CA2092770A1 - Carboxylic acid esters of 2-amino-7-/(1,3-dihydroxy-2-propoxy)methyl/purine, their preparation and their use - Google Patents
Carboxylic acid esters of 2-amino-7-/(1,3-dihydroxy-2-propoxy)methyl/purine, their preparation and their useInfo
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- CA2092770A1 CA2092770A1 CA002092770A CA2092770A CA2092770A1 CA 2092770 A1 CA2092770 A1 CA 2092770A1 CA 002092770 A CA002092770 A CA 002092770A CA 2092770 A CA2092770 A CA 2092770A CA 2092770 A1 CA2092770 A1 CA 2092770A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- Life Sciences & Earth Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
Carboxylic acid esters of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine, their preparation and their use Compounds of the formula 1
Carboxylic acid esters of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine, their preparation and their use Compounds of the formula 1
Description
~92~7~3 HOECHST ARTIENGESEL~SCHhF~ HOE 92/F 080 Dr.WN~St Description Carboxylic acid e~ters of 2-amino-7~1,3-dihydroxy 2-propoxy)methyl]purine, their preparation and their use It has already been found (s~e ~P 452 6803 that subv stitu~ed purin~s of the formula I 1 ~ ,J, N ~ N ¦ R5 possess antiviral acti~ity~
It has now emerged that certain carboxylic acid esters of substituted purines have exceptional antiviral activity and, in addition, exhibit particularly marked bioavail-ability following oral administration.
Accordingly, the invention relates to compounds of the formula 1 Rl, o--R2 0~
~ Nr (1) H N ~`N N
in which the radicals R1 and/or R2, independently of each other, are acyl radicals of the formula -~(=o)-R3 (2), where R3 i~ (cl-c3)-alkyl~ and one of the radicals Rl and R,2 can also be hydrogen, and thei~ phy~iologically tolerated salts.
Particularly Lmportant compounds of the formula 1 a~
previously described are those in which R3 is methyl, and one of the radical~ R1 and R2 can also ~e hydrogen.
The abovementioned compound of the formula 1 in which R3 is methyl is of very particular importance.
The compounds of the formula 1 according to the invention can possess one or mors chiral cen~rs in the acyclic ~ide chain. Th~ compounds are as a r~le pre~ent as racemates; preparation or i~olation of the pure enan-tiomexs is po~ible. ~he invention therefore relates koth to the pure enantiomers and to mixtures thereof, ~uch as, for example, the corresponding rac~mate.
Salts of the compounds according to the invention which are particularly suitable for t;herapeutic purpoæes are salts of physiologically tolerated acids, ~uch as acetic acid, lactic acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid, i~ethionic acid, hydrochloric acid, sulfuric acid or phosphoric acicl.
The present invention furt~ermore relates to a process for preparing compounds according to the invention, wherein the compound of the formula 1' H~ 0~~
r~
N~CN>
H2N l N N
is reacted with carboxylic acids of the formula 3 R4 - COOH (3) 7 ~
where R4 is (Cl-C3~-alkyl, in an organic solYent ~nd in the pre~ence of ~ dehydrating agent and with the addition of a base, to give compound~ of the formula 1, and the monoesters and diesters are subsequently separated from each other u~ing conventional methods.
The abovementioned compvund of the formula 1' can be prepared, for example/ as described in EP 452 ~60.
Dicyclohexylcarbodiimide, for example, i~ a preferred dehydrating agent for caxrying ou~ the abovemen~ioned reaction. Suitabl~ bases are, for e~ample, N,N'-dim~thyl~
aminopyridine or its derivatives.
Examples of suitable organic solvents fo carrying out the reaction are dimethylformamide, N-meth~1-2-pyrroli-done, pyridine, dichloromethane, 1,2-dichloroe~hane or tetrahydrofuran.
For carrying out the raaction, the compound of the ormula 1~ is preferably dissolved sr ~uspended in the organic solvent and, preferably at -10C to ~40~C, in particular at room t~mperature, and with stirring, mixed succe~si~ely with pre~erably at lea~t 2 equivalent~, in particular 2.2-3 equ~valents, of th~ corresponding ~arboxylic acid, where appropriate di solved in the corresponding solvent, with catalytic quantities, prefer-ably 0.2-0.4 equivalents, of N,N-dLmethylaminopyrîdine, and with preferably at least 2 equiv~lents~ in particular 3-5 equivalent~, of dicyclohexylcarb~diimid2, with the mixture sub~equently being etirred at -10C to +50C, preferably at rom room temperature to +40C, or 1-24 hours, preferably 6-10 hours. To complete the r~ac~ion, a ~urther eguivalent of the corresponding carboxylic acid, 0.2 equivalent of N,N-dimethylamino-pyridine and 2 equival~nts of dicyclohexylcarbodiimide are added, where appropriate, after this time and the mixture is stirred for a further 5-24 hours, preferably 5 10 hours. After this; the precipitated dicyclohexylur~a ~ ~ 3 ~
~ 4 -is filtered off and the product according to th~ inven-tion is isolated. The i~olation is effected by chroma-tography, for example, or by crystallization, preferably - after co~centrating the filtrate - by chromato~raphy, for e~ample on silica gel with, for ex~mple, dichloro~
methane/methanol 9/1.
