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Lecture 13

Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine.


Ass. Medvid I.I., ass. Burmas N.I.

Outline
1. Receipt of quinoline and his derivatives. Synthesis of Skraupa and synthesis of DebnerMiller. Physical and chemical properties of quinoline. 2. Receipt of isoquinoline. Synthesis of Bischler-Napieralski. Physical and chemical properties of isoquinoline. 3. Structure, nomenclature, methods of getting and physical and chemical properties of acridine. 4. Methods of getting of sixmember heterocyclic connections with two heteroatoms 5. Structure, classification, nomenclature, physical and chemical properties of pyridazine. 6. Structure, nomenclature, physical and chemical properties of pyrimidine. 7. Structure, nomenclature, physical and chemical properties of barbituric acid 8. Structure, nomenclature, physical and chemical properties of pyrazine. 9. Structure, nomenclature, physical and chemical properties of purine. 10. Structure, nomenclature, physical and chemical properties of uric acid.

11. Structure, nomenclature and properties of azepines. Benzazepine. 12. Structure, nomenclature and properties of diazepine. Benzodiazepine. 13. Oxazepam. Radedrol (nitrazepam). Seduxen (diazepam). 14.Classification of alkaloids. 15. Alkaloids group of pyridine and piperine (nicotine, anabasine, lobeline). 16. Alkaloids group of quinoline (quinine). 17. Alkaloids of group of quinoline and phenanthreneisoquinoline (papaverine, morphine, codeine). 18. Alkaloids group of purine (caffeine, theobromine, theophylline). 19. Alkaloids group of tropane (atropine, scopolamine, cocaine). 20. Alkaloids group of indole (reserpine, strychnine).

1. Obtaining of quinoline and his derivatives. Synthesis of Skraup and synthesis of DebnerMiller. Physical and chemical properties of quinoline.

The impotent condensed of sixmembered heterocycles connections are with one heteroatom is:

quinoline

isoquinoline

acridine

Quinoline, also known as 1-azanaphthalene, 1-benzazine, or benzo[b]pyridine, is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown.

Quinoline is only slightly soluble in cold water but dissolves readily in hot water and most organic solvents. Quinoline is mainly used as a building block to other specialty chemicals. Approximately 4 tonnes are produced annually according to a report published in 2005. Its principal use is as a precursor to 8-hydroxyquinoline, which is a versatile chelating agent and precursor to pesticides. Its 2- and 4-methyl derivatives are precursors to cyanine dyes. Oxidation of quinonline affords quinolinic acid (pyridine-2,3-dicarboxylic acid), a precursor to the herbicide sold under the name "Assert".

The Skraup synthesis is a chemical reaction used to synthesize quinolines. It is named after the Czech chemist Zdenko Hans Skraup (1850-1910). In the archetypal Skraup, aniline is heated with sulphuric acid, glycerol, and an oxidizing agent, like nitrobenzene to yield quinoline. The Skraup synthesis place is taken in three stages.

On the first stage glycerin is under the action of oncentrated H2S04 to dehydration with formation of akrolein:

On the second stage appearing akrolein enters into the reaction of condensation with an aniline:

-H2O

On the third stage of reaction of 1,2dihydroquinoline oxidizes nitrobenzol in to quinoline:

Synthesis of Debner Miller. The reaction is opened in 1881. On the first stage there is krothonic condensation of two molecules of aldehyde .

Further there is cooperation of krothonic aldehyde with aniline.

2-methyl-1,2-dihydroquinoline

2-methyl-quinoline

Chemical properties:

1. Reactions of heteroatom.
quinoline chloride

N-methylquinoline iodide

N-acethylquinoline chloride

2. Reactions of electrophilic and nukleophilic substitutions . Reactions of electrophilic substitution in the molecula of quinoline is entered in position of 5 and 8.

6- quinoline sulphatic acid

Reactions of nukleophilic substitution (is entered in position of 2) .

2- aminoquinoline

2- hydroxyquinoline

3. Reactions of reduction and oxidization.

quinolinic acid

Derivatives of quinoline 8-Hydroxyquinoline is an organic compound with the formula C9H7NO. It is a derivative of the heterocycle quinoline by placement of an OH group on carbon number 8. This colorless compound is widely used commercially, although under a variety of names. It is usually prepared from quinoline-8-sulfonic acid and from the Skraup synthesis from 2-aminophenol.

NaOH

-Na2SO3

8-Hydroxyquinoline is a monoprotic bidentate chelating agent. Related ligands are the Schiff bases derived from salicylaldehyde, such as salicylaldoxime and salen. The roots of the invasive plant Centaurea diffusa release 8-hydroxyquinoline, which has a negative effect on plants that have not co-evolved with it. The complexes as well as the heterocycle itself exhibit antiseptic, disinfectant, and pesticide properties. Its solution in alcohol are used as liquid bandages. It once was of interest as an anti-cancer drug.

[H]
NO 2 OH

O CH 2=CH-C NH 2 OH H

OH
H2SO4

2-

N
OH OH

N
H

SO4

quinozol

2. Receipt of isoquinoline. Synthesis of Bischler-Napieralski. Physical and chemical properties of isoquinoline. Isoquinoline, also known as benzo[c]pyridine or 2-benzanine, is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline derivatives. 1-Benzylisoquinoline is the structural backbone in naturally occurring alkaloids including papaverine and morphine. The isoquinoline ring in these natural compound derives from the aromatic amino acid tyrosine. Isoquinoline is a colourless hygroscopic liquid at room temperature with a penetrating, unpleasant odour. Impure samples can appear brownish, as is typical for nitrogen heterocycles. It crystallizes platelets that have a low solubility in water but dissolve well in ethanol, acetone, diethyl ether, carbon disulfide, and other common organic solvents. It is also soluble in dilute acids as the protonated derivative.

In the Bischler-Napieralski reaction an -phenylethylamine is acylated and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or phosphorus pentoxide. The resulting 1-substituted-3,4-dihydroisoquinoline can then be dehydrogenated using palladium. The following BischlerNapieralski reaction produces papaverine.

1-substituted-3,4dihydroisoquinoline

1-substituted isoquinoline

Chemical properties:
1. Reactions of electrophilic and nukleophilic substitutions . Reactions of electrophilic substitution in the molecula of isoquinoline is entered in position of 5 and 8. Reactions of nukleophilic substitutions tare place in position of 1.

isoquinoline of chloride

N-methylisoquinoline of iodide

2. Reaction of reduction

1,2,3,4tetrahydroisoquinoline

3. Reaction of oxidization

3,4- pyridinedicarbonic acid

3. Structure, nomenclature, methods of getting and physical

and chemical properties of acridine. Acridine was first isolated in 1871 by Carl Grbe and Heinrich Caro. Acridine occurs naturally in coal tar. It is separated from coal tar by extracting with dilute sulfuric acid; addition of potassium dichromate to this solution precipitates acridine bichromate. The bichromate is decomposed using ammonia. Many synthetic processes are known for the production of acridine and its derivatives. A. Bernthsen condensed diphenylamine with carboxylic acids, in the presence of zinc chloride in the Bernthsen acridine synthesis. With formic acid as the carboxylic acid the reaction yields acridine it self, and with the higher homologues the derivatives substituted at the meso carbon atom are generated. Other older methods for the organic synthesis of acridines include condensing diphenylamine with chloroform in the presence of aluminium chloride, by passing the vapours of orthoaminodiphenylmethane over heated litharge, by heating salicylic aldehyde with aniline and zinc chloride to 260 C or by distilling acridone (9-position a carbonyl group) over zinc dust.

