U.S. patent application number 16/853250 was filed with the patent office on 2020-09-17 for deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine compounds.
The applicant listed for this patent is Auspex Pharmaceuticals, Inc.. Invention is credited to Chengzhi ZHANG.
Application Number | 20200290992 16/853250 |
Document ID | / |
Family ID | 1000004856557 |
Filed Date | 2020-09-17 |
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United States Patent
Application |
20200290992 |
Kind Code |
A1 |
ZHANG; Chengzhi |
September 17, 2020 |
Deuterium-Substituted Pyridin- And Pyrimidin-2-yl-Methylamine
Compounds
Abstract
Described are deuterium-substituted pyridin- and
pyrimidin-2-yl-methylamine compounds of structural Formula (I),
which are agonists of 5-hydroxytryptamine receptors. Also described
are pharmaceutical compositions comprising the
deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine
compounds, and methods of use thereof. ##STR00001##
Inventors: |
ZHANG; Chengzhi; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Auspex Pharmaceuticals, Inc. |
North Wales |
PA |
US |
|
|
Family ID: |
1000004856557 |
Appl. No.: |
16/853250 |
Filed: |
April 20, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15709828 |
Sep 20, 2017 |
10626105 |
|
|
16853250 |
|
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62398239 |
Sep 22, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/12 20130101;
C07B 2200/05 20130101 |
International
Class: |
C07D 401/12 20060101
C07D401/12 |
Claims
1. A method of treating or preventing an 5-HT.sub.1A
receptor-mediated disorder, the method comprising administering, to
a patient in need thereof a compound of Formula (I): ##STR00358##
or a pharmaceutically acceptable salt, ester, prodrug, co-crystal,
or solvate thereof, wherein: X is N or C--R.sub.21;
R.sub.1-R.sub.21 are, independently, hydrogen or deuterium; at
least one of R.sub.1-R.sub.21 is deuterium; and at least one of
R.sub.1-R.sub.21 has deuterium enrichment of at least about 1%.
2. The method of claim 1, wherein R.sub.1-R.sub.3 are
deuterium.
3. The method of claim 1, wherein R.sub.4 and/or R.sub.5 is
deuterium.
4. The method of claim 1, wherein R.sub.6 and/or R.sub.7 is
deuterium.
5. The method of claim 1, wherein R.sub.4-R.sub.7 are
deuterium.
6. The method of claim 1, wherein at least one of R.sub.8-R.sub.15
is deuterium.
7. The method of claim 1, wherein at least one of R.sub.16-R.sub.20
is deuterium.
8. The method of claim 1, wherein X is N.
9. The method of claim 1, wherein X is C--R.sub.21.
10. The method of claim 9, wherein R.sub.21 is deuterium.
11. The method of claim 1, wherein at least one of R.sub.1-R.sub.21
has deuterium enrichment of at least about 90%.
12. The method of claim 1, wherein at least one of R.sub.1-R.sub.21
has deuterium enrichment of at least about 95%.
13. The method of claim 1, wherein the compound is:
##STR00359##
14. The method of claim 1, wherein the compound is:
##STR00360##
15. The method of claim 1, wherein the compound is: ##STR00361##
##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366##
##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371##
##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376##
##STR00377##
16. The method of claim 1, wherein the compound is: ##STR00378##
##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383##
##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388##
##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393##
##STR00394##
17. The method of claim 1, wherein the compound is a
pharmaceutically acceptable salt that is a hydrochloride,
hydrobromide, sulfate, formate, acetate, trifluoroacetate,
propionate, succinate, fumarate, citrate, tartrate, glutamate,
benzoate, salicylate, stearate, lactate, mesylate, tosylate,
besylate, phosphate, or maleate salt.
18. The method of claim 1, wherein the 5-HT.sub.1A
receptor-mediated disorder is anxiety, depression, bipolar
disorder, an obsessive-compulsive disorder, a panic attack,
aggression, impulsivity, alcohol abuse, a sexual disorder, a
sleeping disorder, pain, acute pain, postoperative pain, chronic
pain, nociceptive pain, cancer pain, neuropathic pain, psychogenic
pain hypertension, nausea, dizziness, vomiting, regulation of
gastric secretion, obesity, regulation of food intake, an immune
disease, migraine, dyskinesia, akinesia, chorea, ballismus,
dystonia, myoclonus, athetosis, akathisia, ataxia, synkinesia,
tics, bradykinesia, tremor, a movement disorder, Parkinson's
disease, Huntington's disease, Tourette's syndrome, tardive
dyskinesia, muscle spasm, muscle hypertonia, schizophrenia,
drug-seeking behavior, opioid-induced respiratory syndrome,
restless leg syndrome, or L-DOPA-induced dyskinesia.
19. The method of claim 18, wherein the 5-HT.sub.1A
receptor-mediated disorder is anxiety, depression, bipolar
disorder, an obsessive-compulsive disorder, a panic attack,
aggression, impulsivity, alcohol abuse, a sexual disorder, a
sleeping disorder, pain, acute pain, postoperative pain, chronic
pain, nociceptive pain, cancer pain, neuropathic pain, psychogenic
pain hypertension, nausea, dizziness, vomiting, regulation of
gastric secretion, obesity, regulation of food intake, an immune
disease, migraine, dyskinesia, akinesia, chorea, ballismus,
dystonia, myoclonus, athetosis, akathisia, ataxia, synkinesia,
tics, bradykinesia, tremor, a movement disorder, Parkinson's
disease, Huntington's disease, Tourette's syndrome, tardive
dyskinesia, muscle spasms, muscle hypertonia, schizophrenia,
drug-seeking behavior, opioid-induced respiratory syndrome,
restless leg syndrome, or L-DOPA-induced dyskinesia.
20. The method of claim 1, further comprising administering an
additional therapeutic agent in combination with the compound.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 15/709,828, filed Sep. 20, 2017, which claims the benefit
of the priority of U.S. Provisional Patent Application No.
62/398,239, filed Sep. 22, 2016, the disclosures of which are
hereby incorporated by reference, as if written herein, in their
entireties.
TECHNICAL FIELD
[0002] The present invention relates generally to the field of
pharmaceuticals and to methods of treating disorders. More
particularly, provided herein are novel compounds which are
agonists of 5-hydroxytryptamine receptors and are useful in
treating or preventing disorders such as anxiety, depression, and
movement disorders.
BACKGROUND
[0003] The serotonin receptors, also known as 5-hydroxytryptamine
(5-HT) receptors are a group of G protein-coupled receptors (GPCRs)
and ligand-gated channels found in the central and peripheral
nervous system. The serotonin receptors are activated by serotonin,
which is a neurotransmitter and a neuromodulator of the central
nervous system. The 5-HT receptors have been grouped into several
main classes. Among these main classes, the 5-HT.sub.1 class
comprises receptors characterized by a high affinity for serotonin.
The 5-HT.sub.1 class is itself divided into a subclass of receptors
whose pharmacological characteristics and regional distributions in
the central nervous system are distinct.
[0004] The 5-HT.sub.1A receptor is the most widespread of all the
5-HT.sub.1 receptors. In the central nervous system, 5-HT.sub.1A
receptors exist in the cerebral cortex, hippocampus, septum,
amygdala, and raphe nucleus in high densities, while low amounts
also exist in the basal ganglia and thalamus. 5-HT.sub.1A receptor
agonists are involved in neuromodulation, decreasing blood pressure
and heart rate via a central mechanism, by inducing peripheral
vasodilation, and by stimulating the vagus nerve. Activation of
central 5-HT.sub.1A receptors triggers the release or inhibition of
norepinephrine. 5-HT.sub.1A receptor agonists show efficacy in
relieving anxiety and depression.
[0005] Befiradol
[(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-a-
mino]-5 methyl}piperidin-1-yl]methanone; CAS #208110-64-9] is a
selective and high efficacy serotonin 5-HT.sub.1A receptor agonist
(U.S. Pat. Nos. 6,020,345; 7,208,603).
##STR00002##
[0006] Befiradol has been suggested as a treatment for depression,
anxiety, and pain. More recently, befiradol has been under
investigation in the treatment of movement disorders including
Parkinson's disease, Huntington's disease, Tourette's syndrome,
dystonia, L-DOPA-induced dyskinesia, and tardive dyskinesia (WO
2016/005527).
[0007] Befiradol, however, is metabolized in the liver and is
likely subject to extensive cytochrome P.sub.450-mediated oxidative
metabolism. Befiradol is likely metabolized predominantly by
N-dealkylation.
[0008] Adverse effects associated with befiradol may include
dizziness, light-headedness, headache, nausea, somnolence,
insomnia, tachycardia, dry mouth, diarrhea, rash, and the like.
Additionally, some metabolites of befiradol may have undesirable
side effects.
[0009] Accordingly, there is a need for 5-HT.sub.1A receptor
agonists with improved pharmacokinetic properties.
SUMMARY
[0010] Provided are deuterium-substituted pyridin- and
pyrimidin-2-yl-methylamine compounds, which are 5-HT.sub.1A
receptor agonists. Also provided are pharmaceutical compositions
comprising the deuterium-substituted pyridin- and
pyrimidin-2-yl-methylamine compounds, and methods of use thereof,
including methods for treatment or prevention of 5-HT.sub.1A
receptor-mediated disorders by administering, to a patient, the
deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine
compounds or pharmaceutical compositions comprising the
deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine
compounds. Further provided are methods of synthesizing the
deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine
compounds.
DETAILED DESCRIPTION
[0011] Before describing several exemplary embodiments of the
invention, it is to be understood that the invention is not limited
to the details of construction or process steps set forth in the
following description. The invention is capable of other
embodiments and of being practiced or being carried out in various
ways.
[0012] All publications and references cited herein are expressly
incorporated herein by reference in their entirety. However, with
respect to any similar or identical terms found in both the
incorporated publications or references and those explicitly put
forth or defined in this document, then those terms definitions or
meanings explicitly put forth in this document shall control in all
respects.
[0013] Deuterium Kinetic Isotope Effect
[0014] In order to eliminate foreign substances such as therapeutic
agents, the animal body expresses various enzymes, such as the
cytochrome P.sub.450 enzymes (CYPs), esterases, proteases,
reductases, dehydrogenases, and monoamine oxidases, to react with
and convert these foreign substances to more polar intermediates or
metabolites for renal excretion. Such metabolic reactions
frequently involve the oxidation of a carbon-hydrogen (C--H) bond
to either a carbon-oxygen (C--O) or a carbon-carbon (C--C)
.pi.-bond. The resultant metabolites may be stable or unstable
under physiological conditions, and can have substantially
different pharmacokinetic, pharmacodynamic, and acute and long-term
toxicity profiles relative to the parent compounds. For most drugs,
such oxidations are generally rapid and ultimately lead to
administration of multiple or high daily doses.
[0015] The relationship between the activation energy and the rate
of reaction may be quantified by the Arrhenius equation,
k=Ae.sup.-Eact/RT. The Arrhenius equation states that, at a given
temperature, the rate of a chemical reaction depends exponentially
on the activation energy (E.sub.act).
[0016] The transition state in a reaction is a short lived state
along the reaction pathway during which the original bonds have
stretched to their limit. By definition, the activation energy
E.sub.act for a reaction is the energy required to reach the
transition state of that reaction. Once the transition state is
reached, the molecules can either revert to the original reactants,
or form new bonds giving rise to reaction products. A catalyst
facilitates a reaction process by lowering the activation energy
leading to a transition state. Enzymes are examples of biological
catalysts.
[0017] Carbon-hydrogen bond strength is directly proportional to
the absolute value of the ground-state vibrational energy of the
bond. This vibrational energy depends on the mass of the atoms that
form the bond, and increases as the mass of one or both of the
atoms making the bond increases. Since deuterium (D) has twice the
mass of protium (.sup.1H), a C-D bond is stronger than the
corresponding C-.sup.1H bond. If a C-.sup.1H bond is broken during
a rate-determining step in a chemical reaction (i.e. the step with
the highest transition state energy), then substituting a deuterium
for that protium will cause a decrease in the reaction rate. This
phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE).
The magnitude of the DKIE can be expressed as the ratio between the
rates of a given reaction in which a C-.sup.1H bond is broken, and
the same reaction where deuterium is substituted for protium. The
DKIE can range from about 1 (no isotope effect) to very large
numbers, such as 50 or more. Substitution of tritium for hydrogen
results in yet a stronger bond than deuterium and gives numerically
larger isotope effects
[0018] Deuterium (.sup.2H or D) is a stable and non-radioactive
isotope of hydrogen which has approximately twice the mass of
protium (.sup.1H), the most common isotope of hydrogen. Deuterium
oxide (D.sub.2O or "heavy water") looks and tastes like H.sub.2O,
but has different physical properties.
[0019] When pure D.sub.2O is given to rodents, it is readily
absorbed. The quantity of deuterium required to induce toxicity is
extremely high. When about 0-15% of the body water has been
replaced by D.sub.2O, animals are healthy but are unable to gain
weight as fast as the control (untreated) group. When about 15-20%
of the body water has been replaced with D.sub.2O, the animals
become excitable. When about 20-25% of the body water has been
replaced with D.sub.2O, the animals become so excitable that they
go into frequent convulsions when stimulated. Skin lesions, ulcers
on the paws and muzzles, and necrosis of the tails appear. The
animals also become very aggressive. When about 30% of the body
water has been replaced with D.sub.2O, the animals refuse to eat
and become comatose. Their body weight drops sharply and their
metabolic rates drop far below normal, with death occurring at
about 30 to about 35% replacement with D.sub.2O. The effects are
reversible unless more than thirty percent of the previous body
weight has been lost due to D.sub.2O. Studies have also shown that
the use of D.sub.2O can delay the growth of cancer cells and
enhance the cytotoxicity of certain antineoplastic agents.
[0020] Deuteration of pharmaceuticals to improve pharmacokinetics
(PK), pharmacodynamics (PD), and toxicity profiles has been
demonstrated previously with some classes of drugs. For example,
the DKIE was used to decrease the hepatotoxicity of halothane,
presumably by limiting the production of reactive species such as
trifluoroacetyl chloride. However, this method may not be
applicable to all drug classes. For example, deuterium
incorporation can lead to metabolic switching. Metabolic switching
occurs when xenogens, sequestered by Phase I enzymes, bind
transiently and re-bind in a variety of conformations prior to the
chemical reaction (e.g., oxidation). Metabolic switching is enabled
by the relatively vast size of binding pockets in many Phase I
enzymes and the promiscuous nature of many metabolic reactions.
Metabolic switching can lead to different proportions of known
metabolites as well as altogether new metabolites. This new
metabolic profile may impart more or less toxicity. Such pitfalls
are non-obvious and are not predictable a priori for any drug
class.
[0021] Befiradol is a 5-HT.sub.1A receptor agonist. The
carbon-hydrogen bonds of befiradol contain a naturally occurring
distribution of hydrogen isotopes, namely .sup.1H or protium (about
99.9844%), .sup.2H or deuterium (about 0.0156%), and .sup.3H or
tritium (in the range between about 0.5 and 67 tritium atoms per
10.sup.18 protium atoms). Increased levels of deuterium
incorporation may produce a detectable Deuterium Kinetic Isotope
Effect (DKIE) that could affect the pharmacokinetic, pharmacologic
and/or toxicologic profiles of such befiradol in comparison with
the compound having naturally occurring levels of deuterium.
[0022] Befiradol is likely metabolized in humans by oxidation of
hydrocarbons and N-dealkylations. The approach described herein has
the potential to prevent metabolism at these sites. Other sites on
the molecule may also undergo transformations leading to
metabolites with as-yet-unknown pharmacology/toxicology. Limiting
the production of these metabolites has the potential to decrease
the danger of the administration of such drugs and may even allow
increased dosage and/or increased efficacy. All of these
transformations can occur through polymorphically-expressed
enzymes, exacerbating interpatient variability. Further, some
disorders are best treated when the subject is medicated around the
clock or for an extended period of time. For all of the foregoing
reasons, a pharmaceutical with a longer half-life may result in
greater efficacy and cost savings. Various deuteration patterns can
be used to (a) reduce or eliminate unwanted metabolites, (b)
increase the half-life of the parent drug, (c) decrease the number
of doses needed to achieve a desired effect, (d) decrease the
amount of a dose needed to achieve a desired effect, (e) increase
the formation of active metabolites, if any are formed, (f)
decrease the production of deleterious metabolites in specific
tissues, and/or (g) create a more effective drug and/or a safer
drug for polypharmacy, whether the polypharmacy be intentional or
not. The deuteration approach has the potential to slow the
metabolism of befiradol and attenuate interpatient variability.
[0023] Deuterium-substituted pyridin- and
pyrimidin-2-yl-methylamine compounds and pharmaceutical
compositions employing such compounds, certain of which have been
found to modulate the activity of 5-HT.sub.1A receptors have been
discovered, together with methods of synthesizing and using the
compounds, including methods for the treatment or prevention of
5-HT.sub.1A receptor-mediated disorders in a mammal by
administering the compounds as disclosed herein.
[0024] In certain embodiments of the present invention, the
deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine
compounds have a structure corresponding to Formula (I):
##STR00003##
[0025] or a pharmaceutically acceptable salt, ester, prodrug,
co-crystal, or solvate thereof, wherein:
[0026] X is selected from N or C--R.sub.21; R.sub.1-R.sub.21 are
independently selected from hydrogen and deuterium; and at least
one of R.sub.1-R.sub.21 is deuterium.
[0027] In further embodiments, at least two of R.sub.1-R.sub.21 are
deuterium, including at least three of R.sub.1-R.sub.21, at least
four of R.sub.1-R.sub.21, at least five of R.sub.1-R.sub.21, at
least six of R.sub.1-R.sub.21, at least seven of R.sub.1-R.sub.21,
at least eight of R.sub.1-R.sub.21, at least nine of
R.sub.1-R.sub.21, at least ten of R.sub.1-R.sub.21, at least eleven
of R.sub.1-R.sub.21, at least twelve of R.sub.1-R.sub.21, at least
thirteen of R.sub.1-R.sub.21, at least fourteen of
R.sub.1-R.sub.21, at least fifteen of R.sub.1-R.sub.21, at least
sixteen of R.sub.1-R.sub.21, at least seventeen of
R.sub.1-R.sub.21, at least eighteen of R.sub.1-R.sub.21, at least
nineteen of R.sub.1-R.sub.21, and at least twenty of
R.sub.1-R.sub.21. In some embodiments, all of R.sub.1-R.sub.21 are
deuterium.
[0028] In further embodiments, said pharmaceutically acceptable
salt is selected from a hydrochloride, a hydrobromide, a sulfate, a
formate, an acetate, a trifluoroacetate, a propionate, a succinate,
a fumarate, a citrate, a tartrate, a glutamate, a benzoate, a
salicylate, a stearate, a lactate, a mesylate, a tosylate, a
besylate, a phosphate, a maleate, and the like.
[0029] In specific embodiments, said pharmaceutically acceptable
salt is selected from a sulfate and a fumarate.
[0030] In certain embodiments, R.sub.1-R.sub.3 are deuterium.
[0031] In certain embodiments, R.sub.4-R.sub.5 are deuterium.
[0032] In certain embodiments, R.sub.6-R.sub.7 are deuterium.
[0033] In certain embodiments, R.sub.1-R.sub.3 and R.sub.4-R.sub.5
are deuterium.
[0034] In certain embodiments, R.sub.1-R.sub.3 and R.sub.6-R.sub.7
are deuterium.
[0035] In certain embodiments, R.sub.1-R.sub.3, R.sub.4-R.sub.5,
and R.sub.6-R.sub.7 are deuterium.
[0036] In certain embodiments, R.sub.1 is deuterium.
[0037] In certain embodiments, R.sub.2 is deuterium.
[0038] In certain embodiments, R.sub.3 is deuterium.
[0039] In certain embodiments, R.sub.4 is deuterium.
[0040] In certain embodiments, R.sub.5 is deuterium.
[0041] In certain embodiments, R.sub.6 is deuterium.
[0042] In certain embodiments, R.sub.7 is deuterium.
[0043] In certain embodiments, R.sub.8 is deuterium.
[0044] In certain embodiments, R.sub.9 is deuterium.
[0045] In certain embodiments, R.sub.10 is deuterium.
[0046] In certain embodiments, R.sub.11 is deuterium.
[0047] In certain embodiments, R.sub.12 is deuterium.
[0048] In certain embodiments, R.sub.13 is deuterium.
[0049] In certain embodiments, R.sub.14 is deuterium.
[0050] In certain embodiments, R.sub.15 is deuterium.
[0051] In certain embodiments, R.sub.16 is deuterium.
[0052] In certain embodiments, R.sub.17 is deuterium.
[0053] In certain embodiments, R.sub.18 is deuterium.
[0054] In certain embodiments, R.sub.19 is deuterium.
[0055] In certain embodiments, R.sub.20 is deuterium.
[0056] Also provided herein are embodiments according to each of
the embodiments above, wherein X is C--R.sub.21.
[0057] In certain embodiments, R.sub.21 is deuterium.
[0058] Also provided herein are embodiments according to each of
the embodiments above, wherein X is N.
[0059] Also provided herein are embodiments according to each of
the embodiments above, wherein at least one of R.sub.8-R.sub.21 are
deuterium.
[0060] Also provided herein are embodiments according to each of
the embodiments above, wherein all of R.sub.8-R.sub.21 are
deuterium.
[0061] Also provided herein are embodiments according to each of
the embodiments above, wherein every other substituent among
R.sub.1-R.sub.21 not specified as deuterium is hydrogen.
[0062] Without intending to be bound by theory, it is understood
that while compounds of Formula I containing the moiety
##STR00004##
can be synthesized, it is believed that it is unlikely that the
deuterium atom on these moieties will be retained after the
compound is administered to a subject. When administered to a
subject, it is thought that the deuterium in the moiety
##STR00005##
will be exchanged with a hydrogen atom to produce the moiety
##STR00006##
due to the large amount of water present in a subject's body.
Accordingly, embodiments of the invention encompass compounds
comprising one or more
##STR00007##
moieties in addition to one or more
##STR00008##
moieties.
[0063] In certain embodiments are provided compounds as disclosed
herein, wherein at least one of R.sub.1-R.sub.21 independently has
deuterium enrichment of no less than about 1%. In further
embodiments, at least two of R.sub.1-R.sub.21 have deuterium
enrichment of no less than about 1%, including at least three of
R.sub.1-R.sub.21, at least four of R.sub.1-R.sub.21, at least five
of R.sub.1-R.sub.21, at least six of R.sub.1-R.sub.21, at least
seven of R.sub.1-R.sub.21, at least eight of R.sub.1-R.sub.21, at
least nine of R.sub.1-R.sub.21, at least ten of R.sub.1-R.sub.21,
at least eleven of R.sub.1-R.sub.21, at least twelve of
R.sub.1-R.sub.21, at least thirteen of R.sub.1-R.sub.21, at least
fourteen of R.sub.1-R.sub.21, at least fifteen of R.sub.1-R.sub.21,
at least sixteen of R.sub.1-R.sub.21, at least seventeen of
R.sub.1-R.sub.21, at least eighteen of R.sub.1-R.sub.21, at least
nineteen of R.sub.1-R.sub.21, and at least twenty of
R.sub.1-R.sub.21 have deuterium enrichment of no less than about
1%. In some embodiments all of R.sub.1-R.sub.21 have deuterium
enrichment of no less than about 1%.
[0064] In certain embodiments are provided compounds as disclosed
herein, wherein at least one of R.sub.1-R.sub.21 independently has
deuterium enrichment of no less than about 10%. In further
embodiments, at least two of R.sub.1-R.sub.21 have deuterium
enrichment of no less than about 10%, including at least three of
R.sub.1-R.sub.21, at least four of R.sub.1-R.sub.21, at least five
of R.sub.1-R.sub.21, at least six of R.sub.1-R.sub.21, at least
seven of R.sub.1-R.sub.21, at least eight of R.sub.1-R.sub.21, at
least nine of R.sub.1-R.sub.21, at least ten of R.sub.1-R.sub.21,
at least eleven of R.sub.1-R.sub.21, at least twelve of
R.sub.1-R.sub.21, at least thirteen of R.sub.1-R.sub.21, at least
fourteen of R.sub.1-R.sub.21, at least fifteen of R.sub.1-R.sub.21,
at least sixteen of R.sub.1-R.sub.21, at least seventeen of
R.sub.1-R.sub.21, at least eighteen of R.sub.1-R.sub.21, at least
nineteen of R.sub.1-R.sub.21, and at least twenty of
R.sub.1-R.sub.21 have deuterium enrichment of no less than about
10%. In some embodiments all of R.sub.1-R.sub.21 have deuterium
enrichment of no less than about 10%.
