U.S. patent application number 13/431303 was filed with the patent office on 2012-11-01 for ethanamine compounds and methods of using the same.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Michael Balestra, Peter Bernstein, Glen E. Ernst, William Frietze, John P. McCauley, David Nugiel, Lihong Shen.
Application Number | 20120277272 13/431303 |
Document ID | / |
Family ID | 42288011 |
Filed Date | 2012-11-01 |
United States Patent
Application |
20120277272 |
Kind Code |
A1 |
Balestra; Michael ; et
al. |
November 1, 2012 |
Ethanamine Compounds and Methods of Using the Same
Abstract
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine,
pharmaceutically acceptable salts thereof, pharmaceutical
compositions comprising the same, uses of said compound or salt for
therapy of depression and other conditions, and methods of treating
depression and other conditions by administering said compound or
salt.
Inventors: |
Balestra; Michael; (New
Fairfield, CT) ; Bernstein; Peter; (Wallingford,
PA) ; Ernst; Glen E.; (Bear, DE) ; Frietze;
William; (Kennett Square, PA) ; McCauley; John
P.; (Folcroft, PA) ; Shen; Lihong; (West
Chester, PA) ; Nugiel; David; (Cherry Hill,
NJ) |
Assignee: |
ASTRAZENECA AB
Sodertalje
SE
|
Family ID: |
42288011 |
Appl. No.: |
13/431303 |
Filed: |
March 27, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13219892 |
Aug 29, 2011 |
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13431303 |
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12644046 |
Dec 22, 2009 |
8013165 |
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13219892 |
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61140673 |
Dec 24, 2008 |
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Current U.S.
Class: |
514/357 ;
546/329 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 25/04 20180101; A61K 31/4402 20130101; A61P 25/08 20180101;
A61P 25/00 20180101; C07D 213/38 20130101; A61P 25/24 20180101;
C07C 57/15 20130101 |
Class at
Publication: |
514/357 ;
546/329 |
International
Class: |
A61K 31/4402 20060101
A61K031/4402; C07D 213/38 20060101 C07D213/38; A61P 25/24 20060101
A61P025/24 |
Claims
1. A compound that is
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine having the
following structure: ##STR00038## or a pharmaceutically acceptable
salt thereof.
2. Use of a compound or a pharmaceutically acceptable salt thereof
according to claim 1 for the treatment of depression.
4. Use of a compound or a pharmaceutically acceptable salt thereof
according to claim 1 is the preparation of a medicament for the
treatment of depression
5. A method of treating depression in a in a human which comprises
administering to a person in need thereof a therapeutically
effective amount of a compound or a pharmaceutically acceptable
salt thereof according to claim 1.
6. A pharmaceutical composition comprising a compound or
pharmaceutically acceptable salt thereof according to claim 1 and
at least one pharmaceutically acceptable excipient, diluent or
carrier.
Description
RELATED APPLICATIONS
[0001] This is a Continuation in Part of application Ser. No.
13/219,892 filed on Aug. 29, 2011 which is a Continuation of
application Ser. No. 12/644,046 filed on Dec. 22, 2009, now U.S.
Pat. No. 8,013,165, which claims the benefit of Provisional
Application No. 61/140,673 filed on Dec. 24, 2008.
FIELD OF THE INVENTION
[0002] Disclosed herein is at least one ethanamine derivative, at
least one pharmaceutical composition comprising at least one
ethanamine derivative disclosed herein, and at least one method of
using at least one ethanamine derivative disclosed herein for
treating depression. The compounds may also have utility in the
treatment of other diseases, including Parkinson's disease, pain
states, such as neuropathic pain, as well as epilepsy and
neurotrauma.
BACKGROUND OF THE INVENTION
[0003] Depression is a common mental disorder that occurs in
persons of all genders, ages, and backgrounds, affecting about 121
million people worldwide. Symptoms of depression include, but are
not limited to, depressed mood, loss of interest or pleasure,
feelings of guilt or low self-worth, disturbed sleep or appetite,
low energy, and poor concentration, or any combination thereof.
These problems can become chronic or recurrent and lead to
substantial impairments in an individual's ability to take care of
his or her everyday responsibilities.
[0004] Depression is the leading cause of disability as measured by
Years Lived with a Disability (YLDs) and the fourth leading
contributor to the global burden of disease as measured by
Disability Adjusted Life Years (DALYs; i.e., the sum of years of
potential life lost due to premature mortality and the years of
productive life lost due to disability) in 2000. By the year 2020,
depression is projected to reach second place in the ranking of
DALYs calculated for all ages, in both men and women. Today,
depression is already the second cause of DALYs in the age category
15-44 years for both sexes combined. Whereas there are clearly a
number of currently available treatments for depression, a
significant proportion of patients are either incompletely treated
(many residual symptoms remain) or do not respond to treatment at
all. Thus, novel treatments for depression are needed. The present
invention provides compounds, compositions, methods of preparing
the same, and methods of treating depression. Such compounds would
have additional utility in other disorders as well, including pain,
Parkinson's disease, epilepsy and neurotrauma.
SUMMARY OF THE INVENTION
[0005] The present invention provides in this continuation-in-part
application compounds [0006]
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof. [0007]
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof. [0008]
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof [0009]
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof. [0010]
(R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof. [0011]
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof described throughout the
application and in more detail in Examples 7 to 16.
DESCRIPTION OF EMBODIMENTS
[0012] The features and advantages of the invention may be more
readily understood by those of ordinary skill in the art upon
reading the following detailed description. An advantage of the
present invention is the prevention of stilbazole formation.
Stilbazole is an undesirable by-product. The effects of stilbazole
on humans is not yet fully appreciated but a product without
stilbazole would be preferable.
[0013] It is to be appreciated that certain features of the
invention that are, for clarity reasons, described in the context
of separate embodiments, may also be combined to form a single
embodiment. Conversely, various features of the invention that are,
for brevity reasons, described in the context of a single
embodiment, may also be combined so as to form sub-combinations
thereof.
[0014] Unless specifically stated otherwise herein, references made
in the singular may also include the plural. For example, "a" and
"an" may refer to either one, or one or more.
[0015] Embodiments identified herein as exemplary are intended to
be illustrative and not limiting.
[0016] Unless otherwise indicated, any heteroatom with unsatisfied
valences is assumed to have hydrogen atoms sufficient to satisfy
the valences.
[0017] The definitions set forth herein take precedence over
definitions set forth in any patent, patent application, and/or
patent application publication incorporated herein by
reference.
[0018] Definitions of terms used in describing the invention are
set forth herein below. Unless otherwise indicated, the initial
definition provided for a group or term applies each time such
group or term is used individually. Throughout the specification,
groups and substituents thereof may be chosen by one skilled in the
field to provide stable moieties and compounds.
[0019] Unless specified otherwise herein, the nomenclature used
herein generally follows the examples and rules stated in
Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and
H, Pergamon Press, Oxford, 1979.
[0020] The term "about" means.+-.5% of the value it modifies. For
example, "about" 100 means 95 to 105.
[0021] The term "halogen" refers to chlorine, bromine, fluorine,
and iodine.
[0022] The term "pharmaceutically acceptable", as employed herein,
indicates the subject matter being identified as "pharmaceutically
acceptable" is suitable and physiologically acceptable for
administration to a patient/subject. For example, the term
"pharmaceutically acceptable salt(s)" denotes suitable and
physiologically acceptable salt(s).
[0023] The phrase "a compound of formula I, enantiomers thereof,
pharmaceutically acceptable salts thereof, or mixtures thereof" or
similar such phrases, refers to the free base of formula I or
enantiomers thereof, pharmaceutically acceptable salts of formula I
or enantiomers thereof, and/or mixtures of at least one free base
of formula I or enantiomers thereof and at least one
pharmaceutically acceptable salt of formula I or enantiomers
thereof.
[0024] The term "therapeutically effective amount" refers to that
amount of a compound sufficient to modulate one or more of the
symptoms of the condition or disease being treated.
[0025] A selection of in vivo hydrolysable amide forming groups for
hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted
benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate
esters), dialkylcarbamoyl and
N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),
dialkylaminoacetyl and carboxyacetyl. Examples of substituents on
benzoyl include morpholino and piperazino linked from a ring
nitrogen atom via a methylene group to the 3- or 4-position of the
benzoyl ring.
[0026] The present invention provides the compound
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof.
[0027] The present invention provides the compound
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof.
[0028] The present invention provides the compound
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof.
[0029] The present invention provides the compound
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0030] The present invention provides the compound
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0031] The present invention provides the compound
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0032] The present invention provides the compound
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof.
[0033] The present invention provides the compound
(R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof.
[0034] The present invention provides the compound
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof.
[0035] The present invention provides the compound
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine fumarate.
[0036] The present invention provides the compound
(R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine fumarate.
[0037] The present invention provides the compound
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine fumarate.
[0038] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine.
[0039] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine.
[0040] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine.
[0041] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0042] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0043] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0044] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine.
[0045] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
(R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine.
[0046] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine.
[0047] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine fumarate.
[0048] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
(R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine fumarate.
[0049] The present invention provides a method of treating
depression in a human which comprises administering to a person in
need thereof a therapeutic effective amount of a compound or a
pharmaceutically acceptable salt thereof, where the compound is
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine fumarate.
[0050] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is 1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine.
[0051] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine.
[0052] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine.
[0053] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is 1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0054] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is (R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0055] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is (S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0056] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine.
[0057] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is (R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine.
[0058] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is (S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine.
[0059] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine fumarate.
[0060] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is (R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0061] The present invention provides a method of treating major
depressive disorder in a human which comprises administering to a
person in need thereof a therapeutic effective amount of a compound
or a pharmaceutically acceptable salt thereof, where the compound
is (S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine
fumarate.
[0062] The present invention provides a pharmaceutical composition
comprising
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable adjuvant, carrier, or diluent.
[0063] The present invention provides a pharmaceutical composition
comprising
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable adjuvant, carrier, or diluent.
[0064] The present invention provides a pharmaceutical composition
comprising
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable adjuvant, carrier, or diluent.
[0065] The present invention provides a pharmaceutical composition
comprising
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine fumarate
or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable adjuvant, carrier, or diluent.
[0066] The present invention provides a pharmaceutical composition
comprising
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable adjuvant, carrier, or diluent.
[0067] The present invention provides a pharmaceutical composition
comprising
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
fumarate or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable adjuvant, carrier, or diluent.
