CA2113491A1 - Salts of 4-pyrimidinone derivatives, their preparation and their therapeutic application - Google Patents
Salts of 4-pyrimidinone derivatives, their preparation and their therapeutic applicationInfo
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- CA2113491A1 CA2113491A1 CA002113491A CA2113491A CA2113491A1 CA 2113491 A1 CA2113491 A1 CA 2113491A1 CA 002113491 A CA002113491 A CA 002113491A CA 2113491 A CA2113491 A CA 2113491A CA 2113491 A1 CA2113491 A1 CA 2113491A1
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- salts
- tetrazol
- butyl
- phenylethyl
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Ophthalmology & Optometry (AREA)
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- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT
SALTS OF 4-PYRIMIDINONE DERIVATIVES, THEIR PREPARATION
AND THEIR THERAPEUTIC APPLICATION
Alkanolamine salts and basic amino acid salts of derivatives which may exist in three tautomeric forms of formulae (I), (I'), and (I'')
SALTS OF 4-PYRIMIDINONE DERIVATIVES, THEIR PREPARATION
AND THEIR THERAPEUTIC APPLICATION
Alkanolamine salts and basic amino acid salts of derivatives which may exist in three tautomeric forms of formulae (I), (I'), and (I'')
Description
3~ l ~ALTS OF 4--PYRIMIDIMONE DERIVATIVE~3 . T~EIR PREPARA~rION
AND ~rlIEIR ~r~ERApEllTIc APPLICAq!ION
q!he ~ubject o~ the pre~ent invention is the pharmacologically acceptable organic i~alts, and in 5 pzlrti~:ular the alkanolami~e salts ~na basi¢ an~ino ac:id salts o~ 4-pyriDlidinone derivati ve~ which may exist in three tautomeri~ form~ ~orrespo~ding to the formulae (:C), ~I'l and (I~) R~o = h~OH = IllJ~o (I) (I') (1") s in ~hi ch 10 R1 rQpre~3ents a line r or bri~n¢he~ (C1-C7) ~lkyl group, R~ repreqents either ~n D.ryl ~C1~3) ~lkyl group optio~ally substituted on the :nurlaus, or ;~
a heteroaryl (C1-C3) ælXyl group optionally ubstitute~ ~n tha nu¢leu~, and .
5 R~ represellt~ either a COO}I group, or a l~I-tetrazol-5-yl group.
The preferrea ~lts o~ tha i~vantion, are thoi~e i~ which R1 repreisents a butyl group, 20 Rz represents either a phenylethyl group, or a 4- -methoxyphenylethyl group, or a 3-fluoro-4-21 L3~ 1 methoxyphenylethyl group, or a 3,4,5-trîmethoxyphenylet~yl group, or ~ 3-pyridinylethyl group, or ~ ~-pyriainylethyl group and R~ represents ~ tetrazol-5;-yl group~
Among these, the preferrea ~alts are the 8alt8 of 6-butyl-2-(2-phenylethyl)-5-[C2~ tetrazol-5-yl)~ f-biphanyl]-4-yl~methyl~pyri~i~i~ 4(lH)-one.
The s21ts of the invention ca~ be px~pared by methods kno~n to ~ person skilled in the ~rt. Thu~, the compounds of formul~ (I) oan be salified for example with alkanolamine bases like 2-aminoethanol, 2,2~-iminobisethanol, 2,2~,2"-nitrilotriethanol, tris(hydroxymethyl)amino~&thane or N-~ethylgluGamine or with ba~ic amino aci~ like ly~ine or ~rginine i~
~5 ra~e~c or optieally pure form.
~he al~nol~mine~ ~na basic ~ino acids are ~v ilable in com~erce.
The compound~ of For~ul~ ~I) ~na their tauto~eric form~ are des~ribed in European P~tent Applicatio~ No. 0500409 by the Applicant.
~: The ~alifioation of the compound~ of Formula SI) with alkaaolamines and with basic amino acid~
inoreaQeq, ~urpri~ingly, their ~olubility in ~ter buffered to p~ 6.8 an~ impro~e3, al~o surpri~ingly, their ab~orption following admini~tr~tion via the oral route.
The follo~ing Examples illustrate the invention. The ~icroanalyse3 and the IR and NNR
2~ ~3~1 spectr~ co~fir~ the structure of the compoun~
obtai~ed.
