AU631462B2 – Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives
– Google Patents
AU631462B2 – Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives
– Google Patents
Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives
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Publication number
AU631462B2
AU631462B2
AU64720/90A
AU6472090A
AU631462B2
AU 631462 B2
AU631462 B2
AU 631462B2
AU 64720/90 A
AU64720/90 A
AU 64720/90A
AU 6472090 A
AU6472090 A
AU 6472090A
AU 631462 B2
AU631462 B2
AU 631462B2
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Australia
Prior art keywords
group
dibenzodioxazecine
compound
derivatives
hydrogen
Prior art date
1989-10-20
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AU6472090A
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Inventor
Johannes Hubertus Wieringa
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Akzo NV
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Akzo NV
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1989-10-20
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1990-10-18
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1992-11-26
1990-10-18
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Akzo NV
1991-07-11
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1992-11-26
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1992-11-26
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patent/AU631462B2/en
2010-10-18
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Classifications
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07D—HETEROCYCLIC COMPOUNDS
C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 – C07D271/00
C07D273/01—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 – C07D271/00 having one nitrogen atom
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07D—HETEROCYCLIC COMPOUNDS
C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 – C07D271/00
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P25/00—Drugs for disorders of the nervous system
A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Abstract
Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives having the general formula I:
Description
631 t S F Ref: 144568 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE: Class Int Class
I
I Complete Specification Lodged: Accepted: Published: Priority: Related Art: Name and Address of Applicant: Address for Service: Akzo N.V.
Velperweg 76 6824 BM Arnhem THE NETHERLANDS Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: Dibenzodloxazecine and Dibenzodloxaazacycloundecine Derivatives The following statement is a full description of this invention, including the best method of performing it known to me/us 8 0 1 7 c,, 5845/3 1
ABSTRACT
Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives having the general formula I: 0 C^-n or a pharmaceutically acceptable salt or nitrogen oxide thereof, in which RI, R 2
R
3 and R4 each represent independently hydrogen, hydroxy, halogen, cyano, alkyl, alkoxy or CF 3
R
5 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl or acyloxyalkyl; and n represents the number 1 or 2.
The compounds in accordance with the invention are valuable C.N.S. (central nervous systems) active compounds, and in particular possess strong antia* psychotic properties with low propensity to induce S0 extra-pyramidal side effects.
0 0 0 4 0 00 0 0 ft 0 1A DIBENZODIOXAZECINE AND DIBENZODIOXAAZACYCLOUNDECINE
DERIVATIVES
The invention relates to dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives, to processes for their preparation and to pharmaceutical preparations containing the same.
According to a first embodiment of this invention there is provided dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives having the general formula I: 0999 to 6 soo tt 9 o9 o* 99 0 ft 0 909 99 9 9 88f 9 09 9a 0 ft 99 Ri O 3R4
N-R
10 or a pharmaceutically acceptable salt or nitrogen oxide thereof, in which
R
1
R
2
R
3 and R 4 each represent independently hydrogen, hydroxy, halogen, cyano, alkyl, alkoxy or CF 3
R
5 represents hydrogen, alkyl, alkenyl, aralkyl, as herein defined, hydroxyalkyl or acyloxyalkyl; and 15 n represents the number 1 or 2.
