IL41936A - Production of piperazino derivatives of tricyclic azepines diazepines oxazepines and thiazepines certain novel thieno (3,2-c) (1) benzazepines and pharmaceutical compositions containing them - Google Patents
Production of piperazino derivatives of tricyclic azepines diazepines oxazepines and thiazepines certain novel thieno (3,2-c) (1) benzazepines and pharmaceutical compositions containing themInfo
- Publication number
- IL41936A IL41936A IL41936A IL4193673A IL41936A IL 41936 A IL41936 A IL 41936A IL 41936 A IL41936 A IL 41936A IL 4193673 A IL4193673 A IL 4193673A IL 41936 A IL41936 A IL 41936A
- Authority
- IL
- Israel
- Prior art keywords
- compound
- process according
- piperazinyl
- chloro
- formula
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
41 36/3 I3«'n mamn n**V DTS 'stis'-m o*3»s?8op1« ninpn ^T>©anr Vttrm rna^ oa B?KT3a t7 c 2f 7 The production of plperasino derivatives of tricyclic azepines* diazepines, oxazepines and thiazeplnes, certain novel ΐ οηό 5,2«ο7ϊ7 fcenaazepines and pharmaceutical compositions containing them AHBER MB.
Case 500-5 73 IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS The present invention relates to a new process for the production of compounds of formula I, wherein R. is hydrogen, alkoxyalkyl of 2 to 6 carbon atoms in the aggregate thereof alkyl of 1 to 4 carbon atoms , hydroxy- alkyl of 1 to 4 carbon atoms, or acyl oxyalkyl of 3 to 22 carbon atoms in the aggregate thereof, R^ is hydrogen, alkyl, alkoxy or alkyl- thio, wherein the alkyl groups have 1 to 4 carbon atoms, halogen, or trifluoromethyl, and A signifies the structure Zl Z2 whereby - 2 - 500-5273 a) when A denotes Zl, X is a ~c^2 r -0-, -S-, -NH or -N-alkyl group wherein the alkyl group has 1 to 3 carbon atoms , ϊ¾2 is hydrogen, alkyl, dialkylamino- sulphonyl, alkylsulphonyl , wherein the alkyl groups have 1 to 4 carbon atoms, alkoxy or alkylthio of 1 to 4 carbon atoms, halogen, nitro, tri- fluoromethylsulphonyl , trifluoro- methoxy, trifluoromethylthio, acetyl, • cyano or trifluoromethyl , and is hydrogen, halogen or alkyl of 1 to 4 carbon atoms , or b) when A denotes Z2, X is a ~CH2~ or -S- group.
In the substituents R^' R3 an<^ R halogen preferably denotes chlorine or bromine, especially chlorine. When the hydroxyalkyl group of the sub-stituent is acylated, the acyl group preferably contains at most 18 carbon atoms, especially at most 10 carbon atoms. The acyl group is preferably aliphatic and may be saturated or unsaturated. 500-5273 In accordance with the invention a compound of formula I may be obtained, by a process comprising reacting a compound of formula II, wherein X, A and Rj are as defined above, with a metal-amine complex comprising titanium, zirconium, hafnium or vanadium, and a compound of formula III, HN N-R, III wherein R is as defined above. 1 A resulting compound of formula I wherein R^ is acyloxyalkyl may be saponified to produce a compound of formula I wherein R^ is hydroxyalkyl . A resulting compound of formula I wherein R^ is hydroxyalkyl may be esterified to produce a compound of formula I wherein R^ is acyloxyalkyl.
One preferred method of effecting the process of the invention comprises reacting a compound of formula II with a metal-amine complex in the presence of an acid-binding agent. A tertiary amine, e.g. triethylamine, pyridine, dimethyl-aniline or an excess of a compound of formula III may be used as acid-binding agent. At least one raol , preferably, however, two mols of the acid-binding amino compound should be used, calculated on one mol of metal-amine complex.
The reaction is conveniently effected in an organic solvent, e.g. ε·.η aromatic solvent such as toluene, a halogenated aromatic solvent such as chlorobenzene , a halogenated aliphatic solvent such as dichloroethane , or preferably an ether such as anisole. The reaction temperature is not critical within wid<=> limits, and is conveniently from 20°C to 1(ϊΩ°πΓ preferably from 50 to 120 °C .
The metal-amine complex used for the reaction of the invention is preferably obtained by reaction of a halide, preferably the tetrachloride or tetrabromide of titanium, zirconium, hafnium or vanadium, with a compound of formula III, conveniently at a mol ratio of 1:4 respectively. The reaction is conveniently effected in the solvent subsequently used for the reaction between a compound of formula II and the metal-amine complex. The metal halide may be used in the form of a soluble (mono- or di) etherate thereof, - 5 - 500-5273 preferably the anisole dietherate.
It is preferred to use titanium and zirconium and especially titanium.
After the reaction, the compound of formula I may be isolated in conventional manner. The largely insoluble metal compounds present in the reaction mixture may be conveniently removed by conversion into soluble form by the addition of an alcohol, e.g. iso-propanol, and by subsequent precipitation by the addition of aqueous ammonia. The compounds of formula I, obtained in accordance with the invention, may be isolated in knov/n manner for example by crystallization from the reaction mixture from which metal compounds have been removed, after concentrating the reaction mixture, and may be subsequently purified in known manner, e.g. by re-crystallization from isopropanol.
When a compound of formula I wherein is hydroxyalkyl is produced, the reaction product may be obtained in colloidal form, since the hydroxyalkyl group can also react with the metal halide with ester formation. In order to avoid the appearance of too much - 6 - 500-5273 gelatinous material, which could disturb the course of the reaction, it is convenient to effect the reaction in the presence of a large amount of solvent, e.g. chlorobenzene or anisole, preferably in the presence of an excess (10- to 20-fold molar excess) of a tert. amine, e.g. triethylamine .
A compound of formula I wherein R^ is hydroxyalkyl may alternatively be obtained by alkaline saponification of a compound of formula I wherein is an acylated hydroxyalkyl group, e.g. with a dilute sodium hydroxide solution.
