COMPLETE SPECIFICATION
BACKGROUND OF THE INVENTION
The catecholamine-oxidizing enzyme monoamine oxidase-B (MAO-B) has been
hypothesized to be an important determining factor in neurological disorders such as
Parkinson's disease. MAO-B regulates levels of brain neurotransmitters, including
dopamine. Catalysis of neurotransmitters by monamine oxidase also produces hydrogen
peroxide which is a primary originator of oxidative stress which in turn can lead to
cellular damage. Inhibition of MAO-B, along with supplementation of dopamine via
levodopa, is one of the major antiparkinsonian therapies currently in use. Current MAO-
B inhibitors (propargylamines) are irreversible inhibitors.
Inhibitors of monoamine oxidase-A (MAO-A) are useful for the treatment of depression
and anxiety as MAO-A predominantly metabolizes neurotransmitters considered to be
important in these disorders. MAO-A inhibitors may also be useful for the treatment of
panic disorder, obsessive-compulsive disorder and post-traumatic stress disorder.
Reversible monoamine oxidase A inhibitors such as moclobamide are useful for the
treatment of depression and anxiety and have a lower propensity to cause hypertension
than irreversible MAO-A inhibitors.
A number of pyrazolines as selective Monoamine oxidase inhibitors A and B have been
reported. These include:- selective and reversible pyrazoline based MAO-A inhibitors
(Karuppasamy etal., BMC (2010), 18, 1875-1881); selective and reversible pyrazoline
based MAO-inhibitors (Sahoo etal., BMCL (2010), 20, 132-136.) ; pyrazoline bearing
4(3H)-quinazolinone inhibitors of monoamine oxidase (Goekhan-Kelekci etal., BMC
(2009), 17, 675-689.); Pyrazoline-based mycobactin analogues as MAO-inhibitors
(Jayaprakash etal., BMCL (2008), 18, 6362-6368); 1-N-substituted thiocarbamoyl-3-
substituted phenyl-5-(2-pyrolyl)-2-pyrazoline derivatives (Yabanoglu etal., J Neural
Transm (2007), 114, 769-773); novel substituted-4,5-dihydro-(1H)-pyrazole derivatives
as potent and highly selective monoamine oxidase-A inhibitors (Chimenti etal., Chem
Biol Drug Design (2006), 67, 206-214); 1-N-substituted thiocarbamoyl-3-phenyl-5-
thienyl-2-pyrazolines (Ucar etal., Hacettepe Tip Dergisi (2005), 25, 23-34); 1-N-
Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: novel cholinesterase and
selective monoamine oxidase B inhibitors (Ucar etal., Neurosci Lett (2005) 382, 327-
331); 1-N-substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines (Ucar etal., Arch
Pharm (2003) 336, 362-371); anticonvulsant pyrazolines (Soni et al Res Commun Chem
Path (1987) 56, 129-32); monoamine oxidase inhibitory properties of 1, 3, 5-
trisubstituted pyrazolines (Parmar etal J Pharm Sci (1974)) 63, 1152-5).
What are needed are additional Monoamine oxidase inhibitors, particularly compounds
which selectively inhibit the Monoamine oxidase of Monoamine oxidase B over
Monoamine oxidase A.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compounds and pharmaceutical compositions
thereof for inhibiting the biological activity of MAO B and A, in particular the
Monoamine oxidase B and A.
It is an object of the invention to provide for methods of treating disease conditions
which are associated with undesired hydrogen peroxide production and/or monoamines
metabolism.
It is an object of the invention to provide for the treatment of monoamine-mediated
disorders.
It is an object of the invention to provide compounds which selectively inhibit MAO-B
over MAO-A.
The compounds of the invention preferably are characterized by a selectivity ratio for
MAO-B inhibition over MAO-A inhibition of at least about 50, more preferably at least
about 100. MAO inhibition may be determined in vitro by enzyme assays well-known to
those skilled in the art, such as the enzyme assay method described later herein.
It is an object of the invention to provide methods for synthesizing compounds of the
invention and intermediates thereof.
