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GB1597831A - Process for preparing ninhydrin derivatives - Google Patents

Process for preparing ninhydrin derivatives Download PDF

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Publication number
GB1597831A
GB1597831A GB8557/77A GB855777A GB1597831A GB 1597831 A GB1597831 A GB 1597831A GB 8557/77 A GB8557/77 A GB 8557/77A GB 855777 A GB855777 A GB 855777A GB 1597831 A GB1597831 A GB 1597831A
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Prior art keywords
ninhydrin
hydroxy
calculated
found
methyl
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BOUCHARD LAB
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Priority to FR7805825A priority patent/FR2382424A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/86—Ketones containing a keto group bound to a six-membered aromatic ring containing —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms
    • C07D231/36—Oxygen atoms with hydrocarbon radicals, substituted by hetero atoms, attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

(54) PROCESS FOR PREPARING NINHYDRIN DERIVATIVES (71) We, LABORATOIRES BOUCHARD, of 6 Rue Anna Jacquin, Boulogne-sur-Seine (Hauts-de-Seine), France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-- The present invention relates to a process for preparing ninhydrin derivatives, ninhydrin derivatives prepared by this process together with new medicines containing one or more of these derivatives.
According to the invention there is provided a process for the preparation of ninhydrin derivatives having the general formula:
in which R is H or an acyl group, either R, is H, OH, or an unsubstituted or substituted alkoxyl, alkylamino, alkyl, aryl or heteroaryl group, and R2 and R3 which can be the same or different, are H or an unsubstituted or substituted alkyl, aryl, or heteroaryl group, or R1 and R2 may be joined to form an alicyclic or heterocylic ring, and R3 is as defined above, the process comprising reacting ninhydrin in a solvent with a compound which includes at least one labile H atom attached to a carbonyl group, having the following general formula:
where R" R2, and R3 are as defined above, but excluding dimedone, levulinic acid, barbituric acid, acetylacetone, ethyl acetoacetate, ethyl cyanoacetate, diethyl malonate, dibenzoylmethane, indan-1,3-dione, 4-hydroxy-coumarin, 2-hydroxy1,4-naphthaquinone, or antipyrine, in order to effect a condensation reaction, and, if R is acyl, subjecting the product to an acylation reaction.
The solvent in which the condensation reaction takes place is preferably acetic acid or an alcohol.
The present invention further includes new medicaments with useful therapeutic properties, notably anti-inflammatory, analgesic and spasmolytic properties, characterised in that these contain as the active ingredient one or more of the compounds of the general formula I prepared by the process above.
The invention will be described in more detail below by means of various nonlimiting examples of the preparation of compounds according to the present invention, using the process which is also the subject of the invention.
Example I 2-((3,4-dimethoxybenzoyl)-methyl)-2-hydroxy- 1 3-dioxoindane
A mixture of 3.56 g (0.02 mole) of ninhydrin and 3.6 g (0.02 mole) of 3',4'dimethoxyacetophenone is maintained at boiling point in acetic acid for half an hour. The mixture, which clarifies to a clear yellow solution deposits a precipitate on cooling. The precipitate obtained is dried, washed in acetic acid and recrystallised from 50 ml of acetic acid.
3.2 g of white crystalline powder m.p. 1640C is obtained.
Yield: 47%.
Percent analysis C: calculated: 67.12: found: 66.95 H: calculated: 4.74: found: 4.70 In the same way, condensation products of ninhydrin were prepared with: 2'-fluoroacetophenone m.p. 1660C 2',4'-dichloroacetophenone m.p. 1350 C 3',4'-dichloroacetophenone m.p. 154"C 2',4',6'-trimethylacetophenone m.p. 228"C 2'-methoxyacetophenone m.p. 191 0C 3',4',5'-trimethoxyacetophenone m.p. 1730C 2',3',6'-trimethoxyacetophenone m.p. 187"C 9-acetylphenanthrene m.p. 199"C 9-acetylanthracene m.p. l820C 2-acetylfluorene m.p.1980C l-indanone m.p. 178"C l-tetralone m.p. 2070C Example 2 2-((4-carboxybenzoyl)-methyl)-2-hydroxy- 1,3-dioxoindane