Exa~pl~ 1 2-~inoeth~nol ~alt of 6-butyl-2-~2-phenylethyl)-5-~2~ tetrazol-5-yl)~ iphenyl]-4-yl]~ethyl]
pyrimi~ine-4~1H)-o~e 0.191 g ~3.12 mmol) of 2-a~inosthanol i~
solution in 5 ~1 of methanol i~ addea to a ~u~pen~ion of 1.47 g (3 ~mol) of 6-butyl-2-(2 phenylethyl)-5-~t2~-(1~-tetrazol-5-yl)~ biphe~yl]-4-yl]methyl]-pyrimidi~-4(1H)-one in 10 ml of ~ethanol. ~he mixture i8 le~t s~irring ~t room te~per~ture for a few minute~, ~d i~ then filtere~ over cotton and evaporated under vaouum. The foa~ obt~ined is ~issolvsd in 25 ~1 o~
~iahloromethane, ~n~ 20 ml o~ opropyl et~er are ~d~e~ gr~uælly ~ith ~igorous ~tirring. The re20tion mix~ure iB ~llowe~ to st~n~ overniqht at room temperature. Ths pracipltate formed is filtered of~
xinsed with 10 ~1 of dii~opropyl ether ~d driea unaer ~ 20 ~racuum, at so -~, in th~3 pre~ence oP ~ho~phoru~
pentoxide. 1.6 g o~ produot ~re obtai~ed. ~elting point = 127-130C
Example 2 2,2~-iminobisetha~ol ~alt o~ 6-butyl-2-~2-phe~ylethyl~-5-~2r-(1~-tetr~ol-5-yl)[1,~ iphenyl]-4-yl]m~thyl]-pyrimidine-4t1H)-one 0.42 g (4 m~ol) of 2,2~-iminobisethanol in ~olution in 30 ml of methanol i3 added to 1.96 g ~
~ 2~ ~3~9 i ~. 4 mmol) of 6-butyl-2-~2-phenylethyl)-5-[[2~ -tetrazol-5-yl)[l,l~-biphenyl]-4-yl]~ethyl]pyrimidine-4~ one~
The mixture i8 left stirring at room tempexature for a few minutes. It ~ filterea over paper, rin3ed with 10 ml of metha~ol and evaporated u~der vacuu~. The re~idual foa~ i8 reais~olve~ while hot in 20 ml of isopropanol an~ then 20 ml of dii~opropyl ether are added gradually with vigorous stirring. The white precipitate forme~ i8 ~ilterea of~, rinqe~ with 20 ml of diisopropyl ether and it i~ dried unaer v~¢uum, at 55-C, in the prese~¢e of pho~phorus pentoxide. 2~15 g of pro~u~t are ob~ained. Nolting poi~t = 124-126C
Exam~le 3 L~ lysl~e 3alt of 6-butyl-2-(2-phenylethyl)-5- E t2 ~- -(~-tetrazol-5-yl)[l,1~-biphanyl]-~-yl]~ethyl~-j~ pyri~i~in-4~ on~
~ 0.287 g ~1.96 ~mol) of L~ lysine in ¦ ~olution in 15 ~1 of ~ethanol i~ ~ddea to 0.96~ g tl.~6 mmol) of 6-butyl-2-(2-phenylethyl)-5-tr2~-(lH-tetrazol-:: 20 5~yl~[~ biphenyl~-4-yl]methyl]pyrimiain-4l1~)-one.
The mixture i~ left stirring ~t room temperature for a few minutes. It i8 then filtered over cotton, ri~ ed -:-with 5 ml of methanol ana evaporated under va¢uum. ~he `:: :
residual ~hite powder i~ redis~olved while hot in 15 ml of ai~hlor~methana and 30 ml of dii~opropyl ethsr ~re ~ added gr~dually with vigorou~ stirring. The mixture i~
I allo~e~ to ~tand at room temperature ~or 3 ~ay~ an~ the ¦:~ precipitate forme~ i~ then filtered. ~he mother liquor~
~3(1~
are evaporated, an~ the re~i~ual white powder i8 redis~olved in 5 ml o~ dichloro~eth~e, ~nd 10 ~l of diisopropyl ether are a~ded gra~ually wit~ vigoxou~
~tirring. The precipit~te forme~ i8 ~iltered o~. Both precipitates are ¢ombine~ d dried un~er vacuum ~t 50-C in the pre~ence of pho~phorus pentoxide.