These and other objects of the invention shall become apparent from the following
disclosure.

Where in Formula I, R can be 4-Hydroxy, 4-Nitro, 4-Chloro, 4-Methyl, 4-Methoxy, 3-
Nitro, 2-Hydroxy, 2, 4-Dihydroxy and Hydrogen.
The invention is also directed to novel intermediates of the formula I and II where R is
defined as above.
Compounds of formula I and II, and pharmaceutically acceptable salts thereof, are
provided. The compounds of the present invention may take the form or pharmaceutically
acceptable salts. The term "pharmaceutically acceptable salts", embraces salts commonly
used to form alkali metal salts and to form addition salts of free acids or free bases.
Where reference is made to "compound of the invention", it is understood that
pharmaceutically acceptable salts are also included. The nature of the salt is not critical,
provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid
addition salts may be prepared from an inorganic acid or from an organic acid. Examples
of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic,
sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of
organic acids, example of which are formic, acetic, propionic, succinic, glycolic,
gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, salicyclic, 4-hydroxybenzoic,
phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,
benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, stearic, algenic, betahydroxybutyric, salicyclic, galactaric and
galacturonic acid. All of these salts may be prepared by conventional means from the
corresponding compound of formula I and II by reacting, for example, the appropriate
acid with the compound of formula I and II.
The compounds of the present invention may be administered in the form of a
pharmaceutical composition, in combination with a pharmaceutically acceptable carrier.
The active ingredient in such formulations may comprise from 0.1 to 99.99 weight
percent. By "pharmaceutically acceptable carrier" is meant any carrier, diluent or
excipient which is compatible with the other ingredients of the formulation and to
deleterious to the recipient.
The compounds of the invention may be administered to individuals (animals, most
particularly mammals including humans) afflicted with any disorder characterized by
undesirable neurodegeneration resulting from monoamine oxidase activity, particularly
MAO-B activity ("monoamine oxidase mediated disorder"). In particular, the compounds
of the invention are believed useful in treating neurodegeneration and neurodegeneration-
related disorders, by administering to a subject having or susceptible to such
neurodegeneration and neurodegeneration-related disorders and effective amount of a
compound according to formula I and II. Monoamine metabolism is associated with a
variety of disease conditions. Such conditions include, for example, mood disorders,
depression, bipolar disorders, substance-induced mood disorders, anxiety disorders,
cognitive disorders, delirium, amnestic disorders, Alzheimer's disease, schizophrenia,
schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic
disorder, shared psychotic disorder, addictive behaviors, movement disorders, akinesias,
akinetic-rigid syndromes, Parkinson's disease, medication-induced parkinsonism, Gilles
de la Tourette's syndrome, epilepsy, dyskinesias, chorea, myoclonus, tics, dystonia,
obesity, bulimia nervosa, compulsive eating disorders, eating disorders associated with
excessive food intake, osteoarthritis, repetitive motion pain, dental pain, cancer pain,
myofascial pain, perioperative pain, chronic pain, neuropathic pain, post-traumatic pain,
trigeminal neuralgia, migraine, attention-deficit hyperactivity disorder, conduct disorder,
muscular spasms, urinary incontinence, amyotrophic lateral sclerosis, neuronal damage,
ocular damage, retinopathy, macular degeneration of the eye, hearing loss, tinnitus,
emesis, brain edema or sleep disorders in a mammal.