A mixture of 1.78 g (0.01 mole) of ninhydrin and 1.64 g (0.01 mole) of 4acetylbenzoic acid is maintained at boiling point in 10 ml of acetic acid for I hour.
This is allowed to cool and then heptane is added, and then ethyl acetate to make the phase homogeneous. An abundant precipitate then forms, which is dried and recrystallised from a mixture of benzene/thyl acetate.
1.7 g of a white, flaky powder m.p. 229 C is obtained.
Yield: 52%.
Percent analysis: C: calculated: 66.73: found: 66.90 H: calculated: 3.73: found: 3.75 In the same way, condensation products of ninhydrin were prepared with: acetophenone m.p.124"C 4'-fluoroacetophenone m.p. 2510C 2'-chloroacetophenone m.p. 121"C 4'-chloroacetophenone m.p. 106"C 4'-bromoacetophenone m.p. 110"C 2'-methylacetophenone m.p. 1270C 3'-methylacetophenone m.p. 2420C 4'-methylacetophenone m.p. 2250C 2'-hydroxyacetophenone m.p. 158"C 3'-methoxyacetophenone m.p. 122"C 4'-methoxyacetophenone m.p. 134 C acetovanillone m.p. 151"C 2-acetonaphthone m.p. 161"C Example 3 6-((2-hydroxy- 1 ,3-dioxo-2-indanyl)-acetyl)- I ,4-benzodioxane
A mixture of 1.78 g (0.01 mole) of ninhydrin and 1.78 g (0.01 mole) of (1,4benzodioxan-6-yl)methyl ketone is held at reflux temperature for half an hour in 10 ml of acetic acid. The reaction mixture is cooled, heptane and ethyl acetate are added, and it is evaporated under vacuum.
The residue is dissolved in a boiling mixture of benzene/ethyl acetate to which cyclohexane is added until the commencement of precipitation is seen.
By cooling and then drying, 1.1 g of a white micro-crystalline powder m.p.
224"C is obtained.
Yield: 33% Percent analysis: C: calculated: 67.52: found: 67.45 H: calculated: 4.18: found: 4.10 Example 4 4'-bromo-2-(2-hydroxy- 1 ,3-dioxo-2-indanyl)-propiophenone
3.56 g (0.02 mole) of ninhydrin and 4.26 g (0.02 mole) of 4'bromopropiophenone are boiled in 20 ml of acetic acid for 22 hours. After cooling and the addition of a mixture of heptane and ethyl acetate, the mixture is left for one day. A few crystals then form, which are triturated in the reaction medium until an abundant precipitate is formed.
After drying, the crude product is recrystallised from a mixture of cyclohexane and benzene. Crystallization is enhanced by the addition of a small amount df ethanol.
2.8 g of a light, cottony white solid m.p. 1410C is obtained.
Yield: 37%.
Percent analysis: C; calculated: 57.96: found: 58.10 H: calculated: 3.51: found: 3.45 In the same way, condensation products of ninhydrin were obtained with: 4'-methoxypropiophenone m.p. 138"C 4'-fluoropropiophenone m.p. 1350C 4'-chloropropiophenone m.p. 140"C Example 5 2-(benzoyl(phenyl)methyl)-2-hydroxy- 1,3-dioxoindane
3.56 g (0.02 mole) of ninhydrin and 3.92 g (0.02 mole) of desoxybenzoin are held at reflux temperature for 3 hours in 20 ml of acetic acid. After cooling, a precipitate is formed. The crude product obtained is dried, washed in acetic acid, and then recrystallised from 20 ml acetic acid.
3.7 g of white, micro-crystalline powder m.p. 171"C is obtained.
Yield: 52%.
Percent analysis: C: calculated: 77.60: found: 77.51 H: calculated: 4.53: found: 4.62 In the same way, the condensation product is prepared of ninhydrin with: desoxyanisoin m.p. 1700C Example 6 Ethyl 2-(2-hydroxy- 1 ,3-dioxo-2-indanyl)phenylacetate
The same method is used as described in Example 4, except that ethyl phenylacetate is used. This compound, which is much less reactive, requires a reaction time of 24 hours.
After recrystallization from the ternary system ethyl benzeneacetate/cyclohexane, 1.1 g of small creamy-white crystals m.p. 181"C are obtained, for 0.01 mole of each reactant.
Yield: 34%.
Percent analysis: Calculated: C: 70.44: found: 70.05 Calculated: H: 4.98: found: 5.05 Example 7 2-(2-hydroxy- I ,3-dioxo-2-indanyl)-2-phenylpropionic acid
The same method is used as described in Example 4, with a reaction time of 24 hours in this instance.
After recrystallization from a benzene/ethyl acetate mixture, 0.8 g of a white microcrystalline powder m.p. 1800C is obtained for 0.01 mole of each initial compound.
Yield: 25%.
Analysis in percent: C: calculated: 69.74: found: 69.50 H: calculated: 4.55: found: 4.65 Example 8 2-(2-hydroxy- 1 ,3-dioxo-2-indanyl)-6-methoxy- 1 -tetralone
