cas 13745-86-3, 11-Chloro-dibenzo[b,f][1,4]thiazepine

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Synthesis of diverse fused tetracyclic thiazepine-chalcone derivatives by claisen-schmidt condensation reaction and their antimicrobial activity
To develop antimicrobial agent, a series of thiazepine-chalcones was synthesized by Claisen-Schmidt condensation between the couplings of aryl ketone in three steps protocol and different aromatic aldehydes under strong base catalyst at room temperature. The characterization of final products were carried out by IR, 1H & 13C NMR and elemental analysis. The synthesized compounds were also evaluated for their antibacterial and antifungal activities using specific Gram positive and Gram-negative bacterial strains using cup plate method.
Hirani, Jayanti B.,Pandya, Mayank K.,Koradiya, Suresh B.
p. 2860 - 2864
(2020)
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Design of Conjugated Molecules Presenting Short-Wavelength Luminescence by Utilizing Heavier Atoms of the Same Element Group
The introduction of heavy atoms into conjugated molecules often induces a redshift in the emission spectra. Conversely, we report here a blueshifting effect in the absorption and emission bands of a conjugated organic dye by employing a heavier atom from the same element group. Boron complexes having oxygen- and sulfur-bridged structures in the ligand moiety were synthesized, and their optical properties were compared. Significant optical bands in the absorption and luminescence spectra of the sulfur-bridged complex were observed in a shorter wavelength region than those of the oxygen-bridged complex. Theoretical calculations suggest that replacement of the bridging atom by a heavier one should reduce molecular planarity because of the larger atom size. As a result, the degree of electronic conjugation decreases, and this is followed by a blueshift in the optical bands. Finally, a blue-emissive crystal is demonstrated.
Yamaguchi, Madoka,Tanaka, Kazuo,Chujo, Yoshiki
p. 1342 - 1347
(2018)
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INFLUENZA VIRUS REPLICATION INHIBITOR AND USE THEREOF
Disclosed are a compound as shown in formula (I) as an influenza virus replication inhibitor and a preparation method therefor, a pharmaceutical composition comprising the compound and the use of the compound and pharmaceutical composition thereof in the treatment of influenza.
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(2020/08/09)

Preparation method of quetiapine fumarate intermediate
The invention discloses a preparation method of a quetiapine fumarate intermediate. The method comprises the following steps: taking 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepine and oxalyl chlorideas raw materials to prepare 11-chloro-dibenzo[b,f][1,4]thiazepine in an anhydrous organic solvent under the combined action of 4-substituted pyridine and pyridine, wherein the purity of the product is larger than or equal to 97.0%, and the yield is larger than or equal to 90%. The method has mild reaction conditions, good environmental protection performance and a high product yield, and is easyfor industrial production.
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Paragraph 0031-0049

(2019/04/26)

Antibodies to quetiapine haptens and use thereof
Disclosed is an antibody which binds to quetiapine, which can be used to detect quetiapine in a sample such as in a competitive immunoassay method. The antibody can be used in a lateral flow assay device for point-of-care detection of quetiapine, including multiplex detection of aripiprazole, olanzapine, quetiapine, and risperidone in a single lateral flow assay device.
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(2018/01/20)

Design, synthesis and anticancer activity of N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives
Novel N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives were designed, synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR and Mass spectra. The anticancer activities of the newly synthesized compounds were evaluated in vitro against three human cancer cell lines including K562, Colo-205 and MDA-MB 231 by MTT assay. The screening results showed that five compounds (16b, 16d, 16i, 16p and 16q) exhibited potent cytotoxic activities with IC50 values between 20 and 40 μM. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.
Gudisela, Mura Reddy,Srinivasu,Mulakayala, Chaitanya,Bommu, Praveen,Rao, M.V. Basaveswara,Mulakayala, Naveen
p. 4140 - 4145
(2017/08/23)

Methods for Treating Cognitive Disorders Using Inhibitors of Histone Deacetylase
This disclosure relates to compounds for the inhibition of histone deacetylase and treatment of a cognitive disorder or deficit. More particularly, the disclosure provides for compounds of formula (I) wherein Q, J, L and Z are as defined in the specification.
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Paragraph 0413; 0444

(2017/01/23)

