280## CH CH N CH CH H H H H 278
##STR00281## ##STR00282## CH CH N CH CH H H H H 279 ##STR00283##
##STR00284## CH CH N CH CH H H H H 280 ##STR00285## ##STR00286## CH
CH N CH CH H H H H 281 ##STR00287## .sup.tBu CH CH N CH CH H H H H
282 ##STR00288## Ph CH CH N CH CH H H H H 283 ##STR00289##
##STR00290## CH CH CH N CH H H H H 284 ##STR00291## ##STR00292## CH
CH CH N CH H H H H 285 ##STR00293## ##STR00294## CH CH CH N CH H H
H H 286 ##STR00295## ##STR00296## CH CH CH N CH H H H H 287
##STR00297## ##STR00298## CH CH CH N CH H H H H 288 ##STR00299##
##STR00300## CH CH CH N CH H H H H 289 ##STR00301## ##STR00302## CH
CH CH N CH H H H H 290 ##STR00303## ##STR00304## CH CH CH N CH H H
H H 291 ##STR00305## ##STR00306## CH CH CH N CH H H H H 292
##STR00307## .sup.tBu CH CH CH N CH H H H H 293 ##STR00308## Ph CH
CH CH N CH H H H H 294 ##STR00309## cyclohexyl CH CH CH CH CH H H H
H 295 ##STR00310## phenyl CH CH CH CH CH H H H H 296 ##STR00311##
.sup.tBu CH CH CH CH CH H H H Me 297 ##STR00312## .sup.tBu CH CH CH
CH CH H H Me H
Dosage and Administration
[0265] The present disclosure includes pharmaceutical composition
for treating a subject having a neurological disorder comprising a
therapeutically effective amount of a compound of Formulas (I) and
(II), a derivative or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable excipient, carrier or diluent.
The pharmaceutical compositions can be administered in a variety of
dosage forms including, but not limited to, a solid dosage form or
in a liquid dosage form, an oral dosage form, a parenteral dosage
form, an intranasal dosage form, a suppository, a lozenge, a
troche, buccal, a controlled release dosage form, a pulsed release
dosage form, an immediate release dosage form, an intravenous
solution, a suspension or combinations thereof. The dosage can be
an oral dosage form that is a controlled release dosage form. The
oral dosage form can be a tablet or a caplet. The compounds can be
administered, for example, by oral or parenteral routes, including
intravenous, intramuscular, intraperitoneal, subcutaneous,
transdermal, airway (aerosol), rectal, vaginal and topical
(including buccal and sublingual) administration. In one
embodiment, the compounds or pharmaceutical compositions comprising
the compounds are delivered to a desired site, such as the brain,
by continuous injection via a shunt.
[0266] In another embodiment, the compound can be administered
parenterally, such as intravenous (IV) administration. The
formulations for administration will commonly comprise a solution
of the compound of the Formulas (I) and (II) dissolved in a
pharmaceutically acceptable carrier. Among the acceptable vehicles
and solvents that can be employed are water and Ringer's solution,
an isotonic sodium chloride. In addition, sterile fixed oils can
conventionally be employed as a solvent or suspending medium. For
this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid can likewise be used in the preparation of injectables.
These solutions are sterile and generally free of undesirable
matter. These formulations may be sterilized by conventional, well
known sterilization techniques. The formulations may contain
pharmaceutically acceptable auxiliary substances as required to
approximate physiological conditions such as pH adjusting and
buffering agents, toxicity adjusting agents, e.g., sodium acetate,
sodium chloride, potassium chloride, calcium chloride, sodium
lactate and the like. The concentration of compound of Formulas (I)
and (II) in these formulations can vary widely, and will be
selected primarily based on fluid volumes, viscosities, body
weight, and the like, in accordance with the particular mode of
administration selected and the patient's needs. For IV
administration, the formulation can be a sterile injectable
preparation, such as a sterile injectable aqueous or oleaginous
suspension. This suspension can be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation can also be a
sterile injectable solution or suspension in a nontoxic
parenterally-acceptable diluent or solvent, such as a solution of
1,3-butanediol.
