FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
Complete Specification
(See section 10 and rule 13)
TITLE OF THE INVENTION:
Synthesis of 11 -(4"-substituted alkyl/aroyl/aryl)-1 "-piperazinyl, dibenz[b,f](l,4) oxazepines" for antiseptic activity,
APPLICANT
Name: Wagh Sanjay Baburao
Nationality: Indian
Address : Martru Darshan, Opposite Vasant Market, Old Gangapur Naka, Nashik-422 005, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

Title:- Synthesis  of 11-(4-substituted alkyl/aroyl/aryl)-l"-piperazinyl, dibenz[b,f](l,4) oxazepines" for antiseptic activity,
Field of invention:
The present invention relates to a oxazapenes derivatives, its synthesis and its use as an anti psychotic activity, more particularly for treatment of Schizophrenia which is a serious illness affecting about 1% of the world"s population. Its toll in the human sufferings is probably exemplified best by the high suicide rate for people having the disease (Caldwell C, Schizophr. Bull. 1990, 16, 571). In addition the economic losses and cost associated with schizophrenia are substantial. Schizophrenia is a disease of which etiology is unknown. Therefore the search for an effective treatment of complete spectrum of symptoms of disease is still progressing on many fronts.
Back ground of the Invention:-
Schzoprenia is the most common cause of dementia in late life
pathologically is charecterised by the deposition in the brain of
amyloid in extracellular plagues an intracellular neurofibrillay
tangues, to the paten No. US 7060698 which describes about
the derivatives of benzoxzepine which causes the diseases like
alzheimers.
USPT No. 5576315 which descriebs about dibenzoxazepine compounds and methods for treating osteoporosis and ischemia.
USPT No. 3534019 discloses hydrazides of dibenzodiazepine
carboxylic acids.

USPT No. 3917649 and 3992375 sicloses dibenzoxazepine N-carboxylic acid hydrazine compounds.
USPT  No.  455937  discloses  8-Chlorodibenz[b,f]  [1,4]  -oxazepine-l0(HH) - carboxylic acid, 2-(Sulfinyl and sulfonyl containing acyl) hydrazides and intermediates, GB 1522003 discloses 1-acyl -2-(8-Chloro-10,ll-dihydrodibenz [b,f][l,4] oxazepine-10- carbonyl) hydrazine compounds.
Where as in the present invention describes about the synthesis and evaluation of antipsycholic activity of 11-(4-substituted alkyl/aeoyl/ary) -l-piperazinyl,dibenz[b,f|(l,4) oxzepines, which is not reported in the prior art.
The usefulness of the dopamine D2 receptor antagonist such as haloperidol is well established (Gray, J. A. Schizophrenia Bull. 1998, 24,249). Launch of clozapine, which is having dibenzodiazepine core nucleus, has ruled out long held belief that antipsychotic action and extra pyramidal side effects are inseparable. However clozapine is having serious problem side effects as agranulocytosis and weight gain, which limits its use in clinic. Quetiapine, which is having dibenzothiazepine core nucleus, having no electronegative group either at C-2 or C-8 position, but undergo metabolic oxidation into firstly sulfoxide and than in sulfone derivative. Loxapine, which is having a dibezoxazepine as a core structure, exerts its antipsychotic action through blockade of dopamine D2 receptors. However these agents predominately acts by attenuating the dopaminergic transmission in the mesolimbic system of the

brain, thereby only affecting positive symptoms of the disease, and causing extra pyramidal side effects.
In the present study we have designed compounds to be active as an antipsychotic agent without causing serious side effects like agranulocytosis, extra pyramidal side effects and also block the metabolism of the drug, which gives less active metabolites. Loxapine is having electron-withdrawing substituent chlorine at C2 position while in case of clozapine the electron withdrawing substituent chlorine is at Cs, which is away from the piperazine nitrogen. Loxapine on metabolic demethylation produce amoxapine, which is antidepressant.
Taking all above facts in consideration, we have designed the stated compounds. We have synthesized dibenzoxazepine having no electronegative group either at C-2 or C-8 position as that of quetiapine. To avoid the metabolic demethylation and improve lipophilicity of the loxapine we have replaced N-methyl with N-aryl, N-benzoyl or N-acetamido group.
Objects of the present invention:-
Very important object of the present invention is to identify novel compounds as antipsychotic agents with better efficacy and fewer side effects as compared to existing anti-psychotic agents.
A summary of the invention:
The present invention deals with compounds having dibezoxazepine, as core molecular  scaffolding  suitably  substituted  at  11th  position  by  substituent

independently selected from the group consisting of substituted piperazines. The invention also provides methods for the production of these compounds and a method of screening these compounds in antipsychotic animal models Detailed description of the invention: The present invention is concerned with compounds having the formula I)
The compounds of formula (I)
o
(I)
a) Where in R is independently selected from the group consisting of acetamido, benzamido, methyl, methoxy, chloro Phenyl, benzyl and the like their process for manufacture and their usefulness as antipsychotic agents in need, thereof.
Such as an anti-psychotic agents and treatment of mammals having schizophrenia with these agents. Comprising the following steps,
REACTION MECHANISM FOR SYNTHESIS



