U.S. patent application number 11/986280 was filed with the patent office on 2008-06-26 for benzoxazepine compounds, their production and use.
This patent application is currently assigned to Takeda Pharmaceutical Company Limited. Invention is credited to Yasuo Sugiyama, Ryuichi Tozawa, Hidefumi Yukimasa.
Application Number | 20080153801 11/986280 |
Document ID | / |
Family ID | 16986391 |
Filed Date | 2008-06-26 |
United States Patent
Application |
20080153801 |
Kind Code |
A1 |
Yukimasa; Hidefumi ; et
al. |
June 26, 2008 |
Benzoxazepine compounds, their production and use
Abstract
This invention provides new benzoxazepine compounds represented
by the formula: ##STR00001## [wherein R stands for a lower alkyl
group optionally substituted with a hydroxyl group, X stands for an
optionally substituted carbamoyl group or an optionally substituted
heterocyclic group having a deprotonatable hydrogen atom, R.sub.1
stands for a lower alkyl group and W stands for a halogen atom]
having activities of lowering chlesterol-level and lowering
trigluceride-level, and being useful for prophylaxis and therapy of
hyperlipidemia.
Inventors: |
Yukimasa; Hidefumi; (Nara,
JP) ; Sugiyama; Yasuo; (Hyogo, JP) ; Tozawa;
Ryuichi; (Tsukuba, JP) |
Correspondence
Address: |
Edwards Angell Palmer & Dodge LLP
P.O. Box 55874
Boston
MA
02205
US
|
Assignee: |
Takeda Pharmaceutical Company
Limited
|
Family ID: |
16986391 |
Appl. No.: |
11/986280 |
Filed: |
November 19, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11638066 |
Dec 12, 2006 |
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11986280 |
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10606152 |
Jun 24, 2003 |
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11638066 |
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09587947 |
Jun 6, 2000 |
6613761 |
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10606152 |
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09043265 |
Mar 12, 1998 |
6110909 |
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09587947 |
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PCT/JP96/02596 |
Sep 12, 1996 |
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09043265 |
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Current U.S.
Class: |
514/211.05 ;
540/490 |
Current CPC
Class: |
C07D 231/12 20130101;
C07D 413/12 20130101; C07F 9/6527 20130101; C07D 267/14 20130101;
C07F 9/65583 20130101; C07D 233/56 20130101; A61P 9/10 20180101;
C07D 281/10 20130101; C07D 491/10 20130101; C07D 249/08 20130101;
C07D 413/14 20130101; C07D 413/06 20130101 |
Class at
Publication: |
514/211.05 ;
540/490 |
International
Class: |
A61K 31/553 20060101
A61K031/553; A61P 9/10 20060101 A61P009/10; C07D 267/14 20060101
C07D267/14 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 13, 1995 |
JP |
235457-1995 |
Claims
1. A compound represented by the formula (I) ##STR00183## wherein R
stands for a lower alkyl group optionally substituted by hydroxyl
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.sub.1
stands for a lower alkyl group and W stands for a halogen atom, or
a salt thereof.
2. The compound as claimed in claim 1, wherein R is C.sub.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 as claimed in claim 1, wherein R is C.sub.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 as claimed in claim 1, 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 as claimed in claim 1, wherein R.sub.1 is
methyl.
6. The compound as claimed in claim 1, wherein W is chlorine
atom.
7. The compound as claimed in claim 1, wherein X is a carbamoyl
group represented by the formula ##STR00184## wherein R.sub.2 and
R.sub.3 are independently (i) hydrogen, (ii) optionally substituted
hydrocarbon group, (iii) optionally substituted heterocyclic group,
or (iv) acyl group or R.sub.2 and R.sub.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 as claimed in claim 7, wherein R.sub.2 is hydrogen
or C.sub.1-7 alkyl, R.sub.3 is (1) a hydrocarbon group selected
from the group consisting of (a) C.sub.1-4 alkyl, (b) C.sub.3-7
cycloalkyl, (c) C.sub.2-6 alkenyl, (d) C.sub.6-10 aryl and (e)
C.sub.6-10 aryl-C.sub.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.sub.1-6
alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, (ii) phosphono group
which may be mono- or di-substituted by C.sub.1-6 alkyl or
C.sub.2-7 alkanoyloxy-C.sub.1-6 alkyl, (iii) sulfo group, (iv)
sulfonamido which may be substituted by C.sub.1-6 alkyl or
C.sub.6-10 aryl-C.sub.1-4 alkyl, (v) hydroxyl group which may be
alkylated with C.sub.1-3 alkyl, (vi) sulfhydryl group which may be
alkylated with C.sub.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.sub.1-3 alkyl, (ix) amino
which may be mono- or di-substituted by C.sub.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-tetrahydroisoquinolinly and phthalimido, each of said group
may be substituted by C.sub.1-3 alkyl, benzyl or phenyl and (xi) 5-
to 6-membered heterocyclic group selected from the group consisting
of pydinyl, 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.sub.1-4 alkyl, (ii) phosphono which may be mono- or
di-substituted by C.sub.1-6 alkyl or C.sub.2-7
alkanoyloxy-C.sub.1-6 alkyl, (iii) sulfo, (iv) C.sub.1-4
alkylsulfonyl, C.sub.6-10 arylsulfonyl or C.sub.6-10 aryl-C.sub.1-4
alkylsulfonyl, (v) sulfonamido which may be substituted by
C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, (vi) C.sub.1-3
alkyl group which may be substituted by carboxyl group optionally
esterified with C.sub.1-4 alkyl, phosphono which may be mono- or
di-substituted by C.sub.1-6 alkyl, sulfo, sulfonamido which may be
substituted by C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl
and (v) halogen, (2) a heterocyclic group selected from the group
consisting of tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,
4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,
3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl,
4,5-dihydro-5-thioxo-isoxazolyl,
2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-tetrazolyl and
2,3-dihydro-3-thioxo-1,2,4-tetrazolyl, (3) an acyl group selected
from the group consisting of (i) C.sub.2-7 alkanoyl which may be
substituted by 1 to 2 halogen atoms, (ii) C.sub.6-10 arylsulfonyl,
(iii) C.sub.1-4 alkylsulfonyl, and (iv) C.sub.6-10 aryl-C.sub.1-4
alkylsulfonyl, each of said group (ii), (iii) and (iv) may have 1
to 4 substituents selected from the group consisting of C.sub.1-3
alkyl, C.sub.1-3 alkoxy and halogen, or R.sub.2 and R.sub.3
together with adjacent nitrogen form a 5- or 6-membered cyclic
amino selected from the group consisting of piperazinyl, piperidyl,
pyrrolidinyl, 2-oxo-piperazinyl, 2,6-dioxopiperazinyl, morpholinyl
and thiomorpholinyl, each of said group may have 1 to 4
substituents selected from the group consisting of (A) hydroxyl
which may be substituted with C.sub.1-3 alkyl or C.sub.2-7
alkanoyl, (B) carboxyl which may be substituted with C.sub.1-6
alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, (C) phosphono which may
be mono- or di-substituted by C.sub.1-6 alkyl or C.sub.2-7
alkanoyloxy-C.sub.1-6 alkyl, (D) sulfo, (E) sulfonamido which may
be substituted with C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4
alkyl, (F) C.sub.1-6 alkyl or C.sub.2-5 alkenyl which may be
substituted by (i) carboxyl group which may be esterified with
C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, (ii) phosphono
group which may be mono- or di-substituted by C.sub.1-6 alkyl or
C.sub.2-7 alkanoyloxy-C.sub.1-6 alkyl, (iii) sulfo group, (iv)
sulfonamido which may be substituted by C.sub.1-6 alkyl or
C.sub.6-10 aryl-C.sub.1-4 alkyl, (v) hydroxyl group which may be
alkylated with C.sub.1-3 alkyl or C.sub.2-7 alkanoyl, (vi)
sulfhydryl group which may be alkylated with C.sub.1-3 alkyl, (vii)
carbamoyl, (viii) phenyl which may have 1 to 5 substituents
selected from the group consisting of hydroxy, halogen,
aminosulfonyl and amino which may be substituted with C.sub.1-3
alkyl and (ix) amino which may be mono- or di-substituted by
C.sub.1-3 alkyl, or (x) tetrazolyl, (G) amino which may be mono- or
di-substituted with C.sub.1-3 alkyl, (H) cyclic amino group
selected from the group consisting of piperidyl, pyrrolidinyl,
morpholinyl, thiomorpholinyl, 4-methylpiperazinyl,
4-benzylpiperazinyl and 4-phenylpiperazinyl, (I) cyano, (J)
carbamoyl, (K) oxo, (L) heterocyclic group selected from tetrazolyl
and 2,5-dihydro-5-oxo-1,2,4-oxazolyl, (M) carbamoyl substituted
with C.sub.1-4 alkylsulfonyl, C.sub.6-10 arylsulfonyl or C.sub.6-10
aryl-C.sub.1-4 alkylsulfonyl, (N) sulfhydryl which may be alkylated
with C.sub.1-3 alkyl and (O) phenyl which may have 1 to 5
substituents selected from hydroxyl, halogen, aminosulfonyl and
amino which may be substituted with C.sub.1-3 alkyl.
9. The compound as claimed in claim 7, wherein R.sub.2 and R.sub.3
together with the adjacent nitrogen of the carbamoyl form a 5 to
6-membered ring selected from the group consisting of
1-piperazinyl, piperidino, 1-pyrrolidinyl, 2-oxo-1-piperazinyl and
2,6-dioxo-1-piperazinyl, each of the said group may have 1 to 2
substituents of C.sub.1-6 alkyl which may be substituted by (i)
carboxyl which may be esterified with C.sub.1-6 alkyl or C.sub.6-10
aryl-C.sub.1-4 alkyl, (ii) phosphono group which may be mono- or
di-substituted by C.sub.1-6 alkyl or C.sub.2-7 alkanoyl-C.sub.1-6
alkyl, (iii) sulfo group, (iv) sulfonamido which may be substituted
by C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, (v) hydroxyl
group which may be alkylated by C.sub.1-3 alkyl, (vi) sulfhydryl
which may be alkylated by C.sub.1-3 alkyl, (vii) carbamoyl, (viii)
phenyl which may have 1 to 5 substituents selected from the group
consisting of hydroxy, halogen, aminosulfonyl and amino which may
be substituted with C.sub.1-3 alkyl, (ix) amino which may be mono-
or di-substituted by C.sub.1-3 alkyl, or (x) tetrazolyl.
10. The compound as claimed in claim 7, wherein R.sub.2 is hydrogen
or C.sub.1-7 alkyl and R.sub.3 is C.sub.1-4 alkylsulfonyl.
11. The compound as claimed in claim 1, wherein the heterocyclic
group represented by X is tetrazolyl,
4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,
4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,
3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl,
4,5-dihydro-5-thioxo-isoxazolyl,
2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-tetrazolyl, or
2,3-dihydro-3-thioxo-1,2,4-tetrazolyl.
12. The compound as claimed in claim 1, wherein R.sub.1 is methyl,
W is chlorine atom, R is C.sub.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, and X is a
carbamoyl group represented by the formula ##STR00185## wherein
R.sub.2' is hydrogen or C.sub.1-7 alkyl and R.sub.3' is C.sub.1-4
alkyl.
13. The compound as claimed in claim 1, wherein R.sub.1 is methyl,
W is chlorine atom, R is C.sub.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, and X is a
carbamoyl group represented by the formula ##STR00186## wherein R'
is hydrogen or C.sub.1-7 alkyl and n is an integer from 1 to 5.
14. The compound as claimed in claim 1, wherein R.sub.1 is methyl,
W is chlorine atom, R is C.sub.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, and X is a
carbamoyl group represented by the formula ##STR00187## wherein R''
is hydrogen or C.sub.1-4 alkyl.
15. The compound as claimed in claim 1, wherein R.sub.1 is methyl,
W is chlorine atom, R is C.sub.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, and X is
tetrazolyl.
16. The compound as claimed in claim 1, which is
(3R,5S)--N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy--
2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-
,
(3R,5S)--N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-
-2-hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-
e-3-acetamide,
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-m-
ethylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-ben-
zoxazepine-3-acetamide,
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-
-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzazepine-3-a-
cetamide, or a salt thereof.
17. The compound as claimed in claim 1, which is
(3R,5S)--N-methanesulfonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2-
,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-
,
(3R,5S)--N-methanesulfonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)--
7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-
e-3-acetamide,
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,-3-dimethoxyphe-
nyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acet-
ic acid,
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro--
5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acety-
l]piperidine-4-acetic acid,
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphen-
yl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-aceti-
c acid ethyl ester,
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-d-
imethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperi-
dine-4-acetic acid ethyl ester or a salt thereof.
18. The compound as claimed in claim 1, which is
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-
-1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one,
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-m-
ethylpropyl)-1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one,
(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl-7-chloro-5-(2,3-dimethoxyphenyl)--
1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one,
(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dime-
thoxyphenyl)-1,2,3,5-tetrahydro-3-]1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one or a salt
thereof.
19. The compound as claimed in claim 1, which is
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-N-[2-(pyrrolid-
in-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or
a salt thereof.
20. The compound as claimed in claim 1, wherein R is a lower alkyl
group which may be substituted with one or two hydroxyl groups, X
is carbamoyl group, which may have substituent(s) on the nitrogen
atom of the carbamoyl group, said substituent being (1) hydrocarbon
selected from the group consisting of (a) C.sub.1-7 alkyl, (b)
C.sub.3-7 cycloaklyl, (c) C.sub.2-6 alkenyl, (d) C.sub.6-10 aryl
and (e) C.sub.7-14 arylalkyl, 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.sub.1-6
alkyl or C.sub.7-10 arylalkyl, (ii) phosphono group, (iii) sulfo
group, (iv) sulfonamido which may be substituted by C.sub.1-6 alkyl
or C.sub.7-10 arylalkyl, (v) hydroxyl group which may be alkylated
with C.sub.1-3 alkyl, (vi) sulfhydryl group which may be alkylated
with C.sub.1-3 alkyl, (vii) carbamoyl, (viii) phenyl which may have
substituent(s) selected from the group consisting of hydroxyl,
chlorine, fluorine, aminosulfonyl and amino which may be mono or
di-substituted by C.sub.1-3 alkyl, (ix) amino which may be mono- or
di-substituted by C.sub.1-3 alkyl, (x) cyclic amino group selected
from the group consisting of piperidyl, pyrrolidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, 4-methylpiperazinyl,
4-benzylpiperazinyl and 4-phenylpiperazinyl, each of said group may
be substituted by C.sub.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.sub.1-4 alkyl, (ii) phosphono, (iii) sulfo, (iv) sulfonamido
which may be substituted by C.sub.1-6 alkyl or C.sub.7-10
arylalkyl, (v) C.sub.1-3 alkyl group which may be substituted by
carboxyl group optionally esterified with C.sub.1-4 alkyl,
phosphono, sulfo, or sulfonamido optionally substituted with
C.sub.1-6 alkyl or C.sub.7-10 arylalkyl, and (vi) halogen. (2) a
heterocyclic group selected from the group consisting of
tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,
4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,
3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl,
4,5-dihydro-5-thioxo-isoxazolyl,
2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-tetrazolyl and
2,3-dihydro-3-thioxo-1,2,4-tetrazolyl, (3) an acyl group selected
from the group consisting of (i) C.sub.2-7 alkanoyl which may be
substituted by 1 to 2 halogen atoms, (ii) C.sub.6-10 arylsulfonyl,
(iii) C.sub.1-4 alkylsulfonyl, and (iv) C.sub.7-14
arylalkylsulfonyl, each of said group (ii), (iii) and (iv) may have
1 to 4 substituents selected from the group consisting of C.sub.1-3
alkyl, C.sub.1-3 alkoxy and halogen or (4) cyclic amino carbonyl
group, the cyclic amino group being selected from the group
consisting of piperazinyl, piperidyl, pyrrolidinyl,
2-oxo-piperazinyl, 2,6-dioxopiperazinyl, morpholinyl and
thionorpholinyl, each of said group may have 1 to 4 substituents
selected from the group consisting of (i) hydroxyl, (ii) carboxyl
optionally esterified with C.sub.1-4, alkyl, (iii) phosphono, (iv)
sulfo, (v) sulfonamido optionally substituted with C.sub.1-6 alkyl
or C.sub.7-10 arylalkyl, (vi) C.sub.1-3 alkyl or C.sub.2-5 alkenyl
optionally substituted with (i), (ii), (iii), (iv) or (v) defined
above, (vii) amino optionally mono- or di-substituted with
C.sub.1-3 alkyl, (viii) cyclic amino group selected from the group
consisting of piperidyl, pyrrolidinyl, morpholinyl,
thiomorpholinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl and
4-phenylpiperazinyl, (ix) cyano, (x) carbamoyl, (xi) oxo, (xii)
C.sub.1-3 alkoxy, (xiii) heterocyclic group selected from
tetrazolyl and 2,5-dihydro-5-oxo-1,2,4-oxazolyl, and (xiv)
carbamoyl substituted with C.sub.6-10 arylsulfonyl, C.sub.1-4
alkylsulfonyl or C.sub.7-14 arylalkylsulfonyl.
21. A composition which comprises the compound as claimed in claim
1 and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition for inhibiting squalene
synthetase, which comprises the compound as claimed in claim 1 and
a pharmaceutically acceptable carrier.
