Chapter 14 Pharmaceuticals

1. Chapter 14Pharmaceuticals CHM 585 / 490

3. Pharmaceuticals • Industry • Synthetic Considerations • Nabumetone • Methotrexate • Natural Products • Antidepressants • Antihistamines • Chirality • cGMP

4. 10,300 FDA approved drugs in U.S. • 50% of all new drugs currently available worldwide have been launched in the U.S. • The discovery/preclinical stage takes from 3–7 years and only about 1 of every 10,000 compounds evaluated enters human trials Drug Discovery and Development November 2002

7. Top 10 Pharma Companies by 2002 Revenues ($B) Leaders of Life Sciences Dec 2003

8. GlaxoSmithKline • Paxil (SSRI -selective serotonin reuptake inhibitor – depression) • Advaire (for asthma) • Augmentin (for asthma) • Augmentin (antibiotic) • Avandia (diabetes) • Combivir (HIV) • Flonase (allergies) • Imitrex ( migraines)

9. Pfizer • Lipitor (#1 prescribed drug) (cholesterol) $8.6B in revenue • Norvasc (hypertension) • Zoloft (SSRI)

10. Merck • Zocor (cholesterol) • Vioxx (osteoarthritis – joint disease) • Fosamax (osteoporosis – bone loss) • Cozaar (hypertension) • Singulair (asthma)

11. About 12 Years to bring a drug to market

12. $ • Cost for a single new drug averages $1.7 B C & EN December 15, 2003

13. 2003 • $33 B invested in Pharma Research • 86 new medicines • 21 new molecular entities (NMEs) • 14 biologics • 51 additional drugs • Over the past 20 years, for every dollar invested in health care, between $2.40 - $3.00 in gains have been realized R&D Magazine March 2004

14. Top Reasons for Drug Recalls in 2001 • Deviations from cGMP • Subpotency • Stability data failed to support expiration data • Failure of drug to dissolve properly • Wrong packaging • Incorrect labeling • Microbial contamination Drug Discovery and Development November 2002

15. Pharmaceuticals • Industry • Synthetic Considerations • Nabumetone • Methotrexate • Natural Products • Antidepressants • Antihistamines • Chirality • cGMP

16. Nabumetone • See handout for various syntheses and discussion on this NSAID

17. Multistep Syntheses • Even when each step is a high yield step, the overall yield can be low. • For example a 5 step synthesis where each step is a 90% yield reaction has an overall yield of 59% • 0.90 x 0.90 x 0.90 x 0.90 x 09.0 = 0.59

18. $ • For an effective cost position, important to have: • As few steps as possible • High yield reactions • Clean reactions – separation of impurities is critical for pharmaceuticals and can be difficult when impurities are structurally similar to desired product.

19. Methotrexate

20. MethotrexateConvergent Synthesis

21. Pharmaceuticals • Industry • Synthetic Considerations • Nabumetone • Methotrexate • Natural Products • Antidepressants • Antihistamines • Chirality • cGMP

22. “ Natural Products” • Heparin • Premarin • Taxol

23. Heparin • Anticoagulant • By extracting the intestines of pigs • Used for ~ 70 years

24. Lovenox – low molecular weight heparin by Aventis STRUCTURAL FORMULA Fragmin (Pfizer) – another low molecular weight heparin

25. Warafin (Coumadin®) Heparin Clopidogrel (Plavix®) Dipyridamole (Persantine®) Enoxaparin (Lovenox®) Ardeparin (Normiflo®) Dalteparin (Fragmin®) Ticlopidine (Ticlid®) Danaparoid (Orgaran®) Tinzaparin (Innohep®) Aspirin Thrombin Inhibitors Commonly Prescribed Anticoagulants

26. Premarin • Number 1 drug of 1999 list • Steroid • Estrogen drug used for menopause • Made from urine of pregnant horses • Pregnant Mare Urine

27. Steroids • Steroid is a general term for a large number of naturally occurring materials found in plants and animals.

29. Taxol • From the bark of the Pacific Yew tree • Anticancer drug

30. Pharmaceuticals • Industry • Synthetic Considerations • Nabumetone • Methotrexate • Natural Products • Antidepressants • Antihistamines • Chirality • cGMP

31. Classes of Antidepressants • There are five classes of antidepressants • Tricyclics (TCA) • Monoamine Oxidase Inhibitors (MAOIs) • Second-Generation (Atypical) Antidepressants or Heterocyclics • Serotonin-Specific Reuptake Inhibitors (SSRI) • Dual-Action Antidepressants

32. Tricyclics (TCAs) • One of the first classes of antidepressants developed were the tricyclics. • Tricyclics produce a sedative effect by blocking the passage of norepinephrine and serotonin in and out of nerve endings.

