chapter 12 - heterocyclic compounds

Chapter 12

BIOLOGICALLY ACTIVEHETEROCYCLIC COMPOUNDS

H eterocycles form the largest group of organic compounds, and many have important biological properties. Most natural substances as well as synthetic andnatural drugs contain heterocyclic fragments. More precisely, about two thirds ofall organic compounds and over three quarters of drugs belong to heterocyclic compounds.

The main heteroatom that occurs in heterocyclic compounds is nitrogen, but thereare also rings containing oxygen and sulfur.

In previous chapters we have encountered some compounds with the oxygen ornitrogen atom in a cycle. Formally, cyclic anhydrides, lactones and laclides, lactams anddiketopyperazines are heterocycles. But the mentioned compounds have the same chem-istry as their open-chain counterparts: lactones and ordinary esters behave similarly, aswell as lactams and ordinary amides, and so on. These cyclic compounds undergo manyreactions with ring opening that is not typical or genuine heterocycles, therefore theydo not relate to heterocyclic compounds.

12.1. Classification and Nomenclature of Heterocyclic Systems

There is no unified classification of heterocyclic compounds because of their bigvariety (tens of thousands of types are known at present). They are usually classified inaccordance with the following features of their skeleton.

According to the ring size. There are mainly three-, four-, five-, six-, and seven-membered heterocycles. Out of them, five- and six-membered are the most widespread.

\7NH

aziridine

oNH

pyrrole

opyridine

According to the heteroatom incorporated in a ring. As has already been said,the most important are nitrogen-, oxygen-, and sulfur-containing heterocycles.

[)o

furan

[)S

thiopheneo'N

4H-azepine

Biologically Active Heterocyclic Compounds 173

According to the number of heteroatoms and their mutual arrangement in aring. The most common are compounds with one or two heteroatoms, but cycles withmore heteroatoms are also known. Various combinations of heteroatoms are possible(for example, two nitrogens, nitrogen and oxygen, etc.), and heteroatoms can occupythe 1,2, 1,3, and 1,4 positions.

H, N' N' 0 ()ICy (), (),N' N, S NH' H Hpyrazole imidazole thiazole pyrimidine piperazine

According to a degree of unsaturation of a ring, Heterocycles can be dividedinto two subgroups: aromatic and nonaromatic (fully or partly saturated). The former aremuch more important, therefore the main attention in this chapter will be devoted tothem. Besides, fully saturated heterocycles are similar to their acyclic analogues, i.e.secondary amines, ethers, or sulfides.

Aromaticheterocycle

pyrazine

Cyclic amine

Hpiperidine

CyClic ether

otetrahydropyran

According to the number of the rings, In addition to monocyclic compounds,heterocycles with fused rings are well known too, carbocycles also being present in afused-ring system.

benzene + pyrrole benzene + pyridine pyrimidine + imidazole. , ,

,

, ,

'0:;>' '00' '00' 'ce7 ;::-.. I ""Nt ,l, I ~.6:::-... N 1 7 ~ ~ 2- N N g, H , , , , Hindole quinoline isoquinoline purine

The IUPAC nomenclature permits to use trivial and semi-trivial names for manyheterocyclic systems (see Section 2.2.3). Additional examples are given above, includ-ing numbering in the ring if it is not obvious.

12.2. General Characteristics of Principal Heterocycles

Two heterocycles, pyridine and pyrrole, are of fundamental importance for a rea-son that will be considered in the next section.

12.2.1. Aromaticity of Pyridine and Pyrrole

We have partly discussed this problem in Section 3.2.2. Recall that aromatic het-erocycles fall into two general categories: in the first one, a heteroatom supplies one

174 Chapter 12

electron to the aromatic II system, and in the second one, a heteroatom supplies twoelectrons to the aromatic II system. Pyridine is an example of the former, while pyrroleexemplifies the latter.