The target compounds were synthesized starting from amino diphenyl ether (I), was converted to isocynate (II) by phosgination, which upon insitu cyclisation with aluminum chloride catalyzed Friedal crafts acylation gave lactum (III), which was converted to imidyl chloride, (IV) by treating with

phosphorous oxychloride. Condensation of this imidyl chloride with aryl piperazines gave targeted compounds. The structures of the compounds were established by spectral and elemental analysis.
Pharmacological Screening
Catalepsy: Is defined as long-term maintenance of animal in abnormal posture. In mice it is defined as a failure to correct an externally imposed unusual posture over a prolonged period of time. Neurolepsis, which have an inhibitory action on the nigrostrital dopamine system, induce catalepsy.
Procedure: We determined cataleptic effect of our synthesized product by using mice. A group of 5 mice were treated with clozapine & our synthesized compounds. Catalepsy was induced & determined at 05,15,30,60,90&120 min. intervals by means of bar test. The phenomenon was measured as the time, the mouse maintained an imposed position with both fore limbs extended & resting on a 2.5cm high glass bar (0.9cm diameter). The animals were tested twice at each time interval & only greater duration of time was considered. Catalepsy data presented as mean +SEM for a group. The duration of catalepsy was transformed to logarithmic values in order to normalize the data. Results were analyzed using student"s "t" test & p<0.05 was considered significant. An animal was considered cataleptic if it remains on the bar for 60 seconds. Results of this biological assay are summarized in table-2
Antiagressive activity
Foot shocked induced aggression is used for the characterization of centrally active drugs.
Procedure:
The mice weighing 20-25 gm were used & divided into standard & test groups (n=5). The test and standard compounds were administered 30 min. before the mice were placed in a box with a grid floor consisting of copper wire with a distance of 6 mm. A constant current of 1.2 ma was supplied through grid floor.

The fighting behavior consists of vocalization, licking, running; rearing and facing one another with some attempt to attack by hitting, running, biting or boxing were recorded. Latency for first attack was determined. All observations are given as mean +SEM. The data was analyzed by student"s "t" test & p<0.05 was considered significant. An animal was considered cataleptic if it remains on the bar for 60 seconds. Results of this biological assay are summarized in table-3
EXPERIMENTAL PART
[A] Preparation of intermediates
2-aminodiphenyl ether : In a 250 ml stainless steel hydrogenation bottle 8gm 2-nitrodiphenyl ether (0.03M) & 50ml of methanol was taken. To it added 1 gm Raney Nickel as catalyst. The reaction mixture was hydrogenated on catalytic hydrogenator at 70-psi pressure. The hydrogen uptake was completed within 3hrs. The reaction was monitored by TLC. The catalyst was filtered & methanol was distilled off to give 6gm of 2-aminodiphenyl ether. Yield: 93% B.P. =120°C (2mm/Hg)
10,lldihvdro,ll-oxa,dibenz[b,f|fl,4]oxazepine:
Step 1 A slurry of 2-aminodiphenyl ether hydrochloride (5g, 0.022mole) in 40ml 1,2-Dichlorobenzene (ODCB) was heated to 160 - 170°C. A solution of triphosgene (4g) in 20ml ODCB was delivered with a dip tube drop-wise over a period of 2-3 hrs. When the addition was completed, the mixture was then diluted with 15ml ODCB and protected from moisture (solution A).
Step 2: Slurry of 3.3g anhydrous aluminum chloride in 30ml ODCB was heated to 90-100°C in an oil bath under nitrogen atmosphere. Solution A from step I was added slowly (15min), when addition was completed the temperature was raised to 150°C and maintained at the same temperature for 2 hrs. It was cooled to room temperature and 200ml ice water was added. The ODCB was removed by steam distillation which is continued to no more oil is separated in the