[0068] The present invention provides a pharmaceutical composition
comprising 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable adjuvant, carrier, or diluent.
[0069] The present invention provides a pharmaceutical composition
comprising (R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine or
a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable adjuvant, carrier, or diluent.
[0070] The present invention provides a pharmaceutical composition
comprising (S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine or
a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable adjuvant, carrier, or diluent.
[0071] The present invention provides a pharmaceutical composition
comprising 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine
fumarate or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable adjuvant, carrier, or diluent.
[0072] The present invention provides a pharmaceutical composition
comprising (R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine
fumarate or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable adjuvant, carrier, or diluent.
[0073] The present invention provides a pharmaceutical composition
comprising (S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine
fumarate or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable adjuvant, carrier, or diluent.
[0074] The compounds of the present invention may be administered
in the form of a prodrug which is broken down in the human or
animal body to give a compound of the formula I. Examples of
prodrugs include in vivo hydrolysable amides of a compound of
formula I. Various forms of prodrugs are known in the art. For
examples of such prodrug derivatives, see: a) Design of Prodrugs,
edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology,
Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press,
1985); b) A Textbook of Drug Design and Development, edited by
Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and
Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H.
Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.
Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285
(1988); and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692
(1984).
[0075] It will be understood that when compounds of the present
invention contain a chiral center, the compounds of the invention
may exist in, and be isolated as, enantiomeric or as a racemic
mixture. The present invention includes any possible enantiomers,
racemates or mixtures thereof, of the compounds of formula I. The
optically active forms of the compound of the invention may be
prepared, for example, by chiral chromatographic separation of a
racemate, by synthesis from optically active starting materials or
by asymmetric synthesis.
[0076] It will also be understood that certain compounds of the
invention may exist in solvated, for example hydrated, as well as
unsolvated forms. It will further be understood the present
invention encompasses all such solvated forms of the compounds of
formula I.
[0077] The present invention includes compounds in the form of
salts, in particular acid addition salts. Suitable salts include
all known pharmaceutically acceptable salts including those formed
with both organic and inorganic acids. Thus, suitable salts include
those formed from hydrochloric, hydrobromic, sulfuric, phosphoric,
citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric,
maleic, methanesulphonic, and benzenesulphonic acids. Without being
held to any specific salt form it appears that fumaric salts are
particularly suitable.
[0078] The present invention also provides methods of treating
depression including major depressive disorder in a human or other
animal comprising administering a therapeutically effective amount
of any of the compounds, isomers, enantiomers thereof, or
pharmaceutically acceptable salts of the compounds or
pharmaceutically acceptable salts of the isomers, enantiomers,
described herein, or mixture of any of the compounds, isomers,
enantiomers thereof, or pharmaceutically acceptable salts of the
compounds or pharmaceutically acceptable salts of the isomers,
enantiomers, described above. In some embodiments, the human or
other animal will be in need thereof of such treatment.
[0079] In a further aspect, the invention provides methods of
treating neurodegenerative disorders, for example Alzheimer's
disease, Parkinson's disease, Huntington's disease, stroke,
cerebral ischemia, cerebral palsy, the effects of hypoglycemia,
epilepsy, dementia, AIDs related dementia, Olivo-ponto-cerebellar
atrophy, perinatal asphyxia, anoxia, neuronal damage associated
with substance abuse (for example narcotics or cocaine),
retinopathies, schizophrenia, ischemic states after cardiac arrest
or surgical operations, amyotrophic lateral sclerosis (ALS),
coronary bypass disease, or fibromyalgia.
[0080] In a further aspect, the invention provides a low affinity
NMDA antagonist, in particular a compound of formula I, in the
manufacture of a medicament for use in the prevention or treatment
of the above disorders, in particular for the prevention or
treatment of depression including major depressive disorder.
[0081] The present invention also provides uses of any of the
compounds, enantiomers thereof, or pharmaceutically acceptable
salts of the compounds or enantiomers described above for treating
depression in a human.
[0082] The present invention also provides compounds, enantiomers
thereof, or pharmaceutically acceptable salts of the compounds or
enantiomers described above for treating depression in a human.
[0083] The present invention also provides compounds, enantiomers
thereof, or pharmaceutically acceptable salts of the compounds or
enantiomers described above for use in the manufacture of a
medicament for the treatment of depression.
[0084] The compounds according to the present invention may be
administered by any route, including orally, intramuscularly,
subcutaneously, topically, intranasally, intraperitoneally,
intrathoracically, intravenously, epidurally, intrathecally,
intracerebroventricularly and by injection into the joints. In one
embodiment of the invention, the route of administration may be
orally, intravenously or intramuscularly.
[0085] For preparing pharmaceutical compositions from the compounds
of this invention, inert, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, dispersible granules, capsules, cachets, and
suppositories.
[0086] A solid carrier can be one or more substances, which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or tablet disintegrating agents; it can
also be an encapsulating material. In powders, the carrier is a
finely divided solid, which is in a mixture with the finely divided
active component. In tablets, the active component is mixed with
the carrier having the necessary binding properties in suitable
proportions and compacted in the shape and size desired.
[0087] For preparing suppository compositions, a low-melting wax
such as a mixture of fatty acid glycerides and cocoa butter is
first melted and the active ingredient is dispersed therein by, for
example, stirring. The molten homogeneous mixture is then poured
into convenient sized moulds and allowed to cool and solidify.
[0088] Suitable carriers are magnesium carbonate, magnesium
stearate, talc, lactose, sugar, pectin, dextrin, starch,
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a
low-melting wax, cocoa butter, and the like.
[0089] Tablets, powders, cachets, and capsules can be used as solid
dosage forms suitable for oral administration.
[0090] Liquid from compositions include solutions, suspensions, and
emulsions. Sterile water or water-propylene glycol solutions of the
active compounds may be mentioned as an example of liquid
preparations suitable for parenteral administration. Liquid
compositions can also be formulated in solution in aqueous
polyethylene glycol solution.
[0091] Aqueous solutions for oral administration can be prepared by
dissolving the active component in water and adding suitable
colorants, flavoring agents, stabilizers, and thickening agents as
desired. Aqueous suspensions for oral use can be made by dispersing
the finely divided active component in water together with a
viscous material such as natural synthetic gums, resins, methyl
cellulose, sodium carboxymethyl cellulose, and other suspending
agents known to the pharmaceutical formulation art.
[0092] The term "composition" is intended to include the
formulation of the active component with encapsulating material as
a carrier providing a capsule in which the active component (with
or without other carriers) is surrounded by a carrier which is thus
in association with it. Similarly, cachets are included.
[0093] Prophylaxis is expected to be particularly relevant to the
treatment of persons who have suffered a previous episode of, or
are otherwise considered to be at increased risk of, the disease or
condition in question. Persons at risk of developing a particular
disease or condition generally include those having a family
history of the disease or condition, or those who have been
identified by genetic testing or screening to be particularly
susceptible to developing the disease or condition.
[0094] In some embodiments, the pharmaceutical composition is in
unit dosage form. In such form, the composition is divided into
unit doses containing appropriate quantities of the active
component. The unit dosage form can be a packaged preparation, the
package containing discrete quantities of the preparations, for
example, packeted tablets, capsules, and powders in vials or
ampoules. The unit dosage form can also be a capsule, cachet, or
tablet itself, or it can be the appropriate number of any of these
packaged forms.
[0095] The dosage will depend on the route of administration, the
severity of the disease, age and weight of the patient and other
factors normally considered by the attending physician, when
determining the individual regimen and dosage level at the most
appropriate for a particular patient.
[0096] Suitable daily dose ranges are from about 0.05 mg/kg to
about 5.0 mg/kg. Unit doses may be administered conventionally once
or more than once a day; for example, 2, 3, or 4 times a day; more
usually 1 or 2 times a day. A typical dosing regimen would be oral,
intramuscular or intravenous, once or twice a week to once or twice
per day at 3.5 to 350 mg.
[0097] The pharmaceutical composition comprising the compound of
the invention may conveniently be formulated as tablets, pills,
capsules, syrups, powders or granules for oral administration;
sterile parental or subcutaneous solutions, suspensions for
parental administration; or suppositories for rectal
administration; all of which are well known in the art.
[0098] For clinical use, the compounds of the invention are
formulated into pharmaceutical formulations for oral, rectal,
parenteral or any other mode of administration. The pharmaceutical
formulation contains at least one compound of the invention in
combination with one or more pharmaceutically acceptable
ingredients. The carrier may be in the form of a solid, semi-solid
or liquid diluent, or a capsule. These pharmaceutical preparations
are a further object of the invention. Depending on the mode of
administration, the pharmaceutical composition can comprise from
about 0.05% w to about 99% w (percent by weight), or from about
0.05% w to about 80% w, or from about 0.10% w to about 70% w, or
from about 0.10% w to about 50% w, of active ingredient, all
percentages by weight being based on total composition.
[0099] In the preparation of pharmaceutical formulations containing
at least one compound of the present invention in the form of
dosage units for oral administration the compound selected may be
mixed with solid, powdered ingredients, or another suitable
ingredient, as well as with disintegrating agents and lubricating
agents. The mixture is then processed into granules or pressed into
tablets.
[0100] Soft gelatin capsules may be prepared with capsules
containing a mixture of the active compound or compounds of the
invention. Hard gelatin capsules may contain granules of the active
compound. Hard gelatin capsules may also contain the active
compound in combination with solid powdered ingredients.
[0101] Dosage units for rectal administration may be prepared (i)
in the form of suppositories which contain the active substance
mixed with a neutral fat base; (ii) in the form of a gelatin rectal
capsule which contains the active substance in a mixture with
suitable vehicles for gelatin rectal capsules; (iii) in the form of
a ready-made micro enema; or (iv) in the form of a dry micro enema
formulation to be reconstituted in a suitable solvent just prior to
administration.
[0102] Liquid preparations for oral administration may be prepared
in the form of syrups or suspensions, e.g., solutions or
suspensions containing the active ingredient. If desired, such
liquid preparations may contain coloring agents, flavoring agents,
saccharine and carboxymethyl cellulose or other thickening agent.
Liquid preparations for oral administration may also be prepared in
the form of a dry powder to be reconstituted with a suitable
solvent prior to use.
[0103] Solutions for parenteral administration may be prepared as a
solution of at least one compound of the invention in a
pharmaceutically acceptable solvent. These solutions may also
contain stabilizing ingredients and/or buffering ingredients and
are dispensed into unit doses in the form of ampoules or vials.