[0065] In certain embodiments are provided compounds as disclosed
herein, wherein at least one of R.sub.1-R.sub.21 independently has
deuterium enrichment of no less than about 50%, including about
55%, about 60%, about 65%, about 70%, about 75%, about 80%, about
85%, about 90%, about 95%, and about 100%. In further embodiments,
at least two of R.sub.1-R.sub.21 have deuterium enrichment of no
less than about 50%, including about 55%, about 60%, about 65%,
about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,
and about 100%, including at least three of R.sub.1-R.sub.21, at
least four of R.sub.1-R.sub.21, at least five of R.sub.1-R.sub.21,
at least six of R.sub.1-R.sub.21, at least seven of
R.sub.1-R.sub.21, at least eight of R.sub.1-R.sub.21, at least nine
of R.sub.1-R.sub.21, at least ten of R.sub.1-R.sub.21, at least
eleven of R.sub.1-R.sub.21, at least twelve of R.sub.1-R.sub.21, at
least thirteen of R.sub.1-R.sub.21, at least fourteen of
R.sub.1-R.sub.21, at least fifteen of R.sub.1-R.sub.21, at least
sixteen of R.sub.1-R.sub.21, at least seventeen of
R.sub.1-R.sub.21, at least eighteen of R.sub.1-R.sub.21, at least
nineteen of R.sub.1-R.sub.21, and at least twenty of
R.sub.1-R.sub.21. In some embodiments all of R.sub.1-R.sub.21 have
deuterium enrichment of no less than about 50%, including about
55%, about 60%, about 65%, about 70%, about 75%, about 80%, about
85%, about 90%, about 95%, and about 100%.
[0066] In certain embodiments are provided compounds as disclosed
herein, wherein at least one of R.sub.1-R.sub.21 independently has
deuterium enrichment of no less than about 90%, including about
92%, about 94%, about 96%, about 98%, and about 100%. In further
embodiments, at least two of R.sub.1-R.sub.21 have deuterium
enrichment of no less than about 90%, including about 92%, about
94%, about 96%, about 98%, and about 100%, including at least three
of R.sub.1-R.sub.21, at least four of R.sub.1-R.sub.21, at least
five of R.sub.1-R.sub.21, at least six of R.sub.1-R.sub.21, at
least seven of R.sub.1-R.sub.21, at least eight of
R.sub.1-R.sub.21, at least nine of R.sub.1-R.sub.21, at least ten
of R.sub.1-R.sub.21, at least eleven of R.sub.1-R.sub.21, at least
twelve of R.sub.1-R.sub.21, at least thirteen of R.sub.1-R.sub.21,
at least fourteen of R.sub.1-R.sub.21, at least fifteen of
R.sub.1-R.sub.21, at least sixteen of R.sub.1-R.sub.21, at least
seventeen of R.sub.1-R.sub.21, at least eighteen of
R.sub.1-R.sub.21, at least nineteen of R.sub.1-R.sub.21, and at
least twenty of R.sub.1-R.sub.21. In some embodiments all of
R.sub.1-R.sub.21 have deuterium enrichment of no less than about
90%, including about 92%, about 94%, about 96%, about 98%, and
about 100%.
[0067] In certain embodiments are provided compounds as disclosed
herein, wherein at least one of R.sub.1-R.sub.21 independently has
deuterium enrichment of no less than about 95%, including about
96%, about 97%, about 98%, about 99%, and about 100%. In further
embodiments, at least two of R.sub.1-R.sub.21 have deuterium
enrichment of no less than about 95%, including about 96%, about
97%, about 98%, about 99%, and about 100%, including at least three
of R.sub.1-R.sub.21, at least four of R.sub.1-R.sub.21, at least
five of R.sub.1-R.sub.21, at least six of R.sub.1-R.sub.21, at
least seven of R.sub.1-R.sub.21, at least eight of
R.sub.1-R.sub.21, at least nine of R.sub.1-R.sub.21, at least ten
of R.sub.1-R.sub.21, at least eleven of R.sub.1-R.sub.21, at least
twelve of R.sub.1-R.sub.21, at least thirteen of R.sub.1-R.sub.21,
at least fourteen of R.sub.1-R.sub.21, at least fifteen of
R.sub.1-R.sub.21, at least sixteen of R.sub.1-R.sub.21, at least
seventeen of R.sub.1-R.sub.21, at least eighteen of
R.sub.1-R.sub.21, at least nineteen of R.sub.1-R.sub.21, and at
least twenty of R.sub.1-R.sub.21. In some embodiments all of
R.sub.1-R.sub.21 have deuterium enrichment of no less than about
95%, including about 96%, about 97%, about 98%, about 99%, and
about 100%.
[0068] In certain embodiments are provided compounds as disclosed
herein, wherein at least one of R.sub.1-R.sub.21 independently has
deuterium enrichment of no less than about 98%, including about
99%, and about 100%. In further embodiments, at least two of
R.sub.1-R.sub.21 have deuterium enrichment of no less than about
98%, including about 99%, and about 100%, including at least three
of R.sub.1-R.sub.21, at least four of R.sub.1-R.sub.21, at least
five of R.sub.1-R.sub.21, at least six of R.sub.1-R.sub.21, at
least seven of R.sub.1-R.sub.21, at least eight of
R.sub.1-R.sub.21, at least nine of R.sub.1-R.sub.21, at least ten
of R.sub.1-R.sub.21, at least eleven of R.sub.1-R.sub.21, at least
twelve of R.sub.1-R.sub.21, at least thirteen of R.sub.1-R.sub.21,
at least fourteen of R.sub.1-R.sub.21, at least fifteen of
R.sub.1-R.sub.21, at least sixteen of R.sub.1-R.sub.21, at least
seventeen of R.sub.1-R.sub.21, at least eighteen of
R.sub.1-R.sub.21, at least nineteen of R.sub.1-R.sub.21, and at
least twenty of R.sub.1-R.sub.21. In some embodiments all of
R.sub.1-R.sub.21 have deuterium enrichment of no less than about
98%, including about 99%, and about 100%.
[0069] In other embodiments, provided is a compound of intermediate
of Formula (II):
##STR00009##
[0070] or a pharmaceutically acceptable salt, ester, prodrug,
co-crystal, or solvate thereof, wherein:
[0071] X is selected from N or C--R.sub.29; R.sub.22-R.sub.29 are
independently selected from hydrogen and deuterium; and at least
one of R.sub.22-R.sub.29 is deuterium.
[0072] In certain embodiments, R.sub.22-R.sub.24 are deuterium.
[0073] In certain embodiments, R.sub.25-R.sub.26 are deuterium.
[0074] In certain embodiments, R.sub.22 is deuterium.
[0075] In certain embodiments, R.sub.23 is deuterium.
[0076] In certain embodiments, R.sub.24 is deuterium.
[0077] In certain embodiments, R.sub.25 is deuterium.
[0078] In certain embodiments, R.sub.26 is deuterium.
[0079] In certain embodiments, R.sub.27 is deuterium.
[0080] In certain embodiments, R.sub.28 is deuterium.
[0081] In certain embodiments, R.sub.29 is deuterium.
[0082] Also provided herein are embodiments according to each of
the embodiments above, wherein at least one of R.sub.27-R.sub.29
are deuterium.
[0083] Also provided herein are embodiments according to each of
the embodiments above, wherein every other substituent among
R.sub.22-R.sub.29 not specified as deuterium is hydrogen.
[0084] In specific embodiments, the compound or intermediate of
Formula II is selected from:
##STR00010##
[0085] or pharmaceutically acceptable salts, esters, prodrugs,
co-crystals, or solvates thereof.
[0086] Certain compounds disclosed herein may possess useful
5-HT.sub.1A receptor agonist activity, and may be used in the
treatment or prophylaxis of a disorder in which 5-HT.sub.1A
receptor agonist activity plays an active role. Thus, certain
embodiments also provide pharmaceutical compositions comprising one
or more compounds disclosed herein together with a pharmaceutically
acceptable carrier, as well as methods of making and using the
compounds and compositions. Certain embodiments provide methods for
modulating the activity of 5-HT.sub.1A receptors. Other embodiments
provide methods for treating a 5-HT.sub.1A receptor-mediated
disorder in a mammal and/or patient in need of such treatment,
comprising administering to said patient a therapeutically
effective amount of a compound or composition (of Formula I)
according to the present invention. Also provided is the use of
certain compounds disclosed herein for use in the manufacture of a
medicament for the prevention or treatment of a disorder
ameliorated by modulating the activity of one or more 5-HT.sub.1A
receptors.
[0087] The compounds as disclosed herein may also contain less
prevalent isotopes for other elements, including, but not limited
to, .sup.13C or .sup.14C for carbon, .sup.33S, .sup.34S, or
.sup.36S for sulfur, .sup.15N for nitrogen, and .sup.17O or
.sup.18O for oxygen.
[0088] In certain embodiments, the compound disclosed herein may
expose a patient to a maximum of about 0.000005% D.sub.2O or about
0.00001% DHO, assuming that all of the C-D bonds in the compound as
disclosed herein are metabolized and released as D.sub.2O or DHO.
In certain embodiments, the levels of D.sub.2O shown to cause
toxicity in animals is much greater than even the maximum limit of
exposure caused by administration of the deuterium enriched
compound as disclosed herein. Thus, in certain embodiments, the
deuterium-enriched compound disclosed herein should not cause any
additional toxicity due to the formation of D.sub.2O or DHO upon
drug metabolism.
[0089] In certain embodiments, said compound of Formula I is
selected from the group consisting of:
##STR00011## ##STR00012##
[0090] It is noted that in any of the above enumerated compounds of
Formula I, the aromatic rings (i.e. the pyridine ring, the
pyrimidine ring, and/or the phenyl ring) may also contain one or
more deuterium.
[0091] In other embodiments, the compound of Formula I is selected
from:
##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017##
##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022##
##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##
##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032##
##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037##
##STR00038##
[0092] It is noted that in any of the above enumerated compounds of
Formula I, the aromatic rings (i.e. the pyridine ring, the
pyrimidine ring, and/or the phenyl ring) may also contain one or
more deuterium.
[0093] In certain embodiments, the deuterated compounds disclosed
herein maintain the beneficial aspects of the corresponding
non-isotopically enriched molecules while substantially increasing
the maximum tolerated dose, decreasing toxicity, increasing the
half-life (T.sub.1/2), lowering the maximum plasma concentration
(C.sub.max) of the minimum efficacious dose (MED), lowering the
efficacious dose and thus decreasing the non-mechanism-related
toxicity, and/or lowering the probability of drug-drug
interactions.
[0094] Also provided is a pharmaceutical composition comprising a
compound as disclosed herein together with a pharmaceutically
acceptable carrier.
[0095] Also provided is a pharmaceutical composition comprising a
pharmaceutically acceptable carrier together with a compound of
Formula I:
##STR00039##
[0096] or a pharmaceutically acceptable salt, ester, prodrug,
co-crystal, or solvate thereof, wherein:
[0097] X is selected from N or C--R.sub.21; R.sub.1-R.sub.21 are
independently selected from hydrogen and deuterium; and at least
one of R.sub.1-R.sub.21 is deuterium.
[0098] In certain embodiments, R.sub.1 is deuterium.
[0099] In certain embodiments, R.sub.2 is deuterium.
[0100] In certain embodiments, R.sub.3 is deuterium.
[0101] In certain embodiments, R.sub.4 is deuterium.
[0102] In certain embodiments, R.sub.5 is deuterium.
[0103] In certain embodiments, R.sub.6 is deuterium.
[0104] In certain embodiments, R.sub.7 is deuterium.
[0105] In certain embodiments, R.sub.8 is deuterium.
[0106] In certain embodiments, R.sub.9 is deuterium.
[0107] In certain embodiments, R.sub.10 is deuterium.
[0108] In certain embodiments, R.sub.11 is deuterium.
[0109] In certain embodiments, R.sub.12 is deuterium.
[0110] In certain embodiments, R.sub.13 is deuterium.
[0111] In certain embodiments, R.sub.14 is deuterium.
[0112] In certain embodiments, R.sub.15 is deuterium.
[0113] In certain embodiments, R.sub.16 is deuterium.
[0114] In certain embodiments, R.sub.17 is deuterium.
[0115] In certain embodiments, R.sub.18 is deuterium.
[0116] In certain embodiments, R.sub.19 is deuterium.
[0117] In certain embodiments, R.sub.20 is deuterium.
[0118] In certain embodiments, R.sub.21 is deuterium.
[0119] In further embodiments, said pharmaceutically acceptable
salt is selected from a hydrochloride, a hydrobromide, a sulfate, a
formate, an acetate, a trifluoroacetate, a propionate, a succinate,
a fumarate, a citrate, a tartrate, a glutamate, a benzoate, a
salicylate, a stearate, a lactate, a mesylate, a tosylate, a
besylate, a phosphate, a maleate, and the like.
[0120] In specific embodiments, said pharmaceutically acceptable
salt is selected from a sulfate and a fumarate.
[0121] In specific embodiments, at least one of R.sub.1-R.sub.21
has deuterium enrichment of at least 10%.
[0122] In some embodiments, the compounds of Formula I are
effective in the treatment of movement disorders. As used herein,
the term "movement disorder" refers to a group of diseases or
disorders that affect the ability to produce and control body
movement. Such diseases or disorders may be associated with
neurological disorders or conditions associated with neurological
dysfunction. Movement disorders may manifest themselves in abnormal
fluency or speed of movement, excessive or involuntary movement, or
slowed or absent voluntary movement. Akathisia for example, is a
movement disorder characterized by unpleasant sensations of "inner"
restlessness, mental unease, or dysphoria that results in inability
of a patient to sit still or remain motionless. Patients having
movement disorders typically have restless movement, including
rocking from foot to foot and walking on the spot when standing,
shuffling and tramping the legs, rocking back and forth, or
swinging one leg on the other when sitting. In severe cases,
patients constantly pace up and down in an attempt to relieve the
sense of unrest, since the restlessness is felt from wakeup in the
morning to sleep at night.
[0123] Another example of a movement disorder is dyskinesia, which
is characterized by various involuntary movements which can affect
discrete body parts or can become generalized and severely
disabling. Tardive dyskinesia is one example of dyskinesia, which
is characterized by repetitive, involuntary, purposeless movements,
such as grimacing, tongue protrusion, lip smacking, puckering and
pursing of the lips, and rapid eye blinking. Involuntary movements
of the fingers may appear as though the patient is playing an
invisible guitar or piano.
[0124] Without intending to be bound by theory, it is thought that
the neurological disorder or condition which causes the movement
disorder may be associated with dysfunction of the basal ganglia.
The dysfunction may be idiopathic, induced by certain drugs or
infections, or caused by genetic defects.
[0125] Parkinson's disease (PD) is an example of a neurological
disorder associated with dysfunction of the basal ganglia.
Parkinson's disease results in movement disorders and is
characterized by muscle rigidity, tremor, postural abnormalities,
gait abnormalities, a slowing of physical movement (bradykinesia)
and, in extreme cases, a loss of physical movement (akinesia). The
disease is caused by progressive death and degeneration of dopamine
neurons in substantia nigra pars compacta and a dysfunctional
regulation of dopamine neurotransmission. In order to replace the
lost dopamine, Parkinson's disease may be treated with Levodopa
(L-DOPA, a precursor of dopamine), with dopamine agonists or other
agents that act by increasing the concentration of dopamine in the
synaptic cleft.
[0126] Unfortunately, the treatment of Parkinson's disease with
L-DOPA may give rise to dyskinesia (diminished voluntary movements
and presence of involuntary movements) in advanced Parkinson's
disease patients with impaired regulations of dopamine levels. This
specific type of dyskinesia is called L-DOPA Induced Dyskinesia
(LID).
[0127] Movement disorders induced by drug therapy can also be
related to treatment of other neurological or psychiatric diseases.
Examples of such movement disorders include, but are not limited
to, tardive dyskinesia and akathesia, which are commonly developed
as a side effect of long term treatment with neuroleptics for
instance in patients suffering from e.g. schizophrenia.
[0128] In some embodiments, the compounds of Formula I are
effective in the treatment of conditions or diseases known to
respond to modulating the activity of 5-HT.sub.1A receptors,
including but not limited to, anxiety, depression, bipolar
disorder, obsessive-compulsive disorders, panic attacks,
aggression, impulsivity, alcohol abuse, sexual disorders, sleeping
disorders, pain, acute pain, postoperative pain, chronic pain,
nociceptive pain, cancer pain, neuropathic pain, psychogenic pain
hypertension, nausea, dizziness, vomiting, regulation of gastric
secretion, obesity, regulation of food intake, immune diseases,
migraine, dyskinesia, akinesia, chorea, ballismus, dystonia,
myoclonus, athetosis, akathisia, ataxia, synkinesia, tics,
bradykinesia, tremor, movement disorders, Parkinson's disease,
Huntington's disease, Tourette's syndrome, tardive dyskinesia,
muscle spasms, muscle hypertonia, schizophrenia, drug-seeking
behavior, opioid-induced respiratory syndrome, restless leg
syndrome, L-DOPA-induced dyskinesia.
[0129] Also provided is a method of treating or preventing an
5-HT.sub.1A receptors-mediated disorder, the method comprising
administering, to a mammal in need thereof, a therapeutically
effective amount of a compound of Formula I or administering a
pharmaceutical composition comprising a compound of Formula I. In
other embodiments, provides is a method of treating or preventing a
disease selected from anxiety, depression, bipolar disorder,
obsessive-compulsive disorders, panic attacks, aggression,
impulsivity, alcohol abuse, sexual disorders, sleeping disorders,
pain, acute pain, postoperative pain, chronic pain, nociceptive
pain, cancer pain, neuropathic pain, psychogenic pain hypertension,
nausea, dizziness, vomiting, regulation of gastric secretion,
obesity, regulation of food intake, immune diseases, migraine,
dyskinesia, akinesia, chorea, ballismus, dystonia, myoclonus,
athetosis, akathisia, ataxia, synkinesia, tics, bradykinesia,
tremor, movement disorders, Parkinson's disease, Huntington's
disease, Tourette's syndrome, tardive dyskinesia, muscle spasms,
muscle hypertonia, schizophrenia, drug-seeking behavior,
opioid-induced respiratory syndrome, restless leg syndrome, and
L-DOPA-induced dyskinesia, the method comprising administering a
therapeutically effective amount of at least one compound of
Formula I to a mammal in need thereof.
[0130] In certain embodiments, the method further results in at
least one effect selected from the group consisting of: [0131] a)
decreased inter-individual variation in plasma levels of said
compound or a metabolite thereof as compared to the
non-isotopically enriched compound; [0132] b) increased average
plasma levels of said compound per dosage unit thereof as compared
to the non-isotopically enriched compound; [0133] c) decreased
average plasma levels of at least one metabolite of said compound
per dosage unit thereof as compared to the non-isotopically
enriched compound; [0134] d) increased average plasma levels of at
least one metabolite of said compound per dosage unit thereof as
compared to the non-isotopically enriched compound; and [0135] e)
an improved clinical effect during the administration in said
subject per dosage unit thereof as compared to the non-isotopically
enriched compound.
[0136] In certain embodiments, the method further results in at
least two effects selected from the group consisting of: [0137] a)
decreased inter-individual variation in plasma levels of said
compound or a metabolite thereof as compared to the
non-isotopically enriched compound; [0138] b) increased average
plasma levels of said compound per dosage unit thereof as compared
to the non-isotopically enriched compound; [0139] c) decreased
average plasma levels of at least one metabolite of said compound
per dosage unit thereof as compared to the non-isotopically
enriched compound; [0140] d) increased average plasma levels of at
least one metabolite of said compound per dosage unit thereof as
compared to the non-isotopically enriched compound; and [0141] e)
an improved clinical effect during the administration in said
subject per dosage unit thereof as compared to the non-isotopically
enriched compound.
[0142] In certain embodiments, the method affects a decreased
metabolism of the compound per dosage unit thereof by at least one
polymorphically-expressed cytochrome P.sub.450 isoform in the
subject, as compared to the corresponding non-isotopically enriched
compound.
[0143] In certain embodiments, said compound is characterized by
decreased inhibition of at least one cytochrome P.sub.450 or
monoamine oxidase isoform in said subject per dosage unit thereof
as compared to the non-isotopically enriched compound.
[0144] In certain embodiments, said cytochrome P.sub.450 or
monoamine oxidase isoform is selected from the group consisting of
CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9,
CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1,
CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1,
CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1,
CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17,
CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39,
CYP46, CYP51, MAO.sub.A, and MAO.sub.B.
[0145] In certain embodiments, the method reduces a deleterious
change in a diagnostic hepatobiliary function endpoint, as compared
to the corresponding non-isotopically enriched compound.
[0146] In certain embodiments, the diagnostic hepatobiliary
function endpoint is selected from the group consisting of alanine
aminotransferase ("ALT"), serum glutamic-pyruvic transaminase
("SGPT"), aspartate aminotransferase ("AST," "SGOT"), ALT/AST
ratios, serum aldolase, alkaline phosphatase ("ALP"), ammonia
levels, bilirubin, gamma-glutamyl transpeptidase ("GGTP,"
".gamma.-GTP," "GGT"), leucine aminopeptidase ("LAP"), liver
biopsy, liver ultrasonography, liver nuclear scan, 5'-nucleotidase,
and blood protein.
[0147] With respect to the terms used in this disclosure, the
following definitions are provided.
[0148] The singular forms "a," "an," and "the" may refer to plural
articles unless specifically stated otherwise.
[0149] The term "about," as used herein, is intended to qualify the
numerical values which it modifies, denoting such a value as
variable within a margin of error. When no particular margin of
error, such as a standard deviation to a mean value given in a
chart or table of data, is recited, the term "about" should be
understood to mean that range which would encompass the recited
value and the range which would be included by rounding up or down
to that figure as well, taking into account significant
figures.
[0150] When ranges of values are disclosed, and the notation "from
n.sub.1 . . . to n.sub.2" or "n.sub.1-n.sub.2" is used, where
n.sub.1 and n.sub.2 are the numbers, then unless otherwise
specified, this notation is intended to include the numbers
themselves and the range between them. This range may be integral
or continuous between and including the end values.
[0151] As used herein, the term "deuterium enrichment" refers to
the percentage of incorporation of deuterium at a given position in
a molecule in the place of hydrogen. For example, deuterium
enrichment of 1% at a given position means that 1% of molecules in
a given sample contain deuterium at the specified position. Because
the naturally occurring distribution of deuterium is about 0.0156%,
deuterium enrichment at any position in a compound synthesized
using non-enriched starting materials is about 0.0156%. The
deuterium enrichment can be determined using conventional
analytical methods known to one of ordinary skill in the art,
including mass spectrometry and nuclear magnetic resonance
spectroscopy.
[0152] As used herein, the term "is/are deuterium," when used to
describe a given position in a molecule such as R.sub.1-R.sub.21 or
the symbol "D," when used to represent a given position in a
drawing of a molecular structure, means that the specified position
is enriched with deuterium above the naturally occurring
distribution of deuterium. In one embodiment deuterium enrichment
is no less than about 1%, in another no less than about 5%, in
another no less than about 10%, in another no less than about 20%,
in another no less than about 50%, in another no less than about
70%, in another no less than about 80%, in another no less than
about 90%, or in another no less than about 98% of deuterium at the
specified position.
[0153] As used herein, the term "isotopic enrichment" refers to the
percentage of incorporation of a less prevalent isotope of an
element at a given position in a molecule in the place of the more
prevalent isotope of the element.
[0154] As used herein, the term "non-isotopically enriched" refers
to a molecule in which the percentages of the various isotopes are
substantially the same as the naturally occurring percentages.
[0155] Asymmetric centers may exist in the compounds disclosed
herein. Compounds of the present invention containing an
asymmetrically substituted atom may be isolated in optically active
or racemic forms. It is well known in the art how to prepare
optically active forms, such as by resolution of racemic forms or
by synthesis from optically active materials. Asymmetric centers
are designated by the symbols "R" or "S," depending on the
configuration of substituents around the chiral carbon atom. It
should be understood that the invention encompasses all chiral,
diastereomeric, racemic forms, and all geometric isomeric forms,
and mixtures thereof, unless the specific stereochemistry or
isomeric form is specifically indicated. Individual stereoisomers
of compounds can be prepared synthetically from commercially
available starting materials which contain chiral centers or by
preparation of mixtures of enantiomeric products followed by
separation such as conversion to a mixture of diastereomers
followed by separation or recrystallization, chromatographic
techniques, direct separation of enantiomers on chiral
chromatographic columns, or any other appropriate method known in
the art. Starting compounds of particular stereochemistry are
either commercially available or can be made and resolved by
techniques known in the art. Additionally, the compounds disclosed
herein may exist as geometric isomers. The present invention
includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z)
isomers as well as the appropriate mixtures thereof. Additionally,
compounds may exist as tautomers; all tautomeric isomers are
provided by this invention. Additionally, the compounds disclosed
herein can exist in unsolvated as well as solvated forms with
pharmaceutically acceptable solvents such as water, ethanol, and
the like. In general, the solvated forms are considered equivalent
to the unsolvated forms.