[0267] In one embodiment, a compound of Formulas (I) and (II) can
be administered by introduction into the central nervous system of
the subject, e.g., into the cerbrospinal fluid of the subject. The
formulations for administration will commonly comprise a solution
of the compound of Formulas (I) and (II) dissolved in a
pharmaceutically acceptable carrier. In certain aspects, the
compound of Formulas (I) and (II) is introduced intrathecally,
e.g., into a cerebral ventricle, the lumbar area, or the cisterna
magna. In another aspect, the compound of Formulas (I) and (II) is
introduced intraocularly, to thereby contact retinal ganglion
cells.
[0268] The pharmaceutically acceptable formulations can easily be
suspended in aqueous vehicles and introduced through conventional
hypodermic needles or using infusion pumps. Prior to introduction,
the formulations can be sterilized with, preferably, gamma
radiation or electron beam sterilization.
[0269] In one embodiment, the pharmaceutical composition comprising
a compound of Formulas (I) and (II) is administered into a subject
intrathecally. As used herein, the term "intrathecal
administration" is intended to include delivering a pharmaceutical
composition comprising a compound of Formulas (I) and (II) directly
into the cerebrospinal fluid of a subject, by techniques including
lateral cerebroventricular injection through a burrhole or
cisternal or lumbar puncture or the like (described in Lazorthes et
al. Advances in Drug Delivery Systems and Applications in
Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1:
169-179, the contents of which are incorporated herein by
reference). The term "lumbar region" is intended to include the
area between the third and fourth lumbar (lower back) vertebrae.
The terra "cisterna magna" is intended to include the area where
the skull ends and the spinal cord begins at the back of the head.
The term "cerebral ventricle" is intended to include the cavities
in the brain that are continuous with the central canal of the
spinal cord. Administration of a compound of Formulas (I) and (II)
to any of the above mentioned sites can be achieved by direct
injection of the pharmaceutical composition comprising the compound
of Formulas (I) and (II) or by the use of infusion pumps. For
injection, the pharmaceutical compositions can be formulated in
liquid solutions, preferably in physiologically compatible buffers
such as Hank's solution or Ringer's solution. In addition, the
pharmaceutical compositions may be formulated in solid form and
re-dissolved or suspended immediately prior to use. Lyophilized
forms are also included. The injection can be, for example, in the
form of a bolus injection or continuous infusion (e.g., using
infusion pumps) of pharmaceutical composition.
[0270] In one embodiment, the pharmaceutical composition comprising
a compound of Formulas (I) and (II) is administered by lateral
cerebro ventricular injection into the brain of a subject. The
injection can be made, for example, through a burr hole made in the
subject's skull. In another embodiment, the encapsulated
therapeutic agent is administered through a surgically inserted
shunt into the cerebral ventricle of a subject. For example, the
injection can be made into the lateral ventricles, which are
larger, even though injection into the third and fourth smaller
ventricles can also be made.
[0271] In yet another embodiment, the pharmaceutical composition is
administered by injection into the cisterna magna, or lumbar area
of a subject.
[0272] For oral administration, the compounds will generally be
provided in unit dosage forms of a tablet, pill, dragee, lozenge or
capsule; as a powder or granules; or as an aqueous solution,
suspension, liquid, gels, syrup, slurry, etc. suitable for
ingestion by the patient. Tablets for oral use may include the
active ingredients mixed with pharmaceutically acceptable
excipients such as inert diluents, disintegrating agents, binding
agents, lubricating agents, sweetening agents, flavoring agents,
coloring agents and preservatives. Suitable inert diluents include
sodium and calcium carbonate, sodium and calcium phosphate, and
lactose, while corn starch and alginic acid are suitable
disintegrating agents. Binding agents may include starch and
gelatin, while the lubricating agent, if present, will generally be
magnesium stearate, stearic acid or talc. If desired, the tablets
may be coated with a material such as glyceryl monostearate or
glyceryl distearate, to delay absorption in the gastrointestinal
tract.
[0273] Pharmaceutical preparations for oral use can be obtained
through combination of a compound of Formulas (I) and (II) with a
solid excipient, optionally grinding a resulting mixture, and
processing the mixture of granules, after adding suitable
additional compounds, if desired, to obtain tablets or dragee
cores. Suitable solid excipients in addition to those previously
mentioned are carbohydrate or protein fillers that include, but are
not limited to, sugars, including lactose, sucrose, mannitol, or
sorbitol; starch from corn, wheat, rice, potato, or other plants;
cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose
or sodium carboxymethylcellulose; and gums including arabic and
tragacanth; as well as proteins such as gelatin and collagen. If
desired, disintegrating or solubilizing agents may be added, such
as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a
salt thereof, such as sodium alginate.
