Analgesics and Antipyretics Ullmann

Ullmann's Encyclopedia of Industrial Chemistry, Sixth Edition, 2002 Electronic Release
ANALGESICS AND ANTIPYRETICS - Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (Elmar Friderichs, Thomas Christoph,
Helmut Buschmann)
References
Analgesics and Antipyretics

REVISED 2000
ELMAR FRIDERICHS , Grnenthal
GmbH, Center of Research, Aachen, Federal Republic of
Germany
THOMAS CHRISTOPH ,
Grnenthal GmbH, Center of Research, Aachen, Federal Republic of
Germany
HELMUT BUSCHMANN, Grnenthal
GmbH, Center of Research, Aachen, Federal Republic of
Germany
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1. Introduction
Compounds that are used for the treatment of pain, inflammation, and fever are classified into
two main groups according to their mode of action: nonsteroidal anti-inflammatory drugs
(NSAIDs) and so-called centrally acting analgesics.
Nonsteroidal anti-inflammatory drugs are compounds with a predominantly peripheral
mechanism of action. Besides inhibition of pain they exert a more or less pronounced antiinflammatory and fever-reducing effect. In the body key peripheral mediators of pain,
inflammation, and fever are prostaglandins ( Prostaglandins). NSAIDs and related
"peripheral" or "weak analgesics" act via inhibition of cyclooxygenase. Cyclooxygenase is the
key enzyme of prostaglandin synthesis and its inhibition may be the most important, but not the
exclusive mechanism of action of NSAIDs. The supposed additional mechanisms are widely
unknown.
The group of centrally acting analgesics is dominated by the opioid compounds. They act
mainly within the central nervous system, but more recent investigations indicate that an
additional peripheral action component may exist. The endogenous opioid system is the most
important pain control system within the body and opioids are powerful tools for the treatment
of severe pain situations. Central neurotransmitters like noradrenaline and serotonin are
likewise involved in pain inhibition. Directly acting compounds like, e.g., the 2-adrenergic
agonist clonidine as well as indirectly acting inhibitors of noradrenaline and serotonin reuptake
(mainly used as antidepressants) have a definite value as primary analgesics or as co-analgesics
Ullmann's Encyclopedia of Industrial Chemistry, Sixth Edition, 2002 Electronic Release Wiley-VCH. Weinheim. Germany.
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Helmut Buschmann)
in combination with opioids.

Acute pain is an alarm signal to alert the organism to noxious tissue damage, irritation, or
injury. Ongoing, persistent or chronic pain may lose this function and may become a mere
burden to the patient. Pain does not only indicate physical suffering, but involves a strong
mental and emotional component. According to the definition of the International Association
for the Study of Pain "it is an unpleasant sensory and emotional experience associated with
actual or potential tissue damage, or described in terms of such damage".
The nervous system contains an afferent fiber system that is specialized for registration,
transmission, and processing of nociceptive information. In the periphery small unmyelinated
nerve endings, called nociceptors, are activated by mechanical, thermal, or chemical stimuli.
One type, the mechano-heat nociceptor is specialized for thermal and mechanical stimulation,
whereas the so-called polymodal receptor is less specific and responds to all kinds of
mechanical, thermal, or chemical irritation. Mechano-heat nociceptors have a high stimulation
threshold and respond only to strong stimuli. They are linked to small myelinated and rapidly
conducting A fibers which produce a sharp and well located pain sensation. The sharp pain
stimulus activates withdrawal reflexes and has to protect the body against further damage. The
polymodal receptors respond to weaker stimuli including endogenous compounds like
histamine, bradykinin, and prostaglandins. These receptors are mediators of pain and
inflammation and are released by tissue damage. The impulses of polymodal nociceptors are
transmitted more slowly via thicker, unmyelinated C-fibers and provoke a dull, aching, and less
precisely localized pain sensation. The nerve fibers originating from nociceptors are named
primary afferent fibers. They have their cell body in the dorsal root ganglia and project to the
dorsal root of the spinal cord where they form synapses with fibers of the ascending spinothalamic pathway. Most of the spino-thalamic pain fibers pass the thalamus and project to the
limbic system and the cortex. The limbic system is responsible for the emotional component of
pain whereas in the cortex realization and localization of the origin of pain takes place. The
spino-thalamic fibers form connections with the formatio reticularis of the brain stem, inducing
the various vegetative reactions associated with the pain perception such as sweating,
palpitation, nausea, and blood pressure increase.
Inhibitory control of the pain process can take place in the periphery at the level of the
nociceptors or the primary afferents. These are the regions where local anesthetics and NSAIDs
act. Central pain inhibition can take place at the level of the spinal cord, the thalamus, cortex,
and the limbic system. The pain transmission at the level of the spinal cord is under inhibitory
control of descending fibers, which originate in different parts of brain stem, mid brain, and
cortex. They contain opioid synapses as well as noradrenergic and serotoninergic synapses and
represent the descending spinal pain inhibitory system. Inhibitory opioid synapses are not only
found in the spinal cord but are strategically located along the whole pain pathway. Opioid
receptors are found in the cortex, limbic system, and formatio reticularis and this explains why
opioids not only inhibit pain perception but also reduce the emotional component of pain
suffering and mitigate the vegetative pain symptoms.
According to the clinical situation, pain can be classified as acute and chronic pain. Acute pain
is induced by trauma, tissue damage, or disease and has a well defined localization and time
course. Acute pain normally responds well to NSAIDs and opioid analgesics. Chronic pain is
more complex in nature and often contains an inflammatory component. The association with
trauma and lesion can be lost and then pain no longer fulfills its alarming function. Chronic pain
is often a heavy burden to the patient and induces physical, psychological, and social
deterioration. Chronic pain treatment is an important medical challenge.
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Physiologically, pain can be differentiated into nociceptive and neuropathic pain. Nociceptive
pain results from activation of nociceptors by acute or chronic stimulation and is not associated
with damage of nerves. Neuropathic or neurogenic pain in contrast is the result of damage or
dysfunction of the peripheral nerves or of the central parts of the pain processing system.
Examples of neuropathic pain of peripheral origin are deafferentiation pain (stump pain),
diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, and sympathetically
maintained pain like the complex regional pain syndrome. Central neuropathic pain may result
from lesions of the spinal cord or brain lesions following stroke. In chronic cancer pain,
nociceptive pain is often associated with a neuropathic component induced by neoplastic nerve
infiltration or compression of the nerve by tumor growth.
Cancer pain is one of the most important forms of chronic severe pain and guidelines for the
treatment of cancer pain were published by the WHO in 1986 (Fig. (1)).
Meanwhile these guidelines have become the standard not only for treatment of chronic
malignant pain but also for benign chronic and acute pain. The WHO proposal is often
described as "treatment by mouth, by the clock, and by the ladder". That means that for repeated
application of analgesics the oral route should be used. The application interval should be
regular and selection of compounds should follow the increase of potency and efficacy as
indicated in the three-step analgesic ladder. The first step starts with the single use of a nonopioid analgesic. If pain control is insufficient, a weak opioid may be added. If this is not
effective enough, the weak opioid should be replaced by a strong opioid and the non-opioid
may be omitted. Each stage of the treatment may be supplemented by the use of co-analgesics
and other pharmacological and non-pharmacological treatments to improve pain control and to
reduce side effects.
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2.2. para-Aminophenol Derivatives

