Analgesics
Nociception and Pain
Nociception is the mechanism whereby noxious peripheral stimuli are
transmitted to the central nervou...
Pain receptors in our bodies are nerves that transmit pain.
These are free nerve endings located in various body
tissues t...
Acute Vs chronic
Acute pain Chronic pain
Sudden onset
Temporary (disappears
once stimulus is removed)
 can be somatic, ...
Nociceptive Vs Neuropathic
Nociceptive pains result from activation of
nociceptors (Pain receptors)
Neuropathic pains resu...
Somatic Vs Visceral
Somatic pain
Superficial: stimulation of receptors in skin
Deep: stimulation of receptors in muscles, ...
Referred pain
Pain experienced at a point distant to its point of origin
Area of referred pain is supplied by same spinal ...
Somatogenic Vs Psychogenic
Somatogenic pain is a pain originating from an actual
physical cause e.g. trauma, ischaemia etc...
Pain pathway
There are four processes in the pain pathway
Transduction
Noxious stimuli translated into electrical activity...
Cell Membrane Phospholipids
Arachidonic Acid
Endoperoxides
Thromboxane
Prostaglandins Prostacyclin
Toxic Oxygen Radicals
C...
Action of cyclo-oxygenase
COX – 1 enzyme
Constitutive pathway
(stable conc)
phospholipid
Arachidonic acid
Prostaglandins a...
NSAIDS: Mode of action
NSAIDS block both COX-1 and COX-2
This accounts for most of the side effects of NSAIDS
Different ty...
COX-1
Gastric
ulcers
Bleeding
Acute renal
failure
COX-2
Reduce
inflammation
Reduce pain
Reduce
fever
Analgesics / Pain killers are common pain relievers acting centrally
to elevate pain threshold without disturbing consciou...
Aspirin Heroin
Codeine
OpiumIbuprofen
Acetaminophen
Mild
Analgesics / OTC
Strong
Analgesics
Analgesics
Mild analgesics
They work by blocking the enzyme-controlled
synthesis of prostaglandins.
The main effects of prostaglandin...
Natural Painkillers
They are produced naturally in the body.
Endorphins and Enkephalins are the natural
opiates found in t...
Strong analgesics
They temporarily bind to the opiate receptor sites in the brain
preventing the transition of pain impuls...
(iv) σ-receptors - not true opioid receptors, but are the site of action
of certain psychotomimetic drugs, with which some...
Pyrrole acetic acid Derivatives
RName
CH3Tolmetin
ClZomepirac
Aryl aceticacid derivatives
Aryl Propionicacid derivatives
Heteroaryl acetic / Propionic acid derivatives
Oxicams
Selective COX-2 inhibitors
Miscellaneous
Newer agents
(i) Synthesis of Salicylates
a) Synthesis of Aspirin
b) Synthesis of Salsalate
c) Synthesis of Sulphasalazine
(ii) Synthesis of P-amino phenol derivatives
a) Synthesis of Phenacetin
b) Synthesis of par...
(iii) Synthesis of 3,5-pyrazolidine diones
a) Synthesis of phenylbutazone
(iv) Synthesis of Anthranilicacid derivatives
a)...
(v) Synthesis of Indole acetic acid derivatives
a) Synthesis of Indomethacin
(vi) Synthesis of Indene acetic acid derivatives
a) Synthesis of Sulindac
Reformatski is an organic reaction, which conden...
Vii) Synthesis of Pyrrole acetic acid Derivatives
a) Synthesis of Tolmetin Sodium
b) Synthesis of Zomepirac
Viii) Synthesis of Aryl acetic acid derivatives
a) Synthesis of Ibufenac
b) Synthesis of Diclofenac
Wolf-kishner reduction...
ix) Synthesis of Aryl propionic acid derivatives
a) Synthesis of Ibuprofen
b) Synthesis of Fenoprofen
X) Synthesis of Heteroaryl acetic / propionic acid derivatives
a) Synthesis of Caprofen
Xi) Synthesis of Oxicams
a) Synthe...