Coniugated electrons"

I ~ ,',Nonconjugated electrons r---pyridine

IH

pynole

In the both compounds the nitrogen atoms as well as carbons are sp'-hybridized.Pyridine has five carbons in the ring, each of them contributes one electron to the aro-matic 1t system, so that the nitrogen needs to contribute only one electron to bring thetotal six 1t electrons. On the other hand, there are only four sp'-hybridized carbons inpyrrole, so that the nitrogen atom must contribute a pair of electrons to make up six 1telectrons of the aromatic system (for the orbital structure of both heterocycles see Sec-tion 3.2.2).

Example 12.1. Prove that imidazole is an aromatic heterocycle. Draw its orbitalpicture, showing all p orbitals and all lone-pair orbitals.

Solution. The atom N-1 is pyrrole-type nitrogen that has a lone pair of electrons onits unhybridized p orbital. The atom N-3 is pyridine-type nitrogen with one electron on ap orbital.

~. 3H...2N NCi)02 0Figure 12.1. Orbital picture of imidazole.

As a result of such difference in the nitrogen electron demand, pyridine and pyrrolebehave in a different manner with respect to various chemical reagents.

Problem 12.1. Whicl:1 of the following camp l1Ms'iffi~ent re)Tlatic heterocycles?(a) furan, (b) piperidine, (c) pyrimidine, (d) quinolilile.Explain the reason for your choice.

12.2.2. Basicity and Acidity

In pyridine, the lone pair of electrons on the nitrogen atom isnot a part of the aromatic ll-electron system but occupies an sp'orbital in the ring plane (see Fig. 3.4). Consequently, pyridine candonate this lone pair of electrons for accepting a proton and forhydrogen bonding with water. Unlike benzene, it is completely mis-cible with water.


Pyridine forms pyridinium salts in reaction with acids. It is a weakly basic com-pound, with PK...+ 5.2, which is comparable with the value of 4.6 for aniline. Pyridine ishowever much less basic than ammonia and aliphatic amines because the electronega-tivity of an sp"-hybridized nitrogen is greater than that of an sp'-hybridized nitrogen inammonia and in aliphatic amines.

eN: + HO ---.. [OHJO-pyridinium chloride

In pyrrole on the contrary, the nitrogen lone pair of electrons is an essential part ofthe aromatic It system. Pyrrole is an extremely weak base; it has a PK...+ of -3.8, about1D times weaker than pyridine. It can be protonated on carbon rather than on the nitro-gen atom. Protonation of pyrrole would destroy the aromatic system, therefore it belongsto so-called acidophobic heterocycles. At the same time, pyrrole possesses a markedNH-acidity (pK

a17.5 that is in the range of alcohol acidity). Thus, it can be deprotonated

like alcohols in reactions with strong bases, for example, with sodium hydride:

Q + Na~H

pyrrole

--- II). + H,"N-"Na+

sodim pyrrofate

Note that both pyridinium and pyrrolate salts retain aromatic character.

Problem 12.2. Only one of two nitregens in pyrazole is quite basic. Show whieh one iiis, and explain the reason for your choice.

12.2.3. Substitution Reactions in Heterocycles

Electrophilic substitution is a typical reaction not only for aromatic hydrocarbonsbut also for aromatic heterocycles. Influence of a heteroatom on the reactivity of a het-erocycle is similar to that of a substituent in the benzene ring.

In pyrrole, the donating effect of the nitrogen lone pair of electrons increases theelectron density on the ring carbons, thus increasing reactivity of the heterocycle to-wards electrophiles. In pyridine, on the contrary, the pyridine-type nitrogen is an elec-tron-withdrawing atom which decreases the electron density on the carbons (especiallyat the 2, 4, and 6 positions), thus making the heterocycle less reactive in electrophilicsubstitution reactions. According to this, pyrrole and pyridine are referred to as it-exces-sive and It-deficient heterocycle, respectively.

