Intermediates useful for the synthesis of huperzine A

Details Intermediates useful for the synthesis of huperzine A Intermediates useful for the synthesis of huperzine A

2000-03-08

2001-08-07

Huang, Evelyn Mei (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S296000, C546S301000, C546S303000

Reexamination Certificate

active

06271379

ABSTRACT:

FIELD OF INVENTION
The present invention relates to huperzine A, methods for the synthesis of huperzine A, and intermediates useful for the synthesis of huperzine A.
BACKGROUND OF THE INVENTION
Approximately 5-15% of the population of the United States over age 65 (1.24 million) has Alzheimer's disease. This disease is the most frequent cause of institutionalization for long-term care. In 1983, more than $27 billion was spent in the U.S. in health care for Alzheimer's afflicted individuals.
Six basic research areas of Alzheimer's have been defined by R. J. Wurtman,
Scientific Amer.,
62 (1985). These areas include faulty genes, accumulations of amyloid protein, infectious agents, environmental toxins (e g., aluminum and certain unusual amino acids), inadequate blood flow and energy metabolism, and cholinergic deficits.
A number of possible therapeutic interventions are currently under study. These include the use of nerve growth factors (NGF), muscarinic and nicotinic agonists, acetylcholinesterase (AChE) inhibitors, GABA-inverse agonists, NMDA modulators, and others. It is, however, unlikely that any single drug will restore cognition, especially in view of the involvement of a number of different neurotransmitter systems in memory processing.
While it is known that defects in neurotransmitter systems other than cholinergic systems play a role in the memory loss associated with Alzheimer's disease, findings by K. L. Davis, presented at “New Strategies for the Treatment of Alzheimer's Disease,” NIA Meeting (Jan. 8-10, 1990) indicated that administration of AChE inhibitors, such as physostigmine, result in modest cognitive improvement and may prove useful for treating Alzheimer's disease when administered in combination with other drugs such as clonidine, deprenyl or desipramine.
To the extent ACHE inhibitors can serve as useful adjuncts in the treatment of Alzheimer's disease, two relatively new lycopodium alkaloids, (−)-huperzine A and B, isolated from
Huperzia serrata
(Thunb.) Trev., a Chinese folk medicine, appear superior to THA and physostigmine (U.S. Pat. No. 5,177,082 to Yu et al.; J. S. Liu et al.,
Can. J. Chem.,
64, 837 (1986); W. A. Ayer et al., ibid., 67, 1077 (1989), ibid., 67, 1538 (1989)). The structure of (−)-huperzine A (1) is depicted below:
In studies performed in China, these compounds have been found to improve memory and learning in animals (X. C. Tang et al.,
Acta Pharmacol Sin.,
7, 507 (1986)). Additionally, workers at Hoffman LaRoche studied (−)-huperzine A in mice and squirrel monkeys and found it to be an effective cognition enhancer (G. P. Vincent et al.,
Neurosci. Abst.,
13, 884 (1987)). The duration of action of a single dose (2 mg/kg i.m.) of (−)-huperzine A is over 6 hr, a remarkable result in relation to the AChE inhibitory action of physostigmine (0.65 mg/kg i.m.), which has a maximal duration of action of 60 min and which causes considerable side effects (X. C. Tang et al., J.
Neurosci. Res.,
24, 276 (1989)). (−)-Huperzine A has been further tested in 128 patients suffering from myasthenia gravis and found to control the clinical manifestations of the disease in 99% of these cases (Y. S. Cheng,
New Drugs and Clinical Remedies,
5, 197 (1986)).
Other pharmacological agents that circulate systemically but that are targeted to brain tissue have enjoyed only limited success. For such pharmacological agents to enter brain tissue in therapeutically effective concentrations, the blood-brain barrier, a network of tightly joined endothelial cells of central nervous system capillaries, must first be penetrated. Because the membranes of the endothelial cells are phospholipoidal in nature, pharmacological agents that are lipophilic in nature are better able to diffuse through the blood-brain barrier than those that are not (see Marcus E. Brewster et al.,