[0156] As used herein, the term "substituted" means that any one or
more hydrogens on the designated atom or ring is replaced with a
selection from the indicated group, e.g. deuterium, provided that
the designated atom's normal valency is not exceeded.
[0157] As used herein, the term "bond" refers to a covalent linkage
between two atoms, or two moieties when the atoms joined by the
bond are considered to be part of larger substructure. A bond may
be single, double, or triple unless otherwise specified. A dashed
line between two atoms in a drawing of a molecule indicates that an
additional bond may be present or absent at that position.
[0158] As used herein, the term "disorder" is intended to be
generally synonymous, and is used interchangeably with, the terms
"disease" and "condition" (as in medical condition), in that all
reflect an abnormal condition of the human or animal body or of one
of its parts that impairs normal functioning, is typically
manifested by distinguishing signs and symptoms.
[0159] As used herein, the terms "treat," "treating," and
"treatment" are meant to include alleviating or abrogating a
disorder or one or more of the symptoms associated with a disorder;
or alleviating or eradicating the cause(s) of the disorder itself.
In some embodiments, treating refers to inhibiting the
disease-state, i.e., arresting its development and/or relieving the
disease-state, i.e., causing regression of the disease state.
[0160] As used herein, the terms "prevent," "preventing," and
"prevention" refer to a method of delaying or precluding the onset
of a disorder; and/or its attendant symptoms, barring a subject
from acquiring a disorder or reducing a subject's risk of acquiring
a disorder. In some embodiments, preventing refers to precluding a
disease-state from occurring in a mammal, in particular, when such
mammal is pre-disposed to the disease-state but has not yet been
diagnosed as having it.
[0161] As used herein, the term "therapeutically effective amount"
refers to the amount of a compound that, when administered, is
sufficient to prevent development of, or alleviate to some extent,
one or more of the symptoms of the disorder being treated. The term
"therapeutically effective amount" also refers to the amount of a
compound that is sufficient to elicit the biological or medical
response of a cell, tissue, system, animal, or human that is being
sought by a researcher, veterinarian, medical doctor, or
clinician.
[0162] As used herein, the term "subject" refers to an animal,
including, but not limited to, a primate (e.g., human, monkey,
chimpanzee, gorilla, and the like), rodents (e.g., rats, mice,
gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g.,
pig, miniature pig), equine, canine, feline, and the like. The
terms "subject" and "patient" are used interchangeably herein in
reference, for example, to a mammalian subject, such as a human
and/or a canine and/or a feline patient.
[0163] As used herein, the term "combination therapy" refers to the
administration of two or more therapeutic agents to treat (or
prevent) a therapeutic disorder described in the present
disclosure. Such administration encompasses co-administration of
these therapeutic agents in a substantially simultaneous manner,
such as in a single capsule having a fixed ratio of active
ingredients or in multiple, separate capsules for each active
ingredient. In addition, such administration also encompasses use
of each type of therapeutic agent in a sequential manner. In either
case, the treatment (or prevention) regimen will provide beneficial
effects of the drug combination in treating the disorders described
herein.
[0164] As used herein, the term "5-HT.sub.1A receptors-mediated
disorder" refers to a disorder that is characterized by abnormal
5-HT.sub.1A receptor activity, that when modulated ameliorates
other abnormal biochemical processes. A 5-HT.sub.1A
receptors-mediated disorder may be completely or partially mediated
by modulating the activity of 5-HT.sub.1A receptors. In particular,
a 5-HT.sub.1A receptor-mediated disorder is one in which the
modulation of 5-HT.sub.1A receptor activity results in some effect
on the underlying disorder, e.g., administration of 5-HT.sub.1A
receptor agonist results in some improvement in at least some of
the patients being treated.
[0165] As used herein, the term "5-HT.sub.1A receptor agonist"
refers to the ability of a compound disclosed herein to alter the
function of at least one 5-HT.sub.1A receptor. A 5-HT.sub.1A
receptor agonist may trigger the release or inhibition of
norepinephrine. A 5-HT.sub.1A receptor agonist may also increase
dopamine release in the media prefrontal cortex, stiatum, and
hippocampus. In some instances, a 5-HT.sub.1A receptor agonist may
induce the secretion of various hormones including cortisol,
corticosterone, adrenocorticotropic hormone (ACTH), oxytocin,
prolactin, growth hormone, and .beta.-endorphin.
[0166] As used herein, the term "modulating 5-HT.sub.1A receptor
activity" or the like refers to altering the function of at least
one 5-HT.sub.1A receptor by administering a 5-HT.sub.1A receptor
agonist.
[0167] As used herein, the terms "therapeutically acceptable" and
"pharmaceutically acceptable" are used interchangeably and refer to
those compounds (or salts, prodrugs, tautomers, zwitterionic forms,
etc.) which are suitable for use in contact with the tissues of
patients without excessive toxicity, irritation, allergic response,
immunogenicity, are commensurate with a reasonable benefit/risk
ratio, and are effective for their intended use.
[0168] As used herein, the term "pharmaceutically acceptable
carrier," "pharmaceutically acceptable excipient," "physiologically
acceptable carrier," or "physiologically acceptable excipient"
refers to a pharmaceutically-acceptable material, composition, or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent, or encapsulating material. Each component must be
"pharmaceutically acceptable" in the sense of being compatible with
the other ingredients of a pharmaceutical formulation. It must also
be suitable for use in contact with the tissue or organ of humans
and animals without excessive toxicity, irritation, allergic
response, immunogenicity, or other problems or complications,
commensurate with a reasonable benefit/risk ratio.
[0169] As used herein, the terms "active ingredient," "active
compound," and "active substance" refer to a compound, which is
administered, alone or in combination with one or more
pharmaceutically acceptable excipients or carriers, to a subject
for treating, preventing, or ameliorating one or more symptoms of a
disorder.
[0170] As used herein, the terms "drug," "therapeutic agent," and
"chemotherapeutic agent" refer to a compound, or a pharmaceutical
composition thereof, which is administered to a subject for
treating, preventing, or ameliorating one or more symptoms of a
disorder.
[0171] As used herein, the term "release controlling excipient"
refers to an excipient whose primary function is to modify the
duration or place of release of the active substance from a dosage
form as compared with a conventional immediate release dosage
form.
[0172] As used herein, the term "nonrelease controlling excipient"
refers to an excipient whose primary function do not include
modifying the duration or place of release of the active substance
from a dosage form as compared with a conventional immediate
release dosage form.
[0173] As used herein, the term "prodrug" refers to a compound
functional derivative of the compound as disclosed herein and is
readily convertible into the parent compound in vivo. The term
"prodrug" denotes a compound which, upon administration to a
subject, undergoes chemical conversion by metabolic or chemical
processes to yield a compound of the formula, and/or a salt and/or
solvate thereof. For example, compounds containing a carboxy group
can form physiologically hydrolyzable esters which serve as
prodrugs by being hydrolyzed in the body to yield formula compounds
per se. Prodrugs are often useful because, in some situations, they
may be easier to administer than the parent compound. They may, for
instance, be bioavailable by oral administration whereas the parent
compound is not. The prodrug may also have enhanced solubility in
pharmaceutical compositions over the parent compound. A prodrug may
be converted into the parent drug by various mechanisms, including
enzymatic processes and metabolic hydrolysis.
[0174] The term "prodrug" as employed herein includes esters and
carbonates formed by reacting compounds of formula I with alkyl,
alkoxy, or aryl substituted acylating agents employing procedures
known to those skilled in the art to generate acetates, pivalates,
methyl carbonates, benzoates, and the like.
[0175] As used herein, the term "co-crystal" refers to materials
(i.e. solids) that are crystalline single phase materials composed
of two or more different molecular and/or ionic compounds generally
in a stoichiometric ratio which are neither solvates nor simple
salts.
[0176] The compounds disclosed herein can exist as therapeutically
acceptable salts or pharmaceutically acceptable salts. As used
herein, the terms "therapeutically acceptable salt" and
"pharmaceutically acceptable salt" are used interchangeably and
represent salts or zwitterionic forms of the compounds disclosed
herein which are therapeutically acceptable as defined herein. The
salts can be prepared during the final isolation and purification
of the compounds or separately by reacting the appropriate compound
with a suitable acid or base. Therapeutically acceptable salts
include acid and basic addition salts.
[0177] The term pharmaceutically acceptable salt includes acid
addition salts. There are formed, for example, with strong
inorganic acids, such as mineral acids or a hydrohalic acid, with
strong organic carboxylic acid, such as alkanecarboxylic acids of 1
to 4 carbon atoms which are unsubstituted or substituted, for
example, by halogen, such as saturated or unsaturated dicarboxylic
acids, such as hydroxycarboxylic acids, such as amino acids,
benzoic acid, or organic sulfonic acids.
[0178] Suitable acids for use in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic
acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic
acid, benzoic acid, 4-acetamidobenzoic acid, boric acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
cyclohexanesulfamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, phthalic
acid, terephthalic acid, galactaric acid, gentisic acid,
glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic
acid, .alpha.-oxo-glutaric acid, glycolic acid, hippuric acid,
hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic
acid, (+)-DL-lactic acid, lactobionic acid, lauric acid, maleic
acid, (-)-L-malic acid, malonic acid, (+)-DL-mandelic acid,
methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitic acid, pamoic acid, perchloric acid, phosphoric acid,
L-pyroglutamic acid, saccharic acid, salicylic acid,
4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,
p-toluenesulfonic acid, undecylenic acid, and valeric acid.
[0179] Such pharmaceutically acceptable salts may refer to basic
salts formed with inorganic and organic bases. Such salts include
ammonium salts; alkali metal salts, such as lithium, sodium, and
potassium salts; alkaline earth metal salts, such as calcium and
magnesium salts; salts with organic bases, such as amine like salts
(e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine,
and hydrabamine salts); and salts with amino acids like arginine,
lysine, and the like; and zwitterions, the so-called "inner salts."
Nontoxic, pharmaceutically acceptable salts are preferred, although
other salts are also useful, e.g., in isolating or purifying the
product.
[0180] Suitable bases for use in the preparation of
pharmaceutically acceptable salts, including, but not limited to,
inorganic bases, such as magnesium hydroxide, calcium hydroxide,
potassium hydroxide, zinc hydroxide, or sodium hydroxide; and
organic bases, such as primary, secondary, tertiary, and
quaternary, aliphatic and aromatic amines, including L-arginine,
benethamine, benzathine, choline, deanol, diethanolamine,
diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylamine,
ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,
1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,
methylamine, piperidine, piperazine, propylamine, pyrrolidine,
1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,
isoquinoline, secondary amines, triethanolamine, trimethylamine,
triethylamine, N-methyl-D-glucamine,
2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.
[0181] In specific embodiments, fumaric acid (trans-butendioic
acid) is used for the preparation of a pharmaceutically acceptable
salt. The resulting salt is, thus, a fumarate. In other specific
embodiments, sulfuric acid is used for the preparation of a
pharmaceutically acceptable salt. The resulting salt is, thus, a
sulfate. In further embodiments, the pharmaceutically acceptable
salt is selected from selected from a hydrochloride, a
hydrobromide, a sulfate, a formate, an acetate, a trifluoroacetate,
a propionate, a succinate, a fumarate, a citrate, a tartrate, a
glutamate, a benzoate, a salicylate, a stearate, a lactate, a
mesylate, a tosylate, a besylate, a phosphate, a maleate, and the
like.
[0182] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred.
[0183] As used herein, the terms "therapeutically effective amount"
and "pharmaceutically effective amount" are intended to include an
amount of a compound of the present invention alone or an amount of
the combination of compounds claimed or an amount of a compound of
the present invention in combination with other active ingredients
effective to treat or prevent a 5-HT.sub.1A receptor-mediated
disorder.
[0184] While it may be possible for the compounds of the subject
invention to be administered as the raw chemical, it is also
possible to present them as a pharmaceutical composition.
Accordingly, provided herein are pharmaceutical compositions which
comprise one or more of certain compounds disclosed herein, or one
or more pharmaceutically acceptable salts, prodrugs, or solvates
thereof, together with one or more pharmaceutically acceptable
carriers thereof and optionally one or more other therapeutic
ingredients. Proper formulation is dependent upon the route of
administration chosen. Any of the well-known techniques, carriers,
and excipients may be used as suitable and as understood in the
art; e.g., in Remington's Pharmaceutical Sciences. Such carriers
enable the pharmaceutical compositions to be formulated as tablets,
pills dragees, capsules, liquids, gels, syrups, slurries,
suspensions, and the like, for ingestion, application, or
inhalation by the patient. In addition to the active ingredients
(e.g. the compounds of structural Formula I), the pharmaceutical
compositions may contain suitable pharmaceutically acceptable
carriers comprising excipients and auxiliaries which facilitate
processing of the active compounds into preparations which can be
used pharmaceutically. Techniques for formulation and
administration are known in the art.
[0185] The pharmaceutical compositions disclosed herein may be
manufactured in any manner known in the art, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or compression
processes. The pharmaceutical compositions may also be formulated
as a modified release dosage form, including delayed-, extended-,
prolonged-, sustained-, pulsatile-, controlled-, accelerated- and
fast-, targeted-, programmed-release, and gastric retention dosage
forms. These dosage forms can be prepared according to conventional
methods and techniques known to those skilled in the art.
[0186] The compositions include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous,
intraarticular, and intramedullary), intraperitoneal, transmucosal,
transdermal, rectal and topical (including dermal, buccal,
sublingual and intraocular) administration although the most
suitable route may depend upon for example the condition and
disorder of the recipient. Such compositions may be present in the
form of a gel, paste, ointment, cream, lotion, liquid suspension,
dispersion, emulsions, micro-emulsions, microcapsules,
microparticles, vesicular dispersions, and the like.
[0187] The compositions may conveniently be presented in unit
dosage form and may be prepared by any of the methods well known in
the art of pharmacy. Typically, these methods include the step of
bringing into association a compound of the subject invention or a
pharmaceutically salt, prodrug, or solvate thereof ("active
ingredient") with the carrier which constitutes one or more
accessory ingredients. In general, the compositions are prepared by
uniformly and intimately bringing into association the active
ingredient with liquid carriers or finely divided solid carriers or
both and then, if necessary, shaping the product into the desired
formulation.
[0188] Formulations of the compounds disclosed herein suitable for
oral administration may be presented as discrete units such as
capsules, cachets or tablets each containing a predetermined amount
of the active ingredient; as a powder or granules; as a solution or
a suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be presented as a bolus, electuary or
paste.
[0189] Pharmaceutical preparations which can be used orally include
tablets, push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. Tablets may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with binders, inert diluents, or lubricating, surface active
or dispersing agents. Molded tablets may be made by molding in a
suitable machine a mixture of the powdered compound moistened with
an inert liquid diluent. The tablets may optionally be coated or
scored and may be formulated so as to provide slow or controlled
release of the active ingredient therein. All formulations for oral
administration should be in dosages suitable for such
administration. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such
as starches, and/or lubricants such as talc or magnesium stearate
and, optionally, stabilizers. In soft capsules, the active
compounds may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid paraffin, or liquid polyethylene glycols. In
addition, stabilizers may be added. 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.
[0190] The compounds may be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents. The formulations may be presented in
unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in powder form or in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile
liquid carrier, for example, saline or sterile pyrogen-free water,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0191] Formulations for parenteral administration include aqueous
and non-aqueous (oily) sterile injection solutions of the active
compounds which may contain antioxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. Suitable lipophilic solvents or vehicles include fatty oils
such as sesame oil, or synthetic fatty acid esters, such as ethyl
oleate or triglycerides, or liposomes. Aqueous injection
suspensions may contain substances which increase the viscosity of
the suspension, such as sodium carboxymethyl cellulose, sorbitol,
or dextran. Optionally, the suspension may also contain suitable
stabilizers or agents which increase the solubility of the
compounds to allow for the preparation of highly concentrated
solutions.
[0192] 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 (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0193] For buccal or sublingual administration, the compositions
may take the form of tablets, lozenges, pastilles, or gels
formulated in conventional manner. Such compositions may comprise
the active ingredient in a flavored basis such as sucrose and
acacia or tragacanth.
[0194] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter, polyethylene
glycol, or other glycerides.
[0195] Certain compounds disclosed herein may be administered
topically, that is by non-systemic administration. This includes
the application of a compound disclosed herein externally to the
epidermis or the buccal cavity and the instillation of such a
compound into the ear, eye and nose, such that the compound does
not significantly enter the blood stream. In contrast, systemic
administration refers to oral, intravenous, intraperitoneal and
intramuscular administration.
[0196] Formulations suitable for topical administration include
liquid or semi-liquid preparations suitable for penetration through
the skin to the site of inflammation such as gels, liniments,
lotions, creams, ointments or pastes, and drops suitable for
administration to the eye, ear or nose.
[0197] For administration by inhalation, compounds may be delivered
from an insufflator, nebulizer pressurized packs or other
convenient means of delivering an aerosol spray. Pressurized packs
may comprise a suitable propellant such as 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. Alternatively, for administration by inhalation or
insufflation, the compounds according to the invention may take the
form of a dry powder composition, for example a powder mix of the
compound and a suitable powder base such as lactose or starch. The
powder composition may be presented in unit dosage form, in for
example, capsules, cartridges, gelatin or blister packs from which
the powder may be administered with the aid of an inhalator or
insufflator.
[0198] Preferred unit dosage formulations are those containing an
effective dose, as herein below recited, or an appropriate fraction
thereof, of the active ingredient.
[0199] Compounds may be administered orally or via injection at a
dose of from 0.1 to 500 mg/kg per day. The dose range for adult
humans is generally from 5 mg to 2 g/day. Tablets or other forms of
presentation provided in discrete units may conveniently contain an
amount of one or more compounds which is effective at such dosage
or as a multiple of the same, for instance, units containing 5 mg
to 500 mg, usually around 10 mg to 200 mg.
[0200] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration.
[0201] The compounds can be administered in various modes, e.g.
orally, topically, or by injection. The precise amount of compound
administered to a patient will be the responsibility of the
attendant physician. The specific dose level for any particular
patient will depend upon a variety of factors including the
activity of the specific compound employed, the age, body weight,
general health, sex, diets, time of administration, route of
administration, rate of excretion, drug combination, the precise
disorder being treated, and the severity of the disorder being
treated. Also, the route of administration may vary depending on
the disorder and its severity.
[0202] In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of the
compounds may be administered chronically, that is, for an extended
period of time, including throughout the duration of the patient's
life in order to ameliorate or otherwise control or limit the
symptoms of the patient's disorder.
[0203] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of the compounds may be
given continuously or temporarily suspended for a certain length of
time (i.e., a "drug holiday").
[0204] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, can be reduced,
as a function of the symptoms, to a level at which the improved
disorder is retained. Patients can, however, require intermittent
treatment (i.e., administration) on a long-term basis upon any
recurrence of symptoms.
[0205] Disclosed herein are methods of treating a 5-HT.sub.1A
receptor-mediated disorder comprising administering to a subject
having or suspected of having such a disorder, a therapeutically
effective amount of a compound as disclosed herein or a
pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0206] Without intending to be bound by theory, it is thought that
the compounds of Formula I target and modulate the activity of
5-HT.sub.1A receptors. Thus, one or more embodiments are directed
to modulating the activity of 5-HT.sub.1A receptors in order to
treat or prevent a 5-HT.sub.1A receptor-mediated disorder.
[0207] 5-HT.sub.1A receptor-mediated disorders, include, but are
not limited to, anxiety, depression, bipolar disorder,
obsessive-compulsive disorders, panic attacks, aggression,
impulsivity, alcohol abuse, sexual disorders, sleeping disorders,
pain, acute pain, postoperative pain, chronic pain, nociceptive
pain, cancer pain, neuropathic pain, psychogenic pain hypertension,
nausea, dizziness, vomiting, regulation of gastric secretion,
obesity, regulation of food intake, immune diseases, migraine,
dyskinesia, akinesia, chorea, ballismus, dystonia, myoclonus,
athetosis, akathisia, ataxia, synkinesia, tics, bradykinesia,
tremor, movement disorders, Parkinson's disease, Huntington's
disease, Tourette's syndrome, tardive dyskinesia, muscle spasms,
muscle hyptertonia, schizophrenia, drug-seeking behavior,
opioid-induced respiratory syndrome, restless leg syndrome,
L-DOPA-induced dyskinesia, and/or any disorder which can lessened,
alleviated, or prevented by administering a 5-HT.sub.1A receptor
agonist.
[0208] In certain embodiments, a method of treating a 5-HT.sub.1A
receptor-mediated disorder comprises administering to the subject a
therapeutically effective amount of a compound as disclosed herein,
or a pharmaceutically acceptable salt, ester, solvate, co-crystal,
or prodrug thereof, so as to affect: (1) decreased inter-individual
variation in plasma levels of the compound or a metabolite thereof;
(2) increased average plasma levels of the compound or decreased
average plasma levels of at least one metabolite of the compound
per dosage unit; (3) decreased inhibition of, and/or metabolism by
at least one cytochrome P.sub.450 or monoamine oxidase isoform in
the subject; (4) decreased metabolism via at least one
polymorphically-expressed cytochrome P.sub.450 isoform in the
subject; (5) at least one statistically-significantly improved
disorder-control and/or disorder-eradication endpoint; (6) an
improved clinical effect during the treatment of the disorder, (7)
prevention of recurrence, or delay of decline or appearance, of
abnormal alimentary or hepatic parameters as the primary clinical
benefit, or (8) reduction or elimination of deleterious changes in
any diagnostic hepatobiliary function endpoints, as compared to the
corresponding non-isotopically enriched compound.
[0209] In certain embodiments, inter-individual variation in plasma
levels of the compounds as disclosed herein, or metabolites
thereof, is decreased; average plasma levels of the compound as
disclosed herein are increased; average plasma levels of a
metabolite of the compound as disclosed herein are decreased;
inhibition of a cytochrome P.sub.450 or monoamine oxidase isoform
by a compound as disclosed herein is decreased; or metabolism of
the compound as disclosed herein by at least one
polymorphically-expressed cytochrome P.sub.450 isoform is
decreased; by greater than about 5%, greater than about 10%,
greater than about 20%, greater than about 30%, greater than about
40%, or by greater than about 50% as compared to the corresponding
non-isotopically enriched compound.
[0210] Plasma levels of the compound as disclosed herein, or
metabolites thereof, may be measured using the methods described
the art.
[0211] Examples of cytochrome P.sub.450 isoforms in a mammalian
subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1,
CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6,
CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1,
CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11,
CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1,
CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1,
CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.
[0212] Examples of monoamine oxidase isoforms in a mammalian
subject include, but are not limited to, MAO.sub.A, and
MAO.sub.B.
[0213] The inhibition of the cytochrome P.sub.450 isoform is
measured by the method of Ko et al. (British Journal of Clinical
Pharmacology, 2000, 49, 343-351). The inhibition of the MAO.sub.A
isoform is measured by the method of Weyler et al. (J. Biol. Chem.
1985, 260, 13199-13207). The inhibition of the MAO.sub.B isoform is
measured by the method of Uebelhack et al. (Pharmacopsychiatry,
1998, 31, 187-192).
[0214] Examples of polymorphically-expressed cytochrome P.sub.450
isoforms in a mammalian subject include, but are not limited to,
CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5.
[0215] The metabolic activities of liver microsomes, cytochrome
P.sub.450 isoforms, and monoamine oxidase isoforms are measured by
the methods described herein.
[0216] Examples of diagnostic hepatobiliary function endpoints
include, but are not limited to, alanine aminotransferase ("ALT"),
serum glutamic-pyruvic transaminase ("SGPT"), aspartate
aminotransferase ("AST" or "SGOT"), ALT/AST ratios, serum aldolase,
alkaline phosphatase ("ALP"), ammonia levels, bilirubin,
gamma-glutamyl transpeptidase ("GGTP," ".gamma.-GTP," or "GGT"),
leucine aminopeptidase ("LAP"), liver biopsy, liver
ultrasonography, liver nuclear scan, 5'-nucleotidase, and blood
protein. Hepatobiliary endpoints are compared to the stated normal
levels as given in "Diagnostic and Laboratory Test Reference",
4.sup.th edition, Mosby, 1999. These assays are run by accredited
laboratories according to standard protocol.
