Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-23
2002-05-21
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S423000, C549S510000, C549S511000, C560S189000
Reexamination Certificate
active
06392061
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel oxetanone derivative compounds and processes for producing such derivatives which are useful as lipase inhibitors. Further the invention relates to processes for producing salts and for producing pharmaceutical compositions compounds comprising at least one such oxetanone derivative or salt, as well as methods for using such compounds and compositions for inhibiting lipases. In one aspect the invention relates to lipase inhibitors which include on the same molecule an oxetanone derivative portion capable of inhibiting a lipase and a non-absorbable moiety such a polysaccharide, which are covalently linked or are in the form of a salt. In a preferred aspect of the invention the non-absorbable moiety is lipophilic and will associate with oils or fats. An absorbable oxetanone lipase inhibitor may be rendered non-absorbable by covalent linking it directly or indirectly to a non-absorbable moiety and thereby producing a novel non-absorbable lipase inhibitor.
BACKGROUND OF THE INVENTION
Some lipase-inhibiting oxetanones and intermediates for making them are well known. See for example, U.S. Pat. Nos. 5,931,463, 5,175,186, 4.189,438 and 4,202,824. However, there is a need for improved processes for making oxetanones in commercial quantities that are have low toxicity and are essentially not absorbable by the digestive system of mammals such as dogs, cats, non-human primates and human primates.
Lipase inhibitors such as esterastin (2S, 3S, 5S) 3,5-hydroxy-2-hexadeca-7,10-dienoic 1,3-lactone), tetrahydroesterastin (2S, 3S, 5S) 3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like (see U.S. Pat. No. 4,189,438), are well-known as lipase inhibitors and are useful as pancreatic cholesterol esterase inhibitors. While these lipase inhibitor can be obtained by cultivating microbes as described in U.S. Pat. No. 4,189,438, it is believed that examples of successful synthetic procedures for effectively making such compounds in commercially acceptable quantities from intermediates other than those obtained from microbes have not been described in the literature.
Further, esterastin and tetrahydroesterastin are excluded by proviso from the claims of the U.S. Pat. No. 5,175,186, which relates to a synthetic method for making certain analogs of esterastin and tetrahydroesteratin. The specification of that document does not illustrate the direct production of esterastin or tetrahydroesteratin or other (5S) analogs before the 2S, 3S oxetanone (lactone) ring structure is formed. Further page 6, lines 21-44, of the 5,175,186 patent points to an asymetrical hydrogenation synthesis step, which makes obtaining (2S, 3S, 5S) analog compounds before the direct closure of the oxetanone ring problematic. On page 6, when an intermediate compound having the 5 hydroxyl group in the R configuration (6R intermediate), is selectively hydrogenated only the (3S, 4S, 6R) intermediates result, which convert to a final compound having a 2S, 3S, 5R configuration. Likewise, when a only a 6S intermediate is used the (3R, 4R, 6S) hydrogenation intermediates result. The 5,175,186 patent does not illustrate a feasible and efficient solution for resolving such a synthetic difficulty prior to closure of the oxetanone ring.
Accordingly, there is a need in the art for an improved commercial process for efficiently making tetrahydroesterastin and its (2S, 3S, 5S) analogs in a enantiomeric excess of greater than 70% by the use of 2S, 3S, 5S intermediate compounds which are formed prior to the formation of the oxetanone ring structure.
SUMMARY OF THE INVENTION
In one aspect the present invention relates to novel process for making in at least 70% enantiomeric purity a (3S, 4S, 6S) oxetanone compound of the formula (I),:
or a salt thereof
wherein:
R
1
and R
3
are each independently a C
1
to C
18
straight or branched alkyl hydrocarbon chain, and
R
2
is hydrogen or an alcohol protecting group R
10
, wherein R
10
can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, comprising the steps of:
(a) selectively hydrogenating a composition comprising a compound which is a member selected from the group consisting of (6R) tetrahydro-2H-pyran-2-one compound of formula (II) and (6R) 5,6-dihydro-2H-pyran-2,4-dione of formula (IIa):
wherein
R
5
is hydrogen or an alcohol protecting group, which can be replaced by a hydrogen atom via hydrogenation, and R
1
and R
3
are defined as in formula (I), by hydrogenating the compound of formula II with a hydrogenation catalyst selected from the group consisting of PtO
2
, Raney Nichel and the like, and exchanging hydrogen atoms at the 3 and 4 ring positions or oxidizing the 4-oxo group to provide a (3S, 4S, 6R) 4-hydroxy-tetrahydro-2H-pyran-2-one compound of the formula (III):
wherein R
1
and R
3
are defined as in formula (I);
(b) re-protecting the 4-hydroxy group of the compound of formula (II) produced in (a) with an ether protecting group R
6
, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, opening the lactone ring and esterifying the resulting free acid group to provide a (2S, 3S, 5R) [R
7
] 2-[R
3
]-3-[R
6−
oxy]-5-[hydroxy, R
1
] pentanoic acid ester compound of the formula (IV):
wherein
R
1
and R
3
are defined as in formula (I),
R
6
is an alcohol protecting group, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, and
R
7
is an ester group which can be removed by base or acid hydrolysis, or by hydrogenation;
(c) inverting the chirality of the 5-hydroxy group of the compound of formula (IV) produced in step (b), wherein the inversion comprises a step which is a member selected from the group consisting of
(i) a Mitsunobu reaction.
(ii) esterifying the 5-hydroxy group to a carboxylic acid ester such as the trichloroacetic acid ester, and the like, and hydrolyzing the resultant ester in a water ether solvent such as 3:1 H
2
O/ dioxane, and
(iii) esterifying the 5-hydroxy group to a sulfonic acid ester, such as p-toluene sulfonic acid ester and the like, and reacting the ester with an excess of an organic acid salt selected from the group consising of potassium acetate, sodium acetate, tetraethylammonium acetate, and the like, to provide an ester exchange with the organic acid,
wherein the free inverted (5S) 5-hydroxy group of (i) and (ii) is esterified with a hydroxy protecting group R
10
which can be which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, to provide a compound of the formula (V):
wherein
R
1
and R
3
are defined as in formula (I),
R
6
is an alcohol protecting group, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation,
R
9
is an ester group which can be removed by base or acid hydrolysis, or by hydrogenation, and
R
10
is an alcohol protecting group, which can be replaced by a hydrogen atom via ester hydrolysis or hydrogenation ether degradation, and wherein R
10
is selectively removable with respect to the R
6
alcohol protecting group; and
(d) selectively removing the R
6
alcohol protecting group and R
9
ester group of the compound of formula (V) produced in (c), and cyclizing the 3 position alcohol group with the 1 position acid group using a lactone cyclizing catalyst, such as benzene-sulphonyl chloride, in a solvent such as pyridine at a temperature of about −10 to 10° C., and optionally replacing the R
10
alcohol protecting group of formula (V) with a hydrogen atom, to yield a (3S, 4S, 6S) oxetanone compound of the formula (I):
or a salt thereof.
In a preferred aspect, the process provides a compound of formula (I) wherein R1 is undecyl, R
3
is hexyl and R
2
is hydrogen, which is (2S, 3S, 5S) tetrahydroesterastin.
In another aspect the present invention relates to coupling such compound of formula (I) to an acyl compound via an acid or base esterification procedure without inversion of the 5S hydroxy group.
In another aspect
Lev Robert
Trinh Ba K.
Zpro Chemical, Inc.
LandOfFree
Process for making (2S, 3S, 5S) oxetanone derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for making (2S, 3S, 5S) oxetanone derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for making (2S, 3S, 5S) oxetanone derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2821539