WO1992011262A1 - 1-(4-acylaminophenyl)-7,8-methylenedioxy-5h-2,3-benzo-diazepine derivatives and acid addition salts thereof, pharmaceutical compositions containing them and process for preparing same - Google Patents
1-(4-acylaminophenyl)-7,8-methylenedioxy-5h-2,3-benzo-diazepine derivatives and acid addition salts thereof, pharmaceutical compositions containing them and process for preparing same Download PDFInfo
- Publication number
- WO1992011262A1 WO1992011262A1 PCT/HU1991/000053 HU9100053W WO9211262A1 WO 1992011262 A1 WO1992011262 A1 WO 1992011262A1 HU 9100053 W HU9100053 W HU 9100053W WO 9211262 A1 WO9211262 A1 WO 9211262A1
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- WIPO (PCT)
- Prior art keywords
- general formula
- compound
- acid
- methylenedioxy
- defined above
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
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- 238000000034 method Methods 0.000 claims abstract description 38
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- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminum chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 229960000959 amineptine Drugs 0.000 description 1
- VDPUXONTAVMIKZ-UHFFFAOYSA-N amineptine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2C([NH2+]CCCCCCC(=O)O)C2=CC=CC=C21 VDPUXONTAVMIKZ-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 1
- 229960002456 hexobarbital Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- MNWCCLZQTOFQMW-UHFFFAOYSA-N n-[4-(8-methyl-8,9-dihydro-7h-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-5-yl)phenyl]benzamide Chemical compound N=1NC(C)CC2=CC=3OCOC=3C=C2C=1C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 MNWCCLZQTOFQMW-UHFFFAOYSA-N 0.000 description 1
- SXFXNUYJDHOCEH-UHFFFAOYSA-N n-[4-(8-methyl-9h-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-5-yl)phenyl]benzamide Chemical compound C12=CC=3OCOC=3C=C2CC(C)=NN=C1C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 SXFXNUYJDHOCEH-UHFFFAOYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000002891 organic anions Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000021962 pH elevation Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000003568 synaptosome Anatomy 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
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- 208000028325 tonic-clonic seizure Diseases 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- 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
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Definitions
- This invention relates to novel l-(4-acylaminophenyl) -7,8-methylenedioxy-5H-2,3-be ⁇ zodiazepine derivatives of th general formula (I) ,
- R stands for hydrogen or a C ⁇ _ 4 al yl group optionally substituted by a carboxyl or C2-5 alkoxycarbonyl grou and R 1 means an aliphatic ⁇ - ⁇ acyl, benzoyl or phenylacetyl group, as well as their acid-addition salts and pharmaceutical compositions containing these compounds.
- the compounds o the general formula (I) can exist in the form of optically active enantio ers.
- the invention also relates to the race- mates, pure individual enantiomers and any mixture thereof.
- a process for the preparation of the new compounds of general formula (I) and acid addition salts thereof is provided.
- the aim of the present invention is to provide novel 5H-2,3-benzodiazepine derivatives possessing valuable centra nervous system (CNS) effects, namely antidepressive and/or antiparkinsonian action, i.e. showing CNS-stimulating character and more advantageous properties than the l-(4- -aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3 -benzodiazepine (see United States patent specification No. 4,835,152), the single 5H-2,3-benzodiazepine derivative know in this therapeutic area.
- CNS centra nervous system
- the novel compounds of general formula (I) are prepared by ai) transforming a compound of the general formula (III)
- R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, by usin an organic or inorganic acid, then acylating the produc obtained, optionally without separating it, with a C ⁇ _ 6 aliphatic carboxylic acid, benzoic or phenylacetic acid or a reactive derivative of these acids; or -2 ) acylating a compound of the general formula (II) , wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, with C*L_6 aliphatic carboxylic, benzoic or phenylacetic ac or a reactive derivative of these acids; or b) reducing a compound of the general formula (IV) ,
- R 1 is as defined above, by using an inorganic inorganic-organic complex metal hydride in a suitable solvent, to obtain compounds of the general formula (I wherein R 1 is as defined above and R means hydrogen; and, if desired, alkylating a compound of the general formu (I) , wherein R 1 is as defined above and R stands for hydro ⁇ gen, prepared by using any of the above processes a ⁇ ) , a2) b) , with a C ⁇ _4 alkyl halide optionally substituted by a C2 alkoxycarbonyl group or with a C2- 8 dialkyl sulfate in a suitable solvent, in the presence of an acid-binding agent and/or, if desired, hydrolyzing and then treating with an acid a compound of the general formula (I) , wherein R 1 is a defined above and R stands for a C** ⁇ alkyl group substitut by a C 2 -5 alkoxycarbonyl group, to obtain a compound of the general formula (I where
- a compound of the general formula (III) wherein R is as defined above, is transformed to a salt by using an organic or inorganic acid and then the salt of the general formula (II) thus obtained, wherein R is as defined above and X represents an inorganic or organic anion, prefe ably chloride, bromide, hemisulfate or methanesulfonate anion, optionally without separation, is acylated with a C ⁇ aliphatic carboxylic, benzoic or phenylacetic acid or a rea tive derivative of these acids.
- the quaternary nitrogen is present in the 7-membered cycle, therefore the aromatic primary amino group is free and can relatively readily be acylated.
- the acylation can be performed in a suitable solvent or in an excess of the acylating agent. It is particularly preferable to carry out the acylation in an excess of the carboxylic acid anhydride at a temperature between 10 °C and 50 °C. This reaction lasts in general 1 t 5 hours.
- a preferred embodiment of preparing compounds of the general formula (I) , wherein R 1 is as defined above and R means hydrogen comprises reducing a compound of the genera formula (IV) , wherein R 1 is as defined above, by using an inorganic or inorganic-organic complex metal hydride in a suitable solvent.
- an inorganic or inorganic-organic complex metal hydride e.g. lithium aluminum hydride, sodium borohydride, potassium borohydride sodium borohydride-aluminum chloride, sodium cyanoboro- -hydride, sodium dihydro-bis(2-methoxyethoxy)-aluminate, lithium trimethoxyaluminum hydride or sodium borohydride- triethyloxonium fluoborate may be used as complex metal hydrides.
- solvents or solvent mixtures is defined by the reducing agent used in the given case: it should be chosen in such a way that it reacts with the reducing agent very slowly if at all.
- sodium borohydride is used as complex metal hydride
- pyridine is employed as solvent and the reduction is suitably carried out at a temperature between 50 °C and 115 °C.
- compounds of the general formula (I) wherein R stands for C ⁇ _4 alkyl unsubstituted o substituted by a C2-5 alkoxycarbonyl group and R 1 is as defined above, can preferably be prepared also by alkylating a compound of the general formula (I) , wherein R 1 is as defined above and R represents hydrogen, with a C 1 - 4 alkyl halide optionally substituted by a C2-5 alkoxycarbonyl group or with a C2-8 dialkyl sulfate in a suitable solvent, prefer ably dimethylformamide or dimethylacetamide, in the presence of an acid-binding agent such as e.g. an anhydrous alkali metal carbonate or hydrogen carbonate.
- an acid-binding agent such as e.g. an anhydrous alkali metal carbonate or hydrogen carbonate.
- Free carboxylic acids can be obtained by the hydrolys of esters, preferably by using an alkali metal hydroxide in hot 50 % ethanol and liberating the carboxylic acid from it alkali metal salt thus obtained by using an acid, preferabl acetic acid.
- bases of the general formula (I to their acid-addition salts, suitably to pharmaceutically acceptable acid-addition salts, is carried out in a known way, e.g. by dissolving or suspending the base in an appro ⁇ priate solvent and adding the corresponding acid or its sol tion prepared in a suitable solvent.