[0217] Besides being useful for human treatment, certain compounds
and formulations disclosed herein may also be useful for veterinary
treatment of companion animals, exotic animals and farm animals,
including mammals, rodents, and the like. More preferred animals
include horses, dogs, and cats.
[0218] Combination Therapy
[0219] Patients being treated by administration of the 5-HT.sub.1A
receptor agonists of Formula I often exhibit diseases or conditions
that may benefit from treatment with other therapeutic agents.
These diseases or conditions can be of psychological or movement
based or can be related to cardiovascular disorders, metabolic
disorders, pulmonary disorders, metabolic disorders,
gastrointestinal disorders, and the like. Additionally, some
patients being treated by administration of the 5-HT.sub.1A
receptor agonists of Formula I exhibit conditions that can benefit
from treatment with therapeutic agents that are antibiotics,
analgesics, and/or antidepressants and anti-anxiety agents.
[0220] The present invention includes within its scope
pharmaceutical compositions comprising, as an active ingredient, a
therapeutically effective amount of at least one compound of
Formula I, alone or in combination with a pharmaceutical carrier or
diluent. Optionally, compounds of the present invention can be used
alone, in combination with other compounds of the invention (i.e.
additional compounds of Formula I), or in combination with one or
more other therapeutic agent(s).
[0221] In certain embodiments, the method comprises administering,
or co-administering, an additional therapeutic agent in combination
with one or more compounds of Formula I. The compounds disclosed
herein may also be combined or used in combination with other
agents useful in the treatment or prevention of 5-HT.sub.1A
receptor-mediated disorders. Or, by way of example only, the
therapeutic effectiveness of one of the compounds described herein
may be enhanced by administration of an adjuvant (i.e., by itself
the adjuvant may only have minimal therapeutic benefit, but in
combination with another therapeutic agent, the overall therapeutic
benefit to the patient is enhanced).
[0222] Such other agents, adjuvants, or drugs, may be administered,
by a route and in an amount commonly used therefor, simultaneously
or sequentially with a compound as disclosed herein. When a
compound as disclosed herein is used contemporaneously with one or
more other drugs, a pharmaceutical composition containing such
other drugs in addition to the compound disclosed herein may be
utilized, but is not required.
[0223] Thus, in another aspect, embodiments provide methods for
treating 5-HT.sub.1A receptor-mediated disorders in a human or
animal comprising administering to said subject an amount of a
compound of formula I disclosed herein effective to reduce or
prevent said 5-HT.sub.1A receptor-mediated disorder in the subject,
in combination with at least one additional therapeutic agent for
the treatment of said disorder. In a related aspect, embodiments
provide pharmaceutical compositions comprising at least one
compound disclosed herein in combination with one or more
additional therapeutic agents for the treatment of 5-HT.sub.1A
receptor-mediated disorders.
[0224] In certain embodiments, the compounds of Formula I disclosed
herein can be combined with one or more additional 5-HT.sub.1A
receptor agonist (full or partial agonist) including, but not
limited to, aripiprazole, alnespirone, asenapine, bacoside,
amphetamine, adatanserin, befiradol, binospirone, bufotenin,
buspirone, cannabidiol, clozapine, dihydroergotamine, ebalzotan,
eltoprazine, ergotamine, etoperidone, flesinoxan, flibanserin,
gepirone, haloperidol, lamotrigine, ipsapirone, lisuride,
lurasidone, methylphenidate, naluzotan, nefazodone, olanzapine,
osemozotan, perospirone, piclozotan, psilocin, psilocybin,
quetiapine, rauwolscine, repinotan, sarizotan, sunepitron,
tandospirone, tiospirone, trazodone, urapidil, vortioxetine,
vilazodone, zalospirone, ziprasidone, osemozotan, repinotan,
lesopitron, eptapirone, and alnespirone.
[0225] In certain embodiments, the compounds of Formula I disclosed
herein can be combined with one or more 5-HT.sub.1B, 5-HT.sub.1D
and 5-HT.sub.1F receptor agonist, including, but not limited to,
ergotamine, oxymetazoline, sumatriptan, zolmitriptan,
5-carboxamidotryptamine, vortioxetine, ziprasidone, asenapine,
5-(nonyloxy)tryptamine, 5-(t-butyl)-N-methyltryptamine,
5-n-butyrloxy-DMT, eletriptan, and naratriptan.
[0226] In certain embodiments, the compounds of Formula I disclosed
herein can be combined with one or more agents selected from the
group of agents increasing the dopamine concentration of the
synaptic cleft (i.e. dopamine reuptake inhibitors), including, but
not limited to, amineptine, dexmethylphenidate, difemetorex,
fencamfamine, lefetamine, levophacetoperane, medifoxamine,
mesocarb, methylphenidate, nomifensine, pipradrol, prolintane,
pyrovalerone, ketamine, dopamine, L-DOPA, or a dopamine receptor
agonist, including, but not limited to, aripiprazole, quinpirole,
apomorphine, bromocriptine, cabergoline, ciladopa, dihydrexidine,
dinapsoline, doxanthrine, epicriptine, lisuride, pergolide,
piribedil, pramipexole, propylnorapomorphine, quinagolide,
ropinirole, rotigotine, roxindole, and sumanirole.
[0227] In certain embodiments, the compounds of Formula I disclosed
herein can be combined with one or more antidepressant and
antianxiety agents including, without limitation, sertraline,
citalopram, fluoxetine, escitalopram, trazodone, venlafaxine,
desvenlafaxine, bupropion, duloxetine, paroxetine, amitriptyline,
mirtazapine, nefazodone, nortriptyline, alprazolam, bromazepam,
chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam,
lorazepam, oxazepam, temazepam, triazolam, tofisopam, meprobamate,
carisoprodol, tybamate, lorbamate, and the like.
[0228] The compounds disclosed herein can also be administered in
combination with other classes of compounds, including, but not
limited to, norepinephrine reuptake inhibitors (NRIs) such as
atomoxetine; dopamine reuptake inhibitors (DARIs), such as
methylphenidate; serotonin-norepinephrine reuptake inhibitors
(SNRIs), such as milnacipran; sedatives, such as diazepam;
norepinephrine-dopamine reuptake inhibitor (NDRIs), such as
bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors
(SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such
as selegiline; hypothalamic phospholipids; endothelin converting
enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as
tramadol; thromboxane receptor antagonists, such as ifetroban;
potassium channel openers; thrombin inhibitors, such as hirudin;
hypothalamic phospholipids; growth factor inhibitors, such as
modulators of PDGF activity; platelet activating factor (PAF)
antagonists; anti-platelet agents, such as GPIIb/IIIa blockers
(e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists
(e.g., clopidogrel, ticlopidine and CS-747), and aspirin;
anticoagulants, such as warfarin; low molecular weight heparins,
such as enoxaparin; Factor VIIa Inhibitors and Factor Xa
Inhibitors; renin inhibitors; neutral endopeptidase (NEP)
inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors),
such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors,
such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104
(a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522
(also known as rosuvastatin, or atavastatin or visastatin);
squalene synthetase inhibitors; fibrates; bile acid sequestrants,
such as questran; niacin; anti-atherosclerotic agents, such as ACAT
inhibitors; MTP Inhibitors; calcium channel blockers, such as
amlodipine besylate; potassium channel activators; alpha-muscarinic
agents; beta-muscarinic agents, such as carvedilol and metoprolol;
antiarrhythmic agents; diuretics, such as chlorothlazide,
hydrochiorothiazide, flumethiazide, hydroflumethiazide,
bendroflumethiazide, methylchlorothiazide, trichioromethiazide,
polythiazide, benzothlazide, ethacrynic acid, tricrynafen,
chlorthalidone, furosenilde, musolimine, bumetanide, triamterene,
amiloride, and spironolactone; thrombolytic agents, such as tissue
plasminogen activator (tPA), recombinant tPA, streptokinase,
urokinase, prourokinase, and anisoylated plasminogen streptokinase
activator complex (APSAC); anti-diabetic agents, such as biguanides
(e.g. metformin), glucosidase inhibitors (e.g., acarbose),
insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g.,
glimepiride, glyburide, and glipizide), thiozolidinediones (e.g.
troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma
agonists; mineralocorticoid receptor antagonists, such as
spironolactone and eplerenone; growth hormone secretagogues; aP2
inhibitors; phosphodiesterase inhibitors, such as PDE III
inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g.,
sildenafil, tadalafil, vardenafil); protein tyrosine kinase
inhibitors; antiinflammatories; antiproliferatives, such as
methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil;
chemotherapeutic agents; immunosuppressants; anticancer agents and
cytotoxic agents (e.g., alkylating agents, such as nitrogen
mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and
triazenes); antimetabolites, such as folate antagonists, purine
analogues, and pyrridine analogues; antibiotics, such as
anthracyclines, bleomycins, mitomycin, dactinomycin, and
plicamycin; enzymes, such as L-asparaginase; farnesyl-protein
transferase inhibitors; hormonal agents, such as glucocorticoids
(e.g., cortisone), estrogens/antiestrogens,
androgens/antiandrogens, progestins, and luteinizing
hormone-releasing hormone antagonists, and octreotide acetate;
microtubule-disruptor agents, such as ecteinascidins;
microtubule-stabilizing agents, such as paclitaxel, docetaxel, and
epothilones A-F; plant-derived products, such as vinca alkaloids,
epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;
prenyl-protein transferase inhibitors; and cyclosporins; steroids,
such as prednisone and dexamethasone; cytotoxic drugs, such as
azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as
tenidap; anti-TNF antibodies or soluble TNF receptor, such as
etanercept, rapamycin, and leflunimide; and cyclooxygenase-2
(COX-2) inhibitors, such as celecoxib and rofecoxib; and
miscellaneous agents such as, hydroxyurea, procarbazine, mitotane,
hexamethylmelamine, gold compounds, platinum coordination
complexes, such as cisplatin, satraplatin, and carboplatin.
[0229] In some embodiments, a patient presenting with a
psychological disorder or a movement disorder or related condition
may suffer from secondary medical conditions such as one or more of
a cardiovascular disease, a metabolic disorder, a pulmonary
disorder, a peripheral vascular disorder, a gastrointestinal
disorder, or a pain disorder. Such patients may benefit from a
treatment of a combination therapy comprising administration to the
patient one or more compounds of Formula I in combination with at
least one additional therapeutic agent.
[0230] Cardiovascular related diseases or conditions that a patient
may present with include, without limitation, angina including
stable angina, unstable angina (UA), exercised-induced angina,
variant angina, arrhythmias, intermittent claudication, myocardial
infarction including non-STE myocardial infarction (NSTEMI),
pulmonary hypertension including pulmonary arterial hypertension
and chronic thromboembolic pulmonary hypertension, heart failure
including congestive (or chronic) heart failure and diastolic heart
failure and heart failure with preserved ejection fraction
(diastolic dysfunction), acute heart failure, or recurrent
ischemia.
[0231] Therapeutic agents suitable for treating cardiovascular
related diseases or conditions in combination with compounds of
Formula I disclosed herein include anti-anginals, heart failure
agents, antithrombotic agents, antiarrhythmic agents,
antihypertensive agents, and lipid lowering agents.
[0232] Anti-anginals include beta-blockers, calcium channel
blockers, and nitrates. Examples of beta-blockers include, but are
not limited to, metoprolol (Lopressor.RTM., Toprol.RTM. XL),
carteolol (Cartrol.RTM.), acebutolol (Sectral.RTM.), betaxolol
(Kerlone.RTM.), atenolol (Tenormin.RTM.),
bisoprolol/hydrochlorothiazide (Ziac.RTM.), bisoprolol
(Zebeta.RTM.), esmolol (Brevibloc.RTM.), labetalol (Normodyne.RTM.,
Trandate.RTM.), nadolol (Corgard.RTM.), propranolol (Inderal.RTM.),
sotalol (Betapace.RTM.), and timolol (Blocadren.RTM.).
[0233] Examples of nitrates include, but are not limited to,
nitroglycerin, nitrate patches, isosorbide dinitrate, and
isosorbide-5-mononitrate.
[0234] Examples of calcium channel blockers include, but are not
limited to, bepridil (Vascor.RTM.), amlodipine (Norvasc.RTM.,
Lotrel.RTM.), diltiazem (Cardizem.RTM., Tiazac.RTM.), nifedipine
(Adalat.RTM., Procardia.RTM.), felodipine (Plendil.RTM.),
nisoldipine (Sular.RTM.), nimodipine (Nimotop.RTM.), verapamil
(Verelan.RTM., Calan.RTM., Isoptin.RTM.), and nicardipine.
[0235] Agents used to treat heart failure include ACE inhibitors,
diurectics, vasodilators, and cardiac glycosides. Examples of ACE
inhibitors include, but are not limited to, benazepril
(Lotensin.RTM.), captopril (Capoten.RTM.), enalapril
(Vasotec.RTM.), fosinopril (Monopril.RTM.), Lisinopril
(Prinivil.RTM., Zestril.RTM.), moexipril (Univasc.RTM.),
perindopril (Aceon.RTM.), quinapril (Accupril.RTM.), ramipril
(Altace.RTM.), and trandolapril (Mavik.RTM.).
[0236] Examples of diuretics include, but are not limited to,
furosemide (Lasix.RTM.), metolazone (Zaroxolyn.RTM.), bumetanide
(Bumex.RTM.), spironolactone (Aldactone.RTM.), eplerenone
(Inspra.RTM.), and hydrochlorothiazide.
[0237] Examples of vasodilators include, but are not limited to,
hydralazine, diazoxide, prazosin, clonidine, and methyldopa.
Nitrates, ACE inhibitors, potassium channel activators, and calcium
channel blockers may also act as vasodilators.
[0238] Examples of cardiac glycosides include, but are not limited
to, digoxin, digitoxin, and digitalis.
[0239] Examples of antithrombotics include, but are not limited to,
platelet inhibitors, anticoagulants, and thrombolytic agents.
[0240] Examples of platelet inhibitors include, but are not limited
to, clopidogrel (Plavix.RTM.), ticlopidine, acetyl salicylic acid
(aspirin), prasugrel (Effient.RTM.), cilostazol, dipyridamole,
persantine sulfinpyrazone, indomethacin, and glycoprotein IIb/IIa
inhibitors (such as abciximab, tirofiban, and eptifibatide
(Integrelin.RTM.).
[0241] Examples of anticoagulants include, but are not limited to,
warfarin (Coumadin.RTM.), unfractionated heparin, low molecular
weight heparin, danaparoid, lepirudin, argatroban, bivalirudin,
apixaban (Eliquis.RTM.), rivaroxaban, and edoxaban.
[0242] Examples of thrombolytic agents include, but are not limited
to, tissue plasminogen activator (t-PA), tenecteplase (TNK),
streptokinase, and urokinase.
[0243] Antiarrhythmic agents include, but are not limited to,
quinidine, procainamide, amiodarone, dronedarone, lidocaine, and
propafenone.
[0244] Antihypertensive agents include, but are not limited to,
alpha-1-adrenergic antagonists, such as prazosin (Minipress.RTM.),
doxazosin mesylate (Cardura.RTM.), prazosin hydrochloride
(Minipress.RTM.), prazosin, polythiazide (Minizide.RTM.), and
terazosin hydrochloride (Hytrin.RTM.); beta-adrenergic antagonists,
such as propranolol (Inderal.RTM.), nadolol (Corgard.RTM.), timolol
(Blocadren.RTM.), metoprolol (Lopres-sor.RTM.), and pindolol
(Visken.RTM.); central alpha-adrenoceptor agonists, such as
clonidine hydrochloride (Catapres.RTM.), clonidine hydrochloride
and chlorthalidone (Clorpres.RTM., Combipres.RTM.), guanabenz
Acetate (Wytensin.RTM.), guanfacine hydrochloride (Tenex.RTM.),
methyldopa (Aldomet.RTM.), methyldopa and chlorothiazide
(Aldoclor.RTM.), methyldopa and hydrochlorothiazide (Aldoril.RTM.);
combined alpha/beta-adrenergic antagonists, such as labetalol
(Normodyne.RTM., Trandate.RTM.), carvedilol (Coreg.RTM.);
adrenergic neuron blocking agents, such as guanethidine
(Ismelin.RTM.), reserpine (Serpasil.RTM.); central nervous
system-acting antihypertensives, such as clonidine (Catapres.RTM.),
methyldopa (Aldomet.RTM.), guanabenz (Wytensin.RTM.);
anti-angiotensin II agents; ACE inhibitors, such as perindopril
(Aceon.RTM.) captopril (Capoten.RTM.), enalapril (Vasotec.RTM.),
lisinopril (Prinivil.RTM., Zestril.RTM.); angiotensin-II receptor
antagonists, such as candesartan (Atacand.RTM.), eprosartan
(Teveten.RTM.), irbesartan (Avapro.RTM.), losartan (Cozaar.RTM.),
telmisartan (Micardis.RTM.), valsartan (Diovan.RTM.); calcium
channel blockers, such as verapamil (Calan.RTM., Isoptin.RTM.),
diltiazem (Cardizem.RTM.), nifedipine (Adalat.RTM.,
Procardia.RTM.); diuretics; direct vasodilators, such as
nitroprusside (Nipride.RTM.), diazoxide (Hyperstat.RTM. IV),
hydralazine (Apresoline.RTM.), minoxidil (Loniten.RTM.), verapamil;
and potassium channel activators, such as aprikalim, bimakalim,
cromakalim, emakalim, nicorandil, and pinacidil.
[0245] Lipid lowering agents can include, but are not limited to
bezafibrate (Bezalip.RTM.), ciprofibrate (Modalim.RTM.), and
statins, such as atorvastatin (Lipitor.RTM.), fluvastatin
(Lescol.RTM.), lovastatin (Mevacor.RTM., Altocor.RTM.), mevastatin,
pitavastatin (Livalo.RTM., Pitava.RTM.), pravastatin
(Lipostat.RTM.), rosuvastatin (Crestor.RTM.), and simvastatin
(Zocor.RTM.).
[0246] As used herein, examples of metabolic disorders include, but
are not limited to, diabetes (including type I and type II
diabetes), metabolic syndrome, dyslipidemia, obesity, glucose
intolerance, polycystic ovarian syndrome (PCOS), hypertension,
elevated serum cholesterol, and elevated triglycerides.
[0247] Examples of therapeutic agents that may be used to treat
metabolic disorders included, but are not limited to,
antihypertensive agents, lipid lowering agents, insulin,
sulfonylureas, biguanides, alpha-glucosidase inhibitors, and
incretin mimetics.
[0248] As used herein, the term "pulmonary disorder" refers to any
disease or condition related to the lungs. Examples of pulmonary
disorders include, but are not limited to, asthma, chronic
obstructive pulmonary disease (COPD), pulmonary hypertension,
emphysema, and bronchitis.
[0249] Examples of therapeutic agents that may be used to treat
pulmonary disorders include, but are not limited to,
corticosteroids, bronchodilators, and electrolyte supplements.
[0250] As used herein, the term "gastrointestinal disorder" refers
to diseases and conditions associated with the gastrointestinal
tract, including, but not limited to, gastroesophageal reflux
disease (GERD), inflammatory bowel disease (IBD), gastroenteritis,
peptic ulcer disease, pancreatitis, and gastritis.
[0251] Examples of therapeutic agents that may be used to treat
gastrointestinal disorders include, but are not limited to, proton
pump inhibitors, H2 blockers, prostaglandins, and antacids.
[0252] As used herein, the term "peripheral vascular disorder"
refers to disorders related to the blood vessels (arteries and
veins) located outside the heart and the brain, including, but not
limited to, peripheral arterial disease (PAD).
[0253] Pain disorders or conditions that can benefit from a
combination treatment of the 5-HT.sub.1A receptor agonists of
Formula I with other therapeutic agents include, without
limitation, pain, acute pain, postoperative pain, chronic pain,
nociceptive pain, cancer pain, neuropathic pain, psychogenic pain,
and the like. Agents used to treat such pain disorders include,
without limitation, cyclooxygenase-2 (COX-2) inhibitors, such as
celecoxib, valdecoxib, rofecoxib, and the like; opioids, such as
tramadol, and the like; serotonin-norepinephrine reuptake
inhibitors (SNRIs), such as milnacipran, and the like;
norepinephrine-dopamine reuptake inhibitor (NDRIs), such as
bupropion, and the like;
serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs),
such as venlafaxine, and the like; norepinephrine reuptake
inhibitors (NRIs) such as atomoxetine, and the like; dopamine
reuptake inhibitors (DARIs), such as methylphenidate, and the like;
nonsteroidal anti-inflammatory (NSAID) agents, such as
acetylsalicylic acid, naproxen, ibuprofen, indomethacine, and the
like; acetaminophen; and other agents known in the treatment of
pain.
[0254] In other embodiments, a patient presenting with a
psychological disorder or a movement disorder or the like may
suffer from second medical conditions and/or symptoms that may
benefit from the administration of one or more additional
therapeutic agents including, but not limited to antibiotics,
analgesics, antidepressants, and anti-anxiety agents.
[0255] The methods of combination therapy include co-administration
of a formulation containing one or more 5-HT.sub.1A receptor
agonists of Formula I and at least one additional therapeutic
agent, essentially contemporaneous administration of more than one
formulation comprising the 5-HT.sub.1A receptor agonist of Formula
I and the additional therapeutic agents or agents, and consecutive
administration
[0256] Thus, in another aspect, certain embodiments provide methods
for treating 5-HT.sub.1A receptor-mediated disorders in a human or
animal comprising administering to said subject an amount of a
compound disclosed herein effective to reduce or prevent said
disorder in the subject, in combination with at least one
additional agent for the treatment of said disorder. In a related
aspect, certain embodiments provide therapeutic pharmaceutical
compositions comprising at least one compound disclosed herein in
combination with one or more additional agents for the treatment of
5-HT.sub.1A receptor-mediated disorders.
[0257] General Synthetic Methods for Preparing Compounds
[0258] Isotopic hydrogen can be introduced into a compound as
disclosed herein by synthetic techniques that employ deuterated
reagents, whereby incorporation rates are pre-determined; and/or by
exchange techniques, wherein incorporation rates are determined by
equilibrium conditions, and may be highly variable depending on the
reaction conditions. Synthetic techniques, where tritium or
deuterium is directly and specifically inserted by tritiated or
deuterated reagents of known isotopic content, may yield high
tritium or deuterium abundance, but can be limited by the chemistry
required. Exchange techniques, on the other hand, may yield lower
tritium or deuterium incorporation, often with the isotope being
distributed over many sites on the molecule.
[0259] The compounds of Formula I as disclosed herein can be
prepared by methods known to one of skill in the art and routine
modifications thereof, and/or following procedures similar to those
described in the Example section herein and routine modifications
thereof, and/or procedures found in U.S. Pat. Nos. 6,020,345, and
7,208,603, which are hereby incorporated in their entirety, and
references cited therein and routine modifications thereof.
Compounds as disclosed herein can also be prepared as shown in any
of the following schemes and routine modifications thereof.
[0260] Compounds of Formula I may be prepared as shown in the
following reaction schemes and the description thereof, as well as
relevant literature procedures that may be used by one skilled in
the art. Exemplary reagents and procedures for these reactions
appear hereinafter and in the working Examples. Any position shown
as hydrogen may optionally be replaced with deuterium.
[0261] Specifically, compounds of Formula I, wherein X is
C--R.sub.21 may be prepared as showing in the following reaction
Schemes I-IV and the description thereof, as well as relevant
literature procedures that may be used by one skilled in the art.
Exemplary reagents and procedures for these reactions appear
hereinafter and in the working Examples. Any position shown as
hydrogen may optionally be replaced with deuterium.
##STR00040## ##STR00041## ##STR00042##
[0262] Deuterium can be incorporated into different positions
synthetically, according to the synthetic procedures as shown in
Scheme I, by using appropriate deuterated intermediates. For
example, to introduce deuterium at one or more positions of
R.sub.8-R.sub.15, compound 3 with the corresponding deuterium
substitutions can be used. To introduce deuterium at one or more
positions of R.sub.1-R.sub.5 and R.sub.19-R.sub.21, compound 14
with the corresponding deuterium substitutions can be used.
##STR00043## ##STR00044##
[0263] Deuterium can be incorporated into different positions
synthetically, according to the synthetic procedures as shown in
Scheme II, by using appropriate deuterated intermediates. For
example, to introduce deuterium at one or more positions of
R.sub.8-R.sub.15, compound 15 with the corresponding deuterium
substitutions can be used. To introduce deuterium at one or more
positions of R.sub.1-R.sub.5 and R.sub.19-R.sub.21, compound 14
with the corresponding deuterium substitutions can be used.
