Studies on Bioactive Tetrahydro Pyrimidine

2780 words (11 pages) Essay

29th Jan 2018 Chemistry Reference this

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Chapter- 1 General Introduction 1

Chapter 1

General Introduction

1.1 Heterocycles in drug discovery

Currently pharmaceutical manufacturing is facing many problems for research and development due to high costs and changeless existence of moieties in these days.

According to research of human genome we got assumption that at least 1000 genes are involved in identified and non identified disease. For that research about 20,000 human genome had been decoded.

Genetic science suggests that we have to develop 5,000-10,000 new drugs1.because these genes are linked with five and ten protein molecule. So we need to focus in development of low molecular weight drugs. The compounds must be containing specific pharmacokinetic and toxicological properties, which can show the properties of drugs.

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In these days scientists have many techniques to speed up the drug discovery process, like combinatorial chemistry, microwave-assisted organic synthesis, and high- throughput purification2. Actually, it is very difficult to select moiety with less molecular weight because less than 500 atomic mass unit is 10200, of which only 1060 may possess drug-like properties

The proportion is one part in 1057, or roughly the ratio of the mass of one proton to the mass of the sun! The issue is therefore the selection of new molecules from this vast universe that have the potential to be biologically active3.It is important to do research work on medicinal chemistry to synthesis the biologically active bicyclic aromatic heterocycles which should be easily available commercially too.

Here is the list of available bicyclic heterocycles is mainly limited to well-known nitrogen containing compounds, such as quinazolines (1), indoles Chapter- 1 General Introduction 2

(2) and benzimidazoles (3).

Esatlished examples of privileged substructures include benzodiazepines (4), coumarins (5), quinoxalines (6), benzofurans (7) and benzothiophenes (8)5. In order to improve the hit rate in HTS campaigns,.

This library is very helpful to develop active compound in many variety of biological assays.

So many scientists have utilized these structures in such a manner. For example, Nicolau K. C. et al. constructed a library based on the benzopyran (9) privileged scaffold6,

whereas Schultz P. G. et al. made use of the purine (10) scaffold7. Chapter- 1 General Introduction 3

O (9) Benzopyran N N NH N (10) Purine The benzopyran and purine privileged scaffold

1.2 Nomenclature of the fused ring system

As the following chapters deal with the synthesis of bicyclic fused ring systems, its nomenclature is herewith shortly reviewed. The nomenclature follows the following rules:

(1) The individual components are named without any application of fused ring system.

(2) The parent component is represented in the fusion name by citing it last in the name. The parent component is the one with highest priority according to the following criteria:

(a) heterocyclic compounds contains elements in ring.

(b) a component containing the larger ring.

(c) there are so many atoms of elements in the ring.

(d) a component containing the greater variety of heteroatoms.

(3) The attached component is then added as a prefix to the parent component. In the name of the prefix, the terminal ‘e’ is changed to ‘o’.

(4) The bonds of the parent component are indicated by a, b, c…starting with the bond normally occupying the 1,2 positions. The atoms of the attached component are numbered as usual, following the order of numbers in the original heterocycle.

(5) The numbering of the final condensed heterocycle is carried out independently, starting at an atom adjacent to a bridged-head atom, whereby heteroatoms receive the smallest possible number. Chapter- 1 General Introduction 4

1.3 Objective:-

“Synthesis and biological evaluation of 1,2,3,4 tetra hydro pyrimidines” will be done.

To study the pharmacological and medicinal applicationapplication of synthesized compound. Viz;. antimicrobial, immunodilator, antituberculosis, antielergic and radioprotectves.

The synthesis of (AB101 to 145) will be achieved by acid catalysed cyclocondensation of N-(substituted)-3-oxobutanamide, substituted urea derivatives and 4-(phenoxymethyl) benzaldehyde.

The products will be eliminated by spectras,. The newly synthesized compounds will be subjected to various biological activities viz., antimicrobial, anticancer etc..

The synthesis of (AB146 to 190) will be achieved by acid catalysed cyclocondensation of N-(substitutedphenyl)-4-methyl-3-oxopentanamide, substituted urea and 4-(phenoxymethyl) benzaldehyde.

The products will be analyse by spectras.The newly synthesized compounds will be subjected to various biological activities viz., antimicrobial, anticancer etc.

