Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-26
2002-12-31
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S277000, C514S311000, C514S336000, C514S365000, C514S372000, C514S374000, C514S376000, C514S378000, C514S415000, C514S424000, C514S476000, C514S478000, C514S481000, C514S653000, C514S657000
Reexamination Certificate
active
06500849
ABSTRACT:
The present invention relates to 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols. More particularly, the present invention relates to 1-alkyl-, 1-alkenyl-, and 1-alkylnylaryl-2-amino-1,3-propanediols of formula 1.
wherein R is
or
wherein R
5
is CH
3
(CH
2
)
m
C&Xgr;C, CH
3
(CH
2
)
m
CH═CH, CH
3
(CH
2
)
m
CH
2
CH
2
,
CH
3
(CH
2
)
m
CH
2
O, or
wherein m is 3 to 15, n is 0 to 12, and W and X are independently hydrogen, hydroxy, alkyl, alkoxy, halogen, or trifluoromethyl, or
wherein R
23
is loweralkyl; Z is S, O, or C═O; and A is S or O; R
1
is hydrogen, alkyl, Si(R
23
)
2
C(R
23
)
3
wherein R
23
is alkyl,
wherein R
24
is alkyl or
wherein R
6
is hydrogen, alkyl, alkoxy, N(R
21
)
2
wherein R
21
is hydrogen, alkyl, or
wherein W is as above, or
R
2
is hydrogen or alkyl; R
3
is hydrogen, alkyl or
wherein R
6
is as above or NHR
27
wherein R
27
is alkyl; R
35
is
wherein R
36
is alkyl; R
4
is
wherein R
7
is hydrogen or alkyl, C(R
25
)
2
OR
8
wherein R
8
is hydrogen, alkyl, or
wherein R
6
is as above and R
25
is hydrogen or alkyl; R
40
is alkyl or a group of the formula
wherein W is as above; R
1
and R
8
taken together with the oxygen to which they are attached form a group of the formula
wherein R
9
and R
10
are independently hydrogen or alkyl; R
2
, R
3
and R
4
taken together with the nitrogen and oxygen to which they are attached form a group of the formula
wherein W is as above; R
3
and R
4
taken together with the nitrogen and oxygen atoms to which they are attached form a group of the formula
wherein R
2
is as above; R
2
and R
3
taken together with the nitrogen atom to which it is attached form a group of the formula
wherein W is as above; R
3
and R
4
taken together with the nitrogen and oxygen atoms to which they are attached form a group of the formula
wherein R
2
is as above and R
25
is alkyl; R
1
, R
2
and R
3
taken together with the nitrogen and oxygen atoms to which they are attached form a group of the formula
wherein R
26
is alkyl; the optical isomers thereof, or the pharmaceutically acceptable salts thereof, which are useful for reducing inflammation by virtue of their ability to inhibit protein kinase C and thus indicated for the treatment of psoriasis and other skin disorders, for inhibiting tumor or neoplastic cell growth by virtue of their ability to reduce cell proliferation and thus indicated in cancer therapy, and relieving memory dysfunction and thus indicated in the treatment of Alzheimer's disease, and as antibacterial and antifungal agents, alone or in combination with adjuvants.
Preferred 2-amino-1,3-propanediols of the present invention are those wherein R is
R
1
, R
2
, and R
3
are hydrogen and R
5
is CH
3
(CH
2
)
m
CH
2
CH
2
or
Also preferred are compounds wherein R is
R
1
and R
2
are hydrogen; R
4
is
and R
5
is CH
3
(CH
2
)
m
C&Xgr;C.