The mQnoesters can be obtained ~y monitoring the re~ction by thin layer chromatography, terminating it prematurely, and thereafter purifying as described above, for example by chromatography~
The isolation of optically active compounds, which may be necessary, is effected by state-of-the-art methods.
The invention furthermore relates to the use of the compounds of the formula 1 according to the invention as antiviral agents for the treatment or prophylaxis of viral diseasesO
The compounds according to the invention are particularly active against herpes simplex virus type 1, herpes simplex virus type 2, human cytomegalovirus, murine cytomegalovirus, varicella zoster virus, Epstein-Barr virus and human herpes virus 6 ~HV-6).
Additionally, the present invention relates ~o pharma-ceuticals containing at least one of the compounds according to the invention.
The pharmaceuticals according to the in~ention may be used preferably enterally (orally) but also parenterally (intravenously), rectally or locally (topically~. They may be administered in the form of solutions, powders (tablets and capsules including microcapsules), ointments (creams or gels) or ~uppositorieB. Suitable auxiliairy substances for such formulation~ are the pharmaceu~ically cu~tomary liquid or 601id filler~ and ex~enders/
solvents, emulsifiers, lubricant~, taste corrigents, coloran~s andfor buffering ~ubstances. Dosage~ o~ 0.1-10, preferably 0.2-8~ mg/kg of body weight are e~pedient~y administered. They are expediently administered in dosage units whi~h contain at least the effective daily quanti~y of the compounds accordin~ to *he invention, e~g. 30-300, preferably 50-250, mg.
Efficacy against systemic herpes simplex 1 virus (HSV-l) infec~ion: specific pathogen-free NMRI mice, 15-18 ~ in weight, were infected in~raperitoneally with ~SV-l and subse~uently given oral therapy in the :Eorm of the compounds according to the invention. The treatment was first given 3 hours after infection and was then con tinued twice daily for 4 days. ~he success of the treat~
ment was determined on the basis of the course of the disease and the survival rate as compared with the untxeated infection control. ~he latter received phy~io-logical saline solution instead of the compounds accord-ing to the invention. The period of observation was two weeks. ~able 1 shows the resultl3 of this investigation.
Table 1 ~n~iviral efficacy against HSV-1 in the NMRI
mouse on oral administration Ex~mple Dosage Average ~3urvival Survivors/
(~m~1/kg) time (day~) group ~ize 1 9 x 10 ~ 14 days 5/5 9 x 30 > 14 day~ 5/5 9 x 100 > 14 days 5/5 2 9 x 30 5t5 9 x 100 ~/5 3 g x 30 5/5 9 x 100 5/5 7 ~3 Continuation of Table 1 Example Dosage ~verage survival SurviYoxs/
(~moltkg) time ~days~ group ~ize Formula 1, 9 x 10 10.5 i O.7 3~5 R1=~2=H 9 x 30 9.5 t 1.3 1/5 (- compound 9 x 100 5/5 of the formula 1') Control 9 x 10 7.8 t 1.1 1/5 Determination of oral bioavailabili~y:
Rhesus monkey~ were placed in indiYidual cages 24 hour6 before the start of the exp~riment. The feed was with-drawn 12 hours before the start of the experiment~ while unlimited ~uantities of drinking water were avaiIable before and during the experiment. In each case two ~nimals received the compounds ac:cording to the invention and one animal received the compound of the formula 1', in each case at 105 ~mol/kg, administered in a volume of ~0 5 ml of tap water by means of a ~tomach tube. This dose was rinsed down with a further ~0 ml of water.
One anlmal received 42 ~mol/kg of the compound of the formula 1', a~ a concentration of 10 mg/ml in phy~io-logical sodium chloride solution, injected into a vein in the upper arm.
Blood samples were removed from the femoral veins of all the anLmals at variou~ tim~ interval~ up to 24 hours after administration of the subst2nces.
The blood was kept at 4C until it had ~oagulated and was then centrifuged. ~he serum thus obtained was stored at -20C until the fiamples were analyzed. 200 ~l of serum were introduced into a reaction vessel and diluted with 100 ml of water. After addition of 30 ~l of 50~ streng~h 7 '~ ~
trichloroacetic acid, th~ mixture was homogenized in a ~Vor ex Mixer and subsequently centrifuged for 3 minutes. 50 ~1 of the ~upernatant 501ution were ex amined hy ~PLC.
Chromatographic ~eparationo column ~Nucleosil Cl~, 125 x 4.6 mm; mobile phase: phosphoric acid, 0.01 molar;
flow rate: 1.0 ml/min; detection: fluorescence, ex.:
310 nm, em.: 360 nm; retention time: 3.5 min (compound of the formula 1, where R1 is = R2 = Hr i.e. compound of the formula 1').
