US3751415A - 2-nitro-11-(1-piperazinyl)-dibenz(b,f)(1,4)oxazepines - Google Patents

2-nitro-11-(1-piperazinyl)-dibenz(b,f)(1,4)oxazepines Download PDF

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US3751415A
US3751415A US00194514A US3751415DA US3751415A US 3751415 A US3751415 A US 3751415A US 00194514 A US00194514 A US 00194514A US 3751415D A US3751415D A US 3751415DA US 3751415 A US3751415 A US 3751415A
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nitro
dibenz
piperazinyl
acid
oxazepine
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F Kunzle
J Schmutz
F Hunziker
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Sandoz AG
Sandoz Wander Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • ABSTRACT OF THE DISCLOSURE 2 nitro-1l-(1-piperazinyl)-dibenz[b,f] [1,4]oxazepines and its pharmaceutically acceptable acid addition salts are useful as anti-depressants.
  • This invention is generally concerned with new heterocyclic compounds, and more specifically with 2-nitro-11- (1 piperazinyl) dibenz[b,f] [l,4]oxazepine of the forand pharmaceutically acceptable acid addition salts thereof.
  • 2-nitro-11-( l-piperazinyl)-dibenz[b,f] [1,4] oxazepine is obtained when a compound of the formula:
  • a residue capable of being split oif with the hydrogen of amines, which can be bound ionically or covalently to the carbon atom, can most conveniently be represented by halogen, sulphydryl, or alkoxy and alkylthio which may be activated, e.g. methoxy, thiomethyl or p-nitrobenzylthio, or by tosyl.
  • lactam of Formula .III may also be obtained by ring closure of a compound of the formula:
  • nitro-l1-(1-piperazinyl)-dibenz[b,f][1,4]oxazepine is further obtained by ring closure through intramoleeular condensation of an acid amide or acid thioamide of the formula:
  • the ring closure proceeds by way of intermediate steps such as imidochlorides, amidochlorides, imidophosphates, amidophosphates or salt-like derivatives thereof, which, in general, are not isolatable.
  • intermediate steps such as imidochlorides, amidochlorides, imidophosphates, amidophosphates or salt-like derivatives thereof, which, in general, are not isolatable.
  • the condensation of the thioamide is favoured by the presence of mercury(H) salts or by intermediate formation of imidothioethers which may be activated. Heating and, if required, the use of a suitable inert solvent are desirable, and when using phosphorus oxychloride and phosphorus pentachloride addition of catalytic amounts of dimethylformamide or dimethylaniline.
  • R means hydrogen or denotes a removable group, especially a hydrolytically removable group.
  • the ring closure is preferably carried out by heating in the presence of dehydrating agents such as zinc chloride, aluminium chloride, stannic chloride, phosphoric acid, polyphosphoric acid and the like, especially phosphorus oxychloride or phosphorus oxychloride and phosphorus pentoxide, if desired in an inert solvent of suitable boiling point such as benzene or toluene, etc.
  • dehydrating agents such as zinc chloride, aluminium chloride, stannic chloride, phosphoric acid, polyphosphoric acid and the like, especially phosphorus oxychloride or phosphorus oxychloride and phosphorus pentoxide, if desired in an inert solvent of suitable boiling point such as benzene or toluene, etc.
  • the starting material of Formula VIII with a hydrolytically removable group R e.g., carbalkoxy, especially carbethoxy, is cyclicized directly to 2-nitro-1l-(l-piperazinyl) compound by hydrol-" ysisof the removable group.
  • a hydrolytically removable group R e.g., carbalkoxy, especially carbethoxy
  • Other removable groups can be split off after ring closure in a way known per se, e.g., by hydrogenolysis.
  • 2-nitro-11-(1 piperazinyl)-dibenz[b,f][1,4]oxazepine obtained in this manner is crystallizable and reacts with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, maleic acid, succinic acid, tartaric acid, toluene sulphonic acid and the like to form addition salts which are stable in water, in which form the product may also be used.
  • inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, maleic acid, succinic acid, tartaric acid, toluene sulphonic acid and the like to form addition salts which are stable in water, in which form the product may also be used.
  • the 2-nitro-11-(1 piperazinyl)-dibenz[b,f] [1,4]oxazepine has in mice an ED in the locomotor activity test [method of Caviezel and Baillod; Pharmac. Acta Helv. '33, 469 (1958)] of 2.4 mg./kg. p.o.
  • the ED in the antitetrabenazine-test in rats is, for the catalepsy 15.0 mg./kg. i.p. and for the ptosis 7.2 mg./kg. i.p.
  • the median lethal dose LD in mice is 147 mg./ kg. p.o.
  • the compounds of this invention may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs, and parenterally as solutions, suspensions, dispersions, emulsions, and the like, e.g., a sterileinjec'table aqueous suspension.
  • the compositions for oral use may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation.
  • Tablets may contain theactive ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and tale.
  • excipients e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc
  • granulating and disintegrating agents e.g., starch and alginic acid
  • binding agents e.g., starch, gelatin and acacia
  • lubricating agents e.g., magnesium stearate, stearic acid and tale.
  • the tablets may be uncoated or coated by known techniques to
  • suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation 01; such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate),
  • Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin.
  • the injectable compositions are formulated as known in the art and may contain appropriate dispersing or wetting agents and suspending agents identical or similar to those mentioned above. These pharmaceutical preparations may contain up to about 90% of the active ingredient in combination with the carrier or adjuvant.
  • the anti-depressant effective dosage of active ingredient employed for the treatment of depression may vary depending on the particular compound employed and the severity of the condition 'being treated. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of firom about 0.07 milligram to about 50 milligrams per kilogram of animal body weight p.o. For most large mammals in need of said treatment, the total daily dosage is from about 5 to about 400 milligrams. Dosage forms suitable for internal use comprise from about 10 to about milligrams of the 1 active compound in intimate admixture with a solid or containing about 10 to 25 milligrams of active ingredient.
  • the reaction mixture so obtained is added during 2 hours dropwise to a boiling solution of 86.1 g. of anhydrous piperazine in 800 ml. of xylene and 50 ml. of dioxane and heated at reflux for 4 hours.
  • the reaction mixture is poured onto ice/water and rendered alkaline with concentrated soda lye.
  • the xylene phase is washed with water and extracted with 2 N sulphuric acid.
  • the sulphuric acid extracts are washed with toluene and rendered alkaline with concentrated soda lye and the base which separates is extracted with methylene chloride.
  • the organic phase is washed with water, dried over sodium sulphate, filtered through aluminium oxide and evaporated to dryness in vacuo.
  • the products of this invention can be mixed with lactose and granulated with water, 0.5% sodium alginate or 1% gelative solution.
  • the dried granulate is compressed into tablets in the presence of about 5% of talcum, 5% of corn starch and 0.1% of magnesium stearate. In this way, there are obtained, e.g. tablets of the following composition:
  • mg. tablets which are provided with a crackline, can be administered orally in the dosage of /2 to 2 tablets 2 to 5 times, in some cases up to 5 times 4 tablets .per day in the treatment of subjects suffering from states of mental depression and especially agitated forms of depression.
  • Sterile Oral injeetable liquid Ingredients suspension suspension Sodium earboxy methyl cellulose U.S.P.
  • Methyl cellulose Polyvinylpyrrolidone Tmoirhin Benzyl alcohol Magnesium aluminum silicate- Flavor. Color Methyl paraben, U.S.P Propyl parabeu U.S.P Polysorbate 80 (e.g. Tween 80), U P Sorbital solution, 70%, U.S.P
  • vlvu fler agent to adjust pH for desired stability- 1 For injection q.s. to 1 mi. I Q.s. to 5 m1.