0.7 g o~ product i~ obtained. Melting point = 80-120-C
~decompo~ition) [~20 = ~ 5.1 (C = 1%, ~ethanol) Example 4 L-(+)-arqini~e salt of 6-butyl-2-(2-phenylethyl~-5-tl2~ H-tetrazol-5-yl)[~ biphen yl]methyl]pyrimidin-4(1H)-one A suspe~sion of 3.63 g ~7.4 ~mol) o~ 6-butyl-2-~2-phenylethyl)-5-tt2~ -tetrazol-5-yl)[l,1~-biphenyl~-:~ 15 4-yl3methyl]pyrimi~ (lH~-one ~nd 1.29 g l7.~ mmol) of L-(l)-arginine in 75 ml o~ methanol is st;rre~ at roo~ temperature u~til dissolution oocurs. The mixture is ¢oncentrated under vacuu~. The re~i~ual ~oam i~
ta~e~ up in 80 ml of hot dichloromathane, filtered over paper a~d rin~ed with 10 ml of hot dicbloromethane. 120 ~l o~ diisopropyl ether are added gradually with vigorous stirring. The mixture is allowed to stand at roo~ temperature for 3 days an~ the white precipitate obtained is then filtered an~ it is drie~ unaer vacuum, at 50-C, in the presence of pho~phorus pentoxide. 1.2g of product are obtained. Melting point = 120-200-C
(decompoqition) t~]20 = ~ 6.1 ~c = 1~, methanol) Example 5 ~ 2113~
D~-lysine salt o 6-butyl-2-t2-phenylethyl)-S-t[2~
tet~azol-5-yl)Cl,1r-biphenyl]-~-yl]methyl3pyrimidi~-4(1~)-one A ~uspen~ion of 0.980 g ~2 mmol) of 6-butyl-2-~2-phenylethyl~-5-ll2~ Y-tetr.zol-5-yl)ll,1~-biphenyl]-~-yl]m~thyl]pyrimidin~-4~1~) one and 0.292 g (2 ~mol) of DL-lysine in 10 ml o~ methanol i8 stirred ~ntil dis~olution occurs, while heating. Th~ mixture is filtered over paper and ri~ ed with 5 ml of hot lo methanol. 17 ml of diisopropyl ether are then added gr~du~lly with vigorous stirring~ The mixt~re is ~llowed to stand ~t room temperature overnight and the ~ white preoipitate obtained i~ then iltered off, It i~
:: rinsed qu~ae3sively with 10 ml of a lS ~thanol~ opropyl ether ll:1) ~ixtur~ and then ~ith 10 ~1 of ~ opropyl ether ana drie~ unaer vacuum, t 60-C~ in the presence o~ phosphorus pento~ide. 0.95 g o~ pro~uct i~ obtained. ~elting point = 200-204-C ~--~ decomposition) : 2 0 The Gompounds o~ the inve~tion have been the ~ubje~t of pharmacological ~tudies ~hi¢h have demon~
stratea their angiote~in II-antagonising properties.
T~ey were tested on spont~neously hypertensive rat~
treated ~it~ hydrochlorothi~zide.
~: 25 Male rats (8~R, Charles River ~rance) wsighi~g ~00 to 450 g each are used which ~re restrained in a thermostatted chamber ~t 28' C
(relative humidity = 70 to 80%). T~o cuff~ ~re placed ^` 2 ~ l3491 at the base of the tail: a piezoelectric sensor which permits recording of the caudal pulse (and of the heart rate by integration of the signal) and an inflatable 5 pneumatic cuff which allows the blood flow to be stopped when the counter-pressure is equal to the animals systolic blood pressure. The animals are previously trained for the measurement of blood pressure by this method.
The animals are pretreated orally by injecting a hydrochlorothiazide dose of 6 mg/kg in order to increase the circulating angiotensin II level; 30 minutes after the pretreatment, the products to be tested are administered orally in suspension in a 0.2% Tween 15 solution. The animals are placed in the thermostatted chamber and the blood pressure (and the heart rate~ are measured at times 1 hour, 3 hours, 7 hours, 24 hours and 48 hours after the treatment.
The percentage decrease in blood pressure is 20 used to assess the angiotensin II-antagonizing potential of the salts of the invention.
Further tests were conducted to demonstrate the advantages of the salts of the present invention as compared to the corresponding free acids or other salts.
Table 1 shows the solubility in water for 6-butyl-2-(2-phenylethyl)-5-~[2'-(lH-tetrazol-5-yl)~l,l'-biphenol]-4-yl]methyl]pyrimidin-4(lH~-one under free form, under diethanolamine and under DL-lysine salts according to present invention.
2~ ~3~1 Table 1 .