Quetiapine synthesizing method
The invention discloses a quetiapine synthesizing method. O-chlorobenzoic acid with the low price is adopted as a starting material to react with thiophenol, and then ring closure is performed to obtain thioxanthone. Hydroxyl amination and Beckmann rearrangement are performed to obtain a key intermediate dibenzo[b,f][1,4]thiazepines-11-(10H)one, chlorination is performed, then, a reaction is performed on 1-(2-hydroxyethoxy)ethylpiperazine with the existence of acid-binding agent to obtain quetiapine, and the quetiapine and fumaric acid form a salt in an absolute ethyl alcohol system to obtain a product. According to the quetiapine synthesizing method, raw materials are low in price and easy to obtain, the steps are simple, operation is easy, and the cost can be effectively lowered. According to the method, the high-purity quetiapine can be obtained, the liquid phase purity of the obtained semi-fumaric acid quetiapine obtained through salt forming is 99% or above, and the quetiapine synthesizing method can be applied to the field of medicine.
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(2017/06/27)

A Vilsmeier reagent in the 11- chlorine benzoin and [b, f] [1,4] preparation method of allowing to sulfur, nitrogen
The invention discloses a preparation method of 11-chlorodibenzo[b,f][1,4]thiazepine in presence of a Vilsmeier reagent. The preparation method comprises the following steps: by using 10H-dibenzo[b,f][1,4]thiazepine-11-one as shown in a structural formula (I) and the Vilsmeier reagent as shown in a structural formula (III) as raw materials, preparing the 11-chlorodibenzo[b,f][1,4]thiazepine as shown in the structural formula (II) through a heating reaction in an organic solvent, wherein the Vilsmeier reagent is prepared from di-(trichloromethyl)carbonic ester as shown in a structural formula (a) and DMF (Di-Methyl Formamide) as shown in a structural formula (b). The preparation method provided by the invention has the advantages of short reaction time, simplicity and convenience in operation, simple post-treatment, less pollution and low cost and the like and is a chemical synthesis method with a better popularization and application prospect.
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Paragraph 0018-0019

(2017/01/17)

Pyrophosphoryl Chloride: A Green, Reductive Chlorination Reagent Utilized in the One-Pot Synthesis of Quetiapine
A one-pot synthesis of quetiapine from dibenzo[b,f][1,4]thiazepin-11(10H)-one and 4-hydroxyethoxy ethyl piperazine (HEEP) in toluene using N,N-dimethylaniline (DMA) and pyrophosphoryl chloride (P2O3Cl4) as a green reductive chlorination agent is described. A significant shortening of reaction times, a nearly quantitative yield, and high atom economy in the product were observed. The simplicity of the reaction, ease of execution, simple workup, and good yields, together with the use of easily accessible starting materials and an environmentally friendly procedure, are hallmarks of this process.
Mahmoodi,Pourhossein Parizad,Hosseini
p. 1029 - 1034
(2015/08/04)

Antibodies to Quetiapine Haptens and Use Thereof
Disclosed is an antibody which binds to quetiapine, which can be used to detect quetiapine in a sample such as in a competitive immunoassay method. The antibody can be used in a lateral flow assay device for point-of-care detection of quetiapine, including multiplex detection of aripiprazole, olanzapine, quetiapine, and risperidone in a single lateral flow assay device.
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(2014/03/24)

HAPTENS OF QUETIAPINE FOR USE IN IMMUNOASSAYS
The invention relates to compounds of Formula I, wherein R1, R2, and R3 are defined in the specification, useful for the synthesis of novel conjugates and immunogens derived from quetiapine. The invention also relates to conjugates of a quetiapine hapten and a protein.
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(2014/03/25)

Diversified synthesis of novel quinoline and dibenzo thiazepine derivatives using known active intermediates
The novel drug development to control resisting infections in conventional drug therapy is a need of today. Few antiulcer relative derivatives developed by approaching convergent synthesis. The derivatives synthesized successfully are dibenzo thiazepine-pyridine (SLN11-SLN15) and benzimidazole-hydroquinoline based derivatives (SLN16-SLN20). It involved the coupling through microwave, sonication and conventional techniques at final step. The efficient technology identified as sonication technique basically time and yield. The reported compounds were structural characterized by elemental analysis and spectral studies such as 1H, 13C NMR and MS.
Sharada,Satyanarayana Reddy,Sammaiah,Sumalatha
p. 7959 - 7966
(2013/09/23)