Xii) Synthesis of COX-2 inhibitors
a) Synthesis of Celecoxib
Xiii) Synthesis of Miscellaneous agents
a) Synthesis of Nimes...
SAR of Salicylates
-a) Subst. on either the –COOH or –OH grp may affect the potency and toxicity.
-b) Reducing the acidity...
SAR of 3,5-pyrazolidinediones
a) Pharmacological activity is related to the acidic H at 4th posn. Thus, presence of
dicarb...
SAR of Anthranilic acid derivatives
•a) The position of the –COOH group is more important for the activity whereas
the m &...
f) In disubst. derivatives, the nature of two subst. is the same, 2’,3’-disubst. appears to
be the most effective. E.g. Me...
SAR of Indole acetic acid derivatives
a) Replacement of the –COOH group at 3rd posn with other acidic functionalities
decr...
SAR of Pyrrole aceticacid derivatives
a) Replacement of p-Tolyl group with p-chloro benzoyl group produces little effect o...
SAR of COX-2 Inhibitors
- Diaryl heterocycle with Cis-Stilbene moiety and changes in the Para position of one of the
aryl ...
Narcotic Analgesics / Opioid analgesics
These are naturally occurring, semi-synthetic and synthetic drugs, which have morp...
Ia) Hydromorphone derivatives
R’RName
HOHHydromorphone
OHHOxymorphone
H-OCH3Hydrocodone
OH-OCH3Oxycodone
Ib) Dihydromorphi...
Ic) Morphinan derivatives
R’’R’RName
-CH3HHLevorphanol
-CH2-CH=CH2HHLevallorphan
OHHButerphanol
-CH3H-CH3Dextromethorphan
R4R3R2R1Name
HCOOC2H5CH3Meperidine
HCOOC2H5CH3Bemidone
HCOOCH(CH3)2CH3Properidone
HCOC2H5CH3Ketobemidone
CH3COOC2H5CH3Alph...
R4R3R2R1Name
CH3COOCH3Lofentanil
HCH2OCH3Sufentanil
HCH2OCH3Alfentanil
HCOOC2H5Diphenoxylate
HOHLoperamide
III) Methadone / Diphenyl heptanones
R4R3R2Name
-CH2-CH(CH3)N(CH3)2COC2H5C6H5Methadone
-CH(CH3)CH2N(CH3)2COC2H5C6H5Isometh...
R1RName
CH3CH2-CH=C(CH3)2Pentazocine
CH3CH2-CH2-C6H5Phenazocine
CH3Cyclazocine
C=OKetazocine
CH3CH3Metazocine
IV) Benzazoc...
V) Miscellaneous
Vi) Newer Drugs
VII) Narcotic Antagonist
R2R1RName
H-CH2-CH=CH2OHNalorphine
OH-CH2-CH=CH2-C=ONaloxone
(Single =
Bond)
OH-C=ONaltrexone
(Si...
Synthesis of Morphine Analogs
Bischler-Napaieralski reaction is an intramolecular electrophilic
aromatic substitution reaction that allows for the cycli...
Synthesis of Levallorphan & Levorphanol
Knoevenagel condensation is a nucleophilic addition of an active
hydrogen compound to a carbonyl group (aldehyde or ketone...
Synthesis of Meperidines / Phenyl(ethyl)Piperidines
Synthesis of Meperidine / Pethidine
Synthesis of Ketobemidone
Synthesis of Anileridine
Synthesis of Fentanyl Citrate
Synthesis of Alfentanil
Synthesis of Lofentanil
Synthesis of Methadone
Synthesis of Dextromoramide
Synthesis of Benzazocin / Benzomorphan analogs
Synthesis of Pentazocine
Synthesis of Miscellaneous agents
Synthesis of Buprenorphine
Synthesis of Narcotic Antagonists
Synthesis of Nalorphine or N-allyl morphine
Synthesis of Narcotic Antagonists
Synthesis of Naloxone and Naltrexone
SAR of Morphine
(i) Modification on alicyclic ring:
-The alcoholic OH group at C-6 when methylated, esterified, oxidized, ...
(iii) Modification of 30 Nitrogen atom:
-Presence of 30 Nitrogen atom is necessary for good opioid activity.