A pharmaceutical composition comprising a compound of Formula I and II and another
agent selected from the group consisting of: an anti-depressant, an anti-anxiety agent, an
anti-Alzheimer's agent, a sedative, a hypnotic, an anxiolytic, an antipsychotic, a
cyclopyrrolone, an imidazopyridine, a pyrazolopyrimidine, a minor tranquilizer, a
melatonin agonist, a melatonin antagonist, a melatonergic agent, a benzodiazepine, a
barbiturate, a 5HT-2 antagonist, levodopa, an anticholinergic, a trihexyphenidyl
hydrochloride, a COMT inhibitor, an antioxidant, an A2a adenosine receptor antagonist,
a cholinergic agonist, a NMDA receptor antagonist, a serotonin receptor antagonist, a
monoamine oxidase inhibitor, a dopamine receptor agonist, a neuroleptic agent, an
anoretic agent, a selective serotonin reuptake inhibitor, a halogenated amphetamine
derivative, an opiate agonist, a lipoxygenase inhibitor, an interleukin inhibitor, an NMDA
antagonist, an inhibitor of nitric oxide, a non-steroidal antiinflammatory agent, a
cytokine-suppressing antiinflammatory agent, a pain reliever, a potentiator, an H2-
antagonist, simethicone, aluminum hydroxide, magnesium hydroxide, a decongestant, an
antitussive, and an antihistamine.
The compounds may be administered by any route, including oral and parenteral
administration. Parenteral administration includes, for example, intravenous,
intramuscular, intraarterial, intraperitoneal, intranasal, rectal, or subcutaneous
administration. The active agent is preferably administered with a pharmaceutically
acceptable carrier selected on the basis of the selected route of administration and
standard pharmaceutical practice.
The active agent may be formulated into dosage forms according to standard practices in
the field of pharmaceutical preparations. See Alphonso Gennaro, ed., Remington's
Pharmaceutical Sciences, 18th Ed., (1990) Mack Publishing Co., Easton, PA. Suitable
dosage forms may comprise, for example, tablets, capsules, solutions, parenteral
solutions, troches, suppositories, or suspensions. For parenteral administration, the active
agent may be mixed with a suitable carrier or diluent such as water, an oil, saline
solution, aqueous dextrose (glucose) and related sugar solutions, or a glycol such as
propylene glycol or polyethylene glycol. Solutions for parenteral administration
preferably contain a water soluble salt of the active agent. Stabilizing agents,
antioxidizing agents and preservatives may also be added. Suitable antioxidizing agents
include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable
preservatives include benzalkonium chloride, methyl- or propyl-paraben, and
chlorbutanol. For oral administration, the active agent may be combined with one or
more solid inactive ingredients for the preparation of tablets, capsules, or other suitable
oral dosage forms. For example, the active agent may be combined with
carboxymethylcellulose calcium, magnesium stearate, mannitol and starch, and then
formed into tablets by conventional tableting methods. The specific dose of compound
according to the invention to obtain therapeutic benefit will, of course, be determined by
the particular circumstances of the individual patient including, the size, weight, age and
sex of the patient, the nature and stage of the disease, the aggressiveness of the disease,
and the route of administration. For example, a daily dosage of from about 0.01 to about
150 mg/kg/day may be utilized. Higher or lower doses are also contemplated.
The compounds of the present invention are optically active due to
the presence of a chiral carbon atom. The present invention is meant to comprehend
diastereomers as well as their racemic and resolved, enantiomerically pure forms and
pharmaceutically acceptable salts thereof.
The novel compounds of the present invention can be prepared according to the
following general procedures using appropriate materials and are further exemplified by
the following specific examples. The compounds illustrated in the examples are not,
however, to be construed as forming the only genus that is considered as the invention.
The following examples further illustrate details for the preparation of the compounds of
the present invention. Those skilled in the art will readily understand that known
variations of the conditions and processes of the following preparative procedures can be
used to prepare these compounds. All temperatures are degrees Celsius unless otherwise
noted.
SCHEMES
The following are general procedures for preparation of the formula I compounds or
intermediates thereof:
The compounds of present invention or formula I and formula II can be prepared
according to Scheme, as indicated below. In general intermediates 1-10 were prepared
through Claisen-Schmidt condensation of different acetophenone with Anthracene-9-
carboxaldehyde. Compounds of formula I and formula II (compounds 11-20) were
synthesized by the reaction of excess hydrazine hydrate (99%) with 1-10 respectively in
ethanol.

Synthetic scheme for the newly synthesized 3-(Anthracene-9-yl)-5-aryl pyrazolines.
i. EtOH, 60% NaOH, 0°C, stirring 2h, kept at room temp for 2-4 days ii. EtOH,
Hydrazine hydrate (99%), reflux 1-3 h.
