IL31146A - 1,2,4,5-tetrahydro-3h-1,4-benzodiazepin-2,5-diones,their preparation and pharmaceutical compositions containing them - Google Patents

1,2,4,5-tetrahydro-3h-1,4-benzodiazepin-2,5-diones,their preparation and pharmaceutical compositions containing them

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Publication number
IL31146A
IL31146A IL31146A IL3114668A IL31146A IL 31146 A IL31146 A IL 31146A IL 31146 A IL31146 A IL 31146A IL 3114668 A IL3114668 A IL 3114668A IL 31146 A IL31146 A IL 31146A
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Israel
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compounds
formula
effected
group
solvent
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IL31146A
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IL31146A0 (en
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Boehringer Sohn Ingelheim
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Publication of IL31146A publication Critical patent/IL31146A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Description

- 5 , 2 - 1 ■» a τ « ·» τι τ a a - , 1 - 3 S- i τ ' n ti *> ο β - 5 , , 2 , 1 οηικ o' aen mnpn 'tsom onjan ,ο'ΐη'η 1» 2, 4, 5-tetrahydro-3*k-l,4-¾enzodiazepin-2,5-diones, their preparation and pharmaceutical compositions containing them G.H. BOEHRINOER SOHN 31146/2 2 - This invention relates to 1, 2,4, 5-tetrahydro-3H-l , 4- benzodiazepin-2, 5-diones having valuable pharmacological properties, and to processes for the preparation thereof.
According to the present invention there are provided compounds of the general formula in which R^ represents a hydrogen atom or an alkyl group containin 1 to 4 carbon atoms; -¾2 represents an alkyl group containing 1 to 4 carbon atoms or an allyl group; represents a hydrogen or halogen atom or an alkyl group containin ,1 or 2 carbon atoms; represents a hydrogen or halogen atom, a nitro, trifluoro- methyl or cyano group or an alkyl group, containing 1 or 2 carbon atoms; R(- represents a hydrogen or halogen atom, ' a trifluoromethyl group or an alkyl or alkoxy group each containing l or 2 carbon •atoms; and R re r n a e ' The symbol R^ may for example represent a methyl group and R2 a methyl, ethyl, iso-propyl or n-butyl group. The symbols R^ and R^- may for example represent substituents at the 7- or 8-positions of the compounds of formula I and when either represent a halogen atom, the preferred halogen atom is a chlorine atom. The symbol R^ may also for example represent a methyl group.
The preferred value for ^ when it represents a halogen atom is a chlorine atom which may be a substit ent at any position in the phenyl group. Either or both of R^ and Rg may also for example represent methyl groups and R^ may further represent a methoxy group. The symbol R^ preferably represents a substituent at either the 2- or 4-pcsition of the phenyl group to which it is attached.
The compounds according to the invention possess valuable pharmacological properties and in particular psychosedative and anticonvulsive activity. This activity is particularly valuable in warm-blooded animals, for example mice, rats, cats and dogs.
Particularly valuable compounds according to the invention are l-( 2-chlorophenyl )-4-ethyl-8-chloro-l , 2, 4, 5-tetrahydro-3H-l, 4-benzodiazepin-2, 5-dione, and 1-phenyl-4-ethyl-8-chloro-l , 2 , 4, 5-tetrahydro-3H-l, 4-benzodiazepin-2, 5-dione.
According to a further feature of the invention there are provided processes for the preparation of compounds of the general formula I, which comprise: a) cyclisation of a reactive derivative of a carboxylic acid of the formula in which R-^, R2» ^3» ¾ R5 and R6 are as lierein "before defined). The reactive derivatives of the compounds of formula II are compounds in which the carboxyl group has been converted to a group (e.g. an acid halide group) capable of reacting with the hydrogen atom of the -NH-group to effect cyclisation. The acid halide may conveniently first be prepared by reaction of the compound of formula II with a suitable halogenating agent. Cyclisation can if desired be effected in the presence of a tertiary organic base; b) reaction of a compound of formula II (as defined above) with a oarbo¾ylic..-acid (e.g.— cetic acid)—or a halide or anhydride thoroof . of a carboxylic acid. c) heating of a diamide of the formula III (in which R-p I^, R^» R^, R^ and Rg are as hereinbefore defined and X represents a halogen atom) with an alkali metal alcoholate, conveniently in the presence of a solvent.