  • Capsules suitable for oral administration may be prepared by conventional techniques and are useful in treating depression at a dose of one tablet, of capsule, 2 to 4 times a day.

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Abstract

2 - NITRO-11-(1-PIPERAZINYL)-DIBENZ(B,F)(1,4)OXAZEPINES AND ITS PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS ARE USEFUL AS ANTI-DEPRESSANTS.

Description

ABSTRACT OF THE DISCLOSURE 2 nitro-1l-(1-piperazinyl)-dibenz[b,f] [1,4]oxazepines and its pharmaceutically acceptable acid addition salts are useful as anti-depressants.
This application is a continuation-in-part of our pending application Ser. No. 57,316, filed July 22, 1970, now abandoned which in turn is a continuation-in-part of application Ser. No. 797,281, filed Feb. 6, 1969, which issued as U.S. Pat. 3,546,226 on Dec. 8, 1970 which in turn is a continuation-in-part of our earlier application Ser. No. 712,956, filed Mar. 14, 1968, now abandoned.
This invention is generally concerned with new heterocyclic compounds, and more specifically with 2-nitro-11- (1 piperazinyl) dibenz[b,f] [l,4]oxazepine of the forand pharmaceutically acceptable acid addition salts thereof. 2 nitro-11-( l-piperazinyl)-dibenz[b,f] [1,4] oxazepine is obtained when a compound of the formula:
wherein X denotes a residue capable of being split OE With the hydrogen of amines, is reacted with piperazine.
A residue capable of being split oif with the hydrogen of amines, which can be bound ionically or covalently to the carbon atom, can most conveniently be represented by halogen, sulphydryl, or alkoxy and alkylthio which may be activated, e.g. methoxy, thiomethyl or p-nitrobenzylthio, or by tosyl.
Starting materials of the Formula II are obtained by converting the lactam of the formula:
NH-C o o (III) into the thiolactam which may be followed by alkylation, or by reaction of the lactam with a halogenating agent such as phosphorus oxychloride or phosphorus pentachloride, most suitably in the presence of a catalytic amount of dimethylaniline or dimethylformamide. The lactam of United States Patent 0 Formula 111 is itself obtained by ring closure of a compound of the formula:
wherein R denotes hydrogen or lower'alkyl. The lactam of Formula .III may also be obtained by ring closure of a compound of the formula:
NH-C O N 02 NCO N01 2 nitro-l1-(1-piperazinyl)-dibenz[b,f][1,4]oxazepine is further obtained by ring closure through intramoleeular condensation of an acid amide or acid thioamide of the formula:
/NH2 N on wherein Y represents oxygen or sulphur. A purely thermal condensation rarely succeeds with the acid amide but rather with the thioamide which is, for example, obtained from the acid amide by treatment with phosphorus pentasulphide and need not be isolated before the following condensation. Especially in the case of the acid amide it is desirable to perform the ring closure in the presence of condensing agents, such as phosphorus pentachloride, phosphorus oxychloride, phosgene, polyphosphoric acid, and the like. It is assumed that the ring closure proceeds by way of intermediate steps such as imidochlorides, amidochlorides, imidophosphates, amidophosphates or salt-like derivatives thereof, which, in general, are not isolatable. The condensation of the thioamide is favoured by the presence of mercury(H) salts or by intermediate formation of imidothioethers which may be activated. Heating and, if required, the use of a suitable inert solvent are desirable, and when using phosphorus oxychloride and phosphorus pentachloride addition of catalytic amounts of dimethylformamide or dimethylaniline.