+Meffect of nitrogen

tlf))&-H

pyrrole

-I effect of nitrogen

~(~&-:J

pyridine

176 Chapter 12

[)H

A difference in reactivity of pyrrole and pyridine is demonstrated in their bromina-tion reactions. Pyrrole reacts readily with bromine at low temperature to yield the corre-sponding tetrabromo derivative:

~Br_ ~~ +4HBrBr BrH

2,3,4,5-tetrabromopyrroie

In spite of high reactivity of Jt-excessive heterocycles (furan also belongs to thiscategory), proper reaction conditions and specific electrophilic reagents are usually re-quired because of acidophobic character of substrates.

Bromination of pyridine can be carried out under drastic conditions in a low yieldwhere a free-radical mechanism may operate. Electrophilic substitution nearly aiwaystakes place at the 3 position according to the bond polarization:

200-250 "C ~BrtL~ + HBr3-bromopyridine

Another factor decreasing the reactivity of pyridine in electrophilic substitution re-actions is acid-base complexation between the basic nitrogen and the attacking electro-phile, which may by often a proton. This results in the formation of a positive charge onthe ring, further deactivating it. Thus, pyridine does not undergo Friedel-Crafts alkyla-tion and acylation.

Pyridine exhibits nucleophilic properties in the reaction with electrophiles. It behavesas tertiary amine and forms quaternary pyridinium salts when reacting with alkyl halides:

0 &+I + CH,Br.C-J

pyridine

- 0" Br'I

CH,N-methylpyridinium

bromide

The aromatic ring of pyridinium salts is susceptible to nucleophilic attack owing toits high electron-deficiency. For example, a strongly nucleophilic hydride ion reacts withan alkylpyridinium sait by addition, producing non-aromatic 1,4-dihydropyridine deriva-tive (attack of the 2 position is also possible):

&+~(Q+" + H'&. !,J&+

IR

N-aJkylpyridiniumion

H H

-0IR

deri\Elli...e of1,4.


The pyridinium ion is thus reduced, i.e. it acts as an oxidant. This ion is a part of theNAD+ molecule (for details see Section 15.4.2), one of the most important coenzymes inbiological oxidations. So the above equation represents a simplified version of the bio-logical reaction.

In closing this brief overview of reactivity of some heterocycles, it should be addedthat pyridine itself also undergoes nucleophilic substitution. Unlike benzene, it replaceshydrogen (in the form of H-) by an amide ion, NH2-, or hydroxide ion, for example:

oI + Na'N~-sodium amide 120C -H2 ~ H20 ~I -=-.,.~ I + NaOHN~N~ N~2-amiMpyndine

This remarkable reaction is called the Chichibabin reaction (1911) by thename of the Russian chemist and the author of a fundamental textbook on organic chem-istry which was in use up to the middle of the 20th century.

12.3. Five-Membered Rings with One Nitrogen

The pyrrole ring is a structural component of several biologically important com-pounds. It is olten found as a fused-ring system indole. The latter is usually biosynthe-sized from the protein amino acid tryptophan. Indole itself and its 3-methyl derivative,skatole, are the decay products of proteins (both contribute to the odour of feces).

Tryptophan is decarboxylated in vivo to give tryptamine. Many compounds that con-tain the tryptamine skeleton have an effect on the brain and nervous system. For example,serotonin (5-hydroxytryptamine) is a neurotransmitter and vasoconstrictor active in thecentral nervous system. A disturbance in its metabolism leads to schizophrenia.

CH2CHCOOHo ~H2VN1H

tryptophan

-CO2

CH,CH,NH2ovJH

tryptamine

C~CH2NH2HO~

VN1H

serotonin

The tryptamine skeleton is a part of more complex molecules such as alkaloidsreserpine and lysergic acid. The structure of saturated pyrrole called pyrrolidine is afragment of the well-known alkaloid nicotine (for alkaloids see Section 12.6).

The pyrrole ring is a structural component of many vitally important compoundscalled porphyrins. Their parent structure is porphine, a tet-rapyrrolic macrocyclic system (see the draWing). Porphine is atlat symmetrical molecule in which four pyrrole rings are linkedby one-carbon bridges. It forms a conjugated system of eigh-teen It electrons shown in colour (note, that 18 is the HOckel'snumber when n = 4) and is, therefore, aromatic' . This is con-

1 The formula of porphine represents one of the resonance contributing structures.Total amount 01 electrons in conjugation is 26. it also being the HGckel's number.

