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Photochemistry of Drugs: An Overview and Practice - Drugs Photochemistry and Photostability, 1998, 1-73 - DOI 10.1039/9781847550712-00001

Photochemistry of Drugs: An Overview and Practice - Drugs Photochemistry and Photostability, 1998, 1-73 - DOI 10.1039/9781847550712-00001

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Photochemistry of Drugs: An Overview and Practice - Drugs Photochemistry and Photostability, 1998, 1-73 - DOI 10.1039/9781847550712-00001
Published on 01 January 1998 on http://pubs.rsc.org
doi:10.1039/9781847550712-00001
Photochemistry of drugs: An overview and practical problems
Authors: A. Albini, E. Fasani, A. Albini and E. Fasani
Drugs Photochemistry and Photostability, 1998, 1-73
DOI: 10.1039/9781847550712-00001

structure-activity relationships, SARs, analgetics, acetylfentanyl, 3-methylfentanyl, 3MF, TMF, AMF, alphamethylfentanyl, Ohmefentanyl, beta-hydroxy, alpha-methyl, Mefentanyl, 4-methoxymethylcarbonyl, 4-methoxycarbonyl, 4-substituted piperidines, 4,4-disubstituted piperidines, 4-piperidines, 4-substituted, 4,4-disubstituted, fentanil, phentanyl, phentanil, N-phenylethyl-4-piperidones, piperid-4-ones, N-phenylethyl-4-piperidinones, piperidin-4-ones, NPP, ANPP, Sigfreid Sigfried fentanyl opioid opiate synthesis, mu u delta d Kappa K opioid receptor, opiate alkaloid, poppy alkaloids, subutex, suboxone, reducing agents, LiAlH4, lithium aluminum hydride, sodium borohydride, platinum oxide, catalytic hydrogenation, N-debenzylation, morphine-like, Paul A.J. PAJ Adrian Jan Janssen, Pharmaceuticals, pharma, Pharmacy, pharmacology, pharamcokinetics, P. Papaver somniferum, dipipanone, phenadoxone, 4-phenylpiperidines, organic synthesis, novel organic synthesis, 4-anilinopiperidine 4-propionanilinopiperidine 4-anilidopiperidine 4-propionanilidopiperidine chemistry, piperidine nitrogen chemistry, organic heterocyclic nitrogen compounds, opioid chemistry, opioid synthesis, chemical syntheses, pseudoephedrine, ephedra, phenylacetone, phenyl-2-propanone, P2P, methylamine, MDMA, MDA, methamphetamine amphetamine synthesis manufacture precursors, saffrole oil, methylenedioxymethamphetamne, ecstasy, x, XTC, ADAM, EVE, Alexander T. Shulgin, PiHKAL: A Chemical Love Story, TiHKAL, 2-CE, 2-CB, 2-CI, 2CE 2CI 2CB, PEA, phenylethylamines, psychoactive drugs, psychedelic, psychogenic, psychotropic, phenethylamines, Sympathomimetic amines, dopaminergic, serotonin, norepinephrine, noradrenaline, adrenaline, dopamine, catecholamines, central sympathetic parasympathetic nervous system, sympatholytics, parasympatholytics, anxiolytics, diuresis, diuretics, methyltestosterone, 5-alpha-reductase inhibitor, testosterone, dihydrotestosterone, PDE5, viagra, cialis, levitra, Sildenafil citrate, tadalafil, vardenafil, cGMP-specific phosphodiesterase type 5, BPH, benign prostate hyperplasia, avodart, Dutasteride CNS, SSRI, antidepressants, prozac, paxil, Zoloft, venlafaxine, fluoxetine, fluvoxamine, SNRI, Bupropion, Wellbutrin, Zyban, oxirane, MOR, DOR, KOR, naloxone, naltrexone, DXM, dextromethorphan, levorphanol, dextropropoxyphene, dextromoramide, phenacyl, arylmorphan, azabicyclo, azaprocin mixed partial agonist antagonist, binding affinity, EC50 ED50 IC50, concentration molarity osmolarity, molecules, molecular biology, biochemistry, drug substance abuse addiction potential dependency tolerance modulation, science, physics, levomethorphan, Alvimopan, Loperamide, Picenadol, oxycodone, oxycontin, hydromorphone, hydrocodone, darvocet, pethidine, meperidine, demerol, darvon, 