The calculation was effected by evaluating the area undPr the data ~AUD). The metabolic avail~bility of the com-pound of the formula 1~, ollowing oral administration of the compound of Example 1, wa~ on average 37.80% (34.47%
and 41.16~. Following administration ~f the compound of Example 2, a bioavailabilit~ of the compound of the formula 1' of on average 20.11% (23.73% and 16.50%) was achieved (the said compounds are metabolized in the body to compounds of the formula 1~).
By contrast, the bioavailability of the compound of the formula 1~, following oral administration, is on average only 15%.
Determination of oral bioa~ailahility ~mou~e):
The following values for the bioavailabilitie of the ~5 compounds of the formula 1~ were obtained in mice follow-ing oral administration of the compounds according to the invention:
~a~7~
Compound Method of Dose AUD(o >OO~ Bioavail-administration[mg/kg] C(~gxmin)/ml] ability ~YO]
Formul a 1 ' ; .v. 25 13 .39 100 p.o. 1~0 9.23 17.2 Example 1 i.v. 25 13.21 98.6 p.o. 100 27.32 51.1 ~
Example 2 p.o. 100 36.03 67.3 .
Example 3 p.o. 100 38.40 71.7 The present invention is illustrated in more detail by the following examples and by the con ent of ths patent claims.
Examples 1~ Compound of the formula 1 where R1 = R2 z acetyl:
1.2 g (5 mmol) of 2 amino-7-[(1,3-dihydroxy-2-propoxy~-methyl]purine (compound of the formllla 1 where Rl = R2 =
hydrogen; prepared as described in European Patent Application EP 452 6~0 A~ are dissolved in S0 ml of anhydrous dimethylformamide. 0.~3 ml ~11 mmol) of acetic acid, 0.2 g ~1.6 mmol) of N,N-dimethylaminopyridine ~nd 3.96 g (19 mmol) of N,~'-dicyclohexylcarbodiimide are added successi~ely and the mixture is stirxed at room temperature for 6 hour~. After this time, a further O.32 ml (5.5 mmol~ of acetic acid, 0.1 g (O.8 mmol) of N,N-dim~thylaminopyridine and 1.98 g (9.5 ~mol) of N,N~-dicyclohexylcarbodiimide ar~ added and the mixture is stirred at room temperature ~or a further 17 hours.
The precipitated N,N'-dicyclohexylurea is filtered off, the filtrate is concentxated in vacuo and the re~idue is chromatographed on silica gel with dichloromethane/-methanol 9/1 as the eluent mixture. 1.51 g (93.5% of r~
theory)of2 amino-7-[(1~3-bi~-acetoxy-2-propoxy~me hyl]-purine are obtained as ~olorle6s cry~tal~ with a melting point of 158C.
lH-NMR (270 MHz, d6-DMSO) ~ tppm~s 8.65 (~lH), 8.43 5 (8rlH)/ 6-27 (s,2EI), 5.68 (6,,2H), 4.15--3086 ~m,5H3, 1.83 ( s , 6H ) .
2. Compound of the ormula 1 where R1 = R2 = butanoyl:
1.2 g (5 mmol) of 2-amino-7-[(1,3 dihydroxy 2-propoxy)-methyl]purine (compound of the formula 1 where R1 = R2 =
hydrogen; prepared ~s described in ~uropean Patent Application EP 452 680 A) are dissolved in 50 ml of anhydrous dLmethylformamide. 1.0 ml (11 mmol) of butyric acid, 0.2 g ~1.6 mmol~ of N,N-dLmethylaminopyridine ~nd 3.96 g (19 mmol) of N,N'-dicyclohexylcarbodiLmide are added successively and the mixture i~ ~tirred at room temperature for 6 hours. After thi~ time, a further 0.5 ml (5.5 mmol~ of butyric acid, 0.1 g (0.8 mmol) of N,Ndimethylaminopyridine and 1.98 g (9.5 mmol) of N,N'-dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for a further 17 hours.
The precipitated N,N'-dicyclohe~lurea i~ filtered off, the filtrate is concen~rated in vacuo and the residue is chromatographed on siliea gel with dichloromethane/
methanol 9fl as the eluent mixture. 1.84 g (97.1 ~ of theory) of 2~amino-7-[~1,3 bis-butyryloxy-2-propoxy)-methyl]purine are obtained as colorless crystals with a melting point o~ 1~3C.
H-NMR (270 MHz, d6-DMSO) ~ tppm]: 8.64 (~ ), 8.43 (s,lH), 6.27 (s,2H), 5.67 (s,2~), 4.18-3.79 (m,5H), 2.05 (t,4H), 1.42 (m,4H), 0.83 (t~6H).