- the salts are separate either directly by filtration or after evaporating the sol- vent; if desired, the product obtained is suspended or re- crystallized and/or dried under reduced pressure.
- novel compounds of general formula (I) prepared by the process according to the invention possess significant central nervous system effects.
- the behavioural effects of the compounds according to the invention were evaluated on male CFLP mice with an average body weight of 20 g (see Table 1) after oral or intraperitoneal treatment, respectively, by using Irwin's method [Psychopharmacologia, .13., 222 (1968) ] .
- Example 2 The effect of the compound of Example 1 on the motility in mice was more precisely analysed by means of a motimeter functioning on the basis of the capacitive re ⁇ sistance principle. The measurement was immediately commenc after the treatment and lasted for 2 hours. The number of animals was at least 12 in each group. The percentage chang determined from the total counts during 2 hours in relation to the vehicle as control are shown in Table 2. The signifi cance was calculated from the number of counts by using Duncan's test.
- Example 1 exerted in this test an ant depressive effect being similar to that of the reference compound: it resulted in a significant escape-directed fight-strengthening effect even in an oral dose of 3 mg/kg. 4.
- Anti-parkinsonian effect in mice [inhibition of the neurotoxicity of N-methyl-4-phenyltetrahydropyridin (abbreviated: MPTP) ]
- Biochemical investigations were carried out in order 15 elucidate the action mechanism functioning in the anti- depressive and anti-parkinsonian as well as stimulatory effects of the compound of Example 1 and appearing in the pharmacological investigations.
- the reference compound and the compound of Example 1 inhibit the dopamine and MPP + upake into the neuron with the same effectivity.
- the pharmacological activity can be explained by this biochemical effect. 6.
- Other central nervous system effects can be explained by this biochemical effect. 6.
- the animals were orally treated with the test substances and 30 minutes later they received an intravenous dose of 50 mg/kg of hexobarbital inducing narcosis.
- the pro ⁇ longation of the duration of narcosis was measured in relation to the vehicle conrol group.
- mice Compound Anticonvulsive Narcosis-potentiatin
- Oral LD50 > 500 mg/kg
- Intraperitoneal LD50 ⁇ 150 mg/kg
- the compound of Example 1 shows in rodents an antidepressive and anti-parkinsonian effect o the same order as the reference compound.
- the mechanism of action of both molecules is the same: they selectively inhibit the dopamine uptake (and simultaneously the MPP + ) system.
- the compounds of the invention can be used for treating depress ⁇ ive conditions and parkinsonism.
- an indicated oral daily dose is in the range from about 0.05 mg/kg to about 20 mg/kg, prefer ⁇ ably from 0.1 mg/kg to 10 mg/kg, more preferably 1 mg/kg.
- the active compounds of the invention are suitably formulated to pharmaceutical composi- tions by mixing them with nontoxic, inert solid or liquid carriers and/or additives, which are suitable for enteral parenteral administration and are commonly used in the pharmaceutical industry.
- Suitable carriers are e.g. water, gelatin, lactose, starch, pectin, magnesium stearate, stea acid, talc and vegetable oils.
- additives preservatives wetting (surface-active) , emulsifying or dispersing, buffering and aromatizing agents may be used.
- the activ compounds of the invention may be formulated to the usual pharmaceutical compositions, e.g. solid forms (such as mai tablets, dragees and capsules) as well as to injectable solutions, suspensions and emulsions.
- the invention also relates to pharmaceutical compositions containing a compound of the general formula ( or a pharmaceutically acceptable acid-addition salt thereof as active ingredient as well as to a process for preparing these compositions.
- compositions according to the invention can be prepared by commonly known methods.
- the invention also relates to a method for treating depressive illnesses and Parkinson's disease.
- This method comprises administering a therapeutically effective amount an active ingredient of the general formula (I) to the patient in need of such treatment.
- Example 1 The invention is further illustrated by the following non-limiting Examples.
- Example 1 The invention is further illustrated by the following non-limiting Examples.
- the crystalline precipitate was filtered and washed with 5 x 5 ml of ethyl acetate.
- the dry weight of the product was 7.37 g, m.p.: it sintered abov 190 °C and weakly decomposed at 210-212 °C.
- the thus-obtaine methanesulfonate salt of the starting substance could be acetylated as follows: 7.37 g of the powdered salt were suspended in 110 ml o acetic anhydride, the suspension was stirred at room tempera ture for 2 hours, then the crystalline precipitate was filtered, washed with 5 x 10 ml of ethyl acetate and dried t give 6.54 g of methanesulfonate salt of the target compound, m.p. 240-241 °C (with decomposition) .
- the base could be liberated from the methanesulfonate salt of the target compound e.g. in the following way: 6.54 of salt were dissolved in 90 ml of water, the solution was clarified by charcoal, then 3.6 g of sodium hydrogen car ⁇ bonate were portionwise added to the clear solution. The precipitate was filtered, washed with 5 x 10 ml of water an dried to obtain 5.54 g of crude product.
- the starting substance was prepared as follows. 10 g (34 mmol) of l-(4-aminophenyl)-4-methyl-7,8- -methylenedioxy-5H-2,3-benzodiazepine were stirred for 3 hours with 100 ml of acetic anhydride. The crystals formed were filtered, washed with 5x10 ml of anhydrous, ethanol and dried, to yield 9.2 g of raw product, m.p.: 252-254 °C (decomposition) . This product was treated with 45 ml of hot 99.5 % ethanol.
- Example 2 The base was liberated as described in Method A) of Example 1 to obtain 1.36 g of product, m.p.: 226-233 °C (weak decomposition). The meltin point of this product was increased to 237-239 ⁇ C after re crystallization from 40 ml of 99.5 % ethanol to give the aimed compound in a yield of 1.8 g (71.5 %) .
- the 1-(4-benzoylaminophenyl)-4-methyl-7 ,8-methylene- dioxy-5H-2,3-benzodiazepine used as starting substance was obtained as follows.
- Example 6 The process described in Example 6 was followed, exce that methyl iodide was used instead of ethyl bromoacetate, the column chromatography was omitted and the crude product was recrystallized first from 50 % and then from 99.5 % ethanol to give the pure aimed compound, m.p.: 207-209 °C.
- Example 9 l-(4-Acetylaminophenyl)-3-carboxymethyl-4-methyl-7,8- -metnylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine 0.59 g (1.4 mmol) of the compound of Example 6 was boiled with 15 ml of 50 % ethanol and 0.10 g (1.8 mmol) of potassium hydroxide under reflux for 30 to 40 minutes. Afte cooling 0.15 ml (2.5 mmol) of acetic acid was added to the filtered, clear solution to liberate the free carboxylic ac which was then separated by filtration after cooling.
- the dragee-core was coated with sugar and talc in the usual way and then polished by using bee-wax. Each dragee weighed about 100 mg.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to novel compounds of general formula (I), wherein R stands for hydrogen or a C1-4 alkyl group optionally substituted by a carboxyl or C2-5 alkoxycarbonyl group; and R1 means an aliphatic C¿1-6? acyl, benzoyl or phenylacetyl group, and the stereoisomers as well as acid-addition salts of these compounds. The invention also relates to pharmaceutical compositions containing the above compounds as well as to a process for the preparation of the novel compounds of general formula (I). The compounds of the invention possess central nervous system effects, more particularly antidepressive and antiparkinsonian action. They are non-mutagenic in the Ames test. Thus, they can be useful for the treatment of depressive illnesses and parkinsonism.