A general method for acridine synthesis is the cyclisation of N-phenylanthranilic acid or 2(phenylamino)benzoic acid with phosphoric acid. A classic method for the synthesis of acridones is the Lehmstedt-Tanasescu reaction. Acridine and its homologues are stable compounds of weakly basic character.It also shares properties with quinoline which is the single fused homologue. Acridine crystallizes in needles which melt at 110 C. It is characterized by its irritating action on the skin, and by the blue fluorescence shown by solutions of its salts.

Methods of getting:
1. Condensation of diphenylamine with carbonic acids :

diphenylamine

acridine

2. Cyclization N-fenilanthranilic acid on the reaction of DrozdovMahidsonHrihorovsky:

N-fenilanthranilic acid

anhidride chloride N-fenilanthranilic acid

acridone-9

acridole-9

9-chloracridine

9,10-dihydroacridine

acridine

Chemical properties:

Acridine combines readily with alkyliodides to form alkyl acridinium iodides, which are readily transformed by the action of alkaline potassium ferricyanide to N-alkyl acridones. On oxidation with potassium permanganate it yields acridinic acid C9H5N(COOH)2 or quinoline-1,2-dicarboxylic acid. Acridine is easily oxidized by peroxymonosulfuric acid to the acridine amine oxide. The carbon 9-position of acridine is activated for addition reactions. The compound is reduced to the 9,10-dehydroacridine and reaction with potassium cyanide gives the 9-cyano-9,10dehydro derivative. Numerous derivatives of acridine are known and may be prepared by methods analogous to those used for the formation of the parent base. 9-Phenylacridine is the parent base of chrysaniline or 3,6-diamino-9-phenylacridine, which is the chief constituent of the dyestuff phosphine (not to be confused with phosphine gas), a by-product in the manufacture of rosaniline. Chrysaniline forms red-coloured salts, which dye silk and wool a fine yellow; and the solutions of the salts are characterized by their fine yellowish-green fluorescence. Chrysaniline was synthesized by O. Fischer and G. Koerner by condensing orthonitrobenzaldehyde with aniline, the resulting ortho-nitro-paradiamino-triphenylmethane being reduced to the corresponding orthoamino compound, which on oxidation yields chrysaniline.

1.

Reactions of heteroatom.
acridinium chloride

N-oxide of acridine

N-methylacridine iodide

2. Reactions of electrophilic and nukleophilic substitutions .

9-hydroxacridine, acridole-9

9- oxoacridine, acridone-9

3. Reactions of oxidization.

acridinic acid

4. Reactions of reduction.

9,10-dehydroacridine, acridane

Derivatives of acridine
9- Aminoacridine is an antiseptic and disinfectant .

Acidylating flows on aminogroup:

9-N-acethylaminoacridine

9-aminoacridine chloride

arcihine

rivanol

medicinal preparations

COOH O2N Cl

OC2H5 H2N
O

COOH O2N NH

OC2H5

OH OC2H5 -HCl O2 N N
OC2H5 POCl3

POCl3 O2 N

C NH

Cl
OC2H5

NH2 NH3 -HCl O2N N


OC2H5

[H]

O2N

9-amino-2-ethoxy-6-nitroacridine

NH2
OC2H5

COOH HC OH CH3

+ H2N N NH2
OC2H5

COOH HC OH CH3

H2N

ethacridine lactate, rivanol, 6,9 diamimo-2-ethoxyacridine lactate

Sixmembered heterocycles connections are with two heteroatoms


In addition to these three diazines, the bicyclic tetraaza compound, purine, is an important heterocyclic system.

These ring systems, particularly that of pyrimidine, occur commonly in natural products. The pyrimidines, cytosine, thymine, and uracil are especially important because they are components of nucleic acids, as are the purine derivatives adenine and guanine.

The inin nucleus also occurs in such compounds as caffeine (coffee and tea) and theobromine (cacao beans).

4. Methods of getting of sixmember heterocyclic connections with two heteroatoms

CH
HC
maleinaldehide
O

C O O

NH 2 NH 2 - H 2O
O H C N H

N
pyridazine
OH N HO N OH

C CH
2

OC H
2

H N
2

C H ONa
2 5

H O

N O

+ OC H
2 5

C H N
2

O
- C 2H 5O H

C O

Malene ephir

uric

barbituric acid

Cl
PO C l 3 Cl N

N
Cl

6H (Zn)
N
pyrimidine

These method use for obtaining pyridazine and his derivatives

NH2 CH2 CH2 NH2


ethylendiamine

O C + C O

H to - 2 H2 O H
hlioxal

N N

O - H2 O

N N
pyrazine

2,3- dihydropyrazine

N N

NH2 + NH2

O C H HO N - 2 H2O N

N N H
purine

5. Structure, classification, nomenclature, physical and chemical properties of pyridazine.

Pyridazine is a heteroaromatic organic compound with the molecular formulaC4H4N2, sometimes called 1,2-diazine. It contains a six-membered ring with two adjacent nitrogen atoms. It is a colorless liquid with a boiling point of 208 C. Pyridazine has no household use. It is mainly used in research and industry as building block for more complex compounds. The pyridazine structure is found within a number of herbicides such as credazine, pyridafol and pyridate. It is also found within the structure of several pharmaceutical drugs such as cefozopran, cadralazine, minaprine, hydralazine, and cilazapril.

Pyridazine

Other names

1,2-diazine, orthodiazine, oizine Properties

Molecular formula Molar mass Appearance Density Melting point Boiling point

C4H4N2 80.09 g mol1 colorless liquid 1.107 g/cm3 -8C 208C

I-

CH3I N N

HCl ( .) N N
+

ClH

CH3

N-methulpyridazine iodide

CH3COOOH

Pyridazine chloride

N _ N O

N-oxide pyridazine

thethramethyleldiamine

Derivatives of pyridazine

6. Structure, nomenclature, physical and chemical properties of pyrimidine. Three nucleobases found in nucleic acids (cytosine, thymine, and uracil) are pyrimidine derivatives: In DNA and RNA, these bases form hydrogen bonds with their complementary purines. Thus the purines adenine (A) and guanine (G) pair up with the pyrimidines thymine (T) and cytosine (C), respectively.