-The size of ...
SAR of Phenyl (ethyl)piperidines / Meperidine analogs:
-Replacement of C-4 phenyl group of meperidine by H, alkyl, aryl, a...
SAR of Diphenyl Heptanone / Methadone analogs:
-The levo Isomer of Methadone and Isomethadone are twice as effective as th...
Narcotic and Non Narcotic Analgesics
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Narcotic and Non Narcotic Analgesics

A presentation on Analgesics which includes basic terminologies, mechanisms and pathway for pain, pharmacology of pain receptors and synthesis of related medicinal compounds.
Published on: Mar 3, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Narcotic and Non Narcotic Analgesics

  • 1. Analgesics
  • 2. Nociception and Pain Nociception is the mechanism whereby noxious peripheral stimuli are transmitted to the central nervous system. Pain is a subjective experience and difficult to quantify, is very important protective phenomenon that accompanies many pathological conditions and is not always associated with nociception (or) an unpleasant sensory and emotional experience with actual or potential tissue damage. Superficial: - Stimulation of skin & mucous membranes - Fast response Deep: - Arises from muscles, joints, tendons, heart ..etc. - Slow response Analgesia – absence of pain
  • 3. Pain receptors in our bodies are nerves that transmit pain. These are free nerve endings located in various body tissues that respond to thermal, mechanical and chemical stimuli. When stimulated, these pain receptors generate an impulse. The pain results of various impulses arriving at the spinal cord and the brain. When tissues become injured, they release chemicals called prostaglandins and leukotrienes that make the pain receptors more sensitive and thus causing pain.
  • 4. Acute Vs chronic Acute pain Chronic pain Sudden onset Temporary (disappears once stimulus is removed)  can be somatic, visceral, referred Associated anxiety Physiological responses to acute pain include increased RR, HR, BP and reduction in gastric motility – sympathetic response) Persistent – usually lasting more than six months Cause unknown – may be due to neural stimulation or a decrease in endorphins Physiological responses are less obvious especially with adaptation. Psychological responses may include depression
  • 5. Nociceptive Vs Neuropathic Nociceptive pains result from activation of nociceptors (Pain receptors) Neuropathic pains result from direct injury to nerves in the peripheral nervous system
  • 6. Somatic Vs Visceral Somatic pain Superficial: stimulation of receptors in skin Deep: stimulation of receptors in muscles, joints and tendons Visceral pain Stimulation of receptors in internal organs, abdomen and skeleton Often poorly localised as fewer receptors located in viscera Visceral pain can be referred.
  • 7. Referred pain Pain experienced at a point distant to its point of origin Area of referred pain is supplied by same spinal segment as actual site of pain Brain misinterprets signals as coming from somatic regions Knowledge of different types of referred pain is important in clinical diagnosis because in many visceral ailments the only clinical signs is referred pain.
  • 8. Somatogenic Vs Psychogenic Somatogenic pain is a pain originating from an actual physical cause e.g. trauma, ischaemia etc Psychogenic pain is pain for which there is no physical cause. It is not however imaginary pain and can be as intense as somatic pain.
  • 9. Pain pathway There are four processes in the pain pathway Transduction Noxious stimuli translated into electrical activity at sensory nerve endings Transmission Propagation of impulses along spinothalamic pathway. Modulation Transmission is modified Perception Affective / motivational aspect Each of these processes present a potential target for analgesic therapy
  • 10. Cell Membrane Phospholipids Arachidonic Acid Endoperoxides Thromboxane Prostaglandins Prostacyclin Toxic Oxygen Radicals Cyclo-oxygenase C O X Phospholipase Tissue Trauma
  • 11. Action of cyclo-oxygenase COX – 1 enzyme Constitutive pathway (stable conc) phospholipid Arachidonic acid Prostaglandins associated with normal body functions e.g. prostaglandin E2 (for kidney function), prostaglandin I2 (for stomach protection) COX-2 enzyme Induced pathway phospholipid Arachidonic acid Inflammatory prostaglandins
  • 12. NSAIDS: Mode of action NSAIDS block both COX-1 and COX-2 This accounts for most of the side effects of NSAIDS Different types of NSAIDS have different specificities for COX-1 and COX-2 This contributes to differences in side effects between the NSAIDS.