Solutions for parenteral administration may also be prepared as a
dry preparation to by reconstituted with a suitable solvent
extemporaneously before use.
[0104] Combinations wherein a compound of formula (I) or a
pharmaceutically acceptable salt, solvate or in vivo hydrolysable
amide thereof, or a pharmaceutical composition or formulation
comprising a compound of formula (I) is administered concurrently,
simultaneously, sequentially or separately with another
pharmaceutically active compound or compounds selected from the
following:
(i) antidepressants such as agomelatine, amitriptyline, amoxapine,
bupropion, citalopram, clomipramine, desipramine, doxepin,
duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine,
gepirone, imipramine, ipsapirone, maprotiline, nortriptyline,
nefazodone, paroxetine, phenelzine, protriptyline, ramelteon,
reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine,
tranylcypromaine, trazodone, trimipramine, venlafaxine and
equivalents and pharmaceutically active isomer(s) and metabolite(s)
thereof. (ii) atypical antipsychotics including for example
quetiapine, lithium and equivalents thereof and pharmaceutically
active isomer(s) and metabolite(s) thereof. (iii) antipsychotics
including for example amisulpride, aripiprazole, asenapine,
benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine,
debenzapine, divalproex, duloxetine, eszopiclone, haloperidol,
iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine,
paliperidone, perlapine, perphenazine, phenothiazine,
phenylbutylpiperidine, pimozide, prochlorperazine, risperidone,
sertindole, sulpiride, suproclone, suriclone, thioridazine,
trifluoperazine, trimetozine, valproate, valproic acid, zopiclone,
zotepine, ziprasidone and equivalents and pharmaceutically active
isomer(s) and metabolite(s) thereof. (iv) anxiolytics including for
example alnespirone, azapirones, benzodiazepines, barbiturates such
as adinazolam, alprazolam, balezepam, bentazepam, bromazepam,
brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide,
cyprazepam, diazepam, diphenhydramine, estazolam, fenobam,
flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam,
meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam,
reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam,
zolazepam and equivalents and pharmaceutically active isomer(s) and
metabolite(s) thereof. (v) anticonvulsants including for example
carbamazepine, valproate, lamotrogine, gabapentin and equivalents
and pharmaceutically active isomer(s) and metabolite(s) thereof.
(vi) Alzheimer's therapies including for example donepezil,
memantine, tacrine and equivalents and pharmaceutically active
isomer(s) and metabolite(s) thereof. (vii) Parkinson's therapies
including for example deprenyl, L-dopa, Requip, Mirapex, MAOB
inhibitors such as selegine and rasagiline, comP inhibitors such as
Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA
antagonists, Nicotine agonists, Dopamine agonists and inhibitors of
neuronal nitric oxide synthase and equivalents and pharmaceutically
active isomer(s) and metabolite(s) thereof. (viii) migraine
therapies including for example almotriptan, amantadine,
bromocriptine, butalbital, cabergoline, dichloralphenazone,
eletriptan, frovatriptan, lisuride, naratriptan, pergolide,
pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan,
zomitriptan, and equivalents and pharmaceutically active isomer(s)
and metabolite(s) thereof. (ix) stroke therapies including for
example abciximab, activase, NXY-059, citicoline, crobenetine,
desmoteplase, repinotan, traxoprodil and equivalents and
pharmaceutically active isomer(s) and metabolite(s) thereof. (x)
over active bladder urinary incontinence therapies including for
example darafenacin, falvoxate, oxybutynin, propiverine,
robalzotan, solifenacin, tolterodine and equivalents and
pharmaceutically active isomer(s) and metabolite(s) thereof. (xi)
neuropathic pain therapies including for example gabapentin,
lidoderm, pregablin and equivalents and pharmaceutically active
isomer(s) and metabolite(s) thereof. (xii) nociceptive pain
therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib,
valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and
equivalents and pharmaceutically active isomer(s) and metabolite(s)
thereof. (xiii) insomnia therapies including for example
agomelatine, allobarbital, alonimid, amobarbital, benzoctamine,
butabarbital, capuride, chloral, cloperidone, clorethate,
dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam,
hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone,
midaflur, nisobamate, pentobarbital, phenobarbital, propofol,
ramelteon, roletamide, triclofos, secobarbital, zaleplon, zolpidem
and equivalents and pharmaceutically active isomer(s) and
metabolite(s) thereof. (xiv) mood stabilizers including for example
carbamazepine, divalproex, gabapentin, lamotrigine, lithium,
olanzapine, quetiapine, valproate, valproic acid, verapamil, and
equivalents and pharmaceutically active isomer(s) and metabolite(s)
thereof. (xv) analgesics including for example acetaminophen,
ibuprofen, naproxen, hydrocodone, oxycodone, diclofenac, piroxicam,
etodolac, fenoprofen, ketoprofen, ketorolac, loxoprofen,
meclofenamate, meloxicam, gabapentin, paracetamol, morphine,
fentyl, cyclooxygenase-2-inhibitors, celecoxib, etoricoxib,
lumiracoxib, rofecoxib, valdecoxib, codeine, propoxyphene, tramadol
and equivalents and pharmaceutically active isomer(s) and
metabolite(s) thereof.
[0105] Such combination products employ the compounds of this
invention within the dosage range described herein and the other
pharmaceutically active compound or compounds within approved
dosage
[0106] In general, compounds of the present invention can be
prepared in accordance with the following Schemes and the general
knowledge of one skilled in the art and/or in accordance with the
methods set forth in the Examples that follow. Solvents,
temperatures, pressures, and other reaction conditions may readily
be selected by one of ordinary skill in the art. Starting materials
are commercially available or readily prepared by one skilled in
the art.
##STR00001##
[0107] Step 1: A compound in accordance with formula II can be
obtained by treating 2-ethylpyridine with a suitable strong base,
such as, butyl lithium, in an appropriate solvent, such as THF
followed by an aromatic aldehyde.
[0108] Step 2: A compound in accordance with formula III can be
obtained by treating a compound in accordance with formula II with
an appropriate oxidizing agent, such as a Swern oxidation agent, in
an appropriate solvent, such as DCM.
[0109] Step 3: A compound in accordance with formula IV can be
obtained by treating a compound in accordance with formula III with
an appropriate strong base, such as sodium hydride, in an
appropriate solvent, such as THF, and an appropriate alkylating
agent, such as methyl iodide.
[0110] Step 4: A compound in accordance with formula I can be
obtained by treating a compound in accordance with formula IV with
an appropriate amine source, such as ammonia, in an appropriate
solvent, such as methanol, and an appropriate reducing agent, such
as sodium borohydride.
##STR00002##
[0111] A compound in accordance with formula I can be obtained by
treating a compound in accordance with formula V as prepared
according to Panunzio, M. and Zarantonelo, P. Org. Proc. Res. Dev.
(1998) 2 49-59) with a compound in accordance with formula VI
prepared according to Pasquinet et al, Tetrahedron 54 (1998)
8771-8782) in an appropriate solvent, such as THF.
[0112] The present invention also provides methods of preparing
compounds described above comprising:
[0113] a) treating 2-ethylpyridine with a suitable strong base in
an appropriate solvent, followed by an aromatic aldehyde to produce
a compound of formula II
##STR00003##
wherein R corresponds to the optional substituent on Ar.sub.2 in
the compound of claim 1;
[0114] b) treating the compound of formula II with an appropriate
oxidizing agent in an appropriate solvent to produce a compound of
formula III
##STR00004##
[0115] c) treating the compound of formula III with an appropriate
strong base in an appropriate solvent and an appropriate alkylating
agent to produce a compound of formula IV.
##STR00005##
and
[0116] d) treating the compound of formula IV with an appropriate
amine source in an appropriate solvent and an appropriate reducing
agent to produce the compound described above.
[0117] In some embodiments, in a) the suitable strong base is butyl
lithium and the solvent is tetrahydrofuran (THF).
[0118] In some embodiments, in b) the oxidizing agent is a Swern
oxidation agent and the solvent is DCM.
[0119] In some embodiments, in c) the strong base is sodium
hydride, the solvent is tetrahydrofuran (THF), and the alkylating
agent is methyl iodide.
[0120] In some embodiments, in d) the amine source is ammonia, the
solvent is methanol, and the reducing agent is sodium
borohydride.
[0121] The present invention also provides methods of preparing
compounds described above comprising treating a compound of formula
V
##STR00006##
wherein R corresponds to the optional substituent on Ar.sub.2 in
the compounds described above, and wherein R.sub.5 is methyl, with
a compound of formula VI
##STR00007##
wherein K is potassium, or the potassium counterion, in an
appropriate solvent to produce the compounds described above.
[0122] In some embodiments, the solvent is tetrahydrofuran
(THF).
[0123] It will be appreciated that certain of the various ring
substituents in the compounds of the present invention may be
introduced by standard aromatic substitution reactions or generated
by conventional functional group modifications either prior to or
immediately following the processes mentioned above, and as such
are included in the process aspect of the invention. Such reactions
and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction,
reduction of substituents, alkylation of substituents and oxidation
of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art. Particular examples
of aromatic substitution reactions include the introduction of a
nitro group using concentrated nitric acid, the introduction of an
acyl group using, for example, an acyl halide and Lewis acid (such
as aluminium trichloride) under Friedel Crafts conditions; the
introduction of an alkyl group using an alkyl halide and Lewis acid
(such as aluminium trichloride) under Friedel Crafts conditions;
and the introduction of a halogeno group. Particular examples of
modifications include the reduction of a nitro group to an amino
group by for example, catalytic hydrogenation with a nickel
catalyst or treatment with iron in the presence of hydrochloric
acid with heating; oxidation of alkylthio to alkylsulphinyl or
alkylsulphonyl.
[0124] It will also be appreciated that in some of the reactions
mentioned herein it may be necessary/desirable to protect any
sensitive groups in the compounds. The instances where protection
is necessary or desirable and suitable methods for protection are
known to those skilled in the art. Conventional protecting groups
may be used in accordance with standard practice (for illustration,
see Green and Wuts, Protective Groups in Organic Synthesis, 3rd
ed., John Wiley and Sons, 1999). Thus, if reactants include groups
such as amino, carboxy or hydroxy it may be desirable to protect
the group in some of the reactions mentioned herein.
