Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-06
2003-09-02
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S490000
Reexamination Certificate
active
06613761
ABSTRACT:
TECHNICAL FIELD
This invention relates to a benzoxazepine compound having an activity of lowering cholesterol-level and an activity of lowering triglyceride-level and useful for prophylaxis and therapy of hyperlipemia.
BACKGROUND ART
Abnormal increase of concentrations of lipids in plasma is called “hyperlipidemia” or “hyperlipemia”. Serum lipids include cholesterol (cholesterol ester, free cholesterol), phospholipid (lecithin, sphingomyelin, etc.), triglyceride (neutral fat), free fatty acid and other sterols. Increase of cholesterol and triglyceride is especially taken up as a problem from the clinical viewpoint [cf. Common Disease Series No.19 Koshikessho (hyperlipemia) compiled by Haruo Nakamura, published by Nankodo].
Therefore, adequate control of lipid concentration in blood is remarkably important for the prophylaxis or therapy of various diseases related to arteriosclerosis typically exemplified by ischemic heart disease and cerebral infarction. And, hypertriglyceridemia is considered to accompany pancreatic disorders.
As pharmaceutical compositions for lowering cholesterol in blood, attention has been drawn to those for controlling the biosynthesis of cholesterol, besides those of inhibiting its absorption by binding bile acid including, among others, cholestyramine, colestipol (for example, U.S. Pat. No. 4,027,009), and those of suppressing the intestinal absorption of cholesterol by inhibiting acyl coenzyme A cholesterol acyl transferase (ACAT) including melinamide (French Patent No.1476569). As pharmaceutical preparations for controlling the biosynthesis of cholesterol, lovastatin (U.S. Pat. No. 4,231,938), simvastatin (U.S. Pat. No. 4,444,784), pravastatin (U.S. Pat. No. 4,346,227), etc., which are capable of inhibiting especially 3-hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase, are provided for medicinal use. However, when HMG-CoA reductase is inhibited, not only the biosynthesis of cholesterol but the biosynthesis of some other components such as ubiquinone, dolichol and heme A, which are necessary for the living body, is also inhibited, so that occurrences of undesirable side effects to be caused thereby are feared.
While, as agents of lowering triglyceride, fibrinoic acid type compounds, for example, clofibrate (UK Patent 860303) and fenofibrate (German Patent 2250327), are provided for medicines, they are prohibited to use together with statin type compounds for the fear of causing liver-toxicity.
Squalene synthetase is an enzyme taking part in the essential stage of the cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene.
On the other hand, the compounds expected as inhibitors of cholesterol biosynthesis by inhibiting squalene synthetase are disclosed in Journal of Medicinal Chemistry, Vol. 51, No. 10, pp. 1869-1871, 1988, JPA H1(1989)-213288, JPA H2(1990)-101088, JPA H2(1990)-235820, JPA H2(1990)-235821, JPA H3(1991)-20226, JPA H3(1991)-68591, JPA H3(1991)-148288, and U.S. Pat. No. 5,019,390, U.S. Pat. No. 5,135,935, WO9215579 and WO9309115.
Incidentally, hyperlipemia is also called “hyperlipoproteinemia” and is classified into the following six types (WHO classification) taking lipoproteins into consideration.
Type I: hyperchylomicronemia showing increase of chylomicrons,
Type IIa: hyperLDLemia (hypercholesterolemia) showing increase of low-density lipoprotein (LDL),
Type IIb: composite hyperlipemia showing increase of LDL and very-low-density lipoprotein (VLDL),
Type III: abnormal &bgr; lipoproteinemia showing the presence of &bgr; very-low-density lipoprotein (&bgr; VLDL),
Type IV: endogenous hypertriglycerolemia, and
Type V: mixed type hyperlipemia showing increase of VLDL and chylomicrons.
DISCLOSURE OF THE INVENTION
Through intensive investigations from the above viewpoints, the present inventors synthesized, for the first time, a 4,1-benzoxazepine compound with the characteristic feature having specific substituents at 1-, 3-, 5- and 7-positions, and found that this compound has unexpectedly excellent lipid-level lowering activity based on the specific chemical structure, thus accomplishing the present invention.