Paracetamol [103-90-2], acetaminophen, N-(4-hydroxyphenyl)acetamide, C8H9NO2, Mr
151.16, mp 168 169 C.
Synthesis:
a) classical route [125], [134]:
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b) Hoechst-Celanese process:
Clinical use [117]: Paracetamol has analgesic and antipyretic properties, but no relevant antiinflammatory action. It is used for the treatment of various mild to moderate pain conditions and
to reduce fever. Paracetamol is one of the most popular analgesics as single drug or in multiingredient preparations, often in combination with NSAIDs or weak opioids. It is used orally or
rectally as suppositories, the oral dose range is 500 1000 mg every 4 5 h up to 4 g daily.
Side effects are rare and may include hematological reactions, leucopenia, agranulocytosis and
other hypersensitivity reactions. Paracetamol has a narrow therapeutic dose range and
overdosage induces severe liver and renal damage [118] via accumulation of a toxic metabolite,
N-acetylbenzoquinoneimine (NABQI). Acetylcysteine or methionine, which increase
glutathione conjugation of the metabolite, are used as antidote.
Paracetamol is not soluble in aqueous solutions and cannot be given parenterally.
Trade names: Benuron (Germany), Tylenol (USA).
Propacetamol [66532-85-2], 4-(acetylamino)phenyl N,N-diethylglycinate, C14H2ON2O3, Mr
264.33) is a soluble glycine prodrug derivative of paracetamol. It is used as hydrochloride
([66532-86-3], C14H2ON2O3 HCl, Mr 300.79), for intramuscular or intravenous application and
is rapidly metabolized to free paracetamol.
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Trade name: Pro-Dafalgan (Belgium, France).

Phenidine [62-44-2], phenacetin, N-(4-ethoxyphenyl)acetamide, C10H13NO2, Mr 179.22, mp
134 135 C.
Synthesis [125]:
Clinical use: Phenidine is a weak analgesic, antipyretic compound without anti-inflammatory

action. It has been used in combination with other compounds like aspirin, caffeine, or codeine,
but due to hematological and nephrotoxic side effects [119] has been withdrawn from many
markets.
Trade names: Gripponyl (France), Cratodin (Spain).
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4. References
[1] J. G. Hardman et al. (eds.): Goodman and Gilman's The Pharmacological Basis of
Therapeutics, 9th ed., McGraw Hill, New York 1995, pp. 521 555, 557 600, 617
Page: 5