A mixture of 1.78 g (0.01 mole) of ninhydrin and 1.76 g (0.01 mole) of 6-methoxy-l-tetralone is held at boiling point for 20 minutes in 10 ml of acetic acid.
Ethyl acetate (10 ml) is added to the reaction mixture, which has clarified to pale yellow, and then heptane is added until precipitation. The precipitation is left for some hours, and then dried.
The crude product is purified by dissolving it while hot in a mixture of benzene and ethyl acetate and adding hot cyclohexane until precipitation commences.
On cooling, a white crystalline powder of m.p. 157"C separates out.
Yield: 24 g; 71%.
Percent analysis: C: calculated: 71.49: found: 71.35 H: calculated: 4.80: found: 4.90 Example 9 4-(2-acetoxy-1 ,3-dioxo-2-indanyl)-4-butyl-3 ,5-dioxo-l 1,2-diphenylpyrazolidin
5.25 g (0.03 mole) of ninhydrin is dissolved in 120 ml ethanol, then 9.25 g (0.03 mole) of phenylbutazone in 60 ml ethanol, while warming up. The first solution is poured into the second and the mixture is left for 24 hours at room temperature. At the bottom of the container a few white granules form, which are triturated within the liquid, then precipitation is allowed to take place for several hours.
The crude product thus obtained is dried; approximately 9 g of a creamy-white powder is obtained, which is heat-sensitive and which comprises 4-(2-hydroxy-1,3 dioxo-2-indanyl)-4-butyl-3,5-dioxo- 1 ,2-diphenylpyrazolidine. This is subjected to an acetylation reaction to stabilise it. It is suspended in 50 ml of acetic anhydride to which 1 g of sodium acetate has been added. At the end of 3 hours of agitation with a magnetic stirrer at room temperature, the suspension, which has become clear, is diluted with 50 ml of ethanol and after some hours, the whole is poured into 400 ml of distilled water, from whcih the reaction product precipitates in the form of a bright yellow resinous solid, which breaks up into a white powder after 24 hours contact.
This powder is then dried and recrystallized from 150 ml of ethanol. 5.8 g of small white flakes of m.p. 187 C are obtained.
Yield: 38% total from the 2 stages.
Percent analysis: C: calculated: 70.65: found: 70.89 H: calculated: 5.14: found 4.90 N: calculated: 5.49: found: 5.55 0: calculated: 18.12: found: 18.91 Analytical results (NMR proton spectra) of some of the products obtained in Examples I to 8 and some other products according to the invention are set out in Table 1 as follows: TABLE 1 Protonic NMR Spectra of Condensation Products of Ninhydrin with Mono- and Polymethoxy Acetophenones
Condensation Products Characteristic Signals 2-((2-methoxybenzoyl)- 8.0 (s. sharp, 4Hind.) methyl)-2-hydroxy-1,3- 7.7-6.7 (m. 4Harom.) dioxoindane 5.5 (s. 1H, OH) 4.0 (s. sharp, 5H, CH2, OCH3) 2-((3-methoxybenzoyl)- 8.0 (s. sharp, 4Hind.) methyl)-2-hydroxy-1,3- 7.75-7.1 (m. 4Harom.) dioxoindane 5.65 (s. 1H, OH) 4.05 (s. 2H, CH2) 3.85 (s. 3H, OCH3) 2-((4-methoxybenzyl)- 8.0 (s. sharp, 4Hind.) methyl)-2-hydroxy-1,3- 7.9 (d. 2H, H2, H6, J(H2,3, H6,5)=9Hz dioxoindane 6.95 (d, 2H, H3, H5, J(H3,2, H5,6)=9Hz 5.65 (s. 1H, OH) 4.05 (s. 2H, CH2) 3.85 (s. 3H, OCH3) 2-((3,4-dimethoxybenzoyl)- 8.0 (s. sharp, 4Hind.) methyl)-2-hydroxy-1,3- 7.65 (dd. 1H, H6, J(H6,5)=8Hz, J(H6,2)=2Hz dioxoindane 7.35 (d. 1H, H2, J(H2,6)=2Hz 7.0 d. 1H, H5, J(5,6)=8Hz 5.6 (s. 1H, OH) 4.0 (s. 2H, CH2) 3.85 (s, 3H, OCH3) 3.8 (s. 3H, OCH3) 2-((3,5-dimethoxybenzoyl)- 8.0 (s. sharp, 4Hind.) methyl)-2-hydroxy-1,3- 7.05 (d. 2H, H2, H6, J(H2,4, H6,4)=2Hz dioxoindane 6.7 (d. 1H, H4, J(H4,2, H4,6)=2Hz 5.65 (s. 1H, OH) 4.05 (s. 2H, CH2) 3.8 (s. (6H, 20CH3) 2-((2,5-dimethoxybenzoyl)- 8.0 (s. sharp, 4Hind.) methyl)-2-hydroxy-1,3- 7.05 (s. 3Harom.) dioxoindane 5.6 (s. broad, 1H, OH) 4.05 (s. 2H, CH2) 3.95 (s. 3H, OCH3) 3.65 (s. 3H, OCH3) Condensation Products Characteristic Signals 2-((3,4,5-trimethoxybenzoyl) 8.0 (s. sharp, 4111nd.) methyl)-2-hydroxy-l,3- 7.7 (s. 2H, H2, H6) dioxoindane 5.6 (s. broad, 1H, OH) 4.0 (s. 2H, CHz) 3.85 (s. 6H, 20CH3) 3.8 (s. 3H, OCH3) 2-((2,4,6-trimethoxybenzoyl)- 8.0 (s, sharp, 411ind.) methyl)-2-hydroxy-1,3- 6.15 (d. 2H, H3, H5, J(H3,5, H5,3)=3Hz dioxoindane 3.8-3.6 (m. 11H, CH2, 30CH3) 2-((4-hydroxy-3-methoxy- 8.0 (s. sharp, 4Hind.) benzoyl)-methyl-2-hydroxy- 7.6 (dd. 1H, H6, J(H6,5)=9Hz, J(H62)=2Hz 