##STR00045## ##STR00046## ##STR00047##
[0264] Deuterium can be incorporated into different positions
synthetically, according to the synthetic procedures as shown in
Scheme III, by using appropriate deuterated intermediates. For
example, to introduce deuterium at one or more positions of
R.sub.8-R.sub.15, compound 19 with the corresponding deuterium
substitutions can be used. To introduce deuterium at
R.sub.6-R.sub.7, compound 12 with the corresponding deuterium
substitutions can be used. To introduce deuterium at one or more
positions of R.sub.1-R.sub.5 and R.sub.19-R.sub.21, compound 14
with the corresponding deuterium substitutions can be used.
##STR00048## ##STR00049## ##STR00050##
[0265] Deuterium can be incorporated into different positions
synthetically, according to the synthetic procedures as shown in
Scheme IV, by using appropriate deuterated intermediates. For
example, to introduce deuterium at one or more positions of
R.sub.8-R.sub.15, INT-A with the corresponding deuterium
substitutions can be used. INT-A can be prepared from starting
compound A. To introduce deuterium at R.sub.1-R.sub.5,
R.sub.4-R.sub.7, and R.sub.19-R.sub.21, compound 27 with the
corresponding deuterium substitutions and reagents DABCO can be
used.
[0266] Compounds of Formula I, wherein X is N may be prepared as
showing in the following reaction Scheme V and the description
thereof, as well as relevant literature procedures that may be used
by one skilled in the art. Exemplary reagents and procedures for
these reactions appear hereinafter and in the working Examples. Any
position shown as hydrogen may optionally be replaced with
deuterium.
##STR00051## ##STR00052##
[0267] Deuterium can be incorporated into different positions
synthetically, according to the synthetic procedures as shown in
Scheme V, by using appropriate deuterated intermediates. For
example, to introduce deuterium at one or more positions of
R.sub.8-R.sub.15, INT-A with the corresponding deuterium
substitutions can be used. To introduce deuterium at
R.sub.1-R.sub.5, R.sub.4-R.sub.7, and R.sub.19-R.sub.21, compound
28 with the corresponding deuterium substitutions and reagents
DABCO can be used.
[0268] Deuterium can be incorporated into various positions having
an exchangeable proton, such as the amide and amine N-Hs, via
proton-deuterium equilibrium exchange.
[0269] The invention is now described with reference to the
following examples. Before describing several exemplary embodiments
of the invention, it is to be understood that the invention is not
limited to the details of construction or process steps set forth
in the following description. The invention is capable of other
embodiments and of being practiced or being carried out in various
ways.
[0270] The following abbreviations may be employed in the Examples
and elsewhere herein:
[0271] DMA=dimethylacetamide
[0272] DMF=dimethylformamide
[0273] DMSO=dimethyl sulfoxide
[0274] DCM=dichloromethane
[0275] THF=tetrahydrofuran
[0276] TEA=triethylamine
[0277] LDA=lithium diisopropylamide
[0278] IBX=2-iodoxy benzoic acid
[0279] TosCl=4-toluene sulfonyl chloride
[0280] TBAC=tert-butyl acetate
[0281] L=liter
[0282] mL=milliliter
[0283] .mu.L-microliter
[0284] g=gram(s)
[0285] mg=milligram(s)
[0286] mol=moles
[0287] mmol=millimole(s)
[0288] h or hr=hour(s)
[0289] min=minute(s)
[0290] Equiv=equivalent(s)
[0291] H.sub.2=hydrogen
[0292] Ar=argon
[0293] N.sub.2=nitrogen
[0294] RT or R.T.=room temperature
[0295] AT=ambient temperature
[0296] Aq.=aqueous
[0297] HPLC=high performance liquid chromatography
[0298] HPLC R,=HPLC retention time
[0299] LC/MS=high performance liquid chromatography/mass
spectrometry
[0300] MS or Mass Spec=mass spectrometry
[0301] NMR=nuclear magnetic resonance
[0302] NMR spectral data: s=singlet; d=doublet; m=multiplet;
br=broad; t=triplet
[0303] mp=melting point
[0304] All IUPAC names were generated using PerkinElmer.RTM.'s
ChemDraw.
EXAMPLES
Example 1--Comparative
[0305]
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-methylpyridin-2-yl)methy-
l)amino)methyl) piperidin-1-yl)methanone [Befiradol]
##STR00053##
Step 1: 3-chloro-4-fluorobenzoyl chloride
##STR00054##
[0307] To a solution of 3-chloro-4-fluorobenzoic acid (15 g, 86.2
mmol, 1.00 equiv) in dichloromethane (150 mL) under an inert
atmosphere of nitrogen was added N,N-dimethylformamide (315 mg, 4.3
mmol, 0.05 equiv). Then thionyl chloride (50.8 g, 431 mmol, 5
equiv) was added at 0.degree. C. The reaction solution was stirred
for 4 h at 45.degree. C. The resulting mixture was concentrated
under vacuum to afford 15 g (91%) of 3-chloro-4-fluorobenzoyl
chloride as brown oil.
Step 2: 1-[(3-chloro-4-fluorophenyl)carbonyl]piperidin-4-one
##STR00055##
[0309] To a solution of piperidin-4-one hydrochloride (11.6 g, 86.3
mmol, 1.10 equiv) in dichloromethane (120 mL) under an inert
atmosphere of nitrogen was added triethylamine (12.1 g, 120 mmol,
2.00 equiv)) at 0.degree. C. This was followed by the addition of a
solution of 3-chloro-4-fluorobenzoyl chloride [Example 1, Step 1]
(15 g, 78.5 mmol, 1.00 equiv) in DCM (50 mL) dropwise with stirring
at 0.degree. C. in 15 min. The reaction solution was stirred for 1
h at room temperature. The reaction was quenched with water (200
mL). The resulting solution was extracted with dichloromethane
(3.times.200 mL), and the organic layers were combined. The organic
layers were washed with water (3.times.100 mL) and brine
(3.times.100 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:2) to
afford 17 g (85%) of
1-[(3-chloro-4-fluorophenyl)carbonyl]piperidin-4-one as a white
solid. LC-MS: m/z=256[M+H].sup.+.
Step 3:
6-[(3-chloro-4-fluorophenyl)carbonyl]-1-oxa-6-azaspiro[2.5]octane--
2-carbonitril
##STR00056##
[0311] To a solution of 1-[(3-chloro-4-fluorophenyl) carbonyl]
piperidin-4-one [Example 1, Step 2] (2 g, 7.8 mmol, 1.00 equiv) in
dichloromethane (20 mL) was added sodium hydroxide (30.5% in
H.sub.2O) (5.4 mL, 7.00 equiv), TBAC (108 mg, 0.38 mmol, 0.05
equiv) and 2-chloroacetonitrile (1.18 g, 15.6 mmol, 2.00 equiv) at
0.degree. C. The reaction solution was stirred for 1 h at room
temperature. The resulting solution was diluted with water (100
mL). The resulting solution was extracted with dichloromethane
(3.times.100 mL). The organic layers were washed with brine
(3.times.50 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum to afford 1.1 g (48%) of
6-[(3-chloro-4-fluorophenyl)carbonyl]-1-oxa-6-azaspiro[2.5]octane-2-carbo-
nitril as a brown solid. LC-MS: m/z=295[M+H].sup.+.
Step 4:
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-
-hydroxyacetonitrile
##STR00057##
[0313] To a 10-mL teflon reactor was added
6-[(3-chloro-4-fluorophenyl)carbonyl]-1-oxa-6-azaspiro[2.5]octane-2-carbo-
nitrile [Example 1, Step 3] (1.1 g, 3.7 mmol, 1.00 equiv) and
HF/pyridine (2 mL). The resulting solution was stirred overnight at
25.degree. C. The reaction was then quenched by the addition of
water (10 mL). The pH value of the solution was adjusted to 8-9
with potassium carbonate. The resulting solution was extracted with
DCM (3.times.30 mL). The organic layers were washed with water
(3.times.20 mL) and brine (3.times.20 mL). The mixture was dried
over anhydrous sodium sulfate and concentrated under vacuum to
afford 1 g (85%) of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-hydrox-
yacetonitrile as yellow oil. LC-MS: m/z=315[M+H].sup.+.
Step 5: tert-butyl N-[[5-methylpyridin-2-yl]methyl]carbamate
##STR00058##
[0315] To a solution of 5-methylpyridine-2-carbonitrile (3 g, 24.56
mmol, 1.00 equiv) in tetrahydrofuran (30 mL) was added LiAlH.sub.4
(1.4 g, 36.84 mmol, 1.50 equiv) at 0.degree. C. The resulting
solution was stirred for 30 min at 0.degree. C. This was followed
by the addition of H.sub.2O (30 mL), NaOH (2.95 g, 73.7 mmol, 3.00
equiv) and (Boc).sub.2O (8 g, 37 mmol, 1.50 equiv). The resulting
solution was stirred overnight at 25.degree. C. The resulting
solution was extracted with ethyl acetate (3.times.150 mL). The
organic layers were washed with water (3.times.50 mL) and brine
(3.times.50 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:9) to
afford 2 g (37%) of tert-butyl
N-[[5-methylpyridin-2-yl]methyl]carbamate as yellow oil. LC-MS:
m/z=223 [M+H].sup.+.
Step 6: [5-methylpyridin-2-yl]methanamine hydrochloride
##STR00059##
[0317] To a solution of tert-butyl
N-[[5-methylpyridin-2-yl]methyl]carbamate [Example 1, Step 5] (2 g,
9 mmol, 1.00 equiv) in dichloromethane (20 mL) was added hydrogen
chloride (4M in dioxane) (20 mL). The resulting solution was
stirred overnight at 25.degree. C. The resulting mixture was
concentrated under vacuum to afford 1 g (crude) of
[5-methylpyridin-2-yl]methanamine hydrochloride as a yellow
solid.
Step 7:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]met-
hyl)[(5-methylpyridin-2-yl)methyl]amine
##STR00060##
[0319] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-hydrox-
yacetonitrile [Example 1, Step 4] (500 mg, 1.59 mmol, 1.00 equiv)
in methanol (5 mL) was added (5-methylpyridin-2-yl)methanamine
hydrochloride [Example 1, Step 6] (377.38 mg, 2.39 mmol, 1.50
equiv), DABCO (624.2 mg, 5.57 mmol, 3.50 equiv), and Na(CN)BH.sub.3
(120 mg, 1.91 mmol, 1.20 equiv). The resulting solution was stirred
overnight at 25.degree. C. The resulting mixture was concentrated
under vacuum to remove methanol. The resulting solution was diluted
with ethyl acetate (50 mL). The organic layers were washed with
water (3.times.10 mL) and brine (3.times.10 mL). The mixture was
dried over anhydrous sodium sulfate and concentrated under vacuum.
The crude product was purified by Prep-HPLC with the following
conditions: Column, XBridge Prep OBD C18 Column, 19*250 mm; mobile
phase, Water (0.05% NH.sub.4HCO.sub.3) and ACN (33.0% ACN up to
53.0% in 7 min); Detector, UV 254/220 nm to afford 120 mg (20%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]methyl)
[(5-methylpyridin-2-yl)methyl]amine as a white solid.
[0320] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.33-8.30 (m,
1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.42 (m, 2H),
7.32-7.30 (m, 1H), 4.27-4.25 (m, 1H), 3.78 (s, 2H), 3.39-3.06 (m,
3H), 2.72-2.68 (m, 2H), 2.34 (s, 1H), 2.27 (s, 3H), 1.79-1.67 (m,
4H). LC-MS: m/z=394 [M+H].sup.+.
Example 2:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-methylpyridin-2-yl)m-
ethyl)amino)methyl-d.sub.2)piperidin-1-yl)methanone
##STR00061##
[0321] Step 1: methyl 5-methylpyridine-2-carboxylate
##STR00062##
[0323] To a solution of 5-methylpyridine-2-carbonitrile (5 g, 42.3
mmol, 1.00 equiv) in ethanol (40 mL) was added sulfuric acid (10
mL, 4.00 equiv). The resulting solution was stirred for 2 days at
80.degree. C. The reaction mixture was cooled to 25.degree. C. The
resulting mixture was concentrated under vacuum. The resulting
solution was diluted with water (100 mL). The pH value of the
solution was adjusted to 8-9 with potassium carbonate. The
resulting solution was extracted with ethyl acetate (3.times.100
mL). The organic layers were washed with water (3.times.50 mL) and
brine (3.times.50 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum to afford 3 g (43%) of methyl
5-methylpyridine-2-carboxylate as light yellow oil. LC-MS:
m/z=166[M+H].sup.+.
Step 2: (5-methylpyridin-2-yl)methanol
##STR00063##
[0325] To a solution of methyl 5-methylpyridine-2-carboxylate
[Example 2, Step 1] (3 g, 18.3 mmol, 1.00 equiv) in ethanol (20 mL)
and tetrahydrofuran (20 mL) was added CaCl.sub.2 (8.125 g, 549 mmol
4.00 equiv) and NaBH.sub.4 (1.38 g, 36.6 mmol, 2.00 equiv). The
resulting solution was stirred overnight at 50.degree. C. The
solids were filtered out. The filtrate was concentrated under
vacuum. The resulting solution was diluted with ethyl acetate (50
mL). The solids were filtered out. The filtrate was concentrated
under vacuum to afford 2.6 g (88.9%) of
(5-methylpyridin-2-yl)methanol as light yellow oil. LC-MS:
m/z=124[M+H].sup.+.
Step 3: 5-methylpyridine-2-carbaldehyde
##STR00064##
[0327] To a solution of (5-methylpyridin-2-yl)methanol [Example 2,
Step 2] (2 g, 16.24 mmol, 1.00 equiv) in chloroform (25 mL) was
added MnO.sub.2 (18.39 g, 211.53 mmol, 13.00 equiv). The mixture
was stirred overnight at 50.degree. C. The solids were filtered
out. The filtrate was concentrated under vacuum to afford 500 mg
(25%) of 5-methylpyridine-2-carbaldehyde as brown oil. LC-MS:
m/z=122[M+H].sup.+.
Step 4: ethyl 4-fluoropiperidine-4-carboxylate hydrochloride
##STR00065##
[0329] To a solution of 1-tert-butyl 4-ethyl
4-fluoropiperidine-1,4-dicarboxylate [Example 2, Step 3] (15 g,
54.48 mmol, 1.00 equiv) in dichloromethane (150 mL) was added
hydrogen chloride (4M in dioxane) (100 mL). The resulting solution
was stirred overnight at 25.degree. C. The resulting mixture was
concentrated under vacuum to afford 11 g (95%) of ethyl
4-fluoropiperidine-4-carboxylate hydrochloride as a white
solid.
Step 5: ethyl
1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidine-4-carboxylate
##STR00066##
[0331] To a solution of 4-fluoropiperidine-4-carboxylate
hydrochloride (11.8 g, 55.75 mmol, 1.10 equiv) in dichloromethane
(150 mL) was added TEA (10.29 g, 101.69 mmol, 2.00 equiv). This was
followed by the addition of a solution of 3-chloro-4-fluorobenzoyl
chloride (9.76 g, 50.57 mmol, 1.00 equiv) in dichloromethane (10
mL) dropwise with stirring at 0.degree. C. in 15 min. The resulting
solution was stirred for 1.5 h at 0.degree. C. The resulting
solution was diluted with dichloromethane (200 mL). The organic
layers were washed with water (3.times.100 mL) and brine
(3.times.100 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum to afford 18 g (crude) of
ethyl
1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidine-4-carboxylate
as a white solid. LC-MS: m/z=332[M+H].sup.+.
Step 6:
1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidine-4-carboxy-
lic acid
##STR00067##
[0333] To a solution of ethyl
1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidine-4-carboxylate
[Example 2, Step 5] (18.7 g, 56.37 mmol, 1.00 equiv) in water (100
mL) and tetrahydrofuran (100 mL) was added sodium hydroxide (6.78
g, 169.50 mmol, 3.00 equiv). The resulting solution was stirred
overnight at 25.degree. C. The resulting mixture was concentrated
under vacuum. The pH value of the solution was adjusted to 4-5 with
hydrogen chloride (1M). The solids were collected by filtration.
The solid was dried in an oven under reduced pressure to afford 14
g (82%) of
1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidine-4-carboxylic
acid as a white solid. LC-MS: m/z=304[M+H].sup.+.
Step 7:
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.s-
ub.2)methanol
##STR00068##
[0335] To a solution of tetrahydrofuran (100 mL) was added
1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidine-4-carboxylic
acid [Example 2, Step 6] (14.6 g, 48.08 mmol, 1.00 equiv). This was
followed by the addition of BD.sub.3 (1M in tetrahydrofuran) (96
mL, 2.00 equiv) dropwise with stirring at 0.degree. C. in 15 min.
The resulting solution was stirred overnight at 50.degree. C. The
reaction was then quenched by the addition of D.sub.2O (50 mL). The
resulting solution was extracted with ethyl acetate (3.times.100
mL). The organic layers were washed with water (3.times.50 mL) and
brine (3.times.50 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:1) to
afford 8 g (57%) of
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.sub.2)me-
thanol as a white solid. LC-MS: m/z=292 [M+H].sup.+.
Step 8:
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.s-
ub.2)methyl 4-methylbenzene-1-sulfonate
##STR00069##
[0337] To a solution of
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.sub.2)me-
thanol [Example 2, Step 7] (8 g, 27.41 mmol, 1.00 equiv) in
Pyridine (100 mL) was added TosCl (5.76 g, 30.27 mmol, 1.10 equiv)
at 0.degree. C. The resulting solution was stirred overnight at
50.degree. C. The reaction was then quenched by the addition of
D.sub.2O (50 mL). The resulting solution was extracted with
dichloromethane (3.times.150 mL). The organic layers were washed
with water (3.times.50 mL) and brine (3.times.50 mL). The mixture
was dried over anhydrous sodium sulfate and concentrated under
vacuum to afford 7 g (57%) of
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]
(d.sub.2)methyl 4-methylbenzene-1-sulfonate as yellow oil. LC-MS:
m/z=446 [M+H].sup.+.
Step 9:
2-([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](-
d.sub.2)methyl)-2,3-dihydro-1H-isoindole-1,3-dione
##STR00070##
[0339] To a solution of
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.sub.2)me-
thyl 4-methylbenzene-1-sulfonate [Example 2, Step 8] (7 g, 15.68
mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) was added
2-potassio-2,3-dihydro-1H-isoindole-1,3-dione (3.78 g, 20.44 mmol,
1.30 equiv). The resulting solution was stirred for 7 h at
150.degree. C. The reaction mixture was cooled to 25.degree. C. The
reaction was then quenched by the addition of water. The resulting
solution was extracted with dichloromethane (100 mL). The organic
layers were washed with water (3.times.100 mL) and brine
(3.times.100 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:1) to
afford 6.1 g (92%) of
2-([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]
(d.sub.2)methyl)-2,3-dihydro-1H-isoindole-1,3-dione as a light
yellow solid. LC-MS: m/z=421 [M+H].sup.+.
Step 10:
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.-
sub.2)methanamine
##STR00071##
[0341] To a solution of 2-aminoethan-1-ol (100 mL) was added
2-([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](.sup.2H-
2)methyl)-2,3-dihydro-1H-isoindole-1,3-dione [Example 2, Step 9]
(6.1 g, 14.52 mmol, 1.00 equiv). The resulting solution was stirred
for 2 h at 50.degree. C. The reaction mixture was cooled to
25.degree. C. The reaction was then quenched by the addition of
water. The resulting solution was extracted with dichloromethane
(100 mL). The organic layers were washed with water (3.times.100
mL) and brine (3.times.100 mL). The mixture was dried over
anhydrous sodium sulfate and concentrated under vacuum to afford 4
g (95%) of
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.sub.2)me-
thanamine as yellow oil. LC-MS: m/z=291 [M+H].sup.+.
Step 11:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](.-
sup.2H2)methyl)[(5-methylpyridin-2-yl)methyl]amine
##STR00072##
[0343] To a solution of
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](.sup.2H2)m-
ethanamine [Example 2, Step 10] (1 g, 3.44 mmol, 1.00 equiv) in
toluene (10 mL) was added 5-methylpyridine-2-carbaldehyde (417 mg,
3.44 mmol, 1.00 equiv). The resulting solution was stirred for 2 h
at 100.degree. C. The resulting mixture was concentrated under
vacuum to remove toluene. The residue was taken up in methanol (10
mL) and cooled to 0.degree. C., and NaBH.sub.4 (261.44 mg, 6.88
mmol, 2.00 equiv) was added in several portions. The resulting
solution was stirred overnight at 25.degree. C. The resulting
mixture was concentrated under vacuum to remove methanol. The
resulting solution was diluted with ethyl acetate (25 mL). The
organic layers were washed with water (3.times.10 mL) and brine
(3.times.10 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following conditions: Column,
XBridge Prep OBD C18 Column 5 um, 30.times.150 mm; mobile phase,
Water (10 mmol/L NH.sub.4HCO.sub.3) and ACN (32% ACN up to 48% in 7
min); Detector, UV 254/220 nm to afford 120 mg (9%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.sub.2)m-
ethyl)[(5-methylpyridin-2-yl)methyl]amine as a white solid.
[0344] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.33-8.32 (m,
1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.42 (m, 2H),
7.32-7.30 (m, 1H), 4.27-4.25 (m, 1H), 3.78 (s, 2H), 3.39-3.06 (m,
3H), 2.34 (s, 1H), 2.27 (s, 3H), 1.79-1.62 (m, 4H). LC-MS: m/z=396
[M+H].sup.+.
Example 3:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-(methyl-d.sub.3)pyri-
din-2-yl)methyl)amino) methyl)piperidin-1-yl)methanone
##STR00073##
[0345] Step 1: 5-(d.sub.3)methylpyridine-2-carbonitrile
##STR00074##
[0347] To a solution of 5-(bromomethyl)pyridine-2-carbonitrile (6
g, 30.48 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) was added
PPh.sub.3 (12 g, 45.72 mmol, 1.50 equiv). The resulting solution
was stirred overnight at 40.degree. C. This was followed by the
addition of D.sub.2O (100 mL) and KCN (2.4 g, 36.84 mmol, 1.20
equiv). The resulting solution was stirred overnight at 55.degree.
C. The resulting solution was diluted with ethyl acetate (300 mL).
The organic layers were washed with water (3.times.70 mL) and brine
(3.times.70 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (2:1) to
afford 3 g (81%) of 5-(d.sub.3)methylpyridine-2-carbonitrile as a
yellow solid. LC-MS: m/z=122[M+H].sup.+.
Step 2: tert-butyl
N-[[5-(d.sub.3)methylpyridin-2-yl]methyl]carbamate
##STR00075##
[0349] To a solution of 5-(d.sub.3)methylpyridine-2-carbonitrile
[Example 2, Step 1] (1 g, 8.25 mmol, 1.00 equiv) in tetrahydrofuran
(10 mL) was added LiAlH.sub.4 (472 mg, 12.44 mmol, 1.50 equiv) at
0.degree. C. The resulting solution was stirred for 30 min at
0.degree. C. This was followed by the addition of D.sub.2O (10 mL),
sodium hydroxide (331 mg, 8.28 mmol, 1.00 equiv) and (Boc).sub.2O
(2.702 g, 12.38 mmol, 1.50 equiv). The resulting solution was
stirred overnight at 25.degree. C. The resulting solution was
extracted with ethyl acetate (3.times.50 mL). The organic layers
were washed with water (3.times.10 mL) and brine (3.times.10 mL).
The mixture was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:9) to afford 1 g
(54%) of tert-butyl
N-[[5-(d.sub.3)methylpyridin-2-yl]methyl]carbamate as yellow
oil.
[0350] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.39 (s, 1H),
7.65-7.64 (m, 1H), 7.30-7.28 (m, 1H), 4.32 (s, 2H), 1.48 (s,
3H).
Step 3: [5-(d.sub.3)methylpyridin-2-yl]methanamine
hydrochloride
##STR00076##
[0352] To a solution of tert-butyl
N-[[5-(d.sub.3)methylpyridin-2-yl]methyl]carbamate [Example 2, Step
2] (1 g, 4.44 mmol, 1.00 equiv) in dichloromethane (10 mL) was
added hydrogen chloride (4M in dioxane) (10 mL). The resulting
solution was stirred overnight at 25.degree. C. The resulting
mixture was concentrated under vacuum to afford 800 mg (crude) of
[5-(d.sub.3)methylpyridin-2-yl]methanamine hydrochloride as a
yellow solid.