2-nitro-1 1-( 1-piperazinyl)-dibenz[b,f] 1,4]oxazepine is also obtained by dehydration of an urea derivative of the formula:
NH- 0 LONG:
0 (VIII) wherein R means hydrogen or denotes a removable group, especially a hydrolytically removable group. The ring closure is preferably carried out by heating in the presence of dehydrating agents such as zinc chloride, aluminium chloride, stannic chloride, phosphoric acid, polyphosphoric acid and the like, especially phosphorus oxychloride or phosphorus oxychloride and phosphorus pentoxide, if desired in an inert solvent of suitable boiling point such as benzene or toluene, etc. According to the chosen reaction conditions the starting material of Formula VIII with a hydrolytically removable group R e.g., carbalkoxy, especially carbethoxy, is cyclicized directly to 2-nitro-1l-(l-piperazinyl) compound by hydrol-" ysisof the removable group. Other removable groups can be split off after ring closure in a way known per se, e.g., by hydrogenolysis.
2-nitro-11-(1 piperazinyl)-dibenz[b,f][1,4]oxazepine obtained in this manner is crystallizable and reacts with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, maleic acid, succinic acid, tartaric acid, toluene sulphonic acid and the like to form addition salts which are stable in water, in which form the product may also be used.
Analogous dibenz[b,f] [1,4] oxazepines are described in US. patent specification No. 3,458,516 whose scope includes also the 2-nitro 11 (1-piperazinyl) -di-benz[b,f] [1,4]oxazepine of the present invention. These compounds, especially those having a nitro substituent in a benzene nucleus show the typical pharmacological effects of neuroleptics, which are seen e.g. in a reduction of the locomotor activity of the test animals. It has been surprisingly found that the 2-nitro-11-(1-piperazinyl)-dibenz [b,f] [1,4] oxazepine and its acid addition salts of the present invention show besides a relatively strong reduction of the locomotor activity, an extremely intense tetrabenazine antagonising effects, which, according to Stille et al., Arznei-mittelforschungl14, 534 if. (1964), is an indication for an anti-depressant action. Such as antidepressive activity has not been observed for any of the other compounds according to US. patent specification No. 3,458,516. v
The 2-nitro-11-(1 piperazinyl)-dibenz[b,f] [1,4]oxazepine has in mice an ED in the locomotor activity test [method of Caviezel and Baillod; Pharmac. Acta Helv. '33, 469 (1958)] of 2.4 mg./kg. p.o. The ED in the antitetrabenazine-test in rats (method of Stille; loc. cit.) is, for the catalepsy 15.0 mg./kg. i.p. and for the ptosis 7.2 mg./kg. i.p. The median lethal dose LD in mice is 147 mg./ kg. p.o.
For use in the treatment of depression the compounds of this invention may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs, and parenterally as solutions, suspensions, dispersions, emulsions, and the like, e.g., a sterileinjec'table aqueous suspension. The compositions for oral use may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain theactive ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and tale. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation 01; such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate),
'wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monoleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated as known in the art and may contain appropriate dispersing or wetting agents and suspending agents identical or similar to those mentioned above. These pharmaceutical preparations may contain up to about 90% of the active ingredient in combination with the carrier or adjuvant.
The anti-depressant effective dosage of active ingredient employed for the treatment of depression may vary depending on the particular compound employed and the severity of the condition 'being treated. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of firom about 0.07 milligram to about 50 milligrams per kilogram of animal body weight p.o. For most large mammals in need of said treatment, the total daily dosage is from about 5 to about 400 milligrams. Dosage forms suitable for internal use comprise from about 10 to about milligrams of the 1 active compound in intimate admixture with a solid or containing about 10 to 25 milligrams of active ingredient.