3. Compound of the formula 1 where R1 = R2 = propanoyls 1.2 g (5 mmol) of 2-amino~7 [(1,3-dihydroxy 2~propoxy)-methyl]purine (compound of the formula 1 where R1 = R2 =
hydrogen; prepared as described in European Patent Application EP 452 680 A) are dissolved in 50 ml of anhydrous dimethylfoxmamide. O.B2 ml (11 mmol) of 7 P~ ~
propionic acid, 0.2 g (1.6 mmol) of N,N dime~hylamino-pyridine and 3.96 ~ (19 mmol) of ~,N~ dicyclohexyl-carbodiimide are added successively and the mixture i~
stirred at room temperature for 6 hour~. After this t~me, a further 0.41 ml ~5.5 mmol) of propionic acid, 0.1 g (O.8 mmol) of N,N-dimethylaminopyridine and 1.98 g (9.5 mmol) of N,N'-dicyclohexylcarbodiLmide are added and the mixture is ~tirred at room temperature for a further 17 hours. The precipitated N,Nr-dicyclohexylurea is filtered off, the filtrate i5 concentrated in vacuo and the residue is chromatographed on ~ilica ~el with dichloromethane/methanol 9/1 as the eluent mixture.
1.53 5 (87.2% of theory) of 2-amino-7-~(1,3-bis-propionyloxy-2-propoxy)methyl]purin~ are obtained a~
colorless crystal with a melting point of 143C.
H-NMR (270 MHz, d6-DMSO) ~ ~ppm]- 8.64 (s,lH), B.42 (s,lH), 6.2~ (s,2~), 5.67 (s,2H), 4.13 (m,2H), 4.05-3.89 (m,3H), 2.10 (q,4H), 0-92 (t,6H3.
It has now emerged that certain carboxylic acid esters of substituted purines have exceptional antiviral activity and, in addition, exhibit particularly marked bioavail-ability following oral administration.
Accordingly, the invention relates to compounds of the formula 1 Rl, o--R2 0~
~ Nr (1) H N ~`N N
in which the radicals R1 and/or R2, independently of each other, are acyl radicals of the formula -~(=o)-R3 (2), where R3 i~ (cl-c3)-alkyl~ and one of the radicals Rl and R,2 can also be hydrogen, and thei~ phy~iologically tolerated salts.
Particularly Lmportant compounds of the formula 1 a~
previously described are those in which R3 is methyl, and one of the radical~ R1 and R2 can also ~e hydrogen.
The abovementioned compound of the formula 1 in which R3 is methyl is of very particular importance.
The compounds of the formula 1 according to the invention can possess one or mors chiral cen~rs in the acyclic ~ide chain. Th~ compounds are as a r~le pre~ent as racemates; preparation or i~olation of the pure enan-tiomexs is po~ible. ~he invention therefore relates koth to the pure enantiomers and to mixtures thereof, ~uch as, for example, the corresponding rac~mate.
Salts of the compounds according to the invention which are particularly suitable for t;herapeutic purpoæes are salts of physiologically tolerated acids, ~uch as acetic acid, lactic acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid, i~ethionic acid, hydrochloric acid, sulfuric acid or phosphoric acicl.
The present invention furt~ermore relates to a process for preparing compounds according to the invention, wherein the compound of the formula 1' H~ 0~~
r~
N~CN>
H2N l N N
is reacted with carboxylic acids of the formula 3 R4 - COOH (3) 7 ~
where R4 is (Cl-C3~-alkyl, in an organic solYent ~nd in the pre~ence of ~ dehydrating agent and with the addition of a base, to give compound~ of the formula 1, and the monoesters and diesters are subsequently separated from each other u~ing conventional methods.
The abovementioned compvund of the formula 1' can be prepared, for example/ as described in EP 452 ~60.
Dicyclohexylcarbodiimide, for example, i~ a preferred dehydrating agent for caxrying ou~ the abovemen~ioned reaction. Suitabl~ bases are, for e~ample, N,N'-dim~thyl~
aminopyridine or its derivatives.
Examples of suitable organic solvents fo carrying out the reaction are dimethylformamide, N-meth~1-2-pyrroli-done, pyridine, dichloromethane, 1,2-dichloroe~hane or tetrahydrofuran.
For carrying out the raaction, the compound of the ormula 1~ is preferably dissolved sr ~uspended in the organic solvent and, preferably at -10C to ~40~C, in particular at room t~mperature, and with stirring, mixed succe~si~ely with pre~erably at lea~t 2 equivalent~, in particular 2.2-3 equ~valents, of th~ corresponding ~arboxylic acid, where appropriate di solved in the corresponding solvent, with catalytic quantities, prefer-ably 0.2-0.4 equivalents, of N,N-dLmethylaminopyrîdine, and with preferably at least 2 equiv~lents~ in particular 3-5 equivalent~, of dicyclohexylcarb~diimid2, with the mixture sub~equently being etirred at -10C to +50C, preferably at rom room temperature to +40C, or 1-24 hours, preferably 6-10 hours. To complete the r~ac~ion, a ~urther eguivalent of the corresponding carboxylic acid, 0.2 equivalent of N,N-dimethylamino-pyridine and 2 equival~nts of dicyclohexylcarbodiimide are added, where appropriate, after this time and the mixture is stirred for a further 5-24 hours, preferably 5 10 hours. After this; the precipitated dicyclohexylur~a ~ ~ 3 ~
~ 4 -is filtered off and the product according to th~ inven-tion is isolated. The i~olation is effected by chroma-tography, for example, or by crystallization, preferably - after co~centrating the filtrate - by chromato~raphy, for e~ample on silica gel with, for ex~mple, dichloro~
methane/methanol 9/1.