Step 4:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]met-
hyl)[(5-(d.sub.3)methylpyridin-2-yl)methyl]amine
##STR00077##
[0354] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-hydrox-
yacetonitrile [Example 1, Step 4] (600 mg, 1.91 mmol, 1.00 equiv)
in methanol (5 mL) was added
[5-(d.sub.3)methylpyridin-2-yl]methanamine hydrochloride [Example
2, Step 3] (461.46 mg, 2.87 mmol, 1.50 equiv), DABCO (749 mg, 6.68
mmol, 3.50 equiv) and Na(CN)BH.sub.3 (144 mg, 2.29 mmol, 1.20
equiv). The resulting solution was stirred overnight at 25.degree.
C. The resulting mixture was concentrated under vacuum to remove
methanol. The resulting solution was diluted with ethyl acetate (50
mL). The organic layers were washed with water (3.times.10 mL) and
brine (3.times.10 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following: Column, XBridge Prep OBD
C18 Column 5 um, 19.times.150 mm; mobile phase, Water (10 mmol/L
NH.sub.4HCO.sub.3) and ACN (32% ACN up to 35% in 12 min); Detector,
UV 254/220 nm to afford 150 mg (20%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]methyl)
[(5-(d.sub.3)methylpyridin-2-yl)methyl]amine as a white solid.
[0355] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.33-8.32 (m,
1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.42 (m, 2H),
7.32-7.30 (m, 1H), 4.27-4.25 (m, 1H), 3.78 (s, 2H), 3.39-3.06 (m,
3H), 2.72-2.67 (m, 2H), 2.34 (s, 1H), 1.79-1.62 (m, 4H). LC-MS:
m/z=397 [M+H].sup.+.
Example 4:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-(methyl-d.sub.3)pyri-
din-2-yl)methyl-d.sub.2)amino)methyl)piperidin-1-yl)methanone
##STR00078##
[0356] Step 1: tert-butyl
N-[[5-(d.sub.3)methylpyridin-2-yl](.sup.2H.sub.2)methyl]carbamate
##STR00079##
[0358] To a solution of 5-(d.sub.3)methylpyridine-2-carbonitrile
[Example 3, Step 1] (1 g, 8.25 mmol, 1.00 equiv) in tetrahydrofuran
(10 mL) was added LiAlD.sub.4 (521 mg, 12.39 mmol, 1.50 equiv) at
0.degree. C. The resulting solution was stirred for 30 min at
0.degree. C. This was followed by the addition of D.sub.2O (10 mL),
NaOD (3M in D.sub.2O) (2.75 mL, 8.25 mmol, 1.00 equiv), and
(Boc).sub.2O (2.702 g, 12.38 mmol, 1.50 equiv). The resulting
solution was stirred overnight at 25.degree. C. The resulting
solution was extracted with ethyl acetate (3.times.50 mL). The
organic layers were washed with water (3.times.10 mL) and brine
(3.times.10 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:9) to
afford 1 g (54%) of tert-butyl
N-[[5-(.sup.2H.sub.3)methylpyridin-2-yl](.sup.2H.sub.2)methyl]carbamate
as yellow oil. LC-MS: m/z=228 [M+H].sup.+.
Step 2: [5-(d.sub.3)methylpyridin-2-yl] (d.sub.2)methanamine
hydrochloride
##STR00080##
[0360] To a solution of tert-butyl
N-[[5-(.sup.2H.sub.3)methylpyridin-2-yl](.sup.2H.sub.2)methyl]carbamate
[Example 4, Step 1] (1 g, 4.44 mmol, 1.00 equiv) in dichloromethane
(10 mL) was added hydrogen chloride (4M in dioxane) (10 mL). The
resulting solution was stirred overnight at 25.degree. C. The
resulting mixture was concentrated under vacuum to afford 800 mg
(crude) of
[5-(.sup.2H.sub.3)methylpyridin-2-yl](.sup.2H.sub.2)methanamine
hydrochloride as a yellow solid.
Step 3:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]met-
hyl)[(5-(d.sub.3)methylpyridin-2-yl)(d.sub.2)methyl]amine
##STR00081##
[0362] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-hydrox-
yacetonitrile (600 mg, 1.91 mmol, 1.00 equiv) [Example 1, Step 4]
in methanol (5 mL) was added
[5-(d.sub.3)methylpyridin-2-yl](d.sub.2)methanamine hydrochloride
[Example 4, Step 2] (467.0 mg, 2.87 mmol, 1.50 equiv), DABCO (749
mg, 6.68 mmol, 3.50 equiv), and Na(CN)BH.sub.3 (144 mg, 2.29 mmol,
1.20 equiv). The resulting solution was stirred overnight at
25.degree. C. The resulting mixture was concentrated under vacuum
to remove methanol. The resulting solution was diluted with ethyl
acetate (50 mL). The organic layers were washed with water
(3.times.10 mL) and brine (3.times.10 mL). The mixture was dried
over anhydrous sodium sulfate and concentrated under vacuum. The
crude product was purified by Prep-HPLC with the following: Column,
XBridge Prep OBD C18 Column 5 um, 19.times.150 mm; mobile phase,
Water (10 mmol/L NH.sub.4HCO.sub.3) and ACN (32% ACN up to 35% in
12 min); Detector, UV 254/220 nm to afford 160 mg (21%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]methyl)
[(5-(.sup.2H.sub.3)methylpyridin-2-yl)(.sup.2H.sub.2)methyl]amine
as a white solid.
[0363] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.33-8.32 (m,
1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.42 (m, 2H),
7.32-7.30 (m, 1H), 4.27-4.25 (m, 1H), 3.39-3.06 (m, 3H), 2.72-2.67
(m, 2H), 2.34 (s, 1H), 1.79-1.62 (m, 4H). LC-MS: m/z=399
[M+H].sup.+.
Example 5:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-methylpyridin-2-yl)m-
ethyl-d.sub.2)amino) methyl)piperidin-1-yl)methanone
##STR00082##
[0364] Step 1: tert-butyl
N-[[5-methylpyridin-2-yl](d.sub.2)methyl]carbamate
##STR00083##
[0366] To a solution of 5-methylpyridine-2-carbonitrile (2.2 g,
18.6 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) was added
LiAlD.sub.4 (1.17 g, 27.9 mmol, 1.50 equiv) at 0.degree. C. The
resulting solution was stirred for 30 min at 0.degree. C. This was
followed by the addition of D.sub.2O (30 mL), NaOD (3M in D.sub.2O)
(18.6 mL, 55.8 mmol, 3.00 equiv), and (Boc).sub.2O (5.5 g, 25 mmol,
1.50 equiv). The resulting solution was stirred overnight at
25.degree. C. The resulting solution was extracted with ethyl
acetate (3.times.150 mL). The organic layers were washed with water
(3.times.50 mL) and brine (3.times.50 mL). The mixture was dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:14) to afford 2 g (53%) of tert-butyl
N-[[5-methylpyridin-2-yl](d.sub.2)methyl]carbamate as yellow oil.
LC-MS: m/z=225 [M+H].sup.+.
Step 2: [5-methylpyridin-2-yl](d.sub.2)methanamine
hydrochloride
##STR00084##
[0368] To a solution of tert-butyl
N-[[5-methylpyridin-2-yl](d.sub.2)methyl]carbamate [Example 4, Step
1] (2 g, 8.9 mmol, 1.00 equiv) in dichloromethane (20 mL) was added
hydrogen chloride (4M in dioxane) (20 mL). The resulting solution
was stirred overnight at 25.degree. C. The resulting mixture was
concentrated under vacuum to afford 1.35 g (crude) of
[5-methylpyridin-2-yl](d.sub.2)methanamine hydrochloride as a
yellow solid.
Step 3:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]met-
hyl)[(5-methylpyridin-2-yl)(d.sub.2)methyl]amine
##STR00085##
[0370] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-hydrox-
yacetonitrile [Example 1, Step 4] (500 mg, 1.59 mmol, 1.00 equiv)
in methanol (5 mL) was added
(5-methylpyridin-2-yl)(2H.sub.2)methanamine [Example 4, Step 2]
(382.17 mg, 2.4 mmol, 1.50 equiv), DABCO (624.2 mg, 5.57 mmol, 3.50
equiv) and Na(CN)BH.sub.3 (120 mg, 1.91 mmol, 1.20 equiv). The
resulting solution was stirred overnight at 25.degree. C. The
resulting mixture was concentrated under vacuum to remove methanol.
The resulting solution was diluted with ethyl acetate (50 mL). The
organic layers were washed with water (3.times.10 mL) and brine
(3.times.10 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following conditions: Column,
XBridge Prep OBD C18 Column, 19*250 mm; mobile phase, Water (0.05%
NH.sub.4HCO.sub.3) and ACN (36.0% ACN up to 50.0% in 7 min);
Detector, UV 254/220 nm to afford 140 mg (22%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]methyl)
[(5-methylpyridin-2-yl)(d.sub.2) methyl]amine as a white solid.
[0371] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.33-8.30 (m,
1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.42 (m, 2H),
7.32-7.30 (m, 1H), 4.26-4.25 (m, 1H), 3.39-3.06 (m, 3H), 2.72-2.68
(m, 2H), 2.34 (s, 1H), 2.27 (s, 3H), 1.79-1.64 (m, 4H). LC-MS:
m/z=396 [M+H].sup.+.
Example 6:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-(methyl-d.sub.3)pyri-
din-2-yl)methyl-d.sub.2)amino)
methyl-d.sub.2)piperidin-1-yl)methanone
##STR00086##
[0372] Step 1: methyl 5-(d.sub.3)methylpyridine-2-carboxylate
##STR00087##
[0374] To a solution of 5-(d.sub.3)methylpyridine-2-carbonitrile
[Example 3, Step 1] (1.2 g, 9.92 mmol, 1.00 equiv) in ethanol (40
mL) was added D.sub.2SO.sub.4 (15 mL, 4.00 equiv). The resulting
solution was stirred for 2 days at 80.degree. C. The reaction
mixture was cooled to 25.degree. C. with a water bath. The
resulting mixture was concentrated under vacuum. The resulting
solution was diluted with water (100 mL). The pH value of the
solution was adjusted to 8-9 with potassium carbonate. The
resulting solution was extracted with ethyl acetate (3.times.100
mL). The organic layers were washed with water (3.times.50 mL) and
brine (3.times.50 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum to afford 1.2 g (72%) of
methyl 5-(.sup.2H.sub.3)methylpyridine-2-carboxylate as light
yellow oil. LC-MS: m/z=169[M+H].sup.+.
Step 2: [5-(d.sub.3)methylpyridin-2-yl](d.sub.2)methanol
##STR00088##
[0376] To a solution of methyl
5-(d.sub.3)methylpyridine-2-carboxylate [Example 6, Step 1] (1.2 g,
7.14 mmol, 1.00 equiv) in ethanol (20 mL) and tetrahydrofuran (20
mL) was added CaCl.sub.2 (3.16 g, 28.5 mmol 4.00 equiv) and
NaBD.sub.4 (600 mg, 14.3 mmol, 2.00 equiv). The resulting solution
was stirred overnight at 50.degree. C. The solids were filtered
out. The filtrate was concentrated under vacuum. The resulting
solution was diluted with ethyl acetate (50 mL). The solids were
filtered out. The filtrate was concentrated under vacuum to afford
800 mg (87.5%) of
[5-(.sup.2H.sub.3)methylpyridin-2-yl](.sup.2H.sub.2)methanol as
light yellow oil. LC-MS: m/z=129[M+H].sup.+.
Step 3: [5-(d.sub.3)methylpyridin-2-yl](d)formaldehyde
##STR00089##
[0378] To a solution of
[5-(d.sub.3)methylpyridin-2-yl](d.sub.2)methanol [Example 6, Step
2] (800 mg, 6.25 mmol, 1.00 equiv) in chloroform (10 mL) was added
MnO.sub.2 (7.07 g, 81.25 mmol, 13.00 equiv). The mixture was
stirred overnight at 50.degree. C. The solids were filtered out.
The filtrate was concentrated under vacuum to afford 200 mg (25%)
of [5-(d.sub.3)methylpyridin-2-yl](d)formaldehyde as brown oil.
LC-MS: m/z=126[M+H].sup.+.
Step 4:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.-
sub.2)methyl)[(5-(d.sub.3)methylpyridin-2-yl)(d.sub.2)methyl]amine
##STR00090##
[0380] To a solution of
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.sub.2)me-
thanamine [Example 2, Step 10] (464 mg, 1.6 mmol, 1.00 equiv) in
toluene (10 mL) was added
[5-(d.sub.3)methylpyridin-2-yl](d)formaldehyde [Example 6, Step 3]
(200 mg, 1.6 mmol, 1.00 equiv). The resulting solution was stirred
for 2 h at 100.degree. C. The resulting mixture was concentrated
under vacuum to remove toluene. The residue was taken up in
CD.sub.3OD (10 mL) and cooled to 0.degree. C., and NaBD.sub.4
(134.4 mg, 3.2 mmol, 2.00 equiv) was added in several portions. The
resulting solution was stirred overnight at 25.degree. C. The
resulting mixture was concentrated under vacuum to remove methanol.
The resulting solution was diluted with ethyl acetate (25 mL). The
organic layers were washed with water (3.times.10 mL) and brine
(3.times.10 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following conditions: Column,
XBridge Prep OBD C18 Column 5 um, 30.times.150 mm; mobile phase,
Water (10 mmol/L NH.sub.4HCO.sub.3) and ACN (32% ACN up to 48% in 7
min); Detector, UV 254/220 nm to afford 120 mg (18.7%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]
(d.sub.2)methyl)[(5-(d.sub.3)methylpyridin-2-yl)(d.sub.2)methyl]amine
as a white solid.
[0381] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.33-8.32 (m,
1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.42 (m, 2H),
7.32-7.30 (m, 1H), 4.27-4.25 (m, 1H), 3.39-3.06 (m, 3H), 2.34 (s,
1H), 1.79-1.62 (m, 4H). LC-MS: m/z=401 [M+H].sup.+.
Example 7:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperi-
din-4-yl] (d)methyl) [(5-methylpyridin-2-yl)methyl]amine
##STR00091##
[0382] Step 1: 1-benzyl(2,2,6,6-d.sub.4)piperidin-4-ol
##STR00092##
[0384] To a solution of CF.sub.3COOD (10.75 g, 93.48 mmol, 1.00
equiv) was added phenylmethanamine (10 g, 93.32 mmol, 1.00 equiv)
in several portions. The resulting solution was stirred for 30 min
at 25.degree. C. To this was added (d.sub.2)-formaldehyde (20% in
D.sub.2O) (34.40 g, 1.07 mol, 2.30 equiv). The resulting mixture
sonicated for 10 min and then stirred for 1 h at room temperature.
To the resulting clear solution was added
trimethyl(prop-2-en-1-yl)silane (11.72 g, 102.57 mmol, 1.10 equiv).
The resulting solution was stirred overnight at 40.degree. C. The
reaction mixture was cooled to 25.degree. C. The pH value of the
solution was adjusted to 9 with potassium carbonate. The resulting
solution was extracted with ethyl acetate (3.times.100 mL). The
organic layers were dried over anhydrous sodium sulfate and
concentrated under vacuum to afford 7 g (38%) of
1-benzyl(2,2,6,6-d.sub.4)piperidin-4-ol as yellow oil. LC-MS:
m/z=196[M+H].sup.+.
Step 2: (2,2,6,6-d.sub.4)piperidin-4-ol
##STR00093##
[0386] To a solution of 1-benzyl(2,2,6,6-d.sub.4)piperidin-4-ol
[Example 7, Step 1] (7 g, 35.84 mmol, 1.00 equiv) in methanol (100
mL) was added Pd(OH).sub.2/C (0.7 g). The flask was evacuated and
flushed three times with nitrogen, followed by flushing with
hydrogen. The mixture was stirred overnight at room temperature
under an atmosphere of hydrogen (4 atm.). The solids were filtered
out. The filtrate was concentrated under vacuum to afford 5 g
(crude) of (2,2,6,6-d.sub.4)piperidin-4-ol as yellow oil.
Step 3: tert-butyl
4-hydroxy(2,2,6,6-d.sub.4)piperidine-1-carboxylate
##STR00094##
[0388] To a solution of (2,2,6,6-d.sub.4)piperidin-4-ol [Example 7,
Step 2] (5 g, 47.55 mmol, 1.00 equiv) in DCM (60 mL) was added TEA
(11.06 g, 109.31 mmol, 2.30 equiv), and (Boc).sub.2O (12.45 g,
57.05 mmol, 1.20 equiv). The resulting solution was stirred
overnight at 25.degree. C. The resulting solution was diluted with
D.sub.2O. The resulting solution was extracted with DCM
(3.times.100 mL). The organic layers were washed with water
(3.times.50 mL) and brine (3.times.50 mL). The mixture was dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:1) to afford 2.5 g (26%) of tert-butyl
4-hydroxy(2,2,6,6-d.sub.4)piperidine-1-carboxylate as a white
solid.
[0389] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 3.80-3.87 (m,
1H), 1.83-1.87 (m, 2H), 1.71 (s, 1H), 1.46-1.51 (m, 11H).
Step 4: tert-butyl
4-oxo(2,2,6,6-d.sub.4)piperidine-1-carboxylate
##STR00095##
[0391] To a solution of tert-butyl
4-hydroxy(2,2,6,6-d.sub.4)piperidine-1-carboxylate [Example 7, Step
3] (2.5 g, 12.18 mmol, 1.00 equiv) in dichloromethane (70 mL) was
added 4A Sieve (3.75 g), NMO (2.15 g, 18.27 mmol, 1.50 equiv), and
TPAP (214.32 mg, 0.61 mmol, 0.05 equiv) at 0.degree. C. The
resulting solution was stirred for 1.5 h at 25.degree. C. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1:9) to afford 2.3 g (93%) of tert-butyl
4-oxo(2,2,6,6-d.sub.4)piperidine-1-carboxylate as a white
solid.
Step 5: (2,2,6,6-d.sub.4)piperidin-4-One Hydrochloride
##STR00096##
[0393] To a solution of tert-butyl
4-oxo(2,2,6,6-d.sub.4)piperidine-1-carboxylate [Example 7, Step 4]
(2.3 g, 11.31 mmol, 1.00 equiv) in DCM (25 mL) was added hydrogen
chloride (4M in dioxane) (25 mL). The resulting solution was
stirred overnight at 25.degree. C. The resulting mixture was
concentrated under vacuum to afford 2 g (crude) of
(2,2,6,6-d.sub.4)piperidin-4-one hydrochloride as light yellow
solid.
Step 6:
1-[(3-chloro-4-fluorophenyl)carbonyl](2,2,6,6-d.sub.4)piperidin-4--
one
##STR00097##
[0395] To a solution of (2,2,6,6-d.sub.4)piperidin-4-one
hydrochloride [Example 7, Step 5] (2 g, 14.32 mmol, 1.00 equiv) in
DCM (30 mL) was added TEA (2.65 g, 26.14 mmol, 2.00 equiv). This
was followed by the addition of a solution of
3-chloro-4-fluorobenzoyl chloride (3.02 g, 15.75 mmol, 1.10 equiv)
in DCM (10 mL) dropwise with stirring at 0.degree. C. in 15 min.
The resulting solution was stirred for 1.5 h at 0.degree. C. The
resulting solution was diluted with DCM (150 mL). The organic
layers were washed with water (3.times.25 mL) and brine (3.times.25
mL). The mixture was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:2) to afford 2 g
(54%) of
1-[(3-chloro-4-fluorophenyl)carbonyl](2,2,6,6-d.sub.4)piperidin-4-one
as a white solid. LC-MS: m/z=260[M+H].sup.+.
Step 7:
1-[(3-chloro-4-fluorophenyl)carbonyl](d.sub.8)piperidin-4-one
##STR00098##
[0397] To a solution of
1-[(3-chloro-4-fluorophenyl)carbonyl](2,2,6,6-d.sub.4)
piperidin-4-one [Example 7, Step 6] (1.9 g, 7.32 mmol, 1.00 equiv)
in CDCl.sub.3 (15 mL) was added TBD (71.3 mg, 0.512 mmol, 0.07
equiv). The resulting solution was stirred overnight at 25.degree.
C. The resulting mixture was concentrated under vacuum to afford
1.9 g (98%) of
1-[(3-chloro-4-fluorophenyl)carbonyl](.sup.2H.sub.8)piperidin-4-one
as a light yellow solid. LC-MS: m/z=264[M+H].sup.+.
Step 8:
6-[(3-chloro-4-fluorophenyl)carbonyl](d.sub.9)-1-oxa-6-azaspiro[2.-
5]octane-2-carbonitrile
##STR00099##
[0399] To a solution of
1-[(3-chloro-4-fluorophenyl)carbonyl](d.sub.8)piperidin-4-one
[Example 7, Step 7] (1.9 g, 7.20 mmol, 1.00 equiv) in DCM (25 mL)
was added NaOD (3M in D.sub.2O) (16.8 mL, 7.00 equiv), and TBAC
(100 mg, 0.05 equiv). This was followed by the addition of
2-chloroacetonitrile (1.08 g, 14.31 mmol, 2.00 equiv) dropwise with
stirring at 15.degree. C. in 15 min. The resulting solution was
stirred overnight at 25.degree. C. The resulting solution was
diluted with DCM (100 mL). The organic layers were washed with
water (3.times.20 mL) and brine (3.times.20 mL). The mixture was
dried over anhydrous sodium sulfate and concentrated under vacuum.
The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:2) to afford 800 mg (37%) of
6-[(3-chloro-4-fluorophenyl)carbonyl](.sup.2H.sub.9)-1-oxa-6-azaspiro[2.5-
]octane-2-carbonitrile as yellow oil. LC-MS:
m/z=304[M+H].sup.+.
Step 9:
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperidi-
n-4-yl]-2-hydroxy(d)acetonitrile
##STR00100##
[0401] To a 10-mL teflon reactor was added
6-[(3-chloro-4-fluorophenyl)carbonyl](d.sub.9)-1-oxa-6-azaspiro[2.5]octan-
e-2-carbonitrile [Example 7, Step 8] (700 mg, 2.30 mmol, 1.00
equiv) and HF/pyridine (2 mL). The resulting solution was stirred
overnight at 25.degree. C. The reaction was then quenched by the
addition of water (10 mL). The pH value of the solution was
adjusted to 8-9 with potassium carbonate. The resulting solution
was extracted with DCM (3.times.30 mL). The organic layers were
washed with water (3.times.20 mL) and brine (3.times.20 mL). The
mixture was dried over anhydrous sodium sulfate and concentrated
under vacuum to afford 300 mg (crude) of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperidin-4-yl]-
-2-hydroxy(.sup.2H)acetonitrile as yellow oil. LC-MS:
m/z=324[M+H].sup.+.
Step 10:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperidi-
n-4-yl](d)methyl)[(5-methylpyridin-2-yl)methyl]amine
##STR00101##
[0403] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperidin-4-yl]-
-2-hydroxy(.sup.2H)acetonitrile [Example 7, Step 9] (300 mg, 0.924
mmol, 1.00 equiv) in methanol (5 mL) was added
(5-methylpyridin-2-yl)methanamine hydrochloride [Example 1, Step 6]
(220.13 mg, 1.39 mmol, 1.50 equiv), DABCO (364.10 mg, 3.23 mmol,
3.50 equiv) and Na(CN)BH.sub.3 (70.00 mg, 1.11 mmol, 1.20 equiv).
The resulting solution was stirred overnight at 25.degree. C. The
resulting mixture was concentrated under vacuum to remove methanol.
The resulting solution was diluted with EA (50 mL). The organic
layers were washed with water (3.times.10 mL) and brine (3.times.10
mL). The mixture was dried over anhydrous sodium sulfate and
concentrated under vacuum. The crude product was purified by
Prep-HPLC with the following conditions: Column, Xselect CSH OBD
Column 30*150 mm; mobile phase, Water (0.05% TFA) and ACN (20.0%
ACN up to 30.0% in 7 min); Detector, UV 254/220 nm to afford 90 mg
(24%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperid-
in-4-yl](d)methyl)[(5-methylpyridin-2-yl)methyl]amine as a white
solid.
[0404] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.33-8.30 (m,
1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.42 (m, 2H),
7.32-7.30 (m, 1H), 3.78 (s, 2H), 2.72-2.64 (m, 1H), 2.34 (s, 1H),
2.27 (s, 3H). LC-MS: m/z=403 [M+H].sup.+.