The reaction of an anthranilic acid derivative of formula II with for example thionyl chloride, phosphorus pentachloride, phosphorus trichloride or other suitable halogenating agent may preferably be effected in an organic solvent for example benzene, toluene, xylene or a mixture of at least one of these solvents with dimethylformamide . The temperature at which this process may be effected depends upon the starting compound to be used and may for example be between ambient temperature and the reflux temperature of the solvent used. The cyclization reaction of the intermediately formed acid halides takes place spontaneously with the elimination of the corresponding hydrogen halide. In several cases subsequent treatment with a tertiary organic base, e.f . pyridine, may be advantageous and in these cases, he · intermediately formed acid halide need not be isolated.
The reaction of a compound of formula II with an acyl anhydride or an acyl halide as cyclizing agent may preferably be effected in solution in benzene at reflux temperature or in the absence of a solvent at elevated temperature .
The cyclization of a diamide of formula III with the aid of an alkali metal alcoholate, for example a sodium or potassium alcoholate, may be effected in the presence of an anhydrous solvent, for example benzene, toluene or xylene, preferably at an elevated temperature e.g. be prepared by reacting an anhydride of the' corresponding N-phenylanthranilic acid with an ester of the corresponding N-alkylamino acid or more preferably by the amidation of the corresponding N-phenylanthraniloyl chlorides with for example an ester of the corresponding N-alkylamino acid and in either case subsequently hydrolysing the ester formed.
Compounds of the formula III may for example be prepared by amidation of an anhydride of the corresponding N-phenylanthranilic acid or phenylanthraniloyl chloride with a monoalkylamine and subsequent reaction of the amide formed with an a-halogenoacylhalide, preferably in solution in benzene, with the addition of an equivalent quantity of an organic base, Θ.¾. pyridine.
According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising at least one of the compounds according to the invention in association with a pharmaceutical carrier or excipient. Suoh compositions may be in a form suitable for oral, rectal or parenteral use. Suitable forms of administration may for example be tablets, coated tablets, capsules, suppositories, solutions, drops, suspensions or powders; they may be prepared with conventional excipients, binders, carriers, disintegrants or lubricants or with agents which give rise to a prolonged release effect. The compositions may be prepared according to conventional processes.
The compounds may be administered in the form' of dosage units, each dosage unit containing 1-100 mg, preferably 5 - 50 mg of active ingredient.
The following Examples illustrate the invention: - Example 1 l-Phenyl-4-me†hyl-8-chloro-l.2.4.5-tetrahydro-3H-l .4-benzodiazepin-2.5-dione 7.36 g (0.03 mol) of 2-phenylamino-4-chloro-N-methyl--N-carboxymethylbenzamide were dissolved in 50 ml of benzene and 5 ml of dimethylformamide and mixed, with stirring in the cold during 10 minutes, with a solution of 3.1 g of thionylchloride in 10 ml of benzene. The temperature increased to 35°0. Stirring was continued for 2 hours at ambient temperature, the solvent evaporated and the residue taken up in methylene chloride which was shaken with sodium bicarbonate solution to remove acidic, components. The dried methylene chloride layer was evaporated and the residue recrystallized from methylene chloride/isopropy]/ethe . 3.2 g of l-phenyl-4-methyl-8-chloro-l, 2,4, -tetrahydro-3H-l, 4-benzo-diazepin-2, 5-dione of m.p. 209 - 210°C were obtained.
The starting material was obtained as follows: 74 g (0.3 mol) of 2-phenylamino-4-chlorobenzoic acid were suspended in 800 ml of petroleum ether. 62.5 g of phosphorus pentachloride were added with stirring and the mixture heated to approx. 50°C. · The reaction began spontaneously and. ended after 15 minutes. A clear yellow solution was formed over a small quantity of solid material. The solution was filtered hot and after cooling in ice, long, yellow needle-like crystals were obtained which may if desired be recrystallized from isopropy^ether .