PROCESS FOR THE PREPARATION OF QUETIAPINE FUMARATE
The present invention relates to an improved process for the preparation of quetiapine and pharmaceutically acceptable salts. It also relates to improved process for the preparation of intermediates of quetiapine.
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Page/Page column 9-10

(2012/04/04)

Synthesis and antibacterial activities of new dibenzothiazepine derivatives
A number of substituted dibenzo[b,f][1,4]thiazepines analogues carrying heterocyclic and aliphatic moiety attached to C-11 position have been synthesized and evaluated their antibacterial activities against gram positive and gram negative bacteria. Derivatives of imidazole, 2-methyl imidazole and pyrrolidine exhibit significant antibacterial activities.
Mahale, Ganesh D.,Kolekar, Yogesh M.,Kumar, Ashok,Singh, Dharmendra,Kodam, Kisan M.,Waghmode, Suresh B.
p. 1196 - 1201
(2011/10/12)

PROCESS FOR THE SYNTHESIS OF QUETIAPINE
The present invention relates to a process for the synthesis of quetiapine. In particular, a process is provided for the synthesis of quetiapine of formula (A) comprising reacting dibenzo[b,f][1,4]thiazepin-11(10H)-one, intermediate (I) with phosphorous oxychloride to give 11-chlorodibenzo[b,f][1,4]thiazepine, intermediate (II) wherein the said reaction of intermediate (I) to intermediate (II) is performed in an organic solvent in the presence of a mixture of an organic base together with an inorganic base.
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Page/Page column 2

(2011/06/10)

DIBENZOTHIAZEPINE MODULATORS OF DOPAMINE, ALPHA ADRENERGIC, AND SEROTONIN RECEPTORS
The present invention relates to new dibenzothiazepine modulators of D1 receptors, D2 receptors, alpha-1 adrenergic receptors, alpha-2 adrenergic receptors, H1 receptors, 5-HT1A receptors, and/or 5-HT2 receptors, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 25-26

(2010/04/23)

SYNTHESIS OF LL-(4-[2-(2-HYDROXYETHOXY)ETHYL]- PIPERAZINYL)DIBENZO[B,F][1,4]THIAZEPINE AND ITS FUMARATE SALT
This invention broadly relates to a method for synthesizing ll-(4-[2-(2- hydroxyethoxy)ethyl]-piperazinyl)-dibenzo[b,f][l,4]thiazepine hemifumarate salt (Quetiapine hemifumarate) and the intermediate 11- piperazinyldibenzo[b,f][l,4]thiazepine dihydrochloride using phosphorous oxychloride in presence of non-aromatic solvent and condensing with piperazine.
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Page/Page column 6-7

(2010/04/03)

A PROCESS FOR PREPARING QUETIAPINE FUMARATE
The present invention relates to a process for preparing Quetiapine fumarate of formula (I)
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Page/Page column 7-8

(2010/04/06)

PROCESS FOR THE SYNTHESIS OF QUETIAPINE
The present invention relates to a process for the synthesis of quetiapine. In particular, a process is provided for the synthesis of quetiapine of formula (A) comprising reacting dibenzo [b, f ] [1, 4] thiazepin- 11 (10H) -one, intermediate (I) with phosphorous oxychloride to give 11- chlorodibenzo [b, f ] [1, 4] thiazepine, intermediate (II) wherein the said reaction of intermediate (I) to intermediate (II) is performed in an organic solvent in the presence of a mixture of an organic base together with an inorganic base.
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Page/Page column 8-9

(2010/08/09)

PROCESS FOR THE PREPARATION OF QUETIAPINE FUMARATE
The present invention relates to an improved process for the preparation of quetiapine and pharmaceutically acceptable salts. It also relates to improved process for the preparation of intermediates of quetiapine.
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Page/Page column 22-23

(2010/09/18)

A PROCESS FOR PREPARING QUETIAPINE FUMARATE
The present invention relates to an improved process for preparing Quetiapine fumarate of formula (I).
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Page/Page column 11

(2010/08/05)