  • 13. COX-1 Gastric ulcers Bleeding Acute renal failure COX-2 Reduce inflammation Reduce pain Reduce fever
  • 14. Analgesics / Pain killers are common pain relievers acting centrally to elevate pain threshold without disturbing consciousness or altering other sensory modalities. Many analgesics also have antipyretic properties as well. They can be used to reduce fever Some analgesics are also anti-inflammatory and anti-clotting drugs as well Classification: (i) Opioid analgesics / Narcotic analgesics / Morphine like substances – predominantly acts on CNS (ii) Non-opioid analgesics / NSAID – predominantly acts on peripheral nerves
  • 15. Aspirin Heroin Codeine OpiumIbuprofen Acetaminophen Mild Analgesics / OTC Strong Analgesics Analgesics
  • 16. Mild analgesics They work by blocking the enzyme-controlled synthesis of prostaglandins. The main effects of prostaglandins are: The constriction of blood vessels, which helps increase the body temperature. Direct effect on the body’s heat regulating centre, hypothalamus, which produces fever. Increase of the permeability of capillaries which allows water to pass to the tissue and cause pain and swelling.
  • 17. Natural Painkillers They are produced naturally in the body. Endorphins and Enkephalins are the natural opiates found in the part of the brain and the spinal cord that transmit pain impulses. They are able to bind to neuro-receptors in the brain and produce relief from pain. The temporary loss of pain immediately after an injury is associated with the production of these chemicals.
  • 18. Strong analgesics They temporarily bind to the opiate receptor sites in the brain preventing the transition of pain impulses -The opium alkaloids: Opiate: it is a natural or synthetic drug that exerts actions on the body similar to those induced by morphine. Narcotic: is a term generally used for drugs that have both a narcotic and analgesic Narcotic analgesics mainly acts by opioid receptor (GPCR), (i) Mu – responsible for most of the analgesic effects of opioids, and for some major unwanted effects like respiratory depression, euphoria, sedation and dependence (ii) Kappa – Contribute to analgesia at the spinal level, and may elicit sedation and dysphoria, but produce relatively few unwanted effects, and do not contribute to dependence (iii) Delta- important in the periphery, but may also contribute to analgesia
  • 19. (iv) σ-receptors - not true opioid receptors, but are the site of action of certain psychotomimetic drugs, with which some opioids interact Note: All opioid receptors are linked through G-proteins to inhibition of adenylate cyclase. They also facilitate opening of K+ channels (causing hyperpolarisation), and inhibit opening of Ca2+ channels (inhibiting transmitter release). These membrane effects are linked to the decrease in cAMP formation.
  • 20. Pyrrole acetic acid Derivatives RName CH3Tolmetin ClZomepirac Aryl aceticacid derivatives Aryl Propionicacid derivatives
  • 21. Heteroaryl acetic / Propionic acid derivatives Oxicams Selective COX-2 inhibitors
  • 22. Miscellaneous Newer agents
  • 23. (i) Synthesis of Salicylates a) Synthesis of Aspirin b) Synthesis of Salsalate
  • 24. c) Synthesis of Sulphasalazine (ii) Synthesis of P-amino phenol derivatives a) Synthesis of Phenacetin b) Synthesis of paracetamol
  • 25. (iii) Synthesis of 3,5-pyrazolidine diones a) Synthesis of phenylbutazone (iv) Synthesis of Anthranilicacid derivatives a) Synthesis of Flufenamic acid b) Synthesis of Mefenamic acid Ullman condensation is type of Aromatic amination reaction between aryl halogen acids and aryl amines
  • 26. (v) Synthesis of Indole acetic acid derivatives a) Synthesis of Indomethacin
  • 27. (vi) Synthesis of Indene acetic acid derivatives a) Synthesis of Sulindac Reformatski is an organic reaction, which condenses aldehydes or ketones with α-halo esters using a metallic zinc to form β-hydroxy-esters.
