Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1999-02-23
2002-01-01
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S400000, C560S029000
Reexamination Certificate
active
06335444
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for preparing 2-acylamino alcohol derivatives which have a function to enhance or inhibit biosynthesis of glycolipids and also have antiviral, antitumor, metastasis inhibition and nerve cell growth enhancing functions. Furthermore, the present invention relates to novel amino alcohol derivatives which are useful in preparing the 2-acylamino alcohol derivatives.
BACKGROUND OF THE INVENTION
A 2-acylamino alcohol derivative, 2-decanoylamino-3-morpholino-1-phenyl-1-propanol (hereinafter referred to as “PDMP”), represented by the following formula:
has an activity to control biosynthesis of glycolipids, but the activity is greatly different among its four stereoisomers. Therefore, separation of its optically active isomers is carried out by a method in which decanoylaminoacetophenone is condensed with morpholine by Mannich reaction and then reduced with sodium borohydride to obtain PDMP as a mixture of four stereoisomers, resolution of the diastereomers is effected by a crystallization method and then optical resolution of the racemic compounds is effected by a crystallization method (
J. Lipid. Res.,
28:565-571 (1987), and
Advances in Lipid Research,
26:183-213 (1993)).
SUMMARY OF THE INVENTION
An object of the present invention is to provide a process for preparing optically active substances of PDMP having plural asymmetric centers and its analogues using a chiral compound as the starting material at high efficiency, particularly a stereoselective synthesis process which requires no complicated optical resolution step.
Another object of the present invention is to provide novel amino alcohol derivatives which are useful for preparing PDMP and its analogues.
In order to develop a simple and general stereoselective process for preparing PDMP and its analogues, the inventors of the present invention have conducted intensive studies and found as the results that all of the four stereoisomers of PDMP or its analogues can be stereoselectively synthesized by establishing synthetic steps which comprise stereochemically proceeding reactions using, as the main starting material and asymmetric source, an N-protected 2-aminopropanediol which has two asymmetric centers in its molecule in advance and whose amino group is protected with a urethane type protecting group which can be obtained at a reasonable price as a reagent for peptide synthesis use, and have also found novel amino alcohol derivatives as intermediates of the synthetic steps. The present invention has been accomplished based on these findings.
Accordingly, these and other objects of the present invention have been accomplished by a process for preparing a 2-acylamino alcohol derivative which comprises the following steps:
(A) reacting an aminopropanol derivative represented by the following formula (1):
Y—CH
2
—C*H(NHP
1
)—C*H(OH)—R
1
(1)
wherein * represents an asymmetric carbon atom;
P
1
represents an alkyl group or an amino-protecting group;
R
1
represents an alkyl group, a cycloalkyl group or an aryl group; and
Y represents a leaving group,
with an amine represented by R
2
H, wherein R
2
is represented by the following formula (I) to (VI), to synthesize an amino alcohol derivative represented by the following formula (2):
R
2
—CH
2
—C*H(NHP
1
)—C*H(OH)—R
1
(2)
wherein P
1
, R
1
and R
2
each has the same meaning as those defined above,
(B) leaving P
1
from said amino alcohol derivative represented by formula (2) to synthesize an amino alcohol derivative represented by the following formula (3):
R
2
—CH
2
—C*H(NH
2
)—C*H(OH)—R
1
(3)
wherein R
1
and R
2
each has the same meaning as those defined above, and
(C) reacting said amino alcohol derivative represented by formula (3) with a carboxylic acid represented by R
11
COOH or a reactive derivative thereof, wherein R
11
represents an alkyl or alkenyl group having from 3 to 18 carbon atoms which may be substituted with a hydroxyl group, to prepare a 2-acylamino alcohol derivative represented by the following formula (4):
R
2
—CH
2
—C*H(NHCOR
11
)—C*H(OH)—R
1
(4)
wherein R
1
, R
2
and R
11
each has the same meaning as those defined above;
wherein R
3
and R
4
are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxyl-lower-alkyl group, a lower alkoxyalkyl group, an amino-lower-alkyl group, a cycloalkyl group, a hydroxycycloalkyl group, an aralkyl group or a piperazino group which may be substituted with a lower alkyl group;
R
5
represents a hydrogen atom or at least one substituents which are the same or different and are selected from a hydroxyl group, a lower alkyl group, a lower alkoxyl group, a hydroxyl--lower-alkyl group, a carboxyl group, a (lower alkoxyl)carbonyl group, an aralkyl group, a piperidino group, an acyloxy group, an amino group and an amino-lower-alkyl group;
R
6
represents a hydrogen atom or at least one substituents which are the same or different and are selected from the substituents as defined in R
5
;
R
7
represents a lower alkylene group which may be discontinued by an oxygen atom;
R
8
and R
9
are the same or different and each represents a hydrogen atom, a lower alkyl group or a hydroxyl-lower-alkyl group, or R
8
and R
9
represent, together with a nitrogen atom to which they are bound, a piperidino group or a morpholino group which may be substituted with a lower alkyl group;
m is an integer of 2 to 6;
p is an integer of 2 or 3; and
X represents the following formula (VII) or (VIII):
wherein R
10
represents a hydrogen atom, a lower alkyl group, an acyl group, a (lower alkoxyl)carbonyl group or a pyridyl group.
Furthermore, these and other objects of the present invention have been accomplished by the amino alcohol derivatives represented by formula (2).
Moreover, these and other objects of the present invention have been accomplished by the amino alcohol derivatives represented by formula (3).
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, the term “lower” in the “lower alkyl”, “lower alkoxyl” and the like means that the carbon number thereof is from 1 to 6.
Also, the term “alkylene group which may be discontinued by an oxygen atom” means that at least two alkylene groups are linked to each other via at least one oxygen atom.
PDMP and its analogues, have been discovered as glycolipid biosynthesis controlling substances are interesting compounds which also have physiological functions such as antiviral, antitumor, metastasis inhibition, nerve cell growth enhancing and the like. Structurally, they have 2-amino alcohol as the basic nucleus and at least two asymmetric carbon atoms in the molecule. Since functions of four stereoisomers obtained therefrom are different from each other, it is necessary to develop a means for the stereoselective synthesis of these four isomers in studying relationship between structure and function of PDMP and its analogues and developing high active analogues.
As described above, one aspect of the present invention relates to a process for stereoselectively synthesizing the four stereoisomers of PDMP and its analogues using, as the main starting material, a 2-aminopropanediol derivative which has two asymmetric carbon atoms in its molecule and whose amino group is protected with a urethane type protecting group. This process is based on the following new findings.
That is, the stereoselective synthesis of PDMP and its analogues has been achieved by 1) using a chiral compound having two asymmetric carbon atoms in its molecule as the starting material, 2) introducing a leaving group (a mesyl group or the like) into only primary hydroxyl group among primary and secondary hydroxyl groups, and then substituting the leaving group with a primary or secondary amine and 3) constructing all of the reaction steps as keeping the stereochemistry.
The present invention will be described according to the following synthetic steps.
According to the process of the present invention, an optically active aminopropanol deriva
Inokuchi Jin-ichi
Jinbo Masayuki
Oyamada Hidekazu
Gerstl Robert
Seikagaku Kogyo Kabushiki Kaisha
Sughrue Mion Zinn Macpeak & Seas, PLLC
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