WO1998030544A1 - 9,10-dihydroacridine derivatives possessing antimicrobial activity - Google Patents
9,10-dihydroacridine derivatives possessing antimicrobial activity Download PDFInfo
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- WO1998030544A1 WO1998030544A1 PCT/PL1998/000001 PL9800001W WO9830544A1 WO 1998030544 A1 WO1998030544 A1 WO 1998030544A1 PL 9800001 W PL9800001 W PL 9800001W WO 9830544 A1 WO9830544 A1 WO 9830544A1
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- dihydroacridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems 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 carbon atoms of the ring system
- C07D219/08—Nitrogen atoms
Definitions
- the piesent invention concerns new derivatives of 9 10-d ⁇ hydroac ⁇ d ⁇ ne 3 , 6-d ⁇ am ⁇ no- 10-methyl-9, 10-d ⁇ hydroac ⁇ d ⁇ ne, 3 , 6-b ⁇ s(d ⁇ methylam ⁇ no)- 10-methyl-9 10- dihydroac ⁇ dine, salts of 3,6-d ⁇ ammo-10-methyl-9, 10-d ⁇ hydroac ⁇ d ⁇ ne and salts of 3,6- / /s(d ⁇ methylam ⁇ no)-10-methyl-9,10-d ⁇ hydroac ⁇ d ⁇ ne
- the salts undergo autooxidation to 3,6-d ⁇ am ⁇ no-lO-methylac ⁇ d ⁇ n ⁇ m oi 3 6- /?/ ⁇ '(dimethylamino)-10-methylacridinium salts, respectively, in water or alcohol solutions
- the invention provides a process for the manufacture of 3,6-diamino- 10-methyl- 9, 10-dihydroacridine and 3,6-£/s(dimethylamino)-10-methyl-9,10-dihydroacridine of the formula (1), which comprises reacting 3,6-diamino-10-methyl-acridinium or 3,6- t /5(dimethylamino)-10-methylacridinium salt, respectively, preferably chloride, bromide, methylsulphate or nitrate, with a reducing agent, preferably sodium borohydride or sodium ditionite, at the temperature of 0 to 20°C over a period of 1 to 5 hours while stirring intensively the reaction mixture
- the reducing agent as a solid or as a solution in water is added to the solution of 3,6-diamino-10-methylacridinium or 3,6-/ /.v(dimethylamino)- 10-methylacridinium salt in water or methanol-water mixture containing 10 to 60 vol % of methanol.
- the concentration of the salt is in range of 0 05 to 0 25 mole/1 It is preferred that 1 to 3 moles of the reducing agent per 1 mole of the acridinium salt is added at the temperature 0 to 10°C
- the resulting precipitate is filtered off, dried in an argon atmosphere and under reduced pressure, and then extracted with chloroform, ethylene chloride or ethyl ether.
- the extracting solvent is evaporated under reduced pressure and the remaining solid product dried in an argon atmosphere and under reduced pressure using phosphorus pentoxide
- the invention also provides a process for the manufacture of salts of 3 ,6-diamino- 10-methyl-9, 10-dihydroacridine and 3 ,6-/> ⁇ v(dimethylamino)- 10-methyl- 9, 10-dihydroacridine which consists in a reaction of 3,6-diamino- 10-metylacridinium salt or 3.6-A/s(dimethylamino)-10-methylacridinium salt, respectively, preferably chloride, bromide, methylsulphate or nitrate, with a reducing agent, preferably sodium borohydride or sodium ditionite, in water or methanol-water mixture containing 10 to 60 vol % of methanol, at the temperature 0 to 20°C
- a reducing agent preferably sodium borohydride or sodium ditionite
- 1 to 3 moles of the reducing agent is added at 0 to 10°C to the solution containing 0 05 to 0 25 mole/1 of the a
- the dry product of the reduction reaction is dissolved in an alcohol, preferably n-propanol, methanol, or ethanol
- an alcohol preferably n-propanol, methanol, or ethanol
- a water solution of the acid is added It is preferred that the concentration of the acid is in range of 0 1 to 2 0 mole/1 and 1 to 4 moles of the acid per 1 mole of the reduction product is used
- the resulting precipitate is filtered off, washed with an appropriate alcohol and then with ethyl ether, and dried under reduced pressure using phosphorus pentoxide
- the invention is illustrated but not limited by the following Examples
- 3,6- J /3/ ⁇ '(dimethylamino)-10-methyl-9,10-dihydroacridine obtained as described above possesses a strong antimicrobial activity, which was tested and documented for the following bacteria: Staphylococcus aitreus, Escherichia coli, Proteus vulgaris,
- Pseudomonas aeruginosa Bacillus cereus and Bacillus subtilis, and fungi: Candida albicans and Trichophyton mentagrophytes.