Yield 90 - 95$ of theory of m.p. 100 - 101°C. 0.2 mol (53 g) of acid chloride were dissolved in 500 ml of methylene chloride. A solution of 0.2 mol (26.2 g) of vigourous stirring. After approx. 30 minutes the reaction was complete. The methylene chloride phase was separated, dried and evaporated. 75 g of crude ester were obtained, which were dissolved in .200 ml of ethanol. 35 g of caustic potash in 200 ml of water were added and the mixture boiled for 15 minutes under reflux. The alcohol was distilled off, the residue diluted with water, acidified with hydrochloric acid and extracted with methylene chloride.
After drying and evaporating, 75 g of 2-phenylamino-—chloro-N-methyl-N-carboxymethylbenzamide were obtained.
Example 2 l-Phenyl-4-ethyl-8-chloro-l .2.4.5-tetrahydr0-3H-1.4-benzodiazepin-2.5-dione 38.4 g of 2-phenylamino-4-chloro-N-ethyl-N-carboxy-methylbenzamide are dissolved in 250 ml of benzene. 50 ml anhydride of acetic aoid are added and the mixture refluxed for 1 hour0 The acidic components are extracted with sodium bicarbonate solution, the benzene layer dried and evaporated. The residue is recrystallized from methylene chloride-petrol.eum ether. Yield: 26 g of m.p. 193 - 195°0.
Example 3 l-Phenyl-4-ethyl-8-chloro-l.2.4.5-tetrahydro-3H-l.4-benzodiazepin-2.5-dione 1.2 g of sodium methoxide are suspended in 120 ml of toluene. 20 ml of toluene are distilled off, 7.0 g (20 m-mol) of 2-[N-( 2-chloroa tyl)-N-phenylamino]-4-chloro-N-ethylbenzamide are added and the mixture is refluxed with stirring for 2 hours. The reaction mixture is extracted several times with water, the toluene phase dried and t n Ψ from methylene chloride-petroleum ether, 4 g (65$ of theory) of l-phenyl-4-ethyl-8-chloro-l, 2,4, 5-tetrahydro-3H-l, 4-benzodiazepin-2, 5-dione of melting point 193 - 195°C.
The starting material was obtained as follows: 80 g (0.3 mol) of 2-phenylamino-4-chlorobenzoyl chloride were dissolved in 400 ml of methylene chloride, the mixture stirred and cooled and 110 ml of 25$-aqueous ethylamine are dropped in. Stirring is continued for 30 minutes, the methylene chloride phase separated, washed with water, separated again, dried, evaporated and recrystallized from isopropylether.
Yield: 74 g (90$ of theory) of m.p. 101 - 102°C. 17.4 g (0.06 mol) of amide are dissolved in 350 ml of benzene and 4.8 ml of pyridine. 6.8 g of pure a-chloroacetyl chloride in 20 ml of benzene are added with stirring and. the temperature kept at 50°0 for 24 hours. The reaction mixture is washed with water, sodium carbonate solution and once more with water. The solution is then dried and evaporated in vacuo. The residue is recrystallized from methylene chloride-isopropylether .
Yield of 2-[N-( 2-chloroacetyl)-N-phenylamino]-4-chloro-N~ ethyl benzamide: 7.8 g (38$ of theory) of m.p. 167 - 168°C„ The following compounds were prepared by methods analogous to these described above: H ' CH5 H H H . H 162 - 163 6 Ή H H H H · 126 - 127 C2H5 7 .H CH, 8-C1 H 4 H -·' 190 -- 192 3 3 8 H °2H5 8-Cl H 4 ' -CH, H 206: 3 - '207 9 H HC-CH, 8-Cl- H H H ' 178 - 180 ! 5 0H3 .
H CH-. ·■ 8-Cl H - 2 '.-CI H 165 - 167 3 11 H -Cl H. 2 '-01 H 162 - 164 .
H 8-C;F3 H ■H H 192 , C2H5 -> ' 21 H 8-Cl H 3-01 H · .172 ' C2H5 - 173 22 H °2H5 8-CN H H ' H .186 - 187 23' H 8-CF3 H- H • H 169-•170 °2H5 24 •H C2H5 ' 8-CF- H F H 3 ' 155 · H 8-Br H H H . °2Η5· 205 ' .
Example 23 Dragees: 1 dragee core comprises: l-(2-chlorophenyl)-4-ethyl-8-chloro-l, 2,4,5 tetrahydro-3H-l, 4-benzodiazepin-2, 5-dione 10.0 mg lactose 25.5 mg corn starch 13.0 mg gelatin 1.0 mg magnesium stearate 0.5 mg 50.0 mg Preparation: A mixture of the active ingredient, lactose and corn starch is granulated using a 10o aqueous gelatin solution through a 1mm mesh screen, dried at 40°0 and rubbed once more through a screen. The granulate thus obtained is mixed with magnesium stearate and pressed. The dragee cores thus obtained are coated in conventional manner with a shell prepared from an aqueous suspension of sugar, titanium dioxide, talcum and gum arabic. The finished dragees are polished with beeswax.
Weight of dragee: 100 mg.
Example 24 Suppositories: 1-suppository comprises: l-phenyl-4-ethyl-8-chloro-l, 2,4, 5-tetrahydro- 3H-1, -benzodiazepin-2, 5-dione 10.0 mg suppository base (e.g. Witepsol W 45, 1690.0 mg a triglyceride mixture) Preparation The finely pulverized active substance is stirred into the molten suppository base, cooled to 40°C by means of an immersion homogenizer. The molten mass is poured into slightly precooled molds at 35°0.