Chapter- 1 General Introduction 5

1.4 Some Biological importance of pyrimidines and related heterocycles

Recently genetical science is a vast subject of research. To study genetical science, DNA must be decoded. and we know that In the constituents of nucleic acids also pyrimidine exists in form of base. This theory helps treatment of AIDS. The discovery of pyrimidine is itself a big revolution in medical science.

Some examples of pyrimidine derivatives are given below which are existing in nucleic acid.

(1) reveals diabetogenic action in a number of animals8.

. Chapter- 1 General Introduction 6

1.5 Medicinal significance of pyrimidines and related heterocycles.

During the last 20 years, the drugs containing pyrimidine are very useful as chemotherapeutic agents .

1.5.1 Antineoplastics and anticancer agents

Some other examples of pyrimidine antimetabolite are mopidamol (15)18, nimustine (16)19, raltitrexed (17)20, uramustine (18)21 and trimetrixate (19)22. 1-β-D-Arabinosylcytosine (Ara-C, 20)23 . These compounds are useful in treatment of cancer and herpes virus infection.While Gemcitabine (21), is useful in the treatment of murine solid tumours24. Chapter- 1 General Introduction 8

1.5.2 Drugs for hyperthyroidism

Here are the examples of drug for hyperthyroidism without side effects25.

2-Thiouracil (9c), , Propylthiouracil (9d) thiobarbital (9e)

1.5.3 Antifolates, antibacterials and antiprotozoals Chapter- 1 General Introduction 9 Chapter- 1 General Introduction 10

1.5.4 Sulfa drug 1.5.5 Antivirals and anti-AIDS Pyrimidine is containing antiviral properties also. The most popular derivative is 5-Iododeoxyuridine(IDU) (31)37. Chapter- 1 General Introduction 11 Chapter- 1 General Introduction 12 Chapter- 1 General Introduction 13

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1.5.6 Antibiotics Pyrimidine are of multi functional important in medical significance they are good antibiotics also. (42), is used to prevent staphylococcal infections45. While (43), is a cytosine derivative and it is useful in treatment of mycobacteria Gram-positive and Gram-negative bacteria46. The other (44) and (45)45. And some wide spectrums are Puromycin (46) phleomycin (47a), bleomycin (47b) are containing the pyrimidine ring. tubercidine (48) is also antibiotic which is used as antitumour 46. Bleomycin is an effective derivative for tumor like Hodgkin’s lymphoma and disseminated testicular cancer47. Chapter- 1 General Introduction 14

1.5.7 Antifungals Very common disease found on skin, is fungal infection. But Pyrimidine derivatives are very helpful to solve this problem also because they exhibit antifungal properties also. Flucytosine (49)48 is containing fluorine. And widely strains of candida and Cryptococcus49. And for the treatment of aphthous ulceration Hexitidine50 (50) is used. Chapter- 1 General Introduction 15

1.5.8 Anthelmentics Sometime the patient body creates animal with a long thin body having no legs and no bones are called worms. they are of two types pinworms and roundworms51 .They may cause parasitic attack to body. Pyrantel pamoate (51) is a pyrimidine derivative which can depolarize . 1.5.9 Antitubercular drugs Previously only PABA was known antitubercular drug, now a days pyrimidine derivatives also popular in market like Capreomycin (52).which is made by Streptomyces capreolus and used as second-linebacteriostatic antituberculin drug 52, 53. Chapter- 1 General Introduction 16

In comparison of p-aminosalicyclic acid , Viomycin (53) is more tuberculostatic generally It isused in the treatment of experimental T.B. 1.5.10 CNS active agents 1.5.10.1 Sedative/Hypnotic/Antiepileptic agents Anxiolytic, sedative and hypnotic compounds are of very interest and important in medical science. They may have short time or longtime effect to act on body.54, 55 Barbiturates compound series have the needed properties to act as Anxiolytic, sedative and hypnotic compounds. and secobarbital are popular as hypnotic barbiturates56 among medical science users. Hexobarbital, cyclobarbital and propallylonal are popular sedative, hypnotics57. In 1932 Eli Lilly58 was the first researcher of secbutabarbital which was introduce in market with the name of barbitone (8) in starting of twentieth century. Chapter- 1 General Introduction 17

1.5.10.2 Anxiolytic agents The depression and anxiousness of body, both action are require in the surgery science. And these two actions are psychotic disease also. Generally psychoanalysts are blessed of these pyrimidine compounds having the psychoactive properties to treat psychosis. buspirone (55), is used to settle anxiety disorders.. It acts as sedative, anticonvulsant and muscle- relaxant effects59. anxiolytic activity is a good example of our interest62. mezilamine (57) is well known as an antipsychotic agent63. Risoperidone (58) is used as antipsychotic. Effective for anti parkinsonian drug64 1.5.10.3 Pyrimidine anaesthetics Anaesthetics actions are require in the surgery science. Thimylal (59) is used for minor surgery. This compound is family member of pyrimidine.65,66. Saxitoxin (60)65 dinoflagellates so, it is pyrimidine containing natural source.