Pyrimidine

Properties Molecular formula Molar mass Melting point Boiling point C4H4N2 80.088 2022 C 123124 C

Chemical properties
A pyrimidine has many properties in common with pyridine, as the number of nitrogen atoms in the ring increases the ring pi electrons become less energetic and electrophilic aromatic substitution gets more difficult while nucleophilic aromatic substitution gets easier. An example of the last reaction type is the displacement of the amino group in 2-aminopyrimidine by chlorine and its reverse. Reduction in resonance stabilization of pyrimidines may lead to addition and ring cleavage reactions rather than substitutions. One such manifestation is observed in the Dimroth rearrangement. Compared to pyridine, N-alkylation and N-oxidation is more difficult, and pyrimidines are also less basic.

N N

HCl

N N

H
_

NH2 N HO N . HNO3 . H2SO4 HO N

NH2 NO2 N N
2- aminopyridine N

Cl
pyrimidine chloride

4-amino-2-hydroxypyridine

N N NH2

Br2

Br N

N NH2 N

N NaNH2

N N NH2

Derivatives of pyrimidine
Barbituric acid (2,4,6-trihydroxypyrimidine)

Keto-enole and lactam-lactim tautomery

7. Structure, nomenclature, physical and chemical properties of barbituric acid.

Barbituric acid or malonylurea or 4hydroxyuracil is an organic compound based on a pyrimidine heterocyclic skeleton. It is an odorless powder soluble in hot water. Barbituric acid is the parent compound of a large class of barbiturates that have central nervous system depressant properties, although barbituric acid itself is not pharmacologically active.
The compound was discovered by the German chemist Adolf von Baeyer on 4. December 1864the feast of St Barbara and therefore the name given to the compoundby combining urea and malonic acid in a condensation reaction. Malonic acid has since been replaced by diethyl malonate.

Bases of pyrimidine (important derivatives )

These bases are present in nucleinic acids

Vitamin B1 (thiamine) contain pyrimidine and thyazole ring connect through methyl group.

Physiological active form of vitamin B1 in living organisms is cocarboxilaza, which take part in enzyme processes, in hydrocarbon exchange

Orotic acid is primary compound in biosynthesis of pyrimidine bases

8. Structure, nomenclature, physical and chemical properties of pyrazine.


Pyrazine is a heterocyclic aromatic organic compound. It is found in folic acid in the form of pterin. Derivatives like Phenazine are well known for their antitumor, antibiotic and diuretic activity. Pyrazine is less basic in nature than pyridine, pyridazine and pyrimidine. Tetramethylpyrazine (also known as ligustrazine) is reported to scavenge superoxide anion and decrease nitric oxide production in human polymorphonuclear leukocytes. Tetramethylpyrazine is also a component of some herbs in Traditional Chinese Medicine.

Pyrazine

Other names

1,4-Diazabenzene, p-Diazine, 1,4Diazine, Paradiazine, Piazine, UN 1325 Properties

Molecular formula

C4H4N2

Molar mass Appearance


Density Melting point Boiling point Solubility in water

80.09 g/mol White crystals


1.031 g/cm3 52 C 115 C Soluble

Synthesis of pyrazine

Many methods exist for the organic synthesis of pyrazine and derivatives and some of them very old. Staedel-Rugheimer pyrazine synthesis (1876) is the condensation of 1,2-diamine with 1,2-dicarbonil compounds and then oxidation to a pyrazine. A variation is the Gutknecht Pyrazine Synthesis (1879) also based on this selfcondensation but differing in the way that alpha-ketoamine is synthesised (the chlorine compound in the above method is a lachrymatory agent).

The Gastaldi synthesis (1921) is another variation:

Chemical properties of pyrazine


N N H (Na + CH3 CH2 OH) H N

pyperazine
N H

N N

NaNH2, NH3

N
2-aminopyrazine

N
N

NH2
+

N N

CH3COOOH

N _ O

N- oxide pyrazine

9. Structure,

nomenclature, physical and chemical properties of purine.

Purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature. Purines and pyrimidines make up the two groups of nitrogenous bases, including the two groups of nucleotide bases. Notable purines

Purine

Properties Molecular formula C5H4N4 Molar mass Melting point 120.112 214 C

History The name 'purine' (purum uricum) was coined by the German chemist Emil Fischer in 1884. He synthesized it for the first time in 1899. Laboratory synthesis In addition to in vivo synthesis of purines in purine metabolism, purine can also be created artificially. Purine (1) is obtained in good yield when formamide is heated in an open vessel at 170 oC for 28 hours. Procedure: Formamide (45 gram) was heated in an open vessel with a condenser for 28 hours in an oil bath at 170-190 oC. After removing excess formamide (32.1 gram) by vacuum distillation, the residue was refluxed with methanol. The methanol solvent was filtered, the solvent removed from the filtrate by vacuum distillation, and almost pure purine obtained; yield 4.93 gram (71 % yield from formamide consumed). Crystallization from acetone afforded purine as colorless crystals; melting point 218 oC.

Synthesis of purine
Traube method: condnsation 4,5diaminopyrimidines with carbonic acids

The Traube purine synthesis (1900) is a classic reaction (named after Wilhelm Traube) between an amine substutited pyrimidine and formic acid

Chemical properties of purine.


For purine is characteristic of azole tautomery

:
NH
2

Cl
N Cl N Cl NH (1:1)
3

NH N Cl N

N N

N NH

Cl
NH

NH
KOH

adenine
OH
OH N Cl N NH H H 2N N N N NH NH Cl (1:1)
3

OH N Cl N N N H 2N

NH
H

guanine
HNO
2

O HN N N N H O HN

O N N H N H

hypoxanthine

xanthine

Purine is an amphoteric compound

Derivatives of purine

Main derivatives of purine are oxopurines:

Uric acid is colorless crystal compound, bad soluble in water, ethanol and ether, soluble in dilute base solutions and glycerin. Uric acid is dibases acid.

Thauthomeric forms
O HN O N H H N O OH N HO N OH

N H

N H

uric acid
O HN O N H N N H HO N N OH N N H

xanthine O HN N N N N H N OH N N H

hypoxanthine

10. Structure, nomenclature, physical and chemical properties of uric acid.

Uric acid (or urate) is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C5H4N4O3. Uric acid is produced by xanthine oxidase from xanthine and hypoxanthine, which in turn are produced from purine. Uric acid is more toxic to tissues than either xanthine or hypoxanthine. In humans and higher primates, uric acid is the final oxidation (breakdown) product of purine metabolism and is excreted in urine. In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin. The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid. Both uric acid and ascorbic acid are strong reducing agents (electron donors) and potent antioxidants. In humans, over half the antioxidant capacity of blood plasma comes from uric acid.

Salts of uric acid called urats. Urats is bad soluble in water, except salts with litium (Li). In hydroxyform uric acid gives reactions of nucleophilic substitutions.