The esterification of a compound of formula I wherein R^ is hydroxyalkyl may be effected in known manner, e.g. with a reactive acid derivative, e.g. a halide of a corresponding acid, in a solvent such as chloroform, conveniently in the presence of an acid-binding agent such as triethylamine, at room temperature Free base forms of the compounds of formula I produced in accordance with the invention may be converted into their acid addition salt forms in conventional manner and vice versa. Examples of suitable salts are the hydrochlorides, hydrobromides , sulphates, fumarates, maleates and p_-toluenesulphonates . - 6a - 500-5273 Of the known synthetic methods for the production of enamines, the one described in J. Org. Chem. 1967 (32) 213, involves the addition of titanium chloride to a mixture of an amine and an aliphatic ketone. completely different »©» this process, and provides a novel method of amination by reacting a cyclic lactam vrith a preformed complex of an amine and a heavy metal. 41936/3 The compounds of formula II used as startin^^ materials in the process according to the invention, are known or may be produced according to known methods or according to methods described in the Examples hereafter for the production of 10H-thieno [3,2-c] [ljbenz&zepines , or according to methods analogous to any of these methods .
The compounds of formula III, used as starting materials in the process according to the invention arc-known or may be prepared according to known methods or according to methods described in the Examples here-after for the production of 1-tert-butylpiper zine , or according to methods analogous to any of these methods.
For example a compound of formula III wherein is acyloxyalkyl may be obtained bv reacting N-benzylpiperazine with a halo- alcohol, esterifying the hydroxy group of the N-benzyl- ' -hydroxy-piperazine. with a reactive acid derivative, e.g. a halide, especially the chloride of a corresponding acid, and subsequently removing the benzyl group from the resulting compound hydrogenolytically .
Compounds of formula I produced in accordance with the present invention are in general known , but some of them, namely those wherein A is Z2 and X is -CH2-, R1 is hydrogen, alkyl , hydroxyalkyl or alkanoyloxy-alkyl and is hydrogen, halogen or alkyl, are novel and these form part of the present invention. 500-5273 Such compounds are said to exhibit pharmacological properties, e.g. central nervous system activity, some compounds, e.g. 2-chloro-ll- (4-methyl-l-piperazinyl) -dibenzo [b , f ] [1 , 4] thiazepine , being indicated for use as antipsychotic agents. Alternatively such compounds may be used as intermediates to produce further, e.g. heterotricyclic , compounds.
Compounds of formula I not specifically described in the literature are therefore indicated for use in a manner similar to known compounds of formula I In the general formula I, when A denotes Zl, the substituent R is preferably in the 2 or 3 position the substituent is preferably in the 4 position, and when A denotes Zl and Z2, the substituent is preferably in the position 7 or 8, i.e. meta or para to the group or atom X.
•In the following non-limitative Examples all temperatures are indicated in degrees Centigrade, room temperature is a temperature between 20 and 30 °C, unles otherwise indicated. - 9 - 500-5273 EXAMPLE 1: 8-chloro-ll-(^-methyl~l-piperazinyl) -5H- dibenzo[b. e] [1, ] diazepine 840 cc of toluene, 90 cc of anlsole and 79.2 g of titanium tetrachloride are introduced, at room temperature, in a 2* litre sulphonating flask provided with a dropping funnel, reflux condenser and thermometer, whereby a dark brown, clear solution is formed. A mixture of 1β7 g of N -methyl piperazine and 100 cc of toluene is added thereto while cooling externally with water, whereby the temperature rises to 50-55° and the amine complex, in finely divided form, forms a beige to dark brown coloured suspension. 102 g of 8-chloro-lO, ll-dihydro-ll-oxo-5H-dibenzo[b, e] [1, ] -diazepine and 83 g of -methyl piperazine are subsequently added, and the reaction mixture is heated to the boil (110-112°) for 3 hours while stirring.
Cooling is then effected to 60-70°, 125 cc of isopropanol are added, whereby the insoluble titanium compounds formed during the reaction again dissolve. After the addition of 8 g of diatomaceous earth and subsequently 115 cc of concentrated ammonia (about 2 ) , cooling is effected to about 30° while stirring - 10 - 500-572 and the resulting precipitate is filtered off. The filter residue is washed with 2-3 350 cc portions of toluene. The filtrate is subsequently mixed with water, and the organic phase is extracted with dilute, approx. 10 hydrochloric acid. The base is precipitated by the dropwise addition of the hydrochloric acid extract to an excess of dilute ammonia. The precipitate is taken up in ether, the ether solution is washed with water and dried over sodium sulphate. After removal of the ether by evaporation and recrystallization from isopropanol,. 8-chloro-ll-(4 -niethyl-l-piperazinyl) -5H~dibenzo-[b^ejtl^jdiazepine, having a M.P. of 184-185°, is obtained.
EXAMPLE 2; 840 cc of toluene, 90 cc of anisole and 93· 6 of zirconium tetrachloride are introduced at room temperature in a 2.5 litre sulphonating flask - 11 - 5 0-5273 -s. provided with a dropping funnel, reflux condenser and thermometer, whereby a dark brown, clear solution is formed. A mixture of 248 g of N-tert-butyl piperazine and 100 cc of toluene is added thereto while cooling externally with water, whereby the temperature rises to 50-55° and the amine complex, in finel divided form, forms a dark brown coloured suspension. 87 g of morphani|ridin-6-one and 123. g of M-tert-butyl piperazine are subsequently added and the reaction mix ture is heated to the boil (110-112°) for 3 hours while stirring. Cooling is then effected to 60-70°, 125 cc of isopropanol are added, whereby the insoluble zirconium compounds formed during the reaction again dissolve. After the addition of 8 g of diatomaceous earth and subsequently 115 cc of concentrated ammonia (approx. 27 ) cooling is effected to about 3 ° while, stirring and the resulting precipitate is filtered off The filter residue is washed with 2-3 330 cc portions of toluene · The filtrate is subsequently mixed with water and the organic phase is extracted with dilute, approx. 10 hydrochloric acid. The base is precipitated by the dropwise addition of the hydrochloric acid extract to an excess of dilute - 12 - 500-5273 ammonia. The precipitate is subsequently taken up in ether, the ether solution is washed with water and dried over sodium sulphate. After removing the ether by evaporation, the residue is dissolved in acetone and 38 g of maleic acid are added to the solution.