Description
l-(4-ACYLAMINOPHENYL)-7,8-METHYLENEDIOXY-5H-2,3-BENZO- DIAZEPINE DERIVATIVES AND ACID ADDITION SALTS THEREO PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR
PREPARING SAME
This invention relates to novel l-(4-acylaminophenyl) -7,8-methylenedioxy-5H-2,3-beπzodiazepine derivatives of th general formula (I) ,
wherein
R stands for hydrogen or a Cι_4 al yl group optionally substituted by a carboxyl or C2-5 alkoxycarbonyl grou and R1 means an aliphatic ^-β acyl, benzoyl or phenylacetyl group, as well as their acid-addition salts and pharmaceutical compositions containing these compounds.
Due to the asymmetric C-4 carbon atom, the compounds o the general formula (I) can exist in the form of optically active enantio ers. The invention also relates to the race-
mates, pure individual enantiomers and any mixture thereof.
According to an other aspect of the invention, there i provided a process for the preparation of the new compounds of general formula (I) and acid addition salts thereof. The aim of the present invention is to provide novel 5H-2,3-benzodiazepine derivatives possessing valuable centra nervous system (CNS) effects, namely antidepressive and/or antiparkinsonian action, i.e. showing CNS-stimulating character and more advantageous properties than the l-(4- -aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3 -benzodiazepine (see United States patent specification No. 4,835,152), the single 5H-2,3-benzodiazepine derivative know in this therapeutic area.
Now it has been found that the compounds of general formula (I) and their acid-addition salts entirely satisfy the above demands since their effectivity reaches that of th known compound mentioned above and, in opposition to the above compound, they proved to be non-mutagenic in the Ames- test. According to the invention, the novel compounds of general formula (I) are prepared by ai) transforming a compound of the general formula (III)
wherein R is as defined above, to a compound of the general formula (II) ,
wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, by usin an organic or inorganic acid, then acylating the produc obtained, optionally without separating it, with a Cι_6 aliphatic carboxylic acid, benzoic or phenylacetic acid or a reactive derivative of these acids; or -2 ) acylating a compound of the general formula (II) ,
wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, with C*L_6 aliphatic carboxylic, benzoic or phenylacetic ac or a reactive derivative of these acids; or b) reducing a compound of the general formula (IV) ,
CH3
/
H2
wherein R1 is as defined above, by using an inorganic inorganic-organic complex metal hydride in a suitable solvent, to obtain compounds of the general formula (I wherein R1 is as defined above and R means hydrogen; and, if desired, alkylating a compound of the general formu (I) , wherein R1 is as defined above and R stands for hydro¬ gen, prepared by using any of the above processes a^) , a2) b) , with a Cι_4 alkyl halide optionally substituted by a C2 alkoxycarbonyl group or with a C2-8 dialkyl sulfate in a suitable solvent, in the presence of an acid-binding agent and/or, if desired, hydrolyzing and then treating with an acid a compound of the general formula (I) , wherein R1 is a defined above and R stands for a C**^ alkyl group substitut
by a C2-5 alkoxycarbonyl group, to obtain a compound of the general formula (I) , wherein R stands for C__- _ alkyl substi tuted by a carboxyl group and/or, if desired, converting a compound of the general formula (I) thus obtained to an acid-addition salt or, conversely, transforming a salt ob¬ tained to the corresponding free base.
According to a preferred embodiment of the process of the invention, a compound of the general formula (III) , wherein R is as defined above, is transformed to a salt by using an organic or inorganic acid and then the salt of the general formula (II) thus obtained, wherein R is as defined above and X represents an inorganic or organic anion, prefe ably chloride, bromide, hemisulfate or methanesulfonate anion, optionally without separation, is acylated with a C^ aliphatic carboxylic, benzoic or phenylacetic acid or a rea tive derivative of these acids.
In the salts of general formula (II) , the quaternary nitrogen is present in the 7-membered cycle, therefore the aromatic primary amino group is free and can relatively readily be acylated. The acylation can be performed in a suitable solvent or in an excess of the acylating agent. It is particularly preferable to carry out the acylation in an excess of the carboxylic acid anhydride at a temperature between 10 °C and 50 °C. This reaction lasts in general 1 t 5 hours.
A preferred embodiment of preparing compounds of the general formula (I) , wherein R1 is as defined above and R means hydrogen, comprises reducing a compound of the genera
formula (IV) , wherein R1 is as defined above, by using an inorganic or inorganic-organic complex metal hydride in a suitable solvent. For this selective reduction e.g. lithium aluminum hydride, sodium borohydride, potassium borohydride sodium borohydride-aluminum chloride, sodium cyanoboro- -hydride, sodium dihydro-bis(2-methoxyethoxy)-aluminate, lithium trimethoxyaluminum hydride or sodium borohydride- triethyloxonium fluoborate may be used as complex metal hydrides. It is suitable to carry out the reduction in wate ethers, alcohols, aromatic hydrocarbons, pyridine or a mix¬ ture thereof. The use of solvents or solvent mixtures is defined by the reducing agent used in the given case: it should be chosen in such a way that it reacts with the reducing agent very slowly if at all. According to a particularly advantageous embodiment o the process of the invention, sodium borohydride is used as complex metal hydride, pyridine is employed as solvent and the reduction is suitably carried out at a temperature between 50 °C and 115 °C. According to the invention, compounds of the general formula (I) , wherein R stands for Cι_4 alkyl unsubstituted o substituted by a C2-5 alkoxycarbonyl group and R1 is as defined above, can preferably be prepared also by alkylating a compound of the general formula (I) , wherein R1 is as defined above and R represents hydrogen, with a C1-4 alkyl halide optionally substituted by a C2-5 alkoxycarbonyl group or with a C2-8 dialkyl sulfate in a suitable solvent, prefer ably dimethylformamide or dimethylacetamide, in the presence
of an acid-binding agent such as e.g. an anhydrous alkali metal carbonate or hydrogen carbonate.
Free carboxylic acids can be obtained by the hydrolys of esters, preferably by using an alkali metal hydroxide in hot 50 % ethanol and liberating the carboxylic acid from it alkali metal salt thus obtained by using an acid, preferabl acetic acid.
The transformation of bases of the general formula (I to their acid-addition salts, suitably to pharmaceutically acceptable acid-addition salts, is carried out in a known way, e.g. by dissolving or suspending the base in an appro¬ priate solvent and adding the corresponding acid or its sol tion prepared in a suitable solvent. The salts are separate either directly by filtration or after evaporating the sol- vent; if desired, the product obtained is suspended or re- crystallized and/or dried under reduced pressure.
The preparation of the compounds of general formulae (II) and (III) (wherein R is hydrogen) used as starting substances in the process according to the invention is published in the United States patent specification No.
4,835,152. The compounds of general formula (IV), wherein R is as defined above, are new, and are desribed hereinafter the Examples.
As mentioned in the introduction, the novel compounds of general formula (I) prepared by the process according to the invention possess significant central nervous system effects.
The pharmacological activity of the compounds will
hereinafter be illustrated by results achieved in animal tests carried out by using mainly the compound of Example 1. In the comparative investigations l-(4-amino-phenyl)-4- -methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (hereinafter: reference compound; see the United States patent specification No. 4,835,152) was used as reference substance which exerts similar effects but it has proven to be positive in the Ames-test on the TA-98 Salmonella strain after activation.
1. The behavioural effects of the compounds according to the invention were evaluated on male CFLP mice with an average body weight of 20 g (see Table 1) after oral or intraperitoneal treatment, respectively, by using Irwin's method [Psychopharmacologia, .13., 222 (1968) ] .
Table 1 Behavioural effects in mice
Compound Doses (mg/kg) (Example No.) 100 i.o. 200 p.p. Reference compound
2 3
4 5
The number of animals was 5 in each group. SMA: spontaneous motor activity;
f means increase; * means decrease φ: no symptom was observed
Based on the above results, behavioural effects being similar to those of the reference compound could be elicite by using the compound of Example 1.