Chemical properties
O H O N N H H N O N H O 2NaOH
+

H N
_

H N N H

_ +

ONa N

NaO

OH N HO N N OH N H
POCl3

disodium salt of uric acid


Cl

Cl N Cl N N NH

2,6,8-threechlorpurine

Reactions of oxidation

aloxane

urea

alantoine

Murexidnes reaction is the qualitative reaction on uric acid

By heating uric acid with nitrate acid and next adding of ammonium observe purpur-violet color

purpure acid (enole form)

murexide

Reactions of reduction

xanthine

Hypoxantine

and xantine have the same chemical properties as uric acid

N-methyl derivatives of hypoxantine and xantine widely used in pharmacy

Aminopurines
Maine

aminoderivatives of purine adenine and guanine present in nucleinic acids as purines bases.

Sources of uric acid


In many instances, people have elevated uric acid levels for hereditary reasons. Diet may also be a factor. Purines are found in high amounts in animal internal organ food products, such as liver. A moderate amount of purine is also contained in beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran and wheat germ. Examples of high purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy. Moderate intake of purine-containing food is not associated with an increased risk of gout. Serum uric acid can be elevated due to high fructose intake , reduced excretion by the kidneys, and or high intake of dietary purine. Added fructose can be found in processed foods and soda beverages as sucrose, or in some countries, as high fructose corn syrup.

Phenothiazine

Phenothiazine (dibenzo-1,4-thiazine) colorless crystal compound, insoluble in water, diethyl ether, well soluble in hat ethanol.

Method of getting

Chemical properties 1. Alkylation and acylation

2. Oxidation

3. Reaction of electrophilic sybstitution go in location 3 and 7 with oxidation of sulphur


Derivatives of phenothiazine

Pteridine (pyrazino[2,3-d]pyrimidine)
Method of getting: condensation of 4,5diaminopyrimidins with 1,2-dicarbonile compounds

Pteridine is light yellow crystal compound, soluble in water, ethanol, less soluble in diethyl ether and benzole. Pteridine is stable to oxidation, by acting of acids and bases pteridine cycle decompose. Gives reaction of electrophilic substitution, protonate on nitrogen atom in 1 location.

Derivatives of pteridine
Folic

acid (vitamin Bc)

Aloxasine and isoaloxasine


These

compounds include benzyl, pyrazine and hydrate pyriidine cycles

Flavine is a primery compound of riboflavin:

11. Structure, nomenclature and properties of azepines. Benzazepine. Sevenmember heterocyclic ring compounds have received much attention in the past few years owing to its wide range of biological activity.

Azepines are heterocycles of seven atoms, with a nitrogen replacing a carbon at one position.

A well known azepine is caprolactam


Skeletal

formula of caprolactam.

Sevenmember heterocycles which containing nitrogen

Benzazepine: bicyclic structure consisting of fused benzene and azepine rings; many compounds with this structure react with biogenicamine receptors, and so are psychotropic and neurotropic. Examples of benzazepine include fenoldopam and galantamine. fenoldopam galantamine

12. Structure, nomenclature and properties of diazepine. Benzodiazepine.


Diazepine is a sevenmember heterocyclic compound with two nitrogen atoms (e.g., in ring positions 1 and 2) and three double bonds. When diazepine combined with a benzene ring, these is the basis of the benzodiazepine family . In these compounds the nitrogen atoms are at the 1 and 4 positions as, for example, in clobazam (depending on the position of the fused benzene ring, the nitrogen atoms are also in positions number 1 and 4).

5-Phenyl-1,3-dihydro-2H-1,4benzodiazepin-2-on forms the skeleton on many of the most common benzodiazepine pharmaceuticals, such as diazepam (chloro-substituted).

The benzodiazepines are a class of psychoactive drugs with varying hypnotic, sedative, anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic properties, which are mediated by slowing down the central nervous system. Benzodiazepines are useful in treating anxiety, insomnia, agitation, seizures, and muscle spasms, as well as alcohol withdrawal. They can also be used before certain medical procedures such as endoscopies or dental work where tension and anxiety are present, and prior to some unpleasant medical procedures in order to induce sedation and amnesia for the procedure. Benzodiazepines are also used to treat the panic that can be caused by hallucinogen intoxication. Benzodiazepines can cause a physical dependence and a benzodiazepine addiction to develop and upon cessation of long term use a benzodiazepine withdrawal syndrome can occur.

Benzodiazepine receptors also appear in a number of non nervous-system tissues and are mainly of the peripheral benzodiazepine receptor (PBRs) type. These receptors are found in various tissues such as heart, liver, adrenal, and testis. In lymphatic tissues, they modulate apoptosis of thymocytes via reduction of mitochondrial transmembrane potential. PBRs have many other actions on immune cells including modulation of oxidative bursts by neutrophils and macrophages, and inhibition of macrophage secretion of cytokines inhibition of the proliferation of lymphoid cells and secretion of cytokines by macrophages.

13. Oxazepam. Radedrol (nitrazepam). Seduxen O (diazepam).


N Cl

Oxazepam (marketed in English speaking N countries under the following brand names Alepam, Medopam, Murelax, Noripam, Ox-Pam, Purata, Serax and Serepax), is a drug which is a benzodiazepine derivative. Oxazepam Oxazepam has moderate amnesic, anxiolytic, anticonvulsant, hypnotic, 7-clorine-3-hydroxysedative and skeletal muscle relaxant 5-phenil-1,3-dihydro2H-1,4-benzodiazepin-2-on properties compared to other benzodiazepines.
OH

Oxazepam is an intermediate acting benzodiazepine. Oxazepam acts as inhibitor on the central nervous system. The halflife of oxazepam is 4-15 hours. Oxazepam has been shown to suppress cortisol levels.

Oxazepam is an active metabolite formed during the breakdown of diazepam, nordazepam, and certain similar drugs. Oxazepam may be safer than many other benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, but rather it is simply metabolized via glucuronidation. Such means as oxazepam is less likely to accumulate and cause adverse reactions in the elderly or people with liver disease. Oxazepam is similar to lorazepam in this respect. There is preferential storage of oxazepam in some organs including the heart of the neonate. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate and it is recommended to withdraw oxazepam during pregnancy and breast feeding as oxazepam is excreted in breast milk.

H
N

O 2N

Nitrazepam is a nitrobenzodiazepine It is a 1,4 benzodiazepine, with the chemical name 7-nitro-5-phenyl-1,3dihydro-2H-1,4- benzodiazepin-2-on.
Nitrazepam is a type of benzodiazepine drug and is marketed in English speaking countries under the following brand names Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm, Remnos and Somnite.

Nitrazepam

It is a hypnotic drug with sedative and motor impairing properties, anxiolytic, anticonvulsant and skeletal muscle relaxant properties. It is long acting drug, has lipophilic and hepatometabolitic properties via oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors (gammaaminobutyric acid). GABA is a major inhibitor neurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation and control of anxiety and seizures, and slows down the central nervous system.

