Post on 07-May-2015
BENZIMIDAZOLE DERIVATIVES AS H+/K+ ATPASE INHIBITORS
Presented by - Syed Baseeruddin AlviUnder the guidance of mrs.iffath rizwana
INTRODUCTION
GASTRIC ACID HAS BEEN KNOWN FOR MANY DECADES TO BE A KEY FACTOR IN NORMAL UPPER GASTROINTESTINAL FUNCTIONS, INCLUDING PROTEIN DIGESTION AND CALCIUM ABSORPTION AS WELL AS PROVIDING SOME PROTECTION AGAINST BACTERIAL INFECTIONS…..
INAPPROPRIATE LEVELS OF ACID CAN GIVE RISE TO SEVERE PATHOLOGICAL CONDITIONS LIKE GERD (Gastroesophageal reflux disease) PEPTIC ULCERS…etc etc….
THESE IF LEFT UNTREATED COULD BE LIFE THREATENING..
CIMETIDINE
IT IS A CLASSICAL DRUG USED IN THE TREATMENT OF ACID RELATED DISORDERS.
IT ACTS BY BLOCKING H2 RECEPTORS, THEREBY INHIBITING GASTRIC ACID RELEASE.
IT ALSO INHIBITS THE RELEASE OF PENTAGASTRIN, RESPONSIBLE FOR THE STIMULATION OF ACID RELEASE.
THE PARENT COMPOUND OF CIMETIDINE IS HISTAMINE.
SAR OF CIMETIDINE
GUANIDINE ANALOGUE OF HISTAMINE POSSESS WEAK ANTAGONIST ACTIVITY TO THE ACID SECRETORY ACTIVITY OF HISTAMINE.
INCREASING THE LENGTH OF SIDE CHAIN FROM 2 TO 4 CARBONS COUPLED WITH REPLACEMENT OF STRONGLY BASIC GUANIDINE GROUP BY NEUTRAL METHYL THIOUREA FUNCTION LEADS TO BURIMAMIDE.
Burimamide
Guanidine
INSERTION OF ELECTRONEGATIVE THIOETHER IN THE SIDE CHAIN OF METHYLENE GROUP FAVOURS
N- TAUTOMER &
INTRODUCTION OF 5-METHYL GROUP FAVOURS H2 RECEPTOR SELECTIVITY
BECAUSE OF INCREASED TOXICITY REPLACING THIOUREA SULPHUR WITH CYANO-IMINO FUNCTION TO GIVE CIMETIDINE. Metiamide
Cyano-imino function
CYANOGUANIDINE GROUP IS A GOOD BIOISOSTERE FOR THIOUREA GROUP.
RANITIDINE
NITRO KETENE AMINAL GROUP IS OPTIMUM FOR ACTIVITY
PLACING THE SULFUR NEXT TO THE RING LOWERS ACTIVITY
2,5-DISUBSTITUTION IS BEST…
VARIATION ON DIMETHYL AMINO GROUP CAN BE DONE…
OMEPRAZOLE
IUPAC Name : RS)-5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazole
Mol. Mass
– 345.4 gm/mol
C - 17
N – 03
O – 03
S – 01
H – 19
MECHANISM OF ACTION
OMEPRAZOLE – A PRODRUG GETS CONVERTED INTO ITS ACTIVE FORM IN ACIDIC ENVIRONMENT.
IT IS ACTIVATED BY PROTON-CATALYSED PROCESS TO GENERATE A SULFENAMIDE.
SULFENAMIDE INTERACTS COVALENTLY WITH SULFHYDRYL GROUPS OF CYSTEINE RESIDUE IN H+/K+ ATPase
SAR OF OMEPRAZOLE
OMEPRAZOLE CONSISTS OF 3 PARTS –
SUBSTITUTED BENZIMIDAZOLE RING SUBSTITUTED PYRIDINE RING CH2SO CHAIN
SUBSTITUTION OF PYRIDINE RING WITH ALKYL OR ALKOXY GROUPS ( EXCEPT 6- POSITION) GIVES GOOD ANTISECRETORY ACTIVITY
METHOXY GROUP AT FOURTH POSITION OF PYRIDINE RING DONATES ELECTRONS TO PYRIDINE NITROGEN, THEREBY INCREASING THE % OF CATIONIC PYRIDINE.
THIS ALSO INCREASES THE NUCLEOPHILIC CHARACTER OF PPI’s.
CATIONIC PYRIDINE FACILITATES THE INTRAMOLECULAR NUCLEOPHILIC ATTACK AT C2 OF BENZIMIDAZOLE RING LEADING TO THE FORMATION OF ACTIVE SULFENAMIDE AND SULFENIC ACID.
PRESENCE OF METHYL GROUP AT 3 AND 5 POSITIONS ENHANCES NUCLEOPHILIC CHARACTER OF UNIONIZED PYRIDINE NITROGEN.
BENZIMIDAZOLE DERIVATIVES CONTAINING OXYCYCLIC PYRIDINE
THESE DERIVATIVES ARE SYNTHESISED BY REACTING
2-MERCAPTOBENZIMIDAZOLE WITH CHLOROMETHYL OXYCYCLIC
PYRIDINE COMPOUNDS FOLLOWED BY LOW-TEMPERATURE OXIDATION
WITH m-CHLOROPERBENZOIC ACID.
OXYCYCLIC PYRIDINES WERE CONVERTED TO N-OXIDES BY CYANATED OXYCYCLIC PYRIDINE WHICH WAS OBTAINED UNDER TRIMETHYL SILYL CYANIDE CONDITION .UPON FURTHER TREATMENT CHLOROMETHYL OXYCYCLIC PYRIDINES WAS OBTAINED.
THE OXYCYCLIC PYRANO AND FUROPYRIDINES ARE PREPARED BY PALLADIUM CATALYSED CYCLIZATION OF IODOPYRIDINEALLYL ETHER OR BY THERMAL SIGMATROPIC REARRANGEMENT OF 4-PYRIDINE PROPARGYL ETHER
CONCLUSION
INTRODUCTION OF 5-MEMBERED OR 6-MEMBERED OXYCYCLES
TO PYRIDINE POTENTIATED THE INHIBITORY ACTIVITY OF THE
COMPOUNDS WHERE THE SIZE AND POSITION OF ATTACHMENT
OF OXYCYCLES DID NOT PRODUCE ANY SIGNIFICANT CHANGE.
THANK YOU