More specifically, the present invention relates to:
(1) a compound represented by the formula (I)
wherein R stands for a lower alkyl group substituted by 1 to 3 hydroxy group which may be substituted, X stands for an optionally substituted carbamoyl group or an optionally substituted heterocyclic group having a deprotonatable hydrogen atom R
1
stands for a lower alkyl group and W stands for a hydrogen atom, or a salt thereof,
(2) the compound of (1) defined above, wherein R is C
1-6
alkyl which may have 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy,
(3) the compound of (1) defined above, wherein R is C
3-6
branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy,
(4) the compound of (1) defined above, wherein R is 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl or 3-acetoxy-2-acetoxymethyl-2-methylpropyl,
(5) the compound of (1) defined above, wherein R
1
is methyl,
(6) the compound of (1) defined above, wherein W is chlorine atom,
(7) the compound of (1) defined above, wherein X is a carbamoyl group represented by the formula
wherein R
2
and R
3
are independently
(i) hydrogen,
(ii) optionally substituted hydrocarbon group,
(iii) optionally substituted heterocyclic group, or
(iv) acyl group or R
2
and R
3
may form an optionally substituted 5 to 6 membered ring together with the adjacent nitrogen atom, said ring may contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to said nitrogen atom,
(8) the compound of (7) defined above, wherein R
2
is hydrogen or C
1-7
alkyl, R
3
is
1) a hydrocarbon group selected from the group consisting of
(a) C
1-7
alkyl,
(b) C
3-7
cycloalkyl,
(c) C
2-6
alkenyl,
(d) C
6-10
aryl and
(e) C
6-10
aryl-C
1-4
alkyl,
wherein each of said groups (a), (b) and (c) may have 1 to 4 substituents selected from the group consisting of
(i) carboxyl which may be esterified with C
1-6
alkyl or C
6-10
aryl-C
1-4
alkyl,
(ii) phosphono group which may be mono- or di-substituted by C
1-6
alkyl or C
2-7
alkanoyloxy-C
1-6
alkyl,
(iii) sulfo group,
(iv) sulfonamido which may be substituted by C
1-6
alkyl or C
6-10
aryl-C
1-4
alkyl,
(v) hydroxyl group which may be alkylated with C
1-3
alkyl,
(vi) sulfhydryl group which may be alkylated with C
1-3
alkyl,
(vii) carbamoyl,
(viii) phenyl which may have 1 to 5 substituents selected from the group consisting of hydroxy, chlorine, fluorine, aminosulfonyl and amino which may be mono or di-substituted by C
1-3
alkyl,
(ix) amino which may be mono- or di-substituted by C
1-3
alkyl,
(x) cyclic amino group selected from the group consisting of piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, 4-phenylpiperazinyl, 1,2,3,4-tetrahydroisoquinolin and phthalimido, each of said group may be substituted by C
1-3
alkyl, benzyl or phenyl and
(xi) 5- to 6-membered heterocyclic group selected from the group consisting of pyridinyl, imidazolyl, indolyl and tetrazolyl,
and each of said group (d) and (e) may have 1 to 4 substituents selected from the group consisting of
(i) carboxyl which may be esterified by C
1-4
alkyl,
(ii) phosphono which may be mono- or di-substituted by C
1-6
alkyl or C
2-7
alkanoyloxy-C
1-6
alkyl,
(iii) sulfo,
(iv) C
1-4
alkylsulfonyl, C
6-10
arylsulfonyl or C
6-10
aryl-C
1-4
alkylsulfonyl,
(v) sulfonamido which may be substituted by C
1-6
alkyl or C
6-10
aryl-C
1-4
alkyl,
(vi) C
1-3
alkyl group which may be substituted by carboxyl group optionally esterified with C
1-4
alkyl,
Sugiyama Yasuo
Tozawa Ryuichi
Yukimasa Hidefumi
Coleman Brenda
Conlin David G.
Edwards & Angell LLP
O'Day Christine C.
Takeda Chemical Industries Ltd.
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