- a solution of 4 g of sodium borohydride in 80 ml of water was added over a period of 20 minutes to a solution of 10 g of 3,6-diamino-10-methylacridinium chloride in 200 ml of methanol-water mixture (1 : 1 v/v).
- the reacting mixture was stirred at 5°C during the addition of sodium borohydride and for an additional half an hour thereafter, then the temperature was raised to 20 - 25°C and the stirring continued for 1 hour.
- the precipitated product was filtered off, washed twice with cold water and dried using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of 2 - 4 mmHg
- the dry product was extracted with chloroform (4 x 200 ml) at room temperature, then the solvent was distilled off under reduced pressure at the temperature ⁇ 20°C.
- the remaining powder was dried using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of 2 - 4 mmHg.
- the spectroscopic properties of the compound obtained were as follows UV (w ater) ⁇ verse, ax 295 nm ( ⁇ ma 10 300)
- the salts obtained as described above possess a strong antimicrobial activity which was tested and documented for the following bacteria: Slaphylococcus aureus, Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Bacillus cereus and Bacillus sublilis, fungi: Candida albicans and Trichophyton mentagrophytes, and viruses: Hepatitis B (HBV) and Herpes simplex typel (HSV-1).
- bacteria Slaphylococcus aureus, Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Bacillus cereus and Bacillus sublilis
- fungi Candida albicans and Trichophyton mentagrophytes
- viruses Hepatitis B (HBV) and Herpes simplex typel (HSV-1).
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Abstract
The invention concerns new compouds of formula (1) wherein R=H or CH3 and of formula (2) wherein R=H or CH3, HX represents an acid, n is 1 or 2. The compounds possess antimicrobial activity.
Description
9,10-dihydroacridine derivatives possessing antimicrobial activity
The piesent invention concerns new derivatives of 9 10-dιhydroacπdιne 3 , 6-dιamιno- 10-methyl-9, 10-dιhydroacπdιne, 3 , 6-bι s(dιmethylamιno)- 10-methyl-9 10- dihydroacπdine, salts of 3,6-dιammo-10-methyl-9, 10-dιhydroacπdιne and salts of 3,6- / /s(dιmethylamιno)-10-methyl-9,10-dιhydroacπdιne These compounds possess antimicrobial activity
Properties and reactivity of 10-methyl-9, 10-dιhydroacπdιne aie known fi om the monograph Heterocyclic Compounds, Vol 9 (Acπdines), ed R M Acheson Intersci Publ New York 1973, and from the Journal of Physical Chemistry 1991, 95 10240
3,6-Dιamιno-l O-methylacπdιnιum and 3 6-6/s(dιmethylamιno)-10-methyl- acndinium salts are known from the monograph Heterocyclic Compounds, Vol 9
(Acπdines), ed R M Acheson, Intersci Publ , New York 1973 The salts possess antibacterial activity
According to the present invention there are provided the chemical compounds 3,6-dιamιno-10-methyl-9, 10-dιhydroacπdιne and 3,6-6/s(dιmethylamιno)- 10-methyl- 9,10-dιhydroacπdιne of the formula (1) wherein R = H oi R = CH In polai solvents these compounds undergo autooxidation to 3,6-dιamιno-l O-methylacιιdιnιum or 3 6- Z>/s(dιmethylamιno)-10-methylacπdιnιum salts, respectively
The invention also pi ovides salts ot 3,6-dιammo-10-methyl-9 10-dιhydι oacπdιne and ι 6-/j/s(dιmethylamιno)-10-methyl-9, 10-dιhydroacπdιne of the toimula (2) wheiein R = H or R = CH„ respectively, HX represents organic or inorganic acid, wheieas n is 1 oi 2 The salts undergo autooxidation to 3,6-dιamιno-lO-methylacπdιnιιιm oi 3 6-
/?/Λ'(dimethylamino)-10-methylacridinium salts, respectively, in water or alcohol solutions