  • 28. Vii) Synthesis of Pyrrole acetic acid Derivatives a) Synthesis of Tolmetin Sodium b) Synthesis of Zomepirac
  • 29. Viii) Synthesis of Aryl acetic acid derivatives a) Synthesis of Ibufenac b) Synthesis of Diclofenac Wolf-kishner reduction is a chemical rxn that fully reduces a ketone or aldehyde to an alkane. It involved heating the hydrazine with Na-ethoxide in a sealed vessel at about 180 °C. Diethylene glycol (DEG) is usually used as solvent. Willgerodt oxidation is is an organic rxn converting an aryl alkyl ketone to the corresponding amide and carboxylic acid as side rxn product by reaction with Sulphur, Con. NH4OH and pyridine.
  • 30. ix) Synthesis of Aryl propionic acid derivatives a) Synthesis of Ibuprofen b) Synthesis of Fenoprofen
  • 31. X) Synthesis of Heteroaryl acetic / propionic acid derivatives a) Synthesis of Caprofen Xi) Synthesis of Oxicams a) Synthesis of Piroxicam
  • 32. Xii) Synthesis of COX-2 inhibitors a) Synthesis of Celecoxib Xiii) Synthesis of Miscellaneous agents a) Synthesis of Nimesulide
  • 33. SAR of Salicylates -a) Subst. on either the –COOH or –OH grp may affect the potency and toxicity. -b) Reducing the acidity of –COOH grp retains the analgesic action but is devoid of -Anti-inflammatory property. E.g. Salicylamide -c) Placing the –OH grp meta / para to –COOH grp totally abolishes the analgesic activity. d) Subst. with halogens on the aromatic ring will increases the potency as well as -toxicity. e) Subst. of aromatic ring at the 5th posn of salicylic acid increases the anti- inflammatory activity. E.g. Diflunisal SAR of p-amino phenol derivatives a) Esterification of the phenolic grp with methyl or propyl grps produces derivatives with greater side effects than ethyl derivatives. b) Subst. on the N2 atom which reduces the basicity, and also reduce activity unless the subst. is metabolically labile. e.g. acetyl c) Amides derived from –COOH are less active or inactive. e.g. N-phenyl benzamides.
  • 34. SAR of 3,5-pyrazolidinediones a) Pharmacological activity is related to the acidic H at 4th posn. Thus, presence of dicarbonyl grp at 3rd & 5th posn increases the acidity of H atom at the 4th posn. b) Decreasing or eliminating the acidity by removing the acidic H at the 4th posn may completely abolishes anti-inflammatory activity. e.g. 4,4-dialkyl derivatives. c) If acidity is increased too much, anti-inflammatory & Na retaining activity decreases, while other property such as the uricosuric effect increases. d) A single alkyl grp at the 4th posn increases the anti-inflammatory activity. Although n-butyl group increases the activity more. e) Presence of keto group in the γ-posn of the butyl side chain produces the active compound with better anti-inflammatory activity. f) Presence of γ-OH-n-butyl derivative possesses pronounced uricosuric activity but gives lesser anti-inflammatory activity. g) Subst. of 2-phenyl thio ethyl group at the 4th posn produces anti-gout activity e.g. Sulphin pyrazone. i) Presence of both phenyl group is essential for both anti-inflammatory & analgesic activity. g) m-Subst. in one of the aryl rings gives inactive compounds, but p-Subst. with –CH3, -Cl, NO2 or OH in one of the phenyl rings retains the activity. h) Replacement of one of the N2 atom with an O2 atom yields Isoxazole analogs which are as active as pyrazolidinediones.
  • 35. SAR of Anthranilic acid derivatives •a) The position of the –COOH group is more important for the activity whereas the m & p-amino benzoic acid analogs are not active. b) Replacement of –COOH group with the Isosteric tetrazole results in the retention of anti-inflammatory activity. c) Subst. on the anthranilic acid ring generally decreases the activity. d) Subst. on the N-aryl ring can leads to conflicting results. (i.e.) In the UV erythema assay for anti-inflammatory, the order of activity was, 3’> 2’> 4’ for monosubst. With CF3 grp (Flufenamic acid) being particularly potent. e) The opposite order of activity was observed in Rat Paw oedema assay, that is 2’-Cl > 3’-Cl analogs.