6,7-benzomorphans, benzodiazepines, flunitrazepam, xanax, klonopin, clonazepam, alprazolam, diazepam, anticonvulsant, antidiuretic, diabetes, insulin, genetic engineering, formulations, tramadol, ultram, viminol, bromedol, Daniel Lednicer, Philip F. VonVoightlander, A.F. Casy, Parfitt, Opioid Analgesics: Chemistry and Receptors, narcotics, PCP, oxycodone, oxycontin, hydromorphone, hydrocodone, darvocet, pethidine, meperidine, demerol, darvon, Codeine-N-Oxide (Genocodeine) Dihydromorphine-6-glucuronide Hydromorphone-N-Oxide Heroin-7,8-Oxide Morphine-6-glucuronide, 6-Acetylmorphine Morphine-N-Oxide (Genomorphine) Naltrexol Norcodeine Normorphine, NSAIDs, tylenol, ibuprofen, controlled substance schedule I II III IV V 1 2 3 4 5, COX COX-2 COX-1 COX1 COX2 inhibitors, antips
Photochemistry of Drugs: An Overview and Practice - Drugs Photochemistry and Photostability, 1998, 1-73 - DOI 10.1039/9781847550712-00001
Published on 01 January 1998 on http://pubs.rsc.org
doi:10.1039/9781847550712-00001
Photochemistry of drugs: An overview and practical problems
Authors: A. Albini, E. Fasani, A. Albini and E. Fasani
Drugs Photochemistry and Photostability, 1998, 1-73
DOI: 10.1039/9781847550712-00001

structure-activity relationships, SARs, analgetics, acetylfentanyl, 3-methylfentanyl, 3MF, TMF, AMF, alphamethylfentanyl, Ohmefentanyl, beta-hydroxy, alpha-methyl, Mefentanyl, 4-methoxymethylcarbonyl, 4-methoxycarbonyl, 4-substituted piperidines, 4,4-disubstituted piperidines, 4-piperidines, 4-substituted, 4,4-disubstituted, fentanil, phentanyl, phentanil, N-phenylethyl-4-piperidones, piperid-4-ones, N-phenylethyl-4-piperidinones, piperidin-4-ones, NPP, ANPP, Sigfreid Sigfried fentanyl opioid opiate synthesis, mu u delta d Kappa K opioid receptor, opiate alkaloid, poppy alkaloids, subutex, suboxone, reducing agents, LiAlH4, lithium aluminum hydride, sodium borohydride, platinum oxide, catalytic hydrogenation, N-debenzylation, morphine-like, Paul A.J. PAJ Adrian Jan Janssen, Pharmaceuticals, pharma, Pharmacy, pharmacology, pharamcokinetics, P. Papaver somniferum, dipipanone, phenadoxone, 4-phenylpiperidines, organic synthesis, novel organic synthesis, 4-anilinopiperidine 4-propionanilinopiperidine 4-anilidopiperidine 4-propionanilidopiperidine chemistry, piperidine nitrogen chemistry, organic heterocyclic nitrogen compounds, opioid chemistry, opioid synthesis, chemical syntheses, pseudoephedrine, ephedra, phenylacetone, phenyl-2-propanone, P2P, methylamine, MDMA, MDA, methamphetamine amphetamine synthesis manufacture precursors, saffrole oil, methylenedioxymethamphetamne, ecstasy, x, XTC, ADAM, EVE, Alexander T. Shulgin, PiHKAL: A Chemical Love Story, TiHKAL, 2-CE, 2-CB, 2-CI, 2CE 2CI 2CB, PEA, phenylethylamines, psychoactive drugs, psychedelic, psychogenic, psychotropic, phenethylamines, Sympathomimetic amines, dopaminergic, serotonin, norepinephrine, noradrenaline, adrenaline, dopamine, catecholamines, central sympathetic parasympathetic nervous system, sympatholytics, parasympatholytics, anxiolytics, diuresis, diuretics, methyltestosterone, 5-alpha-reductase inhibitor, testosterone, dihydrotestosterone, PDE5, viagra, cialis, levitra, Sildenafil citrate, tadalafil, vardenafil, cGMP-specific phosphodiesterase type 5, BPH, benign prostate hyperplasia, avodart, Dutasteride CNS, SSRI, antidepressants, prozac, paxil, Zoloft, venlafaxine, fluoxetine, fluvoxamine, SNRI, Bupropion, Wellbutrin, Zyban, oxirane, MOR, DOR, KOR, naloxone, naltrexone, DXM, dextromethorphan, levorphanol, dextropropoxyphene, dextromoramide, phenacyl, arylmorphan, azabicyclo, azaprocin