The present invention also relates to compounds of the formulas
RCHO 1a
wherein R is
wherein R
5
is CH
3
(CH
2
)
m
C&Xgr;C, CH
3
(CH
2
)
m
CH═CH, CH
3
(CH
2
)
m
CH
2
CH
2
, or
wherein m is 3 to 15, n is 0 to 12, W and X are independently hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl and Z is S or O; A is S or O; R
40
is alkyl or a group of the formula
wherein W is as above;
wherein R is
wherein R
5
is
CH
3
(CH
2
)
m
C&Xgr;C, CH
3
(CH
2
)
m
CH=CH, CH
3
(CH
2
)
m
CH
2
CH
2
, or
wherein m is 3 to 15, n is 0 to 12, R
16
is hydrogen or a group of the formula
W and X are independently hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, and Z is 0; and
RCH═CHR
4
wherein R is
wherein R
5
is CH
3
(CH
2
)
m
C&Xgr;C, CH
3
(CH
2
)
m
CH═CH, CH
3
(CH
2
)
m
CH
2
CH
2
,
or
wherein m is 3 to 15, n is 0 to 12, and W and X are independently hydrogen, loweralkyl, loweralkoxy, halogen, or trifluoromethyl, Z is S, O, or C═O; and A is S or O, and R
4
is
wherein R
7
is hydrogen or loweralkyl, C(R
25
)
2
OR
8
wherein R
8
is hydrogen, loweralkyl, or
is as above; and
wherein R
5
is CH
3
(CH
2
)
m
C&Xgr;C, CH
3
(CH
2
)
m
CH═CH, CH
3
(CH
2
)
m
CH
2
CH
2
,
or
wherein m is 3 to 15, n is 0 to 12, and W and X are independently hydrogen, loweralkyl, loweralkoxy, halogen, or trifluoromethyl which are useful as intermediates for the preparation of the present 2-amino-1,3-propanediols.
Also included as intermediates for the preparation of the present 2-amino-1,3-propanediols are oxazolidinones of the formula
RCH(OR
1
)CHR
18
R
19
wherein R is
and
wherein R
5
is CH
3
(CH
2
)
m
C&Xgr;C, CH
3
(CH
2
)
m
CH═CH, CH
3
(CH
2
)
m
CH
2
CH
2
,
wherein m is 3 to 25, n is 0 to 12, and W and X are independently hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, Z is S, O, or C═O; and A is S or O; R
1
is hydrogen or
wherein R
6
is hydrogen, alkyl, alkoxy, or
R
18
is halogen or N
3
; and R
19
is a group of the formula
wherein W is hydrogen, loweralkyl, loweralkoxy, halogen, or trifluoromethyl; or a group of the formula
wherein R
20
is loweralkyl.
As used through the specification and appended claims, the term “alkyl” refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 10 carbon atoms. Examples of alkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 3-hexyl, 4-heptyl, 2-octyl, 3-nonyl, 4-decyl and the like. The term “alkanol” refers to a compound formed by a combination of an alkyl group and hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and 2-propanol, 2,2-dimethylethanol, hexanol, octanol, decanol and the like. The term “alkanoic acid” refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic acids are formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid, decanoic acid and the like. The term “halogen” refers to a member of the family fluorine, chlorine, bromine, or iodine. The term “alkanoyl” refers to the radical formed by removal of the hydroxyl function from an alkanoic acid. Examples of alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl and the like. The term “lower” as applied to any of the aforementioned groups refers to a group having a carbon skeleton containing up to and including 8 carbon atoms.
The compounds of the present invention which lack an element of symmetry exist as optical antipodes and as the racemic forms thereof. The optical antipodes may be prepared from the corresponding racemic forms by standard optical resolution techniques, involving, for example, the separation of diastereomeric salts of those instant compounds characterized by the presence of a basic amino group and an optically active acid, those instant compounds characterized by the presence of a carboxylic acid group and an optically active base, or by synthesis from optically active precursors.
The present invention comprehends all optical isomers and racemic forms thereof and all geometric isomers of the compounds disclosed and claimed herein. The formulas of the compounds shown herein are intended to encompass all possible geometric and optical isomers of the compounds so depicted.
The compounds of the present invention that have adjacent chiral centers exist as diastereomers and are distinguished as the erythro- and threo-isomers. The erythro diastereomers are those that become meso, i.e., optically inactive, by virtue of having an element of symmetry in one of the possible conformations, when one of the dissimilar substituents is replaced by the other. The threo diastereomers are those that remain enantiomeric, i.e., optically active, by virtue of lacking an element of symmetry in one of the possible conformations, when one of the dissimilar substitutents is replaced by the other. For example, replacement of the amino group of an erythro-2-amino-1,3-propanediol 9a of the present invention by a hydroxyl group creates a meso-1,2,3-propanetriol 9b, having a plane of symmetry through the carbon backbone of the molecule, as shown below,
and replacement of th
Freed Brian Scott
Hamer Russell Richard Lee
Merriman Gregory Harold
Rauckman Barbara Seavey
Tegeler John Joseph
Aventis Pharmaceuticals Inc.
Chang Ceila
Ort Ronald C.
LandOfFree
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