1,3-dioxoindane 7.4 (d. 1H, H2, J(H26)=2Hz 6.9 (d. 1H, H5, J(H5,6)=9Hz 4.0 (s, 2H, CH2) 3.85 (s. 3H, OCH3) Note The abbreviations used in the above Table have the following meanings: s=singlet (sharp or broad) d=doublet from ortho or meta coupling dd=double doublet from ortho or meta coupling m=massive peak, the two figures indicate the boundaries of the peak "Perkin-Elmer" apparatus at 60 MHz 8 in parts per million with respect to TMS J in Hertz Solvent: (CD3)2CO Summary of the Pharmacological Experiments A-Termination of Acute Toxicity The experimental animals are male mice (Swiss NMRI Han EOPS), Six weeks old. The toxicity was determined by the intra-peritoneal route, at the rate of five mice per dose.
Results The maximum dose always tolerated (DMT) was for all the substances tested (Examples 1 to 6) always greater than or equal to 1,000 mg/kg of animal weight.
B-Determination of Anti-inflammatory Activity Among the number of techniques which have been for studying antiinflammatory properties, the Applicants have chosen an experimental method which results in an acute inflammation of the feet of the mice, and lends itself easily to the study of a large series of compounds: Carrageen oedema This oedema, described by Winter et al (Winter C. A. Risley E. A. and Nuss G.
W. in Proc. Soc. Exp. Biol. Med. 1962 111, 544) for rats and Levey L. (Life Sci.
1969, 8, 601) for mice, permits the initial phases of acute inflammation to be studied, resembling the pathological processes, by reason of the activating and coagulating properties of factor 7 bestowed on carraghenin. In contrast to the above mentioned authors, the Applicants have experimented in a curative fashion, in treating the mice (batches of 10 mice Swiss NMRI Han EOPS by the tested substance) by the digestive route 60 minures after the injection of 0.05 ml of a 1% aqueous solution of carraghenate into the plantar aponeutosis of a rear paw. The animals are sacrificed six hours after the beginning of the test, by rupture of the neck. The rear feet are immediately cut off at the top of the tarsocrural joint, and weighed. The anti-inflammatory activity is expressed as a percentage reduction in oedema in comparison with reference animals only having received the phlogogenary agent. The products according to the invention are tested at a dose of 250 mg/kg of animal weight by the digestive route, compared to two reference antiinflammatory compounds, acetylsalicyclic acid (AAS) and oxyphenebutazone (OPB) which were administered by the same route in doses respectively of 250 and 100 mg/kg, doses corresponding to 1/5 of their lethan dose 50, L (DL50).
The results are summarised in Table 2 as follows: TABLE 2
Anti-inflammatory Activity, Expressed in , Average of Experiments Substance According to the Invention AAS OPB 2-((3,4-dimethoxybenzoyl)-methyl) -2-hydroxy- / 22.76 24.32 20.76 1,3-dioxoindane 2-((3 ,4,5-trimethoxybenzoyl)-methyl)-2-hydroxy 1,3-dioxoindane 27.15 24.32 20.76 2-((2,4,6-trimethoxybenzoyl)-methyl)-2-hydroxy- 1,3-dioxoindane 20.90 24.32 20.76 6-((2-hydroxy-l ,3-dioxo-2-indanyl)-acetyl)- l,4-benzodioxoane 23.73 19.25 22.93 2-((4-methoxybenzoyl)(4-methoxyphenyl) methyl)-2-hydroxy- I ,3-dioxoindane 25.97 19.25 22.93 2-(2-hydroxy- I ,3-dioxo-2-indanyl)-6- methoxy- 1 -tetralone 19.42 19.25 22.93 The pharmacological study has thus clearly demonstrated the antiinflammatory activity of products according to the invention, both as a result of a single dose and as a result of multiple doses. Compared to OBP and AAS which are known medicaments, the compositions conforming to the invention are established to be at least equal if not superior to the compositions known in the prior art, being completely harmless and clearly being much less irritating to the stomach.
The medicaments according to the invention can be administered alone or in combination with other medicaments and by various forms of administration as appropriate, and notably by the oral route, by the parental route, or by the rectal route.
Practical clinical tests on more or less seriously afflicted patients have shown that daily administration of from two to six doses each containing 200 milligrams of medicament according to the invention causes spectacular improvements.