2. The effect of the compound of Example 1 on the motility in mice was more precisely analysed by means of a motimeter functioning on the basis of the capacitive re¬ sistance principle. The measurement was immediately commenc after the treatment and lasted for 2 hours. The number of animals was at least 12 in each group. The percentage chang determined from the total counts during 2 hours in relation to the vehicle as control are shown in Table 2. The signifi cance was calculated from the number of counts by using Duncan's test.
Table 2 Effect on the motility in mice Treatment Doses (m /k ) i.p. Change % Significan
Reference compound 3 10 30
Compound of Example 1 5 10 20 30
N.S.: not significant
It is obvious from the data of Table 2 that the moti¬ lity of mice was similarly increased both by the reference compound and the compound of Example 1.
- 10 -
3. Investigation into the antidepressive effect in rodents 3.1. Antaqonization of reserpine hypothermia in mice These examinations were performed in male CFLP mice using an Ellab thermometer (measurement of the rectal temperature) by the method of Askew [Life Sci. 2., 725 (1963)].
The effects of the reference compound and the compou of Example 1 are shown in Table 3. The measurement was commenced after the treatment by the test substances.
Table 3 Antagonization of reserpine hypothermia in mice
Treatment Doses Difference in the body temperature in relation to th (mg/ g) reserpine control (°C) p.σ. after 0 1 2 3 4 5
*: p < 0.05 **: p < 0.01.
The hypothermic effect of reserpine was significantly antagonized by both molecules.
3.2. Porsolt's test in rats
The escape-directed fight-strengthening effects of th reference compound and the compound of Example 1 in a state of despair were investigated in male OFA rats by using Porsolt's method [Eur. J. Pharmacol. 42, 379 (1978)]. The pre-selected animals were orally treated 3 times (24, 5 and 2 hours, respectively, before the measurement) with the compounds (see Table 4) .
Table 4 Antidepressive effect in rats (Porsolt's test)
Treatment Dose Increase in the Significance* (mg/kg) fighting time
P.O. Vehicle Reference 10 61.6 % p < 0.05 compound 30 159.5 % p < 0.01
Vehicle Compound of 3 40.3 % p < 0.05 Example 1 10 66.8 % p < 0.05 30 110.2 % P < 0.01
*: Calculated from the fighting time by using Duncan's test (R.G.D. Steel and J.H. Tonie: Principles and Procedures of Statistics, 2nd Edition, p. 187, McGraw-Hill Book Co.
The compound of Example 1 exerted in this test an ant depressive effect being similar to that of the reference compound: it resulted in a significant escape-directed fight-strengthening effect even in an oral dose of 3 mg/kg.
4. Anti-parkinsonian effect in mice [inhibition of the neurotoxicity of N-methyl-4-phenyltetrahydropyridin (abbreviated: MPTP) ]
These examinations were carried out in male C57 mice with an average body weight of 25 g by using the method of Mayer et al. [J. Neuroche . 4_7, 1073 (1986)].
This measurement is based on the fact that MPTP, more particularly the MPP+ ion arising from MPTP through an enzymatic way catalyzed by MAO-B and getting into the neuron via the dopamine-uptake system, leads to the destruction of dopaminergic cells. Thus, a status being similar to the Parkinson's disease can experimentally be established. This process can be prevented by compounds showing an anti-par¬ kinsonian action. The effect of the reference compound and compound of Example 1 are summarized in Table 5.
Table 5 Inhibition of the MPTP neurotoxicity in mice
Time of administration of compounds in relation to the treatment with MPTP (hour)
-4
-2
-1
-0.5
+0.5
+1
+2
+4
+6
FCT/HUMStNB
- 13 -
*: Significant difference in relation to the MPTP control N: number of animals Doses: 2 x 30 mg/kg i.p.
5 DA level(MPTP+compound) ~ DA level(MPTP)
Relative effect (%) = x 100
100 - DA level PTP) DA: 'dopamine
According to the data of Table 5 both the reference
10 compound and the compound of Example 1 significantly reduce the dopamine-level decrease induced by the treatment with MPTP. This effect of both compounds appear under the effect of treatments both before and after administration of MPTP.
Biochemical investigations were carried out in order 15 elucidate the action mechanism functioning in the anti- depressive and anti-parkinsonian as well as stimulatory effects of the compound of Example 1 and appearing in the pharmacological investigations.
The direct dopamine receptor-binding studies gave 20 negative results.
5. Inhibition of the dopamine and MPP+ uptake These examinations were carried out on a raw synaptosome preparation from the striatal tissue of the rat brain according to Schacht and Hepter [Biochem. Pharmacol 1 25 3412 (1974)] or Javitch and Snyder [Eur. J. Pharmacol.106, 455 (1985)], respectively. The results are summarized in Table 6.
Table 6 The in vitro inhibition of dopamine and MPP+ uptake
Compound Ic50 (M) Dopamine MPP+
Reference compound 7.6 x 10""6 2.8 x 10~*> Compound of Example l 8.3 x 10~6 8.8 x 10~6
The reference compound and the compound of Example 1 inhibit the dopamine and MPP+ upake into the neuron with the same effectivity. The pharmacological activity can be explained by this biochemical effect. 6. Other central nervous system effects
These measurements were performed in male CFLP mice with a body weight of 20 g.
For the examination of the narcosis-potentiating effect, the animals were orally treated with the test substances and 30 minutes later they received an intravenous dose of 50 mg/kg of hexobarbital inducing narcosis. The pro¬ longation of the duration of narcosis was measured in relation to the vehicle conrol group.
For investigation of the anticonvulsive effect, a tonic-clonic seizure was induced by electric current (10 mA, 2 sec, 0.4 msec) after 1-hour oral pretreatment. The ceasing of tonic extension of the hind legs was evaluated as an anti convulsive effect [Swinyard: J. Pharm. Exp. Ther. 106, 319
(1952)]. The results are summarized in Table 7.
Table 7 Other central nervous system effects on mice Compound Anticonvulsive Narcosis-potentiatin
Reference compound
3
4 5
*: Calculated by using probit analysis ES: electric seizure (electroshock) None of the tested molecules reached the anticonvulsi and narcosis-potentiating effect of the reference compound; however, the compounds of Examples 1 and 2 showed a conside able activity in the anticonvulsive test.
7. Acute toxicity in mice The approximating LD50 values of the compound of Example 1 (after a single treatment with an observation period of 14 days) are as follows:
Oral LD50: > 500 mg/kg
Intraperitoneal LD50: ~ 150 mg/kg
Summing up, it can be stated that, among the compound according to the invention, the compound of Example 1 shows
in rodents an antidepressive and anti-parkinsonian effect o the same order as the reference compound. The mechanism of action of both molecules is the same: they selectively inhibit the dopamine uptake (and simultaneously the MPP+) system.
Considering that cerebral depaminergic systems play an actual and essential role in the motivated behaviour, it may be hoped that molecules acting on this system would show a considerable antidepressive effect in man. This supposition is supported by several drug candidates possessing a similar biochemical mechanism of action with a positive effect in man, such as e.g. bupropion [chemically (±)-2-tert-butyl- amino-3f-chloropropiophenone hydrochloride] or amineptine [chemically 7-(10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5- -yl)aminoheptenoic acid hydrochloride] .
On the other hand, the advantageous effect in the MPTP model of the compound of Example 1, which is similar to tha of the reference compound (MPTP induces Parkinson's disease in man, too) , indicates the possibility of a human anti-par- kinsonian effectivity.
On the basis of the above pharmacological results, the compounds of the invention can be used for treating depress¬ ive conditions and parkinsonism.