Helmut Buschmann)
657.
[2] J. E. F. Reynolds et al. (eds.): Martindale The Extra Pharmacopoeia, 31st ed., The
Royal Pharmaceutical Society, London 1996.
[3] A. Herz (ed.): Handbook of Experimental Pharmacology, vol. 104/I, Opioids I., vol.
104/II, Opioids II, Springer Verlag, Berlin 1993.
[4] T. Dickenson, J. Besson (eds.): Handbook of Experimental Pharmacology. The
Pharmacology of Pain, vol. 130, Springer Verlag, Berlin 1997.
[5] M. Zenz, I. Jurna (eds.): Lehrbuch der Schmerztherapie. Grundlage, Theorie und Praxis
fr Aus- und Weiterbildung. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart
1993.
[6] J. J. Bonica (ed.): The Management of Pain, 2nd ed., Lea & Febiger, 1990.
[7] S. Budavari (ed.): The Merck Index, 12th ed., Merck & Co. Inc., 1996.
[8] P. D. Wall, R. Melzack (eds.): Textbook of Pain, 3rd ed., Churchill Livingstone, New
York 1994.
[9] J. R. Vane et al., "Cyclooxygenases 1 and 2," Annu. Rev. Pharmacol. Toxicol. 38 (1998)
97 120.
[10] C. J. Hawkey: "Cox-2 Inhibitors", Lancet 353 (1999) 307 314.
[11] C. J. E. Niemegeers, P. A. J. Janssen, Drug. Dev. Res. 1 (1981) 83.
[12] G. E. Larijani, M. E. Goldberg, Clin. Pharm. 6 (1987) 275 282.
[13] R. C. Heel et al., Drugs 17 (1979) 81 110.
[14] T. J. Gal, Clin. Pharmacol. Ther. 45 (1989) 66 71.
[15] P. J. Fudala, Clin. Pharmacol. Ther. 47 (1990) 525 534.
[17] I. J. Pachter, R. P. Evens, Drug Alcohol Depend. 14 (1985) 325 338.
[18] F. J. Muhtadi, M. M. A. Hassan, Anal. Profiles Drug Subs. 10 (1981) 93 138.
[19] B. L. Posey, N. S. Kimble, J. Anal. Toxicol. 8 (1984) 68 74.
[20] D. Boven et al., Hum. Toxicol. 3 (1984) Suppl., 1S 238S.
[21] J. L. Malis, J. Pharmacol. Exp. Ther. 194 (1975) 488 498.
[22] J. J. O'Brien, P. Benfield, Drugs 38 (1989) 226 248.
[23] D. K. Wyatt, L. T. Grady, Anal. Profiles Drug Subst. 10 (1981) 357 403.
[24] U. Boerner et al., Drug Metab. Rev. 4 (1975) 39 73.
[25] C. E. Inturrisi et al., N. Engl. J. Med. 310 (1984) 1213 1217.
[26] D. D. Hung, Anal. Profiles Drug. Subst. 7 (1978) 149 169.
[27] G. F. Blane, J. Pharm. Pharmacol. 19 (1967) 367 373.
[28] T. Alford et al., J. Am. Vet. Med. Ass. 164 (1974) 702 705.
[29] R. Hess et al., J. Pharmacol. Exp. Ther. 179 (1971) 474 484.
[30] M. A. Clotz, M. C. Nahata, Clin. Pharm. 10 (1991) 581 593.
[31] J. F. Buchanan, C. R. Brown, Med. Toxicol. 3 (1988) 1 17.
[32] H. A. Friedel, A. Fitton, Drugs 45 (1993) 548 569.
[33] A. Stein, Pharmazie 10 (1955) 180 186.
[34] G. Lindena et al., Schmerz 12 (1998) 195 204.
[35] D. E. Moulin et al., Lancet 337 (1991) 465 468.
Page: 6

Helmut Buschmann)
[36] J. D. Blaine et al. Ann. N. Y. Acad. Sci. 362 (1981) 101 115.
[37] B. C. Rudy, B. Z. Senkowsky, Anal. Profiles Drug Subs. 2 (1973) 339 361.
[38] L. L. Randall, G. Lehmann, J. Pharmacol. Exp. Ther. 99 (1950) 163.
[39] G. D. Olson et al., Clin. Pharmacol. Ther. 21 (1977) 147 157.
[40] R. H. Biskara, Anal. Profiles Drug Subs. 3 (1974) 365 439.
[41] M. Farell et al., Br. Med. J. 309 (1994) 997 1001.
[43] F. J. Muhtadi, Anal. Profiles Drug Subs. 17 (1988) 259 366.
[44] H. J. McQuay, B. J. Anaest. 63 (1989) 213 226.
[45] R. Osborne et al., Clin. Pharmacol. Ther. 47 (1990) 12 19.
[46] B. Holmes, A. Ward, Drugs 30 (1985) 285 312.
[47] J. K. Errick, R. C. Heel, Drugs 26 (1983) 191 211.
[48] W. K. Schmidt, Drug Alcohol Depend. 14 (1985) 339 362.
[49] M. U. Zubair et al., Anal. Profiles Drug Subs. 18 (1989) 195 219.
[50] L. F. McNicholas, W. R. Martin, Drugs 27 (1984) 81 93.
[51] M. M. A. Hasson et al., Anal. Profiles Drug Subs. 14 (1985) 453 489.
[52] M. S. Gold et al., Med. Res. Rev. 2 (1982) 211 246.
[53] I. P. Gonzales, R. N. Brogden, Drugs 35 (1988) 192 213.
[54] B. A. Judson et al., Drug Alcohol Depend. 7 (1981) 325 346.
[56] R. N. Brogden, T. M. Speight, C. S. Avery, Drugs 5 (1973) 6 91.
[57] D. A. Reed, S. H. Schnoll, JAMA 256 (1986) 2562 2564.
[58] H. Schmidthammer, Prog. Med. Chem. 35 (1998) 83 132.
[59] N. P. Fish, N. J. De-Angelis, Anal. Profiles Drug Subs. 1 (1972) 175 205.
[60] L. Morisy, D. Platt, JAMA 255 (1986) 467 468.
[61] F. Weyne et al., Acta anaesth. belg. 19 (1968) 33 45.
[62] W. E. Hoffman et al., Anesthesiology 79 (1993) 107 113.
[63] T. E. Egan, Clin. Pharmacokinet. 29 (1995) 80 94.
[64] I. P. Monk et al., Drugs 36 (1988) 286 313.
[65] M. Goldberg et al., Anesthesiology 63 (1985) 199 201.
[66] M. Hermann et al., Arzneimittel-Forsch. 20 (1970) 977 983.
[67] E. Friderichs et al., Arzneimittel-Forsch. 28 (1978) 122 134.
[68] R. B. Raffa, E. Friderichs, Pain Rev. 3 (1996) 249 271.
[69] R. B. Raffa et al., J. Pharmacol. Exp. Ther. 267 (1993) 331 340.
[70] C. R. Lee et al., Drugs 46 (1993) 313 340.
[71] D. DellaBella, Boll. Chim. Farm. 111 (1972) 5 19.
[72] H. Jacobi, H. D. Dell, Arzneimittel-Forsch. 30 (1980) 1348 1362.
[73] J. R. Vane et al., Annu. Rev. Pharmacol. Toxicol. 38 (1998) 97 120.
[74] J. Berg et al., J. Pharmacol. Toxicol. Meth. 37 (1997) 179 186.
[75] R. J. Waldmann et al., JAMA 247 (1982) 3089 3094.
[76] C. J. Needs, P. M. Brooks, Clin. Pharmacokinet. 10 (1985) 164 177.
Page: 7