1.5.10.4 Diuretics and uricosuri waste fluids, with the result that we need to urinate more often th. xanthine derivatives (61) are members of fused pyrimidine family. caffeine (61a)67, etamiphylline (61b)68, lomiphylline (61c)69, etophylline70 (61d), theophylline (61e)67 and theodrendaline (61f)71 are commanding examples of this problem. 1.5.11.1 Antihypertensives

pyrimidine derivatives are effective as antihypertensive also. Examples are Prazosin (64a), is member of quinozoline family, and it is α1-adrenergic antagonist74, 75. Other are bunazosin (64b)76, terazosin (64c)77 and trimazosin Chapter- 1 General Introduction 19

(64d)78, ketanserin (65)79 and serotonin-S2 is receptor. It is a triaminopyrimidine derivative, minoxidil (66), can be considered similar to Prazosin,by means of action. These drugs are hopeful in treatment of alopecia, male baldness80. More examples of antihypertensives81, 82. Alfuzocin (67)81, is as effective as urapidil (68)82 ,prescribes for urinary obstruction of prostate hyperplasia. 1.5.11.2 Vasodilators This drugs are highly require and demanding in the fast life the cases of cardiovascular disorder are increasing day by day .in activity of daily life patient is attacked by Parkinson’s syndrome in some cases. For this disease xanthine derivatives are used in broad level. cardiovascular disorders83. xantinol nicotinate84 (70b), containing value of nicotinic acid is helpful to support vascular disorders and pimephylline (70a) and pyridophylline85 (70c). A new dopamine stimulant, pirebidil (71)86 is used in ADL( Activity of DailyLiving) for the patient of Parkinson’s syndrome. Chapter- 1 General Introduction 20

1.5.11.3 Cardiotonics/Bronchodialators Bronchitis is an illness like a very bad cough,in which our bronchial tubes become sore and infected. Important pyrimidine derivatives acting as drugs are : xanthine derivatives theophylline (61e), aminophylline (72a)87 andproxyphylline (72b)87. Chapter- 1 General Introduction 21

1.5.12 Antihistaminic pyrimidines Histamine affects directly to central nervous system. This is very sensitive to our body and needed to cure very sharply. Low or higher dose of the medicine may cause dangerous effect to body.Taziphylline (73) is more effective than astemizole and terfenadine88. Other example is temelastine (73a)89. With reference of Radiolabelled studies it came to know that it does not penetrate the Central nervous system. while Icotidine (73b), lacks Central nervous system (CNS) activity. It is working effectively on both H1 and H2 receptors90. Pemirolast (74)91, is used for severe asthma and proved best pyrimidine derivative. piprinhydrinate (75)92 is also good medicine having pyrimidine. 1.5.13 Analgesics and NSAID drugs

Most common problems are seemed in human being are alcoholism and diabetes mellitus .for these different problems many pyrimidine derivatives are being used like Acetiamine (76a)93, bentiamine (76b)93 and Chapter- 1 General Introduction 22

fursultiamine (76c)94 which are lipid-soluble forms of thiamine (vitamin B1) For lower back pain patients Afloqualone (77)95 is the best anti-inflammatory medicine. Epirazole (78)96 and Proquazone (81)99are proved better medicine because of Nonsteroidal character (anti-inflammatory drugs), Ademetionine (79)97 is basic drug of glucosamine and chondroitin therapy. Octotiamine (80)98, is derivative of vitamin B1. Chapter- 1 General Introduction 23

1.5.14 Metabolic electrolytes In metabolic therapy a pyrimidine derivative Orotic acid (82)100 is useful. To prevent heart failure of patient orate is best to synthesize pyrimidine nucleotides biologically in body as they are main constituents of DNA and RNA. . Chapter- 1 General Introduction 24

1.6 Conclusion

Chapter- 1 General Introduction 1

Chapter 1

General Introduction

1.1 Heterocycles in drug discovery

Currently pharmaceutical manufacturing is facing many problems for research and development due to high costs and changeless existence of moieties in these days.