According to a second embodiment of this invention, there is provided a process for the preparation of a compound according to the first embodiment, characterized in that the compound of formula I is prepared by ring closure of a compound having the formula II,
R
2 O
R
3 )n L 1 in which R 1 -R4 and n have the meanings given above, with a) ammonia or an amine H 2
NR
5 whereby in addition to the meanings given above, R 5 in the amine H2NR5 may also be a suitable protective group, which is cleaved after the ring closure to give the group R 5 is hydrogen, which may optionally be replaced by another group R 5 according to the definition given above, when Ll and L 2 represent both a leaving group; or with b) the said amine H 2
NR
5 in the presence of, or followed by a reaction with, a reducing agent, when both L 1 and L 2 represent oxy groups; or c) by direct condensation, when one of LI and L 2 represents a leaving group and the other group -NHR 5 wherein R 5 has the previously given meanings; or ITCW1144ls0p,.doe 1 B d) by reduction of a compound having the formula III 4, 4I 4 44 4 *4 44 .444 4 ‘4 44 44 I 44 44 4 .4 4* 44 4 4 t4 4 44 4 in which Rj-R 5 and n have the meanings given above and each of Q1. and Q2 is two hydrogens (2H) or oxygen with the proviso that at least one of the groups Qi and Q2 represents oxygen, with reduction means conventionally used ir the reduction of an amide or imide; after which the product thus obtained may be converted into its pharmaceutically acceptable salt or into its nitrogen oxide.
According to a third embodiment of this invention, there is provided a pharmaceutical composition containing one or more compounds according to the first 10 embodiment in admixture with pharmaceutically acceptable auxiliaries.
According to a fourth embodiment of this invention, there is provided a method for the treatment or prophylaxis of psychoses in a mamimal requiring said treatment or propylaxis, which method comprises administering to said mammal an effective amount of at least one compound according to the first embodiment, or of a composition according 1 5 to the third embodiment.
The compounds in accordance with the invention are valuable C.N.S. (central nervous systems) active compounds, and in particular possess strong anti psychotic properties with low propensity to induce extra-pyramidal side effects.
TCW1144SB8sp~dae ~1~1111~~
I
1 4 :11 ggtl The term alkyl group in the definition of R 1
-R
5 means an alkyl group with 1-6 carbon atoms, such as methyl, ethyl, isopropyl, pentyl and hexyl. Alkyl groups with 1- 4 carbon atoms are preferred.
The term alkenyl group in the definition of R 5 means an alkenyl group with 2-6 carbon atoms, such as allyl and 2-butenyl. Alkenyl groups with 3 or 4 carbon atoms are preferred.
The term aralkyl group means an alkyl group as defined above, substituted with an aromatic group such as phenyl or naphthyl. The said aromatic group can be substituted with one or more alkyl, halogen, hydroxy or alkoxy groups. Preferably the aralkyl group has 7-12 carbon atoms, such as phenylmethyl, phenylethyl, m,p-dihydroxyphenylethyl, m,p-dimethoxyphenylethyl and phenylpropyl.
The alkyl moiety which is present in the alkoxy group has the same meaning as previously defined for alkyl in the definition of R 1
-R
5 The term hydroxyalkyl group in the definition of R means an alkyl group as defined above, substituted with a hydroxy group.
The acyloxy moiety of the acyloxyalkyl group in the definition of R 5 is derived from a carboxylic acid with 1-18 carbon atoms, especially from an aliphatic or phenylaliphatic carboxylic acid, such as acetic acid, propionic acid, butyric acid, valeric acid, phenylacetic acid and phenylpropionic acid. Acyloxy groups with 8-18 carbon atoms are preferred. Examples are the octanoyloxy, decanoyloxy, lauroyloxy, myristoyloxy, palmitoyloxy, stearoyloxy and cinnamoyloxy groups.
0 4 0B44 3 ,0 Da9 9, 4 4b 3 The term halogen means fluorine, preferably, chlorine.
I Preferred compounds according ti compounds of f ormula I, wherein hydrogen or a 3-chloro group anc More preferred are the compounds i has the value 2.