EXAMPLE 12.8 g. of 2-nitro-10,11-dihydro 11 -oxo-dibenz[b,f] [l,'4]oxazepine M.P. 360 C.) and 5 ml. of N,N-dimethylaniline are heated in 150 ml. of phosphorus oxychloride at reflux for 4 hours. The reaction mixture is then evaporated in vacuo to remove the excess phosphorus oxychloride and the residue is decomposed with ice/water and shaken out immediately with xylene. The xylene phase is washed with dilute hydrochloric acid and water, dried over sodium sulphate, filtered through aluminium oxide and concentrated in vacuo to a volume of 70 ml. The reaction mixture so obtained is added during 2 hours dropwise to a boiling solution of 86.1 g. of anhydrous piperazine in 800 ml. of xylene and 50 ml. of dioxane and heated at reflux for 4 hours. The reaction mixture is poured onto ice/water and rendered alkaline with concentrated soda lye. The xylene phase is washed with water and extracted with 2 N sulphuric acid. The sulphuric acid extracts are washed with toluene and rendered alkaline with concentrated soda lye and the base which separates is extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate, filtered through aluminium oxide and evaporated to dryness in vacuo. The residue is crystallized from acetone/petroleum ether and gives 12 g. of 2-nitro-11-(1- piperazinyl)-dibenz[b,f][1,4]oxazepine of M.P. 190 192 C.
Production of tablets For the manufacture of tablets, the products of this invention can be mixed with lactose and granulated with water, 0.5% sodium alginate or 1% gelative solution. The dried granulate is compressed into tablets in the presence of about 5% of talcum, 5% of corn starch and 0.1% of magnesium stearate. In this way, there are obtained, e.g. tablets of the following composition:
I These mg. tablets, which are provided with a crackline, can be administered orally in the dosage of /2 to 2 tablets 2 to 5 times, in some cases up to 5 times 4 tablets .per day in the treatment of subjects suffering from states of mental depression and especially agitated forms of depression.
Sterile suspension for injection andoral liquid suspension PIIIPOSC.
Weight (mg.)
Sterile Oral injeetable liquid Ingredients suspension suspension Sodium earboxy methyl cellulose U.S.P.
Methyl cellulose Polyvinylpyrrolidone Tmoirhin Benzyl alcohol Magnesium aluminum silicate- Flavor. Color Methyl paraben, U.S.P Propyl parabeu U.S.P Polysorbate 80 (e.g. Tween 80), U P Sorbital solution, 70%, U.S.P
vlvu fler agent to adjust pH for desired stability- 1 For injection q.s. to 1 mi. I Q.s. to 5 m1.
Capsules suitable for oral administration Capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating depression at a dose of one tablet, of capsule, 2 to 4 times a day.
Ingredient: Capsule weight (mg.) 2 nitro 11 (piperazinyl)-dibenz[b,f][1,4]
oxazepine Lactose 290 Total 300 What we claim is:
1. 2 nitro 11 (1 piperazinyl) dibenz[b,f][1,4] oxazepine and its pharmaceutically acceptable acid addition salts.
References Cited UNITED STATES PATENTS 3,660,406 5/1972 Howell 260-268 TR 3,697,523 10/1972 Hunziker 260268 TR 3,705,245 12/1972 Howell 260268 TR DONALD G. DAUS, Primary Examiner US. Cl. X.R. 424-250
US00194514A 1967-03-22 1971-11-01 2-nitro-11-(1-piperazinyl)-dibenz(b,f)(1,4)oxazepines Expired - Lifetime US3751415A (en)

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CH410367A CH481133A (en) 1967-03-22 1967-03-22 Process for the preparation of basic substituted heterocycles
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4053599A (en) * 1976-02-26 1977-10-11 American Hoechst Corporation Piperazionalkylpyrrolobenzoxazalkanes
US5538965A (en) * 1993-12-23 1996-07-23 Allelix Biopharmaceuticals Inc. Dopamine receptor ligands
US5561127A (en) * 1994-12-19 1996-10-01 Allelix Biopharmaceuticals, Inc. Muscarinic receptor ligands
US5576314A (en) * 1994-12-12 1996-11-19 Allelix Biopharmaceuticals Inc. Bicyclic nonane and decane compounds having dopamine receptor affinity
US5602121A (en) * 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. Alkyl-substituted compounds having dopamine receptor affinity
