Description:FIELD OF INVENTION
[0001] The present disclosure relates to the field of medicinal chemistry, in
particular relates to antibacterial compounds, more particularly heterocyclyl
compounds. The present disclosure relates to a process of preparation of the
5 aforementioned compounds.
BACKGROUND OF THE INVENTION
[0002] Bacterial infections account for nearly 7 lakh deaths annually, all over the
world. Over the years, antibiotics have been used drastically to treat bacterial
infections and globally, more than one billion tons of antibiotics have been
10 produced and used. The uncontrolled use of antibiotics has resulted in the
development of antimicrobial resistance (AMR) and multidrug resistance (MDR)
amongst the existing bacterial strains. Bacterial species are known to mutate rapidly
over generations. Antimicrobial resistance (AMR) occurs when microbes evolve
mechanisms that protect them from the effects of antimicrobials (drugs used to treat
15 infections). All classes of microbes can evolve resistance where the drugs are no
longer effective. As a result of drug resistance, antibiotics and other antimicrobial
medicines become ineffective and infections become difficult or almost impossible
to treat, thereby increasing the risk of disease spread, severe illness, disability, and
death. AMR is a natural process that happens over time through genetic changes in
20 pathogens. The misuse and overuse of antimicrobials accelerated the emergence
and spread of AMR, making it difficult to treat, prevent or control infections in
humans, animals and plants. This highlights the need to continually develop new
antibiotics to combat the newly emerging bacterial infections.
[0003] Heterocyclic compounds are cyclic organic compounds which comprise at
25 least one heteroatom such as nitrogen, oxygen or sulphur in the cyclic system.
Nitrogen-containing heterocyclic compounds and their derivatives have been
widely accepted as therapeutic agents. Among the wide category of heterocyclic
compounds, the focus has now been directed towards bis-heterocyclic compounds.
A variety of bis-heterocyclic compounds comprising N, S and O have been studied
30 in medicinal industry as biologically active compounds with properties, such as
2
antifungal, anti-inflammatory, antibacterial, antioxidant and anticancer activity.
Heterocyclyl compounds such as bisindolylmethanes (BIMs) are well-known as
anti-microbial, anti-cancerous, and anti-inflammatory agents. Owing to such an
exquisite biological profile, many protocols were devised for their synthesis based
5 on the use of Lewis/Bronsted acids, ionic liquids etc. However, the side product(s)
formation, use of toxic reagents/oxidants and a high loading of the catalyst were
some of the drawbacks encountered in these methods.
[0004] Over the last few decades, there has been significant progress in developing
heterocyclic compounds which are biologically relevant as drugs to treat such
10 antibiotic resistant bacteria and related diseases or infections. However, there is a
need for developing a facile yet human compatible process to synthesize such
heterocyclyl compounds that could treat a wide range of bacterial strains.
I/We Claim:
1. A process for preparation of compound of Formula I, its pharmaceutically
acceptable salts, stereoisomers, tautomers, polymorphs, solvates,
intermediates, and metabolites thereof,
5
Formula I
wherein
R is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10
carbocyclyl, C6-15 aryl, C2-15 heteroaryl, or C1-15 heterocyclyl, wherein C1-10
10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, C6-15 aryl, C2-15
heteroaryl, or C1-15 heterocyclyl is optionally substituted with one or more
groups selected from halogen, hydroxy, C6-15 aryloxy, cyano, nitro, amino,
C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C3-10 carbocyclyl, C6-
15 aryl, C2-15 heteroaryl, or C1-15 heterocyclyl;
15 A is same or different and is selected from C2-15 heteroaryl ring or C1-15
heterocyclyl ring, and
R' is independently selected from halogen, hydroxy, cyano, nitro, amino, C1-
10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C6-15 aryl, C2-15
heteroaryl, C1-15 heterocyclyl, C6-15 aryloxy, or C1-10 alkoxy, and
20 n is 0 to 2,
the process comprising:
56
reacting a heterocyclyl compound or heteroaryl compound of Formula
II with a carbonyl compound of Formula III in presence of a catalyst to
obtain the compound of Formula I,
wherein LG is selected from hydrogen, halogen, hydroxy, C6-15 aryloxy, C1-
5 10 alkoxy, or optionally protected amines; the catalyst is metal doped
molybdenum sulphide, and the metal is selected from cobalt, nickel, iron,
or lead.