The solution is subsequentl concentrated, ethyl acetate and some ether are added and the resulting precipitate is filtered off. After recrystallization from acetone/ethyl acetate/ether, the resulting 6-( -tert~ . butyl-1-piperazinyl) -morphanyridine maleate has a M.P. of 138-141°.
The 1-ter -butyl piperasine, used as starting material in the above process, may be produced as follows: 1) l-benzyl- -tert-butyl piperazine A solution of 2000 g of bis- (2-chloroethyl) -tert-butylamine in 500 cc of ethanol and a solution of IO95 S of benzylamine in 75° cc of ethanol are simultaneously added dropwise to 1000 cc of boiling ethanol. After the addition is complete, the reaction mixture is heated to the boil for one hour. The mixture is subsequently concentrated in a vacuum - 13 - 500-5273 and the residue is dissolved in dilute hydrochloric acid. The acid solution is washed with ether and is subsequently rendered alkaline with a concentrated, aqueous sodium hydroxide solution. The liberated base is extracted with ether and the ether residue is distilled „ 1-benzyl- -tert-but l piperazine has a B.P. of 160-162° at 12 ram of Hg. 2) l~tert~butyl piperazine 38. g of 1-benz l- -tert-but l piperazine are dissolved in 1200 cc of 99 % ethanol and 10 g of a 5 palladium/charcoal catalyst are added to the resulting solution. The solution is subsequently shaken in a hydrogenation apparatus, in a hydrogen atmosphere (1 atmosphere) and at room temperature, until the take up of hydrogen is complete. Filtration is subsequently effected, the filtrate is concentrated by evaporation in a vacuum and the residue is distilled in a vacuum. 1-tert-butyl piperazine is obtained in the form of a colourless oil, having a B.P. of 66-70° at 12 mm of Hg, which crystallizes upon standing* The crystals have a M.P. of 35- 0°.
By using the processes described in the - 14 - 500-5273 above Examples 1 and 2 and the corresponding starting materials, the following compounds ma be obtained in analogous manner: 5-methyl-ll-(4-methyl-l-piperazinyl) -dibenzo[b, e] [1,4]-diazepine, having a M.P. of 122-124° (from ether/ petroleum ether), 2-chloro-ll-(4-methyl-l~piperazinyl ) ~dibenzo[b, ] [ 1, 4] -thiazepine, having a M.P. of 116-120° (from ether/ petroleum ether), 6-(4-methyl-l-piperazir.yl) -morphantridine, having a M.P. of I38-I390 (from acetone/petroleum ether), 2-methyl-ll-(4-methyl-l-piperazinyl) -dibenzo[b, ] [ 1, 4] -thiazepine, having a M.P. of 99-107° (from petroleum ether), 2-chloro-ll-(4-methyl-l-piperazinyl) -dibenz[b, f] [ 1, 4] -oxazepine, having a M.P. of 104-110° (from petroleum ether), 2-bromo-ll- (4-methyl-l-piperazinyl) -dibenzo[b, f] [1,4] -thiazepine, having a M.P. of 138-I390 (from acetone/ petroleum ether), - 15 500-5273 2-nitro-ll-(4-methyl--l-piperazinyl) -dibenz[b, f] [1, 4] -oxazepine, having a M.P. of 192-193° (from chloroform/ acetone/petroleum ether), 2-dimeth laminosulphony1-11-( -me h 1-1-piperazinyl) -dibenzo[b,f] [1, 4]thiazepine, having a M.P. of 192-193° (from acetone/petroleum ether), 2-dimeth larainosulphonyl-11-(4-rnethyl-l-piperazinyl) -dibenz[b,f] [l,4]oxazepine, having a M.P. of 149-150° (from ether/petroleum ether), 2-methylsulphonyl~ll-(4-methyl-l-piperazinyl) ~ dibenz[b,f] [1, 4]oxazepine, having a M.P. of 178-179° (from acetone/ether/petroleum ether), 2-trifluoromethoxy-ll-(4-methyl-l-piperazxnyl) -dibenz[b,f ] [1,4] joxazepine dihydrochloride monohydrate, having a M.P. of 200-210° (from alcohol/ether), 7-chloro-4-(4-methyl-l-piperazinyl) -thieno[2, 3-b] [1,5] -benzodiazepine, having a M.P. of Ιβ2-ΐ64° (from ethyl acetate), 2-trifluoromethylsulphonyl-ll-(4-methyl~l-piperazinyl) -dibenzo[b,f] [1, 4]thiazepine, having a M.P. of 168-170° - 16 - 500-5273 (from ether/petroleum ether), ^~-' 2-acetyl-ll- ( 4-methyl-l-piperazinyl) -dibenz[b,f] [1,4] -oxazepine, having a M.P. of 116-118 ° (from acetone/ petroleum