Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-20
2001-09-25
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C540S601000, C540S553000, C540S575000, C540S544000, C540S470000, C540S467000, C514S235800, C514S227800, C514S183000, C514S211010, C514S211080, C514S211150, C514S217060, C514S218000, C514S274000, C544S058500, C544S123000, C544S295000, C544S296000, C544S311000, C544S319000, C544S310000
Reexamination Certificate
active
06294542
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to a novel pyrimidinone compounds and the pharmaceutically acceptable salts thereof This invention also relates to a process for preparing the novel pyrimidinone compounds and a pharmaceutical composition containing the pyrimidinone compounds.
2. Background Art
Pyrimidinone derivatives according to this invention and the pharmaceutically acceptable salts thereof are useful as antagonists against angiotensin II, especially, in treatment of cardiovascular diseases caused by binding angiotensin II to its receptor.
Renin-angiotensin system plays a central role in the regulation of blood pressure in human body. Angiotensin II, consisting of eight amino acids, is produced through the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the arterial blood vessels of lung. Angiotensin II interacts with specific receptors present in blood vessels, smooth muscle, kidney, and adrenal gland, to induce the blood pressure and the electrolyte concentration to increase.
Thus, several antagonistic compounds have been developed to inhibit the effect of angiotensin II by selectively blocking its receptors.
Conventionally, peptide antagonists analogous to angiotensin II have been proposed, but their clinical applications have been limited because of their short half-life, oral inertia as well as local increase of blood pressure.
Recently, lots of researches have been reported in connection with non-peptide angiotensin II antagonists (U.S. Pat. No. 4,207,324, 4,340,598, 4,576,958, 4,582,847, and 4,880,804; European Patent Laying-Open Publication Nos. 028,834, 245,637, 253,310, 291,969, 323,841 and 324,377). European Patent Laying-Open Publication Nos. 028,834 and 253,310 disclose Imidazole derivatives substituted by biphenyl (for example, Losartan) and European Patent Laying-Open Publication No. 245,637, imidazopyridine derivatives (for example, L158,809) as potent angiotensin II antagonists.
In European Patent Laying-Open Publication Nos. 407,342, 419,048 and 445,811, pyrimidinone compounds similar to the compounds of this invention in their 6 membered heterocyclic ring structure are disclosed, including nitrogen which is very different from the 5 membered imidazole derivatives. But, the pyrimidinone compounds have lower activities than the imidazole derivatives described in the above mentioned application.
In the meantime, the inventors of this invention have filed a PCT application (WO 96-08476) for a novel compounds having noticeably high activities (in vitro (rabbit aorta), 60~70% inhibition for 10
−8
to 10
−9
mole in vitro blood vessel dilation study) which is 50 times higher than or equal to imidazole derivatives known in the above mentioned application.
DISCLOSURE OF INVENTION
In search of novel pyrimidinone compounds, the inventors of this invention have developed novel pyrimidinone derivatives of thioamid and amidine, which are superior to pyrimidinone derivatives disclosed in the prior art or the said imidazole derivatives in the activities and active time periods.
An object of the invention, therefore, is to provide with novel pyrimidinone derivatives and the pharmaceutically acceptable salts thereof which inhibit the action of angiotensin II effectively with high activities.
In order to achieve the aforementioned objects, the present invention provides with pyrimidinone derivatives and the pharmaceutically acceptable salts thereof having the general formula (I):
wherein:
R
1
is C
1
~C
4
normal or side chain alkyl, cycloalkyl, C
1
~C
4
alkylalkoxy or C
1
~C
4
alkylmercapto;
R
2
is H, halogen, C
1
~C
4
alkyl, aryl or arylalkyl;
R
3
, R
4
is same or different H, C
1
~C
4
normal or side chain alkyl, cycloalkyl, aryl, arylalkyl, C
1
~C
4
alkyl or arylcarbonyl, C
1
~C
4
alkoxycarbonyl, or substituted aminocarbonyl, being optionally substituted by H, halogen, hydroxy, C
1
~C
4
alkoxy, amino, alkylamino or dialkylamino (each alkyl having C
1
~C
5
), C
1
~C
4
alkoxycarbonyl, carboxy, or substituted aminocarbonyl,
R
3
and R
4
are together with N atom forming 4 to 8 membered heterocyclic ring, which can be further substituted with one or two substituents selected from the group consisting of cycloalkyl, aryl or arylalkyl, halogen, hydroxy, and C
1
~C
4
alkoxy, amino, alkylamino or dialkylamino (each alkyl residue having C
1
~C
5
), C
1
~C
4
alkoxycarbonyl, carboxy or substituted aminocarbonyl, and C
1
~C
4
normal or side chain alkyl being optionally substituted by H; and the heterocyclic ring can further include —O—, —S—, —SO—, —SO
2
—, >N—R
5
;
R
5
is H, C
1
~C
4
alkyl, aryl, arylalkyl, substituted alkenyl, pyridyl, pyrimidyl, C
1
~C
4
alkyl or arylcarbonyl, C
1
~C
4
alkoxy carbonyl, substituted aminocarbonyl, CN or SO
2
NR
3
R
4
;
X is S or >N—R
5
; and
Z is CN, COOR
3
, SO
2
NR
3
R
4
or tetrazol-5-yl radical having below general formula,
wherein R
6
is H, t-butyl or triphenylmethyl;
m is 1 or 2; and
n is 1, 2, 3, 4, 5 and 6.