Claims (47)

1. · Compounds of the general formula in whic h " . ·'· · x · » . represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms; . represents an alkyl group containing 1 to 4 carbon atoms or an allyl group; j represents a hydrogen or halogen atom or an alkyl group containing 1 or 2 carbon. atoms; R4 represents a hydrogen or halogen atom, a nitro, trifluoro methyl or cyano group or an alkyl group oaok containing 1 or 2 car .on atoms.; R^ represents a hydrogen or halogen atom, a trifluoromethyl group or an alkyl or alkoxy group each containing 1 or 2 carbon atoms; and Rg repre.sents a hydrogen' or halogen atom or an .alkyl group containing .1 or .2. carbon atoms.
2. Compounds as claimed in claim 1 in which R-^ represents a methyl, ethyl, is.o-propyl or n-butyl group..
3. „ Compounds as. claimed, in claim 1.. or. claim 2 in which ^ represents a chlorine .atom or a methyl, group.
4. Compounds .as claimed in any of the precedin claims in which R^_ represents a chlorine atom.
5. Compounds as claimed in any of the preceding claims in which ^ and R^ represent substituents at the 7-and 8-positions of the formula I.
6. „ Compounds as claimed in any of the preceding claims in which R^ represents a chlorine atom or a methyl or methoxy group.
7. Compounds as claimed in any of the preceding claims in which Rg represents a methyl group.
8. Compounds as claimed in any of the preceding claims in which R^ represents a substituent at either the 2- or 4-position of the phenyl group to which it is attached.
9. l-(2~Chlorophenyl)~4-ethyl-8-chloro-l, 2,4,5-tetrahydro-3H-l , 4-benzodiazepin-2 , 5-dione 0
10. l-Phenyl-4-ethyl-8-chloro-l ,2,4» 5-tetrahydro-3H-1 ,'4-benzodiazepin-2 , 5-dione.
11. Compounds as claimed in claim 1 herein specifically described with the exception of those claimed in claims 9 and 10.
12. A process for the preparation, of compounds of the general formula I» as defined in claim 1 which comprises cyclislng a. reactive .derivative of a carboxylic acid of formula (in which R^, 2» ^> R^, R^' and Rg are as defind in claim 1).
13. A. process as claimed in claim 12 in which the reactive derivative is an acid halide.
14. A process as claimed in claim 12 in which the halide is first prepared "by reacting a compound of the formula II with a halogenating agent.
15. A process as claimed in claim 14 in which the said halogenating agent comprises thionyl chloride, phosphorus pentachloride or phosphorus trichloride.
16. A process as claimed in claim 14 or claim 15 in which the reaction with the halogenating agent is effected in a solvent. '
17. A process as claimed in claim 15 in. which the said solvent comprises "benzene, toluene, xylene or a mixture of at least one of the aforementioned solvents with
18. A process- as claimed in claim 16 or claim 17 in which the reaction with the halogenating agent is. effected at a temperature between ambient temperature and the reflux temperature of the solvent.
19. A process as claimed in any of claims 13 to 18 in which cyclisation is effected in the presence of a tertiary organic base.
20. A process as claimed in claim 19 in which the said organic base comprises pyridine.
21. A process for the preparation of compounds of formula I - as defined in claim 1 which comprises reacting a compound of formula II. (as defind in claim 12) with a oarboxylio of a carboxylic acid . aoid or halide or anhydride -thereof.