Helmut Buschmann)
[77] Am. J. Med. 74 (1983) no. 6A, 1 109.

[78] A. Graul et al., Drugs Future 22 (1997) 711 714.
[79] P. A. Todd, E. M. Sorkin, Drugs 35 (1988) 244 285.
[80] M. Cotton, R. A. Hux, Anal. Profiles Drug Subst. 14 (1985) 491 526.
[81] N. Bellamy, Inflammopharmacology 5 (1997) 139 152.
[82] S. Ravi et al., Postgrad. Med. J. 62 (1986) 773 776.
[83] M. L. Brochier, Eur. Heart J. 14 (1993) 951 957.
[84] J. L. Hommeril et al., Br. J. Anaesth. 72 (1994) 383 387.
[85] M. Busson, J. Int. Med. Res. 14 (1986) 53 62.
[86] W. W. Downie, Semin. Arthritis Rheum. 12 (1982) Suppl. 2, 170 174.
[87] M. M. T. Buckley, R. N. Brogden, Drugs 39 (1990) 86 109.
[88] G. G. Liversidge, Anal. Profiles Drug Subst. 10 (1981) 443 471.
[89] R. Riedel et al., Arzneimittel-Forsch. 31 (1981) 655.
[90] T. Christoph et al., Inflamm. Res. 44 (1995) Suppl. 3 Abstr. W16/17.
[91] T. Pruss et al., Postgrad. Med. J. 66 (1990) Suppl. 4 818 821.
[92] J. A. Balfour et al., Drugs 51 (1996) 639 657.
[93] Pfizer, US 3 591 584, 1971; US 4 469 866, 1984.
[94] J. R. McLean, M. I. Geuckman, Arzneimittel-Forsch. 33 (1983) 627 631.
[95] J. S. Marks, M. H. Gleeson, Br. Med. J. 4 (1975) 442.
[96] G. Engelhardt et al., Inflamm. Res. 44 (1995) 423 433.
[97] H. A. Friedel et al., Drugs 45 (1993) 131 156.
[98] P. A. Todd, S. P. Clissold, Drugs 40 (1990) 91 137.
[99] J. Auclair et al., Curr. Ther. Res. 46 (1989) 782 788.
[100] R. Davis, R. N. Brogden, Drugs 48 (1994) 431 454.
[101] L. G. Miller, Clin. Pharm. 11 (1992) 591 603.
[102] L. E. Westerholm, Br. Med. J. 3 (1973) 339 343.
[103] G. A. Faich, Pharmacotherapy 7 (1987) 25 27.
[104] S. L. Ali, Anal. Profiles Drug Subs. 11 (1982) 483 521.
[105] R. N. Brogden et al., Drugs 22 (1981) 165 187.
[106] J. A. Mitchell et al., Proc. Natl. Acad. Sci. USA 90 (1993) 11693 11697.
[108] L. A. Sorbera et al., Drugs Future 23 (1998) 1287 1296.
[109] A. Whelton et al., JAMA 249 (1983) 2892.
[111] R. N. Brogden, Drugs 15 (1978) 429 450.
[112] Horakova et al., Pharmacotherapeutica (1963) 335 350.
[113] H. Schmitt, Handb. Exp. Pharmacol. 39 (1977) 299 396.
[114] C. Lund et al., Br. J. Anaesth. 63 (1989) 516 519.
[115] D. R. Jasinki et al., Arch. Gen. Psychiatry 42 (1985) 1063 1066.
[116] D. Soyka et al., Schmerz 12 (1998) 419 427.
[117] B. Ameer et al., Ann. Int. Med. 87 (1977) 202 209.
Page: 8

Helmut Buschmann)
[118] R. K. Lewis, F. P. Paloucek, Clin. Pharm. 10 (1991) 765 774.