Chemical Approaches to Brain-Targeting of Biologically Active Compounds, in Drug Design for Neuroscience
435-67 (Alan P. Kozikowski ed., Raven Press, Ltd. 1993).
While huperzine A is a promising candidate for treatment of Alzheimer's disease, extraction of practical quantities from its natural source is difficult. Furthermore, only a limited number of huperzine A synthetic procedures have been disclosed, which are, for the most part, complicated and non-convergent, e.g., Kaneko et al.,
Tetrahedron, Asymmetry
8, 829-832 (1997); Chassaing el al.,
Synth. Conmnun.
27, 61-68 (1997); Kaneko et al.,
Tetrahedron
54, 5485-5506 (1998); Qian et al.,
Tetrahdron Leti.
30, 2089-2090 (1989)).
Accordingly, there remains a need for convergent synthetic methods toward huperzine A and precursors therefor.
SUMMARY OF THE INVENTION
The present invention relates to intermediates, having a structure represented by formula 2 below, that can be converted into huperzine A
wherein:
R
1
is lower alkyl, benzyl, or substituted benzyl;
Y is selected from the group consisting of—NO
2
,—NHR
2
, —NR
3
R
4
, —CH═NOR
5
, —COR
6
, —COCl, —CO
2
R
6
, —C(O)NR
6
R
7
, —CN, —C(S)NR
6
R
7
, —N
3
, —SR
6
, and —N═CR
8
R
9
;
R
2
is an amino protecting group;
R
3
and R
4
are independently selected from the group consisting of —C(O)OR
10
, —C(O)R
10
, allyl, benzyl, substituted benzyl, phenacyl, and 3-acetoxypropyl or R
3
and R
4
may be taken together to form a cyclic imide;
R
5
is selected from the group consisting of hydrogen, lower alkyl, and aryl;
R
6
and R
7
are independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl, and substituted aryl or R
6
and R
7
may be taken together to form a heterocyclic ring;
R
8
and R
9
are independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl, and substituted aryl or R
8
and R
9
may be taken together to form a ring;
R
10
is selected from the group consisting of lower alkyl, substituted lower alkyl, aryl, substituted aryl, adamantyl, cinnamyl, 2-trimethylsilylethyl, 2-phenylethyl, vinyl, allyl, benzyl, and substituted benzyl; and
one broken line is present as a carbon—carbon bond and the other broken line is absent, where the broken line completes an unconjugated carbon—carbon double bond, which double bond may be endocyclic whereby n is 3 or the double bond may be exocyclic whereby n is 2.
The invention also relates to methods for the synthesis of a compounds of formula 2, and methods for conversion of a compound of formula 2 into huperzine A.
In another embodiment, the invention relates to compounds of formula 3 shown below:
wherein:
R
1
is lower alkyl, benzyl, or substituted benzyl;
X is a suitable leaving group;
Y is selected from the group consisting of hydrogen, —NO
2
, —NR
3
R
4
,—CH═NOR
5
, —COR
6
, —CO
2
R
6
, —C(O)NR
6
R
7
, —CN, —C(S)NR
6
R
7
, —N
3
, and —N═CR
8
R
9
;
R
3
and R
4
are independently selected from the group consisting of —C(O)OR
10
, —C(O)R
10
, phenacyl, and 3-acetoxypropyl or R
3
and R
4
may be taken together to form a cyclic imide;
R
5
is selected from the group consisting of hydrogen, lower alkyl, and aryl;
R
6
and R
7
are independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl, and substituted aryl or R
6
and R
7
may be taken together to form a heterocyclic ring;
R
8
and R
9
are independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl, and substituted aryl or R
8
and R
9
may be taken together to form a ring; and
R
10
is selected from the group consisting of lower alkyl, substituted lower alkyl, aryl, substituted aryl, adamantyl, cinnamyl, 2-trimethylsilylethyl, 2-phenylethyl, vinyl, allyl, benzyl, and substituted benzyl.
The invention also relates to methods for the synthesis of a compound of formula 3, and methods for conversion of a compound of formula 3 into a compound of formula 2.
The present invention can be understood more fully by reference to the following detailed description and illustrative examples that are intended to exemplify non-lim

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