In sleep laboratory studies, nitrazepam decreased sleep onset latency. In psychogeriatric in-patients nitrazepam was found to be no more effective than placebo tablets in increasing total time spent asleep. Nitrazepam is most often used to treat shortterm sleeping problems (insomnia), namely difficulty falling asleep, frequent awakening, early awakenings or a combination of theme. Nitrazepam is long acting and is sometimes used in patients who have difficulty in maintaining sleep. Nitrazepam shortens the time required to fall asleep and lengthens the duration of sleep. It is also useful for the treatment of myoclonic seizures and has been used in the treating of seizure disorders in children and also for infantile spasms .

H 3C
N

Cl

(4N-oxide 7-chlorine-1-methyl-

diazepam

Diazepam first marketed as Valium by Hoffmann-La Roche, is a benzodiazepine derivative drug. It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant and amnestic properties. It is commonly used for treating anxiety, insomnia, seizures, muscle spasms, alcohol withdrawal and benzodiazepine withdrawal.

5-phenil-1,3-dihydro-21,4-benzodiazepin-2-ne )

Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1:16 in ethyl alcohol, 1:2 in chloroform, 1:39 in ether, and practically insoluble in water.

The pH of diazepam is neutral (i.e., pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution. Diazepam should be stored at room temperature (1530C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in airtight containers and protected from light. If diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.

Qualitative reactions on benzodiazepines


1. With concentrated acids (H2SO4, HCl, HClO4)
derivatives of benzodiazepines form color salts. 2. Heterocyclic nitrogen atom gives positive reaction with common alkaloids precipitate reagents. 3. Specific reaction on benzodiazepines derivatives is formation of green color after pyrolisis. 4. Formation of azodays after primary hydrolysis:

Nozepam

5. Belshteine probe use for determination of halogens. 6. Noozepam by heating with conc. H2SO4 hydrolyzed with formation of formaldehyde, which forms violet color with fuxinsulfite acid.

14.Classification of alkaloids.
Alkaloids are naturally occurring chemical compounds containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of the group of natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have pharmacological effects and use as medications and recreational drugs. Examples are the local anesthetic and stimulant cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or the antimalarial drug quinine. Some alkaloids have a bitter taste. Alkaloids are usually classified by their common molecular precursors, based on the metabolic pathway used to construct the molecule. When not much was known about the biosynthesis of alkaloids, they were grouped under the names of known compounds, even some non-nitrogenous ones (since those molecules' structures appear in the finished product; the opium alkaloids are sometimes called "phenanthrenes", for example), or by the plants or animals they were isolated from. When more is learned about a certain alkaloid, the grouping is changed to reflect the new knowledge, usually taking the name of a biologically-important amine that stands out in the synthesis process.

Methods of extraction
1.

2.

Extraction as salts: to raw material add water or ethanol with few drops of tartaric acid. All alkaloids forms salts with tartaric acid. For purification to this extract add base and all alkaloids form bases, which obtained by organic solutions. Operation of purification repeat few times. Then solvent separated from alkaloids. Sum of alkaloids is separated on individual compounds. Extraction as bases: to raw material add alkali solution (ammonium, sodium hydrocarbonate or carbonate). Alkaloids bases are extracted by organic solutions. Purification realize by transferring alkaloids to salts and then to bases. Operation of purification repeat few times.

Common precipitate reagents on alkaloids

1.Lyugol, Vagner, Bushard reagents (I2 in KI in different concentraions). 2. Dragendorph reagent (K[BiI4]). 3. Maier reagent (K2[HgI4]). 4. Marme reagent (CdI3 in KI). 5. Zonnenshten reagent (H3PO412MoO32H2O). 6. Sheibler reagent (H3PO412WO32H2O). 7. Berthran reagent (SiO212WO32H2O). 8. 5% Tannin solution. 9. Saturated solution of picric acid.

Special reagents on alkaloids

1. Conc. H2SO4. 2. Conc. HNO3. 3. Erdman reagent (H2SO4 conc.+HNO3 conc.). 4. Phrede reagent ((NH4)2MoO4+H2SO4 conc.). 5. Marki reagent (HCOH+H2SO4 conc.). 6. Mandelin reagent (NH4VO3+H2SO4 conc.). 7. Sodium nithroprusid (Na2[Fe(CN5)No]2H2O).

Pyridine and piperidine group: piperine, coniine, trigonelline, arecoline, arecaidine, guvacine, cytisine, lobeline, nicotine, anabasine, sparteine, pelletierine.
N N H

Pyrrolidine and pyrolisidine group: hygrine, cuscohygrine, platyphylline, nicotine.


N N H

Tropane group: atropine, cocaine, ecgonine, scopolamine, catuabine.


N CH 3

Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine, brucine, veratrine, cevadine.

Isoquinoline group: opium alkaloids (papaverine, narcotine, narceine), sanguinarine, hydrastine, berberine, emetine, berbamine, oxyacanthine.
N

Phenanthrene alkaloids: opium alkaloids (morphine, codeine, thebaine) Phenethylamine group: mescaline, ephedrine, dopamine Indole group:
N H

Tryptamines: serotonin, bufotenine, psilocybin Ergolines (the ergot alkaloids): ergine, ergotamine, lysergic acid Beta-carbolines: harmine, harmaline, tetrahydroharmine Yohimbans: reserpine, yohimbine Vinca alkaloids: vinblastine, vincristine Kratom (Mitragyna speciosa) alkaloids: mitragynine, 7hydroxymitragynine Tabernanthe iboga alkaloids: ibogaine, voacangine, coronaridine Strychnos nux-vomica alkaloids: strychnine, brucine Purine group: N N H

Xanthines: caffeine, theobromine, theophylline

15. Alkaloids group of pyridine and piperine (nicotine, anabasine, lobeline).


Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae) which constitutes approximately 0.63.0% of dry weight of tobacco, with biosynthesis taking place in the roots, and accumulating in the leaves.

CH3
Systematic (IUPAC) name

3-[2-(N-methylpyrrolidil)]pyridine

It functions as an antiherbivore chemical with particular specificity to insects; therefore nicotine was widely used as an insecticide in the past, and currently nicotine analogs such as imidacloprid continue to be widely used.

Chemistry
Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Nicotine easily penetrates the skin. As shown by the physical data, free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at 308 K (35 C; 95 F) in air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects. The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves.

Pharmacology Pharmacokinetics As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier. On average it takes about seven seconds for the substance to reach the brain when inhaled. The half life of nicotine in the body is around two hours. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco and snuff, which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco. Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.

Pharmacodynamics Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS nicotinic receptor. In small concentrations, nicotine increases the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters through less direct mechanisms. In adrenal medulla By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels.

Anabasine is a pyridine alkaloid found in the Tree Tobacco (Nicotiana glauca) plant, a close relative of the common tobacco plant (Nicotiana tabacum). It is similar to nicotine. Its principal (historical) industrial use is as an insecticide. Anabasine is present in trace amounts in tobacco smoke, and can be used as an indicator of a person's exposure to tobacco smoke.