[0125] A suitable protecting group for an amino or alkylamino group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a t-butoxycarbonyl group may be removed, for
example, by treatment with a suitable acid as hydrochloric,
sulfuric or phosphoric acid or trifluoroacetic acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be
removed, for example, by hydrogenation over a catalyst such as
palladium on carbon, or by treatment with a Lewis acid for example
boron tris(trifluoroacetate). A suitable alternative protecting
group for a primary amino group is, for example, a phthaloyl group,
which may be removed by treatment with an alkylamine, for example
dimethylaminopropylamine, or with hydrazine.
[0126] A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example lithium or sodium hydroxide. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as palladium on
carbon.
[0127] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a t-butyl group which may
be removed, for example, by treatment with an acid, for example an
organic acid such as trifluoroacetic acid, or for example a benzyl
group which may be removed, for example, by hydrogenation over a
catalyst such as palladium on carbon.
[0128] The protecting groups may be removed at any convenient stage
in the synthesis using conventional techniques well known in the
chemical art.
EXAMPLES
[0129] The invention is further defined in the following Examples.
It should be understood that the Examples are given by way of
illustration only. From the above discussion and the Examples, one
skilled in the art can ascertain the essential characteristics of
the invention, and without departing from the spirit and scope
thereof, can make various changes and modifications to adapt the
invention to various uses and conditions. As a result, the
invention is not limited by the illustrative examples set forth
hereinbelow, but rather defined by the claims appended hereto.
[0130] All temperatures are in degrees Celsius (.degree. C.).
Unless otherwise stated, operations are carried out at room or
ambient temperature (18-25.degree. C.).
[0131] Unless otherwise noted, commercial reagents used in
preparing the example compounds are used as received without
additional purification.
[0132] Unless otherwise noted, the solvents used in preparing the
example compounds are commercial anhydrous grades and are used
without further drying or purification.
[0133] Unless otherwise noted, the following method is used to
determine nuclear magnetic resonance spectrometry: a Varian Unity
Inova 400 spectrometer operating at 400 MHz for .sup.1H equipped
with a 5 mm inverse detection triple resonance probe for detection
of .sup.1H, .sup.13C, .sup.31P with the magnetic field provided by
a 9.4 Tesla Oxford instruments super-conducting magnet and a Sun
Microsystems SunBlade 1000 workstation as host. Chemical shifts are
reported in parts-per-million (.delta.) from a tetramethylsilane
internal standard.
[0134] Unless otherwise indicated, the following method is used for
mass spectrometer detection: a Waters ZMD quadrupole mass
spectrometer linked to a Waters 1525 LC system with Waters 996
diode array detector. Sample injection is done by a Waters 2700
autosampler. The spectrometer has an electrospray source operating
in positive and negative ion mode. Additional detection is achieved
using a Sedex 65 ELS detector. All m/z ratios are reported as the
M+1 ion.
[0135] Chiral chromatography to separate enantiomers is performed
using a Berger multi gram II supercritical fluid chromatography
(SFC) system equipped with an ADH column, 21.2.times.250 mm in
size, running an isocratic gradient of 15% isopropanol with 0.5%
isopropylamine in CO.sub.2, a flow rate of 70 mL/minute and UV
detection at 230 nm.
[0136] The names of the compounds exemplified herein are generated
using AutoNom 2000 within ISIS/Draw. AutoNom (Automatic
Nomenclature) is a chemical-name-generating program that assigns
systematic IUPAC (International Union of Pure and Applied
Chemistry) chemical names to drawn structures at the press of a
button.
[0137] The following abbreviations are employed herein: ACN:
Acetonitrile; AcOH: acetic acid; CDCl.sub.3; deuterated chloroform;
D.sub.3OD: deuterated methanol; DCM: dichloromethane; DMF:
N,N-dimethylformamide; DMSO: dimethyl sulfoxide; DMSO-d6:
deuterated dimethyl sulfoxide; ELS: evaporative light scattering;
EtOAc: ethyl acetate; equiv: equivalent; Ex.: Example; HPLC: high
performance liquid chromatography; HCl: hydrochloric acid;
H.sub.2O: water; H.sub.2SO.sub.4: sulfuric acid; LAH: Lithium
aluminum hydride; LCMS: liquid chromatography mass spectral
detection; m/z: mass to charge ratio; LDA: lithium diisopropyl
amide; MeOH: methanol; MgSO.sub.4: magnesium sulfate; min.:
minutes; MS: mass spectrum; M.p.: melting point; NaBH.sub.4: sodium
borohydride; n-BuLi: Lithium-1-butanide; NaHCO.sub.3: sodium
bicarbonate; NaOH: sodium hydroxide; Na.sub.2SO.sub.4: sodium
sulfate; NH.sub.4Cl: ammonium chloride; NMR: nuclear magnetic
resonance; N.sub.2: nitrogen gas: room temperature; rt=retention
time; sat.: saturated; THF: tetrahydrofuran; and UV:
Ultraviolet.
Example 1
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine
[0138] The title compound may be prepared by the routes of Example
1A and 1B. Example 1A:
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine via Scheme I
a) 1-Phenyl-2-(pyridin-2-yl)propan-1-ol (2)
##STR00008##
[0140] n-Butyllithium (2.5 M, 15.0 mL, 36.0 mmol) is added
drop-wise to a solution of 2-ethylpyridine (4.1 mL, 36.0 mmol) in
THF (56 mL) at -40.degree. C. The resulting dark red solution is
kept at -30.degree. C. to -20.degree. C. for 1 hour and then cooled
to -60.degree. C. A solution of benzaldehyde (3.7 mL, 36.0 mmol) in
THF (10 mL) is added drop-wise. The reaction mixture is allowed to
warm up to 0.degree. C. for 1 hour and then quenched with aqueous
NH.sub.4Cl solution. The mixture is separated and the aqueous phase
is extracted with ethyl acetate (2.times.50 mL). The extracts are
combined, dried, concentrated and purified by column chromatography
(hexane/ethyl acetate 10:1 to 1:1) to give 2 (7.0 g, 91%) as a
yellow oil. This mixture contained two diastereoisomers (3:1).
.sup.1H NMR (300 MHz, CDCl.sub.3) for the major isomer: .delta.
1.14 (d, J=7.2 Hz, 3H), 2.98 (q, J=6.9 Hz, 1H), 4.70-4.75 (m, 1H),
5.13-5.16 (m, 1H), 6.80-7.39 (m, 8H), 8.34 (d, J=4.8 Hz, 1H).
b) 1-Phenyl-2-(pyridin-2-yl)propan-1-one (3)
##STR00009##
[0142] A solution of DMSO (5.5 mL, 77.5 mmol) in dichloromethane
(10 mL) is added drop-wise to a solution of oxalyl chloride (3.3
mL, 39.0 mmol) in dichloromethane (100 mL) with the internal
temperature under -60.degree. C. The reaction mixture is stirred
for 15 minutes and then a solution of
1-phenyl-2-(pyridin-2-yl)propan-1-ol (2) (7.0 g, 32.8 mmol) in
dichloromethane (10 mL) is added slowly to keep the internal
temperature under -60.degree. C. After 30 minutes, triethylamine
(22.3 mL, 0.16 mol) is added slowly at -78.degree. C. After 15
minutes, the reaction is allowed to warm up to 0.degree. C. for 30
minutes and then quenched with water. The mixture is separated and
the aqueous phase is extracted with dichloromethane (2.times.50
mL). The extracts are combined, washed with brine, dried,
concentrated and purified by column chromatography (hexane/ethyl
acetate 10:1 to 4:1) to give 3 (6.4 g, 91%) as a yellow oil.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.51-1.54 (m, 3H),
4.84-4.92 (m, 1H), 7.03-708 (m, 1H), 7.18-7.20 (m, 2H), 7.30-7.35
(m, 1H), 7.40-7.43 (m, 1H), 7.52-7.57 (m, 1H), 7.95-7.98 (m, 2H),
8.47-8.48 (m, 1H).
c) 2-Methyl-1-phenyl-2-(pyridin-2-yl)propan-1-one (4)
##STR00010##
[0144] A solution of compound 3 (3.0 g, 14.2 mmol) in THF (10 mL)
is added to a suspension of sodium hydride (60%, 0.63 g, 15.6 mmol)
in THF (60 mL) at 0.degree. C. The reaction mixture is kept at the
same temperature for 2 hours and methyl iodide (0.93 mL, 14.9 mmol)
is added at 0.degree. C. The reaction mixture is allowed to warm up
to room temperature overnight and then quenched with water. The
mixture is separated and the aqueous phase is extracted with ethyl
acetate (2.times.40 mL). The extracts are combined, washed with
brine, dried, concentrated and purified by column chromatography
(hexane/ethyl acetate 50:1 to 4:1) to give 4 (2.2 g, 69%) as a
yellow solid.
d) 2-Methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine dihydrochloride
(1)
##STR00011##
[0146] Freshly distilled Ti(O-iPr).sub.4 (11.2 mL, 38.0 mmol) is
added to a solution of 4 (4.4 g, 19.0 mmol) in ammonia in methanol
(7 M, 30 mL). The reaction mixture is stirred at room temperature
for 12 hours and then cooled to 0.degree. C. NaBH4 (1.4 g, 38.0
mmol) is added slowly. The reaction is then warmed up to room
temperature for 3 hours and then poured into ammonium hydroxide (50
mL). The mixture is extracted with ethyl acetate (2.times.50 mL).
The extracts are combined, washed with brine, dried, concentrated
and purified by column chromatography (pretreated with
triethylamine) (DCM/methanol 20:1) to yield the free base of 1 (3.0
g) as a yellow oil. This oil is dissolved in isopropyl acetate (50
mL) and a solution of 5-6 N HCl in isopropyl alcohol (4.0 mL) is
added. The mixture is concentrated, dissolved in methanol,
concentrated and triturated in ether to yield 1 (4.0 g, 60%) as a
white solid. M.p.=188.degree. C. .sup.1H NMR (300 MHz, CD3OD):
.delta. 1.59 (s, 3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m,
2H), 7.38-7.40 (m, 3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz,
1H), 8.56 (t, J=7.8 Hz, 1H), 8.77 (d, J=5.7 Hz, 1H); .sup.13C NMR
(75 MHz, CD3OD): .delta. 22.2, 22.6, 43.7, 62.4, 126.2, 126.4,
128.1, 128.9, 129.6, 133.3, 142.9, 146.9. MS: m/z 227.