INHIBITORS OF HISTONE DEACETYLASE
Compounds which are histone deacetylase inhibitors and their use in treating various disorders, including Alzheimer's Disease.
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Page/Page column 77

(2010/01/29)

PROCESS FOR PREPARING QUETIAPINE AND QUETIAPINE FUMARATE
The invention comprises a process for preparing quetiapine and/or its salts, including, quetiapine fumarate. The process generally comprises reacting dibenzothiazepinone (dibenzo[bf][1,4]thiazepin-11(10H)-one) with phosphorous oxychloride in the presence of triethylamine in an aromatic organic solvent such as toluene or, preferably, xylene at reflux temperature to obtain an aromatic hydrocarbon solution of 11-chloro-dibenzo[bf][1,4]thiazepine. Thereafter, the 11-chloro-dibenzo[bf][1,4]thiazepine is reacted with 2-(2-piperazin-1-ylethoxy)-ethanol to yield, following several processing steps, quetiapine. Compound I can then be further reacted with fumaric acid at elevated temperature to yield quetiapine fumarate. The resulting quetiapine fumarate obtained is suitable for use in pharmaceutical preparations.
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Page/Page column 3; 7-9

(2009/04/24)

An Improved and single pot process for the production of quetiapine hemifumarate substantially free from potential impurities
An improved and single pot process for the preparation of Quetiapine hemifumarate (1), an antipsychotic drug, free from potential impurities is reported with an overall yield of 80%. The reported process for its preparation suffers from the drawback of producing potential impurities identified as 11-piperazin-1- yldibenzo[b,f][1,4]thiazepine (6), 2-(4-dibenzo[b,f][1,4] thiazepin-11- ylpiperazin-1-yl)ethanol (10), dimer (9), and N-methyl- Nphenyldibenzo[ b,f][1,4]thiazapine-11-amine (14). Elimination of these impurities in the process is achieved by chlorination of 3 followed by in situ condensation of obtained 4 with highly pure 8 and subsequently establishing the pH based workup to obtain free base 2, which is further converted to quetiapine hemifumarate salt free from all these impurities. In this report, different aspects of process development such as scheme selection, optimization of different process parameters, identification, synthesis, origin and control of impurities, and development of an accurate analytical method during the development of a scalable process for quetiapine hemifumarate are discussed.
Niphade, Navnath C.,Mali, Anil C.,Pandit, Bhushan S.,Jagtap, Kunal M.,Jadhav, Sanjay A.,Jachak, Madhukar N.,Mathad, Vijayavitthal T.
experimental part
p. 792 - 797
(2010/04/22)

Process for preparing quetiapine fumarate
Provided is an improved synthesis of quetiapine and pharmaceutically acceptable salts.
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(2008/12/07)

INHIBITORS OF HISTONE DEACETYLASE
This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the inven- tion provides for compounds of formula (I) wherein (B), Q, J, L and Z are as defined in the specification
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Page/Page column 116

(2008/12/07)

Identification, isolation, synthesis and characterization of impurities of quetiapine fumarate
In the process for the preparation of quetiapine fumarate (1), six unknown impurities and one known impurity (intermediate) were identified ranging from 0.05-0.15% by reverse-phase HPLC. These impurities were isolated from crude samples using reverse-phase preparative HPLC. Based on the spectral data, the impurities were characterized as 2-[4-dibenzo[b,f][1,4]thiazepine-11-yl-1- piperazinyl]1-2-ethanol (impurity I, desethanol quetiapine), 11-[(N-formyl)-1-piperazinyl]-dibenzo[b,f][1,4]thiazepine (impurity II, N-formyl piperazinyl thiazepine), 2-(2-hydroxy ethoxy)ethyl-2-[2-[4-dibenzo[b,f][1,4] thiazepine-11-piperazinyl-1-carboxylate (impurity III, quetiapine carboxylate), 11-[4-ethyl-1-piperazinyl]dibenzo [b,f][1,4] thiazepine (impurity IV, ethylpiperazinyl thiazepine), 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1- piperazinyl)ethoxy]1-ethyl ethanol [impurity V, ethyl quetiapine), 1,4-bis[dibenzo[b,f][1,4]thiazepine-11-yl] piperazine [impurity VI, bis(dibenzo)piperazine]. The known impurity was an intermediate, 11-piperazinyl-dibenzo [b,f][1,4]thiazepine (piperazinyl thiazepine). The structures were established unambiguously by independent synthesis and co-injection in HPLC to confirm the retention times. To the best of our knowledge, these impurities have not been reported before. Structural elucidation of all impurities by spectral data (1H NMR, 13C NMR, MS and IR), synthesis and formation of these impurities are discussed in detail.
Bharathi,Prabahar,Prasad,Srinivasa Rao,Trinadhachary,Handa,Dandala, Ramesh,Naidu
p. 14 - 19
(2008/09/20)