23. A pharmaceutical-composition for lowering the level of
triglyceride, which comprises the compound as claimed in claim 1
and a pharmaceutically acceptable carrier.
24. A pharmaceutical composition for lowering the lipid-level,
which comprises the compound as claimed in claim 1 and a
pharmaceutically acceptable carrier.
25. A pharmaceutical composition for prophylaxis or therapy of
hyperlipidaemia, which comprises the compound as claimed in claim 1
and a pharmaceutically acceptable carrier.
26. Use of the compound as claimed in claim 1 for manufacturing a
pharmaceutical composition.
27. Use of the compound as claimed in claim 1 for manufacturing a
squalene synthetase inhibitor.
28. Use of the compound as claimed in claim 1 for manufacturing a
pharmaceutical composition for lowering the level of
triglyceride.
29. Use of the compound as claimed in claim 1 for manufacturing a
pharmaceutical composition for lowering the lipid-level.
30. Use of the compound as claimed in claim 1 for manufacturing a
pharmaceutical composition for prophylaxis or therapy of
hyperlipidaemia or coronary sclerosis.
31. A method for inhibiting squalene synthetase in a mammal
comprising administering an effective amount of the compound as
claimed in claim 1 to said mammal.
32. A method for lowering the level of triglyceride in a mammal
comprising administering an effective amount of the compound as
claimed in claim 1 to said mammal.
33. A method for lowering the lipid-level in a mammal comprising
administering an effective amount of the compound as claimed in
claim 1 to said mammal.
34. A method for prophylaxis or therapy of hyperlipidaemia or
coronary sclerosis in a mammal comprising administering an
effective amount of the compound as claimed in claim 1 to said
mammal.
35. A process for producing the compound as claimed in claim 1,
wherein X is an optionally substituted carbamoyl group, which
comprises reacting a compound of the formula: ##STR00188## wherein
the symbols are as defined in claim 1, or a salt thereof with a
compound of the formula: ##STR00189## wherein the symbols are as
defined in claim 7, or a salt thereof.
36. The compound as claimed in claim 1, wherein R is
2,2-dimethyl-3-hydroxypropyl.
Description
TECHNICAL FIELD
[0001] 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
[0002] 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].
[0003] 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.
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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 .beta. lipoproteinemia showing the presence of
.beta. very-low-density lipoprotein (.beta. VLDL), Type IV:
endogenous hypertriglycerolemia, and Type V: mixed type
hyperlipemia showing increase of VLDL and chylomicrons.
DISCLOSURE OF INVENTION
[0009] 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.
[0010] More specifically, the present invention relates to:
(1) a compound represented by the formula (I)
##STR00002##
wherein R stands for a lower alkyl group optionally substituted by
hydroxyl 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.sub.1
stands for a lower alkyl group and W stands for a halogen atom, or
a salt thereof, (2) the compound of (1) defined above, wherein R is
C.sub.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.sub.1-6 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.sub.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
##STR00003##
wherein R.sub.2 and R.sub.3 are independently
[0011] (i) hydrogen,
[0012] (ii) optionally substituted hydrocarbon group,
[0013] (iii) optionally substituted heterocyclic group, or
[0014] (iv) acyl group
or R.sub.2 and R.sub.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.sub.2 is hydrogen or C.sub.1-7 alkyl,
R.sub.3 is
[0015] 1) a hydrocarbon group selected from the group consisting of
(a) C.sub.1-7 alkyl,
[0016] (b) C.sub.3-7 cycloalkyl,
[0017] (c) C.sub.2-6 alkenyl,
[0018] (d) C.sub.6-10 aryl and
[0019] (e) C.sub.6-10 aryl-C.sub.1-4 alkyl;
wherein each of said groups (a), (b) and (c) may have 1 to 4
substituents selected from the group consisting of [0020] (i)
carboxyl which may be esterified with C.sub.1-6 alkyl or C.sub.6-10
aryl-C.sub.1-4, alkyl, [0021] (ii) phosphono group which may be
mono- or di-substituted by C.sub.1-6 alkyl or C.sub.2-7
alkanoyloxy-C.sub.1-6 alkyl, [0022] (iii) sulfo group, [0023] (iv)
sulfonamido which may be substituted by C.sub.1-6 alkyl or
C.sub.6-10 aryl-C.sub.1-4 alkyl, [0024] (v) hydroxyl group which
may be alkylated with C.sub.1-3 alkyl, [0025] (vi) sulfhydryl group
which may be alkylated with C.sub.1-3 alkyl, [0026] (vii)
carbamoyl, [0027] (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.sub.1-3 alkyl, [0028] (ix) amino which may be mono- or
di-substituted by C.sub.1-3 alkyl, [0029] (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-tetrahydroisquinolinyl and phthalimido, each of said group
may be substituted by C.sub.1-3 alkyl, benzyl or phenyl and [0030]
(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 [0031] (i) carboxyl which may
be esterified by C.sub.1-4 alkyl, [0032] (ii) phosphono which may
be mono- or di-substituted by C.sub.1-6 alkyl or C.sub.2-7
alkanoyloxy-C.sub.1-6 alkyl, [0033] (iii) sulfo, [0034] (iv)
C.sub.1-4 alkylsulfonyl, C.sub.6-10 arylsulfonyl or C.sub.6-10
aryl-C.sub.1-4 alkylsulfonyl, [0035] (v) sulfonamido which may be
substituted by C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl,
[0036] (vi) C.sub.1-3 alkyl group which may be substituted by
carboxyl group optionally esterified with C.sub.1-4 alkyl,
phosphono which may be mono- or di-substituted by C.sub.1-6 alkyl,
sulfo or sulfonamido which may be substituted by C.sub.1-6, alkyl
or C.sub.6-10 aryl-C.sub.1-4 alkyl and [0037] (v) halogen,
[0038] 2) a heterocyclic group selected from the group consisting
of tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,
4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,
3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl,
4,5-dihydro-5-thioxo-isoxazolyl,
2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-tetrazolyl and
2,3-dihydro-3-thioxo-1,2,4-tetrazolyl or the salt thereof,
[0039] 3) an acyl group selected from the group consisting of
[0040] (i) C.sub.2-7 alkanoyl which may be substituted by 1 to 2
halogen atoms, [0041] (ii) C.sub.6-10 arylsulfonyl, [0042] (iii)
C.sub.1-4 alkylsulfonyl, and [0043] (iv) C.sub.6-10 aryl-C.sub.1-4
alkylsulfonyl, each of said group (ii), (iii) and (iv) may have 1
to 4 substituents selected from the group consisting of C.sub.1-3
alkyl, C.sub.1-3 alkoxy and halogen, or R.sub.2 and R.sub.3
together with adjacent nitrogen form a 5- or 6-membered cyclic
amino selected from the group consisting of piperazinyl, piperidyl,
pyrrolidinyl, 2-oxo-piperazinyl, 2,6-dioxopiperazinyl, morpholinyl
and thiomorpholinyl, each of said group may have 1 to 4
substituents selected from the group consisting of
[0044] (A) hydroxyl which may be substituted with C.sub.1-3 alkyl
or C.sub.2-7 alkanoyl,
[0045] (B) carboxyl which may be substituted with C.sub.1-6 alkyl
or C.sub.6-10 aryl-C.sub.1-4 alkyl,
[0046] (C) phosphono which may be mono- or di-substituted by
C.sub.1-6 alkyl or C.sub.2-7 alkanoyloxy-C.sub.1-6 alkyl,
[0047] (D) sulfo,
[0048] (E) sulfonamide which may be substituted with C.sub.1-6
alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl,
[0049] (F) C.sub.1-6 alkyl or C.sub.2-5 alkenyl which may be
substituted by [0050] (i) carboxyl group which may be esterified
with C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, [0051]
(ii) phosphono group which may be mono- or di substituted by
C.sub.1-6 alkyl or C.sub.2-7 alkanoyloxy-C.sub.1-6 alkyl, [0052]
(iii) sulfo group, [0053] (iv) sulfonamido which may be substituted
by C.sub.1-6, alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, [0054] (v)
hydroxyl group which may be alkylated with C.sub.1-3 alkyl or
C.sub.2-7 alkanoyl, [0055] (vi) sulfhydryl group which may be
alkylated with C.sub.1-3 alkyl, [0056] (vii) carbamoyl, [0057]
(viii) phenyl which may have 1 to 5 substituents selected from the
group consisting of hydroxy, halogen, aminosulfonyl and amino which
may be substituted with C.sub.1-3 alkyl and [0058] (ix) amino which
may be mono- or di-substituted by C.sub.1-3 alkyl, or [0059] (x)
tetrazolyl,
[0060] (G) amino which may be mono- or di-substituted with
C.sub.1-3 alkyl,
[0061] (H) cyclic amino group selected from the group consisting of
piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,
4-methylpiperazinyl, 4-benzylpiperazinyl, and
4-phenyl-piperazinyl,
[0062] (I) cyano,
[0063] (J) carbamoyl,
[0064] (K) oxo,
[0065] (L) heterocyclic group selected from tetrazolyl and
2,5-dihydro-5-oxo-1,2,4-oxazolyl,
[0066] (M) carbamoyl substituted with C.sub.1-4 alkylsulfonyl,
C.sub.6-10 arylsulfonyl or C.sub.6-10 aryl-C.sub.1-4
alkylsulfonyl,
[0067] (N) sulfhydryl which may be alkylated with C.sub.1-3
alkyl,
[0068] (O) phenyl which may have 1 to 5 substituents selected from
hydroxyl, halogen, aminosulfonyl and amino which may be substituted
with C.sub.1-3 alkyl,
or the salt thereof, (9) the compound of (7) defined above, wherein
R.sub.2 and R.sub.3 together with the adjacent nitrogen of the
carbamoyl form a 5 to 6-membered ring selected from the group
consisting of 1-piperazinyl, piperidyl, 1-pyrrolidinyl,
2-oxo-piperazinyl and 2,6-dioxo-piperazinyl, each of the said group
may have 1 to 2 substituents of C.sub.1-6 alkyl which may be
substituted by [0069] (i) carboxyl which may be esterified with
C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, [0070] (ii)
phosphono group which may be mono- or di-substituted by C.sub.1-6
alkyl or C.sub.2-7 alkanoyloxy-C.sub.1-6 alkyl, [0071] (iii) sulfo
group, [0072] (iv) sulfonamido which may be substituted by
C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, [0073] (v)
hydroxyl group which may be alkylated by C.sub.1-3: alkyl, [0074]
(vi) sulfhydryl which may be alkylated by C.sub.1-3 alkyl, [0075]
(vii) carbamoyl, [0076] (viii) phenyl which may have 1 to 5
substituents selected from the group consisting of hydroxy,
halogen, aminosulfonyl and amino which may be substituted with
C.sub.1-3 alkyl, [0077] (ix) amino which may be mono- or
di-substituted by C.sub.1-3 alkyl, or [0078] (x) tetrazolyl, (10)
the compound of (7) defined above, wherein R.sub.2 is hydrogen or
C.sub.1-7 alkyl and R.sub.3 is C.sub.1-4 alkylsulfonyl, (11) The
compound of term (1) defined above, wherein the heterocyclic group
represented by X is tetrazolyl,
4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,
4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,
3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl,
4,5-dihydro-5-thioxo-isoxazolyl,
2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-tetrazolyl, or
2,3-dihydro-3-thioxo-1,2,4-tetrazolyl, (12) the compound of (1)
defined above, wherein R.sub.1 is methyl, W is chlorine atom, R is
C.sub.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, and X is the carbamoyl group represented by a
formula
##STR00004##
[0078] wherein R.sub.2' is hydrogen or C.sub.1-7 alkyl and R.sub.3'
is C.sub.1-4 alkyl, (13) the compound of (1) defined above, wherein
R.sub.1 is methyl, W is chlorine atom, R is C.sub.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, and X is the carbamoyl group represented by a
formula
##STR00005##
wherein R' is hydrogen or C.sub.1-7 alkyl and n is an integer from
1 to 5, (14) the compound of (1) defined above, wherein R.sub.1 is
methyl, W is chlorine atom, R is C.sub.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, and X is a
carbamoyl group represented by the formula
##STR00006##
wherein R'' is hydrogen or C.sub.1-4 alkyl, (15) the compound of
(1) defined above, wherein R.sub.1 is methyl, W is chlorine atom, R
is C.sub.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, and X is tetrazolyl, (16) the compound of (1)
defined above, which is [0079]
(3R,5S)--N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy--
2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-
, [0080]
(3R,5S)--N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3--
hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzo-
xazepine-3-acetamide, [0081]
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-m-
ethylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-ben-
zoxazepine-3-acetamide, [0082]
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-
-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzazepine-3-a-
cetamide, or a salt thereof, (17) the compound of (1) defined
above, which is [0083]
(3R,5S)--N-methanesulfonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-c-
hloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-
-acetamide, [0084]
(3R,5S)--N-methanesulfonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-
-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-
-3-acetamide, [0085]
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphen-
yl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-aceti-
c acid, [0086]
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-d-
imethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperi-
dine-4-acetic acid, [0087]
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphen-
yl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-aceti-
c acid ethyl ester, [0088]
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-d-
imethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperi-
dine-4-acetic acid ethyl ester or a salt thereof, (18) the compound
of (1) defined above, which is [0089]
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-
-1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one, [0090]
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-m-
ethylpropyl)-1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one, [0091]
(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl-7-chloro-5-(2,3-dimethoxyphenyl)--
1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one, [0092]
(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dime-
thoxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one or a salt thereof,
(19) the compound of (1) defined above, which is [0093]
(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-N-[2-(pyrrolid-
in-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or
the salt thereof, (20) the compound of (1) defined above, wherein R
is a lower alkyl group which may be substituted with one or two
hydroxyl groups, X is carbamoyl group, which may have
substituent(s) on the nitrogen atom of the carbamoyl group,
[0094] said substituent being
(1) hydrocarbon selected from the group consisting of
[0095] (a) C.sub.1-7 alkyl,
[0096] (b) C.sub.3-7 cycloaklyl,
[0097] (c) C.sub.2-6 alkenyl,
[0098] (d) C.sub.6-10 aryl and
[0099] (e) C.sub.7-14 arylalkyl(C.sub.6-10 aryl-C.sub.1-4
alkyl),
wherein each of said groups (a), (b) and (c) may have 1 to 4
substituents selected from the group consisting of [0100] (i)
carboxyl which may be esterified with C.sub.1-6 alkyl or C.sub.7-10
arylalkyl(phenyl-C.sub.1-4 alkyl), [0101] (ii) phosphono group,
[0102] (iii) sulfo group, [0103] (iv) sulfonamido which may be
substituted by C.sub.1-6 alkyl or C.sub.7-10
arylalkyl(phenyl-C.sub.1-4 alkyl), [0104] (v) hydroxyl group which
may be alkylated with C.sub.1-3 alkyl, [0105] (vi) sulfhydryl group
which may be alkylated with C.sub.1-3 alkyl, [0106] (vii)
carbamoyl, [0107] (viii) phenyl which may have substituent(s)
selected from the group consisting of hydroxyl, chlorine, fluorine,
aminosulfonyl and amino which may be mono or di-substituted by
C.sub.1-3 alkyl, [0108] (ix) amino which may be mono- or
di-substituted by C.sub.1-3 alkyl, [0109] (x) cyclic amino group
selected from the group consisting of piperidyl, pyrrolidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl,
4-benzylpiperazinyl and 4-phenylpiperazinyl, each of said group may
be substituted by C.sub.1-3 alkyl, benzyl or phenyl and [0110] (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 [0111] (i) carboxyl which may
be esterified by C.sub.1-4 alkyl, [0112] (ii) phosphono, [0113]
(iii) sulfo, [0114] (iv) sulfonamido which may be substituted by
C.sub.1-6 alkyl or C.sub.7-10-arylalkyl(phenyl-C.sub.1-4 alkyl),
[0115] (v) C.sub.1-3 alkyl group which may be substituted by
carboxyl group optionally esterified with C.sub.1-4 alkyl,
phosphono, sulfo, or sulfonamido optionally substituted with
C.sub.1-6 alkyl or C.sub.7-10 arylalkyl (phenyl-C.sub.1-4 alkyl),
and [0116] (vi) halogen, (2) a heterocyclic group selected from the
group consisting of tetrazolyl,
4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,
4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,
3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl,
4,5-dihydro-5-thioxo-isoxazolyl,
2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-tetrazolyl and
2,3-dihydro-3-thioxo-1,2,4-tetrazolyl, (3) an acyl group selected
from the group consisting of [0117] (i) C.sub.2-7 alkanoyl which
may be substituted by 1 to 2 halogen atoms, [0118] (ii) C.sub.6-10
arylsulfonyl, [0119] (iii) C.sub.1-4 alkylsulfonyl, and [0120] (iv)
C.sub.7-14 arylalkylsulfonyl(C.sub.6-10 aryl-C.sub.1-4
alkylsulfonyl), each of said group (ii), (iii) and (iv) may have 1
to 4 substituents selected from the group consisting of C.sub.1-3
alkyl, C.sub.1-3 alkoxy and halogen or (4) cyclic amino carbonyl
group, the cyclic amino group being selected from the group
consisting of piperazinyl, piperidyl, pyrrolidinyl,
2-oxo-piperazinyl, 2,6-dioxopiperazinyl, morpholinyl and
thiomorpholinyl, each of said group may have 1 to 4 substituents
selected from the group consisting of [0121] (i) hydroxyl, [0122]
(ii) carboxyl optionally esterified with C.sub.1-4 alkyl, [0123]
(iii) phosphono, [0124] (iv) sulfo, [0125] (v) sulfonamido
optionally substituted with C.sub.1-6 alkyl or C.sub.7-10
arylalkyl(phenyl-C.sub.1-4 alkyl), [0126] (vi) C.sub.1-3 alkyl or
C.sub.2-5 alkenyl optionally substituted with (i), (ii), (iii),
(iv) or (v) defined above, [0127] (vii) amino optionally mono- or
di-substituted with C.sub.1-3 alkyl, [0128] (viii) cyclic amino
group selected from piperidyl, pyrrolidinyl, morpholinyl,
thiomorpholinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl and
4-phenylpiperazinyl, [0129] (ix) cyano, [0130] (x) carbamoyl,
[0131] (xi) oxo, [0132] (xii) C.sub.1-3 alkoxy, [0133] (xiii)
heterocyclic group selected from tetrazolyl and
2,5-dihydro-5-oxo-1,2,4-oxazolyl, and [0134] (xiv) carbamoyl
substituted with C.sub.6-10 arylsulfonyl, C.sub.1-4 alkylsulfonyl
or C.sub.7-10, arylalkylsulfonyl(phenyl-C.sub.1-4 alkylsulfonyl),
(21) a composition which comprises the compound of (1) defined
above and a pharmaceutically acceptable carrier, (22) a
pharmaceutical composition for inhibiting squalene synthetase,
which comprises the compound of (1) defined above and a
pharmaceutically acceptable carrier, (23) a pharmaceutical
composition for lowering the level of triglyceride, which comprises
the compound of (1) defined above and a pharmaceutically acceptable
carrier, (24) a pharmaceutical composition for lowering the
lipid-level, which comprises the compound of (1) defined above and
a pharmaceutically acceptable carrier, (25) a pharmaceutical
composition for prophylaxis or therapy of hyperlipidaemia, which
comprises the compound of (1) defined above and a pharmaceutically
acceptable carrier, (26) use of the compound of (1) defined above
for manufacturing a pharmaceutical composition, (27) use of the
compound of (1) defined above for manufacturing a squalene
synthetase inhibitor, (28) use of the compound of (1) defined above
for manufacturing a pharmaceutical composition for lowering the
level of triglyceride, (29) use of the compound of (1) defined
above for manufacturing a pharmaceutical composition for lowering
the lipid-level, (30) use of the compound of (1) defined above for
manufacturing a pharmaceutical composition for prophylaxis or
therapy of hyperlipidaemia or coronary sclerosis, (31) a method for
inhibiting squalene synthetase in a mammal comprising administering
an effective amount of the compound of (1) defined above to said
mammal, (32) a method for lowering the level of triglyceride in a
mammal comprising administering an effective amount of the compound
of (1) defined above to said mammal, (33) a method for lowering the
lipid-level in a mammal comprising administering an effective
amount of the compound of (1) defined above to said mammal, (34) a
method for prophylaxis or therapy of hyperlipidaemia or coronary
sclerosis in a mammal comprising administering an effective amount
of the compound of (1) defined above to said mammal, (35) a process
for producing the compound or the salt thereof of (1) defined
above, wherein X is an optionally substituted carbamoyl group,
which comprises reacting a compound of the formula:
##STR00007##
[0134] wherein the symbols are the same as defined in term (1), or
a salt thereof with a compound of the formula:
##STR00008##
wherein the symbols are the same as defined in (7), or a salt
thereof, (36) the compound of (1) defined above, wherein R is
2,2-dimethyl-3-hydroxypropyl.