ether), 2-tri luoromethyl-ll- (4-methyl-l-piperaziiyl) -dibenz[b, f] [1, 4]oxazepine, the fumarate thereof having a M.P. of 214-216° (from acetone/petroleum ether), 2-trifluoromethylsulphonyl-ll- (4-methyl-l-piperazinyl) -dibenz[b,f] [1, 4]oxazepine, having a M.P. of 120-122° (from ether/petroleum ether), 2-methy.lsulphonyl-ll- (4-ethyl-l-piperazinyl) -dibenz[b, ] [1, 4] oxazepine, having a M.P. of 190-1910 (from acetone/petroleum ether), 4 - (4-methyl-l-piperazinyl) -thieno[2, 3-b] [1, ]benzo-thiazepine, having a M.P. of 112-114° (from absolute ethanol), 4- (4-methyl-l-piperazinyl) -10H-thieno[ 3, 2-c] [1] -benzazepine, having a M.P. of 145-147° (from ether/ petroleum ether), 8-chloro-4-(l-piperazinyl)-10H-thieno[ 3,2-c] [1]~ - 17 - 500-5273 benzazepine, having a M.P* of 8o~100° (from acetone/ water in the presence of charcoal), 8-chloro-4-[4-(2-acetoxyethyl) -1-piperazinyl] -10H-thleno[3, 2-c] [1]benzazepine, having a M.P. of I85-I890 (from ether/petroleum ether), 8-chloro~4-(4-methyl-.l-piperazinyl) -10H-thieno-[3,2-c] [l]benza.zepine, having a M.P. of 193-195° (from acetone/petroleum ether), 2-methylthio-ll-(4~methyl-l-piperazinyl) -dibenz-[b,f J [1, ]oxazepine, having a M.P. of 198-201° (rnaleate), -(4-tert-bityl-l-plperazinyl)-iQH-thieno[^„2-ol Γ11-benzazepine, having a M.P. of 147-176° (maleate), 7-methyl~4-(4-methyl-l-piperazinyl) -10H-thieno~ [3,2-c'J [l]benzazepine, having a M.P. of l80-l8l° (from acetone/petroleum ether), 7-chloro-4-(4-methyl-l-piperazinyl) -10H-thieno-[3,2-c] [l]benzazepine, having a M.P. of 184-185° (from acetone), 7-chloro-4-(4^-hydroxyethyl-l-piperazinyl) -10H-thieno[3,2-c] [ 1 ]benzazepine, having a M.P. of 192-194° - 18 500-5273 (from ethyl acetate) , 8-chloro-4-(4~3-hydroxyethyl-l-piperazinyl-10H-th.ieno[3, 2-c] [l]benzazepine, having a M.P„ of 202-203° (from ethyl acetate), 2-trifluoromethyIsulphony1-11-[ -(β-pentanoylox ethyl) 1-piperazinyl] -dibenz[b,f] [l,4]oxazepine, the oxalate thereof having a M.P. of 213-216°, 2-tri luorometh Isulphon 1-11- ( -β-hydroxyethyl-1-piperazinyl) -dibenz[b,f] [1, 4]oxazepine, having a M.P. of 121-123° (from ether/petroleum ether), 2-trifluoromethyIsulphony1-11-(l-piperazinyl) -dibenz[b,f] [l,4]oxazepine, having a M.P. of 183-I860 (from ether), 2-trifluorome hylsulphonyl-ll-( -^-hydroxypropyl-l-piperazinyl) -dibenz[b,f] [1, ]oxazepine, having a M.P. of I 2-I3 0 (from ethe /petroleum ether), 2-trifluoromethylthio-11- (4- -hydroxyethyl-l-piperazinyl) -dibenz[b, ] [l,4]oxazepine, having a M.P. of 121-123° (from petroleum ether), 2-trifluoromethylsulphonyl-ll-(4-3~oleyloxyethyl-1- - 19 - 500-5273 piperazinyl) diben [b,f] [1,4 joxazepine (oil with an Rf va.lue=0.88 [silicagel SL 254 Antec] using chloroform/cyclohexane/diethyl amine (5:4:1) as eluant and Dragendorff ' s reagent as detection agent), 1, 4-dirnethyl-ll-(4-methyl -l-piperaz.inyl) -dibenz- [b,f][l,4]oxazepine, having a M.P. of 143-1 ° (from ether/petroleum ether), 3, 4-dircethyl«ll-(4-methyl-l-piperazinyl) -dibenz-[b, f 3 [1, 4]oxazepine, having a M.P. of Ιβ7-1β9° (from acetone/petroleum ether), 2,8-dichloro-ll-(4-met yl-l-piperazin l) -dibenz-[b,f][l,4]oxazepine, having a M.P. of 130-1 1° (from acetone/petroleum ether), 4,8-dichloro-ll-(4~methyl-l~piperazinyl) -dibenz-[b, f ] [l,4]oxazepine, having a M.P. of 13 -135° (from acetone/petroleum ether), 4-methyl-8-chloro-ll- (4-methyl-l-piperazinyl) -dibenz~ [b, ] [l,4Joxazepine having a M.P. of I5O-I5I0 (from ether/petroleum ether), 4-methyl-7-chloro-ll- (4-methyl-l-piperazinyl) -dibenz- - 20 - 500-527 [b,f][l, ]oxazepine, having a M.P. of I67-I680 (from acetone/petroleum ether), 2, -dlchloro-ll-(4~methyl-l-piperazinyl) -dibenz-[b, ] [1, 4]oxazepine, having a M.P. of I3 -I380 (from acetone/petroleum ether), 2-chloro-ll- (1-piperazinyl) -dibenz[b3f] [1, ]oxazepine, having a M.P. of 178-I8O0 (from acetone/petroleum ether).