For therapeutical use, an indicated oral daily dose is in the range from about 0.05 mg/kg to about 20 mg/kg, prefer¬ ably from 0.1 mg/kg to 10 mg/kg, more preferably 1 mg/kg. For therapeutical use, the active compounds of the invention are suitably formulated to pharmaceutical composi-
tions by mixing them with nontoxic, inert solid or liquid carriers and/or additives, which are suitable for enteral parenteral administration and are commonly used in the pharmaceutical industry. Suitable carriers are e.g. water, gelatin, lactose, starch, pectin, magnesium stearate, stea acid, talc and vegetable oils. As additives preservatives, wetting (surface-active) , emulsifying or dispersing, buffering and aromatizing agents may be used.
By using the above carriers and additives, the activ compounds of the invention may be formulated to the usual pharmaceutical compositions, e.g. solid forms (such as mai tablets, dragees and capsules) as well as to injectable solutions, suspensions and emulsions.
The invention also relates to pharmaceutical compositions containing a compound of the general formula ( or a pharmaceutically acceptable acid-addition salt thereof as active ingredient as well as to a process for preparing these compositions.
The compositions according to the invention can be prepared by commonly known methods.
The invention also relates to a method for treating depressive illnesses and Parkinson's disease. This method comprises administering a therapeutically effective amount an active ingredient of the general formula (I) to the patient in need of such treatment.
The identification of compounds of the invention was performed by elementary analysis; their purity and structur were proven by thin-layer chromatography (TLC) as well as b
their IR, -"--H-NMR and mass spectra. The date of analysis wer in accordance with the empirical formula within the limits error.
The invention is further illustrated by the following non-limiting Examples. Example 1
1-(4-Acetylaminophenyl)-4-methyl-7,8-methylenedioxy- -3,4-dihydro-5H~2,3-benzodiazepine Method A) To a solution containing 6.0 g (20 m ol) of l-(4-amino phenyl)-4-methyl-7,8-methylenedioxy-3 ,4-dihydro-5H-2,3-benzo diazepine (see United States patent specification No. 4,835,152) in 30 ml of ethyl acetate 1.38 ml (21 mmol) of methanesulfonic acid were added. The crystalline precipitate was filtered and washed with 5 x 5 ml of ethyl acetate. The dry weight of the product was 7.37 g, m.p.: it sintered abov 190 °C and weakly decomposed at 210-212 °C. The thus-obtaine methanesulfonate salt of the starting substance could be acetylated as follows: 7.37 g of the powdered salt were suspended in 110 ml o acetic anhydride, the suspension was stirred at room tempera ture for 2 hours, then the crystalline precipitate was filtered, washed with 5 x 10 ml of ethyl acetate and dried t give 6.54 g of methanesulfonate salt of the target compound, m.p. 240-241 °C (with decomposition) .
The base could be liberated from the methanesulfonate salt of the target compound e.g. in the following way: 6.54 of salt were dissolved in 90 ml of water, the solution was
clarified by charcoal, then 3.6 g of sodium hydrogen car¬ bonate were portionwise added to the clear solution. The precipitate was filtered, washed with 5 x 10 ml of water an dried to obtain 5.54 g of crude product. After recrystalliz tion from 130 ml of isopropanol, 3.11 g (yield 46 %) of product were obtained, m.p.: 221-223 °C (weak decomposition) the melting point of which was increased to 223-225 °C afte digesting with 15 ml of hot benzene.
C19H19N3°3 = 337.385 The hydrochloride salt decomposed at 262-264 °C.
Method B)
After dissolving 15.0 g (44.7 mmol) of l-(4-acetyl- aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo- diazepine in 150 ml of pyridine under mild heating, 10.2 g (0.269 mol) of sodium borohydride were added and the mixture was stirred on an oil bath of 100 °C temperature for 5 hours Then the reaction mixture was cooled to about 25 °C, 150 ml of water were dropwise added under continuous stirring durin 20 minutes, thereafter a mixture containing 180 ml of con- centrated hydrochloric acid and 265 ml of water was added while cooling by ice-water. A yellowish suspension was formed. The precipitate was filtered, washed with 5 x 20 ml of water and dried to yield 15.2 g of salt, m.p. above 250 °C. In order to liberate the base, this salt was suspended i 150 ml of 50 % ethanol, 5.7 g of sodium hydrogen carbonate were portionwise added while stirring, then the suspension was filtered after 30 minutes, washed successively with 3 x 10 ml of 50 % ethanol, with 5 x 20 ml of water, finally
with 20 ml of 50 % ethanol and dried to obtain 10.95 g of a crude product, m.p. : 218-220 °C (weak decomposition) . After digesting this crude product with 50 ml of hot isopropanol and then with 100 ml of hot 99.5 % ethanol, 8.63 g (57.2 %) of the aimed compound were obtained, m.p. : 220-222 °C (weak decomposition) .
The starting substance was prepared as follows. 10 g (34 mmol) of l-(4-aminophenyl)-4-methyl-7,8- -methylenedioxy-5H-2,3-benzodiazepine were stirred for 3 hours with 100 ml of acetic anhydride. The crystals formed were filtered, washed with 5x10 ml of anhydrous, ethanol and dried, to yield 9.2 g of raw product, m.p.: 252-254 °C (decomposition) . This product was treated with 45 ml of hot 99.5 % ethanol. After cooling the crystals were filtered, washed with 3x10 ml of ethanol and dried to obtain 8.68 g (76.1 %) of l-(4-acetylaminophenyl)-4-methyl-7,8-methylene- dioxy-5H-2,3-benzodiazepine, m.p.: 256-258 °C. C 19H17N3°3 = 335.369 Example 2 1-(4-Propionylaminophenyl)-4-methyl-7,8-methylenedioxy- -3, -dihydro-5H-2,3-benzodiazepine Method A)
After adding 1.70 g (4.3 mmol) of powdered l-(4-amino- phenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzo- diazepine methanesulfonate to 10 ml of propionic acid anhydride, the reaction mixture was stirred at 20 °C for 2.5 hours. The precipitated salt was washed with 4 x 5 ml of ethyl acetate and dried to give 1.86 g of product, m.p.:
246-248 °C (decomposition) . The base was liberated as described in Method A) of Example 1 to obtain 1.36 g of product, m.p.: 226-233 °C (weak decomposition). The meltin point of this product was increased to 237-239 βC after re crystallization from 40 ml of 99.5 % ethanol to give the aimed compound in a yield of 1.8 g (71.5 %) .
C20H21N3O3 = 351.412
The same product was obtained with a yield of 65 % b adding first 2.15 mmol of concentrated sulfuric acid, then 4.3 mmol of l-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-
-3,4-dihydro-5H-2,3-benzodiazepine base to the propionic a anhydride and otherwise working as described above.
Method B)
When starting from 1.65 g (4.72 mmol) of l-(4- -propionylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3- -benzodiazepine and otherwise following Method B) of Examp 1 (except that alkalinization was carried out by using 40 aqueous sodium hydroxide solution and the extraction was p formed by using benzene) and recrystallizing the crude product from ethanol, 1.2 g (72.3 %) of the aimed product were obtained, m.p.: 235-236 °C (weak decomposition).
1-(4-Propionylaminophenyl)-4-methyl-7,8-methylenedio -5H-2,3-benzodiazepine used as starting substance was pre¬ pared in the same way as described above for the 4-acetyl- a ino analogue, except that propionic acid anhydride was us instead of acetic acid anhydride, m.p.: 228-230 °C (decompo sition) .
C20H19N3O3 = 349.396.