IMPROVED PROCESS FOR PREPARING QUETIAPINE FUMARATE
Provided is an improved of quetiapine and pharmaceutically acceptable salts.
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Page/Page column 24-25

(2008/12/04)

DIBENZOTHIAZEPINE DERIVATIVES
This invention relates to novel 11-[4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1- y1]dibenzo[b,f][1,4]thiazepine derivatives, their acceptable acid addition salts, solvates, hydrates and polymorphs thereof. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by antagonists of seratonergic 5HT1A and 5HT2 receptors, dopaminergic D1 and D2 receptor, histaminergic H1 receptors, and/or adrenergic αl and α2 receptors.
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Page/Page column 21-22

(2008/12/06)

SYNTHESIS FOR THE PREPARATION OF QUETIAPINE
Process for the synthesis of 2-[2-(4-dibenzo[b,f][1,4]thiazepine-11-yl-piperazine-1-yl)-ethoxy]-ethanol of formula (I) (quetiapine) by reacting the 1-oxodibenzo-[b,f][1,4]thiazepine of formula (II) with phosphorus oxychloride by d) using 1-6 molequivalent of phosphorus oxychloride in an inert solvent and the obtained 11-chlorodibenzo[b,f][1,4]thiazepine compound of formula (IV) without isolation; e) is reacted further in an inert solvent in the presence of a base with 2-[2-(1-piperazinyl)-ethoxy]-ethanol dihydrochloride of formula (III a) or dihydrochloride monohydrate of formula (III b), in the mixture of an inert non-polar and dipolar aprotic solvent; f) in desired case the isolated quetiapine base of formula (I) is reacted with fumaric acid to form the hemifumarate salt thereof.
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Page/Page column 6-8

(2009/01/24)

IRON CATALYZED CROSS-COUPLING REACTIONS OF IMIDOYL DERIVATIVES
Disclosed is a process for preparing a compound of formula A - N=C(D)(B), from a compound of formula A-N=C(E)(B) and a compound of formula D-M using an iron catalyst, where the process has is represented by Equation (I).
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Page/Page column 21; 58

(2010/11/27)

LIQUID FORMULATIONS
The present invention is directed to liquid formulations of the pharmaceutical compound l l-piperazin-l-yldibenzo[b,f][l,4]thiazepine as well as preparations, and pharmaceutical uses thereto.
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Page/Page column 17-18

(2008/06/13)

PROCESSES FOR THE PREPARATION OF THIAZEPINES
The present invention relates to new processes for the preparation of thiazepines and of salts thereof. Specifically the present invention provides simple one-pot processes for the preparation of thiazepines. The invention further relates to the use of essentially the same inert solvent or of a mixture of inert solvents for the preparation of thiazepines and salts thereof, to the use of an about equimolar amount of a starting material and a halogenating agent for the preparation of thiazepines and to compositions useful in the process of the invention.
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Page/Page column 13; 15

(2008/06/13)