The invention provides a process for the manufacture of 3,6-diamino- 10-methyl- 9, 10-dihydroacridine and 3,6-£/s(dimethylamino)-10-methyl-9,10-dihydroacridine of the formula (1), which comprises reacting 3,6-diamino-10-methyl-acridinium or 3,6- t /5(dimethylamino)-10-methylacridinium salt, respectively, preferably chloride, bromide, methylsulphate or nitrate, with a reducing agent, preferably sodium borohydride or sodium ditionite, at the temperature of 0 to 20°C over a period of 1 to 5 hours while stirring intensively the reaction mixture
According to the invention the reducing agent as a solid or as a solution in water is added to the solution of 3,6-diamino-10-methylacridinium or 3,6-/ /.v(dimethylamino)- 10-methylacridinium salt in water or methanol-water mixture containing 10 to 60 vol % of methanol. The concentration of the salt is in range of 0 05 to 0 25 mole/1 It is preferred that 1 to 3 moles of the reducing agent per 1 mole of the acridinium salt is added at the temperature 0 to 10°C The resulting precipitate is filtered off, dried in an argon atmosphere and under reduced pressure, and then extracted with chloroform, ethylene chloride or ethyl ether. The extracting solvent is evaporated under reduced pressure and the remaining solid product dried in an argon atmosphere and under reduced pressure using phosphorus pentoxide
The invention also provides a process for the manufacture of salts of 3 ,6-diamino- 10-methyl-9, 10-dihydroacridine and 3 ,6-/>Λv(dimethylamino)- 10-methyl- 9, 10-dihydroacridine which consists in a reaction of 3,6-diamino- 10-metylacridinium salt or 3.6-A/s(dimethylamino)-10-methylacridinium salt, respectively, preferably chloride, bromide, methylsulphate or nitrate, with a reducing agent, preferably sodium borohydride or sodium ditionite, in water or methanol-water mixture containing 10 to 60 vol % of methanol, at the temperature 0 to 20°C Preferably 1 to 3 moles of the reducing agent, as a solid or as a water solution, is added at 0 to 10°C to the solution containing 0 05 to 0 25 mole/1 of the acridinium salt The product of the reduction reaction is isolated, purified by extraction with chloroform, ethylene chloride or ethyl ether, then dried in an argon atmosphere and under reduced pressure According to the invention the dry product of the reduction reaction is then allowed to react with water solution of an acid
The reaction is carried out at the temperature 10 to 20°C by adding the solid reduction product to water solution of the acid which concentration is in range of 0 05 to 0 40 mole/1 It is preferred that the molar ratio of the acid to the reduction product is in the range of 1 to 4 When the reaction is completed the water is distilled off under reduced pressure, and the remaining solid product is vacuum dried using phosphorus pentoxide
Alternatively, according to the invention the dry product of the reduction reaction is dissolved in an alcohol, preferably n-propanol, methanol, or ethanol To the resulting solution, which concentration is in range of 0 01 to 0 05 mole/1, a water solution of the acid is added It is preferred that the concentration of the acid is in range of 0 1 to 2 0 mole/1 and 1 to 4 moles of the acid per 1 mole of the reduction product is used The resulting precipitate is filtered off, washed with an appropriate alcohol and then with ethyl ether, and dried under reduced pressure using phosphorus pentoxide The invention is illustrated but not limited by the following Examples
Example 1
Preparation of 3, 6-ώamιno-10-met yl-9, 10-dιhydroacrιώne