  • 36. f) In disubst. derivatives, the nature of two subst. is the same, 2’,3’-disubst. appears to be the most effective. E.g. Mefenemic acid g) The –NH group of anthranilic acid is essential for the activity, since replacement of –NH group with O, CH2, S, SO2, N-CH3 or NCOCH3 functionality significantly reduces the activity. SAR of Aryl alkanoic acid derivatives a) All the agents posses a centre of acidity, which can be represented by –COOH, an enol, hydroxamic acid, sulphonamide or tetrazole. b) The centre of acidity is generally located one carbon atom adjacent to a flat surface represented by an aromatic / heteroaromatic ring. c) The distance between these centres is critical because increasing this distance to 2 or 3 carbons generally decreases the activity. d) Susbt. of –CH3 group on the carbon atom separating the aromatic ring tends to increase the anti-inflammatory activity.
  • 37. SAR of Indole acetic acid derivatives a) Replacement of the –COOH group at 3rd posn with other acidic functionalities decreases the activity. Amide analogs are inactive. b) Subst. at R1, useful for increasing anti-inflammatory activity are ranked as C6H4CH2 > CH3 > H c) Acylation of the Indole Nitrogen with aryl / alkyl carboxylic acids results in the decreasing of activity. d) The N-benzoyl derivatives subst. in the Para position with F, Cl, CF3 & S-CH3 groups are the most active. e) At the 5th position, X-subst. activity are ranked as OCH3 > F > N(CH3)2 > CH3 > COCH3 > H than the unsubstituted analogs. f) Presence of Indole ring nitrogen is not essential for activity because the corresponding 1-benzylidenylindene analogs (i.e. Sulindac) is also active. g) CH3 group at 2nd position are more active than aryl subst. analogs. h) Subst. of CH3 group at the α-position of the acetic acid side chain leads to equally active analogs. i) Anti-inflammatory activity is displayed only by the dextrorotatory enantiomer (25 times more active than phenylbutazone)
  • 38. SAR of Pyrrole aceticacid derivatives a) Replacement of p-Tolyl group with p-chloro benzoyl group produces little effect on activity. b) Introduction of –CH3 group in the 4th position and p-chloro benzoyl analog (i.e. Zomepirac) was 4 times as potent as Tolmetin. SAR of Oxicams a) Most active analogs have subst. –CH3 group on the N2 and electron withdrawing subst. like Cl, CF3 on the anilide phenyl group. b) Introduction of heterocyclic ring in the amide chain significantly increases the anti- inflammatory activity. (e.g.) Sudoxicam (2-thiazolyl ring) is potent than Indomethacin. c) Interchanging of benzene ring with Thiophene gives biologically active compounds. (e.g.) Tenoxicam.
  • 39. SAR of COX-2 Inhibitors - Diaryl heterocycle with Cis-Stilbene moiety and changes in the Para position of one of the aryl rings play an important role in the COX-2 selectivity. (e.g) Celecoxib – SO2NH2 grp Parecoxib – SO2NHCOCH3 grp (Prodrug for Valdecoxib) Rofecoxib and Etoricoxib – SO2CH3 grp - The oxidation state on the sulphur is important for selectivity. - Sulfones and Sulfonamides are selective for COX-2 but Sulfoxides and Sulfides are not.