22. A process as claimed in claim 21 in which the compound of formula II is reacted with ace-tio aoid or of acetic acid, a halide or anhydride -thereof.
23. A process as claimed in claim.21. or claim.22 in which the reaction is effected at ..an . elevated temperature,
24. A process as claimed in any of claims 21 to 23 in which the reaction is effected in a solvent.
25. A process as claimed in claim 24 in which the said solvent comprises benzene.
26. A process as claimed in claim 24 or claim 25 which is effected at the reflux temperature of .the solvent used.
27. A process for the ■ preparation of compounds of the general formula I, as defined in claim 1, which comprises heating a compound of the formula (in which -^» 2> R^* R4 > and Rg are as defined in claim 1 and X represents a halogen atom), with an alkali metal alcoholate.
28. A process as claimed in claim 27 in which the said alkali metal alcoholate- is sodium or potassium alcoholate.
29. A process as claimed in claim 27 or claim 28 in which the reaction is effected in an anhydrous solvent .
30. A process as claimed in claim 29 in which the said anhydrous solvent comprises benzene, toluene or xylene.
31. A process as claimed in any of claims 27 to 30 in which the reaction is effected at an elevated temperature.
32. A process as claimed in claim 31 in which the said temperature is the reflux temperature of the solvent .
33. A process, as claimed in claim 12 substantially as herein described.
34. A process as claimed in .claim .1.2 substan ially as herein described in Example 1.
35. . A process as. claimed in .claim ...21..substantially as herein described.
36. A process as claimed i claim 21..substantially as herein described . in. Example.2. .
37. A proce.ss as claimed in..claim..27 substantially ..as herein described.
38. A process as claimed in claim 27 ..substantially as herein described in Example 3 .
39. Compounds of the general, f.ormula I, as defined in claim 1, when prepared by .a ..process, as claime.d in any of claims 12 to 38.
40. Pharmaceutical compositions comprising at least one compound of the formula I, as .defined in claim 1, in association . with a pharmaceutical carrier or excipient .
41. Compositions as claimed... in claim 40 in a form suitable for oral, rectal or parenteral administration,
42. Compositions as claimed in claim 40 or claim 41 in the form of tablets, coated tablets, capsules, suppositories, solutions, drops, suspensions or powders.
43. Compositions as claimed in any of claims- 40 to 42 in the form of dosage units.
44. . Compositions as claimed in claim 43 in which .ea.ch dosage unit contains 1-100 mg of .active ingredient.
45. . Compositions as claimed in claim 44 in which each dosage unit contains 5-50 mg of. active ingredient.
46.' Pharmaceutical compositions as claimed in claim 40 substantially as herein described.
47. Pharmaceutical compositions substantially as herein described in either' of Examples 23 and 24. ■4-&-S Eaoh and overy novol oompound-,—o^a-pe-s-i-t-i-e- , prooeee and method- herein disc os-e-d.
IL31146A 1967-11-24 1968-11-24 1,2,4,5-tetrahydro-3h-1,4-benzodiazepin-2,5-diones,their preparation and pharmaceutical compositions containing them IL31146A (en)