The practice of the invention is illustrated by the following nonlimiting examples.
Example 1
Synthesis of 3-(anthracen-9-yl)-5-(4-nitrophenyl)-4,5-dihydro-1H-pyrazole
Stepl Synthesis of (E)-3-(anthracen-9-yl)-1-(4-nitrophenyl) prop-2-en-1-one
To a solution of 4-nitro acetophenone (0.01M) and 9-anthraldehydes (0.01M) in ethanol
(10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 0°C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The orange precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 1 or (E)-3-(anthracen-9-yl)-1-(4-
nitrophenyl) prop-2-en-1 -one was obtained.
Step2 Synthesis of 3-(anthracen-9-yl)-5-(4-nitrophenyl)-4,5-dihydro-1H-pyrazole
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-(4-nitrophenyl) prop-2-en-1-one was
treated with 10 times excess of hydrazine hydrate (80%) in dry ethanol and refluxed for 3
hours. The hot reaction mixture was then poured into ice-cold water. The solid separated
out was filtered, washed, dried and recrystallized from ethanol to afford respective
pyrazoline or 3-(anthracen-9-yl)-5-(4-nitrophenyl)-4,5-dihydro-1H-pyrazole.
Example 2
Synthesis of 4-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)phenol
Stepl Synthesis of (E)-3 -(anthracen-9-yl)-1 -(4-hydroxyphenyl)prop-2-en-1 -one
To a solution of 4-hydroxy acetophenone (0.01M) and 9-anthraldehydes (0.01M) in
ethanol (10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 0°C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The orange precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 2 or (E)-3-(anthracen-9-yl)-1-(4-
hydroxyphenyl)prop-2-en-1-one was obtained.
Step2 Synthesis of 4-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)phenol
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-(4-hydroxyphenyl)prop-2-en-1-one was
treated with 10 times excess of hydrazine hydrate (80%) in dry ethanol and refluxed for 3
hours. The hot reaction mixture was then poured into ice-cold water. The solid separated
out was filtered, washed, dried and recrystallized from ethanol to afford respective
pyrazoline or 4-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)phenol.
Example 3
Synthesis of 3-(anthracen-9-yl)-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole
Stepl Synthesis of (E)-3 -(anthracen-9-yl)-1 -(4-chlorophenyl)prop-2-en-1 -one
To a solution of 4-chloro acetophenone (0.01 M) and 9-anthraldehydes (0.01M) in ethanol
(10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 0°C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The yellow precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 3 or (E)-3-(anthracen-9-yl)-1-(4-
chlorophenyl)prop-2-en-1-one was obtained.
Step2 Synthesis of 3-(anthracen-9-yl)-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-(4-chlorophenyl)prop-2-en-1-one was
treated with 10 times excess of hydrazine hydrate (80%) in dry ethanol and refluxed for 3
hours. The hot reaction mixture was then poured into ice-cold water. The solid separated
out was filtered, washed, dried and recrystallized from ethanol to afford respective
pyrazoline or 3-(anthracen-9-yl)-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole.
Example 4
Synthesis of 3-(anthracen-9-yl)-5-p-tolyl-4,5-dihydro-1H-pyrazole
Stepl Synthesis of (E)-3-(anthracen-9-yl)-1-p-tolylprop-2-en-1-one
To a solution of 4-methyl acetophenone (0.01M) and 9-anthraldehydes (0.01M) in
ethanol (10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 0°C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The yellow precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 4 or (E)-3-(anthracen-9-yl)-1-p-
tolylprop-2-en-1-one was obtained.
Step2 Synthesis of 3-(anthracen-9-yl)-5-p-tolyl-4,5-dihydro-1H-pyrazole
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-p-tolylprop-2-en-1-one was treated
with 10 times excess of hydrazine hydrate (80%) in dry ethanol and refluxed for 3 hours.
The hot reaction mixture was then poured into ice-cold water. The solid separated out
was filtered, washed, dried and recrystallized from ethanol to afford respective pyrazoline
or 3-(anthracen-9-yl)-5-p-tolyl-4,5-dihydro-1H-pyrazole.