The starting materials for the production of 10H-thieno[3, 2-c] [l]benzazepines may be obtained as follows: J -dihydro-10H-thieno[3, 2-c] [l'Jbenzazepin- -one 14.8 g of 2- (2-amino-phenyl) -thienone, 23.8 g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are heated to the boil at reflux in 180 cc of diethylene glycol for 3 hours. After diluting the reaction mixture with ice water, extraction is effected with ether. The ether phase is washed thrice with water, dried over sodium sulphate and concentrated. 2- (2-aminobenzyl) -thiophene is ob-tained in the form of a light yellow oil having a B.P. of 128-1300 at 0.1 mm of Hg. - 21 - 500-5273 Κ6 cc of a 20 solution of phosgene in toluene are added drop^ίise at -3°> with stirring, to a solution of 9·8 S of the product obtained above in 60 cc of toluene. The reaction mixture is subsequently allowed to warm to room temperature while passing through a stream of phosgene, and is then heated to the boil at reflux for half an hour* After driving out the excess phosgene with a stream of nitrogen, the reaction mixture is concentrated in a vacuum and the residue is distilled. 10.8 g of 2-(2-isocyanato-benzyl) -thiophene, having a B.P. of 108° at 0-05 mm of Hg, are obtained. 10.5 g of 2-(2-isocyanato--benzyl) -thiophene (B.P. 108°/0.05 mm of Hg) are heated to 110° with 105 g of polyphosphoric acid for one hour while stirring. The reaction mixture is subsequently rendered alkaline with a concentrated ammonia solution while cooling internally and externally with ice and the resulting precipitate is filtered off. This is washed with water, dried and crystallized from acetone while treating with charcoal. , -dihydro-10H-thieno[3, 2-c] [l]benzazepin-4-one is obtained in the form of grains having a M.P. of 22 -2360 (between - 22 - 500-5273 I 0 and 200° conversion into bright needles). 8-chioro- or 7-chloro-4, -dihydro-10H-thieno[ 3, 2-c] [ 1 ] benzazepin-4-one 6 g of N-p-toluenesulphonyl-5-chloro (or 4-chloro) -anthranilic acid are heated to the boil at reflux with 10 cc of thionyl chloride for 1 .2 hours After evaporating to dryness in a vacuum, the residue i recrystallized from methylene chloride/petroleum ether. The resulting N-p_-tcluenesulphonyl-5-chloro-anthranilic acid chloride has a M.P« of I34-I360, N-p-toluene-sulphonyl-4-chloro-anthranilic acid chloride has a M.P. of 135-140°.
A solution of 6 g of stannic chloride in 10 cc of carbon disulphide is slowly added dropwise at the boil, under reflux, to a mixture of 7 g of finely pulverized N-p_-toluenesulphonyl-5--chloro (or 4-chloro) -anthranilic acid chloride and 3.4 g of thiophene in 25 cc of carbon disulphide. After the addition is complete, stirring is effected at room temperature for 2 hours. The solvent is subsequently evaporated in a vacuum, the residue is treated with ice water and hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed - 23 - 500-5273 I '-ν..— with 2N hydrochloric acid, water and a saturated aqueous potassium bicarbonate solution, is dried with -;.sodium sulphate and concentrated. The evaporation residue is divided between ether and a 1 normal aqueous sodium hydroxide solution. The aqueous alkaline solution is acidified . with concentrated hydrochloric acid and the resulting precipitate is drawn off by suction. The suction filter residue is washed with water and recrystallized from ethyl acetate/petroleum ether. 2-(2-£-toluenesulphonamido- 5-chloro-phenyl) -thienone has a .P. of 16 -Ιβ7°, 2-(2-£-toluenesulphonamido- -chloro-phenyl) -thienone has a M.P. of 1 0-I4l°. 8.4 g of 2-(2-p_-toluenesulphonamido-5~ chloro (or 4-chloro) -phenyl) -thienone are stirred at room temperature with 100 cc of concentrated sulphuric acid for 4 hours. The reaction product is subsequently poured on ice and the resulting mixture is rendered alkaline with a concentrated aqueous sodium hydroxide solution while cooling. A precipitate is obtained, which is taken up in ether. The ether solution is washed with water, dried with sodium sulphate and concentrated, whereby a residue is obtained. After - 24 - 500-5273 recrystallization from ether/petroleum ether in the presence of charcoal and aluminium oxide, 2-(2-amino~5-chloro-phenyl) -thienone has a M.P. of 97-98° and 2-(2-amino~4-chloro-phenyl) -thienone has a M.P. of 66-72°. 1 '5 g of 2-(2-amino-5-chloro (or 4-chloro) phenylH^lenone, 23.8 g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are heated to the boil at reflux in l80 cc of diethylene glycol for 2 hours. After diluting the reaction mixture with ice water, extraction is effected with ether. The ether phase is washed thrice with water, dried with sodium sulphate and concentrated. 2-(2»amino-5-chloro-benzyl) -thiophene, having a B.P. of I5O-I570 at 0.1 mm of Hg, and 2- (2-amino-4-chloro-benzyl) -thiophene, having a B.P. of 137-140° at 0.05 mm of Hg, are obtained in the form of an oil. 46 cc of a 20 solution of phosgene in toluene are added dropwise at -3°, while stirring, to a solution of 11 g of 2-(2-amino-5-chloro (or 4-chloro) -benzyl) -thiophene in 60 cc of toluene. The reaction mixture is subsequently allowed to warm to room temperature while introducing a stream of phosgene - 25 - 500-5273 and is subsequently heated to the boil at reflux for half an hour. After driving off the excess phosgene with a nitrogen stream, the reaction mixture is concentrated in a vacuum and the residue is distilled. 2-(2-isocyanato-5-chloro-benzyl) -thiophene, having a B.P. of 137-139° at 0.1 mm of Hg, and 2~ (2-isocyanato-4-chloro~benzyl) -thiophene, having a B.P . of 124-125° at 0.05 mm of Hg, are obtained.
Ring closure of 2- (2-isocyanato-5-chloro (or 4-chloro) -benzyl) -thiophene, using the process described above with respect to 2- (2-isocyanato-benzyl) thiophene , yields 8-chloro~4 , 5-dihydro- 10H~thieno[3, 2-c] [l]benzazepin-4-one, having a M.P. of 28O-28I0 (after recrystallization from dioxane/acetone) , and 7-chloro-4, 5-dihydro-10H-thieno[3, 2-c] [l]benzazepin-4-one, having a M.P. of 264-266° (after recrystallization from acetone).
