Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-18
2002-11-26
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S459000
Reexamination Certificate
active
06486201
ABSTRACT:
This application is a 371 of PCT/CN99/00196 Nov. 19, 1999.
THE FIELD OF THE INVENTION
This invention relates to a series of new agarofuran derivatives, their preparation and pharmaceutical composition containing the same as well as pharmaceutical use thereof, particularly for the treatment of anxiety and/or depression.
BACKGROUND
Anxiety is a disease of human central nervous system (CNS) and its incidence is increasing in pace with the increasing competition of the society.
Anxiolytics were reported to be best sales among the CNS medication including benzadiazepine compounds (diazepam etc.), buspirone and fluoxetine. But,some of the side effects and defects have been observed such as resistance, addiction, relapse dr slow effect. So it is necessary to develop new anti-anxiety drugs which have better curative effect and lower unwanted effects.
Agarofuran compounds are contained in Aquillaria agallocha Roxb in which 9 compounds as follows have been reported in the following publications.
Tetrahedron 1963, 19, 1079 (M. L. Maheshwari); Tetrahedron 1963, 19, 1519 (M. L. Mheshwari); Tetrahedron 1965, 21, 115 (K. R. Varma); Phytochemistry 1984, 23, 2068 (K. Yoneda); Phytochemistry 1984, 23, 2066 (T. Nakamish); Acta Pharmaceutica Sinica 1986, 21, 516 (J-S, Yang); Acta Pharmaceutica Sinica 1989, 24,.264 (J-S, Yang); J. Am Chem. Soc. 1967, 89, 5665(H. C. Barret); J. Org. Chem. 1968, 33, 435 (J. A. Marshall); Tetrahedron, 1968, 24, 4917 (C. H. Heathcock); Can. J. Chem. 1968, 46, 2817 (A. Asselin); J. Org. Chem. 1979, 44, 546(G. Buchi); Chinese Chem. Lett. 1991, 2, 425(Q. Liu); Chinese Chem. Lett. 1992, 3, 495 (Q. Liu); J. Org. Chem. 1982, 47, 3254 (J. W. Huffman). All of the reports above were only concerned with chemistry of the compounds without teaching or mentioning their bioactivity.
THE OBJECT OF THE INVENTION
The aim of this invention is to find new anxiolytics, which have better efficacy and lower toxicity.
This invention has made discovery of the following new agarofuran compounds, which have therapeutic effects, particularly anti-anxiety effect, with better safety profile.
SUMMARY DESCRIPTION OF THE INVENTION
The first aspect of the invention relates to compounds of the formula (I) and/or stereoisomers thereof
wherein
a double bond may or may not exist in A ring at position 2-3 or position 3-4; R
1
, R
2
and R
3
are respectively at position 2, 3 or 4. R
1
and R
2
or R
2
and R
3
are independently at position 2, 3, or 4.
R
1
is H, C
2-12
straight or branched alkyl chain, saturated or unsaturated, for unsaturated chain, it may include 1-3 double bonds; the above defined alkyl may be unsubstituted or substituted by one or more substituents such as hydroxyl or carbonyl, said alkyl may also be substituted with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which aryl is unsubstituted or substituted by one or more substitutent such as straight or branched C
1
-C
4
alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; in the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring containing at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
R
2
is H, oxo, hydroxyl, C
1
-C
12
straight or branched alkyl chain, saturated or unsaturated, for unsaturated chain, it may include 1-3 double bonds, the above defined alkyl may be unsubstituted or substituted by one or more substituents such as hydroxyl or carbonyl, said alkyl may also be attached with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which ary is unsubstituted or substituted by one or more substituent such as straight or branched C
1
-C
4
alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; In the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring having at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
R
3
is H, oxo, hydroxyl or halogen.
Provided that, R
1
, R
2
, and R
3
are not H at the same time.
According to the present invention, the compounds of the formula (I) exhibit prominent anti-anxiety activity which is characterized by its fast action, longer duration, lower dosage, higher safety coefficient and accompanied by anti-depression effect.
The another aspect of the invention provides a pharmaceutical composition comprising as active ingredient at least one compound of formula (I) or stereoisomer thereof and a pharmaceutical carrier or excipient.
The invention further includes the compound of formula (I) or composition containing it useful for prevention or treatment of anxiety and/or depression.
The invention further provides a method for prevention and/or treatment of anxiety—depression, which comprises administrating at least one compound of formula (I) or composition containing the same to host who needs prevention and/or treatment.
According to the present invention, compounds of formula (I) have exhibited anti-anxiety activity in elevated plus maze test and social interaction test on rat which are typical pharmacological model for axiolytics. Furthermore, a compound of formula (I) showed antidepressant activity in forced swimming test of mice which is typical pharmacological model for anti-depressants.
DETAILED DESCRIPTION OF THE INVENTION
Specifically, the invention relates to agarofuran derivatives of formula (I) and their stereoisomers,
wherein
a double bond may or may not exist in A ring at position 2-3 or position 3-4; R
1
, R
2
and R
3
are respectively at position 2, 3 or 4. R
1
and R
2
or R
2
and R
3
are independently at position 2, 3, or 4.
R
1
is H, C
2-12
straight or branched alkyl chain, saturated or unsaturated, for unsaturated chain, it may include 1-3 double bonds; the above defined alkyl may be unsubstituted or substituted by one or more substituents such as hydroxyl or carbonyl, said alkyl may also be substituted with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which aryl is unsubstituted or substituted by one or more substitutent such as straight or branched C
1
-C
4
alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; in the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring containing at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
R
2
is H, oxo, hydroxyl, C
1
-C
12
straight or branched alkyl chain, saturated or unsaturated, for unsaturated chain, it may include 1-3 double bonds, the above defined alkyl may be unsubstituted or substituted by one or more substituents such as hydroxyl or carbonyl, said alkyl may also be attached with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which ary is unsubstituted or substituted by one or more substituent such as straight or branched C
1
-C
4
alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; In the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring having at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
R
3
is H, oxo, hydroxyl or halogen.
Provided that, R
1
, R
2
, and R
3
are not H at the same time.
According to the present invention, a preferred group of compounds of formula (I) is indicated as formula (Ia), wherein there is a double bond in A ring at position 2-3; R
1
is defined as above and at position 2; R
2
and R
3
are H, provided that R
1
is not H.
According to the present invention a preferred group of compound of formula (I) is indicated as formula (Ib), wherein there is no double bond in A ring; R
1
and R
2
are both at position 2, wherein R
1
is as previously defined; R
2
is H or OH, R
3
is H, provided that R
1
Fang Hongju
Guo Jiyu
Li Chun
Liu Haifan
Liu Qian
Burns Doane Swecker & Mathis L.L.P.
Institute of Materia Medica, Chinese Academy of Medical Science
McKane Joseph K.
Small Andrea D.
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