2. The process as claimed in claim 1, wherein R is selected from hydrogen, C1-
10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, C6-15 aryl, C2-15
10 heteroaryl, or C1-15 heterocyclyl, wherein C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, C3-10 carbocyclyl, C6-15 aryl, C2-15 heteroaryl, or C1-15 heterocyclyl
is optionally substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, amino, C1-10 alkyl, C1-10 alkoxy, C6-15 aryloxy, C3-10
carbocyclyl, C6-15 aryl, C2-15 heteroaryl, C1-15 heterocyclyl, C2-10 alkenyl, C2-
15 10 alkynyl;
A is same and is a C2-15 heteroaryl ring, and
R’ is independently selected from halogen, hydroxy, cyano, nitro, amino,
C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C6-15 aryl, C6-15
aryloxy, C2-15 heteroaryl, C1-15 heterocyclyl or C1-10 alkoxy, and
20 n is 0 to 2.
3. The process as claimed in claim 1, wherein the heterocyclyl compound or
heteroaryl compound of Formula II is one or more compounds selected from
indole, indazole, 7-azaindazole, 7-azaindole, 4-azaindole, 5-azaindole, 6-
azaindole, benzofuran, dibenzofuran, benzo[d]isoxazole,
25 benzo[b]thiophene, benzo[d]isothiazole, 1,4,5,6-
tetrahydrocyclopenta[b]pyrrole, 2H-pyran, 4H-pyran, 2H-thiopyran, 4Hthiopyran, oxazine, 1,2-dihydroisoquinoline, 1H-isochromene, 2-pyrroline,
57
1H-pyrrole, pyrrolopyrrole, 2-pyrazoline, pyrazole, imidazole, azetidine,
furan, furopyrrole, thiophene, thienopyrrole, carbazole, oxazole, isoxazole,
thiazole, isothiazole, 2,3-dihydroazepine, 2,5-dihydroazepine, azepine, 1,2-
diazepine, 1,3-diazepine, 1,4-diazepine, thiepine, or 1,4-thiazepine; and the
5 heterocyclyl compound or heteroaryl compound is optionally substituted
with one or more groups selected from halogen, hydroxy, cyano, nitro,
amino, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C6-15 aryloxy,
C3-10 carbocyclyl, C6-15 aryl, C2-15 heteroaryl, or C1-15 heterocyclyl.
4. The process as claimed in claim 1, wherein the carbonyl compound of
10 Formula III is selected from C1-10 aliphatic acid, C6-15 aromatic acid, C1-15
heterocyclyl acids, C1-10 aliphatic aldehyde, C1-10 acyl halide, C6-15 aryl
aldehyde, C2-15 heteroaryl aldehyde, C1-15 heterocyclyl aldehyde, C1-10
aliphatic esters, C6-15 aromatic esters, C5-15 heteroaryl esters, C1-15
heterocyclyl esters, C1-10 aliphatic amides, C6-15 aromatic amides, C2-15
15 heteroaryl amides, or C1-15 heterocyclyl amides.
5. The process as claimed in claim 1, wherein the heterocyclyl compound or
heteroaryl compound of Formula II and the carbonyl compound of Formula
III are in a molar ratio range of 2:1 to 10:1.
6. The process as claimed in claim 1, wherein the catalyst is in a weight range
20 of 11 to 27% (w/w) with respect to the total weight of the carbonyl
compound of Formula III.
7. The process as claimed in claim 1, wherein reacting a heterocyclyl
compound or heteroaryl compound of Formula II with a carbonyl compound
of Formula III is carried out at a temperature in a range of 20 to 40 ℃, for
25 a time period in a range of 60 to 240 minutes.
8. The process as claimed in claim 1, wherein the process is carried out in the
presence of a solvent selected from water, acetonitrile, acetone, methanol,
ethanol, propanol, isopropanol, tert-butanol, isobutyl alcohol, 1,3-
propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 1,5-
30 pentanediol, 2-butoxyethanol, dimethyl sulfoxide (DMSO), sulfolane, N,Ndimethylformamide (DMF), diethanolamine, diethylenetriamine,
58
ethylamine, 1,1-dimethylhydrazine, 1,2-dimethylhydrazine,
tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane, methyl
diethanolamine, glycerol, ethylene glycol, propylene glycol, triethylene
glycol, pyridine, N-Methyl-2-pyrrolidone (NMP), or combinations thereof.