33. TCAs • Structures: • Imipramine HCL Amitriptyline HCL Nortriptyline HCL C 19H24N2 HCL C20H23N HCL C19H21N HCL mw: 316.88 mw: 313.86 mw: 299.84 (11)

34. MAOI (MonoAmine Oxidase Inhibitors) Early treatments for depression

35. Serotonin-Specific Reuptake Inhibitors (SSRIs) • SSRIs were discovered in the 1980s • They are better tolerated than some other antidepressants, with less severe side effects and have a wide margin of safety in overdose. • SSRIs inhibit the reuptake of serotonin into the presynaptic neuron. (17)

36. SSRIs • Some examples of SSRIs: 1. Paroxetine (Paxil®) - 1992 2. Fluvoxamine (Luvox®) - 1994 3. Clomipramine (Anafranil®) - 1990 4. Sertraline (Zoloft®) - 1991 5. Fluoxetine (Prozac®) - 1987 6. Venlafaxine (Effexor®) - 1993 7. Citalopram (Celexa®) - 1998 (1)

37. SSRIs - Paxil® • Used for • Depression • OCD (Obsessive Compulsive Disorder) • Social Anxiety • Generates sales in excess of $1.5 billion/year (2000)

38. SSRIs - Prozac® Fluoxetine Hydrochloride

39. SSRIs - Prozac® • First SSRI to be put out on the market. • Indications: • Depression • Obsessive compulsive disorder (OCD) • Bulimia • Others (unlabeled uses) • Sales of Prozac reached 1.2 billion in 1995 and in 2000 reached 2.7 billion for Eli Lilly.

40. SSRIs - Prozac® • Patents • The original synthesis patents were 4,314,081 and 4,194,009 and were approved in 1982 and 1980, respectively, to Eli Lilly and Company. • Synthesis patent 6,028,224 in 2000 to Sepracor Inc. • Other patents owned by Eli Lilly are: • 4,018,985, 4,313,896, 4,590,213, and 4,626,549 • Patents owned by AAI: • 6,258,853, 6,310,250, and 6,310,251

41. SSRIs-Zoloft® • Zoloft® is primarily used to treat: • Major depressive disorder • Obsessive/Compulsive disorder (OCD) • Panic disorder • Post-traumatic stress disorder • Manufactured by Pfizer, Inc. • Blocks the uptake of serotonin into human platelets

42. Pharmaceuticals • Industry • Synthetic Considerations • Nabumetone • Methotrexate • Natural Products • Antidepressants • Antihistamines • Chirality • cGMP

43. Histamine • Histamine acts upon two sites in the body, H1 and H2 sites. H2 sites are located in the gastrointestinal system and H1 sites are located in the respiratory system. • AntihistamineMedication that prevents symptoms of congestion, sneezing, and itchy, runny nose by blocking histamine receptors.

44. Antihistamines • First generation • Chlor Trimetron • Benadryl • Second generation • Do not cause sedation • Do not cross the blood-brain barrier

45. First Generation Antihistamines(Alkylamines) • Chlorpheniramine maleate (Chlor Trimeton®) • Schering (1949) • Currently sold OTC by Schering-Plough Healthcare Products

46. First Generation Antihistamines (Ethanolamines) • Diphenhydramine HCl (Benadryl®) • Parke Davis (1946) • Currently sold OTC by Pfizer, Inc., Warner -Lambert Consumer Healthcare

47. Second Generation Antihistamines • Terfenadine (Seldane®) • Marion Merrell Dow • FDA approved in 1985

48. Second Generation Antihistamines • Terfenadine (Seldane®) • Developed from Haloperidol • Haloperidol - antipsychotic drug having antihistaminic properties • Replaced the phenyl ketone group with phenyl butanol group to inhibit the capability of the drug to pass through the blood-brain barrier

49. Second Generation Antihistamines Terfenadine Haloperidol

50. Second Generation Antihistamines • Terfenadine (Seldane®) • Non-sedating • Caused potentially fatal heartbeat irregularities when taken with certain drugs and foods (1992) • Ketoconozole, erithromycin, grapefruit juice interfered with drug metabolism increasing the concentration of terfenadine in bloodstream • Racemic mixture • One enantiomer caused cardiac toxicity • Removed from market (1997)