/2 - 1029

porphine

178 Chapter 12

firmed by high conjugation energy of porphine which amounts to 840 kJlmol. All theporphyrins (substituted porphines with various side chains at the pyrrole rings) are ex-ceptionally stable compounds that decompose at about 500C.

Porphyrins form metallic complexes in which two NH hydrogens are absent andeach of the four nitrogens is bound to metal in the middle of the structure. The bestknown of these is heme, the iron(II)-porphyrin complex that imparts the red colour toblood.

CH3

CH3

HOOCCH,CH,heme

CH=CH,

CH3

"tamin 8.: R = CH:pH, pyridoxineR = CH=O, pyridoxal and its phosphateR = CH,NH" pyridoxamine

Heme is a constituent of the complex protein hemoglobin responsible for bindingmolecular oxygen in the process of respiration.

Another example of tetrapyrrolic compounds is chlorophyll, the green plant pig-ment essential for photosynthesis. It represents a magnesium-porphyrin complex.

12.4. Six-Membered Rings with One Heteroatom

This group of heterocyclic compounds is the oldest one. Pyridine was discoveredin the mid 19th century and its structure was established in 1869, shortly after the Kekulestructure of benzene had been suggested.

12.4.1. Nitrogen-Containing Heterocycles

The main parent compounds of this type are pyridine and fused-ring heterocyclicsystems of quinoline and isoquinoline. They are found in a small quantity in coal tar.Pyridine is a toxic liquid with unpleasant odour.

All these rings are constituents of many naturally occurring compounds and nu-merous drugs. Some physiologically important pyridine derivatives are related to vitamin86, This is a relatively simple pyridine derivative. The R group at C-4 may be a fragmentof an alcohol, aldehyde, or amine. The vitamin functions as a coenzyme in the intercon-versions of oxo carboxylic acids and amino acids (see Section 14.1.3).

R

HOCH,~OHI!..~CH3

Two pyridine derivatives which relate to vitamin PP are nicotinic acid (Niacin) andits amide (Niacinamide). A substituted nicotinamide Cordiamine (Niacetamide) is usedas a stimulator of the central nervous system.


V COOHnicotinic acid

VCONH,

nicotinamide

Other examples of pyridine containing drugs are hydrazide derivatives of isonico-tinic acid (4-pyridinecarboxylic acid). They are known as tuberculostatic drugs Isoniazid(Tubazid) and Phthivazid. The latter is prepared from Isoniazide by a familiar nucleo-philic reaction with vanillin (an aromatic aldehyde) as shown below:

o NHN=CH-A--OH-c/ '=\....,6 OCH,

Phlhi""id

Nicotinic acid first obtained by oXidation of nicotine is now produced from avail-able P-picoline (3-methylpyridine) and other 3-alkylpyridines also by oxidation, for ex-ample:

VCH, [0). VCOOHJ}-pi'coline nicotinic acid

12.4.2. Oxygen-Containing Heterocycles

Compounds consisting of o)(ygen-containing heterocycles are widespread in na-ture; there are, first of all. cyclic ferms of carbohydrates (see Chapter 13). Unsaturatedsi)(-membered representatives - 2H-pyran and 4H-pyran - are inherently unstable; more-over the lormer is at present unknown. Nevertheless, a group of the naturally occurringpyran derivatives called f1avonoids attracts attention of chemists and biochemistsfor last decades. Basic structures of flavonoids are polycyclic compounds flavan andits 4-oxo derivative flavanone, which may also contain the C-2-C-3 double bond (notshown below):12'

180

oI ,2H-pyran

o4H-pyran

000flavan

"-

flavanone

Cllapter 12

OH

OHOR

OH 0

quercetin (R = H)rutin (A = sugar unit)

A characteristic feature of flavonoids is the presence of several hydroxyl groups(up to six) in all three rings, some of which are often bound to sugar units.