-(-pyperidile)pyridine

Pharmacology Anabasine is a nicotinic acetylcholine receptor agonist. In high doses, it produces a depolarizing block of nerve transmission, which can cause symptoms similar to those of nicotine poisoning and, ultimately, death by asystole. In larger amounts it is thought to be teratogenic in swine.

Lobeline is a natural alkaloid found in "Indian tobacco" (Lobelia inflata), "Devil's tobacco" (Lobelia tupa), "cardinal flower" (Lobelia cardinalis), "great lobelia" (Lobelia siphilitica), and Hippobroma CH3 longiflora. In its pure form it is a white amorphous powder which is freely Systematic (IUPAC) name soluble in water. Lobeline has been used L-(-)-2benzoilmethyle-6-(2-hydroxy- as a smoking cessation aid, and may 2-phenylethyl)-1-methylpyperidine have application in the treatment of other drug addictions such as addiction to amphetamines or cocaine.

Lobeline has multiple mechanisms of action, acting as a VMAT2 ligand, which stimulates dopamine release to a moderate extent when administered alone, but reduces the dopamine release caused by methamphetamine.

16. Alkaloids group of quinoline (quinine).


Quinine Systematic (IUPAC) name (R)-(6methoxyquinolin-4-yl)- (8vinylquinuclidin-2-yl)methanol

Quinine is a natural white crystalline alkaloid having antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine. Quinine was the first effective treatment for malaria caused by Plasmodium falciparum, appearing in therapeutics in the 17th century. Since then, many effective antimalarials have been introduced, although quinine is still used to treat the disease in certain critical situations. Quinine is available with a prescription in the United States. Quinine is also used to treat nocturnal leg cramps and arthritis.
Chemical structure Quinine contains two major fused-ring systems: The aromatic quinoline and the bicyclic quinuclidine .

Qualitative reaction on quinine


Thaleyoquine test: emerald-green color

with conc. H2SO4 blue fluorescence; with sodium nitroprusside - yellow sediment.

Because of its relatively constant and well-known fluorescence quantum yield, quinine is also used in photochemistry as a common fluorescence standard. Quinine (and quinidine) are used as the chiral moiety for the ligands used in Sharpless asymmetric dihydroxylation. Quinine is sometimes added to the recreational drugs cocaine, heroin and others in order to "cut" the product and make more profit.

17. Alkaloids of group of quinoline and phenanthreneisoquinoline (papaverine, morphine, codeine).

Papaverine is an opium alkaloid used primarily in the treatment of visceral spasm, vasospasm (especially those involving the heart and the brain), and occasionally in the treatment of erectile dysfunction. While it is found in the opium poppy, papaverine differs in both structure and pharmacological action from the other opium alkaloids (opiates).
Papaverine Systematic (IUPAC) name

1-(3,4-dimethoxybenzyl)6,7-dimethoxyisoquinoline

Qualitative reactions on papaverine


1. With conc. H2SO4 by heating violet color after heating. 2. With conc. HNO3 yellow color, that after heating becomes orange.

H3CO

H3CO

H3CO

N H3CO CH2 HNO3 H3CO CH2

N HNO3 t C
0

N H3CO O2N CH2

NO2

NO2

H3CO

OCH3

H3CO

OCH3

H3CO

OCH3

3. With bromine water yellow precipitate.

Yellow

Orange

4. With Erdman reagent (H2SO4 conc.+HNO3 conc.) red color. 5. With Phrede reagent ((NH4)2MoO4+H2SO4 conc.) violet color after heating. 6. With Mandelin reagent (NH4VO3+H2SO4 conc.) blue-green color becomes blue.

7. With Marci reagent (HCOH+H2SO4 conc.) at first forms red color, then yellow and at the end orange. By adding bromine water and ammonium appears violet precipitate, which dissolves in alcohols.

H3CO

OCH3

OCH3

OCH3

H3CO

C H2 C H2 C H2

OCH3
2OCH3 SO4

H3CO

N+ H

N+ H

Uses Papaverine is approved to treat spasms of the gastrointestinal tract, bile ducts and ureter and for use as a cerebral and coronary vasodilator in subarachnoid hemorrhage (combined with balloon angioplasty) and coronary artery bypass surgery. Papaverine may also be used as a smooth muscle relaxant in microsurgery where it is applied directly to blood vessels. It is also commonly used in cryopreservation of blood vessels along with the other glycosaminoglycans and protein suspensions. Functions as a vasodilator during cryopreservation when used in conjunction with verapamil, phentolamine, nifedipine, tolazoline or nitroprusside.

Systematic (IUPAC) name 3,6-dihydroxy-N-methyl- 4,5epoxymorphinene-7

Morphine is a highly potent opiate analgesic drug, is the principal active agent in opium, and is considered to be the prototypical opioid. Morphine was in 1803 the first alkaloid isolated from a plant source. Like other opioids, e.g. oxycodone, hydromorphone, and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain, particularly at the synapses of the nucleus accumbens. Morphine has a high potential for addiction; tolerance and both physical and psychological dependence develop rapidly.

Chemistry Chemical structure of morphine in correct 3D configuration. The benzylisoquinoline backbone is shown in blue. Morphine is a benzylisoquinoline alkaloid with two additional ring closures. Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (diacetylmorphine), hydromorphone, and oxymorphone. Replacement of the N-methyl group of morphine with an N-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency.

Morphinene

Qualitative reactions on morphine


1. With Marci reagent purpur color quickly becomes blue-violet (distinctive reaction between morphine and codeine). 2. With ammonium white crystal precipitate dissolves in NaOH. 3. With Phrede reagent at first forms violet color, that changes to blue and by standing to green. 4. With FeCl3 blue color. 6. Oxidation reaction with K3[Fe(CN)6] and FeCl3 blue color:

7. With Mandelin reagent violet color.

8. With Erdmane reagent intense red color:

9. With conc. HNO3 red-orange complex compound:

10. With diazonium salts azoday (red color).

Obtaining derivatives of morphine

Both morphine and its hydrated form are sparingly soluble in water. In five litters of water, only one gram of the hydrate will dissolve. For this reason, pharmaceutical companies produce sulphate and hydrochloride salts of the drug, both of which are over 300 times more watersoluble than their parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, the morphine salts are mixed with small amounts of NaOH to make them suitable for injection. A number of salts of morphine are used, and the opioids Morphine-NOxide (Genomorphine) which is a pharmaceutical which is no longer in common use; and Pseudomorphine, an alkaloid which exists in opium, form as degradation products of morphine.