[The compounds I are prepared in a for analogous compounds. A suitab the ring closure of a compound hay.
pn V 4 4 L I in which R 1
-R
4 and n have the pre~ and Ll and L 2 represent either bi bromine, iodine, or, o the invention are
R
5 is methyl, R, is R2R are hydrogen.
n which additionally n manner commonly used le method consists of ing the formula II, 3I iiously given meanings oth leaving groups or 00MIL UxU grups, or one rerset a .leaving grup andJ the other the group -NHR 5 wherein R 5 has the previously given meaning. When both Land L 2 represent a leaving 2~ 4 group, such as halogen, of which bromine and particularly chlorine are preferred, or a sulphonyloxy group, ring closure resulting in a compound of formula 1 takes place by condensation with ammonia or with an amine H 2
NR
5 wherein RS has the previously given 3dJ meaning. R 5 in the amine H 2
NR
5 may also be a suitable protective group, which is cleaved after ring closure to give the group R 5 is hydrogen, which may optionally be replaced by another group R 5 according to the definition given previously. When both groups L, and L 2 represent oxy groups, the desired product is obtained by reaction with the said amine H 2 NRS in the presence of, or followed by a reaction with, a reducing agent such v m..Nm Wo.- vtmomoo w w*r 4 lithium aluminum hydride, diisobutylaluminum hydride or sodium borohydride.
Another method consists of the reduction of a compound having the general formula III
III
Q2 0000 0 0 00 o 0 00 0 0 00 0 00 0 0 o G0 0 0 *0 0 0 where R 1
-R
5 and n have the previously given meanings, and each of Q 1 and Q 2 is two hydrogens (2H) or oxygen with the proviso that at least one of the groups Q 1 and Q 2 represents oxygen.
The reduction takes place in a manner conventionally employed for the reduction of amides and, imides, for example with the aid of a complex metal hydride such as lithium aluminum hydride, or with diborane or with boronhydride in dimethylsulphide and tetrahydrofuran.
The compounds of formula II used as starting products are prepared in a manner commonly used for the preparation of such compounds. In the flow sheet a number of synthetic routes to these products has been depicted. It is possible to convert a compound of the invention into another compound of the invention after having carried out one of the aforesaid methods of preparation. Thus, for example, compounds of formula I with R 5 H can be alkylated in the usual manner, for instance by reaction with an alkyl, alkenyl, or aralkyl halide, or by acylating the relevant nitrogen atom and then subsequent reduction of the N-acyl compound thus formed.
The introduction of a methyl group is preferably performed through an Eschweiler-Clarke reaction or through a reaction with formaldehyde and sodium cyanoborohydride in a suitable solvent like acetonitrile.
Another usual method consists of converting the amine I, which is substituted at the nitrogen atom (R 5 aralkyl, alkenyl, or alkyl) into the corresponding unsubstituted amine I (R 5 H) by means of a de(ar)alk(en)ylation.
Thus an N-benzyl group can be converted in a simple manner by catalytic hydrogenation, or by reaction with an ester of chloroformic acid, or with cyanogen bromide, followed by hydrolysis of the resultant carbamate, into 1* the corresponding NH group. In the case of a carbamate the compound may also be converted into a compound of formula I with R 5 methyl by conventional reduction a o0 methods.
A conventional hydrolysis of an aromatic alkoxy substituent, and preferably of a methoxy substituent, into the corresponding hydroxy group, for instance by means of an acid such as boron tribromide or hydrobromic acid, may be carried out to obtain compounds of formula I, in which at least one of the groups Ri-R 4 is hydroxy.
An aromatic halogen substituent may be converted into a nitrile by usual methods, for instance by a Rosenmund- S’ von Braun reaction using cuprous cyanide.
I II S The novel compounds of formula I may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as HC1, HBr, HI, H 2 S0 4
H
3 P0 4 acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, or ascorbic acid.
J
S0 6 The nitrogen oxides I are obtained by oxidation of the nitrogen atom by means of peracids, hydrogen peroxide, or oxidizing metal oxides, such as MnO 2 The compounds according to the invention can be processed to pharmaceutical preparations for enteral administration, local application or parenteral administration by mixing with suitable auxiliaries. A suitable form for administration is a tablet, pill, powder, capsule, paste, spray, sirup, ointment, suppository, solution, suspension or emulsion.
o The compounds are usually administered in a dosage of 0 0 00.4 between 0.01 and 50 mg per kg body weight. For 00 0 Col. administration to humans, the dosage is usually between r 1 and 500 mg per day and preferably between 15 and 250 r mg per day.