Example 8--Comparative
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-methylpyrimidin-2-yl)methyl)ami-
no) methyl)piperidin-1-yl)methanone
##STR00102##
[0405] Step 1: 5-methylpyrimidine-2-carbonitrile
##STR00103##
[0407] To a solution of 5-bromopyrimidine-2-carbonitrile (2 g,
10.87 mmol, 1.00 equiv) in toluene (15 mL) under an inert
atmosphere of nitrogen was added
trimethyl-1,3,5,2,4,6-trioxatriborinane (975.4 mg, 16.31 mmol, 1.5
equiv), CsF (1.66 g, 21.74 mmol, 2.0 equiv),
K.sub.3PO.sub.4.3H.sub.2O (4 g, 29.89 mmol, 2.75 equiv) and
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (799.7 mg, 2.17 mmol, 0.2 equiv).
The reaction solution was stirred for 12 h at 100.degree. C. The
solid was filtered out. The filtrate was concentrated under vacuum.
The residue was purified by a silica gel column with ethyl
acetate/petroleum ether (1:1) to afford 0.5 g (38.6%) of
5-methylpyrimidine-2-carbonitrile as white solid. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.: 8.33 (s, 2H), 2.40 (s, 3H).
Step 2: (5-methylpyrimidin-2-yl)methanamine
##STR00104##
[0409] To a solution of 5-methylpyrimidine-2-carbonitrile [Example
8, Step 1] (900 mg, 7.56 mmol, 1.00 equiv) in methanol (15 mL) was
added Pd/C (45 mg). The flask was evacuated and flushed three times
with nitrogen, followed by flushing with hydrogen. The mixture was
stirred for 1 h at room temperature under an atmosphere of hydrogen
(3 atm). The solids were filtered out. The filtrate was
concentrated under vacuum to afford 900 mg (crude) of
(5-methylpyrimidin-2-yl)methanamine as brown oil. LC-MS: m/z=124
[M+H].sup.+.
Step 3: tert-butyl N-[(5-methylpyrimidin-2-yl)methyl]carbamate
##STR00105##
[0411] To a solution of (5-methylpyrimidin-2-yl)methanamine
[Example 8, Step 2] (900 mg, 7.34 mmol, 1.00 equiv) in
tetrahydrofuran (15 mL) was added TEA (3.7 g, 36.7 mmol, 5.00
equiv) and (Boc).sub.2O (1.92 g, 8.82 mmol, 1.50 equiv). The
resulting solution was stirred overnight at 25.degree. C. The
resulting solution was diluted with H.sub.2O (15 mL). The resulting
solution was extracted with ethyl acetate (3.times.50 mL). The
organic layers were washed with water (3.times.20 mL) and brine
(3.times.20 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was purified by
a silica gel column with ethyl acetate/petroleum ether (1:1) to
afford 600 mg (36.7%) of tert-butyl
N-[(5-methylpyrimidin-2-yl)methyl]carbamate as yellow solid. LC-MS:
m/z=224 [M+H].sup.+.
Step 4: (5-methylpyrimidin-2-yl)methanamine hydrochloride
##STR00106##
[0413] To a solution of tert-butyl
N-[(5-methylpyrimidin-2-yl)methyl]carbamate [Example 8, Step 3]
(600 mg, 2.69 mmol, 1.00 equiv) in dichloromethane (10 mL) was
added hydrogen chloride (4M in dioxane) (10 mL). The resulting
solution was stirred overnight at 25.degree. C. The resulting
mixture was concentrated under vacuum to afford 500 mg (crude) of
(5-methylpyrimidin-2-yl)methanamine hydrochloride as a yellow
solid. LC-MS: m/z=124 [M+H].sup.+.
Step 5:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]met-
hyl)[(5-methylpyrimidin-2-yl)methyl]amine
##STR00107##
[0415] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-hydrox-
yacetonitrile [Example 1, Step 4] (450 mg, 1.43 mmol, 1.00 equiv)
in methanol (5 mL) was added (5-methylpyrimidin-2-yl)methanamine
hydrochloride [Example 8, Step 4] (343.2 mg, 2.12 mmol, 1.50
equiv), DABCO (560.6 mg, 5.01 mmol, 3.50 equiv), and Na(CN)BH.sub.3
(108.0 mg, 1.72 mmol, 1.20 equiv). The resulting solution was
stirred overnight at 25.degree. C. The resulting mixture was
concentrated under vacuum to remove methanol. The resulting
solution was diluted with ethyl acetate (50 mL). The organic layers
were washed with water (3.times.10 mL) and brine (3.times.10 mL).
The mixture was dried over anhydrous sodium sulfate and
concentrated under vacuum. The crude product was purified by
Prep-HPLC with the following conditions: Column, XBridge Prep OBD
C18 Column, 19.times.250 mm; mobile phase, Water (0.05%
NH.sub.4HCO.sub.3) and ACN (39.0% ACN in 8 min); Detector, UV
254/220 nm to afford 140 mg (24.9%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]methyl)
[(5-methylpyrimidin-2-yl)methyl]amine as a white solid.
[0416] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.618-8.617 (m,
2H), 7.687-7.664 (m, 1H), 7.516-7.425 (m, 2H), 4.241 (m, 1H), 3.890
(s, 2H), 3.400-3.067 (m, 3H), 2.789-2.738 (m, 2H), 2.340 (s, 1H),
2.257 (s, 3H), 1.799-1.646 (m, 4H). LC-MS: m/z=395 [M+H].sup.+.
Example 9:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-methylpyrimidin-2-yl-
)methyl-d.sub.2)amino) methyl)piperidin-1-yl)methanone
##STR00108##
[0417] Step 1: 5-methylpyrimidine-2-carboxylic acid
##STR00109##
[0419] To a solution of 5-methylpyrimidine-2-carbonitrile [Example
8, Step 1] (2 g, 16.8 mmol, 1.00 equiv) in H.sub.2O (30 mL) was
added sodium hydroxide (1.01 g, 25.2 mmol, 1.50 equiv). The
resulting solution was stirred for 3 h at 50.degree. C. The pH
value of the solution was adjusted to 4-5 with HCl (3M). The
resulting mixture was concentrated under vacuum to remove H.sub.2O.
The resulting solution was diluted with methanol (50 mL). The
solids were collected by filtration. The filtrate was dried over
anhydrous sodium sulfate and concentrated under vacuum to afford 2
g (86.2%) of 5-methylpyrimidine-2-carboxylic acid as a white solid.
LC-MS: m/z=139[M+H].sup.+.
Step 2: methyl 5-methylpyrimidine-2-carboxylate
##STR00110##
[0421] To a solution of methanol (50 mL) was added SOCl.sub.2 (5.17
g, 43.5 mmol, 3.00 equiv) dropwise at 0.degree. C. The resulting
solution was stirred for 0.5 h at 25.degree. C. This was followed
by the addition of 5-methylpyrimidine-2-carboxylic acid [Example 9,
Step 1] (2 g, 14.5 mmol, 1.00 equiv). The resulting solution was
stirred for 1 h at 65.degree. C. The resulting mixture was
concentrated under vacuum to remove methanol and SOCl.sub.2. The
resulting solution was diluted with H.sub.2O (30 mL). The resulting
solution was extracted with ethyl acetate (3.times.30 mL). The
organic layers were dried over anhydrous sodium sulfate and
concentrated under vacuum to afford 2 g (90.7%) of methyl
5-methylpyrimidine-2-carboxylate as a yellow solid. LC-MS: m/z=153
[M+H].sup.+.
Step 3: (5-methylpyrimidin-2-yl)(d.sub.2)methanol
##STR00111##
[0423] To a solution of methyl 5-methylpyrimidine-2-carboxylate
[Example 9, Step 2] (2 g, 13.2 mmol, 1.00 equiv) in MeOD (30 mL)
was added NaBD.sub.4 (1.66 g, 39.2 mmol, 3.00 equiv) at 0.degree.
C. The resulting solution was stirred for 3 h at 25.degree. C. The
reaction was then quenched by the addition of D.sub.2O (10 mL). The
resulting mixture was concentrated under vacuum to remove MeOD. The
resulting solution was extracted with ethyl acetate (3.times.20
mL). The organic layers were dried over anhydrous sodium sulfate
and concentrated under vacuum to afford 1.5 g (90.2%) of
(5-methylpyrimidin-2-yl)(d.sub.2)methanol as a yellow solid. LC-MS:
m/z=127[M+H].sup.+.
Step 4: 2-[bromo(d.sub.2)methyl]-5-methylpyrimidine
##STR00112##
[0425] To a solution of (5-methylpyrimidin-2-yl)(d.sub.2)methanol
[Example 9, Step 3] (1.5 g, 11.9 mmol, 1.00 equiv) in DCM (20 mL)
was added PPh.sub.3 (3.12 g, 11.9 mmol, 1.00 equiv) and NBS (2.12
g, 11.9 mmol, 1.00 equiv) at 0.degree. C. The resulting solution
was stirred for 1 h at 0.degree. C. The reaction was then quenched
by the addition of H.sub.2O (20 mL). The resulting solution was
extracted with DCM (3.times.20 mL). The organic layers were dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:2) to afford 700 mg (31.3%) of
2-[bromo(d.sub.2)methyl]-5-methylpyrimidine as a yellow oil. LC-MS:
m/z=189[M+H].sup.+.
Step 5: 2-(azido(d.sub.2)methyl)-5-methylpyrimidine
##STR00113##
[0427] To a solution of 2-[bromo(d.sub.2)methyl]-5-methylpyrimidine
[Example 9, Step 4] (700 mg, 3.72 mmol, 1.00 equiv) in DMF (10 mL)
was added NaN.sub.3 (605.1 mg, 9.31 mmol, 2.50 equiv). The
resulting solution was stirred for 1 h at 60.degree. C. The
reaction was then quenched by the addition of H.sub.2O (20 mL). The
resulting solution was extracted with ethyl acetate (3.times.20
mL). The organic layers were dried over anhydrous sodium sulfate
and concentrated under vacuum to afford 600 mg (crude) of
2-(azido(d.sub.2)methyl)-5-methylpyrimidine as a yellow oil. LC-MS:
m/z=152[M+H].sup.+.
Step 6: tert-butyl
N-[(5-methylpyrimidin-2-yl)(.sup.2H.sub.2)methyl]carbamate
##STR00114##
[0429] To a solution of 2-(azido(d.sub.2)methyl)-5-methylpyrimidine
[Example 9, Step 5] (600 mg, 3.97 mmol, 1.00 equiv) in
tetrahydrofuran (10 mL) and D.sub.2O (2.5 mL) was added PPh.sub.3
(1.35 g, 5.17 mmol, 1.30 equiv). The resulting solution was stirred
for 2.5 h at 70.degree. C. The reaction was then quenched by the
addition of D.sub.2O (5 mL). This was followed by the addition of
D.sub.2O (2.5 mL), NaOD (3M in D.sub.2O) (1.99 mL, 5.96 mmol, 1.50
equiv) and (Boc).sub.2O (1.30 g, 5.96 mmol, 1.50 equiv). The
resulting solution was stirred overnight at 25.degree. C. The
resulting solution was extracted with ethyl acetate (3.times.30
mL). The organic layers were washed with water (3.times.15 mL) and
brine (3.times.15 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:20) to
afford 500 mg (56%) of tert-butyl
N-[(5-methylpyrimidin-2-yl)(d.sub.2)methyl]carbamate as yellow oil.
LC-MS: m/z=226 [M+H].sup.+.
Step 7: (5-methylpyrimidin-2-yl)(.sup.2H.sub.2)methanamine
hydrochloride
##STR00115##
[0431] To a solution of tert-butyl
N-[(5-methylpyrimidin-2-yl)(d.sub.2)methyl]carbamate [Example 9,
Step 6] (500 mg, 2.22 mmol, 1.00 equiv) in dichloromethane (5 mL)
was added hydrogen chloride (4M in dioxane) (5 mL). The resulting
solution was stirred overnight at 25.degree. C. The resulting
mixture was concentrated under vacuum to afford 500 mg (crude) of
(5-methylpyrimidin-2-yl)(d.sub.2)methanamine hydrochloride as a
yellow solid. LC-MS: m/z=126 [M+H].sup.+.
Step 8:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]met-
hyl)[(5-methylpyrimidin-2-yl)(d.sub.2)methyl]amine
##STR00116##
[0433] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-hydrox-
yacetonitrile [Example 1, Step 4] (978 mg, 3.11 mmol, 1.00 equiv)
in methanol (15 mL) was added
(5-methylpyrimidin-2-yl)(d.sub.2)methanamine hydrochloride [Example
9, Step 7] (500 mg, 3.11 mmol, 1.00 equiv), DABCO (1.22 g, 10.89
mmol, 3.50 equiv) and Na(CN)BH.sub.3 (234.4 mg, 3.73 mmol, 1.20
equiv). The resulting solution was stirred overnight at 25.degree.
C. The resulting mixture was concentrated under vacuum to remove
methanol. The resulting solution was diluted with ethyl acetate (50
mL). The organic layers were washed with water (3.times.10 mL) and
brine (3.times.10 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following: Column, XBridge Prep OBD
C18 Column 5 um, 30.times.150 mm; mobile phase, Water (10 mmol/L
NH.sub.4HCO.sub.3) and ACN (34% ACN up to 34% in 7 min); Detector,
UV 254/220 nm to afford 150 mg (12%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]methyl)
[(5-methylpyrimidin-2-yl)(d.sub.2)methyl]amine as a white
solid.
[0434] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.621-8.620 (m,
2H), 7.687-7.664 (m, 1H), 7.517-7.427 (m, 2H), 4.247 (m, 1H),
3.400-3.079 (m, 3H), 2.787-2.734 (m, 2H), 2.335-2.245 (m, 4H),
1.803-1.650 (m, 4H). LC-MS: m/z=397 [M+H].sup.+.
Example 10:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-(methyl-d.sub.3)pyrimidin-2-yl-
)methyl)amino) methyl)piperidin-1-yl)methanone
##STR00117##
[0435] Step 1: 5-(bromomethyl)pyrimidine-2-carbonitrile
##STR00118##
[0437] To a solution of 5-methylpyrimidine-2-carbonitrile [Example
8, Step 2] (8 g, 40.4 mmol, 1.00 equiv) in CCl.sub.4(100 mL) was
added NBS (8.63 g, 48.5 mmol, 1.2 equiv) and BPO (488.8 mg, 2.02
mmol, 0.05 equiv). The resulting solution was stirred overnight at
80.degree. C. The resulting solution was diluted with H.sub.2O (100
mL). The resulting solution was extracted with DCM (3.times.100
mL). The organic layers were washed with water (3.times.70 mL) and
brine (3.times.70 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:1) to
afford 8 g (a mixture of 5-methylpyrimidine-2-carbonitrile and
5-(bromomethyl)pyrimidine-2-carbonitrile (1:1)) as a yellow solid.
LC-MS: m/z=197[M+H].sup.+.
Step 2: 5-(d.sub.3)methylpyrimidine-2-carbonitrile
##STR00119##
[0439] To a solution of the above mixture of
5-methylpyrimidine-2-carbonitrile and
5-(bromomethyl)pyrimidine-2-carbonitrile (1:1) [Example 10, Step 1]
(8 g, 1.00 equiv) in tetrahydrofuran (100 mL) was added PPh.sub.3
(15.9 g, 60.6 mmol, 1.50 equiv). The resulting solution was stirred
overnight at 40.degree. C. This was followed by the addition of
D.sub.2O (100 mL) and KCN (3.2 g, 36.84 mmol, 1.20 equiv). The
resulting solution was stirred overnight at 55.degree. C. The
resulting solution was diluted with ethyl acetate (300 mL). The
organic layers were washed with water (3.times.70 mL) and brine
(3.times.70 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (2:1) to
afford 700 mg of 5-(d)methylpyrimidine-2-carbonitrile as a yellow
solid. LC-MS: m/z=123 [M+H].sup.+.
[0440] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.69 (s, 2H).
Step 3: 5-(d.sub.3)methylpyrimidine-2-carboxylic acid
##STR00120##
[0442] To a solution of 5-(d.sub.3)methylpyrimidine-2-carbonitrile
[Example 10, Step 2] (700 mg, 5.74 mmol, 1.00 equiv) in D.sub.2O
(10 mL) was added NaOD (3M in D.sub.2O) (2.87 mL, 8.61 mmol, 1.50
equiv). The resulting solution was stirred for 3 h at 50.degree. C.
The pH value of the solution was adjusted to 4-5 with DCl (10% in
D.sub.2O). The resulting mixture was concentrated under vacuum to
remove D.sub.2O. The resulting solution was diluted with methanol
(50 mL). The solids were collected by filtration. The filtrate was
dried over anhydrous sodium sulfate and concentrated under vacuum
to afford 700 mg (86.4%) of
5-(d.sub.3)methylpyrimidine-2-carboxylic acid as a white solid.
LC-MS: m/z=142[M+H].sup.+.
Step 4: (d.sub.3)methyl
5-(d.sub.3)methylpyrimidine-2-carboxylate
##STR00121##
[0444] To a solution of MeOD (15 mL) was added SOCl.sub.2 (1.77 g,
14.89 mmol, 3.00 equiv) dropwise at 0.degree. C. The resulting
solution was stirred for 0.5 h at 25.degree. C. This was followed
by the addition of 5-(d.sub.3)methylpyrimidine-2-carboxylic acid
[Example 10, Step 3] (700 mg, 4.96 mmol, 1.00 equiv). The resulting
solution was stirred for 1 h at 65.degree. C. The resulting mixture
was concentrated under vacuum to remove MeOD and SOCl.sub.2. The
resulting solution was diluted with H.sub.2O (15 mL). The resulting
solution was extracted with ethyl acetate (3.times.15 mL). The
organic layers were dried over anhydrous sodium sulfate and
concentrated under vacuum to afford 700 mg (89.3%) of
(d.sub.3)methyl 5-(d.sub.3)methylpyrimidine-2-carboxylate as a
yellow solid. LC-MS: m/z=159[M+H].sup.+.
Step 5: [5-(d.sub.3)methylpyrimidin-2-yl]methanol
##STR00122##
[0446] To a solution of (d.sub.3)methyl
5-(d.sub.3)methylpyrimidine-2-carboxylate [Example 10, Step 4] (700
mg, 4.43 mmol, 1.00 equiv) in methanol (25 mL) was added NaBH.sub.4
(505.1 mg, 13.3 mmol, 3.00 equiv) at 0.degree. C. The resulting
solution was stirred for 3 h at 25.degree. C. The reaction was then
quenched by the addition of H.sub.2O (10 mL). The resulting mixture
was concentrated under vacuum to remove MeOH. The resulting
solution was extracted with ethyl acetate (3.times.10 mL). The
organic layers were dried over anhydrous sodium sulfate and
concentrated under vacuum to afford 500 mg (88.9%) of
[5-(d.sub.3)methylpyrimidin-2-yl]methanol as a yellow solid. LC-MS:
m/z=128[M+H].sup.+.
Step 6: 2-(bromomethyl)-5-(d.sub.3)methylpyrimidine
##STR00123##
[0448] To a solution of [5-(d.sub.3)methylpyrimidin-2-yl]methanol
[Example 10, Step 5] (500 mg, 3.94 mmol, 1.00 equiv) in DCM (10 mL)
was added PPh.sub.3 (1.03 g, 3.94 mmol, 1.00 equiv) and NBS (701.3
mg, 2.02 mmol, 1.00 equiv) at 0.degree. C. The resulting solution
was stirred for 1 h at 0.degree. C. The reaction was then quenched
by the addition of H.sub.2O (10 mL). The resulting solution was
extracted with DCM (3.times.10 mL). The organic layers were dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:2) to afford 300 mg (40.2%) of
2-(bromomethyl)-5-(d.sub.3)methylpyrimidine as a yellow oil. LC-MS:
m/z=190[M+H].sup.+.
Step 7: 2-(azidomethyl)-5-(.sup.2H.sub.3)methylpyrimidine
##STR00124##
[0450] To a solution of 2-(bromomethyl)-5-(d.sub.3)methylpyrimidine
(300 mg, 1.59 mmol, 1.00 equiv) [Example 10, Step 6] in DMF (8 mL)
was added NaN.sub.3 (258.4 mg, 3.98 mmol, 2.50 equiv). The
resulting solution was stirred for 1 h at 60.degree. C. The
reaction was then quenched by the addition of H.sub.2O (20 mL). The
resulting solution was extracted with ethyl acetate (3.times.20
mL). The organic layers were dried over anhydrous sodium sulfate
and concentrated under vacuum to afford 250 mg (crude) of
2-(azidomethyl)-5-(.sup.2H.sub.3)methylpyrimidine as a yellow oil.
LC-MS: m/z=153[M+H].sup.+.
Step 8: tert-butyl
N-[(5-(d.sub.3)methylpyrimidin-2-yl)methyl]carbamate
##STR00125##
[0452] To a solution of
2-(azidomethyl)-5-(.sup.2H.sub.3)methylpyrimidine [Example 10, Step
7] (250 mg, 1.64 mmol, 1.00 equiv) in tetrahydrofuran (8 mL) and
D.sub.2O (2 mL) was added PPh.sub.3 (560.2 mg, 2.14 mmol, 1.30
equiv). The resulting solution was stirred for 2.5 h at 70.degree.
C. The reaction was then quenched by the addition of D.sub.2O (4
mL). This was followed by the addition of D.sub.2O (2 mL), NaOD (3M
in D.sub.2O) (0.82 mL, 2.46 mmol, 1.50 equiv), and (Boc).sub.2O
(536.3 mg, 2.46 mmol, 1.50 equiv). The resulting solution was
stirred overnight at 25.degree. C. The resulting solution was
extracted with ethyl acetate (3.times.20 mL). The organic layers
were washed with water (3.times.10 mL) and brine (3.times.10 mL).
The mixture was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:20) to afford 300
mg (80.5%) of tert-butyl
N-[(5-(.sup.2H.sub.3)methylpyrimidin-2-yl)methyl]carbamate as
yellow oil. LC-MS: m/z=227 [M+H].sup.+.
Step 9: [5-(d.sub.3)methylpyrimidin-2-yl]methanamine
hydrochloride
##STR00126##
[0454] To a solution of tert-butyl
N-[(5-(d.sub.3)methylpyrimidin-2-yl)methyl]carbamate [Example 10,
Step 8] (300 mg, 1.33 mmol, 1.00 equiv) in dichloromethane (5 mL)
was added hydrogen chloride (4M in dioxane) (5 mL). The resulting
solution was stirred overnight at 25.degree. C. The resulting
mixture was concentrated under vacuum to afford 240 mg (crude) of
[5-(d.sub.3)methylpyrimidin-2-yl]methanamine hydrochloride as a
yellow solid.
Step 10:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]me-
thyl)[(5-(d.sub.3)methylpyrimidin-2-yl)methyl]amine
##STR00127##
[0456] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-hydrox-
yacetonitrile [Example 1, Step 4] (468 mg, 1.49 mmol, 1.00 equiv)
in methanol (5 mL) was added
[5-(d.sub.3)methylpyrimidin-2-yl]methanamine hydrochloride [Example
10, Step 9] (240 mg, 1.49 mmol, 1.00 equiv), DABCO (584 mg, 5.22
mmol, 3.50 equiv) and Na(CN)BH.sub.3 (112.3 mg, 1.79 mmol, 1.20
equiv). The resulting solution was stirred overnight at 25.degree.
C. The resulting mixture was concentrated under vacuum to remove
methanol. The resulting solution was diluted with ethyl acetate (50
mL). The organic layers were washed with water (3.times.10 mL) and
brine (3.times.10 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following: Column, XBridge Prep OBD
C18 Column 5 um, 19.times.150 mm; mobile phase, Water (10 mmol/L
NH.sub.4HCO.sub.3) and ACN (28% ACN up to 29% in 13 min); Detector,
UV 254/220 nm to afford 51 mg (8.6%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]methyl)
[(5-(d.sub.3)methylpyrimidin-2-yl)methyl]amine as a white
solid.
[0457] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.616 (s, 2H),
7.684-7.661 (m, 1H), 7.514-7.423 (m, 2H), 4.242 (m, 1H), 3.889 (s,
2H), 3.393-3.069 (m, 3H), 2.788-2.736 (m, 2H), 2.330-2.257 (m, 1H),
1.798-1.645 (m, 4H). LC-MS: m/z=398 [M+H].sup.+.