Most semi-synthetic opioids, both of the morphine and codeine subgroups, are created by modifying one or more of the following:
1. Saturating, opening, or other changes to the bond betwixt positions 7 and 8 on the morphine carbon skeleton, as well as adding, removing, or modifying functional groups to these positions; saturating, reducing, eliminating, or otherwise modifying the 7-8 bond and attaching a functional group at 14 yields hydromorphinol; the oxidation of the hydroxyl group to a carbonyl and changing the 7-8 bond to single from double changes codeine into oxycodone. 2. Attachment, reduction or modification of functional groups to positions 3 and/or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomes heterocodeine which is 72 times stronger, and therefore six times stronger than morphine 3. Attachment of functional groups or other modification at position 14 (oxymorphone, oxycodone, naloxone) 4. Modifications at positions 2, 4, 5 or 17, usually along with other changes to the molecule elsewhere on the morphine skeleton.

Morphine can be used:

as an analgesic in hospital settings to relieve pain at myocardial infarction pain at sickle cell crisis pain associated with surgical conditions, pre- and postoperatively pain associated with trauma in the relief of severe chronic pain, e.g., cancer pain from kidney stones (renal colic, ureterolithiasis) severe back pain as an adjunct to general anesthesia in epidural anesthesia or intrathecal analgesia as an antitussive for severe cough in nebulized form, for treatment of dyspnea, although the evidence for efficacy is slim. Evidence is better for other routes. as an antidiarrheal in chronic conditions (e.g., for diarrhea associated with AIDS, although loperamide (a non-absorbed opioid acting only on the gut) is the most commonly used opioid for diarrhea).

Codeine Systematic (IUPAC) name 6-hydroxy-N-methyl-3-methoxy4,5-epoxymorphinen-7

Codeine (INN) or methylmorphine is an opiate used for its analgesic, antitussive and antidiarrheal properties. It is by far the most widely used opiate in the world and probably the most commonly used drug overall according to numerous reports over the years by organizations such as the World Health Organization and its League of Nations predecessor agency and others.

It is one of the most effective orally-administered opioid analgesics and has a wide safety margin. It is from 8 to 12 percent of the strength of morphine in most people; differences in metabolism can change this figure as can other medications. Pharmacology Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide. Roughly 5-10% of codeine will be converted to morphine, with the remainder either free, conjugated to form codeine-6glucuronide (~70%), or converted to norcodeine (~10%) and hydromorphone (~1%). It is less potent than morphine and has a correspondingly lower dependence-liability than morphine. Like all opioids, continued use of codeine induces physical dependence and can be psychologically addictive. However, the withdrawal symptoms are relatively mild and as a consequence codeine is considerably less addictive than the other opiates.

Qualitative reactions on codeine


1. With Marci reagent blue-violet color. 2. Formation of apomorphine. After heating with conc. H2SO4 and FeCl3 appears blue color that becomes red after adding 1 drop of dilute HNO3. 3. With conc. HNO3 red color becomes yellow. 4. With AgNO3 orange precipitate Ag3PO4. 5. With Erdman reagent (H2SO4 conc.+HNO3 conc.) -blue color after heating. 6. With Phrede reagent ((NH4)2MoO4+H2SO4 conc.) - green color becomes blue. 7. With Mandelin reagent (NH4VO3+H2SO4 conc.) - green color becomes blue. 8. With sodium nithropruside yellow sediment.

18. Alkaloids group of purine (caffeine, theobromine, theophylline).


Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a psychoactive stimulant drug and a mild diuretic. Caffeine was discovered by a German chemist, Friedrich Ferdinand Runge, in 1819. He coined the term "kaffein", a chemical compound in coffee, which in English became caffeine.

1,3,7-trimethylxanthine, trimethylxanthine,

Caffeine is also part of the chemical mixtures and insoluble complexes guaranine found in guarana, mateine found in mate, and theine found in tea; all of which contain additional alkaloids such as the cardiac stimulants theophylline and theobromine, and often other chemicals such as polyphenols which can form insoluble complexes with caffeine. Caffeine is found in varying quantities in the beans, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants. It is most commonly consumed by humans in infusions extracted from the cherries of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut.

Caffeine present in sugh plants:Coffea arabica, Thea sinensis and Cola acuminata

Thea sinensis

Theobroma cacao

In humans, caffeine is a central nervous system (CNS) stimulant. Beverages containing caffeine, such as coffee, tea, soft drinks and energy drinks enjoy great popularity. Caffeine is the world's most widely consumed psychoactive substance, but unlike many other psychoactive substances it is legal and unregulated in nearly all jurisdictions.

Pharmacology

Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord level at higher doses. Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below.
Metabolism and half-life

Common reaction on caffeine, theobromine and theophylline Murexyde reaction

Specific reactions on caffeine


with 1% solution of tannin white precipitate dissolved in excess of reagent; with 0,1M solution of I2 by the present of HCl brown precipitate dissolved in excess of alkali; with HgCl3 - white precipitate; with sodium nithropruside yellow sediment; with acetylacetone and dimethylamnobenzaldehyde: solution of the substance with acetylacetone and NaOH heat on water bath and then cooling. Add solution of dimethylamnobenzaldehyde and heat ones more, then cooling and add water. Appears intense blue color:

Theobromine Systematic (IUPAC) name 3,7-dimethyl2,3,6,7-tetrahydro-1H-purine-2,6-dione

Theobromine, also known as xantheose, is a bitter alkaloid of the cacao plant, found in chocolate, as well as in a number of chocolate-free foods made from theobromine sources including the leaves of the tea plant, the kola or cola nut, and acai berries. It is in the methylxanthine class of chemical compounds, which also includes the similar compounds theophylline and caffeine. Theobromine is a water insoluble, crystalline, bitter powder; the colour has been listed as either white or colourless. It has a similar, but lesser, effect as caffeine, making it a lesser homologue. Theobromine is an isomer of theophylline as well as paraxanthine. Theobromine is categorized as a dimethylxanthine, which means it is a xanthine with two methyl groups.

Specific reactions on theobromine


theobromine reacts with NaOH and CoCl2, appears evanescent

violet color and separates gray-blue precipitate of cobalt salt. Theophylline in these conditions forms cobalt salt - white sediment with pink tinge:

with HgCl3 - white crystal precipitate; sodium salt of theobromine reacts with AgNO3 forms gelatins mass (silver salt):

A chocolate bar and melted chocolate. Chocolate is made from the cacao bean, which is a natural source of theobromine. The mean theobromine concentrations in cocoa and carob products are:
Item Cocoa Cocoa cereals Chocolate bakery products Chocolate toppings Cocoa beverages Chocolate ice creams Chocolate milks Carob products Mean theobromine content (mg/g) 20.3 0.695 1.47

1.95 2.66 0.621 0.226 0-0.504

Theophylline Systematic (IUPAC) name 1,3dimethyl-7H-purine-2,6-dione

Synthesis Theophylline can be prepared synthetically from dimethylurea and ethyl 2-cyanoacetate.