Applications Claiming Priority (1)

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AT1064767A AT280290B (en) 1967-11-24 1967-11-24 Process for the preparation of new 1-phenyl-4-alkyl-3H-1,4-benzodiazepine-2,5- [1H, 4H] -diones

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IL31146A0 IL31146A0 (en) 1969-01-29
IL31146A true IL31146A (en) 1972-04-27

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AT (1) AT280290B (en)
BE (1) BE724364A (en)
BR (1) BR6804236D0 (en)
CH (1) CH523265A (en)
DE (1) DE1810423B2 (en)
DK (1) DK124950B (en)
ES (2) ES360410A1 (en)
FR (2) FR1593335A (en)
GB (1) GB1173540A (en)
IE (1) IE32504B1 (en)
IL (1) IL31146A (en)
NL (1) NL6815755A (en)
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US3914216A (en) * 1962-12-18 1975-10-21 Boehringer Sohn Ingelheim 1-Phenyl-3H-1,4-benzodiazepine-2,5-(1H,4H)-diones
DE2117438A1 (en) * 1971-04-08 1972-10-19 CH. Boehringer Sohn, 6507 Ingelheim New substituted 1,3-dihydro-2H-1 ^ -benzodiazepine ^ -ones
BE793460A (en) * 1971-12-29 1973-06-28 Boehringer Sohn Ingelheim NEWS 1-ARYL-3H, 1,4-BENZODIAZEPINE-2,5- (1H
US7572788B2 (en) 1999-04-30 2009-08-11 The Regents Of The University Of Michigan Compositions and methods relating to novel compounds and targets thereof
US7276348B2 (en) 1999-04-30 2007-10-02 Regents Of The University Of Michigan Compositions and methods relating to F1F0-ATPase inhibitors and targets thereof
DE60042425D1 (en) * 1999-04-30 2009-07-30 Univ Michigan Use of benzodiazepines for the treatment of autoimmune diseases, inflammation, neoplasia, viral infections and atherosclerosis
US20060025388A1 (en) 1999-04-30 2006-02-02 Glick Gary D Compositions and methods relating to novel compounds and targets thereof
US7691582B2 (en) 2002-09-27 2010-04-06 The Regents Of The University Of Michigan Methods of secretory vimentin detection and modulation
AU2006203946B2 (en) 2005-01-03 2009-07-23 The Regents Of The University Of Michigan Compositions and methods relating to novel compounds and targets thereof
WO2007053193A2 (en) 2005-06-01 2007-05-10 The Regents Of The University Of Michigan Unsolvated benzodiazepine compositions and methods
AU2006308655B2 (en) 2005-11-01 2010-09-23 The Regents Of The University Of Michigan Novel 1,4-benzodiazepine-2,5-diones with therapeutic properties
US7759338B2 (en) 2006-04-27 2010-07-20 The Regents Of The University Of Michigan Soluble 1,4 benzodiazepine compounds and stable salts thereof
WO2007146167A1 (en) 2006-06-09 2007-12-21 The Regents Of The University Of Michigan Compositions and methods relating to novel compounds and targets thereof
WO2008112553A1 (en) 2007-03-09 2008-09-18 The Regents Of The University Of Michigan Compositions and methods relating to novel compounds and targets thereof
EP2146722A4 (en) * 2007-05-10 2011-08-03 Amr Technology Inc Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2009036175A2 (en) 2007-09-14 2009-03-19 The Regents Of The University Of Michigan F1f0-atpase inhibitors and related methods
RU2010122902A (en) 2007-11-06 2011-12-20 Дзе Риджентс оф дзе Юниверсити оф Мичиган (US) BENZODIAPENININE COMPOUNDS APPLICABLE IN TREATMENT OF SKIN CONDITIONS
JP5567573B2 (en) 2008-09-11 2014-08-06 ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン Arylguanidine F1F0-ATPase inhibitors and methods related thereto
US8604023B2 (en) 2009-04-17 2013-12-10 The Regents Of The University Of Michigan 1,4-benzodiazepinone compounds and their use in treating cancer
US8673897B2 (en) 2009-09-18 2014-03-18 The Regents Of The University Of Michigan Benzodiazepinone compounds and methods of treatment using same
EP2501695B1 (en) 2009-11-17 2018-08-29 The Regents Of The University Of Michigan 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties
CN102753179A (en) 2009-11-17 2012-10-24 密执安大学评议会 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties
CA2923835C (en) * 2013-09-11 2022-11-29 The Administrators Of The Tulane Educational Fund Novel anthranilic amides and the use thereof

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IE32504B1 (en) 1973-08-22
IE32504L (en) 1969-05-24
BR6804236D0 (en) 1973-02-08
FR1593335A (en) 1970-05-25
DE1810423C3 (en) 1973-10-11
NL6815755A (en) 1969-05-28
DE1810423A1 (en) 1969-10-09
CH523265A (en) 1972-05-31
AT280290B (en) 1970-04-10
ES360410A1 (en) 1970-11-01
DK124950B (en) 1972-12-11
ES378977A1 (en) 1973-01-16
BE724364A (en) 1969-05-22
SE356979B (en) 1973-06-12
IL31146A0 (en) 1969-01-29
GB1173540A (en) 1969-12-10
FR8310M (en) 1970-11-23
DE1810423B2 (en) 1973-03-22

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