[119] U. C. Dubach et al., N. Engl. J. Med. 308 (1983) 357 362.
[120] K. H. Boltze, H. Kreisfeld, Arzneim.-Forsch./Drug Res. 27 (1977) no. 1, 1300 1312.
[121] R. Coletta et al., Int. J. Clin. Pharmacol. Res. 8 (1988) 295 298.
[122] Parke Davis, FR 1 341 M, 1961.
[123] R. B. Moffett, B. D. Aspergen, J. Am. Chem. Soc. 82 (1960) 1605.
[124] M. Levy et al., Clin. Pharmacokinet. 28 (1995) 216 234.
[125] A. Kleemann, J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances,
Synthesis, Patents, Applications, Thieme, Stuttgart New York, 1999 (available in print
and CD-ROM).
[126] N. Kuhnert, Chem. Unserer Zeit 33 (1999) 213 220.
[127] Merck & Co., US 4 225 730, 1980, (H. Jones, R. Houser.
[128] For alternative synthesis: US 3 992 495, (Merck & Co.).
[129] For alternative synthesis: US 4 131 618, (Merck & Co.).
[130] J. Hannah et al., J. Med. Chem. 21 (1978) 1093.
[131] E. Arrigoni-Martelli, Drugs Future 3 (1978) 28 33.
[132] Lunbeck, GB 656 746, 1948.
[133] D. S. Hoffenberg, C. R. Hauser, J. Org. Chem. 20 (1955) 1496 1500.
[134] Warner-Lambert, US 2 998 450, 1961, (G. Wilbert, J. De Angelis).
[135] Parke Davis, US 3 313 848, 1967; DE 1 149 015, 1961.
[136] P. F. Juby, T. W. Hudyma, M. Brown, J. Med. Chem. 11 (1968) 111 117.
[138] Parke Davis, US 3 138 636, 1964; DE 1 163 846, 1961.
[139] Labs. U.P.S.A., US 3 415 834, 1968; Schering Corp. US 3 337 570, 1967.
[140] K. H. Boltze et al., Arzneim.-Forsch./Drug Res. 30 (1977) no. 2 1314 1325.
[141] N. P. Buu-Hoi et al., Hebd. Seances Acad. Sci. 261 (1965) 2259.
[142] Merck & Co., US 3 161 654, 1964, DE 1 232 150, 1962.
[143] H. Yamamoto et al., Chem. Pharm Bull. 16 (1968) no. 17, 647.
[144] T. Y. Shen et al., J. Am. Chem. Soc. 85 (1963) 488 489.
[145] Byk Gulden, US 4 4 325 962, 1982; DE 1 946 370, 1969.
[146] G. Rainer, U. Krger, K. Klemm, Arzneim.-Forsch./Drug Res. 31 (1981) 649 655.
[147] B. Unterhalt, Drugs Future 7 (1982) 110 111.
[148] Merck & Co., US 3 882 239, 1975; DE 1 039 426, 1970.
[149] R. F. Shuman et al., J. Org. Chem. 42 (1977) 1914 1919.
[150] McNeil, US 3 752 826, 1973; GB 1 428 272, 1973.
[151] J. R. Carson, D. N. McKinstry, S. Wong, J. Med. Chem. 14 (1971) 646 647.
[152] Beecham, US 4 420 639, 1983; DE 2 463 219, 1974.
[153] A. C. Goudie et al., J. Med. Chem. 12 (1978) 1260 1264.
[154] M. Neumann, Drugs Future 6 (1981) 35 36.
[155] C. Prabhakar et al., Org. Process Res. Dev. 3 (1999) 121 125.
[156] Degussa, US 3 513 171, 1970; DE 1 670 522, 1966.
Page: 9

Helmut Buschmann)
[157] Drugs Future 8 (1983) 773 775.

[158] W. v. Bebenburg, K. Thiele, J. Engel, W. S. Sheldrick, Chem. Ztg. 105 (1981) 217
219.
[159] W. v. Bebenburg, G. Steinmetz, K. Thiele, Chem. Ztg. 103 (1979) 387 399.
[160] J. M. Mayer, B. Testa, Drugs Future 22 (1997) 1347 1366.
[161] M. Cleij, A. Archelas, R. Furstoss, J. Org. Chem. 64 (1999) 5029 5035.
[162] Rhne-Poulence, US 3 641 127, 1972.
[163] R. L. Dorfman, Arzneim.-Forsch./Drug Res. 25 (1975) 278 281.
[164] Syntex, US 3 663 584, 1972.
[165] Syntex, US 4 605 758, 1986.
[166] T. Y. Shen, Angew. Chem. Int. Ed. Engl. 11 (1972) 460.
[167] H. R. Bellur, J. R. Ahuja, D. G. Kulkarni, Tetrahedron: Asymmetry 3 (1992) 163
192.
[168] Roussel-Uclaf, DOS 2 055 264, 1970.
[169] G. Ehrhart, H. Ruschig: Arzneimittel, Entwicklung, Wirkung, Darstellung, vol. 1,
Verlag Chemie, Weinheim 1972, pp. 171 172.
[170] I.G. Farben, DRP 476 663, 1922.
[171] Hoffmann-La Roche, DRP 565 799, 1931.
[172] Riedel-deHaen, DE 962 254, 1954.
[173] R. Denss et al., Helv. Chim. Acta 40 (1957) 402.
[174] M. Khn et al., J. Prakt. Chem. 156 (1940) 103.
[175] J. Bchi et al., Helv. Chim. Acta 36 (1953) 75.
[176] Comm. Farmaceutica Milanese, GB 839 057, 1957.
[177] Geigi, US 2 745 783, 1956.
[178] Geigi, US 2 562 830, 1951.
[179] Warner-Lambert, DOS 2 208 351, 1972.
[180] J. G. Lombardino, E. H. Wisemann, J. Med. Chem. 14 (1971) 973.
[181] H. Zinnes et al., J. Med. Chem. 25 (1982) 12.
[182] Drugs Future 17 (1992) 683 686.
[183] J. G. Lombardino, E. H. Wisemann, J. Chiaini, J. Med. Chem. 5 (1973) 493 496.
[184] E. H. Wisemann, Y. H. Chanh, J. G. Lombardino, Arzneim.-Forsch./Drug Res. 26
(1976) 1300 1303.
[185] L. Castaner, E. Arrigoni-Martelli, Drugs Future 2 (1977) 124 127.
[186] Hoffmann-La Roche, DOS 2 537 070, 1975.
[188] Synthex, US 4 347 186, 1982; US 4 458 081, 1984; US 4 873 340, 1989.
[190] A. Guzman, R. A. Toscana, J. M. Young, A. R. Van Horn, J. M. Muchowski, J. Med.
Chem. 29 (1986) 589 591.
[191] J. M. Muchowski et al., J. Med. Chem. 28 (1985) 1037 1049.
[192] F. F. Franco, R. Greenhouse, J. M. Muchowski, J. Org. Chem. 47 (1982) 1682
Page: 10