Claims (4)

WHAT WE CLAIM IS:
1. A process for the preparation of ninhydrin derivatives having the general formula:
in which R is H or an acyl group, either R, is H, OH, or an unsubstituted or substituted alkoxyl, alkylamino, alkyl, aryl or heteroaryl group, and R3 and R3 which can be the same or different, are H or an unsubstituted or substituted alkyl, aryl, or heteroaryl group, or R, and R3 may be joined to form an alicyclic or heterocyclic ring, and R is as defined above, the process comprising reacting ninhydrin in a solvent wltn a compound which includes at least one labile H atom attached to a carbonyl group, having the following general formula:
where1, R2, and R3 are as defined above, but excluding dimedone, levulinic acid, barbituric acid, acetylacetone, ethyl acetoacetate, ethyl cyanoacetate, diethyl malonate, dibenzoylmethane, indan- 1 3-dione, 4-hydroxy-coumarin, 2-hydroxy1,4-naphthaquinone, or antipyrine, in order to effect a condensation reaction, and, if R is acyl, subjecting the product to an acylation reaction.
2. A process according to claim 3, wherein the solvent is acetic acid or an alcohol.
3. A ninhydrin derivative whenever prepared by the process of claim 1.
4. A pharmaceutical preparation containing an inert diluent and at least one ninhydrin derivative according to claim 3, as an active ingredient.
GB8557/77A 1977-03-01 1977-03-01 Process for preparing ninhydrin derivatives Expired GB1597831A (en)