[0135] As the lower alkyl group shown by R, mention is made of
C.sub.1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl. Above
all, C.sub.3-6 alkyl groups are preferable and C.sub.4-5 alkyl
groups are more preferable. Especially, branched C.sub.4--S alkyl
groups such as isobutyl and neopentyl are most preferable. The
substituent of lower alkyl group shown by R includes hydroxyl group
which may be substituted with for example C.sub.2-20 alkanoyl,
C.sub.1-7 alkyl and so on. Specifically, the substituent of lower
alkyl group shown by R includes hydroxyl, acetyloxy, propionyloxy,
t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and
2-aminopropionyloxy. The number of the above substituents ranges
from 1 to 3.
[0136] Examples of R include 2,2-dimethyl-3-hydroxypropyl,
3-hydroxy-2-hydroxymethyl-2-methylpropyl,
3-acetoxy-2,2-dimethylpropyl,
3-acetoxy-2-hydroxymethyl-2-methylpropyl and
3-acetoxy-2-acetoxymethyl-2-methylpropyl.
[0137] The "optionally substituted carbamoyl group" is represented
by the formula
##STR00009##
[0138] The term "hydrocarbon group" described in the specification
includes optionally substituted C.sub.1-7 straight-chain or
branched alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl,
2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl,
4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 2-ethylbutyl,
1-ethylbutyl, neopentyl, hexyl and heptyl), optionally substituted
C.sub.3-7 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cyclohexylmethyl), optionally
substituted C.sub.2-6 straight-chain or branched alkenyl groups
(e.g. vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,
2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl,
3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and
5-hexenyl), optionally substituted C.sub.6-10 aryl groups (e.g.
phenyl and naphthyl groups) and optionally substituted C.sub.6-10
aryl-C.sub.1-4 alkyl groups (e.g. benzyl, phenethyl and
naphthylmethyl).
[0139] Substituents of "optionally substituted C.sub.1-7
straight-chain or branched alkyl groups, optionally substituted
C.sub.3-7 cycloalkyl groups and C.sub.2-6 straight-chain or
branched alkenyl groups" are exemplified by carboxyl groups
optionally esterified with C.sub.1-6 alkyl groups or C.sub.6-10
aryl-C.sub.1-4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl,
butyl, t-butyl, phenyl and benzyl), phosphono group which may be
mono- or di-substituted by C.sub.1-6 alkyl such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl,
neopentyl and hexyl, or C.sub.2-7 alkanoyloxy-C.sub.1-6 alkyl such
as acetyloxy methyl and pivaloyloxymethyl, sulfo group, sulfonamido
group optionally substituted with C.sub.1-6 alkyl groups or
C.sub.6-10 aryl-C.sub.1-4 alkyl groups (e.g. methyl, ethyl, propyl,
isopropyl, butyl, t-butyl and benzyl), hydroxyl group and
sulfhydryl group optionally alkylated with C.sub.1-3 alkyl groups
(e.g. methyl, ethyl and propyl), carbamoyl group, phenyl group
optionally substituted with 1 to 5 substituents (e.g. hydroxyl
group, chlorine, fluorine, aminosulfonyl group, and amino group
optionally substituted with C.sub.1-3 alkyl group (e.g. methyl,
ethyl and propyl)], amino group optionally mono- or di-substituted
with C.sub.1-3 alkyl groups (e.g. methyl, ethyl and propyl), cyclic
amino groups which may further have a hetero atom selected from
oxygen and sulfur as the ring-forming atoms, and which may be
substituted by C.sub.1-3 alkyl, benzyl or phenyl, such as
(piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,
piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl,
4-phenylpiperazinyl, 1,2,3,4-tetrahydroisoquinolinyl, and
phthalimido) and aromatic 5- to 6-membered heterocyclic groups
containing 1 to 4 hetero-atoms selected from N, O and S (e.g.
pyridinyl, imidazolyl, indolyl and tetrazolyl).
[0140] Further, examples of the substituents of C.sub.6-10 aryl
groups and C.sub.6-10 aryl-C.sub.1-4 alkyl groups as the
substituents of the optionally substituted amino groups forming the
carbamoyl group of "optionally substituted carbamoyl groups" shown
by X include carboxyl groups optionally esterified with C.sub.1-4
alkyl groups (e.g. methyl, ethyl, propyl and t-butyl groups),
phosphono group which may be mono- or di-substituted by C.sub.1-6
alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, n-pentyl, isopentyl, neopentyl and hexyl, or or C.sub.2-7
alkanoyloxy-C.sub.1-6 alkyl such as acetyloxy methyl and
pivaloyloxymethyl, sulfo group, C.sub.1-4 alkylsulfonyl (e.g.
methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl
and n-butylsulfonyl), C.sub.6-10 arylsulfonyl (e.g. phenylsulfonyl
and naphthylsulfonyl) or C.sub.6-10 aryl-C.sub.1-4 alkylsulfonyl
(e.g. benzylsulfonyl, phenethylsulfonyl and
naphthylmethylsulfonyl), sulfonamido groups optionally substituted
with C.sub.1-6 alkyl groups or C.sub.6-10 aryl-C.sub.1-4 alkyl
groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl and
benzyl), and C.sub.1-3 alkyl groups (e.g. methyl, ethyl, propyl and
isopropyl) optionally substituted with (i) carboxyl groups
optionally esterified with C.sub.1-4 alkyl group (e.g. methyl,
ethyl, propyl and butyl), (ii) phosphono group which may be mono-
or di-substituted by C.sub.1-6 alkyl such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl,
neopentyl and hexyl, or C.sub.2-7 alkanoyloxy-C.sub.1-6 alkyl such
as acetyloxymethyl and pivaloyloxymethyl, (iii) sulfo group and
(iv) sulfonamido group optionally substituted with C.sub.1-6 alkyl
(e.g. methyl, ethyl, propyl, butyl, pentyl and hexyl) or C.sub.6-10
aryl-C.sub.1-4 alkyl(benzyl and phenethyl), and halogen (fluorine
and chlorine).
[0141] The number of the substituents of "optionally substituted
hydrocarbon group" is 1 to 4, preferably 1 to 2.
[0142] Preferable examples of "optionally substituted heterocyclic
groups" described in the specification include heterocyclic groups
having deprotonizable hydrogen atom optionally having one or two,
preferably one, substituents of substituents such as oxo group and
thioxo groups. As such heterocyclic groups, 5- to 6-membered
heterocyclic groups consisting of 1 to 4, preferably 2 to 3,
hetero-atoms selected from S, O and N are preferable. Specifically,
tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,
4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,
2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,
3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl,
4,5-dihydro-5-thioxo-isoxazolyl,
2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,
2,3-dihydro-3-oxo-1,2,4-tetrazolyl and
2,3-dihydro-3-thioxo-1,2,4-tetrazolyl are exemplified. Especially
tetrazolyl is preferable.
[0143] The term "acyl group" described in the specification refers
to carboxylic acid acyl groups derived from carboxylic acid
(C.sub.2-7 carboxylic acid acyl group e.g. acetyl, propionyl,
butyryl and benzoyl) and optionally substituted C.sub.6-10
arylsulfonyl groups, C.sub.1-4 alkylsulfonyl groups and C.sub.6-10
aryl-C.sub.1-4 alkylsulfonyl groups (e.g. methylsulfonyl,
ethylsulfonyl, phenylsulfonyl, naphthylsulfonyl,
phenylmethylsulfonyl, phenylethylsulfonyl, naphthylmethylsulfonyl
and naphthylethylsulfonyl). As the substituents of aryl-, alkyl-
and arylalkylsulfonyl groups, mention is made of, for example,
C.sub.1-3 alkyl (e.g. methyl, ethyl and propyl), C.sub.1-3 alkoxy
(e.g. methoxy, ethoxy and propoxy), halogen (chlorine, fluorine and
bromine), and 1 to 4, preferably 1 to 2, of them may optionally be
substituted at any substitutable position.
[0144] The above-mentioned carboxylic acid acyl groups may
optionally have 1 to 2 halogen atoms (chlorine, fluorine and
bromine) as substituents.
[0145] The ring formed by R.sub.2 and R.sub.3 together with the
adjacent nitrogen of the carbamoyl refers to optionally substituted
5- or 6-membered cyclic amino which may further have 1 to 3 hetero
atoms selected from nitrogen, sulfur and oxygen as ring
constituting atoms such as piperazinyl, piperidino, 1-pyrrolidinyl,
2-oxo-1-piperazinyl, 2,6-dioxo-1-piperazinyl, morpholinyl and
thiomorpholinyl. These cyclic amino groups may optionally have 1 to
4, preferably 1 to 2, substituents. Examples of those substituents
include hydroxyl group which may be substituted with C.sub.1-3
alkyl or C.sub.2-7 alkanoyl, carboxyl groups optionally esterified
with a C.sub.1-4 alkyl group (e.g. methyl, ethyl, propyl or t-butyl
group) or C.sub.6-10 aryl-C.sub.1-4 alkyl, phosphono group which
may be mono- or di-substituted by C.sub.1-6 alkyl such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl,
neopentyl and hexyl or C.sub.2-7 alkanoyloxy-C.sub.1-6 alkyl such
as acetyloxymethyl and pivaloyloxymethyl, sulfo group and
sulfonamido group optionally substituted with a C.sub.1-6 alkyl
group or a C.sub.6-10 aryl-C.sub.1-4 alkyl group (e.g. methyl,
ethyl, propyl, isopropyl, butyl, t-butyl or benzyl), C.sub.1-6
alkyl which may be substituted by [0146] (i) carboxyl group which
may be esterified with C.sub.1-6 alkyl, or C.sub.6-10
aryl-C.sub.1-4 alkyl, [0147] (ii) phosphono group which may be
mono- or di substituted by C.sub.1-6 alkyl or C.sub.2-7
alkanoyloxy-C.sub.1-6 alkyl, [0148] (iii) sulfo group, [0149] (iv)
sulfonamido which may be substituted by C.sub.1-6 alkyl or
C.sub.6-10 aryl-C.sub.1-4 alkyl, [0150] (v) hydroxyl group which
may be alkylated with C.sub.1-3 alkyl or C.sub.2-7 alkanoyl, [0151]
(vi) sulfhydryl group which may be alkylated with C.sub.1-3 alkyl,
[0152] (vii) carbamoyl, [0153] (viii) phenyl which may have 1 to 5
substituents selected from the group consisting of hydroxy,
halogen, aminosulfonyl, amino which may be substituted with
C.sub.1-3 alkyl and [0154] (ix) amino which may be mono- or
di-substituted by C.sub.1-3 alkyl, or [0155] (x) tetrazolyl, and
C.sub.2-5 alkenyl group (e.g. vinyl and allyl) which may be
substituted by the same group selected among (i) to (x) as
described above for substituents of C.sub.1-6 alkyl, amino groups
optionally mono- or di-substituted with C.sub.1-3 alkyl groups,
cyclic amino groups derived from 5- or 6-membered cyclic amine
which may further have a hetero atom selected from nitrogen, sulfur
and oxygen, and which may be substituted by C.sub.1-3 alkyl, benzyl
or phenyl, such as piperidyl, pyrrolidinyl, morpholinyl,
thiomorpholinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl and
4-phenylpiperazinyl, cyano group, carbamoyl group, oxo group,
heteteocyclic groups optionally substituted with an oxo group or
thioxo group having such a deprotonizable hydrogen atom as
mentioned above (e.g. tetrazolyl and
2,5-dihydro-5-oxo-1,2,4-oxazolyl), carbamoyl groups substituted
with C.sub.1-4 alkylsulfonyl, C.sub.6-10 arylsulfonyl and
C.sub.6-10, aryl-C.sub.1-4 alkyl arylsulfonyl(methylsulfonyl,
ethylsulfonyl, propylsulfonyl, butylsulfonyl, isopropylsulfonyl,
t-butylsulfonyl, phenylsulfonyl and benzylsulfonyl), sulfhydryl
which may be alkylated with C.sub.1-3 alkyl and phenyl which may
have 1 to 5 substituents such as hydroxyl, halogen, aminosulfonyl
and amino which may be substituted with C.sub.1-3 alkyl.
[0156] Examples of "optionally substituted carbamoyl group" shown
by X include
##STR00010##
[0157] Examples of R.sub.2' and R' include hydrogen and C.sub.1-7
alkyl. Among them, hydrogen is preferable.
[0158] Examples of R.sub.3' include C.sub.1-4 alkyl such as methyl,
ethyl, propyl and butyl.
[0159] Examples of C.sub.1-7 alkyl shown by R.sub.2, R.sub.2', R'
are the same as those described in "hydrocarbon group".
[0160] Examples of R'' include hydrogen and C.sub.1-4 alkyl. Among
them, hydrogen is preferable.
[0161] Examples of C.sub.1-4 alkyl shown by R.sub.3' and R''
include methyl, ethyl, propyl, isopropyl, n-butyl and t-butyl.
[0162] Examples of n include 1, 2, 3, 4 and 5.
[0163] Preferable examples of optionally substituted heterocyclic
groups having deprotonizable hydrogen atom, shown by X, include
N-containing (preferably 1 to 4 nitrogen atoms) 5- to 6-membered
heterocyclic groups having Bronsted acid-like active proton, and
those comprising 1 to 4, preferable 2 or 3, nitrogen atom, sulfur
atom and oxygen atom, are preferable. As these substituents,
mention is made of, for example, oxo group and thioxo group, and
one or two, preferably one substituents may be present. As
"optionally substituted heterocyclic groups having deprotonizable
hydrogen atom" shown by X, mention is made of, for example, those
exemplified as "optionally substituted heterocyclic groups" as the
substituents of the "optionally substituted carbamoyl groups" shown
by X, such as tetrazolyl, 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl.