5 9. The process as claimed in claim 1, wherein the process is carried out in open
air or in an atmosphere of inert gas selected from argon, or nitrogen.
10. The process as claimed in claim 1, wherein the process is carried out in
presence or absence of light.
11. The process as claimed in claim 1, wherein the compound of Formula I is
10 purified by column chromatography, liquid chromatography, thin layer
chromatography, crystallization, or distillation.
12. A process for preparing a compound of Formula Ia, its pharmaceutically
acceptable salts, stereoisomers, tautomers, polymorphs, solvates,
intermediates, and metabolites,
15
wherein
R is selected from hydrogen , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10
carbocyclyl, C6-15 aryl, C2-15 heteroaryl, or C1-15 heterocyclyl, wherein C1-10
alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, C6-15 aryl, C2-15
20 heteroaryl, or C1-15 heterocyclyl is optionally substituted with one or more
groups selected from halogen, hydroxy, cyano, nitro, amino, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C6-15 aryloxy, C3-10 carbocyclyl, C6-15
aryl, C2-15 heteroaryl, or C1-15 heterocyclyl; and
59
R' is independently selected from halogen, hydroxy, cyano, nitro, amino, C1-
10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C6-15 aryl, C2-15
heteroaryl, C1-15 heterocyclyl, C6-15 aryloxy, or C1-10 alkoxy; and
R” is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10
5 carbocyclyl, C6-15 aryl, C2-15 heteroaryl, or C1-15 heterocyclyl, wherein C1-10
alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, C6-15 aryl, C2-15
heteroaryl, or C1-15 heterocyclyl are optionally substituted with one or more
groups selected from halogen, hydroxy, cyano, nitro, amino, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C6-15 aryloxy, C3-10 carbocyclyl, C6-15
10 aryl, C2-15 heteroaryl, or C1-15 heterocyclyl;
the process comprising:
reacting indole of Formula IIa with an aldehyde of Formula IIIa in presence
of a catalyst to obtain the compound of Formula Ia,

15
wherein the catalyst is metal doped molybdenum sulphide, and the metal is
selected from cobalt, nickel, iron, or lead.
13. The process as claimed in claim 12, wherein the indole of Formula IIa and
the aldehyde of Formula IIIa are in a molar ratio range of 2:1 to 10:1, and
20 the catalyst is in a weight range of 11 to 27% (w/w), with respect to the
compound of Formula IIIa.
14. The process as claimed in any one of the claims 1 to 13, wherein the
compound of Formula I and the compound of Formula Ia exhibits
antimicrobial properties.
25 15. The process as claimed in any one of the claims 1 to 14, wherein the
compound of Formula I and the compound of Formula Ia exhibits a
60
minimum inhibitory concentration (MIC) in a range of 10 to 130 µg/mL and
minimum bactericidal concentration (MBC) in a range of 70 to 500 µg/mL.
16. A pharmaceutical composition comprising the compound of Formula I or
the compound of Formula Ia obtained by the process as claimed in any one
5 of the claims 1 to 13, and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition as claimed in claim 16, wherein the carrier
is selected from pigments, emulsifiers, extenders, bulking agents, buffers,
diluents, fillers, flavourants, preservatives, absorption enhancers,
dispersants, solvents, controlled release matrices or combinations thereof.
10 18. The pharmaceutical composition as claimed in claim 16, wherein the
composition is in the form of powder, tablet, liquid, or emulsion.
19. A method of treating a disease or a condition to a subject in need thereof,
the method comprising:
administering the compound of Formula I or the compound of Formula Ia
15 obtained by the process as claimed in any one of the claims 1 to 13, or the
pharmaceutical composition as claimed in any one of the claims 16 to 18,
to the subject.
20. The method as claimed in claim 19, wherein the disease or condition is
caused by a bacteria selected from Staphylococcus aureus, Methicillin20 resistant Staphylococcus aureus (MRSA), Bacillus subtilis, Staphylococcus
epidermidis, or Streptococcus pneumoniae.
21. Use of the compound of Formula I or the compound of Formula Ia obtained
by the process as claimed in any one of the claims 1 to 13, or the
pharmaceutical composition as claimed in any one of the claims 16 to 18.