Example 5
Synthesis of 3-(anthracen-9-yl)-5-phenyl-4,5-dihydro-1H-pyrazole
Stepl Synthesis of (E)-3-(anthracen-9-yl)-1-phenylprop-2-en-1-one
To a solution of unsubsituted acetophenone (0.01 M) and 9-anthraldehydes (0.01M) in
ethanol (10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 0°C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The yellow precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 5 or (E)-3-(anthracen-9-yl)-1-
phenylprop-2-en-1-one was obtained.
Step2 Synthesis of 3-(anthracen-9-yl)-5-phenyl-4,5-dihydro-1H-pyrazole
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-phenylprop-2-en-1-one was treated
with 10 times excess of hydrazine hydrate (80%) in dry ethanol and refluxed for 3 hours.
The hot reaction mixture was then poured into ice-cold water. The solid separated out
was filtered, washed, dried and recrystallized from ethanol to afford respective pyrazoline
or 3-(anthracen-9-yl)-5-phenyl-4,5-dihydro-1H-pyrazole.
Example 6
Synthesis of 2-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)phenol
Stepl Synthesis of (E)-3-(anthracen-9-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one
To a solution of 2-hydroxy acetophenone (0.01M) and 9-anthraldehydes (0.01M) in
ethanol (10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 0°C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The yellow precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 6 or (E)-3-(anthracen-9-yl)-1-(2-
hydroxyphenyl)prop-2-en-1-one was obtained.
Step2 2-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)phenol
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one was
treated with 10 times excess of hydrazine hydrate (80%) in dry ethanol and refluxed for 3
hours. The hot reaction mixture was then poured into ice-cold water. The solid separated
out was filtered, washed, dried and recrystallized from ethanol to afford respective
pyrazoline or 2-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)phenol.
Example 7
Synthesis of 4-(3 -(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)benzene-1,3-diol
Step1 Synthesis of (E)-3 -(anthracen-9-yl)-1 -(2,4-dihydroxyphenyl)prop-2-en-1 -one
To a solution of 2,4-dihydroxy acetophenone (0.01M) and 9-anthraldehydes (0.01M) in
ethanol (10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 0°C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The yellow precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 7 or (E)-3-(anthracen-9-yl)-1-(2,4-
dihydroxyphenyl)prop-2-en-1-one was obtained.
Step2 4-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)benzene-1 ,3-diol
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one
was treated with 10 times excess of hydrazine hydrate (80%) in dry ethanol and refluxed
for 3 hours. The hot reaction mixture was then poured into ice-cold water. The solid
separated out was filtered, washed, dried and recrystallized from ethanol to afford
respective pyrazoline or 4-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)benzene-1,3-
diol.
Example 8
Synthesis of 2-(3 -(anthracen-9-yl)-4,5-dihydro-1 H-pyrazol-5-yl)pyridine
Stepl Synthesis of (E)-3-(anthracen-9-yl)-1 -(pyridin-2-yl)prop-2-en-1 -one
To a solution of 2-acetylpyridine (0.01M) and 9-anthraldehydes (0.01M) in ethanol
(10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 0°C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The yellow precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 8 or (E)-3-(anthracen-9-yl)-1-
(pyridin-2-yl)prop-2-en-1-one was obtained.
Step2 2-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)pyridine
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-(pyridin-2-yl)prop-2-en-1-one was
treated with 10 times excess of hydrazine hydrate (80%) in dry ethanol and refluxed for 3
hours. The hot reaction mixture was then poured into ice-cold water. The solid separated
out was filtered, washed, dried and recrystallized from ethanol to afford respective
pyrazoline or 2-(3-(anthracen-9-yl)-4,5-dihydro-1H-pyrazol-5-yl)pyridine.