  • 40. Narcotic Analgesics / Opioid analgesics These are naturally occurring, semi-synthetic and synthetic drugs, which have morphine like action (i. e) relief from pain and depression of CNS associated with drug dependence (Mental and Physical) and withdrawal side effects. Therapeutic Uses - Management of pain (Acute / Chronic / Severe) - Cough Suppression - Treatment of Diaarhoea. - Management of acute pulmonary oedema & acute MI - Pre-operative medication & Intra-operative adjunctive agents in anaesthesia Side effects - Respiratory depression - Physical dependency & addiction - Nausea, Vomiting & Constipation Classification I) Morphine analogs R’RName HHMorphine HC2H5Ethyl morphine HCH3Codeine COCH3COCH3Heroine
  • 41. Ia) Hydromorphone derivatives R’RName HOHHydromorphone OHHOxymorphone H-OCH3Hydrocodone OH-OCH3Oxycodone Ib) Dihydromorphine derivatives RName HDihydromorphine -CH3Dihydrocodeine
  • 42. Ic) Morphinan derivatives R’’R’RName -CH3HHLevorphanol -CH2-CH=CH2HHLevallorphan OHHButerphanol -CH3H-CH3Dextromethorphan
  • 43. R4R3R2R1Name HCOOC2H5CH3Meperidine HCOOC2H5CH3Bemidone HCOOCH(CH3)2CH3Properidone HCOC2H5CH3Ketobemidone CH3COOC2H5CH3Alphaprodine HCOOC2H5Anileridine HHFentanyl II) Meperidine / Phenyl (ethyl) Piperidines
  • 44. R4R3R2R1Name CH3COOCH3Lofentanil HCH2OCH3Sufentanil HCH2OCH3Alfentanil HCOOC2H5Diphenoxylate HOHLoperamide
  • 45. III) Methadone / Diphenyl heptanones R4R3R2Name -CH2-CH(CH3)N(CH3)2COC2H5C6H5Methadone -CH(CH3)CH2N(CH3)2COC2H5C6H5Isomethadone -CH2-CH2N(CH3)2COC2H5C6H5Normethadone COC2H5C6H5Dipanone -CH2-CH(CH3)N(CH3)2C6H5α-Acetyl Methdone C6H5Dextromoramide COC2H5C6H5Phenadoxone -CH(CH3)-CH2N(CH3)2OCOC2H5CH2 C6H5Propoxyphene or Dextropropoxyphene
  • 46. R1RName CH3CH2-CH=C(CH3)2Pentazocine CH3CH2-CH2-C6H5Phenazocine CH3Cyclazocine C=OKetazocine CH3CH3Metazocine IV) Benzazocine / Benzomorphan analogs
  • 47. V) Miscellaneous Vi) Newer Drugs
  • 48. VII) Narcotic Antagonist R2R1RName H-CH2-CH=CH2OHNalorphine OH-CH2-CH=CH2-C=ONaloxone (Single = Bond) OH-C=ONaltrexone (Single = Bond)
  • 49. Synthesis of Morphine Analogs
  • 50. Bischler-Napaieralski reaction is an intramolecular electrophilic aromatic substitution reaction that allows for the cyclization of β- arylethylamides or β-Arylethylcarbamates. The reaction is most notably used in the synthesis of isoquinolines in presence of POCl3. Birch reduction is the organic reduction of aromatic rings in liquid ammonia with sodium, lithium or potassium and an alcohol, such as ethanol and tert-butanol. This reaction is quite unlike catalytic hydrogenation, which usually reduces the aromatic ring all the way to a cyclohexane. It converts aromatic compounds having a benzenoid ring into a product, 1,4-cyclohexadienes, in which two hydrogen atoms have been attached on opposite ends of the molecule.
  • 51. Synthesis of Levallorphan & Levorphanol
  • 52. Knoevenagel condensation is a nucleophilic addition of an active hydrogen compound to a carbonyl group (aldehyde or ketone) followed by a dehydration reaction in which a molecule of water is eliminated (hence condensation). The product is often an alpha, beta conjugated enone. The catalyst is usually a weakly basic amine
  • 53. Synthesis of Meperidines / Phenyl(ethyl)Piperidines Synthesis of Meperidine / Pethidine Synthesis of Ketobemidone
  • 54. Synthesis of Anileridine Synthesis of Fentanyl Citrate
  • 55. Synthesis of Alfentanil
  • 56. Synthesis of Lofentanil
  • 57. Synthesis of Methadone Synthesis of Dextromoramide
  • 58. Synthesis of Benzazocin / Benzomorphan analogs Synthesis of Pentazocine
  • 59. Synthesis of Miscellaneous agents Synthesis of Buprenorphine
  • 60. Synthesis of Narcotic Antagonists Synthesis of Nalorphine or N-allyl morphine
  • 61. Synthesis of Narcotic Antagonists Synthesis of Naloxone and Naltrexone
  • 62. SAR of Morphine (i) Modification on alicyclic ring: -The alcoholic OH group at C-6 when methylated, esterified, oxidized, removed or replaced by halogen means analgesic activity and toxicity increases. -Saturation of the double bond at C-7 results in more potent compound. (e.g). Dihydromorphine, Dihydro codeine -The 14-β-OH group generally increases μ-agonistic property and decreases the antitussive activity. -Bridging of rings through ethylene linkage gives potent derivatives. (e.g) Buprenorphine, Etorphine (1000 times more potent than morphine as μ-agonist) (ii) Modification on phenyl ring: -Aromatic phenyl ring is essential for activity. -Modification on phenolic –OH group decreases the activity. -Any other substitution on phenyl ring decreases the activity.