Example 1B
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine via Scheme II
a) 2-Methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine dihydrochloride
(1)
##STR00012##
[0148] To a stirred solution of benzaldehyde (3.44 mL, 33.92 mmol)
in THF (35 mL) is added a THF solution of lithium
bis(trimethylsilyl)amide (37.3 mL, 37.32 mmol) at 0.degree. C. The
mixture is stirred at 0.degree. C. for 2 hours. To the resulting
solution is added (2-(pyridin-2-yl)propan-2-yl)potassium (6.48 g,
40.71 mmol) at -20 to -15.degree. C. drop-wise prepared in the
following manner: in a dried, nitrogen-flushed flask was placed
potassium 2-methylpropan-2-olate (61.9 mL, 61.89 mmol) (1.0 M in
THF) and diisopropylamine (8.75 mL, 61.89 mmol). The mixture is
cooled to -20.degree. C. and BuLi (30.9 mL, 49.51 mmol) is slowly
added to give a yellow solution. The reaction mixture is then
cooled to -50.degree. C. and 2-isopropylpyridine (5 g, 41.26 mmol)
is added and the mixture stirred 30 minutes. The mixture is then
stirred at -20.degree. C. for 30 minutes, and sat. NH.sub.4Cl is
added. The mixture is extracted with EA (3.times.). Combined EA are
washed with sat. NaCl, dried over Na.sub.2SO.sub.4, filtered and
concentrated by ISCO column (240 g), eluting with 0-70% EA/Hex,
then 5% MeOH/DCM to give
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine (6.07 g, 79%) as
an yellow oil. This oil is dissolved in isopropyl acetate (50 mL)
and a solution of 5-6 N HCl in isopropyl alcohol (4.0 mL) is added.
The mixture is concentrated, dissolved in methanol, concentrated
and triturated in ether to yield 1 (4.0 g, 60%) as a white solid.
M.p.=188.degree. C. .sup.1H NMR (300 MHz, CD3OD): .delta. 1.59 (s,
3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m, 2H), 7.38-7.40 (m,
3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.56 (t, J=7.8
Hz, 1H), 8.77 (d, J=5.7 Hz, 1H); .sup.13C NMR (75 MHz, CD3OD):
.delta. 22.2, 22.6, 43.7, 62.4, 126.2, 126.4, 128.1, 128.9, 129.6,
133.3, 142.9, 146.9. MS: m/z 227.
Example 2
(R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine
##STR00013##
[0150] (R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine is
prepared starting from [0151] racemic
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC
chromatography. This oil is dissolved in isopropyl acetate and a
solution of 5-6 N HCl in isopropyl alcohol is added. The mixture is
concentrated, and triturated in ether to yield 3 as a white solid.
M.p.=188.degree. C. .sup.1HNMR (300 MHz, CD3OD): .delta. 1.59 (s,
3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m, 2H), 7.38-7.40 (m,
3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.56 (t, J=7.8
Hz, 1H), 8.77 (d, J=5.7 Hz, 1H). MS: m/z 227.
Example 3
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine (3)
##STR00014##
[0153] (S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine is
prepared starting from racemic
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC
chromatography. This oil is dissolved in isopropyl acetate and a
solution of 5-6 N HCl in isopropyl alcohol is added. The mixture is
concentrated, and triturated in ether to yield 4 as a white solid.
M.p.=188.degree. C. .sup.1HNMR (300 MHz, CD.sub.3OD): .delta. 1.59
(s, 3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m, 2H), 7.38-7.40
(m, 3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.56 (t,
J=7.8 Hz, 1H), 8.77 (d, J=5.7 Hz, 1H). MS: m/z 227.
An alternative route to generate Example 3 is described below:
##STR00015##
a) 2-Isopropylpyridine
##STR00016##
[0155] 2-Isopropylpyridine was prepared by the method of P. Rocca,
et. al. (Tetrahedron Vol. 54, pp. 8771-8782 (1998). A solution of
2-ethylpyridine (1000 g, 9.332 moles) in anhydrous Tetrahydrofuran
(6000 mL) was cooled to -35.degree. C. by a dry ice/acetone bath.
n-Butyllithium (3970 mL of 2.5 Molar, 9.925 moles) was added at a
fast drop-wise rate over a period of 1.5 hours, while maintaining
the internal temperature at -20.degree. C. to -25.degree. C.
Stirring was continued for an additional 1.5 hours at -20.degree.
C., then the reaction was cooled to -45.degree. C. Iodomethane (642
mL, 1458 g, 10.272 moles) was added at a moderate drop-wise rate
over a period of 1.5 hours, while maintaining the reaction
temperature between -40.degree. C. and -45.degree. C. After the
addition was complete, the mixture was allowed to stir for an
additional 2 hours at -40.degree. C., then was quenched by the fast
drop-wise addition of water (4000 mL) added over a period of 30
minutes. The reaction mixture was cooled to 0.degree. C. and
treated with concentrated Hydrochloric acid (1150 mL) added over a
period of 15 minutes. The mixture was allowed to stir for an
additional hour while warming to 15.degree. C., then was
transferred to a separatory funnel with diethyl ether (2000 mL),
and the layers separated. The aqueous phase was further washed with
diethyl ether (3.times.1000 mL), then made basic (pH=9) by
treatment with solid potassium carbonate. The aqueous mixture was
extracted with diethyl ether (4.times.1000 mL). The combined
extracts were washed with saturated brine (1000 mL) then dried
(anhydrous magnesium sulfate). Filtration, followed by removal of
the solvent under reduced pressure at room temperature, gave the
crude product as a reddish-orange liquid (.about.2000 mL). This
crude product was distilled (twice) at atmospheric pressure through
a three inch, glass vigreaux column, collecting the desired
2-isopropylpyridine (b.p. 158-163.degree. C.) as a light yellow
liquid (926 g, 82% yield). .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta. ppm 8.53 (d, J=4.22 Hz, 1H) 7.59 (td, J=7.59, 1.69 Hz, 1H)
7.16 (d, J=8.01 Hz, 1H) 7.08 (ddd, J=7.38, 4.85, 0.84 Hz, 1H)
2.94-3.25 (m, J=6.91, 6.91, 6.91, 6.91, 6.91, 6.74 Hz, 1H) 1.31 (d,
J=6.74 Hz, 6H).
b) (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide
##STR00017##
[0157] To a solution of (R)-2-methylpropane-2-sulfinamide (1032 g,
8.515 moles) in dichloromethane (14000 mL) was added benzaldehyde
(1000 g, 9.423 moles) in one portion at room temperature. Anhydrous
copper (II) sulfate (2718 g, 17.029 moles) was added in portions as
a solid over a 10-minute period, and washed down with additional
dichloromethane (1000 mL). The reaction mixture was allowed to stir
for 45 hours at room temperature, and was checked for completion by
HPLC. The mixture was filtered through a pad of Celite to remove
the copper (II) sulfate. The filter cake was washed with
dichloromethane (4.times.1500 mL), and the combined filtrates
concentrated under reduced pressure to a cloudy yellow oil (1914 g,
107% of theory). The crude product was subjected to chromatography
over silica gel, eluting with a gradient of 0-10% ethyl acetate in
dichloromethane to yield the purified sulfinamide as a pale yellow
oil (1563 g, 88% yield). .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta. ppm 8.60 (s, 1H) 7.85 (dd, J=7.80, 1.48 Hz, 2H) 7.40-7.62
(m, 3H) 1.27 (s, 9H). MS: m/z 210.
c)
(R)-2-methyl-N-((S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propyl)propane-2-
-sulfinamide
##STR00018##
[0159] To a 1.0 Molar solution of potassium t-butoxide in
tetrahydrofuran (3000 mL, 3.000 moles) was added diisopropylamine
(425 mL, 306.8 g, 3.032 moles). The resulting solution was cooled
by a dry ice/acetone bath to -50.degree. C. n-Butyllithium solution
(980 mL of 2.5 Molar, 2.450 moles) was added drop-wise over a
period of 40 minutes, giving a bright orange solution. The mixture
was allowed to stir for an additional 20 minutes at -25.degree. C.,
then was cooled back down to -55.degree. C. 2-isopropylpyridine (1)
(240.0 g, 1.981 moles) was then added drop-wise over a period of 20
minutes while maintaining the internal temperature between
-50.degree. C. to -55.degree. C., giving a deep, reddish-purple
solution. The mixture was allowed to stir for an additional 2 hours
at -50.degree. C., then was used directly in the next step.
[0160] To the cooled (-50.degree. C.) mixture containing the
2-Isopropylpyridyl anion was added a solution of
(R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (2) (360.0 g,
1.720 moles) in anhydrous tetrahydrofuran (3000 mL), drop-wise over
a period of 3 hours while maintaining the internal temperature
between -50.degree. C. and -55.degree. C. The reaction mixture was
allowed to warm gradually over 3 hours to 0.degree. C., then
checked for completion by working up an aliquot and checking by
HPLC. The reaction was quenched by treatment with saturated sodium
bicarbonate solution (3000 mL), added drop-wise over 20 minutes.
After stirring for an additional 30 minutes, the mixture was
further diluted with water (3000 mL), and divided into three
portions (.about.4500 mL each). Each portion was partitioned with
ethyl acetate (1000 mL), and the layers separated. The combined
aqueous layer was further extracted with ethyl acetate
(3.times.1000 mL). The combined organic extracts were washed with
saturated brine (1500 mL), then dried (anhydrous magnesium
sulfate). Filtration, followed by removal of the solvent under
reduced pressure, left the crude product as a cream-colored solid
(575.8 g, 101.3% crude yield), which was a 9:1 mixture of
diastereomers. The crude material was recrystallized from a mixture
of Hexane/EtOAc (2:1) to give pure desired single diastereomer
(371.9 g, 65.4% yield). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
ppm 8.62 (dd, J=4.85, 1.05 Hz, 1H) 7.52 (td, J=7.80, 2.11 Hz, 1H)
7.09-7.19 (m, 4H) 6.99 (d, J=8.01 Hz, 1H) 6.85-6.94 (m, 2H) 5.80
(d, J=8.01 Hz, 1H) 4.49 (d, J=8.43 Hz, 1H) 1.46 (s, 3H) 1.33 (s,
3H) 1.10 (s, 9H). MS: m/z 331.
d) (S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propan-1-amine
##STR00019##
[0162] To a solution of
(R)-2-methyl-N-((S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propyl)propane-2-su-
lfinamide (1200 g, 3.631 moles) dissolved in dichloromethane (12000
mL) was added 4N hydrogen chloride/dioxane solution (3000 mL, 12.00
moles) in a steady stream over a period of 1 hour at room
temperature. A thick suspension formed, which was continued
stirring for 1.5 hours at 32.degree. C. at which point methanol
(1000 mL) was added to improve stirring. After 30 minutes
additional stirring, all of the solids dissolved, giving a clear
amber solution and indicating complete reaction. The solvents were
removed under reduced pressure leaving a gummy amber residue. The
residue was taken up in distilled water (5000 mL), and the
resulting solution washed with diethyl ether (2.times.1000 mL) to
remove neutral impurities. The acidic solution was treated with
solid Sodium hydroxide (400 g, 10.00 moles) until strongly basic
(pH=11). The resulting aqueous mixture was extracted with
dichloromethane (2.times.1000 mL, then 2.times.500 mL). The
combined organic extracts were dried (anhydrous magnesium sulfate).