mixed partial agonist antagonist, binding affinity, EC50 ED50 IC50, concentration molarity osmolarity, molecules, molecular biology, biochemistry, drug substance abuse addiction potential dependency tolerance modulation, science, physics, levomethorphan, Alvimopan, Loperamide, Picenadol, oxycodone, oxycontin, hydromorphone, hydrocodone, darvocet, pethidine, meperidine, demerol, darvon, 6,7-benzomorphans, benzodiazepines, flunitrazepam, xanax, klonopin, clonazepam, alprazolam, diazepam, anticonvulsant, antidiuretic, diabetes, insulin, genetic engineering, formulations, tramadol, ultram, viminol, bromedol, Daniel Lednicer, Philip F. VonVoightlander, A.F. Casy, Parfitt, Opioid Analgesics: Chemistry and Receptors, narcotics, PCP, oxycodone, oxycontin, hydromorphone, hydrocodone, darvocet, pethidine, meperidine, demerol, darvon, Codeine-N-Oxide (Genocodeine) Dihydromorphine-6-glucuronide Hydromorphone-N-Oxide Heroin-7,8-Oxide Morphine-6-glucuronide, 6-Acetylmorphine Morphine-N-Oxide (Genomorphine) Naltrexol Norcodeine Normorphine, NSAIDs, tylenol, ibuprofen, controlled substance schedule I II III IV V 1 2 3 4 5, COX COX-2 COX-1 COX1 COX2 inhibitors, antips

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Photochemistry
of
Drugs:
An
Overview
and
Practical Problems
Angelo Albini and Elisa Fasani
Department of Organic ChemistryUniversity of Paviav.le Taramelli 10,I-27100 Pavia, Italy
1
INTRODUCTION
Absorption of light
(W
or visible) by the ground state of a molecule
(So)
generateselectronically excited states, either directly (the singlet states) or after intersystem crossingfrom the singlet manifold (the triplet states). Alternatively, triplet states may be generated byenergy transfer from another excited state (a sensitiser). In both multiplicities, very fastinternal conversion leads to the lowest states
(S1
and TI respectively). These states, althoughstill quite short lived (typical lifetime 610-8
s
for
S1
and <lo4
s
for T1) live long enough thata chemical reaction competes with decay to the ground state.Electronically excited states are electronic isomers of the ground state, and notsurprisingly show a different chemistry. These, however, can be understood with the samekind of reasoning that
is
used for ground state chemistry, taking into account that the verylarge energy accumulated in excited states makes their reactions much faster (in the contrarycase, there would be no photochemistry at all, in view of the short lifetimeofthe keyintermediates).
As
an example, ketones are electrophiles in the ground state due to the partialpositive charge on the carbon atom. The reaction with nucleophiles occurs. In the nz* tripletexcited state electrons are differently distributed, and the important thing is now the presenceof an unpaired electron on the non-bonding orbital localised on the oxygen atom. This makesatom transfer
to
that atom
so
fast a process (k-1069-1, many orders of magnitude faster thanany reaction of ground state molecules) that it competes efficiently with the decay of sucha state.On the basis of such principles, the many photochemical reactions now known have beenrationalised. This is shown in many fine books of photochemistry,1-5 which demonstrate boththe dramatic development of this science in the last decades and the high degree ofrationalisation that has been reached. The photoreactions of drugs6 obviously can bediscussed in the same way, and
G.
M.J.