[0164] As "lower alkyl groups" shown by R.sub.1, mention is made of
C.sub.1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, t-butyl, pentyl and hexyl. Among them, C.sub.1-3 alkyl
groups are especially preferable. As R.sub.1, methyl group is
especially preferable from the viewpoint of pharmacological
activity.
[0165] As "halogen atoms" shown by W, mention is made of chlorine,
fluorine, bromine and iodine atom. Among them, chlorine atom is
especially preferable.
[0166] Specifically the following compounds are preferable: [0167]
(3R,5S)--N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy--
2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-
, [0168]
(3R,5S)--N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3--
hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzo-
xazepine-3-acetamide, [0169]
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-m-
ethylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-ben-
zoxazepine-3-acetamide, [0170]
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-
-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzazepine-3-a-
cetamide, [0171]
(3R,5S)--N-methanesulfonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2-
,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-
, [0172]
(3R,5S)--N-methanesulfonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylp-
ropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzo-
xazepine-3-acetamide, [0173]
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphen-
yl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-aceti-
c acid, [0174]
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-d-
imethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl)piperi-
dine-4-acetic acid, [0175]
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphen-
yl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-aceti-
c acid ethyl ester, [0176]
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-d-
imethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperi-
dine-4-acetic acid ethyl ester, [0177]
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-
-1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one, [0178]
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-m-
ethylpropyl)-1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one, [0179]
(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl-7-chloro-5-(2,3-dimethoxyphenyl)--
1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one, [0180]
(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dime-
thoxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one,
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-N-[2-(pyrrolid-
in-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide,
etc.
[0181] As salts of the compound (1), mention is made of
pharmaceutically acceptable salts including inorganic salts such as
hydrochloride, hydrobromide, sulfate, nitrate and phosphate,
organic acid salts such as acetate, tartrate, citrate, fumarate,
maleate, toluenesulfonate and methanesulfonate, metal salts such as
sodium salt, potassium salt, calcium salt and aluminum salt, and
basic salts such as triethylamine salt, guanidine salt, ammonium
salt, hydrazine salt, quinine salt and cinchonine salt.
[0182] Hydrate and non-hydrate of compound (1) are also concluded
in the scope of this invention.
[0183] In the compound represented by the formula (I) or salts
thereof, asymmetric carbons exist at 3- and 5-positions, and
trans-compounds, in which the substituent at 3-position and
substituent at 5-position are faced to the reverse direction
relative to the face of the 7-membered ring, is preferable.
Especially, those in which the absolute configuration at 3-position
is R-configuration and the absolute configuration at 5-position is
S-configuration, are preferable.
[0184] While the compound represented by the above-mentioned
formula (I) or salts thereof can be produced in accordance with,
for example, methods disclosed in EPA567026, WO95/21834 [PCT
application based on Japanese Patent Application H6 (1994)-15531)],
EPA645377 [application based on Japanese Patent Application H6
(1994)-229159] and EPA645378 [application based on Japanese Patent
Application H6 (1994)-229160], or methods analogous to them, they
can be produced also by, for example, the following methods.
[0185] More specifically, the compound of the formula (I) or a salt
thereof can be produced, as shown by, for example, the following
formula, by subjecting a corresponding 3-carboxymethyl compound
(1') to condensation with a compound represented by the formula
##STR00011##
(R.sub.2 and R.sub.3 are defined above)
##STR00012##
[wherein each symbol is of the same meaning as defined above].
[0186] The compound (1) or a salt thereof can be produced by
subjecting the compound represented by the formula (I') to
condensation with the compound represented by the formula
##STR00013##
in a solvent, in the presence of a base when necessary, using a
condensing agent. Examples of the solvent include hydrocarbons such
as benzene, toluene, hexane and heptane, halogenic solvents such as
dichloromethane, dichloroethane, chloroform and carbon
tetrachloride, ethers such as ethyl ether, tetrahydrofuran and
dioxane, acetonitrile and dimethylformamide. As the base, mention
is made of triethylamine, 4-dimethylaminopyridine,
triethylenediamine and tetramethylethylenediamine. As the
condensing agent, mention is made of condensing agents employed for
the synthesis of peptide, as exemplified by dicyclohexyl
carbodiimide, diethyl cyanophosphate and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The compound
represented by the formula
##STR00014##
is used in an amount ranging from 0.5 to 2 molar equivalents,
preferably from 1 to 1.2 molar equivalent, relative to one mole of
the compound shown by the formula (I'), and the condensing agent is
used in an amount ranging from 0.5 to 5 molar equivalents,
preferably from 1 to 2 molar equivalents. The reaction temperature
ranges from 0 to 100.degree. C., preferably from 20 to 50.degree.
C. The reaction time ranges from 0.5 to 24 hours, preferably from
about 1 to about 5 hours.
[0187] The compound (I) or a salt thereof with X as optionally
substituted heterocyclic group having a deprotonizable hydrogen
atom, by X, or the carbamoyl group substituted with the optionally
substituted heterocyclic group having a deprotonizable hydrogen
atom can be produced by converting the carboxyl group in the
carbamoyl group substituted with carboxyl group or a substituent
having carboxyl group, shown by X, into carboxylic acid amido,
subjecting the carboxylic acid amido to dehydration to convert it
further into cyano group, then converting the cyano group into the
optionally substituted heterocyclic group having a deprotonatable
hydrogen atom.
[0188] The above-mentioned conversion of carboxylic acid into
carboxylic acid amido can be conducted in accordance with a per se
known method. For example, a compound with carboxylic acid group is
subjected to condensation with ammonium or ammonium chloride, when
necessary in the presence of a base (e.g. triethylamine,
dimethylaminobenzene, pyridine, potassium carbonate, sodium
carbonate, potassium hydrogencarbonate or sodium
hydrogencarbonate), using a condensing agent such as diethyl
cyanophosphate or dicyclohexyl carboxiimide. As the solvent to be
employed, mention is made of ethers such as diethyl ether,
tetrahydrofuran or dioxane, halogen type solvents such as
dichloromethane, chloroform or carbon tetrachloride,
dimethylformamide and acetonitrile. In these solvents, relative to
one mole of a compound having carboxyl group, 1 to 100, preferably
about 1 to 5, molar equivalent of ammonia or ammonium chloride is
used. The reaction temperature ranges from 0 to 100.degree. C.,
preferably from 0 to 50.degree. C., and the reaction time ranges
from 0.1 to 24 hours, preferably from about 0.5 to about 5
hours.
[0189] For converting the carboxylic acid amido obtained thus above
into cyano group, a compound having carboxylic acid amide is
reacted with thionyl chloride in a solvent such as benzene, hexane,
toluene or xylene to provide corresponding cyano compound.
[0190] The amount of thionyl chloride to be employed ranges,
relative to 1 mole of the compound having carboxylic acid amido,
from 1 to 10, preferably from 1 to 3, molar equivalents. The
reaction temperature ranges from 50 to 200.degree. C., preferably
from 70 to 150.degree. C. The reaction time ranges from 0.5 to 10
hours, preferably from about 0.5 to about 3 hours.
[0191] The above-mentioned conversion of cyano group into the
optionally substituted heterocyclic group having a deprotonizable
proton, e.g. tetrazole ring, can be performed by allowing a
compound having cyano group to react with trimethylsilyl azide and
dibutyltin (IV) oxide in a solvent such as benzene, hexane, toluene
or xylene.
[0192] The amount of trimethylsilyl azide ranges, relative to 1
mole of the compound having cyano group, from 0.5 to 10, preferably
from 1 to 3, molar equivalents, and the amount of dibutyltin (IV)
oxide ranges from 0.01 to 3, preferably from about 0.05 to about 1,
molar equivalents. The reaction temperature ranges from 0 to
200.degree. C., preferably from 50 to 150.degree. C. The reaction
time ranges from 10 to 48 hours, preferably from 15 to 30 hours.
Furthermore, conversion into, for example,
2,5-dihydro-5-oxo-1,2,4-oxadiazole ring can be performed by
allowing hydroxylamine to react with the compound having cyano
group, then by further carbonylating the resultant compound.
Hydroxylamine (1 to 10, preferably 1 to 3, equivalents relative to
1 mole of the compound having cyano group) is allowed to react with
the compound having cyano group in a solvent as exemplified by an
alcohol solvent such as methanol, ethanol and propanol,
dimethylformamide or acetonitrile, in the presence of a base such
as sodium hydrogencarbonate, potassium hydrogencarbonate or
potassium carbonate, at a temperature ranging from 30 to
150.degree. C., preferably from 50 to 100.degree. C., for 1 to 24
hours, preferably about 5 to about 10 hours. For carbonylation of
the compound thus obtained, carbodiimide or phosgene, for example,
is employed for the carbonylating agent, and, as the solvent, for
example, ether type solvents such as diethyl ether,
tetrahydrophosgene or dioxane, halogen type solvents such as
dichloromethane or chloroform, and ethyl acetate are employed. The
amount of the carbonylating agent ranges from 1 to 10, preferably 1
to 3 molar equivalents. The reaction temperature ranges from 30 to
150.degree. C., preferably from 50 to 100.degree. C., and the
reaction time ranges from 1 to 24, preferably from about 3 to about
100 hours.
[0193] In the above-described reaction, the compound, in which the
moiety corresponding to X of the synthetic intermediate is an
esterified carboxyl group or an optically active carboxyl group,
can be obtained by, for example, the method disclosed in
WO095/21834. More specifically, at first, the corresponding racemic
compound is obtained, which is then allowed to react with an
optically active amino acid to form the amido bond, followed by
subjecting the resultant compound to distillation,
recrystallization and column chromatography to separate and purify
the optically active isomer, and then, the amido bond is again
cleaved to give a (3R,5S) compound. Alternatively, by the cleaved
reaction step shown by the formula:
##STR00015##
[wherein Piv stands for pivaloyl group, and other symbols are of
the same meanings as defined above], enzymatic asymmetric
hydrolysis is conducted to give an optically active isomer
(S-configuration) of a benzyl alcohol derivative, then, using this
optically active isomer as the starting material, in accordance
with the method disclosed in EPA567026, to give the above-mentioned
(3R,5S) of the compound (I') as defined above.
[0194] The compound represented by the formula (I) or a salt
thereof in the present invention [hereinafter sometimes called the
compound of the formula (I) or the compound (I)] is low in
toxicity, has a squalene synthetase inhibiting activity and an
activity of lowering the level of triglyceride, and, has an
excellent activity of lowering the level of lipids, and is useful
for the prophylaxis or therapy of hyperlipemia such as
hypercholesteremia and hypertriglycerolemia of mammals (e.g. mouse,
rat, rabbit, dog, cat, cow, pig and man), and also useful for the
prophylaxis or therapy of renal diseases such as nephritis and
nephropathy, arteriosclerosis, ischemic diseases, myocardial
infarction, angina pectoris, aneurysm, cerebral arteriosclerosis,
peripheral arteriosclerosis, thrombosis, diabetes mellitus (e.g.
insulin resistant diabetes), pancreatic disorders and re-stenosis
after percutaneous transluminal coronary angioplasty (PTCA).
[0195] The use of this invention is described in further detail as
follows.
[0196] In view of the triglyceride-lowering activity,
cholesterol-lowering activity and biological properties of the
compound of the formula (I), the compound is especially useful for
the therapy and prophylaxis of hyperlipemia, especially
hypertriglycerolemia, hyperlipoproteinemia and
hypercholesterolemia, and, atherosclerotic diseases caused
therefrom, and, secondary diseases thereof, for example, coronary
diseases, cerebral ischemia, intermittent claudication and
gangrene.
[0197] For the therapy of these diseases, the compound of the
general formula (I) can be used singly or in combination with any
other medicinal ingredients containing a lipid-level lowering agent
or a cholestrol-level lowering agent. In this case, these compounds
are administered, preferably, orally, and, upon necessity, they may
be administered as agents for rectal use in the form of
suppository. Examples of medicinal agents which can be used in
combination with the compound (1) include fibrates [e.g.
chlorofibrate, benzafibrate and gemfibrozil], nicotinic acid, its
derivatives and analogues [e.g. acipimox and probucol), bile acid
binding resins [e.g. cholestyramine and cholestypol], compounds
inhibiting cholesterol absorption (e.g. sitosterol or neomycin],
compounds controlling the biosynthesis of cholesterol [e.g. HMG-CoA
reductase inhibiting agents such as lovastatin, simvastatin and
pravastatin], and squalene epoxidase inhibiting agents [e.g. NB-598
and analogous compounds]. As further agents which can be used in
combination with the compound (1), mention is made of, for example,
oxidosqualene-lanosterolcyclases such as decalin derivatives,
azadecalin derivatives and indane derivatives.
[0198] Additional, the compound of the general formula (I) is
applicable to treatment of diseases related to
hyperchylomicronemia, for example, acute pancreatitis. The
mechanism of occurrence of pancreatitis has been considered that
minute thrombus occurs in pancreatic blood capillary by the action
of chylomicron or by strong topical irritation with the increase of
free fatty acid produced by decomposition of triglyceride by
pancreatic lipase due to hyperchylomicronemia. In view of the
above, since the compound of the formula (I) of this invention has
an activity of lowering the level of triglyceride, it can be used
for the therapy of pancreatitis, and can be used for the therapy of
pancreatitis singly or in combination with a known therapeutic
method. For the therapy of this disease, the compound of the
formula (I) can be administered orally or topically, or it can be
used singly or in combination with a known active compound. As the
agent which can be combined for this purpose, mention is made of,
for example, aprotinin (trasylol), gabexate mesylate (FOY),
nafamostat mesilate (Futhan), citicoline (nicholin) and urinastatin
(miraclide). And, for the purpose of removing pain,
antichlolinergic drugs, non-narcotic analgesics and narcotic drugs
can also be used.
[0199] As further noticeable examples of diseases, to which the
compound of the general formula (I) is applicable, mention is made
of secondary hyperlipemia including, for example, diabetes
mellitus, hypothyroidism, nephrotic syndrome or chronic renal
failure. In many cases, these diseases cause hyperlipemia and the
latter aggravates these diseases, causing a so-called vicious
circle. Taking its lipid-level lowering activity into
consideration, the compound of the general formula (I) is useful
for the therapy and for preventing the aggravation of these
diseases. For this purpose, the compound of the general formula (I)
can be administered singly or in combination with examplary
medicines set forth below. Medicines for diabetes mellitus:
kinedak, benfil, humulin, euglucon, glimicron, daonil, novorin,
monotard, insulins, glucobay, dimelin, rastinon, bacilcon,
deamiline S, iszilins;
Medicines for hypothyroidism: thyroid (thyreoid), levothyroxine
sodium (thyradin S), liothyronine sodium (cylonine, cylomin);
Medicines for nephrotic syndrome: For the therapy using steroid as
the first choice, use is made of, for example, predinisolone sodium
succinate (predonine), prednisolone sodium succinate (predonine),
methyl prednisolone sodium succinate (solu-medrol) and
betamethasone (renderon). And, for anticoagulant therapy, use is
made of antiplatelet medicines such as dipyridamole (persantine)
and dilazep hydrochloride (comelian); Medicines for chronic renal
failure: A combination of diuretics [e.g. furosemide (lasix),
bumetanide (lunetoron) and azosemide (diart)], hypotensive drugs
(e.g. ACE inhibitors (enalapril maleate (renivace)) and Ca
antagonists (Ca antagonistic drugs (maninhilone), .alpha.-receptor
blocking agents is administered, preferably, orally.
[0200] Another possible use of the compound of the general formula
(I) of this invention is to inhibit the formation of thrombus. In
view of the fact that the triglyceride level in blood is an
positive correlation with the blood coagulation factor VII and
intake of .omega.-3 type fatty acid serves to lower the
triglyceride level and, at the same time, the coagulation is
inhibited, it has been considered that hypertriglycemia would
promote the formation of thrombus. Since VLDL (very low density
lipoprotein) of the patients suffering from hyperlipemia increased
more strongly the secretion of plasminogen activator inhibitor from
vascular endothelial cells than that of the patients suffering from
normal lipemia, it is considered that triglyceride (hereinafter TG)
acts to lower the fibrinolytic activity. Therefore, taking the TG
lowering action, the compound of the general formula (I) can be
effectively used for the prophylaxis and therapy of the formation
of thrombus. The compound (1) can be administered singly or in
combination with any of the following exemplary known therapeutic
agents, preferably orally.
[0201] Medicines for prophylaxis and therapy of thrombus formation:
blood coagulation inhibitors [e.g. heparin sodium, heparin calcium,
warfarin calcium (warfarin)], thrombolytic agents [e.g. urokinase],
antiplatelet agents (e.g. aspirin, sulfinpyrazolo (anturane),
dipyridamole (persantine), acropidin (panaldin), cilostazol
(pletaal)].
[0202] The compound (1) can be used orally or non-orally in the
manner of injection, drip infusion, inhalation, rectal
administration or topical administration, as it is or as a
medicinal composition (e.g. powder, granule, tablet, pill, capsule,
injection, syrup, emulsion, elixir, suspension and solution). In
other words, at least one species of the compounds of this
invention can be used singly or in combination with a
pharmaceutically acceptable carrier (e.g. adjuvant, excipent,
forming aid and/or diluent).