A solution of 4 g of sodium borohydride in 80 ml of water was added over a period of 20 minutes to a solution of 10 g of 3.6-diamino-10-methylacridinium chloride in 200 ml of methanol-water mixture (1 1 v/v) The reacting mixture was stiπed at 5°C during the addition of sodium borohydride and for an additional half an houi thereafter, then the temperature was raised to 20 - 25°C and the stirring continued foi 1 hour The precipitated product was filtered off, washed twice with cold (5 - 10°C) water and dried using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of
2 - 4 minHg The dry product was extracted with chloroform (4 x 200 ml) at room temperature, then the solvent was distilled off under reduced pressure at the temperature <20°C The remaining powder was dried using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of 2 - 4 mmHg 3.6 g of 3,6-diamino- 10-methyl-9, 10-dihydroacridine of the formula ( 1 ) wherein
R = H, were obtained as light-orange needles which melted and decomposed at 127°C The solubility of the product was good - in alcohols, acetonitrile, acetone, fairly good - in chloroform, ethers, benzene and very low - in water
Spectroscopic properties of the compound obtained were as follows: 85 UV (methanol): λmax 305 nm (εmax 10 000)
Η NMR (CDC13): δ ppm 3.26 (s, 3H, -CH3), 3.56 (bs, 4H, NH2),
3.69 (s, 2H, CH2), 6.20 (s, 2H), 6.20 - 6.31 (dd, 2H), 6.84 - 6.94 (d, 2H). 3,6-Diamino-10-methyl-9, 10-dihydroacridine obtained as described above 90 undergoes autooxidation to 3,6-diamino-10-methylacridinium cation in polar solvents.
3,6-Diamino-10-methyl-9, 10-dihydroacridine obtained as described above possesses a strong antimicrobial activity which was tested and documented for the following bacteria: Staphylococcits aureus, Escherichia coli, Proteus vulgar is, Pseudomonas aeruginosa, Bacillus cereus and Bacillus subϊi/is, fungi: Candida 95 albicans and Trichophyton mentagrophytes, and viruses: Hepatitis B (HBV) and Herpes simplex typel (HSV-1).
Example 2
Preparation of 3, 6-bis(dimethylamino)-10-melhyl-9,10-dihydroacridine
100 A solution of 3 g of sodium borohydride in 60 ml of water was added over a period of 30 minutes to a solution of 8 g of 3,6-/>/s(dimethylamino)-10-methylacridinium methylsulphate in 300 ml of methanol-water mixture (1 : 3 v/v). The reacting mixture was stirred at 5°C during the addition of sodium borohydride and for an additional half an hour thereafter, then the temperature was raised to 20 - 25°C and the stirring
105 continued for 1 hour. The precipitated product was filtered off, washed three times with cold (5 - 10°C) water and dried using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of 2 - 4 mmHg. The dry product was extracted with chloroform (5 x 150 ml) at room temperature, then the solvent was distilled off under reduced pressure at the temperature <20°C. The remaining powder was dried
1 10 using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of
2 - 4 mmHg.
3,2 g of 3,6-i/'.v(dimethylamino)-10-methyl-9, 10-dihydiOacridine of the formula (1) wherein R = CH3 were obtained as orange crystals which melted and decomposed at
103°C. The solubility of the compound obtained was: good - in alcohols, acetonitrile, acetone, chloroform and fairly good - in ethers, benzene.
Spectroscopic properties of the compound obtained were as follows: UV(methanol): λmax 308 nm (εmax 11000) Η NMR (CDC13) δ ppm 2.93(s, 12H, N(CH3)2 ), 3.39(s, 3H, N-CH3 ),
3.73(s, 2H, CH2 ), 6.26 - 6.36(dd, 4H), 6.97 - 7.00(d, 2H). 3,6-/^/'.s'(dimethylamino)-10-methyl-9, 10-dihydroacridine obtained as described above undergoes autooxidation to 3,6-J7Λ'(dimethyloamino)-10-methylacridinium cation when dissolved in methanol, acetone, acetonitrile, and also as a water suspension.