PROCESS FOR PRODUCING 11-[4-[2-(2-HYDROXYETHOXY)ETHYL]-1-PIPERAZINYL]DIBENZO[b,f][1,4]THIAZEPINE AND A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
A process for producing 11-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo [b,f][1,4]thiazepine [I] and a pharmaceutically suitable acid addition salt is disclosed. Accordingly, thiosalicylic acid [XVI] is reacted with o-halonitrobenzene [XVII] using a phase transfer catalyst to obtain 2-nitro-2'-carboxydiphenylsulphide [XI]. It is hydrogenated in the presence of a noble metal catalyst to obtain 2-amino-2' carboxydiphenyl sulphide [X]. The 2-amino-2'-carboxydiphenylsulphide [X] is reacted with halide or oxyhalide of the phosphorous to obtain in situ iminohalide [VI], which further reacts as such with 1-hydroxyethoxyethylpiperazine or condenses with piperazine to obtain 11-piperazinyldi.benzo[b,f][1,4]thiazepine [XIX] which further reacts with 2- chloroethoxyethanol or reacts with 1-(2-hydroxyethyl)piperazine to give 11-[4-(2-hydroxyethyl)piperazine-1-yl]dibenzo[b,f][ 1,4]thiazepine [XXXI] which further converts to an intermediate 11-[4-(2-substitutedethyl)piperazin-1- yl)dibenzo[b,f][1,4]thiazepine wherein the substituent at the 2-position is selected from mesyloxy or tosyloxy or halo group [XXXII] followed by reaction with ethylene glycol to give quetiapine [1].
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Page/Page column 9; 14; 15

(2008/06/13)

NEW USE OF 11-PIPERAZIN-1YLDIBENZO[B,F][1,4]THIAZEPINE OR ITS PHARMACEUTICALLY ACCEPTABLE SALT AND TO ORAL PHARMACEUTICAL COMPOSITIONS
A method of treating at least one symptom or condition associated with but not limited to: 1) Substance-Related Disorders including but not limited to Substance Dependence, Substance Abuse, Substance Intoxication, Substance Withdrawal, Alcohol-Related Disorders, Amphetamine (or Amphetamine-Like)-Related Disorders, Caffeine-Related Disorders, Cannabis-Related Disorders, Cocaine-Related Disorders, Hallucinogen-Related Disorders, Inhalant-Related Disorders, Nicotine-Related Disorders, Opioid-Related Disorders, Phencyclidine (or Phencyclidine-Like)-Related Disorders, and Sedative-, Hypnotic-or Anxiolytic-Related Disorders. 2) Attention-Deficit and Disruptive Behavior Disorders. 3) Eating Disorders. 4) Personality Disorders including but not limited to Obsessive-Compulsive Personality Disorder. 5) Impulse-Control Disorders, comprising administering an effective amount of Formula I (I) or its pharmaceutically acceptable salt. In another aspect of the invention a pharmaceutical composition is provided comprising an effective amount of Formula I or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent.
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Page/Page column 8-9

(2008/06/13)

Processes for preparing quetiapine and salts thereof
The present invention provides herein a two-step process for preparing pharmaceutically pure quetiapine and salts thereof by obtaining the starting material 11-chloro-dibenzo-thiazepine followed by reacting the 11-chloro-dibenzo-thiazepine with 1-(2-hydroxyethoxy)ethylpiperazine, or its salt, in the presence of an inorganic or organic base in an organic solvent or in a two-phase solvent system. The present invention provides also a novel, one-pot reaction process for preparing pharmaceutically pure quetiapine and salts thereof. The two processes provided herein can be easily, conveniently and inexpensively scaled-up.
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Page/Page column 4; 9

(2010/10/20)

SYNTHESIS OF 11-(4[-(2-HYDROXYETHOXY)ETHYL]-PIPERAZINYL)-DIBENZO[b,f][1,4]THIAZEPINE AND ITS FUMARATE SALT
The invention is directed a method for synthesizing l l-(4-[2-(2- hydroxyethoxy)ethyl]-piperazinyl)-dibenzo[b,f] [l,4]thiazepine (quetiapine) and for recovering quetiapine as its fumarate salt in which dibenzo[b,f][l,4]thiazepine- l l(10H)one is chlorinated in the presence of a trialkyl amine base using a slight molar excess of phosphorous oxychloride to produce l l-chloro-dibenzo[b,f] [l,4]thiazepine which then is alkylated with piperazine to l l-piperazinyldibenzo[b,f] [l,4]thiazepine, which finally is alkylated with 2-(2-chloroethoxy)ethanol.
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Page/Page column 10-11

(2008/06/13)