Following the procedure described in Example 1 or 2 but replacing the starting materials with appropriate compounds in equivalent amounts, the following compounds are prepared: - 2-methoxy-ll- (4-methyl-l-piperazinyl) dibenz' [b,f] [1,4]-oxazepine ; - 26 ~ 500-5273 2-fluoro-ll- (4-methyl-l-piperazinyl)dibenz. >-[b,f] [1 , 4] oxazepine; 2-cyano~ll- (4-methyl-l-piperazinyl) dibenz -[b,f] [1,4] oxazepine; 2,4-difluoro-ll- (4-methyl-l-piperazinyl) dibenz - [b,f] [1,4] oxazepine; 2, 4-dibromo-ll- ( 4-methyl-l-piperazinyl) dibenz -[b,f] [1,4] oxazepine; 8-methoxy-ll- (4-methyl-l-piperazinyl) dibenzo-[b,f] [1, 4] thiazepine; 7-methylthio-ll- (4-methyl-l-piperazinyl) dibenzo-[b,f] [1 , 4] thiazepine; 8-fluoro-ll- (4-methyl-l-piperazinyl) dibenz -[b,f] [1,4] oxazepine; 8-bromo-ll- (4-methyl-l-piperazinyl) dibenz - [b,f] [1 ,4]oxazepine; 8-trifluoromethyl-11- (4-methyl-l-piperazinyl) -5H-dibenzo [b,e] [l,4]diazepine; and 2-nitro-ll- (4p-methoxyethyl-l-piperazinyl) dibenz - [b,f] [l,4]oxazepine.
Production of 1 i quid pbnrnaccuticr.l compositions Solutions, suspensions, emulsions, dispersions, syrups^, and elixirs ir.ay contain the compound of formula I as the active agent, in the form as described in the proceeding example in admixture with any of the conventional excipients utilized for the preparation of such compos t ons, e.g. suspending agents (me thy 1 ce 1 lu 1 os e , tragacanth and sodiun alginate), vetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan n-onoleate) flavouring, colour¬ ing and sweetening agents and preservatives (ethyl-jr-hydroxybenzo- ate.
The following pharmaceutical compositions are formulated vith the indicated amount of active agent using conventional tech¬ niques. The injectable suspension and the oral liquid suspension represent fornulations useful as unit doses. The injectable sus¬ pension is suitable for administration once a day whereas the oral liquid suspension is suitably administered 2 to 4 tines per day for this purpose Ingredients Weight (mg) Sterile inject- oral liquid ablc suspension suspension Compound of formula I, 10 10- acid addition salt Sodium carboxy rcethyl cellulose U.S.P. 1.25 12.5 Methyl cellulose 0.4 Polyvinylpyrrolidone 5 Lecithin 3 Benzyl alcohol 0.01 Magnesium aluminium silicate — 47.^ Flavour - q.s.
Colour — . q.s.
Methyl parabcn,U . S . P . - 4.5 Propyl par ben, U.S. P. - 1.0 Polysorbate 80 (e.g. Tween. 80), U.S.P. - 5 Sorbitol solution, 70 7. ,U.S.P. - 2,500 Buffer agent to adjust pH for desired stability q.s. q.s.
Water · for injection q.s. to q.s. to 1 ml. 5 cl.
Preferred novel compounds of formula I are:-7-chloro- -(4-methyl-l-piperazinyl)-10H-piperazinyl-10H-thieno[3 ,2-c] [1] benzazepine . i
Claims (38)
1. A process for the production of a compound of formula I, wherein R. is hydrogen, alkoxyalkyl of 2 to 6 carbon atoms in the aggregate thereof alkyl of 1 to 4 carbon atoms , hydroxy- alkyl of 1 to 4 carbon atoms , or acyl oxyalkyl of 3 to 22 carbon atoms in the aggregate thereof, is hydrogen, alkyl, alkoxy or alkyl- thio, wherein the alkyl groups have 1 to 4 carbon atoms, halogen, or trifluoromethyl and A signifies the structure Zl Z2 whereby - 28 - 500-5273 a) when A denotes Zl, X is a "CH^, -0-, -S- , -NH or -N-alkyl group wherein the alkyl group has 1 to 3 carbon atoms , is hydrogen, alkyl, dialkylamino- sulphonyl, alk lsulphonyl , wherein the alkyl groups have 1 to 4 carbon atoms, alkoxy or alkylthio of 1 to 4 carbon atoms, halogen, nitro, tri- fluoromethylsulphonyl , trifluoro- methoxy, trifluoromethylthio , acetyl, cyano or trifluoromethyl , and is hydrogen, halogen or alkyl of 1 to 4 carbon atoms , or b) when A denotes Z2, X is a -CH,,- or -S- group, which comprises reacting a compound of formula II, wherein X, A and are as defined above, with a metal-amine complex comprising - 29 - 500-5273 titanium, zirconium, hafnium or vanadium, and a compound of formula III, wherein R is as defined above. 1
2. A process according to claim 1, in which the metal is titanium or zirconium in tetravalent form.
3. A process according to claim 1 or 2 , in which the metal-amine complex is formed by reacting a tetrachloride or tetrabromide of the metal with a compound of formula III.
4. A process according to claim 3, in which the mol ratio of metal tetrachloride or tetrabromide to compound of formula III is substantially 1:4.
5. A process according to any preceding claim, carried out in the presence of an acid-binding agent.
6. A process according to any preceding claim, in which the mol ratio of acid-binding agent to metal- amine complex is at least 2:1.
7. A process according to claim 6, in which the mol ratio of acid- binding agent to metal-amine complex is at least 10:1 and the reaction is carried out in a large amount of solvent. 41 936/3
8. A process according to claim 6 or 7 wherein the acid-binding agent is a tertiary amine.
9. A process according to any preceding claim, carried out in the presence of an aromatic solvent.
10. A process according to claim 9, in which the aromatic solvent is chlorobenzene, toluene or anisole.
11. A process according to any preceding /claim, carried out at a temperature from 20 to 150 °C.
12. A process according to any one of the preceding claims, wherein R3 is hydrogen.
13. A process according to any one of the preceding claims, wherein R2 or is para to the group or atom X. . .
14. A process for the production of a compound of formula I, stated in claim 1, substantially as hereinbefore described with reference to Example 1 to 2.