3,6-J/3/Λ'(dimethylamino)-10-methyl-9,10-dihydroacridine obtained as described above possesses a strong antimicrobial activity, which was tested and documented for the following bacteria: Staphylococcus aitreus, Escherichia coli, Proteus vulgaris,
Pseudomonas aeruginosa, Bacillus cereus and Bacillus subtilis, and fungi: Candida albicans and Trichophyton mentagrophytes.
Example 3. Preparation of the tartrate of 3, 6-diamino-10-methyl-9, 10-dihydroacridine
A solution of 4 g of sodium borohydride in 80 ml of water was added over a period of 20 minutes to a solution of 10 g of 3,6-diamino-10-methylacridinium chloride in 200 ml of methanol-water mixture (1 : 1 v/v). The reacting mixture was stirred at 5°C during the addition of sodium borohydride and for an additional half an hour thereafter, then the temperature was raised to 20 - 25°C and the stirring continued for 1 hour. The precipitated product was filtered off, washed twice with cold water and dried using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of 2 - 4 mmHg The dry product was extracted with chloroform (4 x 200 ml) at room temperature, then the solvent was distilled off under reduced pressure at the temperature <20°C. The remaining powder was dried using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of 2 - 4 mmHg.
Then 2.25 g of the reduction product was added, over a period of 10 minutes, to 50 ml of water solution containing 0.40 mole/1 of tartaric acid while stirring at room temperature. The reacting mixture was stirred for the additional 5 minutes and then
watei was distilled off under vacuum at the temperature <30°C The remaining crystalline product was dried using phosphorus pentoxide at 20 - 30°C under the pressure of 0 1 mmHg
5 15 g of the tartrate of 3,6-diamino-10-methyl-9, 10-dihydroacι idιne of the formula (2) wherein R = H, HX = HOOC(CHOH)2COOH and n = 2 were obtained as light-orange crystals which melted and decomposed at 156°C The solubility of the compound was good - in water and fairly good - in methanol, ethanol, acetonitrile The spectroscopic properties of the compound obtained were as follows
UV (water) λ™, 294 nm (εmax 10 800)
1H NMR (D2O) δ ppm 3 40 (s, 3H, CH.), 3 93 (s, 2H, CH2), 4 58 (s, 4H, CHOH), 7 31-7 35 (s+d, 4H), 7 44-7 47 (d, 2H)
Example 4
Preparation of the sulphate of 3,6-dιamιno-10-methyl-9, 10-dιhydroacrιdιne
A solution of 4 g of sodium borohydride in 80 ml of watei was added ovei a period of 20 minutes to a solution of 10 g of 3,6-diamino-10-methylacridinium chloride in 200 ml of methanol-water mixture (1 1 v/v) Then the procedure of the Example 1 was followed 2 25 g of 3,6-diamino-10-methyl-9.10-dihydroacridine obtained was dissolv ed in 300 ml of methanol To this solution stirred at 10°C. 33 3 ml of water solution containing 0 3 mole/1 of sulphuric acid was added ovei a peπod of 10 minutes The reacting mixture was stirred at 10°C for additional 5 minutes, then the pi ecipitated product was filtered off, washed with methanol and vacuum diied using phosphorus pentoxide
2 70 g of the sulphate of 3,6-diaιnino-10-methyl-9, 10-dihydroacπdine of the formula (2) wherein R = H, HX = H2SO4 and n = 1 weie obtained as light-orange crystalls which melted and decomposed at 148°C The solubility of the compound was fairly good - in water and very low - in methanol, ethanol, acetonitrile
The spectroscopic properties of the compound obtained wei e as follows
UV (water) λma 294 nm (εma, 1 1 000)
Η NMR (D2O) δ ppm 3 43 (s, 3H, -CH.), 3 97 (s, 2H, CH2), 7 02-7 06 (s+d, 4H), 7 36-7 39 (d, 2H)
Example 5
Preparation of the hydrochlortde of 3, 6-dιamιno-10-methyl-9, 10-dιhydroacrιdme
3,6-diamino-10-methylacridinium chloride was reduced according to the