[0203] These pharmaceutical compositions can be prepared by a
conventional method. These compositions can be prepared by usually
mixing/kneading active components with an additive such as
excipients, diluents and carriers. In the present specification,
"non-oral administration" include subcutaneous injection,
intravenous injection, intramuscular injection, intraperitoneal
injection or drip infusion. Injectable compositions, for example, a
sterile injectable aqueous suspension or an oily suspension, can be
prepared by a known method in the relevant field using a suitable
dispersing agent or a moistening agent. The sterile injectable
composition may be a solution or a suspension injectable under
sterile conditions in a non-toxic diluent or a solvent
administrable non-orally, for example, an aqueous solution. As a
vehicle or a solvent which can be employed, mention is made of, for
example, water, a Ringer solution and an isotonic aqueous saline
solution. Further, a sterile non-volatile oil can also be employed
as a common solvent or a suspending solvent. For this purpose, any
non-volatile oil and fatty acid can also be employed, including
natural or synthetic or semi-synthetic fatty oil or fatty acid as
well as natural or synthetic or semi-synthetic mono- or di- or
triglycerides.
[0204] The suppository for rectal use can be prepared by mixing the
drug with a suitable non-irritable excipient, e.g. cocoa butter or
polyethylene glycol which is solid at normal temperatures, liquid
at temperatures in intestinal tube, and melts and release the drug
in rectum.
[0205] As the solid dosage form for oral administration, mention is
made of, for example, powder, granule, tablet, pill and capsule as
mentioned above. The composition of such dosage form as above can
be prepared by mixing and/or kneading a compound as the active
component with at least one species of additives as exemplified by
sucrose, lactose, cellulose, mannitol (D-mannitol), multitol,
dextrin, starch (e.g. corn starch), microcrystalline cellulose,
agar, alginates, chitins, chitosans, pectins, tragacanth gum,
acacia, gelatins, collagens, casein, albumin, synthetic or
semi-synthetic polymers or glycerides. These compositions may
optionally contain further additives, like in usual cases, for
example, an inert diluent, a lubricant such as stearic acid and
magnesium, a preservative such as parabens and sorbins, an
antioxidant such as ascorbic acid, .alpha.-tocopherol and cysteine,
a disintegrant (e.g. floscaromelose sodium), a binder (e.g.
hydroxypropyl cellulose), a thickening agent, a buffering agent, a
sweetening agent, a flavoring agent and perfuming agent. Tablets
and pills may optionally be prepared with enteric coating. As
liquid preparations for oral administration, mention is made of,
for example, a pharmaceutically acceptable emulsion, syrup, elixir,
suspension and solution, and they may optionally contain an inert
diluent such as water and, depending on necessity, an additive.
These liquid compositions for oral administration can be prepared
by a conventional method, for example, mixing the compound as the
active component with an inert diluent and, upon necessity, any
other additive.
[0206] The orally administrable compositions, while varying with
the forms, are incorporated with usually 0.01 to 99 W %, preferably
0.1 to 90 W %, commonly 0.5 to 50% of the compound of this
invention as the active component. The dose for a specific patient
is determined, while taking into consideration age, body weight,
general health conditions, sex, diet, the time of administration,
the method of administration, secretion rate, combination of drugs,
conditions of the disease then the patient is receiving the therapy
and any other factors. A lipid level lowering agent such as a
triglyceride level lowering agent comprising the compound (1) of
this invention is relatively low in toxicity and can be safely
used. Although the daily dose varies depending on the conditions
and body weight of the patient, kinds of the compound,
administration routes and any other factors, a daily dosage per
adult human (about 60 kg body weight) in the case of, for example,
oral administration for the prophylaxis and therapy of hyperlipemia
ranges from about 1 to 500 mg, preferably from about 10 to 200 mg,
of the effective component [compound (I)], and, in the case of a
non-orally administrable composition, the daily dose range from
about 0.1 to 100 mg, preferably from about 1 to 50 mg, commonly
from about 1 to 20 mg in terms of the effective component. Within
this range, no toxicity is observed at all.
BEST MODE OF CARRYING OUT THE INVENTION
[0207] The following Working Examples, formulation examples and
experimental examples are intended to illustrate the present
invention in further detail and should by no means be construed as
limiting the invention.
Examples
Working Example 1
Methyl ester of
N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tet-
rahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-carboxylic acid
##STR00016##
[0209] To a solution of
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrah-
ydro-4,1-benzoxazepine-3-acetic acid (0.5 g) and 0.25 g of
piperidine-4-carboxylic acid methyl ester hydrochloride in
dimethylformamide (10 ml) were added, at room temperature,
diethylcyanophosphonate (0.28 g) and triethylamine (0.38 ml), and
the mixture was stirred for one hour. To the mixture were added
water (100 ml) and ethyl acetate (100 ml). The organic layer was
washed with 1N HCl and a saturated aqueous solution of sodium
hydrogencarbonate, followed by drying over an hydrous magnesium
sulfate. The solvent was distilled off, and the residue was
purified by silica gel column chromatography (eluents: hexane:ethyl
acetate=1:1 (v/v) to afford 0.62 g of a colorless crystalline
product, m.p. 124-126.degree. C.
[0210] Elemental analysis for
C.sub.31H.sub.39ClN.sub.2O.sub.7.0.3H.sub.2O:
TABLE-US-00001 Calcd.: C, 62.84; H, 6.74; N, 4.73 Found: C, 62.78;
H, 6.69; N, 4.72
Working Example 2
[0211] By substantially the same procedure as in Example 1,
compounds shown in [Table 1] were obtained.
TABLE-US-00002 TABLE 1 ##STR00017## Com- pound No. Y m.p. (.degree.
C.) 2-1 ##STR00018## 159-160 2-2 ##STR00019## 110-112 2-3
##STR00020## 200-202 2-4 ##STR00021## 123-125 2-5 ##STR00022##
196-198 2-6 ##STR00023## 169-171 2-7 ##STR00024## 256-258 2-8
##STR00025## 175-177 2-9 ##STR00026## 86-89 2-10 ##STR00027##
154-155 2-11 ##STR00028## 141-142 2-12 ##STR00029## 146-148 2-13
##STR00030## 111-113 2-14 ##STR00031## 125-127 2-15 ##STR00032##
180-180.5 2-16 ##STR00033## 195-197 2-17 ##STR00034## 203-204 2-18
##STR00035## 132-134 2-19 ##STR00036## 197-200 2-20 ##STR00037##
165-166 2-21 ##STR00038## 142-145 2-22 ##STR00039## 209-210 2-23
##STR00040## 123-125 2-24 ##STR00041## 96-98 2-25 ##STR00042##
107-108 2-26 ##STR00043## 142-144 2-27 ##STR00044## 216-218 2-28
##STR00045## 132-134 2-29 ##STR00046## amorphous solid 2-30
##STR00047## amorphous solid 2-31 ##STR00048## amorphous solid 2-32
##STR00049## 104-106 2-33 ##STR00050## 115-116 2-34 ##STR00051##
103-105 2-35 ##STR00052## 193-195 2-36 ##STR00053## 126-128 2-37
##STR00054## 124-127 2-38 ##STR00055## 150-151
Working Example 3
N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetr-
ahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-carboxylic acid
##STR00056##
[0213] The compound (0.5 g) obtained in Example 1 was dissolved in
a mixture of 1N aqueous solution of sodium hydroxide (4 ml),
methanol (10 ml) and tetrahydrofuran (5 ml). The solution was
stirred for one hour at room temperature, to which were added 1N
HCl (50 ml) and ethyl acetate (100 ml). The organic layer was
washed with water and dried over anhydrous magnesium sulfate. The
solvent was removed, and the residue was recrystallized from
hexane-diethyl ether to afford 0.47 g of colorless crystals, m.p.
145-147.degree. C.
[0214] Elemental analysis for
C.sub.30H.sub.37ClN.sub.2O.sub.7.0.3H.sub.2O:
TABLE-US-00003 Calcd.: C, 62.29; H, 6.55; N, 4.84 Found: C, 62.20;
H, 6.65; N, 4.83
Working Example 4
[0215] By subjecting the compound obtained in Example 2 to
substantially the same procedure as in Example 3, compounds shown
in [Table 2] were obtained.
TABLE-US-00004 TABLE 2 ##STR00057## Com- pound No. Y m.p. (.degree.
C.) 4-1 ##STR00058## amorphous solid 4-2 ##STR00059## 137-140 4-3
##STR00060## 214-217 4-4 ##STR00061## 132-136 4-5 ##STR00062##
136-144 4-6 ##STR00063## 157-160 4-7 ##STR00064## 160-170 4-8
##STR00065## 137-139 4-9 ##STR00066## 152-155 4-10 ##STR00067##
145-150 4-11 ##STR00068## 107-110 4-12 ##STR00069## 134-136 4-13
##STR00070## 135-140 4-14 ##STR00071## 147-150 4-15 ##STR00072##
134-136 4-16 ##STR00073## 140-142 4-17 ##STR00074## 137-140 4-18
##STR00075## 228-230 4-19 ##STR00076## 156-159 4-20 ##STR00077##
163-166 4-21 ##STR00078## 165-167 4-22 ##STR00079## 145-147 4-23
##STR00080## amorphous solid 4-24 ##STR00081## 122-124 4-25
##STR00082## 158-160 4-26 ##STR00083## 160-162 4-27 ##STR00084##
200-205 4-28 ##STR00085## amorphous solid 4-29 ##STR00086## 129-132
4-30 ##STR00087## 87-92 4-31 ##STR00088## 162-164 4-32 ##STR00089##
amorphous solid 4-33 ##STR00090## 128-131 4-34 ##STR00091##
142-145
Working Example 5
3-[(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neop-entyl-2-oxo-1,2,3,5-tet-
rahydro-4,1-benzoxazepine-3-acetamino]propylamine hydrochloride
##STR00092##
[0217] An ethanol solution of the compound (0.2 g) obtained in
Example 6-31 and hydrazine-monohydrate (0.10 g) was stirred for one
hour at 70.degree. C. To the reaction mixture was added ethyl
acetate (50 ml). The mixture was washed with water and dried,
followed by distilling off the solvent. The residue was dissolved
in acetate (50 ml), to which was added hydrogen chloride (4N
solution in ethyl acetate) (0.1 ml). The solvent was distilled off,
and the residue was recrystallized from ethanol-diethyl ether to
afford 50 mg of colorless crystals, m.p. 158-163.degree. C.
[0218] Elemental analysis for
C.sub.27H.sub.37Cl.sub.2N.sub.3O.sub.51.7H.sub.2O:
TABLE-US-00005 Calcd.: C, 55.42; H, 6.92; N, 7.18 Found: C, 55.21;
H, 6.90; N, 7.12
Working Example 6
[0219] Employing
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrah-
ydro-4,1-benzoxazepine-3-acetic acid, substantially the same
procedure as in Example 1 was conducted to obtain compounds shown
in [Table 3].
TABLE-US-00006 TABLE 3 ##STR00093## Com- pound No. Y m.p. (.degree.
C.) 6-1 ##STR00094## 95-101 6-2 ##STR00095## 135-230 (decomp.) 6-3
##STR00096## 101-105 6-4 ##STR00097## 270-283 (decomp.) 6-5
##STR00098## 109-111 6-6 ##STR00099## 243-245 6-7 ##STR00100##
amorphous solid 6-8 ##STR00101## 133-135 6-9 ##STR00102## 164-165
6-10 ##STR00103## 99-103 6-11 ##STR00104## 96-98 6-12 ##STR00105##
143-145 6-13 ##STR00106## 136-140 6-14 ##STR00107## 119-122 6-15
##STR00108## 119-121 6-16 ##STR00109## 106-109 6-17 ##STR00110##
amorphous solid 6-18 ##STR00111## 204-206 6-19 ##STR00112## 106-108
6-20 ##STR00113## 111-121 6-21 ##STR00114## 118-120 6-22
##STR00115## 112-119 6-23 ##STR00116## 115-117 6-24 ##STR00117##
112-114 6-25 ##STR00118## 145-148 6-26 ##STR00119## 184-185 2-27
##STR00120## 125-127 2-28 ##STR00121## 145-150 6-29 ##STR00122##
173-174 6-30 ##STR00123## 181-183 6-31 ##STR00124## oil 6-32
##STR00125## 90-95 6-33 ##STR00126## 118-120 6-34 ##STR00127##
147-148 6-35 ##STR00128## 118-121 6-36 ##STR00129## 97-100 6-37
##STR00130## 227-228 6-38 ##STR00131## amorphous solid 6-39
##STR00132## 192-194
Working Example 7
(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-1,2,3,5-tetrahydro-3--
(1H(or 3H)-tetrazol-5-yl)methyl-4,1-benzoxazepin-2-one
##STR00133##
[0220] (1) A dimethylformamide solution of
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrah-
ydro-4,1-benzoxazepine-3-acetic acid (2.0 g), ammonium chloride
(1.2 g) and triethylamine (1.0 ml) was cooled in ice bath. To the
solution were added diethylcyanophosphonate (0.85 g) and
triethylamine (0.5 ml). The mixture was stirred for further 20
minutes, to which was added ice-water, followed by extraction with
ethyl acetate. The organic layer was washed with water, which was
dried over anhydrous magnesium sulfate. The solvent was distilled
off, and the residue was recrystallized from diethyl ether to give
1.0 g of
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrah-
ydro-4,1-benzoxazepine-3-acetamide as colorless crystals, m.p.
170-172.degree. C. (2) The compound (3.2 g) obtained in (1) and
thionyl chloride (1.8 ml) were suspended in toluene (40 ml). The
suspension was stirred for one hour at temperatures ranging from
110 to 120.degree. C. The solvent was removed. To the residue were
added ethyl acetate (100 ml) and a saturated aqueous solution of
sodium hydrogencarbonate (50 ml). The organic layer was dried over
anhydrous sodium sulfate, then the solvent was distilled off. The
residue was purified by silica gel column chromatography (eluents:
hexane:ethyl acetate=3:1 (v/v)) to give 1.7 g of
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-1,2,3,5-tetrahydro-3-
-cyanomethyl-4,1-benzoxazepin-2-one as colorless crystals, m.p.
193-194.degree. C. (3) To a solution of the compound (1.7 g)
obtained in (2) in toluene (20 ml) were added trimethyl silyl azide
(0.45 g) and dibutyltin (IV) oxide (30 mg). The mixture was stirred
for 24 hours at temperatures ranging from 110 to 120.degree. C. The
reaction mixture was concentrated, to which was added diethyl ether
(20 ml), followed by washing with an aqueous solution of sodium
hydroxide. The aqueous layer was acidified with 1N HCl, which was
then subjected to extraction with ethyl acetate. The organic layer
was washed with water, which was then dried over anhydrous sodium
sulfate. The solvent was distilled off, and the residue was
recrystallized from dichloromethane-hexane to give colorless
crystals, m.p. 148-150.degree. C.
[0221] Elemental analysis for
C.sub.24H.sub.28ClN.sub.5O.sub.4.0.5H.sub.2O:
TABLE-US-00007 Calcd.: C, 58.24; H, 5.91; N, 14.15 Found: C, 58.43;
H, 6.18; N, 13.76
Working Example 8
(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-3-(2,5-dihydro-5-oxo--
1,2,4-oxadiazol-3-yl)methyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one
##STR00134##
[0223] To ethanol (15 ml) were added the compound (0.5 g) obtained
in Example 7-(2), hydroxylamine hydrochloride (0.25 g) and sodium
carbonate (0.55 g). The mixture was heated for 8 hours under
reflux. The reaction mixture was concentrated under reduced
pressure, to which were added ethyl acetate (20 ml) and water (20
ml). The organic layer was washed with water, which was then dried
over anhydrous sodium sulfate. The solvent was distilled off. The
residue (0.55 g), carbodiimidazole (0.5 g) and triethylamine (0.3
ml) were dissolved in ethyl acetate (30 ml). The solution was
heated for 6 hours under reflux. The reaction mixture was washed
with water and dried. The solvent was distilled off. The residue
was purified by silica gel column chromatography (eluents:
dichloromethane:methanol:H.sub.2O=250:5:0.5 (v/v)) to give 0.44 g
of colorless crystals, m.p. 130-133.degree. C.
[0224] Elemental analysis for C.sub.25H.sub.28ClN.sub.3O.sub.6:
TABLE-US-00008 Calcd.: C, 59.82; H, 5.62; N, 8.37 Found: C, 59.57;
H, 5.78; N, 7.97
Working Example 9
(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-1,2,3,5-tetrahydro-3--
(tetrazol-5-yl)methyl-4,1-benzoxazepin-2-one sodium salt
##STR00135##
[0226] To a solution of the compound (0.6 g) obtained in Example 7
in methanol (10 ml) was added 1N NaOH (1.02 ml), which was
concentrated under reduced pressure. The concentrate was dissolved
in ethyl acetate (30 ml), which was concentrated under reduced
pressure to leave a powdery residue. To the powdery residue was
added diethyl ether (20 ml), which was filtrated to collect 0.61 g
of a white powdery product.
[0227] Elemental analysis for
C.sub.24H.sub.27ClN.sub.5O.sub.4Na.H.sub.2O:
[0228] Calcd.: C, 54.81; H, 5.56; N, 13.31
[0229] Found: C, 54.59; H, 5.82; N, 13.03
Working Example 10
5-[2-[N-[(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,-
5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidin-4-yl]]1H(or
3H)tetrazole
##STR00136##
[0231] The compound (0.3 g) obtained in Example 6-29 was subjected
to substantially the same procedure as in Example 7-(3) to give
0.25 g of colorless crystals, m.p. 185-187.degree. C.