Examples 3 to 5
The compounds of Examples 3 to 5 were also prepared a described in Method B) of Example l. Exam le 3 1-(4-Benzoylaminophenyl)-4-methyl-7,8-methylenedioxy- -3,4-dihydro-5H-2 ,3-benzodiazepine 24H21N 3°3 = 399.456; it decomposes at 247-248 °C. The 1-(4-benzoylaminophenyl)-4-methyl-7 ,8-methylene- dioxy-5H-2,3-benzodiazepine used as starting substance was obtained as follows.
1.0 ml (15 mmol) of benzoyl chloride, and 2.1 ml (15 mmol) of triethylamine were added to a solution of 4 g (13. mmol) of l-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H- -2,3-benzodiazepine in dichloromethane and the reaction mixture was stirred at 25 °C for 24 hours. The solution was extracted with 3x30 ml of water, 3x20 ml of a 4 % aqueous sodium hydroxide solution and finally with 2x30 ml of distilled water. The organic layer was dried, evaporated at reduced pressure, then the crystalline residue was treated with 20 ml of hot ethanol to yield 3.97 g of raw product, m.p.: 242-243 °C. This raw product was repeatedly treated with 20 ml of hot ethanol, next day it was filtered at 0-5 °C, washed with 3x3 ml of ethanol and dried at 100 °C to obtain 3.85 g (71.3%) of a pure product, m.p.: 246-247 °C (decomposition) .
C24H19N3°3 = 397.40
Example 4
4-Methyl-7,8-methylenedioxy-l-(4-phenylacetylamino-
-phenyl)-3,4-dihydro-5H-2,3-benzodiazepine
C25H23 N 3°3 = 413.483; it decomposes at 213-215 °C. The 4-methyl-7,8-methylenedioxy-l-(4-phenylacetylamin phenyl)-5H-2,3-benzodiazepine used as starting substance wa prepared in the following way.
After adding 0.7 g (3.4 mmol) of DCC and 0.46 g (3.4 mmol) of phenylacetic acid to the solution of 0.5 g (1.7 mmol) of l-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-
-2,3-benzodiazepine in 30 ml of anhydrous methylene chlorid the mixture was stirred at 25 °C for 48 hours and filtered. The precipitate was combined with the evaporation residue o the filtrate and purified by chromatography on silica gel, using a 4:1 mixture of ethyl acetate-methanol as eluent. Th fractions containing the aimed product were evaporated, the residue was boiled with 5 ml of ethanol, cooled down and filtered to obtain 0.60 g (87.72 %) of the aimed product, m.p. : 245-247 °C (decomposition) . Example 5
4-Methyl-7,8-methylenedioxy-l-(4-pivaloylaminophenyl)
-3,4-dihydro-5H-2,3-benzodiazepine 22H25N 3°3 = 379.466; it decomposes at 134-136 °C.
The 4-methyl-7,8-methylenedioxy-l-(4-pivaloylamino- phenyl)-5H-2,3-benzodiazepine used as starting substance wa prepared in the following manner.
1.56 ml (11.2 mmol) of triethylamine and 1.38 ml (11. mmol) of pivaloyl chloride were added to a solution of 3 g
(10.2 mmol) of l-(4-aminophenyl)-4-methyl-7,8-methylenediox -5H-2,3-benzodiazepine in 160 ml of dichloromethane and the reaction mixture was stirred at 25 °C for one hour. The precipitate formed was filtered, washed with 3x5 ml of di- chloromethane, then with 3x20 ml of water and dried to give 1.59 g of the pure product, m.p. 225-227 °C (decomposition) The other portion of the product was isolated from the organic phase. The filtrate was extracted with 3x20 ml of water, then with 3x15 ml of 4 % aqueous sodium hydroxide solution, finally with 2x30 ml of water. The organic layer was subsequently dried and evaporated under reduced pressur The crystalline residue was combined with the former 1.59 g of the product and suspended in 20 ml of hot ethanol. The product was filtered after cooling, washed with 3x3 ml of ethanol and dried to obtain 3.38 g (87.8 %) of the pure product, m.p.: 225-227 °C.
C22H23N3°3 = 377.450.
Example 6
1-(4-Acetylaminophenyl)-3-ethoxycarbonylmethyl-4- methyl-7 ,8-methylenedioxy-3 ,4-dihydro-5H-2,3-
-benzodiazepine
1.26 g (3.7 mmol) of the target compound of Example 1 were dissolved in 5 ml of pure dimethylformamide, then 0.51 (3.7 mmol) of potassium carbonate (anhydrized by heating) an 0.42 ml (3.7 mmol) of ethyl bromoacetate were added while stirring. The reaction mixture was stirred at room tempera¬ ture for 6 hours. Next day the crude product was precipitate by adding 50 ml of water. After filtration, washing with
5 x 4 ml of water and drying, the crude product weighed 1.3 g. This product was purified by column chromatography on Kieselgel GO by using a 4:1 ethyl acetate/benzene mixture f elution. After recrystallization from 10 ml of 50 % ethanol 1.05 g (67 %) of the aimed product were obtained, m.p.: 156-157 °C.
C23H25N3°5 = 423.477. Exam le 7 l-(4-Acetylaminophenyl)-3,4-dimethyl-7,8-methylene- dioxy-3 ,4-dihydro-5H-2 ,3-benzodiazepine
The process described in Example 6 was followed, exce that methyl iodide was used instead of ethyl bromoacetate, the column chromatography was omitted and the crude product was recrystallized first from 50 % and then from 99.5 % ethanol to give the pure aimed compound, m.p.: 207-209 °C.
C20H21N3°3 = 351.412. Example 8
1-(4-Acetylaminophenyl)-3-ethyl-4-methyl-7,8-methylen dioxy-3,4-dihydro-5H-2,3-benzodiazepine The process described in Example 7 was followed, exce that ethyl iodide was used instead of methyl iodide and the recrystallization was carried out with 50 % ethanol. C21H23N3°3 ~ 365.439; m.p.: 185-187 °C. Example 9 l-(4-Acetylaminophenyl)-3-carboxymethyl-4-methyl-7,8- -metnylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine 0.59 g (1.4 mmol) of the compound of Example 6 was boiled with 15 ml of 50 % ethanol and 0.10 g (1.8 mmol) of
potassium hydroxide under reflux for 30 to 40 minutes. Afte cooling 0.15 ml (2.5 mmol) of acetic acid was added to the filtered, clear solution to liberate the free carboxylic ac which was then separated by filtration after cooling. The acid was washed with 4 x 2 ml of 50 % ethanol and then with 3 x 3 ml of water and dried to obtain 0.45 g (81.3 %) of th aimed product which sintered from 162 βC and weakly decomposed at 164-166 °C.
C21H21 3O5 = 395.423. Example 10
Preparation of pharmaceutical compositions a) Divided (grooved) tablets containing 25 mg of l-(4 -acetyla inophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro -5H-2,3-benzodiazepine (compound of Example 1) Ingredients of one tablet:
Active ingredient 25.0 mg
Magnesium stearate 0.5 mg
Stearin 0.5 mg
Talc 1.0 mg Gelatin 1.7 mg
Microcrystalline cellulose 5.0 mg
Maize starch 10.3 mg
Lactose 46.0 mg. b) Dragees containing 12.5 mg of l-(4-acetylamino- phenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzo diazepine
Ingredients of one dragee-core:
Active ingredient 12.5 mg
Magnesium stearate 1.0 mg
Polyvinylpyrrolidone 5.0 mg Maize starch 16.0 mg
Lactose 38.0 mg.
The dragee-core was coated with sugar and talc in the usual way and then polished by using bee-wax. Each dragee weighed about 100 mg.