Specific reactions on theophylline


theophylline forms with CoCl2 salt - white sediment with pink tinge (look at the previous slide); with alkali solution of sodium nitropruside green color dissolved in excess of acid; with HgCl3 - white crystal precipitate; sodium salt of theophylline reacts with AgNO3 forms gelatins mass (silver salt):

Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD or asthma under a variety of brand names. Due to its numerous side-effects, these drugs are now rarely administered for clinical use. As a member of the xanthine family, it bears structural and pharmacological similarity to caffeine. It is naturally found in tea, although in trace quantities (~1 mg/L), significantly less than therapeutic doses. The main actions of theophylline involve: relaxing bronchial smooth muscle increasing heart muscle contractility and efficiency: positive inotropic effect increasing heart rate: positive chronotropic effect increasing blood pressure increasing renal blood flow some anti-inflammatory effects central nervous system stimulatory effect mainly on the medullary respiratory center.

19. Alkaloids group of tropane (atropine, scopolamine, cocaine).


Atropine is a tropane alkaloid extracted from
Systematic (IUPAC) name (8methyl-8-azabicyclo[3.2.1]oct-3yl) 3-hydroxy-2phenylpropanoate; tropinic ester of tropic acid

deadly nightshade (Atropa belladonna), jimsonweed (Datura stramonium), mandrake (Mandragora officinarum) and other plants of the Solanaceae family.

Atropine

Derivatives of tropane

Tropine

Scopine

Echonine

It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects. It is a competitive antagonist for the muscarinic acetylcholine receptor. It is classified as an anticholinergic drug. Being potentially deadly, it derives its name from Atropos.

Physiological effects and uses


Increases firing of the sinoatrial node (SA) and conduction through the atrioventricular node (AV) of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchiole secretions. Generally, atropine lowers the parasympathetic activity of all muscles and glands regulated by the parasympathetic nervous system. Therefore, it may cause swallowing difficulties and reduced secretions. Chemistry and pharmacology Atropine is a racemic mixture of D-hyoscyamine and Lhyoscyamine, with most of its physiological effects due to Lhyoscyamine. Its pharmacological effects are due to the binding with muscarinic acetylcholine receptors. It is an antimuscarinic agent. The most common atropine compound used in medicine is atropine sulfate (C17H23NO3)2H2SO4H2O.

Common reaction on tropane alkaloids rection of Vitaly-Moren


In a porcelain cup to atropine add conc. HNO3 and heat to dry state forms yellow polinitrocompound, dissolve this compound in acetone, addo, 0,5M alcohol solution of KOH. Appears violet color disappears by standing.

Qualitative reactions on atropine with picric acid yellow precipitate; with Marci reagent yellow color; formation of benzaldehyde:

Scopolamine Systematic (IUPAC) name

(-)-(S)-3-hydroxy-2-phenyl-propionic acid (1R,2R,4S,7S,9S)9-methyl-3-oxa9-aza-tricyclo[3.3.1.02,4]non-7-yl ester; Scopinic ester of tropic acid

Scopolamine, known by the names levo-duboisine and hyoscine, is a tropane alkaloid drug with muscarinic antagonist effects. It is obtained from plants of the Solanaceae family (nightshades), such as Datura Stramonium.

It is among the secondary metabolites of these plants. Therefore, scopolamine is one of three main active components of belladonna and stramonium tinctures and powders used medicinally along with atropine and hyoscyamine. Scopolamine has anticholinergic properties and has legitimate medical applications in very small doses. An overdose can cause delirium, delusions, dangerous elevations of body temperature, stupor and death.

History Scopolamine was one of the earlier alkaloids isolated from plant sources, purified forms such as free base and various salts, especially hydrochloride, hydrobromide, hydroiodide and sulphate, since its isolation by German chemists in 1881 and in the form of plant-based preparations since antiquity and perhaps pre-historic times. Physiology Scopolamine acts as a competitive antagonist at muscarinic acetylcholine receptors, specifically M1 receptors; it is thus classified as an anticholinergic,antimuscarinic drug.

Cocaine Systematic (IUPAC) name methyl (1R,2R,3S,5S)-3(benzoyloxy)-8-methyl-8azabicyclo[3.2.1] octane-2carboxylate; methylester of benzoilechonine

Cocaine (benzoylmethyl ecgonine) is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is both a stimulant of the central nervous system and an appetite suppressant.

Specifically, it is a dopamine reuptake inhibitor, a norepinephrine reuptake inhibitor and a serotonin reuptake inhibitor. Its possession, cultivation, and distribution are illegal for non-medicinal and non-government sanctioned purposes in virtually all parts of the world. Although its free commercialization is illegal and has been severely penalized in virtually all countries.

The coca plant, Erythroxylon coca.

Qualitative reactions on cocaine


with KMnO4 violet crystal precipitate:

heating with conc. H2SO4 (specific smell of methylbenzoate, by standing forms crystals of benzoic acid)

20. Alkaloids group of indole (reserpine, strychnine).


Systematic (IUPAC) name 11,17-dimethoxy-16carbmethoxy-18-(3,4,5trimethoxybenzoyloxy)aloyohimbane

N H3CO N H OCH3

H3COOC OCH3

O C O

OCH3

OCH3

Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic behaviors, although because of the development of better drugs for these purposes and because of its numerous sideeffects, it is rarely used today. The antihypertensive actions of Reserpine are a result of its ability to deplete catecholamines (among the others) from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral resistance.

Rauwolfia serpentina

Aloyohimbane
9 10 11 12 8 6 7 5

A
13

B
1

C
2 3

N
21

N H

D
14 15 20 19

E
16 17 18

Reserpine can cause: nasal congestion, nausea, vomiting, weight gain, gastric intolerance, gastric ulceration (due to increased cholinergic activity in gastric tissue and impaired mucosal quality), stomach cramps and diarrhea are noted. The drug causes hypotension and bradycardia and may worsen asthma. Depression can occur at any dose and may be severe enough to lead to suicide. Other central effects are a high incidence of drowsiness, dizziness, and nightmares. Parkinsonism occurs in a dose dependent manner. High doses of reserpine cause fibroadenoma of the breast and malignant tumors of the seminal vesicles among others. Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed. It may also cause hyperprolactinemia.

17 1 2 3 4 16 6

E
15

18

19

A
5

B N 9
10

7 8 13

D
14 21

F
20

C
12 11

G O
22 23

Strychnine

* HNO3

Strychnine is a very toxic (LD50 = 10 mg approx.), colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion. The most common source is from the seeds of the Strychnos nux vomica tree. Strychnine is one of the most bitter substances known. Its taste is detectable in concentrations as low as 1 ppm. Pharmacology Strychnine acts as a blocker or antagonist at the inhibitory or strychnine-sensitive glycine receptor (GlyR), a ligand-gated chloride channel in the spinal cord and the brain. Although it is best known as a poison, small doses of strychnine were once used in medications as a stimulant, a laxative and as a treatment for other stomach ailments. Because of its high toxicity and tendency to cause convulsions, the use of strychnine in medicine was eventually abandoned once safer alternatives became available.

Strychnos Nux Vomica

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