[0232] Elemental analysis for
C.sub.31H.sub.37ClN.sub.6O.sub.5.H.sub.2O:
TABLE-US-00009 Calcd.: C, 58.58; H, 6.39; N, 13.66 Found: C, 58.84;
H, 6.15; N, 13.46
Working Example 11
(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)--
1,2,3,5-tetrahydro-3-[1H (or
3H)-tetrazol-5-yl]methyl-4,1-benzoxazepin-2-one
##STR00137##
[0233] (1) To a solution of
(S)-4-chloro-2-[.alpha.-hydroxy-(2,3-dimethoxyphenyl)methyl]aniline
(2.0 g) and sodium hydrogencarbonate (0.86 g) in ethyl acetate (20
ml) was added dropwise a solution of monoethyl ester of dimethyl
malonic acid chloride (1.3 g) in ethyl acetate (20 ml). The mixture
was stirred for 3 hours under ice-cooling. To the solution was
added water (30 ml), and the organic layer was dried over anhydrous
sodium sulfate. The solvent was distilled off, and the residue was
purified by silica gel column chromatography to give
(S)-2-[N-[2-(2,3-dimethoxy-.alpha.-hydroxybenzyl)-4-chlorophenyl]carbamoy-
l]-2,2-dimethyl acetic acid ethyl ester (2.92 g) as a colorless
oily compound.
[0234] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, t, J=7.4 Hz),
1.37 (3H, s), 1.42 (3H, s), 3.84 (3H, s), 3.89 (3H, s), 4.05-4.19
(3H, m), 6.01 (1H, s), 6.61 (1H, dd, J=1.8, 7.4 Hz), 6.90-7.05 (3H,
m), 7.28 (1H, dd, J=3.0, 8.8 Hz), 8.07 (1H, d, J=8.4 Hz), 9.49 (1H,
br)
(2) To a solution of the compound (2.83 g) obtained in (1) in
tetrahydrofuran (30 ml) was added, under ice-cooling, lithium
aluminum hydride (0.5 g). The mixture was stirred for 3 hours at
room temperature. To the reaction mixture were added a 1N aqueous
solution of sodium hydroxide (13 ml) and water (50 ml), then
insolubles were filtered off. The filtrate was extracted with ethyl
acetate. The extract was washed with water and dried, then the
solvent was distilled off. The residue was purified by silica gel
column chromatography (eluents: hexane:ethyl acetate=1:1 (v/v)) to
give
(S)-[5-chloro-2-(2,2-dimethyl-3-hydroxypropyl)aminophenyl](2,3-dimethoxyp-
henyl)methanol (0.88 g) as a colorless oily compound.
[0235] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.91 (3H, s), 0.93 (3H,
s), 2.95 (2H, s), 3.37 (2H, s), 3.83 (3H, s), 3.88 (3H, s), 5.99
(1H, s), 6.63 (1H, d, J=8.8 Hz), 6.77 (1H, dd, J=1.6, 7.6 Hz), 6.90
(1H, dd, J=1.6, 7.6 Hz), 7.03 (1H, d, J=2.6 Hz), 7.03 (1H, t, J=7.6
Hz), 7.13 (1H, dd, J=2.6, 8.8 Hz)
(3) To a solution of the compound (0.88 g) obtained in (2) in ethyl
acetate (10 ml) was added sodium hydrogencarbonate (0.39 g). To the
mixture was added a solution of monoethyl ester of fumaric acid
chloride (0.45 g) in ethyl acetate (10 ml), which was stirred for
30 minutes at room temperature. The reaction mixture was washed
with water and dried, then the solvent was distilled off. The
residue was dissolved in ethanol (10 ml), to which was added
potassium carbonate (0.70 g). The mixture was stirred overnight at
room temperature. To the reaction mixture was added ethyl acetate
(50 ml), which was washed with water and dried. The solvent was
distilled off, and the residue was recrystallized from ethyl
acetate-hexane to give
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(2,2-dimethyl-3-hydroxypropyl)-
-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl
ester (0.57 g) as colorless crystals, m.p. 188-190.degree. C. (4)
The compound (0.5 g) obtained in (3) was dissolved in a mixture of
tetrahydrofuran (5 ml) and ethanol (3 ml). To the solution was
added a 1N aqueous solution of sodium hydroxide (1 ml), which was
stirred for 20 minutes at 60.degree. C. To the reaction mixture was
added water (50 ml), which was extracted with ethyl acetate. The
extract was dried, and the solvent was distilled off. The residue
was recrystallized from ethyl acetate-hexane to give
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethy-
lpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid
(0.33 g) as colorless crystals, m.p. 199-202.degree. C. (5) To a
solution of the compound (2 g) obtained in (4) and
3-aminopropionitrile (0.29 g) in dimethylformamide (20 ml) were
added, at room temperature, diethyl cyanophosphonate (0.75 g) and
triethylamine (0.51 g). The mixture was stirred for 30 minutes, to
which was added ethyl acetate ester (100 ml). The mixture was
washed with water and dried. The solvent was then distilled off,
and the residue was recrystallized from hexane to give
3-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimeth-ylpr-
opyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]amino]propionitr-
ile (2.25 g) as colorless crystals, m.p. 118-121.degree. C. (6) The
compound (2 g) obtained in (5) and acetic anhydride (0.39 g) were
dissolved in pyridine (20 ml). To the solution was added
dimethylaminopyridine (0.1 g), and the mixture was stirred for 30
minutes at room temperature. The solvent was distilled off, and the
residue was dissolved in ethyl acetate (100 ml). The solution was
washed with 1N HCl and water, followed by drying over anhydrous
magnesium sulfate. The solvent was distilled off to leave
3-[(3R,5S)-1-(3-acetyloxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyph-
enyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]aminopropionitri-
le (2.2 g) as a colorless amorphous solid product.
[0236] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.01 (3H,
s), 2.03 (3H, s), 2.55-2.71 (2H, m), 2.92 (1H, dd, J=8.0, 14.4 Hz),
3.41-3.59 (3H, m), 3.62 (3H, s), 3.72 (1H, d, J=11.2 Hz), 3.86 (1H,
d, J=11.2 Hz), 3.90 (3H, s), 4.33 (1H, dd, J=5.0, 8.0 Hz), 4.56
(1H, d, J=14.2 Hz), 6.26 (1H, s), 6.50-6.60 (1H, br), 6.64 (1H, s),
6.97-7.38 (5H, m)
(7) A solution of the compound (2.2 g) obtained in (6),
triphenylphosphine (2.0 g), diethyl azodicarboxylate (0.87 g) and
triethylsilyl azide (1.3 g) in tetrahydrofuran (10 ml) was stirred
for 2 hours at 60.degree. C. The reaction mixture was concentrated
under reduced pressure. The concentrate was purified by silica gel
column chromatography (eluents: hexane ethyl acetate=1:1 (v/v)) to
give
(3R,5S)-7-chloro-3-[1-(2-cyanoethyl)-1H-tetrazol-5-yl]methyl-5-(2,3-dimet-
hoxyphenyl)-1-(2,2-dimethyl-3-hydroxylpropyl)-1,2,3,5-tetrahydro-4,1-benzo-
xazepin-2-one as a colorless oily compound. This compound was
dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (10
ml), to which was added a 1N aqueous solution of sodium hydroxide
(8 ml). The mixture was stirred for one hour at 60.degree. C. To
the reaction mixture was added water (50 ml), which was acidified
with 1N HCl, followed by extraction with ethyl acetate. The extract
was dried, and the solvent was distilled off. The residue was
recrystallized from ethyl acetate-hexane to give 0.96 g of
colorless crystals, m.p. 158-160.degree. C.
[0237] Elemental analysis for C.sub.24H.sub.28ClN.sub.5O.sub.5:
TABLE-US-00010 Calcd.: C, 57.43; H, 5.62; N, 13.95 Found: C, 57.55;
H, 5.58; N, 13.75
Working Example 12
[0238] The compound obtained in Example 11-(4) was subjected to
substantially the same procedure as in Example 1 to afford
compounds shown in [Table 4].
TABLE-US-00011 TABLE 4 ##STR00138## Compound No. Y m.p. (.degree.
C.) 12-1 ##STR00139## 115-116 12-2 ##STR00140## 121-124 12-3
##STR00141## 133-135 12-4 ##STR00142## 134-137 12-5 ##STR00143##
160-161 12-6 ##STR00144## 116-119
Working Example 13
[0239] The compound obtained in Example 12 was subjected to
substantially the same procedure as in Example 3 to afford
compounds shown in [Table 5).
TABLE-US-00012 TABLE 5 ##STR00145## Compound No. Y m.p. (.degree.
C.) 13-1 ##STR00146## 135-140 13-2 ##STR00147## 162-165 13-3
##STR00148## 228-230 13-4 ##STR00149## 161-165 13-5 ##STR00150##
155-158
Working Example 14
N-Toluenesulfonyl-(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-o-
xo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetylamide
##STR00151##
[0241] To a solution of
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrah-
ydro-4,1-benzoxazepine-3-acetic acid (0.5 g) and
p-toluenesulfonamide (0.22 g) in dichloromethane were added
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (0.27 g) and
dimethylaminopyridine (20 mg). The mixture was stirred for 3 hours
at room temperature, which was concentrated under reduced pressure.
The concentrate was dissolved in ethyl acetate (100 ml). The
solution was washed with water and dried, then the solvent was
distilled off. The residue was purified by silica gel column
chromatography (eluents: dichloromethane:methanol:water=200:10:1
(v/v)) to give 0.6 g of colorless crystals, m.p. 110-113.degree.
C.
[0242] Elemental analysis for
C.sub.31H.sub.35C.sub.1N.sub.2O.sub.7S.H.sub.2O:
TABLE-US-00013 Calcd.: C, 58.81; H, 5.89; N, 4.42 Found: C, 58.73;
H, 5.73; N, 4.62
Working Example 15
N-Methylsulfonyl-[N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl--
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine]-4-acetylam-
ide
##STR00152##
[0244] In substantially the same procedure as in Example 14,
N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tet-
rahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid (0.5 g)
obtained in Example 4-2 and methansulfonamide (0.4 g) were used to
give 0.3 g of colorless crystals, m.p. 158-160.degree. C.
[0245] Elemental analysis for
C.sub.32H.sub.42ClN.sub.3O.sub.8S.0.5H.sub.2O:
TABLE-US-00014 Calcd.: C, 57.09; H, 6.44; N, 6.24 Found: C, 56.85;
H, 6.47; N, 6.09
Working Example 16
N-Methylsulfonyl-(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-ox-
o-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetylamide
##STR00153##
[0246]
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5--
tetrahydro-4,1-benzoxazepine-3-acetic acid and methansulfonamide
were subjected to substantially the same procedure as in Example 14
to afford colorless crystals, m.p. 212.degree. C.
[0247] Elemental analysis for C.sub.25H.sub.31ClN.sub.2O.sub.7:
TABLE-US-00015 Calcd.: C, 55.70; H, 5.80; N, 5.20 Found: C, 55.95;
H, 6.01; N, 4.99
Working Example 17
[0248] By allowing
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrah-
ydro-4,1-benzoxazepine-3-acetic acid to react respectively with
orthomethylphenylsulfonamide, phenylsulfonamide,
isopropylsulfonamide and ethylsulfonamide in substantially the same
manner as in Working Example 14, the corresponding compounds as
shown in Table 6 were produced.
TABLE-US-00016 TABLE 6 ##STR00154## Compound No. R m.p. (.degree.
C.) 17-1 ##STR00155## amorphous solid 17-2 ##STR00156## 158-161
17-3 ##STR00157## 149-150 17-4 Et 135-140
Working Example 18
N-methylsulfonyl-[N-(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-
-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine]-4-carboxami-
de
##STR00158##
[0250] Using the compound produced in Working Example 3 (0.5 g) and
methanesulfonamide (0.1 g), substantially the same procedure as in
Working Example 14 was followed to give 0.41 g of a colorless
crystalline product, m.p. 187-189.degree. C.
[0251] Elemental analysis for
C.sub.31H.sub.40ClN.sub.3O.sub.8S1/2H.sub.2O:
TABLE-US-00017 Calcd.: C, 56.48; H, 6.27; N, 6.73 Found: C, 56.28;
H, 6.41; N, 6.29
Working Example 19
(3R,5S)--N-methylsulfonyl-7-chloro-5-(2,3-dim
ethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4-
,1-benzoxazepine-3-acetamide
##STR00159##
[0253] Using the compound produced in Working Example 11-(4) (0.4
g) and methanesulfonamide (0.1 g), substantially the same procedure
as in Working Example 14 was followed to give 0.075 g of a
colorless crystalline product, m.p. 221-223.degree. C.
[0254] Elemental analysis for
C.sub.25H.sub.31ClN.sub.2O.sub.8S:
TABLE-US-00018 Calcd.: C, 54.10; H, 5.63; N, 5.05 Found: C, 54.30;
H, 5.69; N, 4.87
Working Example 20
(3R,5S)--N-methylsulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2--
hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-
-acetamide
##STR00160##
[0255] (1) To a solution of oxalyl chloride (2.2 ml) in
dichloromethane (120 ml) was added dropwise, at -78.degree. C., a
solution of dimethyl sulfoxide (2.4 ml) in dichloromethane (20 ml).
The mixture was stirred at -78.degree. C. for 10 minutes, to which
was then added a solution of
5-(hydroxymethyl)-2,2,5-trimethyl-1,3-dioxane (2 g) in
dichloromethane (40 ml). The mixture was stirred at -78.degree. C.
for further 15 minutes. To this solution was added triethylamine
(13.2 ml). The mixture was warmed up to 0.degree. C., to which was
added a saturated aqueous solution of ammonium chloride (40 ml).
The organic layer was washed with water and dried over anhydrous
sodium sulfate, followed by distilling off the solvent. The residue
was purified by silica gel column chromatography [eluents:
hexane-ethyl acetate (3:1)] to give 2 g of aldehyde of a colorless
oily compound. To a methanol solution of this aldehyde (2 g) were
added
(S)-4-chloro-2-[.alpha.-hydroxy-(2,3-dimethoxyphenyl)methyl-]aniline
(3.3 g) and acetic acid (0.75 g). The mixture was stirred at room
temperature for 10 minutes, to which was then added sodium
cyanoborohydride (0.8 g). The mixture was stirred at 60.degree. C.
overnight, to which was added water, followed by extraction with
ethyl acetate. The extract was sequentially washed with 1N aqueous
solution of sodium hydroxide and water, which was dried over
anhydrous sodium sulfate. The solvent was distilled off, and the
residue was purified by silica gel column chromatography [eluents:
hexane-ethyl acetate (2:1)] to give 3.7 g of
(S)-[2-(2,2,5-trimethyl-1,3-dioxan-5-ylmethyl)amino-5-chl-orophenyl](2,3--
dimethoxyphenyl)methanol as a colorless oily compound.
[0256] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.81 (3H, s), 1.38-1.45
(6H, m), 3.22 (2H, s), 3.30-3.40 (1H, br), 3.60 (4H, s), 3.83 (3H,
s), 3.89 (3H, s), 4.90-5.00 (4H, br), 5.97 (1H, s), 6.71-7.27 (6H,
m)
(2) To a solution of the compound produced in (1) (3.7 g) in ethyl
acetate (40 ml) was added sodium hydrogencarbonate (1.78 g). To the
mixture was added, at 0.degree. C., monoethyl ester of fumaric acid
chloride (1.41 g). The mixture was stirred at room temperature for
30 minutes. To the solution was added water. The organic layer was
washed with water, which was then dried over anhydrous sodium
sulfate, followed by distilling off the solvent. The residue (5.2
g) was dissolved in ethanol (100 ml), to which was added potassium
carbonate (1.1 g). The mixture was stirred overnight at room
temperature. To the reaction mixture was added water, which was
extracted with ethyl acetate. The extract was dried over anhydrous
sodium sulfate, then the solvent was distilled off. The residue was
purified by silica gel column chromatography [eluents: hexane-ethyl
acetate (2:1) to ethyl acetate] to afford 2.65 g of
(3R,5S)-7-chloro-1-(2,2,5-trimethyl-1,3-dioxan-5-ylmethyl)-5-(2,3-dimetho-
xyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid
ethyl ester (A) and 1.12 g of
(3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-dime-
thoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic
acid ethyl ester (B), both as colorless amorphous solid products.
A: .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s), 1.24 (3H, t,
J=7.0 Hz), 1.36&1.39 (each 3H, s), 2.77 (1H, dd, J=5.8, 16.4
Hz), 3.04 (1H, dd, J=7.8, 16.4 Hz), 3.29 (1H, d, J=12.2 Hz), 3.40
(1H, d, J=12.2 Hz), 3.58 (3H, s), 3.68 (2H, s), 3.89 (3H, s),
4.07-4.19 (3H, m), 4.40 (1H, dd, J=5.8, 7.8 Hz), 4.48 (1H, d,
J=14.2 Hz), 6.16 (1H, s), 6.63 (1H, d, J=1.8 Hz), 6.95-7.45 (6H, m)
B: .sup.1H-NMR (CDCl.sub.3) .delta.: 0.62 (3H, s), 1.25 (3H, t,
J=7.0 Hz), 2.78 (1H, dd, J=5.2, 16.6 Hz), 3.07 (1H, dd, J=8.2, 16.6
Hz), 3.39-3.80 (4H, m), 3.60 (3H, s), 3.89 (3H, s), 4.13 (2H, dq,
J=1.8, 7.0 Hz), 4.20-4.28 (1H, m), 4.41 (1H, dd, J=5.2, 18.2 Hz),
4.85 (1H, d, J=14.6 Hz), 6.12 (1H, s), 6.63 (1H, s), 6.89-7.39 (6H,
m) (3) To an ethanol solution of the compound (A) produced in (2)
(2.25 g) was added a 1N aqueous solution of sodium hydroxide (4.0
ml). The mixture was stirred at 60.degree. C. for one hour, to
which was added water, followed by neutralization with 1N HCl. The
reaction mixture was extracted with ethyl acetate. The extract was
dried over anhydrous sodium sulfate, then the solvent was distilled
off to leave 2.3 g of
(3R,5S)-7-chloro-1-(2,2,5-trimethyl-1,3-dioxan-5-ylmethyl)-5-(2,3-dimetho-
xyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-be-nzoxazepine-3-acetic acid
as a colorless amorphous solid product.