distillate. An off-white residue obtained was extracted with 2 x 200ml boiling acetone, decolourised with active charcoal, which was filtered, the filtrate was then concentrated and cooled to 0°C. White crystalline 11-oxa-dibenzoxazepine 6 was obtained upon filtration. Yield 2.15g, 38% m. p. 287-290°C
11-chloro.dibenzo [b.fl [1.41-oxazepine; 10,lldihydro,ll-
oxa,dibenz[b,f][l,4]oxazepine, 2gm(0.008M), 4ml POC13 and 0.6ml of dimethyl aniline was added and refluxed for l0hrs. The POC13 was distilled under vacuum and the residue was triturated with chloroform and filtered. The filtrate was concentrated under vacuum to give 11-chloro, dibenzo[b.f] [1,4]-oxazepine. Yield: 1.3gm (60%) m.p.: 44-45°C. The target compounds were synthesized by two routes as follows:
A. by condensation of l-(aryl/alkyl/N-arylacetamido) piperazine with 11-
chlorodibenz [b,f][l,4] oxazepine
B. by condensation of 11-piperazinyl-dibenzo [b,f][l,4] oxazepine and its
condensation with benzoylchloride.
Synthesis of chloroacetamide: In 250ml RBF, chloro acetyl chloride 34.63gm (0.03 mol), 11.9ml (0.11 mol) of TEA and dioxane as solvent was placed, cool the reaxction mixture in ice bath below 10°C. Add l0gm (0.1 mol) of aniline with stirring in 1 hour. And stirring was continued for 24-hours. The reaction was monitored on TLC, after completion of reaction; it was dumped in ice cold water. Extract with benzene (2x50ml), washed it with sodium bicarbonate solution (2x50ml), followed by water. Benzene was distilled off to give N-phenyl chloro acetamide. Yield : 12.7gm, m.p. 58 -60°C.
Synthesis of l-(N-ary! acetamido) piperazine: In a 500ml RBF, equipped with condenser, mechanical stirrer, 14.91gm (0.173mole) piperazine and xylene as a solvent was placed. Heating was started and lOgm (0.059mole) chloracetamide was added with stirring in 1 hour. Reflux was continued for

2 hours; reaction mixture was cooled and washed with water (3x50ml) to remove excess piperazine. Yield: 8.9gm, (50%) m.p.: 134 - 136°C.
Following general procedure was adopted for the synthesis of 1,2,3,4,5,6,7,8,9,10,11,12,13,14,20,21,22,23,24 and 25.
Preparation of target compound - ll-[4"-(arvl/ alkyl/ N-arvl acetamidoM"-piperazinyll - dibenz [b,fl [1,41 oxazepine: In a typical experiment, 2.57gm (0.013M) 3-chloro-phenyl piperazine mixed in 10 ml dried and distilled xylene was allowed to boil. To the boiling mixture of this were added lgm (0.0045M) 11-chlorodibenz [b,f][l,4] oxazepine in dried and distilled xylene, slowly in 15 mins. The mixture was allowed to reflux for 5hrs. Xylene was distilled off under vacuum. The residue was then dumped in ice-cold water and extracted with diethyl ether (2x25ml). The ether layer was dried over anhydrous sodium sulphate and ether was evaporated to give the product, which was purified on column chromatography with n-hexane: ethyl acetate (7:3). The yields, melting points and spectral data for the compounds synthesized by this route are summarized in table no. 1.
Synthesis of ll-piperazinyl-dibenzo[b,f|[l,41 oxazepine: In 250ml RBF, equipped with condenser, mechanical stirrer, 16.8g (0.19mole) anhydrous piperazine and 100ml xylene was placed. Heating was started and a solution of 15g (0.065mole) 11-chloro dibenzoxazepine (83) in 50ml xylene was added with stirring in 50ml xylene was added with stirring in hour. Continued reflux for 5 hours, reaction mixture was cooled and washed with water (2 x 100ml) to remove excess piperazine. Xylene was distilled off under vacuum; the pale yellow crystalline powder of 11-piperazinyl dibenzoxazepine was obtained. Yield : 12.7gm, (70%), m.p.: 128 - 130°C.
Following general procedure was adopted for the synthesis of 15,16,17,18,19,26,27,28,29 and 30.
Preparation of target compound- ll-{4"-[arovl/(N-aryl/alkvl acetamido)!-piperazin-r-yl} - dibenzfb.f] [1,41 oxazepine : In a typical experiment, in a 250ml   RBF,  * placed   lOgm   (0.0358mole)   of   11-piperazinyl,

dibenz[b,f][l,4]oxazepine, 4gm (0.039mole) TEA and 50ml dioxane, cool the reaction mixture in ice bath below 10°C. Add 5gm (0.035mole) of benzoyl chloride with stirring in 1 hour and continue stirring for 24 hours. The reaction was monitored on TLC, after completion of reaction, the reaction mixture was dumped in ice cold water. Extract with benzene (2 x 50ml), wash the benzene layer with 20% sodium bicarbonate solution (2 x 50ml), followed by water. Benzene was distilled off to give ll-(4-aroyl/N-alkyl piperazine-1-yl) dibenzoxazepine. The yields, melting points and spectral data for the compounds synthesized by this route are summarized in table no. 2.