180 procedure described in Example 1 Then 2 25 g of the reduction product was dissolved in 400 ml of dry n-propanol. To this solution stirred at room temperature, 10 ml of water solution containing 2 0 mole/1 of hydrochloric acid was added over a period of 10 minutes The precipitated product was filtered off, washed with n-propanol and then with anhydrous ethyl ether and vacuum dried using phosphorus pentoxide
185 2 62 g of the hydrochloride of 3,6-diamino-10-methyl-9, 10-dihydroacridine of the formula (2) wherein R = H, HX = HCl and n = 2 were obtained as light-orange crystals which melted at 191-193°C The solubility of the compound was good - in water, methanol, ethanol and fairly good - in propanol
The spectroscopic properties of the compound obtained were as follows
190 UV (water) λma 294 nm (εmax 11 300) H NMR (D2O) 5 ppm 3 41 (s, 3H, CH3), 3 94 (s, 2H, CH2),
7 02-7 06 (s+d, 4H), 7 35-7 39 (d, 2H)
Example 6
195 Preparation of the hydrochloride of 3,6-lns(dιmethylamιno)-10-melhyl-9, 10-dιhydro- acridwe
A solution of 2 5 g of sodium borohydride in 50 ml of water was added ovei a period of 30 minutes to a solution of 6 g of 3,6-/ /^(dimethylamino)-10-methyl- acridinium methylsulphate in 250 ml of methanol-water mixture (1 3 v/v) Then the
200 procedure of the Example 2 was followed
Then 2 80 g of the product of the reduction reaction was added, over a period of 5 minutes, to 105 ml of a water solution containing 0 20 mole/1 of hydrochloric acid while stirring at the temperature of 10 - 15°C The reacting mixture was stirred for the additional 5 minutes at the same temperature and then water was distilled off under
205 vacuum at the temperature <20°C. The remaining crystalline product was dried using phosphorus pentoxide under the pressure of 0 1 mmHg
3 40 g of the hydrochloride of 3,6-bis(dimethylamino)-10-methyl-9, 10- dihydroacridine of the formula (2) wherein R = CH , HX = HCl and n = 2 were obtained as light-orange hygroscopic crystals which melted and decomposed at 174- 176°C The solubility of the compound was good - in water, methanol, ethanol, fairly good - in acetonitrile
The spectroscopic properties of the compound obtained were as follows UV (water) λmax 295 nm (εmj 10 700)
Η NMR (D2O) δ ppm 3 50 (s, 12H, CH,), 3 61 (s, 3H, CH3), 3 94 (s, 2H, CH2), 7 31-7 35 (s+d, 4H), 7 44-7 47 (d, 2H)
Example 7
Preparation of the citrate of 3,6-bιs(dιmethylammo)- 10-methyl-9, J 0-dιhydroacrιdme
3,6-B/.s(dimethylamino)-10-methylacridinium methylsulphate was reduced according to the procedure described in Example 2 Then 2 80 g of the reduction product was added, all at once, to 120 ml of methanol solution containing 0 20 mole/1 of citric acid while stirring at the temperature of 10 - 15°C The reacting mixture was stirred for the additional 5 minutes at the same temperature and then water was distilled off under vacuum at the temperature <20°C The remaining crystalline product was dried using phosphorus pentoxide under the pressure of 0 1 mmHg
6 57 g of the citrate of 3,6-bis(dimethylamino)-10-methyl-9, 10-dihydroacridine of the formula (2) wherein R = CH3, HX = H02CCH2C(OH)(CO2H)CH2CO2H and n = 2 were obtained as orange, very hygroscopic crystals which melted and decomposed at 78-
80°C The compound was soluble in water, methanol, ethanol, acetonitrile, and insoluble in ether, chloroform, benzene
The spectroscopic properties of the compound obtained were as follows UV (w ater) λ„,ax 295 nm (εma 10 300)
Η NMR (D2O) δ ppm 2 71-2 92 (q, 8H, CH2), 3,28 (s, 12H, CH3),
3,43 (s, 3H, CH.), 3,93 (s, 2H, CH2), 7, 10-7, 17 (s+d, 4H), 7,35-7,38 (d, 2H),
The salts obtained as described above undergo autooxidation to the corresponding 3,6-diamino-10-methylacridinium salts or 3,6-bis(dimethylamino)-10- methylacridinium salts in water or alcohol solutions.