[0257] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, s),
1.35&1.39 (each 3H, s), 2.84 (1H, dd, J=5.4, 16.4 Hz), 3.08
(1H, dd, J=7.8, 16.4 Hz), 3.28 (1H, d, J=12.2 Hz), 3.41 (1H, d,
J=12.2 Hz), 3.58 (3H, s), 3.69 (2H, s), 3.89 (3H, s), 4.16 (1H, d,
J=13.8 Hz), 4.35 (1H, dd, J=5.4, 7.8 Hz), 4.89 (1H, d, J=13.8 Hz),
6.16 (1H, s), 6.65 (1H, d, J=2.0 Hz), 6.96-7.47 (5H, m)
(4) To a solution of the compound produced in (3) (0.15 g) in
dimethylformamide (2 ml) were added methanesulfonamide (29 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride (65 mg)
and dimethylaminopyridine (10 mg). The mixture was stirred
overnight at room temperature, to which was added ethyl acetate (50
ml). The mixture was washed with water, followed by drying over
anhydrous sodium sulfate. The solvent was distilled off, and the
residue was dissolved in acetone (2 ml). To the solution was added
p-toluenesulfonic acid monohydrate (0.1 g). The mixture was stirred
overnight at room temperature, to which was added ethyl acetate (50
ml). The mixture was washed with water, which was dried over
anhydrous sodium sulfate, followed by distilling off the solvent.
The residue was washed with a mixture of ethyl ether and hexane
(1:1), which was filtrated to afford 40 mg of a colorless amorphous
solid product.
[0258] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.63 (3H, s), 2.85-2.92
(2H, m), 3.28 (3H, s), 3.25-3.70 (5H, m), 3.59 (3H, s), 3.89 (3H,
s), 4.43 (1H, t, J=6.1 Hz), 4.78 (1H, d, J=14.2 Hz), 8.16 (1H, s),
6.67 (1H, s), 6.95-7.40 (6H, m)
Working Example 21
N-methylsulfonyl-[N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-
-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]p-
iperidine]-4-acetamide
##STR00161##
[0260] Using the compound (0.5 g) produced in Working Example 13-1
and methanesulfonamide (0.1 g), substantially the same procedure as
in Working Example 14 was followed to give 90 mg of colorless
crystals, m.p. 175-180.degree. C.
[0261] Elemental analysis for
C.sub.32H.sub.42ClN.sub.3O.sub.9S:
TABLE-US-00019 Calcd.: C, 56.50; H, 6.22; N, 6.18 Found: C, 56.70;
H, 6.50; N, 5.90
Working Example 22
(3R,5S)--N-phosphonomethyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2--
oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide
##STR00162##
[0263] To a solution of the compound (1.0 g) produced in Working
Example 2-38 in dichloromethane (5 ml) was added trimethylsilyl
bromide (0.38 g). The mixture was stirred overnight at room
temperature, to which was added ethyl acetate. The mixture was
washed with a 0.5N aqueous solution of sodium hydroxide, a
saturated aqueous solution of ammonium chloride and water, followed
by drying over anhydrous sodium sulfate. The solvent was distilled
off, and the residue was recrystallized from a mixture of ethanol
and diethyl ether (1:10) to afford 0.41 g of colorless
crystals,
[0264] m.p. 152-155.degree. C.
[0265] Elemental analysis for
C.sub.25H.sub.32ClN.sub.2O.sub.8P.1.7H.sub.2O:
TABLE-US-00020 Calcd.: C, 51.28; H, 6.09; N, 4.78 Found: C, 51.20;
H, 6.11; N, 4.77
Working Example 23
N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetr-
ahydro-4,1-benzoxazepine-3-acetyl]-4-phosphonomethylpiperidine
##STR00163##
[0267] Using the compound produced in Working Example 2-37 (2 g),
substantially the same procedure as in Working Example 22 was
followed to afford 1 g of colorless crystals, m.p. 174-175.degree.
C.
[0268] Elemental analysis for
C.sub.30H.sub.41ClN.sub.2O.sub.8P:
TABLE-US-00021 Calcd.: C, 56.12; H, 6.75; N, 4.36 Found: C, 55.95;
H, 6.58; N, 4.05
Working Example 24
5-[[N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5--
tetrahydro-4,1-benzoxazepine-3-acetyl]piperidin-4-yl]methyl]1H(or
3H)-tetrazole
##STR00164##
[0269] (1) To a solution of the compound produced in Working
Example 4-2 (1.5 g) and ammonium chloride (0.7 g) in
dimethylformamide (12 ml) were added, at 0.degree. C.,
triethylamine (2.0 ml) and diethyl cyanophosphonate (0.5 g). The
mixture was stirred for 40 minutes, to which was added water. The
mixture was extracted with ethyl acetate. The extract solution was
washed with water and dried over anhydrous sodium sulfate, followed
by distilling off the solvent. The residue was recrystallized from
hexane-ethyl acetate to afford 1.3 g of an amide compound, m.p.
189-190.degree. C. (2) To a suspension of the compound produced in
(1) (1.0 g) in toluene (20 ml) was added thionyl chloride (1 ml).
The mixture was stirred at 90.degree. C. for 30 minutes. To the
reaction mixture was added a saturated aqueous solution of sodium
hydrogen carbonate. The mixture was to extracted with ethyl
acetate. The organic layer was dried, then the solvent was
distilled off. The residue was purified by silica gel column
chromatography [eluents: hexane-ethyl acetate-methanol (15:10:1)]
to give 0.69 g of colorless crystals,
[0270] m.p. 150-152.degree. C.
(3) Using the compound produced in (2) (0.4 g), trimethylsilyl
azide (0.16 g) and dibutyltin (IV) oxide (20 mg), substantially the
same procedure as in Working Example 7-(3) was followed to afford
0.37 g of colorless crystals, m.p. 168-170.degree. C.
[0271] Elemental analysis for
C.sub.31H.sub.39ClN.sub.6O.sub.5.H.sub.2O:
TABLE-US-00022 Calcd.: C, 59.18; H, 6.58; N, 13.36 Found: C, 59.16;
H, 6.43; N, 13.03
Working Example 25
5-[2-[N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,-
5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidin-4-yl]ethyl]1H (or
3H)-tetrazole
##STR00165##
[0273] The compound produced in Working Example 4-34 (0.3 g) was
subjected to substantially the same procedure as in Working Example
24 to afford 0.25 g of colorless crystals, m.p. 155-158.degree.
C.
[0274] Elemental analysis for
C.sub.32H.sub.41ClN.sub.6O.sub.5.H.sub.2O:
TABLE-US-00023 Calcd.: C, 59.76; H, 6.74; N, 13.07 Found: C, 59.91;
H, 6.75; N, 12.87
Working Example 26
(3R,5S)--N-bis(ethoxy)phosphinylmethyl-7-chloro-5-(2,3-dimethoxyphenyl)-1--
(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine--
3-acetamide
##STR00166##
[0276] Using the compound produced in Working Example 11-(4) (1.0
g) and diethyl aminomethylphosphonate (0.38 g), substantially the
same procedure as in Working Example 1 was followed to afford 1.24
g of colorless crystals, m.p. 138-140.degree. C.
[0277] Elemental analysis for
C.sub.29H.sub.40ClN.sub.2O.sub.9P:
TABLE-US-00024 Calcd.: C, 55.55; H, 6.43; N, 4.47 Found: C, 55.25;
H, 6.47; N, 4.44
Working Example 27
(3R,5S)--N-phosphonomethyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-
,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide
##STR00167##
[0279] The compound produced in Working Example 26 (0.3 g) was
subjected to substantially the same procedure as in Working Example
22 to afford 0.26 g of an amorphous solid compound.
[0280] .sup.1H-NMR (CD.sub.3OD) .delta.: 0.84 (3H, s), 0.93 (3H,
s), 2.75-2.82 (2H, m), 3.20 (1H, d, J=11.4 Hz), 3.40-3.70 (3H, m),
3.58 (3H, s), 3.89 (3H, s), 4.35-4.46 (2H, m), 6.18 (1H, s), 6.53
(1H, d, J=2.2 Hz), 7.08-7.61 (5H, m)
Working Example 28
Bispivaloyloxymethyl
N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tet-
rahydro-4,1-benzoxazepin-3-yl]-4-bis(pivaloyloxymethyl)phosphinylmethylpip-
eridine
##STR00168##
[0282] To a solution of the compound produced in Working Example 23
(0.15 g) and potassium hydroxide (28.2 mg) in water (1.5 ml) was
added a solution of silver nitrate (102 mg). The mixture was
stirred for 15 minutes, then resulting insolubles were collected by
filtration, washed with water and diethyl ether, followed by drying
under reduced pressure. The solid matter thus obtained was
suspended in dichloromethane (2 ml). To the suspension was added
Molecular Sieves (3A) (200 mg), and the mixture was stirred for 40
minutes. To the reaction mixture were added anisole (0.1 g) and
pivaloylmethyl iodide (0.27 g), which was stirred at room
temperature for 40 minutes, followed by filtering off insolubles.
To the filtrate was added ethyl acetate (50 ml). The mixture was
washed with water and dried, followed by distilling off the
solvent. The residue was purified by silica gel column
chromatography [eluents: hexane-ethyl acetate (1:1)) to afford 56
mg of a colorless amorphous solid product.
[0283] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (9H, s), 1.23 (18H,
s), 1.50-1.95 (7H, m), 2.54-2.75 (2H, m), 2.97-3.18 (2H, m), 3.37
(1H, d, J=14.4 Hz), 3.62 (3H, s), 3.89 (3H, s), 3.90-4.00 (1H, m),
4.48-4.54 (3H, m), 5.64 (2H, s), 5.70 (2H, s), 6.27 (1H, s), 6.59
(1H, s), 6.95 (1H, s), 6.95-7.33 (5H, m)
Working Example 29
N-[(3R,5S)-7-chloro-1-(2,2,5-trimethyl-1,3-dioxan-5-ylmethyl)-5-(2,3-dimet-
hoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-
-4-acetic acid ethyl ester
##STR00169##
[0285] Using the compound produced in Working Example 20-(3). (2 g)
and piperidine-4-acetic acid ethyl ester hydrochloride (0.7 g),
substantially the same procedure as in Working Example 1 was
followed to afford 2.4 g of a colorless amorphous solid
product.
[0286] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, s), 1.25 (3H, t,
J=7.2 Hz), 1.36&1.39 (each 3H, s), 1.65-1.82 (4H, m), 1.95-2.08
(1H, m), 2.18-2.26 (2H, m), 2.49-2.63 (1H, m), 2.73 (1H, dd, J=4.8,
15.8 Hz), 2.92-3.06 (1H, m), 3.12 (1H, dd, J=8.2, 15.8 Hz), 3.31
(1H, d, J=12.0 Hz), 3.10 (1H, d, J=12.0 Hz), 3.58 (3H, s), 3.65
(1H, d, J=11.8 Hz), 3.73 (1H, d, J=11.8 Hz), 3.89 (3H, s),
3.94-3.99 (1H, m), 4.04-4.18 (3H, m), 4.46-4.56 (3H, m), 6.16 (1H,
s), 6.60-6.62 (1H, m), 6.95-7.46 (5H, m)
Working Example 30
N-[(3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-di-
methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperid-
ine-4-acetic acid ethyl ester
##STR00170##
[0288] To a solution of the compound produced in Working Example 29
(2.0 g) in acetone (20 ml) were added p-toluenesulfonic acid
monohydrate (35 mg) and water (2 ml). The mixture was stirred at
50.degree. C. for 6 hours. To the reaction mixture was added ethyl
acetate (50 ml). The mixture was washed with a 1N aqueous solution
of sodium hydroxide and water, followed by drying over anhydrous
sodium sulfate. The solvent was distilled off to leave 1.62 g of a
colorless amorphous solid product.
[0289] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.62 (3H, s), 1.00-1.34
(2H, m), 1.26 (3H, t, J=7.4 Hz), 1.70-1.81 (2H, m), 1.95-2.08 (1H,
m), 2.19-2.28 (2H, m), 2.51-2.78 (2H, m), 3.01-3.08 (1H, m), 3.17
(1H, dd, J=9.0, 15.2 Hz), 3.40-3.74 (5H, m), 3.60 (3H, s), 3.89
(3H, s), 3.89-3.94 (1H, m), 4.13 (2H, q, J=7.4 Hz), 4.48-4.54 (2H,
m), 4.83 (1H, d, J=14.6 Hz), 6.13 (1H, s), 6.61 (1H, d, J=1.8 Hz),
6.97-7.44 (5H, m)
Working Example 31
N-[(3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-di-
methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperid-
ine-4-acetic acid
##STR00171##
[0291] To an ethanol solution of the compound produced in Working
Example 30 was added a 1N aqueous solution of sodium hydroxide. The
mixture was stirred at 60.degree. C. for 2 hours. To the reaction
mixture were added water (100 ml) and ethyl acetate (50 ml), which
was acidified with 1N HCl. The organic layer was washed with water
and dried over anhydrous sodium sulfate. The solvent was distilled
off to leave 0.94 g of a colorless amorphous solid product.
[0292] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.63 (3H, s), 1.05-1.36
(2H, m), 1.70-1.85 (2H, m), 1.92-2.05 (1H, m), 2.23-2.32 (2H, m),
2.51-2.80 (2H, m), 2.96-3.23 (2H, m), 3.44-3.70 (5H, m), 3.60 (3H,
s), 3.89 (3H, s), 3.91-4.00 (1H, m), 4.48-4.54 (2H, m), 4.78 (1H,
d, J=15.2 Hz), 6.12 (1H, s), 6.61 (1H, s), 6.97-7.39 (5H, m)
Working Example 32
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-di-
methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperid-
ine-4-acetic acid ethyl ester
##STR00172##
[0294] To a solution of the compound produced in Working Example 30
(0.5 g) in pyridine (5 ml) were added acetic anhydride (0.20 g) and
dimethylaminopyridine (10 mg). The mixture was stirred at room
temperature for 30 minutes. To the reaction mixture was added ethyl
acetate (50 ml). The mixture was washed with 1N HCl and water,
which was then dried, followed by distilling off the solvent. The
residue was purified by silica gel column chromatography (eluents:
ethyl acetate) to afford 0.50 g of a colorless amorphous solid
product.
[0295] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.02 (3H, s), 1.00-1.40
(2H, m), 1.25&1.26 (total 3H, each t, J=7-2 Hz), 1.60-1.80 (2H,
m), 1.92-2.05 (1H, m), 2.00 (3H, s), 2.03 (3H, s), 2.16-2.26 (2H,
m), 2.46-2.65 (1H, m), 2.67-2.77 (1H, m), 2.99-3.19 (2H, m), 3.60
(3H, s), 3.64-4.19 (6H, m), 3.89 (3H, s), 4.44-4.54 (2H, m), 4.67
(1H, d, J=14.6 Hz), 6.23 (1H, s), 6.65 (1H, s), 6.96-7.34 (5H,
m)
Working Example 33
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-di-
methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperid-
ine-4-acetic acid
##STR00173##
[0297] Using the compound produced in Working Example 31,
substantially the same procedure as in Working Example 32 was
followed to afford 0.28 g of a colorless amorphous solid
product.
[0298] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95-1.36 (2H, m), 1.03
(3H, s), 1.71-1.83 (2H, m), 1.93-2.07 (1H, m), 2.00 (3H, s), 2.05
(3H, s), 2.23-2.33 (2H, m), 2.48-2.63 (1H, m), 2.65-2.78 (1H, m),
3.00-3.18 (2H, m), 3.60 (3H, s), 3.65-4.14 (6H, m), 3.89 (3H, s),
4.46-4.56 (2H, m), 4.66 (1H, d, J=14.8 Hz), 6.24 (1H, s), 6.64 (1H,
s), 6.96-7.34 (5H, m)
Working Example 34
(3R,5S)--N-methylsuifonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-c-
hloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-
-acetamide
##STR00174##
[0300] Using the compound produced in Working Example 20 (0.1 g),
acetic anhydride (39 mg) and dimethylaminopyridine (5 mg),
substantially the same procedure as in Working Example 32 was
followed to afford 70 mg of a colorless amorphous solid
product.
