Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-28
2001-02-20
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S287000, C435S005000, C435S238000, C436S815000
Reexamination Certificate
active
06191279
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel dipyrano-quinolinone compounds useful as anti-HIV active agents and a process for the preparation of said compounds. The said novel compounds are effective candidate molecules for the treatment of HIV infected patients. The invention further provides novel pharmaceutical compositions comprising such compounds and a process for the preparation of said compositions.
BACKGROUND
Ever since HIV was identified as the etiological cause of AIDS a decade ago, chemotherapy of AIDS has been a very challenging scientific endeavor. Antiviral nucleoside agents such as AZT, ddC, ddl, d
4
T and 3TC being Reverse Transcriptase (R.T.) inhibitors are approved for clinical use. Although these nucleoside based drugs can extend the life of the patient, they are associated with several side effects and are not capable of curing the disease.
The urge for the promising RT inhibitors to cure AIDS, resulted in the identification of a group of coumarin derivatives isolated (Ref: M R Boyd et al, J. Med. Chem., 1992, 35, 2735-2743) from genus Calophyllum as HIV-1 specific non-nucleoside inhibitors, among which Calanolide A represented by formula II (X=O) is the most potent and is currently undergoing clinical trials (phase III). The structural formula of the above compound is shown herebelow:
Calanolides, a ‘dipyrano-coumarin’ class of compounds are active not only against the AZT-resistant strain of HIV-1, but also against virus strains resistant to some other non-nucleoside inhibitors such as TIBO pyridinone, and neviropine. The main drawbacks of this class of compounds are (a) poor solubility of this class of compounds in the physiological medium and (b) lesser stability of the coumarin ring system in biological environment.
It, thus, would be desirable to prepare the New Chemical Entities (NCEs) having calanolide skeleton but with better therapeutic index. In addition, the NCEs are desirable to overcome the problems associated with calanolides such as stability and solubility in the physiological medium as noted above.
Quinolinones are shown to be part structures of several bio-active compounds with profound bio-efficacy. Unlike the lactone bond in coumarins, the lactam bond in quinolinones is highly stable.
This invention, thus deals with the synthesis of novel ‘dipyrano-quinolinone’ class of compounds related to calanolide structural frame work as NCEs and envisaged to circumvent the problems associated with calanolides and have improved therapeutic indices.
The invention deals with the synthesis of novel and new ‘dipyrano-quinolinone’ class of compounds that is presented in the form of patent, where the major differences in the structural arrangement is the replacement of coumarin ring oxygen (at position 1) of calanolide structure of formula II (X=O) with nitrogen (at position 1) in the new ‘quinolinone’ ring system represented by formula II (X=NH). These quinolinone analogues of calanolides are NCEs and are envisaged as potential candidate molecules as anti-HIV agents. The above replacement is not obvious and needs human effort and ingenuity to achieve it. The synthesis and biological activity of ‘dipyrano-quinolinone’ derivatives is reported for the first time in this patent. The rationale for the synthesis of these ‘dipyrano-quinolinones’ reported in this specification are as follows:
1. Replacement of oxygen (at position 1) of natural products, calanolides, with nitrogen leads to dipyrano-quinolinones as anti-HIV agents with better therapeutic index.
2. The inherent problems associated with naturally occurring calanolides such as metabolic stability and solubility in physiological medium can be circumvented with the new dipyrano-quinolinone derivatives that are reported in this patent.
3. The derivatisation of water-soluble derivatives of these new chemical entities represented in this patent are easily possible.
4. The metabolic stability is expected to enhance due to the presence of nitrogen atom in the skeleton of dipyrano-quinolinones derivative presented in this patent.
5. The structure activity relationship coupled with positive activity against calanolide resistant strain of HIV virus can be explored due to the presence of nitrogen atom in the dipyrano-quinolinone system.
OBJECTS OF THE INVENTION
It is an object of the invention to synthesise novel class of dipyrano-quinolinone compounds and their analogues having calanolide skeleton but with better therapeutic index.
Another objective of the invention is to provide novel dipyrano-quinolinone and their analogues to overcome the problems associated with calanolides such as stability and solubility in the physiological medium.
Yet another object of the invention is to provide novel quinolinone compounds and analogues having highly stable lactam bond, unlike the lactone bond in coumarins.
A further object of the invention is to provide novel quinolinone compounds with water soluble derivatives.
It is also an objective of the invention to provide novel dipyrano-quinolinone compounds and their analogues containing nitrogen atom in the skeleton, which provides enhanced metabolic stability to the compounds.
Still, another object of the invention provides novel processes for the synthesis of said novel compounds that exhibit significant anti-HIV activity and have a ‘dipyrano-quinolinone’ framework. These processes utilize commercial reagents and facilitate large-scale manufacture, and provide this new class of totally ‘synthetic’ entities in sufficient quantities for further biological studies.
DETAILED DESCRIPTION
The Applicant, have now developed synthetic routes for the “New Chemical Entities” having a ‘dipyrano-quinolinone’ frame work that exhibit significant anti-HIV activity. These short synthetic routes utilize commercial reagents and facilitate large scale manufacture, and provide this new class of totally ‘synthetic’ entities in sufficient quantities for further biological studies.
The synthetic protocol developed is suitable for the synthesis of compounds of the following formula I:
wherein R is hydrogen, alkyl optionally substituted about C-1 to C-10, alkenyl optionally substituted about C-1 to C-10 with one or more double bounds, alkynyl optionally substituted about C-1 to C-10 with one or more triple bonds, aryl, hetero aryl, carbocyclic aryl, alkyl aryl, alcyclic compounds, C-1 to C-6 alkyl with terminal dialkyl amino group, thio alkyl, hydroxy alkyl groups;
R
1
is H, lower dialkyl amino alkyls such as methyl, ethyl, propyl, and other alkyl groups or &agr; or &bgr;-amino acid moieties, hydroxy alkyl groups having optionally substituted about C-1 to C-10 carbons, acid amides such as aliphatic acids, aromatic acids, sulphonic acids, trihalo acids;
x—x is either a carbon-carbon single bond or a carbon-carbon double bond;
R
2
and R
3
, R
4
and R
5
are each independently hydrogen and methyl there by resulting in the cis and trans diastereomers as well as enantiomers;
R
4
and R
5
are each independently hydrogen and methyl while R
6
and R
7
are each independently hydrogen and hydroxyl-OR, where R
8
is independently alyl, aryl alkyl, amino alkyl, hydroxy alkyl with C-1 to C-10 carbons, sugars which include mono saccharides both in the furanose form as well as pyranose form, amino sugars, disaccharides, amino acids, small peptides through lower alkyl spacer groups, thereby resulting in the cis and trans diastereomers as well as enantiomers.
Quinolinones are shown to be part structures of several bio-active compounds with profound bio-efficacy.
This present invention provides class of compounds known as ‘dipyrano-quinolinone and their analogues’ having basic structural framework of calanolides. The said novel compounds are represented by structural formula I.
The applicants have discovered that the replacement of oxygen at position 1 in the coumarin of ring calanolide structural formula II (X-O) with nitrogen results in novel ‘quinolinone’ ring compounds represented by formula I (X-NH). These quinolinone compounds and their analogues are potential
Gurjar Mukund Keshao
Ilangovan Aindivelu
Narayanan Ven
Sharma Gangavaram Vasantha Madhava
Aulakh Charanjit S.
Council of Science & Industrial Research
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
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