Free form Diethanolamine DL-Lysine __ salt salt Solubility in insoluble ~2 1,3 water (g/l) _ _ Table 2 shows the kinetic parametars in the rat after oral administration of a suspension of 6-butyl-2-(2-phenylethyl)-5-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]pyrimidin-4(lH)-one under free form, under diethanolamine and under DL-lysine salts according to the 10 present invention, at a dose of 10 mg/kg of free acid.
Table 2 , _ . , Pharmacokinetic Free Diethanolamine DL-Lysine ¦
Parameters form salt salt _ _ _ I , C~ (ng/ml) 61 56 110 :
exr _ C~x represents the maximal concentration : AUCeXp represents the area under the curve :
Table 3 shows the effect of a suspension o~ 6-butyl-2-(2-phenylethyl)-5-[[2'-(lH-tetrazol-5-yl)[l,l'-20 biphenol]-4-yl]methyl]pyrimidin-4(lH)-one under free form, under diethanolamine and under DL-lysine salts according to the present invention in the SHR rat pretreated with hydrochlorothiazide.
2113~
Table 3 _ _ Compounds Dose Decrease of systolic arterial ¦
_ (mg/kg pressu~ e (% vs contro] ) Free form 30 -7 NS -14 -3 NS
5 Diethanolamine 30 -18 -24 -21 -13 salt _ 100 -26 -30 -30 -16 D~-lysine salt 30 -220 -25 -27 -9 : p<O,05 doses are expressed in free acid form 10 These results show that the salification of the compounds of formula (I) with alkanolamines and with basic amino acids increases their solubility in water and their absorption during their administration via the oral route.
15 The salts of the invention can be used for the treatment of various forms of hypertsnsive pathologies and coronary, cardiac, renal or pulmonary insufficiencies as well as for the treatment of glaucoma.
The salts of the invention can also be used in 20 combination with other substances with cardiovascular activity, such as diuretics, ~-blockers, B-blockers, i calcium antagonists or inhibitors of angiotensin I-converting enzyme.
The salts of the inuention can be provided in 25 all pharmaceutical forms appropriate for the treatment by oral, parenteral, intramuscular or rectal administration:
~ ~3~ ~
e.g. as tablets, capsules, hard gelatine capsules, sterile solutions or suspensions, suppositories and the like.
For the treatment of glaucoma, the salts of the invention can be provided in the form of tablets, hard gelatine capsules, injectable solutions or topical eye formulations.
The salts of the invention can be administered 10 to patients in quantities which may range from 1 to 1000 --mg per day and per patient, in one or several doses.
AND ~rlIEIR ~r~ERApEllTIc APPLICAq!ION
q!he ~ubject o~ the pre~ent invention is the pharmacologically acceptable organic i~alts, and in 5 pzlrti~:ular the alkanolami~e salts ~na basi¢ an~ino ac:id salts o~ 4-pyriDlidinone derivati ve~ which may exist in three tautomeri~ form~ ~orrespo~ding to the formulae (:C), ~I'l and (I~) R~o = h~OH = IllJ~o (I) (I') (1") s in ~hi ch 10 R1 rQpre~3ents a line r or bri~n¢he~ (C1-C7) ~lkyl group, R~ repreqents either ~n D.ryl ~C1~3) ~lkyl group optio~ally substituted on the :nurlaus, or ;~
a heteroaryl (C1-C3) ælXyl group optionally ubstitute~ ~n tha nu¢leu~, and .
5 R~ represellt~ either a COO}I group, or a l~I-tetrazol-5-yl group.
The preferrea ~lts o~ tha i~vantion, are thoi~e i~ which R1 repreisents a butyl group, 20 Rz represents either a phenylethyl group, or a 4- -methoxyphenylethyl group, or a 3-fluoro-4-21 L3~ 1 methoxyphenylethyl group, or a 3,4,5-trîmethoxyphenylet~yl group, or ~ 3-pyridinylethyl group, or ~ ~-pyriainylethyl group and R~ represents ~ tetrazol-5;-yl group~
Among these, the preferrea ~alts are the 8alt8 of 6-butyl-2-(2-phenylethyl)-5-[C2~ tetrazol-5-yl)~ f-biphanyl]-4-yl~methyl~pyri~i~i~ 4(lH)-one.
The s21ts of the invention ca~ be px~pared by methods kno~n to ~ person skilled in the ~rt. Thu~, the compounds of formul~ (I) oan be salified for example with alkanolamine bases like 2-aminoethanol, 2,2~-iminobisethanol, 2,2~,2"-nitrilotriethanol, tris(hydroxymethyl)amino~&thane or N-~ethylgluGamine or with ba~ic amino aci~ like ly~ine or ~rginine i~
~5 ra~e~c or optieally pure form.