Flavonoids occur ubiquitously in plants and foods. It is estimated that the meanhuman intake of all f1avonoids is about 100-150 mg per day.Many flavonoids possess multiple biological activities, includ-ing cardiovascular, anticarcinogenic, anti-inflammatory, im-mune-stimulating effects, some of them are used in medi- HOcine as, for example, quercetin (Quertin) and its sugaranalogue rutin (Rutosid).

It is known today that flavonoids take the protectiverole in the human body, saving the latter from destructiveaction of free radicals.

One compound containing a fused pyran ring systemis of no benefit to humans; this is tethahydrocannabinol, apsychotropic component of marijuana.

12.5. Rings with More than One Heteroatomtetrahydrocannabinol

Four important heterocyclic ring systems with more than one heteroatom are imi-dazole, pyrazole, pyrimidine, and purine. Other combinations of heteroatoms are known,of course, but we will be concerned with only nitrogen-containing aromatic heterocycies.

12.5.1. Imidazole and Pyrazole

Imidazole is a little like pyrrole in the follOWing way: the unshared electron pair onthe N-1 atom is delocalized and is a part of the aromatic six n-electron system (seeFigure 12.1). But the unshared electron pair on the N-3 atom is available for protonation.The pKBH, of imidazole is 7.0, so it is about 100 times more basic than pyridine and about10" times more basic than pyrrole. The positive charge in protonated imidazole can bedelocalized over both nitrogens through resonance:

N3f) + H'

I'H

imidazole imidazolium ion

The similar consideration may be applied to pyrazole, which is an isomer of imida-zole. The N-1 atom (pyrrole-type nitrogen) represents the acidic site in both compoundswhereas the C=N nitrogen (pyridine-type nitrogen) is the basic site.

BiologicallY Active Heterocyclic Compounds 181

Example 12.2. As we have just seen, imidazole is much more basic than pyrrole. Atthe same time, imidazole is stronger as an acid too. Suggest an explanation for these facts.

Solufion. It should be reemphasized that the best way for discussing acidity is tocompare stability of conjugate bases, i.e. anions obtained after deprotonation of bothheterocycles.

r;;,Q")-)

pirrolate ion imidazofate ion

The imidazoJate ion is better stabilized due to the presence of the second, elec-tron-withdrawing nitrogen atom. In terms of the resonance theory, this anion representstwo equal contributing structures. Indeed, the pK. of imidazole is 14.2 and that of pyrroleis 17.5. Thus, imidazole is an amphoteric compound.

The imidazole unit is a part of the protein amino acid histidine. In some enzymicreactions, histidine situated on the active site of an enzyme can realize either acidic orbasic catalysis; both are consequence of amphoteric properties of imidazole.

The imidazole derivative histamine that relates to biogenous amines is producedon decarboxylation of histidine in living systems:

Q-~COOHH N~histidine

-CO;,

histamine

Pyrazole itself and its derivatives do not occur in nature, but the pyrazole skeletonis present in some analgesics and antipyretics, for example, in Amidopyrin (Pyramidon)and Analgin (Oipyrone), that have many other synonyms.

CH3'r={N(CH,)2

CH3- N, N)"OI

G,;H,;Amidopyrin

12.5.2. Pyrimidine Derivatives

The most important pyrimidine derivatives are uracil, thymine, and cytosine callednucleic bases (or heterocyclic bases) since they are constituents of nucleic acids.

(~OH

uracil

oCH,...)lNH

~~OH

thymine

N~croH

cytosine

182 Chapter 12

The nucleic bases are capable of existing in several tautomeric forms. A new kindof tautomerism arises for nitrogen-containing heterocycles that have the OH group at-tached to the C=N fragment of a ring system. This phenomenon is called lactim-Iactamtautomerism, and tautomers are known as the lactim form and lactam form. The lactamtautomers are usually the predominant forms at equilibrium.

0{)'/Hf..-~o '.. .