240 The salts obtained as described above possess a strong antimicrobial activity which was tested and documented for the following bacteria: Slaphylococcus aureus, Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Bacillus cereus and Bacillus sublilis, fungi: Candida albicans and Trichophyton mentagrophytes, and viruses: Hepatitis B (HBV) and Herpes simplex typel (HSV-1).
245
Claims
Claims New 9, 10-dihydroacridine derivatives of the formula (1 ) wherein R = H or CH. New 9.10-dihydroacridine derivative according to claim 1 which is 3,6-diamino- 10-methyl-9, 10-dihydroacridine New 9, 10-dihydroacridine derivative according to claim 1 which is 3,6-Λ/ (dιmethyl- amino)- 10-methyl-9, 10-dihydroacridine New 9, 10-dihydroacridine derivatives of the formula (2) wherein R is H or CH,, HX represents an acid, n is 1 or 2 New 9.10-dihydroacπdine derivatives according to claim 4 which are salts of 3, 6-dιamino-10-methyl-9, l 0-dihydroacridine New 9,10-dihydroacridine derivatives according to claim 4 which are salts of
3,6-/)7s(dimethylamino)-10-methyl-9, l 0-dihydroacridine
AMENDED CLAIMS
[received by the International Bureau on 19 June 1998 ( 19.06.98) ; original claims 1-3 cancel led ; remaini ng claims unchanged ( 1 page) ]
4. New 9, 10-dihydroacridine derivatives of the formula (2) wherein R is H or CH3, HX represents an acid, n is 1 or 2.
5. New 9,10-dihydroacridine derivatives according to claim 4 which are salts of 3 ,6-diamino- 10-methyl-9, 10-dihydroacridine.
6. New 9,10-dihydroacridine derivatives according to claim 4 which are salts of 3 ,6->/5(dimethylamino)- 10-methyl-9, 10-dihydroacridine.
Statement under Article 19(1)
As a consequence of the International Search Report the claims 1 to 3 have been cancelled. This cancellation may have the following impact on the description: Lines 2 and 3.
Names: "3 ,6-diamino- 10-methyl-9, 10-dihydroacridine, 3 ,6-3/s(dimethylamino)- 10-methyl-9,l 0-dihydroacridine" should be removed. Line 9.
The following text should be added: "A possibility of the formation of 3, 6-diamino-10-methyl-9,l 0-dihydroacridine in an electroreduction process is mentioned in Journal of Electroanalytical Chemistry, 1992, 338, 133-134." Lines 13 to 17.
All the lines should be removed. Line 18.
The word "also" should be removed. Lines 24 to 40.
All the lines should be removed. Line 41.
The word "also" should be removed. Example 1 and Example 2.
These examples should be removed. Example 3 - should be renumbered to Example 1.
In the line 142 the following text should be added: "3,6 g of 3,6-diamino-10- methyl-9,10-dihydroacridine of the formula (1) wherein R = H, were obtained as light-orange needles which melted and decomposed at 127┬░C."
Example 4 - should be renumbered to Example 2.
In the lines 162 and 163 the text: 'Then the procedure of the Example 1 was followed" should be replaced by the text: "Then the procedure described in the first part of the Example 1 was followed to give 3,6 g of 3,6-diamino-10-methyl- 9, 10-dihydroacridine."
Example 5 - should be renumbered to Example 3.
In the line 181 after the words "described in" the following text should be added: "the first part of the".
Example 6 - should be renumbered to Example 4.