The mQnoesters can be obtained ~y monitoring the re~ction by thin layer chromatography, terminating it prematurely, and thereafter purifying as described above, for example by chromatography~
The isolation of optically active compounds, which may be necessary, is effected by state-of-the-art methods.
The invention furthermore relates to the use of the compounds of the formula 1 according to the invention as antiviral agents for the treatment or prophylaxis of viral diseasesO
The compounds according to the invention are particularly active against herpes simplex virus type 1, herpes simplex virus type 2, human cytomegalovirus, murine cytomegalovirus, varicella zoster virus, Epstein-Barr virus and human herpes virus 6 ~HV-6).
Additionally, the present invention relates ~o pharma-ceuticals containing at least one of the compounds according to the invention.
The pharmaceuticals according to the in~ention may be used preferably enterally (orally) but also parenterally (intravenously), rectally or locally (topically~. They may be administered in the form of solutions, powders (tablets and capsules including microcapsules), ointments (creams or gels) or ~uppositorieB. Suitable auxiliairy substances for such formulation~ are the pharmaceu~ically cu~tomary liquid or 601id filler~ and ex~enders/
solvents, emulsifiers, lubricant~, taste corrigents, coloran~s andfor buffering ~ubstances. Dosage~ o~ 0.1-10, preferably 0.2-8~ mg/kg of body weight are e~pedient~y administered. They are expediently administered in dosage units whi~h contain at least the effective daily quanti~y of the compounds accordin~ to *he invention, e~g. 30-300, preferably 50-250, mg.
Efficacy against systemic herpes simplex 1 virus (HSV-l) infec~ion: specific pathogen-free NMRI mice, 15-18 ~ in weight, were infected in~raperitoneally with ~SV-l and subse~uently given oral therapy in the :Eorm of the compounds according to the invention. The treatment was first given 3 hours after infection and was then con tinued twice daily for 4 days. ~he success of the treat~
ment was determined on the basis of the course of the disease and the survival rate as compared with the untxeated infection control. ~he latter received phy~io-logical saline solution instead of the compounds accord-ing to the invention. The period of observation was two weeks. ~able 1 shows the resultl3 of this investigation.
Table 1 ~n~iviral efficacy against HSV-1 in the NMRI
mouse on oral administration Ex~mple Dosage Average ~3urvival Survivors/
(~m~1/kg) time (day~) group ~ize 1 9 x 10 ~ 14 days 5/5 9 x 30 > 14 day~ 5/5 9 x 100 > 14 days 5/5 2 9 x 30 5t5 9 x 100 ~/5 3 g x 30 5/5 9 x 100 5/5 7 ~3 Continuation of Table 1 Example Dosage ~verage survival SurviYoxs/
(~moltkg) time ~days~ group ~ize Formula 1, 9 x 10 10.5 i O.7 3~5 R1=~2=H 9 x 30 9.5 t 1.3 1/5 (- compound 9 x 100 5/5 of the formula 1') Control 9 x 10 7.8 t 1.1 1/5 Determination of oral bioavailabili~y:
Rhesus monkey~ were placed in indiYidual cages 24 hour6 before the start of the exp~riment. The feed was with-drawn 12 hours before the start of the experiment~ while unlimited ~uantities of drinking water were avaiIable before and during the experiment. In each case two ~nimals received the compounds ac:cording to the invention and one animal received the compound of the formula 1', in each case at 105 ~mol/kg, administered in a volume of ~0 5 ml of tap water by means of a ~tomach tube. This dose was rinsed down with a further ~0 ml of water.
One anlmal received 42 ~mol/kg of the compound of the formula 1', a~ a concentration of 10 mg/ml in phy~io-logical sodium chloride solution, injected into a vein in the upper arm.
Blood samples were removed from the femoral veins of all the anLmals at variou~ tim~ interval~ up to 24 hours after administration of the subst2nces.
The blood was kept at 4C until it had ~oagulated and was then centrifuged. ~he serum thus obtained was stored at -20C until the fiamples were analyzed. 200 ~l of serum were introduced into a reaction vessel and diluted with 100 ml of water. After addition of 30 ~l of 50~ streng~h 7 '~ ~
trichloroacetic acid, th~ mixture was homogenized in a ~Vor ex Mixer and subsequently centrifuged for 3 minutes. 50 ~1 of the ~upernatant 501ution were ex amined hy ~PLC.
Chromatographic ~eparationo column ~Nucleosil Cl~, 125 x 4.6 mm; mobile phase: phosphoric acid, 0.01 molar;
flow rate: 1.0 ml/min; detection: fluorescence, ex.:
310 nm, em.: 360 nm; retention time: 3.5 min (compound of the formula 1, where R1 is = R2 = Hr i.e. compound of the formula 1').