Claims
1. l- (4-Acylaminophenyl) -7 , 8-methylenedioxy-5H-2 , 3- -benzodiazepine derivatives of the general formula (I) ,
wherein R stands for hydrogen or a C1_4 alkyl group optionally substituted by a carboxyl or C -5 alkoxycarbonyl gro and R1 means an aliphatic C_-_-ζ acyl, benzoyl or phenylacety group, and their stereoisomers and acid-addition salts.
2. 1-(4-Acetylaminophenyl)-4-methyl-7,8-m thylenedio -3,4-dihydro-5H-2,3-benzodiazepine.
3. A pharmaceutical composition, which comprises as active ingredient a novel l-(4-acylaminophenyl)-7,8- -methylenedioxy-5H-2,3-benzodiazepine derivative of the general formula (I) , wherein R and R1 are as defined in cla 1, or a pharmaceutically acceptable acid-addition salt thereof in admixture with carriers and/or additives commonl used in the pharmaceutical industry.
4. A process for the preparation of novel l-(4- -acyla ino-phenyl)-7,8-methylenedioxy-5H-2,3-benzodiazepi derivatives of the general formula (I) ,
wherein R stands for hydrogen or a C1-4 alkyl group optionall substituted by a carboxyl or C2-5 alkoxycarbonyl gr and R1 means an aliphatic Cχ-ζ acyl, benzoyl or phenylacet group, and their stereoisomers as well as acid-addition salts, w comprises a-j transforming a compound of the general formula (III) 
wherein R is as defined above, to a compound of the general formula (II) ,
wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, by us an organic or inorganic acid, then acylating the prod obtained, optionally without separating it, with a C aliphatic carboxylic acid, benzoic or phenylacetic ac or a reactive derivative of these acids; or a2) acylating a compound of the general formula (II) , wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, with Cι_6 aliphatic carboxylic, benzoic or phenylacetic acid or a reactive derivative of these acids; or b) reducing a compound of the general formula (IV) ,
wherein R1 is as defined above, by using an inorgani inorganic-organic complex metal hydride in a suitabl solvent, to obtain compounds of the general formula ( wherein R1 is as defined above and R means hydrogen; and, if desired, alkylating a compound of the general for (I) , wherein R1 is as defined above and R stands for hydr gen, prepared by using any of the above processes a.__) , a2) b) , with a Cι_4 alkyl halide optionally substituted by a alkoxycarbonyl group or with a C2-8 dialkyl sulfate in a suitable solvent, in the presence of an acid-binding agen and/or, if desired, hydrolyzing and then treating with an acid a compound of the general formula (I) , wherein R1 is defined above and R stands for a Cι_4 alkyl group substitu by a C2-5 alkoxycarbonyl group, to obtain a compound of t general formula (I), wherein R stands for Cχ-4 alkyl subs tuted by a carboxyl group and/or, if desired, converting compound of the general formula (I) thus obtained to an a addition salt or, conversely, transforming a salt obtaine the corresponding free base.
5. A process as claimed in claim 4, process a^) or which comprises carrying out the acylation with the corresponding carboxylic acid anhydride, preferably in an excess of the carboxylic acid anhydride, at a temperature between 10 °C and 50 °C during 1 to 5 hours.
6. A process as claimed in claim 4, process b) , whi comprises using lithium aluminum hydride, sodium borohydri potassium borohydride, sodium borohydride/aluminum chlori sodium cyanoborohydride, sodium bis(2-methoxyethoxy)alumi hydride, lithium trimethoxyaluminu hydride or sodium boro hydride/triethyloxonium fluoborate and carrying out the re duction in a solvent or solvent mixture which is non-react or slowly reacting to the complex metal hydride employed.
7. A process as claimed in claim 6, which comprises carrying out the reduction with sodium borohydride in pyridine.
8. A process as claimed in claim 4, which comprises carrying out the alkylation in dimethylformamide, in the presence of an anhydrous alkali metal hydrogen carbonate o carbonate as acid-binding agent.
9. A process as claimed in claim 4, which comprises carrying out the selective hydrolysis of compounds of the general formula (I) , containing as R a C*^ alkyl group substituted by a C2-5 alkoxycarbonyl group, by using an alkali metal hydroxide in hot 50 % ethanol and liberating free carboxylic acid derivative by acetic acid.
10. A process for the preparation of a pharmaceutic preparation, which comprises mixing as active ingredient novel 1-(4-acylaminophenyl)-7,8-methylenedioxy-5H-2,3-ben diazepine derivative of the general formula (I) , wherein and R1 are as defined in claim 1, or a pharmaceutically acceptable acid-additon salt thereof, prepared by using a of processes a^) to b) claimed in claim 4, with carriers and/or additives commonly used in the pharmaceutical indu and transforming them to a pharmaceutical composition.
11. Method for treating mammals (including man) suffering from a depressive illness or Parkinson's diseas which comprises administering a therapeutically effective amount of an l-(4-acylaminophenyl)-7,8-methylenedioxy-5H- benzodiazepine derivative of the general formula (I) , whe R and R1 are as defined in claim 1, or a pharmaceutically acceptable acid-addition salt thereof, to a subject in ne of such treatment.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019930701833A KR930703324A (en) | 1990-12-21 | 1991-12-20 | 1- (4-acylaminophenyl) -7,8-methylenedioxy-5H-2,3-benzodiazepine derivatives, acid addition salts thereof, pharmaceutical compositions containing the same and methods for preparing the same |
| JP4502171A JPH06506442A (en) | 1990-12-21 | 1991-12-20 | 1-(4-acylaminophenyl)-7,8-methylenedioxy-5H-2,3-benzo-diazepine derivatives and acid addition salts thereof, pharmaceutical compositions containing the same, and methods for producing the same |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU8397/90 | 1990-12-21 | ||
| HU908397A HU206719B (en) | 1990-12-21 | 1990-12-21 | Process for producing 1-/4-acylamino-phenyl/-7,8-methylenedioxy-5h-2,3-benzodiazepine derivatives, acid addicional salts and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992011262A1 true WO1992011262A1 (en) | 1992-07-09 |
Family
ID=10972602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU1991/000053 WO1992011262A1 (en) | 1990-12-21 | 1991-12-20 | 1-(4-acylaminophenyl)-7,8-methylenedioxy-5h-2,3-benzo-diazepine derivatives and acid addition salts thereof, pharmaceutical compositions containing them and process for preparing same |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0565557A1 (en) |
| JP (1) | JPH06506442A (en) |
| KR (1) | KR930703324A (en) |
| AU (1) | AU9122691A (en) |
| CA (1) | CA2098291A1 (en) |
| HU (1) | HU206719B (en) |
| WO (1) | WO1992011262A1 (en) |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995001357A1 (en) * | 1993-07-02 | 1995-01-12 | Gyógyszerkutató Intézet Kft. | Optically active 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h-2,3-benzodiazepine and process for preparing same |
| EP0699677A1 (en) | 1994-08-31 | 1996-03-06 | Eli Lilly And Company | Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives |
| US5665878A (en) * | 1994-08-31 | 1997-09-09 | Eli Lilly And Company | Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives |
| WO1999007708A1 (en) * | 1997-08-12 | 1999-02-18 | EGIS Gyógyszergyár Rt. | 1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives as ampa/kainate receptor inhibitors |
| WO1999007707A1 (en) * | 1997-08-12 | 1999-02-18 | EGIS Gyógyszergyár Rt. | 8-SUBSTITUTED-9H-1,3-DIOXOLO/4,5-h//2,3/BENZODIAZEPINE DERIVATIVES, AS AMPA/KAINATE RECEPTOR INHIBITORS |
| WO2000053166A3 (en) * | 1999-02-15 | 2000-12-21 | Egyt Gyogyszervegyeszeti Gyar | Use of condensed 2,3-benzodiazepine derivatives for the treatment and prophylaxis of diseases related to the inhibition of lipid peroxidation |
| WO2001004122A3 (en) * | 1999-07-07 | 2001-05-10 | Egyt Gyogyszervegyeszeti Gyar | New 2,3-benzodiazepine derivatives |
| EP1157992A1 (en) * | 1994-08-31 | 2001-11-28 | Eli Lilly And Company | Dihydro-2,3-Benzodiazepine derivatives |
| WO2001098280A3 (en) * | 2000-06-16 | 2002-05-30 | Annovis Inc | 5h-2,3-benzodiazepine antagonists of excitatory amino acid receptors |
| US6638928B1 (en) | 2002-12-03 | 2003-10-28 | Vela Pharmaceuticals, Inc. | Treatment of irritable bowel syndrome and nonulcer dyspepsia with substituted 2,3-benzodiazepines |
| US6649607B2 (en) | 2001-05-18 | 2003-11-18 | Vela Pharmaceuticals, Inc. | Compositions and methods for treating or preventing convulsions or seizures |
| US6858605B2 (en) | 2003-02-04 | 2005-02-22 | Ivax Drug Research Institute, Ltd. | Substituted 2,3-benzodiazepine derivatives |
| US6864251B2 (en) | 2002-12-03 | 2005-03-08 | Vela Pharmaceuticals, Inc. | Treatment of LTB4-mediated inflammatory disorders with optically-pure (R)-2,3-benzodiazepines |
| US7022700B2 (en) | 2002-12-03 | 2006-04-04 | Vela Pharmaceuticals, Inc. | Method of increasing neutrophil production using optically-pure (R)-2,3-benzodiazepines |
| US7745431B2 (en) | 2002-12-03 | 2010-06-29 | Vela Acquisition Corporation | Pharmaceutical composition of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine and uses thereof |
| US7960375B2 (en) | 2003-08-04 | 2011-06-14 | Egis Gyogyszergyar Rt. | 8-chloro-2,3-benzodiazepine derivatives |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4423044A (en) * | 1981-03-12 | 1983-12-27 | Egyt Gyogyszervegyeszeti Gyar | 3,4-Dihydro-5H-2,3-benzodiazepine derivatives and pharmaceutical use thereof |
| US4835152A (en) * | 1986-08-15 | 1989-05-30 | Biogal Gyogyszergyar | 1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and acid addition salts thereof same |
-
1990
- 1990-12-21 HU HU908397A patent/HU206719B/en not_active IP Right Cessation
-
1991
- 1991-12-20 JP JP4502171A patent/JPH06506442A/en active Pending
- 1991-12-20 EP EP92901588A patent/EP0565557A1/en not_active Withdrawn
- 1991-12-20 KR KR1019930701833A patent/KR930703324A/en not_active Withdrawn
- 1991-12-20 AU AU91226/91A patent/AU9122691A/en not_active Abandoned
- 1991-12-20 WO PCT/HU1991/000053 patent/WO1992011262A1/en not_active Application Discontinuation
- 1991-12-20 CA CA002098291A patent/CA2098291A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4423044A (en) * | 1981-03-12 | 1983-12-27 | Egyt Gyogyszervegyeszeti Gyar | 3,4-Dihydro-5H-2,3-benzodiazepine derivatives and pharmaceutical use thereof |
| US4835152A (en) * | 1986-08-15 | 1989-05-30 | Biogal Gyogyszergyar | 1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and acid addition salts thereof same |
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995001357A1 (en) * | 1993-07-02 | 1995-01-12 | Gyógyszerkutató Intézet Kft. | Optically active 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h-2,3-benzodiazepine and process for preparing same |
| EP1593683A3 (en) * | 1994-08-31 | 2006-10-25 | Eli Lilly And Company | Dihydro-2,3-Benzodiazepine derivatives |
| EP0699677A1 (en) | 1994-08-31 | 1996-03-06 | Eli Lilly And Company | Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives |
| US5665878A (en) * | 1994-08-31 | 1997-09-09 | Eli Lilly And Company | Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives |
| US5919954A (en) * | 1994-08-31 | 1999-07-06 | Eli Lilly And Company | Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives |
| US5986114A (en) * | 1994-08-31 | 1999-11-16 | Eli Lilly And Company | Benzopyranol derivatives |
| EP1157992A1 (en) * | 1994-08-31 | 2001-11-28 | Eli Lilly And Company | Dihydro-2,3-Benzodiazepine derivatives |
| WO1999007708A1 (en) * | 1997-08-12 | 1999-02-18 | EGIS Gyógyszergyár Rt. | 1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives as ampa/kainate receptor inhibitors |
| WO1999007707A1 (en) * | 1997-08-12 | 1999-02-18 | EGIS Gyógyszergyár Rt. | 8-SUBSTITUTED-9H-1,3-DIOXOLO/4,5-h//2,3/BENZODIAZEPINE DERIVATIVES, AS AMPA/KAINATE RECEPTOR INHIBITORS |
| US6562810B1 (en) | 1997-08-12 | 2003-05-13 | Egis Gyogyszergyar Rt. | 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives, as AMPA/kainate receptor inhibitors |
| WO2000053166A3 (en) * | 1999-02-15 | 2000-12-21 | Egyt Gyogyszervegyeszeti Gyar | Use of condensed 2,3-benzodiazepine derivatives for the treatment and prophylaxis of diseases related to the inhibition of lipid peroxidation |
| WO2001004122A3 (en) * | 1999-07-07 | 2001-05-10 | Egyt Gyogyszervegyeszeti Gyar | New 2,3-benzodiazepine derivatives |
| WO2001098280A3 (en) * | 2000-06-16 | 2002-05-30 | Annovis Inc | 5h-2,3-benzodiazepine antagonists of excitatory amino acid receptors |
| US6649607B2 (en) | 2001-05-18 | 2003-11-18 | Vela Pharmaceuticals, Inc. | Compositions and methods for treating or preventing convulsions or seizures |
| US7078398B2 (en) | 2001-05-18 | 2006-07-18 | Vela Pharamaceuticals, Inc. | Compositions and methods for treating or preventing convulsions or seizures |
| US6864251B2 (en) | 2002-12-03 | 2005-03-08 | Vela Pharmaceuticals, Inc. | Treatment of LTB4-mediated inflammatory disorders with optically-pure (R)-2,3-benzodiazepines |
| US7022700B2 (en) | 2002-12-03 | 2006-04-04 | Vela Pharmaceuticals, Inc. | Method of increasing neutrophil production using optically-pure (R)-2,3-benzodiazepines |
| US6638928B1 (en) | 2002-12-03 | 2003-10-28 | Vela Pharmaceuticals, Inc. | Treatment of irritable bowel syndrome and nonulcer dyspepsia with substituted 2,3-benzodiazepines |
| US7745431B2 (en) | 2002-12-03 | 2010-06-29 | Vela Acquisition Corporation | Pharmaceutical composition of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine and uses thereof |
| US6858605B2 (en) | 2003-02-04 | 2005-02-22 | Ivax Drug Research Institute, Ltd. | Substituted 2,3-benzodiazepine derivatives |
| US7960375B2 (en) | 2003-08-04 | 2011-06-14 | Egis Gyogyszergyar Rt. | 8-chloro-2,3-benzodiazepine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| HUT59683A (en) | 1992-06-29 |
| AU9122691A (en) | 1992-07-22 |
| CA2098291A1 (en) | 1992-06-22 |
| KR930703324A (en) | 1993-11-29 |
| HU908397D0 (en) | 1991-07-29 |
| EP0565557A1 (en) | 1993-10-20 |
| HU206719B (en) | 1992-12-28 |
| JPH06506442A (en) | 1994-07-21 |
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