Helmut Buschmann)
1688.
[193] Wyeth, US 3 578 671, 1971.
[195] Drugs Future 22 (1997) 711 714.
[196] Searle & Co., US 5 521 207; EP 731 795; WO 9 515 316 (J. J. Talley, T. D. Penning,
P. W. Collins et al.).
[197] American Home Products, US 3 843 681, 1974.
[199] C. A. Demerson, L. G. Humber, A. H. Philipp, J. Med. Chem. 19 (1976) 391 395.
[200] C. A. Demerson, L. G. Humber, T. A. Dobson, R. R. Martel, J. Med. Chem. 18 (1975)
189.
[201] Thomae GmbH, DE 2 756 113, 1979.
[202] G. Trummlitz, G. Engelhardt, U. Busch, Drugs Future 14 (1989) 1047 1048.
[203] Riker, US 3 840 597, 1974; DOS 2 333 643, 1973.
[204] Drugs Future 23 (1998) 1287 1296.
[205] J. Hannah et al., J. Med. Chem. 21 (1978) 1093 1100.
[206] Knoll, DOS 2 726 925, 1977.
[207] T. Hudlicky, G. Butora, S. F. Fearnley, A. G. Gum, M. R. Stabile: "A historical
perspective of morphine synthesis", in: Atta-ur-Rahman (Ed.): Studies in Natural
products Chemistry, Elsevier, Amsterdam 1996, pp. 43 116.
[208] D. Trauner et al., Synthesis 1983 203 204.
[209] J. Mulzer, D. Trauner, Chirality 11 (1999) 475 482.
[211] Boehringer, DRP 247 180, 1912.
Verlag Chemie, Weinheim 1972, 118.
[213] E. Merck AG, DRP 131 980, 1902.
Verlag Chemie, Weinheim 1972, pp. 79, 115.
Verlag Chemie, Weinheim 1972, p. 180.
[216] A. Stein, Pharmazie 10 (1955) 180 186.
[217] Reckitt & Colman, DE 1 620 206, 1966.
[218] Reckitt & Sons Ltd., US 3 433 791, 1969.
[219] K. W. Bentley, D. G. Hardy, Proc. Chem. Soc. (London) 1963, 220.
[220] W. G. Dorner, Chem. Unserer Zeit 15 (1986) 33 46.
[222] Knoll, DRP 607 931, 1935.
[223] Merck, US 2 715 626, 1955.
[224] H. Rapoport, R. Naumann, E. R. Bissel, R. M. Bonner, J. Org. Chem. 15 (1950) 1103
Page: 11

Helmut Buschmann)
1107.
[226] O. Schnider, A. Grssner, Helv. Chim. Acta 34 (1951) 2211 2217.
[227] O. Schnider, J. Hellerbach, Helv. Chim. Acta 33 (1950) 1437 1448.
[228] R. Grewe, Naturwissenschaften 33 (1946) 333 337.
[229] Winthrop, US 2 167 351, 1939, (O. Eisleb).
[230] I. G. Farben, DE 679 281, 1937.
[231] O. Eisleb, Chem. Ber. 74 (1941) 1433 1450.
[232] E. E. Smissman, G. Hite, J. Am. Chem. Soc. 81 (1959) 1201 1203.
[233] I.G. Farben, DRP 752 755, 1942.
[234] H. Kgi, K. Miescher, Helv. Chim. Acta 32 (1949) 2489 2507.
[235] Janssen, US 3 164 600, 1965; US 3 141 823, 1964.
[236] Janssen, DE-OS 2 819 837, 1978.
[237] F. Janssen, J. Torremans, P. A. Janssen, J. Med. Chem. 29 (1986) 2290 2297.
[238] S. J. Hopkins, Drugs Future 6 (1981) 335 337.
[239] Glaxo, EP 383 579, 1990.
[240] Drugs Future 19 (1994) 1088 1092.
[241] P. L. Feldmann et al., J. Med. Chem. 34 (1991) 2202 2208.
[242] Janssen, US 3 998 834, 1976.
[244] W. F. M. Van Bever, C. J. E. Niemegeers, K. H. L. Schellekens, P. A. J. Janssen,
Arzneim.-Forsch./Drug Res. 26 (1976) 1548 1556.
[245] P. G. H. Van Daele et al., Arzneim.-Forsch./Drug Res. 26 (1976) 1521 1531.
[246] Farbw. Hoechst, DBP 865 314, 1941.
[247] Merck & Co., US 2 644 010, 1953.
[248] Abott, US 2 983 757, 1961.
[249] E. M. Schultz, C. M. Robb, J. M. Sprague, J. Am. Chem. Soc. 69 (1947) 2454 2459.
[250] N. R. Easton, J. H. Gardner, J. P. Stevens, J. Am. Chem. Soc. 69 (1947) 2941 2942.
[251] A. A. Larsen, B. F. Tullar, B. Elpern, J. S. Buck, J. Am. Chem. Soc. 70 (1948) 4195
4196.
[252] E. E. Howe, M. Sletzinger, J. Am. Chem. Soc. 71 (1949) 2935.
[253] M. Bockmhl, G. Ehrhart, Justus Liebigs Ann. Chem. 561 (1948) 52 85.
[254] F. I. Carroll, G. A. Brine, T. Chen, D. W. Kohl, C. D. Welch, J. Org. Chem. 41 (1950)
3521 3524.
[255] Janssen, DE 1 117 126; 1956; GB 822 055, 1956.
[256] A. Pohland, H. R. Sullivan, J. Am. Chem. Soc. 75 (1953) 4458 4461; 77 (1955)
3400 3401.
[257] A. Pohland, L. R. Peters, H. R. Sullivan, J. Org. Chem. 28 (1963) 2483 2484.
[258] H. R. Sullivan, J. R. Beck, A. Pohland, J. Org. Chem. 28 (1963) 2381 2385.
[259] Janssen, US 2 898 340, 1959; Searle, US 4 086 234, 1978.
Page: 12