Example 9
Synthesis of 3-(anthracen-9-yl)-5-(3-nitrophenyl)-4,5-dihydro-l H-pyrazole
Stepl Synthesis of (E)-3 -(anthracen-9-yl)-1 -(3-nitrophenyl)prop-2-en-1 -one
To a solution of 3-nitro acetophenone (0.01M) and 9-anthraldehydes (0.01 M) in ethanol
(10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 00C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The orange precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 9 or (E)-3-(anthracen-9-yI)-1-(3-
nitrophenyl)prop-2-en-1-one was obtained.
Step2 3-(anthracen-9-yl)-5-(3-nitrophenyl)-4,5-dihydro-1 H-pyrazole
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-(3-nitrophenyl)prop-2-en-1-one was
treated with 10 times excess of hydrazine hydrate (80%) in dry ethanol and refluxed for 3
hours. The hot reaction mixture was then poured into ice-cold water. The solid separated
out was filtered, washed, dried and recrystallized from ethanol to afford respective
pyrazoline or 3 -(anthracen-9-yl)-5 -(3-nitrophenyl)-4,5-dihydro-1 H-pyrazole.
Example 10
Synthesis of 3-(anthracen-9-yl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole
Stepl Synthesis of (E)-3 -(anthracen-9-yl)-1 -(4-methoxyphenyl)prop-2-en-1 -one
To a solution of 3-nitro acetophenone (0.01M) and 9-anthraldehydes (0.01M) in ethanol
(10ml) was added aqueous solution of sodium hydroxide (60%) drop wise with
continuous stirring at 00C over a period of 45 minutes. The reaction mixture was kept at
room temperature for about 48 hours with occasional shaking. After 48 hours it was
poured into ice-cold water. The orange precipitate obtained was filtered, washed, dried
and recrystallized from dry ethanol. The intermediates 10 or (E)-3-(anthracen-9-yl)-1-(4-
methoxyphenyl)prop-2-en-1-one was obtained.
Step2 3-(anthracen-9-yl)-5-(4-methoxyphenyl)-4,5-dihydro-1 H-pyrazole
Appropriate chalcone or (E)-3-(anthracen-9-yl)-1-(4-methoxyphenyl) prop-2-en-1-
onewas treated with 10 times excess of hydrazine hydrate (80%) in dry ethanol and
refluxed for 3 hours. The hot reaction mixture was then poured into ice-cold water. The
solid separated out was filtered, washed, dried and recrystallized from ethanol to afford
respective pyrazoline or 3-(anthracen-9-yl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-
pyrazole.
The compounds of present invention or compounds related to Formula I and Formula II
were characterized by 'H NMR and FAB mass spectrometry (MS). Melting points were
determined using Thermonik Melting Point Apparatus (Campbell electronics, India) by
capillary method and are uncorrected. Infrared (IR) spectra were taken on a Fourier
Transform Infrared Spectrophotometer IR-Prestige 21 (Shimatzu Corporation, Japan)
from 4000-400 cm-1 using KBr discs. 1H NMR spectra were recorded at 400 MHz in
DMSO-d6 using a Bruker Avance 400 instrument (Bruker Instruments Inc., USA).
Chemical shifts were measured at 5 units (ppm) relative to tetramethylsilane (TMS). Fast-
atom bombardment (FAB) mass spectra were recorded on a Jeol SX 102/DA-6000 mass
spectrometer (Jeol Ltd. Akishima, Tokyo, Japan) using argon/xenon (6 kV, 10 mA) as
FAB gas, m-nitrobenzyl alcohol as matrix, and 10 kV as accelerating voltage at room
temperature. Elemental analysis was performed on a Vario EL III Elemental Analyser
(Elementar, Germany) using sulfanilamide as standard. All chemicals were purchased
from Merck, Spectrochem or CDH, India. Reactions were monitored by thin-layer
chromatography on silica gel plates in either iodine or UV chambers. Intermediates were
characterized by IR spectroscopic analysis and elemental analysis for CHN. In the
elemental analysis, the observed values were within ±0.4% of the calculated values. The
final yields and the physicochemical and spectral data of the compounds 11 to 20 are
presented in Table 1.