Beijersbergen van Henegouwen (p. 74) pointed outsome key points that one should take into account. It is therefore generally possible to predict
   D  o  w  n   l  o  a   d  e   d  o  n   1   9   S  e  p   t  e  m   b  e  r   2   0   1   0   P  u   b   l   i  s   h  e   d  o  n   0   1   J  a  n  u  a  r  y   1   9   9   8  o  n   h   t   t  p  :   /   /  p  u   b  s .  r  s  c .  o  r  g   |   d  o   i  :   1   0 .   1   0   3   9   /   9   7   8   1   8   4   7   5   5   0   7   1   2  -   0   0   0   0   1
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2
Drugs: Photochemistry and Photostability
the photochemical behaviour of a new drug, as
of
any other molecule, or at least to point outthe most likely alternatives.More exactly, as it has been pointed out by Grenhill in a recent review: it is possible toindicate some molecular features that are likely to make a molecule liable tophotodecomposition, even if it is difficult to predict the exact photochemical behaviour of aspecific molecule. This is due to the fact that competition between the chemical reaction(s)and physical decay to the ground state depends in a complex way on the structure (and onconditions). Thus both the efficiency of a photochemical reaction and product distributionmay vary sigruficantly even among closely related compounds and further depend onconditions.At any rate, several chemical functions are expected to introduce photoreactivity (seeScheme
1).
These are:a. The carbonyl group. This behaves as an electrophilic radical in the n7c* excited state.Typical reactions are reduction via intermolecular hydrogen abstraction and fragmentationeither via a-cleavage (“Norrish Type I”) or via intramolecular y-hydrogen abstractionfollowed by
C,-Cp
cleavage (“Norrish Type
II”).
b. The nitroaromatic group, also behaving as a radical, and undergoing intermolecularhydrogen abstraction or rearrangement to a nitrite ester.c. The N-oxide function. This rearranges easily to an oxaziridine and the final products oftenresult from further reaction of this intermediate.d. The
C=C
double bond, liable to
EIZ
isomerisation as well as to oxidation (see case 8).e. The aryl chloride, liable to homolytic and/or to heterolytic dechlorination
f.
Products containing a weak
C-H
bond, e.g. at a benzylic position or
a
to an amine nitrogen.These compounds often undergo photoinduced fragmentations via hydrogen transfer orelectron-proton transfer.g. Sulphides, alkenes, polyenes and phenols. These are highly reactive with singlet oxygen,formed through photosensitisation from the relatively harmless ground state oxygen.Such knctions are present in a very large fraction, if not the majority, of commonly useddrugs. Thus, many drug substances, and possibly most of them, are expected to react whenabsorbing light. However, photodegradation of a drug is of practical significance only whenthe compound absorbs significantly ambient light
(0330
nm),
and even in that case thephotoreaction may be too slow to matter, particularly if concentrated solutions or solids areconsidered. It is important to notice that most information about photoreactions available inthe literature refers to the conditions where such processes are most easily observed andstudied,
viz.
dilute solutions in organic solvents, whereas what matters for drug photostability
are
(buffered) aqueous solutions or the solid state. Under such different conditions thephotoreactivity
of
a drug may be dramatically different. To give but one example,benzophenone triplet
-
probably the most thoroughly investigated excited state
-
is a short-lived species in organic solvents, e. g.
z
ca
0.3
ps
in ethanol, and is quite photoreactive viahydrogen abstraction under such conditions, and in general in
an
organic solution. However,
   D  o  w  n   l  o  a   d  e   d  o  n   1   9   S  e  p   t  e  m   b  e  r   2   0   1   0   P  u   b   l   i  s   h  e   d  o  n   0   1   J  a  n  u  a  r  y   1   9   9   8  o  n   h   t   t  p  :   /   /  p  u   b  s .  r  s  c .  o  r  g   |   d  o   i  :   1   0 .   1   0   3   9   /   9   7   8   1   8   4   7   5   5   0   7   1   2  -   0   0   0   0   1
View Online
 
Photochemistry
of
Drugs:
An
Overview
and Practical Problems
3
b)
0'
/
OH
-W
Products
H
-N\
NO-
-
NO2
a
\
\
\-\
Sens
02
-
Scheme
1
   D  o  w  n   l  o  a   d  e   d  o  n   1   9   S  e  p   t  e  m   b  e  r   2   0   1   0   P  u   b   l   i  s   h  e   d  o  n   0   1   J  a  n  u  a  r  y   1   9   9   8  o  n   h   t   t  p  :   /   /  p  u   b  s .  r  s  c .  o  r  g   |   d  o   i  :   1   0 .   1   0   3   9   /   9   7   8   1   8   4   7   5   5   0   7   1   2  -   0   0   0   0   1
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