04 o0 0 The following examples serve to illustrate the invention.
0 0oo0 Example 1 a t ft «6 0 13-chloro-7 .8,.9,10-tetrahdro–methyl-6H-dibenzo[b Irl,4,71dioxaazacycloundecine (Z-2-butenedioate (l:1.
j A. 5.2 g of sodium methanolate was added portionwise to S a stirred solution of 26.1 g of methyl 2-(4-chloro-2hydroxyphenoxy)benzeneacetate in 260 ml of methanol.
After 1 h of stirring at room temperature the mixture was evaporated to dryness and the residue was dissolved in 260 ml of toluene, to which solution were added 10.1 g of a-chloro-N-methylacetamide, 13 g of potassium carbonate and 2.61 g of active copper powder. The mixture was heated to refluy overnight, cooled down and, after filtration over Hyflo, diluted with 500 nril of toluene. After washings with 2N sodium hydroxide and 7 water, the organic layer was dried over sodium sulphate and evaporated to dryness to obtain 32.5 g of methyl 2-[4-chloro-2-[ (methylamino)carbonyl]nethoxy]phenoxy]benzeneacete.
B. 27.2 g of methyl 2-[4-chloro-2-[[(methylamino) carbonyl]methoxy]phenoxy]benzeneacetate was dissolved in 800 ml of dry tetrahydrofuran and slowly added to a suspension of 8.7 g lithium aluminum hydride in 800 ml of dry tetrahydrofuran. The reaction mixture was stirred overnight at 40 «C and after addition of 35 ml of water stirred for another 1 h. The salts were removed by filtration with suction and the filtrate was evaporated 0 0 in vacuo, to give 20.1 g of 2-[4-chloro-2-[2- 04 4 ~1 (methylamino)ethoxy]phenoxy]benzene ethanol.
T C. A solution of 15 ml of thionylchloride in 200 ml of toluene was added at room temperature to a solution of 20.1 g of 2-[4-chloro-2-[2-(methylamino)ethoxy]phenoxy]benzeneethanol in 400 ml of dry toluene. After 30 min of stirring the mixture was concentrated, dissolved in water and washed with diethyl ether. The aqueous layer O. was basified with 2N sodium hydroxide and extracted with diethyl ether. The ethereal layer was dried over sodium sulphate, concentrated in vacuo and purified by silica chromatography using toluene-ethanol to obtain 12.9 g of 2-[5-chloro-2-[(2-chloroethyl)phenoxy]phenoxy]-N-methyl-ethylamine.
D. A solution of 9.9 g of 2-[5-chloro-2-[(2-chloroethyl)phenoxy phenoxy -N-methyl-ethylamine dissolved in 500 ml of N-methyl-2-pyrrolidone was slowly added to a mixture of 1 1 of N-methyl-2-pyrrolidone and 500 ml of pyridine at 85 °C and stirred overnight at this temperature. Water was added, the mixture was extracted with diethyl ether and the ether layer was washed with water and dried over sodium sulphate. The organic solution was evaporated to dryness and the residue was crystallized from dichioromethane-diethyl ether after addition of 1 eq of maleic acid to obtain 2. 3 g of 3-chloro- 7,8, 9,10-tetrahydro-8-methyl-6H-dibenzo[b, j][1,4,7]dioxaazacycloundecine (Z)-2-butenedioate Mp 145-1L57 0C.
in a similar way was prepared 7,8,9,10-tetrahydro-8methyl-6H-dibenzo~b, j] (l,4,7]dioxaazacycloundecine 2-butenedioate Mp 152 *C.