According to research of human genome we got assumption that at least 1000 genes are involved in identified and non identified disease. For that research about 20,000 human genome had been decoded.

Genetic science suggests that we have to develop 5,000-10,000 new drugs1.because these genes are linked with five and ten protein molecule. So we need to focus in development of low molecular weight drugs. The compounds must be containing specific pharmacokinetic and toxicological properties, which can show the properties of drugs.

In these days scientists have many techniques to speed up the drug discovery process, like combinatorial chemistry, microwave-assisted organic synthesis, and high- throughput purification2. Actually, it is very difficult to select moiety with less molecular weight because less than 500 atomic mass unit is 10200, of which only 1060 may possess drug-like properties

The proportion is one part in 1057, or roughly the ratio of the mass of one proton to the mass of the sun! The issue is therefore the selection of new molecules from this vast universe that have the potential to be biologically active3.It is important to do research work on medicinal chemistry to synthesis the biologically active bicyclic aromatic heterocycles which should be easily available commercially too.

Here is the list of available bicyclic heterocycles is mainly limited to well-known nitrogen containing compounds, such as quinazolines (1), indoles Chapter- 1 General Introduction 2

(2) and benzimidazoles (3).

Esatlished examples of privileged substructures include benzodiazepines (4), coumarins (5), quinoxalines (6), benzofurans (7) and benzothiophenes (8)5. In order to improve the hit rate in HTS campaigns,.

This library is very helpful to develop active compound in many variety of biological assays.

So many scientists have utilized these structures in such a manner. For example, Nicolau K. C. et al. constructed a library based on the benzopyran (9) privileged scaffold6,

whereas Schultz P. G. et al. made use of the purine (10) scaffold7. Chapter- 1 General Introduction 3

O (9) Benzopyran N N NH N (10) Purine The benzopyran and purine privileged scaffold

1.2 Nomenclature of the fused ring system

As the following chapters deal with the synthesis of bicyclic fused ring systems, its nomenclature is herewith shortly reviewed. The nomenclature follows the following rules:

(1) The individual components are named without any application of fused ring system.

(2) The parent component is represented in the fusion name by citing it last in the name. The parent component is the one with highest priority according to the following criteria:

(a) heterocyclic compounds contains elements in ring.

(b) a component containing the larger ring.

(c) there are so many atoms of elements in the ring.

(d) a component containing the greater variety of heteroatoms.

(3) The attached component is then added as a prefix to the parent component. In the name of the prefix, the terminal ‘e’ is changed to ‘o’.

(4) The bonds of the parent component are indicated by a, b, c…starting with the bond normally occupying the 1,2 positions. The atoms of the attached component are numbered as usual, following the order of numbers in the original heterocycle.

(5) The numbering of the final condensed heterocycle is carried out independently, starting at an atom adjacent to a bridged-head atom, whereby heteroatoms receive the smallest possible number. Chapter- 1 General Introduction 4

1.3 Objective:-

“Synthesis and biological evaluation of 1,2,3,4 tetra hydro pyrimidines” will be done.

To study the pharmacological and medicinal applicationapplication of synthesized compound. Viz;. antimicrobial, immunodilator, antituberculosis, antielergic and radioprotectves.

The synthesis of (AB101 to 145) will be achieved by acid catalysed cyclocondensation of N-(substituted)-3-oxobutanamide, substituted urea derivatives and 4-(phenoxymethyl) benzaldehyde.

The products will be eliminated by spectras,. The newly synthesized compounds will be subjected to various biological activities viz., antimicrobial, anticancer etc..

The synthesis of (AB146 to 190) will be achieved by acid catalysed cyclocondensation of N-(substitutedphenyl)-4-methyl-3-oxopentanamide, substituted urea and 4-(phenoxymethyl) benzaldehyde.

The products will be analyse by spectras.The newly synthesized compounds will be subjected to various biological activities viz., antimicrobial, anticancer etc.