15. Compounds of formula I, whenever produced by a process according to any preceding claim. 31
16. A process according to any preceeding claim carried out in the presence of anisole as solvent.
17. A process according to any preceeding claim carried out in the presence of toluene and anisole as solvent.
18. A process according to any preceeding claim, wherein titanium tetrachloride is used to form the metal amine complex.
19. A process according to any preceeding claim carried out at a temperature of from 110° to 112°C in the presence of anisole and toluene.
20. A process according to any preceeding claim carried out at a temperature of from 110° to 112 °C in the presence of anisole and toluene using titanium tetrachloride to form the metal amine complex.
21. A process according to any preceeding claim carried out at reflux in the presence of anisole and toluene using titanium tetrachloride to form the metal amine complex.
22. A process according to any preceeding claim, wherein the compound of formula I is 8-chloro-ll- (4-methyl 1-piperazinyl) -5H-dibenzo tb,e] [l,4]diazepine. - 32 - 41936/3
23. A process according to any preceeding claim, , wherein the compound of formula I is 2-chloro-ll-: (4-methyl- l-piperazinyl) -dibenzotb, f] [1,4] thiazepine.
24. A process according to any preceeding claim, wherein the compound of formula I is 6- (4-methyl-l- piperazinyl ) -morphanthrid'ine .
25. A process according to any preceeding claim, wherein the compound of formula I is 2-chloro-ll- (4- methyl-l-piperazinyl ) -dibenz [b, f] [1,4] oxazepine .
26. A process according to any preceeding claim, wherein the compound of formula I is 2-chloro-ll- (1- piperazinyl) -dibenz [b,f] [ 1 , 4] oxazepine .
27. A process according to any preceeding claim, wherein the compound of formula I is 7-chloro-4- (4- v methyl-piperazinyl) -lOH-thieno [ 3,2-c] [I]benzazepine .
28. A compound of formula I, wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, or - 33 - 41936/2 is hydrogen, halogen or alkyl , and signifies the structure Z2 and X is -CH2~ .
29. . A compound of Claim 28, which is 7-chloro-4- ( 4- methyl-l-piperazinyl) -lOH-thieno [3, 2-c ] [l]benzazepine.
30. A compound of Claim 28, which is 4- (4-methyl-l- piperazinyl) -lOH-thieno [3, 2-c] [1Jbenzazepine .
31. . A compound of Claim 28, which is 8-chloro-4- ( 1- piperazinyl) -lOH-thieno [3 , 2-c] [1] benzazepine.
32. A compound of Claim 28, which is 8-chloro-4- [ - (2-acetoxyethyl) -l-piperazinyl]r-10H-thieno [3, 2-c J [1]-benzazepine .
33. · A compound of Claim 28, which is 8-chloro-4- ( -methyl-l-piperaziny 1) -lOH-thieno [3 , 2-c ] [1]benzazepine .
34. A compound of Claim 28, which is 4- ( -tert-buty 1-1-piperazinyl) -10H-thieno.[3, 2-c] [l]benzazepine .
35. A compound of Claim 28, which is 7-methy 1-4- ( 4-methyl-l-piperazinyli-lOH-thieno [3, 2-c] [l]benzazepine.
36. A compound of Claim 28, which is 7-chloro-4- (4-β-hydroxyethyl-l-piperazinyl) -lOH-thieno [3# 2-c] [l]benz-azepine. ' - 34 - 41 936/1
37. A compound of Claim 28, which is 8-chloro-4- (4-β-hydroxyethyl-l-piperazinyl) -10H-thieno 13 , 2-c] [llbenz-azepine.
38. A compound of any one of Claims 28 to 37 in acid addition salt form. 39 A pharmaceutical composition comprising a compound of. any one of Claims 28 to 38 in free base form or in pharmaceutically acceptable salt form in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH489872A CH569730A5 (en) | 1972-04-04 | 1972-04-04 | |
| CH490172A CH569731A5 (en) | 1972-04-04 | 1972-04-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL41936A0 IL41936A0 (en) | 1973-06-29 |
| IL41936A true IL41936A (en) | 1977-10-31 |
Family
ID=25696493
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL41936A IL41936A (en) | 1972-04-04 | 1973-04-03 | Production of piperazino derivatives of tricyclic azepines diazepines oxazepines and thiazepines certain novel thieno (3,2-c) (1) benzazepines and pharmaceutical compositions containing them |
Country Status (28)
| Country | Link |
|---|---|
| JP (2) | JPS4913189A (en) |
| AR (1) | AR195913A1 (en) |
| AT (1) | AT340428B (en) |
| BE (1) | BE797671A (en) |
| BG (1) | BG21221A3 (en) |
| CA (1) | CA1029372A (en) |
| CH (2) | CH569730A5 (en) |
| CS (1) | CS178125B2 (en) |
| CY (1) | CY990A (en) |
| DD (1) | DD105614A5 (en) |
| DK (1) | DK150850C (en) |
| ES (1) | ES413252A1 (en) |
| FI (1) | FI61029C (en) |
| FR (1) | FR2179071B1 (en) |
| GB (1) | GB1418363A (en) |
| HK (1) | HK11079A (en) |
| HU (1) | HU166524B (en) |
| IL (1) | IL41936A (en) |
| LU (1) | LU67351A1 (en) |
| MY (1) | MY7900116A (en) |
| NL (1) | NL175621C (en) |
| NO (1) | NO138210C (en) |
| PH (1) | PH11180A (en) |
| PL (1) | PL89178B1 (en) |
| RO (1) | RO72458A (en) |
| SE (1) | SE399890B (en) |
| SU (1) | SU457220A3 (en) |
| YU (1) | YU39906B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7403657A (en) * | 1973-03-23 | 1974-09-25 | ||