~he al~nol~mine~ ~na basic ~ino acids are ~v ilable in com~erce.
The compound~ of For~ul~ ~I) ~na their tauto~eric form~ are des~ribed in European P~tent Applicatio~ No. 0500409 by the Applicant.
~: The ~alifioation of the compound~ of Formula SI) with alkaaolamines and with basic amino acid~
inoreaQeq, ~urpri~ingly, their ~olubility in ~ter buffered to p~ 6.8 an~ impro~e3, al~o surpri~ingly, their ab~orption following admini~tr~tion via the oral route.
The follo~ing Examples illustrate the invention. The ~icroanalyse3 and the IR and NNR
2~ ~3~1 spectr~ co~fir~ the structure of the compoun~
obtai~ed.
Exa~pl~ 1 2-~inoeth~nol ~alt of 6-butyl-2-~2-phenylethyl)-5-~2~ tetrazol-5-yl)~ iphenyl]-4-yl]~ethyl]
pyrimi~ine-4~1H)-o~e 0.191 g ~3.12 mmol) of 2-a~inosthanol i~
solution in 5 ~1 of methanol i~ addea to a ~u~pen~ion of 1.47 g (3 ~mol) of 6-butyl-2-(2 phenylethyl)-5-~t2~-(1~-tetrazol-5-yl)~ biphe~yl]-4-yl]methyl]-pyrimidi~-4(1H)-one in 10 ml of ~ethanol. ~he mixture i8 le~t s~irring ~t room te~per~ture for a few minute~, ~d i~ then filtere~ over cotton and evaporated under vaouum. The foa~ obt~ined is ~issolvsd in 25 ~1 o~
~iahloromethane, ~n~ 20 ml o~ opropyl et~er are ~d~e~ gr~uælly ~ith ~igorous ~tirring. The re20tion mix~ure iB ~llowe~ to st~n~ overniqht at room temperature. Ths pracipltate formed is filtered of~
xinsed with 10 ~1 of dii~opropyl ether ~d driea unaer ~ 20 ~racuum, at so -~, in th~3 pre~ence oP ~ho~phoru~
pentoxide. 1.6 g o~ produot ~re obtai~ed. ~elting point = 127-130C
Example 2 2,2~-iminobisetha~ol ~alt o~ 6-butyl-2-~2-phe~ylethyl~-5-~2r-(1~-tetr~ol-5-yl)[1,~ iphenyl]-4-yl]m~thyl]-pyrimidine-4t1H)-one 0.42 g (4 m~ol) of 2,2~-iminobisethanol in ~olution in 30 ml of methanol i3 added to 1.96 g ~
~ 2~ ~3~9 i ~. 4 mmol) of 6-butyl-2-~2-phenylethyl)-5-[[2~ -tetrazol-5-yl)[l,l~-biphenyl]-4-yl]~ethyl]pyrimidine-4~ one~
The mixture i8 left stirring at room tempexature for a few minutes. It ~ filterea over paper, rin3ed with 10 ml of metha~ol and evaporated u~der vacuu~. The re~idual foa~ i8 reais~olve~ while hot in 20 ml of isopropanol an~ then 20 ml of dii~opropyl ether are added gradually with vigorous stirring. The white precipitate forme~ i8 ~ilterea of~, rinqe~ with 20 ml of diisopropyl ether and it i~ dried unaer v~¢uum, at 55-C, in the prese~¢e of pho~phorus pentoxide. 2~15 g of pro~u~t are ob~ained. Nolting poi~t = 124-126C
Exam~le 3 L~ lysl~e 3alt of 6-butyl-2-(2-phenylethyl)-5- E t2 ~- -(~-tetrazol-5-yl)[l,1~-biphanyl]-~-yl]~ethyl~-j~ pyri~i~in-4~ on~
~ 0.287 g ~1.96 ~mol) of L~ lysine in ¦ ~olution in 15 ~1 of ~ethanol i~ ~ddea to 0.96~ g tl.~6 mmol) of 6-butyl-2-(2-phenylethyl)-5-tr2~-(lH-tetrazol-:: 20 5~yl~[~ biphenyl~-4-yl]methyl]pyrimiain-4l1~)-one.