Helmut Buschmann)
[260] Janssen, US 3 714 159, 1973; ED-OS 2 126 559, 1971.

[261] R. A. Stokbroekx et al., J. Med. Chem. 16 (1973) 782 786.
[262] Janssen, DE 1 238 472, 1961.
[263] Gdecke, DE 1 518 959, 1965; Warner-Lambert, US 3 557 126, 1969.
[264] L. E. Overman, C. B. Petty, R. J. Doedens, J. Org. Chem. 44 (1979) 4183 4185.
[265] G. Satzinger, Justus Liebigs Ann. Chem. 758 (1972) 43 64, 65 71; 728 (1969) 64
87.
[266] G. Satzinger, W. Wassermann, F. Zimmermann, Pharm. Ind. 40 (1978) 657 664.
[267] Grnenthal, GB 997 399, 1964; US 3 564 100, 1971 (E. Frankus, K. Flick).
[268] K. Flick, E. Frankus, E. Friderichs, Arzneim.-Forsch./Drug Res. 28 (1978) no. 1, 107
113.
[269] Whitefin Holding, BE 790 747, 1972; US 3 539 589, 1970; DE-OS 2 253 149, 1972.
[270] D. Chiarino et al., Arzneim.-Forsch./Drug Res. 28 (1978) no. 2, 1554.
[271] D. Della Bella, V. Ferrari, V. Frigeni, P. Lualdi, Nature New. Biol. 241 (1973) 282
284.
[272] Bristol-Myers, US 3 775 414, 1973.
[273] J. Monkovic et al., J. Am. Chem. Soc. 95 (1973) 7910.
[274] J. Monkovic, C. Bachand, H. Wong, J. Am. Chem. Soc. 100 (1978) 4609 4610.
[275] American Home, BE 776 173, 1971; DE 2 159 324, 1971.
[276] M. E. Freed, J. R. Potoski, E. H. Freed, G. L. Conklin, J. Med. Chem. 16 (1973) 595
599.
[277] Wyeth, DE-OS 1 941 534, 1969; GB 1 285 025, 1969.
[278] G. Bradley et al., Eur. J. Med. Chem. 15 (1980) 375.
[279] Endo Laboratories, GB 1 119 270, 1968; US 3 332 950, 1967.
[280] L. Castaner, P. J. Roberts, Drugs Future 2 (1977) 613 615.
[281] Merck & Co., US 2 364 833, 1944; US 2 891 954, 1959.
[282] Sterling Drug, BE 611 000, 1961.
[283] S. Archer, N. F. Albertson, L. S. Harris, A. K. Pierson, J. G. Bird, J. Med. Chem. 7
(1964) 123 127.
[284] G. Ehrhart, H. Ruschig: Arzneimittel, Entwicklung, Wirkung, Darstellung, vol.1,
[285] J. Hellerbach, A. Grssner, O. Schnider, Helv. Chim. Acta 39 (1956) 429 440.
[286] O. Schnider, A. Grssner, Helv. Chim. Acta 24 (1951) 2211 2217.
[287] D. M. Paton, Drugs Future 4 (1979) 438 441.
[288] P. Moser, A. Sallmann, I. Wiesenberg, J. Med. Chem. 33 (1990) 2358 2368.
[289] US 3 254 088, 1966; DE 1 183 508, 1962 (M. J. Lewenstein).
[290] R. A. Olofson, R. C. Schnur, L. Bunes, J. P. Pepe, Tetrahedron Lett. 1977 1567
1577.
[291] Endo Laboratories, US 3 332 950, 1967; ED-AS 1 795 707, 1966.
[292] Geigi, US 2 948 718, 1960 (W. Schindler).
[293] DD 133 052, 1977 (R. Mller).
[294] Boehringer Ingelheim, DE 1 303 141, 1961; US 3 236 857, 1966.
Page: 13

Helmut Buschmann)
[295] VEB Arzneimittelwerke Dresden, DE-AS 1 770 874, 1968.