Example 2 0 3-chloro-7 .8,9 .l0-tetralhvdro-8-p~henvlmethvl,-6H-dibpenzo 160. rb~lrl,4,71dioxaalzacvcloundecine (Z)-2-butenedigate 9.1 ml of benzylamine were added to a solution of 7.26 g of 2-bromoethoxy)-l-[2-(2-bromoethyl)phenoxyl-4chlorobenzene in 714 ml of xylene and the mixture was heated to reflux for 24 h. After cooling the precipitate 0 was removed with suction washed with toluene and the filtrate was evaporated to dryness. The residue was chromatographed over silica with toluene-ethaiol (9:1) to yield 4,17 g of 3-chloro-708,9,l0-tetrahydro-8phenylmethyl-6H-dibenzotb, jl) 1,4,7)dioxaazacycloundecine. Rf 0.7 (silica; toluene-ethanol 8:2).
ethyl .,3-ch1oro-.7 ,-t~tetrahYvdro-GUtdihzr b.I 11 .4 .7.d xga~gudqi abxl 4.47 ml of chloroformic acid ethyl eater were added at room temperature to a solution of 4,17 q of .1-chloro- 7,8,9,l0O-totrahydro-0-phenylmethyl-6H-dibonzotb, I3 [11417]dioxaazacycloundecine in 300 ml of toluene. The 9 mixture was heated to reflux overnight, and after cooling shaken with excess of LN hydrochloric acid. The toluene layer was separated and the acid aqueous layer extracted with diethyl ether. The combined organic extracts were shaken with IN hydrochloric acid and water, after which the organic layer was concentrated in vacuo and dried azeotropically to yield 3.78 g of ethyl 3-chloro-7,8,9,10-tetrahydro-6H-dibenzo[bjJ- [1,4,7]dioxaazacycloundecine-8-carboxylate.
0 Rf 0.6 (silica; hexane-acetone 8:2).
ooo0 O go 00 0
R
0 a n no 00 23 «1 0 000 0000 0 000 0 4000 0000 a* 0 6060 0000 a 00 0E88 *0 f 00 6006 0 0 3-chloro-7, 8,9 10-tetrahydro-8-methyl-6H-dibenzorb,i1 r 1,,7l1dioxaazacycloundecine (Z)-2-butenditee j(1:t A suspension of 3.13 g of aluminum trichloride in 110 ml of diethyl ether was added to a suspension of 1.56 g lithium aluminum hydride in 110 mi of diethyl ether and then cooled to approx. 5 0 C, after which a solution of 4.27 g of ethyl 3-chloro-7,8,9,10-tetrahydro-GH-dibenzo- Cb,j(l1,4,7jdioxaazacycloundecine-8-carboxylate 92 ml of totrahydrofuran was slowly added. After 1 h the aluminum complex was decomposed by addition of 21 ml of 1N sodium hydroxide solution. After 30 min stirring the salts were removed with suction and rinsed with dichloromeothane.
After evaporation of the solvent 3.6 g of crude product was obtained, which was purified by silica chromatography with toluene-ethanol to obtain pure 3chloro-7,8,9, 10-tetrahydro-8-mothyl-6H-dibenzobj]- CI,4,7]dioxaazacycloundecine. After conversion into the maleate and recrystallization from ethanol-dioethylethr 2.6 g of 3-chloro-7,89,10-totahydro-8-methyl-6Hdibenzo(b,j)t1,4,73dioxaazacycloundeoine (Z)-2-butonedioate mp 145-1S7 0 C, was obtained.
Example 6,7,8,9-tetrahydro-8-methyl-dibenzo[b,ilf],4,71 dioxazecine hydrochloride A solution of 6.2 g of 2-(2-chloroethoxy)-l-[2-(chloromethyl)phenoxy]benzene in 310 ml ethanol was added at room temperature in 45 min to a solution of 80 ml of methylamine in 1.2 1 of abs. ethanol. The mixture was stirred overnight, concentrated and dissolved in 100 ml of dimethyl sulphoxide. 18.6 ml of triethylamine were added and the reaction mixture was heated to 90-100 °C and stirred overnight. After cooling the mixture was poured into 4.5 1 of ice water and extracted with 3×600 0 0 ml of dichloromethane. The extract was washed with 9 water, dried over sodium sulphate and concentrated in vacuo. The crude product obtained was purified by silica So°, chromatography with dichloromethane-acetone after which the free base was converted into the hydrochloric salt, to obtain 2.12 g of 6,7,8,9-tetrahydro-8methyl-dibenzo[b,i][1,4,7)dioxazecine hydrochloride. Mp o 0 223 °C.