The calculation was effected by evaluating the area undPr the data ~AUD). The metabolic avail~bility of the com-pound of the formula 1~, ollowing oral administration of the compound of Example 1, wa~ on average 37.80% (34.47%
and 41.16~. Following administration ~f the compound of Example 2, a bioavailabilit~ of the compound of the formula 1' of on average 20.11% (23.73% and 16.50%) was achieved (the said compounds are metabolized in the body to compounds of the formula 1~).
By contrast, the bioavailability of the compound of the formula 1~, following oral administration, is on average only 15%.
Determination of oral bioa~ailahility ~mou~e):
The following values for the bioavailabilitie of the ~5 compounds of the formula 1~ were obtained in mice follow-ing oral administration of the compounds according to the invention:
~a~7~
Compound Method of Dose AUD(o >OO~ Bioavail-administration[mg/kg] C(~gxmin)/ml] ability ~YO]
Formul a 1 ' ; .v. 25 13 .39 100 p.o. 1~0 9.23 17.2 Example 1 i.v. 25 13.21 98.6 p.o. 100 27.32 51.1 ~
Example 2 p.o. 100 36.03 67.3 .
Example 3 p.o. 100 38.40 71.7 The present invention is illustrated in more detail by the following examples and by the con ent of ths patent claims.
Examples 1~ Compound of the formula 1 where R1 = R2 z acetyl:
1.2 g (5 mmol) of 2 amino-7-[(1,3-dihydroxy-2-propoxy~-methyl]purine (compound of the formllla 1 where Rl = R2 =
hydrogen; prepared as described in European Patent Application EP 452 6~0 A~ are dissolved in S0 ml of anhydrous dimethylformamide. 0.~3 ml ~11 mmol) of acetic acid, 0.2 g ~1.6 mmol) of N,N-dimethylaminopyridine ~nd 3.96 g (19 mmol) of N,~'-dicyclohexylcarbodiimide are added successi~ely and the mixture is stirxed at room temperature for 6 hour~. After this time, a further O.32 ml (5.5 mmol~ of acetic acid, 0.1 g (O.8 mmol) of N,N-dim~thylaminopyridine and 1.98 g (9.5 ~mol) of N,N~-dicyclohexylcarbodiimide ar~ added and the mixture is stirred at room temperature ~or a further 17 hours.
The precipitated N,N'-dicyclohexylurea is filtered off, the filtrate is concentxated in vacuo and the re~idue is chromatographed on silica gel with dichloromethane/-methanol 9/1 as the eluent mixture. 1.51 g (93.5% of r~
theory)of2 amino-7-[(1~3-bi~-acetoxy-2-propoxy~me hyl]-purine are obtained as ~olorle6s cry~tal~ with a melting point of 158C.
lH-NMR (270 MHz, d6-DMSO) ~ tppm~s 8.65 (~lH), 8.43 5 (8rlH)/ 6-27 (s,2EI), 5.68 (6,,2H), 4.15--3086 ~m,5H3, 1.83 ( s , 6H ) .
2. Compound of the ormula 1 where R1 = R2 = butanoyl:
1.2 g (5 mmol) of 2-amino-7-[(1,3 dihydroxy 2-propoxy)-methyl]purine (compound of the formula 1 where R1 = R2 =
hydrogen; prepared ~s described in ~uropean Patent Application EP 452 680 A) are dissolved in 50 ml of anhydrous dLmethylformamide. 1.0 ml (11 mmol) of butyric acid, 0.2 g ~1.6 mmol~ of N,N-dLmethylaminopyridine ~nd 3.96 g (19 mmol) of N,N'-dicyclohexylcarbodiLmide are added successively and the mixture i~ ~tirred at room temperature for 6 hours. After thi~ time, a further 0.5 ml (5.5 mmol~ of butyric acid, 0.1 g (0.8 mmol) of N,Ndimethylaminopyridine and 1.98 g (9.5 mmol) of N,N'-dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for a further 17 hours.
The precipitated N,N'-dicyclohe~lurea i~ filtered off, the filtrate is concen~rated in vacuo and the residue is chromatographed on siliea gel with dichloromethane/
methanol 9fl as the eluent mixture. 1.84 g (97.1 ~ of theory) of 2~amino-7-[~1,3 bis-butyryloxy-2-propoxy)-methyl]purine are obtained as colorless crystals with a melting point o~ 1~3C.
H-NMR (270 MHz, d6-DMSO) ~ tppm]: 8.64 (~ ), 8.43 (s,lH), 6.27 (s,2H), 5.67 (s,2~), 4.18-3.79 (m,5H), 2.05 (t,4H), 1.42 (m,4H), 0.83 (t~6H).