The mixture i~ left stirring ~t room temperature for a few minutes. It i8 then filtered over cotton, ri~ ed -:-with 5 ml of methanol ana evaporated under va¢uum. ~he `:: :
residual ~hite powder i~ redis~olved while hot in 15 ml of ai~hlor~methana and 30 ml of dii~opropyl ethsr ~re ~ added gr~dually with vigorou~ stirring. The mixture i~
I allo~e~ to ~tand at room temperature ~or 3 ~ay~ an~ the ¦:~ precipitate forme~ i~ then filtered. ~he mother liquor~
~3(1~
are evaporated, an~ the re~i~ual white powder i8 redis~olved in 5 ml o~ dichloro~eth~e, ~nd 10 ~l of diisopropyl ether are a~ded gra~ually wit~ vigoxou~
~tirring. The precipit~te forme~ i8 ~iltered o~. Both precipitates are ¢ombine~ d dried un~er vacuum ~t 50-C in the pre~ence of pho~phorus pentoxide.
0.7 g o~ product i~ obtained. Melting point = 80-120-C
~decompo~ition) [~20 = ~ 5.1 (C = 1%, ~ethanol) Example 4 L-(+)-arqini~e salt of 6-butyl-2-(2-phenylethyl~-5-tl2~ H-tetrazol-5-yl)[~ biphen yl]methyl]pyrimidin-4(1H)-one A suspe~sion of 3.63 g ~7.4 ~mol) o~ 6-butyl-2-~2-phenylethyl)-5-tt2~ -tetrazol-5-yl)[l,1~-biphenyl~-:~ 15 4-yl3methyl]pyrimi~ (lH~-one ~nd 1.29 g l7.~ mmol) of L-(l)-arginine in 75 ml o~ methanol is st;rre~ at roo~ temperature u~til dissolution oocurs. The mixture is ¢oncentrated under vacuu~. The re~i~ual ~oam i~
ta~e~ up in 80 ml of hot dichloromathane, filtered over paper a~d rin~ed with 10 ml of hot dicbloromethane. 120 ~l o~ diisopropyl ether are added gradually with vigorous stirring. The mixture is allowed to stand at roo~ temperature for 3 days an~ the white precipitate obtained is then filtered an~ it is drie~ unaer vacuum, at 50-C, in the presence of pho~phorus pentoxide. 1.2g of product are obtained. Melting point = 120-200-C
(decompoqition) t~]20 = ~ 6.1 ~c = 1~, methanol) Example 5 ~ 2113~
D~-lysine salt o 6-butyl-2-t2-phenylethyl)-S-t[2~
tet~azol-5-yl)Cl,1r-biphenyl]-~-yl]methyl3pyrimidi~-4(1~)-one A ~uspen~ion of 0.980 g ~2 mmol) of 6-butyl-2-~2-phenylethyl~-5-ll2~ Y-tetr.zol-5-yl)ll,1~-biphenyl]-~-yl]m~thyl]pyrimidin~-4~1~) one and 0.292 g (2 ~mol) of DL-lysine in 10 ml o~ methanol i8 stirred ~ntil dis~olution occurs, while heating. Th~ mixture is filtered over paper and ri~ ed with 5 ml of hot lo methanol. 17 ml of diisopropyl ether are then added gr~du~lly with vigorous stirring~ The mixt~re is ~llowed to stand ~t room temperature overnight and the ~ white preoipitate obtained i~ then iltered off, It i~
:: rinsed qu~ae3sively with 10 ml of a lS ~thanol~ opropyl ether ll:1) ~ixtur~ and then ~ith 10 ~1 of ~ opropyl ether ana drie~ unaer vacuum, t 60-C~ in the presence o~ phosphorus pento~ide. 0.95 g o~ pro~uct i~ obtained. ~elting point = 200-204-C ~--~ decomposition) : 2 0 The Gompounds o~ the inve~tion have been the ~ubje~t of pharmacological ~tudies ~hi¢h have demon~
stratea their angiote~in II-antagonising properties.
T~ey were tested on spont~neously hypertensive rat~
treated ~it~ hydrochlorothi~zide.
~: 25 Male rats (8~R, Charles River ~rance) wsighi~g ~00 to 450 g each are used which ~re restrained in a thermostatted chamber ~t 28' C
(relative humidity = 70 to 80%). T~o cuff~ ~re placed ^` 2 ~ l3491 at the base of the tail: a piezoelectric sensor which permits recording of the caudal pulse (and of the heart rate by integration of the signal) and an inflatable 5 pneumatic cuff which allows the blood flow to be stopped when the counter-pressure is equal to the animals systolic blood pressure. The animals are previously trained for the measurement of blood pressure by this method.