In the line 200 the text: " Then the procedure of the Example 2 was followed" should be replaced by the text: "The reacting mixture was stirred at 5┬░C during the addition of sodium borohydride and for an additional half an hour thereafter, then the temperature was raised to 20 - 25┬░C and the stirring continued for 1 hour. The precipitated product was filtered off, washed three times with cold (5 - 10┬░C) water and dried using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of 2 - 4 mmHg. The dry product was extracted with chloroform (5 x 150 ml) at room temperature, then the solvent was distilled off under reduced pressure at the temperature <20┬░C. The remaining powder was dried using phosphorus pentoxide, first in an argon atmosphere and then under the pressure of 2 - 4 mmHg. 3,2 g of 3,6-3/'^dimethylamino)-10-methyl-9,10- dihydroacridine of the formula (1) wherein R = CH3 were obtained as orange crystals which melted and decomposed at 103┬░C."
Example 7 - should be renumbered to Example 5.
In the line 220 the text: "in Example 2." should be replaced by the text: "in the first part of Example 6 to give 3, 6-/3/5(^dimethylamino)-10-methyl-9,l 0-dihydro- acridine."
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU79948/98A AU7994898A (en) | 1997-01-09 | 1998-01-05 | 9,10-dihydroacridine derivatives possessing antimicrobial activity |
| EP98900052A EP0958284A1 (en) | 1997-01-09 | 1998-01-05 | 9,10-dihydroacridine derivatives possessing antimicrobial activity |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PLP.317908 | 1997-01-09 | ||
| PL31790897A PL317908A1 (en) | 1997-01-09 | 1997-01-09 | Novel compound: 3,6-diamino 10-methyl-9,10-dihydroacridine |
| PLP.320573 | 1997-06-13 | ||
| PL32057397A PL320573A1 (en) | 1997-06-13 | 1997-06-13 | Novel compound: 3,6-bis(dimethylamino)-10-methyl-9,10-dihydroacridine |
| PLP.320904 | 1997-06-30 | ||
| PL97320904A PL188279B1 (en) | 1997-06-30 | 1997-06-30 | Novel compounds, 3,6-diamino-10-methyl-9,10-dihydroacridinic salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998030544A1 true WO1998030544A1 (en) | 1998-07-16 |
Family
ID=27354082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL1998/000001 WO1998030544A1 (en) | 1997-01-09 | 1998-01-05 | 9,10-dihydroacridine derivatives possessing antimicrobial activity |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0958284A1 (en) |
| AU (1) | AU7994898A (en) |
| WO (1) | WO1998030544A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001051479A2 (en) * | 2000-01-07 | 2001-07-19 | Warner-Lambert Company | Tricyclic compounds with antiviral activity |
-
1998
- 1998-01-05 WO PCT/PL1998/000001 patent/WO1998030544A1/en not_active Application Discontinuation
- 1998-01-05 AU AU79948/98A patent/AU7994898A/en not_active Abandoned
- 1998-01-05 EP EP98900052A patent/EP0958284A1/en not_active Withdrawn
Non-Patent Citations (3)
| Title |
|---|
| D. SHUKLA ET AL., JOURNAL OF PHYSICAL CHEMISTRY, vol. 95, 1991, pages 10240 - 6, XP002062123 * |
| M. STUDNICKOVA, J. ELECTROANAL. CHEM., vol. 338, no. 1-2, 1992, pages 133 - 44, XP002062121 * |
| O. D. DMITRIEVSKII ET AL., OPTIKA I SPEKTROSKOPIJA, vol. 24, no. 6, 1968, pages 1026 - 7, XP002062122 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001051479A2 (en) * | 2000-01-07 | 2001-07-19 | Warner-Lambert Company | Tricyclic compounds with antiviral activity |
| WO2001051479A3 (en) * | 2000-01-07 | 2002-02-14 | Warner Lambert Co | Tricyclic compounds with antiviral activity |
| US6800656B2 (en) | 2000-01-07 | 2004-10-05 | Warner Lambert Company | Tricyclic compounds and method of treating herpes virus |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0958284A1 (en) | 1999-11-24 |
| AU7994898A (en) | 1998-08-03 |
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