3. Compound of the formula 1 where R1 = R2 = propanoyls 1.2 g (5 mmol) of 2-amino~7 [(1,3-dihydroxy 2~propoxy)-methyl]purine (compound of the formula 1 where R1 = R2 =
hydrogen; prepared as described in European Patent Application EP 452 680 A) are dissolved in 50 ml of anhydrous dimethylfoxmamide. O.B2 ml (11 mmol) of 7 P~ ~
propionic acid, 0.2 g (1.6 mmol) of N,N dime~hylamino-pyridine and 3.96 ~ (19 mmol) of ~,N~ dicyclohexyl-carbodiimide are added successively and the mixture i~
stirred at room temperature for 6 hour~. After this t~me, a further 0.41 ml ~5.5 mmol) of propionic acid, 0.1 g (O.8 mmol) of N,N-dimethylaminopyridine and 1.98 g (9.5 mmol) of N,N'-dicyclohexylcarbodiLmide are added and the mixture is ~tirred at room temperature for a further 17 hours. The precipitated N,Nr-dicyclohexylurea is filtered off, the filtrate i5 concentrated in vacuo and the residue is chromatographed on ~ilica ~el with dichloromethane/methanol 9/1 as the eluent mixture.
1.53 5 (87.2% of theory) of 2-amino-7-~(1,3-bis-propionyloxy-2-propoxy)methyl]purin~ are obtained a~
colorless crystal with a melting point of 143C.
H-NMR (270 MHz, d6-DMSO) ~ ~ppm]- 8.64 (s,lH), B.42 (s,lH), 6.2~ (s,2~), 5.67 (s,2H), 4.13 (m,2H), 4.05-3.89 (m,3H), 2.10 (q,4H), 0-92 (t,6H3.
4. Compound of the formula 1 where R~ = hydrogen and R2 = acetyl:
Colorless crystals, m.p.: 153C, lH-NMR (200 MHz, d6-DMS0) [ppm]: 8-62 (s,lH)~ ~-40 (8,1H), 6.23 (s,2H), 5.63 (m,2H), 4.85 (t,lH3, 4.15-4.00 ~m,lH), 3.95-3.83 (m,lH), 3.72-3.60 (m,lH), 3.40 (m,2H), 1.73 (s,3H).
Colorless crystals, m.p.: 153C, lH-NMR (200 MHz, d6-DMS0) [ppm]: 8-62 (s,lH)~ ~-40 (8,1H), 6.23 (s,2H), 5.63 (m,2H), 4.85 (t,lH3, 4.15-4.00 ~m,lH), 3.95-3.83 (m,lH), 3.72-3.60 (m,lH), 3.40 (m,2H), 1.73 (s,3H).
Claims (8)
1. A compound of the formula I
(1) in which the radicals R1 and/or R2, independently of each other, are acyl radicals of the formula -C(=O)-R3 (2), where R3 is (C1-C3)-alkyl, and one of the radicals R1 and R2 can also be hydrogen, and is physiologically tolerated salts.
(1) in which the radicals R1 and/or R2, independently of each other, are acyl radicals of the formula -C(=O)-R3 (2), where R3 is (C1-C3)-alkyl, and one of the radicals R1 and R2 can also be hydrogen, and is physiologically tolerated salts.
2. A compound of the formula 1 as claimed in claim 1, wherein R3 is methyl, and one of the radicals R1 and R2 can also be hydrogen.
3. A process for preparing compounds of the formula 1 as claimed in claim 1 or 2, wherein the compound of the formula 1' (1') is reacted with carboxylic acids of the formula 3 R4 - COOH (3) where R4 is (C1-C3)-alkyl, in a solvent, such as dimethylformamide, in the presence of a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide, and with the addition of a base, such as N,N-dimethyl-aminopyridine, to give compounds of the formula 1, and the monoesters and diesters are subsequently isolated from each other using conventional methods.
4. A compound of the formula 1 as claimed in claim 1 or 2 for use as an antiviral agent.
5. A compound of the formula 1 as claimed in claim 1 or 2 for use as an anti-herpes agent.
6. A pharmaceutical containing at least one compound of the formula 1 as claimed in claim 1 or 2.
7. The use of compounds of the formula 1 as claimed in claim 1 or 2 for preparing pharmaceuticals for treating viral diseases.