[296] Degussa, DE 1 795 858, 1968; US 3 513 171, 1970.
[297] Drugs Future 8 (1983) 773 775.
[298] W. von Bebenburg, G. Steinmetz, K. Thiele, Chem. Ztg. 103 (1979) 387 399.
[299] W. von Bebenburg, K. Thiele, J. Engel, W. S. Sheldrick, Chem. Ztg. 105 (1981) 217
219.
[300] Rexall, US 3 487 153, 1969.
[301] Riker, US 3 830 803, 1974.
[302] A. F. Casy, R. T. Parfitt: Opioid Analgesics, Chemistry and Receptors, Plenum Press,
New York 1986.
[303] A. J. Grace, Br. Med. J. 281 (1980) 1285.
[304] E. Kalzo, A. Vanino, Clin Pharmacol. Ther. 47 (1990) 639 646.
[305] F. Kaiko et al., Clin. Pharmacol. Ther. 59 (1996) 52 61.
[306] G. Eberhart, H. Ruschig: Arzneimittel, Entwicklung, Wirkung, Darstellung, vol. I,
Verlag Chemie, Weinheim 1972, p. 118.
[307] E. Merck, DRP 411 530, 1925.
[308] K. W. Bentley: The Chemistry of Morphine Alkaloids, Oxford 1954.
[309] F. M. Hauser et al., J. Med. Chem. 17 (1974) 1117.
[310] U. Weiss., J. Am. Chem. Soc. 77 (1955) 5891 5892.
[311] US 2 806 033, 1955 (M. J.Lewenstein, U. Weiss).
[312] R. S. Sinatra, D. M. Harrison, Clin. Pharm. 8 (1989) 541 544.
[313] T. Appelboom, P. Franchimont, Adv. Therapy 11 (1994) 228 234.
[314] P. A. Todd, S. P. Clissold, Drugs 41 (1991) 625 646.
[315] G. L. Plosker, A. J. Wagstaff, Drugs 50 (1995) 1050 1075.
[316] F. G. Mayall et al., Br. Med. J. 309 (1994) 599 600.
[317] Troponwerke, US 3 692 818, 1972, DE 1 939 112, 1969.
[318] Syntex, US 3 896 157, 1975.
[319] Geigi, US 3 558 690, 1971.
first occurrence in article

Analgesics and Antipyretics - Table 1
COX-2 specific inhibitors
Group
Compound
First generation
COX-2 selectivity
Reference
(< 100-fold)
etodolac
10
[73]
meloxicam
10
[73], [74]
Page: 14

Helmut Buschmann)
nimesulide
Second generation
5 100
[73], [74]
(100 1000-fold)
celecoxib
375
[78]
rofecoxib
800
[10]

Mammalian endogenous opioid peptides
Precursor
Endogenous peptide
Amino acid sequence
Pro-opiomelanocortin
-endorphin
YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE
Pro-enkephalin
[MET]enkephalin
YGGFM
[LEU]enkephalin
YGGFL
dynorphin A
YGGFLRRIRPKLKWDNQ
dynorphin B
YGGFLRRQFKVVT
-neoendorphin
YGGFLRKYPK
-neoendorphin
YGGFLRKYP
Nociceptin
FGGFTGARKSARKLANQ
Pro-dynorphin
Pro-nociceptin/OFQ
a
OFQ = orphanin FQ.

Opiod receptor specifity
Receptor type
Selective ligands
Nonselective ligands
Agonist
Antagonist
Agonist
Antagonist
MOR
morphine
CTOP
levorphanol
naloxone
fentanyl
etorphine
naltrexone
levorphanol
naloxone
methadone
DAMGO
KOR
enadoline
nor-BNI
Page: 15

Helmut Buschmann)
-
U50,488
etorphine
naltrexone
levorphanol
naloxone
etorphine
naltrexone
dynorphin
DOR
DPDPE
SNC-80
naltrindol
MOR = mu-opioid receptor. KOR = kappa -opioid receptor. DOR = delta-opioid receptor. DAMGO = [D-Ala2, MePhe 4,
Gly(ol) 5]enkephalin. Enadoline = (5R)-(5,7,8-(-)-N-methyl -N-(7-[1-pyrrolidinyl] -1-oxaspiro[4,5] dec-8-yl)-4benzofuranacetamide, previously CI977. U50,488 = trans-3,4-dichloro -N-methyl -N-[2-(1-pyrrolidinyl) -cyclohexyl] benzeneacetamide methanesulfonate. DPDPE = [D-Pen 2, D-Pen 5]enkephalin. SNC-80 = (+)-4-[(R)--((2S,5R)-4-allyl -2,5dimethyl -1-piperazinyl) -3-methoxybenzyl] -N,N-diethylbenzamide. CTOP = D -Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2. norBNI = nor-binaltorphimine.

Analgesics and Antipyretics - Figure 1
WHO-Guidelines for Cancer pain treatment ("WHO-Ladder")

Analgesics and Antipyretics - Figure 2
Page: 16

Helmut Buschmann)
Simple scheme of the biosynthesis of postraglandins (PG), thromboxanes (TX), and

leukotrienes from arachidonic acid consequent to cell injury (modified after [6])
Page: 17

Helmut Buschmann)
[6]
J. J. Bonica (ed.): The Management of Pain, 2nd ed., Lea & Febiger, 1990.
[10]
C. J. Hawkey: "Cox-2 Inhibitors", Lancet 353 (1999) 307 314.
[73]
J. R. Vane et al., Annu. Rev. Pharmacol. Toxicol. 38 (1998) 97 120.
[74]
J. Berg et al., J. Pharmacol. Toxicol. Meth. 37 (1997) 179 186.
[78]
A. Graul et al., Drugs Future 22 (1997) 711 714.
[117]
B. Ameer et al., Ann. Int. Med. 87 (1977) 202 209.
[118]
R. K. Lewis, F. P. Paloucek, Clin. Pharm. 10 (1991) 765 774.
[119]
U. C. Dubach et al., N. Engl. J. Med. 308 (1983) 357 362.
[125]
A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances, Synthesis, Patents,
Applications, Thieme, Stuttgart New York, 1999 (available in print and CD-ROM).
[134]
Warner-Lambert, US 2 998 450, 1961, (G. Wilbert , J. De Angelis ).
Page: 1

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