[0274] Capsules for oral use include hard gelatin capsules in which
the active ingredient is mixed with a solid diluent, and soft
gelatin capsules wherein the active ingredients is mixed with water
or an oil such as peanut oil, liquid paraffin or olive oil.
[0275] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0276] For transmucosal administration (e.g. buccal, rectal, nasal,
ocular, etc.), penetrants appropriate to the barrier to be
permeated are used in the formulation. Such penetrants are
generally known in the art.
[0277] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate. Formulations suitable for vaginal
administration may be presented as pessaries, tampons, creams,
gels, pastes, foams or spray formulations containing in addition to
the active ingredient such carriers as are known in the art to be
appropriate. For intramuscular, intraperitoneal, subcutaneous and
intravenous use, the compounds will generally be provided in
sterile aqueous solutions or suspensions, buffered to an
appropriate pH and isotonicity. Suitable aqueous vehicles include
Ringer's solution and isotonic sodium chloride. Aqueous suspensions
may include suspending agents such as cellulose derivatives, sodium
alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting
agent such as lecithin. Suitable preservatives for aqueous
suspensions include ethyl and n-propyl p-hydroxybenzoate.
[0278] The suppositories for rectal administration of the drug can
be prepared by mixing the drug with a suitable non-irritating
excipient which is solid at ordinary temperatures but liquid at the
rectal temperatures and will therefore melt in the rectum to
release the drug. Such materials are cocoa butter and polyethylene
glycols.
[0279] The compounds can be delivered transdermally, by a topical
route, formulated as applicator sticks, solutions, suspensions,
emulsions, gels, creams, ointments, pastes, jellies, paints,
powders, or aerosols.
[0280] The compounds may also be presented as aqueous or liposome
formulations. Aqueous suspensions can contain a compound of
Formulas (I) and (II) in admixture with excipients suitable for the
manufacture of aqueous suspensions. Such excipients include a
suspending agent, such as sodium carboxymethylcellulose,
methylcelluose, hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethylene oxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
(e.g., polyoxyethylene sorbitol mono-oleate), or a condensation
product of ethylene oxide with a partial ester derived from fatty
acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan
monooleate). The aqueous suspension can also contain one or morn
preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or
more coloring agents, one or more flavoring agents and one or more
sweetening agents, such as sucrose, aspartame or saccharin.
Formulations can be adjusted for osmolarity.
[0281] Oil suspensions can be formulated by suspending a compound
of Formulas (I) and (II) in a vegetable oil, such as arachis oil,
olive oil, sesame oil or coconut oil, or in a mineral oil such as
liquid paraffin; or a mixture of these. The oil suspensions can
contain a thickening agent, such as beeswax, hard paraffin or cetyl
alcohol. Sweetening agents can be added to provide a palatable oral
preparation, such as glycerol, sorbitol or sucrose. These
formulations can be preserved by the addition of an antioxidant
such as ascorbic acid. As an example of an injectable oil vehicle,
see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The
pharmaceutical formulations can also be in the form of oil-in-water
emulsions. The oily phase can be a vegetable oil or a mineral oil,
described above, or a mixture of these. Suitable emulsifying agents
include naturally-occurring gums, such as gum acacia and gum
tragacanth, naturally occurring phosphatides, such as soybean
lecithin, esters or partial esters derived from fatty acids and
hexitol anhydrides, such as sorbitan mono-oleate, and condensation
products of these partial esters with ethylene oxide, such as
polyoxyethylene sorbitan mono-oleate. The emulsion can also contain
sweetening agents and flavoring agents, as in the formulation of
syrups and elixirs. Such formulations can also contain a demulcent,
a preservative, or a coloring agent.
[0282] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation or
transcutaneous delivery (e.g., subcutaneously or intramuscularly),
intramuscular injection or a transdermal patch. Thus, for example,
the compounds may be formulated with suitable polymeric or
hydrophobic materials (e.g., as an emulsion in an acceptable oil)
or ion exchange resins, or as sparingly soluble derivatives, for
example, as a sparingly soluble salt.