| JPS51135089A (en) * | 1975-05-19 | 1976-11-22 | Hitachi Zosen Corp | Under-water operation assistant ship |
| IT1207417B (en) * | 1982-03-15 | 1989-05-17 | Menarini Sas | AZEPINA-6-ONE WITH ACTIVITIES TRICYCLIC COMPOUNDS DERIVED FROM PHARMACOLOGICAL, AND PROCEDURES OF 5,6-DIHYDRO-11H-DIBENZO (B, E) RELATED MANUFACTURE |
| GB8607684D0 (en) * | 1986-03-27 | 1986-04-30 | Ici America Inc | Thiazepine compounds |
| 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 |
| DK2307389T3 (en) | 2008-06-20 | 2013-04-02 | Astrazeneca Ab | Dibenzothiazepine derivative and uses thereof |
-
1972
- 1972-04-04 CH CH489872A patent/CH569730A5/xx not_active IP Right Cessation
- 1972-04-04 CH CH490172A patent/CH569731A5/xx not_active IP Right Cessation
-
1973
- 1973-01-29 JP JP48011246A patent/JPS4913189A/ja active Pending
- 1973-03-26 DK DK165273A patent/DK150850C/en not_active IP Right Cessation
- 1973-03-27 NO NO1257/73A patent/NO138210C/en unknown
- 1973-03-27 FI FI943/73A patent/FI61029C/en active
- 1973-03-28 SE SE7304365A patent/SE399890B/en unknown
- 1973-03-29 SU SU1900401A patent/SU457220A3/en active
- 1973-03-30 NL NLAANVRAGE7304441,A patent/NL175621C/en active Search and Examination
- 1973-03-30 PH PH14474A patent/PH11180A/en unknown
- 1973-04-02 BE BE129561A patent/BE797671A/en not_active IP Right Cessation
- 1973-04-02 CS CS2346A patent/CS178125B2/cs unknown
- 1973-04-02 RO RO7374359A patent/RO72458A/en unknown
- 1973-04-02 BG BG23138A patent/BG21221A3/xx unknown
- 1973-04-02 PL PL1973161672A patent/PL89178B1/pl unknown
- 1973-04-02 CY CY990A patent/CY990A/en unknown
- 1973-04-02 CA CA167,668A patent/CA1029372A/en not_active Expired
- 1973-04-02 ES ES413252A patent/ES413252A1/en not_active Expired
- 1973-04-02 GB GB1566773A patent/GB1418363A/en not_active Expired
- 1973-04-02 YU YU881/73A patent/YU39906B/en unknown
- 1973-04-03 HU HUWA277A patent/HU166524B/hu unknown
- 1973-04-03 AT AT291173A patent/AT340428B/en not_active IP Right Cessation
- 1973-04-03 DD DD169911A patent/DD105614A5/xx unknown
- 1973-04-03 LU LU67351A patent/LU67351A1/xx unknown
- 1973-04-03 AR AR247360A patent/AR195913A1/en active
- 1973-04-03 JP JP48037479A patent/JPS5142118B2/ja not_active Expired
- 1973-04-03 IL IL41936A patent/IL41936A/en unknown
- 1973-04-04 FR FR7312056A patent/FR2179071B1/fr not_active Expired
-
1979
- 1979-03-08 HK HK110/79A patent/HK11079A/en unknown
- 1979-12-30 MY MY116/79A patent/MY7900116A/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR900007780B1 (en) | Process for preparing condensed pyrrolinone derivatives | |
| GB1593417A (en) | Carbocyclic-fused pyrazolopyridine derivatives | |
| US3962248A (en) | Process for making 11-piperazino-diazepines, oxazepines, thiazepines and azepines | |
| US3704245A (en) | Tricyclic enol ether compounds | |
| GB2190376A (en) | Quinolinecarboxylic acid derivatives | |
| US3400119A (en) | Novel 4, 1-benzothiazepin-2(1h)-ones and 4, 1-benzothiazepines | |
| IL41936A (en) | Production of piperazino derivatives of tricyclic azepines diazepines oxazepines and thiazepines certain novel thieno (3,2-c) (1) benzazepines and pharmaceutical compositions containing them | |
| CA1083149A (en) | Derivatives of 10,11-dihydrobenzo 4,5 cyclohepta l,2- b -pyrazolo 4,3-e pyridine-5 (1h)ones | |
| IE42564B1 (en) | Benzodiazepine derivatives | |
| US3463774A (en) | Novel 4,1-benzothiazepin-2-(1h)-ones and 4,1-benzothiazepines | |
| CS207619B2 (en) | Method of making the new derivatives of 5,11-dihydro-6h-pyrido 2,3-b 1,4 benzodiazepin-6-on | |
| EP0003016A1 (en) | Pyrazino-benzoxazepine and -benzthiazepine derivatives, processes for their production and pharmaceutical compositions containing them | |
| EP1081136A1 (en) | Optically active tetrahydrobenzindole derivatives | |
| GB2061944A (en) | New pyridothienotriazines | |
| US4085111A (en) | 1H-tetrazole derivatives | |
| US3474099A (en) | 4-piperazinyl thienobenzothiazepines | |
| GB2050353A (en) | Substituted pyrido(1,2-a) pyrimidines | |
| IL44489A (en) | Quaternary salts of 11-(8-alkyl-3-nortropanyloxy)-6,11-dihydrodibenzo(b,e)thiepine derivatives,their production and pharmaceutical compositions containing them | |
| US6159981A (en) | 3-substituted pyrido [3',4':4,5] Thieno [2,3-d] pyrimidine derivatives, and production and use of the same | |
| KR0145181B1 (en) | 1,8-benzonaphthyridine derivatives their preparation | |
| EP0315827B1 (en) | Derivatives of quinolinecarboxylic acid | |
| IE42161B1 (en) | Pyrano-quinoline carboxylic acids,processes for their preparation and their use as pharmaceutical agents | |
| US3830814A (en) | N-oxides of dibenzo(b,f)thiepines | |
| NO841443L (en) | POLYCYCLIC CARBON ACID COMPOUNDS, PROCEDURES FOR THEIR PREPARATION AND PREPARATIONS CONTAINING SUCH CARBON ACID COMPOUNDS, AND THEIR USE | |
| IL29571A (en) | 11-substituted dibenzo(b,f)-1,4-oxazepines,dibenzo(b,f)-1,4-thiazepines and dibenzo(b,e)-1,4-diazepines and their preparation |