8. A process for preparing pharmaceuticals as claimed in claim 6, wherein at least one compound of the formula 1 as claimed in claim 1 or 2 is converted into a suitable form for administration, where appropriate with suitable auxiliary substances and/or excipients.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4210221.9 | 1992-03-28 | ||
| DE4210221A DE4210221A1 (en) | 1992-03-28 | 1992-03-28 | Carboxylic acid esters of 2-amino-7- (1,3-dihydroxy-2-propoxymethyl) purine, their preparation and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2092770A1 true CA2092770A1 (en) | 1993-09-29 |
Family
ID=6455313
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002092770A Abandoned CA2092770A1 (en) | 1992-03-28 | 1993-03-26 | Carboxylic acid esters of 2-amino-7-/(1,3-dihydroxy-2-propoxy)methyl/purine, their preparation and their use |
Country Status (24)
| Country | Link |
|---|---|
| EP (1) | EP0563814B1 (en) |
| JP (1) | JPH0656834A (en) |
| KR (1) | KR930019677A (en) |
| CN (1) | CN1077454A (en) |
| AT (1) | ATE188473T1 (en) |
| AU (1) | AU3545093A (en) |
| BR (1) | BR9301327A (en) |
| CA (1) | CA2092770A1 (en) |
| CZ (1) | CZ52093A3 (en) |
| DE (2) | DE4210221A1 (en) |
| DK (1) | DK0563814T3 (en) |
| ES (1) | ES2141738T3 (en) |
| FI (1) | FI931335A (en) |
| GR (1) | GR3032687T3 (en) |
| HU (1) | HU9300885D0 (en) |
| IL (1) | IL105177A0 (en) |
| MA (1) | MA22839A1 (en) |
| MX (1) | MX9301722A (en) |
| NO (1) | NO931134L (en) |
| OA (1) | OA09778A (en) |
| PT (1) | PT563814E (en) |
| SK (1) | SK24393A3 (en) |
| TW (1) | TW216419B (en) |
| ZA (1) | ZA932162B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4311801A1 (en) * | 1993-04-09 | 1994-10-13 | Hoechst Ag | New carboxylic acid esters of 2-amino-7- (1,3-dihydroxy-2-propoxymethyl) purine, their preparation and their use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4008858A1 (en) * | 1990-03-20 | 1991-09-26 | Hoechst Ag | New substd. purine antiviral cpds. |
-
1992
- 1992-03-28 DE DE4210221A patent/DE4210221A1/en not_active Withdrawn
-
1993
- 1993-03-23 TW TW082102143A patent/TW216419B/zh active
- 1993-03-23 KR KR1019930004780A patent/KR930019677A/en not_active Application Discontinuation
- 1993-03-23 MA MA23133A patent/MA22839A1/en unknown
- 1993-03-25 FI FI931335A patent/FI931335A/en unknown
- 1993-03-26 BR BR9301327A patent/BR9301327A/en not_active Application Discontinuation
- 1993-03-26 AT AT93105011T patent/ATE188473T1/en not_active IP Right Cessation
- 1993-03-26 MX MX9301722A patent/MX9301722A/en unknown
- 1993-03-26 NO NO93931134A patent/NO931134L/en unknown
- 1993-03-26 HU HU9300885A patent/HU9300885D0/en unknown
- 1993-03-26 AU AU35450/93A patent/AU3545093A/en not_active Abandoned
- 1993-03-26 DE DE59309918T patent/DE59309918D1/en not_active Expired - Lifetime
- 1993-03-26 PT PT93105011T patent/PT563814E/en unknown
- 1993-03-26 CA CA002092770A patent/CA2092770A1/en not_active Abandoned
- 1993-03-26 ES ES93105011T patent/ES2141738T3/en not_active Expired - Lifetime
- 1993-03-26 SK SK24393A patent/SK24393A3/en unknown
- 1993-03-26 JP JP5067729A patent/JPH0656834A/en active Pending
- 1993-03-26 IL IL105177A patent/IL105177A0/en unknown
- 1993-03-26 EP EP93105011A patent/EP0563814B1/en not_active Expired - Lifetime
- 1993-03-26 OA OA60357A patent/OA09778A/en unknown
- 1993-03-26 ZA ZA932162A patent/ZA932162B/en unknown
- 1993-03-26 DK DK93105011T patent/DK0563814T3/en active
- 1993-03-26 CZ CZ93520A patent/CZ52093A3/en unknown
- 1993-03-27 CN CN93103321A patent/CN1077454A/en active Pending
-
2000
- 2000-02-18 GR GR20000400385T patent/GR3032687T3/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ZA932162B (en) | 1993-10-14 |
| BR9301327A (en) | 1993-10-05 |
| CN1077454A (en) | 1993-10-20 |
| EP0563814B1 (en) | 2000-01-05 |
| MX9301722A (en) | 1993-09-01 |
| ATE188473T1 (en) | 2000-01-15 |
| OA09778A (en) | 1993-11-30 |
| JPH0656834A (en) | 1994-03-01 |
| CZ52093A3 (en) | 1994-01-19 |
| HU9300885D0 (en) | 1993-06-28 |
| NO931134D0 (en) | 1993-03-26 |
| ES2141738T3 (en) | 2000-04-01 |
| IL105177A0 (en) | 1993-07-08 |
| DK0563814T3 (en) | 2000-06-13 |
| AU3545093A (en) | 1993-09-30 |
| FI931335A (en) | 1993-09-29 |
| NO931134L (en) | 1993-09-29 |
| MA22839A1 (en) | 1993-10-01 |
| DE4210221A1 (en) | 1993-09-30 |
| GR3032687T3 (en) | 2000-06-30 |
| EP0563814A3 (en) | 1994-01-19 |
| SK24393A3 (en) | 1993-10-06 |
| KR930019677A (en) | 1993-10-18 |
| EP0563814A2 (en) | 1993-10-06 |
| TW216419B (en) | 1993-11-21 |
| DE59309918D1 (en) | 2000-02-10 |
| PT563814E (en) | 2000-05-31 |
| FI931335A0 (en) | 1993-03-25 |
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