~" ./lactim fonn

=- ~I')I 0H

lactllll1 loon

A group of compounds called barbifurates, whose usage ranges from mild seda-tives to hypnotics and anesthetics, are also pyrimidine derivatives. Examples includeBarbital (Veronal), the first synthetic soporific, Phenobarbital (Luminal), and Amobarbital(Amytal).

R'HC,H,C,H,CH,CH,CH(CH,),

RHC,H,C,H,C,H,

Barbituric acidBarbitalPhenobarbitalAmobarbital

o

~YlNH;;:A~oH

generalloonula of ba/biturates

Barbituric acid exists in solution as a mixture of several tautomeric forms: the ketoand enol forms (keto-enol tautomerism), and the lactim and lactam forms (not all theforms are given below):

tautomeric fonns of barbituric acid

12.5.3. Purine DerivativesPurine itself is not found in nature. Its two derivatives, adenine and guanine, repre-

sent purine components of nucleic acids in addition to three pyrimidine nucleic bases.

guanine

Purine and its derivatives are subjected to prototropic tautomerism caused by hy-drogen migration between the positions N-? and N-9.


'Ct"N cr~,l, I '), l" I ,)4 N g N

, H9H-purine 7H-purine

Crystalline purine is the 9Htautomer as well as adenine and guanine incorporatedinto nucleic acids. Lactim-Iactam tautomerism is possible for guanine.

Three hydroxylated purines are the products of nucleic acid metabolism. These areuric acid (2,6,8-trihydroXYPurine), the final metabolite, xanthine (2,6-dihydroXYPurine), andhypoxanthine (6-hydroxypurine), shown below in the most stable tautomeric forms:

o HH~N>=OoJ-N.JlN

H Huric acid

;;):)H

xanthine hypoxanthine

Water-insoluble uric acid as a relative strong acid (pK" 5.7, pK... 10.3) reacts withalkalis to form two series of salts called urates, for example:

'1~~)=O NaOH. H~~N">---ONa NaOH.o N N O""'N N

H H H Huric acid sodium urate

Qnsoluble)disodium urate

(soluble)

Insduble urates can be deposited in the joints and tendons as stones (or calculi)in some disorder in the human body.

Naturally occurring purine derivatives are N-methylated xanthines such as caffeine(present in coffee, tea, and cola beverages), theophylline (also present in coffee beansand tea leaves), and theobromine (found in cocoa):&c~ CH~ir) ~c~~~ I:) oA i)

I I Ic~ c~ C~

caffeine theophylline theobromine

Caffeine is known as a stimulator of the central nervous system; two other xan-thines are also used in medicine. All the three compounds are sometimes assigned toalkaloids.

12.6. Alkaloids

m Alkaloids are nitrogen-containing, mostly heterocyclic compounds that produce strik-ing physiological effects on animals.

184 Chapter 12

Effects of alkaloids vary greatly from one compound to another. The term alkaloidoriginates from the fact that these substances are "alkali-like", Le. they react with acidsto form soluble salts. Moreover, alkaloids are present in plants as salts with organicacids (oxalic, malic, citric, and others).

Common names are usually used for alkaloids because of the complexity of theirstructures. These names reflect often the botanical source of the substance. The alka-loid papaverine, for example, was isolated from the opium poppy, Papaver somniferum;the alkaloid cocaine - from Eryfhroxylon coca, etc. Sometimes the names of alkaloidsare eccentric: the name of the another opium alkaloid morphine came from Morpheus,the Greek god of dreams; the name of the tobacco alkaloid nicotine came from J. Nicot,a French diplomat who brought tobacco seeds to France in 1560. Names of most alka-loids have the ending -ine that shows the amine nature of the compounds.

Over five thousand alkaloids are known today. The old classification of alkaloidsused phylogenetic features, for example, tobacco alkaloids, coca alkaloids, and so on.The modern classification is based on the structure of a basic heterocyclic system thoughmore than one heterocycle may be present.