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GB8557/77A GB1597831A (en) 1977-03-01 1977-03-01 Process for preparing ninhydrin derivatives
FR7805825A FR2382424A1 (en) 1977-03-01 1978-03-01 NEW NINHYDRINE DERIVATIVES, THEIR METHODS OF PREPARATION AND NEW MEDICINAL PRODUCTS CONTAINING THEM

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU582354B2 (en) * 1983-12-26 1989-03-23 Laboratoires Bouchard Method of treatment using 2-(3,4- dimethoxybenzoyl) methyl 2-hydroxy 1, 3 dioxo indane
EP0398258A1 (en) * 1989-05-16 1990-11-22 Mitsubishi Kasei Corporation Indan-1,3-dione derivative and herbicidal composition containing the same as active ingredient

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816490A (en) * 1985-09-26 1989-03-28 Jouveinal S.A. Novel therapeutic use of a derivative of indane dione and the pharmaceutical compositions intended for this use

Family Cites Families (2)

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Publication number Priority date Publication date Assignee Title
DE2127982A1 (en) * 1971-06-05 1972-12-14 Boehringer Mannheim Gmbh, 6800 Mannheim Virustatic indane-1,3-dione-2,2-derivs - from indanedione and two reagents or from diethylphthalate and methylsulphones
GB1533388A (en) * 1975-02-07 1978-11-22 Creat Ninhydrin-phenol condensation products their preparation and use as therapeutic agents

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU582354B2 (en) * 1983-12-26 1989-03-23 Laboratoires Bouchard Method of treatment using 2-(3,4- dimethoxybenzoyl) methyl 2-hydroxy 1, 3 dioxo indane
EP0398258A1 (en) * 1989-05-16 1990-11-22 Mitsubishi Kasei Corporation Indan-1,3-dione derivative and herbicidal composition containing the same as active ingredient
US5076830A (en) * 1989-05-16 1991-12-31 Mitsubishi Kasei Corporation Indan-1,3-dione derivative and herbicidal composition containing the same as active ingredient
US5110342A (en) * 1989-05-16 1992-05-05 Mitsubishi Kasei Corporation Indan-1,3-dione derivative and herbicidal composition containing the same as active ingredient

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FR2382424B1 (en) 1981-02-13

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