SUBSTITUTED PIPERAZINES OF AZEPINES, OXAZEPINES, AND THIAZEPINES
Described herein are antipyschotic compounds of formula (I) wherein: is an optionally benzo-fused five or six member aromatic ring having zero to three hetero atoms independently selected from N, O, and S; R1 is hydrogen, (C1-6) fluoroalkyl, (C3-6) cycloalkyl, or (C1-4) alkyl, wherein the (C1-4) alkyl is unsubstituted or substituted with hydroxy, methoxy, ethoxy, OCH2CH2OH, -CN, imidazolidin-2-one, phenyl, or tetrazole wherein tetrazole is unsubstituted or substituted with (C1-4) alkyl; R2 is H, halogen, (C1-6) fluoroalkyl, (C3-6) cycloalkyl, OR6, SR6, NO2, CN, COR6, C(O)OR6, C(OH)R6, CONR7R8, phenyl or (C1-6) alkyl, wherein the (C1-6) alkyl is unsubstituted or substituted with a hydroxy; R3 is hydrogen, (C 1-6)fluoroalkyl , (C3-6) cycloalkyl, (C2-6) alkenyl, phenyl, monocyclic heteroaromatic, bicyclic heteroaromatic, or (C1-4)alkyl wherein (C1-4) alkyl is unsubstituted or substituted with a phenyl; R4 and R5 are independently selected from hydrogen, halogen, (C1-6) alkyl, (C1-6) fluoroalkyl, OR9, SR9, NO2, CN, or COR9; R6 is hydrogen, (C1-6) fluoroalkyl, or (C1-6) alkyl; R7 and R8 are independently hydrogen, or (C1-6) alkyl; R9 is hydrogen, (C1-6) fluoroalkyl, (C1-6) alkyl; Alk is (C1-4) alkylene unsubstituted or substituted with a hydroxy; Y is oxygen, sulfur, SO2, or a bond; X is CH2, C=O, S, O, or SO2; Z is hydrogen, halogen, (C1-6) alkyl, (C1-6)fluoroalkyl, -OH, (C1-6) alkoxy, (C1-6) fluoroalkoxy, (C1-6) alkylthio, (C1-6) acyl, (C1-4)alkylsulfonyl, -OCF3, -NO2, - CN, carboxamido which may be substituted on the nitrogen by one or two (C1-4) alkyl groups, and -NH2 in which one of the hydrogens may be replaced by a (C1-4) alkyl group and the other hydrogen may be replaced by either a (C1-4) alkyl group, a (C1-6) acyl group, or a (C1-4) alkylsulfonyl group; the phenyl of R1, R2 or R3 is independently unsubstituted or substituted with one to three substituents independently selected from Z; the monocyclic heteroaromatic of R3 is unsubstituted or substituted with one to three substituents independently selected from Z; the bicyclic heteroaromatic of R3 is unsubstituted or substituted with one to three substituents independently selected from Z; and salts, solvates, and crystal forms thereof. Also described are the use of the compounds of formula (I) as antagonists of the dopamine D2 receptor and as agents for the treatment of psychosis and bipolar disorders, and pharmaceutical formulations of the compounds of formula (I).
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Page/Page column 75-76

(2010/02/11)

Behavioral approach to nondyskinetic dopamine antagonists: Identification of Seroquel
A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-Potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-Induced climbing and antagonism of apomorphine-Induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-Sensitized Cebus monkeys. Initial examination of a few close cogeners of I enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-Hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-Substituted analogues of 6-(piperazin-1-yl)-11H-Dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]-thiazepines and -Oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]-piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-Substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.
Warawa,Migler,Ohnmacht,Needles,Gatos,McLaren,Nelson,Kirkland
p. 372 - 389
(2007/10/03)

NOVEL DIBENZOTHIAZEPINE ANTIPSYCHOTIC
11-[4-[2-(2-Hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1, 4 ] thiazepine is disclosed as a neuroleptic with a much reduced incidence of side effects such as acute dystonia and dyskinesia and tardive diskinesia.
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(2008/06/13)

Process for the preparation of a thiazepine compound
11-(4-[2-(2-Hydroxyethoxy)ethyl]-piperazinyl)-dibenzo[b,f][1,4]thiazepine and the salts thereof possess antiandropaninergic activity, especially antipyschotic activity, and are prepared by reacting 11-piperazinyldibenzo[b,f][1,4]thiazepine with a compound of the formula:-, X-CH2-CH2-O-CH2-CH2OH, (wherein X represent an atom or group removable as an anion and, where appropriate further reaction of the product obtained to yield the free base or salt as desired.
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(2008/06/13)