[0301] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (3H, s),
2.00&2.02 (each 3H, s), 2.85 (1H, dd, J=5.4, 15.4 Hz), 2.98
(1H, dd, J=7.2, 15.4 Hz), 3.26 (3H, s), 3.61 (3H, s), 3.70 (1H, d,
J=14.2 Hz), 3.84 (1H, d, J=11.4 Hz), 3.89 (3H, s), 3.94-3.99 (2H,
m), 4.11 (1H, d, J=11.4 Hz), 4.40 (1H, d, J=6.2 Hz), 4.46 (1H, d,
J=14.2 Hz), 6.28 (1H, s), 6.69 (1H, d, J=1.6 Hz), 6.97-7.43 (5H,
m)
Working Example 35
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxypheny-
l)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic
acid ethyl ester
##STR00175##
[0303] Using the compound produced in Working Example 12-1 (0.5 g),
substantially the same procedure as in Working Example 32 was
followed to afford 0.35 g of a colorless amorphous solid
product.
[0304] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (3H, s), 1.02 (3H,
s), 1.26 (3H, t), 2.02 (3H, s), 3.61 (3H, s), 3.89 (3H, s), 4.14
(2H, q), 4.5 (3H, m), 6.26 (1H, s), 6.62 (1H, s), 6.9-7.4 (5H,
m)
Working Example 36
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxypheny-
l)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic
acid
##STR00176##
[0306] Using the compound produced in Working Example 13-1 (0.37
g), substantially the same procedure as in Working Example 32 was
followed to afford 0.35 g of a colorless crystalline product, m.p.
194-196.degree. C.
[0307] Elemental analysis for C.sub.33H.sub.41ClN.sub.2O.sub.9:
TABLE-US-00025 Calcd.: C, 61.44; H, 6.41; N, 4.34 Found: C, 61.23;
H, 6.18; N, 4.39
Working Example 37
N-[(3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-di-
methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]-4-hydr-
oxypiperidine-4-acetic acid methyl ester
##STR00177##
[0308] (1) To a solution of
(3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-dime-
thoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic
acid ethyl ester (1.0 g) in ethanol (10 ml) was added a 1N aqueous
solution of sodium hydroxide. The mixture was stirred at 60.degree.
C. for one hour. To the reaction mixture was added water, which was
neutralized with 1N HCl, followed by subjecting to extraction with
ethyl acetate. The extract solution was dried over anhydrous sodium
sulfate. The solvent was distilled off, and the residue was
recrystallized from a mixture of ethyl acetate and hexane to afford
0.38 g of
(3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-dime-
thoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic
acid, m.p. 208-210.degree. C. (2) Using the compound produced in
(1) (0.25 g) and 4-hydroxypiperidine-4-acetic acid methyl ester
hydrochloride (0.105 g), substantially the same procedure as in
Working Example 1 was followed to afford 0.125 g of a colorless
amorphous solid product.
[0309] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35-1.84 (6H, m), 2.47
(2H, d), 2.65-2.85 (1H, m), 2.95-3.28 (2H, m), 3.35-3.78 (7H, m),
3.62 (3H, s), 3.73 (3H, s), 3.90 (3H, s), 4.22-4.40 (2H, m), 4.52
(1H, dd), 4.84 (1H, dd), 6.13 (1H, d), 6.62 (1H, m), 6.95-7.43 (5H,
m).
Working Example 38
(3R,5S)-7-Chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-1,2,3,5-tetr-
ahydro-5-(2,3-dimethoxyphenyl)-3-(1H(or
3H)-tetrazol-5-yl)methyl-4,1-benzoxazepin-2-one
##STR00178##
[0310] (1) To a solution of the compound produced in Working
Example 20-(3) (0.5 g), ammonium chloride (0.25 g) and
triethylamine (0.17 g) in dimethylformamide (5 ml) were added
diethyl cyanophosphonate (0.21 g) and triethylamine (0.17 g). The
mixture was stirred at room temperature for 30 minutes, to which
was added ethyl acetate (50 ml). The mixture was washed with water,
which was then dried over anhydrous sodium sulfate, followed by
distilling off the solvent. The residue was purified by silica gel
column chromatography (eluents: ethyl acetate) to give 0.52 g of an
amide compound as amorphous solid. (2) To a solution of
dimethylformamide (41 mg) in acetonitrile (1.5 ml) was added oxalyl
chloride (65 mg) at 0.degree. C. The mixture was stirred for 10
minutes, to which were added a solution of the compound produced in
(1) (0.25 g) in acetonitrile (1.5 ml) and pyridine (82 mg). The
mixture was stirred at 0.degree. C. for 10 minutes. To the reaction
mixture was added ethyl acetate (50 ml). The mixture was washed
with water and dried over anhydrous sodium sulfate, followed by
distilling off the solvent. The residue was purified by silica gel
column chromatography [eluents: hexane-ethyl acetate (2:1)] to give
0.31 g of a nitrile compound. (3) A solution of the compound
produced in (2) (1.0 g) in toluene (15 ml) was subjected to
substantially the same procedure as in Working Example 7-(3), using
trimethylsilyl azide (0.43 g) and dibutyltin (IV) oxide (45 mg) to
give
(3R,5S)-7-chloro-1-(2,2,5-trimethyl-1,3-dioxan-5-ylmethyl)-5-(2,3-dimetho-
xyphenyl)-1,2,3,5-tetrahydro-3-(tetrazol-5-yl)methyl-4,1-benzoxazepin-2-on-
e (1.03 g) as a colorless amorphous solid product. (4) To a
solution of the compound produced in (3) (1.0 g) in acetone (10 ml)
were added p-toluenesulfonic acid monohydrate (50 mg) and water (1
ml). The mixture was stirred at 60.degree. C. overnight. To the
reaction mixture was added water (50 ml), which was extracted with
ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate. The solvent was distilled off, and the residue was
purified by silica gel column chromatography [eluents: ethyl
acetate-methanol (20:1)] to give 0.87 g of a colorless amorphous
solid product.
[0311] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.69 (3H, s), 3.45 (1H,
dd, J=4.4, 14.4 Hz), 3.56-3.75 (5H, m), 3.62 (3H, s), 3.90 (3H, s),
4.29 (1H, dd, J=4.4, 8.8 Hz), 4.63 (1H, d, J=15.2 Hz), 6.18 (1H,
s), 6.67 (1H, d, J=2.2 Hz), 7.05-7.43 (5H, m)
Working Example 39
(3R,5S)-1-(3-Acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-1,2,3,5-tetr-
ahydro-5-(2,3-dimethoxyphenyl)-3-(1H (or
3H)-tetrazol-5-yl)-4,1-benzoxazepin-2-one
##STR00179##
[0313] To a solution of the compound produced in Working Example 38
(0.77 g) in pyridine (7 ml) were added acetic anhydride (0.335 g)
and dimethylaminopyridine (40 mg). The mixture was stirred at room
temperature for 30 minutes, to which was added ethyl acetate (50
ml). The mixture was washed with 1N HCl and water, which was then
dried over anhydrous sodium sulfate, followed by distilling off the
solvent. The residue was washed with ethyl ether-hexane (1:1),
which was filtrated to collect 0.80 g of a colorless amorphous
solid product.
[0314] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (3H, s), 2.03, 2.04
(each 3H, s), 3.40 (1H, dd, J=5.1, 15.8 Hz), 3.55-3.67 (2H, m),
3.65 (3H, s), 3.82-3.91 (2H, m), 3.89 (3H, s), 4.04 (1H, d, J=11.6
Hz), 4.18 (1H, d, J=11.2 Hz), 4.30 (1H, dd, J=5.2, 6.6 Hz), 4.66
(1H, d, J=14.6 Hz), 6.27 (1H, s), 6.69 (1H, d, J=2.2 Hz), 6.95-7.42
(5H, m)
Working Example 40
(3R,5S)--N-(2-(Pyrrolidin-1-yl)ethyl]-7-chloro-1-(3-hydroxy-2-hydroxymethy-
l-3-methylpropyl)-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-ben-
zoxazepine-3-acetamide
##STR00180##
[0315] (1) To a solution of the compound produced in Working
Example 20-(3) (0.5 g) and diethyl cyanophosphonate (54 mg) in
dimethylformamide (1.5 ml) was added 1-(2-aminoethyl)pyrrolidine
(0.16 g). The mixture was stirred at room temperature for 30
minutes, to which was added ethyl acetate (50 ml). The mixture was
washed with water and dried, followed by distilling off the
solvent. The residue was purified by silica gel column
chromatography [eluents: ethyl acetate-methanol-triethylamine
(10:1:0.1) to give
(3R,5S)--N-[2-(pyridin-1-yl)ethyl]-7-chloro-1-(2,2,5-trimethyl-1,-
3-dioxan-5-ylmethyl)-5
(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetam-
ide (0.19 g) as a colorless amorphous solid product. (2) To a
solution of the compound produced in (1) (0.19 g) in
tetrahydrofuran (2 ml) was added conc. HCl (1 ml). The mixture was
stirred at 60.degree. C. for 30 minutes, to which was added water
(50 ml), followed by neutralizing with 1N NaOH. The resultant was
extracted with ethyl acetate, washed with water and dried, followed
by distilling off the solvent. The residue was purified silica gel
column chromatography (eluents: ethyl
acetate-methanol-triethylamine (2:1:0.1) to give 97 mg of a
colorless amorphous solid product.
[0316] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.62 (3H, s), 1.75-1.80
(4H, m), 2.50-2.72 (7H, m), 2.87 (1H, dd, J=7.0, 14.2 Hz),
3.31-3.76 (7H, m), 3.59 (3H, s), 3.89 (3H, s), 4.45 (1H, t), J=6.4
Hz), 4.82 (1H, d, J=15.0 Hz), 6.12 (1H, s), 6.35-6.50 (1H, br),
6.62 (1H, s), 6.99-7.37 (5H, m)
Working Example 41
(3R,5S)--N-Methylsulfonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-
-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide
##STR00181##
[0318] The compound produced in Working Example 19 (1.2 g) was
subjected to substantially the same procedure as in Working Example
39 to give 1.01 g of a colorless crystalline product, m.p.
108-112.degree. C.
[0319] Elemental Analysis for
C.sub.27H.sub.33ClN.sub.7O.sub.9S.1.5H.sub.2O:
TABLE-US-00026 Calcd.: C, 51.96; H, 5.81; N, 4.49 Found: C, 52.01;
H, 5.82; N, 4.30
Working Example 42
(3R,5S)-1-(3-Acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)--
1,2,3,5-tetrahydro-3-[1H(or
3H)tetrazol-5-yl]methyl-4,1-benzoxazepin-2-one
##STR00182##
[0321] The compound produced in Working Example 11 (80 mg) was
subjected to substantially the same procedure as in Working Example
39 to give 25 mg of a colorless amorphous solid product.
[0322] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, s), 0.99 (3H,
s), 2.05 (3H, s), 3.3-3.8 (4H, m), 3.65 (3H, s), 3.89 (3H, s), 4.05
(1H, d), 4.28 (1H, dd), 4.62 (1H, d), 6.27 (1H, s), 6.68 (1H, d),
6.9-7.4 (5H, m)
Formulation Examples
[0323] A therapeutic agent of hyperlipemia containing, as its
effective component, the compound (1) or a salt thereof of this
invention can be formulated in accordance with, for example, the
following prescriptions.
1. Capsules
TABLE-US-00027 [0324] (1)
N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1- 10 mg
neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-
acetyl]piperidine-4-acetic acid (2) Lactose 90 mg (3)
Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1
capsule 180 mg
[0325] (1), (2) and (3) and one half of (4) were blended and the
mixture was granulated, to which was added the balance of (4). The
mixture was filled in a gelatin capsule.
2. Tablets
TABLE-US-00028 [0326] (1)
N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1- 10 mg
neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-
acetyl]piperidine-4-acetic acid (2) Lactose 35 mg (3) Corn starch
150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate
5 mg One tablet 230 mg
[0327] (1), (2), (3), two third of (4) and one half of (5) were
blended and the mixture was granulated, to which were added the
balance of (4) and (5). The mixture was subjected to
compression-molding to provide tablets.
3. Injections
TABLE-US-00029 [0328] (1)
N-[(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1- 10 mg
neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-
acetyl]piperidine-4-acetic acid (2) Inositol 100 mg (3) Benzyl
alcohol 20 mg One ampoule 130 mg
[0329] (1), (2) and (3) were dissolved in distilled water for
injection to make the whole volume 2 ml, which was put in an
ampoule, and the ampoule was sealed. All the processes were
conducted under sterilized conditions.
Experimental Example 1
[0330] Squalene Synthetase Inhibitory Activity
[0331] Assay Method
[0332] The squalene synthetase inhibitory activity was assayed as
follows with the enzyme solutions prepared in accordance with the
method described below.
[0333] More specifically, an enzyme solution (protein content 0.8
.mu.g) prepared in accordance with the method described below was
added to a solution (total volume 50 .mu.l)) containing 5 .mu.M
[1-.sup.3H] farnesyl pyrophosphate (specific activity 25
.mu.Ci/mole), 1 mM NADPH (nicotinamide adenine dinucleotide
phosphate of reduced type), 5 mM MgCl.sub.2, 6 mM glutathione, a
100 mM buffer solution of potassium phosphate (pH 7.4) and a test
drug (used as an aqueous solution or a DMSO solution), then the
reaction was allowed to proceed at 37.degree. C. for 45 minutes. To
the reaction mixture was added 150 .mu.l of a mixture of chloroform
and methanol (1:2) to suspend the reaction, followed by adding 50
.mu.l of chloroform and 50 .mu.l of a 3N solution of sodium
hydroxide. 50 .mu.l of the chloroform layer (lower layer)
containing the reaction mixture having squalene as the principal
component and 3 ml of toluene-based liquid scintillator were mixed,
and its radioactivity was determined by means of a liquid
scintillation counter.
[0334] The squalene synthetase inhibitory activity was expressed in
terms of the concentration inhibiting by 50% the radioactivity
taken into the chloroform layer (IC.sub.50, molar concentration
(M)), as shown in Table 7.
Preparation of Human-Derived Enzyme
[0335] Human hepatic carcinoma cells HepG2 (about 1.times.10.sup.9
cells) obtained by incubation on a Dulbecco-modified Eagle's medium
(37.degree. C. in the presence of 5% CO.sub.2) containing 10% fetal
bovine serum were suspended in 10 ml of an ice-cooled buffer
solution (100 mM potassium phosphate buffer (pH 7.4), 30 mM
nicotinamide and 2.5 mM MgCl.sub.2]. The cells were crashed by
means of ultrasonication (for 30 seconds, twice). The sonicate thus
obtained was subjected to centrifugation for 20 minutes (4.degree.
C.) with 10000.times.g. The supernatant layer was subjected to
further centrifugation for 90 minutes (4.degree. C.) with
105000.times.g. The sediment was then suspended in an ice-cooled
100 mM potassium phosphate buffer (pH 7.4), which was again
subjected to centrifugation for 90 minutes (4.degree. C.) with
105000.times.g. This fraction was suspended in an ice-cooled 100 mM
potassium phosphate buffer solution (pH 7.4) (about 4 mg/ml protein
concentration). This suspension was used as the enzyme
solution.
TABLE-US-00030 TABLE 7 Inhibitory Activity Compound No. (IC.sub.50,
10.sup.-9 M) 4-2 22 4-8 11 4-9 11 4-10 11 4-12 11 4-15 19 4-18 18
4-19 18 4-20 17 4-21 11 4-24 14 4-26 15 4-29 15 4-30 12 4-31 20 7
11 8 12 9 9.5 13-2 18 17-1 13 17-2 9.3 17-3 11 17-4 9.3 18 15 19 32
20 48 21 26 22 8.5 23 12 24 17 25 29 27 20
[0336] As is clear from the above results, the compounds of this
invention have an excellent squalene synthetase inhibitory
activity.
[0337] Experimental Example 2
Assay of Cholesterogenesis in the Liver:
[0338] Cholesterol biosynthesis in the liver of a rat was assayed
as follows. Six-week old Wistar fatty rats were given orally a test
compound [Compound 4-2 (suspended in a 0.5% methyl cellulose
solution)), while the control group was orally given only a 0.5%
methyl cellulose solution. One hour later, sodium acetate labelled
with radioisotope .sup.14C (manufactured by Amasham) was given
intravenously at the tail (10 .mu.Ci/0.3 ml physiological
saline/rat). One hour layer, rats were sacrificed by decapitation,
and 1.5 g of the first lobe of the liver was removed, which was
saponified by immersing in 3.9 ml of an alkaline ethanol solution
(KOH:EtOH=1:2) at 100.degree. C. for two hours, followed by
extraction with 5 ml each portion of petroleum ether three times.
The extract solution was dried, which was dissolved in 3 ml of
ethanol:acetone (1:1). To the solution was added 2 ml of a 0.5%
digitonin-ethanol solution. The mixture was left standing for one
hour. Resulting precipitates were collected as total sterol, and
the radioactivity was measured by means of a liquid scintillation
counter. The results are shown below.
TABLE-US-00031 Cholesterogenesis Amount given inhibitory rate (%)
0.6 mg/kg 80.1% 2.0 mg/kg 90.4%
[0339] As shown in the above results, the compound of this
invention performs an excellent effect of inhibiting the
cholesterogenesis by 80% or more.
INDUSTRIAL APPLICABILITY
[0340] The compounds of this invention have a squalene synthetase
inhibitory activity, a cholesterol lowering activity and a
triglyceride lowering activity, and are useful as a prophylactic
and therapeutic agent of hyperlipemia as an agent of lowering
lipids, and also useful for prophylaxis and therapy of, among
other, arteriosclerosis.
* * * * *