Only a few selected examples are considered in this section with minimal informa-tion on biological or pharmacological activity. Stereochemistry in all presented struc-tures is omitted for simplicity but it should be remembered that almost all alkaloids areoptically active compounds.

12.6.1. Pyridine Alkaloids

The major alkaloid of the tobacco leaves is nicotine, one of the simplest of all alka-loids, that contains besides the pyridine ring also the pyrrolidine ring. Its isomer anabasinefound in the Central Asian plant Anabasis aphylla L. contains the piperidine ring.

rJ?ljbH,nicotine

~1)l) ~.anabasine

The two alkaloids are toxic to humans (effect of nicotine is well-known). It is inter-esting that anabasine as a hydrochloride salt is advised as the aid for breaking the habitof smoking'. Both compounds are used as agricultural insecticides and as raw materialsfor producing nicotinic acid by oxidation (similarly to the reaction described in Section12.4.1).

12.6.2. Quinoline and Isoquinollne AlkaloidsQuinine is the most known and the oldest alkaloid of the quinoline group. It con-

tains an additional and unusual heterocyclic ring system - quinuclidine (non-coloured in

1 The author 01 this book attempted to apply it but unsuccessfully.

Biologically Active Heterocyclic Compounds

CH=CH"

quinine

185

the drawing). Quinine was isolated from cinchona bark in 1820 but the South Americannatives used a decoction of the bark for centuries before this. For many long yearsquinine was a single remedy for malaria.

The group 01 isoquinoline alkaloids amounts over to 1000 substances which arelocated in about thirty plant families. We will be concerned with only several most knownalkaloids of the opium poppy.

Morphine is the main component of opium and was first isolated from it in 1806. Itwas the first alkaloid obtained in a pure form, but its highly complicated structure wasdeduced only in 1925-1927 and finally confirmed by independent masterly synthesis in1952. Morphine remains one of the strongest analgesics though opium has been used inancient Egypt. Unfortunately, it has many disadvantages, and we will not discuss phar-macological and social aspects of morphine applications. The methyl ether of morphinecalled codeine is useful as an anticough agent. It is also isolated from opium and can beproduced by partial methylation of morphine.

ROO~_CH3HOXY'~morphine (R = H)codeine (R = CH,)

Papaverine mentioned above is a relatively simple isoquinoline derivative which isused as an antispasmodic medicine. A synthetic drug No-Spa (Orotaverine) has a simi-lar structure but more pronounced pharmacological effect.

papawtine

OCH3

OCH3No-Spa

12.6.3. Indole Alkaloids

Perhaps, this is the largest group of alkaloids. The indole ring is often condensedwith another cyclic or heterocyclic system as in the following examples where a tryptaminemoiety (see Section 12.3) is coloured:

186

CH:p

reserpine

Chapter 12

2xY'" I r COOHHN hICH:,

lysergic acid

Reserpine, the alkaloid of the Indian snake root, Rauwolfia serpentina, is used as asedative and hypotensive drug. Extracts of the plant have been applied in the Indiannative medicine for centuries.

Lysergic acid and its derivatives are present in the fungus ergot which grows onsome grains. Some of them find an application mainly in gynecology. However, the mostknown derivative of lysergic acid (but miserably known) is its synthetic diethylamide.called LSD 25, an extremely powerful hallucinogen.

12.6.4. Tropane Alkaloids

Tropane is a saturated bicyclic system that consists of the pyrrolidine and piperi-dine rings (the latter is coloured):

tropane and its most stable confonnation

The oldest and the most known alkaloid in this group is cocaine, the first localanesthetic. Its administration is now limited because of toxicity and other side effects.

cocaine

Atropine, the alkaloid of Atropa belladonna and other plants of Solanaceae family,is used in various spheres of medicine, particularly in ophthalmology to dilate the pupil ofthe eye.

Additional Problems

Problem 12.6. Arrange ammonia, pyrrole, qUinoline, and piperidine according to theincrease in their basicity. Explain the reason of your arrangement.

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chapter 12 - heterocyclic compounds

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