US5602124A (en) * 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. 5-HT2 receptor ligands
US5602120A (en) * 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. Benzyl-substituted compounds having dopamine receptor affinity
US5700445A (en) * 1994-12-12 1997-12-23 Allelix Biopharmaceuticals, Inc. N-methyl piperazine compounds having dopamine receptor affinity
US20050192268A1 (en) * 2003-12-22 2005-09-01 Fredrik Ek Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US20050250767A1 (en) * 2003-01-23 2005-11-10 Weiner David M Use of N-desmethylclozapine to treat human neuropsychiatric disease
US20050282800A1 (en) * 2004-04-01 2005-12-22 Bo-Ragnar Tolf Method of synthesis and isolation of solid N-desmethylclozapine and crystalline forms thereof
US20070105836A1 (en) * 2005-10-31 2007-05-10 Lars Pettersson Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders
US20090018119A1 (en) * 2003-01-23 2009-01-15 Acadia Pharmaceuticals, Inc. Use of n-desmethylclozapine to treat human neuropsychiatric disease

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4053599A (en) * 1976-02-26 1977-10-11 American Hoechst Corporation Piperazionalkylpyrrolobenzoxazalkanes
US5798350A (en) * 1993-12-23 1998-08-25 Allelix Biopharmaceuticals, Inc. Dopamine receptor ligands
US5538965A (en) * 1993-12-23 1996-07-23 Allelix Biopharmaceuticals Inc. Dopamine receptor ligands
US6103715A (en) * 1993-12-23 2000-08-15 Allelix Biopharmaceuticals Inc. Dopamine receptor ligands
US5968478A (en) * 1994-12-12 1999-10-19 Allelix Biopharmaceuticals, Inc. N- methyl piperazine compounds having dopamine receptor affinity
US5576314A (en) * 1994-12-12 1996-11-19 Allelix Biopharmaceuticals Inc. Bicyclic nonane and decane compounds having dopamine receptor affinity
US5602120A (en) * 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. Benzyl-substituted compounds having dopamine receptor affinity
US5602124A (en) * 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. 5-HT2 receptor ligands
US5700445A (en) * 1994-12-12 1997-12-23 Allelix Biopharmaceuticals, Inc. N-methyl piperazine compounds having dopamine receptor affinity
US5602121A (en) * 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. Alkyl-substituted compounds having dopamine receptor affinity
US5814628A (en) * 1994-12-12 1998-09-29 Allelix Biopharmaceuticals Inc. Benzyl-substituted compounds having dopamine receptor affinity
US5824676A (en) * 1994-12-12 1998-10-20 Allelix Biopharmaceuticals Inc. 5-HT2 receptor ligands
US5561127A (en) * 1994-12-19 1996-10-01 Allelix Biopharmaceuticals, Inc. Muscarinic receptor ligands
US5674877A (en) * 1994-12-19 1997-10-07 Allelix Biopharmaceuticals Inc. Muscarinic receptor ligands
US20050250767A1 (en) * 2003-01-23 2005-11-10 Weiner David M Use of N-desmethylclozapine to treat human neuropsychiatric disease
US20090018119A1 (en) * 2003-01-23 2009-01-15 Acadia Pharmaceuticals, Inc. Use of n-desmethylclozapine to treat human neuropsychiatric disease
US20050192268A1 (en) * 2003-12-22 2005-09-01 Fredrik Ek Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US20060199798A1 (en) * 2003-12-22 2006-09-07 Fredrik Ek Amino bustituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US7491715B2 (en) 2003-12-22 2009-02-17 Acadia Pharmaceuticals, Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US7517871B2 (en) 2003-12-22 2009-04-14 Acadia Pharmaceuticals, Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US7550454B2 (en) 2003-12-22 2009-06-23 Acadia Pharmaceuticals, Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US7622461B2 (en) 2003-12-22 2009-11-24 Acadia Pharmaceuticals Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US20050282800A1 (en) * 2004-04-01 2005-12-22 Bo-Ragnar Tolf Method of synthesis and isolation of solid N-desmethylclozapine and crystalline forms thereof
US20070105836A1 (en) * 2005-10-31 2007-05-10 Lars Pettersson Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders

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