Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-10
2003-04-01
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S529000, C549S292000, C560S129000
Reexamination Certificate
active
06541511
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel methyl analog of simvastatin, which has the ability to inhibit the synthesis of cholesterol. The compound of the present invention holds promise for the treatment and prophylaxis of hypercholesterolemia and of various cardiac disorders. The invention also relates to a process for making the novel compound.
BACKGROUND OF THE INVENTION
Hypercholesterolemia is a known primary risk factor for the progression of atherosclerosis. High serum cholesterol is regarded as a major risk factor for the development of ischaemic heart disease and there is, therefore, a need for drugs which have the effect of reducing the blood cholesterol levels.
Over the past several years a number of structurally related anti-hypercholesterolemic agents acting by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase have been developed and are now commercially available. The compounds have varied from the natural fermentation products, compactin of structural formula I
and mevinolin of structural formula II
(GB 1,555,831; 2,055,100; 2,073,199) to di- and tetrahydro derivatives thereof (EP 0,052,366); to analogs with different esters in the 8-position of the polyhydronaphthalene moiety, to totally synthetic analogs, wherein the polyhydronaphthalene moiety is replaced by substituted mono-and bicylic aromatics, and biphenyls (EP 0,068,038). In all of these compounds, the homochiral &bgr;-hydroxypyranone ring of structural formula III
or its corresponding ring—opened dihydroxy acid of structural formula IV
was preserved, thereby establishing it as a key structural feature responsible for its HMG-CoA reductase inhibitory activity. Soon afterwards, intense efforts were directed to the design and development of synthetic strategies for selectively modifying the side-chain ester and the lactone moieties of mevinolin.
Analogs of mevinolin by the modification of the 2(S)-methylbutyryl side chain and hexahydronaphthalene nucleus have been extensively studied (W. F. Hoffman et. al J. Med. Chem. 1986; 29: 849 and Gerald E. Stokker, J. Org. Chem. 1994; 59: 5983). These studies led to a series of side chain ester derivatives, the new analogs with more pronounced or reduced activity e.g. simvastatin, which has an extra methyl group in the methylbutyryl side chain and is twice as potent as mevinolin.
Synthetic strategies for modifying the side chain ester and lactone moieties of mevinolin have been described by Ta-Jyh-Lee in J. Org. Chem. 1982; 47: 4750. Mevalonate analogs of structural formula V and VI by substituting hydroxy bearing carbon in the HMG-CoA and mevinolinic acid with a methyl group have been prepared.
However, mevalonate analogs with a methyl group at the 3-position of the &bgr;-hydroxypyranone ring has not been reported in the literature.
SUMMARY OF THE INVENTION
The present invention relates to a novel methyl analog of simvastatin, having HMG-CoA reductase inhibitor activity. The compound of this invention possesses a methyl group in both the orientation (R) and (S), substituted at the 3-position of the &bgr;-hydroxypyranone ring. These may be in the lactone or corresponding dihydroxy acid forms (closed or open).
In the hydrophobic bonding which accounts for the major part of drug receptor bond energy, the methyl groups in a drug molecule plays an important role. However, the biological consequences of methyl groups in the &bgr;-hydroxypyranone ring position of statins have been rarely studied.
An object of the present invention is to provide a novel compound that exhibits significant HMG-CoA reductase inhibitory activity. Accordingly, the present invention provides a compound having the Formula VII,
wherein R
1
is a &bgr;-hydroxypyranone ring, of structural formulae VIIa-d
wherein R
2
is Na, K or NH
4
; R
3
is a methyl group, and its pharmaceutically acceptable salts.
Another object of the present invention is to provide a process for the preparation of said HMG-CoA reductase inhibitor, which comprises reacting simvastatin of Formula VIIIa, which is the lactone form, or of Formula VIIIb, which is the open ring hydroxy acid form,
wherein Z is hydrogen, a metal cation, such as Na, K or NH
4
, with a methylating agent.
A solution of simvastatin is reacted with a methylating agent in the presence of a base at a temperature from about −10° C. to about −60° C. under an atmosphere of nitrogen followed by a suitable aqueous work up and crystallization from organic solvents.
The methylating agent used is an alkyl halide, such as methyl iodide. The base required is used in the form of an alkali metal salt, like lithium pyrrolidide or lithium hexamethyldisilazane (Li-HMDS). Lithium pyrrolidide is generated in situ by the reaction of n-butyl lithium with pyrrolidine in tetrahydrofuran.
The methylation of &agr;-methylene site in the pyranone ring is achieved via ester enolate formed with bases like hexamethyldisilazane (Li-HMDS) or lithium pyrrolidide. Enolization with lithium pyrrolidone during methylation afforded a mixture of (3R) and (3S) isomers of structural formulae (VIIc) and (VIIa), respectively. This low stereoselectivity using lithium pyrrolidone may be attributed to the lower bulk of pyrrolidone group allowing entry from both the faces of pyranone ring. However, due to more steric bulk of Li-HMDS it approaches the pyranone ring from less hindered side, and enolization with Li-HMDS followed by methylation led stereospecifically to the formation of (3R) methyl isomer of simvastatin of structural formula (VIIc).
The methylation reaction is preferably performed without protecting the two hydroxy groups of the open pyranone ring of simvastatin at a temperature from about −25° C. to about −55° C.
Suitable aqueous work-up involves the addition of water to the reaction mixture after the methylation is completed followed by an extraction with organic solvents. Any organic solvent may be used for the extraction and such solvents include water immisicible and partially miscible solvents such as chloroform, dichloromethane, 1,2-dichloroethane, hexanes, cyclohexane, toluene, methyl acetate, ethyl acetate, and the like. The organic phase is washed with a mineral acid to remove the basic impurities. The acids may include hydrochloric acid, sulfuric acid and phosphoric acid.
The product may be obtained by reducing the volume of the organic solvent containing the methyl analog of simvastatin by evaporation, adding a miscible polar solvent and precipitating the desired product by addition of an anti-solvent. The addition of polar solvent greatly reduces the presence of impurities, in the final product. Polar solvent may be selected from the group consisting of a lower alkanol, denatured spirit, isopropanol and the like, ketones such as acetone or esters such as methyl acetate or ethyl acetate, and mixtures thereof. The precipitation may be effected by the addition of appropriate quantities of anti-solvent and include water, alkanes, mixture of alkanes, such as hexane, cyclohexane or cyclopentane, ethers such as isopropyl ethers or aromatic hydrocarbons such as benzene or toluene. The polar solvent and the anti-solvent should be at least partially miscible and preferably completely miscible.
Methods known in the art may be used with the process of this invention to enhance any aspect of this process. The product (isomers) obtained may further be purified by any technique known to a person skilled in the art for example filtration, crystallization, column chromatography, preparative HPLC, TLC or a combination of these procedures.
The in vivo and in vitro biological activity of the methyl analog of simvastatin isomeric compounds of structural formulae VIIc and VIIa was carried out on a HMG-CoA reductase inhibitory model. The compounds were tested at three concentrations (10
−5
, 10
−7
and 10
−9
M) for the in vitro activity.
The results indicated that the compound VIIc possesses significant HMG-CoA reductase inhibitory activity.
The in vivo experiments were conducted using radiolabelled (
14
C)
Kumar Saridi Madhava Dileep
Kumar Yatendra
Thaper Rajesh Kumar
Deshmukh Jayadeep R.
Owens Amelia
Ranbaxy Laboratories Limited
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