The animals are pretreated orally by injecting a hydrochlorothiazide dose of 6 mg/kg in order to increase the circulating angiotensin II level; 30 minutes after the pretreatment, the products to be tested are administered orally in suspension in a 0.2% Tween 15 solution. The animals are placed in the thermostatted chamber and the blood pressure (and the heart rate~ are measured at times 1 hour, 3 hours, 7 hours, 24 hours and 48 hours after the treatment.
The percentage decrease in blood pressure is 20 used to assess the angiotensin II-antagonizing potential of the salts of the invention.
Further tests were conducted to demonstrate the advantages of the salts of the present invention as compared to the corresponding free acids or other salts.
Table 1 shows the solubility in water for 6-butyl-2-(2-phenylethyl)-5-~[2'-(lH-tetrazol-5-yl)~l,l'-biphenol]-4-yl]methyl]pyrimidin-4(lH~-one under free form, under diethanolamine and under DL-lysine salts according to present invention.
2~ ~3~1 Table 1 .
Free form Diethanolamine DL-Lysine __ salt salt Solubility in insoluble ~2 1,3 water (g/l) _ _ Table 2 shows the kinetic parametars in the rat after oral administration of a suspension of 6-butyl-2-(2-phenylethyl)-5-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]pyrimidin-4(lH)-one under free form, under diethanolamine and under DL-lysine salts according to the 10 present invention, at a dose of 10 mg/kg of free acid.
Table 2 , _ . , Pharmacokinetic Free Diethanolamine DL-Lysine ¦
Parameters form salt salt _ _ _ I , C~ (ng/ml) 61 56 110 :
exr _ C~x represents the maximal concentration : AUCeXp represents the area under the curve :
Table 3 shows the effect of a suspension o~ 6-butyl-2-(2-phenylethyl)-5-[[2'-(lH-tetrazol-5-yl)[l,l'-20 biphenol]-4-yl]methyl]pyrimidin-4(lH)-one under free form, under diethanolamine and under DL-lysine salts according to the present invention in the SHR rat pretreated with hydrochlorothiazide.
2113~
Table 3 _ _ Compounds Dose Decrease of systolic arterial ¦
_ (mg/kg pressu~ e (% vs contro] ) Free form 30 -7 NS -14 -3 NS
5 Diethanolamine 30 -18 -24 -21 -13 salt _ 100 -26 -30 -30 -16 D~-lysine salt 30 -220 -25 -27 -9 : p<O,05 doses are expressed in free acid form 10 These results show that the salification of the compounds of formula (I) with alkanolamines and with basic amino acids increases their solubility in water and their absorption during their administration via the oral route.
15 The salts of the invention can be used for the treatment of various forms of hypertsnsive pathologies and coronary, cardiac, renal or pulmonary insufficiencies as well as for the treatment of glaucoma.
The salts of the invention can also be used in 20 combination with other substances with cardiovascular activity, such as diuretics, ~-blockers, B-blockers, i calcium antagonists or inhibitors of angiotensin I-converting enzyme.
The salts of the inuention can be provided in 25 all pharmaceutical forms appropriate for the treatment by oral, parenteral, intramuscular or rectal administration:
~ ~3~ ~
e.g. as tablets, capsules, hard gelatine capsules, sterile solutions or suspensions, suppositories and the like.
For the treatment of glaucoma, the salts of the invention can be provided in the form of tablets, hard gelatine capsules, injectable solutions or topical eye formulations.
The salts of the invention can be administered 10 to patients in quantities which may range from 1 to 1000 --mg per day and per patient, in one or several doses.
Claims (6)
1. Alkanolamine salts and basio amino acid salts of derivatives which may exist in three tautomeric forms of formulae (I), (I') and (I") (I) (r) (I") in which R1 represents a linear or branched (C1-C7)alkyl group, R2 represents either an aryl(C1-C3)alkyl group optionally substituted on the nucleus, or a heteroaryl(C1-C31alkyl group optionally substituted on the nucleus, and R3 represents either a COOH group, or a 1H-tetrazol-5-yl group.
2. Salts according to Claim 1, characterized in that the derivative corresponds to the formula (I) in which R1 represents a butyl group, R2 represents either a phenylethyl group, or a 4-methoxyphenylethyl group, or a 3-fluoro-4-methoxyphenylethyl group, or a 3,4,5-trimethoxyphenylethyl group, or a 3-pyridinylethyl group, or a 4-pyridinylethyl group and R3 represents a 1H-tetrazol-5-yl group.
3. Salts according to claim 1 wherein the said alkanolamine or basic amino acid is 2-aminoethanol, 2,2'-iminobisethanol, L-(+)-lysine, L-(+)- arginine, or DL-lysine.