S 0 4 Example 6 S In an analogous manner as described in Example 5 was a prepared 3-chloro-6,7,8,9-tetrahydro-8-methyl-dibenzo S [b,i][1,4,7]dioxazecine hydrochloride. Mp 221 °C.
SQa
II
FLOW SHEET 0 00a’ h coo tillt 1*1 It 41.
040 )0e -I *49h N H CO rr rrI Ly I 2.i OH1 r(HL rr00 *9 a *iii L t c oaving grup, pohal Br, 01, taylatc, menyLte ~3 ~0
Claims (9)
1. Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives having the general formula I: 4 0 a1 044 9′ 4 04,0 00 9 090 or a pharmaceutically acceptable salt or nitrogen oxide thereof, in which R 1 R 2 R 3 end R 4 each represent independently hydrcgen, hydroxy, halogen, cyano, alkyl, alkoxy or CF; CF3 aq e-ra d»,rnedl R 5 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl or acyloxyalkyl; and n represents the nuzber 1 or 2.
2. Compound according to claim 1, wherein R 5 is methyl, R, is hydrogen or a 3-chloro group and R 2 -R 4 are hydrogen.
3. Compound according to claim 2, wherein n has the value 2.
4. Process for the preparation of a compound according to claim 1, characterized in that the compound of formula I is prepared by ring closure of a compound having the formula II, 0 0 f5 9 l5 480 0 949 194 0 0la sr S 4994 1494 9 4~c 3 6 3 13 in which RI-R 4 and n have the meanings given in cliim 1, with a) ammonia or ar, amine H 2 NR 5 whereby in addition to the meanings given in claim 1, R 5 in the amine H 2 NR 5 may also be a suitable protective group, which is cleaved after ring closure to give the group R 5 is hydrogen, which may optionally be replaced by another group R 5 according to the definition given in claim 1, when L 1 and L 2 represent both a leaving group; or with b) the said amine H 2 NR 5 in the presence of, or followed by a reaction with, a reducing agent, when both L 1 and L 2 represent oxy groups; or c) by direct condensation, when one of L1 and L 2 represents a leaving group and the other the group H’PL° -NHR 5 wherein R 5 has the previously given meanings; or d) by reduction of a compound having the formula III ,1 R3 Q4 in which RI-R 5 and n have the meanings given in claim 1 and each of Q, and Q 2 is two hydrogens (2H) or oxygen with the proviso that at least one e of the groups Q 1 and Q 2 represents oxygen, with reduction means conventionally used for the reduc- tion of an amide or imide; after which the product thus obtained may be converted into its pharmaceut- ically acceptable salt or into its nitrogen oxide.
5. Pharmaceutical composition containing one or more compounds according to claim 1 in admixture with pharmaceutically acceptable auxiliaries. L11~ j,~ -Irc; r. II-~CZ~ Clb~~ -r I1L11 i -14-
6. Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives substantially as hereinbefore described with reference to any one of the Examples.
7. A process for the preparation of dibenzodioxazecine and dibenzodioxa- azacycloundecine derivatives substantially as hereinbefore described with reference to any of the Examples.
8. Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives whenever prepared by the process of claims 4 or 7.
9. A method for the treatment or prophylaxis of psychoses in a mammal requiring said treatment or propylaxis, which method comprises administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 3 or 6 or 8, or of a composition according to claim DATED this TWENTY-SECOND day of SEPTEMBER 1992 Akzo N.V. Patent Attorneys for the Applicant 15 SPRUSON FERGUSON o t C 6 f i 6 CI. e C TCW144608lp,doe
AU64720/90A
1989-10-20
1990-10-18
Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives
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Dibenzodioxazecine and dibenzodioxaazacycloundecine derivatives
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Assignee
Title
AU8314087A
(en)
*
1986-12-30
1988-06-30
Egis Gyogyszergyar Rt.