The pyrimidinone compounds according to the present invention and pharmaceutically acceptable salts thereof exhibit remarkable activities.
Preferable are such compounds wherein R
1
is ethyl, n-propyl, n-butyl, cyclopropyl, etoxy or propoxy; R
2
is H, halogen or C
1
~C
4
normal or side chain alkyl; R
3
and R
4
are same or different H, methyl, ethyl, propyl or butyl , or R
3
and R
4
are together with N atom forming 4 to 8 membered cyclic ring, which can be further substituted with one or two substituents selected from the group consisting of cycloalkyl, aryl or arylalkyl, halogen, hydroxy, C
1
~C
4
alkoxy, amino, alkylamino, or dialkylamino (each alkyl residue having C
1
~C
5
), C
1
~C
4
alkoxycarbonyl, carboxy and substituted aminocarbonyl, and C
1
~C
4
normal or side chainalkyl being optionally substituted by H; and the heterocyclic ring can further include —O—, —S—, —SO—, —SO
2
—, >N—R
5
; R
5
is H, C
1
~C
4
alkyl, aryl, arylalkyl, substitutedalkenyl, pyridyl, pyrimidyl, C
1
~C
4
alkyl or arylcarbonyl, C
1
~C
4
alkoxy carbonyl, substituted aminocarbonyl, CN or SO
2
NR
3
R
4
, more preferably H, C
1
~C
4
alkyl, C
1
~C
4
alkoxy carbonyl, substituted aminocarbonyl, CN or SO
2
NR
3
R
4
; X is S or >N—R
5
; Z is tetrazol-5-yl radical; and m is 1.
Best Mode for Carrying Out the Invention
The Pharmaceutically acceptable salts of the invention include inorganic salts obtainable by reacting corresponding pyrimidinone compounds (I) with hydroxides of alkali metal or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide, carbonate of alkali metal or alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate or magnesium carbonate, or alcoholate of alkali metal or alkaline earth metals such as sodium, potassium, calcium or magnesium, and organic salts obtainable by reacting with organic amine in H
2
O, alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc., tetrahydrofuran, or the mixture thereof.
The compound (I) can be prepared by reacting formula (I) of below-mentioned compound (II).
wherein R
1
, R
2
, R
3
, R
4
, X, Z, m, and n have the meaning defined as above.
Starting materials of the compound of formula II may be prepared by the process which has been disclosed in the PCT application Laying-Open Publication No WO 96-08476 by the present inventors. The compound of formula I, in which X is S, may be easily prepared by reacting compound (II) with P
4
S
10
, bis(tricyclohexyltartar)sulfide or Lawesson's reagent in a dissolvent selected among benzen, dichloromethan or tetrahydrofuran. On the other hand, the compound of formula I, in which X is NR
5
; may be easily prepared from the compound (II) by adding substituted amine after preparation of iminium intermediate by using a reagent such as oxalylchloride, phosphorous oxychloride or ehtyl chloroformate in a dissolvent selected among benzene, ether or tetrahydrofuran.
Representative compounds
Jang Kyung-jin
Kang Jae-seog
Kim Ji-han
Kim Sang-lin
Lee Jae-hyoung
Boryung Pharmaceutical Co. Ltd.
Fish & Richardson P.C.
Ford John M.
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