Chapter- 1 General Introduction 5

1.4 Some Biological importance of pyrimidines and related heterocycles

Recently genetical science is a vast subject of research. To study genetical science, DNA must be decoded. and we know that In the constituents of nucleic acids also pyrimidine exists in form of base. This theory helps treatment of AIDS. The discovery of pyrimidine is itself a big revolution in medical science.

Some examples of pyrimidine derivatives are given below which are existing in nucleic acid.

(1) reveals diabetogenic action in a number of animals8.

. Chapter- 1 General Introduction 6

1.5 Medicinal significance of pyrimidines and related heterocycles.

During the last 20 years, the drugs containing pyrimidine are very useful as chemotherapeutic agents .

1.5.1 Antineoplastics and anticancer agents

Some other examples of pyrimidine antimetabolite are mopidamol (15)18, nimustine (16)19, raltitrexed (17)20, uramustine (18)21 and trimetrixate (19)22. 1-β-D-Arabinosylcytosine (Ara-C, 20)23 . These compounds are useful in treatment of cancer and herpes virus infection.While Gemcitabine (21), is useful in the treatment of murine solid tumours24. Chapter- 1 General Introduction 8

1.5.2 Drugs for hyperthyroidism

Here are the examples of drug for hyperthyroidism without side effects25.

2-Thiouracil (9c), , Propylthiouracil (9d) thiobarbital (9e)

1.5.3 Antifolates, antibacterials and antiprotozoals Chapter- 1 General Introduction 9 Chapter- 1 General Introduction 10

1.5.4 Sulfa drug 1.5.5 Antivirals and anti-AIDS Pyrimidine is containing antiviral properties also. The most popular derivative is 5-Iododeoxyuridine(IDU) (31)37. Chapter- 1 General Introduction 11 Chapter- 1 General Introduction 12 Chapter- 1 General Introduction 13

1.5.6 Antibiotics Pyrimidine are of multi functional important in medical significance they are good antibiotics also. (42), is used to prevent staphylococcal infections45. While (43), is a cytosine derivative and it is useful in treatment of mycobacteria Gram-positive and Gram-negative bacteria46. The other (44) and (45)45. And some wide spectrums are Puromycin (46) phleomycin (47a), bleomycin (47b) are containing the pyrimidine ring. tubercidine (48) is also antibiotic which is used as antitumour 46. Bleomycin is an effective derivative for tumor like Hodgkin’s lymphoma and disseminated testicular cancer47. Chapter- 1 General Introduction 14

1.5.7 Antifungals Very common disease found on skin, is fungal infection. But Pyrimidine derivatives are very helpful to solve this problem also because they exhibit antifungal properties also. Flucytosine (49)48 is containing fluorine. And widely strains of candida and Cryptococcus49. And for the treatment of aphthous ulceration Hexitidine50 (50) is used. Chapter- 1 General Introduction 15

1.5.8 Anthelmentics Sometime the patient body creates animal with a long thin body having no legs and no bones are called worms. they are of two types pinworms and roundworms51 .They may cause parasitic attack to body. Pyrantel pamoate (51) is a pyrimidine derivative which can depolarize . 1.5.9 Antitubercular drugs Previously only PABA was known antitubercular drug, now a days pyrimidine derivatives also popular in market like Capreomycin (52).which is made by Streptomyces capreolus and used as second-linebacteriostatic antituberculin drug 52, 53. Chapter- 1 General Introduction 16

In comparison of p-aminosalicyclic acid , Viomycin (53) is more tuberculostatic generally It isused in the treatment of experimental T.B. 1.5.10 CNS active agents 1.5.10.1 Sedative/Hypnotic/Antiepileptic agents Anxiolytic, sedative and hypnotic compounds are of very interest and important in medical science. They may have short time or longtime effect to act on body.54, 55 Barbiturates compound series have the needed properties to act as Anxiolytic, sedative and hypnotic compounds. and secobarbital are popular as hypnotic barbiturates56 among medical science users. Hexobarbital, cyclobarbital and propallylonal are popular sedative, hypnotics57. In 1932 Eli Lilly58 was the first researcher of secbutabarbital which was introduce in market with the name of barbitone (8) in starting of twentieth century. Chapter- 1 General Introduction 17

1.5.10.2 Anxiolytic agents The depression and anxiousness of body, both action are require in the surgery science. And these two actions are psychotic disease also. Generally psychoanalysts are blessed of these pyrimidine compounds having the psychoactive properties to treat psychosis. buspirone (55), is used to settle anxiety disorders.. It acts as sedative, anticonvulsant and muscle- relaxant effects59. anxiolytic activity is a good example of our interest62. mezilamine (57) is well known as an antipsychotic agent63. Risoperidone (58) is used as antipsychotic. Effective for anti parkinsonian drug64 1.5.10.3 Pyrimidine anaesthetics Anaesthetics actions are require in the surgery science. Thimylal (59) is used for minor surgery. This compound is family member of pyrimidine.65,66. Saxitoxin (60)65 dinoflagellates so, it is pyrimidine containing natural source.