Filtration, followed by removal of the solvent under reduced
pressure, left a thick amber syrup. This residue was further dried
under high vacuum to yield the crude de-protected amine (880.9 g,
107.2% of theory). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm
8.64 (d, J=3.79 Hz, 1H) 7.57 (td, J=7.69, 1.90 Hz, 1H) 7.05-7.30
(m, 7H) 4.48 (s, 1H) 1.47 (br.s., 2H) 1.36 (s, 3H) 1.25 (s, 3H).
MS: m/z 227.
e) (S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propan-1-amine Fumarate
Salt
##STR00020##
[0164] (S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propan-1-amine (821.7
g, 3.63 moles) was dissolved in methanol (5000 mL) giving a
reddish-orange solution. The solution was treated with Norit
decolorizing Carbon (50 g) and stirred at gentle reflux for 2
hours. The hot solution was filtered through a pad of Celite,
giving a light yellow filtrate. The Carbon filter cake was further
washed with hot methanol (2.times.1000 mL), and the washes combined
with the original filtrate. The decolorized solution of (4) was
treated with fumaric acid (421.4 g, 3.63 moles), added as a dry
solid over a period of 5 minutes. The solution was allowed to stir
at room temperature for 30 minutes, then was concentrated under
reduced pressure to remove most of the methanol (6000 mL removed).
The resulting thick amber syrup was diluted gradually with vigorous
stirring with diethyl ether (7000 mL) until crystallization ensued.
The mixture was stirred vigorously until a very healthy crop of
crystals had formed. The mixture was then further diluted with
additional diethyl ether (2000 mL, total volume of 9000 mL) with
vigorous stirring to complete the crystallization. The crystals
were collected by suction filtration and pulled free of liquors.
The crystals were re-suspended in a mixture of 9:1 diethyl
ether/methanol (2000 mL) and stirred vigorously for several
minutes, then re-filtered and pulled dry. The process was repeated
a second time. The white crystals obtained from this treatment were
dried to constant weight in the vacuum oven at 60.degree. C. to
yield (S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propan-1-amine
fumarate salt (1179.3 g, 95% yield). .sup.1H NMR (300 MHz, DMSO-d
6) .delta. ppm 9.19 (br. s., 3H) 8.62 (d, J=3.37 Hz, 1H) 7.71 (td,
J=7.80, 1.69 Hz, 1H) 7.17-7.39 (m, 5H) 6.94-7.17 (m, 2H) 6.51 (s,
2H) 4.64 (s, 1H) 1.35 (s, 3H) 1.26 (s, 3H). .sup.13C NMR (75 MHz,
DMSO-d 6): .delta. ppm 23.7, 25.7, 43.8, 62.7, 121.3, 122.3, 128.0,
128.1, 128.6, 135.5, 137.4, 137.8, 148.7, 164.9, 168.3. MS: m/z
227.
Example 4
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
##STR00021##
[0166] 1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
is prepared according to method 2 using 3-fluorobenzaldehyde
instead of benzaldehyde. The free base was dissolved in EtOAc and a
solution of fumaric acid (1.0 eq) in MeOH is added. The solvent is
removed in vacuo and the residue is triturated with
Et.sub.2O/hexanes (1:1), collected by filtration and air-dried.
.sup.1HNMR (300 MHz, DMSO-d6) .delta. 1.19 (s, 3H), 1.31 (s, 3H),
4.48 (s, 1H), 6.55 (s, 2 H), 6.85-6.95 (m, 2H), 7.01 (t, J=8.9 Hz,
1H), 7.18-7.34 (m, 3H), 7.64-7.77 (m, 1H), 8.59 (d, J=3.8 Hz, 1H).
MS: m/z 245.
Example 5
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
##STR00022##
[0168]
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine is
prepared starting from racemic
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine using
chiral SFC chromatography. The free base was dissolved in EtOAc and
a solution of fumaric acid (1.0 eq) in MeOH is added. The solvent
is removed in vacuo and the residue is triturated with
Et.sub.2O/hexanes (1:1), collected by filtration and air-dried.
.sup.1HNMR (300 MHz, DMSO-d6) .delta. 1.19 (s, 3H), 1.31 (s, 3H),
4.48 (s, 1H), 6.55 (s, 2H), 6.85-6.95 (m, 2H), 7.01 (t, J=8.9 Hz,
1H), 7.18-7.34 (m, 3H), 7.64-7.77 (m, 1H), 8.59 (d, J=3.8 Hz, 1H).
MS: m/z 245.
Example 6
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
##STR00023##
[0170]
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine is
prepared starting from racemic
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine using
chiral SFC chromatography. The free base was dissolved in EtOAc and
a solution of fumaric acid (1.0 eq) in MeOH is added. The solvent
is removed in vacuo and the residue is triturated with
Et.sub.2O/hexanes (1:1), collected by filtration and air-dried.
.sup.1HNMR (300 MHz, DMSO-d6) .delta. 1.19 (s, 3H), 1.31 (s, 3H),
4.48 (s, 1H), 6.55 (s, 2H), 6.85-6.95 (m, 2H), 7.01 (t, J=8.9 Hz,
1H), 7.18-7.34 (m, 3H), 7.64-7.77 (m, 1H), 8.59 (d, J=3.8 Hz, 1H).
MS: m/z 245.
Biological Evaluation
[0171] NMDA receptor antagonist activity can be measured in vitro
by assaying a compound's ability to inhibit binding of the receptor
antagonist
10,11-dihydro-5-methyl-5H-dibenzo[a,d]-cyclohepten-5,10-imine
(MK801) to the receptor. The method is described by Foster and
Wong, Br. J. Pharmacol. 91, 403-409 (1987).
[0172] The IC.sub.50 values of examples 1-6 are set forth in Table
1.
TABLE-US-00001 TABLE 1 Compound of MK801 Binding Example #
IC.sub.50 (.mu.M) Example 1 12 Example 2 6.4 Example 3 35 Example 4
3.3 Example 5 5.5 Example 6 25
Example 7
Determination of the Stereochemical Structure of Example 3
[0173] a) Colorless block crystals of a hemi-hydrate form of the
di-HCl Salt of Example 3 were obtained by slow evaporation of a
MeOH/IPA solution of the compound of Example 3. b) The crystal
structure of the di-HCl hemi-hydrate salt was determined by single
crystal analysis. The anomalous dispersion method of the Cl atoms
in the di-HCl salt was used to establish the absolute crystal
structure.
[0174] Diffraction data were collected at 23.degree. C. on a Bruker
Apex diffractometer. The crystal structure was solved and refined
with a SHELXTL software package.
TABLE-US-00002 TABLE 2 Crystallographic Data (S) # a (.ANG.)
9.1673(7) b (.ANG.) 9.6613(7) c (.ANG.) 10.0944(7) .alpha.
(.degree.) 78.990(1) .beta. (.degree.) 87.385(1) .gamma. (.degree.)
68.228(1) V (.ANG..sup.3) 814.67(10) Z' 2 SG P1 d 1.257 R(F.sup.2)
0.0364
Molecular Structure:
[0175] The crystal structure revealed a hemi hydrate form of the
di-HCl salt. The anomalous dispersion method of the Cl atoms in the
di-HCl salt (the absolute structure factor: f=0.04(3)) established
that in the crystal the molecule of Example 3 had an
(S)-configuration as depicted below as Formula I:
##STR00024##
[0176] In the crystal, two molecules of Formula I, four Cl anions,
and one water molecule exist in an asymmetric unit. Both the amine
N atom and pyridyl N atom are protonated.
Example 8
(S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propan-1-amine fumarate
salt
(a) 2-Isopropylpyridine (vii)
##STR00025##
[0178] 2-Isopropylpyridine (vii) was prepared by the method of P.
Rocca, et. al. (Tetrahedron Vol. 54, pp. 8771-8782 (1998). A
solution of 2-ethylpyridine (1000 g, 9.332 moles) in anhydrous THF
(6000 mL) was cooled to -35.degree. C. by a dry ice/acetone bath.
n-Butyllithium (3970 mL of 2.5 M, 9.925 moles) was added at a fast
drop-wise rate over a period of 1.5 hours, while maintaining the
internal temperature at -20.degree. C. to -25.degree. C. Stirring
was continued for an additional 1.5 hours at -20.degree. C., then
the reaction was cooled to -45.degree. C. Iodomethane (642 mL, 1458
g, 10.27 moles) was added at a moderate drop-wise rate over a
period of 1.5 hours, while maintaining the reaction temperature
between -40.degree. C. and -45.degree. C. After the addition was
complete, the mixture was allowed to stir for a further 2 hours at
-40.degree. C., and then quenched by the fast drop-wise addition of
water (4000 mL) added over a period of 30 minutes. The reaction
mixture was cooled to 0.degree. C. and treated with concentrated
HCl (1150 mL) added over a period of 15 minutes. The mixture was
allowed to stir for an additional hour while warming to 15.degree.