Novel aminoalkanoyl-dibenzo(d,g)(1,3,6)dioxazocines and a process for the preparation thereof
AU589725B2
(en)
*
1985-12-20
1989-10-19
Egis Gyogyszergyar Rt.
Optically active 2-chloro-12-(3-dimethylamino-2- methylpropyl)-12H-dibenzo(d,g)(1,3,6)dioxazocines and a process for the preparation thereof
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Title
NL8006955A
(en)
*
1980-12-22
1982-07-16
Akzo Nv
TRICYCLIC CONNECTIONS.
HU201318B
(en)
*
1987-12-31
1990-10-28
Egyt Gyogyszervegyeszeti Gyar
Process for producing dioxazoline derivatives and pharmaceutical compositions comprising same
1990
1990-10-09
AT
AT90202676T
patent/ATE91487T1/en
active
1990-10-09
DE
DE90202676T
patent/DE69002217T2/en
not_active
Expired – Fee Related
1990-10-09
ES
ES90202676T
patent/ES2058761T3/en
not_active
Expired – Lifetime
1990-10-09
DK
DK90202676.4T
patent/DK0423870T3/en
active
1990-10-09
EP
EP90202676A
patent/EP0423870B1/en
not_active
Expired – Lifetime
1990-10-10
IE
IE362690A
patent/IE903626A1/en
unknown
1990-10-17
KR
KR1019900016499A
patent/KR910007899A/en
not_active
Application Discontinuation
1990-10-17
CA
CA002027838A
patent/CA2027838A1/en
not_active
Abandoned
1990-10-17
ZA
ZA908309A
patent/ZA908309B/en
unknown
1990-10-18
AU
AU64720/90A
patent/AU631462B2/en
not_active
Ceased
1990-10-18
NZ
NZ235741A
patent/NZ235741A/en
unknown
1990-10-19
FI
FI905165A
patent/FI905165A0/en
not_active
IP Right Cessation
1990-10-19
US
US07/601,547
patent/US5106839A/en
not_active
Expired – Fee Related
1990-10-19
PT
PT95634A
patent/PT95634A/en
not_active
Application Discontinuation
1990-10-19
JP
JP2283258A
patent/JPH03209373A/en
active
Pending
Patent Citations (2)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
AU589725B2
(en)
*
1985-12-20
1989-10-19
Egis Gyogyszergyar Rt.
Optically active 2-chloro-12-(3-dimethylamino-2- methylpropyl)-12H-dibenzo(d,g)(1,3,6)dioxazocines and a process for the preparation thereof
AU8314087A
(en)
*
1986-12-30
1988-06-30
Egis Gyogyszergyar Rt.
Novel aminoalkanoyl-dibenzo(d,g)(1,3,6)dioxazocines and a process for the preparation thereof
Also Published As
Publication number
Publication date
NZ235741A
(en)
1992-02-25
PT95634A
(en)
1991-09-13
ZA908309B
(en)
1991-08-28
ATE91487T1
(en)
1993-07-15
IE903626A1
(en)
1991-04-24
CA2027838A1
(en)
1991-04-21
EP0423870B1
(en)
1993-07-14
DE69002217D1
(en)
1993-08-19
KR910007899A
(en)
1991-05-30
DE69002217T2
(en)
1993-10-21
ES2058761T3
(en)
1994-11-01
EP0423870A1
(en)
1991-04-24
FI905165A0
(en)
1990-10-19
JPH03209373A
(en)
1991-09-12
DK0423870T3
(en)
1993-10-11
AU6472090A
(en)
1991-07-11
US5106839A
(en)
1992-04-21
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