1.5.10.4 Diuretics and uricosuri waste fluids, with the result that we need to urinate more often th. xanthine derivatives (61) are members of fused pyrimidine family. caffeine (61a)67, etamiphylline (61b)68, lomiphylline (61c)69, etophylline70 (61d), theophylline (61e)67 and theodrendaline (61f)71 are commanding examples of this problem. 1.5.11.1 Antihypertensives

pyrimidine derivatives are effective as antihypertensive also. Examples are Prazosin (64a), is member of quinozoline family, and it is α1-adrenergic antagonist74, 75. Other are bunazosin (64b)76, terazosin (64c)77 and trimazosin Chapter- 1 General Introduction 19

(64d)78, ketanserin (65)79 and serotonin-S2 is receptor. It is a triaminopyrimidine derivative, minoxidil (66), can be considered similar to Prazosin,by means of action. These drugs are hopeful in treatment of alopecia, male baldness80. More examples of antihypertensives81, 82. Alfuzocin (67)81, is as effective as urapidil (68)82 ,prescribes for urinary obstruction of prostate hyperplasia. 1.5.11.2 Vasodilators This drugs are highly require and demanding in the fast life the cases of cardiovascular disorder are increasing day by day .in activity of daily life patient is attacked by Parkinson’s syndrome in some cases. For this disease xanthine derivatives are used in broad level. cardiovascular disorders83. xantinol nicotinate84 (70b), containing value of nicotinic acid is helpful to support vascular disorders and pimephylline (70a) and pyridophylline85 (70c). A new dopamine stimulant, pirebidil (71)86 is used in ADL( Activity of DailyLiving) for the patient of Parkinson’s syndrome. Chapter- 1 General Introduction 20

1.5.11.3 Cardiotonics/Bronchodialators Bronchitis is an illness like a very bad cough,in which our bronchial tubes become sore and infected. Important pyrimidine derivatives acting as drugs are : xanthine derivatives theophylline (61e), aminophylline (72a)87 andproxyphylline (72b)87. Chapter- 1 General Introduction 21

1.5.12 Antihistaminic pyrimidines Histamine affects directly to central nervous system. This is very sensitive to our body and needed to cure very sharply. Low or higher dose of the medicine may cause dangerous effect to body.Taziphylline (73) is more effective than astemizole and terfenadine88. Other example is temelastine (73a)89. With reference of Radiolabelled studies it came to know that it does not penetrate the Central nervous system. while Icotidine (73b), lacks Central nervous system (CNS) activity. It is working effectively on both H1 and H2 receptors90. Pemirolast (74)91, is used for severe asthma and proved best pyrimidine derivative. piprinhydrinate (75)92 is also good medicine having pyrimidine. 1.5.13 Analgesics and NSAID drugs

Most common problems are seemed in human being are alcoholism and diabetes mellitus .for these different problems many pyrimidine derivatives are being used like Acetiamine (76a)93, bentiamine (76b)93 and Chapter- 1 General Introduction 22

fursultiamine (76c)94 which are lipid-soluble forms of thiamine (vitamin B1) For lower back pain patients Afloqualone (77)95 is the best anti-inflammatory medicine. Epirazole (78)96 and Proquazone (81)99are proved better medicine because of Nonsteroidal character (anti-inflammatory drugs), Ademetionine (79)97 is basic drug of glucosamine and chondroitin therapy. Octotiamine (80)98, is derivative of vitamin B1. Chapter- 1 General Introduction 23

1.5.14 Metabolic electrolytes In metabolic therapy a pyrimidine derivative Orotic acid (82)100 is useful. To prevent heart failure of patient orate is best to synthesize pyrimidine nucleotides biologically in body as they are main constituents of DNA and RNA. . Chapter- 1 General Introduction 24

1.6 Conclusion

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