Example 11:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-(methyl-d.sub.3)pyrimidin-2-yl-
)methyl-d.sub.2) amino)methyl)piperidin-1-yl)methanone
##STR00128##
[0458] Step 1:
[5-(d.sub.3)methylpyrimidin-2-yl](.sup.2H.sub.2)methanol
##STR00129##
[0460] To a solution of (d.sub.3)methyl
5-(d.sub.3)methylpyrimidine-2-carboxylate [Example 10, Step 4] (1
g, 6.33 mmol, 1.00 equiv) in MeOD (15 mL) was added NaBD.sub.4
(797.5 mg, 19.00 mmol, 3.00 equiv) at 0.degree. C. The resulting
solution was stirred for 3 h at 25.degree. C. The reaction was then
quenched by the addition of D.sub.2O (5 mL). The resulting mixture
was concentrated under vacuum to remove MeOD. The resulting
solution was extracted with ethyl acetate (3.times.10 mL). The
organic layers were dried over anhydrous sodium sulfate and
concentrated under vacuum to afford 700 mg (85.7%) of
[5-(d.sub.3)methylpyrimidin-2-yl](.sup.2H.sub.2)methanol as a
yellow solid. LC-MS: m/z=130[M+H].sup.+.
Step 2:
2-[bromo(d.sub.2)methyl]-5-(.sup.2H.sub.3)methylpyrimidine
##STR00130##
[0462] To a solution of
[5-(d.sub.3)methylpyrimidin-2-yl](d.sub.2)methanol [Example 11,
Step 1] (700 mg, 5.42 mmol, 1.00 equiv) in DCM (10 mL) was added
PPh.sub.3 (1.42 g, 5.42 mmol, 1.00 equiv) and NBS (964.8 mg, 5.42
mmol, 1.00 equiv) at 0.degree. C. The resulting solution was
stirred for 1 h at 0.degree. C. The reaction was then quenched by
the addition of H.sub.2O (10 mL). The resulting solution was
extracted with DCM (3.times.15 mL). The organic layers were dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:2) to afford 180 mg (17.4%) of
2-[bromo(d.sub.2)methyl]-5-(d.sub.3)methylpyrimidine as a yellow
oil. LC-MS: m/z=192[M+H].sup.+.
Step 3: 2-[azido(d.sub.2)methyl]-5-(d.sub.3)methylpyrimidine
##STR00131##
[0464] To a solution of
2-[bromo(d.sub.2)methyl]-5-(d.sub.3)methylpyrimidine [Example 11,
Step 2](180 mg, 0.94 mmol, 1.00 equiv) in DMF (5 mL) was added
NaN.sub.3 (153.1 mg, 2.36 mmol, 2.50 equiv). The resulting solution
was stirred for 1 h at 60.degree. C. The reaction was then quenched
by the addition of H.sub.2O (10 mL). The resulting solution was
extracted with ethyl acetate (3.times.10 mL). The organic layers
were dried over anhydrous sodium sulfate and concentrated under
vacuum to afford 100 mg (crude) of
2-[azido(.sup.2H.sub.2)methyl]-5-(.sup.2H.sub.3)methylpyrimidine as
a yellow oil. LC-MS: m/z=155[M+H].sup.+.
Step 4: tert-butyl
N-[(5-(d.sub.3)methylpyrimidin-2-yl)(d.sub.2)methyl]carbamate
##STR00132##
[0466] To a solution of
2-[azido(d.sub.2)methyl]-5-(d.sub.3)methylpyrimidine [Example 11,
Step 3](100 mg, 0.65 mmol, 1.00 equiv) in tetrahydrofuran (4 mL)
and D.sub.2O (1 mL) was added PPh.sub.3 (221.2 mg, 0.84 mmol, 1.30
equiv). The resulting solution was stirred for 2.5 h at 70.degree.
C. The reaction was then quenched by the addition of D.sub.2O (2
mL). This was followed by the addition of D.sub.2O (1 mL), NaOD (3M
in D.sub.2O) (0.33 mL, 0.96 mmol, 1.50 equiv) and (Boc).sub.2O
(212.56 mg, 0.96 mmol, 1.50 equiv). The resulting solution was
stirred overnight at 25.degree. C. The resulting solution was
extracted with ethyl acetate (3.times.10 mL). The organic layers
were washed with water (3.times.5 mL) and brine (3.times.5 mL). The
mixture was dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:20) to afford 120 mg (81%) of
tert-butyl
N-[(5-(d.sub.3)methylpyrimidin-2-yl)(d.sub.2)methyl]carbamate as
yellow oil. LC-MS: m/z=229 [M+H].sup.+.
Step 5: [5-(d.sub.3)methylpyrimidin-2-yl](d.sub.2)methanamine
hydrochloride
##STR00133##
[0468] To a solution of tert-butyl
N-[(5-(d.sub.3)methylpyrimidin-2-yl)(d.sub.2)methyl]carbamate
[Example 11, Step 4] (120 mg, 0.53 mmol, 1.00 equiv) in
dichloromethane (5 mL) was added hydrogen chloride (4M in dioxane)
(5 mL). The resulting solution was stirred overnight at 25.degree.
C. The resulting mixture was concentrated under vacuum to afford
100 mg (crude) of
[5-(d.sub.3)methylpyrimidin-2-yl](d.sub.2)methanamine hydrochloride
as a yellow solid.
Step 6:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]met-
hyl)[(5-(d.sub.3)methylpyrimidin-2-yl)(d.sub.2)methyl]amine
##STR00134##
[0470] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]-2-hydrox-
yacetonitrile [Example 1, Step 4] (211.3 mg, 0.67 mmol, 1.10 equiv)
in methanol (5 mL) was added
[5-(d.sub.3)methylpyrimidin-2-yl](d.sub.2)methanamine hydrochloride
[Example 11, Step 5](100 mg, 0.61 mmol, 1.00 equiv), DABCO (239.1
mg, 2.14 mmol, 3.50 equiv), and Na(CN)BH.sub.3 (46.0 mg, 0.73 mmol,
1.20 equiv). The resulting solution was stirred overnight at
25.degree. C. The resulting mixture was concentrated under vacuum
to remove methanol. The resulting solution was diluted with ethyl
acetate (30 mL). The organic layers were washed with water
(3.times.5 mL) and brine (3.times.5 mL). The mixture was dried over
anhydrous sodium sulfate and concentrated under vacuum. The crude
product was purified by Prep-HPLC with the following: Column,
XBridge Prep OBD C18 Column 5 um, 30.times.150 mm; mobile phase,
Water (10 mmol/L NH.sub.4HCO.sub.3) and ACN (27% ACN up to 27% in
13.5 min); Detector, UV 254/220 nm to afford 46 mg (18.9%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl]methyl)[(5-
-(d.sub.3)methylpyrimidin-2-yl)(d.sub.2)methyl]amine as a white
solid.
[0471] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.617 (s, 2H),
7.684-7.661 (m, 1H), 7.514-7.423 (m, 2H), 4.241 (m, 1H),
3.395-3.067 (m, 3H), 2.781-2.728 (m, 2H), 2.316-2.257 (m, 1H),
1.797-1.631 (m, 4H). LC-MS: m/z=400 [M+H].sup.+.
Example 12:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-methylpyrimidin-2-yl)methyl)am-
ino)methyl-d.sub.2)piperidin-1-yl)methanone
##STR00135##
[0472] Step 1: (5-methylpyrimidin-2-yl)methanol
##STR00136##
[0474] To a solution of methyl 5-methylpyrimidine-2-carboxylate
[Example 9, Step 2] (2.5 g, 16.4 mmol, 1.00 equiv) in methanol (40
mL) was added NaBH.sub.4 (1.87 g, 49.3 mmol, 3.00 equiv) at
0.degree. C. The resulting solution was stirred for 3 h at
25.degree. C. The reaction was then quenched by the addition of
H.sub.2O (40 mL). The resulting mixture was concentrated under
vacuum to remove MeOH. The resulting solution was extracted with
ethyl acetate (3.times.50 mL). The organic layers were dried over
anhydrous sodium sulfate and concentrated under vacuum to afford
1.3 g (63.9%) of (5-methylpyrimidin-2-yl)methanol as a yellow
solid. LC-MS: m/z=125[M+H].sup.+.
Step 2: 2-(bromomethyl)-5-methylpyrimidine
##STR00137##
[0476] To a solution of (5-methylpyrimidin-2-yl)methanol [Example
12, Step 1] (1.3 g, 10.5 mmol, 1.00 equiv) in DCM (30 mL) was added
PPh.sub.3 (2.75 g, 10.5 mmol, 1.00 equiv) and NBS (1.87 mg, 10.5
mmol, 1.00 equiv) at 0.degree. C. The resulting solution was
stirred for 1 h at 0.degree. C. The reaction was then quenched by
the addition of H.sub.2O (30 mL). The resulting solution was
extracted with DCM (3.times.30 mL). The organic layers were dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:2) to afford 700 mg (35.8%) of
2-(bromomethyl)-5-methylpyrimidine as a yellow oil. LC-MS:
m/z=187[M+H].sup.+.
Step 3:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.-
sub.2)methyl) [(5-methylpyrimidin-2-yl)methyl]amine
##STR00138##
[0478] To a solution of
[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.sub.2)me-
thanamine [Example 2 Step 10] (1 g, 3.75 mmol, 1.00 equiv) in DMF
(15 mL) was added 2-(bromomethyl)-5-methylpyrimidine [Example 12,
Step 2] (700 mg, 3.76 mmol, 1.00 equiv) and TEA (569.64 mg, 5.64
mmol, 1.50 equiv). The resulting solution was stirred overnight at
25.degree. C. The reaction was then quenched by the addition of
H.sub.2O (40 mL). The resulting solution was extracted with ethyl
acetate (3.times.50 mL). The organic layers were washed with water
(3.times.20 mL) and brine (3.times.20 mL). The mixture was dried
over anhydrous sodium sulfate and concentrated under vacuum. The
crude product was purified by Prep-HPLC with the following: Column,
XBridge Prep OBD C18 Column 5 um, 30.times.150 mm; mobile phase,
Water (10 mmol/L NH.sub.4HCO.sub.3) and ACN (25% ACN up to 55% in 7
min); Detector, UV 254/220 nm to afford 130 mg (8.7%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoropiperidin-4-yl](d.sub.2)m-
ethyl)[(5-methylpyrimidin-2-yl)methyl]amine as a white solid.
[0479] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.617-8.615 (m,
2H), 7.683-7.660 (m, 1H), 7.514-7.422 (m, 2H), 4.237 (m, 1H), 3.887
(s, 2H), 3.399-3.071 (m, 3H), 2.312 (s, 1H), 2.256 (s, 3H),
1.795-1.629 (m, 4H). LC-MS: m/z=397 [M+H].sup.+.
Example 13:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperidin-4-yl]
(d)methyl) [(5-methylpyrimidin-2-yl)methyl]amine
##STR00139##
[0480] Step 1:
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperidin-4-yl](-
d)methyl)[(5-methylpyrimidin-2-yl)methyl]amine
##STR00140##
[0482] To a solution of
2-[1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperidin-4-yl]-
-2-hydroxy(d)acetonitrile [Example 7, Step 9] (600 mg, 1.848 mmol,
1.00 equiv) in methanol (5 mL) was added
(5-methylpyrimidin-2-yl)methanamine hydrochloride [Example 8, Step
2] (443.5 mg, 2.772 mmol, 1.50 equiv), DABCO (728.2 mg, 6.46 mmol,
3.50 equiv) and Na(CN)BH.sub.3 (140.0 mg, 2.22 mmol, 1.20 equiv).
The resulting solution was stirred overnight at 25.degree. C. The
resulting mixture was concentrated under vacuum to remove methanol.
The resulting solution was diluted with EA (50 mL). The organic
layers were washed with water (3.times.10 mL) and brine (3.times.10
mL). The mixture was dried over anhydrous sodium sulfate and
concentrated under vacuum. The crude product was purified by
Prep-HPLC with the following conditions: Column, XBridge Prep C18
OBD Column 19.times.150 mm; mobile phase, Water (10 mmol
NH.sub.4HCO.sub.3) and ACN (32% ACN in 8 min); Detector, UV 254/220
nm to afford 66 mg (8.6%) of
([1-[(3-chloro-4-fluorophenyl)carbonyl]-4-fluoro(d.sub.8)piperidin-4-yl](-
d)methyl)[(5-methylpyrimidin-2-yl)methyl]amine as a white
solid.
[0483] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.622 (m, 2H),
7.689-7.666 (m, 1H), 7.520-7.428 (m, 2H), 3.894 (s, 2H),
2.792-2.720 (m, 2H), 2.336-2.239 (s, 3H). LC-MS: m/z=404
[M+H].sup.+.
Example 14:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-methylpyrimidin-2-yl)methyl)am-
ino) methyl)piperidin-1-yl-2,2,3,3,5,5,6,6-d.sub.8)methanone
##STR00141##
[0484] Step 1:
2-(1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl-2,2,3,3,5,5,6,6-d.-
sub.8)-2-hydroxyacetonitrile
##STR00142##
[0486]
6-(3-chloro-4-fluorobenzoyl)-1-oxa-6-azaspiro[2.5]octane-2-carbonit-
rile-4,4,5,5,7,7,8,8-d.sub.8 (Example 7, step 4) is treated with
hydrogen fluoride and pyridine to provide
2-(1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl-2,2,3,3,5,5,6,6-d.-
sub.8)-2-hydroxyacetonitrile.
Step 2:
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-methylpyrimidin-2-yl)me-
thyl)
amino)methyl)piperidin-1-yl-2,2,3,3,5,5,6,6-d.sub.8)methanone
##STR00143##
[0488]
2-(1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl-2,2,3,3,5,5,-
6,6-d.sub.8)-2-hydroxy acetonitrile (step 1) and
(5-methylpyrimidin-2-yl)methanamine are treated with
1,4-diazabicyclo[2.2.2] octane and sodium cyanoborohydride to
provide
(3-chloro-4-fluorophenyl)(4-fluoro-4-((((5-methylpyrimidin-2-yl)methyl)am-
ino)methyl)piperidin-1-yl-2,2,3,3,5,5,6,6-d.sub.8) methanone.
[0489] The following compounds in Table 1 can generally be made
using the methods described above:
TABLE-US-00001 TABLE 1 No. Structure 15 ##STR00144## 16
##STR00145## 17 ##STR00146## 18 ##STR00147## 19 ##STR00148## 20
##STR00149## 21 ##STR00150## 22 ##STR00151## 23 ##STR00152## 24
##STR00153## 25 ##STR00154## 26 ##STR00155## 27 ##STR00156## 28
##STR00157## 29 ##STR00158## 30 ##STR00159## 31 ##STR00160## 32
##STR00161## 33 ##STR00162## 34 ##STR00163## 35 ##STR00164## 36
##STR00165## 37 ##STR00166## 38 ##STR00167## 39 ##STR00168## 40
##STR00169## 41 ##STR00170## 42 ##STR00171## 43 ##STR00172## 44
##STR00173## 45 ##STR00174## 46 ##STR00175## 47 ##STR00176## 48
##STR00177## 49 ##STR00178## 50 ##STR00179## 51 ##STR00180## 52
##STR00181## 53 ##STR00182## 54 ##STR00183## 55 ##STR00184## 56
##STR00185## 57 ##STR00186## 58 ##STR00187## 59 ##STR00188## 60
##STR00189## 61 ##STR00190## 62 ##STR00191## 63 ##STR00192## 64
##STR00193## 65 ##STR00194## 66 ##STR00195## 67 ##STR00196## 68
##STR00197## 69 ##STR00198## 70 ##STR00199## 71 ##STR00200## 72
##STR00201## 73 ##STR00202## 74 ##STR00203## 75 ##STR00204## 76
##STR00205## 77 ##STR00206## 78 ##STR00207## 79 ##STR00208## 80
##STR00209## 81 ##STR00210## 82 ##STR00211## 83 ##STR00212## 84
##STR00213## 85 ##STR00214## 86 ##STR00215## 87 ##STR00216## 88
##STR00217## 89 ##STR00218## 90 ##STR00219## 91 ##STR00220## 92
##STR00221## 93 ##STR00222## 94 ##STR00223## 95 ##STR00224## 96
##STR00225## 97 ##STR00226## 98 ##STR00227## 99 ##STR00228## 100
##STR00229## 101 ##STR00230## 102 ##STR00231## 103 ##STR00232## 104
##STR00233## 105 ##STR00234## 106 ##STR00235## 107 ##STR00236## 108
##STR00237## 109 ##STR00238## 110 ##STR00239## 111 ##STR00240## 112
##STR00241## 113 ##STR00242## 114 ##STR00243## 115 ##STR00244## 116
##STR00245## 117 ##STR00246## 118 ##STR00247## 119 ##STR00248## 120
##STR00249## 121 ##STR00250## 122 ##STR00251## 123 ##STR00252## 124
##STR00253## 125 ##STR00254## 126 ##STR00255## 127 ##STR00256## 128
##STR00257## 129 ##STR00258## 130 ##STR00259## 131 ##STR00260## 132
##STR00261## 133 ##STR00262## 134 ##STR00263## 135 ##STR00264## 136
##STR00265## 137 ##STR00266##
138 ##STR00267## 139 ##STR00268## 140 ##STR00269## 141 ##STR00270##
142 ##STR00271## 143 ##STR00272## 144 ##STR00273## 145 ##STR00274##
146 ##STR00275## 147 ##STR00276## 148 ##STR00277## 149 ##STR00278##
150 ##STR00279## 151 ##STR00280## 152 ##STR00281## 153 ##STR00282##
154 ##STR00283## 155 ##STR00284## 156 ##STR00285## 157 ##STR00286##
158 ##STR00287## 159 ##STR00288## 160 ##STR00289## 161 ##STR00290##
162 ##STR00291## 163 ##STR00292## 164 ##STR00293## 165 ##STR00294##
166 ##STR00295## 167 ##STR00296## 168 ##STR00297## 169 ##STR00298##
170 ##STR00299## 171 ##STR00300## 172 ##STR00301## 173 ##STR00302##
174 ##STR00303## 175 ##STR00304## 176 ##STR00305## 177 ##STR00306##
178 ##STR00307## 179 ##STR00308## 180 ##STR00309## 181 ##STR00310##
182 ##STR00311## 183 ##STR00312## 184 ##STR00313## 185 ##STR00314##
186 ##STR00315## 187 ##STR00316## 188 ##STR00317## 189 ##STR00318##
190 ##STR00319## 191 ##STR00320## 192 ##STR00321## 193 ##STR00322##
194 ##STR00323## 195 ##STR00324## 196 ##STR00325## 197 ##STR00326##
198 ##STR00327## 199 ##STR00328## 200 ##STR00329## 201 ##STR00330##
202 ##STR00331## 203 ##STR00332## 204 ##STR00333## 205 ##STR00334##
206 ##STR00335## 207 ##STR00336## 208 ##STR00337## 209 ##STR00338##
210 ##STR00339## 211 ##STR00340## 212 ##STR00341## 213 ##STR00342##
214 ##STR00343## 215 ##STR00344## 216 ##STR00345## 217 ##STR00346##
218 ##STR00347## 219 ##STR00348## 220 ##STR00349## 221 ##STR00350##
222 ##STR00351## 223 ##STR00352## 224 ##STR00353## 225 ##STR00354##
226 ##STR00355## 227 ##STR00356## 228 ##STR00357##
[0490] Changes in the metabolic properties of the compounds
disclosed herein as compared to their non-isotopically enriched
analogs can be shown using the following assays. Compounds listed
above which have not yet been made and/or tested are predicted to
have changed metabolic properties as shown by one or more of these
assays as well.
[0491] Biological Activity Assays
[0492] In Vitro Liver Microsomal Stability Assay
[0493] Human liver microsomal stability assays were conducted at
0.5 mg per mL liver microsome protein with NADPH (2 mM, pH 7.4).
Test compounds were prepared as solutions in DMSO and added to the
assay mixture (1 .mu.M, final concentration in incubation) to be
incubated at 37.+-.1.degree. C. Reactions were initiated with the
addition of cofactor and are stopped at 0, 5, 15, 30, and 45 min
after cofactor addition with stop reagent (acetonitrile). After
quenching, plates containing samples are vibrated for 10 min (600
rpm/min) and then centrifuged at 5594 g for 15 min. Supernatant
fractions were analyzed by LC-MS/MS to determine the percent
remaining and estimate the degradation half-life of the test
compounds. The results are presented in Table 2 below.
TABLE-US-00002 TABLE 2 Example Clearance % Half-life % # change
over d0 change over d0 1 0 0 2 -7.5 8.4 3 -5. 5.6 4 -5.1 5.4 5 -6.7
7.2 6 -9.1 10.0 7 -5.8 6.2 8 0 0 9 3.7 -3.5 10 8.4 -7.7 11 5.5 -5.2
12 2.1 -2.1 13 -0.9 0.9
[0494] In Vitro Metabolism Using Human Cytochrome P.sub.450
Enzymes
[0495] The cytochrome P.sub.450 enzymes are expressed from the
corresponding human cDNA using a baculovirus expression system (BD
Biosciences, San Jose, Calif.). A 0.25 milliliter reaction mixture
containing 0.8 milligrams per milliliter protein, 1.3 millimolar
NADP.sup.+, 3.3 millimolar glucose-6-phosphate, 0.4 U/mL
glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesium
chloride and 0.2 millimolar of a compound of Formula I, the
corresponding non-isotopically enriched compound or standard or
control in 100 millimolar potassium phosphate (pH 7.4) is incubated
at 37.degree. C. for 20 min. After incubation, the reaction is
stopped by the addition of an appropriate solvent (e.g.,
acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial
acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial
acetic acid) and centrifuged (10,000 g) for 3 min. The supernatant
is analyzed by HPLC/MS/MS.
TABLE-US-00003 Cytochrome P.sub.450 Standard CYP1A2 Phenacetin
CYP2A6 Coumarin CYP2B6 [.sup.13C]-(S)-mephenytoin CYP2C8 Paclitaxel
CYP2C9 Diclofenac CYP2C19 [.sup.13C]-(S)-mephenytoin CYP2D6
(+/-)-Bufuralol CYP2E1 Chlorzoxazone CYP3A4 Testosterone CYP4A
[.sup.13C]-Lauric acid
[0496] Monoamine Oxidase A Inhibition and Oxidative Turnover
[0497] The procedure is carried out using the methods described by
Weyler, Journal of Biological Chemistry 1985, 260, 13199-13207,
which is hereby incorporated by reference in its entirety.
Monoamine oxidase A activity is measured spectrophotometrically by
monitoring the increase in absorbance at 314 nm on oxidation of
kynuramine with formation of 4-hydroxyquinoline. The measurements
are carried out, at 30.degree. C., in 50 mM NaP.sub.i buffer, pH
7.2, containing 0.2% Triton X-100 (monoamine oxidase assay buffer),
plus 1 mM kynuramine, and the desired amount of enzyme in 1 mL
total volume.
[0498] Monooamine Oxidase B Inhibition and Oxidative Turnover
[0499] The procedure is carried out as described in Uebelhack,
Pharmacopsychiatry 1998, 31(5), 187-192, which is hereby
incorporated by reference in its entirety.
[0500] 5-Hydroxytryptamine (5-HT.sub.1A) In Vitro Assay
[0501] The in vitro affinity of the compounds for the 5-HT.sub.1A
receptors is determined according to the methods provided in U.S.
Pat. No. 6,020,345, which is hereby incorporated by references in
its entirety.
[0502] 5-hydroxytryptamine (5-HT.sub.1A) Binding Assay
[0503] The study of binding of the compounds to the 5-HT.sub.1A
receptors is determined according to the methods provided in U.S.
Pat. No. 6,020,345, which is hereby incorporated by reference in
its entirety.
[0504] 5-hydroxytryptamine (5-HT.sub.1A) In Vivo Assay
[0505] In vivo evaluation of the agonist activity of the
5-HT.sub.1A receptors for the compounds is determined according to
the methods provided in U.S. Pat. No. 6,020,345, which is hereby
incorporated by references in its entirety.
[0506] D.sub.2 Dopaminergic Receptor Binding Assay
[0507] The study of binding of the compounds to the D2 dopaminergic
receptors is determined according to the methods provided in U.S.
Pat. No. 6,020,345, which is hereby incorporated by reference in
its entirety.
[0508] From the foregoing description, one skilled in the art can
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
[0509] Reference throughout this specification to "one embodiment,"
"certain embodiments," "one or more embodiments" or "an embodiment"
means that a particular feature, structure, material, or
characteristic described in connection with the embodiment is
included in at least one embodiment of the invention. Thus, the
appearances of the phrases such as "in one or more embodiments,"
"in certain embodiments," "in one embodiment" or "in an embodiment"
in various places throughout this specification are not necessarily
referring to the same embodiment of the invention. Furthermore, the
particular features, structures, materials, or characteristics may
be combined in any suitable manner in one or more embodiments.
[0510] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present invention. It will be apparent to those
skilled in the art that various modifications and variations can be
made to the method and apparatus of the present invention without
departing from the spirit and scope of the invention. Thus, it is
intended that the present invention include modifications and
variations that are within the scope of the appended claims and
their equivalents.
* * * * *