  • 63. (iii) Modification of 30 Nitrogen atom: -Presence of 30 Nitrogen atom is necessary for good opioid activity. -The size of the N-substitution only determines the compounds potency, it’s agonistic and it’s antagonistic property. (e.g) N-CH3 leads to good agonistic property. Increased the size of substitution by 3-5 carbon atoms lead to antagonistic property. Still larger substitution on N-atom lead to agonistic property. N-allyl and N-cyclo alkyl group lead to antagonistic property (iv) Modification of Epoxide / Ether bridge: -Removal of 4,5-epoxide bridge in morphine results in morphinans. -Only levo isomer of morphinan possess opioid activity (e.g) levorphanol – more potent than morphine. Dextro isomer possess anti-tussive activity. .
  • 64. SAR of Phenyl (ethyl)piperidines / Meperidine analogs: -Replacement of C-4 phenyl group of meperidine by H, alkyl, aryl, aralkyl and heterocyclic group decreases the analgesic activity. -Introduction of m-OH group on the phenyl ring increases the activity. -Presence of phenyl and ester group at 4th position of 1-methyl piperidine results in optimum activity. -Replacement of the carbethoxy group in Mepiridine by acyloxy group gave better analgesic as well as spasmolytic. -Replacement of phenyl group by phenylethyl derivative is seems to be 3-times as active as Mepiridine. The amino congener is 4 times more active (Anileridine) Enlargement of piperidine ring to 7-membered hexahydro azepine is less active but has low incidence of side effects. (e.g) Proheptazine -Contraction of piperidine ring to pyrrolidine gives more active compound but causes abuse liability (e.g) Alphaprodine and Procilidine. -In fentanyl, the phenyl and acyl groups are separated by Nitrogen. It is 50 times stronger than morphine with minimal side effects. It’s short duration of action makes it well suited for use in anaesthesia. -The C-3 methyl analog with an ester group at C-4 like lofentanil is 8400 times more potent than Meperidine as an analgesic. P-Chloro analog loperamide cannot penetrate BBB sufficiently to produce analgesia. -Diphenoxylate, a structural hybrid of Meperidine and Methadone is devoid of analgesic activity. It is effective in the treatment of diarrhoea.
  • 65. SAR of Diphenyl Heptanone / Methadone analogs: -The levo Isomer of Methadone and Isomethadone are twice as effective as their racemic mixture. -Removal of any one of the phenyl group sharply decreases the activity. -Placement of m-OH group in any of the phenyl ring decreases the analgesic activity. -Replacement of terminal dimethylamino group at R4 by piperidine group decreases the activity. Replacement of propionyl group at R4 by H, OH or acetyloxy group leads to decreased activity, where as amide, pyrrolidinoyl, morpholino group increased the activity by several times (e.g) Dextromoramide SAR of Benzomorphan / Benzazocine analogs: -Trimethyl compound (R1=R2= CH3) is more active than dimethyl (R1=H, R2= CH3) compound. -Placement of N-phenyl ethyl results in more activity than N-Methyl compound. -Placement of –OH group at C-9, decreases the activity. -N-allyl or N-cyclo propyl methyl group confers antagonistic activity (e.g) Levorphanol, Naloxone and Naltrexone.

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