C., then was transferred to a reparatory funnel with diethyl ether
(2000 mL), and the layers separated. The aqueous phase was further
washed with diethyl ether (3.times.1000 mL), then made basic (pH=9)
by treatment with solid potassium carbonate. The aqueous mixture
was extracted with diethyl ether (4.times.1000 mL). The combined
ether extracts were washed with saturated brine (1000 mL) then
dried (anhydrous MgSO.sub.4). Filtration, followed by removal of
the solvent under reduced pressure at room temperature, yielded the
product as a reddish-orange liquid (.about.2000 mL). This product
was distilled (twice) at atmospheric pressure through a three inch,
glass Vigreaux column, collecting the desired 2-isopropylpyridine
(vii) (b.p. 158-163.degree. C.) as a light yellow liquid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. ppm 1.31 (d, 6H), 2.94-3.25 (m,
1H), 8.53 (d, 1H), 7.08 (ddd, 1H), 7.16 (d, 1H), 7.59 (td, 1H)
(b) (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (ix)
##STR00026##
[0180] To a solution of (R)-2-methylpropane-2-sulfinamide (viii)
(1032 g, 8.515 moles) in DCM (14000 mL) was added benzaldehyde (ii)
(1000 g, 9.423 moles) in one portion at room temperature. Anhydrous
copper (II) sulfate (2718 g, 17.03 moles) was added in portions as
a solid over a 10-minute period, and washed in with additional DCM
(1000 mL). The reaction mixture was allowed to stir for 45 hours at
room temperature and then filtered through a pad of diatomaceous
earth. The filter cake was washed with DCM (4.times.1500 mL), and
the combined DCM filtrates concentrated under reduced pressure to a
cloudy yellow oil. The product was subjected to chromatography over
silica gel, eluting with a gradient of 0-10% EtOAc in DCM to yield
the purified sulfinamide (ix) as a pale yellow oil (1563 g, 88%
yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 1.27 (s, 9H),
7.40-7.62 (m, 3H), 7.85 (dd, 2H), 8.60 (s, 1H). MS: m/z 210.
(c)
(R)-2-methyl-N-((S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propyl)propane--
2-sulfinamide (x)
##STR00027##
[0182] To a 1.0 M solution of potassium t-butoxide in THF (3000 mL,
3.000 moles) was added diisopropylamine (425 mL, 306.8 g, 3.032
moles). The resulting solution was cooled with a dry ice/acetone
bath to -50.degree. C. n-Butyllithium solution (980 mL of 2.5 M,
2.450 moles) was added drop-wise over a period of 40 minutes, to
yield a bright orange solution. The mixture was allowed to stir for
an additional 20 minutes at -25.degree. C., then was cooled to
-55.degree. C. 2-Isopropylpyridine (vii) (240.0 g, 1.981 moles) was
then added drop-wise over a period of 20 minutes while maintaining
the internal temperature between -50.degree. C. to -55.degree. C.,
to yield a deep, reddish-purple solution. The mixture was allowed
to stir for an additional 2 hours at -50.degree. C., then was used
directly in the next step.
[0183] To the cooled (-50.degree. C.) mixture containing the
2-isopropylpyridyl anion (vi) was added a solution of
(R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (ix) (360.0 g,
1.720 moles) in anhydrous THF (3000 mL), drop-wise over a period of
3 hours while maintaining the internal temperature between
-50.degree. C. and -55.degree. C. The reaction mixture was allowed
to warm gradually over 3 hours to 0.degree. C., checked for
completion of reaction by working up an aliquot and checking by
HPLC. The reaction was quenched by treatment with saturated
Na.sub.2CO.sub.3 solution (3000 mL), added drop-wise over 20
minutes. After stirring for an additional 30 minutes, the mixture
was further diluted with water (3000 mL), and divided into three
portions (.about.4500 mL each). Each portion was partitioned with
EtOAc (1000 mL), and the layers separated. The combined aqueous
layer was further extracted with EtOAc (3.times.1000 mL). The
combined EtOAc extracts were washed with saturated brine (1500 mL),
and dried (anhydrous MgSO.sub.4). Filtration, followed by removal
of the solvent under reduced pressure, yielded a product as a
cream-colored solid, which was a 9:1 mixture of diastereomers. This
material was recrystallized from a mixture of hexanes/EtOAc (2:1)
to give the pure desired single diastereomer (x) (371.9 g, 65.4%
yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 1.10 (s, 9H),
1.33 (s, 3H), 1.46 (s, 3H), 4.49 (d, 1H), 5.80 (d, 1H), 6.85-6.94
(m, 2H), 6.99 (d, 1H), 7.09-7.19 (m, 4H), 7.52 (td, 1H), 8.62 (dd,
1H). MS: m/z 331.
(d) (S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propan-1-amine (xi)
##STR00028##
[0185] To a solution of
(R)-2-methyl-N-((S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propyl)propane-2-su-
lfinamide (x) (1200 g, 3.631 moles) dissolved in DCM (12000 mL) was
added 4N hydrogen chloride/dioxane solution (3000 mL, 12.00 moles)
in a steady stream over a period of 1 hour at room temperature. A
thick suspension formed, which was continually stirred for 1.5
hours at 32.degree. C. at which point MeOH (1000 mL) was added to
improve stirring. After 30 minutes additional stirring all the
solids dissolved, giving a clear amber solution and indicating
complete reaction. The solvents were removed under reduced pressure
leaving a gummy amber residue. The residue was taken up in
distilled water (5000 mL), and the resulting solution washed with
diethyl ether (2.times.1000 mL) to remove neutral impurities. The
acidic solution was treated with solid sodium hydroxide (400 g,
10.00 moles) until strongly basic (pH=11). The resulting aqueous
mixture was extracted with DCM (2.times.1000 mL, then 2.times.500
mL). The combined DCM extracts were dried (anhydrous MgSO.sub.4).
Filtration, followed by removal of the solvent under reduced
pressure, yielded a thick amber syrup. This residue was further
dried in vacuo to yield a de-protected amine (xi) (880.9 g,
quantitative). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 1.25
(s, 3H), 1.36 (s, 3H), 1.47 (br.s., 2H), .delta. 4.48 (s, 1H),
7.05-7.30 (m, 7H), 7.57 (td, 1H), 8.64 (d, 1H). MS: m/z 227.
(e) (S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propan-1-amine (8)
fumarate salt
##STR00029##
[0187] (S)-2-Methyl-1-phenyl-2-(pyridine-2-yl)propan-1-amine (xi)
(821.7 g, 3.63 moles) was dissolved in MeOH (5000 mL) to yield a
reddish-orange solution. The solution was treated with decolorizing
carbon (50 g) and stirred at gentle reflux for 2 hours. The hot
solution was filtered through a pad of diatomaceous earth, to yield
a light yellow filtrate. The carbon filter cake was further washed
with hot MeOH (2.times.1000 mL), and the washes combined with the
original filtrate. The decolorized solution was treated with
fumaric acid (421.4 g, 3.63 moles), added as a dry solid over a
period of 5 minutes. The solution was allowed to stir at room
temperature for 30 minutes, concentrated under reduced pressure to
remove most of the MeOH (6000 mL removed). The resulting thick
amber syrup was diluted gradually with vigorous stirring with
diethyl ether (7000 mL) until crystallization ensued. The mixture
was stirred vigorously until crystals formed. The mixture was then
further diluted with additional diethyl ether (2000 mL, total
volume of 9000 mL) with vigorous stirring to complete the
crystallization. The crystals were collected by suction filtration
and pulled free of liquors. The crystals were re-suspended in a
mixture of 9:1 diethyl ether/MeOH (2000 mL) and stirred vigorously
for several minutes, then re-filtered and pulled dry. The process
was repeated a second time. The white crystals obtained from this
treatment were dried to constant weight in vacuo at 60.degree. C.
to yield (S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propan-1-amine
fumarate salt (8) (1179.3 g, 95% yield).
[0188] .sup.1H NMR (300 MHz, DMSO-d6) .delta. ppm 1.26 (s, 3H),
1.35 (s, 3H), 4.64 (s, 1H), 6.51 (s, 2H), 6.94-7.17 (m, 2H),
7.17-7.39 (m, 5H), 7.71 (td, 1H), 8.62 (d, 1H), 9.19 (br.s., 3H).
.sup.13C NMR (75 MHz, DMSO-d6): .delta. ppm 23.7, 25.7, 43.8, 62.7,
121.3, 122.3, 128.0, 128.1, 128.6, 135.5, 137.4, 137.8, 148.7,
164.9, 168.3. MS: m/z 227.
Example 9
1-(3-Fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine fumarate
salt, racemate (9)
##STR00030##
[0190] The title compound was prepared according to the method of
Scheme 1 using 3-fluorobenzaldehyde in place of benzaldehyde. The
free base was dissolved in EtOAc and a solution of fumaric acid
(1.0 eq) in MeOH was added. The solvent was removed in vacuo and
the residue triturated with Et.sub.2O/hexanes (1:1), collected by
filtration and air-dried. .sup.1HNMR (300 MHz, DMSO-d6) .delta.
1.19 (s, 3H), 1.31 (s, 3H), 4.48 (s, 1H), 6.55 (s, 2H), 6.85-6.95
(m, 2H), 7.01 (t, J=8.9 Hz, 1H), 7.18-7.34 (m, 3H), 7.64-7.77 (m,
1H), 8.59 (d, 1H). MS: m/z 245.
Example 10
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine fumarate
salt, stereoisomer 1 (10)
##STR00031##
[0192] The title compound was prepared starting from racemic
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine using
chiral SFC. Fractions containing the first eluting peak were
combined and the solvent removed in vacuo to give 0.46 g of free
base, which was dissolved in EtOAc, and a solution of fumaric acid
(1.0 eq) in MeOH was added. The solvent was removed in vacuo and
the residue triturated with Et.sub.2O/hexanes (1:1), collected by
filtration and air-dried to give 650 mg of the title compound with
an ee of 97%. .sup.1HNMR (300 MHz, DMSO-d6) .delta. 1.21 (s, 3H),
1.32 (s, 3H), 4.452 (s, 1H), 6.54 (s, 2H), 6.85-6.94 (m, 2H),
6.97-7.08 (m, 1H), 7.19-7.31 (m, 3H), 7.70 (td, 1H), 8.60 (d, 1H).
MS: m/z 245.
Example 11
1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine fumarate
salt, stereoisomer 2 (11)
##STR00032##
[0194] The title compound was prepared was prepared starting from
racemic 1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine
using chiral SFC. Fractions containing the second eluting peak were
combined and the solvent removed in vacuo to give 0.46 g of free
base, which was dissolved in EtOAc, and a solution of fumaric acid
(1.0 eq) in MeOH was added. The solvent was removed in vacuo and
the residue triturated with Et.sub.2O/hexanes (1:1), collected by
filtration and air-dried to give 638 mg of the title compound with
an ee of 94%. .sup.1HNMR (300 MHz, DMSO-d6) .delta. 1.20 (s, 3H),
1.32 (s, 3H), 4.50 (s, 1H), 6.55 (s, 2H), 6.85-6.94 (m, 2H),
6.97-7.06 (m, 1H), 7.19-7.32 (m, 3H), 7.70 (t, 1H), 8.59 (d, 1H).
MS: m/z 245.