4. Alkanolamine and basic amino acid salts of 6-butyl-2-(2-phenylethyl)-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]pyrimidin-4(1H)-one.
5. DL-lysine salt of 6-butyl-2-(2-phenylethyl)-5-[[2'-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]pyrimidin-4(1H)-one.
6. A pharmaceutical composition comprising a salt as claimed in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9300340A FR2700543B1 (en) | 1993-01-15 | 1993-01-15 | Salts of 4-pyrimidinone derivatives, their preparation and their therapeutic use. |
| FR93.00340 | 1993-01-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2113491A1 true CA2113491A1 (en) | 1994-07-16 |
Family
ID=9443056
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002113491A Abandoned CA2113491A1 (en) | 1993-01-15 | 1994-01-14 | Salts of 4-pyrimidinone derivatives, their preparation and their therapeutic application |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0607077A1 (en) |
| JP (1) | JPH06271548A (en) |
| KR (1) | KR940018365A (en) |
| CN (1) | CN1096783A (en) |
| AU (1) | AU5317694A (en) |
| CA (1) | CA2113491A1 (en) |
| CZ (1) | CZ9494A3 (en) |
| FI (1) | FI940185L (en) |
| FR (1) | FR2700543B1 (en) |
| HU (1) | HUT70193A (en) |
| IL (1) | IL108342A0 (en) |
| NO (1) | NO940131L (en) |
| NZ (1) | NZ250678A (en) |
| PL (1) | PL301900A1 (en) |
| SK (1) | SK4794A3 (en) |
| ZA (1) | ZA94290B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR19990081093A (en) * | 1998-04-25 | 1999-11-15 | 조생현 | Pyrimidinone compound, pharmaceutical composition containing the same, and preparation method thereof |
| GB0914287D0 (en) * | 2009-08-14 | 2009-09-30 | Pci Biotech As | Compositions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2672892B1 (en) * | 1991-02-20 | 1994-01-14 | Synthelabo | DERIVATIVES OF 4-PYRIMIDINONES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
-
1993
- 1993-01-15 FR FR9300340A patent/FR2700543B1/en not_active Expired - Fee Related
-
1994
- 1994-01-11 EP EP94400058A patent/EP0607077A1/en not_active Withdrawn
- 1994-01-14 IL IL10834294A patent/IL108342A0/en unknown
- 1994-01-14 CN CN94100610A patent/CN1096783A/en active Pending
- 1994-01-14 NZ NZ250678A patent/NZ250678A/en unknown
- 1994-01-14 HU HU9400108A patent/HUT70193A/en unknown
- 1994-01-14 NO NO940131A patent/NO940131L/en unknown
- 1994-01-14 CA CA002113491A patent/CA2113491A1/en not_active Abandoned
- 1994-01-14 FI FI940185A patent/FI940185L/en not_active Application Discontinuation
- 1994-01-14 KR KR1019940000599A patent/KR940018365A/en not_active Withdrawn
- 1994-01-14 AU AU53176/94A patent/AU5317694A/en not_active Abandoned
- 1994-01-14 CZ CZ9494A patent/CZ9494A3/en unknown
- 1994-01-14 ZA ZA94290A patent/ZA94290B/en unknown
- 1994-01-14 PL PL94301900A patent/PL301900A1/en unknown
- 1994-01-14 JP JP6002469A patent/JPH06271548A/en active Pending
- 1994-01-14 SK SK47-94A patent/SK4794A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI940185A7 (en) | 1994-07-16 |
| AU5317694A (en) | 1994-07-21 |
| CZ9494A3 (en) | 1994-08-17 |
| NZ250678A (en) | 1994-10-26 |
| JPH06271548A (en) | 1994-09-27 |
| FI940185A0 (en) | 1994-01-14 |
| FR2700543A1 (en) | 1994-07-22 |
| HU9400108D0 (en) | 1994-05-30 |
| ZA94290B (en) | 1994-08-17 |
| EP0607077A1 (en) | 1994-07-20 |
| HUT70193A (en) | 1995-09-28 |
| PL301900A1 (en) | 1994-07-25 |
| NO940131D0 (en) | 1994-01-14 |
| CN1096783A (en) | 1994-12-28 |
| FR2700543B1 (en) | 1995-03-17 |
| SK4794A3 (en) | 1995-01-12 |
| NO940131L (en) | 1994-07-18 |
| IL108342A0 (en) | 1994-04-12 |
| FI940185L (en) | 1994-07-16 |
| KR940018365A (en) | 1994-08-16 |
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