(I) Table No.l Physical properties and spectral data of target compounds synthesized
by method A

Yield(% w/w) M.P.(°C)
Code no. R IR (cm1) PMR
1 XT 78 172-173 1593
2 J f^l 68 115-118 1592,2841.3
3 CI 89 157-160 1587 7.45, m,4H; 7.16, m,4H 7.01, m,4H; 3.67, S,4H 3.30, S, 4H

I Claim,
l.Synthesis of   ll-(4"-substituted   alkyl/aroyl/aryl)-r-piperazinyl,
dibenz[b,f](l,4) oxazepines" for antiseptic activity, of formula (I)
o
(I)
Where in R is independently selected from the group consisting of acetamido,
benzamido, methyl, methoxy, chloro Phenyl, benzyl and the like their process for manufacture and their usefulness as antipsychotic agents in need, thereof. Comprising the following steps,
Taking an amino diphenyl ether (I), was converted to isocynate (II) by phosgination, which upon insitu cyclisation with aluminum chloride catalyzed Friedal crafts acylation gave lactum (III), which was converted to imidyl chloride, (IV) by treating with phosphorous oxychloride. Condensation of this imidyl chloride with aryl piperazines gave targeted compounds,
2. A compound as claimed in claim 2, wherein 3-chloro-phenyl piperazine mixed in 10 ml dried and distilled xylene was allowed to boil to the boiling mixture of this were added lgm (0.0045M) 11-chlorodibenz [b,f][l,4] oxazepine in dried and distilled xylene, slowly in 15 mins, the mixture was allowed to reflux for 5hrs to 7hrs Xylene was distilled off under vacuum, the residue was then dumped in ice-cold water and extracted with diethyl ether (2x25ml), the ether layer was dried over anhydrous sodium sulphate and ether was evaporated

to give the product, which was purified using column chromatography with n-hexane,
3.  Synthesis of  ll-(4"-substituted  alkyl/aroyl/aryl)-l"-piperazinyl,
dibenz[b,f](l,4) oxazepines" for antiseptic activity, of formula (I) such as here
in described with reference to forgoing examples and drawings.
Dated this Day of 2007.
(Signature )
ABSTRACT OF THE INVENTION

Synthesis of of formula (I)

(I)
Where in R is independently selected from the group consisting of acetamido, benzamido, methyl, methoxy, chloro Phenyl, benzyl and the like their process for manufacture and their usefulness as antipsychotic agents in need, thereof.

I Claim,
l.Synthesis of   ll-(4"-substituted   alkyl/aroyl/aryl)-r-piperazinyl,
dibenz[b,f](l,4) oxazepines" for antiseptic activity, of formula (I)
o cCb
(I)
Where in R is independently selected from the group consisting of acetamido, benzamido, methyl, methoxy, chloro Phenyl, benzyl and the like their process for manufacture and their usefulness as antipsychotic agents in need, thereof. Comprising the following steps,
Taking an amino diphenyl ether (I), was converted to isocynate (II) by phosgination, which upon insitu cyclisation with aluminum chloride catalyzed Friedal crafts acylation gave lactum (III), which was converted to imidyl chloride, (IV) by treating with phosphorous oxychloride. Condensation of this imidyl chloride with aryl piperazines gave targeted compounds,
2. A compound as claimed in claim 2, wherein 3-chloro-phenyl piperazine mixed in 10 ml dried and distilled xylene was allowed to boil to the boiling mixture of this were added lgm (0.0045M) 11-chlorodibenz [b,fj[l,4] oxazepine in dried and distilled xylene, slowly in 15 mins, the mixture was allowed to reflux for 5hrs to 7hrs Xylene was distilled off under vacuum, the residue was then dumped in ice-cold water and extracted with diethyl ether (2x25ml), the ether layer was dried over anhydrous sodium sulphate and ether was evaporated

to give the product, which was purified using column chromatography with n-hexane,
3.  Synthesis of  ll-(4"-substituted  alkyl/aroyl/aryl)-r-piperazinyl,
dibenz[b,f](l,4) oxazepines" for antiseptic activity, of formula (I) such as here
in described with reference to forgoing examples and drawings.
Dated this    21 Day of   June 2007.
(Signature)

ABSTRACT OF THE INVENTION
Synthesis of of formula (I)

(I)
Where in R is independently selected from the group consisting of acetamido, benzamido, methyl, methoxy, chloro Phenyl, benzyl and the like their process for manufacture and their usefulness as antipsychotic agents in need, thereof.