Example 12
1-phenyl-2-(pyridin-2-yl)ethanamine dihydrochloride (12)
##STR00033##
[0196] The title compound was prepared as described in WO
93/20052.
Example 13
(S)-1-phenyl-2-(pyridin-2-yl)ethanamine dihydrochloride (13)
##STR00034##
[0198] The racemate of Example 12 was subjected to preparative
chiral chromatography (10 injections of 85 mg in 1 mL methanol) on
a Berger SFC Multigram II system. The column used was a LUX-C2
20.times.250 mm, 5 .mu.M material. The mobile phase was 30%
methanol containing 0.1% diethylamine and 70% carbon dioxide. The
flow was 50 mL/min. Comparison with the elution properties of an
authentic sample with known configuration (as described in WO
93/20052) revealed that the second isomer to elute was the
S-enantiomer. The fractions comprising the second-eluting peak were
pooled and the solvent was evaporated at reduced pressure to give
the (S)-isomer free base as liquid in 335 mg yield.
[0199] The free base (62 mg) was dissolved in ether (5 mL) and 2M
HCl (0.5 mL) was added dropwise to the solution. The mixture was
swirled in the flask for a few minutes before evaporation of the
solvent at reduced pressure. The remaining solid was put under
vacuum (.about.5 mbar) for 5-10 min to yield 85 mg of the title
compound.
[0200] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 3.64
(dd, 1H), 3.83 (dd, 1H), 7.40-7.48 (m, 5H), 7.75 (d, 1H), 7.79 (m,
1H), 8.32 (td, 1H), 8.69 (dd, 1H). MS: m/z 199.
Example 14
(R)-1-phenyl-2-(pyridin-2-yl)ethanamine dihydrochloride (14)
##STR00035##
[0202] The title compound was obtained from the same chiral
chromatography run as example 13. The (R)-enantiomer was the first
isomer to elute and fractions comprising the first eluting peak
were pooled and evaporated in vacuo to a liquid. Preparation of the
dichloride was performed in the same manner as for example 13 with
a similar yield.
[0203] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 3.58
(dd, 1H), 3.75 (dd, 1H), 4.83-4.87 (m, 1H) 7.39-7.48 (m, 5H), 7.64
(d, 1H), 7.70 (m, 1H), 8.21 (m, 1H), 8.66 (dd, 1H). MS: m/z
199.
Example 15
Biological Activity
[0204] NMDA receptor antagonist activity was measured in vitro by
assaying a compound's ability to inhibit binding of the receptor
antagonist
10,11-dihdro-5-methyl-5H-dibenzo[a,d]-cyclohepten-5,10-imine
(MK801) to the receptor. The method is described by Foster and
Wong, Br. J. Pharmacol. 91, 403-409 (1987). Results are shown in
Table 3.
TABLE-US-00003 TABLE 3 Biological activity. Mean Mean Ki Mean
IC.sub.50 Maximum Compound (.mu.M) (.mu.M) effect (%) Ex 1
(racemate) 4.9 12 75 Ex 2 (R) >7.9 >25 64 Ex 3 (S) 1.8 5.7 76
Ex 8 (S, fumarate 3.2 5.1 90 analogue of Ex 3) Ex 9 (racemate) 1.3
3.2 83 Ex 10 (isomer 1) 15 25 87 Ex 11 (isomer 2) 2.5 4.1 97 Ex 13
(S) 2.9 6.6 89
Example 16
Isolation of a Stable CHO/Human NR1/NR2A Cell Line
[0205] Chinese Hamster Ovary (CHO-KI) cells were transfected with
Effectene.sup.R reagent following the manufacturer's instructions.
Cells were triply transfected with plasmids pTet-Off, pTRE2-pur
hNR1, and pGEN IRES Hyg-hNR2A. Transfection was done in medium
containing Ham's F12, 10% FBS, 2 mM L-Glutamine, 200 .mu.M ketamine
and 2 .mu.g/ml doxycycline. 24 hours post transfection, cells were
split 1:10 into medium in which 200 .mu.M ketamine was replaced
with 20 .mu.M MK-801. After an additional 24 hours (48 hours post
transfection), antibiotic selection was performed as follows: 1
.mu.g/ml puromycin, 500 .mu.g/ml hygromycin, and 500 .mu.g/ml
geneticin (G418). After two weeks in the selection medium (with
medium changes every 3-5 days), 15-20 clones developed in the
flask. These clones were pooled and cultured for one more week.
Cells were then clonally plated in two 96-well plates at 1
cell/well by limiting dilution. After three weeks, cells were
trypsinized and each original 96-well plate was divided into two;
one plate was cultured in the presence of 2 .mu.g/ml doxycycline
and the other was cultured for assay without doxycycline. After
three days, the assay plates were screened for functional NMDAR
expression by stimulating with 50 .mu.M glycine/100 .mu.M
glutamate. Two positive clones were expanded and tested for
glutamate dose response with glycine fixed at 30 .mu.M. One clone,
CHO-1H8 gave robust, dose-dependent response to glutamate and was
selected for further characterization.
CHO-1H8 Cell Culture:
[0206] For routine culture, CHO-1H8 cells were maintained in Ham's
F-12+2 mM L-Glutamine (PAA, E15-817), 10% FBS (Sigma, F7442), 1
.mu.g/mL puromycin (Invitrogen A1113802), 250 .mu.g/mL hygromycin
(Invitrogen 10687010), 250 .mu.g/mL geneticin (Invitrogen
11811-098), 1 .mu.g/mL doxycycline (Sigma D9891), and 300 .mu.M of
the NMDA-channel blocker
(R)-.alpha.-amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropanoic
acid (CAS 170847-87-7, Swahn et al., Bioorg. Med. Chem. Lett. 1996,
1635). Cells to be used in functional assay were grown in same
medium as above, but with 1 .mu.g/mL doxycycline replaced by 2
.mu.g/mL tetracycline (Sigma T7660) three days before induction.
Growth medium was replaced every 2-3 days, i.e.
Monday-Wednesday-Friday. For induction of NMDAR expression, CHO-1H8
cells were cultured without doxycycline or tetracycline (but with
CAS 170847-87-7) for 48 hours in medium prepared with Tet
System-Approved FBS (BD Biosciences).
Automated Patch Clamp Experiments:
[0207] Patch clamp experiments permit the detection of currents
through the NR1/NR2A channel in the cell line described above. In
order to monitor block of the NR1/NR2A channel specific currents,
an electrophysiological assay was developed and implemented on the
QPatch16 automated electrophysiology instrument (Sophion).
[0208] NR1/NR2A cells were induced for 48 hours and dissociated
with TrypLE Express (GIBCO, 12604) immediately prior to use. Cells
were resuspended in QPatch storage buffer (500 ml CHO-S-SFM II
(Invitrogen, 12052), HEPES 25 mM, CAS 170847-87-7 (100 .mu.M) at
1-2 million cells per ml and loaded in the QPatch16 instrument.
Cells were pipetted to QPlate wells and whole cell configuration
established using the instrument's integrated fluidics and pressure
controls and following the manufacturer's recommended protocols.
The extracellular bath solution is composed of (mM): NaCl 140, KCl
5, BaCl.sub.2 1, HEPES 5, glucose 3, pH adjusted to 7.35-7.4 using
NaOH. The intracellular solution contains (mM): CsF 120, NaCl 10,
HEPES 10, Na2 phosphocreatine 20, EGTA 10 (in CsOH), Na.sub.2ATP 4,
GTP 0.3, pH adjusted to 7.3 using CsOH. Currents were sampled at 2
KHz and filtered at 1 KHz.
[0209] In order to evaluate effects of test compounds as inhibitors
of NR1/NR2A channels, the channels were first activated by addition
of a NMDAR agonist NMDA (Sigma, M3262) and Glycine (Merck, 3570) to
the extracellular bath solution. NR1/NR2A cells were clamped at -60
mV. NR1/NR2A currents were recorded for 12 sec after activation
with 100 .mu.M NMDA/10 .mu.M Glycine (I.sub.control). Then 0.41
.mu.M of compound in the presence of 100 .mu.M NMDA/10 .mu.M
Glycine was added and recorded for 10 sec followed by washout with
two saline additions (I.sub.test). A baseline recording was done
prior to NR1/NR2A channel activation (I.sub.baseline).
[0210] Similar additions and recordings were done with 1.23 .mu.M,
3.70 .mu.M, 11.11 .mu.M and 33.33 .mu.M of test compounds
sequentially.
[0211] Percent inhibition of NR1/NR2A currents was calculated at
each test compound concentration as
100.times.(1-(I.sub.test-I.sub.baseline/I.sub.control-I.sub.baseline)).
[0212] Percent inhibition values were calculated at each test
compound concentration for each cell and the curve fitting program
GraphPad (V. 4.03, Prism) was used to fit with a Hill equation to
provide IC.sub.50 values and Hill slope values.
NMDA Trapping Data:
[0213] Trapping data was generated as described in Mealing et al.,
J. Pharmacol. Exp. Therapeutics 2001, (297/3), 906-914.
TABLE-US-00004 TABLE 4 Biological data ##STR00036## 3,
(S)-configuration ##STR00037## 13, (S)-configuration Mean IC.sub.50
Compound configuration (.mu.M) Trapping (%) Example 2 (R) 10
Example 3 (S) 3 39 Example 13 (S) 6 53 Example 14 (R) 10
[0214] We show that the greatest NMDA antagonist activity lies with
the (S) enantiomers of both 1-phenyl-2-(pyridin-2-yl)ethanamine and
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine.
[0215] Interestingly, while these two compounds are both designated
(S) by the application of the Cahn-Ingold-Prelog priority rules for
naming stereoisomers of organic compounds, the two compounds have
different geometric configurations. That is, when the structure of
the more potent enantiomer of
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine (Example 3,
(S)-enantiomer) is depicted as in Table 4, the NH.sub.2 moiety lies
below the plane of the paper, whereas when the more potent
enantiomer of 1-phenyl-2-(pyridin-2-yl)ethanamine (Example 13,
(S)-enantiomer) is similarly depicted, the NH.sub.2 moiety lies
above the plane of the paper. This suggests that
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine interacts with the
NMDA receptor in different ways than does
1-phenyl-2-(pyridin-2-yl)ethanamine, as the potencies towards the
NMDA receptor do not correlate with the alignment of the pyridine
moiety, the phenyl moiety and the amino group in space. The greater
activity and lower trapping of
2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine at the receptor
may be attributed to these differences.
* * * * *