IN-VITRO STUDY;
Monoamine Oxidase Assay
Compounds were tested for inhibitory activity against MAO-A and MAO-B. The
compounds of formula I having 3-Nitro group as R (mentioned above) had the highest
selectivity for inhibiting MAO-B. Monoamine oxidase activity of rat liver and human
recombinant MAO-B/A (Sigma Alrich.) was assayed by a method of Holt (Holt etal Anal
Biochem (1997) 244, 384-392) as follows. All inhibitors were dissolved in dimethyl
sulfoxide to a stock solution of 1µM. Human recombinant MAO-B or rat MAO-B was
incubated with inhibitors at several concentrations in a solution containing potassium
phosphate buffer, pH 7.4 and chromogenic solution consisted of 1 mM vanillic acid, 500
uM 4-aminoantipyrine, and 4 U.ml-1 peroxidase type II in 0.2 M potassium phosphate
buffer, pH 7.6 was added and incubated for 90 to 120 minutes at room temperature
(24°C). In controls, equal volumes of DMSO without drug were added to the incubation
mixture. After incubation for 90-120 minutes. Total MAO activity was measured
spectrophotometrically at 498 nm at 37°C for 60 min. A molar absorption coefficient of
4654 M-1. cm-1 was used to calculate the initial velocity of the reaction. Results were
expressed as nmol.h-1.mg-1.The percentage of total products observed at different
inhibitor concentrations was divided by the percentage of the products observed for
protein samples pre incubated for the same time with DMSO. The results are shown in

All references cited herein are incorporated herein by reference. The present invention
may be embodied in other specific forms without departing from the spirit or essential
attributes thereof and, accordingly, reference should be made to the appended claims,
rather than to the foregoing specification, as indication the scope of the invention.
We Claim:
1. A compound of the Formula I where in R relates to different substitution on
phenyl ring such as hydrogen, 4-methyl, 4-methoxy,4-hydroxy, 4-nitro, 3-
nitro, 2,4-dihydroxy, 2-hydroxy and 4-chloro or a pharmaceutically
acceptable salt or any stereoisomer thereof.
2. A compound of the Formula II or a pharmaceutically acceptable salt or any
stereoisomer thereof.
3. A pharmaceutical composition comprising any compound of claims 1 and 2.
4. Monoamine oxidase A and B inhibitory activity of compounds of Formula I
and II or a pharmaceutically acceptable salt or any stereoisomer.
5. A method of treatment involving compounds of Formula I and II or a
pharmaceutically acceptable salt or any stereoisomer for the following
diseases;
mood disorders, depression, bipolar disorders, substance-induced mood
disorders, anxiety disorders, cognitive disorders, delirium, amnestic
disorders, Alzheimer's disease, schizophrenia, schizophreniform disorder,
schizoaffective disorder, delusional disorder, brief psychotic disorder, shared
psychotic disorder, addictive behaviors, movement disorders, akinesias,
akinetic-rigid syndromes, Parkinson's disease, medication-induced
parkinsonism, Gilles de la Tourette's syndrome, epilepsy, dyskinesias,
chorea, myoclonus, tics, dystonia, obesity, bulimia nervosa, compulsive
eating disorders, eating disorders associated with excessive food intake,
osteoarthritis, repetitive motion pain, dental pain, cancer pain, myofascial
pain, perioperative pain, chronic pain, neuropathic pain, post-traumatic
pain, trigeminal neuralgia, migraine, attention-deficit hyperactivity disorder,
conduct disorder, muscular spasms, urinary incontinence, amyotrophic
lateral sclerosis, neuronal damage, ocular damage, retinopathy, macular
degeneration of the eye, hearing loss, tinnitus, emesis, brain edema or sleep
disorders in a mammal in need thereof by administering a therapeutically
effective amount of a composition according to claim 4.

The invention relates generally to compounds of formula I and formula II,
diagrammed below, wherein R is defined in the application, which are useful as
reversible inhibitors of monoamine oxidase-B and/or monoamine oxidase-A, and
therefore useful to treat or prevent neurological diseases or conditions in mammals,
preferably humans.