[0283] The pharmaceutical compositions also may comprise suitable
solid or gel phase carriers or excipients. Examples of such
carriers or excipients include but are not limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[0284] For administration by inhalation, the compounds are
conveniently delivered in the form of an aerosol spray presentation
from pressurized packs or a nebulizer, with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of e.g., gelatin for use in an inhaler or insufflator
may be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0285] In general a suitable dose will be in the range of 0.01 to
100 mg per kilogram body weight of the recipient per day,
preferably in the range of 0.1 to 10 mg per kilogram body weight
per day. The desired dose is preferably presented once daily, but
may be dosed as two, three, four, five, six or more sub-doses
administered at appropriate intervals throughout the day.
[0286] The compounds can be administered as the sole active agent,
or in combination with other known therapeutics to be beneficial in
the treatment of neurological disorders. In any event, the
administering physician can provide a method of treatment that is
prophylactic or therapeutic by adjusting the amount and timing of
drug administration on the basis of observations of one or more
symptoms (e.g., motor or cognitive function as measured by standard
clinical scales or assessments) of the disorder being treated.
Details on techniques for formulation and administration are well
described in the scientific and patent literature, see, e.g., the
latest edition of Remington's Pharmaceutical Sciences, Maack
Publishing Co, Easton Pa. After a pharmaceutical composition has
been formulated in an acceptable carrier, it can be placed in an
appropriate container and labeled for treatment of an indicated
condition. For administration of the compounds of Formulas (I) and
(II), such labeling would include, e.g., instructions concerning
the amount, frequency and method of administration.
Biological Examples
In Vitro Methods
[0287] hPDE10A1 Enzyme Activity:
[0288] 50 .mu.l samples of serially diluted Human PDE10A1 enzyme
were incubated with 50 .mu.l of [.sup.3H]-cAMP for 20 minutes (at
37.degree. C.). Reactions were carried out in Greiner 96 deep well
1 ml master-block. The enzyme was diluted in 20 nM Tris HCl pH7.4
and [.sup.3H]-cAMP was diluted in 10 mM MgCl.sub.2, 40 mM Tris.HCl
pH 7.4 The reaction was terminated by denaturing the PDE enzyme (at
70.degree. C.) after which [.sup.3H]-5'-AMP was converted to
[.sup.3H]-adenosine by adding 25 .mu.l snake venom nucicotidase and
incubating for 10 minutes (at 37.degree. C.). Adenosine, being
neutral, was separated from charged cAMP or AMP by the addition of
200 .mu.l Dowex resin. Samples were shaken for 20 minutes then
centrifuged for 3 minutes at 2,500 r.p.m. 50 .mu.l of supernatant
was removed and added to 200 .mu.l of MicroScint-20 in white plates
(Greiner 96-well Optiplate) and shaken for 30 minutes before
reading on Perkin Elmer TopCount Scintillation Counter.
[0289] hPDE10A1 Enzyme Inhibition:
[0290] To check inhibition profile 11 .mu.l of serially diluted
inhibitor was added to 50 .mu.l of [.sup.3H]-cAMP and 50 .mu.l of
diluted Human PDE10A1 and assay was carried out as in the enzyme
activity assay. Data was analysed using Prism software (GraphPad
Inc.). Representative compounds of this disclosure are shown in the
table below. A compound with the value "A" had an IC.sub.50 value
less than or equal to 200 nM. A compound with the value "B" had an
IC.sub.50 value less than or equal to 1000 nM:
TABLE-US-00003 hPDE10A1 Ex Name IC.sub.50 Band 122
(E)-2-(4-tert-butylphenyl)-N'-(isoquinolin-5- A ylmethylene)
cyclopropanecarbohydrazide 195
(E)-2-(4-tert-butylphenyl)-N'-(isoquinolin-5- B ylmethylene)
cyclopropanecarbohydrazide 196
(E)-2-(biphenyl-4-yl)-N'-(isoquinolin-5- A
ylmethylene)cyclopropanecarbohydrazide 197
(E)-2-(4-tert-butylphenyl)-N'-(1-(isoquinolin-5- B
yl)ethylidene)cyclopropanecarbohydrazide 198
(E)-2-(4-tert-butylphenyl)-N'-(isoquinolin-5- A
ylmethylene)-N-methylcyclopropanecarbohydrazide
* * * * *